Module E-07 Flashcards
Describe development of Basal ganglia
The first neurons generated in the cerebral periventricular zone migrate short distances. They aggregate as subcortical islands of gray matter (basal ganglia or basal nuclei) in the cerebral white matter.
Caudate and Putamen together are called_______
Striatum
Globus Pallidus and Putamen together are called______
Lentiform nucleus
Structures taht modulate motor cortex with Basal ganglia
- Striatum: Caudate, putamen, ventral striatum 2. Globus pallidus: External (lateral) part (GPe), internal (medial) part (GPi) 3. Subthalamic nucleus 4. Substantia Nigra: Pars reticulata (SNr) and pars compacta (SNc)
How do basal ganglia modulate the motor activity of the frontal cortices?
• Basal ganglia receive inputs from cerebral cortex • Basal ganglia modulate thalamus • Thalamus regulates motor cortex • Through the thalamus, basal ganglia participate in the initiation and control of voluntary movement
The substantia nigra projects to the ______ to release _______
striatum; dopamine
What is the effect of the dopamine released by substantia nigra on striatum?
Dopamine regulates basal gangliar function, thus indirectly regulating cortical control of movement
What is the effect of basilar output onto thalamus
- Basal gangliar output inhibits the thalamus, thereby suppressing an excitatory thalamocortical projection. - The degree of thalamic inhibition therefore dictates modulation of cortex-dependent motor activity. - Because lesions affecting the basal ganglia disturb basal gangliar output and hence cortical activity, movement often suffers.
Corticostriatal fibers release ________ to excite striatal neurons
glutamate
What region of the Substantia nigra a) releases neurotransmitter on to striatal cells, b)What neurotransmitter is released , c) what is the effect of the neurotransmitter and d) on which receptor does the neurotransmitter bind?
a) Pars compacta (SNc) b) Dopamine c) excitatory or inhibitory d) D1 (excitatory), D2 (inhibitory)
The substantia nigra receives inhibitory ______ signals from the striatum
GABAergic
GABAergic output from the MEDIAL (internal) part of the globus pallidus (GPi) inhibits cells _________________
GABAergic output from the medial (internal) part of the globus pallidus (GPi) inhibits cells of the ventral anterior and ventral lateral thalamic nuclei
Thalamic cells excite the motor cortex via the release of _______
glutamate
What is the effect of striatum on globus pallidus internal?
– Suppresses activity in the GPi – Decreased output from the GPi increases thalamic activity – Increased thalamic activity increases cortical activity to facilitate movement
What is the effect of Globus Pallidus on Thalamus?
-secretes GABA to suppress thalamic output
Describe Direct Basal Gangliar Motor Loop
What is the effect of Subthalamic nucleus on Globus Pallidus medial?
Releases Glutamate to activate GPi and increase GABA release and thereby suppression of thalamus
Describe the Indirect Basal Gangliar Motor Loop
Effect of Direct circuit on movement
o Striatal output suppresses activity in the GPi
o Decreased output from the GPi increases thalamic activity
o Increased thalamic activity increases cortical activity to facilitate movement
Effect of INDirect circuit on movement
o Striatal output suppresses activity in the GPe
o Decreased output from the GPe increases output from the Sth
o Increased output from the Sth increases activity within the GPi
o Increased activity within the GPi inhibits the thalamus o Decreased thalamic output decreases cortical activity, thereby diminishing movement
Role of Striatal Dopamine in movement
Tonically released dopamine arising from the substantia nigra optimizes the output of the two basal gangliar circuits to normalize movement
Normal Role of Basal Ganglia in Voluntary Movement
- Normal initiation and maintenance of voluntary motor activity depends on basal gangliar output
- Normal basal gangliar activity regulates motor cortices to optimize communications between upper and lower motor neurons
- Optimized communication between upper and lower motor neurons depends on delicately balanced activities of direct and indirect basal gangliar components
o Unbalanced influences of the direct and indirect pathways on the GPi (and hence the thalamus) yield either hypo- or hyperkinesis
What defect causes Hypokinesis in Parkinson’s disease?
pathologically diminished release of striatal dopamine secondary to degeneration of the dopaminergic nigrostriatal tract
– The net effect is increased inhibition of the thalamus, leading to decreased cortical activity and hypokinesis
Effect of Diminished dopamine on the Direct pathway
o Diminished activation of excitatory D1 receptors reduces striatal output within the direct basal gangliar pathway
o Diminished striatal output disinhibits the GPi
o The overly active GPi suppresses the thalamus
o Decreased thalamic activity decreases cortical output, suppressing movement
Effect of Diminished dopamine on the INDirect pathway
o Decreased stimulation of inhibitory striatal D2 receptors disinhibits striatal cells contributing to the indirect pathway
o Increased activity of striatal cells inhibits cells in the GPe
o Decreased activity in the GPe disinhibits the Sth
o Increased excitatory output from the Sth increases activity within the GPi
o Increased activity within the GPi suppresses thalamic activity
o Decreased thalamic activity reduces cortical excitation
o Reduced cortical activity once again diminishes voluntary movement
What causes drug induced Parkinsonism?
