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Chapter 6: Disorders of the Motor System

James Knierim, Ph.D., Department of Neuroscience, The Johns Hopkins University

Last Review 20 Oct 2020

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The previous motor system chapters have deconstructed the motor system into its component parts, in an effort to portray how the brain’s “divide and conquer” strategy assigns different motor control tasks to different brain regions. This chapter describes the types of disorders that result from damage or disease to different parts of the motor system. In the process, the different components of the motor system are reviewed to see how they work together to produce the fluid, effortless body movements that we take for granted. An emphasis is placed on trying to explain the causes and symptoms of motor system disorders in terms of the basic principles of neuroanatomy and neuronal function that you learned in the earlier chapters.

6.1 Lower Motor Neuron Syndrome

The first level of the motor system hierarchy is the spinal cord, the location of the alpha motor neurons that constitute the “final common pathway” of all motor commands. Alpha motor neurons directly innervate skeletal muscle, causing the contractions that produce all movements. Reflex circuits and other circuitry within the spinal cord underlie the automatic processing of many of the direct commands to the muscles (the “nuts and bolts” processing), thereby freeing higher-order areas to concentrate on more global, task-related processing.

Motor system dysfunction can result from damage or disease at any level of the motor system hierarchy and side-loops. Differences in the symptoms that result from damage at different levels allow the clinician to localize where in the hierarchy the damage is likely to be. Damage to alpha motor neurons results in a characteristic set of symptoms called the lower motor neuron syndrome (lower motor neurons refer to alpha motor neurons in the spinal cord and brain stem; all motor system neurons higher in the hierarchy are referred to as upper motor neurons). This damage usually arises from certain diseases that selectively affect alpha motor neurons (such as polio) or from localized lesions near the spinal cord. Lower motor neuron syndrome is characterized by the following symptoms:

1. The effects can be limited to small groups of muscles. Recall that a motor neuron pool is a nucleus of alpha motor neurons that innervate a single muscle (link to Motor Unit Figure 2). Furthermore, nearby motor neuron pools control nearby muscles. Thus, restricted damage to lower motor neurons, either within the spinal cord or at the ventral roots, will affect only a restricted group of muscles.
   
2. Muscle atrophy. When alpha motor neurons die, the muscle fibers that they innervate become deprived of necessary trophic factors and eventually the muscle itself atrophies.
   
3. Weakness. Because of the damage to alpha motor neurons and the atrophy of muscles, weakness is profound in lower motor neuron disorders.
   
4. Fasciculation. Damaged alpha motor neurons can produce spontaneous action potentials. These spikes cause the muscle fibers that are part of that neuron’s motor unit to fire, resulting in a visible twitch (called a fasciculation) of the affected muscle (Figure 6.1).

   Figure 6.1 Fasciculations and fibrillations. Click on buttons to see demonstration.

   
   
5. Fibrillation. With further degeneration of the alpha motor neuron, only remnants of the axons near the muscle fibers remain. These individual axon fibers can also generate spontaneous action potentials; however, these action potentials will only cause individual muscle fibers to contract. This spontaneous twitching of individual muscle fibers is called a fibrillation (Fig. 1). Fibrillations are too small to be seen as a visible muscle contraction. They can only be detected with electrophysiological recordings of the muscle activity (an electromyogram).
   
6. Hypotonia. Because alpha motor neurons are the only way to stimulate extrafusal muscle fibers, the loss of these neurons causes a decrease in muscle tone.
   
7. Hyporeflexia. The myotatic (stretch) reflex is weak or absent with lower motor neuron disorders, because the alpha motor neurons that cause muscle contraction are damaged.
   

6.2 Upper Motor Neuron Syndrome

Damage to any part of the motor system hierarchy above the level of alpha motor neurons (not including the side loops) results in a set of symptoms termed the upper motor neuron syndrome. Some of these symptoms are opposite of those of lower motor neuron disorders. Thus, one of the critical determinations a clinician must make is whether a patient presenting with motor problems has an upper motor neuron disorder or a lower motor neuron disorder.

Upper motor neuron disorders typically arise from such causes as stroke, tumors, and blunt trauma. For example, strokes to the middle cerebral artery, lateral striate artery, or the medial striate artery can cause damage to the lateral surface of cortex or to the internal capsule, where the descending axons of the corticospinal tract collect. The symptoms of upper motor neuron syndrome are:

1. The effects extend to large groups of muscles. Recall from the Motor Cortex chapter that muscles from different body parts are activated by stimulation of parts of motor cortex, consistent with the notion that motor cortex represents movements that are controlled by many joints, rather than individual muscles. Thus, a stroke in a particular part of motor cortex will affect the activation of many muscles in the body. Likewise, a stroke that affects the internal capsule or crus cerebri could affect muscles on the entire contralateral side of the body.
   
