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ORGANIZATION OF THE BASAL GANGLIA
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The term basal ganglia (or basal nuclei) is applied to five interactive structures on each side of the brain (Figure 12–13). These are the caudate nucleus, putamen, and globus pallidus (three large nuclear masses underlying the cortical mantle), the subthalamic nucleus, and substantia nigra. The caudate nucleus and putamen collectively form the striatum; the putamen and globus pallidus collectively form the lenticular nucleus.
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The globus pallidus is divided into external and internal segments (GPe and GPi); both regions contain inhibitory GABAergic neurons. The substantia nigra is divided into a pars compacta, which uses dopamine as a neurotransmitter, and a pars reticulata, which uses GABA as a neurotransmitter. There are at least four neuronal types within the striatum. About 95% of striatal neurons are medium spiny neurons that use GABA as a neurotransmitter. The remaining striatal neurons are all aspiny interneurons that differ in terms of size and neurotransmitters: large (acetylcholine), medium (somatostatin), and small (GABA).
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Figure 12–14 shows the major connections to and from and within the basal ganglia along with the neurotransmitters within these pathways. There are two main inputs to the basal ganglia; they are both excitatory (glutamate), and they both terminate in the striatum. They are from a wide region of the cerebral cortex (corticostriate pathway) and from intralaminar nuclei of the thalamus (thalamostriatal pathway). The two major outputs of the basal ganglia are from GPi and substantia nigra pars reticulata. Both are inhibitory (GABAergic) and both project to the thalamus. From the thalamus, there is an excitatory (presumably glutamate) projection to the prefrontal and premotor cortex. This completes a full cortical-basal ganglia-thalamic-cortical loop.
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The connections within the basal ganglia include a dopaminergic nigrostriatal projection from the substantia nigra pars compacta to the striatum and a GABAergic projection from the striatum to substantia nigra pars reticulata. There is an inhibitory projection from the striatum to both GPe and GPi. The subthalamic nucleus receives an inhibitory input from GPe, and in turn the subthalamic nucleus has an excitatory (glutamate) projection to both GPe and GPi.
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Neurons in the basal ganglia, like those in the lateral portions of the cerebellar hemispheres, discharge before movements begin. This observation, plus careful analysis of the effects of diseases of the basal ganglion in humans and the effects of drugs that destroy dopaminergic neurons in animals, have led to the idea that the basal ganglia are involved in the planning and programming of movement or, more broadly, in the processes by which an abstract thought is converted into voluntary action (Figure 12–6). They influence the motor cortex via the thalamus, and the corticospinal pathways provide the final common pathway to motor neurons. In addition, GPi projects to nuclei in the brainstem, and from there to motor neurons in the brainstem and spinal cord. The basal ganglia, particularly the caudate nuclei, also play a role in some cognitive processes. Possibly because of the interconnections of this nucleus with the frontal portions of the neocortex, lesions of the caudate nuclei disrupt performance on tests involving object reversal and delayed alternation. In addition, lesions of the head of the left but not the right caudate nucleus and nearby white matter in humans are associated with a dysarthric form of aphasia that resembles Wernicke aphasia (see Chapter 15).
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DISEASES OF THE BASAL GANGLIA IN HUMANS
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Three distinct biochemical pathways in the basal ganglia normally operate in a balanced manner: (1) the nigrostriatal dopaminergic system, (2) the intrastriatal cholinergic system, and (3) the GABAergic system, which projects from the striatum to the globus pallidus and substantia nigra. When one or more of these pathways become dysfunctional, characteristic motor abnormalities occur. Diseases of the basal ganglia lead to two general types of disorders: hyperkinetic and hypokinetic. The hyperkinetic conditions are those in which movement is excessive and abnormal, including chorea, athetosis, and ballism. Hypokinetic abnormalities include akinesia and bradykinesia.
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Chorea is characterized by rapid, involuntary “dancing” movements. Athetosis is characterized by continuous, slow writhing movements. Choreiform and athetotic movements have been likened to the start of voluntary movements occurring in an involuntary, disorganized way. In ballism, involuntary flailing, intense, and violent movements occur. Akinesia is difficulty in initiating movement and decreased spontaneous movement. Bradykinesia is slowness of movement.
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In addition to Parkinson disease, which is described below, there are several other disorders known to involve a malfunction within the basal ganglia. A few of these are described in Clinical Box 12–7. Huntington disease is one of an increasing number of human genetic diseases affecting the nervous system that are characterized by trinucleotide repeat expansion. Most of these involve cytosine-adenine-guanine (CAG) repeats (Table 12–1), but one involves CGG repeats and another involves CTG repeats (T refers to thymine). There is also preliminary evidence that increased numbers of a 12-nucleotide repeat are associated with a rare form of epilepsy.
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Parkinson disease has both hypokinetic and hyperkinetic features. It was originally described in 1817 by James Parkinson and is named for him. Parkinson disease is the first disease identified as being due to a deficiency in a specific neurotransmitter (Clinical Box 12–8). In the 1960s, Parkinson disease was shown to result from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The fibers to the putamen (part of the striatum) are most severely affected.
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The hypokinetic features of Parkinson disease are akinesia and bradykinesia, and the hyperkinetic features are cogwheel rigidity and tremor at rest. The absence of motor activity and the difficulty in initiating voluntary movements are striking. There is a decrease in the normal, unconscious movements such as swinging of the arms during walking, the panorama of facial expressions related to the emotional content of thought and speech, and the multiple “fidgety” actions and gestures that occur in all of us. The rigidity is different from spasticity because motor neuron discharge increases to both the agonist and antagonist muscles. Passive motion of an extremity meets with a plastic, dead-feeling resistance that has been likened to bending a lead pipe and is therefore called lead pipe rigidity. Sometimes a series of “catches” takes place during passive motion (cogwheel rigidity), but the sudden loss of resistance seen in a spastic extremity is absent. The tremor, which is present at rest and disappears with activity, is due to regular, alternating 8-Hz contractions of antagonistic muscles.
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CLINICAL BOX 12–7 Basal Ganglia Diseases
The initial detectable damage in Huntington disease is to medium spiny neurons in the striatum. The loss of this GABAergic pathway to the globus pallidus external segment releases inhibition, permitting the hyperkinetic features of the disease to develop. An early sign is a jerky trajectory of the hand when reaching to touch a spot, especially toward the end of the reach. Later, hyperkinetic choreiform movements appear and gradually increase until they incapacitate the patient. Speech becomes slurred and then incomprehensible, and a progressive dementia is followed by death, usually within 10–15 years after the onset of symptoms. Huntington disease affects 5 out of 100,000 people worldwide. It is inherited as an autosomal dominant disorder, and its onset is usually between the ages of 30 and 50. The abnormal gene responsible for the disease is located near the end of the short arm of chromosome 4. It normally contains 11–34 cytosine-adenine-guanine (CAG) repeats, each coding for glutamine. In patients with Huntington disease, this number is increased to 42–86 or more copies; and the greater the number of repeats, the earlier the age of onset and the more rapid the progression of the disease. The gene codes for huntingtin, a protein of unknown function. Poorly soluble protein aggregates, which are toxic, form in cell nuclei and elsewhere. However, the correlation between aggregates and symptoms is less than perfect. It appears that a loss of the function of huntingtin occurs that is proportional to the size of the CAG insert. In animal models of the disease, intrastriatal grafting of fetal striatal tissue improves cognitive performance. In addition, tissue caspase-1 activity is increased in the brains of humans and animals with the disease. Moreover, in mice in which the gene for this apoptosis-regulating enzyme has been knocked out, progression of the disease is slowed.
Another basal ganglia disorder is Wilson disease (or hepatolenticular degeneration), which is a rare disorder of copper metabolism that has an onset between 6 and 25 years of age, affecting about four times as many females as males. Wilson disease affects about 30,000 people worldwide. It is a genetic autosomal recessive disorder due to a mutation on the long arm of chromosome 13q. It affects the copper-transporting ATPase gene (ATP7B) in the liver, leading to an accumulation of copper in the liver and resultant progressive liver damage. About 1% of the population carries a single abnormal copy of this gene but does not develop any symptoms. The disease may develop in a child who inherits the gene from both parents. In affected individuals, copper accumulates in the periphery of the cornea in the eye accounting for the characteristic yellow Kayser-Fleischer rings. The dominant neuronal pathology is degeneration of the putamen, a part of the lenticular nucleus. Motor disturbances include “wing-beating” tremor or asterixis, dysarthria, unsteady gait, and rigidity. Another disease commonly referred to as a disease of the basal ganglia is tardive dyskinesia. This disease indeed involves the basal ganglia, but it is caused by medical treatment of another disorder with neuroleptic drugs such as phenothiazides or haloperidol. Therefore, tardive dyskinesia is iatrogenic in origin. Long-term use of these drugs may produce biochemical abnormalities in the striatum. The motor disturbances include either temporary or permanent uncontrolled involuntary movements of the face and tongue and cogwheel rigidity. The neuroleptic drugs act via blockade of dopaminergic transmission. Prolonged drug use leads to hypersensitivity of D3 dopaminergic receptors and an imbalance in nigrostriatal influences on motor control.
THERAPEUTIC HIGHLIGHTS Treatment for Huntington disease is directed at treating the symptoms and maintaining quality of life because there is no cure. In general, drugs used to treat the symptoms of this disease have side effects such as fatigue, nausea, and restlessness. In August 2008, the US Food and Drug Administration approved the use of tetrabenazine to reduce choreiform movements that characterize the disease. This drug binds reversibly to vesicular monoamine transporters (VMAT) and thus inhibits the uptake of monoamines into synaptic vesicles. It also acts as a dopamine receptor antagonist. Tetrabenazine is the first drug to receive approval for individuals with Huntington disease. It is also used to treat other hyperkinetic movement disorders such as tardive dyskinesia. Chelating agents (eg, penicillamine and trienthine) are used to reduce the copper in the body in individuals with Wilson disease. Tardive dyskinesia has proven to be difficult to treat. Treatment in patients with psychiatric disorders is often directed at prescribing a neuroleptic with less likelihood of causing the disorder. Clozapine is an example of an atypical neuroleptic drug that has been an effective substitute for traditional neuroleptic drugs but with less risk for development of tardive dyskinesia.
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CLINICAL BOX 12–8 Parkinson Disease
There are 7–10 million people worldwide in whom Parkinson disease has been diagnosed. The disease is 1.5 times more prevalent in men than women. Each year in the United States, nearly 60,000 new cases are diagnosed. Parkinsonism occurs in sporadic idiopathic form in many middle-aged and elderly individuals and is one of the most common neurodegenerative diseases. It is estimated to occur in 1–2% of individuals over age 65. Dopaminergic neurons and dopamine receptors are steadily lost with age in the basal ganglia in healthy individuals, and an acceleration of these losses apparently precipitates parkinsonism. Symptoms appear when 60–80% of the nigrostriatal dopaminergic neurons degenerate.
Parkinsonism is also seen as a complication of treatment with the phenothiazine group of antipsychotic drugs and other drugs that block dopaminergic D2 receptors. It can be produced in rapid and dramatic form by injection of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). This effect was discovered by chance when a drug dealer in northern California supplied some of his clients with a homemade preparation of synthetic heroin that contained MPTP. MPTP is a prodrug that is metabolized in astrocytes by the enzyme monoamine oxidase (MOA-B) to produce a potent oxidant, 1-methyl-4-phenylpyridinium (MPP+). In rodents, MPP+ is rapidly removed from the brain, but in primates it is removed more slowly and is taken up by the dopamine transporter into dopaminergic neurons in the substantia nigra, which it destroys without affecting other dopaminergic neurons to any appreciable degree. Consequently, MPTP can be used to produce parkinsonism in monkeys, and its availability has accelerated research on the function of the basal ganglia.
THERAPEUTIC HIGHLIGHTS There is no cure for Parkinson disease, and drug therapies are designed to treat the symptoms. Sinemet, a combination of levodopa (L-dopa) and carbidopa, is the most commonly used drug for the treatment of Parkinson disease. The addition of carbidopa to L-dopa increases its effectiveness and prevents the conversion of L-dopa to dopamine in the periphery and thus reduces some of the adverse side effects of L-dopa (nausea, vomiting, and cardiac rhythm disturbances). Dopamine agonists, including apomorphine, bromocriptine, pramipexole, and ropinirole, have also proven effective in some patients with Parkinson disease. Taken in combination with levodopa, cathechol-O-methyltransferase (COMT) inhibitors (eg, entacapone) are another class of drugs used to treat this disease. They act by blocking the breakdown of L-dopa, allowing more of it to reach the brain to increase the level of dopamine. MAO-B inhibitors (eg, selegiline) also prevent the breakdown of dopamine. They can be given soon after diagnosis and delay the need for levodopa.
In December 2010, investigators at Southern Methodist University and The University of Texas at Dallas reported that they have identified a family of small molecules that shows promise in protecting brain cell damage in diseases such as Parkinson, Alzheimer, and Huntington. This would be a major step forward as the first drug that would act as a neuroprotective agent to stop brain cell death as opposed to merely treating symptoms of the neurologic disease.
The US Food and Drug Administration has approved the use of deep brain stimulation (DBS) as a method for treating Parkinson disease. DBS reduces the amount of L-dopa patients need and thus reduce its adverse side effects (eg, involuntary movements called dyskinesias). DBS has been associated with reducing tremors, slowness of movements, and gait problems in some patients. Surgical treatments in general are reserved for those who have exhausted drug therapies or who have not responded favorably to them. Lesions in GPi (pallidotomy) or in the subthalamic nucleus (thalamotomy) have been performed to help restore the output balance of the basal ganglia toward normal (see Figure 12–15). Another surgical approach is to implant dopamine-secreting tissue in or near the basal ganglia. Transplants of the patient’s own adrenal medullary tissue or carotid body works for a while, apparently by functioning as a sort of dopamine minipump, but long-term results have been disappointing. Results with transplantation of fetal striatal tissue have been better, and there is evidence that the transplanted cells not only survive but make appropriate connections in the host’s basal ganglia. However, some patients with transplants develop dyskinesias due to excessive levels of dopamine.
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A current view of the pathogenesis of the movement disorders in Parkinson disease is shown in Figure 12–15. In healthy individuals, basal ganglia output is inhibitory via GABAergic nerve fibers. The dopaminergic neurons that project from the substantia nigra to the putamen normally have two effects. They stimulate the D1 dopamine receptors, which inhibit GPi via direct GABAergic receptors; and they inhibit D2 receptors, which also inhibit the GPi. In addition, the inhibition reduces the excitatory discharge from the subthalamic nucleus to the GPi. This balance between inhibition and excitation somehow maintains normal motor function. In Parkinson disease, the dopaminergic input to the putamen is lost. This results in decreased inhibition and increased excitation from the subthalamic nucleus to the GPi. The overall increase in inhibitory output to the thalamus and brainstem disorganizes movement.
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Familial cases of Parkinson disease occur, but these are uncommon. The genes for at least five proteins can be mutated. These proteins appear to be involved in ubiquitination. Two of the proteins, α-synuclein and barkin, interact and are found in Lewy bodies. The Lewy bodies are inclusion bodies in neurons that occur in all forms of Parkinson disease. However, the significance of these findings is still unsettled.
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An important consideration in Parkinson disease is the balance between the excitatory discharge of cholinergic interneurons and the inhibitory dopaminergic input in the striatum. Some improvement is produced by decreasing the cholinergic influence with anticholinergic drugs. More dramatic improvement is produced by administration of L-dopa (levodopa). Unlike dopamine, this dopamine precursor crosses the blood-brain barrier and helps repair the dopamine deficiency. However, the degeneration of these neurons continues and in 5–7 years the beneficial effects of L-dopa disappear.