ORIGINAL ARTICLE

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

D. BORSOOK1, E. A. MOULTON1, S. TULLY1, J. D. SCHMAHMANN2 & L. BECERRA1

1PAIN Group, Brain Imaging Center, McLean Hospital, Harvard Medical School, and 2Cerebellar Research Group, Ataxia

Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Massachusetts, USA

AbstractThough human pain imaging studies almost always demonstrate activation in the cerebellum, the role of the cerebellum inpain function is not well understood. Here we present results from two studies on the effects of noxious thermal heat andbrush applied to the right side of the face in a group of healthy subjects (Group I) and a group of patients with neuropathicpain (Group II) who are more sensitive to both thermal and mechanical stimuli. Statistically significant activations andvolumes of activations were defined in the cerebellum. Activated cerebellar structures were identified by colocalization offMRI activation with the ‘MRI Atlas of the Human Cerebellum’. Functional data (obtained using a 3T magnet) weredefined in terms of maximum voxels and volume of activation in the cerebellum. Volume maps were then mapped onto twomillimeter serial slices taken through the cerebellum in order to identify activation within regions defined by the activationvolume. The data indicate that different regions of the cerebellum are involved in acute and chronic pain processing. Heatproduces greater contralateral activation compared with brush, while brush resulted in more ipsilateral/bilateral cerebellaractivation. Further, innocuous brush stimuli in healthy subjects produced decreased cerebellar activation in lobulesconcerned with somatosensory processing. The data also suggest a dichotomy of innocuous stimuli/sensorimotorcerebellum activation versus noxious experience/cognitive/limbic cerebellum activation. These results lead us to proposethat the cerebellum may modulate the emotional and cognitive experience that distinguishes the perception of pain from theappreciation of innocuous sensory stimulation.

Key words: trigemino-cerebellar pathways, chronic pain, allodynia, cerebellar muclei, pain, fMRI, BOLD

Introduction

The cerebellum may have a role in a number of

integrative functions including memory, associative

learning, motor control (1–3), and more recently in

sensory processing including nociception (4). The

structure is traditionally divided into a medial zone

involved in somatic and autonomic reflexes as well as

complex movements; an intermediate zone that is

involved in voluntary movements; and a lateral zone

involved in higher order functions such as memory

and cognitive functions in association with the cortex

including language (5–7). In addition, connections

between the cerebellum and the hypothalamus

suggest a possible role in autonomic function, as

well as a link to limbic structures involved with

emotion (8–10). Thus, the cerebellum appears to be

involved in integrating motor, sensory, autonomic,

and cognitive responses to environmental stimuli

including acute and chronic pain.

Most fMRI studies of pain show activation in the

cerebellum (See Table I) mostly described as either

midline (vermis) or in the cerebellar hemispheres

(11,12). One fMRI report specifically evaluated the

effects of pain in the cerebellum (13). In the latter, a

parametric analysis of the responses to four subject-

applied temperatures, ranging in intensity from

innocuous to painful, suggests that stimulus-inten-

sity could be encoded in the vermis and ipsilateral

hemispheric lobule VI. In addition, a number of

cerebellar areas activated non-discriminately to

different temperatures, including the anterior vermis

(lobules III-V), contralateral lobule VIII, and bilat-

erally in hemispheric lobule III-VI. Here we have

taken separate studies of mechanical and thermal

heat stimuli applied to the region of the right

maxillary division of the trigeminal nerve in a group

of healthy subjects (Moulton et al., submitted) and

in a group of patients with chronic neuropathic pain

(14), and mapped cerebellar activations evoked by

thermal (heat) and mechanical (brush) stimuli.

Cerebellar structures were identified using the atlas

of the cerebellum (15). Although the studies were

separate (14, Moulton et al., submitted), the

Correspondence: David Borsook, MD, PhD, PAIN Group, Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA, USA. E-mail:

dborsook@mclean.harvard.edu

The Cerebellum

2008, –2

ISSN 1473-4222 print/ISSN 1473-4230 online # 200

DOI: 10.10

8 Springer Science + Business Media, LLC

07/s12311-008-0011-6

Online first: 20083 April

252 72

experimental imaging paradigm was similar across

the groups of healthy subjects and patients with a

sensitized pain state (see Methods).

Both data from human and animal studies strongly

implicate the cerebellum in the modulation of pain. In

human studies, for example, transcranial magnetic

stimulation of the cerebellum produces alteration of

sensory thresholds and attenuation of cold pain

sensation (16); functional imaging studies show

cerebellar activation to pain stimuli (see above);

Table I. Functional imaging of cerebellar activation in acute and neuropathic pain studies.

(A) Experimental pain (evoked stimuli).

Paper Method Stimulus Site Dominant activation Ref

Hsieh 1996 PET Ethanol injection R arm I (R) (105)

Casey 1996 PET Thermode L arm B (106)

Cold water bath L hand B

Svensson 1997 PET Laser L arm I (L) (107)

Electric L arm I (L)

Xu 1997 PET Laser L hand I (L) (108)

Derbyshire 1998 PET Hot water bath R hand I (R) (109)

Iadarola 1998 PET Capsaicin injection L arm B (110)

May 1998 PET Capsaicin injection R forehead B (111)

Paulson 1998 PET Thermode L arm I (L – males) (112)

B (females)

Becerra 1999 fMRI Thermode L hand B (113)

Coghill 1999 PET Thermode R arm B (114)

Peyron 1999 PET Thermode R/L hand B (115)

Becerra 2001 fMRI Thermode L hand B (116)

Casey 2001 PET Thermode L arm B (117)

Coghill 2001 PET Thermode R/L arm I (118)

Bingel 2002 fMRI Laser R/L hand B (119)

Derbyshire 2002 PET Thermode R hand B (120)

Helmchen 2003 fMRI Thermode R hand B (121)

Koyama 2003 fMRI Thermode R calf B (122)

Strigo 2003 fMRI Thermode Esophagus B (123)

Upper chest B

Helmchen 2004 fMRI Thermode R hand I (R) (13)

Ibinson 2004 fMRI Electric R arm I (R) (124)

Wager 2004 fMRI Electric R wrist I (R) (125)

Thermode L arm I (L)

Wiech 2005 fMRI Thermode L arm C (R) (126)

Albuquerque 2006 fMRI Thermode R masseter I (R) (127)

Choi 2006 fMRI Hot water bath L finger C (R) (33)

Kong 2006 fMRI Thermode R arm B (128)

Seminowicz 2006 fMRI Electric L arm C (R) (129)

Staud 2006 fMRI Thermode R foot I (R) (62)

B, bilateral; I, ipsilateral; C, contralateral; (L), left; (R), right.

