Basal Ganglia Flashcards
What is hyperkinesia?
Excessive movement, abnormal uncontrolled muscular activity
Hypokinesiw?
Diminished or abnormally slow movement
What is disinhibition?
Loss of inhibition
What are the components of the basal ganglia?
Striatum (STR):
- Caudate
- Putamen
• Globus pallidus:
-External (lateral) part (Gpe/GPL) -Internal (medial) part (Gpi/GPM). The GPi is the chief output nucleus.
- Subthalamic nucleus (Sth)
- Substantia Nigra (SN):
- Pars reticulata (SNr)
- Pars compacta (SNc)
Whats the function of the basal ganglia?
The basal ganglia participates in the initiation and control of voluntary movement
- Basal ganglia receives excitatory(+) input from the cerebral cortex
- Outputs of the thalamus to the cortex are generally excitatory (+)
- Inhibitory inputs into the thalamus from the basal ganglia (−) serve to dampen thalamic excitation of cortical neurons.
Whats the role of the substantia Nigra?
• Substantia Nigra (SN):
- Pars reticulata (SNr)
- Pars compacta (SNc)
• Dopamine released from the SNc regulates the function of the basal ganglia
Where is dopamine released from?
- Dopamine released from the SNc acts on the D1 and D2 receptors in striatum.
- Dopamine released from the SNc indirectly regulates movements through its action on the basal ganglia.
What are the significance of the basal ganglia pathways?
- The thalamus and, indirectly, the frontal cortex are under tonic inhibitory control from GPi.
- This inhibition is modulated by two parallel basal gangliar pathways that originate in and diverge from the Striatum:
- one direct pathway
- one indirect pathway
What is the direct pathway?
The direct pathway disinhibits the thalamus resulting in the facilitation of movement
What is the indirect pathway?
The indirect pathway inhibits the thalamus which diminishes movement
Whats the purpose of the direct pathway?
The direct pathway causes excitation of the motor regions of the cortex and thus facilitates movement
Communication is via two neurotransmitters
- Glutamate (+)
- GABA(-)
How does the direct pathway perform?
- Cortex excites the striatum
- Striatal output inhibits activity of the GPi
- Inhibition the GPi increases thalamic activity (disinhibition of thalamus)
- Thalamic activity excites the cortex to facilitate movement
What is the function of the indirect pathway?
The indirect pathway inhibits the thalamus which diminishes movement.
• Communication is via two neurotransmitters
- Glutamate (+)
- GABA (-)
What is the mechanism of action of the indirect pathway?
- Cortex excites the striatum
- Striatum inhibits the activity of the GPe
- Inhibition of GPe releases the Sth to be active
- Increased output from the Sth excites the GPi
- Excitation of the GPi inhibits the thalamus
- Decreased thalamic output decreases cortical excitation, thereby diminishing movement
What is the modulatory role of dopamine?
- SNc via dopamine further modulates movement
- SNc facilitates movement via excitation of striatal cells (D1R)- direct pathway
- SNc facilitates movement via inhibition of striatal cells (D2R) – indirect pathway
What does research suggest of modulatory dopamine?
- Current research suggests that the dopamine excites the direct pathway but inhibits the indirect pathway.
- Therefore, the action of dopamine is to facilitate movement because it excites the facilitatory (direct) pathway via its excitatory effects on dopamine D1 receptors in regions of the neostriatum that project to the medial pallidal segment, while inhibiting the inhibitory (indirect) pathway that projects initially to the lateral pallidal segment because of the inhibitory effects on dopamine D2 receptors in the neostriatum.
- The result is diminution of excitation from the glutamate-mediated pathway arising from the subthalamic nucleus to the medial pallidal segment.
• In this manner, the overall output of the medial pallidal segment to the
thalamus is diminished, resulting in greater excitation of the motor
regions of cortex, the consequence of which is an increase in movement
What happens when either direct or indirect pathways?
