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The brain contains both generalized and stimulus-type-specific representations of aversive events, but models of how these are integrated and related to subjective experience are lacking. We combined functional magnetic resonance imaging with predictive modeling to identify representations of generalized (common) and stimulus-type-specific negative affect across mechanical pain, thermal pain, aversive sounds and aversive images of four intensity levels each. This allowed us to examine how generalized and stimulus-specific representations jointly contribute to aversive experience. Stimulus-type-specific negative affect was largely encoded in early sensory pathways, whereas generalized negative affect was encoded in a distributed set of midline, forebrain, insular and somatosensory regions. All models specifically predicted negative affect rather than general salience or arousal and accurately predicted negative affect in independent samples, demonstrating robustness and generalizability. Common and stimulus-type-specific models were jointly important for predicting subjective experience. Together, these findings offer an integrated account of how negative affect is constructed in the brain and provide predictive neuromarkers for future studies.

Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm 2 , and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm 2 but not 4 kg/cm 2 . Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm 2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm 2 . Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.

Objective Research suggests abnormalities in reward-based processes in anorexia nervosa (AN). However, few studies have explored if such alterations might be associated with different temporal activation patterns. This study aims to characterize alterations in time-dependent processes in the ventral striatum (VS) during social feedback in AN using functional magnetic resonance imaging (fMRI). Method Twenty women with restrictive-subtype AN and 20 age-matched healthy controls (HC) underwent a social judgment experimental fMRI task. Temporal VS hemodynamic responses were extracted in SPM for each participant and each social condition (acceptance/rejection). Results Compared with age-matched HC, patients with AN showed a significant time by group interaction of peak VS response throughout the task, with a progressive blunting of peak activation responses, accompanied by a progressive increase in baseline activity levels over time. Discussion The results suggest an attenuated response pattern to repetitive social rejection in the VS in patients with AN, together with a difficulty in returning to baseline. The information obtained from this study will guide future, design-specific studies to further explore alterations temporal dynamics.

There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

ObjectiveJuvenile fibromyalgia (JFM) is a chronic widespread pain condition that primarily affects adolescent girls. Previous studies have found increased sensitivity to noxious pressure in adolescents with JFM. However, the underlying changes in brain systems remain unclear. The aim of this study was to characterize pain-evoked brain responses and identify brain mediators of pain hypersensitivity in adolescent girls with JFM.MethodsThirty-three adolescent girls with JFM and thirty-three healthy adolescent girls underwent functional MRI scans involving noxious pressure applied to the left thumbnail at an intensity of 2.5 or 4 kg/cm2 and rated pain intensity and unpleasantness on a computerized visual analogue scale. We conducted standard general linear model analyses and exploratory whole-brain mediation analyses, and computed pain-evoked brain responses within seven major cortical networks.ResultsThe JFM group reported significantly greater pain intensity and unpleasantness than the control group in response to noxious pressure stimuli at both intensities (p2 (Z>3.1, cluster-corrected p2, and greater primary sensorimotor cortex activation in response to 4kg/cm2 mediated the between-group differences in pain intensity ratings (pConclusionWe found heightened sensitivity to noxious pressure stimuli and augmented pain-evoked sensorimotor cortex responses in adolescent girls with JFM, which could reflect central sensitization or amplified nociceptive input.

IntroductionCurrent treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches.Methods and analysisHere we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function.Ethics and disseminationThe study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children’s Hospital Medical Center Review Board as the reviewing IRB. Stanford’s IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories.Trial registration numberNCT04285112.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Interpersonal touch and social support can influence physical health, mental well-being and pain. However, the mechanisms by which supportive touch promotes analgesia are not well understood. In Study 1, we tested how three kinds of social support from a romantic partner (passive presence, gentle stroking and handholding) affect pain ratings and skin conductance responses (SCRs). Overall, support reduced pain ratings in women, but not men, relative to baseline. Support decreased pain-related SCRs in both women and men. Though there were no significant differences across the three support conditions, effects were largest during handholding. Handholding also reduced SCRs in the supportive partner. Additionally, synchronicity in couples’ SCR was correlated with reductions in self-reported pain, and individual differences in synchrony were correlated with the partner’s trait empathy. In Study 2, we re-analyzed an existing dataset to explore fMRI activity related to individual differences in handholding analgesia effects in women. Increased activity in a distributed set of brain regions, including valuation-encoding frontostriatal areas, was correlated with lower pain ratings. These results may suggest that social support can reduce pain by changing the value of nociceptive signals. This reduction may be moderated by interpersonal synchrony and relationship dynamics.

