CASE 48. What part of the cerebellum is responsible for planning and initiation of movement?

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1 CASE 48 A 34-year-old woman with a long-standing history of seizure disorder presents to her neurologist with difficulty walking and coordination. She has been on phenytoin for several days after having been switched from valproic acid. She states she has had an acute change in gait, unclear speech, blurring of vision, tremor with movement, and loss of hand coordination. She has never had symptoms like this before. She denies headache and vertigo or any other complaints. On examination, she has an unstable gait and poor hand-eye coordination. She is noted to have nystagmus along with a fine tremor of the hand when she is moving it. A urine drug screen is negative. She has a computed tomography (CT) scan and lumbar puncture, which are both normal. Phenytoin levels are slightly elevated. She is diagnosed with cerebellar ataxia, probably as a side effect of phenytoin. What part of the cerebellum is responsible for planning and initiation of movement? Is the output of the cerebellar cortex excitatory, inhibitory, or both? What is the neurotransmitter for Purkinje cells?

2 388 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 48: CEREBELLUM Summary: A 34-year-old woman has lack of coordination and cerebellar ataxia secondary to the medication phenytoin. Part of cerebellum responsible for planning and initiation of movement: Cerebrocerebellum (neocerebellum). Output from cerebellar cortex: Inhibitory. Neurotransmitter for Purkinje cells: Gamma-aminobutyric acid (GABA). CLINICAL CORRELATION Ataxia is defined as a loss of muscle coordination. There are many different etiologies, including inheritable diseases, that can result in ataxia. Signs of ataxia may include gait impairment, nystagmus, tremor with movement, loss of coordination, and inability to perform rapid alternating movements. Cerebellar ataxia is differentiated from vestibular-labyrinthine disease because of a lack of vertigo, dizziness, and light-headedness. Acute and reversible ataxia may be seen during intoxication with alcohol, during gasoline and glue sniffing, and after exposure to mercury. Medications such as phenytoin, lithium, barbiturates, and medications for chemotherapy all may result in a reversible ataxia. Other etiologies of ataxia include infection (AIDS), cerebrovascular disease, vitamin deficiency, multiple sclerosis, malignancies, and thyroid disease. Depending on the etiology, the ataxia may be reversible, and so a search for the underlying cause is of paramount importance. APPROACH TO CEREBELLAR PHYSIOLOGY Objectives 1. Understand the general organization of the cerebellum. 2. Know the cerebellar functions. 3. Describe the cellular organization of the cerebellar cortex. Definitions Complex spike: Action potential in a cerebellar Purkinje cell occurring simultaneously in its soma and dendrites, which is stimulated by a single, extraordinarily powerful EPSP that is evoked by a single action potential in a single climbing fiber from the inferior olive. Dysmetria: Abnormal movement characterized by undershoot or overshoot of intended position, associated with an inability to judge distance or scale.