Disturbed activity of direct (D) and indirect (I) circuits yield either hypo- or hyperkinesis
Describe the dopaminergic insufficiency in parkinsons disease
Insufficient release of dopamine alters activity in both direct and indirect pathways to result in
– Reduced activity of the direct pathway
– Increased activity of the indirect pathway
Describe nigrostriatal insufficiency in parkinson disease
– decreasing inhibition of GPi
– Increased thalamic inhibition
– Decreased cortical activity and hypokinesis
Explain the dopaminergic insufficiency in parkinson disease
- In Parkinson’s disease the hypokinetic effect is manifested by the reduced quantities of dopamine released.
- Dopamine acting through D1 receptors in the neostriatum is excitatory to GABAergic neurons, which project to the GPM (direct pathway). Moreover, dopamine acting through D2 receptors in the neostriatum inhibits GABAergic neurons, which project to the GPL segment (indirect pathway).
- When there is diminished dopamine in the neostriatum released onto D1 receptors (dotted lines), the resulting inhibitory output of the neostriatum on the GPM is diminished. This allows for an enhancement of the inhibitory output of the GPM to the thalamus to be increased (thicker arrows).
- The thalamus normally excites the cortex, greater inhibition on the thalamic nuclei by the GPM will cause a weakened input to motor regions of the cortex. Likewise, the projection from the neostriatum, acting through D2 receptors, is inhibitory to the GPL. In turn, the GPL is normally inhibitory to the Sth. Thus, the diminished inhibitory input into the neostriatum from SN allows the neostriatum to exert greater inhibition on GPL, which, in turn, results in a weakened inhibition upon the Sth. Because the Sth normally excites the GPM via a glutamatergic mechanism, the reduced amount of inhibition on the Sth would allow it to exert a greater excitatory effect on the GPM.
- Therefore, the combined effects of reduced dopaminergic inputs into the neostriatum affect both the direct and indirect pathways in such a way as to allow for enhancement of the inhibitory outputs of the GPM on the thalamic projection nuclei and their target regions in motor cortex, causing the hypokinetic movement disorder
What is the background of parkinson ?
Mean age of diagnosis = 55 years of age
• Causes not firmly established, but many genes implicated – Alpha synucleins forming Lewy bodies
• Catecholaminergic cells are among the degenerating cells – Nigral dopaminergic cells
– Noradrenergic pontine locus coeruleus
– Autonomic noradrenergic cells
What are the clinical features of parkinson disease?
The major initial clinical symptoms include
1. Decreased sense of smell (hyposmia)
2. Sleep disturbances (Rapid eye movement (REM)
behavior disorder - RBD)
3. Autonomic dysfunction
The cardinal motor symptoms are:
- Resting Tremor 2. Bradykinesia
- Rigidity
- Postural instability*
What are the manifestations of parkinsons disease?
Other motor manifestations
- Decreased facial expression (masked facies)
- Loss of habituation to glabellar stimulation -Soft, hoarse, monotonous voice
- Decreased arm swing
- Short strides
- Flexion of trunk
- Abnormal postural adjustments
- Akinesia
What are the early stages of parkinsons disease?
Stage 1- mild symptoms of PD are mild and only seen on one side of the body (unilateral involvement) symptoms: tremor of one hand, regidity, clumsy leg, one side of face may be affected, impacting the expression
Stage 2- mild symptoms of PD on both sudes of the body (bilateral involvement) or at the midline symptoms: loss of facial expression on both sides, decreased blinking, speech abnormalities, rigidity of the muscles in the trunk
Describe the moderate stage of parkinsons disease
Stage 3- moderate symptoms of PD are characterized by loss of balamce and slowness of movement
Symptoms: Balance is compromised
Inability to make rapid, automatic and involuntary adjustments
All other symptoms of PD are present
Describe the advanced PD
Stage 4
Severe- Symptoms of PD are severely disabling
Symptoms- Patients may be able to walk and stand unassisted, but they are noticeably incapicated
Patient is unable to live an independent life and needs assistance
Stage 5
Severe- Symptoms of PD are severe and are characterized by an ability to rise
Synotoms: patients fall when standing or turning. May freeze or stumble when walking. Hallucinations or delusions
What is the medical management of PD?
• L-dopa + Carbidopa • Dopamine Receptor Agonists • Dopamine Metabolism Inhibitors • Anticholinergics • Antiviral therapy
What is the medical management of PD?