(B) Studies on cognitive processes affecting pain-related activation.

Paper Method Cognitive process Stimulus Site Effect Ref

Ploghaus 1999 fMRI Anticipation Before heat pain L hand I (L) + (96)

Bantick 2002 fMRI Distraction During heat pain L hand B 2 (130)

Brooks 2002 fMRI Attention During heat pain R hand B + (131)

Distraction During heat pain R hand I (R) +Attention During heat pain L hand I (L) +Distraction During heat pain L hand none

Smith 2002 fMRI Anticipation Before heat pain L hand B + (132)

Gracely 2004 fMRI Catastrophizing During pressure pain L finger I (L) + (83)

Singer 2004 fMRI Empathy Partner in pain (Visual) B + (18)

Wager 2004 fMRI Placebo During heat pain L arm I 2 (125)

Jackson 2005 fMRI Empathy Pain-related pictures (Visual) B + (17)

Wiech 2005 fMRI Distraction During heat pain L arm B 2 (126)

Keltner 2006 fMRI Expectation During heat pain L hand I (L) + (85)

Moriguchi 2006 fMRI Empathy Pain-related pictures (Visual) R + (133)

Ogino 2006 fMRI Imagination Pain-related pictures (Visual) L + (84)

Seminowicz 2006 fMRI Distraction During electric pain L arm C (R) 2 (129)

B, bilateral; I, ipsilateral; (L), left; (R), right; +, increased activation; 2, decreased activation.

253Pain and the cerebellum

empathetic pain also produces similar cerebellar

activation (17,18); and studies of patients with

cerebellar damage impairs detection of somatosen-

sory input changes (19). Animal studies indicate that

cerebellar activation may be modulated by peripheral

afferent sensory inputs (20,21) including pain (22).

The trigeminal system has specific direct or collateral

inputs into the cerebellum (23–26). For example, in

rabbits, the paramedian lobule and the uvula receive

independent trigeminal sensory information from

neurons located in separate regions of the trigeminal

sensory nucleus (23; see Discussion – Trigemino-

cerebellar connections). Deafferentation of the infra-

obital branch of the trigeminal nerve has been

reported to result in reorganization of regions of the

cerebellum including Crus IIa (27). One report

suggests that C-fibers (that are activated by a number

of noxious stimuli including heat), may reach the

cerebellar Purkinje cells through climbing and mossy

fibers (28). Taken together, such clinical and

preclinical data suggest that there are direct and

indirect pathways from sensory systems, including the

trigeminal system, to the cerebellum. The salience of

trigeminal sensory input from the face is not known

but may be interpreted as being important in

orienting the face to protective motor planning (for

example, the blink reflex, nocifensive response to

pain, facial movements). Such processing of sensory

signals may be important in motor planning and

execution (see 29) in which the cerebellum may play

an integrative role. Given that the cerebellum may be

important in modulating sensory stimuli and a motor

response to such stimuli (30), the evaluation of

specific cerebellar functional activity in different

anatomical regions in response to noxious and non-

noxious stimuli in humans may provide insights into

how this structure may integrate or modulate this type

of information.

Methods

Data was obtained from two experiments using a

trigeminal model of pain (for a review, see 31). The

overall approach is shown in Figure 1. In our model,

pain was applied to the right side of the face in the

territory of the second division of the trigeminal

nerve (V2). The two experiments examined: (Group

I) acute noxious thermal pain in healthy subjects

(32), and (Group II) stimuli applied to the same

region of the face in patients with neuropathic pain

(14) affecting the second division of the trigeminal

nerve. All studies were thus similar or identical in the

following aspects – stimulation sites (second division

of the trigeminal nerve, V2); use of the same 3T

scanner; identical equipment for stimulation

(1.661.6 mm thermal contact probe/Peltier;

brush); and all experiments were performed by the

same research team at the same location. The

research protocols were approved by the institutional

IRB and all pain paradigms were conducted in

accordance with the Declaration of Helsinki.

Subjects

All subjects underwent a clinical review of systems

and urine screens for recreational drugs including

phencyclidine, barbiturates, tetra-hydrocannabinol,

opiates, benzodiazepines, amphetamines, and

cocaine. (Cortez Diagnostics 7 Drug RapidDip

INsta-scan). Subjects who were healthy and tested

negative for the drug screens were recruited to the

study. Two groups of subjects were recruited to two

separate studies.

Group I: 12 healthy volunteers (9 men and 3

women), with an average age of 27¡10 years, were

recruited for a study on facial cortical somatotopy

through advertisements circulated in the Boston

metropolitan area. Subjects were imaged once

(Moulton et al., in preparation).

Group II: For details see (14). Only brush and heat

stimuli to the affected side are reported here. Briefly,

6 subjects with right-sided neuropathic pain (1 man

and 5 women), with an average age of 49¡8 years,

were recruited to the study (see Table A). Subjects

were recruited through advertisements placed in the

local newspaper or at physicians’ offices (details are

(C) Neuropathic pain (Evoked stimuli).

Paper Method Pathology Stimulation

Dominant

activation Ref

Derbyshire 2002 PET Back pain Heat pain/R hand B (120)

Albuquerque 2006 fMRI Burning mouth Heat hyperalgesia/R face B (127)

Becerra 2006 fMRI Neuropathy Cold allodynia/R face B (14)

Brush allodynia/R face B

Heat hyperalgesia/R face B

Ducreux 2006 fMRI Syringomyelia Cold allodynia/affected hand I (134)

Schweinhardt 2006 fMRI Neuropathy Brush allodynia/Varied B (135)

Witting 2006 PET Neuropathy Brush allodynia/Varied I (136)

Geha 2007 fMRI Post-herpetic Spontaneous pain/Varied

Neuralgia

(L) (137)

B, bilateral; I, ipsilateral, (L), left.

