https://en.wikipedia.org/wiki/Motor_skill
Motor skills are learnt abilities that stimulate a predetermined movement outcome with maximum certainty, which are attained through ‘motor learning’. Performance is an act of executing a motor skill, and the goal of such is to optimise the rate of success, precision, and to reduce the energy consumption required for performing the skill. Continuous practice of a specific motor skill results in readily improved motor performances, though not all movements are motor skills. Therefore, practice does make perfect, or does it?
What are the different types of motor skills?
(a) Gross Motor Skills
https://en.wikipedia.org/wiki/Gross_motor_skill#Childhood
= They are abilities children acquire as part of their motor learning. When a child reaches 2 years old, they are able to stand vertically, walk and run, walk up stairs without assistance etc. Children build upon these skills, as well as improve and voluntarily control throughout their early childhood, which continues in refinement into their adulthood. Gross movements require the use of large muscle groups and whole body movement, which develop from head-to-toe. Children typically learn to control their head position, stabilise their trunk, and stand up and walk. Experts recommend parents to expose their children to outdoor play time activities in order to develop and refine their better gross motor skills.
Gross motor skills can be further categorised into 2 subgroups:
— Locomotor Skills e.g. running, jumping, sliding, and swimming
— Object-control Skills e.g. throwing, catching and kicking
(b) Fine Motor Skills
https://en.wikipedia.org/wiki/Childhood_development_of_fine_motor_skills
= They are the coordination of small muscle movements that occur usually in coordination with the eyes such as the fingers, hands, and thumb. A British study observed females aged between 4 and 7 years old demonstrated finer motor skills compared to males of the same age range. They found that children begin to use their hands with primitive gestures like grabbing at objects to more precise activities that involve precise hand-eye coordination. It’s known children begin to develop self-care skills by completing daily activities independently around the ages of 2 and 3 such as
— Zipping up or down their clothing
— String together beads with large holes
— Open doors with doorknobs
Ages 3 to 4:
— Manipulate clothing with larger buttons
— Use scissors to cut paper
— Copy simple lined shapes using a pencil
Ages 4 to 5:
— Manipulate kitchen utensils
— Gain dexterity to cut around shapes with a pair of scissors
Ages 6:
— Cut softer foods with a knife
— Tie their own shoes
However, you should note that every child develops at different rates, so the age expectations aren’t always fulfilled.
I’ll delve into the details and timelines of the childhood development of motor skills in another post.
How do humans develop motor skills?
Motor skills develop in different parts of the body along 3 principles:
(i) Cephalocaudal = This includes development from head to toe, and the head develops before the hand. A 2012 study observed infants were able to follow something with their eyes before they can physically interact with it.
(ii) Proximodistal = The development of movements of limbs closer (proximal) to the body occur before other body parts. Hence, fine movements of your fingers develop ultimately in the body. e.g. A baby learns to control the upper arm before the hands or fingers.
(iii) Gross to Specific = Larger muscle movements involving larger muscle groups develop before finer movements. e.g. A child initially can pick up large objects, then learns to pick up small objects fitting between the thumb and fingers.
A 1974 study suggested around the ages of 3 - 5, children’s brains undergo a critical period for the acquisition of motor skills when fundamental neuroanatomic structure demonstrates significant development, elaboration, and myelination over the course of this period. A 2004 study by Malina implicated that children were expected to develop a wide range of basic movement abilities and motor skills unless they suffered from a severe disability. A 2004 study by Rosenbaum et al. divided progression of motor development into 7 stages; (1) reflexive, (2) rudimentary, (3) fundamental, (4) sports skill, (5) growth and refinement, (6) peak performance, and (7) regression. It’s essential to understand that motor development is age-related but is not age dependent. With respect to age, typical developments are expected to attain gross motor skills used for postural control and vertical mobility by the age of 5.
There are 6 aspects of motor development:
— Qualitative = Changes in movement-process results in changes in movement-outcome
— Sequential = Certain motor patterns precede others
— Cumulative = Current movements built upon previous movements
— Directional = Cephalocaudal or proximodistal
— Multifactorial = Numerous-factors impact
— Individual = Dependent on each person
Gender differences can substantially influence motor skills during the childhood stages of development. A 2006 study found girls performed better than boys on visual motor and graphomotor tasks, which suggested girls attained manual dexterity earlier than boys. A 2012 study accounted for the variability of results possibly due to the multiplicity of different assessment tools used. A 2014 study suggested environment factors influence the gender differences in motor skills because "parents and teachers often encourage girls to engage in [quiet] activities requiring fine motor skills, while they promote boys' participation in dynamic movement actions”. Lisa Barrett’s journal article found evidence to support the theory of gender-based motor skills by stating that boys are skilfully equipped in object control and object manipulation skills such as throwing, kicking, and catching. However a 2014 study by Vlachos et al. failed to find evidence on the difference in locomotor skill between the genders, despite improvement after the physical activity intervention. Overall, the predominance of development was on balance skills (gross motor) in boys and manual skills (fine motor) in girls.
What the components of motor development?
— Growth = The size of the body or its increases as the individual progresses toward maturity (i.e. quantitative structural changes)
— Maturation = Qualitative, innate changes helping in advancement to higher levels of functioning.
— Experience or learning = Factors within the environment altering or modifying the appearance of various developmental characteristics through the process of learning.
— Adaptation = The complex interplay or interaction between forces within the individual (nature) and the environment (nurture).
What influences motor development?
— Stress and arousal = This is caused by an imbalance between demand and the capacity of the individual. In this context, arousal defines the interest level in the skill. Moderate stress or arousal levels can achieve optimal performance. e.g. An overqualified worker performing repetitive jobs is in an insufficient arousal state.
— Fatigue = When a person persists with a stressful task, their performance deteriorates, similar to how muscle fatigue is experienced during rapid or endurance exercise. Fatigue is usually caused by over-arousal, which decreases visual acuity or awareness, slows performance (reaction times or movements speed), causes regular mistiming, and disorganises overall performance.
— Vigilance = This is caused by a lack of arousal, and its effects mimic those during fatigue.
— Gender = Studies suggest gender plays an essential role in the child’s development. Girls are more likely to be seen performing fine stationary visual motor-skills, whereas boys predominantly exercise object-manipulation skills. Research on the motor development of preschool-aged children found that girls had a higher likelihood performing fine motor skills such as skipping, hopping, or skills with the use of hands only. On the other hand, boys had a higher likelihood performing gross skills such as kicking or throwing a ball or swinging a bat. There are gender-specific differences in qualitative throwing performance, but not necessarily in quantitative throwing performance. Both male and female athletes demonstrate similar movement patterns in actions involving the humerus and forearm actions but different movement patterns in actions involving the trunk, stepping, and backswing.
What are the stages of motor learning?
Practice causes changes in motor skills, which lead to motor learning. It often involves improving the accuracy of both simple and complex movements in a changing environment. Motor learning is also a relatively permanent skill because it acquires and retains the ability to respond appropriate by selecting the most suitable movements.
(1) Cognitive phase = When a learner is faced with a specific novel task, they consider the main objective of the mission. This requires considerable cognitive activity in order for the learner to determine appropriate strategies to adequately reflect the desired goal. The most successful strategies are retained, while unsuccessful strategies are discarded. This vastly improves performance in a minimal amount of time.
(2) Associative phase = When a learner has finalised the most-effective strategy to perform a task, they begin to subtly adjust their motor performance. This leads to gradual improvements and consistent movements. Although this phase takes time, it improves the fluency, efficiency and aesthetic pleasure of these skills.
(3) Autonomous phase = It takes several months to years to reach this phase, dubbed “autonomous” because the learner is able to “automatically” complete the task with little attention to its own performance. e.g. Walking, talking, or sight reading whilst evaluating simple arithmetic.
How does feedback of a motor skill work?
During the learning process of a motor skill, feedback can either a positive or negative response, which informs the learner on the efficiency of the completed task.
— Inherent feedback = Upon completion of a skill, it transmits sensory information providing feedback on its efficiency. e.g. If a basketball player misses a set shot, this will notify them of the mistakes they need to correct. e.g. If a diver experiences pain or undesirable sensory info, this informs them of the mistakes it needs to correct.
— Augmented feedback = In contrast to inherent feedback, this refers to information that supplements or “augments” the inherent feedback. e.g. If a driver exceeds the speed limit, they are pulled over by the police. Although the driver hadn’t elicited any physical harm, the policeman provides augmented feedback to the driver in order to maximise the safety of his driving habits. e.g. A private tutor educating a new student in specific of study like chemistry, mathematics, English, physics or biology. It decreases the time required to master the motor skill and increases the performance level of the prospect.
— Transfer of motor skills = Practice and experience on a certain task can lead to a gain or loss in the capability for performance in another task. e.g. The initial skills of an outdoor tennis player VS. A non-tennis player learning table tennis for the first time. A example of an negative transfer involves a typist taking longer than expected to adjust to a randomly assigned letter of the keyboard compared to a new typist.
— Retention = This refers to a performance level of a particular skill after a period of no use.
The type of task can effect on the efficiency of retaining the motor skill after a period of non-use:
- Continuous tasks = e.g. Swimming, bicycling, or running. The performance level in these tasks retains proficiency even after years of non-use. It usually requires gross motor skills.
- Discrete tasks = e.g. Playing a musical instrument, video game, or a sport. The performance level in these tasks plummets but can improve compared to a new learner. It usually requires fine motor skills.
Which brain structures are involved in learning motor skills?
Motor skills are localised to regions of the frontal lobe such as the Primary Motor Cortex, the Supplementary Motor Area, and the Premotor Cortex.
— The Primary Motor Cortex is located in the precentral gyrus, and is often visualised as the motor homunculus. A 1993 study explained how Penfield and Rasmussen mapped out the motor homunculus after stimulating certain areas of the motor strip and observing its effects. Areas of the body involved in complex movements, such as the hands, are represented gigantically on the motor homunculus.
— The Supplementary Motor Area (SMA) is located anteriorly to the Primary Motor Cortex. It is responsible for postural stability and adjustment, and coordination of movement sequences.
— The Premotor Cortex is located inferiorly to the SMA. It integrates sensory information from the Posterior Parietal Cortex, and is involved with the sensory-guided planning of movement and initiates the programming of movement.
— A 2012 study suggested the Basal Ganglia is where gender differences in brain physiology is evident. In summary, they are a group of nuclei responsible for a variety of functions, including movement. Both the Globus Pallidus and Putamen are involved in motor skills, with the former involved with the voluntary motor movement, and the latter involved with motor learning. A 2012 study found that the males’ Globus Pallidus and Putamen are larger than that of females.
— A 2001 study suggested the Cerebellum plays a role in learning motor skills. It controls fine motor skills, balance and coordination. Although women tend to demonstrate exceptional fine motor skills, a 2001 study found their cerebellum is smaller than that in men, as well as their brain volume.
— A 2008 study suggested hormones may contribute to gender differences in motor skill. e.g. Women are observed to perform superbly on manual dexterity tasks during periods of high Estradiol and Progesterone levels.
— A 2000 study proposed an evolutionary theory in an attempt to explain the development of gender differences in motor skills. It suggested that men partook the hunter role and provided food for the family, while women stayed at home nurtured their children and performed domestic work. Furthermore, the men’s tasks involved gross motor skill such as chasing after prey, throwing spears and fighting, whereas the women’s tasks involved fine motor skills such as handling domestic tools.
When many of the degrees of freedom involved in performing an action are centrally organised and controlled to abstractly represent movement, they form a motor program. Your CNS can anticipate plan or guide movement in response to signals transmitted through efferent and afferent pathways. A 2005 study outlined the concepts of motor programs below:
— Processing of afferent information (feedback) is too slow for on-going regulation of rapid movements.
— Reaction time (between “go” signal and movement initiation) increases with movement complexity, suggesting that movements are planned in advance.
— Movement is possible even without feedback from the moving limb. Moreover, velocity and acceleration of feedforward movements, such as reaching, are highly proportional to the distance of the target.
— The existence of motor equivalence = The ability to perform the same action in multiple ways. e.g. using different muscles or the same muscles under different conditions. This suggests that a general code specifying the final output exists which is translated into specific muscle action sequences.
— Brain activation precedes that of movement. e.g. The supplementary motor area becomes active one second before voluntary movement.
This suggests feedback information may be combined with another level of control beyond feedback to be used:
1. Before the movement as information about initial position, or perhaps to tune the spinal apparatus.
2. During the movement, when it is either “monitored” for the presence of error or used directly in the modulation of movements reflexively.
3. After the movement to determine the success of the response and contribute to motor learning.
Below is a list of theories that attempt to explain the central organisation of motor programs:
— Response-chaining / Reflex-chaining Hypothesis
= First proposed by William James in 1890, this open-loop hypothesis was one of the earliest descriptions of movement control. It postulated that movements required attention from the first initiated action, which meant each subsequent movement was automatically triggered by response-produced afferent information from the muscles. However, it isn’t possible for ongoing movements to be modified in response to unexpected changes in the environment, because feedback can’t be compared to an internally generated reference value for error checking. Research studies in the 20th century involving deafferented animals and humans suggested that movement doesn’t require feedback, thus providing an incomplete account of movement control.
— Adam’s closed-loop theory
= This hypothesis suggested human motor control relies on processing of afferent information. It is based on basic motor learning research focusing on slow, graded, linear positioning tasks involving error detection and correction to meet goal demands. Learning a new movement requires a “motor program” consisting of 2 states of memory; memory trace and perceptual trace.
— Memory trace is equivalent to recall memory in verbal learning. It initiates the motor movement, chooses its initial direction and determines the earliest portions of the movement. Practice and feedback about movement outcome can strengthen the memory trace.
— Perceptual trace is similar to recognition memory in verbal tasks. It guides the limb to the correct position along a trajectory. In order to accomplish this task, the brain compares incoming feedback to the perceptual trace, which is formed from the sensory consequences of the limb being at the correct/incorrect endpoint in past experience. If an error is detected, the limb is adjusted until the movement is appropriate to the goal of the action. A highly accurate movement increases the usefulness of the perceptual trace collected and retained.
Despite representing an important leap forward in motor learning, the requirement of 1-to-1 mapping between stored states (motor programs) and movements to be made weakened the validity of this theory. Because a vast array of movements require equally large repository of motor programs, it presented an issue associating with the storage capacity of the CNS. Furthermore, the theory fails to explain the formation of motor programs for novel movements.
(b) Schmidt’s Schema Theory
In 1975, Richard Schmidt proposed the schema theory for motor control, suggesting that a motor program contained general rules applying to different environmental or situational contexts through open-loop control process and GMPs (Generalised Motor Program). A 2001 study explained the schema may contain the generalised rules that generate the spatial and temporal muscle patterns to produce a specified movement. Hence, a person learning novel movements may generate a new GMP based on the selection of parameters (reducing the novel movement problem), or refine an existing GMP (reducing the storage problem), depending on prior experience with movement and task context.
Schmidt suggested the 4 things stored in memory after an individual generates a movement are:
— The initial conditions of the movement. e.g. the proprioceptive information of the limbs and body.
— The response specifications for the motor programs, which are the parameters used in the generalised motor program, such as speed and force.
— The sensory consequences of the response, which contain information about how the movement felt, looked and sounded.
— The outcome of that movement, which contains information of the actual outcome of the movement with knowledge of results (KR).
This information is stored in components of the motor response schema, which include the recall schema and recognition schema. The non-isomorphic relationship between recall and recognition schema involves the initial condition and actual outcomes. The differences between them are that recall schema selects a specific response with the use of response specifications, whereas the recognition schema evaluates the response with the sensory consequences. Throughout a movement, the recognition schema compares with the expected sensory information (e.g., proprioceptive and extroceptive) from the ongoing movement occurs in order to evaluate the efficiency of the response. When an error signal is transmitted upon finalising the movement, the schema is then modified based on the sensory feedback and knowledge of results. This theory illustrates that motor learning consists of continuous processes that update the recall and recognition schemas with each subsequent movement.
A 1998 study proposed an alternative viewpoint on the organisation and control of motor programs, which infers a computational process of selecting a motor command (i.e., the input) to achieve a desired sensory feedback (i.e., the output). Selection of the motor command depends on many internal and external variables, such as the current state of the limb(s), orientation of the body and properties of the items in the environment with which the body will interact. Given the vast number of possible combinations of these variables, it provides a difficult challenge for the motor control system to communicate an appropriate command for any given context. The motor system’s strategy on selecting appropriate commands involves a modular approach, where multiple controllers exist such that each controller is suitable for 1 or a small set of contexts. Based on an estimate of the current context, a controller is chosen to generate the appropriate motor command. This modular system may be the most plausible descriptions of both motor control and motor learning because it requires adaptable internal forward and inverse models.
— Forward models describe the forward or causal relationship between system inputs, and predict when sensory feedback will occur.
— Inverse models (controllers) generate the motor command that guarantees a desired change in state, depending on the environmental context.
As an individual is motor learning, the forward and inverse models pair up by tightly coupled responsibility signal within modules. According to the forward model’s predictions and sensory contextual cues, responsibility signals indicate the degree to which each pair should be responsible for controlling current behaviour.
https://www.physio-pedia.com/Motor_Control_and_Learning
https://en.wikipedia.org/wiki/Motor_learning
Motor learning refers to an alteration in the ability to respond to practice or a novel experience. It helps improve the smoothness and accuracy of movements in order to accustom to repetitive complicated movements such as talking, playing the piano, walking / running / jogging, and swimming. Motor learning also plays an essential role in calibrating simple movements like reflexes, in response to changing parameters of the body and environment over time. Research investigates variables that contribute to the development of the body’s motor program (i.e., underlying skilled motor behaviour), sensitivity of error-detection processes, and strength of movement schemas. Motor learning is “relatively permanent” because it requires the body to acquire and retain the appropriate motor response. Therefore, it is unnecessary to consider temporary processes influencing behaviour during practice or experience as learning, but rather transient performance effects. It has been identified that the main components underlying the behavioural approach to motor learning are part of the practice structure and provided feedback. The former manipulates time and organises practice in order to retain optimal information, while the latter influences feedback on the preparation, anticipation, and guidance of movement.
How is practice structured?
According to a 2007 study, contextual interference was originally defined as “function interference in learning responsible for memory improvement”. A 1990 study defined it as "the effect on learning of the degree of functional interference found in a practice situation when several tasks must be learned and are practiced together”. Other studies regard “variability of practice” or “varied practice” as an important component to contextual interference, because it places task variations within learning. Although varied practice may lead to poor performance throughout the acquisition phase, it plays an essential role in developing the schemata, which assembles and improves retention and transfer of motor learning. Despite the performance improvements observed, the limitation of contextual interference was the uncertainty regarding the cause of performance improvements as numerous variables are constantly manipulated. A 2007 literature review identified a few patterns to discuss the improvements recorded in previous experiments that involved the contextual interference paradigm. Although no patterns were identified in the literature, common areas and limitations justifying interference effects were identified nonetheless:
— Although the skills being learned required whole-body movements, most tasks contained independent components.
— Studies that supported the interference effect used slow movements that enabled movement adjustments during movement execution.
— According to studies conducted in 1995 and 2007, bilateral transfer may be elicited through alternate practice condition because information sources can develop from both sides of the body. Despite improvements being recorded, interference effects would not be attributed to their improvements because it would have been a coincidence of task characteristics and schedule of practice.
— There is no precise and agreeable definition for “complex skills”. Nevertheless, studies cite procedural manipulations as a contributor to skill complexity, which may vary between experiments. e.g. changing similarity between tasks.
How is feedback provided during practice?
A 2004 study regarded feedback as a critical variable for skill acquisition, and defined it as any kind of sensory information related to a response or movement. Intrinsic feedback is produced by responses, which normally occurs during a movement and the sources may be internal or external to the body. Example sources of intrinsic feedback are vision, proprioception, and audition. On the other hand, extrinsic feedback is defined as augmented information provided by an external source, in addition to intrinsic feedback. Extrinsic feedback can be categorised as knowledge of performance or knowledge of results.
A 1984 study manipulated the presentation features of feedback information (e.g., frequency, delay, interpolated activities, and precision) in order to determine the optimal conditions for learning.
(i) Knowledge of Performance (KP) = Also known as kinematic feedback, KP refers to information provided to a performer that indicates the quality or patterning of their movement. Examples of such information include displacement, velocity or joint motion. KP is distinct from intrinsic feedback and rather more useful in real-world tasks. Coaches or rehabilitation practitioners often employ this strategy with their respective teams or patients respectively.
(ii) Knowledge of Results (KR) = KR refers to extrinsic or augmented information provided to a performer after a response that indicates the success of their actions with regard to an environmental goal. It may be redundant with intrinsic feedback, especially in real-world scenarios. Nevertheless, in experimental studies, it is considered information provided over and above those sources of feedback that are naturally received when a response is made i.e. response-produced feedback. A 2005 study stated that KR may be verbal or verbalisable.
Researchers often fail to separate the relatively permanent aspect of change in the capability for responding (i.e. indicative of learning) from transient effects (i.e. indicative of performance). Therefore, the solution to this problem was to create a transfer design involving 2 distinct phases. To visualise the transfer design, imagine a 4x4 grid. Write down the titles "Experiment #1" and "Experiment #2” in the column headings. Then indicate the conditions you wish to compare, with the row headings titled "Acquisition" and "Transfer" whereby:
(a) The acquisition block (2 columns) contains test conditions in which some variable is manipulated (i.e. different levels of KR applied) and different groups receive different treatments. This block represents the transient effects of KR (i.e. performance).
(b) The transfer block (2 columns) contains test conditions in which that variable is constant (i.e. application of a common KR level; normally a no-KR condition). When the variable is presented with a no-KR condition, this block represents the persistent effects of KR (i.e. learning). Conversely, if this block is given to subjects in a format where KR is available, transient and persistent effects of KR are convoluted and it is argued not interpretable for learning effects.
What is the functional role of KR and its potential confounding of effects?
KR pertains either temporary or transient (i.e. performance effects) roles. 3 of these roles include (1) motivation, (2) associative function, and (3) guidance. A 1938 study suggested that the motivational influence increases the effort and interest of the performer in the task, which maintains once KR is removed. However, the extent to which interest affects motor learning is currently unknown. A 1999 study proposed that the associative function of KR may be involved in the formation of associations between stimulus and response, known as the Law of Effect. Critics argue that this additional effect won’t account for findings in transfer tasks that manipulate the relative frequency of KR, specifically decreased relative frequency leading to enhanced learning. A 1971 study suggested that the guidance role of KR impacts motor learning via both internal and external sources of feedback. It inferred that as the performer is informed about the errors in performing the task, the discrepancy is used to continually improve their performance in future trials. Nevertheless, a 1984 study explained that the guidance hypothesis postulated the provision of excessive external, augmented feedback (e.g., KR) during practice, which may cause the learner to develop a harmful dependency on this source of feedback. This might lead to stupendous performance during practice but dismal performance at transfer, which indicates poor motor learning. Furthermore, as the performer improves, adaptability of KR conditions is required according to the performer’s skill and difficulty of the task in order to maximise learning.
What is the specificity of learning hypothesis?
According to a 2004 study, this hypothesis infers that learning is most effective when environment and movement conditions that closely resemble those required during performance of the task are included in practice sessions, in order to replicate the target skill level and context for performance. A 1992 study suggested that these benefits of specificity in practice occur as motor learning is combined with physical practice during the learned sport or skill. Recent studies have found that skill learning is accomplished by alternating motor learning and physical performance, creating both sources of feedback work simultaneously. The motor learning process creates a representation of the task where it integrates all relevant information that pertains to task performance. This tightly couples with increasing experience performing the task. Consequently, it removes or adds a significant source of information after a practice period, whether it was present or not, doesn’t deteriorate motor performance. Alternating motor learning and physical practice can ultimately lead to superior performance as opposed to just physical practice only.
Which brain regions are important for the motor learning?
The cerebellum and basal ganglia play critical roles in proper calibration of movement, which is widely conserved across vertebrates from fish to humans. Motor learning helps humans achieve skilled performances, and repetitive training helps develop automaticity to their movements. Research has found that these behaviours include eyeblink conditioning, motor learning in the Vestibulo-Ocular Reflex, and birdsong. A sea slug called the Aplysia californica contains complex processes of the cellular mechanisms responsible for the simple form of learning.
In 2005, Mikhail Lebedev, Miguel Nicolelis and co. demonstrated the phenomenon of cortical plasticity after they incorporated an external actuator controlled through a brain-computer interface into the subject's neural representation. This suggested a type of motor learning occurred during this operation of a brain-computer interface.
At a cellular level, motor learning manifests itself in the neurons of the Motor Cortex. Dr. Emilio Bizzi and co. used single-cell recording techniques to demonstrate certain cells, known as “memory cells” underwent lasting alteration with practice.
At the musculoskeletal level, motor learning is accomplished through motor neurons innervating 1 or more myocytes, which together form a “motor unit”. Perform even the simplest motor task requires precisely-timed coordinated activity of thousands of these motor units. This may indicate that the body organises motor units into modules that correlates to such activities.
What happens if motor learning is disordered? Can it be recovered?
Children with Developmental Coordination Disorder (DCD) suffer from impairments in learning new motor skills, which limits their postural control and causes deficits in sensorimotor coordination. They have an inability to improve performance of complex motor tasks by practice alone. However, a 1993 study found evidence that task-specific training can improve performance of simpler tasks in DCD patients. A 2011 study suggested a correlation between impaired skilled learning and brain activity, particularly, a reduction of brain activity in regions associated with skilled motor practice.
Clinicians utilise motor learning to help apraxia patients with their stroke recovery and neurohabilitation, in order to relearn lost skills through practice and/or training. However, there is an unresolved gap between motor control and motor learning research and rehabilitation practice. Common motor learning paradigms include robot arm paradigms, which apraxia patients are instructed to resist against a hand held device throughout specific arm movements. A 2008 study found that over-learning significantly improved long term retention and minimal effect on performance. According to motor learning practice paradigms that compared the differences of different practice schedules, a 2006 study suggested that repetition of the same movements is inadequate for a disabled patient to relearn a skill. It argued about the ambiguity of the possibility of true brain recovery after repetition alone. Experts suggested that compensation methods develop through pure repetition, and cortical changes (true recovery) occur in response to exposure of challenging tasks. So far, research involving motor learning and rehabilitation practice have focused on stroke victims. They implement a variety of therapies including arm ability training, constraint-induced movement therapy, electromyograph(EMG)-triggered neuromuscular stimulation, interactive robot therapy and virtual reality-based rehabilitation. A 2015 study delivered ischaemic conditioning on its subjects via blood pressure cuff inflation and deflation to the arm in order to facilitate motor learning. For the first in animals and humans, ischaemic conditioning was demonstrated to enhance motor learning, which the subjects retained over time. Their potential benefits extended far beyond stroke to other neuro-, geriatric, and paediatric rehabilitation populations.
I’ll delve into the details of psychomotor learning, sensory-motor coupling and muscle memory in another post.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017756/
https://en.wikipedia.org/wiki/Motor_control
When physiologists discuss motor control, they refer to the systematic regulation of movement in organisms that possess a nervous system. It includes movement functions attributed to reflex and volition. As a field of study, it’s a sub-discipline of psychology or neurology. Recent psychological theories of motor control suggest it as a process humans and animals perform with their brain / cognition to activate and coordinate the muscles and limbs involved in the performance of a motor skill. From a mixed psychological perspective, motor control is fundamentally the integration of sensory information both about the world and the current state of the body. This would determine appropriate set of muscle forces and joint activations to generate some desired movement or action. The process of motor control requires cooperative interaction between the Central Nervous System and the Musculoskeletal System, which makes it a problem of information processing, coordination, mechanics, physics and cognition. Successful motor control is crucial when humans interact with the world, not only determine action capabilities, but regulate balance and stability as well. The organisation and production is regarded as a complex problem, so studying it requires a wide range of disciplines, including psychology, cognitive science, biomechanics and neuroscience. Historically, research questions regarding motor control were defined as either physiological or psychological, depending on whether the focus is on physical and biological properties, or organisational and structural rules. Areas of study related to motor control include motor coordination, motor learning, signal processing and perceptual control theory.
https://en.wikipedia.org/wiki/Hick%27s_law
Named after British and American psychologists, William Edmund Hick and Ray Hyman, Hick’s Law (HIck-Hyman Law) describes the time it takes for a person to make a decision as a result of the possible choices he or she has. It states a proportionally logarithmic relationship between the number of choices and the decision time. It also assesses cognitive information capacity in choice reaction experiments. The amount of time taken to process a certain amount of bits in the Hick–Hyman law is known as the rate of gain of information.
e.g. If you want to justify menu design decisions, you use Hick’s Law to find a given word in an ordered (alphabetical) word list like a menu, given you recognise the name of the command. You would be able to use a subdividing strategy that works in logarithmic time. If the list is randomly ordered like a menu, then you would have to scan every word in that list, consuming linear time, so you can’t apply Hick’s Law in this scenario.
— In 1868, Franciscus Donders was the first to report the relationship between having multiple stimuli and choice reaction time.
— In 1885, J. Merkel discovered the response time is longer when a stimulus belongs to a larger set of stimuli.
— In 1951, Hick initiated his first experiments on this theory using 10 lamps with corresponding Morse code keys. The lamps would light randomly every 5 seconds. The choice reaction time was recorded with the number of choices ranging from 2–10 lamps. Hick then performed a second experiment using the same task, while keeping the number of alternatives at 10. But this time, the participant was instructed to perform the task as accurately as possible for 2 times, then as quickly as possible for their last attempt.
— Hyman’s experiment investigated the relationship between the reaction time and the mean of choices, which featured 8 different lights arranged in a 6x6 matrix. Each light was assigned a name, and the participant was instructed to say the name of the light after it was lit. Their reaction time was recorded. Further experiments changed the number of each different type of light. Based on the results, Hyman determined a linear relationship between reaction time and the information transmitted.
The law explains that given a number (n) of equally probable choices, the average reaction time (T) required to choose among the choices is approximately:
T = b* log2(n+1)
— b = A constant determined empirically by fitting a line to measured data
— The logarithm expresses depth of "choice tree" hierarchy, where log2 indicates a binary search was performed.
— Adding 1 to n takes into account the "uncertainty about whether the participant responds or not, as well as about what response they’ll make.”
In the case of choices with unequal probabilities, the law is generalised as:
T = b*H
— H = Information-theoretical entropy of the decision, defined as:
Similar to Fitt’s Law, Hick’s Law is logarithmic because people subdivide the total collection of choices into categories. This eliminates about 50% of the remaining choices at each step, rather than considering each and every choice one-by-one, which would require linear time.
In 1964 E. Roth demonstrated a correlation between IQ and information processing speed, which is defined as the reciprocal of the slope of the function:
Reaction Time = Movement Time + [log2(n) / (Processing Speed)]
— n = Number of choices
— (Processing Speed) * log2(n) = Time taken to come to a decision
— The stimulus-response compatibility is also known to influence reaction time for the Hick-Hyman Law. This means that the response should be similar to the stimulus itself. e.g. Turning a steering wheel to turn the wheels of an automobile like a car or bus. The action the user performs is similar to the response the driver receives from the car.
In 1971, Jack A. Adams proposed a closed loop system, which he defined it as having “feedback, error detection and error correction as key elements”. He also mentioned “a reference that specifies the desired value for the system, and the output system is fed back and compared to the reference for error detection.” If these references were detected then corrected, a closed loop system would be self-regulating by compensating for deviating from such references. Most of our movements we carry out daily are formed using a continual process of accessing sensory information and we use it to continue the motion with more precision. This type of motor control is called feedback control; a situated form of motor control that relies on sensory feedback about performance and specific sensory input from the environment in which the movement is carried out to control responsive movements. However, this processed sensory input doesn’t necessarily cause conscious awareness of the action. Closed loop control is defined as a feedback based mechanism of motor control, where any act on the environment generates a particular change that affects future performance through feedback. It is best suited to continuously controlled actions, but it fails to work rapidly enough for ballistic actions. Ballistic actions are continuous to the end without conscious thought, even when they no longer are appropriate. Because feedback control relies on sensory information, it operates slower than sensory processing. These movements are subject to a speed/accuracy trade-off, because movement is monitored by sensory processing. The faster the movement is carried out, the less accurate it becomes.
Jack A. Adams also proposed an open loop system, which he defined it as having “no feedback or mechanisms for error regulation”. He describes how inputs influence and get processed by the system to form a suitable output. This is analogous to a traffic light with fixed timing that snarls traffic during heavy loads and impedes the flow during light traffic events. But he notes that the system lacks “compensatory capability”. Nevertheless, some movements occur quite swiftly for the system to integrate all sensory information. Instead it relies on feedforward control to process information quickly. Open loop control refers to a feed forward form of motor control that is used to control rapid, ballistic movements that end before any sensory information can be processed. Most research on open loop control focus on deafferentation studies, often involving cats or monkeys whose sensory nerves have been disconnected from their spinal cords. When monkeys lost all sensory information from their arms, they behaved normally after recovering from the deafferentation procedure. They relearned all skills except for fine motor control. Researchers observed that the open loop control can be adapted to different disease conditions. Therefore they can be used to extract signatures of different motor disorders by varying the cost functional governing the system.
Coordination is a core motor control issue that commands various components of the motor system to act in unison producing movement. The human motor system is composed of many interacting parts at many different organisational levels. A simplistic view to understand its complexity begins with peripheral neurons receiving input from the central nervous system and, in response, innervate the muscles. This, in turn, stimulates the muscles to generate force which actuate joints. The challenge for the motor system is to assemble all important components in the correct orientation and position and solving this problem is an active area of study in motor control research.
https://en.wikipedia.org/wiki/Reflex
https://en.wikipedia.org/wiki/List_of_reflexes
When you touch or step on a hot or sharp surface, you instantly pull yourself away from that object before you could even consciously decide to immediately pull away. How are you doing that? Did some mysterious, magical, supernatural force control your movements temporarily? Nope. This phenomenon is called a reflex or reflex action. It describes an involuntary and nearly instantaneous movement in response to a stimulus. This occurs due to neural pathways called “reflex arcs”, which act on an impulse before that impulse reaches the brain. This automatic response to a stimulus doesn’t receive nor require conscious thought. This coordination of motor components is hard-wired consisting of fixed neuromuscular pathways. Reflexes are typically characterised as automatic and fixed motor responses because they activate quicker than normal physical reactions depending on perceptual processing. They fundamentally stabilise the motor system, which provides immediate compensation for small perturbations and helps maintain fixed execution patterns. Some reflex loops are routed solely through the spinal cord without receiving input from the brain, and thus don’t require attention or conscious control. Whereas, other reflex loops involve lower brain areas and can be influenced by prior instructions or intentions, but they remain independent of perceptual processing and online control. In humans, there are about 50 different reflexes, which are listed below:
https://www.youtube.com/watch?v=v4FyZydgHs0
— Accommodation(-Convergence) Reflex = This reflex action occurs in the eye, which responds to focusing on a near object, then looking at a distant object (and vice versa). It comprises of coordinated changes in vergence, lens shape and pupil size (accommodation). This depends on the Cranial Nerve II (afferent nerve of reflex), superior centres (interneurons) and Cranial Nerve III (efferent nerve of reflex). The ciliary muscles inside yours eye control shape of the lens. Changes in contraction of the ciliary muscles alter the focal distance of the eye, causing nearer or farther images to come into focus on the retina. This process is known as “accommodation”. The reflex, controlled by the parasympathetic nervous system, involves 3 responses; pupil accommodation, lens accommodation, and convergence.
Information collected from the light on each retina is transmitted to the Occipital Lobe via the Optic Nerve and Optic Radiations (after a synapse in the Lateral Geniculate Body of the Posterior Thalamus), where it is interpreted as vision. The peristriate area 19 interprets accommodation, and sends signals via the Edinger-Westphal Nucleus and the Cranial Nerve III to the Ciliary muscle, the Medial Rectus muscle and (via parasympathetic fibres) the Sphincter Pupillae muscle.
When your eyes accommodate, its pupils constrict to increase the depth of focus of the eye in order to block the light scattered by the periphery of the cornea. The lens then increases its curvature to become more biconvex, thus increasing refractive power. The ciliary muscles are responsible for the lens accommodation response.
When your eyes converge, they simultaneously move inwards towards each other in order to focus on near objects more clearly. 3 actions occur simultaneously; adduction of the eyes, contraction of ciliary muscles and constriction of pupils. These actions involves contraction of the medial rectus muscles of the 2 eyes and relaxation of the lateral rectus muscles. The medial rectus attaches to the medial aspect of the eye and its contraction adducts the eye, which is innervated by motor neurons in the oculomotor nucleus and nerve.
3 regions that make up the accommodation neural circuit, the afferent limb, the efferent limb and the ocular motor neurons between the afferent and efferent limb are described below:
i. Afferent Limb = This limb consists of the retina that contains the Retinal ganglion axons in the Optic Nerve, Optic Chiasm and Optic Tract, and Lateral Geniculate Body, and the Visual Cortex.
ii. Efferent Limb = This limb consists of the Edinger-Westphal Nucleus and the oculomotor neurons. The Edinger-Westphal Nucleus sends axons in the Oculomotor Nerve to control the ciliary ganglion which in turn, projects to the short ciliary nerve to control the iris and the ciliary muscle of the eye. Oculomotor neurons projects to the oculomotor nerve to control the medial rectus muscle, and converge the 2 eyes.
iii. Ocular Motor Control Neurons = Interposed between the afferent and efferent limbs of this circuit, these neurons include the Visual Association Cortex. Its function involves determining the image as “out-of-focus” and, in response, send corrective signals via the internal capsule and crus cerebri to the supraoculomotor nuclei. Located immediately superior to the oculomotor nuclei, the supraoculomotor nuclei generates motor control signals that initiate the accommodation response and sends these control signals bilaterally to the oculomotor complex.
Your ears have an acoustic reflex threshold (ART), which is the sound pressure level (SPL) from which a sound stimulus with a given frequency will trigger the acoustic reflex. The ART is a function of sound pressure level and frequency. Humans with normal hearing have an ART of around 70-100 dB SPL, whereas humans with conductive hearing loss (i.e. bad transmission in the middle ear) have a higher ART. The ART is usually 10-20 dB below the discomfort threshold (DT), however the DT is an irrelevant t indicator of the harmfulness of a sound detected. e.g. Industry workers have higher DTs, but the sound is just as harmful to their ears. Your ART can be reduced by the simultaneous presentation of a second tone (facilitator), which can be presented to either ear. This facilitation effect tends to be greater when the facilitator tone has a frequency lower than the frequency of the elicitor (i.e. the sound used to trigger the acoustic reflex).
Most animals’ acoustic reflex involves contraction of both the stapedius and tensor tympani muscles in the middle ear, but humans’ acoustic reflex only involves contraction of the stapedius muscle only, not the tensor tympani. In normal human ears, contraction of the stapedius muscle occurs bilaterally, no matter which ear was exposed to the loud sound stimulation. Nevertheless, the acoustic reflex mostly protects against low frequency sounds. Sounds of volume 20 dB above the ART trigger the reflex, which then decreases the intensity of the sound transmitted to the cochlea by around 15 dB. Furthermore, the reflex also triggers in anticipation of the onset of human vocalisation. This vocalisation-induced stapedius reflex reduces sound intensities reaching the inner ear by about 20 dB. Meanwhile, birds have a stronger stapedius reflex that is invoked just before the bird tweets.
The acoustic reflex protects the Organ of Corti against excessive stimulation (especially that of the lower frequencies) in both humans and animals, but it’s limited. The article “Significance of the stapedius reflex for the understanding of speech” explains the latency of contraction is only about 10ms, but maximum tension may not be reached for 100 ms or more. Another article “Le traumatisme acoustique” argues the latency of contraction is 150 ms with noise stimulus which SPL is at the threshold (ATR), and 25-35 ms at high sound pressure levels. What is agreeable is the amplitude of the contraction grows with the sound pressure level stimulus. Due to this latency, the acoustic reflex cannot protect against sudden intense noises. However, if several sudden intense noises are presented at a pace higher than 2–3 seconds of interval, then acoustic reflex may be able to protect against auditory fatigue. Moreover, the full tension of the stapedius muscle cannot be maintained for an extended period in response to continued stimulation. Therefore, the tension drops to about 50% of its maximum value after a few seconds.
Before you begin testing the Achillex Reflex, ensure the ankle of the patient is relaxed. Support the ball of the foot at least somewhat to put some tension in the Achilles tendon, but note that the ankle mustn’t completely dorsiflex. Then give a small strike on the Achilles tendon using a rubber hammer to elicit the response. If this doesn’t elicit a response, try the Jendrassik maneuver by having the patient cup their fingers on each hand and try to pull the hands apart. If you notice a brisk plantarflexion of the foot, this is considered a positive response, which is graded into Grade 0-4into Grade 0-4 according to the reflex grading system. If a negative response occurs, then the S1 and S2 nerve roots may be damaged and possible sciatic nerve pathology in hypothyroidism. If this reflex is absent, this is due to disk herniations at the levels of L5-S1. If there is reduced reflex response, then this indicates peripheral neuropathy.
Grade 4 ankle hyper-reflexia is also called ankle clonus, which is repetitive ankle dorsiflexion and plantarflexion on passive dorsiflexion of the foot by the examiner till the force applied by the examiner is withdrawn. It is often caused by any spinal cord lesions (i.e. traumatic, neoplastic, pyogenic, vascular above the level of S1). This is due to the spasticity caused by the Upper Motor Neuron type of injury causing hyper reflexia and clonus.
— Arthrokinetic Reflex = Coined by medical researchers Leonard and Manfred Cohen at the University of Pittsburgh’s Medical School, department of Physiology, in 1956, this reflex refers to the manner in which joint movement reflexively activates or inhibits muscle. Since the prefix “Arthro-“ means joints and “kinetic” means motion, this type of reflex refers to the involuntary response that happens when a joint is moved, namely that relevant muscles fire reflexively.
In a 1956 Cohens’ experiment, when a decerebrate cat's knee joint was move, it resulted in muscle activation of the quadriceps or semitendinosus muscle(s), depending on whether the knee joint was moved into flexion or extension. Since its first publication in the American Journal of Physiology (volume 184), the arthokinetic reflex was later documented in other joints and muscle groups such as the Temporomandibular Joint and mandibular musculature. Modern practitioners of physical therapy and rehabilitation theorised the existence of the arthrokinetic reflex can be utilised to address chronic pain conditions such as lower-back pain, or improve sports-related performance by mobilising the joints. Recent research hypothesised the reflex may act as a mechanism to mobilise the hip joint in order to positively aid training of hip abductor torque, whereby Type I and II articular mechanoreceptors inhibit or facilitate muscle tone.
— Asymmetric Tonic Neck Reflex (ATNR) = Also known as the “fencing reflex”, this primitive reflex is found in newborn humans that normally disappears when they are around 6-7 months years old. The characteristic position of the infant's arms and head resembles that of a classically trained fencer. When an infant’s face turns to one side, the ipsilateral arm and leg extend and the contralateral arm and leg flex. Along with other primitive reflexes such as the Tonic Labyrinthine Reflex (TLR), if the ATNR is still present beyond the first 6 months of an infant’s life, this suggests possible developmental delays, at which point the reflex is atypical or abnormal.
e.g. Children suffering from cerebral palsy may have persisting and more pronounced primitive reflexes, which can cause developmental problems for a growing infant. Both the ATNR and TLR hinders functional activities such as rolling, bringing the hands towards each other, or bringing the hands to the mouth. Over time, both reflexes can cause serious damage to the growing child's joints and bones; ATNR causes the spine to curve causing scoliosis, and both the ATNR and TLR causes subluxation of the femoral head or dislocation of the femoral head as it completely moves out of the hip socket. If abnormal reflexes still persist in your child, early intervention involving extensive physical therapy is recommended to ensure the most beneficial course of treatment.
In adults, the ATNR occurs as a result of mechanical forces applied to the head, typically associated with contact sports. It is typically transient, indicating moderate forces being exerted to the brainstem, which results in a traumatic brain injury.
— Babinski Reflex (Plantar Reflex) = Named after neurologist Joseph Babinski, this reflex is activated when the sole of the foot is stimulated with a blunt instrument. In normal adults, the plantar reflex causes a downward response of the hallux, producing flexion. However, if an upward response (extension) of the hallux occurs, this indicates disease of the spinal cord and brain in adults. Although it was first described in medical literature by Babinski in 1896, but it was first identified in art as least as early as Botticelli’s painting titled “Madonna and Child with an Angel”, painted in the mid 15th century.
Physicians rub a blunt instrument or device on the patient’s lateral side of the sole of the foot so as to not cause pain, discomfort, or injury to the skin. They run the instrument along a curve to the toes (metatarsal pads). 3 outcomes that could occur include:
- Flexor: The toes curve down and inwards, and the foot inverts. This is normal in healthy adults.
- Indifferent: There is no response.
- Extensor: The hallux dorsiflexes, and the other toes fan out. This is Babinski’s Sign, which indicates damage to the Central Nervous System if elicited in an adult, but normal if elicited in infants.
If the lesion responsible for Babinski’s sign expands, the area from which the afferent Babinski response elicits also expands. It’s normal to experience the Babinski sign while asleep and after a long period of walking.
