NEUROMOTOR SYSTEM

UPPER MOTOR NEURONS

• cortical motor neurons within M1

• motor neurons within the brainstem (extrapyramidal neurons)

LOWER MOTOR NEURONS

• neurons in the anterior horn of the spinal cord

• neurons within the cranial nerve nuclei within the brainstem

FOUR SYSTEM FOR MOTOR CONTROL

1. Descending Systems

• Upper motor neurons

• Motor cortex

• Brainstem centres

2. Basal Ganglia

• initiation of wanted movement

• suppression of unwanted movement

3. Cerebellum

• coordination of ongoing movement

4. Brainstem circuits and Spinal cord

• lower motor neurons

• local circuit neurons

• motor neuron pools

SKELETAL MUSCLE ESSENTIAL FUNCTIONS

• Movement

• postural maintenance and joint stability

• heat generation (active contraction & shivering)

• venous return (veins rely on valves + SkM pumping)

• lymphatic drainage

• reproduction, digestion, excretion

NEUROMUSCULAR JUNCTION

The specialised connection between the motor nerve ending and skeletal muscle.

• biggest chemical synapse in body

• excitable

• can undergo reinnervation if damaged

MUSCLE ACTION POTENTIAL STEPS

1. AP arrives at nerve terminal

2. Triggers opening of voltage gated calcium channels

3. Calcium influx

4. ACh released by exocytosis at active zones

5. ACh crosses cleft and binds to its ligand gated receptor

6. Ion channels open

7. Na+ in / K+ out

8. Depolarisation of endplate

9. Local current opens voltage gated Na+ channels nearby

10. Na+ entry causes resting potential to rise from -70 to -60mV

11. Triggers muscle AP

12. ACh destroyed by acetylcholinesterase

ACETYLCHOLINESTERASE

• Enzyme in synaptic cleft

• degrades ACh

• recycles choline back to nerve terminal

• Keeps ACh concentration controlled so receptors aren’t desensitised

SAFETY FACTOR

The neuromuscular junction has a high safety factor to ensure endplate potentials never fail to trigger an action potential.

• This is done by there always being enough AChR’s to bring the endplate potential to threshold.

CLUSTERING ACHR’S

Motor nerves release agrin which binds to its muscle receptor LRP4-MuSK, which drives phosphorylation and recruitment of Dok7, which via Rapsyn, clusters AChR’s into a dense patch below the nerve terminal.

• this pathway drives muscle gene expression

• mutations in LRP4, MuSK, Dok7 or Rapsyn reduce AChR density and cause congenital myasthenia gravis.

MOTOR NEURON DISEASE

Total failure of neuromuscular synapses leading to muscle paralysis and death due to respiratory muscles failing to contract.

MOTOR NEURON DISEASE CAUSED BY

1. Loss of neuromuscular connections

2. Death of alpha motor neurons

• nucleocytoplasmic transport defects

• altered RNA metabolism

• mitochondrial dysfunction

• neuroinflammation

• failure of neuromuscular signalling to muscle

MOTOR NEURON DISEASE DRUG TREATMENTS

RILUZOLE

• anti-excitotoxic

• inhibits glutamate release, lowers motor neuron hyper-excitability

EMA

• metabolic

• restores efficient glycolysis in muscle

EDARAVONE

• antioxidant

• lowers reactive oxygen species

PMX205

• anti-inflammatory

• lowers CNS innate immune activation

MYASTHENIA GRAVIS

Partial failure of neuromuscular synapses caused by defects in muscles' postsynaptic region.

• Loss of AChR’s → decrease in muscle AP’s → muscle weakness

MYASTHENIA GRAVIS FORMS

Autoimmune form:

• antibodies directed against AChR’s

Congenital form:

• mutations in LRP4, MuSK, Dok7 and Rapsyn

MYASTHENIA GRAVIS TREATMENT

• acetylcholinesterase inhibitors

• immunotherapy of antibodies

• immunosuppressives (corticosteroids)

• MuSK-IgG4 treatment

LAMBERT EATON SYNDROME

Partial failure of neuromuscular synapses caused by defect in the motor nerve terminal.