254 D. Borsook et al.

provided in a published report, 14). Pain was rated

on a visual analogue scale (VAS; see methods). The

average spontaneous pain rating was 7.7¡0.6

(mean¡SEM), and the reported prior history of

pain evoked by stimuli (e.g., touching the area,

clothing etc) was 7.2¡0.42 years. Subjects were

imaged twice, with the second session coming 2–6

months after their first imaging session. Subjects

attended a screening session where a full medical

examination, medical history, and compliance with

inclusion/exclusion criteria were performed before

enrollment into the study. Medications were dis-

continued for one dosing interval. Note that most of

the subjects were women, and all premenopausal

women were scanned during their mid-follicular

phase (days 5–7) of their menstrual cycle, since

studies suggest that the variation in pain sensitivity

across the menstrual phase is lowest at this time (33)

and more consistent with responses in men.

Experimental paradigm

The experimental paradigm for data acquisition was

similar in each group. In addition, the tools used to

apply stimuli to the face were identical, and the

timing of the application of the brush and thermal

stimuli in both groups was similar. Temperatures

applied were different for Group I (46˚C) and Group

II (threshold-based; see below).

Group I: The experimental paradigm consisted of

one MR scanning visit. Anatomical scans were

collected, followed by separate functional scans for

heat (46˚C) and brush applied to the right V2 area of

the face.

Figure 1. Top: Summary table of the two groups. Bottom: Summary of data acquisition and anatomical mapping.

Table A. Clinical data on patients with trigeminal neuropathic pain.*

Subject Age Gender Affected side Origin of pain Diagnosis Pain medications

1 54 F Right V2 Following Antibiotic Rx Idiopathic facial

Neuropathy

None

2 39 F Right V2 Car accident Post traumatic Tylenol

Facial neuropathy

3 57 F Right Vi/V2/V3 Herpes Zoster Post-herpetic Neurontin

Neuralgia

4 48 F Right V1/V2 Ski accident Post traumatic Buproprion

Facial neuropathy Setraline

Tylenol #3

5 54 M Right V2 Herpes Zoster Post-herpetic None

6 41 F Right V2/V3 Car accident Post traumatic Vicodin

Paroxetine

Clonazepam

*Adapted from our previous study (14).

255Pain and the cerebellum

Group II: The experimental paradigm comprised

of two MR scanning visits, with the second visit

occurring 2–3 months after the first. For each visit,

anatomical scans were collected, followed by func-

tional scans of sensory stimulation to the face. The

sensory stimulation included heat and brush stimuli,

presented in separate blocks. During the functional

scans, sensory stimulation was applied to either the

maxillary division of the trigeminal nerve of the pain-

affected facial location (V2A), or the mirror location

on the unaffected contralateral side (V2U).

Stimuli.

Mechanical stimulation. Brush stimuli, applied by a

Velcro-topped (soft side) stick, were administered at

1–2 Hz (1–2 strokes per second) within the V2 area.

Brush stimuli were applied to the face using a lever

system attached to a wooden frame overlying the MRI

headcoil. Plastic/nylon materials allowed us to brush

the face while standing at the feet of the subject. Thus,

there was no manual reaching into the head coil, and

all movement occurred inferior to the location of the

brain. In Group I, stimuli were applied 3 times, each

for a period of 16 sec separated by 30 sec of no

stimulus. In Group II, stimuli were also applied 3

times, each for 25 sec and 30 sec of rest.

Thermal stimulation. An FDA approved Thermal

Sensory Analyzer (TSA, MEDOC, Haifa, Israel)

was used to deliver heat stimuli through a probe that

has been adapted to rest on the face. The peltier

probe is 1.661.6 cm, or about half the size of the

thumb. Temperatures applied to the V2 area were

different for Group I (46˚C) and II (V2A pain

threshold +1˚C). For both groups, the thermode was

heated at a rate of 4˚C/sec to the target temperature,

which was maintained for 15 sec. The temperature

returned to the baseline at a rate of 4˚C/sec to end

the stimulus event. The inter-stimulus interval was

30 sec, with 3 total stimulus events. For each group,

thermal stimuli were applied using the same timing

as described for the brush. The approach for thermal

stimulation of the face in the magnet has been used

by our group (14,31,32,34) and also recently by

others (35).

Stimulation of the face in the scanner. Prior to stimuli

administration, the right V2 areas of the face to be

stimulated (Group I applied to normal skin; Group

II applied to painful/neuropathic skin) were marked

with a water-soluble pen. A specially designed

module that allowed for placement of thermal

probes and the ability to apply brush stimuli to the

specific regions was used. While in the scanner, the

subjects were told to rate the intensity of stimulus-

evoked pain using an online visual analog scale

(VAS) from ‘No pain’ to ‘Max pain’, a method we

have previously described (36).

Ratings in the scanner. For online ratings of the VAS,

subjects used a dial that could be easily rotated

between index finger and thumb. An onscreen bar was

presented which had ‘no pain’ at one end and ‘max

pain’ at the other. By rotating the dial, a cursor could

be moved along the bar. During a stimulus, subjects

used their left hand to rate their pain. Thus, subjects

rated pain using their hand opposite to the side of the

face that was stimulated, so as to potentially segregate

activity due to sensory vs. motor events.

Imaging parameters

Imaging was carried out in a 3.0 T Siemens Trio

scanner. For anatomical localization, an MPRAGE

was used (16161.6 mm resolution). For Group I,

each functional scan consisted of 33 slices (3.5 mm

isotropic resolution) coronally oriented to match the

brainstem axis and covering the middle region of the

cerebrum. Functional images were acquired in Group

I using Gradient Echo (GE) echo planar imaging

(EPI) sequence with TR/TE52.5s/30 ms, for a total

of 74 volumes per functional scan. For Group II,

functional scans were acquired using a GE EPI

sequence with isotropic resolution of 3.5 mm, 41

slices (no-gaps) were prescribed obliquely perpendi-

cular to the AC-PC axis, a TR/TE52.5 s/30 ms was

used and 128 volumes were acquired per functional

scan. For both groups field map images were acquired

with the same prescription as for the functional

images. These images were then used to correct for

susceptibility-induced distortions in functional scans.

Note that in the case of healthy subjects the whole

cerebellum was scanned, but for the patients approxi-

mately 2/3 of the cerebellum was scanned, with the

posterior component not included (Figure 2). Due to

a limitation of the phase array coil to acquire more

slices (i.e., 41 instead of 33) within the same TR,

approximately 2/3 of the patients (Group II) cerebel-

lum was scanned wit the posterior component not

included (14). Group I had enough coverage with 41

slices to scan the whole cerebellum.

