Cerebellum

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Chapter 13 Cerebellum

The cerebellum, the largest part of the hindbrain, is dorsal to the pons and medulla, and its median region is separated from them by the fourth ventricle. It is joined to the brain stem by three pairs of cerebellar peduncles, which contain afferent and efferent fibres. The cerebellum occupies the posterior cranial fossa, where it is covered by the tentorium cerebelli. It is roughly spherical but somewhat constricted in its median region and flattened; its greatest diameter is transverse. In adults, the weight ratio of cerebellum to cerebrum is approximately 1 : 10; in infants, it is approximately 1 : 20.

The cerebellum is a central part of the major circuitry that links sensory to motor areas of the brain, and it is required for the coordination of fine movement. In health, it provides corrections during movement, which are the bases for precision and accuracy, and it is critically involved in motor learning and reflex modification. It receives sensory information through spinal, trigeminal and vestibulocerebellar pathways and, via the pontine nuclei, from the cerebral cortex and the tectum. Cerebellar output is mainly to those structures of the brain that control movement.

The basic internal organization of the cerebellum is that of a superficial, highly convoluted cortex (a laminated sheet of neurones and supporting cells) overlying a dense core of white matter. The latter contains deep cerebellar nuclei, which give rise to the efferent cerebellar projections. Although the human cerebellum makes up approximately one-tenth of the entire brain by weight, the surface area of the cerebellar cortex, if unfolded, would be about half that of the cerebral cortex. The great majority of cerebellar neurones are small granule cells; they are so densely packed that the cerebellar cortex contains many more neurones than the cerebral cortex. Unlike the cerebral cortex, where a large number of diverse cell types are arranged differently in different regions, the cerebellar cortex contains a relatively small number of different cell types that are interconnected in a highly stereotypical way. Consequently, one region of the cerebellar cortex looks very much like another.

Disease processes affecting the cerebellum or its connections lead to incoordination. Movements of the eyes, speech apparatus, individual limbs and balance are usually affected, which results in nystagmus, dysarthria, incoordination and ataxia. Although all these movements become defective in widespread disease of the cerebellum or its connections, topographical arrangements within the cerebellum lead to a variety of clinically recognizable disease patterns. Thus, in cerebellar hemisphere disease, the ipsilateral limbs show rhythmical tremor during movement but not at rest. The tremor increases as the target is approached, so reaching and accurate movements of the arm are especially difficult. Diseases that affect the ascending spinocerebellar pathways or the midline vermis have a disproportionate effect on axial structures, leading to severe loss of balance. Lesions of outflow tracts in the superior cerebellar peduncles result in a wide-amplitude, severely disabling, proximal tremor that interferes with all movements and may even disturb posture, leading to rhythmic oscillations of the head or trunk so that the patient is unable to stand or sit without support. However, although cerebellar lesions may initially cause profound motor impairment, a considerable degree of recovery is possible. There are clinical reports that the initial symptoms of large cerebellar lesions (caused by trauma or surgical excision) have improved progressively over time.

Although the basic structure of the cerebellum and its importance for normal movement have long been recognized, many of the details of how it functions remain obscure. The main goal of this chapter is to describe the known structure and connections of the cerebellum.

External Features and Relations

The cerebellum consists of two large, laterally located hemispheres that are united by a midline vermis (Figs 13.1–13.3). The superior surface of the cerebellum, which would constitute the anterior part of the unrolled cerebellar cortex, is relatively flat. The paramedian sulci are shallow, and the borders between vermis and hemispheres are indicated by kinks in the transverse fissures. The superior surface adjoins the tentorium cerebelli and projects beyond its free edge. The transverse sinus borders the cerebellum at the point where the superior and inferior surfaces meet. The inferior surface is characterized by a massive enlargement of the cerebellar hemispheres, which extends medially to overlie some of the vermis. Deep paramedian sulci demarcate the vermis from the hemispheres. Posteriorly, the hemispheres are separated by a deep vallecula, which contains the dural falx cerebelli. The inferior cerebellar surface lies against the occipital squama. The shape of the surface facing the brain stem is irregular. It forms the roof of the fourth ventricle and the lateral recesses on each side of it, while the cerebellar peduncles define the diamond shape of the ventricle when viewed from behind. Anterolaterally, the cerebellum lies against the posterior surface of the petrous part of the temporal bone.

Fig. 13.1 Horizontal section through the cerebellum and brain stem.

(Courtesy of Dr. G. J. A. Maart.)

Fig. 13.2 Magnetic resonance images of the cerebellum of a 16-year-old girl. A, Sagittal slice. B, Coronal slice. C, Axial slice.

(Courtesy of Drs. J. P. Finn and T. Parrish, Northwestern University School of Medicine, Chicago, toddp@northwestern.edu.)

Fig. 13.3 Terminology of cerebellar lobes and fissures, using a schematic ‘unrolled’ diagram as a frame of reference. A, Unrolled cerebellar cortex. The lobules are labelled by numbers, and the fissures between the wings are listed. B, Cerebellum viewed from above. C, Median sagittal section of cerebellum. The nodules and wings are numbered and listed. D, Cerebellum viewed from below.

The cerebellar surface is divided by numerous curved transverse fissures that separate its folia and give it a laminated appearance. Deeper fissures divide it into lobules. One conspicuous fissure, the horizontal fissure, extends around the dorsolateral border of each hemisphere from the middle cerebellar peduncle to the vallecula, separating the superior and inferior surfaces. Although the horizontal fissure is prominent, it appears relatively late in embryological development and does not mark the boundary between major functional subdivisions of the cortex. The deepest fissure in the vermis is the primary fissure, which curves ventrolaterally around the superior surface of the cerebellum to meet the horizontal fissures. It appears early in embryological development and marks the boundary between the anterior and posterior lobes.

Because the cerebellar cortex has a roughly spherical shape, the true relations between its parts can sometimes be obscured. Thus, the most anterior lobule of the cerebellar vermis, the lingula, lies very close to the most posterior lobule, the nodule. Deep fissures divide the superior vermis into lobules. The lobules of the superior vermis that belong to the anterior lobe are the lingula, central lobule and culmen. The lingula is a single lamina of four or five shallow folia. Its white core is continuous with the anterior medullary velum. It is separated from the central lobule by the precentral fissure. The central lobule and culmen are continuous bilaterally with an adjoining wing (ala) in each hemisphere. The central lobule is separated from the culmen by the preculminary fissure. The culmen (with attached anterior quadrangular lobules) lies between the preculminary and primary fissures.

Between the primary and horizontal fissures are the simple lobule (with attached posterior quadrangular lobules) and the folium (with attached superior semilunar lobules). These two lobule sets are separated by the posterior superior fissure.

From the back forward, the inferior vermis is divided into the tuber, pyramis, uvula and nodule, in that order (see Fig. 13.3C). The tuber is continuous laterally with the inferior semilunar lobules and separated from the pyramis by the lunogracile fissure. The pyramis and attached biventral lobules (containing an intrabiventral fissure) are separated from the uvula and attached cerebellar tonsils by the secondary fissure. Behind the uvula, and separated from it by the median part of the posterolateral fissure, is the nodule. The tonsils are roughly spherical and overhang the foramen magnum on each side of the medulla oblongata.