The Babinski sign indicates a lesion in the upper motor neuron constituting damage to the Corticospinal Tract. If you elicit a pathological plantar reflex, it’s undoubtedly a serious disease progression. If you elicit a clearly abnormal plantar reflex, you would immediately be under neurological investigation, including CT scanning of your brain or MRI of your spine, and lumbar puncture for the study of cerebrospinal fluid.
Infants usually elicit an extensor response, because the corticospinal pathways aren’t fullly myelinated at this age, so the reflex is not inhibited by the cerebral cortex. When the child turns 1, the extensor response usually disappears giving way to the flexor response. But if the extensor response persists beyond the ages 2-3, this signifies a problem in the brain or spinal cord.
The afferent pathway starts with nociceptive detection in the S1 dermatome, then travels up the Tibial nerve to the Sciatic nerve to roots of L5,S1 and synapse in the anterior horn to elicit the motor response. The efferent pathway involves a motor response back through the L5,S1 roots to the sciatic nerve to its bifurcation. Toe flexors are innervated by the Tibial nerve, whilst toe extensors such as extensor hallicus longus, extensor digitorum longus are innervated by the deep peroneal nerve. Normally in adults, the descending pyramidal control of the reflex arc suppresses extensor withdrawal. However, if this is lost, it leads to upgoing toes in the plantar reflex (Babinski’s sign).
https://www.youtube.com/watch?v=_9vUGimaKCI
— Babkin Reflex = Named after Russian physiologist, Boris Babkin, this reflex occurs in newborn babies, describing varying responses to physical pressure applied to both of their palms. Infants may demonstrate head flexion, head rotation, mouth opening, or a combination of these responses. Smaller, premature infants are more susceptible to the reflex, often occurring around 26 weeks gestation.
In dogs, this reflex is seen to respond to changes in blood volume but experiments have demonstrated its insignificance in primates. Nevertheless, there is evidence of this reflex occurring in humans, especially after delivery of an infant when a large volume (up to 800 mL) of uteroplacental blood returns to the mother's circulation, resulting in tachycardia.
As venous return increases, blood pressure in the in the Superior and Inferior Vena Cava increase. This increases blood pressure in the right atrium, stimulating the atrial stretch receptors (low pressure receptor zones). These receptors, in turn, alert the medullary control centers to increase the heart rate causing tachycardia. Unusually, this tachycardia is mediated by increased sympathetic activity to the sinoatrial node (SAN) whilst parasympathetic activity doesn’t decrease. Increasing heart rate serves to decrease the blood pressure in the Superior and Inferior Venae Cavae by drawing more blood out of the right atrium. This decreases atrial pressure, which draws more blood from the vena cavae, causing a decrease in the venous pressure of the great veins. This continues until right atrial blood pressure returns to normal levels, upon which the heart rate decreases to its original level.
The Bainbridge Reflex is also involved in respiratory sinus arrhythmia. When a human inhales, intrathoracic pressure decreases, triggering increased venous return that gets detected by stretch receptors, which increases the heart rate momentarily during inspiration. This isn’t to be confused with stage 4 of the Valsalva Maneuveur. That refers to the release of high intrathoracic pressure previously generated by forced expiration against a closed glottis. This restores venous return and cardiac output into a vasoconstricted circulation, stimulating the vagus nerve, which slows heart rate, or cause bradycardia.
Baroreceptors are located in the atria of the heart and vena cavae, with the most sensitive baroreceptors found in the carotid sinuses and aortic arch. Axons from carotid sinus baroreceptors travel within the Glossopharyngeal Nerve (CN IX), while axons from aortic arch baroreceptors travel within the Vagus Nerve (CN X). These aforementioned nerves project directly into the Central Nervous System to synapse with neurons of the Nucleus of the Solitary Tract (NTS) in the brainstem. Baroreceptor information is transmitted from NTS neurons to both the sympathetic and parasympathetic neurons within the brainstem.
(1) NTS neurons also projects excitatory axons (glutamatergic) to the Caudal Ventrolateral Medulla (CVLM), activating the CVLM.
(2) An activated CVLM then projects inhibitory axons (GABAergic) to the Rostral Ventrolateral Medulla (RVLM), thus inhibiting the RVLM.
(3) RVLM acts as the primary regulator of the Sympathetic Nervous System, which projects excitatory axons to the sympathetic preganglionic neurons located in the Interomediolateral Nucleus of the spinal cord.
(4) So, in response to elevated blood pressure, baroreceptors activate, which allows the NTS to activate the CVLM, which in turn inhibits the RVLM, thus decreasing activity of the sympathetic branch of the Autonomic Nervous System, leading to a relative decrease in blood pressure.
Likewise, decreased blood pressure lessens the activity of baroreceptors, and instead causes an increase in sympathetic tone via “disinhibition” of the RVLM. Cardiovascular targets of the sympathetic nervous system includes both blood vessels and the heart.
At resting levels of blood pressure, arterial baroreceptor discharge activates some NTS neurons, which then activate excitatory fibers to the Nucleus Ambiguus and the Dorsal Nucleus of Vagus Nerve to regulate the parasympathetic nervous system. These parasympathetic neurons project their axons to the heart and parasympathetic activity slows down cardiac pacemaking and thus heart rate, and elevated more during conditions of elevated blood pressure. Note that the parasympathetic nervous system is primarily directed toward the heart.
Sympathetic and parasympathetic branches of the autonomic nervous system elicit opposing effects on the heart. Sympathetic activation elevates the total peripheral resistance (TPR) and cardiac output (CO) by increasing the contractility of the heart, heart rate, and arterial vasoconstriction, which in turn increases blood pressure. Conversely, parasympathetic activation decreases cardiac output by decreasing heart rate, resulting in lower blood pressure. Sympathetic inhibition would decrease peripheral resistance, while parasympathetic activation would decrease heart rate (reflex bradycardia) and contractility. By coupling sympathetic inhibition and parasympathetic activation, the baroreflex maximises reduction of blood pressure. Conversely, sympathetic activation along with parasympathetic inhibition allows the baroreflex to maximise elevation of blood pressure. When activated, sympathetic neurons release Noradrenaline onto their cardiovascular targets.
Having a prolonged upright posture causes pooling of blood in the lower extremities, which leads to diminished intracardiac volume. This phenomenon is exacerbated under conditions of dehydration. The resultant arterial hypotension is detected by the carotid sinus baroreceptors, and afferent nerve fibres from these baroreceptors triggers autonomic signals that result in increasing cardiac rate and contractility. However, pressure receptors in the wall and trabecular of the half-filled left ventricle may then detect other stimuli, which activates high-pressure C-fibre afferent nerves from these receptors. They respond by transmitting signals triggering bradycardia paradoxically and decreased contractility. This results in additional and relatively sudden arterial hypotension. Von Bezold was the first to describe the bradycardia reaction to Acetic Acid Veratril in the cardiac pacemaker region. Meanwhile, Jarisch identified this particular reaction as the chemoreceptor reflex via the Vagus Nerve, which is relayed in the Solitary Nucleus.
The Bezold-Jarisch Reflex is responsible for the sinus bradycardia often occurring within the first hour following an acute myocardial infarction. It explains the occurrence of atrio-ventricular (AV) node block during acute posterior or inferior myocardial infarction. This reflex has also been proposed as a possible cause of profound bradycardia and circulatory collapse after spinal anaesthesia, as it’s one of the complications of interscalene brachial plexus block. When approaching sensitive areas, the reflex occurs alongside several biologically active chemicals such as Nicotine and Capsaicin. Veratrum alkaloids, Bradykinin, Atrial Natriuretic peptides, Prostanoids, Nitrovasodilators, Angiotensin II Type 1 Receptor (AT1) antagonists and Serotonin agonists may also activate this reflex.
When specific areas of the cerebral cortex are activated, reflex (vasodepressor) syncope or vasovagal syncope occurs, whilst activation of areas in the Anterior Cingulate Gyrus triggers a fainting reaction. Although the exact trigger is not known, reflex syncope has been attributed to activation of the Bezold–Jarisch reflex. Originally described as the cardiorespiratory response to the intravenous injection of veratrum alkaloids, this reflex is known to cause bradycardia, hypotension, and apnea. Research utilising experimental animals discovered that stimulation of arterial baroreceptors or ventricular baroreceptors by many chemicals can also trigger the reflex. These chemicals include Veratrum alkaloids, Nicotine, Capsaicin, Histamine, Serotonin, snake and insect venoms. In humans, coronary injection of contrast material or of thrombolytic agents causes reflex syncope, presuming that ventricular receptors eliciting the Bezold–Jarisch reflex were stimulated. There are theories to suggest that the aforementioned chemical stimuli may activate the same stretch-sensitive Transient Receptor Potential (TRP) channels of arterial baroreceptors, usually activated by high blood pressure. Although those triggers are currently unknown, vagal afferents transmits signals to higher CNS centres, which act through autonomic nuclei in the Medulla to massively stimulate the parasympathetic system and abolish sympathetic tone.
Evidence suggests that the blushing region is anatomically different in structure. For example, your facial skin has more capillary loops per unit area, meaning it contains more vessels per unit volume than other skin areas. In addition, blood vessels in your cheeks are wider in diameter, are nearer to the skin surface, and visibility is less diminished by tissue fluid. These specific characteristics of the architecture of the facial vessels led Wilkin to conclude that “increased capacity and greater visibility can account for the limited distribution of flushing”.
In 1982, Mellander and his colleagues (Andersson, Afzelius, & Hellstrand) found evidence for special vasodilation mechanisms involved in blushing. After studying buccal segments of the human facial veins in vitro, they observed how they responded with an active myogenic contraction to passive stretch and were therefore able to develop an intrinsic basal tone. Mellander et al. demonstrated veins in this specific region also contained β-Adrenoceptors, in addition to the common α-Adrenoceptors. These β-Adrenoceptors elicits dilation of the basal tone of the facial cutaneous venous plexus. Mellander et al. proposed the aforementioned mechanism behind emotional blushing.
In 1997, Drummond partially confirmed this effect in his pharmacological blocking experiments that blocked both α-Adrenergic receptors and β-Adrenergic receptors with Phentolamine and Propranolol respectively, which were introduced transcutaneously by iontophoresis. Using a dual channel laser Doppler flowmeter, Drummond measured blushing of the foreheads of undergraduate students whom were divided into frequent and infrequent blushers according to self-report. The mean age of these students was 22.9, making it favourable for assessing blushing since young subjects are more likely to blush and blush more intensively. They underwent several procedures, one of which was designed to produce blushing. It’s found that blocking α-Adrenergic receptors with phentolamine had no influence on the amount of blushing in frequent or in infrequent blushers. This suggested that release of sympathetic vasoconstrictor tone does not substantially influence blushing. This result was expected because vasoconstrictor tone in the facial area is known to be generally low. Meanwhile, blocking β-Adrenergic receptors with propranolol was found to decrease blushing in both frequent and infrequent blushers. However, despite complete blockade, blood flow still increased substantially during the embarrassment and blushing inducing procedure. Additional vasodilator mechanisms must therefore be involved, which are yet unknown.
In Chapter 13 of his 1872 book The Expression of the Emotions in Man and Animals, Charles devoted it to complex emotional states including self-attention, shame, shyness, modesty and blushing. He described blushing as "... the most peculiar and most human of all expressions.” In 2010, Crozier hypothesised several different psychological and psycho-physiological mechanisms for blushing. In his study The Puzzle of Blushing, he mentions "an explanation that emphasises the blush's visibility proposes that when we feel shame we communicate our emotion to others and in doing so we send an important signal to them. It tells them something about us. It shows that we are ashamed or embarrassed, that we recognise that something is out of place. It shows that we are sorry about this. It shows that we want to put things right. To blush at innuendo is to show awareness of its implications and to display modesty that conveys that you are not brazen or shameless. The blush makes a particularly effective signal because it is involuntary and uncontrollable. Of course, a blush can be unwanted [but the] costs to the blusher on specific occasions are outweighed by the long-term benefits of being seen as adhering to the group and by the general advantages the blush provides: indeed the costs may enhance the signal's perceived value.” A number of techniques may be used to help prevent or reduce blushing. It has also been suggested that blushing and flushing are the visible manifestations of the physiological rebound of the basic instinctual fight / flight mechanism, when physical action is not possible.
https://www.youtube.com/watch?v=h81O_kQUjvE
— Brachioradialis Reflex (Supinator Reflex) = This reflex was first observed during a neurological exam by striking the brachioradialis tendon directly with a reflex hammer when the patient's arm is relaxing. Specifically, at its insertion at the base of the wrist into the radial styloid process, which is the radial side of wrist around 4 inches proximal to base of thumb. It is carried out by the radial nerve (spinal level: C6, C7). This reflex should cause slight pronation or supination and slight elbow flexion. Because the brachioradialis does not cross the wrist, the reflex is expected to not cause wrist extension and/or radial deviation.
— Brain’s Reflex = This reflex is the extension of a hemiplegic flexed arm when a quadrupedal posture is assumed by a human subject. It was first described by a British neurologist named Russell Brain.
— Cervico-collic Reflex (CCR) = This cervical reflex stabilises the head of your body. Afferent sensory changes caused by changes in neck position oppose that stretch by reflexive contractions of neck muscles. Initially, this reflex was thought to be monosynaptic, but the suggestion of long-loop influences are currently being investigated. Like the COR, the CCR may be facilitated by loss of the labyrinthine reflex. In humans, this reflex has longer latencies (about 67.4 ms) than the VCR (about 24.5 ms), giving normal individuals an advantage in head righting over labyrinthine defective subjects.
— Cervico-spinal reflex (CSR) = Also known as the Tonic Neck Reflex, it refers to changes in limb position driven by efferent activity in the neck. Like the COR, the CSR can supplement or interfere with the VSR. 2 neural pathways are proposed to mediate these reflex signals. One of them is an excitatory pathway from the Lateral Vestibular Nucleus and the other is an inhibitory pathway from the medial part of the Medullary Reticular Formation. Their activity leads to limb extension on the side which your chin is pointed to and limb flexion on the contralateral side. Vestibular receptors influence both of these pathways by modulating the firing of medullary neurons in a pattern in contrast to that elicited by neck receptors. The interaction between the effects on the body of vestibular and neck inputs tend to cancel each other out when the head moves freely on the body so that your posture remains stable.
— Cervico-ocular Reflex (COR) = This reflex consists of eye movements driven by neck proprioceptors. Under certain circumstances, the COR supplements the VOR when recovering from vestibular lesions. Normally, the gain of this reflex is quite low but the COR is facilitated when the vestibular apparatus is injured.
https://www.youtube.com/watch?v=PFoKzgLxFzw
— Chaddock Reflex = This diagnostic reflex is similar to the Babinski reflex. Its sign is present when the lateral malleolus is stroked, causing extension of the great toe. This indicates damage to the corticospinal tract. Chaddock’s Sign was identified by Charles Gilbert Chaddock in 1911.
— Churchill-Cope Reflex = This reflex involves distension of the pulmonary vascular bed, as occurs in pulmonary oedema, increase the respiratory rate (tachypnoea). It was first described in 1929 by Edward Delos Churchill and Oliver Cope.
- Nasociliary branch of the Opthalmic branch (V1) of the 5th cranial nerve (Trigeminal Nerve) sensing the stimulus on the cornea only (afferent fibre).
- Temporal and zygomatic branches of the 7th cranial nerve (Facial nerve) initiating the motor response (efferent fibre).
- Centre (Nucleus) in the Pons of the brainstem.
You could diminish or abolish this reflex using contact lenses.
Some neurological exams examine the corneal reflex, particularly in evaluating coma. Damage to the ophthalmic branch (V1) of the 5th cranial nerve would result in the absence of the corneal reflex when the affected eye is stimulated. Stimulation of one cornea normally has a consensual response, with both eyelids normally closing.
When you’re awake, your eyelids spread the tears secreted over the corneal surface, on a typical basis of 2 to 10 seconds. However, blinking is not only dependent on dryness and/or irritation. In the brain, the Globus Pallidus of your Basal Ganglia contains a blinking centre that controls blinking, though external stimuli are still involved. Blinking is also linked with the extraocular muscles, often concurrent with a shift in gaze, which may provide assistance in eye movements.
— Coronary Reflex = This reflex involves the coronary diameter changing in response to chemical, neurological or mechanical stimulation of the coronary arteries, which are stimulated differently from the rest of the vascular system. Coronary arteries constrict in response to N-NItro L-Arginine, Indomethacin, Glibenclamide, Tetraethylammonium Chloride, Caffeine and a cold. Abusing cocaine frequently causes coronary spasms, resulting in a spontaneous myocardial infarction. Coronary arteries dilate in response to Versed (Midazolam), Tetraethylammonium Chloride and Oestrogen. Midazolam is a coronary dilator, whilst Tetraethylammonium Chloride is an inhibitor of the BKCa K+ channel (a high conductance Ca2+-sensitive K+ channel), dose dependently attenuated the vasodilating effect of Midazolam. Oestrogen has been observed abolishing abnormal cold-induced coronary constriction.
Specifically, cough receptors or rapidly adapting irritant receptors are located mainly on the posterior wall of the trachea, pharynx, carina and trachea, and the junction where trachea bisects into the main bronchi. However, cough receptors are less abundant in the distal airways, and absent beyond the respiratory bronchioles. When your cough receptors are stimulated, they send nerve impulses via an afferent pathway involving the Internal Laryngeal Nerve, a branch of the Superior Laryngeal Nerve stemming from the Vagus Nerve (CN X), to the medulla in the brain. Unlike other areas responsible for involuntary actions like swallowing, there is no definitive area that has been identified as the cough centre in the brain.
Shortly after, the brain sends relevant signals down the efferent neural pathway from the cerebral cortex, and medulla via the Vagus and Superior Laryngeal nerves to the glottis, external intercostals, diaphragm, and other major inspiratory and expiratory muscles. The mechanism of a cough is described below:
I) Phrenic nerve innervates your diaphragm, whilst the segmental intercostal nerves innervated your external intercostal muscles. Then the diaphragm and external intercostal muscles contract to create a negative pressure around the lung.
II) Air rapidly flows into the lungs in order to equalise the internal pressure.
III) Our glottis closes due to innervation by the recurrent laryngeal nerve, and the vocal cords contract to close the larynx.
IV) Your abdominal muscles then contract to accentuate the action of the relaxing diaphragm, as well as simultaneous contraction of your other expiratory muscles.
V) Your vocal cords relax and glottis opens, releasing air at over 100 mph (161 kph).
VI) Your bronchi and non-cartilaginous portions of the trachea collapse to form slits through which the air is forced, which clears out any irritants attached to the respiratory lining.
Weak abdominals and respiratory muscles could impair this reflex, which may be caused by disease conditions that lead to muscle weakness or paralysis, by prolonged inactivity, or as outcome of surgery involving these muscles. The cough reflex may weaken and be ineffective due to bed rest because it impacts on the expansion of the chest and limits the amount of air entering the lungs in preparation for coughing. Furthermore, damage to the internal branch of the superior laryngeal nerve, which relays the afferent branch of the reflex arc, may impair this reflex. This nerve is most commonly damaged by swallowing a foreign object, such as a chicken bone, resulting in it being lodged in the piriform recess (in the laryngopharynx) or by surgical removal of said object.
— Cremasteric Reflex = This superficial reflex is observed only in human males. It is elicited by lightly stroking or poking the superior and medial (inner) part of the thigh in any direction. This immediately causes contraction of the Cremaster muscle, which pulls up the testis ipsilaterally. The reflex utilises sensory and motor fibres from 2 different nerves. When the inner thigh is stroked, sensory fibres of the Ilioingual Nerve are stimulated, which activate motor fibres of the genital branch of the Genitofemoral Nerve. This causes the Cremaster muscle to contract and elevate the testis.
In boys, this reflex may be exaggerated which can occasionally lead to a misdiagnosis of cryptorchidism. Men with testicular torsion, upper and lower motor neuron disorders, or a spine injury of L1-L2 may have an absent cremasteric reflex. This also occurs if the Ilioinguinal nerve is accidentally severed during a hernia repair.
Nonetheless, this reflex is handy in recognising testicular emergencies, but it doesn’t eliminate testicular torsion from a differential diagnosis. Though it broadens e possibilities to include epididymitis or other causes of scrotal and testicular pain. In any event, if testicular torsion cannot be definitively eliminated in an expeditious manner, then you require a testicular Doppler ultrasound or exploratory surgical intervention to prevent possible loss of the testicle to necrosis.
When your face is submerged and your nostrils are filled with water, sensory receptors sensitive to wetness within the nasal cavity and other areas of the face supplied by the Trigeminal Nerve (CN V) relay the information to the brain. Then the Vagus Nerve (CN X) produces bradycardia and other neural pathways would elicits peripheral vasoconstriction, which restricts blood from your limbs and all organs. This preserves blood and oxygen for the heart and the brain (and lungs), concentrating flow in a heart–brain circuit, which allows the animal to conserve oxygen. In humans, this reflex isn’t induced when the limbs are introduced to cold water. You will experience mild bradycardia if you hold your breath without submerging your face underwater. When you breathe with your face submerged, the diving response increases proportionally to decreasing water temperature. Nevertheless, when you hold your breath with your face soaked, this induces the greatest bradycardia effect. Apnea with nostril and facial cooling are other triggers of this reflex. In animals, such as dolphin, the diving reflex varies considerably depending on level of exertion during foraging. When deprived of oxygen underwater, children tend to survive longer than adults. But the exact mechanism for this effect is debatable with theories suggesting it may result from brain cooling similar to the protective effects seen in people treated with deep hypothermia.
I) Carotid Body Chemoreceptors:
- During sustained periods of holding your breath while submerged, blood oxygen levels decrease while carbon dioxide levels and acidity increase, as well as stimuli collectively acting upon chemoreceptors located in the bilateral carotid bodies. As sensory organs, the carotid bodies convey the chemical status of the circulating blood to brain centres that regulate neural outputs to the heart and circulation. Studies conducted in ducks and humans indicate that the carotid bodies play an important role in mediating integrated cardiovascular responses of the diving response. This establishes a “chemoflex” characterised by parasympathetic (slowing) effects) on the heart and sympathetic (vasoconstrictor) effects on the vascular system.
II) Circulatory Responses:
- Within a short period of immersion, plasma fluid losses occur due to immersion diuresis. Head-out immersion would cause a blood shift from the limbs and into the thorax, which largely originates from the extracellular tissues and due to the increased atrial volume resulting in a compensatory diuresis. During immersion, plasma volume, stroke volume, and cardiac output would remain higher than normal. This increased respiratory and cardiac workload increases blood flow to the cardiac and respiratory muscles. However, stroke volume isn’t greatly affected by immersion or variation in ambient pressure, but bradycardia reduces the overall cardiac output due to to the diving reflex in breath-hold diving.
- When cold water contacts the human face, it responses with bradycardia, which slows the heart rate by 10-25%. Seals experience more dramatic respiratory and cardiac changes, decreasing from 125 beats per minute to as low as 10 on an extended dive. When humans hold their breath, they display reduced left ventricular contractility and diminished cardiac output, which may be more severe during submersion due to hydrostatic pressure. When heart rate slows down, it reduces cardiac oxygen consumption, and compensates for the hypertension due to vasoconstriction. However, this reduces breath-hold time when the entire body is exposed to cold water as the metabolic rate increases to compensate for accelerated heat loss even when the heart rate is significantly slowed.
- In response to lowered levels of oxygen and increased levels of carbon dioxide, the spleen contracts to release red blood cells and ncreasing the oxygen capacity of the blood, which may begin before the bradycardia event.
- In the context of medicine, “blood shift” is defined as blood flow to the extremities being redistributed to the head and torso during a breath-hold dive. During submersion, peripheral vasoconstriction occurs when resistance vessels limit blood flow to muscles, skin, viscera, and hypoxia-tolerant regions, thereby preserving oxygenated blood for the heart, lungs, and brain. This increased resistance to peripheral blood flow would increase the blood pressure, which is compensated by bradycardia, conditions which are accentuated by cold water. In aquatic animals, their blood volume is approximately 3 times larger per mass than in humans, which is augmented by considerably more oxygen bound to haemoglobin and myoglobin of diving mammals. This enables them prolongation of submersion after minimisation of capillary blood flow in peripheral organs.
- Cardiac arrhythmias are a common characteristic of the human diving response. This occurs because the diving reflex increases activity of the cardiac parasympathetic nervous system that regulates the bradycardia. Furthermore it associates with ectopic beats that are characteristic of human heart function during breath-hold dives. Neural responses to immersion of the face in cold water, distension of the heart due to central blood shift, and the increasing resistance to left ventricular ejection (afterload) by rising blood pressure are effects that may accentuate arrhythmias. They are commonly measured in the electrocardiogram (ECG) during human breath-hold dives. Features of the ECG include ST depression, heightened T-wave, and a positive U-wave following the QRS complex, which are measurements associated with reduced left ventricular contractility and overall depressed cardiac function during a dive.
III) Renal and Water Balance Responses:
- In hydrated subjects, immersion will cause diuresis and excretion of Sodium and Potassium ions. In dehydrated subjects, trained athletes in comparison with sedentary subjects, however, diuresis is reduced.
IV) Respiratory Responses:
- Breathing through a snorkel is limited to shallow depths just below the surface due to the effort required during inhalation to overcome the hydrostatic pressure on the chest. Hydrostatic pressure on the surface of the body due to head out immersion in water causes negative pressure breathing, shifting blood into the intrathoracic circulation. Due to cranial displacement of the abdomen due to hydrostatic pressure, lung volume decreases in the upright position. Moreover, this decrease in lung volume significantly increases resistance to air flow in the airways. Due to ambient pressure and hydrostatic pressure differences between the interior of the lung and the breathing gas delivery, breathing gas density increases. Furthermore, due to higher breathing rates, flow resistance increases, which then increases work of breathing and fatigue of the respiratory muscles. They may be an association between pulmonary oedema and increased pulmonary blood flow and pressure, resulting in capillary engorgement. This may occur during higher intensity exercise while immersed or submersed. Facial immersion at the time of initiating breath-hold is a necessary factor for maximising the mammalian diving reflex in humans.
V) Thermal Balance Responses:
- When unprotected, the human body’s response to cold water immersion progresses from a stress situation to hypothermia and death, at a rate depending on time and water temperature. In the early stages of exposure, hypothermia isn’t a major problem as other stresses are more immediately life-threatening. When your body is immersed in cold water, your initial reaction would be the ‘cold shock response’. It generally begins with a gasp reflex in response to sudden and rapid chilling of the skin. If your head is fully immersed, there is a risk of inhaling water and drowning. Then you experience reflexive hyperventilation and possibly panic and faint if this response isn’t controlled. Cold induced vasoconstriction increases the workload on the heart, which can overload it if it’s weak, possibly leading to cardiac arrest. Within 5-15 minutes immersed in cold water, your body would undergo cold incapacitation. In this stage, blood flow to your extremities would decrease by vasoconstriction as your body attempts to reduce heat loss from the vital organs of the core. This would accelerate cooling of your periphery, and reduce the functionality of the muscles and nerves. The duration of exposure to cause hypothermia varies depending on your health, body mass and water temperature. If you were immediately exposed in cold water unprotected, it would take about 30 mins for you to experience hypothermia.
- How do aquatic animals adapt to cold water immersion? It’s understood that diving mammals have an elastic aortic bulb to help maintain arterial pressure during extended intervals between heartbeats during dives. Seals and dolphins also have high blood volumes, and combined with large storage capacity in veins and retes of its thorax and head. Chronic physiological adaptations of blood include elevated hematocrit, haemoglobin, and myoglobin levels which enables greater oxygen storage and delivery to essential organs during a dive. During the reflex, oxygen expenditure is minimised by energy efficient swimming or gliding behaviour, and regulation of metabolism, heart rate, and peripheral vasoconstriction. Oxygen levels limit the aerobic diving capacity, as well as the rate at which it is consumed. Diving mammals and birds have considerably higher blood volume than terrestrial animals of similar size, as well as a higher concentration of haemoglobin and myoglobin, which helps carry large Oxygen loads. During the dive, haematocrit and haemoglobin levels temporarily increase by reflex splenic contraction, which discharges an additional substantial amount of red blood cells. Furthermore, diving mammals’ brain tissue contains higher levels of neuroglobin and cytoglobin than terrestrial animals. Aquatic mammals seldom dive beyond their aerobic diving limit, which is determined by the Myoglobin Oxygen stored. Their muscle mass is relatively large due to a larger myoglobin content of their skeletal muscles, which provides them a larger reserve. When muscle tissue becomes relatively hypoxic, Myoglobin-bound Oxygen is released, so peripheral vasoconstriction due to the diving reflex makes the muscles ischaemic and promotes early use of myoglobin bound oxygen.
An absence of this reflex indicates radiculopathy within the C6 and C7 or neuropathy within the deep branch of the radial nerve.
In a reflex arc, a series of physiological steps occur very rapidly to produce a reflex. In the case from objects reaching nerves in the back of the throat:
I) A sensory receptor receives an environmental stimulus, and transmits an impulse via an afferent nerve to the Central Nervous System (CNS).
II) The CNS receives this impulse and sends an appropriate response via an efferent nerve (i.e. motor neuron) to effector cells located in the same initial area that can then carry out the appropriate response.
In the case of the pharyngeal reflex, the sensory limb is mediated predominantly by CN IX (glossopharyngeal nerve), whilst the the motor limb is mediated by CN X (vagus nerve).
By touching the posterior pharyngeal wall, this invokes a brisk and brief elevation of the soft palate and bilateral contraction of pharyngeal muscles. Touching the soft palate can lead to a similar reflex response, but, in that case, the sensory limb of the reflex is the CN V (trigeminal nerve). In sensitive individuals, much more of the brain stem may be involved, thus a simple gag may enlarge to retching and vomiting in some.
This reflex is usually activated when attempting to swallow unusually large objects or placing objects in the back of the mouth. Some people, such as sword swallowers, spend years learning to suppress this reflex. In contrast, triggering the reflex is sometimes done intentionally to induce vomiting, by those who suffer from bulimia nervosa. According to a 1995 study "Pharyngeal sensation and gag reflex in healthy subjects”, it’s found that a third of people lack the gag reflex and some people have a hypersensitive gag reflex. This hypersensitivity can lead to issues in various situations, from swallowing a pill or large bites of food to visiting the dentist. It is generally a conditioned response, usually occurring following a previous experience. Several methods to desensitise this hypersensitivity range from relaxation to numbing the mouth and throat to training one's soft palate to get used to being touched. Moreover, 37% of healthy people did not have a gag reflex, yet all subjects except for one still retained an intact pharyngeal sensation. These findings suggest that the muscles controlling the gag reflex remain independent of those that control normal swallowing. Since this reflex is uncommon in healthy people, its predictive value in determining the risk for swallowing disorders is severely limited. However, pharyngeal sensation is rarely absent, which might produce accurate predictions regarding swallowing problems.
Reflexive pharyngeal swallowing is closely related to the gag reflex. This is due to food or other foreign substances being forced back out of the pharynx, and swallowing would force food through the digestive system into the stomach. Its function is to protect the upper respiratory tract by forcing closure of the glottis, thereby preventing any substances getting into the airways and clearing the pharynx of any residual substances by a swallow. This reflex is one of several aero-digestive reflexes. The others are the pharyngoglottal closure reflex and the pharyngo-upper oesophageal sphincter contractile reflex. The pharyngoglottal closure reflex prevents swallowing yet the glottis still closes, while the pharyngo-upper oesophageal sphincter contractile reflex occurs during gastroesophageal reflux episodes. All aerodigestive reflexes either forcibly close the glottis or allow the pharynx to remove particles into the digestive tract that may have been forced back up by both this tract and the upper respiratory tract. They protect the airways from any food or liquids that may spill over from the hypopharynx. The hypopharynx is the most ventral part of the pharynx, and is considered the first area where the digestive tract splits from the airways. However, if the fluid levels exceed the maximum capacity that the hypopharynx can safely hold, then excess fluid will spill into the larynx and then into the lungs. Therefore, these reflexes prevent levels reaching this maximum volume.
Since both the digestive system and the respiratory system are connected by the pharynx, there are many problems and diseases that occur when the body is unable to regulate passage of food and air into the appropriate tracts. Smoking is one of the most preventable cause of damage to these reflexes. A 1998 study demonstrated that, when compared to non-smokers, the threshold volumes for both the pharyngo-upper oesophageal sphincter contractile reflex and reflexive pharyngeal swallowing is increased.
For those who lack a gag reflex and pharyngeal sensation, they may develop symptoms of a number of severe medical conditions, such as damage to the Glossopharyngeal Nerve, Vagus Nerve, or brain death. If there’s unilateral (one-sided) glossopharyngeal nerve (CN IX- sensory component) damage, there won’t be any gag response when the pharyngeal wall on the same side of the damaged nerve is touched. If there is unilateral vagal nerve (CN X- motor component) damage, the soft palate will elevate and pull toward the intact side regardless of the side of the pharynx that is touched. This occurs because the sensory component is intact on both sides, but only the motor nerves supplying one side of the soft palatine and pharyngeal muscles is functional, therefore the contraction of the muscles in the reflex is asymmetrical. If both the glossopharyngeal and vagal nerves are damaged on one side, then stimulation of the normal side elicits only a unilateral response, with deviation of the soft palate to that side; no consensual response is seen. Touching the damaged side doesn’t evoke any response.
https://www.youtube.com/watch?v=-vBZesEaYYs
— Galant Reflex (Galant’s Infantile Reflex, Truncal Incurvation Reflex) = Named after Russian neurologist Johann Susman Galant, this reflex is present at birth and disappears between 4 - 6 months of age. Stroking the skin along the side of an infant’s back will stimulate the infant to swing toward the side that was stroked. If the reflex persists beyond 6 months of age, it is a sign of pathology.
In physiological experiments, scientists investigated this reflex using myoelectric recordings in the colons of animals and humans. Within as little as 15 minutes after eating, recordings showed an increased in electric activity. It also demonstrated this reflex is uneven in its distribution throughout the colon. It’s known that the sigmoid colon is more influenced than the right side of the colon in terms of a phasic response, but the tonic response across the colon remains uncertain. When pressure within the rectum increases, this reflex acts as a stimulus for defecation. A number of neuropeptides have been proposed as mediators of this reflex such as Serotonin, Neurotensin, Cholecystokinin (CCK) and Gastrin. Clinically, this reflex is hypothesised in pathogenesis of irritable bowel syndrome. Sufferers who eat and drink can provoke an overreaction of the gastrocolic response due to their heightened visceral sensitivity. This would lead to abdominal pain, diarrhoea or constipation. Furthermore, the serotonin (5HT3) antagonist Ondansetron decreases the tonic response to stretch.
https://www.youtube.com/watch?v=tPdfGGBqeSU
— Glabellar Reflex (Glabellar Tap Sign) = This reflex is elicited by repetitive tapping on the forehead. In response, individuals would blink in the first several taps. If the blinking persists, this is known as Myerson’s Sign, which is abnormal and a sign of frontal release. It is often seen in people suffering from Parkinson’s Disease. The afferent sensory signals are transmitted by the Trigeminal Nerve, and the efferent signals are transmitted to the Orbicularis Oculi muscle via the Facial Nerve, which in turn reflexively contracts causing blinking.
This reflex operates as a protective feedback mechanism to control the tension of an active muscle by relaxing it before the tendon tension exceeds its maximum load bearing leading to muscle damage. Firstly, place a load on the muscle, the afferent neuron from the Golgi tendon organ fires into the CNS. Secondly, the motor neuron from the spinal cord is inhibited via an IPSP (inhibitory post-synaptic potential), which relaxes the muscle.
I) As excessive tension is applied to a tendon, the Golgi tendon organ (sensor) is stimulated (i.e. above threshold to depolarise).
II) Nerve impulses (i.e. action potentials) arise and propagate along sensory fibre Ib into the spinal cord.
III) Within the spinal cord is an integrating centre, where sensory fibre Ib synapses with and activates an inhibitory interneuron by releasing Glutamate.
IV) The inhibitory interneuron releases Glycine that inhibits (hyperpolarises) the α-motor neuron. V) This reduces the amount of nerve impulses generated in the α-motor neuron. VI) As a result, the muscle relaxes and excess tension is relieved.
The clasp-knife response is a stretch reflex with a rapid decrease in resistance when attempting to flex a joint. However, it is actually thought to be caused by the tendon reflex of the antagonistic muscle of that joint, which gets extended. It is one of the characteristic responses of an upper motor neuron lesion.
This reflex is analogous to the mechanically induced spinal stretch reflex (e.g. knee jerk reflex), but the “primary difference is that H-reflex bypasses the muscle spindle, and, therefore, is a valuable tool in assessing modulation of monosynaptic reflex activity in the spinal cord.” Whilst stretch reflex provides qualitative information about muscle spindles and reflex arc activity, the H-reflex compares performances from different subjects. . In that case, latencies (ms) and amplitudes (mV) of H-wave can be compared as a matter of fact.
H-reflex amplitudes measured by EMG decrease significantly with applied pressure such as massage and tapping to the cited muscle. The amount of decrease is directly proportional on the force of the pressure, with higher pressures resulting in lower H-reflex amplitudes. H-reflex levels return to baseline immediately after the pressure is released except in high pressure cases which had baseline levels returned within the first 10 seconds.
After about 5 days in zero gravity, for instance, in orbit around Earth, the h-reflex diminishes significantly. Experts assume this is due to a marked reduction in the excitability of the spinal cord in zero gravity. Once back on Earth, a marked recovery occurs during the first day, but it can take up to 10 days to return to normal. The H-reflex was the first medical experiment completed on the International Space Station.
This reflex plays a crucial role in keeping the lungs from over-inflating with inspired air. The neural circuit controlling this inflation reflex involves several regions of the CNS, and both sensory and motor components of the vagus nerve. When sensory activity of the pulmonary-stretch lung afferents (via the vagus nerve) increases, it inhibits central inspiratory drive and thus inhibits inspiration and initiation of expiration. Lung afferents also transmit inhibitory nerve impulses to the cardiac vagal motor neurones (CVM) in the Nucleus Ambiguus (NA) and dorsal motor vagal nucleus (DMVN). The CVMs, which send motor fibres to the heart via the vagus nerve, are responsible for tonic inhibitory control of heart rate. Thus, an increase in pulmonary stretch receptor activity inhibits the CVMs and elevates heart rate (tachycardia). This response is normal in healthy individuals and is known as sinus arrhythmias.
For most animals, the reflex plays a major role in establishing the rate and depth of breathing, but this isn’t the case in adult humans at rest. New theories suggest the reflex may determine breathing rate and depth in newborns and in adult humans when tidal volume is more than 1L, as when exercising.
The Hering-Breuer deflation reflex shortens exhalation when the lung is deflated. It is activated either by stimulating stretch receptors or proprioceptors activated by lung deflation. Like the inflation reflex, impulses from these receptors travel afferently via the Vagus Nerve. However, the difference is the afferents terminate on inspiratory centres rather than the Pontine Apneustic Centre. These reflexes appear to play a more minor role in humans than in non-human mammals.
https://www.youtube.com/watch?v=uVI55amnVuk&vl=en
— Hoffman’s Reflex (Finger Flexor Reflex) = Named after neurologist Johann Hoffmann, this reflex test is used to help verify the presence or absence of issues arising from the Corticospinal Tract, including myelopathy. It’s a pathological reflex in a clinical setting that has also been used as a measure of spinal reflex processing (adaptation) in response to exercise training.
This reflex test involves loosely holding your middle finger and flicking the fingernail downward. This allows the middle finger to flick upward reflexively. If the thumb on the same hand flexes and adducts, this is a positive response. This suggests hypertonia, but it can occur in healthy individuals, making it unreliable signs in isolation. In cerebellar diseases, the reflexes may be pendular, and muscle contraction and relaxation tend to be slow, but these are not sensitive or specific to cerebellar signs.
A positive Hoffman’s Sign can be present in an entirely normal patient, commonly found in those who are naturally hyper-reflexive (e.g. 3+ reflexes). Nevertheless, it’s a worrisome finding of a disease process if its presence is asymmetrical, or has an acute onset. This reflex is a deep tendon reflex (spindle fibre) with a monosynaptic reflex pathway in Rexed Iamina IX of the spinal cord, normally fully inhibited by descending input.
This reflex is classified as a dynamic stretch reflex, and its response to all stimuli is monosynaptic. This means sensory neurons of the Trigeminal Mesencephalic Nucleus projects its axons to the Trigeminal Motor Nucleus, which in turn innervates the masseter muscle. This reflex is used to judge the integrity of the upper motor neurons projecting to the trigeminal motor nucleus. Both the sensory and motor aspects of this reflex are through CN V. Although this reflex isn’t part of a standard neurological examination, it is still performed when there are other signs of damage to the trigeminal nerve, nonetheless. The clinical presentation of cervical spondylotic myelopathy shares similarities with Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS). However, a hyperactive jaw reflex suggests the pathology is above the Foramen Magnum. In other words, a normal jaw jerk reflex points the diagnosis toward Cervical Spondylotic myelopathy and away from MS or ALS.
Studies have discovered a significant relationship between gender and the jaw jerk reflex. Electromyographs were used to measure the impulse within the muscle, allowing the amplitude of the impulse to be known and shown on a graph. They were focussed on the masseter and temporalis muscles. The results showed a significantly higher amplitude in females compared to males, meaning a larger impulse. Whenever you’re interpreting ECM results, make sure you take those amplitudes into account because a graph of the female’s response will normally show a higher peak to peak amplitude than a male. Furthermore, the mean latency of the impulse was also found to be shorter in females than in males. This variation in women appears to be constant, and is not affected by the menstrual cycle.
Other studies have discovered a directly proportional relationship between latency of this reflex and age. Latency is defined as the time taken between the chin tap to the first obvious deflection as seen on the subject. Patients aged 75 years and older recorded the most prominent decline in masseter muscle activity. This may be due to a reduction in both tendon and superficial reflexes. Another study reported 52% of the elderly exhibited an absence of this reflex, in an average age of 81.8 years. In healthy elderly people, their jaw muscles hardly display prominent changes in muscular tissue as they mature, as their oral cavities are in constant motor movement (i.e.: performing tasks such as talking and chewing etc.). This constant motion delays the decrease in lean body mass and aids protein retention that comes with age, preventing the muscular tissues from wearing and tearing.
Even if the patient is aware that interlocking their fingers is a distraction in order to elicit a pronounced reflex response, this maneuveur still manages to function properly. It can also be used to distract patients when performing other tests or procedures and any suitable distraction may be used e.g. searching for Romberg’s Sign.
To activate this reflex, physicians strike a patient’s patellar tendon with a reflex hammer just below the patella, which stretches the muscle spindle in the quadriceps muscle. This sends a nerve impulse to the spinal cord and synapses (without interneurons) at the level of L3 in the spinal cord, completely independent of higher centres. From there, an α-motor neuron sends an efferent impulse back to the quadriceps femoris muscle, causing its contraction. This muscle contraction is coordinated with the relaxation of the antagonistic flexor hamstring muscle to cause the kicking motion in the leg. This is a reflex of proprioception that helps maintain posture and balance with minimal effort or conscious thought.
It is a clinical and classic example of the monosynaptic reflex arc. There isn’t any interneuron in the pathway leading to contraction of the quadriceps muscle. Instead the bipolar sensory neuron synapses directly on a motor neuron in the spinal cord. However, there is an inhibitory interneuron used to relax the antagonistic hamstring muscle.
In some cases, this test of a basic automatic reflex may be influenced by the patient consciously inhibiting or exaggerating the response. Therefore, the physician may use Jendrassik Maneuver as a distraction or diversion in order to ensure a more valid reflex test.
If this reflex is decreased or absent, it is known as Westphal’s Sign. Lesions in lower motor neurons and sleep may cause this reflex to diminish or disappear. On the other hand, multiple oscillation of the leg (pendular reflex) following the tap may be a sign of cerebellar diseases. Exaggerated (brisk) deep tendon reflexes such as this can be found in upper motor neuron lesions, hyperthyroidism, anxiety or nervousness. The test itself assesses the nervous tissue between and including the L2 and L4 segments of the spinal cord.
https://www.youtube.com/watch?v=kBDC59pbSZ0
— Menace Reflex = This reflex is 1 of 3 forms of blink reflex. It is the reflex blinking that occurs in response to the rapid approach of an object. It comprises blinking of the eyelids, in order to protect the eyes from potential damage, and turning of the head, neck, or the trunk away from the optical stimulus triggering the reflex.
This reflex is used as a diagnostic procedure in veterinary medicine, in order to determine whether an animal’s visual system, in particular the Cortical Nerve, has suffered from nerve damage. If there is cortical damage, particularly cerebral lesions, it can compromise the menace reflex but other blink reflexes such as the dazzle reflex are left virtually unaffected. The presence or absence of the menace reflex, in combination with other reflexes, indicates a locus of damage.
e.g. An animal suffering from polioencephalomalacia won’t have the menace reflex, but will still have the pupillary light reflex. . Polioencephalomacia damages the visual cortex, impairing the menace reflex, but leaves the Optic Nerve, Oculomotor Nucleus and Oculomotor Nerve intact, leaving the pupillary light reflex unaffected. In contrast, an animal with ocular hypovitaminosis-A will suffer from degeneration of the optic nerve, compromising both reflexes.
