Activity and connectivity of the cerebellum in trigeminal nociception
Introduction
The functional influence of the cerebellum on pain processing is unknown (Saab and Willis, 2003) but gathers increased interest. In a recent metaanalysis Moulton and colleagues showed that multiple cerebellar areas are commonly activated during nociceptive processing in humans (Moulton et al., 2010) and that some of these areas partly overlap with areas processing other aversive sensory input (Moulton et al., 2011). In 2003 it was demonstrated that the cerebellum might compute intensity rating to thermal painful stimuli (Helmchen et al., 2003). Deeper evidence stems from the study of Ruscheweyh and colleagues (Ruscheweyh et al., 2014), which causally linked cerebellar circumscribed damage due to infarction to more sensitivity for painful stimuli, but also deficient inhibition in response to placebo and offset analgesia. This indicates that the cerebellum holds not just a passive role in pain transmission, or possibly just motor reaction to nociceptive input, but plays an important, yet underestimated, role in pain transmission and even pain perception and control.
Although there is ample evidence that the cerebellum might play a significant role in trigeminal nociceptive pain, such a migraine, surprisingly little research went into disentangling this function. Most functional imaging studies show cerebellar activity in migraine and other headache syndromes (May, 2013, May, 2009), however these findings are at best reported but not discussed (May, 2013, May, 2009). Anatomically, the functional involvement of the cerebellum in migraine is supported by direct connection with the spinal trigeminal nucleus in cats (Carpenter and Hanna, 1961) and rats (Huerta et al., 1983). Nevertheless, little is known about functional consequences or even which specific areas of the cerebellum are involved in trigeminal nociception. The two fractured representations of the homunculus in the anterior and posterior part of the cerebellars' hemispheres (Manni and Petrosini, 2004) are candidates, where trigemino-cerebellar projections should terminate in the represented face areas, while a third representation of the homunculus in the cerebellums vermis is under discussion (Rijntjes et al., 1999) and, thereby, serves as a further candidate of trigeminal nociceptive processing. Furthermore, also other lobules might play an important role such as the posterolateral hemisphere (Crus I, Crus II), where the processing of cognition is presumed (Stoodley and Schmahmann, 2011, Timmann et al., 2010), and where pain might be rated cognitively.
Focusing on the cerebellar role in trigeminal pain processing, we used functional magnetic resonance imaging (fMRI) in a large number of healthy subjects during chemosensory nociceptive stimulation of the left nostril to gain a deeper understanding of the cerebellar's activity, modulation and connectivity in trigeminal pain. We verified our findings using an independent control group.
Section snippets
Subjects and experimental design
Fifty-four healthy volunteers (mean age: 26.0±3.9; 31 females) participated in an experiment on trigeminal nociception following the protocol of Stankewitz et al. (2010). The experiment consists of four conditions, namely 1) the transmission of gaseous ammonia (concentration of 2.5%), which induces a painful, trigeminal sensation, 2) the transmission of rose odor and 3) simple air puffs mixed in an constant dry air flow (74.4 ml/s) into the left nostril, while they were breathing through their
Behavior
The subjects reported the ammonia as intense (mean 63.79, STD 15.05 in the main and mean 69.01, STD 19.68 in the control group on a scale from 0 to 100) and as unpleasant (mean 23.34, STD 8.29 in the main and mean 24.27, STD 20.18 in the control group on scale from −50 to 50, were −50 meant very pleasant and 50 very unpleasant), while the rose odor was rated as less intense (mean 37.50, STD 16.50 in the main and mean 34.27, STD 17.48 in the control group) and more pleasant (mean −5.28, STD
Discussion
Using a large cohort and an additional independent control group our results underline that large parts of the cerebellum are not only specifically activated in pain processing but may also play a significant role in pain perception. Trigeminal nociception is associated with a total activation of more than 5% of the total cerebellar volume in numerous lobuli, even contralateral to the stimulated side including all three representations (anterior as well as posterior hemispheres and the vermis)
Acknowledgment
This work was supported by the European Research Council by the 7th Framework EU-project EuroHeadPain (#602633) and by the German Research Foundation, SFB936/A5 to A.M.
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