The nodule and attached flocculi constitute a separate flocculonodular lobe that is separated from the uvula and tonsils by the deep posterolateral fissure. This lobe is richly interconnected with the vestibular nucleus, which is located at the lateral margin of the fourth ventricle.

Functional Divisions

The cerebellum is divided functionally into a body, with inputs mainly from the spinal cord and pontine nuclei, and a flocculonodular lobe, which has strong afferent and efferent connections with the vestibular nuclei (Fig. 13.4). The body is subdivided into a series of regions dominated by their spinal or pontine inputs. The anterior lobe, simple lobule, pyramis and biventral lobules are the main recipients of spinal and trigeminal cerebellar afferents. Pontocerebellar input dominates in the folium, tuber and uvula and in the entire hemisphere, including those regions that receive afferents from the spinal cord.

Fig. 13.4 Diagrams of the flattened cerebellar surface. A, Transverse lobular organization of the afferent spino-, ponto- and vestibulocerebellar connections of the cortex. B, Longitudinal zonal organization of the vermis and hemispheres with the cerebellar and vestibular nuclei.

The mediolateral subdivision of the cerebellum into vermis and hemispheres represents a functional subdivision that is closely related to its output. In mammals, a great increase in the size of the cerebellar hemispheres parallels the development of the cerebral cortex and reflects the importance of the corticopontocerebellar input and of the efferent projections of the cerebellar hemispheres (through the dentate and interposed cerebellar nuclei and the thalamus) to the cerebral cortex.

Cerebellar Peduncles

Three peduncles connect the cerebellum with the rest of the brain (Figs 13.5, 13.6). The middle cerebellar peduncle is the most lateral and by far the largest of the three. It passes obliquely from the basal pons to the cerebellum and is composed almost entirely of fibres arising from the contralateral basal pontine nuclei, with a small addition from nuclei in the pontine tegmentum. The inferior cerebellar peduncle is located medial to the middle peduncle. It consists of an outer, compact fibre tract, the restiform (Latin for ‘rope-like’) body and a medial, juxtarestiform body. The restiform body is a purely afferent system. It receives the posterior spinocerebellar tract from the spinal cord and the trigeminocerebellar, cuneocerebellar, reticulocerebellar and olivocerebellar tracts from the medulla oblongata. The juxtarestiform body is mainly an efferent system. Apart from primary afferent fibres of the vestibular nerve and secondary afferent fibres from the vestibular nuclei, it is made up almost entirely of efferent Purkinje cell axons from the vestibulocerebellum, on their way to the vestibular nuclei, and the uncrossed fibres from the fastigial nucleus. The crossed fibres from the fastigial nucleus, after passing dorsal to the superior cerebellar peduncle, enter the brain stem as the uncinate fasciculus at the border of the juxtarestiform and restiform bodies.

Fig. 13.5 Dissection of the left cerebellar hemisphere and its peduncles.

(Courtesy of Dr. E. B. Jamieson, University of Edinburgh.)

Fig. 13.6 Diagram illustrating the composition of the cerebellar peduncles. A, Dorsal view. B, Lateral view.

The superior cerebellar peduncle contains all the efferent fibres from the dentate, emboliform and globose nuclei and a small fascicle from the fastigial nucleus. It decussates with its opposite number in the caudal mesencephalon, on its way to synapse in the contralateral red nucleus and thalamus. The anterior spinocerebellar tract reaches the upper part of the pontine tegmentum before looping down within this peduncle to join the spinocerebellar fibres entering through the restiform body.

Internal Structure

The white core of the cerebellum branches in diverging medullary laminae, which occupy the central part of the lobules and are covered by the cerebellar cortex. In a sagittal section through the cerebellum, the highly branched pattern of medullary laminae is known as the arbor vitae. The white core consists of the efferents (Purkinje cell axons) and afferents of the cerebellar cortex. Fibres crossing the midline in the white core of the cerebellum and the anterior medullary velum constitute the cerebellar commissure. This consists of an efferent portion, containing decussating fibres from the fastigial nucleus, and an afferent portion, containing fibres of the restiform body and the middle cerebellar peduncle. (In neuroanatomy, the word ‘commissure’ may have two meanings. In one sense, a commissure such as the corpus callosum connects homotopic points on the two sides of the brain. However, in the cerebellum, commissural afferent and efferent fibres are simply crossing the midline. The cerebellum has no callosum-like commissure connecting homotopic points on the two sides.)

Laterally, the medullary laminae merge into a large, central white mass that contains the four cerebellar nuclei: the dentate and the anterior (emboliform) and posterior (globose) interposed and fastigial nuclei (see Fig. 13.4). The dentate nucleus is the most lateral and largest and is an irregularly folded sheet of neurones that encloses a mass of fibres derived mainly from dentate neurones. It resembles a leather purse, the opening of which is directed medially. Fibres stream out through this so-called hilum to form the bulk of the superior cerebellar peduncle. The anterior and posterior interposed and fastigial nuclei lie medial to the dentate nucleus. The anterior interposed nucleus is continuous laterally with the dentate. The posterior interposed nucleus is medial to the anterior nucleus and is continuous with the fastigial nucleus, which is located next to the midline, bordering the fastigium (roof) of the fourth ventricle. Efferent fibres from the interposed nuclei join the superior cerebellar peduncle. A large proportion of the efferent fibres from the fastigial nucleus cross within the cerebellar white matter of the cerebellar commissure. After their decussation, they constitute the uncinate fasciculus (hook bundle), which passes dorsal to the superior cerebellar peduncle to enter the vestibular nuclei of the opposite side (see Fig. 13.6). Uncrossed fastigiobulbar fibres enter the vestibular nuclei by passing along the lateral angle of the fourth ventricle. Some fibres of the fastigial nucleus ascend in the superior cerebellar peduncle.

Cerebellar Cortex

The elements of the cerebellar cortex possess a precise geometrical order, which is arrayed relative to the tangential, longitudinal and transverse planes in individual folia. The cortex contains the terminations of afferent ‘climbing’ and ‘mossy’ fibres, five varieties of neurone (granular, stellate, basket, Golgi and Purkinje), neuroglia and blood vessels.

There are three main layers: molecular, Purkinje cell and granular (Fig. 13.7). The main circuit of the cerebellum involves granule cells, Purkinje cells and neurones in the cerebellar nuclei. Granule cells receive the terminals of the mossy fibre afferents (i.e. all afferent systems except the olivocerebellar fibres). The axons of the granule cells ascend to the molecular layer, where they bifurcate into parallel fibres (so called because they are oriented parallel to the transverse fissures and perpendicular to the dendritic trees of the Purkinje cells on which they terminate). Purkinje neurones are large and are the sole output cells of the cerebellar cortex. Their axons terminate in the cerebellar nuclei and vestibular nuclei. In addition to the dense array of parallel fibres, the dendritic trees of Purkinje cells receive terminals from climbing fibres whose neurones of origin are in the inferior olivary nucleus. The cerebellar cortex thus receives two distinct types of input: olivocerebellar climbing fibres, which synapse directly on Purkinje neurones, and mossy fibres, which connect to the Purkinje cells via granular neurones whose axons are the parallel fibres.

