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The Journal of Pain, Vol 11, No 11 (November), 2010: pp 1083-1094Available online at www.sciencedirect.com

Temporomandibular Disorder Modifies Cortical

Response to Tactile Stimulation

Mary Beth Nebel,*,y Stephen Folger,x Mark Tommerdahl,y Mark Hollins,z

Francis McGlone,k and Gregory Essick**Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.yDepartment of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.zDepartment of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.xDepartment of Physical Therapy Education, Elon University, Elon, North Carolina.kDepartment of Neurological Sciences, University of Liverpool, Liverpool, United Kingdom.

Received2010.SupporteAddress#7455, Ugreg_ess

1526-590

ª 2010 b

doi:10.10

Abstract: Individuals with temporomandibular disorder (TMD) suffer from persistent facial pain and

exhibit abnormal sensitivity to tactile stimulation. To better understand the pathophysiological

mechanisms underlying TMD, we investigated cortical correlates of this abnormal sensitivity to touch.

Using functional magnetic resonance imaging (fMRI), we recorded cortical responses evoked by low-

frequency vibration of the index finger in subjects with TMD and in healthy controls (HC). Distinct

subregions of contralateral primary somatosensory cortex (SI), secondary somatosensory cortex (SII),

and insular cortex responded maximally for each group. Although the stimulus was inaudible, primary

auditory cortex was activated in TMDs. TMDs also showed greater activation bilaterally in anterior

cingulate cortex and contralaterally in the amygdala. Differences between TMDs and HCs in responses

evoked by innocuous vibrotactile stimulation within SI, SII, and the insula paralleled previously reported

differences in responses evoked by noxious and innocuous stimulation, respectively, in healthy individ-

uals. This unexpected result may reflect a disruption of the normal balance between central resources

dedicated to processing innocuous and noxious input, manifesting itself as increased readiness of the

pain matrix for activation by even innocuous input. Activation of the amygdala in our TMD group could

reflect the establishment of aversive associations with tactile stimulation due to the persistence of pain.

Perspective: This article presents evidence that central processing of innocuous tactile stimulation

is abnormal in TMD. Understanding the complexity of sensory disruption in chronic pain could lead to

improved methods for assessing cerebral cortical function in these patients.

ª 2010 by the American Pain Society

Key words: Temporomandibular disorders (TMD), fMRI, cortical imbalance, SI, chronic pain.

Aconsiderable body of evidence suggests that

painful conditions are often accompanied byalterations in cutaneous sensory perception.

Nathan50 reported that localized pain due to peripheralor central lesions can impair the perception of tactilestimuli within the painful region; similarly, provokingpain in patients with pathological pain (eg, tennis el-bow) increases tactile detection thresholds in the areaof pain referral.44 In some clinical conditions, widespreadimpairment of tactile sensitivity has been documented.

July 9, 2009; Revised January 20, 2010; Accepted February 8,

d by NIH grant P01 NS045685.reprint requests to: Gregory Essick, 2112 Old Dental Building, CBniversity of North Carolina, Chapel Hill, NC 27599-7455. E-mail:[email protected]

0/$36.00

y the American Pain Society

16/j.jpain.2010.02.021

Patients with chronic cervicobrachialgia69 and persistentpatellofemoral pain38 demonstrate systemic elevation ofvibrotactile detection thresholds compared to healthycontrols. Although the clinical presentations of theseconditions differ, there is increasing recognition that sys-tematic assessment of somatosensory perception in dis-orders characterized by persistent pain would greatlyaid diagnosis and evaluation of treatment efficacy.

