pain and the brain: specificity and plasticity of the ... · review pain and the brain:...

Review

Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain

A. Vania Apkarian a,b,!, Javeria A. Hashmi a, Marwan N. Baliki aaDepartment of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USAbDepartments of Anesthesia and Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Descartes proposed that all observable human behavior could bedivided into 2 categories, the simple and the complex. Simplebehaviors were those in which a given sensation always, determin-istically, produced the same behavioral response. . .. Complexbehaviors, in contrast were those in which the linkage betweensensation and action was unpredictable and subject to the vagariesof volition. . .. They were produced when sensory data were trans-mitted from the nervous system to the nonmaterial soul, the soulmade a decision about what course of action to undertake, and thisvolitional command was then passed to the machinery of the bodyfor execution.From Paul W. Glimcher, 2003, Decisions, Uncertainty, and the Brain

1. Introduction

The state of our understanding of the interaction between painand the brain is undergoing a veritable revolution,with newsurpris-ing observations accumulating at a fast pace. A cursory search inPubMed for the term: ‘‘functional AND MRI AND pain AND brain’’identifies875papers and138 reviews.Wewill not goover thismate-rial. Here we highlight ideas regarding the transition of the humanbrain from acute to chronic pain, based primarily on human func-tional andanatomical brain imaging studies,whereweexaminecur-rent advances in understanding, possible underlying mechanisms,and discuss implications regarding both the properties of the brain,our understanding of pain, and possible novel therapeutic venues.

Aristotle categorized pain as an ‘‘affect,’’ separating it from pri-mary senses. On the other hand, Descartes illustrated a skin tonerve to brain pathway for the transduction of a burning stimuluson the skin to a pain qualia. This dichotomy persists in the discus-sion of pain mechanisms to this day. It has been exemplified byopposing positions by classic pain scientists such as Hardy andBeecher, and Ed Perl, Ron Melzack, and Pat Wall. Pat Wall in factused Descartes drawings as a means of ridiculing the reductionistattitude that most pain scientist exhibited at his time and that con-tinues unabated in current research. The IASP definition of pain(http://www.iasp-pain.org/) ducks the issue by marrying the 2

concepts together, and by also stating that pain is subjective andmay not be related to an actual injury. This position, however,poses a new quandary: if pain is subjective and minimally relatedto a stimulus why, and how, do we study its related brain activity?Similarly, if pain is both sensory and emotional, how well have wefaired in disentangling these components in the brain? And how dothese modalities differ between acute and chronic pain? We tacklethese issues here, attempting to demystify current understandingof the brain in pain by emphasizing mechanistic implications of re-search in the field.

2. Brain representations for acute pain: how much further pastphrenology?

Human functional brain imaging, since its inception in early1990s, has concentrated heavily on examining brain propertiesfor acute painful stimuli in healthy subjects. This is not surprising,as mapping stimulus–response representations imposes fewermethodological challenges than studying chronic pain [94]; yetthere still remain many unanswered critical questions regardingrepresentation/encoding/processing of acute pain in the brain. Wewill not cover this topic in detail. However, important new conceptsare highlighted providing the opportunity to then contrast proper-ties of brain circuitry between acute pain and clinical pain.

A large number of studies have demonstrated a network of brainareas consistently activated with acute thermal, mechanical, andchemical painful stimuli [4,15,100,101,112]. These brain areas, orsome sub-set, super-set, of them have been labeled as the ‘‘painma-trix’’ and used as a brain signature for an activity pattern associatedwith pain. The data reviewed here argue against this notion by indi-cating that there is no unitary set of brain regions that one canequate to presence of pain. This is especially true for distinct clinicalchronic pain conditions that show unique brain activity patterns.Therefore, the spatial patterns seen for acute pain, although consis-tent across many laboratories and brain imaging paradigms, areonly valid in healthy subjects and only for acute pain. Localizing aconsistent set of brain regions activated with acute pain has beenan important step forward (see, for example, review [20]). How-ever, until we delineate functional roles of involved regions andthe temporal dynamics of interactions [5,79], our understandingof this circuitry remains at the level of modern phrenology (brain-based phrenology) and even of epi-phenomenology. Unless the

0304-3959/$36.00 ! 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.pain.2010.11.010

! Corresponding author at: Department of Physiology, Northwestern University,Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA. Tel.: +1312 5030404; fax: +1 312 5035101.

E-mail address: [email protected] (A.V. Apkarian).

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specificity, causality, capturing of features, and calculations of un-ique parameters of pain and its spatiotemporal dynamics are iden-tified, the existing ‘‘pain maps’’ provide little more than evidencefor responses that may all be unessential, for example, atten-tional/motoric/autonomic/anxiety/fear shifts in the presence or inanticipation of impending pain [1].

Correlation to stimulus parameters, primarily its intensity, is 1metric used to differentiate between brain regions activated withacute pain. However, this leads to a majority of brain regions thatare identified to be active in acute pain showing such correlations[85,25]. Yet, Coghill et al. used this approach and were able to iden-tify that brain regions encoding painful stimulus intensities are pri-marily in the hemisphere contralateral to the stimulated body site[24]. The same group examined the discrimination between stim-ulus localization and stimulus intensity to further subdivide thebrain areas related to acute pain [80], and advance the exciting no-tion that pain, similar to vision and audition, may also comprise aventral, in this case, intensity coding stream, and a dorsal, spatiallocalization stream. We as well as other groups have emphasizedthe need to identify brain activity relative to the subjective percep-tion of pain [27,64,41,59,68]. After all, we all accept that the brainshould reflect perception, and in fact the classical view has beenthat even peripheral primary afferent nociceptors show a close cor-respondence in their stimulus–response curves to the psychophys-ical power function that one observes for thermal or mechanicalpainful stimuli in humans. On the other hand, group averagedafferent activity seems to fail to correlate with ratings of perceivedpain [71]. Thus, it is not clear whether there even exist differencesin brain activity for stimulus presentation versus subjective per-ception, and it is possible that brain activity based on stimulus orperception parameters are both looking at the same brain regionswith minor changes in interpretational emphasis. Thus, we arriveat a fundamental question: namely, is subjective perception of paindistinguishable from brain regions better representing painfulstimuli? If the distinction exists, then the latter areas would bemore properly labeled as nociceptive regions, while the formerwould be pain-perceptive areas. This distinction in fact would cor-respond to Descartes idea of the difference between the simple andcomplex categories, with the simple executed by sensory pathwayswhich must be integrated with the subjectivity (Descartes’ soul) togive rise to perceived pain.

