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Review
. 2010 Oct 5;65(1):14-27.
doi: 10.1016/j.brainresrev.2010.05.005. Epub 2010 May 27.

The Cerebellum and Pain: Passive Integrator or Active Participator?

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Free PMC article
Review

The Cerebellum and Pain: Passive Integrator or Active Participator?

Eric A Moulton et al. Brain Res Rev. .
Free PMC article

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.

Conflict of interest statement

The authors declare no conflicts of interest regarding the contents of this manuscript.

Figures

Figure 1
Figure 1
Cerebellar Anatomy. A) Location of the cerebellar nuclei beneath the cerebellar cortex, as viewed from the posterior aspect of the human cerebellum. B) Lobular organization of the human cerebellum. C) Magnified view of the microstructural organization of a representative lobule, highlighting the Purkinje cells and the main cerebellar inputs from the inferior olive and pontine nuclei. Figure modified with permission [pending] from (Ramnani, 2006).
Figure 2
Figure 2
Cortical and sub-cortical connectivity to and from the cerebellum. A) Descending afferent input to the primate cerebellum (orange arrow). Cortical (gray box) and sub-cortical areas send neural inputs to the cerebellum through either the pontine nuclei (green) and inferior olive (purple). Descending connectivity based on (Cerminara et al., 2009; Schmahmann, 1996). B) Ascending efferent output from the primate cerebellum (orange arrow). Ascending connectivity based on (Haines and Dietrichs, 1984; Haines et al., 1997; May et al., 1990; Schmahmann, 1996). Abbreviations: dorsolateral prefrontal cortex (DLPFC), frontal eye fields (FEF), inferior parietal lobule (IPL), primary motor cortex (M1), periaqueductal gray (PAG), parahippocampal gyrus (PHG), primary somatosensory cortex (S1), supplementary motor area (SMA), superior parietal lobule (SPL), superior temporal gyrus (STG), superior temporal sulcus (STS), primary visual cortex (V1), zona incerta (ZI).
Figure 3
Figure 3
Cutaneous nociceptive afferents to the cerebellum. A) Spino-pontocerebellar path. Stimulation of C fiber nociceptors activates mossy fibers that project to the cerebellum through an unknown pathway. B) Spino-olivocerebellar path. C fiber nociceptors convey neural input through the post-synaptic dorsal column (PSDC) in the spinal cord to the inferior olive to activate climbing fibers that project to the cerebellum. A-delta fiber nociceptors stimulation activates climbing fibers through an unknown pathway.
Figure 4
Figure 4
Activation estimate likelihood (ALE) meta-analysis of cerebellar activations reported by experimental (n=56 experiments, 195 foci) and pathological pain studies (n=20 experiments, 54 foci). ALE is a quantitative meta-analysis method that statistically evaluates the spatial distribution of activation foci across studies (Turkeltaub et al., 2002). Activation foci from experimental and pathological pain studies (Table 1) were entered as coordinates in Montreal Neurological Institute (MNI) space. Foci originally reported in Talairach coordinates were transformed into MNI space using the “Convert Foci” tool in GingerALE 2.0 (www.brainmap.org/ale/), which considers the analysis software used for spatial normalization in the reporting paper (i.e. FSL/SPM/Other). After MNI transformation, images were oriented such that the side of unilateral pain always occurred on the same side of the image (left). ALE maps were generated using GingerALE (Eickhoff et al., 2009; Laird et al., 2005), with a false discovery rate of p<0.001 and a minimum cluster volume of 150 mm3. ALE maps are displayed on the Colin27 in MNI space via Mango (ric.uthscsa.edu/mango/). The “Cerebellar Atlas” images in the right column show the corresponding slices from the MRI Atlas of the Human Cerebellum (Schmahmann et al., 2000). Experimental and pathological pain both activates vermal lobules IV/V, and bilateral hemispheric lobule VI. Abbreviations: contralateral to pain (C), Crus I (Cr I), ipsilateral to pain (I).
Figure 5
Figure 5
Cerebellar fMRI activation relating to pain, motor, and non-motor functions. A) Noxious thermal stimuli (pain threshold +1°C) applied to the right side of the face in neuropathic pain patients (Borsook et al., 2008) [with permission pending]. Crosshairs indicate approximate location of globose/fastigial deep cerebellar nuclei. B) Brushing of allodynic (painfully sensitive) skin on the right side of the face in neuropathic pain patients (Borsook et al., 2008) [with permission pending]. Crosshairs indicate approximate location of dentate deep cerebellar nucleus. C) Nociceptive leg withdrawal from noxious electrical stimuli applied to the left tibial nerve (Dimitrova et al., 2003) [with permission pending]. Crosshairs indicate approximate location of fastigial deep cerebellar nuclei. D) Anticipation of painful heat (yellow) and application of painful heat to the dorsum of the left hand (red) (Ploghaus et al., 1999) [with permission pending]. E) Observing one’s partner feeling pain (red) and experiencing pain oneself (green) from noxious electrical stimuli applied to the dorsum of the right hand (Singer et al., 2004) [with permission pending]. F) ALE meta-analysis of cerebellar activation elicited by a variety of tasks (Stoodley and Schmahmann, 2009) [with permission pending]. Abbreviations: anterior (A), left (L), posterior (P), right (R).

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