Overview




Parkinson's disease is a disorder of the brain that leads to shaking, tremors, and difficulty with walking, movement, and coordination. Parkinson's disease most often develops after age 50. It is one of the most common nervous system disorders of the elderly. Sometimes Parkinson's disease occurs in younger adults. It affects both men and women. In some cases, Parkinson's disease runs in families. When a young person is affected, it is usually because of a form of the disease that runs in families. Parkinson's is rare in children. It may occur because the nerves are not as sensitive to dopamine.


Nerve cells use a brain chemical called dopamine to help control muscle movement. Parkinson's disease occurs when the nerve cells in the brain that make dopamine are slowly destroyed. Without dopamine, the nerve cells in that part of the brain cannot properly send messages. This leads to the loss of muscle function. The damage gets worse with time. Exactly why these brain cells waste away is unknown. The dopamine that is slowly destroyed is found in the basal ganglia of your brain.



Functional Anatomy




The Basal Ganglia are a somatotopically organized grouping of nuclei located deep to the cortex that surround the Thalamus and are superior to the brainstem. Their function is the processing of information in regards to the execution of movement. Its main parts are the Caudate, Putamen, Globus Pallidus, Subthalamic Nucleus (STN), and Substantia Nigra. The Caudate and Putamen make up the Striatum and are the main receptors for input to the Basal Ganglia from other areas. The Corpus Striatum is the same as the Striatum but it includes the Globus Pallidus, and the Lenticular Nucleus consists of the Putamen and Globus Pallidus. The Globus Pallidus has both an internal (GPi) and an external segment (GPe). The Substantia Nigra also has two parts -- the pars compacta (SNc) and pars reticulata (SNr). The GPe, STN, and SNc are involved in the internal processing within the Basal Ganglia pathways. The two main output nuclei are the SNr and GPi.
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Input and Output pathways

The substantia nigra pars compacta projects to both direct pathway and indirect pathways neurons in the striatum. Because there are two different types of dopamine receptors, substantia nigra activity excites the direct pathway and inhibits the indirect pathway. The net effect of the direct pathway is to excite motor cortex, and the net effect of the indirect pathway is to inhibit motor cortex. Thus, the loss of the nigrostriatal dopaminergic pathway upsets the fine balance of excitation and inhibition in the basal ganglia and reduces the excitation of motor cortex. From one’s knowledge of the effects of the nigrostriatal pathway on the direct and indirect pathways, it becomes straightforward to see why the loss of this pathway results in the poverty of movement symptomatic of Parkinson’s disease. Because the nigrostriatal pathway excites the direct pathway and inhibits the indirect pathway, the loss of this input tips the balance in favor of activity in the indirect pathway. Thus, the GPint neurons are abnormally active, keeping the thalamic neurons inhibited. Without the thalamic input, the motor cortex neurons are not as excited, and therefore the motor system is less able to execute the motor plans in response to the patient’s volition.
The direct pathway starts with cells in the striatum that make inhibitory connections with cells in the GPint. The GPint cells in turn make inhibitory connections on cells in the thalamus. Thus, the firing of GPint neurons inhibits the thalamus, making the thalamus less likely to excite the neocortex. When the direct pathway striatal neurons fire, however, they inhibit the activity of the GPint neurons. This inhibition releases the thalamic neurons from inhibition, allowing them to fire to excite the cortex. Thus, because of the “double negative” in the pathway between the striatum and GPint and the GPint and thalamus, the net result of exciting the direct pathway striatal neurons is to excite motor cortex.
The nigrostriatal projection
An important pathway in the modulation of the direct and indirect pathways is the dopaminergic,nigrostriatal projection from the substantia nigra pars compacta to the striatum. Direct pathway striatal neurons have D1 dopamine receptors, which depolarize the cell in response to dopamine. In contrast, indirect pathway striatal neurons have D2 dopamine receptors, which hyperpolarize the cell in response to dopamine. The nigrostriatal pathway thus has the dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway. Because of this dual effect, excitation of the nigrostriatal pathway has the net effect of exciting cortex by two routes, by exciting the direct pathway (which itself has a net excitatory effect on cortex) and inhibiting the indirect pathway (thereby disinhibiting the net inhibitory effect of the indirect pathway on cortex). The loss of these dopamine neurons in Parkinson’s disease causes the poverty of movement that characterizes this disease, as the balance between direct pathway excitation of cortex and indirect pathway inhibition of cortex is tipped in favor of the indirect pathway, with a subsequent pathological global inhibition of motor cortex areas.
In ways that are not understood, this reduction of thalamic excitation interferes with the ability of the motor cortex to generate commands for voluntary movement, resulting in the poverty of movement of Parkinsonian patients. It is as if all of the motor programs stored in cortex are constantly inhibited by the indirect pathway, with not enough excitation of the direct pathway for the desired motor program to become activated.
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Presentation of topic

