motor control and disease

All movements in skeletal muscle are initiated by what?

Lower motor neurons

Fritsch and Hitzig

Discovered that stimulation of part of the cortex elicits contraction of contralateral body muscles
Region became known as the motor cortex

What are neurons found in the brain that control motor function called?

Upper motor neurons

Upper motor neurons

Originate in the cerebral cortex and travel down to the brain stem or spinal cord

Lower motor neurons

Begin in the spinal cord and go on to innervate muscles and glands throughout the body

Sherrington and Penfield

Correlated the site of stimulation with the location of muscle contraction and demonstrated a topographic map

Where is the lower body represented on a topographic map?

Medially

Where is the upper body represented on a topographic map?

Laterally

Axial muscles

Trunk movement

Proximal muscles

Shoulder, elbow, pelvis, knee movement

Distal muscles

Extremities such as hands, feet and digits

Motor unit

Motor neuron and all the muscle fibres it innervates

Motor neuron pool

All the motor neurons that innervate a single muscle

Rod-shaped clusters

Motor neuron pools are grouped into rod-shaped clusters within the spinal cord

Distal muscles are innervated by motor neurons whose cell bodies are?

Lateral

Proximal muscles are innervayed by motor neurons whose cell bodies are?

Medial

How do upper motor neurons project their axons to lower motor neurons?

Via descending tracts of the spinal cord

Corticospinal tract (CST)

From cortex to the spinal cord
Lateral pathway
Large axonal distance to synapse directly from the cortex to the spinal cord

Where do axons of the CST originate?

Axons of CST originate from large pyramidal cells layer 5 of the motor cortex

Where is the main input in the motor cortex?

To stellate cells in layer 4

Where are the main outputs of the motor cortex?

Layers 3,5 and 6

Betz cells

Large pyramidal cells in layer 5 of the motor cortex where axons of the corticospinal tract originates

Lateral pathways

Corticospinal tract and rubrospinal tract

Function of motor cortex upper motor neurons

Fine voluntary control of more distal structures

Where do outputs to the lower body originate?

Medial motor cortex

Where do axons of the corticospinal tract have to cross the midline?

Pyramidal decussation in the medulla

Where do brainstem upper motor neurons project?

Ipsilaterally

Where do motor cortex upper motor neurons project?

Contralaterally

What motor neurons control axial muscles?

Medial motor neurons of the brainstem

Ventromedial pathways

Vestibulospinal
Reticulospinal
Tectospinal

Vestibulospinal tract

Head balance and turning

Tectospinal tract

Orientating response

Reticulospinal tracts

Control antigravity reflexes

How do the upper motor neurons in the cortex influence spinal cord circuits?

1. By activation of voluntary movement direct to the spinal cord via CST
2. By anticipation of movement which activates an indirect projection to axial muscles via the reticular formation

Where does movement anticipation start?

Pre-motor area (PMA)

Where does movement initation occur?

Primary motor cortex (M1)

MND

Motor neuron disease

Amyotrophic lateral sclerosis

Degenerative disorder of motor neurons in the spinal cord and brainstem

Sclerosis

Hardening

What neurons are affected in MND?

Upper and lower motor neurons

What is MND characterised by?

Muscle atrophy
Sclerosis of the lateral spinal cord

What is the mark of degeneration of axons in the CST?

Sclerosis of the lateral spinal cord

What happens to the body with lower motor neuron degeneration?

Muscle paralysis
Loss of muscle tone due to loss of stretch reflexes
Severe muscle atrophy
Patients die from lung dysfunction due to atrophy of intercostal muscles

What happens to the body with upper motor neuron degeneration?

Muscle weakness
Spasticity due to increased muscle tone due to failure of modulation of stretch reflex
Hyperactive reflexes
Loss of fine voluntary movement
Patients die from loss of input to bulbar muscles via the corticobulbar tract

Bulbar muscles

Tongue and pharynx

Excitotoxicity

Overstimulation of a neuron by glutamate which leads to neuronal cell death

Riluzole

Blocks glutamate release
Treatment for MND
Only delays the disease by a couple of momnth

SOD1

Superoxide dismutase
Key enzyme that mops up free radicals that accumulate in metabolically active cells
Mutation in this gene is seen in patients with MND

Spinal motor neurons

Lower motor neurons

Where do upper motor neurons reside?

Brainstem and cortex

Function of upper motor neurons in the brainstem

Posture

Function of upper motor neurons in the cortex

Voluntary movements

How does the basal ganglia and cerebellum influence movement?