• poor release of neurotransmitter → muscle weakness

Treatment:

• K+ channel blocker to increase ACh release

DUCHENNE MUSCULAR DYSTROPHY

Caused by an inherited genetic defect in the dystrophin gene.

PRE-DIAGNOSIS:

• born without visual symptoms

ACUTE PHASE:

• inflammation

• muscle necrosis

• muscle weakness

CHRONIC PHASE:

• wheel-chair dependent

• muscle wasting

• cardiac myopathy

• diaphragm weakening

DYSTROPHIN

Transduces contractile force across the plasma membrane protecting it from tearing.

Loss of dystrophin = Ca2+ influx + activation of proteases + membrane damage = creatine kinase release in blood as a biomarker of muscle damage.

DUCHENNE MUSCULAR DYSTROPHY TREATMENT

ANTI-INFLAMMATORY DRUGS

• corticosteroids (bad long term)

• prostaglandin pathway modulators

GENE THERAPY

• AVV-mediated

RATE MODULATION

• Increased frequency of muscle APs = increased muscle fibre tension

• maximal contraction = tetanus

• this increases SINGLE muscle fibre tension

MOTOR UNIT RECRUITMENT

• Activation of additional motor units to increase tension in whole muscle

• 1 motor unit = 1 motor neuron + all muscle fibres it innervates

HENNEMAN’S SIZE PRINCIPLE

Neurons with smaller cell bodies are activated first and larger ones activated last.

• Slow twitch = myosin 1, small motor neurons

• Fast fatigue-resistant = myosin2A, medium motor neurons

• Fast fatigued = myosin2B, large motor neurons

COMPOUND MUSCLE ACTION POTENTIALS

The summed electrical signal from all motor units activated within a muscle.

INPUT CONTROL TO MOTOR NEURON OUTPUT

1. AFFERENT (SENSORY) INPUT

• reflex arcs

2. PRIMARY MOTOR CORTEX

• direct, heirarchical, pyramidal (corticospinal)

3. MULTI-NEURONAL MOTOR SYSTEM

• indirect, parallel, extrapyramidal (brainstem, basal ganglia, cerebellum)

PROPRIOCEPTION

• Every muscle contraction is accompanied by sensory feedback

• allows brain to compute limb position

• intended vs actual movement

PROPRIOCEPTORS

MUSCLE SPINDLE

• within muscle belly

• relative changes in muscle length, movement, velocity

GOLGI-TENDON ORGANS

• muscle tendons/connective tissue attachments

• muscle tension and force

JOINT RECEPTORS I - IV

• joint capsule

• capsule tension, ligament tension, pain

MUSCLE SPINDLES

• 𝛄 = neuromuscular synapses at end of intrafusal muscle fibres (efferent)

• sensory connections at centre of intrafusal muscle fibres (afferent)

INTRAFUSAL FIBRE TYPES

Nuclear chain fibres

• sensitive to muscle length

Nuclear bag fibres

• sensitive to velocity of length change

𝛄 MOTOR NEURON IMPORTANCE

⍺ motor neuron activation with 𝛄 motor neurons keep intrafusal fibres taut during contraction, preserving spindle sensitivity throughout the movement.

SPINAL CORD ORGANISATION

Motor neuron cell bodies are organised into motor columns:

Lateral Motor Column:

• innervates limb appendicular muscles

• distal muscles for fine movement

Medial Motor Column:

• innervates axial (trunk) muscles

• posture and whole body orienting

INTERNEURONS

• Connection between afferent inputs and motor neurons

• ipsilateral and contralateral across segment levels

• coordinate activity of muscle groups and their afferents

POST-SYNAPTIC GATING

Monosynpatic reflex

• inhibition of neurons ability to fire

• constantly active at low level

• Ex. reciprocal inhibition (knee-jerk reflex)

CONVERGENCE REFLEX

• multiple inputs onto one motor neuron

• enhance stretch reflex

DIVERGENCE REFLEX

• one sensory input distributed to many motor neurons

• ex. walking

BRAIN STEM INPUTS

1. Proprioception (muscle spindles, golgi-tendon organs, joint receptors)

2. Vestibular apparatus (head position/balance)

3. Eyes (visual context for posture)

BRAIN STEM OUTPUTS

Modify motor neuron output for:

