The cerebellum and vestibular system

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14 The cerebellum and vestibular system

Randy W. Beck, Matthew D. Holmes

Introduction

The cerebellum has traditionally been considered as a sensory motor integration centre involved in monitoring and modulating motor function in the spine, head, and limbs. The cerebellum receives afferent input from the spinal cord and sensory receptors via the spinocerebellar tracts as well as from the brainstem and cerebral cortex.

The input and output connections flow through the superior, inferior, and middle cerebellar peduncles which connect the cerebellum to the brainstem. The flocculonodular lobe is involved in the control of posture, eye movement, and certain autonomic responses via its connections with vestibular nuclei. The anterior lobe and posterior parts of the vermis receive input from the axial regions of the body and project to medial descending pathways. The lateral parts of the cerebe-llum and the central vermis are considered the ’neocerebellum’ and are thought to play a role in the planning of movement rather than the execution of movement.

It is now widely accepted that the cerebellum also plays a part in controlling affect, emotion, and cognition, especially the lateral component of the cerebellum, which is referred to as the neocerebellum or cerebrocerebellum.

The prefix ’neo’ indicates that this component of the cerebellum is the newest region to develop in human evolution. It is therefore the most advanced region of the cerebellum and its development parallels the growth of the lateral aspects of the cerebral hemispheres, the association cortices, and those areas associated with advanced communication, higher consciousness, and skilled use of the digits.

It is now clear that the cerebellum and vestibular systems also play a role in the integration of sensory information that is essential for generating appropriate responses to environmental stimuli and for a variety of other functions including constructing a perception of ourselves in the universe; controlling muscle movement; maintaining balance; maintaining internal organ and blood flow functionality; maintaining cortical arousal; and developing active plasticity in neural networks which allows environmental conditioning to occur. The importance of the cerebellum in the overall function of the neuraxis is demonstrated by the fact that there are approximately 20 million corticopontocerebellar fibres projecting between the cerebellum and the cortex, compared to only about 1 million corticospinal fibres supplying the cortical output to the voluntary muscles of the body. The integration function of the cerebellum is evident, as the input-to-output or afferent-to-efferent ratio in the cerebellum is approximately 40:1.

Anatomy of the cerebellum

The cerebellum is composed of an outer covering of grey matter, the cerebellar cortex, the internal white matter, and three pairs of deep cerebellar nuclei arranged on either side of the midline. The deep nuclei are the fastigial, interposed, and the dentate nuclei. The bulk of the output of the cerebellum emerges from these three nuclei.

The cerebellum lies behind the pons and medulla in the posterior cranial fossa (Fig. 14.1). It is separated from the cerebrum by an extension of dura mater, the tentorium cerebelli, and from the pons and medulla by the fourth ventricle (Fig. 14.2). It is somewhat smaller than the cerebrum but this difference varies with age, being 1/8 the size of the adult cortex but only 1/20 the size of the infant cortex.

image

Figure 14.1 The location of the cerebellum. The cerebellum lies behind the pons and medulla in the posterior cranial fossa.

(from Drake et al. 2010. Gray’s Anatomy for Students 2nd edn. Churchill Livingstone, with permission)

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Figure 14.2 The relationship of the cerebellum to the cortex.

(from Drake et al. 2010. Gray’s Anatomy for Students 2nd edn. Churchill Livingstone, with permission)

The cerebellum is derived from the rhombencephalon, along with its homologues the pons and medulla, and is connected to the brainstem via three peduncles. These peduncles, together with the anterior and posterior medullary velum, are the main routes of entry or exit from the cerebellum. The inferior cerebellar peduncle, also known as the restiform body, conveys a number of axon projections into the cerebellum including (Figs 14.3 and 14.4):

The middle cerebellar peduncle or brachium pontis is the largest of the cerebellar peduncles, and contains the massive afferent corticopontocerebellar pathways. The middle peduncle is composed of axon projection fibres from the pontine nuclei to the contralateral cerebellum (Figs 14.3 and 14.4). The primary projections from the cerebral cortex to the cerebellum include premotor and supplementary motor areas (area 6), primary motor areas (area 4), primary sensory areas (areas 3, 1, and 2), and association and limbic cortices.

