Basal Ganglia

Fortunato Battaglia, MD, PhD

BASAL GANGLIA
The Basal Ganglia are nuclei that play a role in control of movement
by regulating the activity of upper motor neurons.

Some Nuclei Facilitate Movement, whereas others Suppress Movement.

The Basal Ganglia are interconnected with the Cerebral Cortex and
play some poorly-understood role in Cognitive & Limbic Function.

Most of the Basal Ganglia are derived from the Telencephalon.

The Subthalamic Nucleus (Diencephalic) and Substantia Nigra

(Mesencephalic) are functionally integrated with the Telencephalic
derivatives.
INTERNAL CAPSULE - CAUDATE & LENTIFORM NUCLEI

THALAMUS

CAUDATE

LENTIFORM

AMYDGALA PLANE OF SECTION

OF NEXT SLIDE
HORIZONTAL SECTION

INSULA CAUDATE (HEAD)

LENTIFORM:
PUTAMEN
GLOBUS PALLIDUS
Medial Segment
Lateral Segment

CAUDATE (TAIL)

THALAMUS
BASAL GANGLIA TERMINOLOGY
STRIATUM (NEOSTRIATUM) - Caudate Nucleus & Putamen

PALLIDUM (PALEOSTRIATUM) - Globus Pallidus (Medial & Lateral)

LENTIFORM NUCLEUS - Putamen & Globus Pallidus

And the two related nuclei:

SUBTHALAMIC NUCLEUS

SUBSTANTIA NIGRA - Pars Compacta & Pars Reticularis

NEOSTRIATUM & SUBTHALAMUS SUBSTANTIA NIGRA
TEND TO SUPPRESS MOVEMENT TENDS TO ENHANCE MOVEMENT
DISEASES : HYPERKINESIAS DISEASES : HYPOKINESIAS

Neostriatum

Substantia Nigra

Subthalamus
GENERAL OBSERVATIONS

THERE IS NO MAJOR SENSORY INPUT TO THE BASAL GANGLIA.

NO MOTOR TRACTS ORIGINATE IN THE BASAL GANGLIA.

THE BASAL GANGLIA INFLUENCE MOVEMENT BY REGULATING

THE ACTIVITY OF UPPER MOTOR NEURONS.

A LOOP THROUGH THE BASAL GANGLIA LINKS CEREBRAL CORTEX

WITH MOTOR CORTEX.

MAJOR INPUTS ARE EXCITATORY (EXCEPT SOME DOPAMINERGIC)

MAJOR OUTPUTS ARE INHIBITORY (TO THE THALAMUS)

MOTOR TRACTS - MEDIAL & LATERAL GROUPS
MOTOR CORTEX

MIDBRAIN & UPPER MOTOR NEURON

RED NUCLEUS
VESTIBULAR NUCLEI
PONS & MEDULLA
RETICULAR FORMATION

LOWER MOTOR NEURON

SKELETAL
MUSCLE
GENERAL OBSERVATIONS
MAJOR INPUTS TO THE NEOSTRIATUM:

CEREBRAL CORTEX TO MEDIUM SPINY NEURONS

(including collaterals of other cortical projections)

Medium spiny neurons of different types are concentrated in patches of

cells or within a continuous matrix in which the patches are embedded.

(A) Glutamatergic inputs from Areas 4, 3,1&2, & 18 & 19

mainly to the matrix of the striatum

(B) Glutamatergic inputs from Association and Limbic

cortex and Frontal Eye Fields to patches of medium
spiny neurons in the striatum
ADDITIONAL OBSERVATIONS
GABA+SP/ENK medium spiny neurons in the Neostriatum
project to and inhibit neurons in the Globus Pallidus and
Substantia Nigra (pars reticularis):

(A) Striatopallidal Pathway (B) Striatonigral Pathway

GABA neurons in the Globus Pallidus Medial Segment

provide the major OUTPUT by tonically inhibiting the
Thalamic Nuclei (Ventral Anterior & Ventral Lateral nuclei).

The VA & VL nuclei project to and excite Primary motor

and Supplementary Motor Cortex. Additional thalamic
projections are to Premotor and Prefrontal Cortex.
ADDITIONAL OBSERVATIONS

Reciprocal Connections Form Internal Loops:

(A) Between Striatum and Substantia Nigra (pars compacta)

These are GABA + SP & DA respectively.