2. Atrophy is rare. Because alpha motor neurons are present, muscles will continue to receive trophic agents necessary for their survival. A mild amount of atrophy may result from disuse, but it will not be as pronounced as that resulting from a lower motor neuron disorder.
   
3. Weakness. Upper motor neuron disorders produce a graded weakness of movement (paresis), which differs from the complete loss of muscle activity caused by paralysis (plegia).
   
4. Absence of fasciculations. Because alpha motor neurons themselves are spared, fasciculations do not occur.
   
5. Absence of fibrillations. Likewise, fibrillations do not occur.
   
6. Hypertonia. Upper motor neuron disorders result in an increase in muscle tone. Recall that descending motor pathways can modulate the intrinsic circuitry that is present in the spinal cord. This modulatory input can be either inhibitory or excitatory. Through mechanisms that are not well understood, the loss of descending inputs tends to result in an increased firing rate of alpha and/or gamma motor neurons. The higher firing rate causes an increase in the resting level of muscle activity, resulting in hypertonia.
   
7. Hyperreflexia. Because of the loss of inhibitory modulation from descending pathways, the myotatic (stretch) reflex is exaggerated in upper motor neuron disorders. The stretch reflex is a major clinical diagnostic test of whether a motor disorder is caused by damage to upper or lower motor neurons.
   
8. Clonus. Sometimes the stretch reflex is so strong that the muscle contracts a number of times in a 5-7 Hz oscillation when the muscle is rapidly stretched and then held at a constant length. This abnormal oscillation, called clonus, can be felt by the clinician.
   
9. Initial contralateral flaccid paralysis. In the initial stages after damage to motor cortex, the contralateral side of the body shows a flaccid paralysis. Gradually, over the course of a few weeks, motor function returns to the contralateral side of the body. This gradual recovery of function results from the ability of other motor pathways to take over some of the lost functions. Recall that there are multiple descending motor pathways by which high-order information can reach the spinal cord. Thus, descending pathways such as the rubrospinal and the reticulospinal tracts, which receive direct or indirect cortical input, can take over the function lost by the damage to the corticospinal tract. Moreover, primary motor cortex itself is capable of reorganizing itself to recover some lost function. Thus, if the part of motor cortex that controls a certain body movement is damaged, neighboring parts of the motor cortex that are undamaged can, to some extent, alter their function to help compensate for the damaged areas. The one major exception to the recovery of function is that fine control of the distal musculature will not be regained after a lesion to the corticospinal tract. Recall that there are direct connections from primary motor cortex neurons to alpha motor neurons controlling the fingers. These connections presumably underlie our abilities to manipulate objects with great precision and to do such tasks as playing a piano and performing microsurgery. None of the other descending pathways have direct connections onto spinal motor neurons, and none of them can compensate for the loss of fine motor control of the hands and fingers after damage to the corticospinal tract.
   
10. Spasticity. A clinical sign of upper motor neuron disorder is a velocity dependent resistance to passive movement of the limb. If the clinician moves a patient’s limb slowly, there may be little resistance to the movement. As the passive movement becomes quicker, however, at a certain point the muscle will sharply resist the movement. This is referred to as a “spastic catch.” The mechanism for this spasticity is not entirely known, but altered firing rate of gamma motor neurons and their regulating interneurons may be involved, as well as an increase in alpha motor neuron activity, causing an inappropriately powerful stretch reflex to a fast stretch of the muscle. Sometimes, the resistance becomes so great that the autogenic inhibition reflex is initiated, causing a sudden drop in the resistance; this is referred to as the clasp-knife reflex.

    Figure 6.2 Babinski sign.

    
    
11. Babinski sign. A classic neurological test for corticospinal tract damage is the Babinski test. In this test, the clinician strokes the sole of the foot firmly with an instrument. This elicits a normal plantar response in normal individuals, as the toes curl inward. In patients with an upper motor neuron disorder, however, an abnormal extensor plantar response is elicited, as the big toe extends upward and the remaining toes fan out. This is called a positive Babinski sign (Figure 6.2). Interestingly, the positive Babinski sign is normal in infants for the first 2 years of life. During development, however, the reflex changes to the normal adult pattern, presumably as corticospinal circuits mature.
    

In addition to the above symptoms, damage to the motor cortex and association cortex can result in impairments in motor planning and strategies and in an inability to perform complex motor tasks. Performance of simple tasks is intact, but patients are unable to perform complex, practiced tasks. This symptom is known as apraxia. For example, patients may be unable to arrange a set of blocks to match an example block-structure in front of them. They can move the blocks individually, but cannot come up with a motor plan to arrange them properly. This disorder is known as constructional apraxia. Other apraxias include dressing apraxia (inability to dress oneself) and verbal apraxia (inability to coordinate mouth movements to produce speech).

