Neuromuscular Communication and Motor Control Notes

Neuromuscular Communication

Microstructure of Skeletal Muscle

• The structural unit of a muscle is the muscle cell.
• There are approximately 270 million muscle cells in the human body.
• Muscle cells are also known as muscle fibers due to their length (1-3 inches on average, some at 24-28 inches) and thinness (0.0004-0.004 inches).
• Muscle fibers grow in both length and diameter, with diameter increasing up to 5 times until adulthood.
• Strength training (heavy resistance and low repetitions) can lead to substantial increase in muscle cell diameter, termed hypertrophy.

Muscle Fiber Composition

• Muscle fibers are composed of thin fibers called myofibrils.
• Myofibrils consist of finer threads called myofilaments:
  • Thick myofilaments (containing the protein myosin)
  • Thin myofilaments (containing the protein actin)
• Sarcomere delineated by Z-lines.

Contraction

• During stimulation of the muscle cell, the motor neuron releases the neurotransmitter acetylcholine (ACh).
• ACh travels across the neuromuscular junction.
• ACh binds to a post-synaptic nicotinic ACh receptor.
• This binding causes a change in the receptor conformation, allowing an influx of sodium ions and initiation of a post-synaptic action potential.
• The action potential travels along T (transverse) tubules until it reaches the sarcoplasmic reticulum.
• The electrical excitation of the sarcolemma, when propagated as a muscle action potential, triggers events inside the cell, resulting in the development of contractions.

Role of $Ca^{++}$

• In the sarcoplasmic reticulum, the depolarized membrane activates voltage-gated L-type calcium channels, present in the plasma membrane.
• Calcium concentrations in the sarcoplasm are responsible for the movement of the filaments.
• Increases in calcium concentration in the sarcoplasm start the filaments sliding; decreases turn them off.
• When a muscle is relaxed, there is a relatively low calcium concentration in the sarcoplasm because the sarcoplasmic reticulum (SR) membrane contains calcium pumps that actively move calcium from the sarcoplasm into the SR, utilizing ATP to power these pumps.

How Filaments Move

• ATP acts to "power" the contraction.
• The physical shortening occurs due to shape changes in the myosin heads as they form, break, and reform bonds to the actin filament.
• The myosin heads contain binding sites for ATP.
• Immediately upon the binding of the high-energy myosin head to actin, the ATP breaks down to ADP and an organic phosphate.
• As these particles are released, the myosin head changes shape, producing a power stroke as the head swivels toward the center of the sarcomere.
• This action draws the actin filament past the myosin filament toward the H zone, effectively producing a mechanical shortening (force).

Physiology of Skeletal Muscle Contraction - Events at the Myofilaments

• The active site on actin is exposed as $Ca^{2+}$ binds troponin.
• The myosin head forms a cross-bridge with actin.
• During the power stroke, the myosin head bends, and ADP and phosphate are released.
• A new molecule of ATP attaches to the myosin head, causing the cross-bridge to detach.
• ATP hydrolyzes to ADP and phosphate, which returns the myosin to the "cocked" position.

Steps of Muscle Contraction

1. ATP binds to myosin, making it detach from actin (ATP = Freedom).
2. ATP turns into ADP, releasing energy to convert myosin heads into a "cocked" state.
3. Calcium binds to troponin, which exposes sites on actin that myosin can grab.
4. Myosin then completes a power stroke, pushing on the actin (Actin Movement).

Relaxation

• Relaxation occurs with the cessation of the muscle action potential.
• Acetylcholinesterase in the synaptic cleft of the myoneural junction rapidly degrades acetylcholine, causing its effect to be short-lived.
• The muscle action potential ends, and the membrane pumps of both the sarcolemma and SR membrane actively move ions to re-establish the resting membrane potential across the sarcolemma and to actively sequester calcium in the SR.
• With the calcium concentration in the sarcomere reduced, the troponin-tropomyosin complex regains its resting shape, covering the binding sites on actin and effectively preventing crossbridge formation. The sarcomeres then return to their resting lengths.

Review on Electrical and Chemical Signaling for Muscle Contraction

1. Electrical signal from motor neuron.
2. Release of neurotransmitter (Ach) from the axon terminal into the neuromuscular junction.
3. Ach binding to AChR and opening $Na^+$ channels.
4. $Na^+$ influx resulting in depolarization.
5. If it passes the threshold, resulting in an action potential (AP), which travels down to the T tubule.
6. Voltage-depended $Ca^{++}$ channels open, releasing $Ca^{++}$ from SR.
7. $Ca^{++}$ binding allows for the myosin binding sites on actin to be available.
8. Myosin forms a bridge with actin.
9. ADP and P release from the myosin head allows it to bend, pulling the actin (power stroke).
10. ATP binding to the myosin head causes it to detach from actin.
11. This process repeats until $Ca^{++}$ is cleared out.