(B) Between Globus Pallidus and Subthalamic Nucleus

These are GABA + SP & Glutamate respectively.
 MOTOR,
BASAL GANGLIA PREMOTOR &
SUPPLEMENTARY
CONNECTIONS MOTOR CORTEX

+
VA and VL THALAMIC NUCLEI
SUPERIOR
GLUTAMATE COLLICULUS
GABA + SP
GABA + ENK
ACETYLCHOLINE
DOPAMINE

THALAMUS
SUBSTANTIA
NIGRA
Compacta &
SUBTHALAMUS
Reticularis
FUNCTIONAL CONSIDERATIONS
The Basal Ganglia can either Facilitate or Suppress
Movement.

The Principal OUTPUT of the Basal Ganglia (from both

Globus Pallidus and the Substantia Nigra - pars reticularis)
tonically inhibits the Thalamus. Activity in medium spiny
neurons of the striatum modulates thalamic neurons which
then relay excitatory signals to upper motor neurons.

Modulation of Thalamic neurons which project to and

excite Motor Areas of the Cerebral Cortex may either
enhance or diminish movement.
 Direct Pathway
(Express Route)
CORTEX
Glutamate (+)

PUTAMEN
GABA (-)
Glutamate (+) (GPe)
(STN)

GP interna
GABA (-)

VA/VL THALAMUS
 DIRECT PATHWAY THROUGH THE
BASAL GANGLIA (Facilitates Movement):

+
+
_

GLUTAMATE +
VA and VL
GABA + SP THALAMIC NUCLEI
GABA + ENK
ACETYLCHOLINE
DOPAMINE
 Indirect Pathway
(long route)
CORTEX
Glutamate (+)
PUTAMEN
GABA (-)
GP externa
Glutamate (+) GABA (-)
STN
Glutamate (+)
GP interna
GABA (-)
VA/VL THALAMUS
 INDIRECT PATHWAY THROUGH THE
BASAL GANGLIA (Suppresses Movement):

+
+ _

GLUTAMATE +
GABA + SP VA and VL
THALAMIC NUCLEI
GABA + ENK
ACETYLCHOLINE _
DOPAMINE
SUBTHALAMUS
FUNCTIONAL CONSIDERATIONS
DIRECT PATHWAY (the accelerator) :

Excitation of inhibitory (GABA+SP) neurons in

the Striatum disinhibits output neurons of
the Thalamus (or Superior Colliculus for eye
movements), thus enhancing movement.

INDIRECT PATHWAY ( the brake) :

Excitation of inhibitory (GABA+ENK) neurons in

the Striatum disinhibits output neurons of the
Subthalamus which increases inhibition of Thalamic
or Collicular neurons, thus diminishing movement.

THE MODULATORY EFFECT OF THE BASAL GANGLIA

RESULTS FROM A BALANCE OF THESE PATHWAYS.
 What is missing?
–Effect of DA on pathways
•Direct Pathway: Stimulates
•Indirect Pathway: Inhibits
•Overall Excitatory
DA in the Indirect Pathway

Dopamine (-)

Substantia Nigra
pars compacta
 DA in Direct Pathway

Dopamine (+)

Substantia Nigra
pars compacta
 Direct and Indirect Motor Loops
CORTEX CORTEX
Glutamate (+) Glutamate (+)
(+) DA (--) PUTAMEN
PUTAMEN GABA (-)

GABA (-) GP externa

Glu(+) (GPe) GABA (-) Glu(+)
(STN) STN
Glutamate (+)
GP interna GP interna
GABA (-) GABA (-)
VA/VL THALAMUS
VA/VL THALAMUS
FUNCTIONAL CONSIDERATIONS
Dopamine may facilitate movement by acting on both
direct and indirect pathways. Dopamine acts on D1
receptors to enhance release of GABA+SP and on D2
receptors to inhibit release of GABA+ENK.
(Excites direct pathway; inhibits indirect pathway)

Thus, Dopamine enhances movement.

