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Can neuroimaging studies identify pain endophenotypes in humans?

Irene Tracey
Abstract | Pain is a complex, multidimensional experience that has defied our understanding for centuries. Through the advent of noninvasive neuroimaging techniques, we have been able to examine the human brain and its response to nociceptive inputs. As a result, our knowledge of which brain regions are critical for generating an acute pain experience has grown, as has our understanding of how cognitive, emotional, contextual and various physiological factors influence the pain experience. Furthermore, we have been able to identify key processes within the brain that underpin the transition to and maintenance of chronic pain states, as well as highlight the dramatic consequences of chronic pain on the brains structure and neurochemistry. Building upon this knowledge, we are now in a position to consider whether any of these brain imaging phenotypes of acute or chronic pain should be considered as useful endophenotypes; thereby enabling us to relate the complex genetics that underpin everyday pain sensitivity or chronic pain states to intermediate biomarkers. This endophenotypic approachthe focus of this Reviewsimplifies the connection between genes and behavior and is needed for complex disorders like chronic pain.
Tracey, I. Nat. Rev. Neurol. 7, 173181 (2011); published online 8 February 2011; doi:10.1038/nrneurol.2011.4

Introduction
Pain as an acute, warning symptom is essential: it saves lives. By contrast, chronic painpain that persists indefinitely beyond the resolution of the initiating injuryis maladaptive. Approximately 20% of the adult population in the Western world are thought to have a chronic pain disorder; however, treatment strategies for chronic pain are lacking and, consequently, many patients have to live with unbearable pain.1 As a result, chronic pain is associated with appreciable health-care and socioeconomic costs.2,3 Measurable markers of the pain state could aid the development of drug treatments for both acute and chronic pain, but the identification of such markers that are trusted by medical, legislative and approval bodies is a major challenge. At present, a blood test cannot confirm that someone is in pain. The reason why the establishment of a measurable pain marker is so challenging is because pain is a complex, multidimensional experience that can be influenced by several physiological and psychological factors. Pain does not exist independently but, like other experiences felt in response to environmental stimulation, is generated within the brain. Pain is, therefore, a subjective experience that is not readily quantifiable and, to date, only behavioral responses resulting from painful stimuli can be easily measured. For humans, the reporting of pain is largely mediated via language, which can be limiting, as patients must assign a number or a word to represent a multidimensional experience. This disconnection between the perception (experience) and the report of pain (behavior) makes research into,
Competing interests The author declares no competing interests.

and management of, pain a challenge. Neuroimaging techniques provide one possible means of bridging this gap, as neuroimaging studies have identified areas of the brain that are activated in response to nociceptive stimuli and underlie our experience of pain. Another frontier development in the pain field has been the realization that both normal acute pain and the progression to a chronic pain state following injury, infection or disease have genetic bases. 4 Our understanding of the genetic complexity of pain increases each year. Nevertheless, a need still exists for measures such as endophenotypes that might reflect, in a simplified manner, the outcomes of the complex genetic bases underpinning acute and chronic pain as well as how the environment influences these genes as we develop into adults. Neuroimaging studies could potentially identify such endophenotypes. In this Review, I provide an overview of the neuroimaging literature relevant to the pain field and highlight possible pain endophenotypes that future studies could further explore.

Endophenotypes
Endophenotypes are measurable components (for example, biochemical, neuroanatomical or cognitive characteristics) of a disease or condition that have simpler links to genetic underpinnings than the disease syndrome itself.5 Pain endophenotypes could fill the gap between pain behavior and the genes associated with the elusive processes that underlie the experience of pain. Thus, such endophenotypes could help address questions relating to the etiology of pain, something that is much needed in the pain field.

Oxford Center for Functional Magnetic Resonance Imaging of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. irene@fmrib.ox.ac.uk

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Key points
Activity within multiple brain regions is required for the experience of pain Neuroimaging studies have increased our understanding of how various brain regions generate and/or modulate the perception of pain Genetic make-up influences many aspects of acute and chronic pain, but the relationship between genes and pain-related behavior is complex and remains to be fully resolved Neuroimaging studies might identify functional, structural or biochemical endophenotypes for pain that can help us understand the relationship between genetics and pain conditions

Neuroimaging is considered to be a useful tool for the discovery of endophenotypes in psychiatric disorders, and this technique has the capacity to allow identification of aberrant patterns of brain activity or aberrant structures in the human brain that are predictive of chronic pain or the development of this condition. Establishment of a link between a neuroimaging signature or endo phenotype and a specific genetic marker has not yet been achieved in the pain field. Indeed, only one neuroimaging study has attempted to connect brain activity associated with the experience of pain to genetic data.6 Nevertheless, the potential of neuroimaging studies to identify genetic factors associated with pain is considerable. The idea that certain people have a high probability of developing chronic pain in the future is supported by studies that have identified preoperative factors that are predictive of persistent postoperative pain.7 Furthermore, several studies have shown that family members of patients with chronic pain have a higher incidence of pain than family members of patients with nonchronic pain, indicating that chronic pain has a genetic component.810

Pain imaging endophenotypes

Functional MRI (fMRI), PET, magnetoencephalography (MEG) and scalp EEG are commonly used to study the neural basis of pain. Researchers are also increasingly using other magnetic resonance-based measures, such as diffusion tensor imaging, spectroscopy, volumetric imaging and arterial spin labeling, to assess pain-related changes in the brain, so as to gain further insights into the neurobiology of pain, particularly chronic pain. Many excellent reviews have been written that summarize the findings of neuroimaging studies.1116 With this large body of work, we are perhaps uniquely poised to exploit these neuroimaging findings and to begin developing them as robust endophenotypes.

effects, which can be beneficial during stressful circumstances, such as during escape from danger when injured. Unfortunately, the RVM can also enhance nociception following inflammation and injury.1820 Clearly, this pronociceptive effect is protective during recovery from injury and promotes tissue repair, but the failure of such an effect to resolve after the tissue has healed may result in chronic pain.19 Agenetically driven imbalance in the antinociceptive and pronociceptive activity within the RMV, probably involving 5hydroxytryptaminergic and nor epinephrinergic mechanisms, may represent a possible pain endo phenotype. Although such an endophenotype has yet to be associated with activity in the brainstem, several neuroimaging studies have shown that activity within this brain region occurs during experimental or clinical hyperalgesia.21 In fact, activity within the periaqueductal gray (PAG) and the mesencephalic pontine reticular formation (MPRF) has been strongly associated with the development of hyperalgesia,22,23 and evidence suggests that the MPRF is specifically involved in the maintenance of central sensitizationthe mechanism underlying secondary hyperalgesia.24 In addition, studies investigating the effect of hormones on pain experiences have identified a potential role for the brainstems descending modulatory system in this process; hormones have been reported to exhibit pronociceptive and antinociceptive influences.25,26 The brainstem is also the main route through which cognitive and contextual factors influence an individuals experience of pain.27 As considerable variation exists in activation of the brainstems descending modulatory system between healthy individuals and patients with pain,2830 these data suggest that activity within this system could represent a realistic imaging endophenotype of pain.