Group Activity Questions

• Q1: Drug FO4 for motor function disorder. Possible mechanisms:
  • A. Blocking the sodium channels on the post synapse of the neuromuscular junction
  • B. Degrading acetylcholinesterase at the synapse
  • C. Inhibiting ATP breakdown into ADP and P
  • D. Increasing the threshold for action potentials at the post synapse
• Q2: Drug acts on sarcoplasmic reticulum. What would you NOT expect?
  • A. Increased cross-bridge formation with myosin and actin
  • B. Increased calcium release from sarcoplasmic reticulum
  • C. Increased depolarization at the post synapse
  • D. Z-lines getting closer to each other

Managing Muscle Contraction

• Skeletal muscles are made up of thousands of muscle fibers.
• A single motor neuron may directly control a few fibers within a muscle, or hundreds to thousands of muscle fibers.
• All of the muscle fibers controlled by a single motor neuron constitute a motor unit.

Motor Unit Size

• The size of the motor unit determines how fine the control of movement can be.
  • Small motor units → precise control (e.g., eye muscles).
  • Large motor units → gross control (e.g., leg muscles).

Recruitment and Muscle Tone

• Recruitment is the ability to activate more motor units as more force (tension) needs to be generated.
• There are always some motor units active, even when at rest. This creates a resting tension known as muscle tone, which helps stabilize bones & joints.
• Hypertrophy – "stressing" a muscle (i.e., exercise) causes more myofilaments/myofibrils to be produced within muscle fibers, resulting in more force (strength) as well as larger size.

Control of Movement: The Sensorimotor System

The Movement

• Movement is a physical displacement in time and space of the location of a body or body part (e.g., moving an arm forward).
• Action is defined as a voluntary movement directed to a goal (e.g., moving arm forward to reach a cup of tea).
  • Transitive actions: oriented towards an object (e.g., reaching for a cup of tea).
  • Intransitive actions: not oriented towards an object (e.g., waving a hand to say hello).

Brain and Movement

• Different brain regions of the motor system participate in observable movement execution and internal action processes.
• Internal action processes include:
  • Having the intention to move.
  • Planning a movement or a sequence of movements.
  • Implementing this order by sending commands to the muscles.

Different Levels of Movement Organization

• To perform postures in a meaningful order, we need:
  • Visual information about our body posture and movement timing.
  • Mental representations of these movements in motor control.
  • Organization of these representations, decision-making, and execution of actions.
• The sensorimotor system allows us to control the output to create voluntary movement.

Three Principles of Sensorimotor Function

1. The sensorimotor system is hierarchically organized.
2. Motor output is guided by sensory input.
3. Learning can change the nature and the locus of sensorimotor control.

Hierarchical Organization of the Sensorimotor System

• Analogy to a company structure:
  • Association Cortex (company president): Specifies general goals rather than specific plans of action.
  • Secondary Motor Cortex
  • Primary Motor Cortex
  • Brainstem Motor Nuclei
  • Muscles (workers)
  • Behavior

Motor Output Guided by Sensory Input

• Efficient companies monitor their own activity and use this information to fine-tune their activity.
• The sensorimotor system uses the following to monitor the body’s responses and provide sensory feedback:
  • The eyes.
  • The organs of balance.
  • The receptors in the skin.
  • Muscles.
  • Joints.

Learning and Sensorimotor Control

• During the initial stages of motor learning, each individual response is performed under conscious control.
• Later on, after much practice, individual responses become organized into continuous integrated sequences of action.
• Example: Walking, swimming, lay up.
• It becomes harder to think actions through into smaller steps instead of doing it automatically as one continuous movement.

Sensorimotor Hierarchy

• Association Cortex (Highest Level)
• Secondary Motor Cortex (Middle Level)
• Primary Motor Cortex
• Sensorimotor cortex
• Basal ganglia
• Thalamus
• Brainstem Motor Nuclei (Local Level)
• Brainstem
• Muscles
• Behavior
• Motor neurons (Final common pathway)
• Cerebellum
• Afferent neurons
• Muscle fibers
• Receptors

Sensorimotor Association Cortex

• Posterior Parietal Cortex
• Dorsolateral Prefrontal Association Cortex
• The association cortex specifies general goals, not the specific details.

Posterior Parietal Association Cortex

• For movement in space, the nervous system must know:
  • The original position of the parts of the body (point of initiation).
  • The positions of any external objects with which the body is going to interact.
• The posterior parietal association cortex plays an important role in integrating these two kinds of information, directing behavior and attention.