Objective: Juvenile fibromyalgia (FM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of juvenile FM. This study was undertaken to characterize gray matter volume (GMV) alterations in juvenile FM patients for the first time, and to investigate their functional and clinical relevance. Methods: Thirty-four female adolescents with juvenile FM and 38 healthy adolescents underwent a structural magnetic resonance imaging examination and completed questionnaires assessing core juvenile FM symptoms. Using voxel-based morphometry, we assessed between-group GMV differences and associations between GMV and functional disability, fatigue, and pain interference in juvenile FM. We also studied whether validated brain patterns predicting pain, cognitive control, or negative emotion were amplified/attenuated in juvenile FM patients and whether structural alterations reported in adult FM were replicated in adolescents with juvenile FM. Results: Compared to controls, juvenile FM patients showed GMV reductions in the anterior midcingulate cortex (aMCC) region (family-wise error corrected P [PFWE-corr ] = 0.04; estimated with threshold-free cluster enhancement [TFCE]; n = 72) associated with pain. Within the juvenile FM group, patients reporting higher functional disability had larger GMV in inferior frontal regions (PFWE-corr = 0.006; TFCE estimated; n = 34) linked to affective, self-referential, and language-related processes. Last, GMV reductions in juvenile FM showed partial overlap with findings in adult FM, specifically for the anterior/posterior cingulate cortices (P = 0.02 and P = 0.03, respectively; n = 72). Conclusion: Pain-related aMCC reductions may be a structural hallmark of juvenile FM, whereas alterations in regions involved in emotional, self-referential, and language-related processes may predict disease impact on patients' well-being. The partial overlap between juvenile and adult FM findings strengthens the importance of early symptom identification and intervention to prevent the transition to adult forms of the disease.

Supportive touch has remarkable benefits in childbirth and during painful medical procedures. But does social touch influence pain neurophysiology, ie, the brain processes linked to nociception and primary pain experience? What other brain processes beyond primary pain systems mediate their analgesic effects? In this study, women (N = 30) experienced thermal pain while holding their romantic partner's hand or an inert device. Social touch reduced pain and attenuated functional magnetic resonance imaging activity in the Neurologic Pain Signature (NPS)-a multivariate brain pattern sensitive and specific to somatic pain-and increased connectivity between the NPS and both somatosensory and "default mode" regions. Brain correlates of touch-induced analgesia included reduced pain-related activation in (1) regions targeted by primary nociceptive afferents (eg, posterior insula, and anterior cingulate cortex); and (b) regions associated with affective value (orbitofrontal cortex), meaning (ventromedial prefrontal cortex [PFC]), and attentional regulation (dorsolateral PFC). Activation reductions during handholding (vs holding a rubber device) significantly mediated reductions in pain intensity and unpleasantness; greater pain reductions during handholding correlated with greater increases in emotional comfort, which correlated with higher perceived relationship quality and (a trend toward) greater perceived closeness with the romantic partner. The strongest mediators of analgesia were activity reductions in a brain circuit traditionally associated with stress and defensive behavior in mammals, including ventromedial and dorsomedial PFC, rostral anterior cingulate cortex, amygdala/hippocampus, hypothalamus, and periaqueductal gray matter. Social touch affects core brain processes that contribute to pain and pain-related affective distress in females, and should be considered alongside other treatments in medical and caregiving contexts.

Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17) and thirty adult (ages 35-55) females underwent a functional MRI scan involving acute experimental pain. Participants received 12 ten-second noxious pressure stimuli which were applied to the left thumbnail at 2.5 and 4 kg/cm2, and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared to adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm2, but not 4 kg/cm2. Adolescents showed greater medial-lateral prefrontal cortex (PFC) and supramarginal gyrus activation in response to 2.5 kg/cm2, and greater medial PFC and rostral anterior cingulate responses to 4 kg/cm2. Adolescents showed augmented pain-evoked responses in the Neurologic Pain Signature and greater activation in the default mode (DMN) and ventral attention (VAN) networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in DMN and VAN regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides the first evidence of augmented pain-evoked brain responses in healthy female adolescents involving regions important for nociceptive, affective and cognitive processing, in line with their augmented sensitivity to low-intensity noxious stimuli.

Pain is a uniquely individual experience. Previous studies have highlighted changes in brain activation and morphology associated with inter- and intra-individual pain perception. In this study we sought to characterize brain mechanisms associated with individual differences in pain in a large sample of healthy participants (N = 101). Pain ratings varied widely across individuals. Moreover, individuals reported changes in pain evoked by small differences in stimulus intensity in a manner congruent with their pain sensitivity, further supporting the utility of subjective reporting as a measure of the true individual experience. However, brain activation related to inter-individual differences in pain was not detected, despite clear sensitivity of the BOLD signal to small differences in noxious stimulus intensities within individuals. These findings raise questions about the utility of fMRI as an objective measure to infer reported pain intensity.

