motor control and disease Flashcards by R B

motor control hierarchy

basal ganglion and cerebellum –>
descending systems (upper motor neurons): motor cortex and brainstem centres –>
spinal cord and brainstem circuits (lower motor neurons): local circuit neurons (sensory inputs here) and motor neuron pools (output to skeletal muscles)

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circuits for simple reflexes

local circuit control of spinal motor neurons by spinal sensory neurons
all movements from skeletal muscle are initiated by LMNs
spinal cord has central pattern generators - complex behaviour without input from brain

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upper vs lower motor neurons

UMN:
motor cortex = planning, initiating, directing voluntary movements
brainstem centres = basic movements and postural control
control motor function in brain

LMN:
local circuit neurons = integration of LMNs and sensory inputs
motor neuron pools = output to skeletal muscles

UMNs always synapse on LMNs (or their interneurons) and LMNs always synapse on muscle fibres

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somatotopic mapping of motor cortex

lower body represented medially
upper body represented laterally

mapped on cortex in similar way to somatosensory map

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somatic motor system (3 types of muscles and where they innervate)

control of LMNs in ventral horn of spinal cord - innervation of striated muscle to control movement

axial muscles = head and trunk movement
proximal muscles = shoulder, elbow, pelvis, knee movement
distal muscles = hands, feet, digits movement

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LMNs - connection to muscle fibres

each fibre receives input from a single alpha LMN
each LMN innervates fibres of just one muscle - can innervate more than one fibre

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LMN - motor unit and motor neuron pools

motor unit = motor neuron and all the muscle fibres it innervates

motor neuron pool = all the motor neurons that innervate a single muscle
grouped in rod-shaped cluster in spinal cord - over several vertebral segments (found using retrograde tracing in the muscle

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LMN - somatotopic organisation of motor pools

mediolateral position of a motor pool reflects whether it innervates proximal or distal muscle
therefore organised mediolaterally and rostro-caudally

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LMN - CST

LMNs have direct input from UMNs which project axons down spinal cord

corticospinal tract (CST) is a lateral pathway of spinal cord for voluntary movement
CST axons originate in layer V of motor cortex
CST axons project directly from cortex to ventral horn
axons cross the midline in pyramidal decussation in medulla –> project laterally in spinal cord –> synapse laterally to LMN circuits which control distal muscles

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LMN - pyramidal cells and CST

pyramidal cells of the motor cortex project axons into the corticospinal tract
axons of CST derive from large pyramidal cells in layer V aka Betz cells
motor cortex has 6 layers -> main inputs in layer IV, main outputs from layers III, V, VI

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UMN - in motor cortex

fine voluntary control of more distal structures
mainly project contralaterally via CST to muscles for precise limb movement
also project via corticobulbar tract to hypoglossal nucleus in brainstem to control movements of tongue - human speech

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UMN - in brainstem

to medial motor pools
for posture and balance
ventromedial pathways project mainly ipsilaterally and medially in spinal cord:
- vestibulospinal tract = head balance and turning - with inputs from vestibular system
- tectospinal tract = orienting response - inputs from visual system via superior colliculus
- reticulospinal tract = antigravity reflexes

synapse to medially located LMN circuits which control axial muscles

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integration of postural control and voluntary movement

when lifting a lever, the first muscles to contract are in the legs
anticipatory feedforward mechanism - preadjusts body posture to compensate for forces that will be generated when lifting the lever

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indirect cortical control of LMNs (from 2 areas of motor cortex)

feedforward mechanisms - UMNs influence spinal cord circuits by 2 routes:
- from area 6 (premotor area - PMA) = anticipate movement –> indirect projection to axial muscles via reticular formation
- from area 4 (primary motor cortex) = activates voluntary movement –> direct to spinal cord via CST

activity in PMA (anticipation) precedes area 4 (voluntary movement)

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motor neuron disease (MND)

aka amyotrophic lateral sclerosis (ALS)
degenerative disease of motor neurons
amyotrophic = no nourishment of muscles so muscle atrophy (wastes away)
sclerosis = hardening/scarring of lateral spinal cord from degeneration of axons in CST

famous case = Lou Gehrig - baseball player, development can be seen by decrease in batting rate. died 3 years after contracting