Care is utmost important when testing the menace reflex. Waving an object close to an animal's eyes or face doesn’t necessarily demonstrate a functioning menace reflex. This is partly due to the animal’s ability to sense such objects and react to them via senses other than sight. Clinical testing of this reflex usually involves precautions such as waving an object from behind a sheet of glass, so as to shield the animal from any drafts caused by the motion of the object through the air, which it might otherwise sense. Such reactions to non-visual stimuli are a widespread cause of false positives and false negatives when pet owners test their own animals for the presence of the menace reflex.
The neural pathway responsible for this reflex comprises the Optic (II) and Facial (VII) Nerves. It is mediated by Tectobulbar fibres in the rostral colliculi of the Midbrain projecting from the Optic Tract to Accessory Nuclei. There it projects to the Spinal Cord and lower motor neurons that innervate the head, neck, and body muscles affected by the reflex. The Facial Nerve is mediated through a corticotectopontocerebellar pathway.
https://www.youtube.com/watch?v=PTz-iVI2mf4
— Moro Reflex = Sometimes referred to as the startle reaction, startle response, startle reflex or embrace reflex, this reflex is named after paediatrician Ernst Moro. It is present at birth, peaks in the first month of life, and begins to disappear around 2 months of age. This reflex likely occurs if the infant’s head suddenly shifts position, the temperature changes abruptly, or they are startled by a sudden noise. It stimulates the baby to extend their legs and head while their arms jerk and out with the palms up and flex their thumbs. Shortly afterward, they bring their arms together and clench their hands into fists prior to their loud cries. The Moro reflex normally disappears by 3 - 4 months of age, it may last up to 6 months. Bilateral absence of the reflex may be linked to damage to the infant’s CNS, while a unilateral absence could indicate an injury due to birth trauma (e.g. a fractured clavicle or injury to the brachial plexus). In some cases, infants with Erb’s Palsy or some other form of paralysis may lack this reflex. In human evolutionary history, the Moro reflex may have helped infants cling to the mother while being carried around. If the infant lost its balance, the reflex caused the infant to embrace its mother and regain its hold on the mother's body.
— Muscular Defence = This reflex contracts the abdominal muscles upon mechanical force to the abdomen, serving as protection. It’s specifically a visceromotor reflex, since the parietal peritoneum and viscera are involved in generating the reflex.
https://www.youtube.com/watch?v=EiwD6s8dmu4
— Oppenheim’s Sign = This reflex involves dorsiflexion of the great toe caused by irritation downward of the medial side of the tibia. It is one of a number of Babinskin-like responses. Its presence indicates a damage to the pyramidal tract. It is named after Hermann Oppenheim.
— Optical Reflex = This reflex is slower than the corneal reflex and is mediated by the visual cortex, residing in the Occipital Lobe of the brain. The reflex is absent in infants under 9 months.
To elicit optokinetic nystagmus:
(1) Get an optokinetic drum and rotate it in front of the patient.
(2) Ask the patient to look at the drum as you rotate it slowly.
(3) If you don’t have an optokinetic drum, move a strip of paper with alternating 2-inch black and white strips across the patient's visual field.
(4) Pass it in front of the patient's eye at reading distance while instructing the patient to look at it as it rapidly moves by.
(5) A nystagmus develops in both adults and infants with normal vision.
(6) The nystagmus consists of initial slow phases in the direction of the stimulus (smooth pursuits), followed by fast, corrective phases (saccade).
(7) This indicates an intact visual pathway.
Another effective method is to hold a mirror in front of the patient and slowly rotate the mirror to either side of the patient. If the patient has an intact visual pathway, they will maintain eye contact with themselves. This compelling optokinetic stimulus forces reflex slow eye movements.
OKN can be used as a crude assessment of the visual system, particularly in infants. If factitious blindness or malingering is suspected, it’s important to check for OKN to check whether the visual pathway is intact or not.
https://www.youtube.com/watch?v=6fIIbY0WD_M
— Parachute Reflex = This reflex occurs in slightly older infants when they are held upright and their body is rotated quickly to face forward (as in falling). It stimulates the baby to extend their arms forward as if to break a fall, even though this reflex appears long before the baby walks.
https://www.youtube.com/watch?v=TidY4XPnFUM
— Palmar Grasp Reflex = This primitive reflex is exhibited by the foetus in utero as early as 16 weeks into the gestation period, persisting until 5 - 6 months of age. Place an object in an infant’s hand and stroke the palm. You would notice that the baby’s hand will close reflexively, as the object is grasped via palmar grasp. The strength of the grip is unpredictably variable because it may support the child’d weight, their grip may suddenly release without warning. The reverse motion can be induced by stroking the back or side of the hand.
If this reflex persists beyond 2 - 4 months, it delays or affects important functions like grasping a rattle, releasing objects from the hand and hand manipulation skills. In adults, the persistence of this reflex is a pathological frontal release sign that may signifies frontal lobe damage, or a sign of anterior cerebral artery syndrome.
https://www.youtube.com/watch?v=6tBar9qihQA
— Palmomental Reflex (PMR) = This primitive reflex consists a twitch of the chin muscle elicited by stroking a specific part of the palm. It’s observed in infancy and usually disappears as the brain matures during childhood but disruption to the normal cortical inhibitory pathways can make this reflex reappear. Therefore, it’s an example of a frontal release sign. In order to elicit this reflex, briskly stroke the thenar eminence with a thin stick, from proximal (edge of wrist) to distal (base of thumb) with moderate pressure. If a single visible twitch of the ipsilateral mentalis muscle (chin muscle on the same side as the hand tested) is observed, this is considered a positive response.
https://www.youtube.com/watch?v=e69XZJ9DEj0
— Photic Sneeze Reflex = Also known as Autosomal Compelling Helio-Ophthalmic Outburst (ACHOO) syndrome or colloquially sun sneezing, this reflex is a condition that causes sneezing response to several stimuli, such as looking at bright lights or periocular (surrounding the eyeball) injection. This affects 18-35% of America’s population, but its exact mechanism of action is not well understood. This reflex is inherited in an autosomal dominant manner, for instance, if the father contains the gene responsible for the ACHOO syndrome, he will pass on that gene to his offspring 50% of the time, thus his son or daughter can inherit the gene.
The photic sneeze effect is a genetic tendency to begin sneezing upon exposure to bright light, occasionally many consecutive times due to naso-ocular reflex, A 2015 study found that the severity of this condition increases after a person was immersed in light after spending time in a dark environment. Although the syndrome is thought to affect about 18-35% of the human population, it is relatively harmless and not widely studied. The first person to contemplate this strange phenomenon was in 350 BCE by Greek philosopher Aristotle, who explored when looking at the sun causes a person to sneeze in The Book of Problems: "Why does the heat of the sun provoke sneezing?” He hypothesised that the sun’s heat caused sweating inside the nose, which triggered a sneeze in order to remove the moisture. In the 17th century, English philosopher Francis Bacon disproved Aristotle’s theory by facing the sun with his eyes closed, which didn’t elicit the ordinary sneeze response. Bacon therefore concluded that the eyes played a vital part in triggering photic sneezing. He proposed that upon staring at the sun's light made the eyes water, moisture proceeded to seep into the nose and irritate it, causing a sneeze. Although plausible, scientists later determined this theory to also be false because sun-induced sneezing occurs too quickly after sunlight exposure. In fact, the process of watering of the eyes is too slow, so it wasn’t regarded as a vital part in triggering the reflex. Today, the scientific community mainly focused on a hypothesis proposed in 1964 by Henry Everett, who was the first to call light-induced sneezing “The Photic Sneeze Effect.” Since the nervous system transmits signals at an extremely fast pace, Dr. Everett hypothesised that the syndrome was linked to the human nervous system, perhaps caused by the confusion of nerve signals. However, the genetic basis of photic sneezing still remains unclear, and single genes responsible for this condition have yet to be discovered and studied. However, the condition often occurs within families, and it has been suggested that light-induced sneezing is a heritable, autosomal-dominant trait. A 2010 study demonstrated a correlation between photic sneezing and a single nucleotide polymorphism (SNP) on chromosome 2.
i. What are the symptoms?
The manifestations of this reflex include uncontrollable sneezing in response to a stimulus, which normally would not produce a sneeze in people who lack the trait. The sneezes generally occur in bursts of 1 to 10 sneezes, followed by a refractory period that can last as long as 24 hours. The most common manifestation is photic sneezing, which is triggered by exposure to a bright light. It suggests the reflex is activated by a change in light intensity instead of a specific wavelength of light. A 1995 study conducted by the School of Optometry at the University of Alabama at Birmingham reported 67% of photic sneezers were female, and 94% were Caucasians. It also found statistically significant correlations between photic sneezing and the presence of a deviated nasal septum. It demonstrated that photic sneezing is more likely to be acquired than inherited.
During surgeries in and around the eye, such as corneal transplant surgery, surgeons often inject local anaesthetic into the patient’s eye. After this eye injection, such as that undergone in a retrobulbar or peribulbar block, it can often elicit a sneeze from the patient. During these procedures, the patient may be sedated prior to the periocular injection. As soon as the needle inserts into the eye, the patient would start to sneeze, which often forces the anaesthesiologist to remove the needle from the eye before injecting the local anaesthetic in order to avoid damaging the patient's eye. Another symptom of this reflex is called ‘gustatory rhinitis’, which causes individuals to sneeze after eating, particularly after the consumption of spicy foods. Another example of a stimulus causing uncontrollable sneezing is ‘stomach fullness’. Those who exhibit this symptom or disorder i.e. snatiation, undergo uncontrollable fits of 3–15 sneezes immediately after eating large meals that completely fill the stomach, regardless of the type of food eaten. However, snatiation mustn’t be confused with an allergic reaction of any kind. Unfortunately this condition isn’t well understood, less so than photic sneezing and sneezing in response to periocular injection, though it appears to be inherited in an autosomal dominant fashion.
ii. What are the risks?
- Disease Transmission: Sneezing generally doesn’t pose any risks to the individual, rather more of an annoyance than a risk of injury. Nevertheless, the sneezing fits have dangerous implications during certain scenarios and activities, such as operating a vehicle, or while undergoing operations (dental, optical) and having bright lights directed towards the patient's face. The most universal risk of sneezing is spreading germs, viruses, bacteria causing disease. Bacterial infections can spread to susceptible uninfected people via the transmission of microscopic organisms trapped in the droplets of fluid expelled by a sneeze. Common bacteria spread by sneezing include bacterial meningitis, strep. throat and tuberculosis. Viral infections spread by expulsion of viruses would have its mucous membrane evaporated in the air to become a droplet nucleus, which can be inhaled by another person, thus spreading the virulent infection. Examples of virulent infections spread by sneezing include measles, mumps, rubella and influenza.
- Vehicle operation: If you sneeze while operating a vehicle like a car, truck or bus, your eyes would be closed for about 1.2 seconds. This could result in injury to yourself, your passengers, and damage to the vehicle and/or surroundings. Because pilots are frequently exposed to bright sunlight, photic sneezing can disrupt their precise reactions required to successfully control the aircraft. If pilots of fighter aircraft experienced uncontrollable sneezing fits during aerial combat, this could incapacitate them when their situational awareness needs to at its maximum. This could disrupt their ability to land on an aircraft carrier or shoreline safely if their precise movements and quick reflexes are compromised. Any amount of sneezing while attempting to land could cause the pilot to lose control, potentially resulting in disaster and death.
- Medical procedures: Patients undergoing periocular or retrobulbar injections are sedated by propofol, which can cause them sneeze uncontrollably. This often occurs upon insertion of a needle into or around their eye. The violent and uncontrollable movement of the head during a reflexive sneeze could potentially damage the patient’s eye if the needle isn’t removed before the sneeze occurs.
iii. What is the pathophysiology?
There is ongoing debate about the true cause and mechanism of the sneezing fits brought about by this reflex. Sneezing usually occurs in response to irritation in the nasal cavity, which results in an afferent nerve fibre signal propagating through the ophthalmic and maxillary branches of the Trigeminal Nerve to the Trigeminal Nerve Nuclei in the brainstem, which it gets interpreted. Then an efferent nerve signal propagates to different parts of the body, such as mucous glands and the thoracic diaphragm, thus producing a sneeze. On the other hand, photic sneezes are caused by a wide variety of stimuli. A 1984 study postulated a genetic factor responsible for increasing the probability of this reflex being activated, which is the C allele on the rs10427255 SNP. However the mechanism by which this gene increases the probability of this response is still unknown.
- Optic-trigeminal summation: When the ophthalmic branch of the trigeminal nerve is stimulates, it may enhance the irritability of the maxillary branch, which increases the probability of sneezing. This is similar to the mechanism by which photophobia develops by persistent light exposure relaying signals through the optic nerve and trigeminal nerve to increase sensitivity of the ophthalmic branch. If this increased sensitivity occurred in the maxillary branch instead, a sneeze could result instead of photophobia.
- Parasympathetic generalisation: The parasympathetic nervous system (PNS) contains many neighbouring fibres responding to different stimuli. When one stimulus activates multiple nerve fibres of the PNS, this results in parasympathetic generalisation. A 1995 study suggested that sensory input from the eyes could travel to neurons in the cortex responsible for interpreting such signals, as well as neighbouring neurons involved in sneezing, due to the generalisation. This could lead to a sneeze in response to a stimulus other than nasal irritation.
- Increased light sensitivity: When the Trigeminal Nerve is directly stimulated, it’s possible this could increase light sensitivity in the Ocular Nerve. An example of direct stimulation would be plucking an eyebrow or pulling hair. If this was done on people who demonstrate the photic sneeze reflex, this would induce sneezing while they look at bright light.
- Propofol-induced inhibitory suppression: If a patient uncontrollably sneezes during a periocular injection while being sedated by propofol, this is likely caused by the drug. A 2008 study found that propofol temporarily suppresses inhibitory neurons of the trigeminal nucleus in the brainstem, which is the "sneeze centre" of the brain. This sequence of events leads to increased sensitivity to stimulation and reduced threshold for involuntary responses. In this hypersensitive state, the periocular injection stimulates the ophthalmic and/or maxillary branch of the trigeminal nerve. This results in summation in the trigeminal nuclei, which cause the unconscious patient to sneeze.
While this phenomenon is poorly understood, a 1987 research study demonstrated that antihistamines used to treat rhinitis due to seasonal allergies may also reduce the occurrence of photic sneezes in people affected by both conditions. A 2015 study found that those affected by photic sneezing experience relief by shielding their eyes and/or faces with hats, scarves, and sunglasses.
The pupillary light reflex neural pathway on each side has 1 afferent limb and 2 efferent limbs.
(1) The afferent limb transmits nerve signals within the Optic Nerve (CN II) carrying sensory input, and each efferent limb transmits nerve signals along the Oculomotor Nerve (CN III).
(2) Anatomically, the afferent limb consists of the Retina, Optic Nerve, and the Pretectal Nucleus in the midbrain, at the level of Superior Colliculus.
(3) Retinal Ganglion Cells project fibres through the Optic Nerve to the ipsilateral Pretectal Nucleus.
(4) The efferent limb consists of pupillary motor output from the Pretectal Nucleus to the Ciliary Sphincter muscle of the iris.
(5) The Pretectal Nucleus projects crossed and uncrossed fibres to the ipsilateral and contralateral Edinger-Westphal Nuclei, located in the midbrain.
(6) Each Edinger-Westphal Nucleus projects preganglionic parasympathetic fibres that exit with Oculomotor Nerve.
(7) Those nerve fibres synapse with postganglionic parasympathetic neurons in the ciliary ganglion, which then innervate the ciliary sphincter.
(8) Each afferent limb has 2 efferent limbs, 1 ipsilateral and 1 contralateral. The ipsilateral efferent limb transmits nerve signals for direct light reflex of the ipsilateral pupil, while the contralateral efferent limb causes consensual light reflex of the contralateral pupil.
The pupillary response to light isn’t purely reflexive, but is rather modulated by cognitive factors, such as attention, awareness, and the brain’s interpretation of visual input. e.g. If a bright light is shone on one eye, and a dim light is shone on the other eye, perception alternates between the 2 eyes causing a phenomenon known as ‘binocular rivalry’. It simply means that occasionally the dim light is perceived, and at other times the bright light, but never both simultaneously. According to several 2013 studies, this demonstrates that the pupillary light reflex is modulated by visual awareness. In a similar scenario, when you covertly pay attention at a bright stimulus, compared to a dark stimulus, even when visual input is identical, both of your pupils will constrict. Moreover, the magnitude of this reflex following a distracting probe strongly correlates with the extent to which the the probe captures visual attention and interferes with task performance. It’s evident that this reflex is modulated by visual attention and trial-by-trial variation in visual attention. Finally, other 2013 studies have found that an image subjectively perceived as bright (e.g. a picture of the sun) then elicits a stronger pupillary constriction compared to imaged that is perceived as less bright (e.g. a picture of an indoor scene), even when the objective brightness of both images remains constant. This demonstrates that this reflex is modulated by subjective (as opposed to objective) brightness.
In addition to controlling the amount of light entering the eye, the pupillary light reflex is a useful diagnostic tool to test the integrity of the sensory and motor functions of the eye. Under normal conditions, the pupils of both eyes respond in identical fashion to the same light stimulus, regardless of which eye is being stimulated. When light enters one eye, it constricts its pupil (direct response) and the other pupil of the unstimulated eye (consensual response). The comparison between the direct and consensual responses in both eyes helps localise a lesion.
e.g. If a direct response in the right pupil isn’t spontaneously followed by a consensual response in the left pupil, this indicates a problem with the motor connection to the left pupil due to damage in the Oculomotor Nerve or Edinger-Westphal Nucleus of the brainstem. If both eyes’ response to stimulation of the left eye is normal but light stimulation of the right eye doesn’t generate a response, this indicates damage to the sensory input from the right eye around the right retina or Optic Nerve. Emergency room physicians routinely assess the pupillary reflex in order to assess brainstem function. Normally, pupils react (i.e., constrict) equally, but a lack of the pupillary reflex or an abnormal pupillary reflex indicates damage to the optic nerve or oculomotor nerve, brainstem death and depressant drugs, such as barbiturates.
https://www.youtube.com/watch?v=v7_Y_jg2soc
— Rooting Reflex = In human infants, this reflex is present at birth (age of appearance 28 weeks) and disappears around 4 months of age, as it gradually transitions to voluntary control. This reflex also lends assistance in the act of breastfeeding. A newborn infant will turn its head toward anything that strokes its cheek or mouth. Then they will search for the object by moving its head in steadily decreasing arcs until the object is found. Once the baby familiarises to this particular response (if breastfed, approximately 3 weeks after birth), they will move directly to the object without searching.
— Righting Reflex = Also known as the Labyrinthine Righting Reflex, this reflex corrects the orientation of the body when it is taken out of its normal upright position. When the vestibular system initially detects the body lack of uprightness, it causes the the head to return to its original position as the rest of the body follows. This perception of head movement t involves the body sensing linear acceleration or the force of gravity through the otoliths, and angular acceleration through the semicircular canals. It uses a combination of visual, vestibular, and somatosensory inputs to conduct postural adjustments when the body is displaced from its normal vertical position, which creates an ‘efference copy’. This indicates that the brain compares expected posture and perceived posture in the cerebellum, and corrects any difference accordingly. The reflex takes 6 or 7 weeks to perfect, but can be affected by various types of balance disorders.
This reflex involves complex muscular movements in response to a stimulus. When the brain is startled, it evokes anticipatory postural adjustments, or a series of muscle movement involving the function of the midbrain. Data from recent studies support the generation of these movements from circuits in the spine connected to the Supplementary Motor Area, the Basal Ganglia, and the Reticular Formation.
What are reference frames?
Reference frames are responsible for the perception of visual input for the appropriate righting reflex function, which helps create a representation of space for comparison to expected orientation. There are 3 types of reference frames our eyes use to perceive vertical orientation, which are consistently updated in order to rapidly adapt to process changes in vestibular input.
(i) Allocentric:
This describes a visual reference frame according to the arrangement of objects in an organism's environment. A “rod-and-frame” test relies on this reference frame to alter the subject’s perception of virtual objects, which causes a slight body tilt as the subject believes to be correcting for the shift.
(ii) Egocentric:
This reference frame refers to a proprioceptive reference frame according to the organism’s body position in space. It relies heavily on somatosensory information, or feedback from the body's sensory system. Muscle vibrations create an abnormal somatosensory signal that alters a subject's perception of their body’s location.
(iii) Geocentric:
This reference frame involves visual inputs to help detect the verticality of an environment through gravitational pull. The sole of your feet contains skin receptors that detect the force of gravity that help play an important role in maintaining standing or walking balance. Your abdominal organs also contain receptors that provide geocentric information. “Roll-tilt” tests are used to this reference frame function by mechanically moving a subject’s body in one direction or another.
This reflex is described as a 3-neuron arc system composed or primary vestibular neurons, vestibular nuclei neurons, and target motoneurons. Input from the vestibular system is received by sensory receptors in the hair cells of the semicircular canals and the otoliths, which are then processed in the vestibular nuclei. The cerebellum is responsible for processing “efference copies”, which compares expectations of the body's posture with its current orientation. The difference between expected posture and actual posture is corrected by motorneurons in the spinal cords, which help control muscle movements for righting the body.
These automatic postural adjustments associates with 2 similar reflexes: the vestibulo-ocular reflex (VOR) and the vestibulocollic reflex (VCR). The VOR involves movement of the eyes while the head turns to remain fixated on a stationary image, while the VCR involves controlled movement of neck muscles for correction of the head's orientation. During VOR, the semicircular canals transmits vestibular information to the brain and correct eye movements in the direction opposite to the head movement by projecting excitatory fibres to motor neurons on the side opposite to the head rotation. Neurons in the otoliths control not only these signals for control of eye movements, but also signals for correction of head movement through the neck muscles. The righting reflex utilises both the VOR and VCR to help adjust the body back into its original position. Visual information under the control of these reflexes creates greater stability for more accurate postural correction.
A series of visual acuity tests can examine vestibular function:
- Static visual acuity test = This investigates a patient's ability to view an object from a distance by placing the patient at a certain distance from a letter fixed on a screen.
- Dynamic visual acuity test = This investigates a patient's ability to control eye movements by following letters that appear on a screen.
The difference between these 2 test results determines the patient's fixation ability and vestibuloocular reflex (VOR) efficiency.
Body tilt experiments can examine the presence of vestibular reflexes. The Dix-Hallpike maneuver instructs patients with vestibular disorders to be seated with their legs extended and their head rotated 45 degrees. The patient is then instructed to lie down on the table and checked for nystagmus, or uncontrollable eye movements. If nystagmus is present, it indicates dysfunction of the vestibular system, which can lead to dizziness and inability to complete a righting reflex.
Proprioceptive ability tests are used by therapists by asking their patients to identify a certain limb or joint is located without looking at it. These tests are often conducted on uneven surfaces, including sand and grass.
In recent times, leg and foot rotation tests are used to investigate changes in neuron activity within the labyrinth, or in the inner ear. When a person’s head is rotated whilst the leg and foot are rotated 90 degrees, the vestibular signals cause the brain to inhibit movement in the direction of the rotation. Simultaneously, muscles on the opposite side activate in an attempt to correct for the displacement.
Because visual input plays a critical role in proper righting reflex function, any vision impairment would be detrimental. Blind patients heavily rely on vestibular input due to lack of visual input, promoting rewiring in the visual cortex in order to accommodate other senses taking control especially hearing. Developmentally blind patients have a larger portion of the brain dedicated to vestibular and somatosensory input than patients with normal visual function. Environmentally blind patients rely on neuroplasticity to develop new neural connections where visual inputs once were, and vestibular therapy may enhance this ability.
Many inner ear disorders can cause dizziness, leading to dysfunctional righting reflex action. Common inner ear disorders can cause vertigo in patients, either acutely or chronically. Labyrinthitis, or inflammation of the inner ear, causes imbalances that require therapeutic exercises to overcome. Patients with severe inner ear disorders thus debilitating vertigo may require a labyrinthectomy, or removal of their inner ear organs. Imbalances may result from the surgery, but therapy can help overcome the symptoms.
- Benign Paroxysmal Positional Vertigo (BPPV) = This disorder is caused by breakage of a piece of otoconia from the otoliths. When the otoconia floats freely in the inner ear fluid, it causes disorientation and vertigo. A nystagmus test is used to test for BPPV, such as the Dix-Hallpike Maneuver. Treatment for BPPV includes antihistamines and anticholinergics, which can alleviate the symptoms without surgical removal of the free otoconia.
- Méniére’s Disease = This disease is thought to be a balance disorder due to fluid buildup in the inner ear. This can result from a number of factors, such as head injury, ear infection, genetic predisposition, chemical toxicity, allergies, or syphilis. Note that syphilis can cause some patients to develop the disease later in life. The symptoms of this disease include pressure in the ears, ringing in the ears, vertigo, nystagmus, or uncontrollable eye movements. Unfortunately there is no known treatment for the disorder, however symptoms can be treated with water pills to thin out ear fluid, a low-salt diet, and anti-nausea medication.
- Other Disorders = Vestibular and balance disorders attribute to a number of contributing factors such as a high-salt diet, high caffeine intake, high sugar intake, Monosodium Glutamate (MSG) intake, dehydration, or food allergies. All these aforementioned dietary factors contribute to symptoms of vertigo and it’s recommended for balance disorder patients to avoid them. Other disorders can have symptoms of vertigo associated with them such as epilepsy, migraine, stroke, or multiple sclerosis. Infectious diseases can also cause vertigo, such as Lyme Disease and meningitis.
The righting reflex is also observed in other animals, for instance, cats. Their righting reflex allow them to land on their feet after a fall. As a cat falls, it turns its head, rotates its spine, aligns its hindquarters, and arches its back to minimise injury. The car reaches free fall to accomplish this, which is lower than that of humans in free fall. Hence, cats are able to land on the ground in a relaxed body form to prevent serious injury. No wonder we think cats have 9 lives but it turns out they still only have 1 life. Bats have a unique vestibular system anatomy because their balance system is oriented 180 degrees opposite to that of humans. This allows them to perform powerful feats of flight while hunting in the dark. This ability couples vestibular function with sensory echolocation to hunt prey, but they lack a righting reflex similar to most mammals. When bats are exposed to zero-G, they don’t undergo the series of righting reflexes that most mammals do to correct orientation because they are accustomed to resting upside-down.
https://www.youtube.com/watch?v=jxU0E4jhsko
— Scratch Reflex = This reflex responds to activation of sensory neurons whose peripheral terminals are located on the surface of the body. These sensory neurons can be activated by stimulation with an external object such as a parasite on the body surface, while other sensory neurons respond to a chemical stimulus that produces an itch sensation. When you feel an itch, the nearest limb to that itch will reach towards and rub against the site on the body surface that has been stimulated. This reflex has been extensively studied to understand the functioning of neural networks in vertebrates. Despite decades of research, key aspects of the scratch reflex are still unknown, such as the neural mechanisms by which the reflex is terminated.
This reflex is generally a rhythmic response and results from several animal studies indicated that spinal neural networks known as Central Pattern Generators (CPGs) are responsible for the generation and maintenance of the scratch reflex. It’s known that the supraspinal structures aren’t recruited to generate this reflex, but rather the reflex is programmed into the spinal cord of spinal animals. A 2005 animal study found that these spinal CPGs generate and maintain the reflex, as well as produce it without movement-related sensory feedback, albeit diminished in accuracy. Recordings indicate that feedback modulates the timing and intensity of scratching, in the form of phase and amplitude changes in nerve firing. A 2003 study labelled a number of regions on the surface of the body relating to the scratch reflex.
- One of those regions is the ‘pure form domain’ , which elicits only 1 form of the scratch reflex, when stimulated.
- In the context of this reflex, a ‘form’ is a movement-related strategy used by the animal to perform the scratch. e.g. To scratch the upper back, humans are limited to one scratch form, that is, raising their elbow above their shoulder to access their upper back.
- In addition to pure form domains, there also exist a number of ‘transition zones’ that can be successfully targeted by more than one form of the reflex. These transition zones usually lie at the boundary of two pure form domains.
Researchers also coined a few terms describing the scratch reflex movements themselves.
- Pure movement: This form of the scratch response is utilised to respond to the stimulus.
- Switch movement: This occurs in a transition zone, which is characterised by the smooth switching between 2 different scratch forms in response to the stimulus.
- Hybrid movement: This also occurs in a transition zone, but it is characterised by 2 rubs during each scratch cycle. Each rub is derived from one pure form movement.
Current research on hybrid and switch movements at transition zones indicates that the CPGs responsible for scratch generation are modular and share interneurons. This implicates that the path of the moving limb is smooth and uninterrupted during both switch and hybrid movements. EMG recordings suggest that reciprocal inhibition between hip-related interneurons in the CPG for the scratch reflex isn’t necessary for the production and maintenance of the hip-flexor rhythm. This evidence further supports the findings on switch and hybrid movements, which suggest a modular organisation of unit generator CPGs is used in combination to achieve a task.
A 2004 study has found that scratch response continues even after afferent input from the stimulated zone ceases. Seconds after the scratch ceased, the neural networks involved in the generation of the scratch reflex were still readily sensitive. During this period of increased excitability, stimuli normally too weak to trigger a scratch response are capable of eliciting a scratch response in a site specific manner. This excitability is due to the long time constant of NMDA receptors. Research has also demonstrated that voltage-gated calcium channels play a role in increasing the excitability of spinal neurons.
Initial experiments on the scratch reflex in dogs revealed that the spinal cord has circuits capable of summing inputs, after when initial solitary inputs were too weak to generate a response. A 1989 study involving successive spinal transections in a turtle model identified the distribution of spinal CPGs distributed throughout the spinal segments was asymmetrical. Furthermore, the site specificity of the scratch response indicated that the spinal circuitry had a built-in map of the body. This explained how the spinal CPGs generated a scratch response targeting the site of the stimulus independent of supraspinal structures. Research also uncovered that form selection is intrinsic to the spinal cord, which suggests it is accomplished using the summed activities of populations of broadly tuned interneurons shared by various unit CPGs. In addition, intracellular recordings have illustrated that motor neurons receive at least 2 types of inputs from spinal CPGs, which include inhibitory post-synaptic potentials (IPSPs) and excitatory post-synaptic potentials (EPSPs). This implies that scratch CPGs are responsible for both the activation and deactivation of muscles during the scratch response. A 2008 study suggested that the scratch reflex shares interneurons and CPGs with other locomotor tasks such as walking and swimming, as well as the concept of mutual inhibition between networks playing a major role in behavioural choice in the spinal cord. These suggestions are supported by observations in a 2005 study, which indicates the scratch reflex was particularly difficult to induce in animals already involved in a different locomotive task, such as walking or swimming.
A 2006 study indicated that neurons in the motor cortex may play a role in the modulation of the scratch reflex, despite it being produced without supraspinal structures. When pyramidal tract neurons were stimulated, they modulated the timing and intensity of scratch reflex. Extensive research also identified that involvement of supraspinal structures in the modulation of the rhythmic elements of this reflex. Current theories infer that efference copies from CPGs travel to the cerebellum via spinocerebellar pathways. These signals then modulate the activity of the cerebellar cortex and nuclei, which in turn regulate descending tract neurons in the vestibulospinal, reticulospinal, and rubrospinal tracts. However, there isn’t much else known about the specifics of supraspinal control of the scratch reflex so far.
https://www.youtube.com/watch?v=IlWho9NxR5c
— Shivering = Also known as shuddering, this bodily function is found in warm-blooded animals in response to cold temperatures. When their core temperature decreases, the shivering reflex is activated to maintain homeostatic thermoregulation. Skeletal muscles oscillate in small movements in order to generate warmth by expending energy. Shivering also occurs in response to a fever, as an feverish person may feel cold because the temperature set point is raised by the hypothalamus. This increased set point causes the body temperature to rise (pyrexia), but make the patient feel cold until the new set point is reached. Severe chills with shivering care called rigours, which occur because the patient's body is shivering in a physiological attempt to increase body temperature to the new set point.
The primary motor centre for shivering is located in the posterior hypothalamus near the wall of the 3rd ventricle. This brain region is normally inhibited by signals from the heat centre in the anterior hypothalamic-preoptic area but is excited by cold signals from the skin and spinal cord. Therefore, the primary motor centre activates when body temperature dips below the critical temperature level. The resultant increased muscle activity intentionally generates heat as a byproduct and utilised as warmth. Newborn babies, infants, and young children experience a greater (net) heat loss than adults because they cannot shiver to maintain body heat, hence they rely on non-shivering thermogenesis. Children have an increased amount of brown adipose tissue due to increased vascular supply, and high mitochondrial density, When they are cold-stressed, both of their oxygen consumption and levels of noradrenaline increases. Noradrenaline then reacts with lipases in brown fat to decompose fat into triglycerides. The triglycerides are then metabolised to Glycerol and non-esterified fatty acids, which are then further degraded in the urgent heat-generating process to form CO2 and water. Chemically, the proton gradient situated in mitochondria generate the proton electromotive force is ordinarily used to synthesise ATP. However this step is bypassed to produce heat directly. There are different types of shivering; ’post-anaesthetic shivering’ occurs after a surgical operation, and ‘psychogenic shivering’ occurs due to mere cognition in humans.
As humans age, their functional capacity of the thermoregulatory system alters, which reduces their resistance to extreme temperatures. The elderly would have a diminished or, worse, absent shiver response, which results in a significant drop in mean deep body temperature upon exposure to cold. Standard tests of thermoregulatory function show a markedly different rate of decline of thermoregulatory processes in different ageing individuals.
Sneezing occurs foreign particles or sufficient external stimulants pass through the nasal hairs to reach the nasal mucosa. This triggers the release of histamines, irritating the nerve cells in the nose, which sends nerve signals to the brain to initiate the sneeze through the Trigeminal Nerve Network. The brain then relates this initial signal, in response, activates the pharyngeal and trachael muscles to expand the the nasal and oral cavities, which results in a powerful release of air and bioparticles. The powerful nature of a sneeze is attributed to its involvement of numerous organs of the upper body such as the face, throat, and chest muscles. Sneezing is also triggered by sinus nerve stimulation caused by nasal congestion and allergies. The neural regions involves in this reflex are located in the brainstem along the ventromedial part of the Spinal Trigeminal Nucleus and the adjacent Pontine-Medullary Lateral Reticular Formation. This brain region appears to mediate the epipharyngeal, intrinsic laryngeal and respiratory muscles. The combined activity of these muscles serve as the basis for the generation of a sneeze.
It is known that some people sneeze during the initial phases of sexual arousal. Experts theorise that the phenomenon might arise from a case of crossed wires in the autonomic nervous system, which regulates a number of functions in the body, including stimulating the genitals during arousal. Since the nose contains erectile tissue, this phenomenon may help prepare the vomeronasal organ for increased detection of pheromones. Sneezing during menstruation may result in a sudden vaginal menses emission.
While generally harmless in healthy individuals, sneezes spread disease through the infectious aerosol droplets. Every sneeze releases 40,000 droplets, with a volume ranging from 0.5 to 5 μm. To reduce the disease transmission, it’s recommended to place your forearm or the inside of your elbow in front of your nose and mouth before you sneeze. A 2016 study has found an declining trend of using your hand to cover your sneeze as it is often viewed as inappropriate, since it promotes spreading germs through human contact (such as handshaking) or by commonly touched objects (such as door knobs or handles).
Examples of preventive measures include: deep exhalation of the air in the lung, holding your breath in while counting to 10 or gently pinching the bridge of your nose for several seconds. Certain methods proven to reduce sneezing generally advocate reducing interaction with irritants such as:
- Banishing pets outdoors to avoid animal dander
- Continuously and timely remove any dirt and dust particles through proper housekeeping
- Replace filters for furnaces and air-handling units, air filtration devices and humidifiers
- Avoiding industrial and agricultural zones
In English-speaking countries, whenever we hear or see someone sneeze with an “ahchoo or achoo”, we commonly respond "[May God] bless you” or a German word “Gesundheit” meaning "good health”. Why do we do that? Several hypotheses propose reasons for the custom arose of saying "bless you" or "God bless you" in the context of sneezing:
- Historians suggested it came into normal use during the plague pandemics of the 14th century. Blessing the individual after demonstrating such a symptom was thought to prevent possible impending death due to the lethal disease.
- During Renaissance times, a superstition arose that claimed a person’s heart briefly stopped heating during the sneeze. It encouraged everyone to say “bless you” as a sign of prayer that the heart would not fail.
- It was also believed that if you say “(God) bless you”, you won’t catch the flu, cold, or any other forms of sickness.
Other cultures have similar traditions:
- In Muslim countries, after a person sneezes they often say “Al-ḥamdu lillāh” (Arabic: الحمد لله) meaning “Praise to God”. Their companion would often say to their “Yarhamuk-Allah”, meaning "May Allah have mercy on you." The sneezing person often says “Yahdikum-ullah wa yuslihu balakum”, meaning "May Allah guide you and render sound your state of affairs."
- In Iran, people commonly respond to sneezing with the Persian phrase "عافیت باشه", which translates to "health", similar to common European expressions.
- In India, people respond with Krishna, similar to a blessing in western cultures.
- In Slovakia, after a person sneezes, it’s customary to say "Na zdravie!”, meaning "For health!”. It’s recommended to say “Ďakujem”, which means "Thanks". This is also the case in Finland, where "terveydeksi" means "for health”.
- In Turkey, after a person sneezes, it’s customary to say "Çok yaşa" which means "Live long”. It’s recommended to say "Sen de gör”, meaning "May you see too [that I lived long enough]".
- In Telugu, a reciprocation to someone's sneeze is "chiranjeeva sataish" (చిర౦జీవ), meaning "may you live long" (from Sanskrit).
- In Tamil, a reciprocation to someone's sneeze is “Dheergaiyish”, meaning "may you live long" (from Sanskrit).
- In Japanese entertainment, a character's sneeze frequently means that someone elsewhere is talking about said character by coincidence.
- In China, after a person sneezes, it’s customary to say “百岁” (Bai Sui), meaning “live long!”.
Sneezing also occurs in many animals including cats, dogs, chickens, and iguanas. African wild dogs use sneezing as a form of communication, especially when considering a consensus in a pack on whether or not to hunt.
https://www.youtube.com/watch?v=2zr-ZR3xeAs
— Snout Reflex = Also known as a “pout”, this involves pouting or pursing of the lips elicited by light tapping of the closed lips near the midline. The muscles around the lips contract, which causes the mouth to resemble a snout. In a neurological exam, the presence of this reflex indicates brain damage or dysfunction. Along with the “suck”, palmomental reflexes and other reflexes, the snout is considered a frontal release sign. These reflexes are normally inhibited by the Frontal Lobe, but this inhibition can be lifted if the frontal lobes are damaged. Normally this is present in infancy, however when the child turns one year old, it’s hypothesised they are primitive or archaic reflexes. Frontal release signs are observed in disorders affecting the frontal lobes, such as dementias, metabolic encephalopathies, closed head injuries and hydrocephalus. All of these disorders produce diffuse cerebral damage in areas and systems in addition to the frontal lobes and pyramidal system, so diagnosis is difficult to be confirmed based solely on frontal release signs.
https://www.youtube.com/watch?v=PhOleckx1-Y
— Startle Evoked Movement (SEM, startReact) = This reflex is an involuntary initiation of a planned action in response to a startling stimuli. While the classic startle reflex involves involuntary protective movements, SEM involves a variety of arm, hand and leg movements including wrist flexion, and rising onto your tiptoes. They are also performed faster than voluntary movements, whilst retaining the same muscle activation characteristics. This reflex forms the foundation of studying the interactions between the brain, spinal cord and brainstem to produce movement, which provides a potential avenue of exploration for rehabilitation strategies for those with neurological impairments.
It’s typical for SEM to reduce the time it takes to perform an action compared to voluntary conscious control. e.g. A 1999 study recorded voluntary arm extension occured roughly 170 ms after a "Go" signal, while SEMs for arm extension occured between 65-77 ms. Due to this faster reaction time, and considering conduction velocity, it’s unlikely cortical involvement was responsible for these movements.
In order for SEM to occur, a subject must be waiting to perform an action when a startling stimuli is encountered. This is typically achieved by initially presenting the subject with a “Ready” signal, which indicates that they should prepare to conduct a specified action; then playing a startling acoustic stimuli (SAS) before the "Go" signal the subject is anticipating to see or hear.
A 2013 study found that muscles lacking reticulospinal tracts aren’t susceptible to SEM, which suggests SEM can be used as evidence for reticulospinal tract connections to the muscles governing grasp of the human hand. Recent studies investigated people suffering from cortical damage such as a stroke also discovered their capability of performing SEM. A 2012 experiment used SEM to stimulate stroke survivors to perform arm movements as fast as unimpaired people, despite being slower when performing the same action voluntarily. A 2013 study found that people with pure hereditary spastic paraplegia, a condition that affects the corticospinal tract, are susceptible to SEM as well.
https://www.youtube.com/watch?v=HQxZfSRd7H8
— Sucking Reflex = Linked to the rooting reflex and breastfeeding, this reflex is common to all mammals, and is present at birth. It allows the child to instinctively suck anything that touches the roof of their mouth, and simulate a child’s natural eating process. There are 2 stages of the action:
(1) Expression: This step is activated when a mother’s nipple is positioned between their baby’s lips and contacts their palate. The baby will instinctively press the nipple between their tongue and palate to suck out the breastmilk.
(2) Milking: This step involves the tongue moving from the areola to the nipple, coaxing the breastmilk from the mother to be swallowed by the baby.
When you stand upright, you begin to lean to one side. This stretches the postural muscles that are closely connected to the vertebral column on the opposite side. The muscle spindles in those muscles detects this stretching, and the stretched muscles contracts to correct your posture. Other examples (followed by the involved nerves) are responses to stretch created by a force upon a muscle tendon:
- Jaw Jerk (CN V)
- Biceps reflex (C5/C6)
- Brachioradialis Reflex (C6)
- Extensor Digitorum Reflex (C6/C7)
- Triceps Reflex (C6/C7)
- Patellar Reflex (L2-L4)
- Ankle Jerk Reflex (S1/S2)
Another example is a group of fibres in the calf muscle, which synapse with motor neurons supplying muscle fibres in the same muscle. When your calves suddenly stretch, it causes a reflex contraction as the spindles sense the stretch and propogates an action potential to the motor neurons which then cause your calves, in this context, the soleus-gastrocnemius group of muscles to contract. Like the patellar reflex, this reflex can be enhanced by the Jendrassik Maneuver.
https://www.youtube.com/watch?v=QW5p2G4EtP0
— Swimming Reflex = This reflex involves placing an infant face down in a pool of water. Then they will instinctively begin to paddle and kick in a swimming motion. This reflex usually disappears when the child is between 4 - 6 months old. Despite the infant displaying a normal response by paddling and kicking, placing them in water can be a very risky procedure. The risks involve infants swallowing a large amount of water while performing this task, therefore caregivers should proceed with caution. It’s advised to postpone swimming lessons for infants
https://www.youtube.com/watch?v=YZWuOUGDvFU
— Symmetrical Tonic Neck Reflex (SNTR) = This primitive reflex is a bridging or translational brainstem reflex that plays an important role during a child’s development when they transition from lying on the floor to quadruped crawling or walking. It normally emerges during the first year of an infant's life and is diminished by the age of 2–3 years. In order to execute the transition successfully, the baby is required to unlink the automatic movement of the head from the automatic movement of the arms and legs in order to progress beyond this development stage. Normally, the STNR is fully developed by 6 - 8 months and then significantly diminishes by 2 - 3 years. If this reflex is retained beyond 2–3 years to such a degree that it "modifies voluntary movement”, it suggests "immature and abnormal reflex development”. This could have broad implications on the child’s later development.
To test the SNTR, place the child in quadruped position on the floor and passively flex its head forward and then extend it backwards. You would then expect a forward head flexion response that causes flexion of the upper extremities and extension of the lower extremities. Meanwhile, extending the head will cause extension of the upper extremities and flexion of the lower extremities. This reflex assists the child to transition to quadruped or crawling position but does not allow crawling because when the neck flexes forward, the upper limbs flex and lower limbs extend. It isn’t normally easily seen or elicited in normal infants but may be seen in an exaggerated form in many children with cerebral palsy.
https://www.youtube.com/watch?v=Fo5S9a2u_9c
— Triceps Reflex = Also known as a Deep Tendon Reflex, it elicits involuntary contraction of the Triceps Brachii muscle. It is initiated by Cervical Spinal Nerve 7 nerve root. Neurological examinations test for this reflex to assess the sensory and motor pathways within the C7 and C8 spinal nerves. To test this reflex, tap the triceps tendon with the sharp end of a reflex hammer while the forearm is relaxed and bent at a right angle to the arm. Sudden contraction of the triceps muscle causes extension, indicating a normally functioning reflex.
The arc involves stretch receptors in the triceps tendon, from where information travels through the C7/C8 nerve root to the spinal cord, and the motor signal for contraction returns through the radial nerve.