One condition in which local and widespread sensorydisturbances have been examined is temporomandibulardisorder (TMD),a nonspecific diagnosis representing a con-stellation of conditions characterized by persistent facialpain and impaired oral function.14 TMD, the most commonchronic orofacial pain condition in the United States,impacts approximately 12% of the population.13 Individ-uals with TMD frequently report pain in widespread bodyareas,30,74 suggesting that central pathophysiologicalprocesses contribute to the persistence of pain. In

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1084 The Journal of Pain TMD Modifies Cortical Tactile Responsivity

addition, TMD is associated with several comorbidfunctional syndromes including fibromyalgia (18%),56

vulvar vestibulitis,77 and irritable bowel syndrome (64%).1

Vibrotactile sensibility on the face of TMD patients ischaracterized by elevated detection threshold34 and im-paired frequency discrimination,33 a process shown torely on intact somatosensory cortex.42 Outside of thepainful region, a marginal increase in vibrotactile detec-tion threshold33 is overshadowed by perceptual amplifi-cation of the intensity of suprathreshold tactile stimuli.32

One interpretation of the association between persis-tent pain and abnormal tactile sensibility is that thereis a disturbance in the normal balance between corticalnoxious and nonnoxious processing. Animal studiesand neural network modeling indicate that regions ofsomatosensory cortex dominated by input from differentspinal pathways interact disadvantageously when nor-mal input is disrupted, for instance, by dorsal columntransection.67 Tissue injury and inflammation have alsobeen shown to alter cortical responsivity to noxiousand nonnoxious stimulation in animal models of arthri-tis.29,43 In addition, neuroimaging studies of phantomlimb pain reveal a correlation between corticalreorganization of somatic processing and themagnitude of pain experienced;5,20 however, paincoexists with extensive sensorimotor deafferentationwhich also contributes to cortical reorganization.Whether the vibrotactile perception impairmentsobserved in individuals with TMD pain likewise reflectan abnormal topography of cortical somatosensoryprocessing remains to be determined.

The purpose of the present study was to determine, us-ing functional magnetic resonance imaging (fMRI),whether the decreased sensitivity to touch observed inTMD is associated with alterations in the magnitudeand location of brain activity evoked by low-frequencyskin vibration.

Methods

SubjectsTwenty-five women consented to a protocol approved

by the Institutional Review Board at UNC-Chapel HillMedical Center. The sample population was restrictedto women because the prevalence of TMD is significantlyhigher in women; 2 to 1 in the general population and 8to 1 in the clinical setting.8 Thirteen participants fulfilledResearch Diagnostic Criteria (RDC) for TMD,14 averageage (SD) was 28.7 (7.6) years; the other 12 participantswere neurologically healthy controls whose averageage was 28.8 (7.9) years. Immediately prior to the imag-ing session, each participant completed the Short-formMcGill Pain Questionnaire (SF-MPQ) to assess her currentlevel of pain.47

StimulationWhile in the MRI scanner, low-frequency vibration

(tactile flutter) was applied to the distal pad of the rightindex finger using a purpose-designed piezoelectric tac-tile stimulator (PTS).22 Tactile stimuli were applied to the

hand rather than to the temporomandibular region toidentify the presence of global abnormalities in centralsomatosensory processing that could not be attributedto abnormalities in stimulus-evoked afferent activityfrom the site of the patients’ pain complaints. A staticsurround limited the stimulation to a region under the8-mm-diameter Teflon contactor, which was attachedto the bender element. Consistent with previous neuro-imaging investigations of somatosensory cortex in pri-mates, a 26-Hz sinusoidal stimulus with peak-to-peakamplitude of 400 mm was used. Flutter stimulation nearthis frequency generates robust and repeatable opticalintrinsic signal (OIS) responses within the postcentral gy-rus in squirrel monkeys.61 Flutter-stimulus events were 4seconds in duration and repeated every 32 seconds to al-low adequate observation of the hemodynamic responseto each event. Subjects were instructed to keep their eyesclosed and to focus attention on the presence of thestimulus. Twenty-three of the 25 subjects participatedin 2 imaging sessions during which 2 functional imagingseries of tactile flutter were completed. Each imaging se-ries consisted of 14 flutter-stimulus presentations for a to-tal of 56 events. Two subjects (1 TMD) completed a singleimaging session for a total of 28 events. At the end ofeach imaging series, subjects were asked to rate the aver-age intensity of the flutter stimulus using a labeled mag-nitude scale with the following anchor points: feltnothing (0), barely detectable (1.5), weak vibration (5),moderate vibration (16), strong vibration (33), verystrong (50), and most intense vibration imaginable(100). Subjects were instructed to choose the most appro-priate label range to describe the intensity of the stimu-lus and then convert that label into a number. Subjectswere familiarized with the scale and presented with 2test stimuli to rate before entering the scanner room.