Information is coded in the brain at different scales for different phenomena: locally, distributed across regions and networks, and globally. For pain, the scale of representation is controversial. Although generally believed to be an integrated cognitive and sensory phenomenon implicating diverse brain systems, quantitative characterizations of which regions and networks are sufficient to represent pain are lacking. In this meta-analysis (or mega-analysis) using data from 289 participants across 10 studies, we use model comparison combined with multivariate predictive models to investigate the spatial scale and location of acute pain representation. We compare models based on (a) a single most pain-predictive module, either previously identified elementary regions or a single best large-scale cortical resting-state network module; (b) selected cortical-subcortical systems related to evoked pain in prior literature (‘multi-system models’); and (c) a model spanning the full brain. We estimate the accuracy of pain intensity predictions using cross validation (7 studies) and subsequently validate in three independent holdout studies. All spatial scales convey information about pain intensity, but distributed, multi-system models better characterize pain representations than any individual region or network (e.g. multisystem models explain >20% more of individual subject pain ratings than the best elementary region). Full brain models showed no predictive advantage over multi-system models. These findings quantify the extent that representation of evoked pain experience is distributed across multiple cortical and subcortical systems, show that pain representation is not circumscribed by any elementary region or conical network, and provide a blueprint for identifying the spatial scale of information in other domains.Significance StatementWe define modular, multisystem and global views of brain function, use multivariate fMRI decoding to characterize pain representations at each level, and provide evidence for a multisystem representation of evoked pain. We further show that local views necessarily exclude important components of pain representation, while a global full brain representation is superfluous, even though both are viable frameworks for representing pain. These findings quantitatively juxtapose and reconcile divergent conclusions from evoked pain studies within a generalized neuroscientific framework, and provide a blueprint for investigating representational architecture for diverse brain processes.Author NoteData storage supported by the University of Colorado Boulder “PetaLibrary”. Research funded by NIMH R01 MH076136, NIDA R01 DA046064 and NIDA R01 DA035484. Lauren Atlas is supported in part by funding from the Intramural Research Program of the National Center for Complementary and Integrative Health, National Institutes of Health (ZIA-AT000030). Marina Lopez-Sola is supported by a Serra Hunter fellow lecturer program. We would like to thank Dr. Christian Buchel for contributing data to this project, and Dr. Marta Čeko for comments and feedback on the manuscript.

OBJECTIVE Contextual factors can transform how we experience pain, particularly if pain is associated with other positive outcomes. Here, we test a novel meaning-based intervention. Participants were given the opportunity to choose to receive pain on behalf of their romantic partners, situating pain experience in a positive, prosocial meaning context. We predicted that the ventromedial prefrontal cortex (vmPFC), a key structure for pain regulation and generation of affective meaning, would mediate the transformation of pain experience by this prosocial interpersonal context. METHODS We studied fMRI activity and behavioral responses in 29 heterosexual female participants during (1) a baseline pain challenge and (2) a task in which participants decided to accept a self-selected number of additional pain trials to reduce pain in their male romantic partners ("accept-partner-pain" condition). RESULTS Enduring extra pain for the benefit of the romantic partner reduced pain-related unpleasantness (t = -2.54, p = .016) but not intensity, and increased positive thoughts (t = 3.60, p = .001) and pleasant feelings (t = 5.39, p < .0005). Greater willingness to accept the pain of one's partner predicted greater unpleasantness reductions (t = 3.94, p = .001) and increases in positive thoughts (r = .457, p = .013). The vmPFC showed significant increases (q < .05 FDR-corrected) in activation during accept-partner-pain, especially for women with greater willingness to relieve their partner's pain (t = 2.63, p = .014). Reductions in brain regions processing pain and aversive emotion significantly mediated reductions in pain unpleasantness (q < .05 FDR-corrected). CONCLUSIONS The vmPFC has a key role in transforming the meaning of pain, which is associated with a cascade of positive psychological and brain effects, including changes in affective meaning, value, and pain-specific neural circuits.

Objective The purpose of this systematic review is to systematically review the evidence relating to findings generated by multivariate pattern analysis (MVPA) following structural or functional magnetic resonance imaging (fMRI) to determine if this analysis is able to: a) Discriminate between individuals with musculoskeletal pain and healthy controls, b) Predict pain perception in healthy individuals stimulated with a noxious stimulus compared to those stimulated with a non-noxious stimulus. Methods MEDLINE, CINAHL, Embase, PEDro, Google Scholar, Cochrane library and Web of Science were systematically screened for relevant literature using different combinations of keywords regarding structural and functional MRI analysed with MVPA, both in individuals with musculoskeletal pain and healthy controls. Reference lists of included articles were hand-searched for additional literature. Eligible articles were assessed on risk of bias and reviewed by two independent researchers. Results The search query returned 18 articles meeting the inclusion criteria. Methodological quality varied from poor to good. Seven studies investigated the ability of machine-learning algorithms to differentiate patient groups from healthy control participants. Overall, the review demonstrated that MVPA can discriminate between individuals with MSK pain and healthy controls with an overall accuracy ranging from 53% to 94%. Twelve studies utilized healthy control participants (using them as their own controls), during experimental pain paradigms aimed to investigate the ability of machine-learning to differentiate individuals stimulated with noxious stimuli from those stimulated with non-noxious stimuli, with ‘pain’ detection rates ranging from 60% to 94%. However, significant heterogeneity in patient conditions, study methodology and brain imaging techniques resulted in various findings that make study comparisons and formal conclusions challenging. Conclusion There is preliminary and emerging evidence that MVPA analyses of structural or functional MRI are able to discriminate between patients and healthy controls, and also discriminate between noxious and non-noxious stimulation. No prospective studies were found in this review to allow determination of the prognostic or diagnostic capabilities or treatment responsiveness of these analyses. Future studies would also benefit from combining various behavioural, genotype and phenotype data into analyses to assist with development of sensitive and specific signatures that could guide future individualized patient treatment options and evaluate how treatments exert their effects.

A relevant aspect in osteoarthritic pain is neural sensitization. This phenomenon involves augmented responsiveness to painful stimulation and may entail a clinically worse prognosis. We used functional magnetic resonance imaging (fMRI) to study pain sensitization in patients with knee osteoarthritis. Sixty patients were recruited and pain sensitization was clinically defined on the basis of regional spreading of pain (spreading sensitization) and increased pain response to repeated stimulation (temporal summation). Functional magnetic resonance imaging testing involved assessing brain responses to both pressure and heat stimulation. Thirty-three patients (55%) showed regional pain spreading (simple sensitization) and 19 patients (32%) showed both regional spreading and temporal summation. Sensitized patients were more commonly women. Direct painful pressure stimulation of the joint (articular interline) robustly activated all of the neural elements typically involved in pain perception, but did not differentiate sensitized and nonsensitized patients. Painful pressure stimulation on the anterior tibial surface (sensitized site) evoked greater activation in sensitized patients in regions typically involved in pain and also beyond these regions, extending to the auditory, visual, and ventral sensorimotor cortices. Painful heat stimulation of the volar forearm did not discriminate the sensitization phenomenon. Results confirm the high prevalence of pain sensitization secondary to knee osteoarthritis. Relevantly, the sensitization phenomenon was associated with neural changes extending beyond strict pain-processing regions with enhancement of activity in general sensory, nonnociceptive brain areas. This effect is in contrast to the changes previously identified in primary pain sensitization in fibromyalgia patients presenting with a weakening of the general sensory integration. This study was supported in part by the Ministry of Economy and Competitiveness of Spain (grant PSI2014- 53524-P) and the Merck Investigator Studies Program (grant MISP-IISP41059). We thank to the Agency of University and Research Funding Management of the Catalonia Government for their participation in the context of Research Group SGR2014-1673. BJH is supported by a National Health and Medical Research Council of Australia (NHMRC) Clinical Career Development Award (1124472).

Resumen Introduccion La artrosis de rodilla es causa de dolor e incapacidad funcional. Uno de los problemas para evaluar la eficacia de los analgesicos ha sido la falta de medidas objetivas de dolor, aunque la resonancia magnetica funcional (RMf) ha surgido como un medio util para objetivar la respuesta del cerebro a la estimulacion dolorosa. Hemos investigado el efecto del condroitin sulfato (CS) sobre la respuesta del cerebro a la estimulacion dolorosa de la rodilla en pacientes con artrosis mediante RMf. Metodos Veintidos pacientes recibieron CS (800 mg/dia) y 27 placebo y fueron evaluados inicialmente y despues de 4 meses de tratamiento. En cada sesion de RMf se aplico presion dolorosa sobre la interlinea de la rodilla y en la superficie de la rotula. El resultado se cuantifico como la atenuacion de la respuesta cerebral a la estimulacion dolorosa de la rodilla. Resultados La RMf de la maniobra rotuliana mostro una reduccion de la activacion en la region de la sustancia gris periacueductal del mesencefalo significativamente mayor durante el tratamiento con CS que en la condicion de placebo. El grupo de CS, pero no el de placebo, mostro ademas una reduccion de la activacion en la representacion cortical de la pierna tras el tratamiento. No se observaron efectos del CS con presion dolorosa sobre la interlinea de la rodilla. Conclusiones La RMf fue sensible para objetivar los efectos del CS sobre la respuesta del cerebro a la presion dolorosa sobre el cartilago rotuliano-femoral, que es un resultado coherente con la accion conocida del CS sobre la regeneracion de los condrocitos. El presente trabajo muestra nuevamente la utilidad de la RMf para objetivar los efectos del tratamiento en el dolor de origen artrosico.

Information about others’ experiences can strongly influence our own feelings and decisions. But how does such social information affect the neural generation of affective experience, and are the brain mechanisms involved distinct from those that mediate other types of expectation effects? Here, we used fMRI to dissociate the brain mediators of social influence and associative learning effects on pain. Participants viewed symbolic depictions of other participants’ pain ratings (social information) and classically conditioned pain-predictive cues before experiencing painful heat. Social information and conditioned stimuli each had significant effects on pain ratings, and both effects were mediated by self-reported expectations. Yet, these effects were mediated by largely separable brain activity patterns, involving different large-scale functional networks. These results show that learned versus socially instructed expectations modulate pain via partially different mechanisms—a distinction that should be accounted for by theories of predictive coding and related top-down influences., Our experience of pain can be affected by our expectations about how much pain we will feel. Here, the authors show that both social information-driven expectations, and those based on personal experience, are both able to modulate pain, but by different neural pathways.

While pain has been identified as a major health issue for adolescents, brain mechanisms of pain processing in this population remain unclear. Previous findings from adult studies may not be applicable given that the adolescent brain, particularly prefrontal cortex (PFC), has not been fully developed. This study was conducted to characterize pain sensitivity, pain-evoked brain responses, and the brain regions mediating the relationship between the stimulus intensity and pain perception in adolescents. Thirty adolescents (ages 13-17) and thirty adults (ages 35-55) underwent functional MRI scans involving acute pain. They received 12 noxious pressure stimuli (2.5 or 4 kg/cm2, each lasting 10 seconds, applied to the left thumbnail) and rated pain intensity and unpleasantness on a 0-100 computerized visual analogue scale. Adolescents reported greater pain intensity (t=2.77, p=0.008) and unpleasantness (t=2.66, p=0.01) in response to stimulations at 2.5 kg/cm2. These differences disappeared at 4 kg/cm2 (pain intensity: t=0.39, p=0.700; pain unpleasantness: t=0.97, p=0.337). A significant group by stimulus intensity interaction effect (F=7.52, p=0.008) was found in pain intensity ratings using a mixed-design ANOVA. Adolescents had greater dorsolateral and dorsomedial PFC as well as supramarginal gyrus activations in response to stimuli at 2.5kg/cm2, and greater rostral anterior cingulate and dorsomedial PFC activations in response to stimuli at 4kg/cm2 (Z>3.1, p

Patients with fibromyalgia (FM) show characteristically enhanced unpleasantness to painful and nonpainful sensations accompanied by altered neural responses. The diagnostic potential of such neural alterations, including their sensitivity and specificity to FM (vs healthy controls) is unknown. We identify a brain signature that characterizes FM central pathophysiology at the neural systems level. We included 37 patients with FM and 35 matched healthy controls, and analyzed functional magnetic resonance imaging responses to (1) painful pressure and (2) nonpainful multisensory (visual-auditory-tactile) stimulation. We used machine-learning techniques to identify a brain-based FM signature. When exposed to the same painful stimuli, patients with FM showed greater neurologic pain signature (NPS; Wager et al., 2013. An fMRI-based neurologic signature of physical pain. N Engl J Med 2013;368:1388-97) responses. In addition, a new pain-related classifier ("FM-pain") revealed augmented responses in sensory integration (insula/operculum) and self-referential (eg, medial prefrontal) regions in FM and reduced responses in the lateral frontal cortex. A "multisensory" classifier trained on nonpainful sensory stimulation revealed augmented responses in the insula/operculum, posterior cingulate, and medial prefrontal regions and reduced responses in the primary/secondary sensory cortices, basal ganglia, and cerebellum. Combined activity in the NPS, FM pain, and multisensory patterns classified patients vs controls with 92% sensitivity and 94% specificity in out-of-sample individuals. Enhanced NPS responses partly mediated mechanical hypersensitivity and correlated with depression and disability (Puncorrected < 0.05); FM-pain and multisensory responses correlated with clinical pain (Puncorrected < 0.05). The study provides initial characterization of individual patients with FM based on pathophysiological, symptom-related brain features. If replicated, these brain features may constitute objective neural targets for therapeutic interventions. The results establish a framework for assessing therapeutic mechanisms and predicting treatment response at the individual level.

In a previous study (Krishnan, 2016) we identified a whole-brain pattern, the Vicarious Pain Signature (VPS), which predicts vicarious pain when participants observe pictures of strangers in pain. Here, we test its generalization to observation of pain in a close significant other. Participants experienced painful heat (Self-Pain) and observed their romantic partner in pain (Partner-Pain). We measured whether (i) the VPS would respond selectively to Partner-Pain and (ii) the Neurologic Pain Signature (NPS), a measure validated to track somatic pain, would selectively respond to Self-Pain, despite the high interpersonal closeness between partners. The Partner-Pain condition activated the VPS (t = 4.71, p = 0.00005), but not the NPS (t = -1.03, p = 0.308). The Self-Pain condition activated the NPS (t = 13.70, p < .00005), but not the VPS (t = -1.03 p = 0.308). Relative VPS-NPS response differences strongly discriminated Partner-Pain vs. Self-Pain (cross-validated accuracy=97%, p < .000001). Greater interpersonal closeness between partners predicted greater VPS responses during Partner-Pain (r = 0.388, p = 0.050) and greater unpleasantness when observing the romantic partner in pain (r = 0.559, p = 0.003). The VPS generalizes across empathy paradigms and to an interactive social setting, and strongly activates when observing a close significant other in pain. VPS responses may be modulated by relevant interpersonal relationship factors. Self-Pain and Partner-Pain evoke non-overlapping large-scale neural representations.

Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder.

Multivariate pattern analysis (MVPA) has become an important tool for identifying brain representations of psychological processes and clinical outcomes using fMRI and related methods. Such methods can be used to predict or ‘decode’ psychological states in individual subjects. Single-subject MVPA approaches, however, are limited by the amount and quality of individual-subject data. In spite of higher spatial resolution, predictive accuracy from single-subject data often does not exceed what can be accomplished using coarser, group-level maps, because single-subject patterns are trained on limited amounts of often-noisy data. Here, we present a method that combines population-level priors, in the form of biomarker patterns developed on prior samples, with single-subject MVPA maps to improve single-subject prediction. Theoretical results and simulations motivate a weighting based on the relative variances of biomarker-based prediction—based on population-level predictive maps from prior groups—and individual-subject, cross-validated prediction. Empirical results predicting pain using brain activity on a trial-by-trial basis (single-trial prediction) across 6 studies (N = 180 participants) confirm the theoretical predictions. Regularization based on a population-level biomarker—in this case, the Neurologic Pain Signature (NPS)—improved single-subject prediction accuracy compared with idiographic maps based on the individuals' data alone. The regularization scheme that we propose, which we term group-regularized individual prediction (GRIP), can be applied broadly to within-person MVPA-based prediction. We also show how GRIP can be used to evaluate data quality and provide benchmarks for the appropriateness of population-level maps like the NPS for a given individual or study.

Objective Fibromyalgia (FM) is a disorder characterized by chronic pain and enhanced responses to acute noxious events. However, the sensory systems affected in FM may extend beyond pain itself, as FM patients show reduced tolerance to non-nociceptive sensory stimulation. Characterizing the neural substrates of multisensory hypersensitivity in FM may thus provide important clues about the underlying pathophysiology of the disorder. The aim of this study was to characterize brain responses to non-nociceptive sensory stimulation in FM patients and their relationship to subjective sensory sensitivity and clinical pain severity. Methods Functional magnetic resonance imaging (MRI) was used to assess brain response to auditory, visual, and tactile motor stimulation in 35 women with FM and 25 matched controls. Correlation and mediation analyses were performed to establish the relationship between brain responses and 3 types of outcomes: subjective hypersensitivity to daily sensory stimulation, spontaneous pain, and functional disability. Results Patients reported increased subjective sensitivity (increased unpleasantness) in response to multisensory stimulation in daily life. Functional MRI revealed that patients showed reduced task-evoked activation in primary/secondary visual and auditory areas and augmented responses in the insula and anterior lingual gyrus. Reduced responses in visual and auditory areas were correlated with subjective sensory hypersensitivity and clinical severity measures. Conclusion FM patients showed strong attenuation of brain responses to nonpainful events in early sensory cortices, accompanied by an amplified response at later stages of sensory integration in the insula. These abnormalities are associated with core FM symptoms, suggesting that they may be part of the pathophysiology of the disease.

Objective.The aim of our study was to investigate the effects of naproxen, an antiinflammatory analgesic drug, on brain response to painful stimulation on the affected knee in chronic osteoarthritis (OA) using functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled study.Methods.A sample of 25 patients with knee OA received naproxen (500 mg), placebo, or no treatment in 3 separate sessions in a randomized manner. Pressure stimulation was applied to the medial articular interline of the knee during the fMRI pain sequence. We evaluated subjective pain ratings at every session and their association with brain responses to pain. An fMRI control paradigm was included to discard global brain vascular effects of naproxen.Results.We found brain activation reductions under naproxen compared to no treatment in different cortical and subcortical core pain processing regions (p ≤ 0.001). Compared to placebo, naproxen triggered an attenuation of amygdala activation (p = 0.001). Placebo extended its attenuation effects beyond the classical pain processing network (p ≤ 0.001). Subjective pain scores during the fMRI painful task differed between naproxen and no treatment (p = 0.037). Activation attenuation under naproxen in different regions (i.e., ventral brain, cingulate gyrus) was accompanied by an improvement in the subjective pain complaints (p ≤ 0.002).Conclusion.Naproxen effectively reduces pain-related brain responses involving different regions and the attenuation is related to subjective pain changes. Our current work yields further support to the utility of fMRI to objectify the acute analgesic effects of a single naproxen dose in patients affected by knee OA. The trial was registered at the EuropeanClinicalTrials Database, “EudraCT Number 2008-004501-33”.

BackgroundDespite knowledge of amygdala involvement in fear and anxiety, its contribution to the pathophysiology of obsessive–compulsive disorder (OCD) remains controversial. In the context of neuroimaging studies, it seems likely that the heterogeneity of the disorder might have contributed to a lack of consistent findings.AimsTo assess the influence of OCD symptom dimensions on amygdala responses to a well-validated emotional face-matching paradigm.MethodCross-sectional functional magnetic resonance imaging (fMRI) study of 67 patients with OCD and 67 age-, gender- and education-level matched healthy controls.ResultsThe severity of aggression/checking and sexual/religious symptom dimensions were significantly associated with heightened amygdala activation in those with OCD when responding to fearful faces, whereas no such correlations were seen for other symptom dimensions.ConclusionsAmygdala functional alterations in OCD appear to be specifically modulated by symptom dimensions whose origins may be more closely linked to putative amygdala-centric processes, such as abnormal fear processing.

Human brain mechanisms of pain have been well studied in adults. However, similar research in adolescents is lacking. Directly extrapolating adult findings to adolescents can be problematic, given that the prefrontal circuitry, which plays an important role in modulating pain responses, remains immature until adulthood. In this ongoing study, we characterized brain responses to pressure pain in eighteen healthy adolescents between ages 13 and 17 using functional magnetic resonance imaging (fMRI). Twelve ten-second noxious pressure stimuli (2.5-4kg/cm2) were applied to the participants’ left thumbnail using a pneumatic device, which reliably evoked pain experience in all subjects (on a 0-100 computerized visual analogue scale, pain intensity: mean(std)=28.00(15.78), t=7.53, p

Background Functional neuroimaging studies have provided consistent support for the idea that obsessive-compulsive disorder (OCD) is associated with disturbances of brain corticostriatal systems. However, in general, these studies have not sought to account for the disorder's prominent clinical heterogeneity. Methods To address these concerns, we investigated the influence of major OCD symptom dimensions on brain corticostriatal functional systems in a large sample of OCD patients (n = 74) and control participants (n = 74) examined with resting-state functional magnetic resonance imaging. We employed a valid method for mapping ventral and dorsal striatal functional connectivity, which supported both standard group comparisons and linear regression analyses with patients' scores on the Dimensional Yale-Brown Obsessive-Compulsive Scale. Results Consistent with past findings, patients demonstrated a common connectivity alteration involving the ventral striatum and orbitofrontal cortex that predicted overall illness severity levels. This common alteration was independent of the effect of particular symptom dimensions. Instead, we observed distinct anatomical relationships between the severity of symptom dimensions and striatal functional connectivity. Aggression symptoms modulated connectivity between the ventral striatum, amygdala, and ventromedial frontal cortex, while sexual/religious symptoms had a specific influence on ventral striatal-insular connectivity. Hoarding modulated the strength of ventral and dorsal striatal connectivity with distributed frontal regions. Conclusions Taken together, these results suggest that pathophysiological changes among orbitofrontal-striatal regions may be common to all forms of OCD. They suggest that a further examination of certain dimensional relationships will also be relevant for advancing current neurobiological models of the disorder.

Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype.

INTRODUCTION: Knee osteoarthritis is causing pain and functional disability. One of the inherent problems with efficacy assessment of pain medication was the lack of objective pain measurements, but functional magnetic resonance imaging (fMRI) has emerged as a useful means to objectify brain response to painful stimulation. We have investigated the effect of chondroitin sulfate (CS) on brain response to knee painful stimulation in patients with knee osteoarthritis using fMRI. METHODS: Twenty-two patients received CS (800mg/day) and 27 patients placebo, and were assessed at baseline and after 4 months of treatment. Two fMRI tests were conducted in each session by applying painful pressure on the knee interline and on the patella surface. The outcome measurement was attenuation of the response evoked by knee painful stimulation in the brain. RESULTS: fMRI of patella pain showed significantly greater activation reduction under CS compared with placebo in the region of the mesencephalic periaquecductal gray. The CS group, additionally showed pre/post-treatment activation reduction in the cortical representation of the leg. No effects of CS were detected using the interline pressure test. CONCLUSIONS: fMRI was sensitive to objectify CS effects on brain response to painful pressure on patellofemoral cartilage, which is consistent with the known CS action on chondrocyte regeneration. The current work yields further support to the utility of fMRI to objectify treatment effects on osteoarthritis pain. This work was supported in part by the Ministry of Science and Innovation of Spain (Grant SAF2010-19434) and by Bioiberica, SA, Barcelona. M. López-Solà and J. Deus are part of the Research Group SGR 1450 from the Agency of University and Research Funding Management of the Catalan Government and M. López-Solà is supported by the post-doctoral fellowship Beatriu de Pinós awarded by the Agency for the Management of University and Research funding (Agència de Gestió d’Ajuts Universitaris i de Recerca; AGAUR), from the Catalan Government (2010 BP_A 00136).

Resting-state fMRI (RS-fMRI) has become a useful tool to investigate the connectivity structure of mental health disorders. In the case of major depressive disorder (MDD), recent studies regarding the RS-fMRI have found abnormal connectivity in several regions of the brain, particularly in the default mode network (DMN). Thus, the relevance of the DMN to self-referential thoughts and ruminations has made the use of the resting-state approach particularly important for MDD. The majority of such research has relied on the grand averaged functional connectivity measures based on the temporal correlations between the BOLD time series of various brain regions. We, in our study, investigated the variations in the functional connectivity over time at global and local level using RS-fMRI BOLD time series of 27 MDD patients and 27 healthy control subjects. We found that global synchronization and temporal stability were significantly increased in the MDD patients. Furthermore, the participants with MDD showed significantly increased overall average (static) functional connectivity (sFC) but decreased variability of functional connectivity (vFC) within specific networks. Static FC increased to predominance among the regions pertaining to the default mode network (DMN), while the decreased variability of FC was observed in the connections between the DMN and the frontoparietal network. ERC Advanced Grant: DYSTRUCTURE (to G.D.); Contract grant number: 295129; Contract grant sponsor:/nSpanish Research Project; Contract grant number: PSI2013-42091- P; Contract grant sponsor: European Union Seventh Framework Programme (FP7-ICT Human Brain Project; Contract grant number: 604102; Contract grant sponsor: del Carlos III Health Institute (to C.S.M.); Contract grant number: CP10/00604

Understanding how humans represent others’ pain is critical for understanding pro-social behavior. ‘Shared experience’ theories propose common brain representations for somatic and vicarious pain, but other evidence suggests that specialized circuits are required to experience others’ suffering. Combining functional neuroimaging with multivariate pattern analyses, we identified dissociable patterns that predicted somatic (high versus low: 100%) and vicarious (high versus low: 100%) pain intensity in out-of-sample individuals. Critically, each pattern was at chance in predicting the other experience, demonstrating separate modifiability of both patterns. Somatotopy (upper versus lower limb: 93% accuracy for both conditions) was also distinct, located in somatosensory versus mentalizing-related circuits for somatic and vicarious pain, respectively. Two additional studies demonstrated the generalizability of the somatic pain pattern (which was originally developed on thermal pain) to mechanical and electrical pain, and also demonstrated the replicability of the somatic/vicarious dissociation. These findings suggest possible mechanisms underlying limitations in feeling others’ pain, and present new, more specific, brain targets for studying pain empathy. DOI: http://dx.doi.org/10.7554/eLife.15166.001, eLife digest The ability to experience others’ pain is a cornerstone of empathy, and binds us together in times of hardship. However, we have not yet fully understood the complex interactions in the brain that make people empathetic to others’ suffering. One possibility is that we experience others’ pain through the activation of the same brain regions as those that enable us to experience physical pain ourselves. To test this idea, Krishnan et al. compared patterns of brain activity in human volunteers as they experienced pain (from heat being applied to their forearm or foot) or watched images of others’ hands or feet being injured. While watching these images, the volunteers were asked to try to imagine that the injuries were happening to their own bodies. The patterns of brain activity that arose when the volunteers observed someone else in pain did not overlap with the patterns produced when the volunteers experienced pain themselves. Instead, seeing someone else in pain activated regions involved in taking another person’s perspective. This process, which is known as mentalizing, involves thinking about the other person’s thoughts, intentions and preferences. Thus within the brain, the experience of observing someone else in pain is distinct from that of experiencing physical pain in oneself. The results presented by Krishnan et al. raise new questions about how the brain regions involved in empathy help us to relate to other people when they experience different types of pain. Future studies should explore the factors that influence our ability to adopt another’s perspective, and whether it might be possible to improve this ability. DOI: http://dx.doi.org/10.7554/eLife.15166.002

BACKGROUND: A brain-derived neurotrophic factor (BDNF) prodomain single-nucleotide polymorphism resulting in a valine to methionine substitution (Val66Met) has been associated with depression-related phenotypes and brain alterations involving regions consistently associated with major depressive disorder (MDD). The aim of our study was to evaluate the association of regional gray matter (GM) volume within the hippocampus and other unpredicted regions at the whole-brain level with the BDNF Val66Met polymorphism in MDD patients with melancholic features and their impact on treatment outcome. METHODS: A sample of 37 MDD inpatients was assessed with three-dimensional magnetic resonance imaging (1.5-T scanner). GM volume was analyzed with voxel-based morphometry (VBM) using Statistical Parametric Mapping (SPM5). The BDNF Val66Met variant was genotyped using SNPlex technology. MDD patients were classified according to genotype distribution under a dominant model of inheritance and thus comparing Val66 homozygotes (n = 22) versus Met66 carriers (n = 15). RESULTS: A significant GM volume reduction in the left hippocampus was observed in Met66 carriers. Conversely, in the same group, a volume increase in the right orbitofrontal cortex was detected. Moreover, a significant negative correlation between left hippocampal volume and days to remission was found in Val66 homozygotes, whereas right orbitofrontal volume was inversely correlated to days to remission in Met66 carriers. CONCLUSIONS: Our results suggest that the Val66Met BDNF variant may have a differential impact on the brain structure of melancholic patients with possible treatment outcome implications. Language: en

Although the fear of being scrutinized by others in a social context is a key symptom in social anxiety disorder (SAD), the neural processes underlying the perception of scrutiny have not previously been studied by func- tional magnetic resonance imaging (fMRI). We used fMRI to map brain activation during a perception-of- scrutiny task in 20 SAD patients and 20 controls. A multi-dimensional analytic approach was used. Scrutiny perception was mediated by activation of the medial frontal cortex, insula – operculum region and cerebellum, and the additional recruitment of visual areas and the thalamus in patients. Between-group comparison demonstrated signi fi cantly enhanced brain activation in patients in the primary visual cortex and cerebellum. Functional connectivity mapping demonstrated an abnormal connectivity between regions underlying general arousal and attention. SAD patients showed signi fi cantly greater task-induced functional connectivity in the thalamo-cortical and the fronto-striatal circuits. A statistically signi ficant increase in task-induced functional connectivity between the anterior cingulate cortex and scrutiny-perception-related regions was observed in the SAD patients, suggesting the existence of enhanced behavior-inhibitory control. The presented data indicate that scrutiny perception in SAD enhances brain activity in arousal–attention systems,suggesting that fMRI may be a useful tool to explore such a behavioral dimension.

Background Whole-brain imaging approaches may contribute to the characterization of neuroanatomic alterations in major depression, especially in clinically homogenous patient groups such as those with melancholic features. We assessed brain anatomic alterations, both cross-sectionally and longitudinally, in patients with melancholic depression using a whole-brain voxel-wise approach. Methods Whole-brain magnetic resonance images were collected from a relatively aged sample of 70 consecutively recruited major depressive disorder inpatients with melancholic features and from a group of 40 healthy control subjects. All patients were clinically followed for at least 2 years, and a subset of 30 depressive patients and 20 control subjects were rescanned after a 7-year period. Imaging data were analyzed with voxel- and tensor-based morphometry techniques. Results Melancholic patients showed gray matter reductions in the left insula and white matter increases in the upper brainstem tegmentum. Male patients showed gray matter decreases in the right thalamus, and periventricular white matter reductions were specifically observed in older patients. Volume decreases in the left insula, hippocampus, and lateral parietal cortex predicted a slower recovery after treatment initiation. In longitudinal assessment, white matter of the upper brainstem tegmentum showed a different temporal evolution between groups. Additionally, bilateral gray matter reductions in the insulae were associated with the number of relapses during follow-up. Conclusions Structural alterations were identified in regions potentially related to relevant aspects of melancholia pathophysiology. Longitudinal analyses indicated region-specific interactions of baseline alterations with age as well as a significant association of clinical severity with focal changes occurring over time.