If this reflex is absent (areflexia), it’s essential to try again with reinforcement, with the patient clenching his or her teeth just as the reflex hammer strikes. This indicates the presence of several medical conditions like myopathy, neuropathy, spondylosis, sensory nerve disease, neuritis, potential lower motor neuron lesion, or poliomyelitis. Other medical problems that may cause irregularities with this reflex include hyperthyroidism.
If this reflex is too sensitive (hyper-reflexia), this indicates a potential upper motor neuron lesion.
https://www.youtube.com/watch?v=HZriJqf1w2I
— Tonic Labyrinthine Reflex (TLR) = This primitive reflex is found in newborn humans, which involves tilting the head back while lying on the back. In response, the back stiffen and even arch backwards, the legs straighten, , stiffen, and push together, the toes point, the arms bend at the elbows and wrists, and the hands clench to become fists or the fingers curl. If this reflex is present beyond the newborn stage (first 6 months of age), this suggests an abnormal extension pattern or extensor tone, which is indicative of developmental delays and/or neurological abnormalities.
e.g. People with cerebral palsy would still elicit the TLR in a more pronounceable manner, which would cause problems for the maturing child. It hinders functional activities such as rolling, bringing the hands together, or even bringing the hands to the mouth. Long term developmental abnormalities include serious damage to the growing child's joints and bones, and the head of the femur subluxating or dislocating from the Acetabulum.
This reflex is active during the receptive relaxation of the stomach in response to swallowing of food (prior to it reaching the stomach). When food enters the stomach, a "vagovagal" reflex travels from the stomach to the brain, and then back again to the stomach, subsequently causing active relaxation of the smooth muscle in the stomach wall. If vagal innervation is disrupted, this increases intra-gastric pressure, which can cause vomiting due to the inability of the proximal stomach smooth muscle to undergo receptive relaxation.
During the gastric phase of digestion, vagal afferents become activated when both the corpus and fundus of the stomach distend secondary to the entry of a food bolus. This stimulates mechanical receptors located in the gastric mucosa, which stimulates the vagus afferents. Then vagal efferents complete the reflex circuit by stimulating post-ganglionic muscarinic nerves, which release Acetylcholine to stimulate 2 end effects. Those effects are (1) stimulation of the parietal cells in the body of the stomach to release H+, and (2) stimulation of the ECL cells of the lamina propria of the body of the stomach to release Histamine. Furthermore, peptidergic neurons are also stimulated by vagal efferents to release gastrin-releasing-peptide. Meanwhile, Delta cells are inhibited to reduce the inhibition of Gastrin release.
— Vestibulocollic Reflex (VCR) = This postural reflex acts on the neck musculature in order to stabilise the head. Your otoliths or semicircular canals sense the neck movement, which in response, causes reflex head movement. The neural pathways mediating this reflex are as yet uncertain.
— Vestibulospinal Reflex (VSR) = This postural reflex stabilises the body according to the timing (dynamic vs. static / tonic) and sensory input (canal, otolith or both). It also implies motor output to skeletal muscle below the neck (i.e. excludes the neck reflex).
I) When your head tilts (rolls) to one side, both the canal and otoliths are stimulated.
II) This activates both the Vestibular Nerve and Vestibular Nucleus.
III) They transmit nerve impulses via the Lateral and Medial Vestibulospinal Tracts to the Spinal Cord.
IV) Extensor activity is induced on the side to which the head is inclined, and flexor activity is induced on the opposite side.
When the body is pitched, extensor tone changes according to the position of your head with respect to the horizontal. Extensor tone reaches its maximum when the angle of your head is 45 degrees with respect to horizontal (i.e. head is positioned nose up as an additional 45 degrees towards upright). Extensor tone reaches its minimum when your head is positioned nose-down and pointing an additional 45 degrees down. There is also a “righting reflex”, which refers to reflex movements occurring as the position of the head or body changes, creating a tendency to return the head or body to the normal posture. The brain receives vestibular, visual and somatosensory input in order to activate the reflex.
In another animals, the gravity organs and eyes are strictly connected. e.g. Fishes move its eyes reflexively when its tail is moved. In humans, their semicircular canals, neck muscle “stretch” receptors, and the utricle (gravity organ) help contribute to VOR and most other reflexes responsive to acceleration. In addition, maintenance of balance is mediated by stretching neck muscles and the pull of gravity on the utricle (otolith organ) of the inner ear. Furthermore, the VOR has both rotational and translational components. When your head rotates about any axis (horizontal, vertical, or torsional), distant visual images are stabilised by oppositely rotating eyes. e.g. During walking, your head tends to translate, hence the visual fixation point is maintained by rotating gaze direction in the opposite direction, by an amount that depends on distance.
The VOR is primarily initiated by nerve signals from the vestibular system in the inner ear. The semicircular canals detect head rotation and drive the rotational VOR, whereas the otoliths detect head translation and drive the translational VOR. The semicircular canals sends nerve impulses via the Vestibular Nerve (Cranial Nerve VIII) through the Vestibular Ganglion and terminate in the Vestibular Nuclei in the brainstem. Then these nuclei fibres cross contralaterally to the Cranial Nerve VI Nucleis (Abducens Nucleus). There they synapse with 2 pathways: (1) —> Lateral Rectus of the eye via the Abducens Nerve —> Abducens Nucleus —> Medial Longitudinal Fasciculus —> contralateral Oculomotor Nucleus. The motorneurons in the Oculomotor Nucleus drive eye muscle activity, specifically activating the Medial Rectus muscle of the eye through the Oculomotor Nerve.
(2) Vestibular Nucleus —> Ascending tract of Dieters —> ipsilateral Medial Rectus motorneuron. In addition, there are inhibitory vestibular pathways to the ipsilateral abducens nucleus, but no direct vestibular neuron to medial rectus motoneuron pathway is known to exist.
An indirect pathway, responsible for driving the velocity of eye rotation, builds up the position signal requires to prevent the eye from rolling back to the centre when the head stops moving. When the head moves slowly, position signals dominate over velocity signals, thus making this indirect pathway crucial. In 1987, David A. Robinson discovered that the eye muscles require this dual velocity-position drive, which lead him to propose that it originated in the brain by mathematically integrating the velocity signal and then sending the resulting position signal to the motoneurons. In which case, Robinson’s hypothesis was confirmed with the discoveries of the 'neural integrator' for horizontal eye position in the Nucleus Prepositus Hypoglossi in the medulla, as well as the neural integrator for vertical and torsional eye positions in the interstitial nucleus of Cajal in the midbrain. Those aforementioned neural integrators also generate eye position for other conjugate eye movements such as saccades and smooth pursuit.
For example, if your head turns clockwise as seen from above, then excitatory impulses propagate from the semicircular canal on the right side via the Vestibular Nerve (Cranial Nerve VIII) through Scarpa’s Ganglion and terminate in the right Vestibular Nuclei in the brainstem. From this nuclei excitatory fibres cross to the left Abducens Nucleus. There they project and stimulate the Lateral Rectus of the left eye via the Abducens Nerve. In addition, the Medial Longitudinal Fasciculus and Oculomotor Nuclei activate the Medial Rectus muscles on the right eye. The resultant outcome would be counter-clockwise rotation of both eyes. Furthermore, some neurons from the right Vestibular Nucleus directly stimulate the right Medial Rectus motorneurons, and inhibits the right Abducens Nucleus.
In order to achieve clear vision, head movement must be compensated almost immediately, hence the VOR must enact rapidly. Otherwise, vision would correspond to a photograph taken with a shaky hand. Therefore nerve impulses from the semicircular canals propagate directly to the eye muscles via only 3 neurons, and is correspondingly called the three neuron arc. As a result, the amount of lag head movements cause affect eye movements are minimised to less than 10 ms, making the VOR one of the fastest reflexes in the human body.
This reflex can be tested by the rapid head impulse test or Halmagyi–Curthoys test. Rapidly moving your head side to side forcibly, and if your eyes succeed to remain to look in the same direction, then this is a positive result. If there is a reduction in function of the right balance system, there may be caused by a disease or an accident, which compromises the proper sense of a quick head movements to the right. Consequently, no compensatory eye movement is generated and the patient is unable to fixate a point in space during this rapid head movement. The caloric reflex test examines the VOR response by attempting to induce nystagmus by pouring cold or warm water into the ear. Another attempt is bi-thermal air caloric irrigations, which involves administering warm and cool air into the ear.
After the determination of an intact cervical spine, a VOR test is performed on comatose patients by turning their head to one side. If their brainstem is intact, their eyes is expected to move conjugately away from the direction of turning (as if still looking at the examiner rather than fixed straight ahead). Negative “doll’s eyes” would stay fixed midorbit, which indicates a comatose patient’s brainstem is dysfunctional.
Currently VORs can only be comprehensively tested in specially equipped laboratories, which occasionally provide valuable diagnostic information. However, they can be time-consuming and expensive to administer. For instance, the scleral search coil is used to assess the VOR.
The following steps are performed to diagnose brainstem death:
(1) Use the caloric test to examine the VOR
(2) Slowly inject at least 50 ml of ice-cold water over 60 s into each external auditory meatus in turn to determine whether any eye movements occur or not.
(3) Directly inspect the tympanic membrane for clear access.
(4) Rotate the head at 30° to the horizontal plane, unless this positioning is contraindicated by the presence of an unstable spinal injury.
Performing the diagnosis of brainstem death requires a certain code of practice, written by the Academy of Medical Royal Colleges.
https://www.youtube.com/watch?v=C3KjLBT0o9c
— Walking / Stepping Reflex = This reflex is present at birth, though infants this young cannot support their own weight. When the soles of their feet touch a flat surface they will attempt to walk by placing 1 foot in front of the other. It disappears around 5–6 months as infants start attempting to walk after this reflex disappears.
The word ‘yawn’ is a continuation of a number of Middle English forms, yanen from Old English ġānian, and yenen, yonen from Old English frequentatives ġinian, ġionian, from a Germanic root *gīn-. The Germanic root has Indo-European cognates, from a root *g̑hēi- found also with -n- suffix in Greek χαίνω "to yawn", and without the -n- in English gap, gum "palate" and gasp (via Old Norse), Latin hiō, hiatus, and Greek chasm, chaos. The Latin term used in medicine is oscitatio (anglicised as oscitation), from the verb oscito "to open the mouth”. Pandiculation is defined as the act of yawning and stretching simultaneously.
There are a number of theories that attempt to explain why humans and other animals yawn by proposing possible triggers for this behaviour. However, there are comparatively few theories that attempt to explain the primary evolutionary reason for the yawn.
(i) A 2013 study suggested that yawning occurs when a person’s blood contains increased amount of carbon dioxide and therefore requires an influx of oxygen (or expulsion of carbon dioxide). A 2005 study contradicts this fact by arguing that yawning reduces oxygen intake compared to normal respiration. A 2007 study reputed both proposals that neither increased oxygen intake nor reduced carbon dioxide outtake in air decreased yawning.
(ii) Another 2013 article proposed that animals subject to predation or other dangers are prepared to physically exert themselves at any given moment. It suggests that yawning, especially psychological "contagious" yawning, may have developed as a way of maintaing alertness amongst a group of animals. If an animal is drowsy or bored, its alertness may have dwindled. Therefore, the "contagious" yawn could be an instinctual reaction to a signal from one member of the group reminding the others to stay alert.
(iii) A 2007 study suggested that yawning may be linked to nervousness, which often indicates the perception of an impending need for action. Anecdotal evidence highlights the way yawning increases a person’s state of alertness. e.g. Paratroopers have been noted to yawn in the moments before they exit the aircraft.
(iv) Studies conducted in 2007 and 2008 stated that yawning plays a role in maintaining brain temperature. Researchers proposed that yawning helps keep mammalian brains within a narrow and functional temperature range. One group of participants had cold packs attached to their foreheads, while another group of participants were instructed to breathe strictly-nasally. The latter group demonstrated reduced contagious-yawning when watching videos of people yawning. Similarly a 2011 study by Guttmann and Dopart extended the notion that yawning also plays a role in body thermoregulation. When a subject wore earplugs, they yawned producing a slight breeze, which was caused by the flux of air moving between the subject's ear and the environment. Therefore, they determined that a yawn causes 1 of 3 possible situations to occur: (1) The brain cools down due to an influx or outflux of oxygen, (2) intracranial pressure is reduced by an outflux of oxygen or (3) intracranial pressure is increased by an influx of air caused by increased cranial space.
(v) Another theory suggested yawns are caused by the neurotransmitters ) in the brain that affect emotions, mood, appetite, and other phenomena, which include Serotonin, Dopamine, Glutamic Acid, and Nitric Oxide. As more (or fewer) of these compounds are released into the brain, the frequency of yawning increases. Conversely, increased amounts of opioid neurotransmitters, such as endorphins, in the brain reduces the frequency of yawning. Individuals who suffer from opioid withdrawal exhibit increased frequency in yawning. Patients taking the selective Serotonin reuptake inhibitors (SSRIs) Paxil (Paroxetine HCI) or Celexa (Citalopram) have been observed yawning more often, particulatly during the first 3 months. Anecdotal reports stated that users of psilocybin mushrooms yawned excessively while inebriated, which often associated with excess lacrimation and nasal mucosal stimulation, especially while “peaking” (i.e. undergoing the most intense portion of the psilocybin experience). While opioids have been demonstrated to reduce yawning and lacrimation provoked by psilocybin, it remains unclear whether the same neural pathways that induced this yawning as a symptom of opioid abstinence in habituated users are the mode of action in mushroom users.
(vi) A 2010 study found that people suffering from Multiple Sclerosis and Brain Stem Ischaemic Stroke demonstrate excessive yawning, which suggests these different disorders affect common neurological pathways and hormone levels. A 2011 study found that increased levels of the stress hormone Cortisol in the saliva of human subjects following yawning, due to activation of the hypothalamus-pituitary-adrenal (HPA) axis. This finding supports the Thompson Cortisol Hypothesis, which proposes elevations of Cortisol during yawning episodes.
One question boggles my mind is “Why is yawning contagious?” A 2005 article suggested yawning may be a herd instinct, giving certain animal species an evolutionary advantage. Some theories suggest that yawning synchronises mood in gregarious animals, similar to the howling of the wolf pack. It demonstrates fatigue to other members of the group in order to synchronise sleeping patterns and periods. A 2013 study by Garrett Norris monitored the behaviour of students who were instructed to wait in a reception area and found a connection (supported by neuro-imaging research) between empathic ability and yawning. In 1508, Erasmus noted yawning’s contagious characteristic and the French proverbialised the same idea to "Un bon bâilleur en fait bâiller sept” meaning "One good gaper makes seven others gape”. It’s quite often that if one person yawns, another person would “empathetically” yawn. Even if you observe someone else’s yawning face, read or think about yawning, or look at picture of someone yawning, you will still yawn. A possible cause for contagious yawning may attribute to mirror neurons in the Frontal Cortex of certain vertebrates. A 2000 study found that these mirror neurons activate if they are exposed to a stimulus from conspecific (same species) and occasionally interspecific organisms. There’s a proposal that mirror neurons play a role in imitation, which lies at the root of much human learning, such as language acquisition. A 2007 study noticed that, in contrast to typically developing children, viewing videos of other people yawning doesn’t increase the yawning frequency of young children with autism spectrum disorders. Their results showed that autistic children actually yawned less during the videos of yawning than during the control videos, which supports the claim that contagious yawning is related to empathic capacity. A 2011 behavioural study conducted by Ivan Norscia and Elisabetta Palagi in the University of Pisa, Italy found evidence of a relationship between yawn contagion and empathy. Among other variables such as nationality, gender, and sensory modality, their results revealed only social bonding predicted the occurrence, frequency, and latency of yawn contagion. Furthermore, they found the rate of contagion was greatest in response to kin, then friends, then acquaintances, and lastly strangers. In terms of of both occurrence of yawning and frequency of yawns, related individuals showed the greatest contagion, whereas longer delays occurred amongst strangers and acquaintances in the yawn response (latency) compared to friends and kin. Hence, this lead to their conclusion that yawn contagion may be primarily driven by the emotional closeness between individuals.
A 1994 study observed 2 classes of yawning among primates, and observed them perceive it as a threat gesture in a way of maintaining order in the primates' social structure. Studies on chimpanzees and stumptail macaques conducted in 2004 and 2006 respectively found other members of their own species yawning, which partly confirms the contagious phenomenon of yawning. The Discovery Channel’s show MythBusters used a small-scale, informal study to test this concept and concluded plausibility of yawning being contagious, although there is dispute regarding the statistical significance of this finding. In his 2007 study, Gordon Gallup hypothesised that yawning may be a means of keeping the brain cool, as well as that "contagious" yawning may be a survival instinct inherited from our evolutionary past. He explained that during human evolutionary history, our ancestors were subject to predation and attacks by other groups. If every member of the group yawned in response to seeing someone yawn, this increases the whole group vigilance and suspicious of any danger that may arise. A 2008 study conducted in the University of London suggested that the "contagiousness" of yawns by a human can be passed onto dogs based on the observation that 21 out of 29 dogs yawned when a stranger yawned in front of them, but didn’t yawn when the stranger only opened his mouth. In 2010, Helt and Eigsti demonstrated that dogs, like humans, became susceptible to contagious yawning gradually. While dogs older than 7 months caught the humans’ yawns, younger dogs were immune to contagion. Furthermore, when dogs were relaxed and sleepy, nearly half of them responded to the human's yawn. This suggested that the dogs imitated not just the yawn, but also the physical state that yawns typically reflected.
A 2009 study on gelada baboons found that yawning was contagious between individuals, especially those that were socially close. This may suggest that emotional proximity rather than spatial proximity is an indicator of yawn contagion. So far, not much evidence for the occurrence of contagious yawning linked to empathy outside of primates has been found. However, the Canidae species, such as the domestic dog and wolf, have demonstrated contagious yawning in response to human yawns by reading human communication behaviours. However, this ability makes it difficult to ascertain whether yawn contagion among domestic dogs is deeply rooted in their evolutionary history or is a result of domestication. A 2014 study found that wolves were capable of yawn contagion, as well as the social bond strength between individuals having an impact on the frequency of contagious yawning in wolves. This supports previous research that link contagious yawning to emotional proximity. A 2015 study on budgerigars (Melopsittacus undulatus), a species of social parrots, also found evidence of its contagious yawning. This indicates yawning may have evolved several times in different lineages, but it may not often be related to social closeness.
People suffering from certain neurological and psychiatric disorders, such as schizophrenia and autism, demonstrate an impaired ability to infer the mental states of others. In some cases, yawn contagion may be used to evaluate their social inference or empathy. It’s known that Autism Spectrum Disorder (ASD) is a developmental disorder that severely affects social and communicative development, including empathy. A 2010 study reinforced this fact after discovering a diminished susceptibility to contagious yawn compared to the control group of typically-developing children. Since atypical development of empathy is reported in ASD, there is also evidence of contagious yawning and the capacity of empathy sharing common neural and cognitive mechanisms. Similarly, patients suffering neurological and psychiatric disorders, such as schizophrenia, demonstrate an impaired ability to empathise with others, which makes contagious yawning one means of evaluating such disorders. In his 2005 study, Canadian psychiatrist Heinz Lehmann claimed that increases in yawning could predict recovery in schizophrenia, which could provide enhanced insight into its connection to the underlying causes of empathy.
A 2017 study disputed the evidence of yawn contagion being related to empathy. The issue was empathy is a notoriously difficult trait to measure, and current literature on this subject lacks substance. It argued that there is inconsistency regarding the same animals species displaying a connection between contagious yawning and social closeness. Because various researchers use slightly different measures of empathy, this makes comparisons between studies difficult, creating substantial bias that could lead to significant correlations between the 2 tested variables in published studies.
In animals, yawning may be a warning signal from one animal species to another in the same group.
- Charles Darwin’s The Expression of the Emotions in Man and Animals stated that baboons yawn to threaten their enemies, possibly by displaying their large canine teeth.
- A 1987 study found Siamese fighting fish yawned only when they spotted a conspecific (same species) or their own mirror-image, which often accompanies aggressive attack.
- Guinea pigs also yawn displaying their impressive incisor teeth, which signifies dominance or anger. This often accompanies teeth chattering, purring and scent marking.
- Adelie penguins yawn as part of their courtship ritual. They face off and the males engage in an “ecstatic display” by opening their beaks and pointing their faces skyward. This trait has also been observed among emperor penguins, and researchers are attempting to understand the reasons why these 2 different penguin species share this trait, despite sharing a different habitat.
- Snakes yawn to realign their jaws after a meal and expand their trachea.
- A 2005 study found that dogs, and occasionally cats, often yawn after seeing people yawn and feel uncertainty. It suggests that dogs are adept at reading human communication actions but it’s unclear whether if this phenomenon is rooted in evolutionary history or a result of domestication.
- Fish also yawn to increase their oxygen intake.
- Other animals observed to yawn include the barred owl, crabeater seal (lobodon carinophaga), juvenile Japanese macaque, pony, male lion, cat, Bengal tiger, jaguar, and hippopotamus (Hippopotamus amphibius)
Primitive Reflexes:
Also known as infantile, infant or newborn reflexes, they are defined as reflex actions originating in the Central Nervous System demonstrated by normal human infants, rather than neurologically intact adults, in response to particular stimuli. They are suppressed by development of the frontal lobes as a child matures. Older children and adults afflicted with atypical neurology (e.g. cerebral palsy) may retain these reflexes and reappear in adulthood. This may attribute to certain neurological conditions like dementia (e.g. frontotemporal degenerations), traumatic lesions, and strokes. Children and adults with cerebral palsy and typical intelligence can learn to suppress these reflexes, but they might resurface under certain conditions like an extreme startle reaction. Furthermore, primitive reflexes may be limited to those areas affected by the atypical neurology. For example, humans with cerebral palsy that have their legs affected retain the Babinski reflex but having normal speech. Humans with hemiplagia may notice the reflex in the foot on the affected side only.
Physicians use primitive reflexes to primarily test for suspected brain injury or certain dementias such as Parkinson’s Disease in order to assess frontal lobe functioning. If they aren’t being suppressed properly, they are referred to as “frontal release signs”. Atypical primitive reflexes are currently being researched as potential early warning signs of autistic spectrum disorders. Primitive reflexes are also mediated by extrapyramidal functions, many of which are present at birth. They usually disappear as the pyramidal tracts gain functionality with progressive myelination. However, they may reappear in adults or children with loss of function of the pyramidal system due to a variety of reasons. However, with the advent of Amiel Tison method of neurological assessment, the importance of assessing such reflexes in the paediatric population has declined.
Unintegrated / Persistent Reflexes refers to reflexes failing to be suppressed in infancy. Their persistence relate to academic struggles and learning difficulties. e.g. Children with persistent ATNR and TLR had lower reading and spelling scores.
High-risk newborns refers to neonates with a significant chance of mortality or morbidity within their first month of life. They often show abnormal responses of primitive reflexes, or lack a response entirely, so their performance often varies in response depending on the reflex. e.g. One infant may have a normal Moro reflex, but have an abnormal or absent walking reflex. There’s a direct proportional relationship between the normal performance of primitive reflexes in newborns and Apgar scores and birth weight, but an inversely proportional relationship with hospitalisation time after birth, which overall improves mental state. A recent cross-sectional study assessing primitive reflexes in 67 high-risk newborns, used a sample method to evaluate responses of the sucking, Babinski and Moro reflexes. The results of the study highlighted the fact that the sucking reflex was performed normally most often (63.5%), followed by the Babinski reflex (58.7%), and the Moro reflex (42.9%). It concluded that high-risk newborns presented more periodic abnormal and absent responses of primitive reflexes, and that each reflex varied in response.
https://en.wikipedia.org/wiki/Preflexes
Preflexes are defined as latent capacities in the musculoskeletal system that auto-stabilise movements using non-linear visco-elastic properties of muscles when they contract. Loeb coined the term “preflex” as part of the zero-delay, intrinsic feedback loop. Unlike stabilisation methods utilising neurons such as reflexes and higher brain control, preflexes occur with minimal time delay. Its main disadvantage is that it works only to stabilise the main movements of the musculoskeletal system.
It’s known human muscles possess non-linear visco-elastic properties during their contraction, which helps autocorrect movements during isotonic exercises, and at different velocities. This is handy when a commanded action is perturbated, such as a step into a hole causing the foot to unexpectedly stretch down. The non-linear visco-elastic properties of muscles interact with these perturbation-induced velocity and length differences such that they counteract directly the effects upon the body of the perturbation in its duration. A 2000 study noted that part of the resistance to perturbation is passive due to the nonlinear increase in passive tension and joint torques produced by muscular and other soft tissues. A 2009 study highlighted tissue prestress as a preflexive property constituting a basal level of passive tension, which increases joint passive stiffness and stability due to its presence in antagonistic tissues of a joint.
Muscles contain different systems that allows the operation of evolutionary selection of preflex stabilisation. e.g. Deltoid muscles consist of at least 7 segments with different bone bone attachments and neural control. Each muscle segment contains a complex internal structure penetrating each muscle unit consisting of a tendon, aponeurosis, and a fascicle of active contractile and passive elements. Variations can exist in the internal architecture of the fibre orientation relative to a muscle’s line of action, like those found in pennate muscles. The complexities of the different visco-elastic length- and velocity-force relationships of these subparts allows for the adaptive selection of structurally complex muscle biocomposites with highly task-tuned nonlinear visco-elastic length- velocity- force relationships. Therefore, this provides the adaptive opportunity for evolution to modify the visco-elastic reactions of the musculoskeletal system so they counteract perturbations without the need for spinal or higher levels of control.
The following are examples of preflexes:
- Leg Step Recovery: Helmeted guineafowl like many other bipedal birds walk upon rough ground. When a guineafowl's leg steps into a hole, a instant unconscious velocity and length change in the muscles that span its leg joints occurs. This length/velocity discrepancy interacts with the nonlinear length and velocity-force relationships that have evolved in response to such a disruption with the result that the leg extends further into the hole, and thus keeps the bird’s body stable and upright.
- Leg Wiping: This preflex is one of the intrinsic musculoskeletal properties of a frog’s leg, rather than neurally mediated spinal reflexes. It helps stabilise its wiping movements at irritants when the leg movement is instigated.
- Squat Jumps: This is found in humans during preflex stabilisation. When a a person explosively jumps up from a squat position, the leg muscles then act to provide a minimal time delay against perturbations from the vertical.
— “Sharing” = This characteristic relies on the combined actions of all the components making up the synergy to execute a particular motor task. There are often more components involved than are strictly needed for the particular task, but the control of that motor task is distributed across all components nonetheless. For example, the 2-finger force production task requires participants to generate a fixed amount of force by pushing down on 2 force plates with 2 different fingers. This task involves generating a particular force output by combining the contributions of the participant’s independent fingers. While the force produced by any single finger can vary, this variation is constrained by the action of the other such that the desired force is always generated.
— “Stability” & “Flexibility” = These characteristics are provided by co-variation in motor tasks. For example, consider the 2-finger force production task again. If 1 finger didn’t produce adequate force, this could be compensated for by the other finger. Therefore, the components of a motor synergy are expected to change their action to compensate for the errors and variability in other components that could affect the outcome of the motor task. This provides flexibility allowing for multiple motor solutions to particular tasks, as well as motor stability by preventing errors in individual motor components from affecting the task itself.
Synergies also simplify the computational difficulties of motor control such as coordinating the numerous degrees of control in the body. This problem is regarded as challenging due to the tremendous complexity of the motor system and the different levels at which this organisation can occur (neural, muscular, kinematic, spatial, etc.). Because the components of a synergy are functionally coupled for a specific task, execution of motor tasks can be accomplished by activating the relevant synergy with a solitary neural signal. There is no requirement for independent control of all of the relevant component because of the consequential emergence of automatic organisation of the systematic covariation of components. Actions can be executed through synergies with minimal executive control because they are functionally connected. This is similar to how reflexes are physically connected and thus don’t require control of individual components by the central nervous system. Beside motor synergies, sensory synergies have been proposed to play an important role in integrating the mixture of environmental inputs before providing low-dimensional information to the CNS thus guiding the recruitment of motor synergies.
While synergies represent coordination derived from peripheral interactions of motor components, motor programs are specific, pre-structured motor activation patterns that are generated and executed by a central controller (for instance, the brain). They represent the top-down approach to motor coordination, rather than the bottom-up approach offered by synergies. Although sensory information is most likely used to sense the current state of the organism and determine the appropriate goals, motor programs are executed in an open-loop manner nonetheless. Once the program has been executed, it cannot be altered online by additional sensory information. Recent studies of rapid movement execution has uncovered evidence for the existence of motor programs, as well as the the difficulty associated with changing those movements once they have been initiated. For instance, if you ask people to make fast arm swings, they will find it difficult to halt that movement even when a "STOP" signal is provided after the movement has been initiated. This reversal difficulty persists even if the stop signal is presented after the initial "GO" signal but before the movement actually begins. These findings suggest that once selection and execution of a motor program begins, it must run to completion before another action can be taken. This effect has been observed even when the movement that is being executed by a particular motor program is prevented from occurring at all. If you attempt to execute particular movements (such as pushing with the arm), you would unknowingly arrest the action of your body before any other movement can actually take place. Therefore you present identical muscle activation patterns as when they are allowed to complete their intended action in the first place. Those patterns include stabilising and support activation that doesn’t actually generate the movement.
Despite the undisputed evidence for the existence of motor programs, it was still met with criticisms. One of which concerns the problem of storage. If each movement an organism could generate requires its own motor program, then it suggests that organism possesses an unlimited repository of such programs. However where are they stored? It’s unknown where is it kept. Aside from the enormous memory requirements such a facility would take, no motor program storage area in the brain has yet been identified. The 2nd problem concerns novelty in movement: If a specific motor program is required for any particular movement, then how would one ever produce a novel movement? At best, an individual would have to practice any new movement before executing it with any success. However, at worst, they would be incapable of new movements because no motor program would exist for new movements. These difficulties have led to a more nuanced notion of motor programs known as “generalised motor programs”. A “generalised motor program” is a program for a particular class of action, rather than a specific movement. It is parameterised by the context of the environment and the current state of the organism.
An important issue for coordinating the the motor system is the problem of the redundancy of motor degrees of freedom. Many actions and movements are executed in multiple ways because functional synergies controlling those actions are able to co-vary without changing the outcome of the action. . This is possible because there are more motor components involved in the production of actions than are generally required by the physical constraints on that action. e.g. Your arm has 7 joints that determine the position of your hand in the world. However, only 3 spatial dimensions are required to specify any location the hand could be placed in. This excess of kinematic degrees of freedom means that there are multiple arm configurations that correspond to any particular location of the hand.
Russian physiologist Nikolai Bernstein pioneered the earliest and most influential work on the study of motor redundancy. His research primarily investigated how coordination was developed for skilled actions. He observed that the redundancy of the motor system made it possible to execute actions and movements in a multitude of different ways while achieving equivalent outcomes. This equivalency in motor action means that there won’t be 1-to-1 correspondence between the desired movements and the coordination of the motor system required to execute those movements. Any desired movement or action doesn’t have a particular coordination of neurons, muscles, and kinematics that make it possible. This motor equivalency problem became known as the “degrees of freedom problem” because it is a product of having redundant degrees of freedom available in the motor system.
Model Based Control Strategies:
Perception plays a crucial role in motor control because it carries relevant information about objects, environments and bodies. It is then being used in organising and executing actions and movements. What is perceived and how the subsequent information is used to organise the motor system is a current and ongoing area of research.
Most model based strategies of motor control rely on perceptual information, and assume that this information is not always useful, veridical or constant. For instance, optical information is constantly interrupted by eye blinks, motion is obstructed by random objects in the environment, distortions can change the appearance of object shape. Model based and representational control strategies rely on accurate internal models of the environment, which are constructed from a a combination of perceptual information and prior knowledge, as the primary source information for planning and executing actions, even in the absence of perceptual information.
(a) Inference and Indirect Perception:
When models of the perceptual system assume indirect perception, they refer to the notion that the world they’re perceiving is different to the actual environment. Before its perception, environmental information must go through several stages, with each transition between these stages introducing more ambiguity. The things we actually perceived is the mind's best guess about occurrences in the environment based on previous experience. Support for this idea comes from the Ames Room illusion, where a distorted room causes the viewer to see objects known to be a constant size as growing or shrinking as they move around the room.
https://en.wikipedia.org/wiki/Internal_model_(motor_control)
In the context of control theory, an internal model refers to a process simulating the response of the system in order to estimate the outcome of a system disturbance. This principle was first articulated by B.A. Francis and W.M. Wonham in 1976 as an explicit formulation of the Conant and Ashby good regulator theorem. It argues that the motor system is controlled by the constant interactions of the “plant” and the “controller”. The plant is the body part being controlled, while the internal model itself is part of the controller. . Information from the controller, such as the CNS, feedback information, and the efference copy. is sent to the plant which moves accordingly. Internal models can be controlled through either feedforward or feedback control. Feed-forward control computes its input into a system using only the current state and its model of the system, but it doesn’t use feedback, so it is unable to correct for errors in its control. Nevertheless in feedback control, some of the system’s output is fed back into the system’s input, which it then makes adjustments or compensates for errors from its desired output.
2 primary types of internal models have been proposed: forward models and inverse models. In simulations, models can be combined together to solve more complex movement tasks.
(b) Forward Models:
Forward models take the input of a motor command to the “plant” and output a predicted position of the body. The motor command input to the forward model can be an efference copy. and the output from that model (i.e. the predicted position of the body). The actual and predicted position of the body may differ due to noise introduced into the system by either internal because body sensors may be imperfect or of sensory noise), or external sources which may be unpredictable forces from outside the body. If there is a difference between actual and predicted body positions, this information is fed back as an input into the entire system again so that an adjusted set of motor commands can be formed to create a more accurate movement.
(c) Inverse Models:
Inverse models use the desired and actual position of the body as inputs to estimate the necessary motor commands that transforms the current position into the desired one. e.g. An arm reaching task involves the desired position (or a trajectory of consecutive positions) of your arm being input into the the postulated inverse model. In response, the model generates the motor commands needed to control the arm and bring it into this desired configuration. These models also closely associate with the Uncontrolled Manifold Hypothesis (UMH).
Information Based Control:
This type of motor control is an alternative model that strategises movement and action organisations based on perceptual information about the environment, rather than on cognitive models or representations of the world. A 2006 study explains how the actions of the motor system are organised by information about the environment and information about the agent’s current state. These strategies often treat the environment and the organism as a single system, hence proceed with action as a natural consequence of the interactions of this system. A core assumption of this strategy describes environmental perceptions enriched in information and veridical for the purposes of producing actions, which counters the assumptions of indirect perception made by model based control strategies.
(d) Direct Perception:
In the context of cognition, direct perception refers to the philosophical notion of naïve or direct realism, which predicates on the assumption that our perceptions perfectly illustrate the world around us. In 1986, James J. Gibson’s theory of “ecological perception” emphasised importance of the environment, particularly in the (direct) perception of how the environment of an organism affords various actions to the organism. The issue with indirect perception concerns physical information about object in our environment being unavailable due to the ambiguity of sensory information. Proponents of direct perception suggest that the relevant information encoded in sensory signals isn’t the physical properties of objects, but rather the action opportunities the environment affords. According to Gibson, these “affordances” are directly perceived transparently, thus preclude the need for internal models or representations of the world. They exist as a byproduct of the interactions between an agent and its environment, and thus perception is an “ecological” endeavour, depending on the whole agent/environment system rather than on the agent in isolation.
Because affordances are action possibilities, perception may be directly connected to the production of actions and movements. A 1984 study proposed that perception provides information on the specification of the organisation and control of actions, and the motor system is "tuned" to respond to specific type of information in particular ways. Through this relationship, environmental information dictates control of the motor system and the execution of actions. For example, a doorway “affords” passing through, but a wall doesn’t. But how can you pass through that doorway? This can be specified by the visual information received from the surrounding environment, and information perceived about your own body. Combining this information determines the pass-ability of a doorway, but not a wall. Furthermore, the act of moving towards and passing through the doorway generates more information, which in turn specifies further action. We can conclude that actions and perceptions are critically linked and one cannot be fully understood without the other.
(e) Behavioural Dynamics:
This is a behavioural control theory that treats perceptual organisms as dynamic systems while responding to informational variables with actions in a functional manner, which builds on the assumptions of direct perception. This means that actions unfold as the natural consequence of the interaction between the organisms and the available information about the environment, which is specified in body-relevant variables. So far, research in behavioural dynamics has mainly focused on locomotion, where visually specified information (such as optic flow, time-to-contact, optical expansion, etc.) is used to determine appropriate navigation of the environment. The interaction forces between the human and the environment also affect behavioral dynamics as seen in by the ‘neural control of limb stiffness’.
What is the physiological basis of motor control?
(i) Motor Units
All daily tasks, like walking to the bathroom, talking to one of your friends or eating dinner, can’t be performed without the use of multiple muscles that help innervate the necessary body parts to move properly to complete specific tasks. Every muscle in your body consists of motor units which are innervated by 10s, 100s, or 1000s of motor nerve branches. e.g. Rectus Femoris muscle contains approximately 1 million muscle fibres, controlled by around 1000 motor nerves. Every motor unit is categorised either Type I (slow twitch) or Type II (fast twitch), based on the consistent (homogeneous) composition type of the muscle fibre. However, every muscle contains several different combinations of 2 types of motor units (heterogeneous).
There are 3 primary types of muscle fibres:
Whenever you make a conscious decision to move your body to accomplish a certain task, your brain transmits a nerve impulse signal to a specific motor unit through the spinal cord. This stimulates that motor unit to contract muscle fibres within that group to generate movement. Since there is no partial firing in the motor unit, all the muscle fibres within the unit will contract at once with different intensities, forces and speeds.
(ii) Mechanism and Structure
- Low- and high-threshold motor units
Small motor units with fewer muscle fibres, known as low threshold motor units, are recruited for low intensity tasks such as typing on a keyboard, clicking a mouse or tapping a phone screen. They consist of Type I fibres, which have slower contraction velocities, thus provide less force for daily basic movement. Larger motors units with numerous muscle fibres consisting of Type II fibres, known as high threshold motor units, are recruited for more intense tasks such as sprinting.
- Order of motor unit recruitment
When you’re lifting a heavy object such as a dumbbell during a workout, both low-threshold and high threshold motor units are recruited to compensate forces required. Even when you’re lifting a lighter object like a fork, the energy created by the low threshold motor units is sufficient to complete the task.
- Fibres Vs Nerves
The type of muscle fibre (Type I vs. Type II) recruited is regulated by the nervous system. Your brain acts as a central information centre that sends out electrical signals to the nerves, which then control and connect to motor units. For 2 different motor units present, your body adopts it with 2 different nerves to control them. i.e. Fast twitch motor units are controlled by fast-twitch nerves while Slow twitch motor units are controlled by slow twitch nerves. A 1986 study substituted a nerve from a motor unit once connected to a slow-twitch muscle fibre with with a nerve that are designated for a fast-twitch fibre. This resulted in the slow-twitch fibre behaving identically as a fast-twitch fibre. Conversely, when the process was reversed, the fast twitch fibre performed as a slow twitch fibre as well. However, it wasn’t possible for the nerves to transform from fast motor nerves into slow motor nerves and vice versa.
https://en.wikipedia.org/wiki/Cerebellum
A major of the hindbrain of all vertebrates is the cerebellum (Latin for “little brain”). In humans, this brain region plays a key role in motor control, as well as other cognitive functions such as attention, language, regulation of fear and pleasure responses. Although the cerebellum doesn’t initiate movement, it contributes to precision, coordination and accurate timing. It usually receives inputs from sensory systems of the spinal cord and from other parts of the brain, and integrates these inputs to fine-tune motor activity. Damage to the cerebellum produces disorders in fine movement, equilibrium, posture and motor learning in humans.
The name cerebellum is a diminutive of cerebrum (brain), which translates literally as little brain. The Latin name is a direct translation of the Ancient Greek παρεγκεφαλίς (paregkephalis), which was first used in the works of Aristotle, the first known writer to describe the structure. Historically, a variety of Greek or Latin-derived names have been used, including cerebrum parvum, encephalion, encranion, cerebrum posterius, and parencephalis.
The earliest anatomists were able to identify the cerebellum by its distinctive appearance. Aristotle and Herophlus (quoted in Galen) named it the παρεγκεφαλίς (paregkephalis), as opposed to the ἐγκέφαλος (egkephalos) or brain proper. The earliest surviving description was written by Galen who speculated that the cerebellum was the source of motor nerves. The next significant development wasn’t published until the Renaissance, when Vesalius briefly discussed the anatomy of the cerebellum and Thomas Willis discussed it in more detail in 1664. More anatomical work was performed in the 18th century, but the first insights into the function of the cerebellum weren’t obtained obtained until early in the 19th century. In 1809, Luigi Rolando established discovered that damage to the cerebellum resulted in motor disturbances. In the first half of the 19th century, Jean Pierre Flourens discovered that animals with cerebellar damage could still move, but lost coordination (strange movements, awkward gait, and muscular weakness). However, this coordination can be recovered after the lesion unless the lesion was quite extensive. By the beginning of the 20th century, the scientific community widely accepted the cerebellum as the primary driver of motor control, which produced several detailed descriptions of the clinical symptoms associated with cerebellar disease in humans.
The gross anatomy of the cerebellum consists of a tightly a tightly folded layer of cortex, with white matter underneath and a fluid-filled ventricle at the base. 4 deep cerebellar nuclei are embedded in the white matter, with each part of the cortex consisting of the same small set of neuronal elements being laid out in a highly stereotyped geometry. At an intermediate level, the cerebellum and its auxiliary structures is segregated into several 100 or 1000 independently functioning modules called "microzones" or “microcompartments". The cerebellum is located in the Posterior Cranial Fossa, with the 4th ventricle, Pons and Medulla located anteriorly. It is separated from the overlying Cerebrum by a layer of leathery Dura Mater, the Tentorium Cerebelli, with connections with other parts of the brain travelling through the pons. The cerebellum is derived from the Metencephalon, which is the upper part of the Rhombencephalon or “hindbrain”. Like the cerebrum, it is divided into 2 hemispheres, separated by a narrow midline zone called the “vermis”. (Vermis is Latin for “worm”.) A set of large folds conventionally divides the overall structure into 10 smaller “lobules”. The cerebellum contains more neurons than the total amount from the rest of the brain because it contains numerous granule cells. However, it only takes up 10% of the total brain volume. The number of neurons that make up the cerebellum is related to the number of neurons that make up the neocortex. The ratio between the number of neurons in the cerebellum and in the neocortex is about 3.6, which is conserved across many different mammalian species.
Its unique surface appearance is due to the tightly folded layer of grey matter called the “cerebellar cortex”. Each ridge or gyrus in this layer is called a “folium”. If you unfold the human cerebellar cortex, you would end up with a layer of neural tissue about 1 metre long and 5 cm wide, giving a total area of about 500 cm^2. It’s incredible how such a large area is packed inside a volume with dimensions 6 cm × 5 cm × 10 cm (300 cm^3). Underneath the cerebellar cortex lies the white matter, which is mainly made up of myelinated nerve fibres running to and from the cortex. Embedded within the white matter is called the “arbor vitae” (or tree of life), which is a branched, tree-like appearance in cross-section. This section contains 4 Deep Cerebellar Nuclei, composed of grey matter.
There are 3 paired Cerebellar Peduncles that connect the Cerebellum to different parts of the nervous system, which are called the Superior (SCP), Middle (MCP) & Inferior Cerebellar Peduncles (ICP), named according to their position relative to the vermis.
— The SCP projects efferent fibres via Thalamic Nuclei to Upper Motor Neurons in the cerebral cortex, with its fibres arising from deep cerebellar nuclei.
— The MCP connects to the Pons and receives input from it mainly from the Pontine Nuclei. Input to the Pons is also from the Cerebral Cortex, which relays it from the Pontine Nuclei via Transverse Pontine fibres to the Cerebellum. The MCP is the largest of the 3 peduncles and its afferent fibres are grouped into 3 separate fascicles, which direct their inputs to different parts of the cerebellum. — The ICP receives input from afferent fibres from the Vestibular Nuclei, Spinal Cord and the Tegmentum. Output from the ICP projects to the Vestibular Nuclei and the Reticular Formation via efferent fibres.
Based on the surface appearance, 3 distinct lobes can be identified within the cerebellum. Above the primary fissure is the Anterior Lobe, below the primary fissure is the Posterior Lobe, and below the posterior fissure is the Flocculonodular Lobe. These lobes divide the cerebellum from rostral to caudal (in humans, top to bottom). Nevertheless, there is a more essential distinction along the medial-to-lateral dimension on the context of function. With the exception of the Flocculonodular Lobe, the cerebellum can be parsed functionally into a medial sector called the Spinocerebellum and a larger lateral sector called the Cerebrocerebellum. A narrow strip of protruding tissue along the midline is labelled as the Cerebellar Vermis.
— The Flocculonodular Lobe is the smallest region with its distinct functions and connections, and is often called the Vestibulocerebellum. It is known as the oldest part in evolutionary terms (archicerebellum), which is responsible for balance and spatial orientation. It primarily connects with the Vestibular Nuclei, as well as receives visual and other sensory input. If the vestibulocerebellum is damaged, it disrupts a human’s balance and gait.