Imaging ParametersScanning was performed on a Siemens Magnetom Al-

legra, head-dedicated 3.0T scanner system (Siemens AG,Erlangen, Germany) with 40-mT/m gradients and a 30-cm radio frequency (RF) volume coil. Subject head mo-tion was restricted using foam cushions, and earplugsand earphones were worn by subjects to reduce scannernoise. A total of 160 contiguous, high-resolution imagescovering the entire brain were acquired using a magneti-zation prepared rapid gradient echo (MPRAGE) T1-weighted sequence (TR: 1,700 ms, Echo Time [TE]: 4.38ms, Flip angle: 8, 1-mm isotropic sampling). These struc-tural images were aligned near-axially, parallel to theplane underlying the rostrum and splenium of the corpuscallosum, and were used for coregistration with the func-tional data. Whole-brain functional images consisted of50 slices collected using a gradient echo pulse sequencesensitive to blood oxygenation level dependent (BOLD)contrast with echo planar k-space sampling at a repeti-tion rate (TR) of 3,000 ms (TE: 30 ms, Flip angle: 90, Imagematrix: 64 � 64, isotropic voxel size: 3mm3). The func-tional images were aligned similarly to the structural im-ages. A semi-automated, high-order shimming programensured global field homogeneity. Imaging series began

Nebel et al The Journal of Pain 1085

with 2 discarded RF excitations to allow the change in netmagnetization of the sample following excitation toreach steady state equilibrium.

Figure 1. Active Regions. Masks of the main effect response toskin flutter for the control group only in yellow, the TMD grouponly in blue, and for both groups in green. A cluster meanthreshold of z > 2.5 and a cluster corrected significance of P <.05 were used. Activation masks are overlayed on average ana-tomical images for all 25 subjects.

Image Data AnalysisBefore any statistical analyses were performed, the fol-

lowing preprocessing steps were applied to the fMRIdata to remove task-independent variability using FMRIBSoftware Library (FSL) version 4.1.2:63,73 1) brainextraction for nonbrain removal;62 2) subject motioncorrection using MCFLIRT:36 3) temporal realignment toadjust for slice acquisition order using Fourier-spacetime-series phase shifting; 4) spatial smoothing usinga Gaussian filter with a FWHM 5-mm kernel to boostthe signal-to-noise ratio of the data; 5) grand-mean in-tensity scaling of the entire 4D dataset by a single factor;and 6) high-pass temporal filtering to remove low-frequency artifacts. Functional images of each subjectwere coregistered to structural images in native space,and structural images were warped into MontrealNeurological Institute (MNI) stereotaxic space to allowfor intersubject comparison. The same transformationmatrices used for structural-to-standard transformationswere then applied to the coregistered functional images,and all registrations were performed using an inter-modal registration tool (affine, 12 degrees of freedom).Voxel-wise temporal autocorrelation was estimatedand corrected using FMRIB’s Improved Linear Model.37

Onset times of tactile flutter events were used to gener-ate a regressor to model the hemodynamic response(HDR) to the stimulus. Model fitting generated whole-brain images of parameter estimates and variances,representing average signal change from baseline.Group-wise activation images were calculated usingFMRIB Local Analysis of Mixed Effects (FLAME), with a clus-ter mean threshold of z > 2.5 and a cluster corrected signif-icance of P < .05.4,73 Following statistical thresholding,mixed effects group contrast images were restricted tovoxels in which a significant, cluster corrected HDR wasevoked by skin flutter in either group composing thecontrast. The Julich histologic atlas16,18 and the Harvard-Oxford cortical and subcortical structural atlases (HarvardCenter for Morphometric Analysis, Charlestown, MA)were used to localize activation clusters. The final fMRIanalysis step consisted of extracting average BOLD timecourses from functional regions of interest (ROIs) identi-fied to differentiate groups based on whole-brain analy-ses described above. Peak responses were comparedbetween groups in these regions.

Results

Self-Reported Present PainOn average, TMD subjects reported their present pain

intensity on the day of testing to be 2.4 on a 10-cmvisual analog scale with end labels of no pain (0) andworst possible pain (10). Control subjects reported anaverage present pain intensity of .16 out of 10 on theday of testing.

Perceptual RatingsOn average, the TMD group rated the intensity of the

flutter stimulation as 32.0 (SD = 15.4), corresponding toa level of ‘‘strong’’ on the labeled magnitude scale whilethe control group rated the intensity of the same stimulias only 19.2, on average (SD = 12.5), corresponding tomoderately intense. A t-test indicated that this differ-ence in mean perceived intensity was significant (P = .03).

Imaging Data

Individual Group Analysis

In a repeated-measures analysis, no significant differ-ences in the response to tactile flutter were observed be-tween imaging sessions for either group; accordingly,for each subject who completed 2 sessions, data fromthe 2 sessions were combined in subsequent analyses.For both groups, skin flutter evoked significant

Table 1. Regions Activated by Skin Flutter in Controls

CONTROLS MONTREAL NEUROLOGIC INSTITUTE COORDINATES (MM)

SIDE REGION CLUSTER SIZE (VOXELS) X Y Z ZMAX

C SII OP1 3,275 �50 �28 20 6.83

SII OP4 �46 �6 8 6.68

Insula �40 �2 12 6.59

SI �54 �24 56 6.08

I Anterior Insula 106 40 6 4 3.82


I Inferior Parietal Lobule 880 56 �40 56 5.75

SII OP1 64 �28 28 5.32

I,C Anterior Cingulate 177 2 26 38 4.49

I Middle Frontal Gyrus 340 38 46 22 4.66

C Superior Frontal Gyrus 145 �34 54 12 4.26

Abbreviations: C, side contralateral to the site of skin stimulation; I, side ipsilateral to the site of skin stimulation.

NOTE. Only clusters with a mean threshold of z > 2.5 and a cluster corrected significance of P < .05 are listed. Up to 4 local maxima in each cluster are listed.


hemodynamic responses in established somatosensoryprocessing areas, namely contralateral primary somato-sensory cortex (SI), bilateral secondary somatosensorycortex (SII), and bilateral insular cortex. In addition, ro-bust responses were evoked in both groups in sensory as-sociation areas, bilateral anterior cingulate cortex (ACC),and ipsilateral inferior parietal lobule, as well as in ipsi-lateral middle frontal gyrus, an area associated with at-tention to transient targets. Fig 1 illustrates thepattern of activation for each group in these regions,and Table 1 indicates the MNI coordinates of all signifi-cant activation clusters in the control group whileTable 2 lists the coordinates of all significant activationclusters in the TMD group. Up to 4 local maxima withineach activation cluster are listed since several clustersspan more than 1 cortical region.

Between-Group Analyses

Different patterns of activation in response to skinflutter were observed for the TMD and control groups.Direct comparison of (control–TMD) and (TMD–control)flutter contrasts revealed areas within the above-mentioned clusters in which 1 group demonstratedsignificantly greater activation than the other; Table 3lists MNI coordinates of all active regions demonstratinga significant group effect.

SI

Both the control group and the TMD group displayedsignificant responses in contralateral SI and SII; however,Fig 2 illustrates the distinct patterns of activation withinthese regions for the 2 groups. SI activation for thecontrol group (A in Fig 2) was posterior and lateral toSI activation for the TMD group (B in Fig 2) accordingto the MNI coordinates listed in Table 3. Fig 2 also indi-cates average hemodynamic time courses for bothgroups derived from contralateral SI voxels identifiedby the whole-brain analysis to differentiate betweengroups. In the posterior region of area 1, the responseof the control group was significantly greater than thatof the TMD group 3 to 9 seconds after the onset of skinflutter stimulation (P < .01 for all 3 time points); see A

in Fig 2. In the more anterior portion of SI, the peak ofthe TMD HDR at 3 seconds was significantly greaterthan that of the controls (P < .04); see B in Fig 2.

SII and Primary Auditory Cortex (A1)

Separation between groups also occurred in contralat-eral SII, with the mass of the control HDR (C in Fig 2)residing in parietal operculum subregions OP1 andOP415,17 and with the TMD group’s SII activationextending from OP1 (D in Fig 2) across the Sylvian fissureand into neighboring primary auditory cortex (E in Fig 2).Local maxima were identified on either side of the Syl-vian fissure in both TMD activation maps (Table 2) andTMD–control contrast maps (Table 3). Using the Julichhistologic atlas, it was determined that 20% of the con-tralateral SII cluster listed in Table 3 resided in primaryauditory cortex (A1).48 No statistical difference was ob-served between the time to or magnitude of peak TMDHDR in SII and A1. On the ipsilateral side, no region ofSII demonstrated greater activation to skin flutter inthe control group than in the TMD group. The TMDgroup showed greater activation than the control groupin OP1 and again this activation extended into primaryauditory cortex (Fig 3); approximately 24% of the clusterlabeled ipsilateral SII in Table 3 was located in ipsilateralA1.

SII and A1 are located adjacently on opposite banks ofthe Sylvian fissure, and previous research has suggestedthat extensive overlap may occur in fMRI responsesevoked by tactile and auditory stimulation when dataare combined across subjects due to their close anatom-ical proximity.53 To verify that activation of primary audi-tory cortex was not caused by a misregistration ofindividual subject data onto the standard atlas, weinspected subject responses on their individual high-resolution anatomical images. Activation of contralat-eral A1 was found in all 13 TMD subjects and activationof ipsilateral A1 was found in 9 of 13 TMD subjects. Fig4 contains fMRI activations evoked by tactile stimulationfrom 2 exemplary TMD subjects and 1 healthy control;activation clearly extends into A1 for both TMD subjectsbut remains in SII for the control subject.

Table 2. Regions Activated by Skin Flutter inTMDs

TMDS

MONTREAL NEUROLOGIC

INSTITUTE COORDINATES (MM)

SIDE REGION

CLUSTER SIZE

(VOXELS) X Y Z ZMAX

C SI 351 �52 �36 56 4.60

SI �54 �18 54 4.57

C SII OP1 623 �52 �20 14 5.73

A1 �48 �22 12 4.88

I SII 204 50 �20 16 4.16

A1 46 �20 10 3.23

C Anterior Insula 331 �34 14 4 5.28

Anterior Insula �40 12 �10 4.16

C Posterior Insula 286 �40 �10 �6 5.28

Amygdala �24 �10 �12 4.46


Anterior Insula 32 26 2 4.28

C Pallidium 147 �12 4 �4 4.72

I Midbrain 558 6 �18 �16 4.61

I Thalamus 4 �18 0 4.37

C Thalamus �16 �22 2 3.36

I Planum Temporale 52 56 �32 18 4.10

C Inferior Parietal Lobule 51 �40 �54 44 4.03

I Inferior Parietal Lobule 186 58 �46 50 4.49

C Paracingulate Gyrus 1,154 �4 14 44 5.32

I Paracingulate Gyrus 8 16 46 5.07

I Anterior Cingulate 4 38 14 4.79

C Anterior Cingulate �6 32 18 4.24

I Frontal Pole 37 38 46 2 3.83

I Middle Frontal Gyrus 164 48 34 26 4.43

Abbreviations: C, side contralateral to the site of skin stimulation; I, side ipsilat-

eral to the site of skin stimulation.

NOTE. Only clusters with a mean threshold of z > 2.5 and a cluster corrected sig-

nificance of P < .05 are listed. Up to 4 local maxima in each cluster are listed.


Insula, ACC, and Amgydala

Fig 5 depicts brain areas outside of those regions tradi-tionally associated with tactile processing in which theTMD group showed greater activation than controls. Al-though both groups displayed bilateral ACC activation,the control group’s ACC HDR was surpassed in magni-tude and spatial extent by the HDR of the TMD group;see A in Fig 5. The between-group flutter contrast also re-vealed a dissociation of the HDR in contralateral insularcortex. The control group demonstrated greater evokedactivity in an anterior region of the insula while con-versely, the TMD group showed greater evoked activityin a more posterior region (B in Fig 5). Unexpectedly, ac-tivation evoked by skin flutter was also greater for theTMD group in the contralateral amygdala; refer to C inFig 5.