– Antipsychotic drugs like Phenothiazines, (DA receptor blockers)
– Depletors of DA stores (e.g., reserpine)
– Toxic contaminants (MPTP)
What produces MPTP?
a contaminant produced during improper preparation of a synthetic narcotic
How does MPTP induce Parkinsonism?
by damaging nigral mitochondria
What receptors do phenothiazines block ?
D2 receptors
How do phenothiazines cause drug induced Parkinsonism?
by limiting dopamine-mediated inhibition of striatal neurons of the indirect pathway
How does reserpine cause Drug-induced Parkinsonism?
may diminish striatal dopaminergic transmission to affect both the direct and indirect pathways
What is Vascular Parkinsonism?
Strokes interrupting the nigrostriatal pathway that may cause parkinsonism, affecting both direct and indirect pathways
Other Parkinsonian Conditions
- Drug-induced
- Vascular – Strokes disrupting nigrostriatal pathway
- Traumatic – Multiple blows to the head can damage the midbrain, yielding a syndrome with parkinsonian features
- Postencephalitic – Viral encephalitis can lead to nigral degeneration
- Neoplastic – Tumors can disturb the nigrostriatal system
What pathways are affected in Vascular Parkinsonism?
affecting both direct and indirect pathways
What is Dementia Pugilistica?
- a parkinsonian syndrome brought about due to multiple blows to the head as in boxers
- The midbrain flexes during traumatically induced acceleration of the forebrain, which can tear small mesencephalic blood vessels and shear axons
- The dura forming the tentorial notch may also interact unfavorably with the nearby midbrain during excessive cranial acceleration
- Cumulative effects of blows to the head may damage nigral (and other) cells
What is degenrated that leads to Postencephalitic Parkinsonism?
- due to degeneration of the SNc
- caused by Encephalitis Lethargica
What causes Neoplastic Parkinsonism?
Neoplasia can impact the substantia nigra or its output pathway to the striatum
What is Huntington’s disease?
an autosomal dominant condition with Hyperkinesis that tends to strike younger adults
What is the first presentation of Huntington’s Disease and what is usually the early indicator of onset?
first present as emotional dysregulation (disinhibition, impulsivity, emotional lability, etc.), motor system failure may be the sole early indicator of onset
Describe the progression of Huntington’s
- Facial/oral musculature is often affected early (uncontrolled grimacing, eyebrow-raising and lingual protrusion)
- The hands are often the next body parts to show choreatic activity, often assuming a piano-playing posture
- Progression of the disease is highly variable, but life-expectancy is approximately two decades after diagnosis
Which pathway is effected in Huntington’s that causes the HyperKinesis?
- Destruction of striatal neurons (bilaterally) expressing D2 receptors
- Reduced inhibition of thalamus via indirect pathway
- Increased cortical activity, leading to hyperkinesis
Which pathway is mainly affected in Huntington’s?
Indirect pathway
Name 4 other Choreatic Disorders
1) Sydenham Disease
2) Drug induced Chorea
3) Hyperballismus
4) Athetosis
What causes Sydenham Disease?
It is an autoimmune disease that arises months after rheumatic fever causing choreatic movements
age of onset of Sydenham disease
between 5 and 15 years
Recovery time for Sydenham’s Disease
Recovery tends to be complete within about 6 weeks
What drugs result in Drug induced Chorea?
Treatment with l-dopa (for Parkinson disease) or some anticonvulsants may produce chorea consequent to altered transmission within the basal ganglia
What is Athetosis?
Slow continuous writhing (athetoid) movements can reflect striatal or thalamic injury
What is Hemiballismus?
Flinging and rotational movements of the limbs that arise from contralateral subthalamic injury
Whta causes Hemiballismus?
reflects unilateral stroke related injury to the subthalamus
What is damaged in Hemiballismus?