Information Sources for PPAC

• PPAC receives substantial information from multiple sensory systems:
  • The visual system.
  • The auditory system.
  • The somatosensory system.
• PPAC outputs go to:
  • The areas of motor cortex.
  • The dorsolateral prefrontal association cortex.
  • Secondary motor cortex.
  • Frontal eye field (controls eye movements).

Damage to the Posterior Parietal Cortex

• Deficits in:
  • Perception
  • Memory of spatial relationships
  • Accurate reaching and grasping
  • Control of eye movement
  • Attention
  • Proprioception (awareness of limb positioning)
• Most Striking examples:
  • Apraxia
  • Contralateral neglect

Apraxia

• Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements.
• Apraxic patients have difficulty performing specific movements when they are asked to do so, even though they are perfectly able to perform the movement at any other time when they are not thinking about it.
• Usually caused by unilateral damage to the left posterior parietal cortex or its connections; symptoms are bilateral.

Types of Apraxia

• Conceptual apraxia: Difficulty remembering which tool or object to use for a task (e.g., knowing a comb is for hair).
• Ideational apraxia: Difficulty remembering all the steps and the order of steps needed to complete a task (e.g., writing and mailing a letter).
• Ideomotor apraxia: Difficulty moving the correct joints of the body or coordinating joint movement such that the tool makes the correct movement in space (e.g., slicing bread with improper elbow and shoulder movements).

Contralateral Neglect

• Not being able to respond to stimuli on the side of body opposite to the side of the brain lesion, in the absence of simple sensory or motor deficits.
• Most patients often behave as if half (mostly left) of their body doesn’t exist due to large lesions to (mostly right) posterior parietal lobe, and they fail to appreciate the problem.
• Egocentric left is partially defined by gravitational coordinates (tilting the head does not change the field of neglect).

Dorsolateral Prefrontal Association Cortex

• Receives projections from posterior parietal cortex.
• Sends projections to areas of secondary motor cortex, to primary motor cortex, and the frontal eye field.
• Plays a role in:
  • Evaluation of external stimuli.
  • The initiation of voluntary reactions to them.

Neurons in Dorsolateral Prefrontal Association Cortex

• Studies with monkeys identified the role of neurons as the monkeys identify and respond to objects.
• Neurons in this area fire first (of all cortical neurons) right before the response to an object and continue to fire until the response is complete.
• Suggesting that decisions to initiate voluntary movement may be made in this area, but these decisions depend on critical interactions with posterior parietal cortex.

Secondary Motor Cortex

• Premotor cortex.
• Supplementary motor area.
• Cingulate motor areas.

Characteristics of Secondary Motor Cortex

• Receives much of its input from association cortex.
• Sends much of its output to primary motor cortex.
• Four areas of secondary motor cortex:
  • The supplementary motor area.
  • The premotor cortex.
  • Two cingulate motor areas.
• Neurons in the secondary cortex areas often become more active just before the initiation of a voluntary movement and stay active throughout the movement.

Role of Secondary Motor Cortex

• Involved in the programming of specific patterns of movements after taking general instructions from the dorsolateral prefrontal cortex (PFC).
• Brain-imaging studies reflect brain activity measured while the subject is either imagining her own performance of a particular series of movements or planning the performance of the same movement.

Observation and Brain Activity

• fMRI study used to study differences in brain activity between watching an action that one has learned to do and an action that one has not.
• Assessed whether the brain processes of action observation are modulated by the expertise and motor repertoire of the observer.

Mirror System

• Bilateral activations in premotor cortex and some parietal areas when expert dancers viewed movements that they had been trained to perform compared to movements they had not.
• The supplementary motor area and motor cortex are typically not activated unless an element of movement preparation is also involved.

Mirror Neurons

• The human brain contains specialized parietal-premotor circuits (‘‘mirror system’’) that are activated when observing and understanding the actions of others.
• Mirror neurons are neurons that fire when one performs a particular goal-directed movement or when she observes the same movement performed by another.
• One should ask whether these areas contain a truly motor representation or simply general knowledge about the observed action.

Visual Familiarity or Motor Familiarity

• Activations show the interaction between subject gender and performer gender for gender-specific moves, minus the same interaction for common moves. This difference between two-way interactions reveals the additional activation associated when the subject observes a move for which he or she possesses the motor schemata, compared to observing moves for which he or she does not possess the motor schemata.

Mental Imagery

• Mental imagery: the ability to simulate in the mind information that is not currently perceived by the senses.
• Has been used in sport and music to enhance performance.
• Mental training: Symbolic rehearsal of a physical activity in the absence of any gross-muscular movements.