Data analysis

The image analysis package fsl 3.2 (FMRIB,

University of Oxford, UK; www.fmrib.ox.ac.uk/fsl)

and in-house programs implemented via MATLAB

(Release 7.2, Mathworks Inc., Natick, MA, USA)

were used for data processing. For both groups, head

motion correction, spatial smoothing (Group I:

6 mm Gaussian kernal; Group II: 5 mm), and pre-

whitening was performed using fsl tools. For Group

I, a high-pass filter of 75 sec was also used. The

general linear model (GLM) was utilized (fsl) for

individual subject statistical analysis. For Groups I

and II a contrast explanatory variable was con-

structed comparing periods of stimulation with

resting periods based on the temperature or brush

256 D. Borsook et al.

stroking temporal profiles (14, Moulton et al., in

preparation). For Group I, a mixed-effect analysis

was performed using fsl after transformation of

individual results to a standard brain (MNI

Standard Brain). For Group II, we combined all

subjects and both visits to report aggregate results

using a fixed effects approach. For both groups,

thresholds were determined from a partition of the

statistical map distribution utilizing a gaussian

mixture model approach (37). This approach

determines statistical thresholds from a partition of

the statistical map distribution by deconstructing the

overall statistical map into several optimized

Gaussian distributions. The group activation map

(zstat image) obtained from standard statistical

analysis is further classified using a generalized

mixture model approach (37). The classification

scheme produces a series of classes (active, deactive,

belonging to the null distribution). Each voxel has a

probability to be in a particular class. Each class (or

the others) has a corresponding map in which each

voxel depicts the probability that it belongs to its

class. Thresholding the activation class map with

pw0.5 (standard in classification schemes) allow us

Figure 2. Masks defined from functional scans used for cerebellar activation for Group I – Healthy Controls (Top) and Group II – Patients

(Bottom). MNI coordinates were adjusted to match the cerebellar atlas (15) – see text.

257Pain and the cerebellum

to determine a mask for which voxels can be

considered active. The mask is then applied to the

original zstat image.

In order to align fMRI images with the atlas, fMRI

images were transformed. The transformation con-

sisted of flipping the x-coordinate (atlas is in

neurological convention while fMRI images are in

radiological convention). Furthermore, fMRI data

was rendered over a 26262 mm3 template while

the atlas was on a 16161 mm3 atlas. The most

superior and inferior axial MRI images of the

cerebellum were matched with the atlas and labeled

accordingly in Figures 2–6 with the actual coordi-

nates in MNI space.

Anatomical evaluation of cerebellar activations

To measure regions activated in the cerebellum, we

first evaluated zmax and the volume of activations.

These measures were mapped using an automated

approach to identify regions activated (38). Once

zmax and volumes of activation were recorded, co-

ordinates of zmax were transformed onto the cere-

bellum atlas (15). This was necessary because the

MNI standard does not correspond precisely to the

Talairach-based cerebellum atlas. Cerebellar activa-

tions were then determined using the following

approach: activations were grouped into the following

domains: Vermis, Hemisphere, and Cerebellar nuclei

(dentate, eboliform, globose, and fastigial) as defined

in the Atlas (15). Vermal and hemisphere activations

were defined in the horizontal plane by examination of

the identical slice with the Atlas, which displays

specific coordinates in mm (Figure 3). To identify

activations of the nuclei, significant activations were

evaluated relative to the Atlas in the horizontal,

coronal, and sagittal planes (Figure A).

In this report, we use ‘cluster’ to refer to a group

of activated voxels that by statistical and spatial

extension can be considered as a single focus of

activation. A cluster is recorded in terms of peak

activation coordinates and its volume. If a cluster’s

Figure 3. Cerebellar vermal and hemisphere activations. Top: Serial sections with number indicating z axis as taken from the Atlas of

Schmahmann et al. Bottom: Mapping activations using MRI Atlas of Human Cerebellum (15). In this case the figure shows horizontal slice

251 from the atlas and the funtional activations mapped onto the same horizontal anatomical section acquired in the study. Note that the

numbers for the functional maps represent n-1 to match the cerebellar atlas cordinates. See text.

258 D. Borsook et al.

volume of activation encompassed any of the regions

within the cerebellum (i.e., lobule, vermis, or

nucleus), that region was considered active within

that cluster. We also include cerebellar structures

encompassed within the extension of each cluster in

a specific region (lobule, vermis or nucleus).

Common activations for healthy vs. neuropathic

The main focus of this report is to localize specific

activation in the cerebellum to thermal and mechanical

stimuli in these two groups, performed in separate

studies. Although not an optimal comparison due to

confounding issues (viz., un-matched controls for age,

gender, pain level, disease state, and medications) we

compared thermal and mechanical stimuli for the

‘neuropathic state’ vs. the ‘healthy state’. To identify

common activations for brush and for heat for Group I

and Group II, overlapping maps were created.

Since subjects rated pain intensity using the hand

opposite to the side of the face that was stimulated,

activity in the cerebellum may also be observed due

Figure 4. Activations for heat and brush – Group I. Circles mark activation within nuclei. MNI coordinates were adjusted to match the

cerebellar atlas (15) – see text.

259Pain and the cerebellum

to the motor input. The left hand was used to rate

both brush and heat. In order to evaluate the

potential contribution of the motor task, we eval-

uated overlapping areas of activation in the cerebel-

lum in each group separately.

Results

The results are presented as activations for heat and

brush in healthy subjects and in patients with

neuropathic pain (sensitized state; see 14).

Group I: Healthy subjects

Psychophysical ratings. During the functional scan,

heat to V2 produced significantly greater pain

intensity ratings than the near zero values

recorded for brush (paired-t-test t(11)53.72,

pv0.01). The mean (¡SE) pain intensity

ratings for brush were 0.04¡0.04, while the

ratings for heat were 2.59¡0.69. Only one subject

reported pain with brushing, with his average rating

being 0.5.

Figure 5. Activations for heat – Group II. MNI coordinates were adjusted to match the cerebellar atlas (15) – see text.

