A multistudy analysis reveals that evoked pain intensity representation is distributed across brain systems.

Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical-subcortical systems developed from prior literature ("multisystem models"); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains.

Tracking temporal response dynamics in the ventral striatum during social feedback in anorexia nervosa: A functional magnetic resonance imaging exploratory study.

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.

Transforming Pain With Prosocial Meaning: A Functional Magnetic Resonance Imaging Study.

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.

Group-regularized individual prediction: theory and application to pain.

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.

Brain functional correlates of emotion regulation across adolescence and young adulthood.

Few studies have examined the neural correlates of emotion regulation across adolescence and young adulthood. Existing studies of cognitive reappraisal indicate that improvements in regulatory efficiency may develop linearly across this period, in accordance with maturation of prefrontal cortical systems. However, there is also evidence for adolescent differences in reappraisal specific to the activation of "social-information processing network" regions, including the amygdala and temporal-occipital cortices. Here, we use fMRI to examine the neural correlates of emotional reactivity and reappraisal in response to aversive social imagery in a group of 78 adolescents and young adults aged 15-25 years. Within the group, younger participants exhibited greater activation of temporal-occipital brain regions during reappraisal in combination with weaker suppression of amygdala reactivity-the latter being a general correlate of successful reappraisal. Further analyses demonstrated that these age-related influences on amygdala reactivity were specifically mediated by activation of the fusiform face area. Overall, these findings suggest that enhanced processing of salient social cues (i.e., faces) increases reactivity of the amygdala during reappraisal and that this relationship is stronger in younger adolescents. How these relationships contribute to well-known vulnerabilities of emotion regulation during this developmental period will be an important topic for ongoing research.

Dynamic functional connectivity reveals altered variability in functional connectivity among patients with major depressive disorder.

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. Hum Brain Mapp 37:2918-2930, 2016. © 2016 Wiley Periodicals, Inc.

A neural mediator of human anxiety sensitivity.

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.

Amygdala activation and symptom dimensions in obsessive-compulsive disorder.

BACKGROUND: Despite 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. AIMS: To assess the influence of OCD symptom dimensions on amygdala responses to a well-validated emotional face-matching paradigm. METHOD: Cross-sectional functional magnetic resonance imaging (fMRI) study of 67 patients with OCD and 67 age-, gender- and education-level matched healthy controls. RESULTS: The 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. CONCLUSIONS: Amygdala 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.

Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.

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.

Reduced Cortico-Cortical Resting-State Connectivity in Sensory Systems Related to Bodily Pain in Juvenile Fibromyalgia.

OBJECTIVE: Juvenile-onset fibromyalgia (JFM) is a paradigmatic chronic pain condition for which the underlying neurobiological substrates are poorly understood. This study examined, for the first time, data-driven resting-state functional connectivity (rsFC) alterations in 37 female adolescents with JFM compared with 43 healthy female adolescents and identified associations with bodily pain. METHODS: Whole-brain voxel-wise rsFC alterations were assessed using the intrinsic connectivity contrast, a measure of node centrality at each voxel, and seed-based analyses for interpretability. We studied the relationship between rsFC alterations in somatosensory systems and the location and extension of bodily pain. RESULTS: Adolescents with JFM had voxel-wise rsFC reductions in the paracentral lobule (PCL)/primary somatosensory cortex (S1) (T = 4.89, family-wise error corrected p-value (pFWE) < 0.001) and left midcingulate cortex (T = 4.67, pFWE = 0.043). Post hoc analyses revealed reduced rsFC spanning major cortical sensory hubs (T > 4.4, pFWE < 0.030). Cortico-cortical rsFC reductions within PCL/S1 in JFM occurred in locations innervated by bodily areas where the pain was most frequent (F = 3.15; positive false discovery rate = 0.029) and predicted widespread pain (T > 4.4, pFWE < 0.045). Conversely, adolescents with JFM had increases in PCL/S1-thalamus (T = 4.75, pFWE = 0.046) and PCL/S1-anterior insula rsFC (T = 5.13, pFWE = 0.039). CONCLUSION: Reduced cortico-cortical sensory integration involving PCL/S1 and spanning the sensory systems may underly critical pain sensory features in youth with JFM. Reduced sensory integration is paralleled by augmented cross-talk between sensory and affective/salience-processing regions, potentially indicating a shift toward more affectively colored sensory experiences to the detriment of specific sensory discrimination.

Neurophysiology of Resilience in Juvenile Fibromyalgia.

