Basal Ganglia Handout Battag

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 TEND TO SUPPRESS MOVEMENT DISEASES : HYPERKINESIAS

SUBSTANTIA NIGRA TENDS TO ENHANCE MOVEMENT 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 & RED NUCLEUS

UPPER MOTOR NEURON

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, PREMOTOR & SUPPLEMENTARY MOTOR CORTEX

BASAL GANGLIA CONNECTIONS _

VA and VL THALAMIC NUCLEI

+

SUPERIOR COLLICULUS

GLUTAMATE GABA + SP GABA + ENK ACETYLCHOLINE DOPAMINE THALAMUS

SUBTHALAMUS

SUBSTANTIA NIGRA Compacta & 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 GABA + SP GABA + ENK ACETYLCHOLINE DOPAMINE

+ VA and VL THALAMIC NUCLEI

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 GABA + ENK ACETYLCHOLINE DOPAMINE

+ VA and VL THALAMIC NUCLEI

_ 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 (+)

PUTAMEN GABA (-) Glu(+)

(+) DA (--)

(GPe) (STN)

GP interna GABA (-)

VA/VL THALAMUS

PUTAMEN GABA (-)

GP externa GABA (-)

Glu(+)

STN Glutamate (+)

GP interna GABA (-)

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, PREMOTOR & SUPPLEMENTARY MOTOR CORTEX

BASAL GANGLIA CONNECTIONS _

VA and VL THALAMIC NUCLEI

+

GLUTAMATE GABA + SP GABA + ENK ACETYLCHOLINE DOPAMINE THALAMUS

SUBTHALAMUS

SUBSTANTIA NIGRA Compacta & 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 early manifestation of parkinsonism

Tremor often improves or 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 akineticrigid 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)