Primary Motor Cortex

• The major point of convergence of cortical sensorimotor signals.
• The major, but not the only, point of departure of sensorimotor signals from the cerebral cortex.

Primary Motor Cortex Function

• Organized somatotopically (according to a map of the body).
• The somatotopic layout of the human PMC is referred to as the motor homunculus.
• Most of the PMC is dedicated to controlling parts of the body that are capable of intricate movements, such as the hands and the mouth.
• Each site in the PMC receives sensory feedback from receptors in the muscles and joints that the site influences as well as the skin for general pattern of feedback.

Proximity of face and hand on PMC

Phantom sensation occurs in an amputated hand if the face is touched. Why does that occur?

Damage to Primary Cortex

• Has less effect than one might expect.
• Lesions may cause:
  • Disruption in the ability to move one body part (i.e., fingers) independently of others.
  • Reduced speed, accuracy, and force of movements.
• Does NOT eliminate voluntary movement or cause paralysis!
• This is due to parallel pathways that descend directly from secondary motor cortex to subcortical motor circuits without passing through primary motor cortex.

Cerebellum and Basal Ganglia

• Neither is part of the sensorimotor hierarchy.
• Both interact with different levels of the hierarchy, coordinating and modulating its activities.

Cerebellum

• Receives:
  • Information from primary and secondary motor cortex.
  • Information about descending motor signals from brain stem nuclei.
  • Feedback from motor responses via somatosensory and vestibular systems.
• Compares these three sources of input and correct ongoing movements that deviate from their intended course (inspector for the company).

Damage to Cerebellum

• Loss in precise control in direction, force, velocity, and amplitude of movements.
• Loss in ability to adapt patterns of motor output to changing conditions.
• Difficulty in maintaining steady postures, and attempts to do so frequently lead to tremor.
• Severe disturbances in balance, gait, speech, and control of eye movement.
• Difficulty in learning new sequences.

Basal Ganglia

• Main components:
  • The striatum (caudate nucleus and putamen).
  • The globus pallidus.
  • The substantia nigra.
  • The nucleus accumbens.
  • The subthalamic nucleus.
• Contribute few fibers to descending motor pathways, unlike cerebellum.
• Basal ganglia are involved in a variety of cognitive functions (procedural & response learning), in addition to their role in the modulation of motor output.
• Major role: Part of neural loops that receive cortical inputs from various cortical areas and transmit it back to cortex via the thalamus.
  • Many of these loops carry signals to and from the motor areas of the cortex.

Basal Ganglia Functions - Summary

• Compare proprioceptive information and movement commands.
• Sequence movements.
• Regulate muscle tone and muscle force.
• May be involved in selecting and inhibiting specific motor synergies.

Functional Brain Imaging of Sensorimotor learning

PET study by Jenkins and colleagues (1994).
Subjects performed 2 different sequences of key presses.
(4 keys, each sequence was 4 presses long).
Performed every 3 seconds, with tones indicating when and whether the press was correct.
There were 3 conditions: Rest, newly learned sequence, and well-practiced sequence.

Sequences of Finger Movements Recorded by PET

Activation patterns during newly learned vs. well-practiced sequences

Summary and main findings

1. Posterior parietal cortex (PPC) was activated during the performance of both newly-learned and well- practiced sequence, but it was more active during the newly-learned sequence.
   Consisted with the hypothesis that the PPC integrates sensory stimuli (in this case, tones) that are used to
   guide motor sequences and that PPC is more active when subjects are attending more to the stimuli (during
   early stages of learning)

2. Dorsolateral prefrontal cortex (PFC) was activated during the performance of the newly learned sequence but not the well-practiced sequence.
   This suggests that the dorsolateral PFC plays an important role when motor sequences are being performed largely under conscious control (early stages of learning)

Summary and main findings

3. Secondary motor cortex→ Contralateral premotor cortex was more active during newly- learned sequences
   Premotor cortex plays a major role when the performance is guided largely by sensory input
   Supplementary motor cortex was bilaterally active during well-rehearsed sequences
   Supplementary motor areas play an important role when the performance is largely INDEPENDENT of sensory stimuli.
4. Contralateral basal ganglia were equally activated.
   Although there may be differential activation of subpopulations of neurons during the two conditions which
   may not have been detected because of the poor spatial resolution of PET.

Summary and main findings

5. Contralateral primary motor and somatosensory cortexes were equally activated.
   Consistent with the fact that the motor elements
   were same during both sequences
6. The cerebellum was bilaterally activated during both, but was more active during the newly
   learned sequence.
   Cerebellum plays a prominent role in motor learning