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MND - neuropathology - effect on UMNs and LMNs

lower motor neuron disease:
- muscle paresis or paralysis
- loss of muscle tone - loss of stretch reflexes
- severe muscle atrophy
- usually die from lung dysfunction (due to atrophy in intercostal muscles)

upper motor neuron disease:
- muscle paresis
- increased muscle tone = spasticity - from failure to modulate stretch reflex - too tight
- hyperactive reflexes
- loss of fine voluntary movement
- usually die from loss of input to bulbar muscles (tongue and pharynx) via corticobulbar tract

intellect is never compromised - Stephen Hawking

MND - aetiology (cause)

neurodegenerative disease
cause not well understood

one theory = excitotoxicity - overstimulation (typically by glutamate) leads to neuronal cell death
vicious cycle of glutamate release - particularly in hypoxic conditions (too little oxygen e.g. after cardiac arrest, stroke, brain trauma)
drug therapy = Riluzole which blocks glutamate relase - only delays disease by a couple months

10% have a clear genetic basis:
mutation in gene encoding superoxide dismutase (SOD1) - enzyme that clears up free radicals that accumulate in metabolically active cells
other genes affect variety of cellular processes - not fully understood

brain components in initiation of movement

motor cortex (AF4) - telencephalon

basal ganglia - forebrain
- caudate putamen
- globus pallidus
- subthalamic nucleus

ventral lateral nucleus of thalamus - diencephalon

substantia nigra (midbrain)

basal ganglia - motor loop

motor cortex connects to the basal ganglia - feeback to premotor area (area 6) via ventrolateral complex of the thalamus (VLo) to control initiation of movement

can take 2 pathways: direct and indirect

basal ganglia - motor loop - direct pathway

with no cortical input:
globus pallidus internal segment (GPi) tonically (continually) inhibits the VLo

with input from cortical regions:
1. input converges on the striatum (contains caudate putamen - CP)
2. caudate putamen inhibits the GPi
3. GPi no longer inhibits VLo
4. VLo activates area 6 and initiates movement

allows integration of many cortical inputs
high speed - idea that the engine is running with the GPi as the “break” which is released

basal ganglia - motor loop - indirect pathway

modulates the direct pathway with the substantia nigra (SN) and GP external segment (GPe)
GPe inhibits the GPi - but GPe is inhibited by CP
SN acts via CP to maintain balance between inhibition and activation of VLo - has input from decision making and emotion centres - risk reward judgements to slow an otherwise fast circuit

modulation of direct pathway:
excitatory element of SN –> inhibits GPi –> stops inhibition of VLo –> activates area 6 for movement - through DIRECT pathway

indirect pathway:
inhibitory element of SN –> SN inhibits CP –> stops inhibition of GPe –> inhibits GPi –> stops inhibition of VLo –> activation of area 6 for movement

degeneration here leads to Huntingtons

cerebellum role in motor learning

modulates UMNs - no direct connections to spinal cord
used in learned execution of planned, voluntary, multi-joint movements
instructs motor cortex about direction, timing, and force of movement
based on predictions of outcomes based on past experience of movements - therefore practice helps with motor learning

cerebellum and “muscle memory”

strengthening or weakening of existing neural pathways - no new pathways being made
memory is in the neurons - not the muscles
muscle memory = motor learning in cerebellum
there is evidence for memory within muscles but in relation to speed of regaining muscle mass e.g. stop going gym then start again

cerebellum loop with motor cortex

cerebellum receives input from many cortical areas (esp sensory cortex) via corticopontocerebellar projection
also receives sensory info from spinal cord and vestibular system
projects back into motor cortex (area 4) via the thalamus (VLc - ventrolateral) (no direct output to spinal cord)

function = detect and correct differences between intended and actual movement (motor-error) and records this to build into prediction for next time movement is made

cerebellum lesion = cerebellar ataxia - poorly integrated movement (dyssynergia)

cerebellum and mad cow disease

BSE - bovine spongiform encephalitis causes cerebellar ataxia casued by neuronal degeneration from prion (a self-replicating protein) human version = Creutzfeld-Jacob Diseae (CJD)

Parkinson's disease - incidence

2nd most common neurodegenerative disorder 1:100 people over age of 60 85-90% of cases are sporadic 10-15% of cases are genetic - mutations