• balance

• stabilisation

• alignment of head/body with gravity

• protective responses

Achieved via two mechanisms:

• Rapid, stereotyped feedback (reflex)

• Pre-programmed feedforward (anticipatory) control

Don’t need higher order processing from motor cortex to modify motor neuron output

BRAINSTEM MOTOR CENTRES

Vestibular Nuclei

• recieve vestibular afferents with regards to head position relative to gravity

Reticular Formation

• connections from premotor regions & coordinate lower motor neuron pools

Superior Colliculus

• Integrates eyes, vestibular and proprioceptive input

Red Nucleus

• Plays a role in motor learning

VESTIBULAR NUCLEI

LATERAL

• maintaining stance

• proximal muscles of limbs

MEDIAL AND SUPERIOR

• coordination of eyes with head movements

INFERIOR AND DORSAL

• integrates afferents and cerebellum to higher centres

FEEDBACK

• Rapid, stereotyped, reflex like

• fixed space-time organisation

• triggered AFTER disturbance is detected

FEED-FORWARD

• pre-programmed based on experience

• unlike simple reflexes

• scale of response is refined with repitition

FEEDBACK VS FEEDFORWARD EXAMPLE

Standing on platform that is suddenly pulled backwards and fall.

FEEDBACK

• Proprioceptors closest to distrubance (ankle, foot)

• vision and vestibular

• combine to pull body back upright

FEEDFORWARD

• if repeated brain anticipates the disturbance

• amplitude of correction is smaller

• don’t fall as far due to quickened reflex

VOLUNTARY MOVEMENT

1. MOTOR CORTEX

• ‘I chose to move’

• ‘how should i move’

2. BASAL GANGLIA

• ‘what action should i perform’

3. CEREBELLUM

• ‘is the movement unfolding as expected’

MOTOR CORTEX

Goal → Plan → Command → Movement

Consists of:

• Primary motor cortex

• Premotor cortex

• Supplementary motor area

• Prefrontal cortex

• Posterior parietal cortex

PRIMARY MOTOR CORTEX (M1)

• motor commands

• executes movements via spinal cord → motor neurons → muscles

PREMOTOR CORTEX

• guided movement preperation

• how should i move?

SUPPLEMENTARY MOTOR AREA

• internally guided action sequences

• what action/sequence should i initiate?

PREFRONTAL CORTEX

• goal / intention

• what do i want to do?

POSTERIOR PARIETAL CORTEX

• spatial / sensory context

• where is the object and my body?

CORTICOSPINAL NEURONS

• Upper motor neurons

• layer V of M1

• largest, longest projecting neurons in nervous system

Somatotopic organisation:

• more at muscles requiring fine complex control

• less at muscles that are less refined

• disproportionate representation = motor homunculus

CORTICOSPINAL TRACT

• descending corticospinal neurons

• anterior and lateral divisions

• cross at medulla pyramids

• causes each hemisphere to control opposite side of body

CORTICOBULBAR TRACTS

• fibres destined for cranial nerve motor nuclei (face, neck, head)

• cross earlier in brainstem

DIRECT CONNECTIONS

• Lateral corticospinal neurons

• direct excitatory connections to motor neurons

• for fine movement control

INDIRECT CONNECTIONS

• spinal interneurons

• can excite or inhibit different motor neuron pools

• dual direct/indirect wiring can produce spasticity

SUPPLEMENTARY MOTOR CORTEX AND REHEARSAL

Performing finger flexion activates:

• Somatomotor/somatosensory areas

Performing finger movement sequence activates…

• Somatomotor/somatosensory areas + supplementary motor cortex

Mentally rehearsing finger movement sequence activates…

• just supplementary motor cortex

Therefore, SMA plans actions independently regardless of their physical execution.