260 D. Borsook et al.

Activation by heat and brush. Figure 4 shows serial

sections (2 mm thick) through the cerebellum

matching to the horizontal (z) axis of the cerebellar

atlas (15) showing activation following heat

(Figure 4 – top) or brush (Figure 4 – bottom)

stimulation. Based on the data, tables of activation

clusters (for max voxel, volume, coordinates for each

max volume) were created. Table IIA shows

activations following noxious heat. A total of 6

clusters met the criteria for significance (see

Methods). For increased signal, 2 clusters

contralateral to the stimulus and 2 clusters

ipsilateral were significant. For the larger volumes

activated (cerebellum_6_R545.92 cm3 or

cerebellum_6_L51.30 cm3) more than one

cerebellar region was observed within each cluster.

Two clusters showed significantly decreased

activation (Table IIB). For both increased and

decreased signal, activation was found in the

cerebellar hemispheres (n58) or dentate nucleus

(n52). A total of 5 right-sided (5 increased)

activations and 5 left-sided activations (3

Figure 6. Commonly activated areas for heat and brush for healthy subjects and neuropathic patients. MNI coordinates were adjusted to

match the cerebellar atlas (15) – see text.

261Pain and the cerebellum

Figure A. Method for evaluating cerebellar nuclei activations. Top: The location of the cerebellar nuclei within the x, y and z planes

(coordinates with atlas limits) defined by the Atlas (Schmahmann et al., 2004). D, dentate nucleus, E, emboliform nucleus; F, fastigial

nucleus; and G, globose nucleus. Bottom: Two examples of evaluating activation in nuclei by examination of activation in the x,y and z

planes. In both examples the activation maps are mapped onto the MRI and anatomical sections from the Atlas of Schmahmann et al. (15).

262 D. Borsook et al.

increased, 2 decreased) were observed in specific

cerebellar regions.

Following brush applied to the right side of the

face, two clusters were observed for both increased

(Table IIIA) and decreased (Table IIIB) activation.

One cluster for decreased signal change

(Cerebelum_4_5_L) was large (volume 37.4 cm3)

and encompassed 6 cerebellar regions. For brush,

activation was predominantly bilateral in cerebellar

regions as noted in Table IIIB. Figure 4 (bottom)

shows increased and decreased signal activation

following brush through 2 mm serial slices in the

cerebellum. A total of 12 activations were observed

in the cerebellar hemisphere regions and 2 in the

cerebellar nuclei (the latter only for decreased

signal).

On closer inspection of Figure 4, heat produces

more activation in vermal lobules V and VI

compared with brush (region IX). Activations in

the cerebellar hemispheres were widely distributed.

Of note, decreased activations were observed for

brush in region IV and for heat in lobule V, in both

cases in the right hemisphere. Some differences in

the lamina activated included VIIIA where noxious

heat activated seemed to produce greater activation.

Group II: Neuropathic pain patients

Psychophysical ratings. As reported in Becerra et al.

(14), the average spontaneous pain rating of the

affected area was 7.7¡0.6 (mean¡SEM), and the

reported prior history of pain evoked by stimuli (e.g.,

Table II. Healthy subjects (heat).

(A) Increased signal change.

Cluster

Cerebellar

regions

Vox Vol

cluster

zstat max

cluster

Coordinates zmax

x y z

Cerebellum_6_R VIIB_R 5.92 4.2898 18 254 228

CrII_R

Dentate_R

VI_R

Cerebellum_7b_R VIIB_R 0.26 3.3082 6 274 244

Cerebellum_6_L CRII_L 1.30 3.7647 222 262 234

Dentate_L

Cerebellum_Crus2_L CRII_L 0.20 3.3097 230 272 240

(B) Decreased signal change.

Cluster

Cerebellar

regions

Vox Vol

cluster

zstat max

cluster

Coordinates zmax

x y z

Cerebellum_IV_L IV_L 0.92 3.1881 222 238 218

Cerebellum_6_L VI_L 0.37 2.8163 228 244 228

Table III. Healthy subjects (brush).

(A) Increased signal change.

Cluster

Cerebellar

regions

Volume

(cm3)

zstat max

cluster

Coordinates zmax

x y z

Cerebellum_8_R VIIIB_R 0.24 3.0868 18 274 256

Cerebellum_6_L VI_L 0.38 3.2978 222 268 228

(B) Decreased signal change – brush.

Cluster

Cerebellar

regions

Volume

(cm3)

zstat max

cluster

Coordinates zmax

x y Z

Cerebellum_4_5_L VIIIB_R/L 37.4 4.75 210 242 216

IX_R/L

Dentate_R/L

VI_R/L

V_R/L

IV_R/L

Vermis_8 VIIIA 0.22 2.623 0 266 236

263Pain and the cerebellum

touching the area, clothing etc) was 7.2¡0.42.

Subjects heat pain threshold (measured prior to

scanning was 37.7¡0.6 (scan 1) and 39.2¡0.5˚C(scan 2) – indicating that this was below the normal

range of around 43˚C. During the scanning the

subjects online VAS reporting of pain for brush and

heat were 4.0¡0.77 and 5.8¡0.79 respectively.

Activation by heat and brush. Figure 5 shows

increased (red) and decreased (blue) activation

through sequential 2 mm horizontal sections of the

cerebellum following heat (Figure 5 – top) and for

brush (Figure 5 – bottom) applied to the right V2

division of the face. Table IVA shows increased

signal change for clusters in the cerebellum following

heat applied to the affected areas on the right side of

the face in patients with neuropathic pain. Only one

area showed decreased signal (Table IVB). For all

activations, regions that met levels of significance for

increased activation were mostly contralateral (n511

vs. ipsilateral n55) to the stimulus. Activation was

predominantly in the cerebellar hemispheres. The

dentate nucleus was activated bilaterally.

Brush applied to the affected region of the face in

the neuropathic patients produced the most activa-

tions (21 clusters; 36 regions) for increased and

decreased signal change (Tables VA and VB). Many

of the clusters had voxel volumes of w100 (see

Table VA). Most of these were ipsilateral or in the

vermis (n527 regions) which contrasted to the heat

stimulus in these patients.

Comparing Group I and Group II

The comparison really reflects differences between

mild pain (Group I) and more significant pain

(Group II) as a result of allodynia. Figure 6 shows

activations in serial 2 mm sections through the

cerebellum, common to heat (Figure 6 – top) or

brush (Figure 6 – bottom) for healthy and neuro-

pathic patients. As can be seen from the figure, there

are only 2–3 activations that overlap. There was

overlap in activation in number of cerebellar regions

following heat including lobule VI (L[eft]/R[ight]);

lobule V (L/R); lobule Crus I (CrI) (L). In the case

of brush, common activations were observed in

lobule VI (L/R), a small activation in lobule IX, and

lobule CrI (L/R). Thus there was a common

activation pattern for both stimuli in lobule VI (L/

R) and lobule CrI (L). These common activations

may represent motor activity, as subjects were told to

rate their pain using their left hand (see Methods).

Discussion

In this study we compared activations in the

cerebellum following thermal and brush stimuli

applied to the same region of the face (V2 or

maxillary division of the trigeminal nerve) in two

groups of subjects – healthy controls and neuro-

pathic pain patients derived from two separate

studies. In the latter, all patients had thermal and

dynamic mechanical allodynia (i.e., reported pain to

Table IV. Neuropathic subjects (heat).

(A) Increased signal change.

Cluster Cerebellar regions Volume (cm3) zstat max cluster

Coordinates zmax

x y z

Cerebellum_6_L X_L 18.53 4.9975 232 236 238

VIIB_R

VI_R/L

VIIB_L

CrI_R

Dentate_R/L

V_R/L

IV_L

III

Cerebellum_Crus1_R CrI_R 1.02 3.4409 42 250 234

No ROI identified VIIIB_R 0.38 3.3187 12 262 262

Cerebellum_6_L VI_L 0.82 3.4799 232 266 220

Cerebellum_Crus1_L CrI_L 0.26 2.6322 238 248 236

Cerebellum_Crus1_L CrI_L 0.47 3.5677 246 262 226

Cerebellum_Crus1_L CrI_L 0.53 3.7231 246 258 230

Cerebellum_Crus1_L CrI_L 0.20 3.115 254 262 226

(B) Decreased signal change.

Cluster Cerebellar regions Volume (cm3) zstat max cluster

Coordinates zmax

x y z

Cerebellum_8_L VIIA_L 0.78 3.6578 236 260 254

264 D. Borsook et al.

normally non-noxious thermal and mechanical

(brush) stimuli). Both stimuli produced more pain

in the patients than heat and brush in healthy

subjects. Overall, heat and brush produced relatively

few activations in healthy subjects while a larger

number of activations were observed in patients. In

the latter group, with brush-induced pain (allodynia)

produced more activation than heat. In patients,

heat and brush had mirrored asymmetrical activa-

tion patterns: noxious heat produced a predomi-

nantly contralateral activation in the patient (and

healthy) group, while brush produced a greater

number of activations in the ipsilateral cerebellar

hemispheres (more so in patients than in healthy

subjects). A number of studies have reported

cerebellar activation following noxious stimuli and

these are summarized in Table I with a summary of

reports of cerebellar activation in acute experimental

pain (Table IA), cognitive influences on cerebellar

activation (Table IB) and in neuropathic pain

(Table IC). Note that most of the activations from

noxious stimuli were bilateral and or ipsilateral. Our

results show that cerebellar activation is observed in

distinct regions in response to brush and heat in two

different groups as discussed below.

Heat and brush activation in healthy subjects: Cognitive

vs. sensory processing

Our data show that heat produced activation in areas

thought to be involved in cognitive processing (39)

(i.e., lobules CrII and VIIB) and in sensory-cognitive

Table V. Neuropathic subjects (brush).

(A) Increased signal change.

Cluster Cerebellar Regions Volume (cm3) zstat max Cluster

Coordinates zmax

x y z

Cerebellum_6_R VIIB_R 9.67 5.8835 32 262 230

CrII_R

CrI_R

VI_R

Cerebellum_6_R VI_R 0.28 3.6028 38 242 232

Cerebellum_8_R VIIIA_R 0.59 3.801 16 266 256

Cerebellum_4_5_R V_R 0.22 3.3338 8 256 218

Vermis_7 VIIB 0.65 3.6009 6 268 226

Vermis_9 IX 0.37 3.6141 4 260 242

Cerebellum_9_R IX_R 0.30 3.6149 4 256 248

Vermis_6 VI 0.74 4.2462 2 268 212

Vermis_8 VIIIA 0.38 3.9221 2 262 236

Vermis_4_5 IV/V 0.53 4.0999 0 254 212

Vermis_4_5 III 0.42 4.1865 0 246 26

Vermis_8 VIIIA 1.01 3.9685 22 264 234

Cerebellum_4_5_L V_L 1.46 4.3947 24 260 216

No ROI identified Dentate_L 1.77 4.8849 216 256 228

No ROI identified White matter_L 0.61 4.4094 222 254 240

Dentate_L

No ROI identified Dentate_L 1.63 5.1305 222 254 232

Cerebellum_8_L VIIIA_L 0.89 4.2204 224 240 246

No ROI identified CrII_L 1.35 4.3673 230 252 240

CrI_L

Cerebellum_6_L VI_L 0.22 3.0393 234 246 232

(B) Decreased signal change.

Cluster Cerebellar Regions Volume (cm3) zstat max Cluster

Coordinates zmax

x y z

No ROI identified V_R 0.48 0.93465 26 232 234

No ROI identified IV_R 0.26 22.4171 12 238 232

No ROI identified VIIIB_R 41.30 0.97867 212 232 228

IX_R/L

VIIIA_R/L

Dentate_R/L

CrI_R/L

IX

VI_R/L

V_R/L

IV_R/L

III

265Pain and the cerebellum

processing (VI). However, in healthy subjects brush

stimuli produced predominantly decreased signal in

areas involved in sensory-motor integration (lobules

IV, V and VI), and in secondary sensory processing

(lobule VIIIB). Thus, there is a differentiation of

increased cognitive cerebellar regional activity for a

low heat stimulus vs. a predominant decrease in the

sensory processing component for brush. We infer

from these results that there is a distinct difference in

cerebellar mechanisms integrating information for

mild thermal heat vs. brush, the latter producing

activation almost completely restricted to cerebellar

sensory processing.

