Phylogenetic and functional aspects can be combined (to an approximation) by dividing the cerebellum into strips, as shown in Figure 25.1. The median strip contains the cortex of the vermis, together with the fastigial nucleus in the white matter close to the nodule (Figure 25.2). This strip is the vestibulocerebellum; it has two-way connections with the vestibular nucleus. It controls the responses of that nucleus to signals from the vestibular labyrinth. The fastigial nucleus also projects to the gaze centers of the brainstem (Ch. 24).

Figure 25.1 Zonation of cerebellum. The central nuclei are represented separately.

Figure 25.2 Transverse section of lower pons and cerebellum showing the position of the central and vestibular nuclei.

A paramedian strip, the spinocerebellum, includes the paravermal cortex and the globose and emboliform nuclei (Figure 25.2). The two nuclei are together called the interposed nucleus. The spinocerebellum is rich in spinocerebellar connections. It is involved in the control of posture and gait.

The remaining, lateral strip is much the largest and takes in the wrinkled dentate nucleus (Figure 25.2). This strip is the pontocerebellum, because it receives a massive input from the contralateral nuclei pontis. It is also called the neocerebellum, because the nuclei pontis convey information from large areas of the cerebral neocortex (phylogenetically the most recent). The neocerebellum is uniquely large in the human brain.

Microscopic Anatomy

The structure of the cerebellar cortex is uniform throughout. From within outward, the cortex comprises granular, piriform, and molecular layers (Figure 25.3).

Figure 25.3 Cerebellar cortex. (A) Cell layers. (B) Afferent systems. (C) Internuncial neurons. (D) Efferent system.

The granular layer contains billions of granule cells, whose somas are only 6–8 µm in diameter. Their short dendrites receive so-called mossy fibers from all sources except the inferior olivary nucleus. Before reaching the cerebellar cortex, the mossy fibers, which are excitatory in nature, give off collateral branches to the central nuclei.

The axons of the granule cells penetrate to the molecular layer where they divide in a T-shaped manner to form parallel fibers. The parallel fibers run parallel to the axes of the folia. They make excitatory contacts with dendrites of Purkinje cells.

The granular layer also contains Golgi cells (see later).

The piriform layer consists of very large Purkinje cells. The fan-shaped dendritic trees of the Purkinje cells are the largest dendritic trees in the entire nervous system. The fans are disposed at right angles to the parallel fibers.

The dendritic trees of Purkinje cells are penetrated by huge numbers of parallel fiber axons of granule cells, each one making successive, one per cell, synapses upon dendritic spines of about 400 Purkinje cells. Not surprisingly, stimulation of small numbers of granule cells by mossy fibers has a merely facilitatory effect upon Purkinje cells. Many thousands of parallel fibers must act simultaneously to bring the membrane potential to firing level.

Each dendritic tree also receives a single climbing fiber from the contralateral inferior olivary nucleus. In stark contrast to the one-per-cell synapses of parallel fibers, the olivocerebellar fiber divides at the Purkinje dendritic branch points and makes thousands of synaptic contacts with dendritic spines. A single threshold pulse applied to one climbing fiber is sufficient to elicit a short burst of action potentials from the client Purkinje cell. Climbing fiber effects on Purkinje cells are so powerful that, for some time after they cease firing, the synaptic effectiveness of bundles of parallel fibers is reduced. In this sense, the Purkinje cells remember that they have been excited by olivocerebellar fibers.

The axons of the Purkinje cells are the only axons to emerge from the cerebellar cortex. Remarkably, they are entirely inhibitory in their effects. Their principal targets are the central nuclei. They give off collateral branches also, mainly to Golgi cells.

The molecular layer is almost entirely taken up with Purkinje dendrites, parallel fibers, supporting neuroglial cells, and blood vessels. However, two sets of inhibitory neurons are also found there, lying in the same plane as the Purkinje cell dendritic trees. Near the cortical surface are small, stellate cells, and close to the piriform layer are larger, basket cells. Both sets are contacted by parallel fibers, and they both synapse on Purkinje cells. The stellate cells synapse upon dendritic shafts whereas the basket cells form a ‘basket’ of synaptic contacts around the soma, as well as forming axo-axonic synapses upon the initial segment of the axon. A single basket cell synapses upon some 250 Purkinje cells.

The final cell type in the cortex is the Golgi cell, whose dendrites are contacted by parallel fibers and whose axons divide extensively before synapsing upon the short dendrites of granule cells. The synaptic ensemble that includes a mossy fiber terminal, granule cell dendrites, and Golgi cell boutons is known as a glomerulus (Figures 25.4, 25.5).