Cholinergic Interneurons (aspiny neurons) in the striatum

are believed to interact with Dopaminergic nerve terminals
and to modulate activity of GABA neurons that project to
the globus pallidus and substantia nigra.

The interaction is antagonistic so that normally, there is a

balance between the effects of dopamine and acetylcholine.
The role of basal ganglia disinhibition in the generation of saccadic eye movements.
 MOTOR,
BASAL GANGLIA PREMOTOR &
SUPPLEMENTARY
CONNECTIONS MOTOR CORTEX

+
VA and VL THALAMIC NUCLEI

GLUTAMATE
GABA + SP
GABA + ENK
ACETYLCHOLINE
DOPAMINE

THALAMUS
SUBSTANTIA
NIGRA
Compacta &
SUBTHALAMUS
Reticularis
LESIONS OF THE BASAL GANGLIA
GENERAL OBSERVATIONS:

(1) Lesions result in - disorders of movement.

(2) Movement may be increased (HYPERKINESIA)
or decreased (HYPOKINESIA).

(3) There is no paralysis or loss of muscle strength.

(4) Muscle Tone may be increased or decreased

(DYSTONIA).

Rigidity - constant, increased tone in agonist and

antagonist muscles without hyperactive
myotatic reflexes. Increased resistance
to passive movement.
LESIONS OF THE BASAL GANGLIA
GENERAL OBSERVATIONS:

(5) There may be involuntary movements

(RESTING TREMORS) of various types.

These are considered Release Phenomena -

the expression of intact neural structures
deprived of controlling influences.

(6) Several Basal Ganglia diseases appear to result from

changes in levels of specific neurotransmitters.
SPECIFIC DISEASES (DYSKINESIAS)

(A) HYPERKINESIAS - too much movement,

muscles are generally hypotonic:

(1) Chorea Minor (Sydenham’s Chorea)

Occurs in children as a sequel to rheumatic fever.

It is self-limiting and recovery is complete.
SPECIFIC DISEASES (DYSKINESIAS)
(A) HYPERKINESIAS - too much movement,
muscles generally hypotonic:
(2) Huntington’s Chorea

Inherited as an autosomal dominant trait.

The Huntingtin gene on chromosome 4 contains a
CAG expansion, resulting in an abnormally long
polyglutamine region which may cross-link with
tubulin or other cytoplasmic proteins.
Manifest in adult life (about age 40) by spontaneous
Choreiform movements followed later by Dementia
caused by loss of neocortical neurons.
Age of onset is inversely correlated with length
of the CAG repeat (Anticipation).

Muscles are hypotonic but there is no decrease in

muscle strength.
SPECIFIC DISEASES (DYSKINESIAS)
Degenerative changes in GABA neurons which project to
the globus pallidus and substantia nigra, as well as in
Cholinergic Interneurons.

Loss of GABA+ENK neurons to the GP (lateral segment)

decreases excitation of the GP (medial segment) by
the Subthalamus and disinhibits the Thalamus which
then produces the undesired movements.

Choreiform movements are believed to be caused by

excessive Dopaminergic activity and diminished
GABAergic and Cholinergic activity.

Antidopaminergic therapy tends to reduce the choreiform

movements but there is no therapy which produces
significant improvement.
HUNTINGTON’S CHOREA -
LOSS OF ACETYLCHOLINE & GABA
+
_x
x_
+ +
x

_
+
GLUTAMATE
GABA + SP _
GABA + ENK _
ACETYLCHOLINE
DOPAMINE Decreased excitation to GPi
(3) Hemichorea

Choreiform movements on one side of the body only.

Usually caused by a vascular lesion of contralateral

basal ganglia.

(4) Tardive Dyskinesia

Iatrogenic disease resulting from chronic

administration of phenothiazines (antipsychotics),
resulting in upregulation of dopamine receptors.

Patients have choreoathetoid movements

similar to those seen in other choreas.
(5) Hemiballismus

Consists of wild, flailing movements of the limbs

on one side and is usually caused by a vascular
lesion of the contralateral Subthalamic Nucleus.

Loss of subthalamic neurons disinhibits the thalamus.

Movements cease during sleep and general anesthesia.

Muscles are hypotonic.