— The medial zone of the anterior and posterior lobs constitutes the spinocerebellum, also known as paleocerebellum, which is responsible for fine-tuning body and limb movements. It receives proprioceptive input from the dorsal columns of the spinal cord (including the spinocerebellar tract) and from the Cranial Trigeminal Nerve, as well as from visual and auditory systems. The spinocerebellum projects its fibres to deep cerebellar nuclei, which in turn projects to both the cerebral cortex and the brain stem, thus providing modulation of descending motor systems.
— The lateral zone, also the largest part, constitutes the cerebrocerebellum, also known as neocerebellum. It receives input exclusively from the cerebral cortex (especially the Parietal Lobe) via the Pontine Nuclei to form cortico-ponto-cerebellar pathways. It projects fibres mainly to the ventrolateral Thalamus, which in turn connects to motor areas of the Premotor Cortex and Primary Motor Area of the cerebral cortex and to the Red Nucleus. However this is debate regarding the functions of the lateral cerebellum. Recent studies suggest the cerebrocerebellum is responsible for planning movement prior to occurring, evaluation of sensory information for action and other purely cognitive functions, such as determination of verbs that appropriately fits with a certain noun (as in "drive" for “car”).
The cerebellar circuit is composed of 2 types of neurons; Purkinje Cells and Granule Cells, and 3 types of axons; Mossy Fibres, Climbing Fibres and Parallel Fibres. 2 main neural pathways through the cerebellar circuit originate from Mossy Fibres and Climbing Fibres, both of which eventually terminate in the deep cerebellar nuclei. Mossy Fibres project direct to the deep nuclei, giving rise to the the following pathway: Mossy Fibres → Granule Cells → Parallel Fibres → Purkinje Cells → Deep Nuclei. Whereas, Climbing Fibres connect to Purkinje Cells, and project collaterals directly to the deep nuclei. Each input from Mossy Fibres and Climbing Fibres carry fibre-specific information to the cerebellum, which accompanies Dopaminergic, Serotonergic, Noradrenergic, and Cholinergic inputs involved in global modulation. The cerebellar cortex is divided into 3 layers:
— The bottom layer contains the thick granular layer, which is densely packed with Granule Cells, along with interneurons, Golgi Cells, Lugaro Cells and unipolar brush cells.
— The middle layer contains the narrow Purkinje layer, which contains the cell bodies of Purkinje cells and Bergmann glial cells.
— The top layer contains the molecular layer, which contains flattened dendritic trees of Purkinje cells, as well as the huge array of Parallel Fibres penetrating the Purkinje cell dendritic trees at right angles. It also contains 2 types of inhibitory interneurons: Stellate Cells and Basket Cells, which both form GABAergic synapses onto Purkinje cell dendrites.
(a) Purkinje Cells
https://en.wikipedia.org/wiki/Purkinje_cell
Known as Purkinje neurons, they are a class of GABAergic neurons. Named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterised them in 1839. These cells are some of the largest neurons in the brain, with an intricately elaborate dendritic arbor, characterised by a large number of dendritic spines. Within the Purkinje layer of the cerebellum, these cells are aligned like dominoes stacked one in front of the other. Their large dendritic arbors form nearly 2D layers that are penetrated by Parallel Fibres from deeper-layers. These parallel fibres make relatively weaker excitatory (Glutamatergic) synapses to spines in the Purkinje cell dendrite. Meanwhile, Climbing Fibres originating from the Inferior Olivary Nucleus in the Medulla provides powerful excitatory input to the proximal dendrites and cell soma. Up to 200,000 Parallel Fibres pass through the Purkinje neuron's dendritic arbor orthogonally to form a Granule-cell-Purkinje-cell synapse with a single Purkinje cell. Each of them receives approximately 500 climbing fibre synapses, which all originate from a single Climbing Fibre. Both Basket and Stellate cells provide inhibitory (GABAergic) inputs to the Purkinje Cells, with Basket Cells specifically synapsing on the Purkinje cell axon initial segment and Stellate Cells onto the dendrites. Purkinje Cells then propagate inhibitory signals to the deep cerebellar nuclei, and constitute the sole output of all motor coordination in the cerebellar cortex.
The Purkinje layer of the cerebellum contains the cell bodies of the Purkinje cells and Bergmann glia, which express a larger number of unique genes. A 2004 study proposed the presence of Purkinje-specific gene markers after comparing the transcriptome of Purkinje-deficient mice with that of wild-type mice. 1 example of such gene markers is the Purkinje cell protein 4 (PCP4) in knockout mice, which exhibit impaired locomotor learning and markedly altered synaptic plasticity in Purkinje neurons. Recent studies have found that PCP4 accelerates both the association and dissociation of Calcium (Ca2+) with Calmodulin (CaM) in the cytoplasm of Purkinje cells, and its absence impairs the physiology of these neurons.
Several recent studies have found evidence in mice and humans that bone marrow cells either fuse with or generate cerebellar Purkinje cells, as well as play a role in repair of central nervous system damage either by direct generation or by cell fusion. A 2015 study uncovered further evidence of a common stem cell ancestor among Purkinje neurons, B-Lymphocytes, and Aldosterone-producing cells of the human adrenal cortex.
Purkinje Cells display 2 distinct forms of electrophysiological activity:
— Simple Spikes = A 1999 Raman and Bean study found they occur at frequencies of 17 – 150 Hz. This occurred either spontaneously or when Purkinje cells are activated synaptically by the parallel fibres, the axons of the granule cells. It is a a single action potential followed by a refractory period of about 10 ms.
— Complex Spikes = A 2000 study found they occur slowly at frequencies of 1 — 3 Hz. It’s a stereotyped sequence of action potentials with very short inter-spike intervals and declining amplitudes. They are characterised by an initial prolonged large-amplitude spike, followed by a high-frequency burst of smaller-amplitude action potentials. This is due to activation of Climbing Fibres and generation of calcium-mediated action potentials in the dendrites. A 1996 physiological study demonstrated that complex spikes occurred at baseline rates around 1 Hz and never at rates much higher than 10 Hz, which correlated with Climbing Fibre activation, while simple spikes are produced by a combination of baseline activity and Parallel Fibre input. Complex spikes are often followed by a pause lasting several 100 ms during which simple spike activity is suppressed.
Studies conducted in 1977 (Llinas and Hess) and 1980 (Llinas and Sugimori) found that Purkinje Cells spontaneously show electrophysiological activity in the form of trains of spikes stimulated by both Sodium and Calcium ions. In 1989, P-type calcium channels were named after Purkinje cells, where they were initially encountered, which were found to be crucial in cerebellar function. A 2005 study found that activation of the Purkinje cell by climbing fibres shifted its activity from a quiet state to a spontaneously active state and vice versa, which performed like a toggle switch. However, a 2006 study reputed these findings by suggesting that such toggling by Climbing-Fibre inputs occurs predominantly in anaesthetised animals and that Purkinje cells in awake behaving animals generally operated almost continuously in the upstate. Studies in 2006 and 2009 supported the former after finding evidence of Purkinje cell toggling in awake cats. A 2014 study constructed a computational model of the Purkinje cell that demonstrated the intracellular calcium computations responsible for toggling. A 2001 study suggested that Purkinje cell dendrites release endocannibinoids, which transiently downregulate both excitatory and inhibitory synapses. A 2012 study implicated that the intrinsic activity mode of Purkinje cells was set and regulated by the Sodium-Potassium (Na+ -K+) pump. A 2014 study was concerned that the pump might not be simply a homeostatic, “housekeeping” molecule for ionic gradients. Instead, it suggested it may be a computation element in the cerebellum and the brain. A 2004 study noted that mutations in the Na+ -K+ pump causes rapid onset dystonia parkinsonism, causing pathology of cerebellar computation. A 2011 study confirmed those findings by using the poison Ouabain to block Na+ -K+ pumps in the cerebellum of a live mouse, which induced ataxia and dystonia. Numerical modelling of experimental data suggests that the Na+ -K+ pump produces long quiescent punctuations (>> 1 s) to Purkinje neuron firing in vivo, which suggests it plays a computational role. Studies in 2015 have found that alcohol inhibited Na+ -K+ pumps in the cerebellum, which implicates its likely method of corruption of cerebellar computation and body co-ordination. A 2008 study found that Purkinje neurons expresses Calbindin. A 2017 rat study found that Calbindin staining of a rat brain after unilateral chronic sciatic nerve injury suggested that Purkinje neurons may be newly generated in the adult brain, which initiated the organisation of new cerebellar lobules.
In humans, the normal function of Purkinje cells can be affected by a variety of causes such as toxic exposure due to alcohol or lithium, autoimmune diseases, genetic mutations causing spinocerebellar ataxias, gluten ataxia, Unverricht-Lundborg Disease, or autism. There are some neurodegenerative diseases that doesn’t have a known genetic basis, such as the cerebellar type of multiple system atrophy or sporadic ataxias. According to a 2012 study, gluten ataxia is an autoimmune disease triggered by the ingestion of gluten, which causes an irreversible death of Purkinje cells. Recent studies conclude that early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression. Furthermore, they found less than 0% of people with gluten ataxia presented gastrointestinal symptoms, yet about 40% have intestinal damage. This accounts for 40% of ataxias of unknown origin and 15% of all ataxias.
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by an unstable polyglutamine expansion within the Ataxin 1 protein, which impairs mitochondria in Purkinje cells. This leads to premature degeneration of the Purkinje cells, which compromises motor coordination and eventually causes death.
Some domestic animals are known to develop a condition where the Purkinje cells begin to atrophy shortly after birth, called cerebellar abiotrophy. Its symptoms include ataxia, intention tremors, hyperreactivity, lack of menace reflex, stiff or high-stepping gait, apparent lack of awareness of foot position (occasional standing or walking with a foot knuckled over), and a general inability to determine space and distance). A similar condition called cerebellar hypoplasia occurs when Purkinje cells fail to develop in utero or die off before birth.
The genetic conditions ataxia telangiectasia and Niemann Pick disease type C, and cerebellar essential tremor all cause a progressive loss of Purkinje cells. In Alzheimer's disease, spinal pathology, and loss of dendritic branches of the Purkinje cells are occasionally observed. The rabies virus can also damage Purkinje cells as migrates from the site of infection in the periphery to the central nervous system.
(b) Granule Cells
https://en.wikipedia.org/wiki/Cerebellar_granule_cell
Cerebellar granule cells are among the smallest and most numerous neurons in the brain. Note that the term “granule cell” is used for several unrelated types of small neurons in various parts of the brain. In human brains, it’s estimated there are about 50 billion Granule Cells in the cerebellum, which constitute about 3/4 of the brain's neurons.
Their cell bodies are compact into a thick granular layer at the bottom of the cerebellar cortex. Each Granule Cell emits 4—5 dendrites, with each dendrite ending in an enlargement called a dendritic claw. These enlargements are sites of excitatory input from Mossy Fibres and inhibitory input from Golgi cells. The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where they bisect. Each branch travels horizontally to form a Parallel Fibre, and vertical branch splits into 2 horizontal branches to give rise to a distinctive "T" shape. Each Parallel Fibre runs for an average of 3 mm in each direction from the junction, for a total length of about 6 mm, which is approximately 1/10 of the total width of the cortical layer. They pass through the dendritic trees of Purkinje cells, communicating with 1 in 3-5 Purkinje Cells they pass, which adds up to a total of 80-100 synaptic connections with Purkinje cell dendritic spines. Granule cells release Glutamate and therefore exert excitatory effects on their targets.
In normal development, endogenous Sonic Hedgehog signaling stimulates rapid proliferation of cerebellar granule neuron progenitors (CGNPs) in the external granule layer (EGL). During the late embryogenesis and early postnatal period, the cerebellum develops with CGNP proliferation in the EGL peaking during early development (P7, postnatal day 7, in the mouse). As CGNPs terminally differentiate into cerebellar granule neurons (CGNs), they migrate to the internal granule layer (IGL) to form the mature cerebellum (by P20, post-natal day 20 in the mouse). Mutations that abnormally activate Sonic hedgehog signaling predispose to cancer of the cerebellum (medullablastoma) in humans with Gorlin Syndrome and in genetically engineered mouse models.
Granule Cells receive all of their input from Mossy Fibres, but outnumber them 200 to 1 (in humans). Therefore, the granule cell population activity state retains all the information delivered by the mossy fibres, but recoded in a much more expansive way. Due to their miniature size and density, record the spike activity in behaving animals is quite challenging, which limits the amount of available and reliable data to form theories on. In 1969, David Marr suggested that Granule Cells encode combinations of mossy fibre input. This is based on the idea that each granule cell receives input from only 4–5 mossy fibres, but they wouldn’t respond if only one of its inputs was active unless more than one were active. This "combinatorial coding" scheme would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibres alone would permit.
(c) Mossy Fibres
https://en.wikipedia.org/wiki/Mossy_fiber_(cerebellum)
They are one of the major inputs to the cerebellum, as well as receives many sources such as the cerebral cortex, which sends input to the cerebellum via the pontocerebellar pathway. Other sources include the Vestibular Nerve and Nuclei, the Spinal Cord, the Reticular Formation, and feedback from Deep Cerebellar Nuclei. These axons enter the cerebellum via the Middle and Inferior Cerebellar Peduncles, where some branch to connect with deep cerebellar nuclei. There, they ascend into the white matter of the cerebellum, where each axon branches to innervate granule cells in several cerebellar folia.
The pathway is so named for a unique synapse formed by its projections called the mossy fibre rosette. The fine branches of their axons twist through the granule cell layer, and then slightly enlarge to indicate synaptic contacts. These contacts give the appearance of a classic Gray's Type 1 synapse, which indicates they release excitatory (glutamatergic) neurotransmitters. Sensory information relayed from the Pons through the Mossy fibres to the Granule cells is then sent along the Parallel Fibres to the Purkinje Cells for processing. Extensive branching in white matter and synapses to granular cells ensures that input from a single mossy fibre axon can influence processing in many Purkinje cells.
(d) Climbing Fibres
https://en.wikipedia.org/wiki/Climbing_fiber
They are a series of neuronal projections from the Inferior Olivary Nucleus in the Medulla Oblongata. These axons penetrate the Pons and enter the Cerebellum via the Inferior Cerebellar Peduncle to synapse with Deep Cerebellar Nuclei and Purkinje Cells, with each Climbing Fibre synapsing with 1 — 10 Purkinje Cells.
Early in development, Purkinje Cells are innervated by numerous Climbing Fibres. As the cerebellum matures, these inputs gradually disappear until a single climbing fibre input synapses a single Purkinje cell. They release powerful, excitatory input to the cerebellum to generate complex spike excitatory postsynaptic potential (EPSP) in Purkinje cells, which plays a central role in motor behaviours.
They transmit information from various sources such as the Spinal Cord, Vestibular System, Red Nucleus, Superior Colliculus, Reticular Formation and sensory and motor cortices. When Climbing Fibres are activated, they send motor error signals to the cerebellum to assist with motor timing. In addition to the control and coordination of movements, recent studies theorise they likely play important roles in sensory processing and cognitive tasks by encoding the timing of sensory input independently of attention or awareness. A 2004 study found these fibres undergo remarkable regenerative modifications in response to injuries of the CNS by generating new branches through sprouting to innervate surrounding Purkinje cells in the case they lose their CF innervation. This kind of injury-induced sprouting has been demonstrated to require the growth associated protein GAP-43.
(e) Deep Cerebellar Nuclei
https://en.wikipedia.org/wiki/Deep_cerebellar_nuclei
The cerebellum has 4 deep cerebellar nuclei embedded in the white matter. From lateral to medial, they are the Dentate, Emboliform, Globose, and Fastigial. Some animals, including humans, lack distinct emboliform and globose nuclei, and instead have a single, fused interposed nucleus. In animals that contain distinct Emboliform and Globose nuclei, the term interposed nucleus is often used to refer collectively to these two nuclei.
They receive inhibitory (GABAergic) inputs from Purkinje Cells in the cerebellar cortex and excitatory (glutamatergic) inputs from Mossy Fibre and Climbing Fibre pathways. Most output fibres of the cerebellum originate from these nuclei, except for those from the Flocculonodular Lobe systems. Instead, they synapse directly on Vestibular Nuclei bypassing the deep cerebellar nuclei.
Most of these neurons have large cell bodies and spherical dendritic trees with a radius of about 400 μm and release Glutamate. They project to a variety of targets outside the cerebellum. A minority of them have small cell bodies and release GABA exclusively to the Inferior Olivary Nucleus, where Climbing Fibres are located. Thus, the nucleo-olivary projection provides an inhibitory feedback to match the excitatory projection of climbing fibers to the nuclei. A 2004 study has found evidence that each small cluster of nuclear cells projects to the same cluster of olivary cells that send climbing fibres to it, along with consistent matching topography in both directions. In cats, when a Purkinje cell axon enters 1 of the deep nuclei, it branches to communicate with both large and small nuclear cells, but the total number of cells synapsed is only about 35. Conversely, a single deep nuclear cell receives input from approximately 860 Purkinje cells.
Each pair of deep nuclei associates with a corresponding region of cerebellar surface anatomy.
— The Dentate Nuclei are deep within the lateral hemispheres
— The Interposed Nuclei are located in the paravermal (intermediate) zone
— The Fastigial Nuclei are in the Vermis
These structural relationships are generally maintained in the neuronal connections between the nuclei and associated cerebellar cortex.
— The Dentate Nucleus receives most of its connections from the lateral hemispheres.
— The Interposed Nuclei receives input mostly from the paravermis.
— The Fastigial Nucleus receives afferents from the vermis.
(f) Compartments
From the viewpoint of gross anatomy, the cerebellar cortex appears to be a homogeneous sheet of tissue. But, from the viewpoint of microanatomy, all regions of this long sheet of tissue appears to have identical internal structures. A 2005 study has discovered the structure of the cerebellum is compartmentalised into zones, which are then divided into smaller compartments known as microzones.
A 2005 study first coined the concept of a compartmental structure from its investigations of the receptive fields of cells in various parts of the cerebellar cortex. It’s known that each body part maps to specific points in the cerebellum to form an arrangement that has been called "fractured somatotopy”, in spite of the numerous repetitions of the basic map. Researchers would immunostain the cerebellum to identify certain types of protein markers called “zebrins”. They are named as such because they give rise to a complex pattern reminiscent of the stripes on a zebra. The stripes generated by zebrins and other compartmentalisation markers are oriented perpendicular to the cerebellar folds, making them narrow mediolaterally and extended longitudinally. Despite different markers generate different sets of stripes, the widths and lengths vary as a function of location, they all have the same general shape nonetheless.
An Oscarsson 1979 study proposed that cortical zones are partitioned into smaller units called microzones, which is defined as a group of Purkinje cells all having the same somatotopic receptive field. A 2005 study found these microzones contained 1000 Purkinje cells each, arranged in a long, narrow strip, and oriented perpendicular to the cortical folds. A 2004 study by Richard Apps and Martin Garwicz discovered that Purkinje cell dendrites are flattened in the same direction as the microzones extend, while Parallel Fibres cross them perpendicularly. Usually about 10 climbing fibres activate Purkinje cells belonging to the same microzone. Neurons from the Inferior Olivary Nucleus that projected these Climbing Fibres to the same microzone are coupled by gap junctions, which account for their synchronisation. This causes Purkinje cells within a microzone to unleash correlated complex spike activity on a millisecond time scale. Furthermore, Purkinje cells within the same microzone project to the same small cluster of output cells within the Deep Cerebellar Nuclei. Finally, the axons of Basket Cells are longer longitudinally than mediolaterally, which confines them largely to a single microzone. Consequently, this strengthens cellular interactions within a microzone than those between different microzones. In summary, microzones themselves form part of a larger entity called a “multizonal microcomplex”. A microcomplex contains several spatially separated cortical microzones, which all project to the same group of deep cerebellar neurons, as well as group of coupled olivary neurons that connect to all of the included microzones and the deep nuclear area.
What are the functions of the cerebellum?
Scientists have known that the cerebellum is associated with motor control after examinations of animals and humans with cerebellar damage. It’s known that cerebellar dysfunction causes issues with motor control on the ipsilateral side of the body as the damaged half of the cerebellum. Although motor activity can be generated effortlessly, it hinders precision, resulting in erratic, uncoordinated, or incorrectly timed movements. To test cerebellar function, patients are asked to reach for a target object with the tip of the finger at their arm’s length. If the patient moves their fingertip rapidly in a straight trajectory, then they are considered as healthy. If the patient reaches slowly and erratically with many mid-course corrections, then it indicates cerebellar damage. A challenge for physicians is to detect deficits in non-motor functions. Thus, a 1985 study concluded that the cerebellum basically calibrates the detailed form of a movement, rather than initiate movements or to decide which movements to execute. Functional imaging studies conducted at the beginning of the 21st century noticed the cerebellum was activated in relation to language, attention, and mental imagery. Correlation studies have found evidence of interactions between the cerebellum and non-motor areas of the cerebral cortex, as well as a variety of non-motor symptoms in patients with cerebellar damage particularly those affected by “cerebellar cognitive affective syndrome” or Schmahmann's syndrome. A 2011 study estimated more than half of the cerebellar cortex is interconnected with association zones of the cerebral cortex based on the functional mapping of the cerebellum using fMRI. A researcher named Kenji Doya implicated that the cerebellum’s function was best understood in terms of the neural computations it performs rather than the behaviours it affects. It suggested that the cerebellum consists of independent modules, all with the same geometrically regular internal structure, thus presumably performs the same computation. In that case, the input and output connections of a module with motor areas directly influences motor behaviour. On the other hand, if the connections are with areas involved in non-motor cognition, then the module will show other types of behavioural correlates. Recent studies implicated that cerebellum regulates many differing functional traits such as affection, emotion and behaviour. In his 1999 and 2000 studies, Kenji Doya proposed the cerebellum is involved in predictive action selection based on "internal models" of the environment or a device for supervised learning.
Although a full understanding of cerebellar function remains elusive, at least 4 important principles have been identified:
(i) Feedforward Processing: This type of signal processing is defined as unidirectionally through the system from input to output, with little recurrent internal transmission. The tiny recurrence consists of mutual inhibition because of the lack of mutually excitatory circuits. This mode of operation prohibits the cerebellum from generating self-sustaining patterns of neural activity. In general, when signals are processed by each stage in sequential order upon entry before they can leave.
(ii) Divergence and Convergence: In the human cerebellum, information from 200 million Mossy Fibre inputs diverge to 40 billion Granule Cells, whose Parallel Fibre outputs then converge onto 15 million Purkinje Cells. 1000s of Purkinje Cells lined up longitudinally belong to a single microzone, whose input originates from as many as 100 million parallel fibres. Hence, they focus their own output down to a group of less than 50 Deep Nuclear Cells. Hence, the cerebellar network receives its inputs, extensively processes them through its rigorously structured internal network, and propagates its results through a small number of output cells.
(iii) Modularity: The cerebellar network is functionally divided into many independent modules, with each module having similar internal structure, but different inputs and outputs. According to Apps and Garwicz, a “module” is a multizonal microcompartment that consists of a small cluster of neurons in the Inferior Olivary Nucleus, a set of long narrow strips of Purkinje cells in the cerebellar cortex (microzones), and a small cluster of neurons in one of the deep cerebellar nuclei. Different modules share input from mossy fibres and parallel fibres of varying independent function.
(iv) Plasticity: Synapses between Parallel fibres and Purkinje cells, and between Mossy fibres and Deep nuclear cells, are both susceptible to neuroplasticity or having its strength modified. In a single cerebellar module, since input from as many as a billion parallel fibres converge onto a group of less than 50 deep nuclear cells, the influence of each Parallel Fibre on those nuclear cells is variable. This arrangement allows tremendous flexibility for fine-tuning the relationship between the cerebellar inputs and outputs.
How is the cerebellum involved in motor learning?
There is ongoing debate regarding the cerebellum’s direct role in motor learning and whether it merely serves to provide signals that promote learning in other brain structures. According to David Marr and James Albus, climbing fibres may provide a teaching signal that induces synaptic modification in synapses between Parallel Fibres and Purkinje Cells. Despite Marr assuming that climbing fibre input would strengthen synchronously activated parallel fibre inputs, many subsequent cerebellar-learning models, however, supported Albus’s assumption that climbing fibres provide error signals that would weaken synchronously activated parallel fibre inputs. Some of these later models, such as the 1982 Adaptive Filter model of Fujita attempted to understand cerebellar function in terms of optimal control theory. A 1996 experimental study found mixed results supporting the idea that climbing fibre sends error signals. A 1977 pioneering study by Gilbert and Thach on monkeys found that Purkinje cells increased complex spike activity during a reaching task, which is known to reliably indicate activity of the cell's climbing fibre input during periods of poor performance. Several studies on motor learning in cats observed complex spike activity at the presence of a mismatch between an intended movement and the actual executed movement. A 1996 study of the Vestibulo-ocular Reflex found that climbing fibre activity indicated "retinal slip”, though how this phenomenon occurs is not well understood.
One of the most extensively studied cerebellar learning tasks is the eyeblink conditioning paradigm. When a neutral conditioned stimulus (CS) such as a tone or a light is repeatedly paired with an unconditional stimulus (US), such as air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will eventually elicit a blink before the US, a conditioned response (CR). In 2003, experimental studies have found that lesions either at a specific part of the interposed nucleus or a few specific points in the cerebellar cortex would abolish learning of a conditionally timed blink response. When cerebellar outputs were pharmacologically inactivated, leaving the inputs and intracellular circuits intact, motor learning still occurred even when the animal failed to respond. On the other hand, when intra-cerebellar circuits were disrupted, no learning took place. These results strongly support the theory that motor learning occurs inside the cerebellum.
What are some theories and computational models about the Cerebellum?
Many theories about the cerebellum are postulated by the large base of knowledge about its anatomical structure and behavioural functions. “Learning theories” conceptualise synaptic plasticity within the cerebellum to account for its role in learning, whilst “performance theories” account for aspects of ongoing behaviour on the basis of cerebellar signal processing. Several theories of both types have been formulated as mathematical models and simulated using computers.
The earliest “performance” theory was the “delay line” hypothesis, first coined by Valentino Braitenberg and Roger Atwood in 1958. It proposed that slow propagation of signals along parallel fibres imposes predictable delays that allow the cerebellum to detect time relationships within a certain window. However, a 1997 study disputed this theory, which Braitenberg didn’t agree with and argued for modified versions. In 2002, Richard Ivry advocated his hypothesis that the cerebellum functions essentially as a timing system. In 1982, the Tensor Network Theory coined by Pellionisz and Llinás provided an advanced mathematical formulation of the fundamental computation performed by the cerebellum, which transform sensory into motor coordinates.
Most of the “learning” theories were derived from publications by Marr and Albus. Marr’s 1969 study theorised that the cerebellum is a component tasked to learn by associating elemental movements encoded by Climbing fibres with Mossy fibre inputs that encode the sensory context. In 1971, Marr also proposed that a Purkinje cell functions as a perceptron i.e. a neurally inspired abstract learning device. The difference between the Marr and Albus theories is that Marr assumed that Climbing fibre activity strengthened parallel fibre synapses, whereas Albus proposed that they would be weakened. Albus also formulated his version as a software algorithm called a CMAC (Cerebellar Model Articulation Controller), which has been tested in a number of applications.
How is cerebellum supplied?
The cerebellum is provided with blood from 3 paired major arteries: Superior Cerebellar Artery (SCA), Anterior Inferior Cerebellar Artery (AICA) and Posterior Inferior Cerebellar Artery (PICA). The SCA supplies the upper region of the cerebellum, which divides at the upper surface and branches into the Pia Mater where the branches anastomose with those of the AICA and PICA. The AICA supplies the front part of the undersurface of the cerebellum, while the PICA arrives at the undersurface, where it divides into a medial and lateral branches. The medial branch continues backward to the cerebellar notch between the 2 hemispheres of the cerebellum. The lateral branch supplies the under surface of the cerebellum, as far as its lateral border, where it anastomoses with the AICA and the SCA.
What happens if the cerebellar is damaged?
Damage to the cerebellum often causes motor-related symptoms, but the details of which depent on the region of the cerebellum involved and the way it is damaged.
— Damage to the Flocculonodular Lobe causes a loss of equilibrium / balance, as well as an altered, irregular walking gait, with a wide stance.
— Damage to the lateral zone typically affects skilled voluntary and planned movements. This consequently causes errors n the force, direction, speed and amplitude of movements. Other manifestations include hypotonia (decreased muscle tone), dysarthria (problems with speech articulation), dysmetria (problems judging distances or ranges of movement), dysdiadochokinesia (inability to perform rapid alternating movements such as walking), impaired check reflex or rebound phenomenon, and intention tremor (involuntary movement caused by alternating contractions of opposing muscle groups).
— Damage to the midline portion disrupts whole-body movements.
— Damage to the lateral portion disrupts fine movements of the hands or limbs.
— Damage to the upper portion impairs gait and other problems with leg coordination.
— Damage to the lower portion disrupts coordination or accuracy of movements of the arms and hands, and causes difficulties in speed. This complex of motor symptoms is called ataxia.
Neurologists identify cerebellar problems in patients through examinations that assess their gait, finger-pointing and posture. If there is cerebellar dysfunction, MRI scans are used to illustrate any structural alterations that may exist. Recent studies have noted that cerebellar damage can cause stroke, haemorrhage, cerebral oedema, tumours, alcoholism, physical trauma (such as gunshot wounds or explosives), and chronic degenerative conditions such as olivopontocerebellar atrophy. A 2007 study found that some forms of migraine headache may temporarily cause dysfunction of the cerebellum, with variable severity. A 2015 study discovered that infection can cause cerebellar damage in such conditions such as the prion diseases, and a variant of Guillain-Barré syndrome called Miller Fisher syndrome.
It’s known that ageing affects the structure of the cerebellum, which differ from other parts of the brain. In 2015, a study on an epigenetic biomarker of tissue age called an “epigenetic clock” evaluated that the cerebellum is the youngest brain region (and body part) in centenarians, which is about 15 years younger than expected. A 2005 study found that the least age-related alteration in gene expression patterns in the cerebellum’s of older humans, compared to their cerebral cortex. Some studies reported decreases in the nerve cell population or tissue tissue, but it lacks concrete and detailed data.
So far, scientists know that congenital malformation, hereditary disorders, and acquired conditions influences cerebellar structure and, consequently, cerebellar function. Most causative conditions are irreversible, and the palliative care is the only possible treatment for people afflicted with these problems. A 1987 study used ultrasound scans to visualise the foetal cerebellum at 18-20 weeks of pregnancy, as well as screen for foetal neural tube defects, which has a sensitivity rate of up to 99%.
According to a 1995 study, in normal development, endogenous Sonic Hedgehog signalling stimulates rapid proliferation of cerebellar granule neuron progenitors (CGNPs) in the external granule layer (EGL). During late embryogenesis and the early postnatal period, the cerebellum begins to develop. During early development (postnatal day 7 in the mouse), CGNP proliferation in the EGL peaks. As CGNPs terminally differentiate into cerebellum granule cells (CGNs), they migrate to the internal granule layer (IGL) to form the mature cerebellum (by post-natal day 20 in the mouse). Recent studies found that mutations that abnormally activate Sonic hedgehog signalling predispose to cancer of the cerebellum (medulloblastoma) in humans with Gorlin Syndrome and in genetically engineered mouse models.
— People with either Dandy-Walker Syndrome and Joubert Syndrome have congenitally malformed or underdeveloped (hypoplasia) cerebellar vermis, and rarely an absent cerebellum.
— People with inherited neurological disorders Machado-Joseph Disease, Ataxia Telangiectasia, and Friedreich’s Ataxia have cerebellums that progressively degenerate.
— People with some forms of Arnold-Chiari malformation have their cerebellar tissue herniated due to congenital brain malformations outside the cerebellum.
— Recent studies have found that patients with the idiopathic progressive neurological disorders Multiple System Atrophy and Ramsay Hunt Syndrome Type I have cerebellar degeneration.
— People suffering from the autoimmune disorder paraneoplastic cerebellar degeneration have tumours elsewhere in the body triggering an autoimmune response that causes neurodegeneration in the cerebellum.
— A 2006 study found that an acute deficiency of vitamin B1 (Thiamine), as seen in beriberi and in Wernicke-Korsakoff Syndrome, or Vitamin E deficiency can cause cerebellar atrophy.
— Patients afflicted with Huntington’s Disease, Multiple Sclerosis, Essential Tremor, Progressive Myoclonus Epilepsy, and Niemann-Pick Disease also have atrophied cerebellums.
— Exposure to toxins including heavy metals or pharmaceutical or recreational drugs can also cause cerebellar atrophy.
Recent studies have proposed that the cerebellum plays crucial roles in pain processing. So far, it’s known that the cerebellum receives pain input from both descending Cortico-cerebellar pathways and ascending Spino-cerebellar pathways, via the Pontine nuclei and Inferior olives. Some pain information transfers to the motor system to induce a conscious motor avoidance of pain. The grading of this motor response depends on the pain intensity. A 2017 study suggested that both direct and indirect pain inputs induce long-term pain avoidance behaviour, resulting in chronic posture changes. Consequently, this functionally and anatomically remodels the vestibular and proprioceptive nuclei. Thence, chronic neuropathic pain would induce macroscopically and anatomically remodel the hindbrain, including the cerebellum. The magnitude of this remodelling and the induction of neuron progenitor markers implicates the vital role adult neurogenesis contributes to these alternations.
How did the cerebellum evolve in other animals?
Is the structure of the human cerebellum similar to other animals?
A 2008 study found that the cerebellar circuits are similar across all vertebrate classes including fish, reptiles, birds, and mammals. A 1977 study found that this is analogous with well-developed brains in cephalopods, such as octopuses. This suggests that the cerebellum performs functions important to all animal species with a brain. However, the cerebellums in amphibians, lampreys, hagfish are quite different in size and shape, making them barely distinguishable from the brainstem. Although the spinocerebellum is present in these animal groups, the primary structures are small, paired-nuclei corresponding to the vestibulocerebellum. Mammals have the largest cerebellums, which is larger than birds and reptiles. The cerebellum in mammals including humans is a pair of large and convoluted lobes, but it is a single median, smooth or grooved lobe in other animal groups. A large portion of the mammalian cerebellum by mass is the neocerebellum, whilst in other vertebrate, it is the spinocerebellum. The cerebellum of cartilaginous and bony fishes is relatively enormous and complex, which structurally differs from the mammalian cerebellum. Fish cerebellum lack discrete deep cerebellar nuclei, but do contain a distinct type of cell distributed across the cerebellar cortex as the primary targets of Purkinje cells. e.g. In a family of weakly electrosensitive freshwater fish called mormyrid fish, their cerebellum are bigger than other parts of their brain combined. Their brains have a special structure called the valvula, which contains an unusually regular architecture and receives much of its input from the electrosensory system.
The hallmark of the mammalian cerebellum is lateral lobe expansion, which mainly communicate with the neocortex. It’s hypothesised that during the evolution from monkeys into great apes, their lateral lobes expanded, in tandem with the frontal lobes of the neocortex. In ancestral hominids, and Homo sapiens until the middle Pleistocene period, their cerebellums and frontal lobes continued to expand. A 2005 study postulated that during recent times in human evolution, the relative size of the cerebellum increased whilst the neocortex reduced in size. A 2009 study found that compared to the rest of the brain, the human cerebellum expanded in size while the cerebrum contracted in size. A 2003 study noted that the development and implementation of motor tasks, visual-spatial skills and learning is localised in the cerebellum, and its growth associates with increased human cognitive abilities. Compared to monkeys, humans and apes have 2.7 times larger lateral hemispheres of the cerebellum. Researchers question whether the development of the cerebellum closely associates with the rest of the brain or cerebellar neural activities dominated the Hominidae evolution. Because the cerebellum plays responsible roles in cognitive functions, its increased size may correlate to its cognitive expansion.
Are there brain structures similar to the cerebellum in other animals?
The only known cerebellum-like mammalian brain structure is the Dorsal Cochlear Nucleus (DCN), which is 1 of 2 primary sensory nuclei that receive input directly from the Auditory Nerve. Instead of Purkinje Cells, they have a set of GABAergic neurons called Cartwheel Cells that receive Parallel fibre input, rather than inputs from neurons resembling Climbing Fibres. The DCN is mostly developed in rodent and other small animals, but reduced in primates. However further research is required to understand its function.
Most species of fish and amphibians have a lateral line system that detects pressure waves underwater. They have a unique brain region that receives primary input from the lateral line organ, the medial Octavolateral Nucleus, which is a cerebellum-like structure that contains Granule cells and Parallel fibres. In electrosensitive fish, their electrosensory system directs input to the dorsal octavolateral nucleus, which also contains a cerebellum-like structure. In ray-finned fishes, their Optic Tectum contains a cerebellum-like marginal layer.
It seems that all of the known cerebellum-like anatomy is primarily elicits sensory output rather than motor output. Despite having Granule Cells projecting Parallel Fibres to Purkinje-like neurons with modifiable synapses, none of them have Climbing fibres. This suggests they directly receive input from peripheral sensory organs. A 2008 study speculated that these cerebellum-like structures transform sensory inputs in a sophisticated manner, in order to compensate for changes in body posture. A 1997 study by James M. Bower and others argued that the cerebellum itself is fundamentally a sensory structure that contributes to motor control by moving the body in a manner that allows it to control the resulting sensory signals. However, recent studies provided a firm point of view that the mammalian cerebellum directly influences motor output.
https://en.wikipedia.org/wiki/Motor_coordination
Your cerebellum plays a critical role in a type of neural control of movement called motor coordination. Motor coordination combines body movements generated by the kinematic (such as spatial direction) and kinetic (force) parameters, which result in intended actions. This is achieved when subsequent parts of the same movement, or the movements of several limbs or body parts combine in well timed, smooth, and efficient manner with respect to the intended goal. This process involves integrating proprioceptive information that detail the position and movement of the musculoskeletal system with the neural processes in the brain and spinal cord that are tasked to control, plan, and relay motor commands. Damage to the cerebellum or its connecting structures and pathways impairs coordination, known as ataxia.
Examples of motor coordination include standing up from a seated position, pouring water into a cup, walking, or reaching for a pencil. These reliable, proficient and repetitive movements are created but rarely reproduced exactly in their motor details such as joint angles when pointing or standing up from sitting.
Pick up a bottle of wine and pour it into a glass. Did that action seem apparently easy to execute? You would think so but are you aware that this ease of movement is due to a combination of complex tasks that are processed at different levels? The levels of processing include:
(1) For the prehension movement to the bottle, your reach and hand configuration have to be coordinated.
(2) When you’re lifting the bottle, the load and the grip force applied by your fingers need to be coordinated to account for weight, fragility, and slippage of the glass.
(3) When you’re pouring the wine from the bottle to the glass, the actions of both your arms, with one holding the glass and the other that is pouring the wine, need to be coordinated with each other.
This coordination also involves all of the hand-eye coordination processes, which I’ll discuss later. Furthermore, the brain interprets actions as spatial-temporal patterns and during which each hand performs a different action simultaneously, bimanual coordination is involved. Additional levels of organisation are required depending on whether you will drink from the glass, pass it to someone else, or simply place it on a table.
https://en.wikipedia.org/wiki/Degrees_of_freedom_problem
First formulated by Russian neurophysiologist Nikolai Bernstein, the degrees of freedom (DOF) problem / motor equivalence problem in motor control concerns the possibilities for humans or animals to perform a movement in order to achieve the same goal. In general, simple 1-to-1 correspondence between a motor problem (or task) and a motor solution to the problem doesn’t exist under normal circumstances. The challenge for scientists is to understand how the nervous system selects which particular DOFs to use in a movements. The abundance of DOFs is almost certainly an advantage to the mammalian and the invertebrate nervous systems. The redundant DOFs the human body has are:
— Anatomical DOFs at its muscles and joints
— Kinematic DOFs regarding movements having different trajectories, velocities, and accelerations and yet achieve the same goal
— Neurophysiological DOFs regarding multiple motor neurons synapsing on the same muscle, and vice versa.
The computational process to which the nervous system "chooses" a subset of these near-infinite DOFs is a scientific mystery and an obstacle to understanding motor control and motor learning.
The study of motor control historically categorised into 2 broad areas: “Western neurophysiological studies” and "Bernsteinian" functional analysis of movement. The latter predominated in motor control, as Bernstein's theories were strongly supported and are considered founding principles of the field as it exists today.
In the latter 19th and early 20th centuries, many scientists believed that all motor control came from the spinal cord according to the results of their experiments. When they stimulated frogs, they demonstrated patterned movement or “motor primitives”, and spinalised cats were observed to walk. These beliefs correlated with advocation of strict nervous system localisationism during that period. Due to the observation that stimulation of the frog spinal cord in different places produced different movements, they postulated that all motor impulses were localised in the spinal cord. However, the central dogma of neuroscience gradually disintegrated the fixed structure and localisation. Nowadays, scientists know the Primary Motor Cortex and Premotor Cortex at the highest level are responsible for most voluntary movements. Modern animal models on motor control, spinal cord reflexes and central pattern generators are still being conducted in this field of study.
Although Lashley first formulated the motor equivalence problem in 1933, it was Nikolai Bernstein who articulated the DOF problem in its current form. According to Bernstein, the problem results from infinite redundancy yet flexibility between movements, thence the nervous system quickly selects a particular motor solution every time it acts. This means that no single muscle acts in isolation, but rather large numbers of "nervous centres" cooperate in order to make a whole movement possible. Nervous impulses from different parts of the CNS may converge on the periphery to combine to produce motion. Nevertheless, scientists still experience difficult understanding the coordinating the facts linking impulses to a movement. Bernstein's rational understanding of movement and prediction of motor learning via “plasticity” was regarded as revolutionary for his time. Bernstein also thought that movements had to reflect the information contained in the "central impulse” in a certain manner. He then recognised that effectors and feedback were both crucial components to movement. Thus, Bernstein was one of the first to understand movement as a closed circle of interaction between the nervous system and the sensory environment, rather than a simple arc toward a goal. In 1967, he defined motor coordination as a means for overcoming indeterminacy due to redundant peripheral DOFs. When the amount of DOFs increases, the nervous system has to increase the complexity of its , delicate organisational control.
Because humans successfully adapted to survive their harsh environment for many years, reflexes were considered the "most important" movements, especially the rapid pain or defensive reflexes. Most human movements occur under voluntary control, which was historically under-emphasised or once disregarded altogether. Nevertheless, Bernstein viewed voluntary movements that revolved around a “motor problem” where the nervous system required 2 factors to function. Those factors include (1) a full and complete perception of reality through multisensory integration, and (2) objectivity of perception through constant and correct recognition of signals by the nervous system. The presence of both factors assist the nervous system in selecting the appropriate motor solution.
What are the difficulties of the DOFs problem?
(a) Counting degree of freedom:
The complexity of the neuromuscular system of the human body makes this problem quite difficult to tackle. One of the largest difficulties in motor control is quantifying the exact number of DOFs in the complex neuromuscular system of the human body. In addition to having redundant muscles and joints, muscles may span multiple joints, further complicating the system. Because the properties of muscle change as the muscle length itself changes, it increases the difficulty of creating and understanding accurate mechanical models. Although individual muscles are innervated by multiple nerve fibres (motor units), the manner in which these units are recruited is similarly complex. While each joint is commonly understood as having an agonist-antagonist pair, not all joint movement is controlled locally. Finally, movement kinematics are not identical even when performing the same motion repeatedly. This is due to natural variation in position, velocity, and acceleration of the limb even during seemingly identical movements.
(b) Types of Studies:
Another difficulty in motor control is unifying the different ways to study movements. Nonetheless, 3 distinct areas of motor control study have emerged:
i. Limb Mechanics = These studies focus on the peripheral motor system as a filter, which converts patterns of muscle activation into purposeful movement. In this paradigm, the building block is a motor unit and complex models are constructed to understand the multitude of biological factors influencing motion. In 2004, these models have increased in complexity as multiple joints or additional environmental factors such as ground reaction forces are introduced.
ii. Neurophysiology = These studies model the motor system as a distributed and hierarchical system with the spinal cord regulating involuntary movements such as stretch reflexes, the cortex regulating voluntary movements such as reaching for an object, and the brainstem performing a function in between both aforementioned functions. Such studies investigate the manner in which the primary motor cortex (M1) controls planning and execution of motor tasks. They traditionally used animal models with electrophysiological recordings and stimulation to enhance understanding of human motor control.
iii. Motor behaviour = This studies focus on the adaptive and feedback properties of the nervous system in motor control. It’s known that the motor system rapidly adapts to changes in its mechanical environment while simultaneously producing smooth movements. They deeply investigate the components behind this remarkable feedback process, as well as the variables controlled by the nervous system. Moreover, they attempt to identify the variables that less tightly regulated and its method of implementation. Common paradigms of study include voluntary reaching tasks and perturbations of standing balance in humans.
(c) Abundance or Redundancy
The nature of the DOF problem poses a few questions.
- Does the nervous system experience difficulty in selecting DOFs?
- Is it necessary for an abundance of DOFs to ensure evolutionary survival?
