Motor Control 2:

The Basal Ganglia and Cerebellum

Cerebellum
- closely involved with brainstem mechanisms
- control of muscle tone
- sensorimotor coordination
- motor learning

Basal Ganglia
- integration of sensory and motor information
- cortex  basal ganglia  cortex loop (via thalamus)
Neither project directly beyond the brain

Basal ganglia and Motor Disorders

- Parkinson’s Disease
- Huntington’s Disease
 The Cerebellum

Neuroscience: Exploring the Brain. Bear et al.

- control of muscle tone

- sensorimotor coordination
- motor learning
Cerebellum:
3 functional and anatomical components

(1) Spino-cerebellum (medial region of cerebellum)

Connections and Function

• Sensory input from the spinal cord
• Output to the reticular formation and red nucleus
• then to motor cortex, and via this:
- output to spinal cord
- control over axial musculature and posture
Result of damage
Hypotonia (reduced muscle tone)
Ataxia (unsteady, staggering gait)
Dysmetria (inaccurate termination of movement) and ‘intention tremor’
 Cerebellum:
functional and anatomical components

(2) Vestibulo-cerebellum (caudal region of cerebellum)

Connections and Function

• input from and output to vestibular nucleus
• control over posture/balance, also eye movement

Result of damage
Slow saccades (fast tracking ocular movement impaired)
Nystagmus (due to failed vestibulo-oculomotor integration)
Ataxia (unsteady, staggering gait)
(3) Cerebro- (ponto-) cerebellum (lateral hemispheres
of the cerebellum)

Connections and Function

an intracerebral motor loop

Cortex  pons  cerebellum  dentate nucleus (deep

cerebellar nuclei)  ventrolateral thalamus  cortex (M1)

• instructs the primary motor cortex (M1)

regarding movement direction, timing and force

• compares intended movements with actual movements

and sends compensatory instructions to M1
(3) Cerebro- (ponto-) cerebellum (lateral hemispheres
of the cerebellum)

Result of damage

Incoordination / ataxia unsteady, staggering gait

Dysmetria ‘intention tremor’ - inaccurate termination of movement

Asynergy uncoordinated agonist & antagonist muscles

Dysarthria inarticulate speech - poor oropharyngeal muscular

control
 Circuitry of the cerebellar cortex

Fig 24.13 bear

Circuitry of the cerebellar cortex

Mossy DEEP CEREBELLAR Climbing

NUCLEI
fibre fibre
 Circuitry of the Cerebellar Cortex
INPUTS:

1. climbing fibres input from inferior olive

- excitatory and act on Purkinje cells

2. mossy fibres from brainstem nuclei

- indirectly excite Purkinje cells
via parallel fibres of Granule cells

[~1011 Granule cells = about 50% of all CNS neuron]

[each P cell receives ~200,000 parallel fibres]

OUTPUTS:

1. Only Purkinje cells – project to Deep Cerebellar Nuclei

Circuitry of the Cerebellar Cortex

Deep Cerebellar Nuclei (DCN) cells can 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)

→ an ‘error signal’
Comparator/ timer/ regulator functions
MOTOR PLAN
what should have happened

cerebellum
comparison

DCN what has happened

intended movement
(afference copy)
actual movement
(efference copy
(sensory feedback)
Comparator/ timer/ regulator functions
MOTOR PLAN?
what should have happened

cerebellum
comparison

DCN what has happened

compensatory output to
brain stem and
thalamus
Summary - Cerebellar function

1. regulates posture indirectly by adjusting output of major

descending motor pathways

2. acts as a comparator, identifying and correcting

discrepancies between intended movement 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 cortex

• relays back to the cortex via

To brainstem
& spinal cord
thalamus
BASAL Ventrolateral
GANGLIA thalamus
Neuroscience: Exploring the Brain. Bear et al.

