LECTURE - Basal Ganglia

What is the direct pathway of the basal ganglia?

- Cortex excites striatum - Striatum inhibits globus pallidus - Globus pallidus inhibited allows VA/VL of thalamus to act as it wishes - VA/VL of thalamus excites Area 6 - Area 6 excites Area 4

What is athetosis?

Slow, writhing movements that prevent patients from obtaining a fixed position of affected limb(s)

What can excess discharge from basal ganglia cause?

Slowing of movement (hypokinesia)

What is ballism?

Wild, failing movements (usually seen on one side of the body as hemiballismus)

Describe the relationship between dopamine and Ach and how this impacts individuals with Parkinson's disease.

- Striatal dopamine can modulate Ach release via inhibition - With decreased dopamine in PD, the excitatory Ach pathways are overactive (due to no inhibition) - PD symptoms can be caused by cholinergic influence (secondary to loss of dopamine)

True/False: Paralysis is common in Parkinson's disease.

False, paralysis does not occur in PD. Paralysis is common in cerebral lesions

True/False: Anticholinergic drugs are used independently to treat Parkinson's disease.

False, they are usually used in conjunction with levodopa or other antiparkinson drugs

One surgical option for Parkinson's disease is implantation of dopamine-producing cells into the substantia nigra. Where do these cells come from?

Fetal mesenchymal tissue or cultures of human chromaffin cells

What are side effects related to levodopa?

GI and cardiovascular side effects

What is Huntington's disease?

Genetically transmitted disease associated with dementia, chorea, and early death

In sagittal cuts of the brain, what part of the caudate nucleus is most visible?

Head and tail

What are examples of hyperkinesia?

Resting tremors, athetosis, chorea, and ballism

True/False: Dopamine agonists (when used alone) do not usually cause dyskinesias and fluctuations in motor responses.

True

True/False: Dopamine does not cross the BBB.

True

True/False: Parkinson's disease is not commonly associated with intention tremors.

True, movements in PD are accurate; tremors are usually at rest with PD

Where do the basal ganglia project to?

VA/VL thalamic nuclei and other brainstem motor centers

What is the indirect motor pathway of the cortex?

Cortex excites striatum >> striatum inhibits globus pallidus externus >> GPe doesn't function as it wants (doesn't inhibit subthalamic nucleus) >> subthalamic nucleus excites globus pallidus internus >> GPi inhibits VA/VL of the thalmus >> movement is inhibited

How much levodopa makes it to the brain?

1-3% of administered portion

What is hypokinesia?

Abnormal decrease in motor activity and mobility

How does levodopa cross the BBB?

Active transport process

What category of drug is related to the following side effects? : Mood changes, confusion, hallucinations, drowsiness, cardiac irregularities, blurred vision, dry mouth, nausea, vomiting, constipation, and urinary retention

Anticholinergic drugs

How do anticholinergic drugs work?

Blocking Ach receptors in the basal ganglia >> decrease levels of Ach

In frontal cuts of the brain, what part of the caudate nucleus is most visible?

Body

What drug can be prescribed with levodopa to change its dosage requirements?

Carbidopa (peripheral decarboxylase inhibitor)

What makes up the striatum?

Caudate nucleus and putamen

What are the 5 parts of the basal ganglia?

Caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra

In Huntington's disease, how to cognitive and motor symptoms first appear?

Clumsiness and slurred speech

What is Sinemet?

Combination drug of carbidopa and levodopa

What is Parkinson's disease?

Disease that results from loss of dopamine-producing neurons in the substantia nigra pars compacta

What part of the basal ganglia is most often associated with hypokinesia?

Dysfunction of the substantia nigra

What are some adverse effects of levodopa therapy?

Dyskinesias, behavioral changes, & diminished response

What is end-of-dose akinesia? How is this resolved?

Effectiveness of the drug wears off prior to the next dose; degreased dosage given more frequently

What are the intralaminar nuclei of the thalamus related to?

Emotional aspects of pain/old pain

What symptoms are commonly associated with Parkinson's disease?

Hypokinesia, rigidity, resting tremor, bradykinesia, difficulty initiating movement, facial expressions are reduced/absent, lack reflex responses to perturbations

In Parkinson's disease, what response does the lack of dopamine also cause?

Increase in activity in cholinergic pathways

What are common characteristics of hypokinesia?

Increased muscle tone, difficulty initiating and stopping movements, abnormal postures

What can reduced discharge from basal ganglia cause?

Involuntary movements (hyperkinesia)

When should levodopa therapy be started in patients with Parkinson's disease?

Left to the discretion of the physician; some believe long term use has decreased effectiveness whereas others believe the treatment should be started as soon as possible because there is no advantage to delaying

What happens when levodopa is taken orally?

Levodopa absorbed by GI tract >> converted to dopamine by the enzyme dopa decarboxylase

If the substantia nigra excites the direct pathway, what is the end motor result?

Motor area 6 & 4 are excited

If the substantia nigra inhibits the indirect pathway, what is the end motor result?

Motor cortices 6 & 4 are excited

What is the end motor result of the cortex's indirect pathway?

Movement is inhibited

What are some side effects related to dopamine agonists?

Nausea, vomiting, postural hypotension, CNS-related side effects (confusion, hallucinations)

What is chorea?

Nearly continuous series of rapid movements (particularly distal extremities)

How do dopamine agonists work?

Normalize endogenous dopamine activity and have a neuroprotective effect on substantia nigra neurons

Describe the on-off phenomenon related to Levodopa.

Off period: effectiveness may suddenly and spontaneously decrease On period: remission of symptoms that occur spontaneously or after taking a dose This on-off pattern can repeat several times throughout the day

How is levodopa administered?

Orally; 500-1000mg/day typical

What is levodopa?

Precursor to dopamine that crosses BBB readily

What makes up the lentiform nucleus?

Putamen and globus pallidus

Explain the pathway that occurs when substantia nigra inhibits the indirect pathway.

Substantia nigra inhibits indirect pathway of the striatum >> globus pallidus externus is facilitated >> GPe inhibits subthalamic nucleus >> subthalamic nucleus cannot do what it wants (it wants to excite globus pallidus internus) >> GPi does not do what it wants (it was to inhibit VA/VL of thalamus) >> VA/VL of thalamus is free to excite motor area 6 >> motor area 6 excites motor area 4

Describe the drug holiday strategy used with Levodopa.

Taking a break (3 days to 3 weeks) from the medicine to cleanse the system; done with the hope that medicine can be resumed at a lower dosage with better results