Motor systems II

Cerebellum

• closely involved with brainstem mechanisms- unconscious movement

• control of muscle tone

• sensorimotor coordination

• motor learning

basal ganglia

• integration of sensory and motor information

• cortex —> basal ganglia —> cortex loop (via thalamus)

Cerebellum + basal ganglia

• Loop pathways in brain, take info from cortex and send it back to a different part of the cortex

• coming from premotor areas, partly goes back to primary motor cortex

• like each other less than cerebellum + brainstem 

Spino-cerebellum

• medial region of cerebellum

• sensory input from spinal cord- sensory info mixing with motor info, unconscious muscle contractions keep you upright

• output to the reticular formation + red nucleus 

• then to motor cortex, and via this:

  • output to spinal cord

  • control over axial musculature and posture

damage causes:

• hypotonia

• ataxia

• dysmetria and intention tremor

vestibulo-cerebellum

• caudal region of cerebellum 

• input from and output to vestibular nucleus 

• control over posture/balance, also eye movement 

damage causes: 

• slow saccades (fast tracking ocular movement impaired)- abnormal eye movement

• mystagmus (due to failed vestibulo-oculomotor integration

• ataxia

cerebro-(ponto)-cerebellum

• lateral hemispheres of cerebellum

• an intracerebral motor loop

• instructs the primary motor cortex (M1)

  • regarding movement direction, timing and force

• compares intended movements w/actual- compensatory instructions to rectify movements that aren’t going as planned

• damage causes:

  • incoordination/ataxia

  • dysmetria

  • asynergy- uncoordinated agonist and antagonist muscles

  • dysarthria- inarticulate speech, poor oropharyngeal muscular control

cerebro-(ponto)-cerebellum loop

• cortex —> pons —> cerebellum —> dentate nucleus (deep cerebellar nuclei) —> ventrolateral thalamus —> cortex (M1)

outline the inputs of the cerebellar cortex

• climbing fibres input from inferior olive

  • excitatory and act on purkinje cells

• mossy fibres from brainstem nuclei

  • indirectly excite purkinje cells via parallel fibres of granule cells

outline the outputs of the circuitry of the cerebellar cortex

• only purkinje cells- project to deep cerebellar nuclei

• deep cerebellar nuclei receiving sensory information directly + indirectly (going into network and back out through purkinje fibres)

• purkinje fibre receives lots of input coming from parallel fibres coming from granule cells, also input from climbing fibres 

how does the circuitry of the cerebellar cortex talk to each other?

deep cerebellar nuclei (DCN) cells compare input from mossy and climbing afferent input 

before (via collaterals from axons to P cell- excitatory) and after cerebellar processing (via inhibitory P cell output) 

results in an error signal if inputs don’t match 

draw the circuitry of the cerebellar cortex 

ataxia

unsteady, staggering gait

functional components:

1. spino cerebellum

2. cerebro-ponto-cerebellum

   1. vestibulo-cerebellum

dysmetria

inaccurate termination of movement

functional component:

• spino-cerebellum

  • cerebro-ponto-cerebellum

hypotonia

reduced muscle tone

spino-cerebellum

slow saccades + nystagmus

impaired eye movement, vestibulo-cerebellum

dysathria

inarticulate speech due to poor oropharyngeal muscular control

cerebro-ponto-cerebellum

summarise the functions of the cerebellum

1. regulates posture indirectly by adjusting output of major descending motor pathways

2. acts as a comparator, identifying and correcting discrepancies between intended and actual movement

3. acts as a timer, sequencing motor activation resulting in smooth performance

4. role in motor memory, and in instigating learned motor sequences when appropriate

not required for perception or muscle activation

cortico-basal ganglia-cortical loop

• integrates motor and sensory information from the cortex 

• relays back to the cortex via thalamus 

• motor circuit output to premotor/SMA cortex

• selection and initiation of voluntary movement 

basal ganglia —>ventrolateral thalamus—>motor cortex—>brainstem + SC

Draw the Motor loop of cortico-basal ganglia-cortical loop

• Signal from BG to thalamus = inhibitory

• Need to switch off inhibitory output to move

• Switching off inhibitory output means thalamus can get excited, sends excitatory signal to cortex 