• motor circuit output to premotor/SMA cortex

• selection and initiation of voluntary movement

The Motor Loop

SMA
CORTEX
PFC

THALAMUS DISINHIBITION

BASAL
basal ganglia GANGLIA
‘outflow’
The basal ganglia
structures generally included:

- the caudate nucleus

- putamen Striatum (STR)
- nucleus accumbens

- globus pallidus (GP) - internal (GPi) and external (GPe)

reticulata (SNr)
- substantia nigra pars compacta (SNc)

- subthalamic nucleus (STN)

Internal organisation of the basal ganglia:
direct and indirect pathways

• from the striatum, cortical input is relayed to two major

output areas within the basal ganglia, SNr and GPi
• 'direct' pathways, striato-nigral and striato-pallidal GPi
• 'indirect' pathway projections via GPe and STN
• opposing effects on thalamocortical output
• balance between the ‘direct’ and ‘indirect’ pathways

• Dopamine, derived from SNc, plays a key modulatory role

 The Basal Ganglia – basic circuit

CORTEX Glutamate
+ GABA
+ + Dopamine
STRIATUM

- THALAMUS
GPe -
Subthalamic
- STN - nucleus
STN Globus palidus
+ GPe/i -
external/internal
SNc
+ -
SNr / GPi SNr/c - Substantia nigra
reticulata/compacta

Basal ganglia output INHIBITS excitatory drive to motor cortex

 Basal Ganglia –
Dopamine & the Direct Pathway
The direct pathway
D1
receptors
CORTEX
+ serves to promote
movement
+
+ STRIATUM Dopamine acts on
THALAMUS excitatory D1
- receptors
on striato – GPi/SNr
neuron
SNc
-
SNr / GPi This further reduces
BG output and
facilitates movement
 Basal Ganglia –
Dopamine & the Indirect Pathway
The indirect pathway

D2 CORTEX
+ serves to suppress
movement
receptors
+
- STRIATUM Dopamine acts on
inhibitory D2
- THALAMUS
GPe - receptors
- STN
on striato – GPe
neuron
+ +
SNc This reduces STN
SNr / GPi
activity, & BG output
and also
facilitates movement
The Basal Ganglia and Motor Dysfunction

imbalance
between the direct and indirect pathways 
motor dysfunction

hypokinetic disorders:
e.g. Parkinson's disease

hyperkinetic disorders:
e.g. Huntington's disease
Ballism
Tardive Dyskinesia
 Parkinson’s Disease

• tremor (usually resting tremor)

• bradykinesia (slowness of movement)
• rigidity (resistance to passive movement)

• Affects 0.1% of pop. under 50 y.o.; > 50 y.o.  1%

• Progressive disorder: → dementia; depression;
bladder disturbance
• Average survival after manifestation ~15 years

• primary pathology :
progressive degenerative loss (> 80%) of
nigro-striatal dopaminergic pathway
 Parkinson’s Disease

CORTEX Glutamate
Dopamine loss in basal
+ GABA
ganglia
+ + Dopamine
STRIATUM  excessive inhibition of
thalamo - cortical
- THALAMUS
pathway,
GPe -
Subthalamic
- STN -
nucleus
STN Globus palidus driven by ↑ activity in
+ GPe/i -
external/internal
SNc
+ - subthalamic nucleus
SNr / GPi SNr/c - Substantia nigra (STN)
reticulata/compacta

Treatment –
• Dopamine replacement drugs (eg. L-DOPA)
• Surgical lesion / inactivation of STN
Treatments for PD

• Many drugs to boost dopamine in brain

- L-DOPA
- dopamine agonists
- drugs that reduce dopamine breakdown (MAO-B inhibitors)

• Deep brain stimulation

• No treatments address the underlying degeneration

http://commons.wikimedia.org/wiki/File:Catecholamines_biosynthesis.svg#mediaviewer/File:Catecholamines_biosynt
Treatment of
Parkinson’s Disease
Dopamine replacement therapy
Reduces rigidity and hypokinesia

L-DOPA
Metabolised to produce dopamine by
"Catecholamines biosynthesis" by NEUROtiker - own work.