CEREBELLUM - BASAL GANGLIA LOOP

Cortex → basal ganglia → thalamus → cortex

• action selection

• ex. initiating walking

CEREBELLUM - CEREBELLAR LOOP

Cortex → cerebellum → thalamus → cortex

• prediction / correction

  • ex. correcting balance while walking

CEREBELLUM SUB-DIVISIONS

1. Vestibulocerebellum

2. Spinocerebellum

3. Cerebrocerebellum

VESTIBULOCEREBELLUM

input = vestibular apparatus

output = lateral vestibular nucleus

function = balance, eye movement coordination

SPINOCEREBELLUM

input = proprioceptors

output = spinal cord

function = muscle tone, correct ongoing movement, coordination of voluntary movement

CEREBROCEREBELLUM

input = cerebral cortex

output = premotor cortex

function = planning + initiation of voluntary movement, storage of procedural memory

MOVEMENT IMPROVEMENT

1. Internal prediction = what should happen

2. Sensory feedback = what actually happened

Difference = motor error = improve future movement

DEEP CEREBELLAR NUCLEI

• Dentate nucleus

• Interposed & fastigial nuclei

• vestibular nuclei

• Excitatory inputs from mossy and climbing fibres

• inhibitory inputs from Purkinje cells

EXAMPLE COMPARATOR CIRCUIT

1. Motor command send to spinal cord → ⍺ motor neurons → muscle

2. Copy of motor command sent to cerebellum

3. Proprioceptors report back sensory consequences of actual movement

4. Cerebellum compares copy of command and sensory feedback

5. Any mismatch is computed and an updated motor command is sent out

ATAXIA

Damage of cerebellum reflects faulty integration of proprioceptive information

• irregular reach

• undershoot/overshoot movements due to impaired predicting vs sensing

BASAL GANGLIA

The cortex proposes action, the basal ganglia decides which one wins.

The striatum is involved in:

• Motor

  • start walking, reach, stop movement

• Cognitive

  • switch task, make decision, change strategy

• Motivation

  • seek reward, avoid punishment, repeat rewarding behaviour

BASAL GANGLIA CIRCUIT

STRIATUM

• caudate

• putamen

• nucleus accumbens

GLOBUS PALLIDUS

• external and internal

SUBSTANTIA NIGRA

• Pars compacta

• Pars reticulata

NEUROTRANSMITTERS

• Glutamate (excit)

• GABA (inhib)

• Dopamine (excit + inhib)

SUBTHALAMIC NUCLEUS

BASAL GANGLIA - MOTOR LOOP

Motor cortex → putamen → globus pallidus → thalamus

• movement execution and selection

BASAL GANGLIA - PREFRONTAL LOOP

prefrontal cortex → caudate → globus pallidus + substantia nigra → thalamus

• decision making, switching strategy

BASAL GANGLIA - LIMBIC LOOP

Limbic system → ventral striatum → ventral pallidum → thalamus

• emotion, value, reward, motivation

UPPER VS LOWER MOTOR NEURON LESIONS

• losing lower MN removes pathway completely

• losing upper MN leaves lower MN intact

LOWER LESIONS

• weakness or paralysis

• severe atrophy

• hypoactive superficial and deep reflexes

UPPER LESIONS

• weakness

• mild or no atrophy

• hyperactive deep reflexes after intital period of spinal shock

WHY IS MUSCLE MASS PRESERVED IN UPPER MN LESIONS

• Lower MN is intact meaning spinal circuitry can drive flexion/extension even without descending cortical input

• This maintains muscle mass, venous return and body heat generation even without voluntary control

SPASTICITY IN UPPER MN LESIONS

• losing descending input causes hyperactive reflexes and increased muscle tone

• spasticity = caused by loss of inhibitory modulation

THE BABINSKI SIGN

Damage to corticospinal descending pathways causes extensor plantar response.

• indicates incomplete upper MN control of spinal motor circuitry and a clinical sign of corticospinal lesion.

Voltage gated Calcium channels at the neuromuscular synapse are found:

At sites active zones.

MYASTHENIA GRAVIS IS CAUSED BY

A loss of acetylcholine receptors.

MUSCLE SPINDLES ARE INNERVATED BY

gamma motor neurons and type Ia and type II sensory neurons.

If the spinocerebellum division of the cerebellum is damaged, which of the following is likely to be MOST compromised?

Postural control of muscles

THE MAIN INHIBITORY NEUROTRANSMITTER WITHIN THE SPINAL CORD IS

Glycine (spinal cord)

GABA (is the brain)