There is no cure for Parkinson’s disease, but a number of effective treatments exist. The earliest effective treatment was developed when it was first discovered that Parkinson’s disease was caused by a loss of dopaminergic neurons. Because dopamine itself does not cross the blood-brain barrier, L-Dopa, a chemical precursor to dopamine, was used to replenish the supply of dopamine. Amazingly, flooding the system with L-Dopa resulted in profound improvements in the symptoms of patients. Unfortunately, this improvement is temporary, and typically symptoms return after a number of years.
Surgical intervention, such as making lesions to the globus pallidus internal segment, has shown effectiveness in some patients. In recent years, a new therapy, deep brain stimulationof the subthalamic nucleus, has been gaining in popularity. In this treatment, an electrical stimulator is implanted in the subthalamic nucleus. When the electrical current is turned on to stimulate the nucleus, the patient’s symptoms disappear immediately. It is not known why this procedure works, or what its long-term efficacy is. Because the projection from the subthalamic nucleus is excitatory onto globus pallidus neurons, which inhibit the thalamus, it is paradoxical that such stimulation should increase motor cortex activity. One thought is that the stimulation might actually overload the subthalamic nucleus, thereby inhibiting it and disinhibiting the thalamus.
The reasoning behind these treatments is because this disease is a result of a disruption between the balances of the direct versus the indirect pathway. This balance is tipped more towards the indirect pathway resulting in less facilitation and more inhibition of movement. This disruption is caused by lesions of the Substantia Nigra pars compacta.
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Summary

Understandings of the Basal Ganglia and the pathways in the Basal Ganglia have been essential to the discovery and treatment of Parkinson’s disease. While treatment is limited there are ways to help with the symptoms of this disease. Parkinson's disease is one of the most common neurological disorders; second only to Alzheimer's disease, and therefore an understanding of the Basal Ganglia has given doctors a way to treat their patients who deal with Parkinson's disease. Despite the fact that the Basal Ganglia are only a grouping of nuclei in the brain, it is clear that it is extremely important in the regulation and control of human movement.

Glossary


Tremor - shaking
Lesion - a region in an organ or tissue that has suffered cellular damage through injury or disease
Subthalamic Nucleus - involved in the indirect pathway; sends the only excitatory input within the Basal Ganglia to the output nucle
Substantia Nigra - located in the midbrain; has 2 parts, the pars reticulata is 1 of the output nuclei, the pars compacta sends dopaminergic projections to the Cortex and Striatum
Striatum - the input nuclei of the Basal Ganglia; consists of the Caudate and Putamen
Corpus Striatum - consists of the Caudate, Putamen, and Globus Pallidus
Lenticular Nucleus - consists of the Putamen and Globus Pallidus
Output Nuclei - GPi and SNr
Glutamate - a neurotransmitter used within the Basal Ganglia to send excitatory input
Gamma-aminobutyric acid (GABA) - a neurotransmitter used in inhibition
Dopamine - an important neurotransmitter used in both excitation and inhibition
Thalamus - relays information to the Cortex
Caudate - 1 of 2 Basal Ganglia nuclei that receive input from the Cortex and other areas
Putamen - the other Basal Ganglia nucleus that receives input from the Cortex and other areas
Globus Pallidus - has both an internal segment, which is involved in output from the Basal Ganglia to the Thalamus, and an external segment, which is involved in the indirect pathway and synapses on the Subthalamic Nucleus

Suggested Readings

  1. http://neuroscience.uth.tmc.edu/s3/chapter04.htmlChapter on the basal ganglia
  2. http://neuroscience.uth.tmc.edu/s3/chapter06.htmlChapter on the disorders of the basal ganglia
  3. http://thalamus.wustl.edu/course/cerebell.html Overview of the basal ganglia

Questions

Multiple Choice
  1. What type of receptors do the Striatal neurons of the indirect pathway have?
A) D1
B) cholinergic
C) excitatory
D) D2
  1. The corpus striatum is composed of:
a) Caudate nucleus, putamen, globus pallidus
b) Substantia nigra, subthalamic nucleus
c) Caudate nucleus, substantia nigra, subthalamic nucleus
d) Globus pallidus externus, globus pallidus internuse
e) Substantia nigra reticula, substantia nigra compacta, Putamen

  1. The neurotransmitters involved in the internal circuitry of the basal ganglia include
a) GABA
b) Glutamate
c) Dopamine
d) Seratonine
e) A,B and C
f) A and B
g) All of the above

  1. Which of the basal ganglia nuclei receive direct cortical input?
a). Claustrum and amydala
b). Centromedian nucleus and subthalamic nucleus
c.)Substantia nigra pars compacta and globus pallidus external
d.) Globus pallidus internal and substantia nigra pars reticulata
e.) Caudate and putamen

True/False
  1. T/F - A treatment of Parkinson's disease is to surgically lesion the Subthalamic Nucleus?
  2. T/F - Onset of Parkinson's disease commonly occurs in people between the ages of 20 - 50?
  3. T/F - Nearly all incoming information enters the basal ganglia through the striatum.
Short Answer
  1. Diagram the direct and indirect pathways that either allow or inhibit movement.
  2. List the major inputs of the basal ganglia, where they project, as well as the major neurotransmitters used.
  3. What are some common symptoms and treatments of Parkinson's disease?


Answers
Multiple choice
  1. D
  2. A
  3. E
  4. E
True/False
  1. T
  2. F
  3. T

References
  1. Knierim J. Neuroscience Online, Section 3 - Motor Systems, Chapter 4 - The Basal Ganglia. http://neuroscience.uth.tmc.edu/s3/chapter04.html
  2. Chakravarthy V, Denny J, Raju B. What do the basal ganglia do? A modeling perspective. Biological Cybernetics 103: 237-253, 2010.
  3. Brodal, Per. The Central Nervous System: Structure and Function. New York: Oxford UP, 2004. Print.
  4. Sheperd, Gordon M. The Synaptic Organization of the Brain. New York: Oxford UP, 2004. Print.
  5. Knierim J. Neuroscience Online, Chapter 6 – Disorders of the Motor Systemshttp://neuroscience.uth.tmc.edu/s3/chapter06.html