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Chapter: Medical Physiology: Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

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Clinical Syndromes Resulting from Damage to the Basal Ganglia

Aside from athetosis and hemiballismus, which have already been mentioned in relation to lesions in the globus pallidus and subthalamus, two other major dis-eases result from damage in the basal ganglia. These are Parkinson’s disease and Huntington’s disease.

Clinical Syndromes Resulting from Damage to the Basal Ganglia

Aside from athetosis and hemiballismus, which have already been mentioned in relation to lesions in the globus pallidus and subthalamus, two other major dis-eases result from damage in the basal ganglia. These are Parkinson’s disease and Huntington’s disease.

Parkinson’s Disease

Parkinson’s disease, known also as paralysis agitans, results from widespread destruction of that portion of the substantia nigra (the pars compacta) that sends dopamine-secreting nerve fibers to the caudate nucleus and putamen. The disease is characterized by (1) rigid-ity of much of the musculature of the body, (2) invol-untary tremor of the involved areas even when the person is resting at a fixed rate of 3 to 6 cycles per second, and (3) serious difficulty in initiating movement, called akinesia.

The causes of these abnormal motor effects are unknown. However, the dopamine secreted in the caudate nucleus and putamen is an inhibitory transmit-ter; therefore, destruction of the dopaminergic neurons in the substantia nigra of the parkinsonian patient the-oretically would allow the caudate nucleus and putamen to become overly active and possibly cause continuous output of excitatory signals to the corticospinal motor control system. These signals could overly excite many or all of the muscles of the body, thus leading to rigidity.

Some of the feedback circuits might easily oscillate because of high feedback gains after loss of their inhi-bition, leading to the tremor of Parkinson’s disease. This tremor is quite different from that of cerebellar disease because it occurs during all waking hours and therefore is an involuntary tremor, in contradistinction to cere-bellar tremor, which occurs only when the person per-forms intentionally initiated movements and therefore is called intention tremor.

The akinesia that occurs in Parkinson’s disease is often much more distressing to the patient than are the symp-toms of muscle rigidity and tremor, because to perform even the simplest movement in severe parkinsonism, the person must exert the highest degree of concentration. The mental effort, even mental anguish, that is necessary to make the desired movements is often at the limit of the patient’s willpower. Then, when the movements do occur, they are usually stiff and staccato in character instead of smooth. The cause of this akinesia is still spec-ulative. However, dopamine secretion in the limbic system, especially in the nucleus accumbens, is often decreased along with its decrease in the basal ganglia. It has been suggested that this might reduce the psychic drive for motor activity so greatly that akinesia results.

Treatment with l-Dopa. Administration of the drugL-dopa to patients with Parkinson’s disease usually ame-liorates many of the symptoms, especially the rigidity and akinesia. The reason for this is believed to be that L-dopa is converted in the brain into dopamine, and thedopamine then restores the normal balance between inhibition and excitation in the caudate nucleus and putamen. Administration of dopamine itself does not have the same effect because dopamine has a chemical structure that will not allow it to pass through the blood-brain barrier, even though the slightly different struc-ture of L-dopa does allow it to pass.

Treatment with l-Deprenyl. Another treatment forParkinson’s disease is the drug L-deprenyl. This drug inhibits monoamine oxidase, which is responsible for destruction of most of the dopamine after it has been secreted. Therefore, any dopamine that is released remains in the basal ganglial tissues for a longer time. In addition, for reasons not understood, this treatment helps to slow destruction of the dopamine-secreting neurons in the substantia nigra. Therefore, appropriate combinations of L-dopa therapy along with L-deprenyl therapy usually provide much better treatment than use of one of these drugs alone.

Treatment with Transplanted Fetal Dopamine Cells.

Transplantation of dopamine-secreting cells (cells obtained from the brains of aborted fetuses) into the caudate nuclei and putamen has been used with some short-term success to treat Parkinson’s disease. However, the cells do not live for more than a few months. If persistence could be achieved, perhaps this would become the treatment of the future.

Treatment by Destroying Part of the Feedback Circuitry in the Basal Ganglia. Because abnormal signals fromthe basal ganglia to the motor cortex cause most of the abnormalities in Parkinson’s disease, multiple attempts have been made to treat these patients by blocking these signals surgically. For a number of years, surgical lesions were made in the ventrolateral and ventroante-rior nuclei of the thalamus, which blocked part of the feedback circuit from the basal ganglia to the cortex; variable degrees of success were achieved—as well as sometimes serious neurological damage. In monkeys with Parkinson’s disease, lesions placed in the subthal-amus have been used, sometimes with surprisingly good results.

Huntington’s Disease (Huntington’s Chorea)

Huntington’s disease is a hereditary disorder that usually begins causing symptoms at age 30 to 40 years. It is characterized at first by flicking movements in indi-vidual muscles and then progressive severe distortional movements of the entire body. In addition, severe dementia develops along with the motor dysfunctions.

The abnormal movements of Huntington’s disease are believed to be caused by loss of most of the cell bodies of the GABA-secreting neurons in the caudate nucleus and putamen and of acetylcholine-secreting neurons in many parts of the brain. The axon terminals of the GABA neurons normally inhibit portions of the globus pallidus and substantia nigra. This loss of inhibi-tion is believed to allow spontaneous outbursts of globus pallidus and substantia nigra activity that cause the distortional movements.

The dementia in Huntington’s disease probably does not result from the loss of GABA neurons but from the loss of acetylcholine-secreting neurons, perhaps espe-cially in the thinking areas of the cerebral cortex.

The abnormal gene that causes Huntington’s disease has been found; it has a many-times-repeating codon, CAG, that codes for multiple extra glutamine amino acids in the molecular structure of an abnormal neu-ronal cell protein called huntingtin that causes the symp-toms. How this protein causes the disease effects is now the question for major research effort.

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