Figure 25.4 A synaptic glomerulus. +/− indicates excitation/inhibition.

Figure 25.5 Ultrastructure of a synaptic glomerulus. The arrows point to six axodendritic synapses between a mossy fiber (MF) and granule cells. GN, nucleus of granule cell.

(Reproduced with permission from Pennese, E. (1994) Neurocytology. Fine Structure of Neurons, Nerve Processes and Neuroglial Cells. New York: Thieme.)

Spatial effects of mossy fiber activity (Figure 25.6)

As already noted, cerebellar afferents other than olivocerebellar ones form mossy fiber terminals after giving off excitatory collaterals to one of the deep nuclei. The afferents excite groups of granule cells, which in turn facilitate many hundreds of Purkinje cells. Along most of the beam of excitation, known as a microzone, the Purkinje cells begin to fire, and to inhibit patches of cells in one of the deep nuclei. At the same time, weakly facilitated Purkinje cells along the edges of the microzone are shut off by stellate and basket cells. As a result, the beam of excitation is sharply focused. The excitation is terminated by Golgi cell inhibition of the granule cells that initiated it. Powerful excitation will last longer because highly active Purkinje cells inhibit underlying Golgi cells through their collateral branches.

Figure 25.6 Scheme of effects of mossy fiber activity.

1 Mossy fiber stimulating a granule cell (Gr).

2 Beam of parallel fiber activity follows simultaneous activation of many granule cells.

3 Activation of on-line Purkinje cells (P1) results in selective inhibition of neurons within the appropriate central cerebellar nucleus.

4 Activation of stellate (S) and basket cells (B) inhibits off-line Purkinje cells (P2).

5 Golgi cells (Go) terminate granule cell activity.

6 Intense on-line activity can be sustained by inhibition of Golgi cells by Purkinje cells.

Representation of Body Parts

Representation of body parts in the human cerebellar cortex is currently under investigation by means of fMRI. These investigations, along with some evidence from clinical cases, indicate the presence of somatotopic maps in the anterior and posterior lobes (Figure 25.7).

Figure 25.7 Upper surface of cerebellum showing position of somatotopic maps, based on animal experiments.

The maps have been worked out in some detail in laboratory animals during movements. The maps for movement match up with maps of skin, eye, ear, and visceral representation worked out by stimulation of body parts. The expression fractionated somatotopy refers to the patchy nature of the representation of body parts. Simple representations like those in Figure 25.7 are likely to be quite inaccurate in view of the vast areas of cortex buried in the fissures.

Figure 25.8, based on PET scans, shows simultaneous activation of the left motor cortex and right cerebellum during repetitive movements of the fingers of the right hand.

Figure 25.8 Representation of fMRI activity (viewed from behind) in a volunteer executing repetitive movement of the fingers of the right hand.

(From a series kindly provided by Professor J. Paul Finn, Director, Magnetic Resonance Research, Department of Radiology, David Geffen School of Medicine at UCLA, California, USA.)

Afferent Pathways

From the muscles and skin of the trunk and limbs, afferent information travels in the posterior spinocerebellar and the cuneocerebellar tract and enters the inferior cerebellar peduncle on the same side. Comparable information from the territory served by the trigeminal nerve enters all three cerebellar peduncles.

Afferents from spinal reflex arcs run in the anterior spinocerebellar tract, which reaches the upper pons before looping into the superior cerebellar peduncle.

Special sense (visual, auditory, vestibular) pathways comprise tectocerebellar fibers entering the superior peduncle from the ipsilateral midbrain colliculi, and vestibulocerebellar fibers from the ipsilateral vestibular nucleus.

Two massive pathways enter from the contralateral brainstem. The pontocerebellar tract enters through the middle peduncle, and the olivocerebellar tract enters through the inferior peduncle.

Reticulocerebellar fibers enter the inferior peduncle from the paramedian and lateral reticular nuclei of the medulla oblongata.

Finally, aminergic fibers enter all three peduncles from noradrenergic and serotonergic cell groups in the brainstem. Under experimental conditions, both kinds of neurons appear to facilitate excitatory transmission in mossy and climbing fiber terminals.