3 CLINICAL CASES 389 DISCUSSION The cerebellum occupies 10% of the brain volume but contains more than 50% of the neurons. Most of the neurons are in the outer mantle of gray matter, the cerebellar cortex, but nearly all cerebellar output originates from cell bodies in the four pairs of deep cerebellar nuclei (dentate, emboliform, globose, and fastigial). Together, the emboliform and globose nuclei are called the interposed nucleus. All the incoming and outgoing axons pass through only three large tracts: the superior, middle, and inferior peduncles. The vast majority of axons in these tracts (> 97%) are afferent to the cerebellum. Anatomically, the cerebellar cortex is divided into an anterior lobe, a posterior lobe, and a flocculonodular lobe. Also important, however, are the functional divisions (orthogonal to the lobular divisions) into lateral and intermediate parts of each hemisphere and the central vermis. The flocculonodular lobe (vestibulocerebellum) is the most primitive part of the cerebellar cortex, and through its connections from primary vestibular afferents and to the lateral vestibular nuclei, it functions in the control of balance and eye movements. The vermis and intermediate hemispheres receive somatosensory inputs from the spinal cord and thus are called the spinocerebellum. The vermis receives somatic sensory input from proximal parts of the body and head as well as visual, auditory, and vestibular input. It projects via the fastigial nucleus to cortical and brainstem regions that control proximal muscles of the body. It is important for modulating motor programs involved in posture, locomotion, and gaze. The intermediate part of the hemisphere receives somatic sensory input from the limbs and projects by way of the interposed nucleus to lateral corticospinal and rubrospinal systems to control distal muscles. The lateral part of each hemisphere (cerebrocerebellum or neocerebellum) evolved most recently and receives input solely from the cerebral cortex. It projects via the dentate nucleus and ventrolateral nucleus of the thalamus to cerebral cortical areas involved in motor control. It functions to help plan complex motor actions and consciously assess errors in movement. Many parts of the cerebellum are important for motor learning. During the initial stages of much motor learning, conscious effort is required and most of the activity is in the cerebral cortex. However, as learning proceeds, much of the activity is shifted to the cerebellum. Learning in the cerebellum involves temporally precise interactions within Purkinje cells between excitatory input from climbing fibers and excitatory input from parallel fibers. The complex spikes generated by climbing fiber activity result in considerable Ca 2+ influx, which promotes synaptic plasticity. The cerebellar synaptic plasticity allows novel motor patterns to be programmed at least partly in the cerebellum, allowing skilled movements to be executed almost automatically, with little or no conscious effort. Although the cerebellar cortex contains an enormous number of neurons, it is composed of only three layers (external molecular, Purkinje cell, and

4 390 CASE FILES: PHYSIOLOGY internal granular) and five types of neurons: Purkinje, granule, basket, stellate, and Golgi. The two major inputs to the cerebellar cortex are climbing fibers from the inferior olivary nuclei and the mossy fibers, which bring input from the cerebral cortex as well as from proprioceptors all over the body through pontine nuclei and spinocerebellar tracts. Both sets of fibers have collaterals that also excite neurons in the deep cerebellar nuclei. The climbing fibers are much less numerous, but each directly and very strongly excites a few (1 to 10) Purkinje cells. Indeed, each action potential in a climbing fiber causes each postsynaptic Purkinje cell to reach action potential threshold simultaneously in the soma and dendrites (generating a complex spike). The abundant mossy fibers excite granule cells in the granular layer, each of which provides weak excitatory input to many Purkinje cells through parallel fibers. Each Purkinje cell is excited by approximately 200,000 parallel fibers but only a single climbing fiber. Basket and stellate cells also are excited by granule cells, but they inhibit the Purkinje cells. Inhibition of the Purkinje cells also comes from the Golgi cells, which are excited directly by mossy fiber collaterals. These inhibitory interneurons release GABA, which opens Cl channels. Because the Cl equilibrium potential (E Cl ) is near the resting potential and opening of these channels tends to clamp the membrane potential close to E Cl, GABA release strongly opposes concomitant excitatory input to the postsynaptic neuron. The Purkinje cells also release GABA, inhibiting neurons in the deep cerebellar nuclei that otherwise are tonically active. Thus, the entire output of the cerebellar cortex is inhibitory. In contrast, the neurons in the deep cerebellar nuclei excite neurons in the brainstem and thalamus. The cerebellar cortex provides precisely timed inhibitory control that modulates the excitatory output of the deep cerebellar nuclei and vestibular nuclei. In this regard, the cerebellum acts as an inhibitory modulator of motor activity initiated in the cerebral cortex, similar to the way the basal ganglia inhibit motor activity. Thus, lesions of the cerebellum, like lesions of the basal ganglia, do not produce paralysis or sensory deficits. Depending on the site of injury, cerebellar lesions disturb balance (flocculonodular lobe) or produce ataxia, slurred speech, dysmetria, and an inability either to stop movements promptly or to alternate opposing movements rapidly (anterior and posterior lobes). COMPREHENSION QUESTIONS [48.1] Most axons in the superior, middle, and inferior peduncles are which of the following? A. Afferent to the cerebellum B. Axons of Golgi cells C. Axons of Purkinje cells D. Parallel fibers of granule cells E. Projections from neurons in the deep cerebellar nuclei