Fig. 13.7 General organization of the cerebellar cortex. A single folium has been sectioned vertically, both in its longitudinal axis (right side of the diagram) and transversely. The two asterisks on the left face indicate recurrent collateral branches of Purkinje cell axons.

Both parallel and climbing fibres excite the Purkinje cells, but they differ greatly in their firing characteristics and their effect on the cells. Purkinje cell axons in turn inhibit their target neurones in the cerebellar nuclei. The cerebellar nuclei project to all the major motor control centres in the brain stem and cerebrum. The stellate, basket and Golgi cells are inhibitory interneurones, which connect the cortical elements in complex geometrical patterns.

The molecular layer is approximately 300 to 400 µm thick. It contains a sparse population of neurones, dendritic arborizations, non-myelinated axons and radial fibres of the neuroglial cells. Purkinje cell dendritic trees extend toward the surface and spread out in a plane perpendicular to the long axis of the cerebellar folia. Purkinje cell dendrites are flattened. The lateral extent of the Purkinje cell dendrites is approximately 30 times greater in the transverse plane than in a plane parallel to the cerebellar folia. Parallel fibres are the axons of granule cells, the stems of which ascend into the molecular layer, where they bifurcate at T-shaped branches. The two branches extend in opposite directions as parallel fibres along the axis of a folium. Parallel fibres terminate on the dendrites of the Purkinje cells and Golgi cells, which they pass on their way, and on the basket and stellate cells of the molecular layer. Dendritic trees of Golgi neurones reach toward the surface. Unlike the flattened dendritic tree of the Purkinje cell, Golgi cell dendrites span the territory of many Purkinje neurones longitudinally as well as transversely. These dendrites receive synapses from parallel fibres. Some Golgi cell dendrites enter the granular layer, where they contact mossy fibre terminals. The cell bodies of Golgi neurones lie below, in the superficial part of the granular layer. The molecular layer also contains the somata, dendrites and axons of stellate neurones (which are located superficially within the molecular layer) and of basket cells (whose somata lie deeper within the molecular layer). Climbing fibres, which are the terminals of olivocerebellar fibres, ascend through the granular layer to contact Purkinje dendrites in the molecular layer. Radiating branches from large epithelial (Bergmann) glial cells give off processes that surround all neuronal elements, except at the synapses. At the surface of the cerebellum, their conical expansions join to form an external limiting membrane.

The Purkinje cell layer contains the large, pear-shaped somata of the Purkinje cells and the smaller somata of epithelial (Bergmann) glial cells. Clumps of granule cells and occasional Golgi cells penetrate between the Purkinje cell somata.

The granular layer (see Fig. 13.7) is approximately 100 µm thick in the fissures and 400 to 500 µm thick on foliar summits. There are approximately 2.7 million granular neurones per cubic millimetre. It has been estimated that the human cerebellum contains a total of 4.6 × 10¹⁰ granule cells and that there are 3000 granule cells for each Purkinje cell.

In summary, the granular layer consists of the somata of granule cells and the start of their axons; dendrites of granule cells; branching terminal axons of afferent mossy fibres; climbing fibres passing through the granular layer en route to the molecular layer; and the somata, basal dendrites and complex axonal ramifications of Golgi neurones. Cerebellar glomeruli are synaptic rosettes consisting of a mossy fibre terminal that forms excitatory synapses on the dendrites of both granule cells and Golgi cells.

Of the five cell types described, the first four are inhibitory, liberating γ-aminobutyric acid (GABA), and the fifth is excitatory, liberating L-glutamate. Figure 13.8 summarizes their main connections.

Fig. 13.8 Diagrammatic representation of the main circuits of the cerebellar cortex. The cortex is indicated by the grey background.

Purkinje cells have a specific geometry that is conserved in all vertebrate classes (see Fig. 13.7). They are arranged in a single layer between the molecular and granular layers. Individual Purkinje cells are separated by approximately 50 µm transversely and 50 to 100 µm longitudinally. Their somata measure 50 to 70 µm vertically and 30 to 35 µm transversely. The subcellular structure of the Purkinje cell is similar to that of other neurones. One distinguishing feature is subsurface cisterns, often associated with mitochondria, that are present below the plasmalemma of somata and dendrites and may penetrate into the spines. They are intracellular calcium stores, which are important links in the second messenger systems of the cell.

One or sometimes two large primary dendrites arise from the outer pole of a Purkinje cell. From these, an abundant arborization, with several orders of subdivision, extends toward the surface. Branches of each neurone are confined to a narrow sheet in a plane transverse to the long axis of the folium. Proximal first- and second-order dendrites have smooth surfaces with short, stubby spines and are contacted by climbing fibres. Distal branches show a dense array of dendritic spines, which receive synapses from the terminals of parallel fibres. Inhibitory synapses are received from basket and stellate cells and from the recurrent collaterals of Purkinje cell axons, which contact the shafts of the proximal dendrites. The total number of dendritic spines per Purkinje neurone is approximately 180,000.

The axon of a Purkinje cell leaves the inner pole of the soma and crosses the granular layer to enter the subjacent white matter. The initial axon segment receives axo-axonic synaptic contacts from distal branches of basket cell axons. Beyond the initial segment, the axon enlarges, becomes myelinated and gives off collateral branches. The main axon ultimately forms a plexus in one of the cerebellar or vestibular nuclei. The recurrent collateral branches end on other Purkinje cells and on basket and Golgi neurones.

Basket and stellate cells are the neurones of the molecular layer. Their sparsely branched dendritic trees and the ramifications of their axons lie in a plane approximately perpendicular to the long axis of the folium—that is, in the same plane as the Purkinje cell dendritic tree. Stellate cells are located in the superficial molecular layer, and their axons synapse with the shafts of Purkinje cell dendrites. Both stellate and basket cells receive excitatory synapses from parallel fibres passing through their dendritic trees. Basket cells lie in the lower third of the molecular layer. Their somata receive synapses from Purkinje cell recurrent collaterals and from climbing and mossy fibres, as well as from the parallel fibres. Basket cell axons increase in size away from their somata and run deep in the molecular layer just above the Purkinje cells. Continuing for approximately 1 mm, each covers the territories of 10 to 12 Purkinje neurones. Collaterals of the basket cell axons ascend along Purkinje cell dendrites and descend toward Purkinje cell somata and initial axonal segments, forming pericellular networks, or ‘baskets,’ around them. Branches from each basket cell axon also extend in the direction of the long axis of the folium to an additional three to six rows of Purkinje neurones, flanking the axon. It follows that as many as 72 Purkinje cell neurones may receive synapses from a single basket neurone.

Most Golgi cell somata occupy the superficial zone of the granular layer, adjoining the Purkinje cell somata. Their dendrites radiate into the molecular layer. Unlike Purkinje cells, the dendritic trees of Golgi cells are not flattened, appearing much the same in transverse and longitudinal foliar section. In both planes they overlap the territories of several neighbouring Purkinje and Golgi cells. Some Golgi dendrites, however, divide in the granular layer and join cerebellar glomeruli, where they receive excitatory synaptic contacts from mossy fibres. The axon of the Golgi cell arises from the base of the cell body or proximal dendrite and immediately divides into a profuse arborization that extends through the entire thickness of the granular layer. The volume of the territory occupied by the axonal ramifications corresponds approximately to that of its dendritic tree in the molecular layer and it overlaps with the axonal arborizations of adjacent Golgi cells. The main synaptic input to Golgi cell dendrites is from parallel fibres in the molecular layer. Purkinje cell recurrent collaterals and mossy and climbing fibres also terminate on their proximal dendrites and, more sparsely, on their somata.

