Clinical Note

The Parkinson's-Reversing Breakthrough

What is Parkinsons Disease

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Basal Ganglia Dysfunction

The principles of excitation-disexcitation/ inhibition-disinhibition are particularly important in formulating strategies for specific drug therapies used in treating certain motor disorders such as Parkinson's disease (Fig. 5A). For reasons that are not yet understood, there is a pronounced degenerative decline in the number of dopami-nergic cells in the substantia nigra in certain individuals. As these dopaminergic cells die, the nigrostriatal pathway degenerates. The resulting motor disorder, Parkinson's disease, affects approximately 1% of the population over the age of 50. Symptoms of the disorder are rhythmic tremor at rest, rigidity, difficulty in initiating movement (akinesia), and slowness in execution of movement (bradykinesia). Simple motor programs are less affected than more complex ones. Patients cannot execute simultaneous or sequential motor programs, indicating a defect in the use of motor plans for complex motor acts. They cannot activate motor plans for normal rapid movements. The loss of dopaminergic input to the basal ganglia loop decreases the output from the basal ganglia to the thalamus and removes the excitatory boost necessary for maintaining the critical level of stimulation to the SMA. The treatment for Parkinson's disease is the oral administration of L-DOPA (L-dihydroxyphenylalanine), the precursor of dopamine. This increases dopa-mine synthesis in the dopamine-producing cells that survive. The treatment is relatively effective in alleviating the symptoms, but it does not alter the course of the disease or stop further degeneration of substantia nigra cells.

Another neurologic condition that results from basal ganglia dysfunction is Huntington's chorea (see Fig. 5B). In this case, decreased muscle tone is combined with spastic, or involuntary chorei-form (dancelike), movements of the extremities. Patients also develop dementia, indicating a broader involvement of other brain areas, although motor abnormalities routinely appear first. Death usually occurs within 15 years of onset of symptoms. The condition results from an initial selective loss of GABAergic neurons within the neostriatum. Other striatal neurons degenerate as the disease progresses. Because the direct projection of the basal ganglia to the thalamus is inhibitory, the activity of the thalamus is facilitated (disinhibited) in Huntington's chorea. The abnormal excitation of the motor cortex by the thalamus is thought to be the cause of the uncontrolled movements.

Another motor abnormality associated with basal ganglia structures is hemiballismus, a hyperkinetic disorder that results in violent flinging of extremities on one side. The disorder is the result of unilateral damage to the subthalamus, often associated with stroke. With less glutamate being released from the damaged subthalamic nucleus, there is less excitatory drive to the globus pallidus; thus, less GABA is released to inhibit the thalamus. As with Huntington's chorea, less inhibitory control over the thalamus causes more excitation of the SMA.

excitatory; the two intervening connections (caudate/ putamen to globus pallidus and globus pallidus to thalamus) are inhibitory. Even with two inhibitory synapses within the circuit, the overall system operates as a positive feedback loop. This is achieved by having the two inhibitory synapses arranged in series so that the first inhibitory neuron suppresses activity in the second inhibitory neuron. The decrease in inhibitory input to the next neuron, a process called disinhibition, is equivalent to direct excitation.

Circuits employing disinhibition are common elements of central nervous system pathways. As is the case with the basal ganglia motor loop, this type of pathway is usually tonically active and highly sensitive over a broad response range. Tonic activity generated throughout the cortex as a result of incoming sensory information and ongoing motor activity is funneled into the loop, allowing the basal ganglia to sort and summate the information before sending it back to the motor cortex, in particular the SMA. In this way, the

FIGURE 4 Connections of the nigrostriatal pathway. Within the basal ganglia motor loop, glutamate is the major excitatory neurotransmitter ( + ) and y-aminobutyric acid (GABA) is the major inhibitory neurotransmitter (—). An exception is seen with dopamine, the neurotransmitter for the nigrostriatal pathway. Dopamine from the substantia nigra (pars compacta region) is excitatory to the direct pathway and inhibitory to elements of the indirect pathway. This circuit shifts the balance between the direct and indirect paths, lowering the level of inhibitory control over the thalamus and thus maintaining a high level of excitatory thalamic input to the motor cortex.

A. Hypokenetic disease

B. Hyperkenetic disease

A. Hypokenetic disease

B. Hyperkenetic disease

loop serves to set the appropriate excitatory tone for the SMA.

THE MOTOR LOOP: INDIRECT PATHWAY

Further control of this excitatory feedback loop is achieved by inhibitory actions of the indirect basal ganglia loop. In this pathway, cortical input to the striatum is sent to the external segment of the globus pallidus and then to the subthalamus before converging on the globus pallidus (internal segment)/substantia nigra. Note that the direct and indirect pathways have opposite effects on the globus pallidus/substantia nigra. Thus, the final outcome of the indirect pathway is disexcitation (i.e., inhibition) of the cortex, whereas the direct pathway causes cortical stimulation. Although it may be somewhat confusing to sort through the particulars of each synaptic relay in these pathways, it is important to understand the principles of disinhibition and disexcitation and how they affect the overall activity of the motor cortex.

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