Indirectly by regulating the function of upper motor neurons

What makes up the basal ganglia?

Caudate, Putamen, Globus pallidus and subthalamic nucleus

VLo

Ventral lateral complex of the thalamus

Where is the SN?

Midbrain

Striatum

Caudate nucleus and putamen

How does the motor cortex control the initation of movement?

Motor cortex connects to the basal ganglia which feedbacks to the premotor area via the VLo
Known as the motor loop

Motor loop

Motor cortex cortex connects to basal ganglia
Basal ganglia feedbacks to the premotor area via the VLo
Controls initiation of movement

Direct pathway of initiating movement

1. No cortical input - global pallidus internal segment tonically inhibits the VLo
2. Input from cortical regions converge on the striatum
3. Striatum inhibits inhibitory activity of the GPi releasing the VLo
4. Activate area 6 and initiate movement

What areas make up the motor cortex?

Area 4 and 6

Describe the indirect pathway of initiating movement

Inhibition of GPi by GPe is inhibited by the striatum and so the VLo in inhibited
Inhibitory input from the SN decreases the inhibition by the striatum allowing activation of the VLo

Function of the SN in initiating movement

Acts via the striatum to maintain balance between inhibition and activation of the VLo

How does the SN act via the direct pathway?

Excitatory input from the SN stimulates VLo activation by activating the inhibition of the GPi

Most common neurodegenerative disorder

Alzheimer's

Second most common neurodegenerative disorder

Parkinson's

How common is Parkinson's disease?

1 in 100 people over the age of 60

What percentage of Parkinson's cases are sporadic?

85-90%

What percentage of Parkinson's cases are caused by genetic mutations?

10-15%

Motor symptoms of Parkinson's

Resting tremor
Hypokinesia
Bradykinesia
Akinesia
Increased muscle tone
Shuffling gait and flexed posture
Mask-like expression

Hypokinesia

Insufficiency of movement

Bradykinesia

Very slow movement

Akinesia

No movement

Non-motor symptoms of Parkinson's disease

Mood disorders
Loss of sense of smell

What causes Parkinson's disease?

Loss of dopamine due to a loss of dopaminergic neurons in the SN

Where is 80% of the brain's dopamine found?

Basal ganglia specifically the SN

Lewy bodies

Intracellular protein aggregates present in the SN of patients with PD

Side effects of L-DOPA

Increase in motor response fluctuations and drug related dyskinesias

Dyskinesias

Involuntary movements

What does reduced dopaminergic input from the SN to the striatum lead to?

Increased activity of the indirect pathway and decreased activity of the direct pathway

How does increased activity of the indirect pathway but decreased activity of the direct pathway lead to reduced movement?

Less inhibition of the GPi so its inhibitory activity is increased
Decreased activity of the VLo
Less motor cortex activation

How common is Huntington's disease?

3-7 people per 100000

How is Huntington's disease passed on?

Inherited

Symptoms of Huntington's disease

Early: Hyperkinesia
Dyskinesia
Later: Loss of movement and dystonia, dementia and personality disorder

Dystonia

Muscle spasms

What causes Huntington's disease?

Autosomal dominant gene that results in neuronal degeneration initially in the indirect pathway then later in the direct pathway

Inclusion bodies

Aggregates of virus particles
Present in Huntington's disease

Chorea

Movements that are sudden, random, and involuntary

What causes hyperkinesis in early Huntington's disease?

Degeneration in the striatum reduces the indirect pathway inputs to the GPe
This increases inhibition of the GPi so the VLo is dis-inhibited and there is inappropriate initiation of movement

What causes akinesis in late Huntington's disease?

Striatal direct path and GPe neurons degenrate releasing the GPi to over inhibit the VLo

What regulates the basal ganglia?

SN

High penetrance

If you have the mutation it is likely you will get the disease

Low penetrance

Even if you have the mutation you are unlikely to get the disease

2 examples of genes that predispose you to PD

SNCA and GBA1

Mutation that causes Huntington's disease

HTT

What do PD genes encode?

Proteins involved in protein degradation pathways or mitochondrial function

Is there a cure for HD?

No

Mutant HTT protein causes what?

Extended stretches of poly-glutamine which contributes to aggregation of proteins in inclusion bodies in affected neurons

Function of cerebellum in movement

Detects and corrects difference between the intended movement and the actual movement

Lesions to the cerebellum lead to

Cerebellar ataxia