- excitatory output to the GPi decreases
- Decreased excitation of the GPi disinhibits the thalamus, yielding increased cortical excitation
- Increased cortical activity may produce contralateral ballismus
Whta lesion usually occur with Parkinson’s disease?(besides the Nigral dopaminergic cells)
- Catecholaminergic cells are generally vulnerable
- The pontine locus coeruleus, which contains noradrenergic neurons, readily degenerates
- Even peripheral noradrenergic cells, such as those providing sympathetic inputs to the heart, degenerate, yielding orthostatic hypotension and hence increased vulnerability to injurious falls
Mean age of diagnosis for Parkinson’s
55 years
Treatments for Parkinson’s disease
- Front line therapy: L-dopa and carbidopa
- Agonists of Striatal Dopamine Receptors
- Drugs that Enhance Striatal Dopamine Release
- Inhibitors of Dopamine Metabolism (MAO-B and COMT inhibitors)
- Anticholinergics
- Ablative Surgical Treatments
- Deep Brain Stimulation
What are the Front line therapies for Parkinson’s?
- Oral l-dopa increases dopamine synthesis in surviving neurons of the SNc
- Carbidopa reduces peripheral metabolism of l-dopa (peripheral decarboxylase inhibitor)
- Treatment with l-dopa/carbidopa becomes less effective over several years
– Responses also variable over hours (patients may benefit from transgastric catheterization)
Why does treatment with I-dopa and carbidopa become less effectuve over years?
the number of dopaminergic neurons in the SNc (the target of l-dopa) further declines
Effect of Agonists of Striatal Dopamine Receptors
- Agonists of D2 receptors interact with the indirect basal gangliar circuit
- Agonists of both D1 and D2 receptors may beneficially interact with both the direct and indirect basal gangliar circuits
Effect of Dopamine release enhancers
may reduce akinesia and rigidity
o The drug may promote the release of dopamine and/or block acetylcholine receptors (also weakly blocks NMDA receptors)
o Psychiatric side-effects reported
What are the 2 enzymes that Dopamine metabolism inhibitor therapies Target
1) MAO-B
2) COMT
Effect of MAO-B inhibitors
o suppress the breakdown of dopamine in the CNS
o It may improve responses or delay the need for other therapies
Effect of COMT inhibitors
prolongs the longevity of the neurotransmitter, thereby promoting movement
(May be given in addition to l-dopa and carbidopa)
Effect of Acetylcholine in striatal pathway
Acetylcholine excites striatal neurons that express D2 receptors
ACh and dopamine exert opposing effects on striatal neurons expressing D2 receptors
Effect of Muscarinic antagonists on striatal pathway
supress acetylcholine-mediated excitation of striatal neurons
Effect of Anticholinergics
- With decreased output from the striatum to GPe, output from the GPi decreases indirectly
- Decreased output from the GPi increases the ability of the thalamus to excite the cortex and normalize motor function in Parkinson disease
- Resting tremor appears to be preferentially vulnerable to muscarinic antagonists
Side-effects of Anticholinergics
o Acutely, patients may be drowsy and confused
o Chronically, Parkinson disease-related dementia may be promoted
What regions are targeted in surgical abaltion for Parkinson’s disease and why?
- Subthalamus- reduce the excitatory inputs to the GPi, thereby disinhibiting the thalamus
- Globus pallidus internal- directly reduces inhibitory input to the thalamus. The disinhibited thalamus is free to restore cortical excitation to reverse hypokinesia
What is an undesirable side effect of surgical ablation of the subthalamic nuclei?
Ballismus
What regions are targetted in deep brain stimulation therapy and what is the effect of each?
- Thalamus - directly increases the excitatory output to the cortex
- Globus pallidus - activation of local inhibitory neurons to decrease inhibitory output to the thalamus
- Subthalamus - ?
What is the Mean onset of Huntington’s disease?
40 years of age
What is “boxcar ventricles”?
With degeneration of striatal cells and efferent tracts along with frontal cortices, lateral ventricular enlargement is seen
Drugs used for Huntington’s Disease
1) Antidepressants
2) Antichoreatic (D2 antagonists and VMAT inhibitors)
Effect of D2 antagonists
o The drugs disinhibit surviving striatal neurons forming part of the indirect loop, ultimately decreasing excitation of cortex to reduce chorea.
o The therapy requires surviving striatal neurons that express D2 receptors.
Efficacy of the drugs declines as the disease progresses.
Side effects of D2 antagonists
may adversely affect swallowing, speech, and gait
Effects of Vesicular monoamine transporter (VMAT) inhibitors.
o Reduce the movement of dopamine into vesicles, thereby diminishing exocytosis.
o Reduced dopamine levels may disinhibit surviving striatopallidal cells within the indirect loop.