Olivocerebellar tract

The sensorimotor cortex projects, via corticospinal collaterals, in an orderly, somatotopic manner on to the ipsilateral inferior and accessory olivary nuclei. The order is preserved in the olivary projections onto the body maps in the contralateral cerebellar cortex (from principal nucleus to the posterior map, from the accessory nuclei to the anterior map). Under resting conditions in animal experiments, groups of olivary neurons discharge synchronously at 5–10 Hz (impulses/second). The synchrony is probably due to the observed presence of electrical synapses (gap junctions) between dendrites of neighboring neurons. In the cerebellar cortex, the response of Purkinje cells takes the form of complex spikes (multiple action potentials in response to single pulses), because of the spatiotemporal effects of climbing fiber activity along the branches of the dendritic tree.

When a monkey has been trained to perform a motor task, increased discharge of Purkinje cells during task performance takes the form of simple spikes produced by bundles of active parallel fibers. If an unexpected obstacle is introduced into the task (e.g. momentary braking of a lever that the monkey is operating), bursts of complex spikes occur each time the obstacle is encountered. As the animal learns to overcome the obstacle so that the task is completed in the set time, the spike bursts dwindle in number and finally disappear. This is just one of several experimental indicators that the inferior olivary nucleus has a significant teaching function in the acquisition of new motor skills.

The olive receives direct ipsilateral projections from the premotor and motor areas of the cerebral cortex, and from the visual association cortex, providing an apparently suitable substrate for its activities. It is also in touch with the outside world through the spino-olivary tract (Ch. 15).

In theory, the red nucleus of the midbrain could function as a novelty detector because it receives collaterals both from cortical fibers descending to the olive and from cerebellar output fibers ascending to the thalamus. Much of the largest output from the red nucleus is to the ipsilateral olive, which it appears to inhibit. Upon detection of a mismatch between a movement intended and a movement organized, the red nucleus could release the appropriate cell groups in the olive until the two are harmonized.

As mentioned in Chapter 15, motor adaptation is primarily a function of the cerebellum. Here the cerebellum oversees modification of routine motor programs in response to changes in the environment, e.g. walking uphill vs walking on the flat. Experimental evidence indicates that prolonged motor adaptation, e.g. walking over a period of weeks while wearing an ankle plaster cast, is accompanied by long-term potentiation (LTP) of cerebellothalamic synapses, thereby facilitating the influence of the cerebellum on the motor cortex.

Motor sequence learning, for example learning to walk during infancy, is a function of the basal ganglia (Ch. 33).

Efferent Pathways (Figure 25.10)

From the vestibulocerebellum (fastigial nucleus), axons project to the vestibular nuclei of both sides, through the inferior cerebellar peduncle. The contralateral projection crosses over within the cerebellar white matter.

Figure 25.9 Recording from a Purkinje cell dendrite. The complex spike elicited by activation of a climbing fiber has depressed the frequency of the simple spikes elicited by a parallel fiber. LTD, long-term depression.

Motor learning is believed to be achieved by means of a phenomenon called long-term depression. This refers to depression of ongoing parallel fiber activity for up to several hours, following a burst of complex spikes (Figure 25.9). Both neurons concerned are glutamatergic and Purkinje dendrites possess both AMPA and metabotropic receptors. The key molecule in the interaction is the second messenger protein kinase C (PKC), which is activated by parallel fiber activity and mediates protein phosphorylation in ion channels. The molecular sequence is as illustrated in Figure 8.8. Complex spikes are associated with a large increase in intracellular calcium and this interacts with PKC to diminish the postsynaptic response of the AMPA receptors to glutamate stimulation.

Figure 25.10 Principal cerebellar efferents. Arrows indicate directions of impulse conduction.

Vestibulocerebellar outputs to the medial and superior vestibular nuclei control movements of the eyes through the medial longitudinal fasciculus (Chs 17, 23). A separate output to the lateral vestibular nucleus (of Deiters) of the same side controls the balancing function of the vestibulospinal tract. Some Purkinje axons skirt the fastigial nucleus and exert direct tonic inhibition on Deiters’ nucleus.

From the interposed nucleus of the spinocerebellum, axons emerge in the superior cerebellar peduncle. They terminate mainly in the contralateral reticular formation and red nucleus. Those reaching the pontomedullary reticular formation regulate the functions of the reticulospinal tracts in relation to posture and locomotion. Those ascending to the red nucleus may be involved in motor learning.

From the neocerebellum, the massive dentatorubrothalamic tract forms the bulk of the superior cerebellar peduncle. It decussates with its opposite number in the lower midbrain and gives collaterals to the red nucleus before synapsing in the ventral lateral nucleus of the thalamus. The onward projection from the thalamus is to the motor cortex.

