Percept-related activity in the human somatosensory system:functional magnetic resonance imaging studies

Carlo Adolfo Porroa,b,*, Fausta Luib, Patrizia Facchina, Marta Maierona, Patrizia BaraldibaDip. Scienze e Tecnologie Biomediche, Univ. di Udine, P.le Kolbe 4, I-33100 Udine, Italy

bDip. Scienze Biomediche, Univ. di Modena e Reggio Emilia, Via Campi 287, I-41100 Modena, Italy

Received 8 October 2004; accepted 8 October 2004

Abstract

In this paper, we review blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies addressingthe neural correlates of touch, thermosensation, pain and the mechanisms of their cognitive modulation in healthy human subjects. There is

evidence that fMRI signal changes can be elicited in the parietal cortex by stimulation of single mechanoceptive afferent fibers atsuprathreshold intensities for conscious perception. Positive linear relationships between the amplitude or the spatial extents of BOLD fMRIsignal changes, stimulus intensity and the perceived touch or pain intensity have been described in different brain areas. Some recent fMRI

studies addressed the role of cortical areas in somatosensory perception by comparing the time course of cortical activity evoked by differentkinds of stimuli with the temporal features of touch, heat or pain perception. Moreover, parametric single-trial functional MRI designs havebeen adopted in order to disentangle subprocesses within the nociceptive system.

Available evidence suggest that studies that combine fMRI with psychophysical methods may provide a valuable approach forunderstanding complex perceptual mechanisms and top-down modulation of the somatosensory system by cognitive factors specificallyrelated to selective attention and to anticipation. The brain networks underlying somatosensory perception are complex and highly

distributed. A deeper understanding of perceptual-related brain mechanisms therefore requires new approaches suited to investigate thespatial and temporal dynamics of activation in different brain regions and their functional interaction.D 2004 Elsevier Inc. All rights reserved.

Keywords: Somatosensory perception; Cerebral cortex; Attention; Anticipation; Functional magnetic resonance imaging

1. Introduction

Exteroceptive somatosensory systems allow us to gatherinformation about environmental stimuli impinging upon theskin and superficial mucosae as well as about contactbetween body parts. Common perceptual aspects of somato-sensory systems include identification of stimulus quality(vibrotactile, warm or cold, painful), intensity coding, spatialand temporal discrimination as well as attribution of hedonicqualities to stimuli (for a discussion of pain and thermalsensations as belonging to interoceptive vs. exteroceptivesystems, see Refs. [1,2]). Conscious perception is likely toresult from a complex interaction between sensory systemsand frontoparietal association areas, which do not subservestimulus identification per se [3].

In the present review, we will briefly summarize theresults of recent functional magnetic resonance imaging(fMRI) studies aimed at understanding the relationshipsbetween central nervous system activity, somatosensoryperception and its cognitive modulation in healthy humansubjects. Readers are referred to other reviews for surveys ofprevious brain imaging literature (e.g., Refs. [4–6]).

2. Methodological aspects

So far, fMRI studies of the somatosensory system havebeen performed mainly using blood oxygenation level-dependent (BOLD)-sensitive approaches. BOLD fMRIallows an indirect estimation of neural activity by detectinglocal hemodynamic changes, which are closely related to theintegrated synaptic activity of nerve cells under physiolog-ical circumstances [7–9]. The relationship between sensorystimuli and the associated fMRI signal changes is dependent

0730-725X/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mri.2004.10.003

* Corresponding author. Tel.: +39 059 2055341; fax: + 39 059 2055363.

E-mail address: porro@unimore.it (C.A. Porro).

Magnetic Resonance Imaging 22 (2004) 1539–1548

on the stimulus–response function of the investigated neuralsystem and on the characteristics of neurovascular cou-pling. This latter relationship can show both linear andnonlinear dynamics in experimental models [8,10–13]. Alinear relationship has been found between the amplitude ofearly somatosensory-evoked potentials, a measure of syn-chronized synaptic activity, and the BOLD fMRI responsesin the human somatosensory cortex, following electricalstimulation of the median nerve at different intensities [14];however, this does not hold for all conditions [15].

In earlier fMRI studies, a block experimental design wasfrequently adopted: brain activity was compared amongshort periods, each characterized by continuous (or repeat-ed) innocuous or noxious stimulation. A single perceptualjudgement was usually obtained at the end of each block,thus preventing appreciation of time-related changes.Another disadvantage of block designs is the difficulty todiscriminate between brain activity related to anticipationor actual stimulus processing (see below). The BOLDfMRI technique has a better temporal resolution thanpositron emission tomography (PET) (although it is con-strained by slow temporal dynamics of the hemodynamicresponse), which makes it more suitable to trace changes inthe functional activity of discrete brain areas over time.Some recent fMRI studies addressed the role of corticalareas in somatosensory perception by comparing the timecourse of cortical activity evoked by different kinds ofstimuli with the temporal features of touch, heat or painperception [16–20]. This approach is based on theassumption that time-dependent changes in consciousperception must be mirrored by similar changes of neuro-nal activity and therefore of the hemodynamic responsesobserved within those cerebral structures that participate inthis process. Online continuous information about evokedperceptions during the imaging experiment has been usedin order to isolate central correlates of pain intensity coding[21,22] (Fig. 1) or of cold-evoked sensations with unique

temporal features [19,20]. The importance of onlineperceptual measurements is emphasized by the recentdemonstration of a rapid deterioration of performance overtime (for intervals of 4–14 s) in a delayed discriminationtask of the intensity of thermal or noxious input [23].

By adopting event-related paradigms, one can estimatethe hemodynamic response following a single execution ofbrief tasks. A voxelwise characterization of such responseallows to determine its relationship to different aspects ofthe stimulus and of the subject’s performance in distinctbrain regions. Parametric single-trial functional MRIdesigns have already been adopted in order to disentanglesubprocesses within the nociceptive system [24].

It is worth emphasizing that finding correlations betweenperceptual aspects and functional activity levels of selectedbrain regions is indicative of, but does not by itself prove, acausal role of these same regions. This can be betterexplored by combining fMRI with other techniques withbetter temporal resolution such as evoked potentials [25],magnetoencephalography [26] or transcranial magneticstimulation, which allows selective interference with elec-trical cortical activity [27].