Heat and brush activation in patients: Cognitive vs.

sensory processing

In patients, both heat and brush produces pain (see

Figure 1) when applied to the area of the face

affected by nerve damage resulting in the clinical

condition of neuropathic pain. Heat pain produced

activation in regions involved in sensory-motor

processing (anterior lobe, lobules III–V, and lobules

VI and VIIIA), but also included areas involved in

cognitive processing (lobule CRI). The activation

pattern was not very different from heat in healthy

subjects. For brush-induced allodynia, activation in

the cerebellum was observed in sensorimotor regions

in lobules III to V, putative secondary somatosen-

sory regions (lobule VIII; (40)), vestibular regions

(lobule IX), cognitive regions (lobules VIIB, CRI,

CRII), and prominent dentate nucleus activation.

The distribution of sensory and cognitive activation

following brush may result from the nature of the

sensation: pain, dysesthesia, differential input by the

same fiber type (Aß fibers) that normally conveys the

sensation of mechanical stimuli such as brush. Thus,

there might be additive inputs from the trigeminal

nuclei that connect with various brain regions

including the cerebellum in response to mechanical

stimuli as well as painful stimuli. In the current

study, there is nothing disrupting cerebellar function

(i.e., no injury), rather, cognitive cerebellar regions

are active in the cognitive state. Thus, the cerebel-

lum appears to be active in its sensorimotor as well

as its cognitive and limbic regions for situations in

which a subject’s experience of a stimulus is painful.

Trigemino-cerebellar pathways

Possible pathways mediating noxious (thermal and

mechanical) and innocuous (mechanical) informa-

tion to the cerebellum have been described using

electorphysiological and anatomical tracing techni-

ques in mammals and birds (21,25,41–46).

Relatively few trigeminal afferents project to the

cerebellar nuclei (47) and most project to the

cerebellar cortex. Trigeminal afferents are reported

to arise in the the nucleus interpolaris,nucleus oralis

and principal nucleus, and project ipsilaterally to the

three cerebellar cortical regions – the lobulus

simplex and part of lobule V, rostral folia of the

paramedian lobule with surrounding parts of crus I

and II, and lobule IX (48). Some projections are

observed from the mesencepahlic nucleus and

nucleus caudalis directed to vermal regions. In a

study of trigeminocerebellar projections in sheep,

secondary trigeminocerebellar connections have

been described in some detail using tract tracing

techniques (49). The results indicate most of the

cerebellar cortex receives bilateral (but mostly

ipsilateral) fibers from the trigeminal nuclei (except

flocculus, ventral paraflocculus and lobules I–IV)

with some topographic organization (mesencephalic

nucleus to the anterior lobe, lobules VI, VIII and

dorsal paraflocculus; principal nucleus to all lobules

in vermis and hemispheres). These projections have

not been described in man. Our results may be

interpreted in the light of these studies. For noxious

heat, the primary inputs are to the trigeminal

nucleus caudalis and interpolaris (50–52), and based

on the rat data, projections would be to vermal

regions. Non-noxious brush stimuli are transmitted

via the main or principal sensory nucleus and have

collateral projections to the more caudal nuclei (53–

57). Inputs to the trigeminal nucleus are complex

(see (31) for a review) and given patterns we observe

(e.g., heat pain activating a disproportionate number

of Crus I and Crus II regions and painful brush

activating a large number of vermal regions), it is

difficult to extrapolate from the animal studies. In

addition, many indirect pathways, for example, the

trigemino-olivary-cerebellar projection (46) may also

contribute. MRI tract-tracing studies may help

delineate these pathways in humans (58,59).

Pain and the cerebellum

Although there are numerous pain studies that

report activation in the cerebellum, only one group

has reported activation in specific cerebellar regions

(13,60). In these two prior studies, the authors

employed a similar method for producing heat, but

applied heat to the hand in healthy subjects.

Activations were reported in the anterior vermis

(lobules II–V), and bilaterally in the hemispheres

(lobules III–VI). These activations were observed

predominantly ipsilateral to the stimulus. The

studies were performed in healthy volunteers.

Other studies have shown activation in the cerebel-

lum to temporal summation of C-fiber evoked pain,

and suggest cerebellar activation may correlate with

premotor activity (61,62). In our studies, we

observed more widespread activations within the

vermis and hemispheres for the patient group and in

the nuclei. Based on our current understanding of

input-output systems of the cerebellum the activa-

tions in the cerebellar cortex are a result of afferent

266 D. Borsook et al.

sensory inputs (63), including pain (64,65), while

activation in the nuclei relate to outputs (66).

Decreased activations were also observed in the

present study (Tables IB–IVB). If decreased activa-

tion represents inhibitory processing (67,68), we

interpret these changes as such and relate to

inhibitory systems in cerebellar cortical regions.

The cerebellum has been called ‘the great

modulator of neurologic function’ (69). It has

outputs to numerous limbic structures (including

the hippocampus, amygdala, intralaminar thalamic

nuclei, the hypothalamus, the periaqaueductal gray

(70–75) and thus may influence emotion, cognition,

and sensory function – all dimensions involved in the

response to pain or pain modulation. Having said

this, the role of the cerebellum in emotional

processing remains controversial (see 76).

The role of the cerebellum in nociception has been

reviewed by Saab and Willis (4). In preclinical

studies, cerebellar stimulation modulates thalamic

neural responses to painful stimuli (77) and also

modulates the intensity of a visceral nociceptive

reflex in rats (78). Conversely, nociceptive stimuli

modulate the activity of cerebellar Purkinje cells

(22,64,65). Pharmacological manipulation of the

cerebellum also produces analgesia. For example,

microinjection of morphine into the anterior cere-

bellum of rats produced analgesia that was reversible

by systemic naloxone (79). In addition, the same

authors reported that brief electrical stimulation of

the same area resulted in analgesia after the

stimulation ended. Lesions of the cerebellar vermis

in rats results in a larger increase in the threshold to

the reaction to electrical shock in rats compared with

lesions of the cerebellar cortex (80). Human studies

have not been able to produce controlled lesions or

stimulation for pain, although cerebellar stimulation

has been used for motor disorders (81). Pain

imaging studies across the spectrum from visceral

(82) to somatic, acute to chronic (83) all show

cerebellar activation. Few other structures are

activated in such a consistent manner. In addition

to responding to direct pain stimulation, activation is

reported across a number of pain experiments

including imagination of pain (84), modulation of

pain (85) and perception of pain in others (17),

empathy (18), and acupuncture stimulation (86).