The superior peduncle or brachium conjunctivum supports both afferent and efferent fibres. The efferent fibres compose the following tracts:

Noradrenergic neurons in the locus ceruleus project to Purkinje dendrites in the molecular layer and with granule cells in the granular layer (Bloom et al. 1971; Kimoto et al. 1981). Dopaminergic fibres arising from the neurons in the ventral mesencephalic tegmentum project to the Purkinje and granule neurons of interposed and lateral cerebellar nuclei (Simon et al. 1979). Serotonergic afferent fibres arise from the raphe nuclei of the brainstem and terminate in both the molecular and granule layers (Takeuchi et al. 1982).

The anterior and posterior medullary velum also supports some decussating fibres of the superior cerebellar peduncles and trochlear nerve. The velum also supports fibres originating in the peduncles of the flocculus.

The cerebellar surface is a striking example of natural economics in that it contains parallel convolutions or folia running in a transverse direction on the surface of the cerebellum that increase the surface area of the cerebellar cortex and give the cerebellum a tree-like appearance (Fig. 14.6). There are three primary lobes, anterior, posterior, and flocculonodular, on the cerebellar surface which are further dived into ten lobules. The cerebellum can be divided into nine regions along the vermis, which is a small unpaired structure in the median portion of the cerebellum separating the two large lateral masses. These nine regions are listed in Table 14.1 from anterior to posterior (see also Fig. 14.7). There are two major fissures that divide the cerebellum into three main lobes, and a number of other fissures that divide each lobe into its respective lobules.

Table 14.1 Lobes and lobules of the cerebellum

Anterior lobe Primary Fissure Posterior lobe Horizontal Fissure   Posterolateral Fissure Nodule Flocculonodular lobe

Embryological development of the cerebellum

Early in the third month of development, the cerebellum appears as a dumbbell-shaped mass on the roof of the hindbrain vesicle. A number of transverse grooves representing the fissures begin to appear on the dorsal surface of the cerebellum. Later in the third month the posterolateral fissure becomes the first landmark to demarcate its adjacent lobes from one another and results in the separation of the flocculonodular lobe from the remainder of the cerebellum.

At the same time, the primary fissure begins to cut into the surface of the cerebellum, separating the anterior from the posterior lobe and other smaller fissures develop on the inferior surface.

The cerebellum expands dorsally and the inferior aspects of the hemispheres undergo the greatest increase in size, causing the inferior vermis to be buried between them, thus forming the vallecula, which is a deep groove on the inferior surface.

From a functional point of view, we need to consider three main regions within the cerebellum. These three regions are derived from the archicerebellum, palaeocerebellum, and neocerebellum, based on their time of appearance through evolutionary history (phylogeny).

The archicerebellum is the first region to appear in phylogeny and comprises the flocculi, their peduncles, the nodulus, and the lingula. The archicerebellum is the oldest and most medial portion of the cerebellum. In humans, archicerebellum contributes to the vestibulocerebellum, which comprises the flocculonodular lobe and the lingula (see Fig. 14.7) (Brodal 1981). As its new name would indicate, the vestibulocerebellum is the region of the cerebellum that communicates most intimately with the vestibular system. In fact, the vestibular nuclei of the brainstem share similar relationships with the cortex of the archicerebellum as the deep cerebellar nuclei share with the cortex of the palaeo- and neocerebellum. They therefore serve functionally as a cerebellar nuclear complex. The vestibulocerebellum also contains the only cerebellar cortical cells that leave the body of the cerebellum before synapsing. In the other regions of the cerebellum, the output cells of the cerebellar cortex synapse on neurons of the deep cerebellar nuclei. The stimuli from these neurons evoke inhibitory postsynaptic potentials (IPSPs) in the deep cerebellar nuclei.

Phylogenically, the palaeocerebellum is next to develop. Apart from the lingula, it comprises the anterior lobe, the pyramid, and uvula of the posterior vermis. This separated the archicerebellum into two parts, the lingula anteriorly and the flocculonodulus posteriorly (Brodal 1981). The palaeocerebellum contributes to the spinocerebellum, which is involved in a variety of parameters associated with movement.