Anticipatory Function of the Cerebellum

The cerebellum has a sophisticated function in relation to postural stabilization, and postural fixation, as indicated by the following examples.

Postural stabilization

Figure 25.11 illustrates anticipatory contraction of the gastrocnemius serving to stabilize a trunk about to receive a displacement impetus produced by contraction of the biceps brachii. In more general terms, displacement of the upper trunk away from the center of gravity by a voluntary movement of the head or upper limb is anticipated by the cerebellum. Having read instructions delivered from premotor areas of the frontal lobe (Ch. 29) concerning the intended movement, the cerebellum ensures proportionate contractions of postural muscles in a bottom-up manner, from leg to thigh to trunk, in order to keep the center of gravity in the midline between the feet. Damage to the cerebellar vermis affects normal anticipatory activation, via the lateral vestibulospinal tract, of slow-twitch, close-to-the-bone muscle bundles, with consequent failure to counter the effect of gravity displacement produced by movement of any body part (see Clinical Panel 25.1).

Figure 25.11 Postural stabilization. The subject is pulling a stiff spring attached to the wall. Flexion of the elbow during contraction of biceps brachii tends to pull the trunk forward (arrow). This movement is prevented by equivalent contraction of the gastrocnemius, exerting downward pressure on the forefoot, which tends to thrust the trunk backward (arrow). Simultaneous electromyographic (EMG) recordings show that onset of (automatic) gastrocnemius contraction precedes voluntary biceps contraction by 80 ms.

(Adapted from Nashner.)

Clinical Panel 25.1 Midline lesions: truncal ataxia

Lesions of the vermis occur most often in children, in the form of medulloblastomas in the roof of the fourth ventricle. These tumors expand rapidly and produce signs of raised intracranial pressure: headache, vomiting, drowsiness, papilledema. In the recumbent position there may be no abnormality of motor coordination in the limbs. A dramatic feature is an inability to stand upright without support – a state of truncal ataxia. This tumor, which is highly sensitive to radiotherapy, attacks the pathway from the vermis to the nucleus of the vestibular nerve. The ataxia reflects malfunction of the lateral vestibular nucleus and consequently of the (lateral) vestibulospinal tract. Deficient antigravity function in this uncrossed pathway causes the child to fall to the more affected side on attempting to stand or walk.

Nystagmus can usually be elicited on visual tracking of the examiner’s finger from side to side. Scanning movements of the eyes are also inaccurate owing to poor control of the gaze centers by the vermis.

Damage to the anterior lobe is associated with failure of the reticulospinal tracts to anticipate the gravitational effects produced by locomotion (see Clinical Panel 25.2).

Clinical Panel 25.2 Anterior lobe lesions: gait ataxia

Disease of the anterior lobe is most often observed in chronic alcoholics. Postmortem studies reveal pronounced shrinkage of the cortex of the anterior lobe, with up to 10% loss of granule cells, 20% loss of Purkinje cells, and 30% reduction in the thickness of the molecular layer. The lower limbs are most affected, and a staggering, drunken gait is evident even when the individual is sober. Some degree of correction may be exercised by voluntary control.

Instability of station with the feet together, and failure to ‘toe the line’ on walking, are present even when the eyes are open. A head tremor at 3 Hz is usually present. As the disease progresses, a peripheral sensory neuropathy may be added, giving rise to signs of sensory ataxia (Ch. 15) in addition. Tendon reflexes may be depressed in the lower limbs owing to loss of tonic stimulation of fusimotor neurons via the pontine reticulospinal tract. Consequent reduction of monosynaptic reflex activity during walking may eventually result in stretching of soft tissues, with hyperextension of the knee joint during standing.

Postural fixation

Figure 25.12 illustrates an experiment where the subject was instructed to execute sudden wrist extension and to maintain the extended wrist posture for 2 seconds, while electromyographic records were being taken from prime wrist extensors (extensors carpi radialis longus and brevis) and a prime antagonist (flexor carpi radialis). The readout revealed that the antagonist began to contract prior to completion of the movement, and that it played ‘shivering ping pong’ with the prime mover during the fixation period. The contribution of the antagonist is to prevent spontaneous oscillatory torques (tremors) caused by viscoelastic properties of the muscles. It has been shown that this ‘freeze’ arrangement can be disrupted in healthy volunteers by transcranial electromagnetic stimulation aimed at the superior cerebellar peduncle, and in disease of the lateral cerebellar lobe (see Clinical Panel 25.3).