3. Brain fMRI activity related to tactile perception

The pathways and neural centers involved in processinginformation from low-threshold mechanoreceptors of theskin, carried by fast-conducting myelinated afferent fibers,have been extensively investigated in nonhuman primates.Different cortical regions including the anterior parietalcortex [primary somatosensory cortex (SI)], the lateral andposterior parietal cortex as well as motor-related areasresponding to mechanical stimuli have been identified[28,29]. Humans appear to have an expanded somatosen-sory cortical network; indeed, brain regions showingincreased activity during vibrotactile input and tactilerecognition extend beyond the parietal lobe, including

Fig. 1. Temporal correlations between fMRI signal changes and perceptual aspects of pain. Cortical clusters showing positive (white) or negative (black)

correlations with the perceived pain intensity (rz.5), in an experimental paradigm of somatic pain lasting several minutes, are shown in a paramedian sagittal

plane passing through the contralateral parietal operculum/insular cortex (left). Online measurements of pain intensity were recorded throughout the

experiment. Note that fMRI signals in a positively correlated cluster encompassing the putative secondary somatosensory cortex and posterior insula (SII/IC)

increased before the onset of pain, during the anticipatory phase (right).

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portions of the frontal, cingulate, temporal and insularcortices [4,30,31].

A great number of fMRI studies have dealt with thecentral representation of nonnoxious mechanical input inhumans, especially with regard to fine-grain somatotopy(e.g., Refs. [30,32–34]) and functional identification ofdifferent somatosensory areas in the parietal cortex [35,36].Relatively few studies, however, investigated stimulus–response or perception–response relationships in the mecha-noceptive system.

An interesting question concerns the minimum amountof afferent information (in terms of number of primarysensory neurons and of discharge frequency) sufficient toinduce central sensory correlates — namely, a measurablechange of fMRI cortical activity coupled with consciousdetection. This issue has been nicely addressed by Trullsonet al. [37], who employed peripheral microneurography toselectively stimulate mechanoreceptive fibers of the mediannerve during fMRI acquisition at 3 T. Electrical stimulationat 30 Hz of seemingly single nerve fibers evoked a pressure(slowly adapting fibers) or flutter (rapidly adapting fibers)sensation referred to their receptive fields located on theglabrous surface of one hand; this was associated with twodistinct fMRI foci in SI (one on the anterior wall of thepostcentral gyrus and the other, more posterior, on the gyralcrown) and one focus in the secondary somatosensorycortex (SII) in the parietal operculum. These findingssuggest, on one hand, a rather wide divergence in thecentral termination of thalamocortical axons carryinginformation from single sensory units and, on the other, agood sensitivity of the BOLD fMRI technique, allowing todetect discrete sensory input at the cortical level.

Linear fMRI signal increases (reflected by the intensityand/or spatial extent of the response) have been found in SIwith increasing intensities of transcutaneous electricalstimulation [14,15,38,39] or increasing amplitudes ofvibrotactile input [40]. These findings are likely to reflectintensity-dependent changes in the activity of specific cort-ical populations or the additional involvement of adjacentpopulations, respectively. A frequency-dependent linearincrease of the BOLD and perfusion-weighted fMRI res-ponse in SI has also been observed for stimuli in the 5–100Hz range, which can reflect both excitatory and inhibitoryactivities [41]. By contrast, the fMRI responses in theparietal operculum, including SII, exhibited variable or norelationship with stimulus intensity in the nonnoxiousrange [38,40,42].

There is evidence that the central correlates of tactilestimuli vary according to their hedonic qualities, at least insome regions. Rolls et al. [43] showed that pleasant touch tothe palm of the hand (induced by velvet) induced greateractivation in the medial orbitofrontal cortex than did a moreintense but affectively neutral tactile stimulus (induced bywood). Additional areas activated by pleasant but not byneutral stimuli included a rostral portion of the midcingulatecortex (for nomenclature and discussion of the different

anatomical and functional subdivisions of the cingulategyrus, see Ref. [44]) and an area in or near the amygdala. Ina case study of a patient lacking large myelinated afferents,activation of slow-conducting unmyelinated (C) afferents ofthe hairy skin produced a poorly localized, faint sensation ofpleasant touch that was associated with activation of theinsular region but not of SI and SII [45]. These findingsbegin to identify limbic systems that may underlie emo-tional, hormonal and affiliative responses to skin contact.

3.1. Crossmodal cortical representations and plasticity

Identifying objects and features of surfaces by touch isusually an active exploratory process that requires theintegration of cutaneous and proprioceptive information,efferent control and comparison with stored representations[29]. During tactile recognition, a large distributed networkof cerebral and cerebellar cortical regions that includesvisual extrastriate regions in occipital, parietal, inferiortemporal and ventral temporal cortices is activated; intemporal regions, a supramodal, category-related represen-tation of object form takes place [31,46–48]. These fMRIresults add to those from different techniques, demonstratinga role of extrastriate visual areas in some tactile discrimi-nation tasks [49–51].

Over the past decade, considerable interest has beenfocused on the functional reorganization of the humancortex to adapt to environmental needs or during recoveryfrom body or brain damage. A discussion of fMRI mappingstudies of plasticity in the somatosensory system is beyondthe scope of the present review (see Refs. [52,53]), and onlya few examples will be given here. In blind subjects, bothBraille reading and nonsense dots discrimination areassociated with fMRI signal increases of the primary visualarea in addition to higher-order visual cortices; because puremotor or sensory tasks do not lead to an activation of thestriate cortex [54,55], its involvement in blind subjects isconceivably related to a high-order rearrangement of brainfunctions. Another interesting issue regards cortical plastic-ity in amputees. Reorganization of sensory pathways occursvery soon after limb amputation in humans [56], potentiallybecause of the unmasking of ordinarily silent inputs ratherthan sprouting of new axon terminals. The rearrangement ofcortical somatosensory and motor maps occurring in limbamputees may, however, constitute an example of maladap-tive plasticity, inasmuch as its extent has been shown to berelated to phantom limb pain [57].

4. Brain fMRI activity related to thermal perception

Cool and warm contact stimuli have been reported toevoke a widespread bilateral cortical network including theSII and insula, lateral prefrontal, orbitofrontal and cingulatecortices [58]. Considerable intersubject variability has beenfound, with consistent activations in the anterior/midcingu-late cortex and posterior insula [59,60]; a nonsomatotopicactivation was found in SI [61].

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Davis et al. [20] evoked paradoxical heat sensations(namely, a perception of heat when the actual skin temper-ature is at or below neutral) with alternating periods of coldand neutral temperature stimuli applied to the thenareminence of the right hand. In each subject, the occurrenceof paradoxical heat sensations was tracked online duringfMRI; the time signature of perceptual ratings was used as asearch tool to locate brain regions whose fMRI time coursecorrelated with the percepts. An across-subjects conjunctionanalysis revealed a single cortical region whose activitytightly correlated with the paradoxical heat reports in allsubjects. This region was primarily located in the rightanterior–midinsular cortex ipsilateral to the thermal stimula-tion site, with some extension into the adjacent frontaloperculum. These findings are consistent with a recent reportof an evoked warmth sensation during electrical stimulationof the insula [62] and with the localization of evokedpotentials during excitation of C warmth receptors [63].

The lateralization of the paradoxical heat response to theright insula is also interesting in light of the proposed role ofthis region in bsubjective feeling statesQ [64,65] and inaspects of attention, awareness and salience [66,67].

5. Brain fMRI activity related to pain perception

Acute pain differs from other sensory experiences for itsalmost inescapable link with negative affect as well as forvegetative andmotor reactions integrated at different levels ofthe central nervous system [68–70]. In agreement with theknown widespread distribution of nociceptive informationwithin the neuraxis in experimental animals [71], imaging

studies have demonstrated distributed cortical and subcorticalsystems, often involving the two hemispheres, encodingthermal pain intensity in humans [72–75]. This systemincludes both structures of the blateralQ (SI and SII, posteriorinsular cortex) and bmedialQ [perigenual anterior cingulate(pACC) and midcingulate cortex, prefrontal cortex] corticalpain systems [76] as well as the supplementary motor area,periaqueductal gray region, thalamus, basal ganglia andcerebellum. Few studies have directly compared the centralcorrelates of pain provoked by different kinds of stimuli; anincrease in the spatial extent of frontal activation during cold-vs. heat-induced pain has been described [77], which cantentatively be ascribed to perceptual differences in the qualityof stimulation (see also Ref. [19]).

The forebrain pain system partly overlaps structuresinvolved in processing non-noxious input, but painful stimuliinduce higher fMRI signal increases than non-noxious onesin different brain regions (e.g., Refs. [58,78–80]). A directcomparison between the cortical correlates of touch andpressure pain using event-related fMRI [81] showed that,besides common activations in the contralateral postcentralgyrus and parietal operculum, pain was associated with astronger involvement of the contralateral midanterior insula,anterior portion of the midcingulate cortex and dorsolateralprefrontal cortex (Fig. 2). Other recent event-related fMRIstudies revealed cortical foci with graded responses to theintensity of heat stimuli, activated during both perceivedwarmth and pain [24,82]. These foci might be related toclusters of wide-dynamic range neurons (showing increasingresponse magnitude to stimuli of increasing stimulusintensity, from the innocuous to noxious range) in SI [83].

Fig. 2. Comparison between the fMRI activity induced in the same subjects by punctate stimuli of the right hand dorsum, in the nonnoxious (touch, top row)

and noxious (pain, bottom row) range of intensity. Group maps (random-effect analysis, P b.001) are superimposed on standard anatomical MR images from

axial planes at different levels (0–56 mm) above the horizontal plane passing through the anterior and posterior commissures. In the insular cortex (IC),

midcingulate cortex (MC), lateral prefrontal cortex (PFC) and premotor (PM) cortex, the extent of fMRI signal increases was greater during pain than during

touch. No significant difference between the two conditions was found in the contralateral primary (SI) and secondary (SII) somatosensory cortices. C and I

indicate contralateral and ipsilateral to the stimulated hand, respectively.

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Other cortical regions such as the anterior insula and SII/posterior insula showed mainly nociceptive-specific clus-ters. More complex stimulus–response functions are foundin the amygdala and pACC cortex [24]. As pointed out byDavis [84], the interpretation of studies comparing theintensity of fMRI signal changes induced by nonnoxiousand noxious stimuli is not straightforward, given thepotential overlap in various proportions of different neuronalpopulations (low threshold, wide-dynamic range and noci-ceptive specific) in single voxels. The analysis of othercharacteristics of the fMRI responses such as their temporaldynamics may prove useful in this regard.

It has been suggested that both the frequency of impulsedischarges and the total number of activated neurons arecritical for encoding noxious events and discriminating theirintensity [69,85]. Accordingly, positive linear relationshipsbetween the amplitude or the spatial extents of BOLD fMRIsignal changes and the perceived pain intensity have beendescribed in the midcingulate cortex and/or SI duringdifferent kinds of noxious stimulation [16,78,86,87]. Inten-sity-independent cortical activity changes have been ob-served in dorsolateral frontal and posterior parietal areas,mainly in the right hemisphere [24,74,75,88–90]; they canbe ascribed to nonspecific processing of somatosensoryinformation or attentional mechanisms.

5.1. Sensory-discriminative vs. affective processing

Because pain intensity and unpleasantness are, in mostinstances, highly correlated during experimental pain, theirneural correlates are difficult to isolate. However, hypnoticsuggestions targeting sensory or affective aspects of pain ledto modulation of SI or midcingulate activity, respectively[91,92]. A recent PETstudy showed that selective attention tounpleasantness of painful laser stimuli resulted in increasedregional cerebral blood flow (rCBF) in bilateral pACC,orbitofrontal cortices and contralateral amygdala, whereasselective attention to the location of painful stimuli increasedrCBF in contralateral SI and inferior parietal cortices [93].These latter results emphasize the role of pACC, a crucialarea for integrating cognitive, emotional and vegetativeactivities [94,95], in the affective dimension of pain. Pain-related modulation of fMRI signals in other regions involvedin reward and emotion circuitry such as the nucleusaccumbens/ventral striatum [78] and the orbitofrontal cortex[43] has also been demonstrated.

5.2. Temporal analysis of pain-related activity

Cortical clusters exhibiting positive correlations with painintensity over time have been found in SI, anterior insula,anterior midcingulate, motor and premotor cortical areas in anexperimental model characterized by prolonged chemicalnoxious stimulation of the subcutaneous tissue [16,17,21].Clusters showing negative correlations with the psychophys-ical time profile were also found, predominantly in the medialparietal and pACC/medial prefrontal cortices. Decreases infMRI signals can be caused by different mechanisms

[7,96–98]. fMRI signal decreases in pACC/medical pre-frontal cortex can be related to affective processing and tothe interruption of ongoing brain activity [99] because ofthe intrusive nature of pain in conscious experience.

fMRI can, in principle, be used to identify the brain areassubserving sensory processes characterized by specific timecourses, from stimulus identification to thermal innocuousand pain perception [18,100]. Using online psychophysicalrecordings, a complex cortical and subcortical array hasbeen described, showing signal changes time locked, in eachindividual, to the prickle sensation evoked by cold noxiousstimuli [19].

5.3. Brain correlates of hyperalgesia

After tissue injury, a leftward shift of the painpsychophysical stimulus–response function commonlyoccurs, leading to painful sensations induced by nonnoxiousstimuli (allodynia) or amplifying the response to moderatelynoxious stimuli (hyperalgesia). fMRI studies on healthyvolunteers have shown that punctate hyperalgesia anddynamic mechanical allodynia are associated with BOLDsignal increases in the prefrontal cortex, in comparison withthe same kind of stimulation in normal skin [101,102]; inthe latter study, higher activity was found in contralateral SIand posterior association cortex and bilateral SII/insula. Inthe study by Baron et al [101], activation in the middlefrontal gyrus (including parts of areas 6, 8 and 9) wassignificantly related to the perceived intensity. Evidence foramplified processing of mechanical [103] and warm [104]stimuli in parietal, insular and cingulate cortices have alsobeen obtained in fibromyalgic patients, who are character-ized by decreased pain thresholds. These studies begin toshed light on the neural systems involved in centralsensitization of nociceptive circuits in physiological andpathophysiological conditions.

6. Cognitive modulation of somatosensory systems

The brain mechanisms underlying cognitive modulationof the somatosensory system represent an important issueboth on theoretical and practical grounds [4,70,105]. Thereis evidence that some cortical areas involved in somatosen-sory perception can be activated by purely mental processes,in the absence of actual stimulation (e.g., during mentalimagery of touch [106] or during empathy for pain [107]).Attention and anticipation effects on somatosensory pro-cessing have been extensively investigated using differentbrain mapping techniques including fMRI.

6.1. Attentional effects

Modulation by attention of ongoing stimulus-evokedactivity has been described by electrophysiological experi-ments in the primary somatosensory cortex of the macaquemonkey [108,109]. Comparable findings have been reportedby functional imaging studies on humans. Tasks requiringactive conscious involvement increase the intensity and/or

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spatial extent of cortical fMRI activity during somatosen-sory stimulation, with respect to passive conditions [40].Attentional modulation of parietal activity evoked bynonnoxious electrical [15,38] or tactile stimuli [110,111]has been described both in contralateral SI and bilateral SIIusing fMRI; these findings confirm and extend those ofearlier studies, which suggested a hierarchy to attentionalmodulation in the somatosensory system, with the greatesteffects being observed in secondary and association areas[4,112]. Other recent studies have explored the mechanismsunderlying crossmodal links in selective attention [113,114].

The effects of diverting attention on forebrain processingof noxious thermal stimuli have been investigated usingdifferent cognitively demanding or distracting tasks[87,90,115–118]. In different fMRI studies, decreases innoxious-evoked activity have been found in the anteriorinsula [116,117], midcingulate cortex and contralateral andipsilateral thalami [87,117]. In contrast, fMRI activity wasrelatively increased in the orbitofrontal cortex and pACC,parallel to a decrease in pain scores [117,118].

Attentional effects may be exerted at different levels ofthe somatosensory system and involve activation of brainstem modulatory centers [119,120]. In a recent studyemploying covariation analysis, a functional interactionwas found between the orbitofrontal cortex and pACC, theperiaqueductal gray and posterior thalamus during painstimulation and distraction but not during pain stimulationper se [118]. These findings reinforce the hypothesis thatthese cortical regions may be the source of attentionalmodulation under emotional influences [105]. Conversely,pain modulates the activity of regions involved in semanticcognition such as Broca’s area [121].

6.2. Effects of anticipation on cortical somatosensorysystems

PETstudies from different groups have provided evidencethat anticipation per se, in the absence of actual somatosen-sory input, affects regional cerebral blood flow in specificcortical areas [122–124]. Over the last 5 years, the character-istics and spatial distribution of anticipation-related changesin cortical activity have been described in more detail usingfMRI. One striking finding has been that fMRI changes of thesame sign occur in overlapping cortical areas during actualstimulation and during uncertain anticipation — namely,when subjects are unaware of the precise timing and/orquality (noxious/nonnoxious) of the stimulus. This holds foranticipation of tickling [125] and of pain [17,126]. Thespatial overlap between anticipation- and stimulus-relatedfMRI changes is remarkable. For instance, fMRI signalsincrease during anticipation in the appropriate somatotopicarea of the contralateral SI but decrease in other SI portions[17,125]. Parietal, cingulate and insular cortical clustersencoding pain intensity undergo, during uncertain anticipa-tion, fMRI signal changes of the same sign as thosedisplayed during pain, although weaker are less intensive(on average, 30–40% as large [17,126]). Increased fMRI

signals, occurring after anticipatory cues in different portionsof the pain system, have also been noted by other researchers(e.g., in the midcingulate cortex and anterior insula [107],contralateral sensorimotor cortex, SII and amygdala [80]).Moreover, Sawamoto et al. [127] described modulation of theinnocuous heat-related activity of cortical clusters in themidcingulate cortex and parietal operculum/posterior insulainduced by uncertain expectation of noxious input. Altogeth-er, these findings suggest a selective top-down influence ofanticipation on both the basal activity of cortical somatosen-sory system and on processing subsequent stimuli; botheffects can contribute to the effects of anticipation onsomatosensory perception [70,127].

Anticipation can also induce fMRI signal changes in othercortical populations unrelated to somatosensory processing.Ploghaus et al. [128] described foci in the anterior cingulate,anterior insular and cerebellar cortices that were selectivelyactivated during anticipation of acute thermal pain but notduring anticipation of warmth or during actual thermalstimulation. Porro et al. [126] found cortical clusters whosefMRI signal time courses were related to the heart rate profile,showing selective changes of activity during the waitingperiod. These clusters had different functional characteristicsfrom and showed limited spatial overlap with clusters whosefMRI signals were related to the psychophysical painintensity profile; however, both populations were involvedduring anticipation of pain [126]. These findings unravel acomplex pattern of brain activity during anticipation ofnoxious input, likely related both to changes in the level ofarousal (see Ref. [129]) and to cognitive modulation of thepain system. An important practical implication of theabovementioned results is that anticipation effects must betaken into account when designing fMRI experiments aimedat investigating the functional organization of the somato-sensory system in order to disentangle processing somato-sensory information from its anticipation. Event-relatedfMRI protocols are better suited in this regard.

Interestingly, anticipation of analgesia induced by place-bo treatment decreases brain activity in pain-related brainregions [80].

7. Concluding remarks

Studies that combine fMRI with psychophysical methodsprovide a valuable approach for understanding complexperceptual mechanisms and top-down modulation of thesomatosensory system by cognitive factors. The underlyingbrain networks are complex and highly distributed andinvolve both serial and parallel circuitry [29,71,76,130]. Adeeper understanding of the brain mechanisms involvedin somatosensory perception therefore requires newapproaches suited to investigate the spatial and temporaldynamics of activation in different brain regions and theirfunctional interaction. Improving the spatial resolution offMRI is one important issue [9]. The simultaneousassessment of several hemodynamic response parameters

C.A. Porro et al. / Magnetic Resonance Imaging 22 (2004) 1539–15481544

can also aid in obtaining more comprehensive measures ofbrain function. For instance, combining magnitude, delayand width maps can lead toward quantitative mental chron-ometry [131]. Furthermore, the development and applicationof refined tools for evaluating functional connectivitybetween neural populations [132–135] will hopefullyprovide new insights into bottom-up and top-down mech-anisms in somatosensory perception.

Acknowledgments

This study was supported by a grant from MIUR (ItalianMinistry for University and Research): FIRB grant no.RBNE018ET9.

References

[1] Craig A. Pain mechanisms: labeled lines versus convergence in

central processing. Annu Rev Neurosci 2003;26:1–30.

[2] Price DD, Greenspan JD, Dubner R. Neurons involved in the

exteroceptive function of pain. Pain 2003;106:215–9.

[3] Baars BJ, Ramsoy TZ, Laureys S. Brain, conscious experience and

the observing self. Trends Neurosci 2003;26:671–5.

[4] Burton H, Sinclair R. Attending to and remembering tactile stimuli: a

review of brain imaging data and single-neuron responses. J Clin

Neurophysiol 2000;17:575–91.

[5] Casey K, Bushnell MC. Pain imaging. Seattle7 IASP Press; 2000.

[6] Porro CA. Functional imaging and pain: behavior, perception, and

modulation. Neuroscientist 2003;9:354–69.

[7] Lauritzen M. Relationship of spikes, synaptic activity, and local

changes of cerebral blood flow. J Cereb Blood Flow Metab 2001;21:

1367–83.

[8] Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A.

Neurophysiological investigation of the basis of the fMRI signal.

Nature 2001;412:150–7.

[9] Ugurbil K, Toth L, Kim D-S. How accurate is magnetic resonance

imaging of brain function? Trends Neurosci 2003;26:108–13.

[10] Birn RM, Saad ZS, Bandettini PA. Spatial heterogeneity of the

nonlinear dynamics in the fMRI BOLD response. Neuroimage

2001;14:817–26.

[11] Nielsen A, Lauritzen M. Coupling and uncoupling of activity-

dependent increases of neuronal activity and blood flow in rat

somatosensory cortex. J Physiol 2003;533:773–85.

[12] Devor A, Dunn AK, Andermann ML, Ulbert I, Boas DA, Dale AM.

Coupling of total hemoglobin concentration, oxygenation, and neural

activity in rat somatosensory cortex. Neuron 2003;39:353–9.

[13] Sheth SA, Nemoto M, Guiou M, Walker M, Pouratian N, Toga AW.

Linear and nonlinear relationships between neuronal activity, oxygen

metabolism, and hemodynamic responses. Neuron 2004;42:347–55.

[14] Arthurs OJ, Williams EJ, Carpenter TA, Pickard JD, Boniface SJ.

Linear coupling between functional magnetic resonance imaging and

evoked potential amplitude in human somatosensory cortex. Neuro-

science 2000;101:803–6.

[15] Arthurs OJ, Johansen-Berg H, Matthews PM, Boniface SJ. Attention

differently modulate the coupling of fMRI BOLD and evoked

potential signal amplitudes in the human somatosensory cortex. Exp

Brain Res 2004;157:269–74.

[16] Porro CA, Cettolo V, Francescato MP, Baraldi P. Temporal and

intensity coding of pain in human cortex. J Neurophysiol 1998;80:

3312–20.

[17] Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M,

et al. Does anticipation of pain affect cortical nociceptive circuits?

J Neurosci 2002;22:3206–14.

[18] Chen J-I, Ha B, Bushnell MC, Pike B, Duncan GH. Differ-

entiating noxious- and innocuous-related activation of human

somatosensory cortices using temporal analysis of fMRI. J

Neurophysiol 2002;88:464–74.

[19] Davis KD, Pope GE, Crawley AP, Mikulis DJ. Neural correlates of

prickle sensation: a percept-related fMRI study. Nat Neurosci

2002;5:1121–2.

[20] Davis KD, Pope GE, Crawley AP, Mikulis DJ. Perceptual illusion of

bparadoxical heatQ engages the insular cortex. J Neurophysiol

2004;92:1248–51.

[21] Baraldi P, Lui F, Facchin P, Maieron M, Crisi G, Porro CA.

Perceptual coding of pain intensity: where in the brain? 9th

International Conference on Functional Mapping of the Human

Brain, June 19–22, New York, NY. Neuroimage 2003;19(2).

[22] Borras MC, Becerra LR, Ploghaus A, Gostic JM, DaSilva A,

Gozalez RG, et al. FMRI measurement of CNS responses to

naloxone infusion and subsequent mild noxious thermal stimuli in

healthy volunteers. J Neurophysiol 2004;91:2723–33.

[23] Rainville P, Doucet J-C, Fortin M-C, Duncan GH. Rapid deteriora-

tion of pain sensory-discriminative information in short-term

memory. Pain 2004;110:605–15.

[24] Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C, Buchel C.

Painful stimuli evoke different stimulus–response functions in the

amygdala, prefrontal, insula and somatosensory cortex: a single-trial

fMRI study. Brain 2002;125:1326–36.

[25] Peyron R, Frot M, Schneider F, Garcia-Larrea L, Mertens P, Barral

FG, et al. Role of operculoinsular cortices in human pain processing:

converging evidence from PET, fMRI, dipole modeling, and

intracerebral recordings of evoked potentials. Neuroimage 2002;17:

1336–46.

[26] Schulz M, Chau W, Graham SJ, McIntosh AR, Ross B, Ishii R,

et al. An integrative MEG–fMRI study of the primary somato-

sensory cortex using cross-modal correspondence analysis. Neuro-

image 2004;22:120–33.

[27] Pascual-Leone A, Walsh V, Rothwell J. Transcranial magnetic

stimulation in cognitive neuroscience — virtual lesion, chronom-

etry, and functional connectivity. Curr Opin Neurobiol 2000;10:

232–7.

[28] Romo R, Hernandez A, Salinas E, Brody CD, Zainos A, Lemus L,

et al. From sensation to action. Behav Brain Res 2002;135:105–18.

[29] Kaas JH. Somatosensory system. In: Paxinos G, Mai JK, editors. The

human nervous system. San Diego (Calif)7 Elsevier Academic Press;

2004. p. 1059–92.

[30] Francis ST, Kelly EF, Bowtell R, Dunseath WRJ, Folger SE,

McGlone F. fMRI of the responses to vibratory stimulation of digit

tips. Neuroimage 2000;11:188–202.

[31] Pietrini P, Furey ML, Ricciardi E, Gobbini MI, Carolyn Wu MH,

Cohen L, et al. Beyond sensory images: object-based representation in

the human ventral pathway. Proc Natl Acad Sci U S A 2004;101:

5658–63.

[32] Ruben J, Schwiemann J, Deuchert M, Meyer R, Krause T, Curio G,

et al. Somatotopic organization of human secondary somatosensory

cortex. Cereb Cortex 2001;11:463–73.

[33] Blankenburg F, Ruben J, Meyer R, Schwiemann J, Villringer A.

Evidence for a rostral-to-caudal somatotopic organization in human

primary somatosensory cortex with mirror-reversal in areas 3b and 1.

Cereb Cortex 2003;13:987–93.

[34] Iannetti G, Porro CA, Pantano P, Romanelli PL, Galeotti F, Cruccu

G. Representation of different trigeminal divisions within the

primary and secondary human somatosensory cortex. Neuroimage

2003;19:906–12.

[35] Disbrow E, Roberts T, Krubitzer L. Somatotopic organization of

cortical fields in the lateral sulcus of Homo sapiens: evidence for SII

and PV. J Comp Neurol 2000;418:1–21.

[36] Moore CI, Stern CE, Corkin S, Fischl B, Gray AC, Rosen BR, et al.

Segregation of somatosensory activation in the human rolandic

cortex using fMRI. J Neurophysiol 2000;84:558–69.

C.A. Porro et al. / Magnetic Resonance Imaging 22 (2004) 1539–1548 1545

[37] Trullson M, Francis ST, Kelly EF, Westling G, Bowtell R, McGlone

F. Cortical responses to single mechanoreceptive afferentmicrosti-

mulation revealed with fMRI. Neuroimage 2001;13:613–22.

[38] Backes WH, Mess WH, van Kranen-Mastenbroek V, Reulen JPH.

Somatosensory cortex responses to median nerve stimulation: fMRI

effects of current amplitude and selective attention. Clin Neuro-

physiol 2000;111:1738–44.

[39] Krause T, Kurth R, Ruben J, Schwiemann J, Villringer K, Deuchert

M, et al. Representational overlap of adjacent fingers in multi-

ple areas of human primary somatosensory cortex depends on

electrical stimulus intensity: an fMRI study. Brain Res 2001;899:

36–46.

[40] Nelson AJ, Staines WR, Graham SJ, McIlroy WE. Activation in

SI and SII; the influence of vibrotactile amplitude during

passive and task-relevant stimulation. Cogn Brain Res 2004;19:

174–84.

[41] Kampe KKW, Jones RA, Auer DP. Frequency dependence of the

functional MRI response after electrical median nerve stimulation.

Hum Brain Mapp 2000;9:106–14.

[42] Torquati K, Pizzella V, Della Penna S, Franciotti R, Babiloni C,

Rossini PM, et al. Comparison between SI and SII responses as a

function of stimulus intensity. Neuroreport 2002;13:813–9.

[43] Rolls ET, O’Doherty J, Kringelbach ML, Francis S, Bowtell R,

McGlone F. Representations of pleasant and painful touch in the

human orbitofrontal and cingulate cortices. Cereb Cortex 2003;13:

308–17.

[44] Vogt BA, Hof PR, Vogt LJ. Cingulate gyrus. In: Paxinos G, Mai JK,

editors. The human nervous system. San Diego (Calif.)7 ElsevierAcademic Press; 2004. p. 916–49.

[45] Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck G,

et al. Unmyelinated tactile afferents signal touch and project to

insular cortex. Nat Neurosci 2002;5:900–4.

[46] Amedi A, Jacobson G, Hendler T, Malach R, Zohary E. Convergence

of visual and tactile shape processing in the human lateral occipital

complex. Cereb Cortex 2002;12:1202–12.

[47] Grefkes C, Weiss PH, Zilles K, Fink GR. Crossmodal processing of

object features in human anterior intraparietal cortex: an fMRI study

implies equivalencies between humans and monkeys. Neuron

2002;35:173–84.

[48] Reed CL, Shoham S, Halgren E. Neural substrates of tactile object

recognition: an fMRI study. Hum Brain Mapp 2004;21:236–46.

[49] Zangaladze A, Epstein C, Grafton S, Sathian K. Involvement of

visual cortex in tactile discrimination of orientation. Nature 1999;

401:587–90.

[50] Sathian K, Zangaladze A. Feeling with the mind’s eye: contribution

of visual cortex to tactile perception. Behav Brain Res 2002;135:

127–32.

[51] Merabet L, Thut G, Murray B, Andrews J, Hsiao S, Pascual-Leone

A. Feeling by sight or seeing by touch? Neuron 2004;42:173–9.

[52] Elbert T, Rockstroh B. Reorganization of human cerebral cortex: the

range of changes following use and injury. Neuroscientist 2004;10:

129–41.

[53] Rossini PM, Dal Forno G. Integrated technology for evaluation of

brain function and neural plasticity. Phys Med Rehabil Clin N Am

2004;15:263–306.

[54] Sadato N, Okada T, Honda M, Yonekura Y. Critical period for cross-

modal plasticity in blind humans: a functional MRI study. Neuro-

image 2002;16:389–400.

[55] Gizewski ER, Gasser T, de Greiff A, Boehm A, Forsting M. Cross-

modal plasticity for sensory and motor activation patterns in blind

subjects. Neuroimage 2003;19:968–75.

[56] Borsook D, Becerra L, Fishman S, Edwards A, Jennings CL,

Stojanovic M, et al. Acute plasticity in the human somatosensory

cortex following amputation. Neuroreport 1998;9:1013–7.

[57] Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N. Phantom

movements and pain. An fMRI study in upper limb amputees. Brain

2001;124:2268–77.

[58] Zhang W-T, Jin Z, Huang J, Zhang L, Zeng Y-W, Luo F, et al.

Modulation of cold pain in human brain by electric acupoint

stimulation: evidence from fMRI. Neuroreport 2003;14:

1591–6.

[59] Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Functional MRI

study of thalamic and cortical activations evoked by cutaneous heat,

cold, and tactile stimuli. J Neurophysiol 1998;80:1533–46.

[60] Kwan CL, Crawley AP, Mikulis DJ, Davis KD. An fMRI study of

the anterior cingulate cortex and surrounding medial wall activations

evoked by noxious cutaneous heat and cold stimuli. Pain 2000;85:

359–74.

[61] Berman HH, Kim KHS, Talati A, Hirsch J. Representation of

nociceptive stimuli in primary sensory cortex. Neuroreport 1998;9:

4179–87.

[62] Ostrowsky K, Magnin M, Ryvlin P, Isnard J, Guenot M, Mauguiere

F. Representation of pain and somatic sensation in the human insula:

a study of responses to direct electrical cortical stimulation. Cereb

Cortex 2002;12:376–85.

[63] Iannetti G, Truini A, Romaniello A, Galeotti F, Rizzo C, Manfredi

M, et al. Evidence of a specific spinal pathway for the sense of

warmth in humans. J Neurophysiol 2003;89:562–70.

[64] Craig AD. How do you feel? Interoception: the sense of the

psychological condition of the body. Nat Rev Neurosci 2002;3:

655–66.

[65] Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ. Neural

systems supporting interoceptive awareness. Nat Neurosci

2004;7:189–95.