Each granule cell has a spherical nucleus, 5 to 8 µm in diameter, with a mere shell of cytoplasm containing a few small mitochondria, ribosomes and a diminutive Golgi complex. Granule cells give rise to three to five short dendrites that end in claw-like terminals within the synaptic glomeruli. The fine axons of granule cells enter the molecular layer and branch at a T-junction to form parallel fibres passing in opposite directions over a distance of several millimetres. Terminals located along the parallel fibres give them a beaded appearance and are sites of synapses on the dendrites of Purkinje, stellate, basket and Golgi cells in the molecular layer. Most numerous are the synapses with Purkinje dendritic spines. It has been estimated that 250,000 parallel fibres cross a single Purkinje dendritic tree, although every parallel fibre may not synapse with the dendritic tree it crosses.

Two very different excitatory inputs serve the cerebellar cortex: climbing fibres and mossy fibres. Climbing fibres arise only from the inferior olivary nucleus. Olivocerebellar fibres cross the white matter and enter the granular layer, where they branch to form climbing fibres. Each climbing fibre innervates a single Purkinje cell. There are about 10 times as many Purkinje cells as there are cells in the inferior olive, so each olivocerebellar fibre branches into approximately 10 climbing fibres. Individual climbing fibres pass alongside the soma of a Purkinje cell and then branch to make numerous synapses on the short, stubby spines that protrude from the proximal segments of Purkinje cell dendrites.

Mossy fibres take their origin from the spinal cord, trigeminal, dorsal column and reticular nuclei of the medulla and from the pontine tegmentum and basal pons. Like climbing fibres, they are excitatory, but they contrast sharply in their anatomical distribution and physiological properties. As each mossy fibre traverses the white matter, its branches diverge to enter several adjacent folia. Within each folium, these branches expand into grape-like synaptic terminals (mossy fibre rosettes) that occupy the centre of cerebellar glomeruli.

Noradrenergic and serotoninergic fibres form a rich plexus in all layers of the cerebellar cortex. The aminergic fibres are fine and varicose and form extensive cortical plexuses; their release of noradrenaline (norepinephrine) and serotonin is assumed to be non-synaptic, and their effects are paracrine, involving volumes of tissue. The serotoninergic afferents of the cerebellum take their origin from neurones in the medullary reticular formation, other than the raphe nuclei. The noradrenergic, coeruleocerebellar projection, when active, inhibits Purkinje cell firing not by direct action but by β-adrenergic receptor–mediated inhibition of adenylate cyclase in the Purkinje cells. The presence of dopamine in elements of the cerebellar cortex is still disputed. Cerebellar afferents have been traced from dopaminergic cells in the ventral tegmental area, and dopamine D2 and D3 receptors are present in the molecular layer. A similar plexus of thin, choline acetyltransferase–containing fibres is centred on the Purkinje cell layer. The origin of this cholinergic plexus is not known.

The connections of the cerebellum are organized in two perpendicular planes, corresponding to the planar organization of the cerebellar cortex. Efferent connections of the cortex are disposed in parasagittal sheets or bundles that connect longitudinal strips of Purkinje cells with specific cerebellar or vestibular nuclei. The climbing fibre afferents to a Purkinje cell zone from the inferior olive display a similar zonal disposition. Cerebellar output is organized in modules, with a module consisting of one or more Purkinje cell zones, their cerebellar or vestibular target nucleus and their olivocerebellar climbing fibre input. Modular function is determined by the brain stem projections of the cerebellar or vestibular target nucleus. A general feature of the modular organization of the cerebellum is that GABAergic neurones in the cerebellar nuclei project to the subnuclei of the contralateral inferior olive, which give rise to their respective climbing fibre afferents. These recurrent connections are known as nucleo-olivary pathways.

Mossy fibre afferent systems from precerebellar nuclei in the spinal cord and the brain stem terminate in the granular layer of certain lobules in transversely oriented terminal fields. The transverse lobular arrangement of the mossy fibre afferents is enforced by the transverse orientation of the parallel fibres, which are axons of the granule cells and constitute the second link in the mossy fibre–parallel fibre input of the Purkinje cells. Parallel fibres cross and terminate on Purkinje cells belonging to several successive modules as they course through the molecular layer.

Purkinje cells can be activated in two different ways. Granule cell activity generates simple spikes, which resemble the response of other neurones in the brain, whereas activation by a climbing fibre produces a prolonged depolarization on which several spike-like waves are superimposed. The rate of firing of single and complex spikes also differs markedly. Whereas the Purkinje cell may fire simple spikes at a rate of hundreds per second, complex spikes occur at very low frequencies, seldom more than three or four per second.

Purkinje cell activity is regulated by local Golgi, basket and stellate cells. Like Purkinje cells, Golgi cells have a rich dendritic tree that extends through the molecular layer. Unlike Purkinje cells, the Golgi cell dendrites are not restricted to a plane transverse to the folia, and their axons do not leave the cerebellar cortex. Golgi cells regulate firing by presynaptic inhibition of the mossy fibre afferents, so they act as a governor, or rate limiter, of Purkinje cell activity. Stellate and basket cells synapse directly on Purkinje cells and are powerful inhibitors of their activity.

Structural and Functional Cerebellar Localization

Because the cerebellar cortex is largely uniform in microstructure and microcircuitry, it seems likely that its basic mode of operation is also uniform. The most obvious input for this operation is provided by the mossy fibre afferents, which carry information from all levels of the spinal cord, and specialized sensory and motor information relayed from the cerebral cortex and subcortical motor centres. The most obvious output from the cerebellum is directed at motor systems. Purkinje cells are organized in modules, which are discrete, parallel zones that converge on different cerebellar output nuclei coupled to different motor systems in the brain stem, spinal cord and cerebral cortex. Cerebellar function is therefore determined by temporal and spatial factors (e.g. inhibitory interneurones of the cerebellar cortex), which regulate the access of a particular combination of mossy fibre–parallel fibre inputs to an appropriate output. Plastic changes in the response properties of Purkinje cells, in the form of long-term depression of the parallel fibre–Purkinje cell synapses, may also contribute. Short-term and long-term changes in the response properties of Purkinje cells are under the influence of the climbing fibres.

A double, mirrored localization exists in the anterior and posterior cerebellum (Fig. 13.9). The anterior lobe, simple lobule, pyramis and adjoining lobules of the hemisphere of the posterior lobe all receive branches from the same mossy and climbing fibres and project to the same cerebellar nuclei. The efferent pathways of these regions monitor the activity in the corticospinal tract and in the subcortical motor systems descending from the vestibular nuclei and reticular formation. The inputs to the cerebellum and the outputs from it are organized according to the same somatotopic patterns, but the orientation of these patterns is reversed. The representation of the head is found principally in the simple lobule and caudally in a corresponding region of the posterior lobe. The double representation of the body follows in rough somatotopic order. Vestibular connections of the cerebellum display a similar double representation in the most rostral lobules of the anterior lobe and far caudally in the vestibulocerebellum (Fig. 13.10).