2.1. Distinct brain areas can be called nociceptive or perceptive

Implicit in all studies in which brain activity is related to stim-ulus parameters is the notion that these parameters are uniformlyreflected in perceived subjectivity of pain, and of course in a groupaverage this is certainly correct (see, for example Fig. 1 in Balikiet al. [9]). Yet, when one asks subjects to continuously rate theirperception of pain, for a constant thermal stimulus applied to thesame body site in all subjects, we observe large interindividual var-iability of responses [9] (Fig. 1, top panel). Furthermore, based ondifferences in stimulus properties, there are marked effects ofadaptation and sensitization on pain dynamics [51]. This observa-tion per se indicates that brain imaging studies, where individualsubjective differences in perceived pain are not taken into account,a large portion of the brain response variability is directly due toacross-subject differences in perceived pain. On the other hand,variability of perceived pain in contrast to the constancy of thestimulus provides the opportunity of differentiating between brainareas that better correlate with each, that is, distinguishing be-tween representation of physical stimulus parameters, nociceptiveregions, from regions better reflecting subjectivity or perception ofpain.

Parts of anterior cingulate (ACC) show a high incidence of acti-vation in pain tasks [4]; as a result, ACC is commonly dubbed as the

main brain region signaling pain, or emotional pain. Yet single unitrecordings from the region in awake human beings do not shownociceptive-responsive cells. Instead, ACC neurons seem to re-spond to cognitively demanding situations, including those withemotional valence [29], implying that the region is more involvedin anticipation of salient conditions. It is also important to notethat a large number of nonpainful tasks activate various portionsof the cingulate cortex. Similar to the ACC, the insular cortex showsa very high incidence of activation in pain tasks [4], and parts of theregion are dubbed signaling either sensory or emotional/affectiveproperties of pain. Electrical stimulation of posterior parts of theinsula in human beings does give rise to pain-like sensations[68]. In addition, some lesion studies imply that insults to theinsula may decrease pain perception [13,88]. A more recent study,on the other hand, shows that unilateral insula lesions increase,rather than decrease, thermal pain responsiveness [99]. Similarlyto ACC, insula is also activated for a very large number of nonpain-ful tasks [58].

Given the importance of the cingulate and insula in pain per-ception, we analyzed these regions for spatial segregation alongthe dimensions of nociceptive representation versus pain percep-tion, using published data [9]. Fig. 1 (bottom panel) shows the spa-tial segregation of the 2 brain regions along stimulus–perceptionrepresentation. We observe that the anterior portion of the cingu-late and the posterior insula better reflect pain perception, whereaslarge portions of both structures are mainly related to thermalstimulus properties.

2.2. Strength of relationship between brain activity and painconsciousness

The fact that we can localize brain areas that preferentially en-code subjective perception of pain first implies that the transfor-mation from stimulus space to subjectivity is a cortical process,the details of which remain to be understood. It also raises theimportant question of the extent to which this region reflects painsubjectivity, which also impinges on issues regarding conscious-ness and pain. To date, human beings lack physical theories of con-sciousness. As a consequence, the best evidence we can advance ofrelationships between consciousness and biological processes canbe correlative. The strength of evidence for the portion of insulabetter related to pain perception is shown in Fig. 2. The figure illus-trates that the brain activity, as determined by functional magneticresonance imaging (fMRI), in this insular region reflects the magni-tude of subjective pain every time a participants indicates that indi-vidual’s perceived magnitude of pain, with a linear correlationbetween brain activity and magnitude of subjective perception.Therefore, there is a very tight relationship between this area ofthe brain and pain consciousness. Besides a second more lateralextension of the region in the prefrontal cortex, no other brain re-gion has shown such a representation of subjective pain. On theother hand, as Fig. 2 shows, the region also faithfully reflectedbrain activity for rating the magnitude of visual stimuli. Therefore,we can state that this area is unique in reflecting pain subjectivitybut is not specific to any particular sensory modality. We have thusproposed that the area is instead specialized in extracting subjec-tive magnitudes in general [9], and argue the notion that the insu-lar stream of information processing, in analogy to the dorsal andventral visual streams that encode ‘‘where’’ and ‘‘what’’ may beextracting a signal in relation to subjective ‘‘how much.’’ Thus wepropose that conscious perception of pain is the end-product ofthe transformation of nociceptive information to a magnitude,achieved in a brain region that also extracts magnitudes for visuallengths, and in analogy also perhaps visual brightness, auditoryloudness, olfactory pungency, etc. – relationships that remain tobe systematically studied.

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2.3. Temporal transformation of pain representation: fromanticipation to perception to relief

The fact that pain is processed far more slowly by the nervoussystem than any of the other sensory modalities makes it an idealsensation with which fMRI brain activity can be segmented in thetime domain to component circuitry that process incoming infor-mation and spatiotemporally extract specific features. Yet anotherfundamental property of pain is its salience, which simply corre-sponds to the common experience that the prospect of impendingpain or the experience of pain both engage one’s attention, forcing

a motivational state in which the subject needs to make decisionsas to the immediate future. Of course, proper anticipation ofimpending pain is fundamental for survival and must thus be clo-sely linked to reward, motivation, and decision making [33]. Brainactivations to signals anticipating impending pain has been studiedby a number of groups [12,19,82–84,107]. For the most part, thesestudies concentrate on examining distortions of brain activity forthe stimulus in the presence of anticipatory cues, as well as brainresponses to the cue itself. In a recent study, we demonstrated thatnucleus Accumbens (NAc) signals anticipation of pain perceptioneven when the stimuli are applied randomly and in the absence

Fig. 1. Segregating the cingulate and insular cortices along the stimulus and subjective perception dimensions for acute thermal pain. (A) Variability of subjective ratings ofpain is illustrated for 4 subjects. (B) Temporal and intensity properties for a constant thermal stimulus that was applied to the skin on the back. (C) Variability of correlationbetween the stimulus and ratings for the 16 subjects in the study. (D) Contrasting cingulate gyrus and insula activity between stimulus and perception identifies statisticallysignificant regional differences in each area along these dimensions. Green circles are regions where activity was extracted and correlated either with the stimulus orindividual subject perceptions, corresponding bar graphs are in the right, which indicate the sign and extent of difference between representation of stimulus and perception.Anterior cingulate and posterior insula are regions best related to pain perception. All data are derived from the study described by Baliki et al. [9].

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of any external cues [11]. At the start of an unpredictable painfulthermal stimulus, NAc activity captured the rate of change of thestimulus applied on the skin, an activity that preceded the stimulusitself as well as the related perception. In Fig. 3, we reanalyze thosedata by contrasting brain activity among 3 epochs, anticipation(early activity at start of stimulus), perception, and relief (lateactivity at stimulus end). The results indicate segregated networksthat preferentially are involved in each epoch, with anticipationengaging NAc, mid-cingulate, and anterior insula; perception acti-vating anterior cingulate, mid- and posterior insula, and large por-tion of dorsal striatum; and pain relief engaging brainstem activity,especially the periaqueductal grey (PAG). The brain networks iden-tified in Fig. 3 complement those illustrated in Fig. 2, in that re-gions involved in anticipation are also regions that better relateto stimulus, rather than perception, encoding. The PAG activity issimilar to earlier brain imaging observations of the region signalingpain relief [31,32,110] and consistent with the region being in-volved in descending anti-nociceptive modulation, as repeatedlyshown in animal studies. The main point of Fig. 3 is the illustrationthat distinct portions of brain regions known to be involved inacute pain show a specific spatiotemporal evolution, as these areasextract distinct types of information in relation to the nociceptivestimulus and ensuing subjective perception of pain.

The networks identified in Fig. 3 were determined using a priorivectors that would define the types of information that can be ex-tracted within a given time window. An alternative approach todetermining the spatiotemporal evolution of information flow dur-ing pain perception would be to interrogate the properties of brainareas identified to be active during the task. The latter approachwas used in a recent study [9], and the main outcome is illustratedin Fig. 4. Fourteen brain regions were observed active during ratingof acute thermal pain. The thermal stimulus peak (after convolvingwith fMRI hemodynamic function) on average preceded the peakperception by approximately 8 s. Within this time window, onecould then examine the sequence of activations across the 14 brainareas by determining each region’s peak activity. Moreover, as theshape of the brain activity differs between brain regions, its simi-larity can be tested to the stimulus and perception. These 2 param-eters provide a 2-dimensional space within which the 14 brainregions can be localized. Fig. 4 shows that the amygdala andmid-ACC peak before the stimulus itself peaks. Thus, the mid-ACC, now together with the amygdala, is again showing an antici-patory response. We then observe a sequence of activations inbrain regions that are consistent with being more nociceptive,including the thalamus, dorsal striatum, supplementary motorarea, and nociceptive insula, all of which peak just after the stim-ulus peaks and their activity patterns show better similarity tothe stimulus. On the other hand, perception-related magnitude re-gion of the insula peaks much later, just preceding perception, andits activity better correlates with perception. Thus we observe aspatiotemporal sequence of activity that is consistent and comple-mentary to the sequence identified in Fig. 3. The information trans-formation from the NAc, amygdala, and mid ACC, to the thalamusand nociceptive insula, and finally to perceptive/magnitude encod-ing insula closely corresponds to Coghill’s notion of a ventralstream specialized in processing intensity of painful stimuli [80].Thus, detailed information processing steps can be observed andparceled in the human with fMRI, especially for acute pain wherethe sequence of transitions from stimulus to perception is slow en-ough to enable such analyses.

2.4. Medial and lateral pain systems and emotional and sensoryrepresentations

Two elegant studies first established that human brain activitymay be subdivided along emotional and sensory components[53,86], in whichmid-ACCwas identified as beingmodulated by af-fect andprimary somatosensory cortexby sensoryproperties of painperception. Complementary evidence along these lineswere studiesby Zubieta et al. [111], who showed distinct brain activations corre-lated to the sensoryor affective componentsof theMcGill PainQues-tionnaire (MPQ). These observations build on notions that date tothe beginning of the twentieth century when Sherrington [97], in1906, advanced the idea that pain has both sensory and emotionalqualities, andHeadandHolmes [52], in1911,distinguishedbetweenprotopathic and epicritic pathways. Ideas that were further pro-pounded in the 1960s [69] regarding a medial and lateral spinotha-lamic pathways, with the former being involved in affect and thelatter in sensory encoding. Yet this concept has not progressedmuchfurther, and the notion of segregating brain activity for acute painalong these 2 dimensions remains relatively weak. For instance, itshould be noted that many spino-cephalad pathways show consid-erable crosstalk [42,49]. Amajordifficulty is inherent in the IASPdef-inition, stating that pain is always unpleasant, based on the fact thatintensity of pain and magnitude of unpleasantness of pain are al-most always highly correlatedwith each other. Therefore, renderingdistinctions between these components is difficult. Despite theweak evidence regarding segregation of sensory and affectivemechanisms of pain, authors almost arbitrarily assign the tag of

Fig. 2. Insular region that reflects pain perception shows a one-to-one relationshipwith each epoch where pain is reported. Moreover, this area also just as faithfullyencodes perceived magnitudes for bars displayed visually. Thus, the brain areaaccurately reflecting pain subjectivity seems to be encoding magnitudes in generaland thus lacks specificity. (A) Illustration of the method used for generating thescattergrams in (B). For each epoch of perceived pain, the magnitude of peak painrating is extracted and correlated to the peak fMRI BOLD activity identified withinthe thermal stimulus time window (illustrated in red boxes). (B) Left figure showsthe region of the insula that encodes perceived pain and perceived magnitude oflengths of visual bars (circled region is right magnitude related insula, mag-INS).First scattergram is the epoch-by-epoch pain perception to BOLD relationship,across all subjects. Second scattergram is for the visual magnitude-rating task.Correlation coefficients are indicated and closely match for both sensory dimen-sions. Data and figure adapted from the study described in Baliki et al. [9].


sensory or affective to various brain regional activations, relyingmostly on the classical anatomy that shows that lateral thalamicregions project to primary and secondary somatosensory regions,whereas medial thalamic projections target limbic and frontalcortex. The case for insular activity is worst, as even the anatomicalguide fails for this brain region.

It has recently been argued that an alternative approach to dis-tinguishing between sensory representation and affect would be toexamine the brain from the viewpoint of motivation [33]; with thisapproach, we were able to identify that NAc activity not only sig-nals anticipation of impending pain but seems to also calculatethe reward value of pain relief at stimulus cessation by integratinginformation from the magnitude region of the insula in healthysubjects [11]. The motivational approach provides the opportunityto test the emotional valuation of pain by behavioral and decision-making measures independent of sensory encoding. Yet this line ofwork, especially for pain, remains in its infancy.

2.5. Overall summary

The section above illustrates the brain dynamics for acute pain.The brain regions involved and their properties provide a back-ground relative to which we can contrast brain activity for clinicalpain conditions.

3. Functional properties of the brain in chronic clinical pain

Clinically, the most relevant conditions in which human brainimaging can have a substantial impact are chronic conditions, asthey remain most poorly understood and minimally treatable byexisting therapies. The IASP definition of chronic pain is eitherbased on duration of pain persisting past an inciting event(arbitrary number of 3–6 months) or pain extending past the heal-ing process from the initial injury. We have commented on theinadequacy of this definition [3] and also proposed possible

Fig. 3. Segregating brain activity for acute thermal pain perception between anticipation, perception and pain relief identifies distinct networks sequentially activated duringperception of acute pain. Three vectors separated in time were contrasted for a thermal painful stimulus that was a randomized sequence of stimuli where intensity durationand inter-stimulus intervals were not predictable. The anticipation vector identified increased activity preferentially related to only the start of the stimulus; while perceptionwas identified by subjective ratings of pain; and relief period was identified for increased activity in the time window when the stimulus was returning to baseline. (A) Threeseparate and complementary networks are identified. (B) Differential activity for the 3 phases of pain perception is illustrated for indicated regions (green circles in A).A = anticipation, P = perception, R = relief. Data are derived from the study described in [11].


extensions based on the recent brain imaging evidence [2]. Thechallenge in studying clinical chronic pain conditions is to distilthe relevant pain from other confounds and, relate brain activitydirectly to this clinical pain. As most chronic pain conditions re-main minimally controlled by therapeutics, and as therapeutics,especially pharmacological approaches with central action, willalso interfere nonspecifically with brain activity, there remains lit-tle leeway of options for such brain imaging studies. A number ofrecent reviews summarize fundamental findings regarding brainactivity and anatomical changes in chronic pain [3,61,100]. Ad-vances in understanding complex regional pain syndrome (CRPS)in the context of cortical reorganization has also been reviewed[95].

3.1. Specificity of brain activity relative to spontaneous fluctuations ofthe pain of chronic back pain

Even though many chronic pain patients show signs of allo-dynia and/or hyperalgesia to various stimuli applied to the skin,by far the most prominent exhibition of chronic pain is uncon-trolled, ongoing pain in the absence of any external stimulation.We have uncovered that this spontaneous pain has characteristicfluctuations (in the scale of seconds to minutes) that are distinctfor different types of chronic pain and that cannot be mimickedby healthy subjects pretending to have pain [35]. Therefore contin-uous ratings of these fluctuations can be used as a tool to studyspontaneous pain-related brain activity. In fact, given that contin-uous ratings can capture spontaneous pain, the subjective percep-tual rating of pain becomes a universal tool with which one cantease out specific pain components, as the same exact approachcan be used to rate a stimulus, such as described above for thermalpain, it can also be used to provoke clinically relevant pains, suchas localized allodynia and hyperalgesia, as well as spontaneouspain (after properly correcting for motor, cognitive, and attentionalconfounds). We have used this technique to identify brain activityfor spontaneous pain in chronic back pain patients [8]. The surprisewas that the brain region best reflecting high magnitude of backpain was localized to the medial prefrontal cortex (mPFC),

extending into anterior ACC, a region not anticipated by acute painstudies. Additionally, brain areas observed for acute pain, like por-tions of the insula and mid-ACC were only active transiently andonly when the back pain magnitude was on the increase. These re-sults are exciting because, for the first time, we are able to observebrain activity reflecting the subjective perception of the pain thatchronic back pain patients come to the clinic to complain about(or an objective marker for the Cartesian soul of back pain). Weinterpret the transient activity as a nociceptive signal from theperiphery, which then is converted into a sustained emotional suf-fering signal in mPFC.

These observations are based on patients’ own ratings in whichthe experimenter has no control and cannot discern whether thepatient is actually reporting anything factually related to the phe-nomenon of interest or is simply rating whatever comes to thatindividual’s mind. This in fact is a major weakness of many similarbrain-imaging studies and requires an alternative approach toidentify veracity of the results. We overcome this limitation byperforming an across-subject correlation analysis examining therelationship between intensity and duration of back pain to brainactivity. Fig. 5 shows that mPFC activity tightly correlates withamount of pain the patients reported just before starting brainscans, and also that the insular cortex activity correlates with thenumber of years each subject had been suffering from back pain.Thus, the 2 fundamental clinical properties of the back pain arecaptured at a high enough correlation strength that we can statethat, looking at these brain regions in other such patients, weshould be able to predict their back pain magnitude and durationwithin 20% error. These findings were reproduced in a secondgroup of chronic back pain patients and were also compared withbrain activity for rating a thermal painful stimulus applied to theskin on the back. When insular and mPFC activity was examinedin these patients and in healthy subjects, we found that mPFCactivity was related to spontaneous pain but not with thermal pain,

Fig. 4. Temporal sequence of brain activity for thermal painful stimuli determinedin relation to anticipated peak for the stimulus (vertical line at 10 s from stimulusstart) and actual reported peak of pain perception (vertical line at 17 s). Verticalscale is similarity of brain activity shape to the stimulus and perception shapes(negative values are better correlations to stimulus shape while positive values arebetter correlations to perception, determined for specific BOLD activity extractedfor all regions listed on the right). The anterior cingulate (ACC) and amygdala(Amyg) peak at times prior to the stimulus peak, implying that these regions aremore related to anticipation of impending pain. The thalamic activity (Thal) peaksjust after the stimulus and best reflects stimulus shape. Nociceptive insula (noci-INS) and magnitude insula (mag-INS) are segregated by time and shape similarity,reflecting their respective functional labels. The blue curve approximates the brainspatio-temporal evolution of nociceptive information being transformed intosubjective consciousness of pain. BG = basal ganglia; DPc = dorsal prefrontal cortex;IPS = inferior parietal sulcus; SMA = supplementary motor area; VPc = ventralprefrontal cortex. Adapted from [9].

Fig. 5. Brain activity for rating spontaneous fluctuations of back pain in chronicback pain patients show a strong correlation with intensity and duration of thecondition across all participating patients. The observed correlations are strongenough that we can assert that the task can be used to predict intensity andduration of chronic back pain in individual subjects within an error of 20%. Figureadapted from [8].


while the insula activity was related to the thermal pain but notspontaneous pain. With this technique, we were able to demon-strate a double dissociation for representation of perceived magni-tudes between acute thermal pain and spontaneous chronic backpain.

Thus we can assert that, at least in this group of chronic pain pa-tients, different brain areas encode the perceived magnitude fordistinct types of pain. The prevalent expectation for brain activityin chronic pain is a sustained or enhanced activation of the brainareas already identified for acute pain. This view is partly impliedby the chronic pain definition and by notions of specificity theoryor labeled line theory of pain (where supraspinal organization andrepresentation of pain is assumed to be through fixed and immu-table routes). This is exactly what we do not see. Instead these re-sults imply that functional anatomy or physiology or somecombination of both have changed in the brain of chronic back painpatients. Below we elaborate on underlying possible mechanismsfor this reorganization.

It is also important to remember that the close relationships be-tween fundamental properties of back pain and activity in mPFCand insula are correlational, and that both mPFC and insula re-spond to a long list of cognitive and emotional states. Thus, thephrenology of observing these areas activated and interpretingthem as evidence for existence of pain is false. In fact, even takinginto account the underlying dynamic network is most likely a poor(linear) underestimation of the total brain state that constitutessuch a condition, and we suspect that current concepts of the brainencoding any given perceptual/cognitive condition remains verylimited.

3.2. Specificity of brain activity across multiple chronic pain conditions

As explained above, the approach of continuous rating of fluctu-ations of pain may be applied for a variety of conditions. Besidesback pain, we have now studied brain activity for spontaneous painin postherpetic neuralgia and its modulation by a lidocaine patchtherapy [39], in chronic pelvic pain patients (manuscript in prepa-ration), and in osteoarthritis (manuscript submitted); in addition,in post-herpetic neuralgia we have examined brain activity for tac-tile allodynia, and in osteoarthritis for mechanical painful stimula-tion of the arthritic knee. The brain activations observed in thesevarious pain groups are summarized in Fig. 6A. What is commonbetween all the brain maps is the presence of pain. Thus we canask the simple question as to what brain areas are commonly ac-tive between these conditions, which would identify the centerof pain perception, irrespective of the type of pain. Unfortunatelythe conjunction across all results in an empty map, suggesting thatdistinct clinical pain involve unique brain regions. The figure alsoillustrates that thermal or mechanical acute painful stimuli inhealthy subjects or in chronic pain, in this case osteoarthritis, theyessentially activate very similar regions. On the other hand, brainactivity for spontaneous pain seems to involve different brain re-gions for distinct chronic pain groups. To better illustrate thispoint, we show group-average magnitude of brain activity in 2 lim-bic brain areas and 2 sensory areas and for a variety of groups andstimuli, illustrating a complex gradient of brain activity acrossthese brain areas that distinguishes between stimulus types andchronic pain types.

Fig. 6B addresses the issue of specificity of brain activity for var-ious pain conditions from the viewpoint of a single brain regionand in relation to individual subjects’ activity. As mPFC is activatedfor spontaneous fluctuations of chronic back pain, we interrogateits activity across a number of other acute and chronic pain condi-tions, and observe that it has a very high accuracy is distinguishingchronic back pain from other chronic pain conditions and fromacute pain in healthy subjects.

3.3. Presence of chronic pain interferes with brain processing ingeneral

Above we concentrated on the evidence for specific brain activ-ity signatures for acute and chronic pain. Given the salience ofpain, one expects that presence of pain will distort brain processingof other information. Interaction between acute pain and sensoryand emotional distractions has been repeatedly documented[62,63,105,106]. Here we briefly review the accumulating evidenceregarding chronic pain. Our first main observation of chronic painstate disrupting brain processing was observed in postherpeticneuralgia patients. We have studied these patients before and afterlidocaine patch treatment, in an open-label study in which sponta-neous pain was significantly decreased with the therapy. As the pa-tients rated their ongoing pain on a visual bar, we tested the ideathat whole-brain activity may be modulated by the intensity ofthe chronic pain for both the pain and non-pain tasks [39]. Fig. 7shows that posterior parietal activity is generally decreasedwhereas prefrontal medial and lateral activity is increased for bothtask with intensity of this pain. Parietal decreased activity suggeststhat brain attentional networks are attenuated by the chronic pain,whereas the frontal increased activity may be due to cognitive andemotional enhanced processing. Yet, the observed brain regionsmodulated are vast and complex, and undoubtedly other process-ing abilities are distorted in these patients. In a second, more sys-tematic approach to the question, we examined brain activitydifferences between healthy subjects and chronic back pain pa-tients for rating the fluctuations of a visual bar. Performance wasmatched between the groups and increased brain activity alsomatched. On the other hand, decreased activity was significantlydifferent [10]. As the brain regions in the decreased activity corre-sponds to a specific brain network, default-mode network, wetested the balance between positively and negatively correlatednetworks and could show that the overall balance of these net-works is shifted in the chronic back patients. These results suggestthat the brain in the resting state (brain activity in the absence ofsubjects doing anything specific) should also be distorted inchronic pain conditions, and this in fact has now been assertedfor a number of clinical conditions [21,22,66,75]. The study byMalinen et al. [66] is noteworthy, as the authors extend the obser-vations of distorted resting state networks to also report that thefrequency of brain activity during rest is higher in the insula andanterior cingulate in chronic pain patients (Fig. 8). We have beenable to replicate the latter result in chronic back pain patientsand additionally to demonstrate that the increase in power at thehigh-frequency range is related to the characteristics of the backpain (manuscript in preparation). It should be mentioned thatstudying chronic pain patients’ brain during rest promises to beyet another fruitful venue that should inform us of the globaldynamical properties of the human brain in pain. How do suchchanges come about? Are they specific for different clinical condi-tions? To what extent are they driven by anatomy, behavior, orperipheral reorganization? And how are they modulated by thera-peutics? These are all exciting and addressable questions.

3.4. Chronic pain distorts motivational value of analgesia

Above we concentrated on the evidence for specific brain activ-ity signatures for acute and chronic pain. Here we identify interac-tions between motivational systems in acute pain and how theyare modified by chronic pain. Acute pain plays a protective rolein that its presence elicits the motivation to escape or avoid expo-sure to minimize further damage and its termination provides asense of relief. Together these processes contribute to predictingthe utility and costs of competing goals and in behavioral decisionsin the presence of conflict between potential threat and reward.


Chronic pain lacks these motivational advantages and instead im-poses a persisting stress on these protective and adaptive systems.Only 1 paper has addressed chronic pain from the view of moti-vated behavior, and the results are surprising and unexpected [11].

We [8,9,11] and Derbyshire et al. [30], in an earlier study, haveshown that the perceived magnitude of thermal pain and related

representation of the stimulus and perception do not differbetween chronic back pain patients and healthy subjects. On theother hand, a number of studies do demonstrate increased brainactivity for mechanical pain in distinct chronic pain conditions[41,43,81]. It is not clear where the discrepancy between thesestudies lies; is it due to differences in sensory modality tested, ie,

Fig. 6A. Brain activity patterns for various clinical chronic pain conditions. Activity maps: are group-averaged responses for different pain conditions. Activity maps: Thermalpain, knee-pressure-induced pain in healthy subjects, and in osteoarthritis patients (OA) show similar patterns of brain activity, implying that all 3 results correspond to acutepain activity. In contrast, brain activity for spontaneous pain in different clinical conditions (chronic back pain [CBP], osteoarthritis [OA], pelvic pain [CPPS], and PHN, post-herpetic neuralgia [PHN]) show different activity patterns, engaging to different extents sensory and limbic brain areas. In PHN, tactile allodynia and spontaneous pain evokerelatively distinct brain regions too. Bar graphs: Magnitude of activity in 2 limbic regions (mPFC and Amygdala) and 2 sensory regions (thalamus and insula) are compared for4 groups: healthy subjects for thermal pain, Healthy th; chronic back pain patients for spontaneous pain, CBP sp; post-herpetic neuralgia for spontaneous pain, PHN sp, andfor tactile allodynia, PHN al). Thermal pain and PHN allodynia show larger activity in the sensory regions, while spontaneous pain in CBP and PHN evoke more limbic activity.


mechanical central sensitization but not thermal, or to technicaldifferences? Still, the lack of evidence for thermal hyperalgesia inchronic back pain seems convincing. On the other hand, whenbrain activity is contrasted for thermal pain between healthy con-trols and chronic back pain patients, we observe NAc activity dis-tinguishing between the groups [11]. Moreover, the difference inNAc activity between the groups could be attributed to its phasicresponse at the end of a thermal stimulus, with healthy subjectsshowing a signal that reflects prediction of reward, whereas the pa-tients showing a signal that is instead more consistent with a lackof predicted reward and even perhaps a disappointment. TheseNAc responses reflect that chronic pain patients anticipate

analgesia from acute pain and, in this way, the value associatedwith acute pain is distorted in these patients. In fact, this reversalof signal was strong enough that it distinguished the groups ataccuracy of more than 90%. The result is remarkable because it isindependent of the subjective pain perception. Thus, this distortedassessment of analgesia is not captured in the conscious pain rat-ings; instead it is should be regarded as a subconscious evaluationthat must, in turn, color subsequent actions/decisions.

In search of a brain source for the distorted NAC activity, weexamined its connectivity to the rest of the brain in both groups.The identified networks were distinct. In healthy subjects, NAcwas mainly correlated to the insula, whereas in the patients itwas better correlated with mPFC. Moreover, the strength of con-nectivity between NAc and mPFC was in direct proportion of theamount of back pain that any given patient reported experiencing(Fig. 9). The strength of this across patient correlation of connectiv-ity implies that the more someone is in back pain, the more infor-mation is shared between the 2 brain regions; this parameter canalso be viewed as an objective measure that can identify the mag-nitude of back pain with a paradigm whereby the participant is noteven aware of what is being measured. The patients were basicallysignaling that they prefer to keep this acute pain on their skin andare disappointed when it ceases, although their conscious rating ofthe painful stimulus and brain activity for the pain perception wereidentical to healthy subjects’ perception and brain activity. To cap-ture the impact of this NAc signal on perception, we examined rat-ings of spontaneous pain in another group of chronic back painpatients during the thermal stimulation and could demonstratethat this stimulus was actually analgesic to their spontaneous pain,to the surprise of the patients and only when patients specificallydirected their attention to their own pain (Fig. 10). The mecha-nisms regarding the transition of NAc from sharing informationwith insula (healthy subjects) switching to sharing informationwith mPFC comes (chronic pain patients) remain to be studied.Also, how prevalent this switch is across different chronic paingroups, its relationship to conscious versus unconscious events,and a myriad related questions remain to be addressed. The study,in a sense, demonstrates that one can explore the impact of theemotion of pain outside of the sensory/affective, entangled, per-ception representation, and that the components of the Cartesiansoul can be broken into their constituent subconscious parts inthe brain, which in turn influence conscious behavior outside orindependent of sensory representation.

4. Distortions of brain anatomy in chronic pain

About 10 years ago, we presented the first evidence for brainmetabolite abnormalities, asmeasuredbymagnetic resonance spec-troscopy (MRS), in chronic back pain patients [44–46].Wepredictedin those studies that brain gray matter should show atrophy, and in2004 we published the first results for brain gray matter distortionsin chronic back pain [7]; since then, a steadily accumulating litera-ture has been documenting evidence for brain morphologicalchanges in multiple clinical pain conditions: back pain [90],fibromyalgia [54,57,65,92], CRPS [40], knee osteoarthritis [87], irri-table bowel syndrome [14,28], headaches [55,89,91,104], chronicvulvar pain [93], and in female individuals with menstrual pains[102], as well as in animal models of chronic pain [70,96]. The evi-dence for metabolic changes with chronic pain has come moreslowly, as only a handful of studies have been done on the topic[36,47,103]. Metabolic and morphological approaches are comple-mentary techniques and comparisons of outcomeswith both shouldenhance understanding of underlying mechanisms. However, MRSremains technically underdeveloped and fraught with confounds,as a result its impact on brain neuroscience in general has lagged.

Fig. 6B. Brain activity in medial prefrontal cortex (mPFC) shows high specificity forchronic back pain. Magnitude of mPFC regional activity (as identified in chronicback pain patients) across 5 groups of subjects. Each symbol represents anindividual subject. The threshold indicated by broken green line distinguisheschronic back pain (CBP) from pelvic pain (CPPS), osteoarthritis (OA), post-herpeticneuralgia (PHN) for spontaneous pain, and healthy subjects for acute pain (healthy)at an accuracy greater than 90%. The number of subjects studied in each group isindicated above.

Fig. 7. Intensity of ongoing chronic postherpetic neuropathy pain changes brainactivity and thus cognitive processing in a complex pattern, for pain and non-paintasks. The figure is adapted from a study [39] in which postherpetic neuropathypatients were studied before and after lidocaine application on the painful skin.Each patient was scanned at 3 time points relative to the drug therapy. In all casesthe patients performed 2 different tasks: in the pain task they continuously ratedthe fluctuations of their spontaneous pain (left), and in the visual task they ratedfluctuations of a bar varying in time (right). The relationship between brain activityand intensity of ongoing pain was determined using a covariate analysis, in whichthe related pain intensity for each functional magnetic resonance imaging (fMRI)scan was used to determine the effect of this parameter on brain responses. Acrosssubjects and across all scans, average variation of brain activity is displayed for bothtasks. The presence of the chronic pain effects activity in both tasks across largebrain areas, rather similarly, increasing activity in some areas (red) and decreasingthem in others (blue).


Fig. 11 illustrates some of the pain conditions for which braingray matter properties have been reported to be abnormal. Our ini-tial morphometric study and a number of subsequent studies dem-onstrate that specific regional gray matter decreases correlate withduration of chronic pain, its intensity, and even the interaction be-tween both factors [7,40,57], suggesting that the properties of theclinical conditions are influencing brain morphology. Brain mor-phometry studied in fibromyalgia patients by multiple researchers[18,54,57,65,92,109] have shown a regional decrease in gray mat-ter density [18,57,109], whereas others show an increase [92], and1 study shows no change at all [54]. Another study failed to dem-onstrate a relationship among pain intensity, duration, and graymatter density, and the authors interpret the lack of these relation-ships as evidence that observed anatomical abnormalities may beused as evidence for a brain predisposition for chronic pain [18].Such variability of outcomes is unlikely to be a reflection of the pa-tients studied. Instead it is more probably because of the fact thatmorphometric studies are complicated and that subtle technicaldifferences can bias outcomes; the most important confound isintegrity of acquired anatomical MRI scans, in which a few poorbrain images may lead to opposite conclusions. Inadequate regis-tration and/or segmentation can also give rise to false outcomes.Unfortunately there are no standard techniques for identifying

such errors, and very few groups perform quality control checkson acquired brain images. Using strict quality control procedures,we have now studied this question across multiple chronic painpatient groups in contrast to healthy subjects; our results indicatethat in chronic back pain, osteoarthritis, and CRPS, we observe onlydecreased regional gray matter density, and these decreases arespecific to each type of chronic pain (manuscript in preparation).The most important message from these gray matter studies isthe suggestion that distinct chronic pain conditions have differen-tial impacts on brain anatomy. A number of groups recently re-ported on the reversibility of brain morphometric changes withpain relief (Fig. 12), and most agree that at least some brain regio-nal morphometric properties do reverse when pain is substantiallyrelieved [48,78,87]. These early reports need to be examined morecomprehensively and are yet important, as they indicate that atleast some of the morphological changes must be a direct conse-quence of the presence of the pain, and most likely the underlyingmechanism is based on synaptic plasticity that tracks the impact ofthe pain on the brain.

Mechanisms responsible for brain gray matter morphologicalchanges remain unclear [67]. The available evidence suggestsmulti-plemechanisms becausemorphological changes can be observed atearly timepoints from initial injury aswell as after longperiods from

Fig. 8. In chronic pain patients and in the absence of any specific task (resting state) activity in the insula and anterior cingulate, but not in the precuneus/visual cortex,fluctuate at higher frequencies than in control subjects. Power spectral density as a function of frequency is shown for each individual subject. Figure from [66].

Fig. 9. Distinct functional connectivity between nucleus accumbens and the rest of the brain are observed in chronic pain patients in contrast to healthy subjects. This shift inconnectivity is tightly correlated to the magnitude of back pain reported by the patients. (A) Healthy: Functional connectivity between nucleus accumbens and the rest of thebrain in healthy subjects. We observe extensive bilateral insula involvement. (A) CBP: Functional connectivity for nucleus accumbens in chronic back pain patients. Functionalconnectivity is shifted away from the insula to medial prefrontal cortex. (B) Strength of connectivity between nucleus accumbens and medial prefrontal cortex in relation tothe magnitude of back pain reported. Each red symbol is an individual chronic back pain patient; blue circles are healthy controls. The higher the magnitude of spontaneouspain of back pain the stronger is the correlation between mPFC and NAc, implying more information sharing between these 2 brain regions. Figure adapted from [11].


Fig. 10. Chronic back pain patients report a decrease in the magnitude of their back pain during a thermal painful stimulus applied to the skin on their back. They seem toonly realize this fact when they are specifically instructed to attend to their own back pain. A. Group average ratings of either the magnitude of thermal painful stimulus (red)or spontaneous fluctuations of back pain (blue), for a stimulus pattern shown below (grey) that is unpredictable in intensity and duration. Every time the stimulus is feltpainful it seems to induce a decrease in spontaneous pain. B. Average stimulus pain perception (red) and spontaneous back pain perception (blue) relative to start and end ofthermal stimulus (black). Rating of the stimulus intensity and back pain were done separately. C. When the back pain patients rate the stimulus, they judge the experience asunpleasant (red). But for the same stimulus when they rate their own back pain the experience is judged to be significantly more pleasant (blue). Figure adapted from [11].

Fig. 11. Brain regional gray matter decreases in a number of chronic pain conditions. (A) Bilateral dorsolateral prefrontal cortex and unilateral thalamic gray matter decreasesin chronic back pain, from [7]. (B) Insula and cingulate cortex gray matter decreases in irritable bowel syndrome, from [26]. Multiple brain regions show decrease gray matterdensity in (C) fibromyalgia, from [57], and in (D) tension headache, from [91]. The illustrated data are the earliest reports of brain morphological changes in various painconditions. The list of additional pain conditions impacting brain anatomy is expanding very quickly.


injury, best illustrated in 2 animal studies [70,96]. If regional graymatter changes are more than just a reflection of local extracellularchanges in water, which may occur based on changes in concentra-tion of channels of proteinswithin neurons and/or glia, then proper-ties of axons connected to the regional neurons involved shouldchange as well. In a very simple way, if decreased gray matter den-sity corresponds to neuronal death, then underlying white matterdensity or connectivity should also be modified reflecting suchchanges. We probed this issue by examining the integrity of brainwhitematter in chronic pain patients and also by relating graymat-ter changes to underlying white matter properties in patients withcomplex regional pain syndrome (CRPS) relative tomatchedhealthycontrols [40]. White matter properties can now be studied by diffu-sion tensor imaging (DTI). This technologyhasdramaticallymaturedin the last fewyears and provides powerful toolswithwhich one canpose exciting new questions about axonal properties of the human

brain, regarding local integrity (based on measures of fractionalanisotropy, FA) as well as the properties of white matter tracts(quantified by probabilistic tractography) [74]. Using a combinationof voxel-basedmorphometry and DTI, we could demonstrate regio-nal decreased graymatter density and regional whitematter abnor-mality demonstrated by local decrease in FA in the patients.Moreover, both FA value decreases and gray matter density de-creaseswere accompanied by changes inwhitematter connectivity.However, changes in connectivity were target specific, with someprojections showing increases and other decreases. These resultsagain suggest that multiple complex mechanisms underlie brainmorphometric changes, some of whichmay be regarded as markersfor predisposition for the observed chronic pain condition. In addi-tion, we documented the first evidence for global reorganization oftheCRPSbrain.Wefirst showeda strong linear relationshipbetweenwhole neocortex gray matter volume (after correcting for age

Fig. 12. Evidence for brain gray matter density recovery with cessation of chronic pain. (A) Left panel shows brain regions decreased in gray matter density in chronicosteoarthritis patients. Right panel shows brain regions where gray matter density increases following joint replacement and cessation of pain in osteoarthritis patients.Generally similar brain regions seem to changes with the presence and cessation of chronic pain. Adapted from [87]. (B) Brain regional morphometry changes in post-traumatic headache. Gray matter density changes are shown for 2 brain regions in patients that develop chronic pain (3 months) and 1 year later when the pain subsided(1 year). In both areas, gray matter signal recovers to original levels when pain symptoms subside. Adapted from [78].


effects) and whole neocortex white matter mean FA values acrosshealthy subjects. To our knowledge, this is the first evidence for sucha global relationship, and it implies thatmyelin properties or axonaldensity properties adjust in relation to brain size in normal subjects.This relationship was completely disrupted in CRPS patients, inwhom we could find no significant relationship between whole-brain FA and neocortical gray matter volume. Therefore, across thewhole brain, the gray matter to white matter relationship is dis-rupted in these patients, implying that changes in 1 of these com-partments is not being properly compensated for in the othercompartment (Fig. 13),which in turn implies that, aboveandbeyondthe local gray and whitematter changes that we documented, thereare also across the brain large-scale morphological changes associ-atedwith chronic pain.Mechanismsandparameters controlling thislarger scale reorganization also remain to be studied.

5. Learning, and forgetting, and a brain circuitry model fortransition to chronic pain

We have previously argued that chronic pain can be viewed as astate of continuous learning coupled with reduced opportunity for

forgetting [2,3,72]. Thousands of studies illustrate the potency ofpainful events to induce learning in which mechanisms of learningare investigated using Pavlovian paradigms, the majority of whichuse pain (electrical shock) as the unconditioned stimulus withwhich various events are associated. Such studies repeatedly showthat single painful stimuli are learned and remembered for weeksand months. Such studies also illustrate that once the associatedlearning occurs, the extinction of this association requires repeatedexposure of the organism to the conditioned stimulus in the absenceof the painful event. As chronic pain is fundamentally a state of con-tinuous presence of pain, we can then conclude that it is also a stateof continuous acquisition of associations with random events sur-rounding the organism, especially at time points when the pain ishigh.Moreover, as the pain remains unremitting, the organism doesnot have the opportunity of extinguishing these random associa-tions, which requires frequent exposure to the same environmentin the absence of pain. In fact we suggest that the contradiction be-tween the subject’s conscious knowledge that the pain is not associ-atedwith the environment and the brain circuitry that continuouslymake such associationsmay be the core cognitive/emotional sourceof the suffering that chronic pain patients experience.