[66] Downar J, Crawley AP, Mikulis DJ, Davis KD. A multimodal

cortical network for the detection of changes in the sensory

environment. Nat Neurosci 2000;3:277–83.

[67] Downar J, Crawley AP, Mikulis DJ, Davis KD. A cortical network

sensitive to stimulus salience in a neutral behavioral context across

multiple sensory modalities. J Neurophysiol 2002;87:615–20.

[68] Willis WDJ. The pain system. The neural basis of nociceptive

transmission in the mammalian nervous system. Pain Headache

1985;8:1–346.

[69] Price DD. Psychological and neural mechanisms of pain. New York7Raven; 1988.

[70] Price DD. Psychological mechanisms of pain and analgesia. Seattle7IASP Press; 1999.

[71] Willis WD, Westlund KN. Pain system. In: Paxinos G, Mai JK,

editors. The human nervous system. San Diego (Calif.)7 ElsevierAcademic Press; 2004. p. 1125–70.

[72] Derbyshire SWG, Jones AKP, Gyulai F, Clark S, Townsend D,

Firestone LL. Pain processing during three levels of noxious

stimulation produces different patterns of central activity. Pain

1997;73:431–45.

[73] Derbyshire SW, Jones AK, Creed F, Starz T, Meltzer CC, Townsend

DW, et al. Cerebral responses to noxious thermal stimulation in

chronic low back pain patients and normal controls. Neuroimage

2002;16:158–68.

[74] Coghill RC, Sang CN, Maisog JM, Iadarola MJ. Pain intensity

processing within the human brain: a bilateral, distributed mecha-

nism. J Neurophysiol 1999;82:1934–43.

[75] Tflle TR, Kaufman T, Siessmeier T, Lautenbacher S, Berthele A,

Munz F, et al. Region-specific encoding of sensory and affective

components of pain in the human brain: a positron emission

tomography analysis. AnnNeurol 1999;45:40–7.

[76] Treede R, Kenshalo D, Gracely R, Jones AKP. The cortical

representation of pain. Pain 1999;79:105–11.

[77] Tracey I, Becerra LR, Chang I, Breiter HC, Jenkins L, Borsook D,

et al. Noxious hot and cold stimulation produce common patterns

of brain activation in humans: a functional magnetic resonance

imaging study. Neurosci Lett 2000;288:159–62.

[78] Becerra LR, Breiter HC, Wise R, Gonzalez RG, Borsook D. Reward

circuitry activation by noxious thermal stimuli. Neuron 2001;32:

927–46.

C.A. Porro et al. / Magnetic Resonance Imaging 22 (2004) 1539–15481546

[79] Ferretti A, Babiloni C, Del Gratta C, Caulo M, Tartaro A,

Bonomo L, et al. Functional topography of the secondary

somatosensory cortex for nonpainful and painful stimuli: an fMRI

study. Neuroimage 2003;20:1625–38.

[80] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson

RJ, et al. Placebo-induced changes in fMRI in the anticipation and

experience of pain. Science 2004;303:1162–7.

[81] Lui F, Baraldi P, Corradini M, Serafini M, Stefani R, NIchelli P, et al.

Touch or pain? An event related fMRI study. 9th International

Conference on Functional Mapping of the Human Brain, New York.

Neuroimage 2003;19(2).

[82] Buchel C, Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C.

Dissociable neural responses related to pain intensity, stimulus

intensity, and stimulus awareness within the anterior cingulate

cortex: a parametric single-trial laser functional magnetic resonance

imaging study. J Neurosci 2002;22:970–6.

[83] Kenshalo DR, Iwata K, Sholas M, Thomas DA. Response properties

and organization of nociceptive neurons in area 1 of monkey primary

somatosensory cortex. J Neurophysiol 2000;84:719–29.

[84] Davis KD. Neurophysiological and anatomical considerations in

functional imaging of pain. Pain 2003;105:1–3.

[85] Coghill RC, Morrow TJ. Functional imaging of animal models of

pain: high resolution insights into nociceptive processing. In: Casey

KL, Bushnell MC, editors. Pain imaging. Seattle7 IASP Press; 2000.

[86] Davis KD, Taylor SJ, Crawley AP, Wood ML, Mikulis DJ.

Functional MRI of pain- and attention- related activation in the

human cingulate cortex. J Neurophysiol 1997;77:3370–80.

[87] Frankenstein U, Richter W, McIntyre MC, Remy F. Distraction

modulates anterior cingulate gyrus activations during the cold

pressor test. Neuroimage 2001;14:827–36.

[88] Coghill RC, Gilron I, Iadarola MJ. Hemispheric lateralization of

somatosensory processing. J Neurophysiol 2001;85:2602–12.

[89] Downar J, Mikulis DJ, Davis KD. Neural correlates of the prolonged

salience of painful stimulation. Neuroimage 2003;20:1540–51.

[90] Peyron R, Garcia-Larrea L, Gregoire M-C, Costes N, Convers P,

Lavenne F, et al. Haemodynamic brain responses to acute pain in

humans. Sensory and attentional networks. Brain 1999;122:1765–79.

[91] Rainville P, Duncan G, Price D, Carrier B, Bushnell M. Pain affect

encoded in human anterior cingulate but not somatosensory cortex.

Science 1997;277:968–71.

[92] Hofbauer R, Rainville P, Duncan G, Bushnell M. Cortical

representation of the sensory dimension of pain. J Neurophysiol

2001;86:402–11.

[93] Kulkarni B, Jones AKP, Elliott R, Bentley D, Derbyshire SW,

Youell P, et al. Cortical processing of affective versus sensory-

discriminative aspects of pain — a PET study. Proceedings of the

10th World Congress in Pain. Seattle7 IASP Press; 2002. p. 378.

[94] Devinsky O, Morrell M, Vogt B. Contributions of anterior cingulate

cortex to behavior. Brain 1995;118:279–306.

[95] Bush G, Luu P, Posner MI. Cognitive and emotional influences in

anterior cingulate cortex. Trends Cogn Sci 2000;4:215–22.

[96] Shmuel A, Yacoub E, Pfeuffer J, Van de Moortele PF, Adriany G,

Hu X, et al. Sustained negative BOLD, blood flow and oxygen

consumption response and its coupling to the positive response in

the human brain. Neuron 2002;36:1195–210.

[97] Smith AT, Williams AL, Singh KD. Negative BOLD in the visual

cortex: evidence against blood stealing. Hum Brain Mapp

2004;21:213–20.

[98] Stefanovic B, Warnking JM, Pike GB. Hemodynamic and metabolic

responses to neuronal inhibition. Neuroimage 2004;22:771–8.

[99] Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA,

Shulman G. A default mode of brain function. Proc Natl Acad Sci

U S A 2001;98:676–82.

[100] Apkarian A, Darbar A, Krauss B, Gelnar P, Szevereny N.