Fig. 13.9 Diagram of localizations in the cerebellar cortex. Somatosensory, pink; visual and acoustic, blue; vestibular, yellow.

Fig. 13.10 Vestibulocerebellar mossy fibre projections. A, Primary vestibulocerebellar projections from the bipolar neurones of the vestibular ganglion. B, Secondary vestibulocerebellar projections from the vestibular nuclei. C, Sagittal section showing the distribution of both sets of afferents.

The folium, tuber, uvula, tonsil and posterior biventral lobule all receive an almost pure pontine mossy fibre input. Climbing fibres from the inferior olive and mossy fibres from the basilar and tegmental pontine nuclei relay visual and acoustic information from the respective cerebral association areas and midbrain tectum to the folium and tuber that are thought to represent a vermal visual and acoustic area (see Fig. 13.9). The efferent connections of this area travel via the fastigial nucleus to gaze centres in the pons and midbrain.

CASE 1 Cystic Astrocytoma of the Cerebellum

A 34-year-old woman complains of increasing headache, especially on arising in the morning, accompanied by forceful vomiting, with or without nausea, and blurring of vision. She exhibits papilloedema on funduscopic examination. Her gait is broad based and unsteady, and she has impaired dexterity in the right hand, with virtually unintelligible handwriting and a prominent crescendo intention tremor on the right finger-to-nose test.

Imaging demonstrates a large cystic lesion in the right cerebellar hemisphere, with compression of the fourth ventricle and secondary enlargement of the aqueduct and the lateral ventricles. At surgery, a well-defined mass is found at the margin of the cyst, a so-called mural nodule with the histological characteristic of a low-grade astrocytoma.

Discussion: This patient demonstrates a cerebellar deficit ipsilateral to the cystic astrocytoma in the right cerebellar hemisphere, along with features of secondary hydrocephalus (headache, vomiting, blurring of vision) due to compression of the fourth ventricle. As is generally the case with lesions in a cerebellar hemisphere, the clinical manifestations are ipsilateral to the lesion.

In a young person, the appearance of such a lateralized cerebellar syndrome might initially raise the possibility of von Hippel–Lindau disease, a form of familial neuroectodermal dysplasia characterized by a cerebellar hemangioblastoma (sometimes cystic), typically accompanied by an angiomatous malformation in the retina and sometimes cystic or angiomatous lesions in the liver, pancreas and kidney.

Afferent Connections of the Cerebellum

Afferent connections of the cerebellum include the mossy fibres and the climbing fibres. Mossy fibre systems terminate bilaterally in transversely oriented ‘lobular’ areas. The terminations of different mossy fibre systems overlap considerably (see Fig. 13.4). Climbing fibres from different subnuclei of the inferior olive terminate contralaterally, on discrete longitudinal strips of Purkinje cells. This longitudinal pattern closely corresponds with the zonal arrangement in the corticonuclear projection (Fig. 13.11).

Fig. 13.11 Cerebellar corticonuclear and corticovestibular projections. The widespread projection from flocculonodular lobe to vestibular nucleus is not arrowed but is indicated in green.

(Based on data from Voogd, J., 1964. The Cerebellum of the Cat. Proefschr. Van Gorcum, Assen; and from Voogd, J., Bigaré, F., 1980. Topographic distribution of olivary and corticonuclear fibers in the cerebellum: a review. In: Courville, J., de Mountigny, I., y Latha, R.E. (Eds.), The Inferior Olivary Nucleus. Raven Press, New York, pp. 207–234.)

Spinocerebellar and Trigeminocerebellar Fibres

The spinal cord is connected to the cerebellum through the spinocerebellar and cuneocerebellar tracts and through indirect mossy fibre pathways relayed by the lateral reticular nucleus in the medulla oblongata. These pathways are all excitatory in nature and give collaterals to the interposed and fastigial nuclei before ending on cortical granule cells.

The posterior spinocerebellar tract takes its origin from the posterior thoracic nucleus at the base of the dorsal horn in all thoracic segments of the spinal cord (Fig. 13.12). It enters the inferior cerebellar peduncle, gives collaterals to the cerebellar nuclei and terminates, mainly ipsilaterally, in the vermis and adjoining regions of the anterior lobe and in the pyramis and adjoining lobules of the posterior lobe. The posterior thoracic nucleus receives primary afferents of all kinds from the muscles and joints of the lower limbs, which reach the nucleus via the gracile fasciculus. It also receives collaterals from cutaneous sensory neurones. Accordingly, the tract transmits proprioceptive and exteroceptive information about the ipsilateral lower limbs. Very fast conduction is required to keep the cerebellum informed about ongoing movements. The axons in the posterior spinocerebellar tract are the largest in the central nervous system, measuring 20 µm in external diameter. The upper limb equivalent of the posterior spinocerebellar tract is the cuneocerebellar tract.

Fig. 13.12 Spinocerebellar (red) and cuneocerebellar (blue) mossy fibre projections overlap extensively in the culmen (C), pyramis (P) and related intermediate areas of the cortex.

The anterior spinocerebellar tract is a composite pathway. It informs the cerebellum about the state of activity of spinal reflex arcs related to the lower limb and lower trunk. Its fibres originate in the intermediate grey matter of the lumbar and sacral segments of the spinal cord (see Fig. 13.12). They cross near their origin and ascend close to the surface as far as the lower midbrain before looping down in the superior cerebellar peduncle. Most fibres cross again in the cerebellar commissure; thus, their distributions to the cerebellar nuclei and cortex appear to be the same as those of the posterior tract.

The rostral spinocerebellar tract originates from cell groups of the intermediate zone and horn of the cervical enlargement. Although considered to be the upper limb and upper trunk counterpart of the anterior spinocerebellar tract, most of its fibres remain ipsilateral throughout their course. It enters the inferior cerebellar peduncle and terminates in the same cerebellar nuclei and folia as the cuneocerebellar tract.

The cuneocerebellar tract contains exteroceptive and proprioceptive components that originate from the cuneate and external cuneate nuclei, respectively. The primary afferents travel in the cuneate fasciculus. The tract itself is predominantly uncrossed and ends in the posterior half of the anterior lobe. Exteroceptive and proprioceptive mossy fibre components of the tract terminate differentially in the apical and basal part of the folia. The exteroceptive component overlaps the pontocerebellar mossy fibre projection in the apices of the folia of the anterior lobe.

Comparable sets of ipsilateral proprioceptive and interceptive cerebellar projections exist for the extensive territory of the trigeminal brain stem nuclei. These nuclei also project to the ipsilateral inferior olive, relaying there to the contralateral cerebellar cortex and deep nuclei. The cortical representation of the head is directly behind the primary fissure.