During extreme movements, humans may exhaust the limits of their DOFs, which leaves the nervous system only 1 choice, thus making DOFs finite. Bernstein suggested that the abundance of DOFs allows motor learning to occur, wherein the nervous system rapidly "explores" the set of possible motor solutions before settling on an optimal solution. e.g. Walking and riding a bicycle. Finally, additional DOFs allows patients with brain or spinal cord injuries to often retain movement while relying on a reduced set of biochemical DOFs. In 1998, Gelfand believed the "degrees of freedom problem" may be a misnomer and preferred it as the "motor equivalence problem" with redundant DOFs offering an evolutionary solution to this problem.
What are some hypotheses and proposed solutions to the DOFs problem?
One of the first hypotheses was Fitt’s Law, which states that a trade-off must occur between movement speed and movement accuracy in a reaching task. Since then, many other theories have been offered.
(1) Optimal Control Hypothesis:
According to recent studies, optimal control is defined as "optimising motor control for a given aspect of task performance," or as a way to minimise a certain "cost" associated with a movement, which is a general paradigm for understanding motor control. The “cost function” varies depending on the task-goal; for instance, a 2004 study by Todorov explains that minimum energy expenditure might be a task-variable associated with locomotion, while precise trajectory and positional control could be a task-variable associated with reaching for an object. On the other hand, the “cost function” may be sophisticated due to being a functional instead of function, as well as related the representations in the internal space. e.g. A 2010 study found that the speech produced by biomechanical tongue models (BTM) is controlled by the internal model that helps minimise the length of the path travelled in the internal space under the constraints related to the executed task (e.g., quality of speech, stiffness of tongue), making it realistic. A 2007 study pointed out that "reduce degrees of freedom in a principled way” is essentially the goal of optimal control. A year later, Reza & Krakauer identified 2 key components of all optimal control systems, which are a "state estimator” and adjustable feedback gains based on task goals. A state estimator informs the nervous system about its performance, including afferent sensory feedback and an efferent copy of the motor command. Moreover, Todorov suggested a component of these adjustable gains may be a "minimum intervention principle”, where the nervous system only performs selective error correction rather than heavily modulating the entirety of a movement.
— Open and Closed-loop models =
Open-loop models generally ignore the role of sensory feedback, while closed-loop models incorporate sensory feedback including delays and uncertainty associated with the sensory systems involved in movement. They gives open-loop models simplicity and severe limitations because they model movement as prerecorded in the nervous system, thus ignoring sensory feedback. Therefore, it fails to model variability between movements with the same task-goal. The primary challenge for both models is identifying the “cost” associated with a movement. Todorov suggested the most likely choice for a common performance criterion is a mix of cost variables such as minimum energy expenditure and a "smoothness" function.
— Learning and Optimal Control =
Bernstein suggested that as humans learn a movement, their bodies first instinctively reduce the DOFs by stiffening the musculature in order to have tight control. Then they gradually “loosen up” and explore the available DOFs as they adapt to the task, until finally evaluate an optimal solution. In terms of optimal control, a 2009 study postulated that the nervous system uses an optimal control search strategy to learn how to find task-specific variables. It found optimal tuning in adaptation of a visuomotor reaching task, which minimised the cost of movement trajectories. This suggested that both nonadaptive and adaptive processes of optimal control is regulated by the nervous system. Rather than being a control variable, it indicated that consistent movement trajectories and velocity profiles are the natural outcome of an adaptive optimal control process.
— Limits of Optimal Control =
A 2010 study expressed concerns on the limitations of the optimal control theory because it lacks knowledge regarding the precise execution of a control strategy by the nervous system. So far, the theory explains that certain information must be obtained before it is able to make a behavioural prediction such as the costs and rewards of a movement, the constraints on the task and the state estimation. Todorov and Krakauer acknowledge that multiple operational time-scales complicate the process, including sensory delays, muscle fatigue, changing external environment, and cost-learning.
(2) Muscle Synergy Hypothesis:
This hypothesis proposes that the nervous system controls muscle synergies or groups of co-activated muscles, instead of individual muscles, in order to reduce the number of musculoskeletal DOFs upon which the nervous system operates. A 2007 study defined muscle synergy as “a vector specifying a pattern of relative muscle activation”, and proposed that, when they are absolutely activated, “a single neural command signal would modulate that muscle synergy”. It’s known that each synergy contains a multitude of muscles with fixed ratios of co-activation, and a multitude of synergies can contain the same muscle. Researchers suggest that muscle synergies emerge from interactions between constraints and properties of the nervous and musculoskeletal systems. This reduces the amount of computational effort exerted by the nervous system than individual muscle control because fewer synergies are required to explain a behaviour than individual muscles. Furthermore, J. Lucas McKay and Lena Ting suggested that synergies themselves may change as new behaviours are learned and/or optimised. Nevertheless, they may be innate to a certain extent, as suggested by postural responses of humans at very young ages.
A 2003 study pointed out that this hypothesis suggests synergies are low-dimensional, thus a few of them adequately account for a complex movement. Recent studies on frogs, cats, and humans used electromyography (EMG), and applied principal components analysis and non-negative matrix factorisation to "extract" synergies from muscle activation patterns. They uncovered similarities in synergy structure across different tasks such as kicking, jumping, swimming and walking in frogs. Moreover, studies on stroke patients observed less synergies in certain tasks, hence reduce motor performance. This adds plausibility to the muscle synergy hypothesis, suggesting robust formulation of a synergy lying at the lowest level of a hierarchical neural controller.
(3) Equilibrium Point Hypothesis & Threshold Control:
This hypothesis states that all movements are generated by the nervous system through a gradual transition of equilibrium points along a desired trajectory. A “equilibrium point” is defined as a field of zero force, when agonist-antagonist muscles are balanced against each other. Equilibrium point control is also called “threshold control” because CNS outputs to the periphery modulate the threshold length of each muscle. This suggests that motor neurons command peripheral muscles to change the force-length relationship within the muscle, which shifts the system's equilibrium point. A 1965 study proposed that the muscles and spinal reflexes are directly tasked to estimate limb dynamics, rather than the nervous system itself. A 2010 study argued that this hypothesis suited the design of biomechanical robots controlled by appropriated internal models.
(4) Force Control and Internal Models:
This hypothesis states that the nervous system calculates and direct specifies forces to determine movement trajectories and reduce DOFs. According to the theory, the nervous system forms internal models, which represent the body's dynamics in terms of the surrounding environment. This means the nervous system’s responsibility is to generate torques based on predicted kinematics, a process called inverse dynamics. In 2003, David Ostray suggested feed-forward (predictive) and feedback models of motion in the nervous system may play a role in this process.
(5) Uncontrolled Manifold (UCM) Hypothesis:
This hypothesis states that the nervous system controls particular variables relevant to performance of a task, while leaving other variables open to variance. The “uncontrolled manifold” is defined as the set of variables not affecting task performance, which controlled variables being perpendicular to this set in Jacobian space. e.g. In a sit-to-stand task, the head and centre-of-mass position in the horizontal plane are more tightly controlled than other variables such as hand motion. A 2010 study indicated that the quality of tongue's movements produced by bio-robots was practically didn’t correlate with the tongue’s stiffness, since it was controlled by a specially designed internal model. Therefore it claimed that quality of speech was a relevant parameter for speech production, rather than tongue stiffness. Furthermore, it found that strictly prescribing the stiffness’ level to the tongue's body affected speech production and generated variability, which doesn’t significantly contribute to quality of speech. A 1999 study explained that the UCM hypothesis is plausible in Bernsteinian terms because the nervous system can only control variables relevant to task performance, rather than individual muscles or joints.
What are the different types of motor coordination?
(i) Inter-Limb
This concerns how movements are coordinated across limbs. In 1985, J.A.Scott Kelso and co. proposed that coordination can be modelled as coupled oscillators using the HKB (Haken, Kelso and Bunz) model. Temporal coordination plays a key role in coordinating complex inter-limb tasks. e.g. The free pointing movement of the eyes, hands, and arms directing at the same motor target, where coordination signals transmit simultaneously to their effectors. Bimanual tasks (involving 2 hands) require synchronisation of the functional segments of both hands. A 2010 study postulated the existence of a higher, "coordinating schema” that calculates the time required to perform each individual task and coordinates it using a feedback mechanism. Several brain areas are observed to contribute to temporal coordination of the limbs required for bimanual tasks. They include the Premotor Cortex (PMC), the Parietal Cortex, the mesial motor cortices, the Supplementary Motor Area (SMA), the cingulate motor cortex (CMC), the Primary Motor Cortex (M1), and the Cerebellum.
(ii) Intra-Limb
This coordination plans trajectories in the Cartesian planes, which reduces computational load and the DOFs for a given movement. This constrains the limbs to act as one unit instead of sets of muscles and joints, similar to "muscle synergies" and "coordinative structures." For instance, the Hogan and Flash minimum-jerk model predicts the parameter controlled by the nervous system is the spatial path of the hand, i.e. the end-effector. This implies the movement being planned in the Cartesian coordinates. A 1983 study demonstrated that the end-effector followed a regularised kinematic pattern, which related movement's curvature to speed. It also showed the central nervous system’s devotion to its coding. A 2005 study proposed the joint-space model, which postulated the motor system planned movements in joint coordinates. It explained that the controlled parameter is the position of each joint contributing to the movement. The task that the subject is assigned can change the control strategies for goal directed movement. 2 different conditions were tested: (1) Subjects moved the cursor in their hand to the target, and (2) subjects moved their free hand to the target. Each condition yielded different trajectories: (1) straight path and (2) curved path.
(iii) Eye-Hand (Hand-eye)
https://en.wikipedia.org/wiki/Eye–hand_coordination
This type of coordination concerns eye movements coordinating with and influencing hand movements, as well as the visual input processing that guides the act of reaching and grasping along with proprioception of the hands to guide the eyes. Eye-hand coordination has been studied in many activities as diverse as moving solid objects such as wooden blocks, archery, sporting performance, music reading, computer gaming, copy-typing, and tea-making. Humans such as you and me rely on hand-eye coordination to perform everyday tasks. If you lack hand-eye coordination, you wouldn’t be able to carry out simple actions such as picking up a plate from the table or playing Mario Kart.
A 2009 study by Vidoni and co. noted that human gaze behaviour depends on the task being performed, and humans typically exhibited proactive control to guide their movement. A 2001 study found that humans fixate their eyes on a target before their hands are motivated to engage in a movement. This indicated that a human’s eyes provided spatial information for their hands. Moreover, the eyes appeared to be fixated onto a goal for a hand movement for a variable amount of time. Occasionally they remain fixated until completion of the task, and at other times, they scouted ahead toward other objects of interest before the hand was stimulated to grasp and manipulate the object.
Humans use eye-guided hand movements for core exercises, where their eyes generally direct the movement of the hands to targets. Their visual input includes initial information of the object, including its size, shape, and possibly grasping sites. Their brain processes this information to determine the force the fingertips need to exert to engage in a task. A 2009 study by Liesker and co. found that eye-gaze movement occurs in sequential tasks during important kinematic events such as changing the direction of a movement or when passing perceived landmarks. This correlates with the task-search-oriented nature of the eyes and its relationship with the movement planning of the hands. It also relates with the errors between motor signal output and consequences perceived by the eyes and other senses important for corrective movement. A 2009 study by Bowman and co. found that the eyes tend to “refixate” on a target to refresh the memory of its shape. In general, refixation updates our brain for changes in a target’s shape or geometry in drawing tasks involved in relating visual input and hand movement to produce a copy of the perceived stimulus. A 2009 study by Lazzari and co. discovered an increasingly linear relationship between planning time and movement execution in high accuracy tasks in response to vast amounts of visual stimuli.
A 2009 study by Ren and Crawford found that humans aimed their eye movement toward the hand without vision using proprioception, while minimising errors associating with eye movement toward the hand without vision. They demonstrated proprioception of limbs, in both active and passive movement, resulted in eye saccade overshoots when the hands are being used to guide eye movement. Further research is required to understand the cause of these hand-guided eye saccade overshoots.
What are the neural mechanisms of eye-hand coordination?
Its complexity is due to involvement of every part of the central nervous system involved in vision: eye movements, touch, and hand control. The neural control of eye-hand coordination includes the eyes, the cerebral cortex, subcortical structures (such as the cerebellum, basal ganglia, and brainstem), spinal cord, and the peripheral nervous system. Other areas involved in eye–hand coordination and control of eye saccades and hand-reach are the frontal and parietal cortex.
A 2008 fMRI study by Gomi suggested the Parieto Occipital Junction played a role in transforming peripheral visual input for reaching with the hands. It’s known this junction has subdivisions for reach, grasp, and saccades. A 2009 study by Jackson and co. suggested the Posterior Parietal Cortex was involved in relating proprioception and the transformation of motor sensory input to plan and control movement with regard to visual input. Many of these brain areas also demonstrate eye position signals for transforming visual signals into motor commands. Researchers have found the medial intraparietal cortex was responsible for gaze-centered remapping of responses during eye movements in both monkeys and humans. Nevertheless, when individual neurons were recorded in these areas involved in reach, they often showed some saccade-related responses and the saccade areas often show some reach related responses. Whilst there is plausible evidence of a relationship between reach and saccades, further research is required to fully understand this phenomenon.
What conditions can affect motor control?
https://en.wikipedia.org/wiki/Parkinson%27s_disease
https://www.youtube.com/watch?v=VIEUEV9wlyI
(A) Parkinson’s Disease (PD)
George H.W. Bush Senior (1924 - 2018), Muhammad Ali (1942 - 2016) and Mao Zedong (1893 - 1975) are amongst many famous people who passed away from Parkinson’s Disease. Famous people who have been diagnosed with Parkinson’s Disease include Billy Connolly, Neil Diamond, Michael J. Fox, Alan Alda, Linda Ronstadt, Michael Richard Clifford, Maurice Grant, James Levine, and Brian Grant. Since their official diagnosis, they all have kickstarted their respective awareness campaigns to inform the public about the deadliness of this disease. Charity fundraisers of PD foundations have also appeared to collect donations to fund research into curing this disease.
Parkinson’s Disease is a long-term degenerative disorder of the central nervous system that disrupts the motor system.
How is PD classified?
The movement difficulties observed in PD are called “parkinsonism”, which is also observed in other disorders. Parkinsonism is defined as bradykinesia combined with 1 of 3 other physical signs: Muscular (lead-pipe or cogwheel) rigidity, tremor at rest, and postural instability. PD is the most common form of “idiopathic parkinsonism”, which doesn’t have a known identifiable cause. Identifiable causes of parkinsonism include toxins, infections, side effects of drugs, metabolic derangement, and brain lesions such as strokes. Several neurodegenerative disorders also may present with “atypical parkinsonism” or “Parkinson plus” syndromes, which have some additional features that distinguish them from PD. Those disorders include Multiple System Palsy, Progressive Supranuclear Palsy, Corticobasal Degeneration, and Dementia with Lewy Bodies (DLB). Scientists occasionally refer to PD as a synucleiopathy because of abnormal accumulation of α-Synuclein protein in the brain, as a way to distinguish it from other neurodegenerative diseases, such as Alzheimer’s Disease. Dementia with Lewy bodies is another synucleinopathy that shares pathological similarities with PD, especially with the subset of PD cases with PD’s dementia. A 2009 study admitted the relationship between PD and DLB is complex and poorly understood. It may represent parts of a continuum with variable distinguishing clinical and pathological features or prove to be separate diseases.
How was PD discovered?
https://en.wikipedia.org/wiki/History_of_Parkinson%27s_disease
Parkinson’s Disease was named after British apothecary James Parkinson, when he published An Essay on the Shaking Palsy in 1817. Other scientists before had already described features of the disease that would bear his name, while knowledge of the disease and its treatments significantly improved in the 20th century. PD was then known as paralysis agitans, meaning ‘shaking palsy’. The term “Parkinson’s Disease” wasn’t coined until 1865 by William Sanders and later popularised by French neurologist Jean-Martin Charcot.
The first known sources of symptoms that resembled those of PD was around 12th century BC by an Egyptian papyrus, who mentioned a king drooling with age. The Bible contained a number of references to tremor. In 10th century BC, an Ayurvedic medical treatise described a disease that evolved with tremor, lack of movement, drooling and other symptoms that resembled PD. The first remedies of PD were derived from the mucuna family, which was rich in L-DOPA. Galen wrote about a disease that caused tremors only at rest, postural changes and paralysis. However, since the publication of Galen’s observations, the next known references unambiguously relating to PD would be published until the 17th and 18th centuries century when several authors wrote about elements of the disease. Like Galen, Franciscus Sylvius distinguished tremor at rest from other tremors, while Johannes Baptiste Sagar and Hieroymus David Gaubius described ‘festination', which was a term for the characteristic gait of PD. John Hunter’s thorough description of the disease may have provided Parkinson the idea of collecting and describing patients with "paralysis agitans”. Finally, Auguste François Chomel’s pathology treatise included several descriptions of abnormal movements and rigidity matching those seen in PD.
Neurologists like Trosseau, Gowers, Kinnier, Wilson, Erb and Charcot made further additions to the knowledge of the disease with their respective studies between 1868 and 1881. Among other advances, Charcot made the distinction between rigidity, weakness and bradykinesia. Furthermore he championed the renaming of the disease in honour of Parkinson.
In 1897, Édouard Brissaud proposed the first theory on the anatomical substrate of PD, suggesting it originated in the Subthalamus Nuclei or Cerebral Peduncle caused by an ischaemic lesion. In 1912, Frederic Lewy described a pathologic finding in affected brains, which was later named “Lewy Bodies”. In 1919, Konstantin Tretiakoff was the first to recognise the Substantia Nigra was the main cerebral structure affected. However, it wasn’t widely accepted until further studies published by Hassler in 1983 confirmed Tretiakoff’s finding. During the 1950s, Arvid Carlsson’s work on Dopamine and Oleh Hornykiewicz’s work on the role of PD advanced progress on the underlying chemical changes in the brain. This led to Carlsson winning a Nobel Prize.
In the early 1990s, the neurology clinic at Robert Wood Johnson Medical School (RWJMS) somehow located an Italian family that encompassed at least 5 generations of more than 400 individuals and at least 60 members with PD, and traced their ancestors to the small village of Contursi, Italy. In 1995, the RWJMS team joined with the National Centre for Human Genome Research at the National Institutes of Health to take advantage of the laboratory resources available from the NIH in an effort to locate the gene causing PD in the Contursi family. In 1996, the team found the first Parkinson disease-causing mutation (PARK1) in the brain protein, α-synuclein. Within days of the PARK1 discovery, α-synuclein was discovered to be the major component of Lewy bodies within brain cells of PD patients. In 1998, mutations in the Parkin gene in autosomal recessive juvenile parkinsonism were discovered. Between 2002 and 2005, DJ-1 gene mutations, PINK1 and LRRK2 gene mutations were identified in Japanese and European families. In 2003, Heiko Braak described the pathological staging in PD.
During the 19th century, Charcot, Erb and others described the positive albeit modest effects on tremor of anticholinergic alkaloids obtained from the plant of the belladona. In 1939, the first trials of modern surgery for tremor consisted of the lesioning of some of the basal ganglia structures, which improved over the next 20 years. However this surgery lesioned the corticospinal pathway with paralysis rather than cause tremor. At the time, anticholinergics and surgery were the only treatments until development of Levodopa. In 1911, Casimir Frank synthesised the first administrations of Levodopa, but it wasn’t recognised as an effective treatment until the mid 20th century. It wasn’t until 1967 that Levodopa entered clinical practice, and in 1968, it was reported to improve the symptoms of PD patients, which revolutionised the management of PD. By the late 1980s, Deep Brain Stimulation (DBS) was introduced by Alim-Louis Benabid and co. at Grenoble, France, as a possible treatment and it was approved for clinical use by the FDA in 1997.
What are the signs and symptoms of PD?
https://en.wikipedia.org/wiki/Signs_and_symptoms_of_Parkinson%27s_disease
It’s known that Parkinson’s Disease affects movement, hence produces motor symptoms. It also causes non-motor symptoms such as dysautonomia, cognitive neurobehavioral problems, and sensory and sleep difficulties.
(i) Motor symptoms
There are 4 cardinal symptoms in PD: slowness of movement (bradykinesia), tremor, rigidity, and postural instability. Typical PD patients initially display asymmetric distribution of cardinal symptoms, but as the disease worsens, it gradually progresses to show bilateral symptoms. Other motor symptoms include gait and posture disturbances such as decreased arm swing, a forward-flexed posture, using small steps when walking, speech and swallowing disturbances, and a mask-like facial expression or small handwriting.
Parkinsonism:
— Tremor = Although 30% of PD patients don’t have tremor at disease onset, a majority develop it as the disease progresses. Usually, it is initially a rest tremor, meaning it occurs when limb is at rest and disappears when the patient voluntarily moves and sleeps. Tremor is most apparent at the most distal part of the limb, typically appearing in only a single arm or leg at onset. This becomes bilateral during the progressive course of the disease. The frequency of PD tremor is between 4 and 6 Hertz (cycles per second). This pronation-supination tremor is often described as “pill-rolling” because the index finger contacts the thumb to perform a circular movement.
— Rigidity = This symptom is characterised by increased muscle tone, producing stiffness and resistance to movement in joints. It associates with joint pain during the initial stages of the disease. When the limbs of a PD patient are passively moved by others, a “cogwheel rigidity” is commonly seen. Cogwheel-like or ratchety jerks occur due to moving articulation as opposed to the normal fluid movement. When a muscle is externally forced to move, it initially resists, but adequate force can partially move the muscle until it resists again, and only with further force, can it be moved again. Tremor and increased tone combined is considered to cause cogwheel rigidity.
— Bradykinesia & Akinesia = Bradykinesia is defined as slowness of movement, while akinesia is defined as absence of movement. It associates with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement. In the early stages of PD, bradykinesia is the most disabling symptom that causes problems when performing daily life tasks regulated by fine motor control such as writing, sewing, or getting dressed. Bradykinesia isn’t equal for all movements or times because it is modified by the activity or emotional state of the subject to point where patients struggle to walk but easily ride bike. Generally, patients have less difficulties during provision of an external cue. A 2008 study by Jankovic observed that excited immobile patients are capable of making quick movements such as catching a ball (or instinctively sprint at the scream of “fire”). This phenomenon, known as kinesia paradoxica, suggests that PD patients have intact motor programmes, but have difficulties accessing them in the absence of an external trigger, such as a loud noise, marching music, or a visual cue that requires them to avoid an obstacle.
— Postural Instability = This symptom is observed during the late stages of PD, leading to impaired balance and frequent falls, as well as bone fractures. Up to 40% of patients experience falls and around 10% fall on a weekly basis, with the number of falls correlating to the severity of PD. It is caused by a failure of postural reflexes, along with other disease-related factors such as orthostatic hypotension or cognitive and sensory changes.
Gait & Posture Disturbances:
— Shuffling Gait = Short steps with feet barely leaving the ground, making patients easier to trip over small obstacles.
— Decreasing Arm Swing
— Turning ‘en bloc = Rigid necks and trunks, which requires multiple small steps to accomplish a turn.
— Camptocormia = Stooped, forward-flexed posture. People with severe PD have their head and upper shoulders bent perpendicularly relative to their trunk.
— Festination = A combination of stooped posture, imbalance, and short steps. This leads to a progressively faster gait, often resulting in falls.
— Gait Freezing = Also called motor blocks, it is a manifestation of akinesia. Gait freezing is characterised by the sudden inability to move the lower extremities which usually lasts less than 10 seconds. It worsens in tight, cluttered spaces while attempting to initiate gait or turning around, or approaching a destination. Appropriate treatment and behavioural techniques such as marching to command or following a given rhythm improves this symptom.
— Dystonia = Abnormal l, sustained, painful twisting muscle contractions that often affect the foot and ankle (mainly toe flexion and foot inversion), which often interferes with gait.
— Scoliosis = Abnormal curvature of the spine
Speech & Swallowing Disturbances:
— Hypophonia = Soft Speech
— Monotonic Speech = Sound quality is soft, hoarse, and monotonous
— Festinating Speech = Excessively rapid, soft, poorly intelligible speech
— Drooling = Caused by weak, infrequent swallowing
— Dysphagia = Impaired swallowing in relation to inability in initiating the swallowing reflex or by longer laryngeal or oesophageal movement. This can lead to aspiration pneumonia.
— Dysarthria = A form of speech disorder
Other:
— Fatigue
— Hypomimia = Mask-like face
— Difficulty rolling in bed or rising from a seated position
— Micrographia = Small, cramped handwriting
— Impaired fine-motor dexterity and motor coordination
— Impaired gross-motor coordination
— Akathisia = An unpleasant desire to move, often related to medication
— Re-emergence of primitive reflexes
— Glabellar Reflex
(ii) Neuropsychiatric symptoms
Neuropsychiatric disturbances caused by PD includes cognition, mood, and behaviour problems, which can be as disabling as motor symptoms. In most cases, cognitive disturbances (such as dementia) emerge later stages of the disease progression. A 2017 study uses the ‘1-year rule’ in terms of the onset of parkinsonism in PD relative to dementia as an arbitrary criterion to clinically distinguish Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). Dementia onset within 12-months of or at the same time as motor dysfunctions are qualified as DLB, whereas in PDD, parkinsonism had to precede dementia by at least 1 year.
A 2007 study found that some PD cases apparently had cognitive disturbances arise in the initial stages of the disease. Nevertheless, a substantial proportion of patients suffer from mild cognitive impairment as the disease advances. The most common deficits in non-demented patients include:
— Executive Dysfunction = Impaired set shifting, poor problem solving, and fluctuations in attention among other difficulties
— Bradyphrenia = Slowed cognitive speed
— Memory problems = Difficulty in recalling learned information. However, recognition is less impaired than free recall, which points towards a retrieving problem more than to an encoding problem.
— Problems in verbal fluency tests
— Visuospatial skills difficulties = Inability to recognise faces and perceive line orientation
Deficits tend to aggravate with time, developing in many cases into dementia. PD patients increase their risk of dementia 6-fold, and the overall rate in sufferers is approximately 30%. Moreover, prevalence of dementia increases in relation to disease duration, which increases to about 80%. Having dementia reduces quality of life in disease sufferers and caregivers, increases mortality, and increases probability of moving to a nursing home. Cognitive manifestations and dementia are usually accompanied by behaviour and mood alterations. The most frequent mood difficulties include:
— Depression (~ 58%) = This symptom was originally recognised as "melancholia" by James Parkinson in his 1817 essay. A 2008 study’s estimates of the prevalence rates of depression in PD patients varied widely according to the population sampled and methodology used. Nevertheless, PD patients increase their risk of depression later in the disease course. Recent studies suggest that depression occurs consequently rather than an emotional reaction to disability.
— Apathy (~ 54%)
— Anxiety (~ 49%) = About 70% of PD patients diagnosed with pre-existing depression would progress to develop anxiety. About 90% of PD patients with pre-existing anxiety subsequently develop depression, apathy, or abulia.
PD patients may also demonstrate:
— Obsessive-compulsive behaviours such as craving, binge eating, hypersexuality, pathological gambling, punding, or others. This correlates with Dopamine dysregulation syndrome associating with PD medications.
— Psychotic symptoms generally associates with Dopamine therapy.
— Psychosis, or impaired reality testing are either hallucinations, which are typically visual, but less commonly auditory, tactile, gustatory, or olfactory, or delusions (irrational beliefs).
— In the initial stages, patients usually have insight so that their hallucinations are benign, but have poor prognostic implications. Hallucinations are often stereotyped without containing emotional content. Combined with increased risk of dementia, this worsens psychotic symptoms, and mortality. A 2010 study found about 5-10% of treated PD patients suffer from delusions, which are considerably more disruptive in terms of paranoia, of spousal infidelity or family abandonment. Psychosis is regarded as an independent risk factor for nursing-home placement.
Hallucinations can occur in parkinsonian syndromes for a variety of reasons. Firstly, they may result from overlapping symptoms between PD and dementia with Lewy bodies, where Lewy Bodies are present in the visual cortex. Secondly, they may be brought about by excessive dopaminergic stimulation. Although most hallucinations are visual, often involving familiar people or animals, and non-threatening in nature, which comforts some patients, their caregivers beg to differ. They often view this symptom quite disturbing, and their occurrence is a major risk factor for hospitalisation. Treatment options consist of modifying the dosage of dopaminergic drugs administered daily by adding an antipsychotic drug such as Quetiapine, or offering caregivers a psychosocial intervention to help them cope with the hallucinations.
(iii) Sleep Problems
PD medications worsens sleep problems, despite being a core feature of the disease. Common symptoms include:
— Excessive daytime somnolence
— Insomnia = This is characterised by sleep fragmentation
— Disturbances in Rapid Eye Movement (REM) sleep = This involves disturbingly vivid dreams, and REM behaviour disorder, which is characterised by acting out of dream content. This symptom appears in 1/3 of patients and is regarded as a risk factor for PD in the overall population.
(iv) Impaired Perception
— Impaired proprioception = Lack of awareness of bodily position in 3D space
— Hyposmia or Anosmia = Reduction or loss of sense of smell
— Paresthesias
(v) Autonomic Problems
— Orthostatic hypotension = This leads to dizziness and fainting
— Oily skin
— Urinary incontinence & Nocturia (Waking up in the night to urinate)
— Altered sexual function = Profound impairment of sexual arousal, behaviour, orgasm, and drive.
— Excessive sweating
(vi) Gastrointestinal Symptoms
— Constipation and Gastric Dysmotility = This is due to the appearance of Lewy bodies and Lewy neurites in the neurons that control gut functions before these disrupting the function of the Substantia Nigra.
(vii) Neuro-ophthalmological symptoms
— Decreased blink rate
— Irritation of the eye surface
— Alteration in the tear film
— Visual hallucinations
— Decreased eye convergence
— Blepharospasm
— Abnormalities in ocular pursuit, ocular fixation and saccadic movements
— Difficulties opening the eyelids = PD sufferers driving on the road are less accurate in spotting landmarks and roadsigns.
— Limitations in the upward gaze
— Blurred vision
— Diplopia (double vision) = This is caused by a reduced eye convergence
What are the causes of PD?
https://en.wikipedia.org/wiki/Causes_of_Parkinson%27s_disease
Most PD cases are idiopathic, meaning they don’t have a specific known cause. A minority of cases attribute to known genetic cases. Other factors such as environmental toxins, herbicides, pesticides, and fungicides, have been associated with the risk of developing PD, but no causal relationships have been proven.
(a) Genetic Factors
Around 15% of individuals with PD have a 1st-degree relative who contracted the disease. A 2009 study found at least 5% -15% of cases are known to occur because of a mutation in one of several specific genes, transmitted in either an autosomal dominant or recessive pattern. Modern studies identified genes implicated in autosomal-dominant PD include PARK1 and PARK4, PARK5, PARK8, PARK11 and GIGYF2 and PARK13, which code for α-synuclein (SNCA), UCHL1, leucine-rich repeat kinase 2 (LRRK2 or Dardarin), LRRK2 and Htra2 respectively. Other studies suggest other genes such as PARK2, PARK6, PARK7 and PARK9 which code for Parkin (PRKN), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2 respectively play a role in the development of autosomal-recessive PD. Another study identified mutations in additional genes that code for SNCA, LRRK2 and Glucocerebrosidase (GBA) as potential risk factors for sporadic PD. A 2008 study concluded that all genes except for LRRK2 account for only a small minority of cases of PD.
— SNCA (α-synuclein) = α-Synuclein is the main component of Lewy Bodies, and it is a biomarker in PD. Missense mutations of the gene, as well as duplications and triplications of the locus containing it have been detected in different groups with familial PD. Recent studies discovered a correlation between α-Synuclein expression levels and disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication. Although missense mutations in SNCA are rare, multiplications of the SNCA locus account for around 2% of familial cases. A 2009 study found SNCA gene multiplications in asymptomatic carriers, which indicates its incomplete or age-dependent penetrance.
— LRRK2 = Also known leucine-rich repeat kinase 2 or PARK8, this gene encodes for a protein called Dardarin. The name ‘dardarin’ derives from a Basque word for ‘tremor’, as the gene was first identified in families from England and the north of Spain. A 2002 study found that mutations in LRRK2 gene mostly cause familial and sporadic PD, which accounts for about 5% of individuals with a family history of PD and 3% of sporadic cases. However unequivocal proof of causation only exists for a small number of mutations currently identified. A 2011 study by Dawson and co. suggested mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, which is an aspect of both idiopathic and genetic PD. A 2011 study by Chen-Plotkin and co. discovered mutations in the progranulin gene causes corticobasal degeneration seen in dementia, which may have relevance in PD cases.
— GBA = Mutations is the GBA gene are known cause Gaucher’s Disease. A 2011 genome-wide association study by Nalls and co. successfully identified mutated alleles with low penetrance in sporadic cases. However, a 2012 study concluded that Mendelian genetics aren’t strictly observed in GBA mutations found in inherited parkinsonism. Incidentally, it proposed both both gain-of-function and loss-of-function GBA mutations contribute to parkinsonism through effects such as increased α-synuclein levels. In PD patients, the odds ratio (OR) for carrying a GBA mutation was 5·43 (95% CI 3·89–7·57), which confirmed that GBA mutations are a common risk factor for PD.
Below is a summarised table of genes underlying familial Parkinson’s Disease:
A 2014 study by Goldman suggested exposure to pesticides, metals, solvents, and other toxicants lead to development of PD. However, there hasn’t been any definitive causal relationship being established yet. Recent studies revealed individuals sustaining head injuries (concussions) increased their risk of acquiring PD.
— Pesticides = There is evidence from recent epidemiological, animal, and in vitro studies to suggest that exposure to pesticides increases the risk of PD. A 2012 meta-analysis discovered a risk ratio of 1.6 for exposure to a pesticide, with herbicides and insecticides displaying the highest risk. They also found rural living, well-drinking, and farming associated with PD risk, which partly explains exposure to pesticide. Several studies reported Organochlorine pesticides (including DTT) doubles the risk of PD.
— Metals = In certain countries, lead (Pb) was found in gasoline until 1995 and paint until 1978. It’s known exposure to Pb damages the nervous system in various ways. Studies revealed that people with elevated Pb levels doubled their risk of PD. However, epidemiological studies on Pd reputed this claim after failing to found much evidence on this correlation. Other studies suggested Iron (Fe) being responsible for the aetiology of PD, but there is no concrete evidence that environmental exposure to it is associated with PD.
— Head Injuries = A 2018 study suggested that mild head injuries or concussions can increase the veteran’s risk of PD later on in their lives. This relates to similar concussions suffered by many American athletes on the sports field or drivers in a motor vehicle crash every year. A 2012 study suggested NFL players have a 3-fold increase risk of Alzheimer’s and Parkinson’s Disease.
— Exercise = This factor is considered the main protections against neurodegenerative disorders including PD. A 2013 study categorised different types of exercise interventions as either aerobic or goal-based. Since aerobic exercise includes physical activity that increases heart rate, it provides benefits to the brain through biochemical mechanisms that promote neuroplasticity, or rewiring of the brain circuitry. On the other hand, goal-based exercises are often developed with a physical therapist’s guidance to use movement to achieve improvements in motor task performance and motor learning. A 2008 study admitted that while exercise consistently yielded health benefits, it noted that further research is required to understand the optimal interventional benefit.
— Caffeine Consumption = A 2012 study by Tsuboi randomised people into groups of individuals (smokers and nonsmokers) in terms of rates of caffeine consumption, and then monitored their susceptibility to PD. The results of this study indicated that higher coffee/caffeine intake is associated with a significantly lower incidence of PD, independent of smoking.
(c) Other factors
— Polymorphism of CYP2D6 gene = The CYP2D6 gene is primarily expressed in the liver and is responsible for the enzyme cytochrome P450 2D6. Studies in 2004 and 2012 found that mutations in this gene combined with pesticide exposure increased the likelihood of developing PD 2-fold. Furthermore, those with the CYP2D6 mutation but avoided pesticides didn’t have risk of developing PD increased. It’s believed that pesticides elicited a “modest effect” on those who lack the mutation.
What is the pathophysiology of PD?
https://en.wikipedia.org/wiki/Pathophysiology_of_Parkinson%27s_disease
PD elicits changes in the neurobiological activity that kills the dopaminergic neurons in the Substantia Nigra as a result. Several mechanisms are neuronal death in PD have been proposed but not many of them are well understood. 5 proposed major mechanisms for neuronal death in Parkinson's Disease include:
(1) Protein Aggregation = Also known as bundling, or oligomerisation of proteins, the increased presence of α-synuclein in the brains of PD patients is insoluble that it aggregates to form Lewy Bodies (LBs) in neurons. A 2009 suggested that LBs lead to other effects that cause cell death. Regardless, LBs are widely recognised as a pathological marker of PD. LBs initially appear in the Olfactory Bulb, Medulla Oblongata, and Pontine Tegmentum, but patients are asymptomatic. As the disease progresses, they develop in the Substantia Nigra, areas of the midbrain and basal forebrain, and in the neocortex. A 2012 study by Stefanis substantiates this mechanism as α-synuclein lacks toxicity when they are unable to oligomerise. Since heat-shock proteins (HSPs) assist in refolding proteins susceptible to aggregation, they beneficially affect PD when overexpressed. This means reagents responsible for neutralising aggregated species protect neurons in cellular models of α-synuclein overexpression.
(2) Autophagy Disruption = This mechanism involves inner components of a cell disintegrating and recycled for further use. Studies in 2008 and 2008 demonstrated that autophagy plays a key role in brain health, which helps regulate cellular function. If the autophagy mechanism is disrupted, this leads to several different types of diseases like PD. In neurodegenerative diseases, autophagy doesn’t disintegrate oligomers quickly enough to clear the aggregated protein and maintain regular cell function. Failure to clear protein bundles or other harmful molecules, cells could begin to alter their function and eventually undergo cell death. In PD, autophagy dysfunction is shown to cause dysregulated mitochondria degradation.
(3) Changes in Cell Metabolism
= This mechanism involves the energy-generating organelle, or the powerhouse of the cell, mitochondria. Recent studies found that mitochondrial function is disrupted in PD patients, which inhibits energy production and resulting in cell death. Several studies in recent years hypothesised that mitochondrial dysfunction in PD associates with the PINK1 and Parkin complex, which is demonstrated to stimulate autophagy of mitochondria (also known as mitophagy. PINK1 is a protein that normally transports into a functional mitochondria, but it accumulates on the surface of impaired mitochondria. Accumulated PINK1 then recruits Parkin, which initiates the breakdown of dysfunctional mitochondria. According to a 2009 study, this mechanism acts as “quality control”. In PD, the genes encoding PINK1 and Parkin proteins are believed to be mutated, therefore preventing the breakdown of impaired mitochondria, causing abnormal function and morphology of mitochondria and eventually cell death. A 2006 study found that mitochondrial DNA (mtDNA) mutations accumulate with age, which indicates the susceptibility to this mechanism of neuronal death increasing with age. Another mitochondrial-related mechanism for cell death in PD is the production of Reactive Oxygen Species (ROS). ROS are highly reactive molecules that contain oxygen, which disrupts functions within the mitochondria and the rest of the cell. As humans age, their mitochondria lose its ability to remove ROS yet still maintain their production of ROS. This leads to increases in net production of ROS and eventually cell death. A 2017 study by Puspita et al. demonstrated that the Mitochondria, the Endoplasmic Reticulum, α-synuclein, and Dopamine levels all contribute to oxidative stress and PD symptoms. Oxidative stress may play a role in mediating separate pathological events that together ultimately result in cell death in PD, which may be the common denominator underlying multiple processes. Oxidative stress also causes oxidative DNA damage that accumulates in the mitochondria of the Substantia Nigra of PD patients, which leads to nigral neuronal cell death.
(4) Neuroinflammation
One major cell type involved in neuroinflammation is Microglia, which are recognised as the Innate Immune cells of the CNS. Normally, microglia actively scour their environment and alter their cell morphology significantly in response to neural injury. Rapid activation of microglia causes acute inflammation in the brain. Over time, this progresses to chronic inflammation causing the degradation of tissue and of the blood–brain barrier. This is when microglia generate ROS and release signals to recruit peripheral immune cells for an inflammatory response. In addition, microglia have 2 major states:
— M1 = Microglia are activated and secrete pro-inflammatory factors
— M2 = Microglia are deactivated (at rest) and secrete anti-inflammatory factors.
In normal humans, microglia are usually in M2 state, but in PD patients, they can transition to M1 due to the presence of α-synuclein aggregates. The pro-inflammatory factors M1 Microglia secrete can kill motor neurons. Therefore, those dying neurons releases factors that increase the activation of M1 microglia, which leads to a positive feedback loop accelerating neuronal cell death.
(5) Blood-Brain Barrier (BBB) Breakdown
The BBB is made up of 3 cell types that tightly regulate the flow of molecules in and out of the brain, which are Endothelial Cells, Pericytes, and Astrocytes. In a 2011 study, BBB breakdown has been identified in the Substantia Nigra in PD. Protein aggregates or cytokines from neuroinflammation may interfere with cell receptors and alter their function in the BBB. A 2013 study noted that Vascular Endothelial Growth Factor (VEGF) and VEGF factors are dysregulated in PD. When VEGF binds to its receptor, it normally leads to cell proliferation, but this process is disrupted in PD. Hence, it halts cellular growth and prevents new capillaries formation via angiogenesis. A 2008 study found cell receptor disruption disrupts the cell’s ability to adhere to one another with adherens junctions.
The Substantia Nigra has an abundance of dopaminergic neurons that helps regulate motor control and learning. Dopamine also activates motor neurons in the CNS. When motor neurons are activated, they transmit action potentials to motor neurons in human legs. In PD patients, about 50-60% of motor neurons have degenerated, which decreases Dopamine levels by up to 80%. This inhibits the ability ability for neurons to generate and transmit a signal, which ultimately causes the characteristic Parkinsonism gait with symptoms such as hunched and slowed walking or tremors.
How is PD diagnosed?
To assess for PD, physicians initially check your medical history and conduct a neurological examination. They administer small Levodopa doses, and any resulting improvement in motor impairment confirms the PD diagnosis. If autopsies discover Lewy Bodies in neurons of the midbrain, this is usually removes all doubt that the patient has PD. The clinical course of the illness over time may not reveal the classic symptoms of PD, therefore it requires periodical review of the clinical presentation to confirm accuracy of the diagnosis. A 2006 study found that stroke and narcotics can secondarily produce parkinsonism. It’s important to rule out Parkinson plus syndromes such as Progressive Supranuclear Palsy and Multiple System Atrophy, as anti-Parkinson’s medications are typically less effective at controlling symptoms in those syndromes. A 2002 study found that faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself. A 2004 study refer genetic forms with an autosomal dominant or recessive pattern of inheritance as familial Parkinson's disease or familial parkinsonism.
Medical organisations created diagnostic criteria to ease and standardise the diagnostic process, especially in the early stages of the disease. A few widely known organisations are the UK Queen Square Brain Bank for Neurological Disorders and the U.S. National Institute of Neurological Disorders and Stroke. The Queen Square Brain Bank criteria requires slowness of movement (bradykinesia) as well as either rigidity, resting tremor, or postural instability, though other possible causes of these symptoms must be ruled out. Finally 3+ of the following supportive features are required during onset or evolution:
— Unilateral onset
— Tremor at rest
— Progression in time
— Asymmetry of motor symptoms
— Response to Levodopa for at least 5 years
— Clinical course of at least 10 years
— Appearance of dyskinesis induced by the intake of excessive Levodopa
A 2016 meta-analysis and systematic review reported an overall high accuracy in 80.6% of PD diagnoses and 82.7% of diagnoses using the Brain Bank criteria.
A 2010 study reported that computed tomography (CT) scans of PD patients usually appeared normal, but MRI increases its accuracy over time. MRI with either iron-sensitive T2* or SWI sequences at a magnetic field strength of at least 3T can eliminate the characteristic 'swallow tail' imaging pattern in the dorsolateral Substantia Nigra, with 98% sensitivity and 95% specificity for PD. Diffusion MRI demonstrate its ability to distinguish PD and Parkinson plus syndromes, though a 2010 study is still investigating its diagnostic value. Physicians use both CT and MRI to rule out other diseases that are secondary causes of parkinsonism, such as encephalitis and chronic ischaemic insults, as well as infrequent entities such as basal ganglia tumours and hydrocephalus. PET and SPECT scans are used to directly measure Dopamine-related activity in the Basal Ganglia in order to rule out drug-induced parkinsonism. However, this activity is observed in both PD and Parkinson-plus disorders, which makes these scans unreliable.
How do you manage PD?
https://en.wikipedia.org/wiki/Management_of_Parkinson%27s_disease
So far there is no cure for Parkinson’s Disease, therefore it requires a broad-based program including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. Only certain medications or surgery provides relief from the symptoms. The main families of drugs prescribed by physicians to treat motor symptoms are Levodopa, Dopamine agonists and MAO-B inhibitors.
What are the current treatments of PD?
1. Medications
(a) Levodopa (L-DOPA)
According to a 2006 study, L-DOPA converts into Dopamine in the dopaminergic neurons by Dopa-Decarboxylase. Since motor symptoms are produced by low Dopamine levels in the Substantia Nigra, administering L-DOPA temporarily diminishes the motor symptomatology. Only 5-10% of L-DOPA is also to cross the blood-brain barrier, whilst 90-95% is often metabolised to Dopamine elsewhere. This stimulates a wide variety of side effects including nausea, dyskinesias, and stiffness.