The brainstem Neurons in the spinal cord that transmit information regarding noxious events to higher centers within the brain receive descending control from supraspinal regions. This powerful modulatory input, which is unique to pain, is integrated within the rostral ventromedial medulla (RVM), and activity within this part of the brainstem determines whether the nociceptive information is prioritized (this system is called the descending modulatory system).17 Thus, activity within the RVM can provide important antinociceptive
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Cortical and subcortical networks Nociception is neither necessary nor sufficient to induce pain, despite being the most frequent cause of this condition. As a result, pain is currently defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. 31 Nociception typically leads to pain, but the latter is influenced by a range of other factors (see above), and the level of pain that is actually experienced and reported is often not linearly related to the nociceptive input.16,32 A pain-like experience can also occur in the absence of nociception; for example, during empathy for others,33,34 in individuals who have never experienced pain,35 and in the nocebo response.36 Central poststroke pain and phantom limb pain are other examples that illustrate the latent capacity of the brain to elicit a painful experience without concomitant peripheral nociceptive inputs.3739 Prior failure to associate cortical activity or cortical lesions to the experience of pain had encouraged the view that pain had little true cortical representation.40,41 Studies in patients with epilepsy, however, have shown that direct electrical stimulation of the posterior insular region can lead to painful sensations being reported.42,43
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The posterior insula region might not be necessary or sufficient for individuals to experience pain, since electrical stimulation of this region might also activate other cortical regions. Nevertheless, invasive direct brain stimulation techniques, as well as other less invasive techniques such as transcranial magnetic stimulation and transcranial direct cortical stimulation,44 have tremendous potential for redefining our understanding of the cortical representation of pain experiences. Using less invasive measures, such as PET and fMRI, we have now identified several cortical regions in humans that are considered to be important for the perception of pain. The primary and secondary somatosensory cortices, the posterior, mid and anterior insula, the anteri or cingulate and the prefrontal cortices are routinely activated, often bilaterally, during painful experiences. Furthermore, activity in subcortical areas such as the PAG, hypothalamus, amygdala, hippo campus and cerebel lum has also been directly related to the experience of pain. Thus, activity within several diverse regions of the brain seems to be required for pain perception.14,16,45 As a result, the concept of a cerebral signature for pain that is bespoke for an individual has been put forward. This concept is considered to reflect how the various cognitive, emotional, contextual, structural and chemical factors combine to produce the unique multi dimensional experience of pain.16 Interestingly, and of relevance considering the epilepsy studies mentioned above, the insular cortex has been identified as the most consistently activated region during painful experiences.45 Remarkably, none of the brain regions identified abovecommonly but perhaps unhelpfully referred to as the pain matrixis uniquely associated with pain; they are often involved in other behavioral sensory, cognitive and emotional experiences. Some of these regions within the so-called matrix exhibit correlated activity with sensory or emotional descriptions of the painful experience, suggesting that they have a significant role in pain generation, but again these areas are not exclusively activated during pain experiences.4648 Thus, while activity in any one of these brain regions cannot represent a pain endophenotype, perhaps the concerted activity of these areasthe cerebral signaturemight achieve this goal? As the combined activity of these brain regions is critical for the experience of pain, then surely disruption of the pain matrixfor example, by cortical lesions should produce numbness to pain? Unfortunately, such lesions rarely have this effect; thus, arguing against the utility of cerebral signatures as endophenotypes.49,50 By contrast, very small infarcts in the dorsal posterior insula can produce complete and selective loss of pain and thermoception,51,52 but how these lesions disrupt the pain matrix is unclear. factors, so that an optimal behavioral response is produced, then, in my own view, pain is unlikely to be uniquely represented by such a primary cortical area. By contrast, nociceptive stimuli could theoretically be processed by a specific brain area. To date, however, we have not unequivocally identified a primary nociception cortex (N1)a region of the cortex that exclusively encodes and processes noxious stimuli. Our inability to identify a P1 or N1 makes the study published by Mazzola and colleagues in 2009 of particular interest.43 These researchers showed that direct electrical stimulation of the posterior two-thirds of the insular cortex evoked a specific experience of pain. The temptation exists to suggest that this brain area is the long sought-after P1; however, in this study, pain was only evoked by stimulation of a few posterior insular stimulation points, and this technique caused pain in 25% of the patients with epilepsy who were tested. Furthermore, the insula is a frequent source of seizures, yet patients with epilepsy rarely have painful experiences during these attacks compared with other sensory disturbances.53 The dorsal posterior insular cortex, however, is known to receive nociceptive input via a spinothalamocortical pathway, and is organized in a somatotopical manner. These observations have been confirmed in fMRI studies examining the processing of cool temperatures, noxious heat stimuli,54 muscle pain55 and noxious tactile stimuli.56 Such studies have also shown that pain evoked by hypnosis or through recollection of a painful experience activate many of the areas that are activated by physically induced pain; however, in these two situations, activity in the posterior insula is either attenuated or absent.33,57,58 These data, in combination with the results of studies showing that the human dorsal posterior insula cortex is strongly activated by temperature and noxious heat,59,60 indicate that for nociception and temperature sensations, this cortical area might be the primary cortical sensory area,61 but for a pain experience, further brain regions must be recruited or involved. If the dorsal posterior insula is key to nociception, then a very simple somatotopically based imaging endophenotype for patients with chronic pain who have a clear nociceptive element to their pain could be suggested. Recent, across-modality somatotopic nociceptive studies suggest N1 might also include areas within the operculum, such as the secondary somatosensory cortex or S2.62 Nevertheless, an endophenotype is still required for the areas in the brain where the hurt of pain is produced, as nociception does not always produce pain, as discussed above.