The condition tends to improve or evolve into chorea

or athetosis in time.
 Hemiballismus
CORTEX
+
Glutamate (+)
PUTAMEN
GABA (-)
GP externa
Glutamate (+) GABA (-)
STN
Glutamate (+)
GP interna
GABA (-)
VA/VL THALAMUS
Hemiballism
 Magnetic resonance imaging scan
showing a limited area of increased signal
on the subthalamic region.
There was no other abnormality.
(6) Athetosis

Consists of slow, spontaneous, worm-like movements

which are exagerated by voluntary movements, and
is often accompanied by hypertonia (exception to
the general rule) resulting in abnormal persistence
of limb and trunk postures.

Lesions of the Putamen probably result from ischemia.

Athetosis is often seen in cerebral palsy.

A T2-weighted axial magnetic resonance image (MRI) of the brain
shows a high signal intensity lesion at the right putamen

Moyamoya disease is a cerebrovascular disorder

characterized by the narrowing or occlusion
of major blood vessels leading into the brain,
and the formation of abnormal blood
vessels called moyamoya vessels
(B) HYPOKINESIAS - too little movement,
muscles generally hypertonic:
(1) Parkinson’s Disease (PD)

Principal features appear to be caused by degeneration

of Dopaminergic Neurons in the Substantia Nigra.
Degenerate neurons contain cytoplasmic inclusions
called Lewy bodies. There is a lesser degeneration of
other biogenic amine-containing neurons in the
Locus Ceruleus and Raphe Nuclei.

Patients have difficulty initiating movement (Hypokinesia)

and movement is slowed (Bradykinesia).

They have a characteristic Stooped Posture and

Shuffling Gait.
Muscle tone is increased (Hypertonia), in both flexors
and extensors and passive movement of the arm
against resistance results in Lead Pipe Rigidity or a
stepwise movement called Cogwheel Rigidity.

Spontaneous movements of the wrist and fingers

(Pill-rolling Tremors) are rhythmic and diminished
during volitional movments and during sleep.

Myotatic reflexes are essentially normal but normal

swinging of the arms when walking is lost.

Facial expression is fixed and unresponsive to emotion

(Masked Face).
Motor deficits are the most prominent features but
cognitive impairment, depression and dementia may
appear in later stages of the disease.

Therapy presumes a loss of balance between

Dopaminergic and Cholinergic mechanisms in
the striatum.

The imbalance may result in decreased release of

GABA by striatal neurons projecting to the globus
pallidus (medial segment) and substantia nigra
(pars reticularis), and increased inhibition of thalamic
neurons that project to motor cortex, resulting in
decreased motor neuron activity and difficulty in
movement.
PARKINSONISM - ETIOLOGY
Genetic susceptibility to environmental factors likely plays a role.

MPP+ (from MPTP contained in some contaminated opioid drugs)

inhibits complex I of the electron transport chain and results
in an increase in free radicals and lipid peroxidation and in
degeneration of DA neurons.

A defect in mtDNA coding for complex I of the electron transport

chain may play a role in idiopathic PD, as there is a 30-40%
decrease in complex I in the substantia nigra in PD.

There is an excess of iron in the brain in PD and in some other

diseases (Friedreich’s ataxia, Hallervorden-Spatz disease).
Pathology of Parkinson's disease
ETIOLOGY CONTINUED
Mutations of the alpha-Synuclein gene cause some familial cases.
This protein co-localizes with synaptophysin and appears to play
a role in regulating the presynaptic vesicular pool.

A fragment of alpha-synuclein is a major component of Lewy bodies

and of the senile plaques of Alzheimer’s disease. Lewy bodies also
contain ubiquitin.

Other familial cases are caused by a mutation of the parkin gene.

Parkin is a ubiquitin ligase. The alpha-Synuclein in Lewy bodies is
highly ubiquitinated.