Fig. 14. A model regarding brain circuitry involved in the transition from acute to chronic pain. Nociceptive information, perhaps distorted by peripheral and spinal cordsensitization processes, impinges on limbic circuitry (Hippo, hippocampus; NAc, nucleus accumbens; and Amyg, amygdala). The interaction of limbic circuitry with prefrontalprocesses determines the level at which a certain pain condition transitions to a more emotional state. The limbic circuitry also provides learning/modulation signals to therest of the cortex inducing functional and anatomical distortions that reflect the suffering and coping strategies of specific chronic pain conditions. Nociceptive signals alsoprovide the brain with modulatory signals, and are in turn controlled by the state of suffering of the individual as well as limbic changes in arousal and motivation, throughdescending modulatory pathways.

Fig. 13. Whole-brain relationship between gray and white matter is disrupted in chronic complex regional pain syndrome subjects. Left panel shows that white matterfractional anisotropy (FA; measured for group average skeleton which insures that the tissue examined has 95% probability of being white matter) is correlated to totalneocortical volume of the brain (after correcting for age effects). Right panel depicts similar data in complex regional pain syndrome patients, and shows that the relationshipis destroyed. In both panels, each symbol represents the brain of a subject: red indicates healthy controls; blue indicates patients. Adapted from [40].


Within this theoretical construct of chronic pain, we can nowposit a general model of the brain circuitry regarding the transitionfrom acute to chronic pain, based on the evidence presented aboveand coupling these observations to anatomical and physiologicalobservations (Fig. 14). We first emphasize that nociceptive infor-mation accesses the cortex throughmultiple pathways and not justby the spinothalamic projection (the majority of human brainimaging results continue to be interpreted in relation to the spino-thalamic pathway). Even within the spinothalamic system medialthalamic cortical projections access large portions of the frontalcortex targeting mainly superficial layers [73]. This pathway is areticulo-thalamocortical network that relays widespread nocicep-tive information to widespread cortical regions and most likelyprovides modulatory influences on large prefrontal cortical pro-cesses. Other nociceptive pathways such as the parabrachial-amygdala projections, spinal basal ganglia projections, spinalhypothalamic and spinal prefrontal projections [17,38,56,77] andother monosynaptic and polysynaptic spinal-reticular-cortical pro-jections provide ample opportunities for nociceptive informationaccessing various cortical circuitry and modulating such circuitryas a function of a continuous barrage of nociceptive inputs associ-ated with chronic pain. Thus, continuous nociceptive input tosupraspinal targets both reorganizes memories and their associa-tions within the cortex, and reorganizes motivational and memoryconsolidation properties of the limbic cortex.

The human functional brain imaging studies for chronic painpoint to the recurring theme that chronic pain conditions engagepreferentially medial prefrontal cortical areas as well as subcor-tical limbic regions, especially portions of the dorsal and ventralbasal ganglia [16], amygdala [76], and hippocampus [60]. Eventhough different types of chronic pain and different perceptionsin such patients engage distinct cortical and subcortical regions,by and large, all of them show a shift away from brain regionsengaged in sensory processing of pain toward regions encodingemotional and motivational subjective states. The continuousactivation of these limbic/emotional structures must result inshifts in valuation (some of which are reviewed above), andthese shifts would in turn modulate cortical learning and mem-ory processes [34,108]. Moreover, the shift in valuation in turninfluences nociceptive processing in the spinal cord, coupledwith or further strengthened by shifts in prefrontal cortical emo-tional shifts. These descending modulatory systems provide yetanother source of spinal cord central sensitization, as demon-strated in animals models [37], and are probably more importantis human chronic pain conditions.

The details of the mechanisms across the brain network in-volved in chronic pain remain fuzzy, will undoubtedly continueto change with new observations, and certainly require more stud-ies. As a result, the model that we present here (Fig. 14) is inten-tionally kept imprecise and is designed to indicate only a globalconstruct.

6. Summary and conclusions

The functional imaging studies summarized here first show thatthe subjectivity of pain can be captured by objective markers ofbrain activity, and that the general approach of searching for brainevents closely related to the consciousness of pain provides a pow-erful concept with which acute and chronic pain can be studiedand contrasted with each other. The approach even results inunraveling brain unconscious events that color motivation and val-uation independent of conscious perception as a consequence ofliving with chronic pain. The comparison between differentchronic pain conditions reveals that underlying brain activity isdistinct with a general trend toward engaging limbic and

paralimbic structures. The morphological studies show that thebrain structure undergoes changes at multiple spatial and tempo-ral scales, which are for the most part specific to the type of chronicpain studied. That some of these changes are reversible by cessa-tion of chronic pain speaks to the specificity of the processes andalso demonstrate that chronic pain may in fact by used as a uniquetool with which the dynamics of brain plasticity can be studied atmultiple spatial and temporal scales.

Based on the functional and morphological reorganization ofthe brain in chronic pain, we advance a brain circuitry model forthis transition in which the primary drive is assumed to be theability of pain to induce long-term memories by reinforcing learn-ing mechanisms. We do not want to disregard the myriad ofperipheral, spinal cord, and brainstem descending modulatorychanges that have been described to accompany persistent orchronic pain, as documented in animal models for such conditions.Instead we think that these peripheral and central sensitizationevents simply exaggerate the reorganization of limbic circuitrythat in turn reflect their effects on prefrontal cortical evaluationof pain as well as provide the learning signals with which interac-tions between various cortical circuitry adapt to the suffering andcoping that is specific to each clinical chronic pain condition.

Correspondences between physiological and morphologicalreorganization, as well as with metabolic changes, should pointto specific cognitive and sensory and motor ability changes thatundoubtedly accompany distinct chronic pain conditions in spe-cific patterns. We have taken some small steps in this direction[6,98]; however much more needs to be done, as the array of cog-nitive impairments documented in chronic pain is large [50] andtheir unique contributions and relations to specific clinical casesremains to be systematically approached.

Anatomical and functional specificity of the brain in distinctchronic pain conditions perhaps seems as a new complication.However it suggests the possibility of unique therapies by target-ing the underlying specific pathways for each type of chronic pain(see, for example [23,72,100]). Moreover, it suggests that suchtherapies can be tested with very specific, objective brain-derivedmarkers [34], even bypassing conscious reports.

Acknowledgments

This work is funded by NIH NINDS NS035115, NS057704, andby an anonymous foundation (to M.N. Baliki). The authors declarethat they have no conflict of interest.

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