Parkinson's disease - symptoms

motor: hypokinesia - paucity (insufficiency) of movement bradykinesia - very slow movements akinesia - no movements increased muscle tone - rigidity resting tremor @ 4-5 Hz ("pill-rolling") shuffling gate, fixed posture, impaired balance mask-like expression non-motor: mood disorders, loss of smell

Parkinson's disease - cause

loss of dopamine - single neurotransmitter deficiency dying of dopaminergic (DA-ergic) neurons in substantia nigra (contains ~80% of DA) degeneration of DA-ergic neurons is marked by presence of Lewy bodies - intracellular protein aggregates

Parkinson's disease - therapy

L-DOPA = L-dihydroxyphenylalanine intravenous L-DOPA = dramatic (but brief) reversal of symptoms in PD patients gradual increases in oral L-DOPA = significant and longer benefits beneficial effects of L-DOPA only last for ~5 years acts by boosting capacity of surviving DA-ergic neurons in SN to make DA - does not stop degeneration of SN neurons eventually there are insufficient SN neurons left to make DA side effects: increase in motor response fluctuations and drug related dyskinesias (erratic movements) severe cases - surgical removal of Gpi (pallidotomy) recent ideas: deep brain stimulation to inhibit GPi hyperactivity

Parkinson's disease - effect of loss of DA on basal ganglia

increased activity of indirect pathway decreased activity of direct pathway SN inhibition of CP is broken therefore INDIRECT PATHWAY increases: GPe is inhibited by CP --> activation of GPi --> inhibition of VLo --> area 6 isn't activated --> less motor cortex activation and movement SN activation of CP is broken therefore DIRECT PATHWAY decreases: GPi isn't inhibited --> VLo is inhibited --> area 6 isn't activated --> less movement hypokinesis = reduced movement

Huntington's disease - incidence

3-7 people per 100,000 with european ancestry less in other ethnic groups rare, hereditary, progressive, fatal

Huntington's disease - symptoms

early = hyperkinesia (restlessness) or dyskinesia (erratic movements), chorea (jerky and twitchy movements) late = akinesia (inability to perform movements), dystonia (muscle spasms), dementia, personality disorders (psychosis)

Huntington's disease - cause

autosomal dominant genetic diseae results in neuronal degeneration - initially in indirect pathway components of striatum, subsequently the direct pathway components and the GPe

Huntington's disease - basal ganglia involvement in early vs late

early: striatum degeneration reduces indirect path inputs to GPe --> stops inhibiting GPe --> increased inhibition of Gpi --> VLo is activated --> inappropriate initiation of movement (too much area 6 activation) causes hyperkinesis, chorea later: direct pathway degenerates - CP stops inhibiting GPi indirect pathway degenerates - GPe neurons degenerate GPi is not inhibited by either pathway --> over-inhibition of the VLo - lack area 6 activation causes akinesis (lack movement)

PD vs HD - inheritance

PD is mostly sporadic/idiopathic (85-90%) HD is rarely sporadic

PD vs HD - incidence

PD is common - 1% in >60 year olds HD is rare - 0.005%

PD vs HD - gene mutations

PD = mutations in multiple genes predispose the condition - rare with high penetrance e.g. SNCA - common with low penetrance e.g. GBA1 HD = mutations in HTT (encoding Huntingtin protein) cause it - only specific mutations means you are certain to get the disease at some point - onset varies

PD vs HD - gene functions

PD = encode proteins in protein degradation pathways (e.g. Parkin, SNCA - causes Lewy Body protein aggregation) or in mitochondrial function (e.g. PINK1, DJ-1) HD = HTT protein function is unclear - potentially in intracellular transport mutant HTT contains extended stretched of poly-glutamine (polyQ) which contributes to aggregation of proteins in inclusion bodies in affected neurons

areas other than motor cortex in motor control

basal ganglia acts as a funnel for info from prefrontal and motor cortices which it filters to choose what to act upon - also input from sensory cortex also inputs from: area 5 and 7 - perceptions of body in space and time --> therefore decision to act uses sensory info about body in environment with planning info (area 6 and prefrontal) when initiating movement modulated by SN with inputs from emotional and decision-making areas to evaluate risk/reward