Review
The cerebellum: organization, functions and its role in nociception

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Abstract

Our vision of the cerebellum has been gradually transformed throughout the last century from a ‘little brain’ to a ‘neuronal machine’ capable of multitasks, all arguably based on a principle computational model. We review here the main functions of the cerebellum in light of its organization and connectivity. In addition to providing a clear and extensive review of the cerebellar literature, we emphasize the role of the cerebellum in nociception, which is novel to the neurophysiology of pain. However, it is premature to conclude that the cerebellum influences sensory experience in the absence of clinical data.

Introduction

The cerebellum is often referred to as the ‘little brain’ or as a ‘neuronal machine’. Arguably, the ‘little brain’ coordinates many functions of the brain based on the Marr–Albus model [4], [68]. The cerebellum influences mainly motor behavior, eye movement and conditioning [11], [21], [30], [39], [45], [50], [51], [52], [96], [97], [107], [116]. Cerebellar projections are also thought to influence respiration [124], [125], cognition [37], [106], and mediate detection of sensory discrepancy [10] and prediction of sensory events [83], in addition to being involved in autism [95], and schizophrenia [37], [59], [111].

In 1987, Ekerot and colleagues reported that nociceptive stimulation evokes activity in pathways and neurons of the cerebellum. In parallel, many recent imaging studies have confirmed an increased cerebellar activity in humans following peripheral nociceptive stimulation. Based on these and other studies suggesting a cerebellar influence on nociceptive responses, we review here the cerebellar role in nociception and other functions. We first elaborate on the morphology and connectivity of this ‘neuronal machine’ in terms of input pathways and output functions from historical and analytical perspectives. We then bring together recent novel findings linking the cerebellum to nociception within a unified framework of thought largely based on a classical model of learning and plasticity. In the end, however, we caution against assuming a cerebellar influence on pain in the absence of clinical evidence.

Section snippets

Gross anatomy

The gross anatomy of the cerebellum varies across species. In fish for example, the cerebellum consists of a central mass, the corpus cerebelli, and two lateral granular eminences, also known as the auricles in cartilaginous fish [121]. In birds and mammals, the cerebellum is foliated. In birds, the folia radiate from a common center, whereas the folial pattern in mammals is more complicated and interrupted by many transverse fissures. The deep primary and posterolateral fissures divide the

The cerebellar cortex

The morphology of the cerebellum is highly regular and a strikingly economical use of space is achieved by compartmentalization and maximum connectivity. Neurons in the cerebellar cortex are classified into granular, stellate, basket, Golgi, and Purkinje cells (for a review refer to [31]), with the most abundant type being the granule cell [42]. Axons of granule cells are unmyelinated and ascend from the granular to the superficial and relatively cell-poor molecular layer of the cortex where

Motor functions

The midline vermis of the cerebellum and its intermediate parts constitute the spinocerebellum and receive mostly ascending spinal cord information concerning peripheral events. The hemispheres form the cerebrocerebellum. The major input to these parts arises from the cerebral cortex and relays through the pontine nuclei. Motor functions of the cerebellum were earlier supported by detailed lesion studies in humans [30] that do not provide clear evidence for a somatotopic motor control of body

Proprioceptive input

About 20 spinocerebellar paths terminating as mossy or climbing fibers in the anterior lobe have been identified. A comparative study of the neurons of origin of the spinocerebellar afferents in the rat, cat and squirrel monkey was performed by Snyder and colleagues [113]. Among these paths a minority carry information primarily about peripheral events. The best known and, according to Ekerot and colleagues [32], the only convincing examples are the dorsal spinocerebellar tract (DSCT) and its

Cerebellar modulation of nociceptive phenomena

Cerebellar lesions and chemical or electrical stimulation may lead to modulation of nociceptive phenomena. For example, microinjection of morphine into the anterior part of the cerebellum in rats produces profound analgesia [27]. These effects can be reversed with intraperitoneal administration of naloxone as well as by focal electrical stimulation of the anterior part of the cerebellum. In monkeys, elevation of nociceptive thresholds occurs following stimulation of cerebellar areas “associated

Possible model for the cerebellar modulation and coordination of nociception

The cerebellum is a valid model for the study of plasticity and learning that is based on phenomena such as long-term depression (LTD) at a cellular level [31], [55], [61], [87]. According to neuronal network theories, the cerebellum exerts feed-forward control by referring to ‘control error’ signals conveyed through the climbing fibers [4], [68], [55]. Therefore, the inferior olive may be considered as a comparator for errors in performance, whether sensory-motor [35], or cognitive [22]. The

Can the ‘little brain’ control pain?

Pain cannot be defined in physical terms; hence, we often refer to pain in terms of nociceptive phenomena. Clearly, Purkinje cells encode nociceptive information that is subsequently decoded by the deep cerebellar nuclei, the brain stem, and the spinal cord or the brain. When animals are subjected to noxious stimuli under deep anesthesia, it could be argued that the cerebellum is only concerned with coordinating a motor response that is not executed due to the paralytic effects of anesthesia.

Acknowledgements

This work was supported by grants NS 09743 and NS 12255. The authors wish to thank Mrs Lindie Nanninga for her assistance in preparing this manuscript.

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