N - Motor Systems 2

The Basal Ganglia + Cerebellum

Cerebellum + Basal Ganglia

Cerebellum:

• closely involved with brainstem mechanisms

Basal Ganglia:

• integration of sensory + motor info

neither project directly beyond the brain

The Cerebellum

• sensorimotor coordination

• control of muscle tone

• motor learning

Cerebellum: 3 function + anatomical components

1. Spino-cerebellum (medial regions)

• sensory input from the spinal cord

• output to the reticular formation + red nucleus

• cerebellum → motor cortex → spinal cord control over axial musculature + posture

2. Vestibular-cerebellum (caudal region)

• input from + output to vestibular nucleus (ventromedial pathway)

• control over posture/balance

3. cerebrocerebellum (aka pontocerebellum)

• an intracerebral loop

• cortex → cerebellum → cortex (M1)

• instructs the primary motor cortex (M1)

  • movement direction, timing, force

• compares intended movements with actual movements sends compensatory instructions to M1

Layers of cerebellar cortex

• molecular layer (top)

• purkinje cell layer

• granule cells layer

• white matter (bottom)

Deep cerebellar nuclei (DCN)

• DCN cells can compare input from mossy + climbing afferent input

• before (via axons to P-cell) and after cerebellar processing (via inhibitory P cell output)

Cerebellum: comparing (image)

• DCN sends an error signal to brain stem + thalamus if movement is not right

Intention tremor + dysmetria

• damage to cerebellum

• can’t draw square - go off track

• go off track when bringing finger to nose

Function after damage to cerebellum

Symptom	Description	Functional Component
Ataxia	Unsteady, staggering gait	Spino-cerebellum, Cerebro-(ponto-)cerebellum, Vestibulo-cerebellum
Dysmetria	Inaccurate termination of movement	Spino-cerebellum, Cerebro-(ponto-)cerebellum
Hypotonia	Reduced muscle tone	Spino-cerebellum
Slow saccades / Nystagmus	Impaired eye movement	Vestibulo-cerebellum
Dysarthria	Inarticulate speech due to poor oropharyngeal muscular control	Cerebro-(ponto-)cerebellum

The Basal Ganglia: Cortico-basal ganglia-cortical loop

• integrates motor + sensory info from the cortex

• relays back to cortex via thalamus

• motor circuit output to premotor/SMA cortex

• selection and initiation of voluntary movement

The Motor Loop (image)

The basal ganglia structures include:

• striatum (STR):

  • the caudate nucleus

  • putamen

  • nucleus accumbens

• subthalamic nucleus (STN)

• globus pallidus (GP):

  • external (GPe)

  • internal (GPi)

• substantia nigra:

  • reticulata (SNr)

  • pars compacta (SNc)

Direct + indirect pathways

• from striatum - cortical input is relayed to 2 major basal ganglia areas = SNr + GPi

• ‘direct’ pathways - striato-nigral + stiato-pallidal (GPi)

• ‘indirect’ pathways projections via GPe + STN

• opposing effects on thalamocortical output

• balance between direct + indirect pathways

• dopamine (from SNc) - plays key modulatory role

The basal ganglia - basic circuit

Direct pathway + dopamine

• the direct pathway serves to promote movement

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

Indirect pathway + dopamine

• the indirect pathway serves to suppress movement

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

• decreased STN activity

• decreased BG output

• = facilitates movement (bc basal ganglia movement usually inhibits cortical action)

The BG and Motor Dysfunction

• imbalance between the direct + indirect pathways = motor dysfunction

• hypokinetic disorders e.g. Parkinson’s disease

• hyperkinetic disorders e.g. Huntington’s disease, Hemiballism, Tardive Dyskinesia

Parkinson’s Disease

• tremor

• bradykinesia (slowness of movement)

• rigidity (resistance to passive movement)

primary pathology:

• progressive degenerative loss of nigro-striatal dopaminergic pathway

Neurobiology of PD

• dopamine loss in BG

• leads to excessive inhibition of thalamo-cortical pathway

• accompanied / driven by increase activity in STN (subthalamic nucleus)

Treatments for PD (1)

• many drugs to boost dopamine in brain = replacement therapy:

  • L-DOPA

  • dopamine receptor agonists

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

• deep brain stimulation

Treatments for PD (2)

Dopamine replacement therapy:

• reduces rigidity + hypokinesia

L-DOPA:

• metabolised to produce dopamine by DOP-decarboxylase

• but L-DOPA will also elevate NAdr synthesis in sympathetic NS

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

Surgical treatment of Parkinson’s Disease

surgical lesion / inactivation of STN

Huntington’s disease

• excessive ‘choreiform’ movement

• uncontrollable, rapid motor patterns disrupts normal motor activity

• later stages - psychiatric disturbance, dementia

neurobiology:

• loss of striatal output neurons in indirect pathway - suppression of STN

• = suppression of STN

• = dominance of direct pathway

• decreased GB output

• = overactive thalamocortical pathway

Huntington’s disease: Drug Treatments

• symptomatic relief only

• Tetrabenazine - VMAT inhibitor, decreased DA storage + release

• Chlorpromazine - DA receptor antagonist

• Baclofen - GABA-B receptor agonist

Other hyperkinetic disorders: Hemiballismus

Cause:

• damage to subthalamic nucleus (usually unilateral stroke)

Effect:

• violent flailing movements of limbs (contralateral to damage)

Other hyperkinetic disorders: Tardive Dyskinesia

Cause:

• long-term exposure to antipsychotic dopamine receptor antagonist drugs

Effect:

• uncontrolled movement, especially of facial + trunk muscles