• L-dopa + Carbidopa • Dopamine Receptor Agonists • Dopamine Metabolism Inhibitors • Anticholinergics • Antiviral therapy
What is the surgical management of PD?
- Surgical ablation
* Deep brain stimulation
Describe front line therapy for PD
- Oral L-dopa (L-dihydroxyphenylalanine) increases dopamine synthesis in surviving neurons of the SNc
- Carbidopa reduces peripheral metabolism of L-dopa
• The L-dopa + Carbidopa combination is commonly used
in the treatment of Parkinson’s disease.
• Treatment with L-dopa/carbidopa becomes less effective over several years
What are the dopamine metabolism inhibitors?
• Inhibitors of MAO
– Blockage of monoamine oxidase – B (MAO-B)
• May improve responses to or delay the need for other therapies
• Inhibitors of COMT
– Catechol-O-methyltransferase inhibitors may be
given in addition to L-dopa and carbidop
What are the dopamine receptor agonists?
• Drugs that activate either or both D1 and D2 receptors can normalize movement, bypassing degenerating nigrostriatal neurons and acting
directly on postsynaptic receptors.
What is the significance of anticholinergics?
Acetylcholine excites striatal neurons that express D2 receptors
- ACh (acting on muscarinic receptors) and dopamine (acting on D2 receptors) exert opposite effects on striato-pallidal cells
- Muscarinic antagonists (binding to muscarinic receptors) therefore suppress acetylcholine-mediated excitation of striatal neurons in the indirect pathway.
- Useful for management of tremors
What is the importance of increased release of striatal dopamine?
Antiviral therapy may benefit some manifestations of Parkinson disease (e.g., akinesia, rigidity)
– May promote the release of dopamine and/or block ACh receptors (also weakly blocks NMDA receptors)
What structures removed in surgical ablation?
Subthalamus
Globus pallodus internus
What are the stimulation sites in deep brain stimulation?
Thalamus
Globus pallidus
Subthalamus
What can incuce parkinson like conditions?
Drugs
– Antipsychotic drugs (Dopamine receptor blockers)
– Depletors of dopamine stores (e.g., reserpine)
– Toxic contaminants (MPTP:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
• Vascular disease
– Strokes disrupting nigrostriatal pathway
• Trauma
– Multiple blows to the head can damage the midbrain, yielding a syndrome
with parkinsonian features
• Encephalitis
– Viral encephalitis can lead to nigral degeneration
• Neoplasia
– Tumors can disturb the nigrostriatal system
What is the relationship of Striatal Neuronal Degeneration and Huntington Disease?
- Degeneration of GABAergic neurons that project to the GPe
- Greater inhibition of the Sth by the GPe
- Reduced excitation of the GPi by the Sth
- Reduced inhibition of thalamus via indirect pathway
- Increased cortical excitation, leading to hyperkinesis
What is the background 8nfo of Huntington?
Autosomal dominant disease
- Mean onset is 40 years of age
- The juvenile form of the disease is usually fatal before the age of 21 years
• Degeneration of brain is broadly evident
– Prefrontal and striatal cells highly vulnerable, yielding enlarged ventricles
Summarize the clinical presentation of huntington disease
- Chorea: Wild, uncontrolled abrupt and jerky movements of the distal musculature (dance-like movements)
- Depression
- Dementia
What drugs are used for huntington ?
• Antidepressants
– for combating associated
depression
• D2 receptor antagonists
– exert some antichoreatic effect (assuming some surviving striatal neurons expressing this receptor)
• Vesicular monoamine transporter (VMAT) inhibitors
– dopamine-depleting agents helps to reduce hyperkinesis
What is athetosis?
Athetosis
Slow, involuntary writing movements, with a propensity to affect the
upper limbs
– Striatal or thalamic injury can yield continuous writhing
What are the choreatic disorders?
Sydenham Disease
– Linked to childhood rheumatic fever
• Drug-induced
– Treatment of Parkinson disease may yield choreatic movements
What are Hemiballismus?
- Ballismus: violent flinging and rotatory movements of the limbs
- Hemiballismus arises from contralateral Sth injury
- Reduced excitation of the GPi disinhibits the thalamus
- Increased cortical excitation
- One side of the body is affected
