motor control and disease Flashcards
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)
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
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
somatotopic mapping of motor cortex
lower body represented medially
upper body represented laterally
mapped on cortex in similar way to somatosensory map
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
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
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
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
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
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
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
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
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
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)
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
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