5 CLINICAL CASES 391 [48.2] Major functions of cerebellar cortex include which of the following? A. Directly exciting alpha motor neurons B. Exciting deep cerebellar nuclei C. Generating motor patterns that subserve the scratch reflex D. Learning and controlling novel movement patterns E. Recognizing emotionally potent stimuli [48.3] Activity in climbing fibers will do which of the following? A. Cause release of GABA from climbing fiber terminals B. Evoke complex spikes in Purkinje cells C. Have no effect in the flocculonodular lobe D. Strongly excite neurons in deep cerebellar nuclei E. Weakly depolarize Purkinje cells Answers [48.1] A. About 97% of the axons in the peduncles connecting the cerebellum to the rest of the brain are afferent to the cerebellum. The output of the cerebellar cortex is conveyed exclusively by the Purkinje cells, which although large and powerful are not numerous. [48.2] D. One of the most important functions of the cerebellar cortex is to learn and control novel patterns of movement and posture. Cerebellar learning and other cerebellar functions are not implemented by direct actions on motor neurons (answer A) or spinal pattern generators (answer C) but instead modulate activity in the motor cortex by patterned inhibition (not excitation, as in answer B) of deep cerebellar nuclei, which excite thalamic neurons, which in turn excite neurons in motor cortex. The cerebellum is much less important for processing emotional information (answer E) than for controlling the spatial accuracy and temporal coordination of movement. [48.3] B. A single action potential in a single climbing fiber evokes a complex spike in each of the Purkinje fibers (1 20) on which the climbing fiber synapses. The complex spike, which is activated by glutamate released from the climbing fiber, is an overshooting action potential generated simultaneously in the soma and dendrites. This is the strongest synaptic connection known in the central nervous system (CNS). In contrast, synapses from the climbing fibers to neurons in deep cerebellar nuclei are very weak. Climbing fibers strongly excite Purkinje cells in all regions of the cerebellar cortex.

6 392 CASE FILES: PHYSIOLOGY PHYSIOLOGY PEARLS The cerebellar surface is divided anatomically into the anterior lobe, posterior lobe, and flocculonodular lobe, but the most important functional divisions are the vermis, intermediate hemispheres, and lateral hemispheres. Most axons in the peduncles that connect the cerebellum to the brainstem are afferent, and the afferents make excitatory connections in both the deep cerebellar nuclei and the cerebellar cortex. The cerebellar cortex forms an inhibitory loop, which is excited, along with the deep cerebellar nuclei, by proprioceptive, vestibular, and cerebral cortical input, and which feeds back to inhibit the deep cerebellar nuclei. Each output neuron of the cerebellar cortex, the Purkinje cell, is weakly excited by each of approximately 200,000 parallel fibers from cerebellar granule cells (which are activated by numerous mossy fibers from brainstem nuclei and the spinal cord) and strongly activated by a single climbing fiber originating in the inferior olivary nucleus. Purkinje cells, along with the inhibitory interneurons in the cerebellar cortex (basket, stellate, and Golgi), release GABA, which opens postsynaptic Cl channels to hold the postsynaptic potential close to the resting potential. Major functions of the cerebellum include modulating intrinsic motor programs involved in posture, locomotion, and gaze as well as motor planning and the unconscious control of novel motor patterns acquired during motor learning. Lesions of the cerebellum fail to produce paralysis or sensory deficits, but instead can disturb balance and produce ataxia, slurred speech, dysmetria, and an inability to stop movements efficiently or alternate different movements rapidly. REFERENCES Johnson DA. The cerebellum In: Johnson LR, ed. Essential Medical Physiology. San Diego, CA: Elsevier Academic Press; 2003: Ghez C and Thach WT. The cerebellum. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neuroscience. New York, NY: McGraw-Hill; 2000: