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. 2007 Oct 19;29(12):1327–1342. doi: 10.1002/hbm.20470

Representation of UV‐B‐induced thermal and mechanical hyperalgesia in the human brain: A functional MRI study

Frank Seifert 1,†, Isabella Jungfer 2,†, Martin Schmelz 3, Christian Maihöfner 1,2,✉
PMCID: PMC6870857  PMID: 17948883

Abstract

Surrogate models of pain and hyperalgesia allow the investigation of underlying mechanisms in healthy volunteers. Here, we investigated brain activation patterns during mechanical and heat hyperalgesia in an inflammatory human pain model using functional magnetic resonance imaging. Heat and mechanical hyperalgesia were induced on the right forearm by UV‐B application in 14 healthy subjects. All four conditions (nonsensitized heat and nonsensitized mechanical pain, sensitized heat and sensitized mechanical pain) were perceptually matched. A 2 × 2 factorial analysis was performed. Areas with main effect of sensitization were insula, anterior cingulate cortex (ACC), prefrontal cortices (PFC), parietal association cortices (PA), thalamus, and basal ganglia. A main effect of modality with more activation during heat hyperalgesia was found in primary somatosensory cortex (S1), ACC, PFC, and PA. A main effect of modality with more activation during mechanical hyperalgesia was found in secondary somatosensory cortices, posterior insula, and contralateral inferior frontal cortex (IFC). An interaction of sensitization and modality was found bilaterally in IFC. Areas with similar effects of sensitization in both stimulus modalities were ACC, bilateral anterior insula and bilateral IFC. We conclude that different types of hyperalgesia in a human surrogate model of inflammatory pain produce different brain activation patterns. This is partly due to a differential processing of thermal and mechanical pain and an interaction of sensitization and modality in the caudal portion of the IFC. Finally, the data provide evidence for the existence of a common “sensitization network” consisting of ACC, bilateral anterior insula, and parts of the IFC. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

Keywords: pain, hyperalgesia, fMRI, surrogate model, brain, somatosensory system

INTRODUCTION

Pain is a phenomenon with sensory‐discriminative, motivational‐affective, motor, and autonomic subdimensions. Over the last few years efforts have been made using functional imaging studies to encode brain processing of pain and to decipher the underlying neuronal network. This network, considered as the “neuronal matrix of pain” [Melzack, 1999], consists of primary (SI) and secondary (SII) somatosensory areas, insular cortices, anterior cingulate cortex (ACC), and prefrontal cortices (PFC). There is accumulating evidence that these areas are linked to different aspects of the human pain sensation [Treede et al., 1999]. In general, a “lateral” (SI, SII, and posterior insula) and a “medial” (ACC, PFC, and anterior insula) pain system has been distinguished. The lateral system seems to predominantly encode the sensory discriminative component, whereas the medial system encodes the affective‐motivational subdimension [Hofbauer et al., 2001; Maihofner and Handwerker, 2005; Maihofner et al., 2006b; Rainville et al., 1997; Treede et al., 1999].

Basically, pain can be nociceptive or neuropathic [Woolf and Mannion, 1999]. Nociceptive pain is a complex sensation preventing bodily harm and maintaining body integrity. If tissue damage takes place, a set of excitability changes in the peripheral and central nervous system may lead to pain hypersensitivity in the inflamed and surrounding tissue. In contrast, neuropathic pain is a pathological condition without biological advantage that causes suffering and distress [Jensen and Baron, 2003; Woolf and Mannion, 1999]. Such maladaptive pain typically results from damage to the nervous system. Both pain after tissue damage and neuropathic pain can be either spontaneous ongoing or stimulus evoked. During these conditions activity within the “neuromatrix of pain” can be increased or additional brain areas can be recruited [Apkarian et al., 2005]. Stimulus‐evoked pathological pain sensations can be divided into allodynia or hyperalgesia [Ochoa and Yarnitsky, 1993]. Allodynia is a condition where normally innocuous stimuli evoke pain. Hyperalgesia means that painful stimuli are found to be more painful than normal. Different somatosensory submodalities can be involved in allodynia or hyperalgesia, e.g., touch, cold, or heat. Imaging studies have investigated surrogate models of evoked pain [Baron et al., 1999; Iadarola et al., 1998; Maihofner and Handwerker, 2005; Maihofner et al., 2003, 2004; Witting et al., 2001; Zambreanu et al., 2005] or patients with neuropathic pain [Ducreux et al., 2006; Hsieh et al., 1995; Maihofner et al., 2005, 2006a; Mailis‐Gagnon et al., 2003; Petrovic et al., 1999; Peyron et al., 2004; Witting et al., 2006]; for a detailed review see Apkarian et al. [2005] and Tracey [2005]. However, often only one submodality of stimulus‐evoked pain, e.g., mechanical or thermal, has been investigated or primary and secondary hyperalgesia have been compared [Maihofner and Handwerker, 2005]. Therefore, to compare brain activations of different submodalities of hyperalgesia, we induced both heat and mechanical hyperalgesia, using the UV‐burn model [Bickel et al., 1998; Hoffmann and Schmelz, 1999] in healthy volunteers. The resulting areas of mechanical and heat hyperalgesia allowed us to compare the brain processing of both conditions directly and at balanced intensities. An advantage of the UV‐B model is that the induced hyperalgesia is stable over long time and broadly follows the erythema response and does not extend beyond the irradiated area, so that at least by the use of small radiated areas the resulting hyperalgesia is highly localized to the area of inflammation [Harrison et al., 2004], although greater radiated areas are reported to induce relevant secondary hyperalgesia [Sycha et al., 2005].

METHODS

Subjects

A total of 14 healthy subjects [six males, eight females, mean age 25.14 ± 1.07 years) participated in the study. The volunteers were informed about the procedures of the study but were unaware of the specific experimental goals. Informed consent was obtained from all participants before the experiments and the study adhered to the tenets of the Declaration of Helsinki. The study was approved by the local ethics committee. All subjects were already experienced in psychophysical studies. The stimulation site was the middle aspect of the right volar forearm in all subjects.

Experimental Design

Our experimental design was a 2 × 2 factorial blocked design with the factors sensitization (hyperalgesia, no hyperalgesia) and modality (heat pain, mechanical pain).

Induction of Experimental UV‐B‐Induced Hyperalgesia

At least 8 weeks before the experimental session, the individual minimal erythema dose (MED) for UV‐B irradiation was established at the right forearm using a calibrated UV source (290–320 nm, Saalmann multitester SBB LT 400, Saalmann Medizintechnik, Herford, Germany). For this purpose, five circular spots with a diameter of 1.5 cm at the ventral side of the left forearm were irradiated with increasing intensities of UV‐B radiation (0.02–0.06 J/cm2). One day prior to the experimental sessions, a skin area on the ventral side of the forearm was irradiated with UV‐B receiving threefold of the individual MED. No spontaneous, ongoing pain was reported at the irradiated spots. As described previously [Bickel et al., 1998; Koppert et al., 2004], an erythema and mechanical and heat hyperalgesia developed within 24 h (see “Results” section), which were restricted to the irradiated area. Subjects were told to avoid additional sun or artificial UV exposure.

Psychophysical Testing

Psychophysical testing was performed outside the scanner on the day of the fMRI measurements previously to the scans and in the same subjects.

Thermal Simulation

Thermal stimuli were applied by a Peltier‐driven thermotest device with a probe size of 30 × 30 mm2 (TSA‐II, NeuroSensoryAnalyzer, Medoc Advanced Medical Systems, Rimat Yishai, Israel) inside and 3 cm outside the UV‐radiated area. The temperatures that were used ranged from 35 to 53.5°C. The temperature was increased stepwise for 0.5°C starting from a baseline temperature of 32°C. The time interval between each stimulus interval was 30 s. Pain ratings were obtained using a numeric rating scale (NRS) ranging from 0 to 100. For fMRI measurement, only the temperature intensity, which was rated “40” on the NRS was used to measure brain activity during mechanical and heat pain and hyperalgesia at identical perceptual pain levels.

Mechanical Stimulation

Mechanical stimuli were delivered by a mechanical impact stimulator [Kohlloffel et al., 1991; Maihofner et al., 2006b] inside and 3 cm outside the UV‐radiated area. Preliminary tests with a pin‐prick stimulator revealed that secondary hyperalgesia does not exceed the erythema border more than 2 cm. Briefly, a pneumatically driven plastic projectile (weight 0.5 g; diameter 5 mm) guided by a 31‐cm‐long barrel provided painful impact stimuli on the subject's skin. With this device different pain intensities can be provoked according to the velocity of the projectile [Kohlloffel et al., 1991; Maihofner et al., 2006b]. Impact stimulation was applied in a block design with a frequency of 1 Hz. Each stimulation block lasted for 21 s, interrupted by a baseline of 21 s. Five stimulation blocks were applied over the course of the experiment. The following velocities were applied: 12, 16, 20, 24, 28, 32 m/s in ascending order. Again, pain ratings were obtained using an NRS ranging from 0 to 100. The NRS values were used to calculate stimulus‐response functions. For fMRI measurement, only matched intensities of pain at NRS = 40 were used to measure brain activity during mechanical and heat pain and hyperalgesia at identical perceptual pain levels.

fMRI

Image Acquisition

Echoplanar images were collected on a 1.5 T MRI scanner (Sonata, Siemens Medical Solutions, Erlangen, Germany) using the standard head coil. For each subject, four time series (mechanical impact stimulation, heat stimulation, mechanical hyperalgesia, heat hyperalgesia) of 93 whole‐brain images were obtained with a gradient‐echo, echo‐planar scanning sequence (EPI; TR 3 s, time to echo 40 ms, flip angle 90°; field of view 220 mm2, acquisition matrix 64 × 64, 16 axial slices, slice thickness 4 mm, gap 1 mm). The first four images were discarded to account for spin saturation effects. A T1‐weighted three‐dimensional magnetization‐prepared rapid acquisition gradient echo sequence (MPRAGE) scan (voxel size = 1.0 × 1.0 × 1.0 mm3) was recorded in the same session as the functional measurements for the recording of the individual brain anatomy.

fMRI Study Design and MRI Sequence Order

MRI sequences were assessed in the following order: anatomical scout, MPRAGE, EPI in randomized order (i.e., heat stimulation, heat hyperalgesia, mechanical stimulation, mechanical hyperalgesia).

fMRI Data Analysis

Data analysis, registration, and visualization were performed with the fMRI software package BrainVoyager 2000, V4.9. (http://www.brainvoyager.com). Data were motion‐corrected using sinc interpolation. Preprocessing furthermore included Gaussian spatial (FWHM = 4 mm) and temporal (FWHM = 3 volumes) smoothing of the functional data. Afterwards, the functional data were transformed into a standard stereotactic space and linear‐interpolated to 3 × 3 × 3 mm3 [Talairach and Tournoux, 1988]. A block design with two conditions (stimulus, baseline) was applied with each block lasting 21 s in which seven images were acquired. Each stimulation protocol served to obtain appropriate reference functions reflecting experimental and baseline conditions (stimulus = 1, baseline condition = 0). The stimulation protocols were convoluted with a canonical hemodynamic response function. The reference functions served as independent predictors for a general linear model. As implemented in the BrainVoyager software package, a z‐transformation of the functional volume time courses for each subject was applied to take account of different baseline signal levels. Group analysis was performed resulting in T‐statistical activation maps for the conditions heat hyperalgesia and mechanical hyperalgesia. Contrast comparisons were performed to test for differences between experimental conditions (heat hyperalgesia vs. perceptually matched heat pain on nonsensitized skin, mechanical hyperalgesia vs. perceptually matched mechanical pain on nonsensitized skin, heat hyperalgesia vs. mechanical hyperalgesia). The contrast comparison of heat pain vs. mechanical pain on nonsensitized skin was presented in a previous study [Maihofner et al., 2006b]. The 2 × 2 factorial design allowed us to separate brain areas with a main effect of sensitization, brain areas with a main effect of modality, brain areas with a main effect of both factors and brain areas with an interaction of sensitization and modality. For that purpose, the following contrasts were calculated: (i) effect of sensitization, averaged across both modalities, (ii) effect of modality, averaged across both sensitization states, and (iii) the interaction contrast of sensitization and modality. Those areas with a main effect of at least one the factors or with an interaction of both factors were analyzed further to delineate the nature of the main effects and interactions by means of the parameter estimates of all four conditions. Furthermore, a conjunction analysis was performed to delineate those areas with (i) similar effects of sensitization regardless of modality and (ii) similar effects of modality regardless of sensitization state. For all contrasts, corresponding P‐values were corrected for multiple comparisons using Bonferroni correction over all voxels. Maps were thresholded at P < 0.0005 (activations during different conditions) and P< 0.05 (comparisons between different conditions) (uncorrected, two‐tailed) as indicated and at a minimum cluster size of 300 mm3. The cluster size criterion was used as a conservative measure to minimize false positive activations [Maihofner and Handwerker, 2005].

Statistical Analysis

The psychophysical data are presented as mean ± SEM. Statistical evaluation was performed using the STATISTICA software package. To assess statistically significant differences between pain thresholds the Wilcoxon matched pairs test was used. P values < 0.05 were considered to be statistically significant.

RESULTS

Psychophysics

Mean stimulus‐response functions for heat pain, heat hyperalgesia, mechanical impact pain, and mechanical hyperalgesia are shown in Figure 1. The stimulus‐response functions show a consistent increase in pain ratings to heat and mechanical stimulation with a significant leftward shift of the corresponding stimulus‐response functions. The individual stimulus intensity (temperature or velocity) that induced a pain intensity rated as “40” on an NRS ranging from 0 to 100 was chosen for the fMRI experiment. The mean stimulus intensities to provoke a pain rating of “40” on the NRS for heat pain and heat hyperalgesia were (49.5 ± 0.53)°C and (45.25 ± 0.03)°C (P < 0.005, U‐Test). The mean impact velocities to evoke this pain intensity were 24.86 ± 2.07 m/s and 21.0 ± 1.98 m/s (NS, U‐Test, Wilcoxon Mached Pairs‐Test), the mean cumulated ratings were 33.73 ± 2.68 and 45.27 ± 2.83 (P < 0.005, U‐test) on an NRS ranging from 0 to 100 for mechanical impact pain and mechanical impact hyperalgesia. Thus, in both modalities significant hyperalgesia could be induced and pain intensity was matched in all four conditions.

Figure 1.

Figure 1

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Psychophysical testing. (A) Stimulus‐response functions for heat pain inside and outside the area of UV‐B application. The stimulus–response functions showed a consistent increase in pain ratings to heat stimulation with a leftward shift of the stimulus‐response functions. The respective pain ratings were significantly higher inside the area of UV‐B exposure. *Indicates P < 0.05, U‐test. Means ± SEM. (B) Stimulus‐response functions for mechanical impact pain inside and outside the area of UV‐B application. The stimulus‐response functions showed a consistent increase in pain ratings to mechanical impact‐stimulation with a leftward shift of the stimulus‐response function (P < 0.005 for the cumulated ratings, U‐test). Means ± SEM.

Brain Activations During UV‐B‐Induced Heat‐ and Mechanical Hyperalgesia

The hypothesis of the present study was that the cerebral processing of heat and mechanical hyperalgesia might differ. Figure 2A,B shows the corresponding group activation maps for the conditions “heat hyperalgesia” (Fig. 2A) and “mechanical hyperalgesia” (Fig. 2B). Corresponding Talairach‐coordinates, T‐scores, Bonferroni‐corrected P‐values and cluster sizes are depicted in Table I. Axial brain slices are referred by their superior–inferior position relative to the AC‐PC line. Prominent activations during heat hyperalgesia (Fig. 2A) were seen in contralateral S1 cortex (slices +45 to +55), contralateral M1 cortex (slices +35 to +55), bilateral S2 cortex (slices +20 to +35), bilateral parietal association cortex (PA) (slices +35 to +45), bilateral insular cortex (slices 0 to +10), bilateral ACC (slices +35 to +45), ipsilateral posterior cingulate cortex (PCC) (slice +35), bilateral PFC (SFC, MFC, IFC) (slices +10 to +25), and bilateral inferior parietal lobulus (IPL) (slices +35). During mechanical hyperalgesia (Fig. 2B) activations were seen in contralateral S1 cortex (slice +45), contralateral M1 cortex (slices +45 to +55), bilateral S2 cortex (slices +10 to +20), bilateral PA (slices +35 to +45), bilateral insular cortex (slices 0 to +10), bilateral cingulate cortex (ACC) (slices +35 to +45), bilateral PCC (slice +35), bilateral PFC (SFC, MFC, IFC) (slices 0 to +45), and bilateral IPL (slices +20). Furthermore, during both conditions strong activations of bilateral basal ganglia (slices 0 to + 20) and thalamus (slices + 10) were observed.

Figure 2.

Figure 2

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Regions of cerebral activations related to the hyperalgesia conditions: (A) heat hyperalgesia and (B) mechanical hyperalgesia. Group activations were registered onto a Talairach‐transformed brain in axial view, thresholded at T > 4, P < 0.0005, uncorrected for multiple comparisons and a cluster threshold of 300 voxels. For statistical comparison T‐statistic contrast maps comparing (C) heat hyperalgesia vs. heat pain and (D) mechanical hyperalgesia vs. mechanical pain are depicted. The group statistic contrast maps are registered onto a Talairach‐transformed brain, thresholded at T > 2, P < 0.05 uncorrected for multiple comparisons and a cluster threshold of 300 voxels. Activations seen in the left hemisphere are contralateral to the stimulation side. The Talairachcoordinates, T‐scores, Bonferroni‐corrected P values and cluster sizes are depicted in Table I. Abbreviations: ACC, anterior cingulate cortex; PCC, posterior cingulate cortex, TH, thalamus; SFC, superior frontal cortex; MFC, middle frontal cortex; IFC, inferior frontal cortex, S1, primary somatosensory cortex; S2, secondary somatosensory cortex; PA, parietal association cortex.

Table I.

Regions of cerebral activations

Region Side X Y Z BA T‐score P‐value (corr.) Cluster size (mm3)
Heat hyperalgesia
S1 Contralateral −42 −36 49 3/40 4.403 0.000225 1,864
M1 Contralateral −34 −23 52 4 5.175 0.000001 1,783
S2 Ipsilateral 52 −24 28 — 7.108 0.000001 7,375
S2 Contralateral −51 −20 22 — 6.388 0.000001 3,584
Anterior insula Ipsilateral 38 16 10 13 7.722 0.000001 11,522
Anterior insula Contralateral −34 18 9 13 7.410 0.000001 6,449
ACC Ipsilateral 7 22 38 24/32 7.20 0.000001 3,817
ACC Contralateral −4 16 36 24/32 6.354 0.000001 2,209
SFC Ipsilateral 21 46 38 8 6.801 0.000001 474
MFC/SFC Ipsilateral 36 40 30 9 8.78 0.000001 10,121
MFC/SFC Contralateral −28 48 28 9 6.42 0.000001 2,353
IFC Ipsilateral 51 10 11 44 6.11 0.000001 4,789
IFC Contralateral −48 4 8 44 5.87 0.000001 1,598
IPL Ipsilateral −54 −35 29 40 5.695 0.000001 925
IPL Contralateral −47 −36 31 40 6.819 0.000001 930
PA Ipsilateral 42 −44 40 7/40 7.77 0.000001 12,225
PA Contralateral −39 −36 44 7/40 6.59 0.000001 10,501
TH Ipsilateral 12 −11 13 — 6.85 0.000001 1,149
TH Contralateral −12 −12 7 — 5.55 0.000001 331
BG Ipsilateral 18 10 9 — 8.452 0.000001 3,270
BG Contralateral −13 8 13 — 7.798 0.000001 4,218
Heat hyperalgesia vs. normal heat pain
S1 Contralateral −34 −40 55 3/40 2.993 0.002774 203
Anterior insula Ipsilateral 38 1 9 13 3.657 0.000256 1,916
Anterior insula Contralateral −37 10 12 13 4.418 0.000010 3,652
ACC Ipsilateral 1 16 35 24/32 3.070 0.002147 809
ACC Contralateral −3 14 35 24/32 3.561 0.000371 415
SFC Ipsilateral 16 47 39 8 3.763 0.000169 1,102
MFC/SFC Contralateral −7 43 29 9 3.606 0.000313 653
MFC Ipsilateral 37 36 25 10 3.595 0.000326 1,156
IFC Ipsilateral 53 12 9 44 2.400 0.016438 2,042
PA Ipsilateral 41 −46 43 7/40 3.152 0.001627 1,870
PA Contralateral −30 −47 49 7 3.419 0.000631 1,034
TH Ipsilateral 11 −13 11 — 2.818 0.004842 288
Mechanical hyperalgesia
S1/M1 Contralateral −32 −19 53 3/4 7.774 0.000001 2,451
S2 Ipsilateral 52 −21 17 — 11.801 0.000001 11,895
S2 Contralateral −47 −24 17 — 12.625 0.000001 14,939
Anterior insula Ipsilateral 39 16 10 13 10.403 0.000001 13,699
Anterior insula Contralateral −37 15 11 13 9.600 0.000001 12,123
ACC Ipsilateral 5 16 41 24/32 7.459 0.000001 1,246
ACC Contralateral −3 2 43 24/32 7.632 0.000001 3,077
MFC Ipsilateral 37 39 24 9/10 9.080 0.000001 14,542
MFC Contralateral −31 44 25 9/10 6.643 0.000001 1,607
IFC Ipsilateral 50 8 19 44 10.409 0.000001 6,800
IFC Contralateral −49 5 14 44 10.387 0.000001 3,662
IPL Ipsilateral 52 −33 30 40 8.880 0.000001 4,863
IPL Contralateral −49 −34 27 40 9.482 0.000001 3,036
PA Ipsilateral 45 −43 40 7/40 8.068 0.000001 8,981
PA Contralateral −46 −38 31 7/40 9.027 0.000001 4,341
TH Ipsilateral 12 −8 15 — 8.715 0.000001 2,143
TH Contralateral −10 −13 13 — 7.567 0.000001 1,197
BG Ipsilateral 15 8 12 — 8.170 0.000001 2,759
BG Contralateral −13 7 13 — 9.051 0.000001 3,604
Mechanical hyperalgesia vs. normal mechanical pain
S1 Contralateral −28 −37 57 1/2/3/5 3.240 0.001200 244
S2 Ipsilateral 41 −20 16 — 4.011 0.000061 2,244
S2 Contralateral −49 −15 14 — 4.251 0.000021 4,003
Anterior insula Ipsilateral 39 14 11 13 5.130 0.000001 12,416
Anterior insula Contralateral −32 13 10 13 5.189 0.000001 10,676
ACC Ipsilateral 5 23 34 24/32 3.954 0.000077 2,414
ACC Contralateral −2 10 32 24/32 4.904 0.000001 1,486
MFC Ipsilateral 32 38 32 9 3.815 0.000137 4,879
MFC/SFC Contralateral −23 43 33 9 3.516 0.000440 1,191
IFC Ipsilateral 49 13 8 44 4.270 0.000020 4,263
IFC Contralateral −45 12 10 44 4.121 0.000038 2,203
IPL Ipsilateral 53 −40 32 40 3.381 0.000724 4,636
IPL Contralateral −48 −51 27 40 3.544 0.000397 2,254
PA Ipsilateral 40 −50 38 7/40 3.637 0.000277 3,781
PA Contralateral −32 −52 25 39/40 3.709 0.000210 790
TH Ipsilateral 12 −10 14 — 5.028 0.000001 3,681
TH Contralateral −10 −11 13 — 5.271 0.000001 4,573
PCC Ipsilateral 1 −34 25 23 5.787 0.000001 3,128
PCC Contralateral −4 −35 28 23 4.252 0.000021 3,326
BG Ipsilateral 16 13 11 — 3.911 0.000093 440
BG Contralateral −15 8 9 — 4.044 0.000053 750
Heat hyperalgesia vs. mechanical hyperalgesia
Areas more activated during heat hyperalgesia
S1 Contralateral −41 −30 43 2/3/40/5 3.235 0.001222 4,783
ACC Ipsilateral 3 28 32 24/32 2.425 0.015316 889
ACC Contralateral −3 31 32 24/32 2.707 0.006809 290
MFC/SFC Ipsilateral 5 61 20 10 2.770 0.005619 1,219
SFC Ipsilateral 15 40 51 8 3.047 0.002320 491
MFC/SFC Contralateral −32 54 18 9/10 2.645 0.008184 846
PA Ipsilateral 39 −38 47 7/40 3.256 0.001135 1,991
PA Contralateral −28 −48 49 7 3.706 0.000212 4,557
Areas more activated during mechanical hyperalgesia
S2 Ipsilateral 51 −20 15 — 7.228 0.000001 12,368
S2 Contralateral −45 −24 16 — 7.284 0.000001 17,482
Insula Ipsilateral 45 6 1 13 3.950 0.000079 620
Insula Contralateral −42 7 9 13/44 5.335 0.000001 4,759
IFC Contralateral −43 19 11 44/45 4.861 0.000001 2,730
IPL Contralateral −46 −35 23 40 5.606 0.000001 3,128
Main effect of sensitization averaged across both modalities
PA Ipsilateral 19 −63 42 7 3.718 0.000202 2,665
PA Contralateral −30 −44 47 7 3.472 0.000519 1,142
SFC/DLPFC Ipsilateral 28 43 31 9 4.471 0.000008 5,027
SFC/DLPFC Contralateral −27 47 34 9 3.847 0.00012 598
ACC Ipsilateral 3 17 36 24/32 3.954 0.000078 2,276
ACC Contralateral −3 13 36 24/32 4.8 0.000002 1,971
IFC Ipsilateral 49 6 23 6/9/44 4.15 0.000034 5,661
IFC Contralateral −50 −1 16 6/9/44 5.085 0.000001 2,886
PCC Ipsilateral 4 −23 32 23 3.652 0.000262 2,777
PCC Contralateral −2 −28 32 23 4.551 0.000005 3,292
Anterior insula Ipsilateral 34 22 8 13 4.811 0.000002 5,390
Anterior insula Contralateral −34 22 8 13 4.787 0.000002 3,928
Posterior insula Ipsilateral 36 −17 15 13 3.133 0.001736 1,023
Posterior insula Contralateral −40 −12 11 13 3.903 0.000096 1,304
BG Ipsilateral 12 2 12 — 4.501 0.000007 2,262
BG Contralateral −12 6 13 — 4.863 0.000001 4,470
Thalamus Ipsilateral 9 −17 10 — 4.411 0.000010 1,866
Thalamus Contralateral −9 15 11 — 5.158 0.000001 2,232
Main effect of modality averaged across both sensitization states
Areas more activated during heat stimulation
SI Contralateral −35 −32 55 3 2.189 0.0285 694
PA Ipsilateral 16 −66 43 7 2.853 0.004345 4,018
PA Contralateral −25 −54 51 7 2.467 0.0136 2,596
SFC/DLPFC Ipsilateral 28 50 34 9 3.239 0.001204 475
SFC/DLPFC Contralateral −24 47 32 9 3.45 0.000563 1,863
ACC Contralateral −3 15 35 32 2.116 0.00006 1,964
Areas more activated during mechanical stimulation
S2 Ipsilateral 55 −23 14 — 7.673 0.000001 5,130
S2 Contralateral −50 −34 16 — 7.757 0.000001 4,937
Posterior insula Ipsilateral 43 −10 13 13 5.429 0.000001 1,672
Posterior insula Contralateral −38 −10 13 13 6.457 0.000001 4,933
IFC Contralateral −53 −3 21 6/9/44 4.599 0.000004 1,564
Interaction of sensitization and modality
Caudal IFC/PCG Ipsilateral 44 3 9 44 3.332 0.00001 752
Caudal IFC/PCG Contralateral −49 7 8 44 2.87 0.0040 596
Conjunction analysis: areas with similar effect of sensitization during both modalities
ACC Ipsilateral 2 14 38 24/32 829
ACC Contralateral −1 14 37 24/32 490
Anterior insula Ipsilateral 39 22 7 13 2,026
Anterior insula Contralateral −34 15 12 13 1,605
IFC Ipsilateral 51 13 8 44 1,972
IFC Contralateral −50 12 11 44 905
Conjunction analysis: areas with similar effect of modality during both sensitization states
Heat stimulation
S1 Contralateral −33 −35 48 3 4,035
PA Ipsilateral 15 −72 41 7 742
PA Contralateral −15 −67 44 7 797
Mechanical stimulation
S2 Ipsilateral 57 −21 13 — 4,251
S2 Contralateral −50 −29 15 — 5,826
Posterior insula Ipsilateral 44 −15 11 13 1,463
Posterior insula Contralateral −38 −21 14 13 4,914
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S1, primary somatosensory cortex; M1, primary motor cortex; S2, secondary somatosensory cortex; PA, parietal association cortex; IPL, inferior parietal lobule; SFC, superior frontal cortex; MFC, middle frontal cortex; IFC, inferior frontal cortex; DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; PCG, precentral gyrus; TH, Thalamus; BG, basal ganglia. P‐values are corrected for serial correlations.

Calculation of T‐statistic Contrast Maps

To further compare cerebral activations during both types of hyperalgesia in more detail, we calculated three contrast maps. Corresponding Talairach‐coordinates, T‐scores, Bonferroni‐corrected P values and cluster sizes of significantly different activated brain regions are depicted in detail in Table I. In a first statistical map, we compared brain activations during heat hyperalgesia vs. heat stimulation on normal skin (Fig. 2C). Significantly increased activations during heat hyperalgesia were found in bilateral insular cortices (slices 0 to +10), bilateral PA (slice +45), bilateral ACC (slice +35), bilateral PCC (slice +35), and bilateral PFC (SFC, MFC) (slices +10 and +35).

In a second statistical map, we compared brain activations during mechanical hyperalgesia with those during mechanical stimulation on normal skin (Fig. 2D). Significantly increased activations during the hyperalgesic pain were found in contralateral S1 cortex (slice +45), contralateral M1 cortex (slices +45 to +55), bilateral S2 cortex (slice +10), bilateral PA (slices +35 to +45), bilateral insula cortex (slices 0 to +10), bilateral cingulate cortex (ACC) (slices +35 to +45), bilateral PCC (slice +35), bilateral PFC (SFC, MFC, IFC) (slices 0 to +45), and bilateral IPL (slices +20).

A third statistical map was calculated by comparing brain activations during heat hyperalgesia with those of mechanical hyperalgesia (Fig. 3). Heat hyperalgesia (coded in red/yellow) activated to a significant greater extent bilateral PFC (SFC, MFC) (slices +20 to +55), bilateral anterior cingulate gyrus (ACC) (slice +35), contralateral PCC (slice +35), and PA (slices +35 to +55). In contrast, mechanical hyperalgesia (coded in blue/green) led to significantly more BOLD increase in bilateral S2 cortex (slices +10 to +20), and posterior insular cortex (slices 0 to +10).

Figure 3.

Figure 3

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The T‐statistic contrast map compares the conditions “heat hyperalgesia” vs. “mechanical hyperalgesia”. Areas activated more during heat hyperalgesia are coded in red/yellow, those more activated by mechanical hyperalgesia are coded in blue/green. The group statistic contrast maps are registered onto a Talairach‐transformed brain, thresholded at T > 2, P < 0.05 uncorrected for multiple comparisons and a cluster threshold of 300 voxels. Activations seen in the left hemisphere are contralateral to the stimulation side. The Talairach‐coordinates, T‐scores, Bonferroni‐corrected P values and cluster sizes are depicted in Table I. Abbreviations: ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; TH, thalamus; SFC, superior frontal cortex; MFC, middle frontal cortex; IFC, inferior frontal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; PA, parietal association cortex; IPL, inferior parietal lobule.

Calculation of Factor Main Effects and Interactions

Two other contrast maps with the main effects of the two factors—sensitization and modality—were calculated. Areas with a main effect of sensitization are depicted in Figure 4A. Significantly increased activations during hyperalgesia, averaged across both modalities, were found in bilateral PFC (SFC, MFC, IFC; slices +20 to +55), with most prominent increases in bilateral dorsolateral prefrontal cortex (DLPFC; slice +35), bilateral posterior anterior cingulate gyrus (pACC; slice +35), bilateral anterior insula cortex (slices 0 to +10), bilateral posterior insula cortex (slices 0 to +10), bilateral PCC (slice +35), bilateral bilateral thalamus (slice +10), bilateral basal ganglia (slice +10), and bilateral PA (slices +35 to +55).

Figure 4.

Figure 4

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Main effects of the factors “sensitization” and “modality”. The T‐statistic contrast maps show (A) the main effect of sensitization, averaged across both modalities, and (B) the main effect of modality, averaged across both sensitization states. Areas that are coded red/yellow in (A) showed a significantly greater response during the sensitized state compared with the nonsensitized state. Areas that are coded in red/yellow in (B) showed a significantly greater response to heat stimuli than to mechanical stimuli. Areas that are coded in blue/green in (B) showed a significantly greater response to mechanical stimuli than to heat stimuli. The group statistic contrast maps are registered onto a Talairach‐transformed brain, thresholded at T > 2, P < 0.05 uncorrected for multiple comparisons and a cluster threshold of 300 voxels. Activations seen in the left hemisphere are contralateral to the stimulation side. The Talairach‐coordinates, T‐scores, Bonferroni‐corrected P values and cluster sizes are depicted in Table I. Abbreviations: ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; TH, thalamus; SFC, superior frontal cortex; MFC, middle frontal cortex; IFC, inferior frontal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; PA, parietal association cortex. The mean parameter estimates (beta values) for each condition in (C) areas with a main effect of sensitization, (D) areas with a main effect of modality, and (E) areas with a main effect of sensitization and modality are shown. Error bars indicate SEM.

Areas with a main effect of modality (those more activated by heat stimuli are coded in red/yellow, those more activated by mechanical stimuli are coded in blue/green) are depicted in Figure 4B. Areas significantly more activated during heat stimuli compared with mechanical stimuli, averaged across both sensitization states, are the contralateral primary somatosensory cortex (S1), the bilateral PFC (SFC, MFC, IFC; slices +20 to +55), with most prominent activity increases in DLPFC (slice +35), and the bilateral PA (slices +35 to +45). Areas with significant greater activation during mechanical stimuli compared with heat stimuli, averaged across both sensitization states, were the bilateral secondary somatosensory cortex (S2; slices +10 to +20), bilateral posterior insular cortex (slices 0 to +10), and contralateral IFC (slice +20).

To address the hypothesis of our study, we calculated an interaction contrast of sensitization and modality. Significant sensitization–modality interaction was found bilaterally in the caudal portion of the inferior frontal cortex (IFC; Fig. 5).

Figure 5.

Figure 5

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Interaction contrast. The (A) T‐statistic contrast map shows interaction of the factors “sensitization” and “modality” only located bilaterally at the caudal part of inferior frontal cortex (IFC). The (B) mean parameter estimates of the four conditions reveal the nature of sensitization–modality interaction: only mechanical stimuli on sensitized skin lead to increased activation in this subregion of the IFC. The group statistic contrast maps are registered onto a Talairach‐transformed brain, thresholded at T > 2, P < 0.05 uncorrected for multiple comparisons and a cluster threshold of 300 voxels. Activations seen in the left hemisphere are contralateral to the stimulation side. The Talairach‐coordinates and cluster sizes are depicted in Table I.

Calculation of Conjunction Contrasts

A first conjunction contrast analysis revealed those areas with a similar effect of sensitization irrespective of modality (Fig. 6A). This network consists of the bilateral posterior ACC (slice +35), the bilateral insula cortex (slice 0 and +10), and the bilateral IFC (slice +10). A second conjunction contrast (Fig. 6B) revealed a common activation pattern for heat stimuli irrespective of sensitization state in contralateral S1 cortex (slice +45 and +55) and bilateral PA (slices +45 to +55); and for mechanical stimuli irrespective of sensitization state in bilateral secondary somatosensory cortex (S2) (slices +10 to +20), bilateral posterior insular cortex (slices 0 to +10).

Figure 6.

Figure 6

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Common activation patterns: Conjunction analysis reveals areas with (A) similar effect of sensitization regardless of modality and (B) similar effect of modality regardless of sensitization state. Areas that are coded red/yellow in (A) showed a similar effect of sensitization during heat and mechanical stimuli. Areas that are coded in red/yellow in (B) showed a similar response to heat stimuli in the nonsensitized and the sensitized area. Areas that are coded in blue/green in (B) showed a similar response to mechanical stimuli in the nonsensitized and the sensitized area. The group statistic contrast maps are registered onto a Talairachtransformed brain, thresholded at T > 2, P < 0.05 uncorrected for multiple comparisons and a cluster threshold of 300 voxels. Activations seen in the left hemisphere are contralateral to the stimulation side. The Talairach‐coordinates and cluster sizes are depicted in Table I. Abbreviations: ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; TH, thalamus; SFC, superior frontal cortex; MFC, middle frontal cortex; IFC, inferior frontal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; PA, parietal association cortex. The mean parameter estimates (beta values) for each condition in (C) areas with a common effect of sensitization and (D) areas with a common effect of modality are shown. Error bars indicate SEM.

DISCUSSION

In the present fMRI study we show that different types of UV‐B‐induced hyperalgesia, i.e., heat and mechanical hyperalgesia, result in different patterns of brain activation even when pain intensities were perceptually matched. Stronger activations in secondary somatosensory cortex (S2) and posterior insular cortex during mechanical hyperalgesia and increased PFC and PA activations during heat hyperalgesia suggest that different central pathways are involved in different types of hyperalgesia. Factor analysis revealed that the basis of the differences is both a differential processing of thermal and mechanical pain, and an interaction of sensitization and modality in the caudal portion of the IFC.

Basically, irradiation with UV‐B causes a release of inflammatory mediators, such as prostaglandins, histamine, bradykinin, and serotonin. After exposure to inflammatory amounts of UV radiation, polymodal nociceptors develop spontaneous activity [Urban et al., 1993] and increased responses to noxious heat [Szolcsanyi, 1987]. Heat hyperalgesia is a peripheral mechanism induced by sensitization of c‐nociceptors [Schmelz et al., 2003; Schmidt et al., 1995]. In contrast, mechanical impact hyperalgesia of the UV‐B model is likely to result from both peripheral and central sensitization [Klein et al., 2005]. Central sensitization is induced by c‐fiber discharge, but mediated by A‐fibers [Ziegler et al., 1999]. This study was performed to answer the question whether the two types of hyperalgesia are processed differentially or if there is a “common hyperalgesia network”.

A Common “Sensitization Network” Consisting of ACC, Anterior Insula, and Frontal Cortices

A significant sensitization‐induced increase in activation was found in both modalities in a widespread network of cortical and subcortical brain regions: the ACC, anterior and posterior insula, prefrontal cotices (SFC, MFC, IFC), PCC, PA, basal ganglia, and thalamus. These areas are consistent with those previously reported to be involved in processing of painful stimuli in the hyperalgesic state [Baron et al. 1999; Ducreux et al., 2006; Lorenz et al., 2002; Maihofner and Handwerker, 2005; Maihofner et al., 2003, 2004, 2005, 2006a; Schweinhardt et al., 2006; Zambreanu et al., 2005]. Only minor effect of sensitization was found in primary somatosensory cortex (S1) and no effect of sensitization was found in the secondary somatosensory cortex (S2). Interestingly, a conjunction analysis of the effect of sensitization across both types of hyperalgesia revealed a common, for both modalities identical increase in activity only in the ACC, the bilateral anterior insula and parts of the bilateral IFC. All three regions are known to be involved in cognitive‐emotional evaluation of pain. This shift from areas involved in sensory‐discriminative processing to areas with a pivotal role in affective‐motivational evaluation in the presence of a pathological painful state can be interpreted as an adaptation on the biological needs: the evaluation of the biological meaning of the pain gains more importance than spatial and intensity coding.

The anterior cingulated gyrus (ACC) has an important role in processing the affective‐motivational component of pain [Apkarian et al., 2005; Sewards and Sewards, 2002; Vogt, 2005; Vogt and Sikes, 2000]. According to Vogt [2005] the cingulate gyrus can be divided into an anterior subgenual part (sACC) and an anterior perigenual part (pACC), the midcingulate cortex (MCC), and the posterior cingulated cortex (PCC). Other authors refer the MCC as the posterior ACC [Buchel et al., 2002; Maihofner and Handwerker, 2005; Mohr et al., 2005]. In our study, prominent activation was found in the posterior ACC (mainly BA 24 and, to lesser extend BA 32), a region activated constantly in pain‐imaging studies [Apkarian et al., 2005]. Although there is evidence for pain‐intensity coding in the posterior ACC [Mohr et al., 2005; Tolle et al., 1999], its most important role seems to be the cognitive and affective evaluation of nociceptive input [Apkarian et al., 2005; Buchel et al., 2002; Mohr et al., 2005; Tolle et al., 1999]. Hypnotic suggestions which altered the subjective affective component of painful stimuli also increased or decreased activation of ACC [Faymonville et al., 2000; Rainville et al., 1997, 1999]. During distraction tasks the cingulo‐frontal cortex exerts top‐down modulation of the PAG and posterior thalamus [Valet et al., 2004]. The region is activated during anticipation of pain [Hsieh et al., 1999] and during expectation of pain [Sawamoto et al., 2000]. Activity within posterior ACC (also known as the midcingulate region) (BA 24, “the sensory part”) was found to be decreased during distraction from painful stimuli, whereas activity in perigenual cingulate (BA 32, “the cognitive part”) was increased [Bantick et al., 2002; Frankenstein et al., 2001; Valet et al., 2004]. Furthermore, negative emotional context amplified pain‐related responses of the ACC [Phillips et al., 2003; Ploghaus et al., 2001] and empathy for pain of others activates the rostral ACC (Singer et al., 2004]. The anterior cingulate area that was found to be activated similarly during thermal and mechanical hyperalgesia as revealed by conjunction analysis in the present study, was also the posterior ACC, i.e., mainly Brodmann area 24 according to Vogt and colleagues [Vogt and Sikes, 2000; Vogt et al., 1995, 1996, 2005]. The PCC has recently been reported to be activated during mechanical hyperalgesia [Zambreanu et al., 2005] and by selective activation of mechano‐insensitive c‐nociceptors, which play a crucial role in inflammatory pain, but not by stimulation of polymodal c‐nocicepors [Ruehle et al., 2006]. Therefore, the PCC seems to play an important role in the processing of hyperalgesia. This is also in line with our present results, as the PCC showed strong activations during both hyperalgesia conditions.

The insular cortex is a multidimensional integration site for pain [Brooks and Tracey, 2007; Craig and Bushnell, 1994; Craig et al., 1996, 2000]. It has direct input from the thalamus, thus is connected to the lamina I spinothalamic pathway, and has output to PFC, striatum, and PA [Craig, 2003c]. Its important role in pain processing is mirrored by somatotopic arrangement [Brooks et al., 2005; Hua le et al., 2005]. In particular, the caudal anterior part has been reported to have pain intensity coding abilities, whereas the rostral anterior part seems to be involved in nociceptive processing during pathological pain states [Schweinhardt et al., 2006]. Moreover, the anterior part of the insula is shown to play a crucial role in interoception and homeostasis [Craig, 2002, 2003a, b] and is important for afferent autonomic integration and emotions [Craig, 2005].

We found a prominent sensitization‐related increase in activation during both modalities in PFC with the most prominent increase in the DLPFC. Interestingly, the bilateral caudal part of the IFC was the only region with a significant interaction of sensitization and modality. Several previous functional imaging studies demonstrated PFC activity during experimental [Baron et al., 1999; Iadarola et al., 1998; Maihofner and Handwerker, 2005; Witting et al., 2001] or clinical forms of hyperalgesia [Ducreux et al., 2006; Maihofner et al., 2005]. In a previous study done by our group, stronger activations of GC, contralateral MFC (BA 9), and anterior insula by primary (heat‐) compared with secondary (mechanical‐) hyperalgesia correlated to higher ratings of the stimulus‐related unpleasantness [Maihofner and Handwerker, 2005]. A PET study comparing heat allodynia to normal heat pain [Lorenz et al., 2002] found increased activation of a medial thalamic pathway to frontal cortices during the allodynia condition, exemplified as a shift toward the medial pain system including the frontal cortex and GC. Numerous studies have demonstrated the crucial role for the PFC for psychological modulation of pain. The PFC (especially MFC and ACC) was activated during anticipation of pain [Hsieh et al., 1999; Ploghaus et al., 1999]. Pain‐evoked activity increased mainly in orbitofrontal cortices during distraction from pain when performing a cognitive task [Bantick et al., 2002; Petrovic et al., 2000]. Furthermore, the PFC (SFC) was activated during expectation of pain [Ploghaus et al., 2000]. Also, attention to painful stimuli resulted in increased DLPFC activity [Peyron et al., 1999]. Particularly, the DLPFC seems to exert active control on pain perception by modulating corticosubcortical and corticocortical pathways [Lorenz et al., 2003]. The modulatory function of the PFC on nociceptive processing has also been demonstrated by its prominent role in the placebo effect. Placebo analgesia was associated with increased activity during anticipation of pain in the dorsolateral prefrontal and orbitofrontal cortex, but was related to decreased brain activity in pain‐sensitive brain regions, including the thalamus, insula, and ACC [Wager et al., 2004]. Interaction between stimulus modality and sensitization state was found in the bilateral caudal part of the IFC. The IFC is regularly activated in pain‐imaging studies. However, its functional relevance is largely unknown. Interestingly, this region was recently reported to be pivotally involved in imitation of facial emotional expression [Lee et al., 2006]. We did not measure facial grimacing during the two pain modalities, so we cannot exclude a contribution of this factor to the observed difference. Altogether, there seems to be a global role for the PFC in the regulation of inhibition and excitation in distributed neural networks. It is suggested that the PFC exerts an inhibitory control of noxious input and thus represents one of the central structures for pain modulation.

Differential Processing of Stimulus Modality

Factor analysis further revealed that the main difference between heat and mechanical hyperalgesia is a differential processing of thermal and mechanical pain per se. Heat hyperalgesia, i.e., comparison of brain activations during thermal stimulation inside and outside the area of UV‐application, led to activations of primary and secondary somatosensory cortices (S1 and S2), associative‐somatosensory cortices (PA), insula, cingulate cortex (ACC), and PFC (SFC, MFC, IFC). In direct T‐statistical comparison of heat vs. mechanical hyperalgesia, heat hyperalgesia activated to significantly greater extent the anterior insula, PA, PFC (SFC, MFC and IFC), and anterior cingulate gyrus (ACC), the latter both attributed to the medial pain system. One possible factor accounting for that difference aside the modality could be the different dynamic aspects of the stimuli: heat pain was applied tonic, mechanical pain phasic. It has been shown that the aversive component is greater for tonic pain than for phasic pain [Chen and Treede, 1985). This would fit to the increased frontal activations during heat hyperalgesia compared with mechanical hyperalgesia. Another contributing factor could be a stronger activation of the descending inhibitory control system due to the tonic character of the heat stimuli. Especially, the DLPFC, which was activated more during heat stimuli in our study was reported to play a pivotal role in descending pain modulation [Lorenz et al., 2003]. Also the spatial extend of the stimuli may contribute to the modality differences observed. It was shown that larger areas of pain application resulted in increased fMRI responses in S1 [Apkarian et al., 2000]. Moreover, heat hyperalgesia led to significant stronger activation in bilateral parietal cortex (PA). This area belongs to associative‐somatosensory cortices and has a role as somatosensory integration center for spatial information and environmental processes. Its involvement in pain processing has been documented several times in both experimental [Maihofner et al., 2004; Witting et al., 2001] and neuropathic pain [Hsieh et al., 1995; Maihofner et al., 2005]. It may be hypothesized that activation during hyperalgesic states reflects higher sensory integration processes and that this region is involved in directing attention to and processing of painful stimuli.

Mechanical hyperalgesia, thus comparison of brain activations during mechanical impact stimulation inside and outside the area of UV application showed significantly more activation of secondary somatosensory cortices (S2), anterior and posterior insula, PFC, ACC, PA, PCC, basal ganglia, and thalamus. This pattern of activation is consistent with previous literature investigating brain activation during mechanical hyperalgesia [Baron et al., 1999; Iadarola et al., 1998; Maihofner and Handwerker, 2005; Maihofner et al., 2004; Witting et al., 2001; Zambreanu et al., 2005] despite the use of different methods for the induction of hyperalgesia. When compared with heat hyperalgesia, mechanical hyperalgesia led to an increased activation of secondary somatosensory cortex (S2) and posterior insular cortex. The lateral pain system consists of primary (S1) and secondary (S2) somatosensory cortices. It encodes the sensory‐discriminative component of pain. S2 responses to thermal laser stimuli encoded gradually the intensity of stimuli from sensory threshold up to a level next to pain threshold but showed a ceiling effect for higher painful intensities [Frot et al., 2007]. The significant dominance of mechanical stimuli in S2 activation may be attributed to spatial encoding of the exact pain location to plan withdrawal. It is possible that increased S2 activation is due to an attentional drive toward the mechanical stimulus, given that attentional processes can significantly influence somatosensory response [Johansen‐Berg et al., 2000]. Aside from modality, the difference might be also a result of the phasic character of the mechanical impact stimulation, especially in consideration of a previously described S2 ceiling effect to graded painful stimuli [Frot et al., 2007].

The posterior insular cortex was also more strongly activated during mechanical hyperalgesia. This cortical region encodes the intensity [Coghill et al., 1999; Craig et al., 2000], the laterality [Brooks et al., 2002], and the somatotopy [Brooks et al., 2005] of nociceptive stimuli. This area seems to be more involved in the triggering of affective recognition of, and motor reaction to, noxious stimuli, whereas S2 would be more dedicated to finer‐grain discrimination of stimulus intensity, from nonpainful to painful levels [Frot et al., 2007].

In summary, in the present study we found that different types of hyperalgesia produce different brain activation patterns. We found a dominance of prefrontal and cingulate cortex activity during heat hyperalgesia and a dominance of S2 and posterior insula during mechanical hyperalgesia at weighted pain intensities. The basis of the differences was the differential processing of thermal and mechanical pain, and, to a minor extent, an interaction of sensitization and modality in the caudal portion of the IFC. Moreover, the data give evidence for the existence of a common “sensitization network” consisting of ACC, bilateral anterior insula and parts of the IFC.

Acknowledgements

We thank Gabi Göhring‐Waldeck for excellent technical assistance. We are indebted to Dr. Richard Carr and anonymous reviewers for useful comments on the manuscript.

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