DiscussionTo the best of our knowledge, the present report is the

only examination of brain activity evoked by innocuousvibrotactile digit stimulation in TMD patients. The grossmorphology of cortical activation elicited by skin flutterin our controls was similar to patterns previously re-

ported,22,40,46 including contiguous activation of SI andSII.6 The results are also consistent with the hypothesisthat, in TMD, differences exist in the location and magni-tude of cortical processing of vibrotactile stimulation,adding more evidence to our understanding of the dis-ruption of the somatosensory system in a chronic paincondition.

The finding that, on average, TMD subjects perceivedflutter stimulation as more intense than controls is con-sistent with published reports of TMD patients experi-encing perceptual amplification of innocuous levels ofpressure stimulation, rating weak pressures as moreintense compared to controls.32 These ratings shouldbe interpreted with caution since we did not performa rigorous calibration of the scale with each participantto minimize intersubject differences in its use.

SIGroup comparisons revealed differences between con-

trols and TMDs in evoked activity within the hand regionof SI. The SI hand region is composed of a number of cy-toarchitectonically defined subdivisions (areas 3a, 3b, 1,and 2) and the Julich histologic atlas indicated that theSI cluster in which the control group demonstratedgreater activation than the TMD group belonged toarea 1, while the SI cluster in which the TMD groupshowed greater activation than controls was more ante-rior and medial (Table 3), and spanned areas 1 and3b.26,27 Attempting to assign cytoarchitectonic labels tofMRI activation foci is prone to error due to substantialimage processing and intersubject variability;27 however,areas 3b and 1 are traditionally regarded as the SI corefor processing input from cutaneous receptors. The sta-bility of the location and spatial extent of SI activityevoked by flutter of increasing intensity has been dem-onstrated by OIS61 and fMRI monkey studies,76 suggest-ing that this group difference in the location ofmaximal response is not simply reflective of greater tac-tile intensity experienced by TMDs. Painful and innocu-ous stimuli appear to drive different neuronalpopulations within somatosensory cortex, and the gen-eral orientation of the shift in maximal BOLD responsebetween controls and TMDs is similar to the pattern ofresponse observed when comparing activity evoked byinnocuous and noxious stimulation of the hand in bothhealthy humans49,52,64 and in squirrel monkeys;65,66,71

the fringe of SI that responds to painful stimulation ofthe hand is anterior and medial to the core SI handtactile locus.

Changes in SI tactile responsivity have been studied inpatients with other persistently painful conditions withmixed results. Using fMRI to study complex regionalpain syndrome (CRPS), Pleger et al55 observed a reductionin SI activity evoked by tactile stimulation in CRPS com-pared to healthy controls, while the CRPS subjects inthe magnetoencephalography (MEG) study of Vartiai-nen et al68 demonstrated enhanced SI responsivity to tac-tile stimulation compared to controls. Accounting formethodological differences, we consider both of theseresults consistent with our findings. The SI subregion in

Table 3. Active Regions Demonstrating a Significant Group Effect

CONTROLS > TMDS MONTREAL NEUROLOGIC INSTITUTE COORDINATES (MM)

SIDE REGION CLUSTER SIZE (VOXELS) X Y Z ZMAX

C Insula 145 �44 �2 12 5.22

SII OP4 �48 �4 8 4.75

C SII OP1 222 �60 �22 24 4.41

C SI 54 �60 �26 46 3.82

SI area 1 �52 �30 56 3.63

TMDS > CONTROLS

C Thalamus 501 �8 �28 �2 4.91

I Thalamus 12 �24 8 4.37

C SI area 1 102 �54 �22 52 4.17

SI area 3b �46 �18 52 3.91

C Planum Temporale 289 �54 �30 14 4.09

SII OP1 �50 �22 14 3.96

SII OP1 �44 �34 20 3.93

A1 �44 �24 8 3.44

I A1 189 44 �22 6 4.57

SII OP1 48 �24 18 4.31

C Insula 46 �48 �10 �8 3.86

C Anterior Cingulate 731 �6 2 40 5.10

I Anterior Cingulate 4 8 40 4.90

C Amygdala 22 �24 �10 �12 3.94

Abbreviations: C, side contralateral to the site of skin stimulation; I, side ipsilateral to the site of skin stimulation.