Olivocerebellar Fibres

Efferent Connections of the Cerebellum

The output of the cerebellum consists of the inhibitory projections of the Purkinje cells to the cerebellar and vestibular nuclei, and the efferent connections of the cerebellar nuclei to motor centres in the brain stem and, through the thalamus, the motor cortex. Their effects on movement are always indirect, because there are no direct projections from the cerebellar nuclei to motor neurones. Disynaptic connections of the Purkinje cells in the anterior vermis and vestibulocerebellum with motor neurones controlling oculogyric and proximal limb muscles are mediated by the vestibular nuclei. The vermis also influences these motor neurones bilaterally through multisynaptic pathways that involve the fastigial and vestibular nuclei and the reticular formation (Fig. 13.13). The vermis cannot be considered as a single module. Each half of the vermis is composed of several modules (each made up of a longitudinal Purkinje cell zone and a target nucleus) and their supporting climbing fibre afferent projections.

Fig. 13.13 Efferent connections of the vermis. Connections of the A zones of the vermis and flocculonodular lobe with the fastigial nucleus are indicated, along with those of the B zone with the lateral vestibular nucleus. Some vestibular efferents ascend bilaterally to the ocular motor nuclei and thalamus; others descend to the spinal cord. Motor nuclei of the third (3), fourth (4) and sixth (6) cranial nerves are indicated.

Each cerebellar hemisphere influences movements of the ipsilateral extremities by way of projections to the dentate and interposed (emboliform and globose) nuclei, which in turn project to the contralateral red nucleus, thalamus and motor cortex (Fig. 13.14).

Fig. 13.14 Efferent connections of the cerebellar hemisphere. Purkinje cell zones and their target nuclei are indicated with the same colours. Efferent fibres from the motor cortex and from the very small magnocellular red nucleus recross and descend to the upper part of the spinal cord.

CASE 2 Olivopontocerebellar Atrophy

A 58-year-old man observes the gradual onset of ataxia of gait, with frequent falls and progressing incoordination of limbs. With the passage of time, he develops incapacitating orthostatic hypotension. Urinary incontinence, impotence and increasing stigmata (tremor, rigidity) of Parkinsonism become evident, and mental confusion and ultimately dementia appear.

Examination during the course of his illness demonstrates a demented man with profound gait and truncal ataxia, ataxia of all limbs, dysarthria, nystagmus and inability to stand or walk owing to profound postural hypotension. There is modest cogwheel rigidity of the limbs with a resting tremor, along with increased reflex activity in the legs and bilateral extensor plantar responses. Pes cavus deformities are observed.

Discussion: This man suffers from olivopontocerebellar atrophy (OPCA) along with a variety of neural deficits, of which ataxia is the most prominent; he also has associated autonomic dysfunction with orthostatic (postural) hypotension. Anatomically, the most outstanding lesions involve the derivatives of the so-called rhombic (Essek’s) lip, with striking degeneration and atrophy in the basis pontis, especially involving the pontocerebellar pathways in the middle cerebellar peduncles and sometimes the cerebellar white matter; in the olivary complex; and in the arcuate nuclei of the pons and medulla. Changes are often encountered in the substantia nigra, including the presence of Lewy bodies, as well as a variety of structures involved with autonomic control in both the spinal cord and brain stem, perhaps as part of a more widespread disease process usually referred to as multiple system atrophy (MSA). When orthostatic hypotension dominates the clinical presentation, the rubric Shy–Drager syndrome is sometimes applied.

Corticonuclear and Corticovestibular Fibres

Purkinje cells of each hemivermis project to the ipsilateral fastigial and vestibular nuclei. Purkinje cells of the hemisphere project to the interposed and dentate nuclei. Although the cerebellar cortex is organized in strips of Purkinje cell zones that project to different cerebellar and vestibular nuclei, the borders between these strips are not apparent in the structure of the cortex when it is examined histologically using conventional staining methods. The vermis of the anterior lobe and simple lobule consist of two parallel strips, A and B, of Purkinje cells (see Figs 13.11, 13.13). The medial strip (A zone) projects to the rostral pole of the fastigial nucleus, and the lateral strip (B zone) projects to the lateral vestibular nucleus. The B zone does not continue beyond the simple lobule. The cortex of the entire caudal vermis, which projects to the fastigial nucleus, is included in the A zone. The folium and tuber, which represent a region of the cerebellum that receives a visual input and are involved in the accurate calibration of saccades, project to the caudal pole of the fastigial nucleus. The pyramis, uvula and nodule can be subdivided into several Purkinje cell zones. However, the significance of their connections with the cerebellar and vestibular nuclei is not well understood. Corticovestibular projections to the superior, medial and inferior vestibular nuclei, but not to the lateral nucleus, take their origin from the nodule and the adjacent region of the uvula.

The intermediate region consists of two strips of Purkinje cells (C1 and C3 zones), which project to the anterior interposed nucleus. They flank a single zone (C2) that projects to the posterior interposed nucleus (see Figs 13.11, 13.14). The rest of the hemisphere projects to the dentate nucleus. There are indications that the hemisphere can be subdivided into two zones that project to the caudolateral zone and rostromedial parts of the dentate nucleus. The neurones of the caudolateral dentate are generally smaller than those of the rostromedial dentate, and the convolutions are broader. The efferent connections of the flocculus are mainly with the superior, medial and inferior vestibular nuclei and resemble those from the nodule and uvula.

Cerebellovestibular and Cerebelloreticular Fibres

Efferent Connections of the Fastigial Nucleus

The fastigial nucleus is connected bilaterally with the vestibular nuclei and the medullary and pontine reticular formation (see Figs 13.11, 13.14). Smaller crossed connections either ascend to the midbrain and diencephalon or descend into the spinal cord. Small GABAergic neurones give rise to nucleo-olivary fibres, which terminate in the medial accessory olive. The uncinate fasciculus is the major efferent pathway of the fastigial nucleus. Its fibres cross in the rostral part of the cerebellar commissure and pass dorsal to the superior cerebellar peduncle, to enter the vestibular nuclei from their lateral side. Uncrossed fibres enter the vestibular nuclei through the juxtarestiform body (see Fig. 13.6). The distribution of the fastigial projection is bilateral, but with a contralateral preponderance (see Fig. 13.13). Crossed and uncrossed projections end in the medial and inferior vestibular nuclei. They also cross these nuclei to terminate in the medial reticular formation. Some crossed fibres can be traced caudally into the spinal cord. A small fascicle of crossed fibres from the fastigial nucleus ascends along the superior cerebellar peduncle and is distributed bilaterally to the dorsal tegmentum, central grey matter and deep layers of the superior colliculus and the nuclei of the posterior commissure. Fibres terminate bilaterally in the ventrolateral nucleus and the intralaminar nuclei of the thalamus.

Cerebellovestibular Connections

The relationship between the cerebellum and the vestibular nuclei is complex (see Fig. 13.13). In addition to the vestibulocerebellum (nodule, adjacent folia of the uvula and flocculus), the main vermis and the fastigial nucleus project to the vestibular nuclei. The vestibulocerebellum projects to the superior, medial and inferior vestibular nuclei. Neurones of these nuclei, which receive an input from the vestibular nerve and project to the nuclei controlling eye movements (vestibulo-ocular relay cells), are among the main targets of the Purkinje cells of the nodule and flocculus. Through these connections with vestibulo-ocular relay neurones, the flocculus is involved in the long-term adaptation of compensatory eye movements, the generation of smooth eye movements used to pursue an object and the suppression of the vestibulo-ocular reflex during smooth pursuit. The function of the nodule in the control of eye movement is not as well understood.