Indeed many aspects of sensory discrimination

described above pertain to anticipation, error pre-

diction, cognitive responses, attention, and integra-

tion of the brain’s response to sensation (87).

Little is known about the specific role of the

cerebellum in nociceptive processing. Are these

systems generic to sensory processing, or is there

specific modulation relating to pain and integrating

the CNS response including autonomic, cognitive,

emotional and sensory dimensions? Although the

cerebellum has been considered to be involved in

cognitive behaviors, no clinical or preclinical studies

have yet shown a role in acute or chronic pain.

Recent work has considered many pain responses as

learned (88,89) and the role of the cerebellum is still

unclear. The possible role of the cerebellum in pain

processing may be considered in the light of several

theoretical formulations:

(i) The cerebellum may optimize performance by

modulating behavior automatically according

to context (39) such as the need to integrate

appropriate motor function. This modulation

may be applied to learned behaviors in pain

(sensory) processing, as the cerebellum has

been considered to be involved in monitoring

and adjusting sensory acquisition (90). The

cerebellum is considered to be involved in

controlling error signals, and may be a com-

parator for errors in somatosensory processing

(64,65,91,92). Such error signals may play a

role, for example, in wrongly executed move-

ment (4).

(ii) Cerebellar processing may play an important

role in response to expected vs. unexpected events.

The cerebellum may play a bigger role in

processing unexpected events than expected

events. In a recent imaging study of sponta-

neous trigeminal neuralgia (Borsook et al.,

under review), no activation was observed in

the cerebellum following evoked (expected) tics

but activation was observed following sponta-

neous (unexpected tics). This type of informa-

tion may infer a role in processing anticipatory

sensory input with a high level of temporal

accuracy, and optimize temporal responses in

the sensory and integrative systems (93,94).

For example, measures of cerebellar activity

using MEG in response to electric shocks of the

median nerve suggests that the signals are

probably elicited by the first afferent sensory

volley from peripheral nerve endings and

mediated by spinocerebellar (cuneocerebellar)

tracts (95). The results imply strong coherent

activation of cerebellar neuronal populations

after purely sensory stimulation based on

observation of changes notes measured in

millisecond scale temporal resolution.

Whether the cerebellum is directly involved in

anticipation of pain (96) or plays an integrative

role is unknown.

(iii) The cerebellum may play an integrative role

with respect to sensory information flow to and

from the somatosensory cortex. Alterations in

somatosensory cortex have been reported in

patients with cerebellar lesions (97), and

altered sensory processing has also been

reported in such patients (19). In the latter

study, the authors report that the cerebellum

may be involved in pre-attentive detection of

incoming somatosensory inputs.

267Pain and the cerebellum

Methodological limitations

A number of methodological caveats apply to this

report:

(i) Separate studies. The data for heat and brush

were from two different studies and although

many processes were the same (3T magnet,

number of stimuli, exactly the same method

used for applying the stimuli etc), there are a

number of differences. Differences in the

scanning were present for stimulation sites

and number of times subjects were scanned

(twice in Group II). However as reported in

our paper (14) we did not observe significant

differences to pain thresholds prior to scan-

ning, or differences in activation for the two

scans. Patients were scanned twice to enhance

the power or the study.

(ii) Un-matched studies. The main data reported

relate to separate activation patterns to heat

and brush in two groups – healthy and

neuropathic pain. As noted data reported here

were derived from two prior studies (Moulton

et al., in preparation; (14)) that were not

specifically designed to compare activation

between healthy and neuropathic pain sub-

jects. As a consequence, the groups were not

matched for age or gender, or ongoing back-

ground pain. While some issues can be

addressed in a proper comparison of such

data, there are a few that are always proble-

matic when using a patient group. These

include the disease state for which there are

no good surrogate models (except perhaps

capsaicin hyperalgesia, but this does not

reflect the underlying changes in neuropathic

pain including altered chemical, anatomical

and functional processes observed in neuro-

pathic pain (98–100). In addition, patients are

usually on or have been on medication for

long periods of time, and thus a true compar-

ison is very difficult. What we show in the

comparison are essentially areas of activation

that are common or different between these

groups. One way to interpret this may be the

effects of a low level input to heat and brush in

Group I and a high level input to heat and

brush in Group II. Such a group would still

have some inherent inequities e.g., analgesics.

(iii) Motor function. Another confound may relate

to the motor function by left hand movements

for rating pain that could have produced

activation within the cerebellum, since the

cerebellum is well known to be involved in

motor integration (101). The common and

similar activation sites for both heat and brush

stimuli suggest that motor activation is present

but does not encompass all of the regions

demonstrated in the two cohorts. Further, we

do not see common activation in the dentate

nuclei. In an fMRI study, activation in

cerebellar output nuclei (dentate) showed

increases only when subjects experienced

cutaneous stimulation alone but showed little

activation in nuclei with combined sensory

stimulation and coordinated movements of

the hand (see (102)). This and other imaging

studies (103,104) suggest that the cerebellum

has an important role in sensory discrimina-

tion.

(iv) Cerebellar acquisition. The cerebellum was not

fully imaged in the patient cohort, potentially

missing activation in the most posterior aspect

of the cerebellum. However, healthy subjects,

that had full coverage of the cerebellum, did

not display activation beyond y5274, the

posterior extent for the patient group, and

hence our common activation results are likely

valid.

(v) Differences in pain responses. In addition, heat

applied in the control subjects produced mild

pain whereas the pain produced by heat in the

neuropathic pain subjects was more severe. An

increase in the intensity of pain would

probably enhance cerebellar activation.

Conclusions

Cerebellar sensorimotor regions are activated by

touch, whereas cerebellar lobules thought to be

involved in cognitive and emotional processing are

activated during noxious stimulation both in healthy

subjects and in those with neuropathic pain. These

results led us to propose that the cerebellum

modulates the emotional and cognitive experience

that distinguishes the perception of pain from the

appreciation of innocuous sensory stimulation.

These results add to the weight of preclinical and

clinical imaging studies in healthy subjects and

patients that demonstrate cerebellar activation by

painful stimulation, but a clinical condition in which

there is altered pain processing as a result of

cerebellar lesions in humans has not yet been

described.

Acknowledgements

This work was supported by a grant from NINDS

(NS 042721).

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