Such factors may alter mitochondrial function and induce apoptosis

and the associated production of reactive oxygen species, proteases
and nucleases and lipid peroxidation.
PARKINSONISM - OTHER FORMS
Dementia with Lewy bodies

Progressive Supranuclear Palsy

Postencephalitic (Encephalitis Lethargica)

Drug-induced (Phenothiazines)

Traumatic (Boxing)

CO Poisoning

Chronic Manganese Intoxication

 Primary Symptoms
Appear slowly and in no particular
order
Tremor
Rigidity
Bradykinesia
Gait Disorder
Loss of Balance
 Tremor
May start with a slight tremor in one
hand or arm and spread to involve
both arms and legs .
Most common when patients are at
rest or under emotional stress.
Usually worse on one side of the
body.Some patients may not
experience tremor symptom at all
Tremor of one hand is a frequent Tremor often improves or
early manifestation of parkinsonism disappears with purposeful function

Difficulty in performing simple manual functions

( e.g. doing up a shirt button ) may be initial symptom
 Rigidity
Muscular stiffness and
decreased muscle tone are
demonstrated by increased
resistance to passive
movements of joints such as
elbows, wrists, and neck
 Bradykinesia
Means “slowness of movement”
Slow movement and difficulty in
initiating movement .Poor handwriting,
inability to button clothes and difficulty
in rising from low chairs.Muscles in face
may also be slow, giving a mask-like
expression with reduced eye-blinking &
a stare
Speech may be slow and reduced in
volume and expressiveness
 Gait Disorder
Tend to walk with short shuffling steps
Body may be bent forward and unsteadiness
on turns is common
Walk using toe-first gait whichcontributes to
the shuffle
Some patients have brief halts (“freezing”) &
find it difficult to resume
Postural Instability
Decline of postural reflexes,
causing a loss of balance
Posture is stooped and knees are
flexed when walking causing
patient to be unsteady in walking
or turning and falls may occur
PARKINSONISM - THERAPY
L-DOPA + Carbidopa

DA receptor agonists

DA reuptake inhibitors

MAO inhibitors

COMT inhibitors

Anticholinergics

Pallidotomy or Thalamotomy

Deep Brain Stimulation (of the Globus Pallidus and STN)

Implantation of DA-producing cells (from adrenal medulla,

embryonic tissue or other sources)
 Surgical Treatments
Three types of surgery are currently used
for the treatment of Parkinson's disease:
•Pallidotomy
•Thalamotomy
•Deep Brain Stimulation
•Fetal nigral cells transplantation
 Huntington's Disease
1. Age of Onset: usually between the ages of 30 and 50

2. Location of Lesions: caudate, putamen, globus

pallidus and cerebral cortex.

3. Clinical Presentation: may begin with some

combination of mood and personality changes, cognitive
decline, clumsiness, extrapyramidal motor
abnormalities, especially chorea (bursts of movement).
Thus two types of symptoms occur:
a. Behavioral and cognitive changes, leading to dementia
b. Increasingly severe movement disorder

4. Pathogenesis: loss of projection neurons in basal

ganglia with resulting deficiency of GABA, enkephalin,
and substance P.

5. Inheritance pattern: autosomal dominant

Chorea
(+)- -[11C]DTBZ binding in a normal control (A),
a patient with nonrigid choreiform Huntington’s
disease (HD) (B), and a patient with akinetic-
rigid HD (C). (+)- -[11C]DTBZ binding is
reduced more in the akinetic-rigid than in the
choreiform patient. Note that reductions are
most prominent in the posterior putamen in the
patients.
Transplantation- increased activity striatum
 Dystonia
Neurologic movement disorder-sustained muscle
contractions producing twisting and repetitive movements and abnormal posture and positions
 Myoclonus

Sudden, brief, shock-like movements

FOUR PARALLEL CHANNELS FOR INFORMATION
PROCESSING THROUGH THE BASAL GANGLIA

MOTOR CHANNEL: PUTAMEN - GP - MOTOR CORTEX

OCULOMOTOR: BODY OF CAUDATE - GP - FRONTAL EYE FIELDS

CHANNEL

COGNITIVE CHANNEL: HEAD OF CAUDATE - GP - FRONTAL CORTEX

LIMBIC: VENTRAL STRIATUM - VENTRAL PALLIDUM - LIMBIC CORTEX

CHANNEL
Cognition, Non-motor Behaviors
Dorsolateral prefrontal circuit
(cognitive tasks)

Lateral orbitofrontal loop

(socially appropriate responses)

Anterior cingulate circuit

(procedural learning)