NOTE. Only clusters with a mean threshold of z > 2.5 and a cluster corrected significance of P < .05 are listed. Up to 4 local maxima in each cluster are listed.


which our chronic pain group showed decreased activitycompared to controls was located near the crown of thepostcentral gyrus, making it difficult to detect using MEGwhich is intrinsically insensitive to radially oriented flow.A weaker magnet in the Pleger study necessitated theuse of larger voxels and increased spatial smoothing; par-tial volume effects could have caused blurring of activitywithin the 2 distinct SI subregions we identified to showopposing group effects, with the net effect beingdecreased evoked activity in the chronic pain state.

SII and A1The group differences we observed in the SII response

to flutter appear to be consistent with comparisons of SIIresponsiveness to innocuous versus noxious stimulationin healthy subjects. The contralateral SII locus of activa-tion for the control group was anterior to the SII locusof activation for the TMD group. One of the earliestmonkey electrophysiological studies suggested that an-terior SII consisted of neurons responsive to tactile inputwhile posterior SII included polysensory and nociceptiveneurons.72 In a more recent meta-analysis of reported SIIactivations from human functional imaging studies ofhand stimulation, Eickhoff et al15 found that SII voxels as-sociated with nonpainful stimulation, situated at theborder between cytoarchitectonically defined OP1 andOP4, were anterior to SII voxels in OP1 associated withpain-related activity. Additionally, Ferretti et al19 demon-strated 2 distinct SII subregions of activation in theanterior-posterior direction, with only the posterior sub-region of activation exhibiting modulation due to painintensity. The activation of the posterior subregion of

SII by innocuous stimulation in our TMD group furthersuggests that this stimulation engaged circuits normallyreserved for processing noxious stimulation.

Both groups exhibited a BOLD response in ipsilateralSII. However, the response of the TMD group was greaterin magnitude and spatial extent. Pain-related activity hasbeen shown to be more widely dispersed on both sides ofthe cortex than activity evoked by innocuous vibrotactilestimulation in pain-free subjects,11,12 and rat models ofneuropathic pain have demonstrated bilateral increasesin somatosensory cortex responsivity.45 Thus, the recruit-ment of additional SII processing resources on the ipsilat-eral side in TMD further implicates an influence of TMDpain on the processing of the vibrotactile stimuli.

Given that many activities that produce tactile sensa-tions also produce sound, it is not surprising that a grow-ing body of evidence suggests that tactile stimulationcan activate auditory cortex,9,21,23,24,59 and thathorizontal connections between auditory cortex andsomatosensory cortex exist.7,10,23 This close anatomicaland physiological relationship between cortical regionsnominally belonging to separate modalities may helpto explain behavioral interactions between hearingand touch.28,39,75 What is surprising is that our TMDgroup, using conservative spatial smoothing,59 showedgreater activation in primary auditory cortex than ourcontrol group. The results suggest that the posterior sub-region of SII (activated in our TMD group) has readier ac-cess to A1, by reason of anatomical proximity, than doesthe anterior subregion of SII (activated in our HC group),raising the intriguing possibility that behavioral interac-tions between somatosensation and hearing might bemore substantial in TMD patients than in controls, and

Figure 2. Comparison of mean percent signal change for controls and TMDs in subregions of somatosensory cortices contralateral tothe stimulation site. (A) The subregion of SI in which controls showed greater activation than the TMD group was posterior to (B) thesubregion of SI in which the peak of activation was greater for TMDs than controls. (C) and (D) Similar dissociations in activation werefound between the groups in SII with the greater evoked response in the TMD group extending to primary auditory cortex (E). *In-dicates a statistically significant difference in the average percent signal change between groups at a particular time. Outlined regionsare according to the Julich histological atlas.


that auditory responses to some stimuli occur even whenthey are inaudible to the ear. Indeed, somatosensory in-put can modulate the intensity and character of tinni-tus,54 the symptoms of which are more common inindividuals with TMD than in the general population.25

Further investigation of the connectivity between so-matosensory and auditory cortex in the human brain isneeded before any definite conclusions can be drawn.

Insula, ACC, and AmgydalaAlso surprising was that flutter stimulation evoked ac-

tivity in the contralateral amygdala of our TMD group. Toour knowledge, no neuroimaging investigation of in-nocuous tactile stimulation in humans has demonstrateda significant response in the amygdala; however, animalstudies have provided evidence of amygdala sensitiza-

tion following the induction of an inflammatory chronicpain state,51 and have emphasized the role of the amyg-dala31,51 as well as the insula35 and ACC60 in the modula-tion of pain behavior, all 3 of which showed greateractivation in our TMD group than in our control group.The amygdala plays a critical role in learning the associa-tion between aversive and neutral stimuli in classical con-ditioning,41 and amygdala activation in response towhat should be an affectively neutral stimulus could beconsistent with the hypothesis proposed by Apkarian3

that chronic pain is a state of continuous learning inwhich aversive associations are continuously made withincidental events, like innocuous tactile stimulation,due to the persistent presence of pain.3 Drawing conclu-sions about the emotional implications of amygdala acti-vation is beyond the scope of this study, and given theassociation between TMD and hypervigilance,57 we

Figure 4. Representative fMRI of SII and A1 activations duringfinger stimulation in individual subjects. The Sylvian fissure is de-noted by a black line overlaying individual activation maps. Theparietal operculum (SII) is located above the Sylvian fissure whilethe transverse temporal gyrus (A1) is located below the Sylvianfissure. Only clusters with a mean threshold of z > 2.5 and a clus-ter corrected significance of P < .05 are shown. Skin flutter eli-cited BOLD activations on both sides of the Sylvian fissure inTMD subjects (A) and (B) but only in SII in controls (C). HC,Healthy Control.

Figure 3. Comparison of mean percent signal change in SII andprimary auditory cortex ipsilateral to the site of skin stimulation.The TMD group demonstrated greater activation in both (A) ip-silateral SII and (B) ipsilateral A1. Unlike on the contralateralside, there was no subregion of ipsilateral SII in which controlsexhibited greater activation than TMDs in response to skin flut-ter. *Indicates a statistically significant difference in the averagepercent signal change between groups at a particular time. Out-lined regions are according to the Julich histological atlas.


must also recognize the possible influence of attentionaldifferences on processing in the insula2 and ACC.70 How-ever, the expectation of pain has been shown to increasethe BOLD response evoked by nonpainful stimulation inthe insula and ACC,58 and similar to the dissociation ofgroup activations we observed within SI and SII, the sub-region of the insula in which our TMD group showedmaximal activity reportedly responds to noxious butnot to innocuous stimuli.49

A limiting factor of the present study is our samplesize; although the number of subjects included in thisstudy is comparable to many functional neuroimaging

investigations, it may be small considering the heteroge-neity in the clinical presentation of TMD. Despite thisheterogeneity, we detected a disruption in the corticalprocessing of innocuous vibrotactile digit stimulationin TMD, and considered together, these subtle, yet signif-icant differences suggest cortical plasticity in TMD, whichprimes areas to respond to innocuous vibrotactile inputthat normally would not, including parts of the pain ma-trix and auditory cortex. Further investigation of how

Figure 5. Comparison of mean percent signal change for controls and TMDS in (A and B) affective and (C) emotional processingareas. *Indicates a statistically significant difference in the average percent signal change between groups at a particular time.


these processing differences are influenced by concur-rent acute pain could help to explain their functionalsignificance. Improving our understanding of the com-plexity of sensory disruption in chronic pain could allowfor the development of more accurate chronic painmodels needed to test and improve the efficacy of ther-apeutic interventions.

AcknowledgmentsThe authors would like to thank Steven Smith and MRI

technologists Kathy Wilber, Amber Abernethy, JamesBarnwell, and Emilie Kearns for assistance with data ac-quisition as well as Ollie Monbureau and Mike Youngfor technical assistance.


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