The dorsal posterior insula cortex Despite intensive research, an area of the brain that is analogous to the primary visual cortex and may be termed the primary pain cortex (P1) has not been identified. As pain is an experience that can be influenced dramatically by cognitive, emotional and contextual
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The prefrontal-limbic-brainstem network Imaging studies have shown that activity in frontal, limbic and brainstem regions is required for the cognitive control of pain. The frontal-limbic regions are reciprocally connected to the brainstem and, therefore, indirectly exert inhibitory control over neurons within the spinal cord that transmit nociceptive information to the brain. Functional imaging studies have shown that activity in the prefrontal cortex (PFC) reduces the magnitude of pain or hyperalgesia,63,64 suggesting
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that the PFC can regulate the amount of pain an individual perceives. Distraction from pain involves activity in the cingulofrontal cortex, thalamus and PAG via top-down gating mechansims. 28,29,65 A strong belief that pain can be controlled can induce analgesia, and this type of an algesia is associated with activity in the ventrolateral PFC. 66 Activity in the PFC is also associated with episodes of emotional detachment, when the suffering element of pain is absent. 67 Negative emotional responses can heighten the experience of pain, and the ventro lateral PFC seems to regulate these responses via interactions with the nucleus accumbens and the amygdala.68,69 Furthermore, reducing the fear of pain, via extinction learning, requires activation of the ventro medial PFC;70,71 however, anxiety levels can rise if extinction learning fails to lower such fear, which can exacerbate a pain experience via parahippocampal mechanisms.7274 Brain interference approaches targeting the motor cortex or prefrontal cortical regions have been shown to provide pain relief, indicating that these brain areas are involved in driving top-down modulatory influences on key pain-encoding brain targets.44,7580 In rodents, activity in the amygdala is required for the inhibition of pain during stress, but can also facilitate pain behaviors during injury.81 Elegant studies have shown that activation of extracellular signal-regulated kinase within the amygdala alone can produce behavioral hypersensitivity that is typically observed during inflammation, but does not lead to behavior associated with nociception.82 Few reports of amygdala activity during painful experi ences in humans exist,8385 but with improvements in imaging techniques and the progression towards imaging at ultra-high field strengths, this situation will probably change and the precise role that the amygdala has in the experience of pain may be clarified. In summary, the frontal-limbic-brainstem network could be important in producing the emotional, cognitive, threatening and fear-provoking elements that probably underpin the stressful experience associated with pain and, as a spatial network, might be a useful imaging endophenotype for a pain experience. However, limiting an endophenotype to a simple spatial representation is probably not sensible. with conscious detection of the noxious stimuli.89 Thus, consciousness of pain might occur following integration of nociceptive information from multiple cortical regions, as suggested is necessary for perception by a study from a non-pain-related field.90 The exploration of cortical processing dynamics at the timescale at which neurons communicate and integration of data from such studies with the results from fMRI-based and PET-based studies, which provide high spatial resolution but poor temporal resolution, should be prioritized.
Predicting pain from brain dynamics How the arrival of nociceptive information into cortical areas alters brain dynamics to allow processing of nociceptive information to be prioritized over competing stimuli should be examined; as these brain dynamics could represent an endophenotype that predicts the development of pain. In an elegant MEG study, Gross and colleagues91 showed that nociceptive stimuli induced 6095Hz gamma oscillations in the primary somato sensory cortex. The amplitudes of these oscillations varied with stimulus intensity and showed a positive correlation with pain intensity.91 Moreover, painful stimuli were associated with stronger gamma oscillations than unperceived stimuli of equal stimulus intensity. Thus, gamma oscillations related to activity in the somato sensory cortex might be objective indicators of painful experiences and, possibly, pain endophenotypes. Assessment of pain sensitivity at various levels of consciousness (through use of anesthetic agents) or during varying stages of sleep in combination with recording of brain activity using high-density EEG or fMRI can provide a means of understanding how brain dynamics generate and influence the experience of pain. To date, substantial practical difficulties have limited the number of such studies, but further investigations of this type are under way.9295 Dynamic causal modeling and psychophysiological interaction analyses are relatively new techniques that have the potential to further our understanding of pain. These techniques use data from EEG, MEG, fMRI or PET studies to investigate brain dynamics and cortical coupling,9698 and are being applied in the field of pain to considerable effect. Such analyses take us beyond a simple spatial representation of pain towards a networkbased understanding of this condition that better reflects the dynamic nature of the pain experience. As such, use of various imaging techniques coupled to these analysis methods could potentially identify novel pain endophenotypes. Personality traits Work from my group has highlighted how baseline fluctuations in neural activity determine whether an experience of pain arises from noxious stimulation. In an fRMI study, we found that prestimulus functional connectivity between the anterior insula and the PAG determined whether near-threshold nociceptive stimulation was perceived as painful.99 Furthermore, we found that the connectivity between the anterior insular and the PAG
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Brain dynamics As mentioned above, the experience of pain requires activity within various regions of the brain. Nevertheless, how pain arises from the flow of information between these different brain regions is largely unknown, as investigating this phenomenon requires a multimodal approach, of which few published studies exist.86 In humans, the earliest intracortical electrical potentials evoked by noxious laser stimuli applied to the hand occur at similar time points in the parietal insular region and in the mid cingulate cortex, suggesting that nociceptive information is processed in parallel by these regions.87,88 This finding supports my suggestion that brain areas in addition to the insula are necessary to encode painful experiences. Furthermore, a human EEG study has shown that late, rather than early, laser-evoked responses were associated
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was weaker in individuals who were highly anxious than in individuals who were not anxious, and that the highly anxious individuals had lower pain thresholds. These findings suggest that personality traits, which are presumably underpinned by genetic factors, could influence the perception of pain via descending cortical control within the brainstem. Alternatively, an anxious and painvigilant personality might arise from ineffective intrinsic regulation of nociception.100 One could hypothesize that among healthy individuals, those with high trait anxiety and pain vigilance display a different endophenotype in terms of their brain dynamics to those with low trait anxiety and pain vigilance, and that the former might be susceptible to developing chronic pain should they sustain an injury, or develop an infection or a disease.
Resting state networks Our ability to detect, analyze and determine changes in the brains resting state networks (RSNs) has improved considerably over the past 5years, even though we still do not know exactly what RSNs signify.101103 The default mode network (DMN) is one such RSN and includes the medial prefrontal cortex, medial temporal lobes, pos terior cingulate cortex and retropslenial cortex. Activity in the various brain regions that make up the DMN is highly correlated when an individual rests with eyes closed and does not perform any explicit task. Studies utilizing fMRI or PET have shown that patients with chronic back pain can have abnormal patterns of intrinsic brain activity in the DMN.104 Furthermore, increasing spontaneous pain intensity in patients with fibromyalgia has been shown to correlate with stronger intrinsic connectivity between the insula and both the DMN and the right executive attention network. This finding indicates that resting brain activity within various brain regions is associated in some way to spontaneous pain in this condition;105 however, the functions of RSNs are unknown and, at present, under debate.106 Furthermore, while our understanding of neurovascular coupling and how this phenomenon influences RSNs is limited, the possibility exists that vascularvascular coupling and rhythms in blood vessel networks contribute to these signals; thus, caution is required when interpreting RSN data. Nevertheless, abnormalities in RSNs have been shown to occur in neurological conditions other than fibro myalgia, as well as in psychiatric disorders (such as depression) and in aging.107 In fact, one study has provided evidence of a link between a genetic polymorphism associated with Alzheimer disease and an abnormality in a RSN involving the hippocampi,108 indicating that these networks are viable endophenotypes. Further studies, however, are needed to ascertain the significance of resting state abnormalities in chronic pain and their utility as endophenotypes.109

levels within the insula of patients with fibro myalgia decrease after successful treatment. 110 Furthermore, these alterations in glutamate levels were associated with changes in experimental and clinical pain reports, and brain activity as measured by fMRI.110 The same group has also shown that patients with fibro myalgia had significantly higher glutamate and glutamine levels within the right posterior insula than did healthy controls, and that high levels of glutamate were associated with low pressure pain thresholds in both patient and control groups.111 Valdes and colleagues have extended this work and have shown that patients with fibromyalgia have higher levels of glutamate compounds in the right amygdala than healthy controls.112 Moreover, among patients with fibromyalgia, those who reported the most pain, fatigue and depressive symptoms had significantly higher inositol levels in the right amygdala and right thalamus than those patients who reported their pain as moderate.112 We must, however, be cautious when interpreting the findings from the above studies, as glutamate is found throughout the brain and is a key component of numerous physiological and patho physiological processes. Nevertheless, the spatial specificity of the observed changes in glutamate levels identified by Harris etal. and Valdes and colleagues suggest that these changes in glutamate levels might be potential biomarkers and endophenotypes of pain states.

Quantitative arterial spin labeling Quantitative arterial spin labeling is a technique that uses magnetically labeled endogenous water in blood as a diffusible tracer to measure whole-brain cerebral blood flow.113 As this technique is quantitative and does not require a changing stimulus or task, it can be used to detect changes in perfusion that are associated with tonic stimuli. Thus, quantitative arterial spin labeling provides us with the opportunity to identify the neural correlates that underpin the main symptom that patients with chronic pain report: unrelenting, ongoing pain. Note that, to date, most imaging studies have examined phasic acute pain. Quantitative arterial spin labeling studies are in their infancy, but promise to redefine our understanding of the brain regions that are critically involved in sustaining a tonic pain experience and to potentially identify novel pain endophenotypes.114116 Imaging inflammation and microglia Considerable preclinical evidence indicates that neuro inflammation in the spinal cord might contribute to chronic pain states.117 Microglia are activated in areas of neuro inflammation, and PET studies have shown that binding of 11C-PK11195a ligand for activated microgliais increased in the thalamus contralateral to the injured nerve in patients with peripheral nerve injuries compared with healthy controls.118 Furthermore, proton MRS studies have shown that patients with chronic pain have elevated levels of myoinositola putative marker of microglial activationin the thalamus compared with healthy controls.119,120 Thus, inflammatory processes within the brain seem to be important for the development of chronic pain states. The relevance of these inflammatory
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Novel pain neuroimaging techniques

Proton magnetic resonance spectroscopy Proton magnetic resonance spectroscopy (MRS) can identify biochemical changes that are related to pain states. Harris and colleagues have shown that increased glutamate
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Descending modulatory system Brainstem: 5-hydroxytryptaminergic and/or norepinephrinergic pathways Psychological factors such as anxiety, depression, expectation or catastrophizing Prefrontal-limbic-brainstem networks

Neurochemical tone Opioidergic and/or dopaminergic function: basal levels of excitatory and inhibitory neurotransmitters Structural integrity: resilience Cortical thickness: volumetric changes and integrity of white matter connections Neuroimaging endophenotypes? Genes

Nociceptive input to N1? Dorsal posterior insula, S2 or operculum

activityhypoactivity 127129 and hyperactivity 104,130,131in the PFC. This finding is perhaps not surprising, since this brain region is thought to have a key role in pain modulation, as discussed above. Examination of the timecourse of structural and activity-related changes within the PFC during the transition to and throughout a chronic pain state might be important, as changes within this brain region might represent an endophenotype of the chronification process.

Brain dynamics Oscillations and RSNs

Pain experience, report and behavior

Nociceptioninjury

Figure 1 | Factors involved in generating and influencing pain perception. The factors shown above probably have measurable genetic bases and concomitant neuroimaging-based endophenotypes. Abbreviations: N1, primary nociception cortex; RSN, resting state network; S2, second somatosensory area.

processes to the development of chronic pain should be assessed, as these processes could represent potential endophenotypes for pain chronicity.

Other techniques The array of neuroimaging techniques that are available to noninvasively explore the human CNS increases each year and many of these techniques are being applied to the pain field. Spinal cord imaging, optical imaging and nearinfrared spectroscopy are just a few of the techniques that have the potential to increase our understanding of the molecular, structural, chemical and functional changes that underpin either an acute pain experience or the changes that occur during the transition from acute to chronic pain.121124

Imaging the effects of chronic pain

Disrupting emotional regulation The ability to regulate cognition and emotions during episodes of pain is crucial for patients with chronic pain to develop the adaptive behaviors that help them cope with their symptoms.125 My group have shown that experimentally induced sadness in healthy individuals can cause dysfunction in the emotional regulatory network. This dysfunction was associated with activity in the inferior frontal gyrus and amygdala and was also associated with the study participants rating the unpleasantness of pain as high.126 Real-time fMRI has been shown to provide powerful biofeedback to patients with chronic pain.30 The biofeedback helped train these patients with chronic pain to regulate their emotions and cognition, and to modulate activity within the anterior cingulate cortex (ACC); modulation of ACC activity was associated with the patients reporting less pain.30 Considerable evidence indicates that patients with chronic pain have altered functional
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The prefrontal cortex and resilience to pain Human neuroimaging studies have shown that living with chronic pain is associated with maladaptive plasticity and neurotoxicity within the brain.132 Furthermore, the PFC is a major site of potential, but as yet unproven, neurodegeneration in patients with chronic pain.133,134 Imaging studies have identified volumetric changes in the PFC, but how these changes relate to possible cell loss is unknown. To understand how chronic pain might cause neurodegeneration within the brain, carefully controlled longitudinal studies in preclinical pain models have to be conducted. Such studies are under way and, to date, the results confirm the brain volume findings from the above human neuroimaging studies, but histological evidence to confirm neuronal death is still oustanding.135,136 These findings have prompted us to ask whether susceptibility to chronic pain can be predicted on the basis of preinjury PFC cortical thickness. At present, we do not know the answer to this question; however, we do know that decreases in ventromedial PFC volume are associated with altered levels of anxiety and depression137 and, in humans, fear extinction is positively correlated with activity within and the thickness of the ventral medial PFC.138,139 Thus, considering that the PFC has a key regulatory role in pain, abnormalities in PFC volume could be associated with an increased risk of developing chronic pain, and PFC thickness could represent a pain endophenotype that reveals an individuals susceptibility to developing chronic pain. Even if chronic pain does lead to changes in brain structure, these changes seem to be reversible. Two studies, including one from my group, have examined structural changes within the brain in response to having painful osteoarthritis of the hip and found that the voxelbased morphometric changes identified preoperatively were reversed and normalized following successful surgery (that is, surgery that led to pain relief ). 140,141 Clearly, we have much to learn with regard to what these voxel-based morphometric changes reflect given they can be reversed in some instances. Endogenous chemical tone Abnormal brain neurochemistry is evident across a range of chronic pain states, as illustrated by several ligand-based PET studies examining the opioidergic and dopaminergic systems. These studies highlight widespread changes in either the endogenous release of opioids and dopamine or receptor expression for these neurochemicals.142149 The fact that a genetically based imbalance in the opioidergic and dopaminergic systems
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produces a chemical tone that is an endophenotype indicating chronic pain itself or perhaps predicting the development of chronic pain post injury is an intriguing hypothesis. Certainly the one geneticspain-imaging experiment suggests that chemical tone is relevant and is the only example of a pain imaging endophenotype: this study, which involved healthy individuals, linked changes in opioidergic function, as detected by PET, to polymorphisms in the catecholO-methyltransferase gene and changes in behavioral pain report in response to a tonic pain stressor.6 robustly detects a painful event, distinguishes acute and/ or phasic pain from ongoing tonic pain, or indentifies chronic pain with elements of suffering? Here, I have discussed the latest noninvasive tools that are already being used to identify potential imaging-based endophenotypes for pain. Figure1 summarizes the factors that probably have a genetic basis, key roles in influencing acute and chronic pain experiences, and identifiable imaging endophenotypes. The question now is how do we progress the field so that these imaging phenotypes recorded from cohorts of healthy people and patients with pain reflect the underlying complex genetic basis of chronic pain in an individual and, thereby, provide much needed, measurable endophenotypes for pain? This endeavor is surely our goal in the next era of pain imaging.

Conclusions and future directions

Neuroimaging studies that have identified surrogate measures of pain have firmly brought the problem of pain back into the brain. Yet, we still rely heavily on behavioral reporting to determine pain levels. What about determination of pain in the minimally conscious, the anesthetized, and the very young or elderly, all of whom can potentially feel pain without being able communicate their experience94,150,151how reliably can we interpret their neuroimaging patterns if ongoing pain is believed to be present? In short, are we at a stage where we can interpret a brain map or endophenotype reliably without knowing the concomitant behavioral report; that is, adopt a brain-reading approach that is analogous to approaches being undertaken in advanced cognitive neuro imaging studies? 152,153 What would the chemical, functional response or perhaps structural endophenotype be that
1. Finnerup, N.B., Otto, M., McQuay, H.J., Jensen,T.S. & Sindrup, S.H. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118, 289305 (2005). 2. Stewart, W.F., Ricci, J.A., Chee, E., Morganstein,D. & Lipton, R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290, 24432454 (2003). 3. Breivik, H., Collett, B., Ventafridda, V., Cohen, R. & Gallacher, D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur. J.Pain 10, 287333 (2006). 4. Lacroix-Fralish, M.L. & Mogil, J.S. Progress in genetic studies of pain and analgesia. Annu. Rev. Pharmacol. Toxicol. 49, 97121 (2009). 5. Gottesman, I.I. & Gould, T.D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J.Psychiatry 160, 636645 (2003). 6. Zubieta, J.K. etal. COMT val158met genotype affects -opioid neurotransmitter responses to a pain stressor. Science 299, 12401243 (2003). 7. Kehlet, H., Jensen, T.S. & Woolf, C.J. Persistent postsurgical pain: risk factors and prevention. Lancet 367, 16181625 (2006). 8. Katon, W., Egan, K. & Miller, D. Chronic pain: lifetime psychiatric diagnoses and family history. Am. J.Psychiatry 142, 11561160 (1985). 9. Bachiocco, V., Scesi, M., Morselli, A.M. & Carli, G. Individual pain history and familial pain tolerance models: relationships to post-surgical pain. Clin. J.Pain 9, 266271 (1993). 10. Buskila, D., Neumann, L., Hazanov, I. & Carmi, R. Familial aggregation in the fibromyalgia syndrome. Semin. Arthritis Rheum. 26, 605611 (1996). 11. Wiech, K. & Tracey, I. The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage 47, 987994 (2009).

Review criteria
A literature search of PubMed was performed for papers written in English and published up to June 2010 that covered the main topics of this Review. The terms used in these searches were mostly derived from my knowledge of the key authors who have contributed to the literature in recent years, within the domains I chose to discuss in the article. Terms were also selected that related to the techniques and concepts covered in the article. Full articles were subsequently obtained and, where appropriate, references within selected articles were followed up for further reading and, if relevant, were included.

12. Bushnell, M., Apkarian, A V. in Wall and Melzacks Textbook of Pain (eds McMahon, S.B. & Koltzenburg, M.) 107124 (Churchill Livingstone, London, 2005). 13. Bingel, U., Schoell, E. & Buchel, C. Imaging pain modulation in health and disease. Curr. Opin. Neurol. 20, 424431 (2007). 14. Apkarian, A.V., Baliki, M.N. & Geha, P .Y. Towards a theory of chronic pain. Prog. Neurobiol. 87, 8197 (2009). 15. Borsook, D. & Becerra, L.R. Breaking down the barriers: fMRI applications in pain, analgesia and analgesics. Mol. Pain 2, 30 (2006). 16. Tracey, I. & Mantyh, P .W. The cerebral signature for pain perception and its modulation. Neuron 55, 377391 (2007). 17. Fields, H. in Wall and Melzacks Textbook of Pain (eds McMahon, S.B. & Koltzenburg, M.) 125142 (Churchill Livingstone, London, 2005). 18. Gebhart, G.F. Descending modulation of pain. Neurosci. Biobehav. Rev. 27, 729737 (2004). 19. Porreca, F., Ossipov, M.H. & Gebhart, G.F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319325 (2002). 20. Suzuki, R., Rygh, L.J. & Dickenson, A.H. Bad news from the brain: descending 5HT pathways that control spinal pain processing. Trends Pharmacol. Sci. 25, 613617 (2004). 21. Gwilym, S.E. etal. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum. 61, 12261234 (2009). 22. Moulton, E.A. etal. Capsaicin-induced thermal hyperalgesia and sensitization in the human trigeminal nociceptive pathway: an fMRI study. Neuroimage 35, 15861600 (2007).

23. Zambreanu, L., Wise, R.G., Brooks, J.C., Iannetti, G.D. & Tracey, I. A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain 114, 397407 (2005). 24. Lee, M.C., Zambreanu, L., Menon, D.K. & Tracey, I. Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans. J.Neurosci. 28, 1164211649 (2008). 25. Vincent, K., Moore, J., Kennedy, S. & Tracey, I. Blood oxygenation level dependent functional magnetic resonance imaging: current and potential uses in obstetrics and gynaecology. BJOG 116, 240246 (2009). 26. Smith, Y.R. etal. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J.Neurosci. 26, 57775785 (2006). 27. Wiech, K., Ploner, M. & Tracey, I. Neurocognitive aspects of pain perception. Trends Cogn. Sci. 12, 306313 (2008). 28. Tracey, I. etal. Imaging attentional modulation of pain in the periaqueductal gray in humans. J.Neurosci. 22, 27482752 (2002). 29. Valet, M. etal. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during painan fMRI analysis. Pain 109, 39408 (2004). 30. deCharms, R.C. etal. Control over brain activation and pain learned by using real-time functional MRI. Proc. Natl Acad. Sci. USA 102, 1862618631 (2005). 31. Merskey, H. & Bogduk, N. (eds) Classification of Chronic Pain (IASP Press, 1994). 32. Tracey, I. Getting the pain you expect: mechanisms of placebo, nocebo and

NATURE REVIEWS | NEUROLOGY

2011 Macmillan Publishers Limited. All rights reserved

VOLUME 7 | MARCH 2011 | 179

REVIEWS
reappraisal effects in humans. Nat. Med. 16, 12771283 (2010). Singer, T. etal. Empathy for pain involves the affective but not sensory components of pain. Science 303, 11571162 (2004). Loggia, M.L., Mogil, J.S. & Bushnell, M.C. Empathy hurts: compassion for another increases both sensory and affective components of pain perception. Pain 136, 168176 (2008). Danziger, N., Faillenot, I. & Peyron, R. Can we share a pain we never felt? Neural correlates of empathy in patients with congenital insensitivity to pain. Neuron 61, 203212 (2009). Kong, J. etal. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J.Neurosci. 28, 1335413362 (2008). Flor, H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. 1, 182189 (2002). Boivie, J., Leijon, G. & Johansson, I. Central poststroke paina study of the mechanisms through analyses of the sensory abnormalities. Pain 37, 173185 (1989). Boivie, J. Chapter 48 Central post-stroke pain. Handb. Clin. Neurol. 81, 715730 (2006). Head, H. & Holmes, G. Sensory disturbances from cerebral lesions. Brain Research 34, 102254 (1911). Penfield, W. & Boldrey, E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60, 389443 (1937). Ostrowsky, K. etal. Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb. Cortex 12, 376385 (2002). Mazzola, L., Isnard, J., Peyron, R., Guenot, M. & Mauguiere, F. Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex. Pain 146, 99104 (2009). Mhalla, A., de Andrade, D.C., Baudic, S., Perrot,S. & Bouhassira, D. Alteration of cortical excitability in patients with fibromyalgia. Pain 149, 495500 (2010). Apkarian, A.V., Bushnell, M.C., Treede, R.D. & Zubieta, J.K. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J.Pain 9, 463484 (2005). Rainville, P ., Duncan, G.H., Price, D.D., Carrier, B. & Bushnell, M.C. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277, 968971 (1997). Schweinhardt, P . etal. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32, 256265 (2006). Coghill, R.C., Sang, C.N., Maisog, J.M. & Iadarola, M.J. Pain intensity processing within the human brain: a bilateral, distributed mechanism. J.Neurophysiol. 82, 19341943 (1999). Berthier, M., Starkstein, S. & Leiguarda, R. Asymbolia for pain: a sensory-limbic disconnection syndrome. Ann. Neurol. 24, 4149 (1988). Starr, C.J. etal. Roles of the insular cortex in the modulation of pain: insights from brain lesions. J.Neurosci. 29, 26842694 (2009). Greenspan, J.D., Lee, R.R. & Lenz, F.A. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 81, 273282 (1999). Birklein, F., Rolke, R. & Muller-Forell, W. Isolated insular infarction eliminates contralateral cold, cold pain, and pinprick perception. Neurology 65, 1381 (2005). 53. Nair, D.R., Najm, I., Bulacio, J. & Luders, H. Painful auras in focal epilepsy. Neurology 57, 700702 (2001). 54. Brooks, J.C., Zambreanu, L., Godinez, A., Craig,A.D. & Tracey, I. Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging. Neuroimage 27, 201209 (2005). 55. Henderson, L.A., Gandevia, S.C. & Macefield,V.G. Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study. Pain 128, 2030 (2007). 56. Bjornsdotter, M., Loken, L., Olausson, H., Vallbo,A. & Wessberg, J. Somatotopic organization of gentle touch processing in the posterior insular cortex. J.Neurosci. 29, 93149320 (2009). 57. Raij, T.T., Numminen, J., Narvanen, S., Hiltunen, J. & Hari, R. Brain correlates of subjective reality of physically and psychologically induced pain. Proc. Natl Acad. Sci. USA 102, 21472151 (2005). 58. Albanese, M.C., Duerden, E.G., Rainville, P .& Duncan, G.H. Memory traces of pain in human cortex. J.Neurosci. 27, 46124620 (2007). 59. Craig, A.D., Chen, K., Bandy, D. & Reiman, E.M. Thermosensory activation of insular cortex. Nat. Neurosci. 3, 184190 (2000). 60. Keltner, J.R. etal. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J.Neurosci. 26, 44374443 (2006). 61. Craig, A.D. How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. Neurosci. 3, 655666 (2002). 62. Baumgartner, U. etal. Multiple somatotopic representations of heat and mechanical pain in the operculo-insular cortex: a high-resolution FMRI study. J.Neurophysiol. 104, 28632872 (2010). 63. Lorenz, J., Minoshima, S. & Casey, K.L. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126, 10791091 (2003). 64. Seifert, F. etal. Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia. J.Neurosci. 29, 61676175 (2009). 65. Bantick, S.J. etal. Imaging how attention modulates pain in humans using functional MRI. Brain 125, 310319 (2002). 66. Wiech, K. etal. Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J.Neurosci. 26, 1150111509 (2006). 67. Wiech, K. etal. An fMRI study measuring analgesia enhanced by religion as a belief system. Pain 139, 467476 (2008). 68. Wager, T.D., Davidson, M.L., Hughes, B.L., Lindquist, M.A. & Ochsner, K.N. Prefrontalsubcortical pathways mediating successful emotion regulation. Neuron 59, 10371050 (2008). 69. Ochsner, K.N. etal. Your pain or mine? Common and distinct neural systems supporting the perception of pain in self and other. Soc. Cogn Affect. Neurosci. 3, 144160 (2008). 70. Phelps, E.A., Delgado, M.R., Nearing, K.I. & LeDoux, J.E. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897905 (2004). 71. Quirk, G.J., Garcia, R. & Gonzalez-Lima, F. Prefrontal mechanisms in extinction of conditioned fear. Biol. Psychiatry 60, 337343 (2006). 72. Schiller, D., Levy, I., Niv, Y., LeDoux, J.E. & Phelps,E.A. From fear to safety and back: reversal of fear in the human brain. J.Neurosci. 28, 1151711525 (2008). 73. Fairhurst, M., Wiech, K., Dunckley, P . & Tracey, I. Anticipatory brainstem activity predicts neural processing of pain in humans. Pain 128, 101110 (2007). 74. Ploghaus, A. etal. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J.Neurosci. 21, 98969903 (2001). 75. Tsao, H., Galea, M.P . & Hodges, P .W. Driving plasticity in the motor cortex in recurrent low back pain. Eur J Pain 14, 832839 (2010). 76. Brighina, F. etal. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J.Neurol. Sci. 227, 6771 (2004). 77. Fierro, B. etal. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability. Exp. Brain Res. 203, 3138 (2010). 78. Knotkova, H. & Cruciani, R.A. Non-invasive transcranial direct current stimulation for the study and treatment of neuropathic pain. Methods Mol. Biol. 617, 505515 (2010). 79. Antal, A. & Paulus, W. Transcranial magnetic and direct current stimulation in the therapy of pain [German]. Schmerz 24, 161166 (2010). 80. Antal, A., Terney, D., Kuhnl, S. & Paulus, W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J.Pain Symptom Manage. 39, 890903 (2010). 81. Neugebauer, V., Li, W., Bird, G.C. & Han, J.S. The amygdala and persistent pain. Neuroscientist 10, 221234 (2004). 82. Carrasquillo, Y. & Gereau, R.W. 4th. Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception. J.Neurosci. 27, 15431551 (2007). 83. Bornhovd, K. etal. Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: asingle-trial fMRI study. Brain 125, 13261336 (2002). 84. Petrovic, P ., Carlsson, K., Petersson, K.M., Hansson, P . & Ingvar, M. Context-dependent deactivation of the amygdala during pain. J.Cogn. Neurosci. 16, 12891301 (2004). 85. Petrovic, P ., Ingvar, M., Stone-Elander, S., Petersson, K.M. & Hansson, P . A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 83, 459470 (1999). 86. Iannetti, G.D. etal. Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans. Neuroimage 28, 708719 (2005). 87. Frot, M. & Mauguiere, F. Dual representation of pain in the operculo-insular cortex in humans. Brain 126, 438450 (2003). 88. Frot, M., Mauguiere, F., Magnin, M. & GarciaLarrea, L. Parallel processing of nociceptive Adelta inputs in SII and midcingulate cortex in humans. J.Neurosci. 28, 944952 (2008). 89. Lee, M.C., Mouraux, A. & Iannetti, G.D. Characterizing the cortical activity through which pain emerges from nociception. J.Neurosci. 29, 79097916 (2009). 90. Schurger, A., Pereira, F., Treisman, A. & Cohen,J.D. Reproducibility distinguishes conscious from nonconscious neural representations. Science 327, 9799 (2010). 91. Gross, J., Schnitzler, A., Timmermann, L. & Ploner,M. Gamma oscillations in human primary somatosensory cortex reflect pain perception. PLoS Biol. 5, e133 (2007). 92. Magnin, M. etal. Thalamic deactivation at sleep onset precedes that of the cerebral cortex in humans. Proc. Natl Acad. Sci. USA 107, 38293833 (2010).

33.

34.

35.

36.

37.

38.

