The cerebellum and pain: Passive integrator or active participator?

doi:10.1016/j.brainresrev.2010.05.005

Brain Research Reviews

Volume 65, Issue 1, 5 October 2010, Pages 14-27

https://doi.org/10.1016/j.brainresrev.2010.05.005 Get rights and content

Abstract

The cerebellum is classically considered to be a brain region involved in motor processing, but it has also been implicated in non-motor, and even cognitive, functions. Though previous research suggests that the cerebellum responds to noxious stimuli, its specific role during pain is unclear. Pain is a multidimensional experience that encompasses sensory discriminative, affective motivational, and cognitive evaluative components. Cerebellar involvement during the processing of pain could thus potentially reflect a number of different functional processes. This review will summarize the animal and human research to date that indicates that (1) primary afferents conduct nociceptive (noxious) input to the cerebellum, (2) electrical and pharmacological stimulation of the cerebellum can modulate nociceptive processing, and (3) cerebellar activity occurs during the presence of acute and chronic pain. Possible functional roles for the cerebellum relating to pain will be considered, including perspectives relating to emotion, cognition, and motor control in response to pain.

Introduction

The cerebellum is implicated in several neurological and psychiatric disorders (Gilman, 2000, Schmahmann, 2004). It is involved in a number of integrative functions, including: memory, associative learning, motor control (Ito, 2006, Schmahmann, 1991, Stoodley and Schmahmann, 2009), and more recently in somatosensory processing, including nociception (Saab and Willis, 2003). Nociception represents the neural circuitry that underlies the perception of pain, a multidimensional experience that encompasses sensory discriminative, affective motivational, and cognitive evaluative components (Melzack and Casey, 1968). Though most fMRI studies of pain show activation in the cerebellum (Table 1) (Apkarian et al., 2005, Borsook et al., 2008, Peyron et al., 2000), little is known about the specific role of the cerebellum in nociceptive processing. The purpose of this review is to summarize recent findings that suggest that the cerebellum may have a role in nociceptive processing and in pain. The review will cover a basic overview of the anatomy and connectivity of the cerebellum, the evidence that nociceptive afferents project to the cerebellum, the modulatory effects of cerebellar stimulation on nociceptive processing, how cerebellar activity has been linked to the perception of pain, and what pain-related activation in the cerebellum could functionally reflect.

Section snippets

Overview of cerebellar anatomy

The neural circuitry in the cerebellar cortex has a uniform structure featuring a three-layered sheet (Fig. 1) (Eccles et al., 1967, Palay and Chan-Palay, 1974, Voogd and Glickstein, 1998). Purkinje cells are the largest neurons in the cerebellum in terms of cell body diameter. Their cell bodies are aligned in a single row to make up the Purkinje cell layer in the cerebellar cortex. Purkinje cells are inhibitory and provide the sole neural output from the cerebellar cortex. In terms of gross

Cortical and sub-cortical connectivity to and from the cerebellum

The cerebellum receives massive cortical input through two major relays in the brainstem: the pontine nuclei and the inferior olive (Fig. 2). With the identification of cortical connections to and from the cerebellum, distinctive cerebrocerebellar loops have been discovered that have been proposed to process motor control and cognitive functions (Jissendi et al., 2008, Kelly and Strick, 2003, Middleton and Strick, 2001, Schmahmann, 1996, Schmahmann and Pandya, 1997). Different parts of the

Nociceptive cerebellar afferents

Though neuroanatomical tracers have shown that the cerebellum receives inputs from cutaneous primary afferents (Edgley and Gallimore, 1988, Randic et al., 1981, Snyder et al., 1978), direct evidence that it receives nociceptive afferents comes from electrophysiological studies. These studies suggest that afferent input from nociceptors reach the cerebellum, as stimulation of nociceptors evokes neural activity in the cerebellum (Fig. 3) (Ekerot et al., 1987a, Ekerot et al., 1987b, Hayashi et

Nociception is modulated by cerebellar stimulation

Inferences from electrical and/or pharmacological stimulation of different parts of the cerebellum imply a modulatory role in nociceptive processing (Table 2). Electrical stimulation of the cerebellar lateral nucleus in rats modulates the encoding of noxious stimuli in intralaminar parafasicular neurons in the thalamus (Liu et al., 1993). In squirrel monkeys, electrical stimulation of the intermediate portion of the anterior cerebellar lobe can raise nociceptive thresholds to tail shock (Siegel