Differentiating cortical areas related to pain perception from stimulus

identification: temporal analysis of fMRI activity. J Neurophysiol

1999;81:2956–63.

[101] Baron R, Baron Y, Disbrow E, Roberts TL. Brain processing of

capsaicin-induced secondary hyperalgesia. Neurology 1999;53:

548–57.

[102] Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker

HO. Neural activation during experimental allodynia: a functional

magnetic resonance imaging study. Eur J Neurosci 2004;19:

3211–8.

[103] Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic

resonance imaging evidence of augmented pain processing in

fibromyalgia. Arthritis Rheum 2002;46:1333–43.

[104] Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH.

Functional imaging of pain in patients with primary fibromyalgia.

J Rheumatol 2004;31:364–78.

[105] Petrovic P, Ingvar M. Imaging cognitive modulation of pain

processing. Pain 2002;95:1–5.

[106] Yoo S-S, Freeman DK, McCarthy III JJ, Jolesz FA. Neural substrates

of tactile imagery: a functional MRI study. Neuroreport 2003;14:

581–5.

[107] Singer T, Seymour B, O’Doherty J, Kaube H, Dolan RJ, Frith CD.

Empathy for pain involves the affective but not sensory components

of pain. Science 2004;303:1157–62.

[108] Hyvarinen J, Poranen A, Jokinen Y. Influence of attentive behavior

on neuronal responses to vibration in primary somatosensory cortex

of the monkey. J Neurophysiol 1980;43:870–82.

[109] Hsiao S, O’Shaugnessy D, Johnson K. Effects of selective attention

on spatial form processing in monkey primary and secondary

somatosensory cortex. J Neurophysiol 1993;70:444–7.

[110] Johansen-Berg H, Christensen V, Woolrich M, Matthews PM.

Attention to touch modulates activity in both primary and secondary

somatosensory areas. Neuroreport 2000;11:1237–41.

[111] Hamalainen H, Hiltunen J, Titievskaja I. fMRI activations of SI and

SII cortices during tactile stimulation depend on attention. Neuro-

report 2000;11:1673–6.

[112] Johansen-Berg H, Lloyd DM. The physiology and psychology of

selective attention to touch. Front Biosci 2000;1:D894 -D904.

[113] Macaluso E, Frith CD, Driver J. Supramodal effects of covert spatial

orienting triggered by visual or tactile events. J Cogn Neurosci

2002;14:389–401.

[114] Spence C. Multisensory attention and tactile information processing.

Behav Brain Res 2002;135:57–64.

[115] Bushnell M, Duncan G, Hofbauer R, Chen J-I, Carrier B. Pain

perception: is there a role for primary somatosensory cortex? Proc

Natl Acad Sci U S A 1999;96:7705–9.

[116] Brooks CW, Nurmikko TJ, Bimson WE, Singh KD, Roberts N. fMRI

of thermal pain: effects of stimulus laterality and attention. Neuro-

image 2002;15:293–301.

[117] Bantick SJ, Wise R, Ploghaus A, Clare S, Smith SM, Tracey I.

Imaging how attention modulates pain in humans using functional

MRI. Brain 2002;125:310–9.

[118] Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B,

et al. Distraction modulates connectivity of the cingulo-frontal cortex

and the midbrain during pain — an fMRI analysis. Pain

2004;109:399–408.

[119] Villemure C, Bushnell MC. Cognitive modulation of pain: how do

attention and emotion influence pain processing? Pain 2002;95:

195–9.

[120] Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, et al.

Imaging attentional modulation of pain in the periacqueductal gray in

humans. J Neurosci 2002;22:2742–8.

[121] Remy F, Frankenstein U, Mincic A, Tomanek B, Stroman PW. Pain

modulates cerebral activity during cognitive performance. Neuro-

image 2003;19:655–64.

[122] Drevets W, Burton H, Videen T, Snyder AZ, Simpson JR, Raichle

ME. Blood flow changes in human somatosensory cortex during

anticipated stimulation. Nature 1995;373:249–52.

[123] Chua P, Kraus M, Toni I, Passingham R, Dolan R. A functional

anatomy of anticipatory anxiety. Neuroimage 1999;9:563–71.

C.A. Porro et al. / Magnetic Resonance Imaging 22 (2004) 1539–1548 1547

[124] Hsieh J, Stone-Elander S, Ingvar M. Anticipatory coping of pain

expressed in the human anterior cingulate cortex: a positron emission

tomography study. Neurosci Lett 1999;262:61–4.

[125] Carlsson K, Petrovic P, Skare S, Petersson KM, Ingvar M. Tickling

expectations: neural processing in anticipation of a sensory stimulus.

J Cogn Neurosci 2000;12:691–703.

[126] Porro CA, Cettolo V, Francescato MP, Baraldi P. Functional activity

mapping of the mesial hemispheric wall during anticipation of pain.

Neuroimage 2003;19:1738–47.

[127] Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M,

Fukuyama H, et al. Expectation of pain enhances responses to

nonpainful somatosensory stimulation in the anterior cingulate cortex

and parietal operculum/posterior insula: an event-related functional

magnetic resonance imaging study. J Neurosci 2000;20:7438–45.

[128] Ploghaus A, Tracey I, Gati J, Clare S, Menon R, Matthews P, et al.

Dissociating pain from its anticipation in the human brain. Science

1999;284:1979–81.

[129] Critchley HD, Mathias CJ, Dolan RJ. Neural activity in the human

brain relating to uncertainty and arousal during anticipation. Neuron

2001;29:537–45.

[130] Craig A. Pain mechanisms: labeled lines versus convergence in

central processing. Annu Rev Neurosci 2003;26:1–30.

[131] Bellgowan PSF, Saad ZS, Bandettini PA. Understanding neural

system dynamics through task modulation and measurement of

functional MRI amplitude, latency, and width. Proc Natl Acad Sci

U S A 2003;100:1415–9.

[132] Buchel C. Perspectives on the estimation of effective connectivity

from neuroimaging data. Neuroinformatics 2004;2:169–74.

[133] Mechelli A, Price CJ, Friston KJ, Ishai A. Where bottom-up meets

top-down: neuronal interactions during perception and imagery.

Cereb Cortex 2004;14:1256–65.

[134] Sun FT, Miller LM, D’Esposito M. Measuring interregional

functional connectivity using coherence and partial coherence

analyses of fMRI data. Neuroimage 2004;21:647–58.

[135] van de Ven VG, Formisano E, Prvulovic D, Roeder CH, Linden DE.

Functional connectivity as revealed by spatial independent compo-

nent analysis of fMRI measurements during rest. Hum Brain Mapp

2004;22:165–78.

C.A. Porro et al. / Magnetic Resonance Imaging 22 (2004) 1539–15481548