The neocerebellum was the most recent component to arise in phylogeny and comprises the posterior lobes apart from the pyramid and uvula. This developed in parallel with the expansion of the neopallium and neocortex of the brain and the posterior aspects of the thalamus, which reflects the extent of the association cortices of the brain. Both anterior and posterior lobes of the cerebellum have sensory motor maps of the complete body surface, which overlap each other exactly. The neocerebellum contributes to the cerebrocerebellum, which is thought to be involved in a wide range of activities including memory and learning.

The cerebellum was traditionally seen as a sensory motor integration centre involved in monitoring and modulating motor function in the spine, head, and limbs. It is now widely accepted that the cerebellum also plays a part in controlling affect, emotion, and cognition – especially the lateral component of the cerebellum, which is referred to as the neocerebellum or cerebrocerebellum.

The prefix ’neo’ indicates that this component of the cerebellum is the newest region to develop in human evolution. It is therefore the most advanced region of the cerebellum and its development parallels the growth of the lateral aspect of the cerebral hemispheres (the association cortices) and those areas associated with advanced communication, higher consciousness, and skilled use of the digits.

The layers of the cerebellar cortex

The cerebellar cortex is divided into three distinct layers: the molecular, Purkinje, and granule layers. The molecular layer is composed of axons of granule cells, known as parallel fibres, running parallel to long axis of the folia, Purkinje dendrites, basket cell interneurons, and stellate cell interneurons, both of which are inhibitory interneurons. The basket cells have long axons that run perpendicular to parallel fibres and synapse with Purkinje dendrites. They also synapse directly to some Purkinje cell bodies. The basket cells form synapses anterior and posterior to the parallel fibre beams, therefore resulting in inhibition of neighbouring parallel fibres. This is thought to produce a type of centre-surround antagonism. Stellate cells have smaller axons that inhibit local Purkinje cells and synapse on the distal aspect of their dendrites. Both basket cells and stellate cells are excited by parallel fibres.

The next layer, the Purkinje layer, consists of the only output fibres of the cerebellar cortex, the Purkinje cells. The dendrites of Purkinje cells project outwards to the molecular layer. Purkinje cells have recurrent collaterals that inhibit adjacent Purkinje cells and Golgi type II neurons.

The granule layer consists of Golgi neurons and granule cells. Granule cell bodies form the core of the cerebellar glomeruli (they are activated by mossy and climbing fibres) and receive axodendritic synapses from Golgi cells. Golgi cells promote inhibition of up to 10 000 granule cells and are also activated by mossy and climbing fibres in the granule cell layer. This promotes the sharpening of inputs in the cerebellar cortex by suppressing weak excitatory postsynaptic potentials (EPSPs).

The cellular interactions of the cortical cells result in one inhibitory output tract, from Purkinje cells which synapses on the deep cerebellar and vestibular nuclei. There are two main input tracts to the cerebellum, each of which is excitatory. The two input tracts consist of climbing fibres, which are actually the axons of neurons which reside in the contralateral inferior olive, and the mossy fibres, which are axons of neurons of a variety of pontomedullary reticular nuclei and axons of neurons in laminae VI and VII of the spinal cord (Ito 1984). As discussed earlier, aminergic neurons in the brainstem also project to the cerebellum.

The climbing fibres first give off collateral projections to the deep cerebellar nuclei before synapsing on granule, Golgi, basket, and Purkinje cells in the cerebellar cortex (Gilman et al. 1981; Van der Want et al. 1989). Only one synapse per Purkinje cell occurs; however, many Purkinje cells are innervated by a single climbing fibre so that a single climbing fibre spike produces a burst of Purkinje cell activity. The mossy fibres influence the Purkinje activity indirectly via synapses on granule cells. The parallel fibres of the granule cells in turn synapse on the Purkinje cells directly or via basket or stellate interneurons. Each parallel fibre excites a long array of about 500 Purkinje neurons, whereas each Purkinje neuron receives input from approximately 200 000 parallel fibres (Gilman 1992) (Fig. 14.12).

All of the cerebellar neurons of the cortex are inhibitory except the granule cells. The Purkinje inhibitory output is exerted on the spontaneously active nuclear cells. Thus, the nuclear cells must have a strong ’pacemaker’ potential or a powerful excitatory input to match the inhibition resulting from the Purkinje cells. The latter excitatory input may be manifested in excitatory impulses from axon collaterals of mossy and climbing fibres that each give off before synapsing in the cerebellar cortex.

The cerebellum receives information about all commands originating in the motor and association areas of the brain via the climbing fibres of the inferior olive. These olivary neurons also receive input from descending midbrain and telencephalic structures. Climbing fibres detect differences between actual and expected sensory inputs rather than simply monitoring afferent information. Neurons in the inferior olive are electronically coupled through dendrodendritic synapses and therefore can fire in synchrony. The synchronous inputs produce complex spikes in multiple Purkinje cells. In turn, the electrotonic coupling is under efferent control by GABA-ergic fibres from the deep cerebellar nuclei so that they can be functionally disconnected. This results in the selection of specific combinations of Purkinje cells. Climbing fibres modulate synaptic efficacy of parallel fibres by reducing strength of EPSPs of parallel fibres and by inducing selective long-term depression in synaptic strength of parallel fibres active concurrently (within 100–200 ms). Long-term depression depends on prolonged voltage-gated calcium influx.

Damage to the cerebellar cortex or inferior olive leads to inability to adapt. The largest input to the cerebellum is from the contralateral cerebral cortex. This is known as the corticopontocerebellar pathway. There are approximately 20 million neurons in this pathway compared to only 1 million neurons in the corticospinal pathway of the spinal cord.

Functional regions of the cerebellum

The axons of the Purkinje cells project to the deep cerebellar nuclei as well as to the vestibular nuclei. The cerebellum, via these output nuclei, is able to exert descending influences on the spinal cord as well as ascending influences on the cerebral cortex. These outputs can be separated into three components:

The first component originates in the cortex of the vermis and flocculonodular lobes and acts on the fastigial and vestibular nuclei. The fastigial nucleus and its efferent targets, the vestibular nuclei, are often referred to as the vestibulocerebe-llum and are involved in limb extension and muscle tone in the neck and trunk to maintain posture, as well as eye movements. Being the earliest to arise in evolutionary history and embryological development, the vestibulocerebellum serves the most primitive function of the cerebellum. It receives extensive inputs from sensory receptors throughout the head and body that provide us with spatial coordinates for the purpose of spatial orientation and self-awareness.

This includes information from the retina and advanced visual processing systems of the brain, auditory and vestibular neurons including mono- and polysynaptic connections from the inner ear, and muscle and joint receptors particularly from the spine via the vestibular nuclei.

Fastigial efferent fibres can be crossed and uncrossed. The crossed fibres project via the uncinate fasciculus of the superior cerebellar peduncle to the super colliculus bilaterally, and to the interstitial nucleus of Cajal (Ito 1984). Some fibres also project to the ventral lateral and ventral posterior lateral nuclei of the thalamus via the superior cerebellar peduncle. The uncrossed fibres form the fastigiobulbar projections whose bulk forms the smaller juxtarestiform body. These fibres project to all four of the ipsilateral vestibular nuclei and the ipsilateral reticular formation (Batton et al. 1977). The fastigial nuclei fire after the commencement of movement. This nucleus receives large inputs from the periphery and sends few projections to the motor cortex. The fastigial nucleus is involved in the feedback mechanisms of the cerebellum.

The second component originates in the intermediate areas of the cerebellar hemispheres and projects to the interposed nuclei. Some neurons from the interpositus nuclei project through the superior peduncles to synapse on magnocellular neurons of the contralateral red nucleus (Asanuma et al. 1983). The majority, however, synapse on neurons of the contralateral thalamic nuclei of the ventral lateral pars caudalis and ventral posterolateral pars oralis. These thalamic neurons fire almost simultaneously to the primary motor cortex and are involved in efferent copy mechanisms. Efferent copy mechanism compares the intended programme from the cortex to the cerebellum’s knowledge of the state of the organism. Corrections are sent to the brain prior to the movement being carried out. This minimises the time delay in regulating evolving movements in a changing environment.

The inability to carry out a motor programme because of apparent weakness in muscles may in fact be due to a disturbance in midline cerebellar function. An example can illustrate the concept. As an arm or leg is raised or moved away from the body a greater demand is placed on postural mechanisms, which then may fail because of poor reinforcement by medial descending motor pathways from the brainstem and cerebellum.

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