Figure 25.12 Postural fixation. The subject was instructed to perform sudden wrist extension and to briefly hold the extended posture. Electromyographic recordings show that wrist flexors come into action before completion of the movement. In the ‘hold’ position note alternation of electrical activity between agonist and antagonist. Antagonist EMG activity is much weaker, as indicated by the scale bars on the left.

(Adapted from Topke et al., 1999.)

Clinical Panel 25.3 Neocerebellar lesions: incoordination of voluntary movements

Disease of the neocerebellar cortex, dentate nucleus, or superior cerebellar peduncle leads to incoordination of voluntary movements, particularly in the upper limb. When fine purposive movements are attempted (e.g. grasping a glass, using a key), an intention tremor (action tremor) develops: the hand and forearm quiver as the target is approached owing to faulty agonist/antagonist muscle synergies around the elbow and wrist. The hand may travel past the target (‘overshoot’). Because cerebellar guidance is lost, the normal smooth trajectory of reaching movements may be replaced by stepped flexions, abductions, etc. (’decomposition of movement’).

Rapid alternating movements performed under command, such as pronation/supination, become quite irregular (dysdiadochokinesia). The ‘finger-to-nose’ and ‘heel-to-knee’ tests are performed with equal clumsiness whether the eyes are open or closed – in contrast to performance in posterior column disease, where performance is adequate when the eyes are open (Ch. 15).

Speech is impaired both with regard to phonation and to articulation. Phonation (production of vowel sounds) is uneven and often tremulous owing to loss of smoothness of contraction of the diaphragm and the intercostal muscles. The terms ‘explosive’ and ‘scanning’ have been applied to this feature. Articulation is slurred because of faulty coordination of impulses in the nerves supplying the lips, mandible, tongue, palate, and the infrahyoid muscles.

Signs of neocerebellar disorder sometimes originate in the midbrain or pons rather than in the cerebellum itself. The lesion responsible (usually vascular) interrupts one or other cerebellothalamic pathway (or both, if the lesion is at the decussation of the superior cerebellar peduncles).

Clinical Disorders of the Cerebellum

Diseases involving the cerebellum usually involve more than one lobe and/or more than one of the three sagittal strips. However, characteristic clinical pictures have been described in association with lesions of the vermis (Clinical Panel 25.1), of the anterior lobe (Clinical Panel 25.2), and of the neocerebellum (Clinical Panel 25.3).

The Cerebellum and Higher Brain Functions

PET and fMRI provide information about regional changes in blood flow and oxygen consumption. ‘Movement maps’ such as those in Figure 25.8 are derived from simple repetitive movements such as opening and closing a fist. A striking feature of movement maps is how small and how medial they are. Prior to PET, it was assumed that the lateral expansion of the human posterior lobe was necessary for manual dexterity. It now appears that the lateral expansion may be associated with cognitive functions (e.g. thinking), having an anatomical base in linkages with the lateral prefrontal cortex of the cerebral hemisphere. Lateral cerebellar activity seems to be greatest during speech, with a one-sided predominance consistent with a possible linkage (via the thalamus) with the motor speech area of the dominant frontal cortex (Ch. 30). Something more than mere motor control may be involved, because lateral cerebellar activity is greater during functional naming, e.g. ‘dig’, ‘fly’, than during object identification, e.g. ‘shovel’, ‘airplane’.

Cerebellar cognitive affective syndrome is the summary term recently introduced to indicate cerebral functional deficits that follow sudden severe damage to the cerebellum, e.g. thrombosis of one of the three pairs of cerebellar arteries, or the unavoidable damage inflicted during removal of a cerebellar tumor. Such patients show cognitive defects in the form of diminished reasoning power, inattention, grammatical errors in speech, poor spatial sense, and patchy memory loss. If the vermis is included in the damage, affective (emotional) symptoms appear, sometimes in the form of flatness of affect (dulling of emotional responses), other times in the form of aberrant emotional behavior. The cognitive affective syndrome is temporary, and it is of interest that it may be associated with reduction of blood flow (on PET) in one or more of the association areas linked to the cerebellum by corticopontocerebellar fibers. Recent studies in monkeys have shown that, in addition to its well-known thalamocortical projection to the motor cortex, the cerebellum also ‘drives’ thalamic neurons projecting to association areas serving cognitive and affective functions.