DOPA-decarboxylase in DA-ergic
neuron

BUT L-DOPA will also elevate NAdr

synthesis in sympathetic NS
Non-brain penetrating carbidopa or
benserazide co-administered to inhibit
peripheral DOPA decarboxylase
hesis.svg
 L-DOPA: problems

• Effectiveness diminishes over 2-5 years

primarily due to progressive nature of the disease:
↓DA-ergic nerve terminals
↓capacity to convert L-DOPA to dopamine

Result: ↑ L-DOPA dose frequency

eventual development of:
• ‘ON – OFF’ effect sudden transitions between symptom relief
and hypokinesia
• dyskinesias (involuntary writhing movements)
Alternatives to L-DOPA
Directly-Acting Dopamine Receptor Agonists

Bromocriptine / Pergolide (fairly) non-selective

Pramipexole / Ropinirole more D2 receptor selective
(newer)

Apomorphine reserved for advanced stage PD

and ‘OFF’ L-DOPA episode treatment

Problems include:

Nausea/emetic effects (especially apomorphine)

Psychotomimetic effects
Alternatives to L-DOPA

Selegiline MAO-B inhibitor

selectively elevates [DA]
Amantidine a dopamine releaser
Muscarinic ACh Receptor antagonists: e.g. benzhexol
offsets local circuit consequences of DA deficiency on
cholinergic striatal interneuron

• drugs can be used alone or as adjuncts (‘add-ons’) with L-

DOPA
Surgical treatment of Parkinson’s Disease

Glutamate
CORTEX Dopamine loss in basal
+ GABA ganglia
+ + Dopamine
STRIATUM
 excessive inhibition of
- THALAMUS thalamo - cortical
GPe - pathway
Subthalamic
- STN -
nucleus driven by ↑ activity in
STN
+ GPe/i -
Globus palidus subthalamic nucleus
external/internal
SNc
+ - (STN)
SNr / GPi SNr/c - Substantia nigra
reticulata/compacta

Surgical lesion / inactivation of STN:

DEEP BRAIN STIMULATION (DBS)
Treatments for PD

• Many drugs to boost dopamine in brain

- L-DOPA remains key (‘Awakenings’, Oliver Sacks)

- dopamine agonists
- drugs that reduce dopamine breakdown (MAO-B inhibitors

• Deep brain stimulation

• No treatments yet reduce the underlying degeneration

Huntington’s Disease

• Excessive “choreiform” movement

• Uncontrollable, relatively rapid motor patterns
disrupts normal motor activity
• Later stages → psychiatric disturbance, dementia

• Autosomal dominant disorder, 4p16

• Genetics – expanded (CAG) repeat in huntingtin gene
• Prevalence ca. 1 in 15,000
• Peak age onset 40-45 yr
• Progressive deterioration over 10-25 years

• Primary pathology (in early stages) is loss of striatal

output neurons in indirect pathway
 Huntington’s Disease (2)
loss of striatal output
CORTEX Glutamate neurons in indirect
+ GABA pathway
+ + Dopamine → suppression of STN
STRIATUM
→ predominance of
- THALAMUS direct pathway
GPe - → ↓ BG output
Subthalamic
- STN -
nucleus → overactive
STN Globus palidus
+ GPe/i -
external/internal
thalamocortical
SNc
+ - pathway
SNr/c - Substantia nigra
SNr / GPi reticulata/compacta → involuntary movement

Treatment – none specific as yet, only symptomatic relief

 Huntington’s Disease

Drug Treatments (symptomatic relief only)

Tetrabenazine VMAT inhibitor, ↓ DA storage, & release

Chlorpromazine DA antagonist (antipsychotic)
Baclofen GABA-B agonist, ↓ spinal reflexes
(intrathecal)
Other Hyperkinetic Disorders of BG origin
Hemiballismus

Cause: damage to subthalamic nucleus

(usually by unilateral intracerebral thrombosis)
Effect: violent flailing movements of limbs
contralateral to damaged side

Tardive Dyskinesia

Cause: increased dopamine receptor sensitivity,

due to long-term exposure to antipsychotic
dopamine receptor antagonist drugs
Effect: uncontrolled movement, especially of facial and
trunk muscles

NB. dopamine therapy in PD can also → acute dyskinesia

Reading

Bear, Connors & Paradiso ‘Neuroscience, Exploring the Brain’

(4th edition) Ch. 14

Rang & Dale’s ‘Pharmacology’ (8th Edition) Ch.40

“Neurodegenerative Disease” (appropriate parts)
Barker & Barasi ‘Neuroscience at a Glance’

Kandel, Schwartz & Jessell, ‘Principles of Neural Science’, (5th

Edn.). Ch. 43, Ch.44 (appropriate parts).