Paralysis

A section or crush of the spinal cord will result in paralysis of all parts of the body below the damaged region. Even though such an injury occurs in the spinal cord, it is not considered a lower motor neuron disorder, as the alpha motor neurons themselves are not directly damaged. If the damage occurs at the cervical level, then all four limbs will be paralyzed (quadriplegia). If the damage occurs below the cervical enlargement, then only the legs are paralyzed (paraplegia). Other terms used to describe patterns of paralysis are hemiplegia (paralysis to one side of the body) and monoplegia (paralysis of a single limb).

6.3 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.

Figure 6.3 Parkinson’s disease results from degeneration of the nigrostriatal pathway. Three therapeutic interventions are L-Dopa therapy, pallidotomy, and deep brain stimulation.

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.

Figure 6.4 Huntington’s disease results from degeneration of the indirect pathways cells of the striatum.

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.

Figure 6.5 Hemiballismus results from unilateral damage to the subthalamic nucleus.

 

6.4 Disorders of the Cerebellum

Like the basal ganglia, the cerebellum has historically been considered part of the motor system because damage to it produces motor disturbances. Unlike the basal ganglia, damage to the cerebellum does not result in lack of movement or poverty of movement. Instead, cerebellar dysfunction is characterized by a lack of movement coordination. Also unlike basal ganglia (and motor cortex), damage to the cerebellum causes impairments on the ipsilateral side of the body.

1. Ataxia is a general term used to describe the general impairments in movement coordination and accuracy that accompany cerebellar damage. There are two major forms of cerebellar ataxia.
   1. Disturbances of posture or gait result from lesions to the vestibulocerebellum. Patients have difficulty maintaining posture because of the loss of the fine-control mechanisms programmed by cerebellar circuits that translate vestibular signals into precise, well-timed muscle contractions to counter small sways in the body. As a result, patients often develop abnormal gait and stances to compensate. For example, the feet are often spaced widely apart when the patient stands still, as this provides a more stable base to maintain balance. In addition, patients display a staggering gait, with a tendency to fall toward the side of the lesion. This gait resembles that of a drunken individual; indeed, alcohol is known to affect the firing of Purkinje cells, which may explain the loss of coordination that accompanies inebriation.
   2. Decomposition of movement results from the loss of the cerebellum’s ability to coordinate the activity and timing of many muscle groups to produce smooth, fluid movements. Instead, cerebellar patient decompose each movement into its component parts, performing them in serial, rather than all at once in a coordinated fashion.

      Figure 6.6 Dysdiadochokinesia. A normal subject can easily perform rhythmic movements like rapidly pronating and supinating the hands and forearms (click NORMAL). A patient with a cerebellum lesion cannot perform this task

2. Dysmetria refers to the inappropriate force and distance that characterizes target-directed movements of cerebellar patients. For example, in attempting to grab a cup, they may move their hand outward with too much force or may move it too far, with the result of knocking over the cup instead of grabbing it.
3. Dysdiadochokinesia refers to the inability of cerebellar patients to perform rapidly alternating movements, such as rapidly pronating and supinating the hands and forearms (Figure 6.6). This diagnostic sign results from the lack of the cerebellum’s ability to coordinate the timing of muscle groups, alternately contracting and inhibiting antagonistic muscles, to produce the rhythmic movements.
4. Scanning speech refers to the often staccato nature of speech of cerebellar patients. The production of speech is a motor act, as muscles of the jaw, tongue, and larynx need to work in unison to produce words and sounds. Cerebellar patients have difficulty in coordinating these muscle groups appropriately, and therefore their speech tends to be slow and disjointed.
5. Hypotonia is another symptom of cerebellar damage. There is a decreased, pendulous myotatic reflex, as the decreased muscle resistance tends to cause the limb to swing back and forth after the initial reflex contraction.
   

6. Figure 6.7 Intention tremor. A normal subject can make a directed movement to a target (click NORMAL). A patient with a cerebellum lesion displays an intention tremor, in which the movement starts smoothly toward the target but then oscillates back and forth until the hand slowly contacts the target (click ABNORMAL).

   Intention tremor refers to the increasingly oscillatory trajectory of a cerebellar patient’s limb in a target-directed movement (Figure 6.7). For example, the hand will start out on a straight path toward the target, but as it gets closer, the hand begins to move back and forth, and the patient must slow down the movement and very carefully approach the target. Note that this tremor contrasts with the resting tremor of Parkinson’s disease, which disappears when the movement is made. Intention tremor is absent when the hand is still, but appears toward the end of a target-directed movement.
7. Nystagmus is an oscillatory movement of the eyes, resulting from damage to the vestibulocerebellum. Recall that one function of the cerebellum is to fine-tune the gain of the vestibuloocular response. Damage to the cerebellum can disrupt this circuitry, resulting in a continuing oscillation of the eyes.
8. Delay in initiating movements. Cerebellar patients take longer to initiate movements, often because they must actively plan sequences of movements that are performed effortlessly by normal individuals.
9. In addition to movement disorders, cerebellar patients also demonstrate subtle cognitive deficits, such as an impaired ability to estimate time intervals.

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