Cerebellar activity and the perception of pain

Though pain neuroimaging studies often report cerebellar activation (Fig. 4; Table 1), fMRI has only recently been applied to specifically addressing the nociceptive activity in the cerebellum and its relationship to pain. Helmchen et al., 2003, Helmchen et al., 2004 have identified differential patterns of cerebellar responses to innocuous and noxious thermal stimuli. Evidence suggests that nociceptive-specific activation is processed in the deep cerebellar nuclei, anterior vermis, and

Functional aspects of the cerebellum non-specific to pain

The cerebellum has been correlated with a wide variety of different cortical functional areas (Habas et al., 2009, Krienen and Buckner, 2009, O'Reilly et al., 2009, Stoodley and Schmahmann, 2009, Strick et al., 2009). While the cerebellum appears to activate during the perception of pain, noxious stimuli may activate other processes related to pain, but not necessarily exclusive to it. Since pain itself is a multidimensional experience, other such functional processes that could be elicited

Conclusions

An improved knowledge of the cerebellar function in relation to pain has potential implications for the discovery of new understanding for pain control. Currently, less than a handful of studies have even attempted to discern the function of the cerebellum in regards to pain. Pain does not necessarily have a singular impact on what may be a variety of cerebellar functions, given that pain is a multi-dimensional experience itself. Based on relatively scant evidence, we speculatively propose that

Acknowledgments

This work has been supported by a K01 grant from NIDA to EA (DA25289), a K24 grant from NINDS to DB (NS064050), and the Birmingham foundation and the MINDLink foundation (JDS). The authors declare no conflicts of interest regarding the contents of this manuscript.

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ReviewThe cerebellum and pain: Passive integrator or active participator?

Abstract

Introduction

Section snippets

Overview of cerebellar anatomy

Cortical and sub-cortical connectivity to and from the cerebellum

Nociceptive cerebellar afferents

Nociception is modulated by cerebellar stimulation

Cerebellar activity and the perception of pain

Functional aspects of the cerebellum non-specific to pain

Conclusions

Acknowledgments

Pain

Eur. J. Pain

Neuron

Neuroimage

Pain

Neuroimage

Eur. J. Pain

Neuroimage

Int. Rev. Neurobiol.

Neuroimage

Neuroimage

Pain

Neuroimage

Neuroimage

Prog. Brain Res.

Pain

Pain

Pain

Int. Rev. Neurobiol.

Pain

Neurosci. Lett.

Neurosci. Lett.

Prog. Brain Res.

Pain

Pain

Prog. Neurobiol.

Neuroimage

J. Neuroradiol.

Neuroimage

Pain

Neuroscience

Lancet

Pain

Brain Res.

Trends Neurosci.

Chronic back pain is associated with decreased prefrontal and thalamic gray matter density

J. Neurosci.

Anatomical and physiological foundations of cerebellar information processing

Nat. Rev. Neurosci.

Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study

Magn. Reson. Med.

Trigeminal neuropathic pain alters responses in CNS circuits to mechanical (brush) and thermal (cold and heat) stimuli

J. Neurosci.

Central cancellation of self-produced tickle sensation

Nat. Neurosci.

Comparison of evoked vs. spontaneous tics in a patient with trigeminal neuralgia (tic doloureux)

Mol. Pain

Human cerebellar responses to brush and heat stimuli in healthy and neuropathic pain subjects

Cerebellum

The corticopontine projection in the rhesus monkey

Origin and principles of organization. Brain.

Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain

J. Neurophysiol.

Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography

J. Neurophysiol.

The periaqueductal grey modulates sensory input to the cerebellum: a role in coping behaviour?

Eur. J. Neurosci.

Different brain activation patterns to pain and pain-related unpleasantness during the menstrual cycle

Anesthesiology

Some midbrain and diencephalic projections to the inferior olive in the rat

Pain intensity processing within the human brain: a bilateral, distributed mechanism

J. Neurophysiol.

Hemispheric lateralization of somatosensory processing

J. Neurophysiol.

Review
The cerebellum and pain: Passive integrator or active participator?