— Carbidopa and Benserazide are peripheral Dopa Decarboxylase Inhibitors that inhibit the metabolism of L-DOPA in the periphery, thereby increasing L-DOPA delivery to the CNS. Therefore, they are often prepared to be combined with L-DOPA. Existing Carbidopa / Levodopa drugs are Co-careldopa with trade names Sinemet, Pharmacopa, Atamet), and existing Benserazide / Levodopa drugs are Co-careldopa with trade name Madopar. A 2009 study noted that compulsive Levodopa overdoses and punding associates with Dopamine dysregulation syndrome.
— Tolcapone inhibits the Catechol-O-MethylTransferase (COMT) enzyme, which normally degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa. Therefore, it often accompanies other peripheral dopa decarboxylase inhibitors to complement L-DOPA. However, due to its possible side effects such as liver failure, it is limited in its availability.
— Entacapone is similar to Tolcapone, but it doesn’t significantly alter liver function and is able to maintain adequate inhibition of COMT over time. It is available for treatment alone (COMTan) or combined with Carbidopa and L-DOPA (Stalevo).
(b) Dopamine Agonists
They bind to dopaminergic postsynaptic receptors to elicit a biochemical effect similar to L-DOPA. They are often administered on their own as an initial therapy for motor symptoms to delay motor complications. They help reduce the off-periods in the late stages of PD. Examples include Bromocriptine, Pergolide, Pramipexole, Ropinirole, Piribedil, Cabergoline, Apomorphine, and Lisuride. Dopamine Agonists produce significant side effects including somnolence, hallucinations, insomnia, nausea, and constipation. They occasionally appear at the minimal clinically efficacious dose, which forces the physician to alter the agonist or drug being administered. While they delay motor complications, it also controls worse symptoms. Nevertheless, they are adequately effective to manage symptoms in the initial stages of the disease. Dyskinesias with Dopamine agonists are rare in younger patients, but more common in older patients along with other side effects. A 2004 study found that patients preferred Dopamine agonists as the initial treatment. However, it’s important to note that higher doses of these agonists can lead to a wide variety of impulse-control disorders.
(c) MAO-B Inhibitors
They increase the level of dopamine in the basal ganglia by blocking its metabolisation by an enzyme called Monoamine Oxidase (MAO). For instance, Selegiline and Rasagiline inhibit Monoamine Oxidase-B (MAO-B), which normally disintegrates Dopamine secreted by the dopaminergic neurons. This results in higher levels of L-DOPA in the striatum. They improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the initial stages of the disease. However, they produce more adverse effects and are less effective than L-DOPA. Although they are useful in reducing fluctuations between on and off periods, there are less efficacious in the advanced stages of the disease. Metabolites of Selegiline include L-amphetamine and L-methamphetamine could result side effects such as insomnia, as well as stomatitis.
(d) Other drugs
There is evidence to indicate that other drugs such as Amantadine and Anticholinergics are useful in treating motor symptoms of early and late-stage PD, but they mustn’t be viewed as first-choice treatments.
— Clozapine (Clozaril) is used for psychosis. A 2009 study concluded this drug has the highest efficacy and lowest risk of extrapyramidal side effect.
— Cholineresterase Inhibitors is used for dementia.
— Modafinil is used for day somnolence.
— Atomoxetine is used for executive dysfunction.
— Donepezil (Aricept) may help prevent falls in people with Parkinson’s, because it increases levels of Acetylcholine.
— Atypical antipsychotics such as Quetiapine (Seroquel), Ziprasidone (Geodon), Aripiprazole (Abilify), and Paliperidone (Invega) are used to treat psychotic symptoms.
2. Surgery:
Since the discovery of L-DOPA, treating PD with surgery was restricted to only a few cases. Surgery is only used for patients with advanced PD when drug therapy is insufficient in treating the symptoms. This means less than 10% of PD sufferers qualify as suitable candidates for a surgical response. There are 3 different mechanisms of surgical response for PD:
(e) Neuroablative Lesion Surgery
This technique uses heat to locate and destroy brain regions responsible for producting Parkinsonian neurological symptoms. The procedures generally involves a thalamotomy and/or pallidotomy. A thalamotomy destroys parts of the Thalamus, particularly the Ventralis Intermedius, to suppress tremor in 80-90% of patients. If rigidity and akinesia are apparent, the Subthalamis Nucleus becomes the site of ablation. A pallidotomy destroys the Globus Pallidus (interna) in patients with PD who suffer from rigidity and akinesia.
(f) Deep Brain Stimulation (DBS)
DBS is presently the preferred method of surgical treatment because it does not destroy brain tissue, its effects are reversible, and it tailors to individuals at their particular stage of disease. DBS employs 3 hardware components:
— Neurostimulator = Also known as an implanted pulse generator (IPG), it generates electrical impulses used to modulate neural activity. It is powered by a battery and encased in titanium. It is usually implanted under the patient’s collarbone, and connects to the lead by the subcutaneous extension. This extends from outside the skull under the scalp down into the brain to the target of stimulation.
— Lead wire = This directs impulses to a number of metallic electrodes towards the tip of the lead near the stimulation target
— Extension wire = This connects the lead wire to the IPG.
The preoperative targeting of proper implantation sites can be accomplished using either the indirect and direct methods.
I. Indirect: This method uses computer tomography (CT), magnetic resonance imaging (MRI), or ventriculography to locate the anterior and posterior commissures. Then it employs predetermined coordinates and distances from the intercommissural line to define the target area. Subsequent histologically defined atlas maps can also be used to verify the target area.
II. Direct: This method applies stereotactic preoperative MRI to help visualise and target deep nuclei. It takes the anatomic variation of the nuclei’s size, position, and functional segregation into account.
In both methods, electrophysial functional mapping is used to verify the target nuclei but it increases the risks of haemorrhages, dysarthria or tetanic contractions. A 2012 study discovered a MRI type called susceptibility-weighted imaging can effectively distinguish between different deep brain nuclei. A 2010 study recommended DBS to PD patients without important neuropsychiatric contraindications who suffer motor fluctuations and tremor badly controlled by medication, or to those who are intolerant to medication. Furthermore, to support their recommendation, they found its effectiveness in suppressing symptoms of PD, especially tremor.
3. Diet:
https://en.wikipedia.org/wiki/Dietary_management_of_Parkinson%27s_disease
A 1981 study suggested antioxidants as a dietary prevention strategy preventing PD because they scavenge free radicals such as reactive Nitrogen and Oxygen, preventing their build-up and limiting the destruction of dopamine-producing neurons. A 2001 study suggested a Mediterranean-like diet consisting of many food containing antioxidants such as complex phenols, vitamins C and E, and carotenoids. A typical Mediterranean diet consists of a high intake of vegetables, legumes, fruits, and cereals, olive oil (unsaturated fatty acids), and fish, and low to moderate intake of animal foods such as dairy, meats, poultry. Recent studies suggested that diets rich in dairy products increased the likelihood of developing PD. Additionally, a 1996 study suggested intake of animal fats may associated with development of PD. A 2007 study suggested diets resulting in high plasma urate decreases the risk of developing PD due to urate’s ability to reduce oxidative stresses by scavenging Peroxynitrite and Hydroxyl radicals.
A 1996 study suggested no special diet is required for subjects with PD, but instead a well balanced diet because of the increased energy and improved effectiveness of drugs it elicits. Since many patients express energy decrease, it’s recommended to consume smaller meals. A example balanced diet includes high fibre foods (such as vegetables, dried peas, beans, whole grain foods, pasta, rice, and fresh fruit). It helps reduce constipation, low saturated fats and cholesterol, low sugar and salt intake, plenty of water, and limited alcohol intake.
A diet low in excessive protein is recommended since L-DOPA competes with these dietary proteins for access to the blood and brain, which improves the effectiveness of PD drugs. Physicians recommend the drug be taken so that it is not affected by digestion. A 2006 study suggested consuming L-DOPA 30 minutes before eating or at least 1 hour afterwards. Moreover, a protein redistribution diet is recommended to be eaten in the afternoon unless dyskinesias develops. It’s important to consume plenty of water along with the intake of L-DOPA to ensure quicker absorption of the PD drug. Furthermore, caffeine uptake should be limited to prevent thirst and allow the medication to reach the brain. In order to reduce nausea, consuming carbidopa (Sinemet), sugary drinks to calm the stomach, and avoidance of orange and grapefruit juices due to high acidity.
4. Rehabilitation:
Despite the lack of credible studies, there is partial evidence that rehabilitation can improve speech and mobility problems. Recent studies suggest regular physical exercise and/or therapy to help maintain and improve mobility, flexibility, strength, gait speed, and quality of life, as well as constipation. There is evidence to imply that exercise interventions improves the physical functioning, health-related quality of life, and balance and fall risk of PD patients. A 2008 review found no adverse events or side effects occurred following any of the exercise interventions. Researchers propose 5 mechanisms by which exercise enhances neuroplasticity:
— Intensive activity maximises synaptic plasticity.
— Complex activities promote greater structural adaptation
— Rewarding activities increase dopamine levels and therefore promote learning/relearning.
— Dopaminergic neurons are highly responsive to exercise and inactivity (“use it or lose it”).
— Disease progression can be slowed if exercise is introduced at an early stage of the disease.
(g) Exercise
Recent studies have concluded that regular physical exercise with or without physiotherapy provides improvements to mobility, flexibility, strength, gait speed, and quality of life. Generalised relaxation techniques such as gentle rocking is observed to decrease excessive muscle tension and improve flexibility and and range of motion in PD patients with rigidity. A 2007 study listed other effective techniques such as slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques known to improve relaxation. A variety of strategies known to improve functional mobility and safety can address gait changes such as hypokinesia (slowness of movement), shuffling and decreased arm swing. This results in improved gait speed, base of support, stride length, trunk and arm swing movement. Moreover, other exercise strategies include utilising assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and varying environments (surfaces, inputs, open vs. closed).
A 2015 study found that strengthening exercises improved strength and motor functions in patients with primary muscular weakness and weakness in relation to inactivity in mild to moderate PD cases. It involves patients exercising at their peak for 45 mins to 1 hour after medication. A 2001 resistance training study geared towards the lower legs that lasted for 8 weeks lead to increases in abdominal strength and improvements in stride length, walking velocity and postural angles. A 2009 study recommended deep diaphragmatic breathing exercises to improve chest wall mobility and vital capacity in order to manage the forward flexed posture and respiratory dysfunctions in advanced PD.
Whole Body Vibration (WBV) is an exercise training technique performed on a vibratory platform that complements standard physical rehabilitation programs for PD sufferers. Recent studies concluded that WBV only elicited short-term benefits in motor ability, as reflected by United Parkinson’s Disease Rating Scale (UPDRS) tremor and rigidity scores.
(h) Rhythmic Auditory Stimulation (RAS)
RAS is a neurological rehabilitation technique that uses external sensory stimulation that compensates for the loss of motor regulation. It is mediates by sound, hence it relies on the strong interaction between auditory and motor neural system. A 2013 study observed how this technique improves the PD patient’s gait speed and stride length by synchronising their footsteps on the emitted sound, which can be "metronome-like" cues or complex music. A 2009 study noted that physical and occupational therapist use this technique to support rhythmic exercise (nordic walking). It may also be used as a auto-rehabilitation technique for patients living at home.
(i) Cuing
A 2007 study found that visual auditory, and somatosensory cuing devices are also used in conjunction with walking aids to improve gait in PD patients. A 2015 article discovered these cuing strategies have been implemented in an 'app' called Parkinson Home Exercises. Although it’s challenging to initiate motor movements during gait (e.g., freezing gait) amongst the clinical population, a 2010 study demonstrate promise for these devices providing external stimulation to cue for the next step to take place.
(j) Gait Training
Task-specific gait training aims to improve gait long-term for PD patients. Past research studies utilised body weight support systems during gait training. Therapists suspend individuals from an overhead harness with straps around the pelvic girdle as they walk on a treadmill. A 2002 study concluded this form of gait training improves long-term walking speed and a shuffling gait following a 1-month intervention period.
(h) Speech and occupational therapy
Studies in 2006 expounded the Lee Silverman Voice Treatment (LSVT), a widely practiced treatment for speech disorders associated with PD. Alongside speech therapy, LSVT aims to increase vocal loudness, improve voice and speech function with an intensive approach for 1 month. A 2012 study conclude that LSVT significantly improved the proportion of words understood by the listeners. A 2008 study recommended prosodically-based treatments to assist PD patients with dysarthria, characterised by reduced speech intelligibility. Occupational therapy (OT) aims to maximise the participation rate of PD patients in activities of their daily living in order to enhance health and quality of life. OT may improve motor skills and quality of life in its duration, but it requires further stringent study.
(l) Music therapy
Music therapy consists of choral singing, voice exercise and rhythmic and free body movements. A 2000 study concluded that it elicited benefits on PD patients’ emotions, as well as their bradykinesia and quality of life. However it doesn’t provide sufficient motor benefit.
5. Palliative Care:
When dopaminergic treatments lose their effectiveness, palliative care is often required in the ultimate stages of the disease. It aims to achieve maximum quality of life for PD patients and those surrounding them like family members and friends. The challenges for palliative include:
— Caring for patients at home whilst providing adequate care
— Reducing or withdrawing dopaminergic drug intake to reduce drug side effects and complications
— Preventing pressure ulcers by management of pressure areas of inactive patients
— Facilitating the patient's end-of-life decisions for the patient, and friends and relatives involved.
6. Other treatments:
A 2010 study found repetitive transcranial magnetic stimulation (rTMS) temporarily improved levodopa-induced dyskinesias, though its usefulness in PD research is an open field. Acupuncture, the practice of qigong or t’ai chi were suggested as possible treatments but their effectiveness on symptoms lacks evidence. Natural L-DOPA can be found in fava and velvet beans which can relief PD symptoms, however people should be vary of the risks of overdosing on them. The risks include life-threatening adverse reactions such as Neuroleptic Malignant Syndrome. Faecal transplants has been suggested to improve symptoms but further research is required.
In 2016, Haiyan Zhang of Microsoft Research Cambridge developed a wearable device that serves to to dampen the tremors of a patient's hand and fingers thereby restoring normal functions, however this isn’t a treatment per se. A 2018 research study by Ben-Pazi et al. is evaluating the use of telemedicine in movement disorders such as PD, which requires patients and their caregivers access to Internet-enabled technologies. However, remote visits with a specialist may be cost-effective compared to in-person visits.
What’s the epidemiology of PD?
Parkinson’s Disease is the 2nd most common neurodegenerative disorder after Alzheimer’s Disease and affects approximately 7 million people worldwide and 1 million people in the USA. The proportion in a population at a given time is about 0.3% in industrialised countries. A 2006 study found that PD is more common in the elderly and rates rise from 1% in those over 60 years of age to 4% of the population over 80, which makes the mean age of onset around 60 years. 5–10% of cases are young onset PD, which begin between the ages of 20 and 50. A 2015 study found that more males are affected than females at a ratio of around 3:2. The number of new PD cases every year is between 8 and 18 per 100,000 person–years.
Many risk factors and protective factors have been proposed in relation to theories concerning possible mechanisms of the disease. Unfortunately, there wasn’t any empirical evidence to conclusively relate those factors to PD.
How is research progressing on PD?
https://en.wikipedia.org/wiki/Parkinson%27s_disease_clinical_research
Parkinson’s disease clinical research includes clinical trials, medical research, research studies, and clinical studies. Any scientific study investigates the effects on human subjects in order to satisfactorily answer difficult questions regarding aetiology diagnostic approaches or new treatments. Clinical research and clinical trials on PD lack patients participating, which contributes to the delay in developing novel effective drugs and treatments. So far, no new PD treatments expected in the short term, but several lines of research are active for new treatments. They include:
(i) Animal models = Parkinsonian symptoms may be manifested by MPTP when lit by synthetic opiate MPPP. Other predominant toxin-based models investigate Rotenone (a insecticide), Paraquat (a herbicide), and Maneb (a fungicide). Models based on toxins are commonly used in primates and transgenic mice.
(ii) Gene Therapy = In vivo gene therapy uses somatic-cell gene transfer to alter gene expression in brain neurochemical systems. Other gene therapies use a noninfectious virus to transport a gene into a specific area of the brain. Once the gene integrates into the DNA of brain cells, it produces an enzyme that helps manage PD symptoms or protects the brain from further damage caused by PD. A 2010 study delivered genes called Neurturin and gilial cell-derived neurotrophic factor (GDNF) to the putamen in patients with advanced PD. GDNF was observed to protect dopaminergic neurons in vitro and animal models of parkinsonism. Since Neurturin is structural and functional analogue of GDNF, it elicited the same effect. Unfortunately, these results couldn’t be replicated in double-blind studies, which may be due to the distribution factor as the trophic factor was insufficiently distributed throughout the target place. A 2011 study used andeno-associated viral vectoe (AAV2) to deliver glutamic acid decarboxylase (GAD) into the Subthalamic Nucleus, which is an enzyme that mediates production of GABA. The results showed promise in the randomised, double-blind gene therapy trial for a neurodegenerative disease.
(iii) Neuroprotective treatments
These treatments aim to slow down, stop, or reverse the progression of PD. Researchers are attempting to develop neuroprotective agents for PD, and other neurodegenerative brain disorders. So far, no proven neuroprotective agents or treatments are available for PD patients. Theoretically, neuroprotective therapy protects dopaminergic neurons from premature degeneration and death. Depending on the genetic risk, and when other treatments lose their ineffectiveness due to the progression of the disease, this neuroprotection may prevent from manifesting symptoms of PD. If true, this would delay the introduction of L-DOPA.
Several molecules have been proposed as potential neuroprotective treatments, but none of them conclusively reduce degeneration in clinical trials. Beginning in 2010, a study currently investigates theoretical neuroprotective agents such as anti-apoptotic drugs (Omigapil, CEP-1347), antiglutamatergic agents, Monoamine Oxidase inhibitors (Selegiline, Rasagiline), promitochondrial drugs (Coenzyme Q10, Creatine), Calcium Channel Blockers (Isradipine) and Growth Factors (GDNF).
Beginning in 2013, a research study is currently investigating possible vaccines for PD that may produce cells that alters the immune system’s response to Dopamine loss. It successfully reversed PD symptoms in mice, thus far, and clinical trials involving humans are still ongoing.
(iv) Neural transplantation
A 2010 study suggested foetal, porcine, carotid or retinal tissues in cell transplants for PD patients. Despite initial evidence of the beneficial impacts of mesencephalic Dopamine-producing cell transplants, they elicited little effect on PD. Furthermore, the excess release of dopamine by the transplanted tissue lead to dystonias. Other studies suggested stem cell transplants as they are easy to manipulate, and survive and improve behavioural abnormalities of rodents upon transplantation into its brains. Another proposal involves using induced pluripotent stem cells from adult humans, however it has to overcome the ethical controversy.
(v) Astrocytes
Recent animal models manipulated glial precursor cells to produce astrocytes that repaired neurological damage caused by PD. A 2014 study implanted immature astrocytes into the brains of rats affected with PD, which lead to health restoration and stability, as well as rebuilding neural connections. This allowed the nerve cells to resume normal activity. However successful long-term therapy involving astrocytes not only has to shield the brain from attacks, but also ensure successful repair of dopaminergic neurons damage to other brain cell populations. Dysfunction of astrocyte can lead to multiple neurological disorders.
After astrocytes were transplanted, they rescued all dopaminergic neurons, interneurons and synaptophysin. Rescuing interneurons and synaptophysin can restore information processing and movement control, communication between nerve cells respectively. This leads to full recovery of motor levels, which essentially reverses all PD symptoms.
How can people prevent themselves from PD?
Recent studies recommend exercise during middle age and caffeinated beverages such as coffee as they decrease the risk of PD later in life. A 2017 study discovered that cigarette or smokeless tobacco smokers reduce their likelihood to develop PD compared to non-smokers, which correlates to consumption of tobacco, however this mechanism that underlies this effect is still unknown. There is still scientific debate whether antioxidants, such as vitamins C and E, and high-fat or fatty acid diets protect against developing PD given the contradicting studies. Nevertheless, a 2015 study indicated that non-steroidal anti-inflammatory drugs (apart from aspirin) and calcium channel brokers reduce the incidence of developing PD.
https://en.wikipedia.org/wiki/Huntington%27s_disease
https://www.youtube.com/watch?v=IuSaXiRVqg0
Huntington’s Disease (HD), also known as Huntington’s Chorea, is an inherited disorder causing the death of neurons.
What are the signs and symptoms of HD?
Symptoms of HD are often noticed between 35 and 45 years old, but it can occur at any age from infancy to old age. The early stages of HD subtly changes a human’s personality, cognition, and physical skills. A 2010 study inferred that the physical symptoms may be noticed before cognitive and behavioural symptoms. The onset, progression and extent of cognitive and behavioural symptoms varies significantly between individuals, while physical symptoms are consistently observed.
A 2007 study noted the most characteristic initial physical symptoms are called chorea, which are jerky, random, and uncontrollable movements. In the initial stages, chorea may be general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. At least 3 years down the track, more obvious signs of motor dysfunction become apparently clear such as rigidity, writhing motions or abnormal posturing. This suggests that impairments to psychomotor functions have worsened, affecting muscle control. This leads to physical instability, abnormal facial expression, and difficulties in chewing, swallowing, and speaking. Studies in 2008 noted that eating difficulties commonly lead to significant weight loss, hence malnutrition. Sleep disturbances and seizures have also been observed in recent studies. In juvenile HD, the progression of the aforementioned symptoms is more rapid and exhibition of chorea is brief, while rigidity is more apparent.
Cognitive abilities that become impaired include executive functions, which are responsible for planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. As the disease progresses, memory deficits become apparent ranging from short-term memory deficits to long-term memory difficulties, including deficits in episodic memory, procedural memory and working memory. As the disease progresses to the later stages, cognitive issues ultimately manifest to dementia. This pattern of worsening deficits is described as a “subcortical dementia syndrome” to distinguish it from the typical effects of cortical dementias e.g. Alzheimer’s Disease.
A 2007 study reported neuropsychiatric manifestations of HD include anxiety, depression, decreased emotion display (blunted affect), egocentrism, aggression, compulsive behaviour, beginning or worsening addictions like alcoholism, gambling and hypersexuality. A 2006 study also reported patients experienced difficulty in recognising others’ negative expressions. It’s estimated that rates for lifetime prevalence of psychiatric disorders varies between 33% and 76%. Accounts of sufferers and their families describe how distressing their symptoms are, as it affected their daily functioning and constituting reason for institutionalisation. HD patients have suicidal thoughts and attempted to commit suicide more often than the general population. A 2012 study reported HD patients often had reduced awareness of chorea, cognitive and emotional impairments. When a mutant Huntingtin protein is expressed throughout the body, it causes abnormalities in peripheral tissues outside the brain including muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.
Below are rates of behavioural symptoms in HD reported by a 2007 study by van Dujin et al.:
— Irritability = 38-73%
— Apathy = 34-76%
— Anxiety = 34-61%
— Depressed Mood = 33-69%
— Obsessive and compulsive = 10-52%
— Psychotic = 3-11%
How was HD discovered?
The symptoms of HD were first recognised since at least the Middle Ages, but no one then identified nor understood its causes until fairly recently. It was originally called simply ‘chorea’, "hereditary chorea" or "chronic progressive chorea" for the jerky dancelike movements associated with the disease. Charles Oscar Waters, Charles Gorman and Johan Christian Lund published early descriptions of HD as a form of chorea from the 1840s - 1860s. In 1872, George Huntington published the first thorough description of the disease stating the exact pattern of inheritance of autosomal dominant disease before the rediscovery by scientists of Mendelian inheritance.
In 1968, a Californian psychoanalyst named Milton Wexler established the Hereditary Disease Foundation (HDF) in order to vamp up searches for the cause of HD, because his wife Leonore Sabin was diagnosed with HD earlier that year. The foundation was critical in the recruitment of over 100 scientists in the beginning of the US-Venezuela Huntington’s Disease Collaborative Research Project in 1979. In 1983, the project’s scientists landed a major breakthrough with their discovery of the approximate location of a causal gene through their extensive studies focusing on 2 isolated Venezuelan villages, Barranquitas and Lagunetas. These populations were specifically chosen because of the unusually high prevalence of HD, estimated to be over 18,000 people with most of them from a single extended family. In 1993, the research group used novel DNA-marking methods to isolate the precise causal gene at 4p16.3, which officially made it the first autosomal disease locus focus discovered by genetic linkage analysis. The development of transgenic mice in 1996 expanded the experimental scope of modelling HD in various types of animals. It accelerated their metabolisms, reducing their lifespans, hence producing definitive research results in a shorter period. In 1997, mTT fragments were discovered to misfold and produce nuclear inclusions, which has shaped future studies to conduct extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.
The condition was originally called “Huntington’s Chorea, but this has been substituted for “Huntington’s Disease” because not all patients develop chorea and due to the importance of cognitive and behavioural problems.
What’s the epidemiology of HD?
About 5-10 per 100,000 people are affected by HD worldwide with an equal gender ratio, but this prevalence varies geographically due to ethnicity, local migration and past immigration patterns. Most people of Western European descent are afflicted with this disease, averaging around 7 per 100,000 people, lower than the rest of world e.g. 1 per million people of Asian and African descent. A 2013 epidemiological study conducted between 1990 and 2000 found the average prevalence for people of UK descent was 12.3 per 100,000. About 700 per 100,000 people living in the Maracaibo region of Venezuela suffer from HD, which is one of the highest incidences for an isolated population. Other areas of high localisation were discovered in Tasmania, Australia and specific regions of Scotland, Wales and Sweden. The local founder effect may have increased the prevalence of HD in geographically isolated areas habited by historically emigrated carriers. A 2012 study found that despite Icelanders being descendants the early Germanic tribes of Scandinavia, Iceland has a rather low prevalence of 1 per 100,000. A 2015 study found that Finland also had a low incidence of 2.2 per 100,000 Finnish people.
What are the causes of HD?
Humans have 2 copies of the Huntingtin gene (HTT) that codes for the Huntingtin (HTT) protein. The gene contains a repeated section called a trinucleotide repeat (TNR), which varies between individuals in terms of length between generations. If the TNR is present in a healthy individual, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces a mutant Huntingtin gene (mHTT). The functions of a mHTT are responsibly for the pathological changes that lead to the disease symptoms.
The HTT gene is located on the short arm of Chromosome 4 at 4p16.3, consisting of a repeating sequence of 3 DNA bases: Cytosine - Adenine - Guanine (CAG). The multiple CAG repeats (…CAG CAGCAGCAG…) is an example of a trinucleotide repeat. CAG is the 3-letter genetic code (codon) for an amino acid called Glutamine. A series of CAG repeats would produce a chain of Glutamine known as a polyglutamine tract (or polyQ tract), and the repeated section is known as a PolyQ region.
The table classifies the different amounts of TNRs and resulting disease status according to the number of CAG repeats:
Over 28 Trinucleotide CAG repeats leads to instability during replication, which worsens with an increasing number of repeats repeat. Thus usually creates new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the TNR, which leads to changes in the number of repeats in successive generations. e.g. An unaffected with 30 CAG repeats may pass on a copy of the HTT gene with an increase of 10 CAG repeats to 40, which reduces the age of onset and increases the severity of disease. If this phenomenon occurs in successive generations, this is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis, with maternally inherited alleles usually maintaining its repeat length, whereas paternally inherited alleles have a higher probability of expanding CAGs. There are rare cases of HD being caused by a new mutation, which neither parent has over 36 CAG repeats.
If both parents have an expanded HTT gene, this increases the offspring’s risk of inheriting a mHTT gene to 75%. If either parent has 2 expanded copies, the risks increases to 100%. Though both scenarios are extremely rare.
How does HD affect people?
A 2004 study found the HTT protein interacts with over 100 other proteins, demonstrating multiple biological functions. So far, researchers haven’t fully understand the behaviour of mHTT, but it’s toxic to certain cell types, particularly in the brain. HTT proteins can be found in abundance in the brain and testes, as well as the liver, heart, and the lungs. The function of HTT in humans is currently not well understood, but it’s known to interact with proteins involved in transcription, cell signalling, and intracellular transporting. A 2005 genetically modified animal study found that HTT plays a role in embryonic development, because absence of HTT lead to embryonic death. It’s known that:
— HTT activates Caspases, an enzyme that plays a role in catalysing apoptosis and removing cells, which damages the Ubiquitin-Protease system.
— HTT acts as an anti-apoptotic agent that prevents programmed cell death and controls the production of brain-derived neurotrophic factor (BDNF). BDNF is a protein that protects neurons and regulates their creation during neurogenesis.
— HTT facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription.
— Increased HTT gene expression increases production of HTT protein, which improves brain cell survival and reduces the harmful effects of mHTT.
— Reduced HTT gene expression leads to increased production of mHTT protein, which may elicit toxic effects.
A 2003 study observed the mHTT protein is more prone to cleavage, creating shorter fragments containing the polyglutamine expansion. A 2015 study explained these protein fragments had a propensity to undergo misfolding and aggregation, yielded fibrillar aggregates in the congregation of non-native polyglutamine β-strands from multiple proteins via hydrogen bonds. Over time, the aggregates accumulate to form inclusion bodies within cells, which ultimately disrupts neuron function. These inclusion bodies are found in both the cell nucleus and cytoplasm which indirectly interfere neuronal function. However, there are contradictions between studies regarding its toxicity and defensive prowess. Recent studies have identified mHTT interact with Chaperone proteins, which normally help fold proteins properly and remove misfolded proteins. The polyglutamine tract may elicit toxic effects on neurons, impairing its energy production and disrupting gene expression. A 2017 study suggested HD causes mitochondrial dysfunction in striatal cells as there is evidence of mitochondrial metabolism deficiency. A 2016 study explained that impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of ROS (reactive oxygen species). Furthermore, when mHTT interacts with numerous proteins in neurons, it leads to an increased vulnerability of glutamine, hence excitotoxic effects damaging numerous cellular structures. Recent studies suggest that Glutamine causes expression of excitotoxins, even in normal amounts.
A 2007 study by Walker found that HD initially affects the Neostriatum composed of the Caudate Nucleus and Putamen, which are part of the Basal Ganglia. Other disrupted brain areas include the Substantia Nigra, layers 3, 5 and 6 of the Cerebral Cortex, the Hippocampus, Purkinje Cells in the Cerebellum, lateral tuberal nuclei of the Hypothalamus, and parts of the Thalamus. They are affected according to their structure and the types of neurons they contain, and cell loss in those regions correspond to their size reduction. Studies noted striatal spiny neurons projecting to the external Globus Pallidus had the highest vulnerability, while interneurons and spiny cells projecting to to the internal pallidum weren’t as vulnerable. A 2007 study by Lobsiger and Cleveland found an abnormal increase in Astrocytes and activation of microglia in the brain’s of HD patients.
Damage to the Basal Ganglia leads to the erratic and uncontrolled reinstatement of the inhibitions, which results in awkward or unintentional initiations of motion, or involuntary abrupt freezing of motion. This may explain the characteristic erratic movements associated with chorea observed in HD patients, which are classified as a type of hyperkinetic dysarthria. A 2013 study implied that impairing the basal ganglia’s ability to inhibit undesirable movements would inevitably decrease the HD patient’s ability to verbally communicate and swallow (dysphagia).
A 2017 study found a chain of 18 Glutamines on CREB-binding protein (CBP), which is a transcriptional coregulator that plays an essential role in maintaining cell function by activating gene transcription for survival pathways. These Glutamines on CBP directly interact with the increased amount of Glutamine on the HTT chain, which pulls CBP away from its typical location adjacent to the cell nucleus. A 2001 study found that HTT’s polyglutamine-containing domain binds to the Acetyltransferase domain on CBP, that leads to CBP being pulled away. This may explain the lack of CBP inside the autopsied brains of HD patients. A 2006 study found that overexpression of CBP minimises cell death induced by the polyglutamine-containing domain of HTT.
How is HD diagnosed?
(a) Clinical
A physical examination, in combination with a psychological examination, can confirm the beginning of disease onset. Medical consultants often notice excessive unintentional movements of any part of the patient’s body. If those movements occur abruptly, and randomly in terms of timing and distribution, then it suggests a HD diagnosis. Cognitive or behavioural symptoms are rarely diagnosed initially, but they become recognisable in hindsight or in later stages of the disease. Physicians use the unified Huntington’s disease rating scale (UHDRS) to measure the disease progression, which evaluates an overall rating system based on motor, behavioural, cognitive, and functional assessments. Medical imaging techniques, such as computerised tomography (CT) scans, and magnetic resonance imaging (MRI), are used to illustrate atrophy of the caudate nuclei early in the disease. Moreover, cerebral atrophy can be observed in the advanced stages of HD. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), tracks changes in brain activity before the onset of physical symptoms, however these experimental tools aren’t used clinically.
(b) Predictive genetic testing
The genetic test for HD involves a blood test that counts the number of CAG repeats in each of the HTT alleles. The cutoffs include:
— >26 repeats = Indicates a “negative test”, hence it won’t associate with HD. It suggests the patient doesn’t carry the expanded copy of the HTT gene and won’t develop HD.
— 27-35 repeats = Intermediate allele (IA), or large normal allele — Not associated with symptomatic disease, but may expand upon further inheritance to give symptoms in offspring.
— 36-39 repeats = Incomplete or reduced penetrance allele (RPA) — May cause symptoms, usually later in adult life. 60% max risk of symptoms by 65 years, and 70% risk of symptoms by 75 years.
— 40+ repeats = Full penetrance allele (FPA) — Indicates a “positive test” or “positive result”, but it shouldn’t be considered a diagnosis because symptoms won’t initiate for decades after. The result implies the risk of developing HD increasing from 50% to 100% or is eliminated.
Undergoing genetic testing before the possible onset of symptoms requires personal motivation, which has proven to be a life-changing event. Walker states that it helps aid in career and family decisions, which would not have been possible prior to 1993. A 2013 survey found 50-70% of at-risk individuals expressed interest in receiving genetic tests, but less were inclined to select predictive gene testing. Since there is not cure, over 95% of individuals at risk of inheriting HD don’t proceed with testing. Not disclosing the risk of developing HD may generate anxiety and increase stress levels of individuals. Irrespective of the result, although stress levels decreased 2 years after being tested, the risk of suicide increases after confirmation of a positive test result. Even if individuals were informed of their non-diagnosis, they may experience survivor guilt with regard to family members who are affected. A 2012 study implicated the possibility of discrimination, like gender, against those diagnosed with HD. It recorded higher rates of discrimination within personal relationships than health insurance or employment relations. A 2012 study suggested genetic counselling for HD as a means of informing, advising and supporting patients in their initial decision-making, as well as throughout all stages of the testing process.
(c) Preimplantation genetic diagnosis (PDG)
This process involves genetically testing embryos developed through IVF (in vitro fertilisation) for HD. 1 or 2 embryonic cells are extracted from an embryo made up of 4-8 cells, which are then tested for genetic abnormality. This is then used to ensure embryos affected with HD gene aren’t implanted, and therefore any offspring won’t inherit the disease. Other forms of PDG, such as non-disclosure or exclusion testing, permit at-risk people to have HD-free offspring without revealing their own parental genotype. This removes information regarding their destiny of developing HD or otherwise. Exclusion testing compares the embryos’ DNA with that of the parents and grandparents in order to avoid inheriting the chromosomal region that contains the HD gene from the affected grandparent. Non-disclosure testing replaces disease-free embryos in the uterus without disclosing the parental genotype hence parental risk for HD.
(d) Prenatal Testing
A prenatal diagnosis of an embryo or foetus in the womb acquires foetal genetic material through chorionic villus sampling. If the pregnancy is within the 14-18 week period, then an amniocentesis can be performed. During an amniocentesis, the physician scavenges the amniotic fluid surrounding the baby for any indicators of the HD mutation. Prenatal testing is often performed when:
— A parent has been diagnosed with HD
— A parent had been genetically tested for the expansion of the HTT gene
— A patent has a 50% chance of inheriting HD.
Counselling is recommended for parents to discuss their options, including termination of the pregnancy and on the difficulties of a child with the identified gene.
A 2013 study explained a non-invasive prenatal diagnosis can be performed for at-risk pregnancies due to an affected male partner. This procedure analyses cell-free foetal DNA in a blood sample collected from the mother (via venipuncture) during the 6-12 week period of pregnancy. It doesn’t carry a procedure-related risk of miscarriage (excepting via needle contamination).
(e) Differential Diagnosis
Based on the typical symptoms and a family disease of the disease, about 99% of HD diagnoses are confirmed by genetic testing to contain the expanded TNR causing HD. A majority of the 1% diagnoses are linked to HD-like (HDL) syndromes, which have an unknown cause. A minority of HDL syndromes are caused by mutations in the Prion Protein gene (HDL1), the Junctophilin 3 gene (HDL2), a recessively inherited unknown but poorly understood gene (HDL3) only found in 2 families, and a gene that encodes the TATA box-binding protein (SCA17, HDL4). Other autosomal dominant diseases that can be misdiagnosed as HD include Dentatorubral-Pallidoluysian Atrophy and Neuroferritinopathy. There are autosomal recessive disorders resembling sporadic cases of HD including Chorea Acanthocytosis, and Pantothenate Kinase-associated neurodegeneration.
How is HD managed?
Sadly, this is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms.
(a) Therapy
Nutrition management is increasingly essential as the disease progresses in order to manage weight loss and eating difficulties due to dysphagia and other muscle dis-coordination. Thickening agents are added to liquids in order to make them easier and safer to swallow. Therapists remind HD patients to eat slowly and take smaller bites in order to avoid the event of choking. If eating becomes hazardous or uncomfortable, a percutaneous endoscopic gastrostomy (PEG) is available to them. PEG involves permanently attaching a feeding tube through the abdomen into the stomach, reducing the risk of aspirating food and providing effective nutritional management. Assessment and management by speech-language pathologists with experience in HD is recommended before proceeding with any therapy.
Physical therapy is useful as a non-invasive and non-medication-based means of managing the physical symptoms. According to the consensus guidelines on physiotherapy in Huntington's disease published by the European HD Network, physiotherapists may implement fall risk assessment and prevention, and teach the patients strengthening, stretching, and cardiovascular exercises, as well as prescribe walking aids. They can also prescribe breathing exercises and airway clearance techniques if the patient begins to develop respiratory problems. Early implementation of rehabilitation interventions may prevent loss of function and provide maximum benefit, translating into long term maintenance of motor and functional performance. If they were implemented during the late stage, it aims to compensate for motor and functional losses. Physiotherapists can develop home exercise programs for appropriate people with the purpose of long-term independent management. A 2013 study found an increasing number of HD sufferers are switching to palliative care to improve their quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.
(b) Medications
Tetrabenazine, as well as neuroleptics and benzodiazepines can treat and reduce chorea. Anti-parkinsonian drugs can treat hypokinesia and rigidity, while valproic acid can treat myoclonic hyperkinesia. Selective Serotonin reuptake inhibitors and Mirtazapine can treat depression, while atypical antipsychotic drugs can treat psychosis and behavioural problems. Nevertheless, it’s recommended to consult with a specialist neuropsychiatrist to discuss long-term treatment with a combination of medications.
(c) Education
Genetic counselling provides benefits to individuals and their families, and society at large, who have inherited or are at risk of inheriting HD. It updates their knowledge, dispels any unfounded beliefs, and tables future options and plans. Those options include family planning choices, care management, and other considerations.
How is research on HD progressing?
Research has focused on understanding the function of HTT, how mHTT differs or interferes with it, and the brain pathology produced by HD. Researchers use in vitro methods, animal models and human volunteers to help understand the fundamental mechanisms that cause the disease and for supporting the early stages of drug development. Transgenic animal models featuring nermatode worms, Drosophila fruit flies, mice, rats, sheep, pigs or monkeys that express mHTT begin to develop progressive neurodegeneration and HD-like symptoms. Other research are investigating different strategies to prevent or slow down the progression of HD. Disease-modifying strategies can be broadly grouped into 3 categories:
(i) Reducing Huntingtin production
Gene silencing is used to decrease the production of the mHTT protein, responsible for HD. A 2011 study conducted gene silencing experiments in mouse models that lead to reductions of mHTT expression, hence improvements in symptoms. Studies in 2011 demonstrated the safety of non-allele specific RNAi and ASO gene silencing in mice and the large, human-like brains of primates. A 1987 study attempted to identify polymorphisms present on only 1 allele and produce gene silencing drugs that target polymorphisms in only the mutant allele, while leaving the wild-type allele untouched. In 2015, the first 'gene silencing' trial involving human HD patients(ii) was initiated to test the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology. A 2016 study used a novel 'single-molecule counting’ immunoassay to detect and quantify mHTT protein for the first time in cerebrospinal fluid (CSF) from HD mutation-carriers in 2015. This provided a direct way to assess the effectiveness of Huntingtin-lowering treatments. A 2017 study is currently investigating gene splicing techniques in an effort to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9.
(ii) Improving cell survival
Approaches that aim to improve cell survival include:
— Correction of transcriptional regulation using Histone Deacetylase Inhibitors
— Modulation of Huntingtin aggregation
— Improvements to metabolism and mitochondrial function
— Restoration of synaptic function
(iii) Neuronal replacement
Stem cell therapy involves transplanting stem cells into affected brain regions to eliminate and replace damaged neurons. A 2008 study tested this technique in animal models and preliminary human clinical trials and yielded mixed results. Nevertheless, stem cells still possess a future therapeutic potential to alleviating symptoms of HD.
(iv) Clinical trials
A 2014 article stated several clinical trials of new experimental treatments are underway and planned in Huntington's disease. A 2012 study conducted human trials to dismiss compounds that failed to prevent or slow progression of HD such as Remacemide, Coenzyme Q10, Riluzole, Creatine, Minocycline, Ethyl-EPA, Phenylbutyrate and Dimebon.
https://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis
https://en.wikipedia.org/wiki/Ice_Bucket_Challenge
Do you remember the Ice Bucket Challenge? No one knows exactly who coined the idea but multiple sources point to possible co-founders who were diagnosed with ALS like Boston College alumnus Pete Frates, Pat Quinn and Corey Griffin.
How is ALS classified?
ALS is part of the a family of motor neuron diseases such as Primary Lateral Sclerosis (PLS), Progressive Muscular Atrophy (PMA), Progressive Bulbar Palsy (PBP), Pseudobulbar Palsy (PP), and Monomelic Amyotrophy (MMA).
What are the signs and symptoms of ALS?
ALS causes degeneration of the upper motor and lower motor neurons, which leads to muscle weakness, atrophy, and muscle spasms throughout the body. This compromises an individual’s ability to initiate and control all voluntary movement. However, bladder and bowel function and the extraocular muscles are usually spared until the terminal stages of the disease.
In the initial stages, symptoms can be subtle and are often overlooked. The earliest symptoms include muscle weakness and/or muscle atrophy, difficulty swallowing or breathing, cramping, or stiffness of affected muscles. Muscle weakness can affect the arms or legs, and speech becomes slurred and nasal. The first body parts affected by initial ALS symptoms is determined by the first motor neuron being damaged.
— In limb-onset ALS, the first symptoms appear in the arms or legs. If the legs are affected first, patients would perceive awkwardness, and often trip, or stumble while walking or running. This means individuals walk with a “dropped foot” as they gentle drag their foot along the ground. If the arms are affected first, they experience difficulty completing tasks that require manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock.
— In bulbar-onset ALS, the first symptoms include difficulties producing speech or swallowing. Patients would have slurred, nasal in character, or quieter speech, as well as loss of tongue mobility.
— In respiratory-onset ALS, the first symptoms affect the intercostal muscles that play a role in breathing.
As the disease progresses, patients would experience increasing difficulty moving, swallowing (dysphagia), and speaking or producing legible words (dysarthria). Symptoms involving damage to upper motor neurons include tight and stiff muscles (spasticity, muscle spasms), and exaggerated reflexes (hyperreflexia) including an overactive gag reflex and Babinski’s Sign. Symptoms involve damage to lower motor neurons include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscle observed beneath the skin (fasciculations). A 2014 article implies that twitching is a side effect rather than a diagnostic symptom because it either occurs after or accompanies weakness and atrophy. As the disease progresses, it spreads throughout the body manifesting into loss of voluntary motion of the arms and legs, inability to speak and swallow food and own saliva, and inability to cough and breathe voluntarily. A 2008 study measured disease progression is slower in people younger than 40, and who are mildly obese. Furthermore, a 2011 study found this slowed disease progression elicits symptoms restricted primarily to one limb. Conversely, progression accelerates and prognosis worsens in those with bulbar-onset ALS, respiratory-onset ALS and frontotemporal dementia.
In the late stages of the disease, the risk of choking or of aspirating food into the lungs increases. A lack of voluntary eating would lead to malnutrition, and a lack of voluntary breathing would lead to aspiration pneumonia. As the diaphragm and intercostal muscles of the rib cage weaken, this compromises the rhythmic breathing process, diminishing vital capacity and inspiratory pressure in terms of lung function. Patients with respiratory-onset ALS may experience breathing difficulties prior to significant limb weakness. Most ALS patients pass away due to respiratory failure or pneumonia.
What is the epidemiology of ALS?
ALS is the most common motor neuron disease in adults and the 3rd most common neurodegenerative disease after Alzheimer’s Disease and Parkinson’s Disease.
More thorough studies are required to estimate the rates of ALS in much of he world, including Africa, parts of Asia, India, Russia, and South America. It’s estimated people living in several geographic clusters in the Western Pacific have up to 50–100 times higher than the rest of the world, including Guam, the Kii Peninsula of Japan, and Western New Guinea.
People of all races and ethnic background may be affected by ALS, but it’s more common in Caucasians than in Africans, Asians, or Hispanics. A 2015 study found that the prevalence of American Caucasians with ALS was 5.4 per 100,000 people, and the prevalence of African-Americans with ALS was 2.3 per 100,000 people. The Midwest had the highest prevalence of the 4 US Census regions with 5.5 per 100,000 people, followed by the Northeast (5.1), the South (4.7), and the West (4.4).
There are also differences in the genetics of ALS between different ethnic groups. A 2017 study found the most common ALS gene amongst Europeans is C9orf72, followed by SOD1, TARDBP, and FUS, while the most common ALS gene amongst Asians is SOD1, followed by FUS, C9orf72, and TARDBP.
ALS can affect people at any age, but the peak incidence is between 50–75 years, and decreases dramatically after 80 years for reasons still unknown. ALS occurring in the elderly might go undiagnosed because of comorbidities, difficulty consulting a neurologist, or their health deteriorating from an aggressive form of ALS. A 2011 study found that sporadic ALS usually starts around the ages of 58 to 63 years, while familial ALS starts earlier, usually around 47 to 52 years. A 2016 study predicts the number of ALS cases worldwide will increase by 150,000+ in the next 20+ years, or by 69%, due to the ageing population in developing countries.
How was ALS discovered?
Charles Bell published the first ever descriptions of this disease around 1824. In 1850, François-Amilcar Aran was the first to describe the disorder as a “progressive muscular atrophy”, which merely featured degeneration of the upper motor neurons. In 1869, Jean-Martin Charcot discovered the connection between the symptoms and the underlying neurological problems. In his 1874 paper, Charcot introduced the term “amyotrophic lateral sclerosis”. Alfred Vulpian in 1886, and Pierre Marie and his student Patrikios in 1918, described regional variants of ALS known as “flail arm syndrome”.
In 1993, the first gene associated with ALS was identified as SOD1, which led to the development of the first animal model of ALS the following year i.e. transgenic SOD1 mouse. This led to the development and gradual approval of a drug called Riluzole worldwide throughout the 1990s. In 2006, researchers discovered a protein called TDP-43 as a major component of the inclusion bodies observed in the neurons of patients suffering from both ALS and frontotemporal dementia (FTD). A 2008 study traced the TDP-43 protein back to mutations in the TARDBP gene, which accounts for familial ALS. A 2011 study found non-coding repeat expansions in C9orf72 gene to be the major cause of ALS and FTD. Since 2015, Edaravone has been approved as an ALS drug worldwide except Europe, thus far.
Amyotrophic originates from the Greek word amyotrophia: a- means “no”, myo means “muscle”, and trophia means “nourishment”. Hence amytrophia means “no muscle nourishment”, which refers to the loss of nerve impulses usually transmitted by motor neurons to the muscle cells. Lateral refers to areas in the spinal cord where the affected motor neurons that control muscle are located. Scleorsis means “scarring” or “hardening”, referring to the death of motor neurons in the spinal cord. In 1933, British neurologist Russell Brain coined the term “motor neuron disease” to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease. Some countries, especially the USA, name ALS as “Lou Gehrig’s Disease”, after the famous American baseball player Lou Gehrig. He was diagnosed with ALS in 1938, which forced him to retire from baseball, and ultimately died from the disease in 1941. Americans interchangeably use the terms “ALS” or “Lou Gehrig’s Disease for all forms of the disease, including classical ALS, progressive bulbar palsy, progressive muscular atrophy, and primary lateral sclerosis. Europeans merely use “ALS” for all forms of the disease. British, Welsh, Scottish, Irish and Australians use the “motor neuron disease” (MND) for all forms of the disease except for classical ALS. They refer that to as “ALS”, describing the loss of both upper and lower motor neuron involvement.
What are the causes of ALS?
The exact cause of ALS is currently unknown, though genetic factors and environmental factors may play a pivotal role in causing ALS.
(1) Genetic Factors:
https://en.wikipedia.org/wiki/Genetics_of_amyotrophic_lateral_sclerosis
So far, more than 25 genes have been identified to be linked with ALS as of June 2018, which collectively account for about 70% of cases of familial ALS (fALS) and 15% of cases of sporadic ALS (sALS). A 2011 study estimated about 5–10% of cases of ALS are directly inherited from the parents with first-degree relatives of any individual affected by ALS having a 1% risk of developing ALS. A 2014 study stated that ALS has an oligogenic mode of inheritance, which is defined as mutations in 2 or more genes are needed to cause disease.
The SOD1 gene produces the Cu-Zu Superoxide Dismutase 1 (SOD1) enzyme, which is a powerful antioxidant that protects the body from damage caused by toxic free radicals generated in the mitochondria called Superoxide. Mutations to the SOD1 gene is associated with around 20% of familial ALS and 5% of sporadic ALS. To date, over 110 different mutations in SOD1 correlates with the disorder, with some having a long clinical course (e.g. H46R), and others having an exceptionally aggressive course (e.g. A4V). A defect in SOD1 could be a loss or gain of function that can be toxic, whereas a loss of SOD1 function leads to accumulated DNA damage. When less SOD1 is produced, the defences against oxidative stress fail, leading to an accumulation of free radicals damaging DNA and proteins within cells, thence upregulates apoptosis. So far, 180 different SOD1 mutations are known to cause familial ALS. A 2006 study proposed aggregate accumulation of mutant SOD1 disrupts cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins. A number of hypotheses attempt to explain the structural instability that cause misfolding of mutant SOD1:
— Glutamate excitotoxicty caused by reduced astroglial glutamate transporter EAAT2
— Mitochondrial abnormalities increases the amount of misfolded SOD1 being deposited in the spinal cord mitochondria. This leads to defects in mitochondrial transport causing energy depletion, disruption in Ca2+ buffering, activating synaptic dysfunction, and loss of neurons.
— Impaired axonal structure or transport defects compromises neurotrophic signalling, which disrupts anterograde and retrograde axonal transport.
— Free radical-mediated oxidative stress causing cytotoxicity.
A 2016 study suggested potential therapeutic targets of SOD1-ALS include SOD1 maturation and proteins regulating intracellular copper level. A 2002 discovered a DNA oxidation product called 8-oxG created by a mutant SOD1 gene. It is a well-established marker of oxidative DNA damage that accumulates in the mitochondria of spinal motor neurons of ALS patients.
(b) UBQLN2
This gene encodes for the production of a protein called Ubiquilin 2, which is a member of the ubiquilin family and is responsible for controlling the degradation of ubiquitinated proteins. Mutations in the UBQLN2 gene interfere with protein degradation, which leads to neurodegeneration and causes dominantly inherited, chromosome X-linked ALS and ALS/dementia.
(c) TARDBP
This gene encodes for the production of TDP-43 protein, which regulates RNA expression. Mutations in the TARDBP gene causes defects in RNA processing, which leads to protein inclusions typical in RNA, and contribute to the pathogenesis of the disease.
(d) TBK1, SQSTM1, OPTN
These genes are involved in producing a maturing autophagosome during autophagy. A 2016 study discovered mutations in the TBK1 gene contributed to formation of the disease. Since the TBK1 protein is haploinsufficient, that is, mutations in the gene halts production of that respective protein, it prevents phosphorylation of the p62 and Optineurin proteins. As a result, motor neurons can no longer produce a functional autophagosome, which inhibits autophagy.
(e) C9orf72
This gene produces a protein involved in the trafficking of an autophagosome during autophagy. The C9orf72 protein normally interacts with other proteins like SMCR8 and WDR41 by pertaining the role as the Rab GDP-GTP exchange factor in vesicular transport during autophagy. Mutations in the C9orf72 gene would inhibit the formation of the respective protein, which would prevent he active transport of the autophagsome, thence inhibiting autophagy.
(f) FUS
This gene encodes for the “Fused in Sarcoma” (FUS) protein, which is associated with 1–5% of familial ALS and less than 1% of sporadic ALS. It is an RNA-binding protein with a similar function to TDP-43.
(g) Mitochondria
Mitochondrial abnormalities, such as increased free radical production and impaired ATP production due to SOD1 and TDP-43 mutations, have been noticed as possible causes of ALS, but there mechanisms are still unproven. In sporadic cases of ALS, increased levels of markers of oxidative stress have been recorded, including 8-Oxo-2’-Deoxyguanosine and 4-Hydroxynonenal. Trauma and exposure to certain chemicals may play a role in worsening oxidative stress. However a 2017 clinical trial study by D’Amico et. al. failed to support this hypothesis due to anti-oxidants and methodological limitation. They proposed that dysregulation of glutaminergic neurotransmission may be caused by excessive oxidative stress of astrocytes. A 2017 study by Kevin Talbot suggested that because maturing cells lose their ability to buffer against the genetic changes due to increasing oxidative stress, it results in the death of sensitive cells. This incorporates both the genetic mutations of RNA binding proteins and oxidative stress that may cause ALS. Both ALS and frontotemporal dementia share an underlying pathophysiology, such as dysregulated microRNA activity (possibly caused by a TDP-43 mutation), given their co-occurence and symptomatic overlap. Nevertheless, a 2014 study argued against the assumption of a causal role of microRNA dysregulation.
(2) Environmental Factors:
Around 90% of ALS cases have unknown cause due to lack of family history of the disease. A 2015 study suggested various proposed factors including exposure to environmental toxins, alcohol and tobacco consumption during military service. A 2016 meta-analysis review found conclusive evidence for a correlation between ALS and chronic occupational exposure to lead. It’s known farmers are exposed tn o heavy metals other than lead, beta-carotene intake, and head injury, However, there is insignificant evidence for omega-3 fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid. A 2017 study conducted by the United States for Disease Control and Prevention analysed ALS deaths of Americans from 1985 to 2011, and discovered a majority of them were white collar, such as in management, financial, architectural, computing, legal, and education jobs. Studies in 2009 and 2015 proposed other potential risk factors including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, but they remain unconfirmed. Studies in 2012 and 2016 suggested exposure to various pesticides, including the Organochlorine insecticides Aldrin, Dieldrin, DDT and Toxaphene as possible risk factors.
Recent studies, reviews and meta-analyses concluded that there is little evidence to suggest traumatic head injury, physical activity, sports like soccer and American football, and smoking are possible risk factors for developing ALS.
What is the pathophysiology of ALS?
Patients with ALS have both of their upper and lower motor neurons degenerated. ALS patients with frontotemporal dementia experience neurodegeneration throughout their frontal and temporal lobes. The pathological hallmark of ALS is the presence of inclusion bodies in the cytoplasm of motor neurons, which are abnormal aggregations of protein. 97% of ALS cases involve TDP-43 protein as the main component of the inclusion bodies, while 3% of ALS cases involve SOD1 or FUS protein as a major component of the inclusion bodies. The gross pathology of ALS include:
— Skeletal muscle atrophy
— Motor cortex atrophy
— Sclerosis of the corticospinal and corticobulbar tracts
— Thinning of the hypoglossal nerves (which control the tongue)
— Thinning of the anterior roots of the spinal cord.
It suggests initial ALS symptoms begin in a single spinal cord region, and then progressively spread throughout the nervous system. A 2017 study suggested Prion-like propagation of misfolded proteins from cell to cell may account for this disease progression.
So far, scientists don’t fully understand why motor neurons degenerate in ALS, hence they propose many different cellular and molecular processes in an attempt to explain this bizarre neurodegeneration. The genes currently known to cause ALS are categorised into 3 general categories based on their normal function:
(i) Protein degradation
It’s known that mutant SOD1 protein stick together to form intracellular aggregations inhibiting protein degradation, which are commonly observed in sporadic ALS. A 2017 recent hypothesised that misfolded mutant SOD1 causes misfolding and aggregation of wild-type (wt) SOD1 in neighboring neurons in a prion-like manner. Other genes that lead to protein degradation when mutated in ALS include VCP, OPTN, TBK1, and SQSTM1. The genes implicated in ALS that play critical roles in maintaining the cytoskeleton and for axonal transport include DCTN1, PFN1, and TUBA4A.
(ii) The Cytoskeleton
C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. A hexanucleotide repeat expansion (i.e. a series of 6 nucleotides repeated over and over) of the gene manifests its mutant behaviour and become pathologic. Normal people have 30 repeats, while patients affected by e familial ALS, frontotemporal dementia or sporadic ALS have 100s or 1000s of repeats. 3 proposed mechanisms of disease caused by C9ord72 repeats include deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein.
(iii) RNA processing
TDP-43 is a nuclear protein that encodes for RNA-binding proteins. In virtually all ALS cases, TDP-43 aggregates in the cytoplasm of motor neurons, despite TARDBP mutations being rare. FUS is another RNA-binding protein that has a similar function to TDP-43, which causes ALS when the FUS gene is mutated. Recent studies suggested that mutations in the TARDBP and FUS genes increase the binding affinity of the low-complexity domain, causing their respective proteins to misfold and aggregate in the cytoplasm. This may cause misfolding of normal protein both within and between cells in a prion-like manner. Consequently, this decreases levels of RNA-binding protein in the nucleus, which prohibits their target RNA transcripts from undergoing normal processing. Other RNA metabolism genes such as ANG, SETX and MATR3 have been implicated to cause ALS.
A common mechanism in all forms of ALS is excitotoxicity, or neuronal death caused by excess levels of intracellular Calcium due to overstimulation by Glutamate, an excitatory neurotransmitter. It’s known that motor neurons are the most sensitive to excitotoxicity than other neuronal types because they have the least calcium-buffering capacity and contain the AMPA receptor, which has high Calcium ion permeability. Excitatory amino acid transporter 2 (EAAT2) normally acts as the main transporter to remove Glutamate from the synapse. In ALS, EAAT2 levels are decreased, which lead to increased synaptic glutamate levels and excitotoxicity. Currently, Riluzole inhibits glutamate release from pre-synaptic neurons, which can modestly prolong survival in ALS patients. Nevertheless, it’s unclear whether this mechanism is responsible for its therapeutic effect.
How is ALS diagnosed?
Despite the loss of upper and lower motor neurons in a single limb are firm signs of ALS, there currently isn’t a reliable examination that provides a definite diagnosis of ALS. In the meantime, physicians scourge for symptoms and signs of ALS and perform a series of tests to rule out similar diseases. Then they obtain the patient’s full medical history and conduct a neurologic examination at regular intervals to assess whether the symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity worsen.
ALS diagnosis is based on the El Escorial Revised criteria and the Awaji criteria. However, the El Escorial Revised criteria has poor sensitivity for the early stages of ALS, at around 62.2%. The Awaji criteria has better sensitivity, especially for bulbar-onset ALS, at around 81.1%. Both criteria sets have a a specificity of about 98%.
The challenge for physicians is to develop appropriate tests to exclude the possibility of other conditions that elicit similar symptoms to ALS. Electromyography (EMG) can detect electrical activity in muscles, specifically nerve conduction velocity (NCV). Any NCV abnormalities detected could suggest the presence of peripheral neuropathy or myopathy rather than ALS. Although magnetic resonance imaging (MRI) recordings seem normal in early stage ALS, it can reveal signs of other manifestations that directly the symptoms, such as a spinal cord tumour, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis. Blood and urine tests, as well as routine laboratory tests, may be ordered to eliminate the possibility of other diseases known as “ALS mimic disorders”. e.g. A muscle biopsy can be performed for a suspecting myopathy rather than ALS. The infectious diseases that can cause ALS-like symptoms include:
— Human immunodeficiency virus (HIV)
— Human T-Lymphotropic Virus (HTLV)
— Lyme Disease
— Syphilis
Neurological disorders that can cause ALS-like symptoms include:
— Multiple Sclerosis
— Post-polio syndrome
— Multifocal motor neuropathy
— CIDP
— Spinal Muscular Atrophy
— Spinal and Bulbar Muscular Atrophy
— Myasthenic Syndrome (Lambert-Eaton syndrome)
— Benign Fasciculation Syndrome
How is ALS managed?
There is currently no cure for ALS. Therefore, the aim of management is to treat the symptoms and provide supportive care, in order to improve quality of life and prolong survival. This care is best provided by multidisciplinary teams of healthcare professionals, whom advise ALS patients to attend a multidisciplinary ALS clinic in order to prolong survival, minimise hospitalisations, and improve quality of life.
(a) Medications
— A 2011 study found Riluzole modestly prolonged survival by about 2-3 months, or longer for those with bulbar-onset ALS. However its mechanism of action isn’t well understood but researchers infer it limits the release of Glutamate from pre-synaptic neurons. A 2012 study found its common side-effects include nausea and asthenia (lack of energy).
— Edaravone has been found to modestly slow disease progression in early-stage ALS, but the sample size is quite shallow. However its mechanism of action in ALS is unknown and its effectiveness on ALS lacks evidence. A 2017 suggested Edaravone protect motor neurons from oxidative stress, though its side-effects include bruising and gait disturbance. Edaravone treatments cost around $140,000US a year, which requires daily hour-long IV infusions for 10 days in a two-week period, followed by 2 weeks break away from the drug. A 2018 study found that fatigue from these daily infusions or from daily travel to an infusion center may decrease quality of life. While debate is still ongoing, ALS patients are reminded to be knowledgable of the time commitment, high cost, and limited therapeutic benefit before beginning treatment.
Other medications may be administered to reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm.
— Gabapentin, Pregabalin, and Tricyclic Antidepressants (e.g. Amitriptyline) alleviate neuropathic pain.
— Nonsteroidal anti-inflammatory drugs (NSAIDs), Acetaminophen, and Opioids alleviate nociceptive pain.
— Selective Serotonin Reuptake Inhibitors (SSRIs) or tricyclic antidepressants can treat depression.
— Benzodiazepines can treat anxiety.
Although there are treatments to treat the symptoms, there aren’t any effective medications that specifically treat cognitive impairment/frontotemporal dementia (FTD).
— Baclofen and Tizanidine can treat spasticity.
— Scopolamine, Amitriptyline, or Glycopyrrolate can treat sialorrhea (difficulty swallowing one’s own saliva).
— A 2017 review recommended Mexiletine to treat muscle cramps.
(b) Breathing Support
— Non-Invasive Ventilation (NIV): This primarily treats respiratory failure in ALS, which proved to be effective in improving both survival and quality of life in ALS patients by about 48 days. It uses a face or nasal mask connected to a ventilator that provides intermittent positive pressure to support breathing. It’s recommended for ALS patients to avoid continuous positive pressure because it increases difficulty of breathing. Because the first sign of respiratory respiratory failure occurs during sleep, which is decreased gas exchange (hypoventilation), NIV is initially used only at night. Symptoms associated with nocturnal hypoventilation include interrupted sleep, anxiety, morning headaches, and daytime fatigue. However, NIV doesn’t always improve the quality of life nor prolong survival of ALS patients with poor bulbar function compared to those with normal or only moderately impaired bulbar function.
— Invasive Ventilation: This technique bypasses the nose and mouth (the upper airways) by directly inserting a tube connected to a ventilator through an incision in the trachea (tracheostomy). Although it prolongs survival, especially ALS patients younger than 60, it doesn’t treat the underlying neurodegenerative process. Because it doesn’t slow down the loss of motor function and decrease the difficulty of communication, it would lead locked-in syndrome causing muscle paralysis except the extraocular muscles, hence decrease quality of life.
(c) Therapy
Physical, occupational, and speech therapists help set goals and promote benefits for ALS sufferers by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.
Occupational therapists use special equipment such as assistive technology to enhance the patients’ independence and safety throughout the course of ALS. They instruct them to perform gentle, low-impact aerobic exercises such as activities of daily living, walking, swimming, and stationary bicycling to help strengthen unaffected muscles, improve cardiovascular health, and alleviate fatigue and depression. They also recommend range of motion and stretching exercises to help prevent painful spasticity and shortening (contracture) of muscles. It’s important to ensure the ALS patients minimise muscle strains, as muscle exhaustion can worsen ALS symptoms, rather than improve them. They suggest using assistant devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs to help maintain mobility. This ensures ALS sufferers can retain as much safety and independence in activities of daily living as possible.
Speech-language pathologists work with ALS sufferers to improve their communication and formation of verbal speech. They educate them adaptive strategies such as techniques to help them speak louder and more legibly. During the course of ALS, speech-language pathologists recommend using augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head mounted laser pointers, alphabet boards, or yes/no signals.
(d) Nutrition
Preventing weight loss and malnutrition in people with ALS are key aspects in improving both survival and quality of life. Initially, dysphagia is managed by implementing dietary changes and modifying swallowing techniques. Such changes include consuming thicker liquids like fruit nectar or smoothies, as well as soft, moist foods , or adding fluid thickeners to thin fluids like water and coffee.
For ALS patients losing 5% or more of their body weight or unable safely swallowing food and water, physicians insert a feeding tube into them by percutaneous endoscopic gastrostomy (PEG). It can be either a gastrostomy tube (inserted through the wall of the abdomen into the stomach), or nagogastric tube (inserted through the nose and down the oesophagus into the stomach). ALS patients prefer a gastrostomy tube over a nagogastric tube because it is the most appropriate long-term and comfortable with least risk of oeseophageal ulcers. A 2015 study recommended that PEG insertion should be used on patients with advanced ALS and low vital capacities, as long as they are on NIV during the procedure.
(e) Palliative Care
It aims to relieve symptoms and improve quality of life without treating the underlying disease. It’s recommended to begin discussions of end-of-life issues upon confirmation of ALS diagnosis in order for patients to reflect on their preferences for end-of-life care and learn to avoid any unwanted interventions or procedures. This provides
How is research on ALS progressing?
Research on ALS has focused on animal models of the disease, its mechanisms, ways to diagnose and track it, and treatments.
(a) Disease Models
— In vitro: This strategy introduces the disease to cell cultures in petri dishes, where motor neurons grow and gene expression is manipulated. Researchers use the CRISPR/Cas9 technique to knock-out/in genes associated with ALS in order to mimic the human model of ALS for a faster onset of the disease. This allows high-throughput screening for drug candidates for ALS.
A 2017 study discussed the use of induced pluripotent stem cells (iPSC) to investigate familial ALS by isolating a skin fibroblast from a familial or sporadic ALS patient and reprogramming them into a motor neuron to study ALS. Recent results have shown promise its effectiveness on reducing the pathophysiological signs caused by known gene mutations associated with ALS, as well as differentiating into new mature neurons.
— In vivo: This strategy uses animal models to study ALS and to search for a potential therapy such as Saccharomyces cerebivisiae (a species of yeast), Caenorhabditis elegans (a roundworm), Drosophila melanogaster (common fruit fly), Danio rerio (zebrafish), Mus musculus (house mouse), and Rattus Norvegicus (common rat). Currently none of these models perfectly represents ALS in humans, as they are based on mutant gene overexpression. This means multiple copies of the mutant human gene are inserted into the transgenic model, and the human nervous system is more complex than other animal nervous systems. As of 2018,
(b) Potential Treatments
From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs). Every drug except Riluzole was ineffective in clinical trials in humans including antiviral drugs, anti-excitotoxic drugs, growth factors, neurotoxic factors, anti-inflammatory drugs, total lymphoid irradiation, antioxidants, anti-apoptotic drugs and drugs restoring mitochondrial function. Recent reviews found mixed evidence of the effectiveness and safety of stem cell based therapies, even though they can provide additional proteins and enzymes like neurotrophic factors and insulin-like growth factor 1 to help prolong survival and control ALS symptoms. Other medications such as Masitinib, Lamotrigine, Dextromethorphan, Gabapentin, BCAAs, Vitamin E, Acetylcysteine, Selegiline, Amantadine, Cyclophosphamide, β-Adrenergic agonist drugs and various neurotrophic factors demonstrate some promise in both in-vitro and in-vivo models of ALS, but they fail to replicate positive results in human ALS models.
In 2017, Brown and Al-Chalalbi developed a new technique called antisense oligonucleotides that targets specific sequences associated with the C9ORF72 gene in an attempt to slow down the progression of ALS and reduce toxicity. In 2004, Eva Ekestern investigated adeno-associated viruses as a method of delivering drugs and other proteins and genetic components to the central nervous system and aid in protecting neurons from damage caused by ALS.
In 2019, a new ALS/MND drug developed by Australian researchers called Copper-ATSM (Cu-ATSM) has successfully completed its first phase 1 clinical trial. So far, preliminary results show promise in its potential as an effective therapeutic. Thence, phase 2 clinical trials will commence later this year and researchers are optimistic this novel drug can demonstrate to alleviate symptoms of ALS in humans.
https://en.wikipedia.org/wiki/Cerebral_palsy
https://www.youtube.com/watch?v=csKRVW-HN0E&t=262s
Cerebral Palsy (CP) is a group of permanent movement disorders that appear in early childhood. “Cerebral” means “of, or pertaining to, the cerebrum or the brain” and "palsy" means "paralysis, generally partial, whereby a local body area is incapable of voluntary movement”.
CP’s classification is based on the types of motor impairment of the limbs or organs, and restrictions to the activities a healthy person would usually perform with no issue.
— Spastic CP:
= Spasticity is almost exclusively present, and by far the most common type of overall CP, occurring in upwards of 70% of all cases. Symptoms include hypertonia and a neuromuscular mobility impairment stemming from an upper motor neuron lesion in the brain and the corticospinal tract or motor cortex. This leads to impairments in some spinal nerve receptors that normally receive GABA, which causes hypertonia in the muscles signalled by those damaged nerves.
— Ataxic CP:
= Occurs in about 5-10% of all cases of CP, which makes it the least frequent form of CP. The pathology includes damage to cerebellar structures, which compromises motor coordination, muscle movements and balance, specifically in their arms, legs, and trunk. A 2009 study found that ataxic CP causes hypotonia. A 2008 study found it commonly manifests into intention (action) tremor when executing precise movements, such as tying shoe laces or writing with a pencil. This symptom progressively worsens as the movement persists, which causes tremors in the hand. As your hand approaches accomplishment of the intended task, it intensifies the tremors, exponentially increasing the difficulty of completing the task.
— Athetoid CP:
Also known as dyskinetic cerebral palsy (ADCP), it causes pathology in the basal ganglia through lesions during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. Symptoms of ADCP include both hypertonia and hypotonia, due to the sufferer’s loss of muscle tone control. Clinical diagnosis of ADCP typically occurs within 18 months of birth, according to motor function and neuroimaging techniques. A 2007 study classified ADCP as a non-spastic, extrapyramidal form of CP, which can be divided into 2 different groups: choreoathetoid and dystonia. Choreo-athetonic CP elicits involuntary movements most predominantly in the facial muscles and extremities, whereas Dystonic ADCP elicits slow, strong muscle contractions locally or throughout the whole body.
— Mixed CP:
The symptoms are a combination of athetoid, ataxic and spastic CPs, with each to varying degree.
CP is also classified according to the topographic distribution of muscle spasticity:
— Diplegic = Bilateral involvement with leg involvement greater than arm involvement
— Hemiplegic = Unilateral movement
— Quadriplegic = Bilateral involvement with arm involvement equal to or greater than leg involvement.
What are the signs and symptoms of CP?
A 2006 study defined CP as “a group of permanent disorders of the development of movement and posture, causing activity limitation, attributing to non-progressive disturbances that occurred in the developing foetal or infant brain”. Furthermore, CP elicited difficulties with thinking, learning, feeling, communication and behaviour often co-occurring. A 2013 study reported about 28% of CP cases had epilepsy, 50% experienced communication difficulties, and at least 42% experienced visual problems, and 23-56% experienced learning disabilities.
The signs of CP include abnormal muscle tone, reflexes, or motor development and coordination caused by primary and permanent neurological lesions, leading to secondary and progressive orthopaedic manifestations. Muscle-tendon units and bone develop unevenly, which eventually leads to bone and joint deformities. Initially, deformities are dynamic but progressively become static that manifest into joint contractures. These deformities cause increasing gait difficulties manifesting into tip-toeing gait, due to tightness of the Achilles tendon, and scissoring gait, due to tightness of the hip adductors. However, recent articles report diversity in the orthopaedic manifestations of CP in children such as increased, normal or low muscle tone.
Babies born with severe cerebral palsy often have an irregular posture, and their bodies are either floppy or stiff. This occasionally accompanies with other birth defects such as spinal curvature, a small jawbone, or a small head. Symptoms may linger, disappear or become apparent as a child ages. A 2012 study found CP becomes apparent when the baby reaches the developmental stage of 6 - 9 months and begins to mobilise. This is when preferential use of limbs, asymmetry, or gross motor developmental delay is observed. Furthermore, most children with CP drool, which leads to social rejection, impaired speaking, damage to clothing and books, and mouth infections. A 2016 study reported an average of 55.5% of people with CP experience lower urinary tract symptoms, commonly with excessive storage issues instead of voiding issues. Those with voiding issues and pelvic floor overactivity can deteriorate in adulthood and lead to upper urinary tract dysfunction.
— Skeleton:
A 2016 study suggested people with CP are at risk of low bone mineral density. A 2014 study found the bone shafts of CP patients are often gracile, and continues to thin during growth. A 2009 study found that articular cartilage may atrophy caused by muscular imbalances due to abnormal joint compression, which leads to narrowed joint spaces. Depending on the degree of spasticity, a person with CP may exhibit a variety of angular joint deformities. Spasticity and abnormal gait hinders proper or full bone and skeletal development, which compromises height compared to the average healthy person. Children affected by CP and have high GMFCS (Gross Motor Function Classification System) levels are at risk of contracting low trauma fractures in their legs, which compromises their ability to walk. This further impacts on their mobility strength, experience of pain, and school attendance or child abuse suspicions. Recent studies found hip dislocation and ankle equinus or planter flexion are the 2 most common deformities among CP children, in addition to hip and knee flexion deformities. Moreover, CP patients would experience torsional deformities of long bones such as the femur and tibia. A 2016 study estimated between 21-64% of CP children younger than 10 may develop scoliosis and hip dislocation / migration, which correlates with higher levels of impairment on the GMFCS.
— Eating:
Due to sensory and motor impairments, CP patients experience difficulty preparing food, holding utensils, or chewing and swallowing. A 2010 study observed a CP baby was unable to suck, swallow, or chew, which may activate gastro-oesophageal reflux. This could be cause over- or undersensitivity around and in the mouth. Self-feeding can be difficult due to imbalance in the seated position, improper control of the head, mouth and trunk, inability to bend the hips adequately in order for the arms to stretch forward to reach and grasp food or utensils, and lack of hand-eye coordination. This could manifest into dental problems, as well as pneumonia due to undetected aspiration of food or liquids. This increases the risk of malnutrition, especially those with oropharyngeal issues.
— Language:
Speech and language disorders are common in people with CP. Studies in 2010 and 2014 recorded incidence of dysarthria between 31% to 88%, and around 25% of CP patients are non-verbal, respectively. A 2013 study also found those speech problems associate with poor respiratory control, laryngeal and velopharyngeal dysfunction, and oral articulation disorders due to restricted movement in the oral-facial muscles.
— Pain and Sleep:
A 2004 study reported pain in CP caused by inherent deficits associated with the condition, as well as numerous procedures children typically face. A 2017 study reported CP patients experiencing pain also experienced worse spasms. Pain often corresponds with tight or shortened muscles, abnormal posture, stiff joints, unsuitable orthosis, etc. caused by hip migration or dislocation.
A 2006 study estimated a high likelihood of chronic sleep disorders secondary to both physical and environmental factors. A 2015 study recorded higher rates of sleep disturbances among CP children compared to typically developing children. A 2012 study observed higher rates of CP babies suffering from stiffness crying and difficulty tucking in to sleep compared to non-disabled babies.
— Associated disorders:
They include intellectual disabilities, seizures, muscle contractures, abnormal gait, osteoporosis, communication disorders, malnutrition, sleep disorders, and mental health disorders, such as depression and anxiety. Moreover, functional gastrointestinal abnormalities may also arise, causing bowel obstruction, vomiting, and constipation. A 2006 study found adults with CP suffer from ischemic heart disease, cerebrovascular disease, cancer, and trauma more often. A 2017 study found that CP patients who are obese or a more severe GMFCS assessment are potential risk factors for multimorbidity.
What is the epidemiology of CP?
A 2013 study recorded CP affects about 2.1 per 1000 live births, and about 1 per 1000 children born at term. A 2006 study suggested CP may likely those living in poor financial circumstances. 2002 study recorded higher CP rates in males than females, and 1.3 times more common in European males than European females. Between the 1970s and 1990s, a 2013 study recorded a increase in the prevalence of CP, which may be caused by increases in low birth weight of infants and increases in survival rates of infants. This may be due to the disability rights movement challenging perspectives around the worth of infants with disability, as well as the Baby Doe Law. As of 2005, advances in healthcare of pregnant mothers and their newborns failed to decrease the prevalence of CP. Instead it increases with premature or very low-weight babies regardless of the quality of care.
How was CP discovered?
CP has been known since antiquity with a decorated grave marker dating from around the 15th to 14th century BCE illustrating a figure with a small leg and using a crutch. The oldest physical evidence of CP most likely originated from the mummy of Siptah, an Egyptian Pharoah who ruled from about 1196 to 1190 BCE and was 20 when he died. The medical literature of the ancient Greeks discussed paralysis and weakness of the arms and legs, describing it as ‘palsy’, which comes from the Greek words παράλυση or πάρεση, meaning paralysis or paresis respectively. The works of the school of Hippocrates (460–c. 370 BCE), and the manuscript On the Sacred Disease described a cluster of problems that closely resonates with the modern understanding of cerebral palsy. Around the early decades of the 1800s, a number of publications on brain abnormalities by Johann Christian Reil, Claude François Lallemand and Philippe Pinel shaped the modern understanding of CP, with later research on brain anatomy and physiology correlated different brain lesions with specific symptoms. An English surgeon named William John Little (1810–1894) was the first scientist to extensively study CP and stated that it resulted from around the time of birth. Later he identified risk factors including a different delivery, a preterm birth and perinatal asphyxia. The spastic diplegia form of CP became to be Little’s Disease. In the 1880s British neurologist, William Gowers linked paralysis in newborns to difficult births by which he named the problem "birth palsy" and classified birth palsies into two types: peripheral and cerebral.
What are the causes of CP?
CP is caused by abnormal development or damage in the developing brain, which can occur during pregnancy, delivery, the first month of life, or less commonly in early childhood. In 2013, John Yarnell identified neurological structural problems in 80% of CP cases, particularly in the white matter. More than 75% of CP cases are thought to be caused by unknown neurobiological issues during pregnancy. In certain cases, the cause is currently unknown. However, typical causes of CP have been suggested such as problems in intrauterine development (e.g. exposure to radiation, infection, foetal growth restriction), hypoxia of the brain (thrombotic events, placental conditions), birth trauma during labor and delivery, and complications around birth or during childhood. A 2015 study on African newborns proposed birth asphyxia, high bilirubin levels and infections of the CNS are the main causes of CP.
— Preterm Birth:
A 2009 study recorded 40-50% of all children who develop CP were born prematurely. About 75-90% of these cases are believed to be caused by complications occurring around the time of birth, or just after birth. A 2011 study found multiple-birth infants have a higher risk of developing CP compared to single-birth infants, as well as have a higher likelihood of being born with a low birth weight. A 2013 study recorded about 6% of newborns developed CP whose birth weight was between 1 - 1.5kg, as well as 11% of newborns born before 28 weeks of gestation. Studies in 2012 suggested genetic factors may contribute in prematurity and cerebral palsy generally, as well as those born between 34 and 37 weeks have 0.4% risk of developing CP.
— Term infants:
Babies born at term are vulnerable to many risk factors including placental problems, birth defects, low birth weight, inhaling meconium into the lungs, birth delivery using either instruments or an emergency Caesarean section, birth asphyxia, postnatal seizures, respiratory distress syndrome, low blood sugar, and infections in the baby. However, recent studies casted doubt over the role of birth asphyxia and placental size in attributing to CP.
— Genetics:
A 2016 study recorded about 2% of all CP cases are inherited in an autosomal recessive manner, which associates with Glutamate Decarboxylase-1.
— Early childhood:
A 2017 study suggested other causes of CP include toxins, severe jaundice, lead poisoning, physical brain injury, stroke, abusive head trauma, hypoxia to the brain, and encephalitis or meningitis. But further research is required to conclusively prove these possible causes attribute to CP.
— Others:
A 2007 study suggested certain infections in the mother can triple the risk of their children developing CP. One of them is known as chorioamnionitis, which infects the foetal membranes. A 2012 study suggested Intrauterine and neonatal insults, albeit infectious, poses a serious risk of developing CP. A 2005 study hypothesised some cases of CP are caused by the death of an identical twin during early pregnancy. A 2017 study found that Rh blood type incompatibility causes the mother’s immune system to attack the baby's red blood cells.
How is CP diagnosed?
CP diagnosis involves checking a person’s medical history and conducting a physical examination like a general movements assessment, which measures movements occurring spontaneously among those less than 4 months of age. Physicians would easily notice the symptoms of the most severely affected children early, leading to a diagnosis around 2 years old. Children with milder symptoms would have their diagnosis delayed to about 5 years old or older. Once diagnosis is confirmed, further diagnostic tests are optionally conducted including neuroimaging techniques like CT and MRI. Either of these techniques are capable of revealing treatable conditions, such as hydrocephalus, porencephaly, arteriovenous malformation, subdural hematomas and hygromas, and a vermian tumour in about 5-22% of the time. This signifies the likelihood of associated conditions, such as epilepsy and intellectual disability.
How is CP managed?
https://en.wikipedia.org/wiki/Management_of_cerebral_palsy
CP management focuses on developing treatments as part of the aim of maximising a patient’s independence and community engagement such as childhood therapy to improve gait and walking. Because cerebral palsy has "varying severity and complexity" across the lifespan, a 2016 article considered a collection of conditions for management purposes such as a multidisciplinary approach. This aims to maximise individual function, choice and independence" in line with the International Classification of Functioning, Disability and Health’s goals. A 2017 article outlined a multidisciplinary team including a paediatrician, a health visitor, a social worker, a physiotherapist, an orthotist, a speech and language therapist, an occupational therapist, a teacher specialising in helping children with visual impairment, an educational psychologist, an orthopaedic surgeon, a neurologist and a neurosurgeon.
(a) Lifestyle
= Therapists recommend physical activity for CP patients in order to improve their cardiorespiratory endurance, strengthen muscle and reduce sedentary behaviour. However, it depends on the caregivers' perception of the benefits of CP patients performing such exercise as muscle functionality decreases with age. Despite the lack of plausible supporting evidence, the amount of recommended exercise advised has to be unique to the demands of the sport in question, the effect of the individual’s condition on performance, and the potential to cause worsening of the condition.
(b) Therapy
— Physiotherapy: These programs encourage the patient to build a strength base for improved gait and volitional movement, combined with stretching programs to limit contractures. Physiotherapists educate parents of children with CP correct positioning and handling of their child for activities of daily living.
— Speech Therapy: This aims to control muscles of the mouth and jaw, and ultimately improve communication. A 2004 study recommended to begin speech therapy prior to a child with CP attending their first class and then continue throughout the school years.
— Biofeedback: This therapy helps CP patients learn to control their affected muscles.
— Massage Therapy: This aims to relax tense muscles, strengthen muscles, and keep joints flexible.
— Gait Analysis: This describes gait abnormalities in children, and gait training aims improve walking speed in children and young adults with CP.
— Occupational Therapy: This aims to help adults and children maximise their function, adapt to their limitations and live as independently as possible. Occupational therapists negotiate with families strategies to address all of their concerns and priorities for their affected child.
— Constraint-induced movement therapy (CIMT): This technique aims to cope with hemiplegia by forcing the patient to learn to use their affected limbs, whilst they constrain their unaffected limbs.
(c) Assistive technology
This is used to promote the independence of people with disabilities. Common assistive technologies provided to CP patients include patient lifts, electric wheelchairs, orthotics, seating systems, mealtime aids (e.g. large-handled cutlery, slip-resistant mats), mobility aids, standing frames, non-motorised wheelchairs, augmentative and alternative communication, and speech-generating devices. A 2017 study has shown promise in 3D printing of customised orthotics on-demand.
Orthotic devices such as ankle-foot orthoses (AFOs) can be prescribed to objectively correct and/or prevent deformity, provide a base of support, facilitate training in skills, and improve the efficiency of gait. It aims to positively impact on all temporal and spatial parameters of gait, i.e. velocity, cadence, step length, stride length, single and double support, as well as energy expenditure. A 2006 study found that children with CP using orthoses, such as casts and splints, have their joint abnormalities corrected or prevented, joints stabilised, undesired movements avoided, desired movements executed, and permanent muscle shortening avoided. A 2001 study noted that they allow children with CP with dress easier or maintain hygiene.
Children afflicted with CP using appropriate seating equipment and wheelchairs have their body stabilised, allowing the use of their arms for other activities, therefore independence. It’s important to combine this with accessible housing.
(d) Medication:
— Botulinum Toxins = This drug is injected into spastic or dystonic muscles, in order to reduce the painful muscle hypertonus, which facilitates. bracing and the use of orthotics. A 2015 article recommended low doses of BoTox in a way to reduce severe side-effects including BoTox hypersensitivity and severe allergic responses to the drug.
— Biphosphonates = This drug treats osteoporosis in adults.
— Anticholinergics = This drug reduces drooling, but may cause constipation as a side-effect.
— Oral Baclofen or Diazepam = These drugs reduce spasticity, with Baclofen working at the spinal level long-term, while Diazepam works short-term.
(e) Surgery:
— Orthopaedic surgery = This helps correct fixed deformities and improve the functional capacity and gait pattern of children with CP such as ankle equinus and hip adduction deformity, hence sublaxation. It consists of tendon releases, lengthening, transposition and corrective osteotomies. e.g. Fixed/static ankle equinus is usually managed by Gastrocnemius-Soleus aponeurotic lengthening or tendon Achilles lengthening, while hip subluxation/dislocation is usually managed by adductor musculature release with or without a Psoas tendon release together with femoral and pelvic osteotomies.
— Baclofen pump = When the patient is a young adult, this is inserted in the left abdomen connecting to the spinal cord. There, the pump releases doses of baclofen to alleviate continuous muscle flexion. The pump can be adjusted if muscle tone is worse at certain times of the day or night, thus it’s appropriate for individuals with chronic, severe stiffness or uncontrolled muscle movement throughout the body.
— Rhizotomy = This procedure severs nerves that innervate limbs most affected by movements and spasms. It aims to reduce spasms and allow more flexibility and control of the affected limbs and joints
— Tracheotomy
— Dental surgery
— Diagnostic endoscopy
— Nissen fundoplication
— Gastrostomy = This aims to deal with eating difficulties. It involves inserting a feeding tube through an orifice through the belly skin and into the stomach.
— Total hip arthroplasty = This surgical technique aims to reduce pain caused by hip dislocation.
(f) Others
— Whole-body vibration = This aims to improve speed, gross motor function and femur bone density in children with cerebral palsy.
— Aquatic therapy = Also known as hydrotherapy, it involves children with CP exercising in water rather than on land, which may increase interest and require different kinds of movement such as jumping or skipping with less impact on their joints.
— Hip surveillance = This monitors a child with CP at risk of hip dislocation, which can be confirmed with radiography.
— Music therapy = This aims to motivate or relax children as an auditory feedback. It involves children with CP learning to play percussion instruments and piano as part of groupwork in therapy.
— Video game rehabilitation = In the modern era, children are motivated to engage in video gameplay. However, more credible research is required to associate video games with improved balance and motor skills.
— Service dogs = This assists people suffering from seizures caused by their CP.
— Yoga = Carers use this technique as part of the physical therapies to develop basic motor skills in children with CP.
(g) Research
So far, research into CP covers children and adolescents, and less so adults. Stem cell therapy, cell-based treatments and deep brain stimulation are proposed as possible CP treatments. A 2016 study implicated research in genetics and genomics, teratology, and developmental neuroscience may yield improved understanding of CP. Genetic testing may discover the aetiology or comorbidities for various types of CP, which may lead to the clarification of the classification systems for CP. Recent reviews have found the neuroplasticity requires intensive research as a possible treatment for CP.
If you want to know the names of every movement disorder, click on the link below.
https://en.wikipedia.org/wiki/Movement_disorders
Prior to participation in upcoming job internships, sports matches, Olympic events, military service and ceremonies, graduate positions, specialist roles, fitness program, mountaineering and orienteering, religious sessions, space and special intelligence missions, you are instructed by your managers, bosses, employers, or superiors to undergo training or practice simulation sessions. Moreover, prior to your theatric, playwright, opera, musical, acting, orchestral or choir ensemble performance, you would need to undergo rehearsals. But why?
I’ll answer that question in another post.