39. 40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

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2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
93. Hofbauer, R.K., Fiset, P ., Plourde, G., Backman,S.B. & Bushnell, M.C. Dosedependent effects of propofol on the central processing of thermal pain. Anesthesiology 100, 386394 (2004). 94. Davis, M.H. etal. Dissociating speech perception and comprehension at reduced levels of awareness. Proc. Natl Acad. Sci. USA 104, 1603216037 (2007). 95. Mhuircheartaigh, R.N. etal. Cortical and subcortical connectivity changes during decreasing levels of consciousness in humans: afunctional magnetic resonance imaging study using propofol. J.Neurosci. 30, 90959102 (2010). 96. Fastenrath, M., Friston, K.J. & Kiebel, S.J. Dynamical causal modelling for M/EEG: spatial and temporal symmetry constraints. Neuroimage 44, 154163 (2009). 97. Friston, K. Causal modelling and brain connectivity in functional magnetic resonance imaging. PLoS Biol. 7, e33 (2009). 98. Friston, K.J. & Dolan, R.J. Computational and dynamic models in neuroimaging. Neuroimage 52, 752765 (2010). 99. Ploner, M., Lee, M.C., Wiech, K., Bingel, U. & Tracey, I. Prestimulus functional connectivity determines pain perception in humans. Proc. Natl Acad. Sci. USA 107, 355360 (2010). 100. Fair, D.A. etal. Development of distinct control networks through segregation and integration. Proc. Natl Acad. Sci. USA 104, 1350713512 (2007). 101. Raichle, M.E. Two views of brain function. Trends Cogn. Sci. 14, 180190 (2010). 102. Raichle, M.E. & Snyder, A.Z. A default mode of brain function: a brief history of an evolving idea. Neuroimage 37, 10831090 (2007). 103. Fair, D.A. etal. The maturing architecture of the brains default network. Proc. Natl Acad. Sci. USA 105, 40284032 (2008). 104. Baliki, M.N. etal. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J.Neurosci. 26, 1216512173 (2006). 105. Napadow, V. etal. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 62, 25452555 (2010). 106. Morcom, A.M. & Fletcher, P .C. Does the brain have a baseline? Why we should be resisting a rest. Neuroimage 37, 10731082 (2007). 107. Greicius, M. Resting-state functional connectivity in neuropsychiatric disorders. Curr. Opin. Neurol. 21, 424430 (2008). 108. Filippini, N. etal. Distinct patterns of brain activity in young carriers of the APOE-4 allele. Proc. Natl Acad. Sci. USA 106, 72097214 (2009). 109. Malinen, S. etal. Aberrant temporal and spatial brain activity during rest in patients with chronic pain. Proc. Natl Acad. Sci. USA 107, 64936497 (2010). 110. Harris, R.E. etal. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum. 58, 903907 (2008). 111. Harris, R.E. etal. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 60, 31463152 (2009). 112. Valdes, M. etal. Increased glutamate/glutamine compounds in the brain of patients with fibromyalgia: a MR spectroscopy study. Arthritis Rheum. 62, 18291836 (2010). 113. Detre, J.A., Leigh, J.S., Williams, D.S. & Koretsky, A.P . Perfusion imaging. Magn. Reson. Med. 23, 3745 (1992). 114. Tracey, I. & Johns, E. The pain matrix: reloaded or reborn as we image tonic pain using arterial spin labelling. Pain 148, 359360 (2010). 115. Owen, D.G., Clarke, C.F., Ganapathy, S., Prato,FS. & St Lawrence, K.S. Using perfusion MRI to measure the dynamic changes in neural activation associated with tonic muscular pain. Pain 148, 375386 (2010). 116. Owen, D.G., Bureau, Y., Thomas, A.W., Prato,F.S. & St Lawrence, K.S. Quantification of pain-induced changes in cerebral blood flow by perfusion MRI. Pain 136, 896 (2008). 117. Milligan, E.D. & Watkins, L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 10, 2336 (2009). 118. Banati, R.B. etal. Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury. Neuroreport 12, 34393442 (2001). 119. Pattany, P .M. etal. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am. J.Neuroradiol. 23, 901905 (2002). 120. Fukui, S., Matsuno, M., Inubushi, T. & Nosaka, S. NAcetylaspartate concentrations in the thalami of neuropathic pain patients and healthy comparison subjects measured with 1H-MRS. Magn. Reson. Imaging 24, 7579 (2006). 121. Jongen, J.L. etal. Autofluorescent flavoprotein imaging of spinal nociceptive activity. J.Neurosci. 30, 40814087 (2010). 122. Slater, R. etal. Cortical pain responses in human infants. J.Neurosci. 26, 36623666 (2006). 123. Brooks, J.C. etal. Physiological noise modelling for spinal functional magnetic resonance imaging studies. Neuroimage 39, 680692 (2008). 124. Eippert, F., Finsterbusch, J., Bingel, U. & Buchel,C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009). 125. Leeuw, M. etal. The fear-avoidance model of musculoskeletal pain: current state of scientific evidence. J.Behav. Med. 30, 7794 (2007). 126. Berna, C. etal. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness. Biol. Psychiatry 67, 10831090 (2010). 127. Mayer, E.A. etal. Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain 115, 398409 (2005). 128. Jones, A.K. & Derbyshire, S.W. Reduced cortical responses to noxious heat in patients with rheumatoid arthritis. Ann. Rheum. Dis. 56, 601607 (1997). 129. Gundel, H. etal. Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder. Pain 137, 413421 (2008). 130. Apkarian, A.V., Thomas, P .S., Krauss, B.R. & Szeverenyi, N.M. Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain. Neurosci. Lett. 311, 193197 (2001). 131. Gracely, R.H. etal. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 127, 835843 (2004). 132. Tracey, I. & Bushnell, C. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J.Pain 10, 11131120 (2009). 133. May, A. Chronic pain may change the structure of the brain. Pain 137, 715 (2008). 134. Apkarian, A.V. etal. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J.Neurosci. 24, 1041010415 (2004). 135. Seminowicz, D.A. etal. MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage 47, 10071014 (2009). 136. Metz, A.E., Yau, H.J., Centeno, M.V., Apkarian,A.V. & Martina, M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc. Natl Acad. Sci. USA 106, 24232428 (2009). 137. Pezawas, L. etal. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J.Neurosci. 24, 1009910102 (2004). 138. Milad, M.R. etal. Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc. Natl Acad. Sci. USA 102, 1070610711 (2005). 139. Milad, M.R. etal. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446454 (2007). 140. Gwilym, S.E., Fillipini, N., Douaud, G., Carr, A.J. & Tracey, I. Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty; a longitudinal voxelbasedmorphometric study. Arthritis Rheum. 62, 29302940 (2010). 141. Rodriguez-Raecke, R., Niemeier, A., Ihle, K., Ruether, W. & May, A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J.Neurosci. 29, 1374613750 (2009). 142. Willoch, F. etal. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 108, 213220 (2004). 143. Jones, A.K. etal. Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis. Br.J.Rheumatol. 33, 909916 (1994). 144. Jones, A.K., Watabe, H., Cunningham, V.J. & Jones, T. Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET. Eur. J.Pain 8, 479485 (2004). 145. Harris, R.E. etal. Decreased central mu-opioid receptor availability in fibromyalgia. J.Neurosci. 27, 1000010006 (2007). 146. Wood, P .B. etal. Fibromyalgia patients show an abnormal dopamine response to pain. Eur. J.Neurosci. 25, 35763582 (2007). 147. Wood, P .B. etal. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J.Pain 8, 5158 (2007). 148. Scott, D.J., Heitzeg, M.M., Koeppe, R.A., Stohler, C.S. & Zubieta, J.K. Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J.Neurosci. 26, 1078910795 (2006). 149. Maarrawi, J. etal. Differential brain opioid receptor availability in central and peripheral neuropathic pain. Pain 127, 183194 (2007). 150. Boly, M. etal. Perception of pain in the minimally conscious state with PET activation: an observational study. Lancet Neurol. 7, 10131020 (2008). 151. Antognini, J.F., Buonocore, M.H., Disbrow, E.A. & Carstens, E. Isoflurane anesthesia blunts cerebral responses to noxious and innocuous stimuli: a fMRI study. Life Sci. 61, PL349PL354 (1997). 152. Haynes, J.D. etal. Reading hidden intentions in the human brain. Curr. Biol. 17, 323328 (2007). 153. Sakai, K. & Passingham, R.E. Prefrontal set activity predicts rule-specific neural processing during subsequent cognitive performance. J.Neurosci. 26, 12111218 (2006).

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