The vestibular nuclei are the main source of mossy fibre afferents to the nodule. Their projection to the flocculus is relatively minor. Most mossy fibres that terminate in the flocculus arise from the reticular formation and relay optokinetic and visual information.

The lateral vestibular nucleus, which lacks an input from the labyrinth and receives Purkinje cell axons from the B zone of the anterior vermis, can be regarded as a displaced cerebellar nucleus. It gives rise to the lateral vestibulospinal tract, which descends to all levels of the spinal cord. It is avoided by the efferent pathways from the fastigial nucleus, which terminate more ventrally on large neurones in the magnocellular part of the medial vestibular nucleus and in the medial reticular formation. The medial and inferior vestibular nuclei receive a major input from the vestibular nerve. They give rise to bilaterally ascending and descending tracts, which course in the medial longitudinal fasciculus. The ascending tract is composed predominantly of the axons of vestibulo-ocular relay cells. The descending fibres form the medial vestibulospinal tract, which is particularly involved in head righting reflexes when the trunk is tilted.

Fastigial fibres, which terminate in the reticular formation, stimulate the bilaterally descending medullary reticulospinal tracts. The A zone of the vermis exerts a bilateral influence on ventromedially located spinal interneurones and motor neurones that innervate axial, truncal and proximal limb muscles. Some fibres of the uncinate tract descend as far as the cervical cord, where they terminate on the same motor neurones. The B zone exerts an influence on ipsilateral interneurones and motor neurones of the same system through its projection to the lateral vestibular nucleus and the lateral vestibulospinal tract.

The projections of the fastigial nucleus to the thalamus are relatively minor. They are bilateral, as a result of the recrossing of the crossed ascending fibres of the uncinate fasciculus. Their targets include parts of the ventrolateral nucleus and the intralaminar, centrolateral and parafascicular nuclei. Fibres that terminate in the ventrolateral nucleus lie medial to the terminations of fibres from the dentate and interposed nuclei. This region of the ventrolateral nucleus projects to the upper region of the motor cortex and sends collaterals to the medullary reticular formation, which influences ventromedial interneurones and motor neurones in lumbar and sacral segments of the spinal cord via the medullary reticulospinal tracts.

The caudal region of the fastigial nucleus receives Purkinje cell axons from the folium and tuber, an area of the vermis that receives visual inputs. It projects to the contralateral horizontal gaze centre, or paramedian pontine reticular formation, and to the vertical gaze centre, or rostral interstitial nucleus of the medial longitudinal fascicle, and, bilaterally, to deep layers of the superior colliculus. These projections probably mediate the adaptation of saccades by the vermal visual area.

The cerebellum influences visceromotor systems via the projections of the fastigial nucleus to the parasolitary nucleus (a region bordering the viscerosensory nuclei of the solitary tract), the dorsal visceromotor nucleus of the vagus, the central grey matter, the serotoninergic raphe nuclei of the pons and medulla and the noradrenergic nucleus of the locus coeruleus.

Other pathways from the cerebellar nuclei terminate on precerebellar relay nuclei that give rise to mossy or climbing fibres. Recurrent circuits involving the fastigial nucleus include the nucleus reticularis tegmenti pontis and a projection from the fastigial nucleus to the medial accessory olive. Nucleo-olivary projections arise from all the cerebellar nuclei, are crossed and contain GABA as a neurotransmitter. The connections of the fastigial nucleus with the reticular nuclei are excitatory.

Cerebellar nuclei also project to the contralateral interstitial nucleus (of Darkshevich), which lies at the boundary between the midbrain and the diencephalon. This nucleus projects to the medial accessory olive via the central tegmental tract. The fastigial nucleus controls the climbing fibre output of the medial accessory olive, via both its nucleo-olivary projection and its connection to the nucleus of Darkshevich.

Cerebellorubral and Cerebellothalamic Fibres

The axons of neurones in the dentate and interposed nuclei leave the cerebellum in the superior cerebellar peduncle. The superior peduncles, including their nucleo-olivary component, decussate in the caudal midbrain (see Fig. 13.14). Each peduncle then gives off a small descending branch carrying fibres that terminate in the medial reticular formation of the pons and medulla and the pontine tegmental reticular nucleus (see Fig. 13.14). The nucleo-olivary fibres join this descending branch and terminate in the inferior olive in a strictly orderly manner. The ascending branch is distributed to the midbrain and diencephalon, mainly to the red nucleus and thalamus. The anterior interposed nucleus projects to the magnocellular part of the red nucleus. In humans, this projection is very small, and it gives rise to a relatively trivial rubrospinal tract that crosses in the caudal midbrain and terminates on lateral medullary interneurones and a small number of motor neurones in the upper cervical spinal cord.

The anterior interposed nucleus projects to lateral parts of the ventrolateral nucleus of the thalamus, which are connected with elements of the motor cortex projecting to axial and proximal limb muscles, and to the reticular formation of the pons and medulla. It also projects to the pontine tegmental reticular nucleus and to basal pontine nuclei, both of which give rise to mossy fibres. Its nucleo-olivary efferents terminate in the rostral half of the dorsal accessory olive.

The projections of the posterior interposed nucleus are very similar to those of the fastigial nucleus. The two nuclei share projections to the cord, the superior colliculus, the central grey matter and the raphe nuclei. Nucleo-olivary projections from the globose nucleus and the recurrent globose nucleus–interstitial nucleus–inferior olivary nucleus pathway converge on the rostral half of the medial accessory olive. The thalamic projections overlap those from the fastigial and anterior interposed nuclei.

The dentate nucleus projects to the contralateral parvocellular red nucleus and the thalamus. The central tegmental tract takes its origin from the parvocellular red nucleus and terminates on the principal nucleus of the olive. The thalamic projection to the ventrolateral nucleus overlaps those of the other cerebellar nuclei. The inferior and lateral parts of the dentate nucleus project into the most medial region of the ventrolateral nucleus, which in turn projects to the premotor area of the frontal lobe.

The thalamus receives a massive input from other major motor systems, in addition to the input it receives from the cerebellum. In particular, the output of the basal ganglia is relayed to the thalamus by a projection from the globus pallidus. Available evidence suggests that these two great subcortical motor systems terminate on different regions in the ventral thalamus and project to different targets in the motor and premotor cortex.

Cerebellar Functions

Anticipatory Function

The vermis of the cerebellum is involved in taking anticipatory action to maintain upright posture when objects are picked up. For example, when a book is taken down from a shelf, the first muscle groups to be activated are not the flexors of the shoulder, elbow or fingers but the plantar flexors of the ankle. Contraction of the ankle flexors causes the forefeet to push the lower limbs and trunk backward at the moment the hand grasps the book. Once the lift gets under way, the erector spinae muscles correct for the combined weight of the book and the reaching arm to prevent forward sway of the head and trunk. Labyrinthine receptors simultaneously inform the cerebellum of any forward movement of the head, and appropriate antigravity thrust is exerted via one or both lateral vestibulospinal tracts. Damage to the vermis may cause total loss of the anticipatory function of the trunk musculature, with the result that any reaching movement may cause the patient to fall in the direction of reach (see later). Damage to the anterior lobe may also compromise the anticipatory function, in this case by deterioration or severance of its linkage with the pontine and medullary reticular nuclei, with resultant gait ataxia.

