6. Disorders of the Motor System
Part 2 of 3

James Knierim, Ph.D.
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Disorders of the Basal Ganglia

The basal ganglia have historically been considered part of the motor system because of the variety of motor deficits that occur when they are damaged.  The types of symptoms that result from basal ganglia disorders can be divided into two classes: dyskinesias, which are abnormal, involuntary movements, and akinesias, which are abnormal, involuntary postures.  Because the basal ganglia were once considered to form a separate, “extrapyramidal” motor system, these symptoms are called extrapyramidal disorders.

Dyskinesias

1. Resting tremors are most often associated with Parkinson’s disease.  When the patient is at rest, certain body parts will display a 4-7 Hz tremor.  For example, the thumb and forefingers will move back-and-forth against each other in a characteristic tremor called “pill-rolling tremor.”  The tremor stops when the body part engages in active movement.
2. Athetosis is characterized by involuntary, writhing movements, especially of the hands and face.
3. Chorea, which derives from the Greek word for “dance,” is characterized by continuous, writhing movements of the entire body.  It is viewed by some as an extreme form of athetosis.  Chorea is most closely identified with Huntington’s disease.
4. Ballismus is characterized by involuntary, ballistic movements of the extremities.
5. Tardive dyskinesia can result from the long-term use of antipsychotic drugs that target the dopamine system.  It is characterized by involuntary movements of the tongue, face, arms, lips, and other body parts.  It is thought to occur as the result of an imbalance between the D1 and D2 receptors, thereby favoring the direct pathway over the indirect pathway. 

Akinesias

1. Rigidity is a resistance to passive movement of the limb.  Unlike spasticity, rigidity does not depend on the speed of the passive movement.  In some patients, this resistance is so great that it is referred to as lead-pipe rigidity, because moving the patient’s limb feels like bending a lead pipe.  In some patients, this rigidity is coupled with tremors and is called cogwheel rigidity, as moving the limb feels to the clinician like the catching and release of gears.  As with spasticity, the mechanism is not entirely understood, but may result from continuous firing of alpha motor neurons causing a continual contraction of the muscle.
2. Dystonia is the involuntary adoption of abnormal postures, as agonist and antagonist muscles both contract and become so rigid that the patient cannot maintain normal posture.
3. Bradykinesia refers to a slowness, or poverty, of movement.

A number of well-known movement disorders are associated with basal ganglia dysfunction.  We shall concentrate on 3 of the most well-understood: Parkinson’s disease, Huntington’s disease, and hemiballismus.  To understand how these disorders result in the specific symptoms, it is necessary to review the circuit anatomy of the basal ganglia that was presented in the Basal Ganglia chapter.

Parkinson’s disease

Parkinson’s disease results from the death of dopaminergic neurons in the substantia nigra pars compacta.  It is characterized by a resting tremor, but the most debilitating symptom is severe bradykinesia or akinesia.  In advanced cases, patients have difficulty initiating movements, although involuntary, reflexive movements can be normal.  It is as if the loss of the substantia nigra neurons has put a brake on the output of motor cortex, inhibiting voluntary motor commands from descending to the brain stem and spinal cord.

Although the cause of Parkinson’s disease is still not known, much has been learned in the past 15 years from the development of an animal model of Parkinson’s disease.  This model was discovered by accident when a number of young patients presented with symptoms remarkably similar to Parkinson’s disease.  These patients were drug addicts who had been taking an artificially manufactured drug called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyradine).  This drug destroyed the dopaminergic neurons in the substantia nigra, leading to a Parkinsonian disorder.  Laboratory animals injected with MPTP have since become a leading model for understanding the disease and developing treatments.

How does the loss of the dopaminergic neurons cause the poverty of movements associated with Parkinson’s disease (Figure 6.3)?  Recall from the Basal Ganglia chapter that 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.  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. 

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 (pallidotomy), has shown effectiveness in some patients.  In recent years, a new therapy, deep brain stimulation of 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.

Huntington’s disease

Huntington’s disease (also known as Woody Guthrie Disease) is a genetic disorder that is caused by an abnormally large number of repeats of the nucleotide sequence CAG on chromosome 4.  Normal individuals have 9-35 repeats of this sequence; mutations that cause larger repeats give rise to Huntington’s disease.  It is an autosomal dominant mutation, such that the offspring of a patient with Huntington’s disease has a 50% chance of inheriting the mutation.  Individuals with the mutated gene will invariably develop Huntington’s disease, usually near middle age.  The affected gene codes for a protein known as huntingtin, the function of which is not known.  The effect of the mutated version of the gene, however, is to kill the indirect pathway neurons in the striatum, particularly those of the caudate nucleus.

Huntington’s disease is also known as Huntington’s chorea because it is characterized by a continuous, choreiform movements of the body (especially the limbs and face).  In addition, the disease in advanced stages is associated with dementia.  There is at present no cure or effective treatment for Huntington’s disease.

Why does the loss of indirect pathway neurons in the striatum cause the dyskinesias of Huntington’s disease (Figure 6.4)?   Recall that the net effect of the indirect pathway is to inhibit motor cortex.  With the loss of these neurons, the excitatory effect of the direct pathway is no longer kept in check by the inhibition of the indirect pathway.  Thus, the motor cortex gets too much excitatory input from the thalamus, disrupting its normal functioning and sending involuntary movement commands to the brain stem and spinal cord.  Because inappropriate motor programs are not inhibited normally, the cortex continuously sends involuntary commands for movements and movement sequences to the muscles.

Hemiballismus

Hemiballismus results from a unilateral lesion to the subthalamic nucleus, usually caused by a stroke.  This lesion results in ballismus on the contralateral side of the body, while the ipsilateral side is normal (hence the term hemiballismus).  The involuntary, ballistic movements result from the loss of the excitatory subthalamic nucleus projection to the globus pallidus (Figure 6.5).  Because the globus pallidus internal segment normally inhibits the thalamus when excited, the loss of the subthalamic component lessens the inhibition of the thalamus, making it more likely to send spurious excitation to the motor cortex.  Some surgical operations have been performed to relieve the symptoms of hemiballismus, and new pharmacological treatments are in use to relieve the disorder.

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