• PFC gives excitatory signal to BG, switches off output, thalamus is now disinhibited

• BG needs to suppress other potentially conflicting motor pathways, moderates information 

Striatum

Part of basal ganglia

• caudate nucleus

• putamen

• nucleus accumbens

Basal ganglia (all the major structures)

• caudate nucleus

• putamen

• nucleus accumbens

• globus pallidus (GP)- internal and external

• substantia nigra

• subthalamic nucleus (STN)

Sub-types of globus pallidus

Internal = GPi

External = GPe

Sub-types of substantia nigra

Reticulata (SNr)

Pars compacta (SNc)

Name the direct pathways of the basal ganglia

• striato-nigral pathway

• striato-pallidal pathway GPi

Where do the indirect pathways project?

via GPe and STN 

Outline the types of pathway in the basal ganglia

• From striatum, cortical input relayed to two major output areas w/in the basal ganglia, SNr and GPi

• opposing effects on thalamocortical output 

• balance between the direct and indirect pathways 

• dopamine plays a key modulatory role 

Draw the basic circuit of the basal ganglia 

• Ignore cortex to STN pathway 

Draw the direct pathway of the basal ganglia

Direct pathway BG

• promotes movement

• striatum gets excited, releasing GABA which inhibits SNr/GPi, inhibiting SNr/GPi inhibits thalamus

• dopamine acts on excitatory D1 receptors on striato-GPi/SNr neurons

• this further reduces BG output and facilitates movement

Draw the indirect pathway of the basal ganglia

Indirect pathway BG

• suppresses movement

• dopamine acts on inhibitory D2 receptors on striato-GPe neurons

• this reduces STN activity, BG output and facilitates movement 

• GABAergic cells different cells in striatum to the ones that go down the indirect pathway

How can the basal ganglia cause motor dysfunction?

• imbalance between the indirect and direct pathways —> motor dysfunction

• hypokinetic disorders such as HD, ballism, tardive dyskinesia

• hyperkinetic disorders such as PD

Parkinson’s disease symptomology

• tremor- resting not intention

• bradykinesia - slowness of movement

• rigidity- resistance to passive movement

• dementia, depression, bladder disturbance

PD pathology

Progressive degenerative loss of the nigro-striatal dopaminergic pathway

Over 80% lost by the time symptoms start + diagnosis is made 

Excessive inhibition of thalamo-cortical pathway

Accompanied/driven by increase in subthalamic nucleus

Draw how PD affects the circuitry of the BG

Treatments for PD

• drugs to boost dopamine in brain:

  • L-DOPA = dopamine precursor

  • dopamine agonists

  • drugs to reduce dopamine breakdown (MAO-B inhibitors)

• Deep brain stimulation

  • Inhibit STN

• No treatments address the underlying degeneration

Dopamine replacement therapy for PD

• reduces rigidity and hypokinesia

• L-DOPA metabolised to produce dopamine by DOPA-decarboxylase in DA-ergic neuron

• But L-DOPA also elevates NAdr synthesis in sympathetic NS

• Non-brain penetrating carbidopa or benserazide co-administered to inhibit peripheral DOPA decarboxylase 

Huntington’s disease symptomology

• excessive ‘choreiform’ movement

• uncontrollable, relatively rapid motor patterns disrupts normal motor activity

• later stages —> psychiatric disturbance, dementia

Primary pathology HD

In early stages:

loss of striatal output neurons in indirect pathway

• suppression of STN 

• predominance of direct pathway

• reduced BG output

• overactive thalamocortical pathway

• involuntary movement 

HD treatments

Only symptomatic relief

• Drugs that inhibit VMAT, reduce DA storage and release

• drugs that are DA antagonists (antipsychotic)

• Drugs that are GABA-B agonists, reduce spinal reflexes

Hemiballismus

• caused by damage to subthalamic nucleus (usually by unilateral stroke)

• effect: violent flailing movements of limbs contralateral to damaged side

tardive dyskenesia

• caused by long-term exposure to antipsychotic dopamine receptor antagonist drugs

• uncontrolled movement, especially of facial and trunk muscles