Postural Fixation

The posterolateral region of the cerebellum is required to prevent oscillation of distal limb parts caused by the viscoelastic properties of the muscles in response to sudden movements. If a volunteer is instructed to exert rapid wrist extension and maintain the extended posture for 2 seconds, electromyographic records taken from the prime movers and antagonists reveal that the antagonists begin to contract before completion of the movement and continue to contract and relax several times in alternating fashion with the prime movers, although with much less force, during the measured fixation period. This ‘freeze’ control of the wrist can be disrupted by disease of the contralateral posterior lobe, resulting in an action tremor.

Motor Learning

Experiments with monkeys have shown that when a novel motor skill is being learned, the olivocerebellar climbing fibre system becomes active when errors are made. The inferior olivary complex appears to be involved in correction, based on receipt of a copy of the intended movement from collateral branches of the corticospinal tract. Cerebellar output via the superior cerebellar peduncle is also copied on to the parvocellular red nucleus and projected from there to the inferior olive, where it can be compared with the original. Short bursts of climbing fibre activity depress the Purkinje cells responsible for producing the errors. Most human cerebellar disorders involve the anterior or posterior lobe, or both, or their outflows, causing the monitoring system to be lost and learned movements to become clumsy.

Many motor skills require precise timing, which involves an extreme degree of cooperation between prime movers and their antagonists. For example, reading a printed page requires that the scanning eyes snap back to the beginning of a line, time after time. Even small errors may result in dyslexia, whereby slight incoordination of eye movements causes the letters of a word to appear jumbled. Clinical testing of timing can be performed easily by checking the ability to perform rhythmic movements, such as repetitive pronation–supination (Fig. 13.15).

Fig. 13.15 A and B, Functional magnetic resonance imaging of a volunteer executing repetitive finger movements of the right hand. The arm–trunk areal activity is attributable to a stabilization function.

(Courtesy of Drs. J. P. Finn and T. Parrish, Northwestern University School of Medicine, Chicago.)

Higher Functions

The cerebellum is currently believed to participate in higher brain functions. This is not unexpected, in view of the two-way linkages (via the thalamus) that exist between the cerebellum and the association and paralimbic areas of the cerebral cortex. Its role appears to be one of assistance rather than of generation. For example, during speech, the right posterolateral region of the cerebellum is active bilaterally, which reflects its role in coordinating the muscles involved. However, there is a right-sided predominance, which is consistent with a possible linkage (via the thalamus) with the motor speech area of the left frontal cortex. Moreover, because right lateral cerebellar activity is even greater during functional naming (e.g. ‘dig,’ ‘fly’) than during object identification (e.g. ‘shovel,’ ‘airplane’), cognitive as well as motor functions are compromised by cerebellar disorders.

Cerebellar Dysfunction

Midline Lesions: Truncal Ataxia

Isolated lesions of the vermis are produced in children by medulloblastomas in the roof of the fourth ventricle. In the recumbent position, there may be no abnormality of motor coordination in the limbs, but there is a progressive inability to stand upright without support, a state known as truncal ataxia. These tumours, which are highly sensitive to radiotherapy, attack the pathway from the vermis to the nuclei of the vestibular nerves. The ataxia reflects malfunction of the linkage between the vermis and the lateral vestibular nucleus, which means that the antigravity support normally driven by the lateral vestibulospinal tract is lost or impaired. Nystagmus can be elicited during visual tracking of the examiner’s finger from side to side, reflecting disruption of the labyrinthine connections. Scanning movements of the eye are inaccurate because the vermis no longer controls the gaze centres effectively.

CASE 3 Medulloblastoma

A 4-year-old complains of headache, drowsiness and occasional diplopia; he is unsteady on his feet, with frequent falls. Examination demonstrates truncal ataxia, sometimes accompanied by incoordination of the limbs; variable ophthalmoparesis; and papilloedema on funduscopic examination.

Discussion: Medulloblastoma typically presents with a midline cerebellar syndrome, with hydrocephalus and resultant increased intracranial pressure. Clinically, it can be distinguished from ependymoma involving the fourth ventricle by the early appearance of nausea and vomiting in the latter, due to involvement of the fourth floor of the ventricle, including the area postrema. Cranial nerve palsies may appear with either tumour, and increasing intracranial pressure is typical of both.

The predominance of signs suggesting primary involvement of the vermis distinguishes medulloblastoma from cystic (or solid) astrocytoma of the cerebellum, which typically involves a cerebellar hemisphere rather than the vermis (although midline astrocytomas may cause diagnostic confusion).

Anterior Lobe Lesions: Gait Ataxia

Disease of the anterior lobe is most often observed in chronic alcoholics and presumably results from prolonged thiamine deficiency. Postmortem studies reveal pronounced shrinkage of the cortex of the anterior lobe. There can be losses of up to 10% of granule cells and 20% of Purkinje cells, and a 30% reduction in the thickness of the molecular layer. The principal anatomical effect is atrophy of the connections between the anterior lobe and interposed nuclei and the reticulospinal pathways involved in normal locomotion. Incoordination of the lower limbs leads to a staggering gait and inability to perform heel-to-toe walking.

Tendon reflexes may be depressed in the lower limbs because of the loss of tonic stimulation of fusimotor neurones via the pontine reticulospinal tract. This causes a reduction of monosynaptic reflex activity during walking, which may eventually produce stretching of soft tissues, a phenomenon that can result in hyperextension of the knee joint during standing.

CASE 4 Alcoholic Cerebellar Degeneration

A middle-aged chronic alcoholic experiences a subacutely evolving disorder of gait, with lurching and frequent falling. Examination demonstrates a broad-based ataxic gait and ataxia with the heel–knee–shin test bilaterally. In contrast, there is little or no evidence of cerebellar deficit involving the upper extremities, and the speech is virtually normal. There is no nystagmus. With the exception of signs of a mild polyneuropathy, the remainder of the examination is normal.

Discussion: The clinical features of a subacute evolving ataxia of the gait and of the legs, with good preservation of cerebellar function in the upper extremities and little if any other deficit, is typical of so-called alcoholic cerebellar degeneration occurring on a background of long-standing poor nutritional intake. The relatively restricted clinical syndrome, affecting primarily gait and the lower extremities, is explained by the observed distribution of lesions in the cerebellar cortex, involving predominantly the superior vermis and anterolateral portion of the cerebellar hemispheres—in accordance with known somatotopic localization in the cerebellar cortex (Fig. 13.16). All neurocellular components of the cerebellar cortex may be involved; Purkinje cells are most liable to damage. Secondary changes may be noted in the deep cerebellar nuclei. In some cases, features of Wernicke’s encephalopathy are noted, prompting the suggestion that both disorders reflect a vitamin, perhaps thiamine, deficiency.

Fig. 13.16 Alcoholic cerebellar degeneration. Section through the vermis of the cerebellum demonstrating gross atrophy of the superior vermis, in contrast to preservation of the inferior vermis.

(From Victor, M., Adams, R.D., Mancall, E.L. A restricted form of cerebellar degeneration occurring in alcoholic patients. Arch. Neurol. 1959; 1(6): 579–688. Copyright © 1959 American Medical Association. All rights reserved.)