Objective: Juvenile fibromyalgia (JFM) is a chronic pain syndrome predominantly affecting adolescent girls. Resilience may be a protective factor in coping with pain, reducing affective burden, and promoting positive outlooks. Brain regions affected in JFM overlap with those linked to resilience, particularly in the default-mode network (DMN). We investigate the role of resilience on core somatic and affective symptoms in JFM and assess the neurophysiological substrates for the first time. Methods: Forty-one girls with JFM and 40 pain-free adolescents completed a resting-state fMRI assessment and self-report questionnaires. We used clustering analyses to group JFM participants based on resilience, and principal component analyses to summarize core somatic and affective symptoms. We estimated whole-brain and within-DMN connectivity and assessed differences between higher and lower resilience JFM groups and compared their connectivity patterns to pain-free participants. Results: The higher resilience JFM group had less affective (T=4.03; p<.001) but similar core somatic symptoms (T=1.05; p=.302) than the lower resilience JFM group. They had increased whole-brain (T's>3.90, pFDR's<.03) and within-DMN (T=2.20, p=.03) connectivity strength, and higher connectivity between DMN nodes and self-referential, regulatory, and reward-processing regions. Conversely, higher DMN-premotor connectivity was observed in the lower resilience group. Conclusion: JFM participants with higher resilience were protected affectively but not in core somatic symptoms. Greater resilience was accompanied by higher signal integration within the DMN, a network central to internally oriented attention and flexible attention shifting. Crucially, the connectivity pattern in highly resilient patients resembled that of pain-free adolescents, which was not the case for the lower resilience group.

Gray Matter Adaptations to Chronic Pain in People with Whiplash-Associated Disorders are Partially Reversed After Treatment: A Voxel-based Morphometry Study.

Gray matter (GM) changes are often observed in people with chronic spinal pain, including those with chronic whiplash-associated disorders (CWAD). These GM adaptations may be reversed with treatment, at least partially. Pain neuroscience education combined with exercise (PNE+Exercise) is an effective treatment, but its neural underlying mechanisms still remain unexplored in CWAD. Here, we performed both cross-sectional and longitudinal voxel-based morphometry to 1) identify potential GM alterations in people with CWAD (n = 63) compared to age- and sex-matched pain-free controls (n = 32), and 2) determine whether these GM alterations might be reversed following PNE+Exercise (compared to conventional physiotherapy). The cross-sectional whole-brain analysis revealed that individuals with CWAD had less GM volume in the right and left dorsolateral prefrontal cortex and left inferior temporal gyrus which was, in turn, associated with higher pain vigilance. Fifty individuals with CWAD and 29 pain-free controls were retained in the longitudinal analysis. GM in the right dorsolateral prefrontal cortex increased after treatment in people with CWAD. Moreover, the longitudinal whole-brain analysis revealed that individuals with CWAD had decreases in GM volumes of the left and right central operculum and supramarginal after treatment. These changes were not specific to treatment modality and some were not observed in pain-free controls over time. Herewith, we provide the first evidence on how GM adaptations to CWAD respond to treatment. PERSPECTIVE: This article presents which gray matter adaptations are present in people with chronic pain after whiplash injuries. Then, we examine the treatment effect on these alterations as well as whether other neuroplastic effects on GM following treatment occur.

Mindfulness-based cognitive therapy neurobiology in treatment-resistant obsessive-compulsive disorder: A domain-related resting-state networks approach.

Mindfulness-based cognitive therapy (MBCT) stands out as a promising augmentation psychological therapy for patients with obsessive-compulsive disorder (OCD). To identify potential predictive and response biomarkers, this study examines the relationship between clinical domains and resting-state network connectivity in OCD patients undergoing a 3-month MBCT programme. Twelve OCD patients underwent two resting-state functional magnetic resonance imaging sessions at baseline and after the MBCT programme. We assessed four clinical domains: positive affect, negative affect, anxiety sensitivity, and rumination. Independent component analysis characterised resting-state networks (RSNs), and multiple regression analyses evaluated brain-clinical associations. At baseline, distinct network connectivity patterns were found for each clinical domain: parietal-subcortical, lateral prefrontal, medial prefrontal, and frontal-occipital. Predictive and response biomarkers revealed significant brain-clinical associations within two main RSNs: the ventral default mode network (vDMN) and the frontostriatal network (FSN). Key brain nodes -the precuneus and the frontopolar cortex- were identified within these networks. MBCT may modulate vDMN and FSN connectivity in OCD patients, possibly reducing symptoms across clinical domains. Each clinical domain had a unique baseline brain connectivity pattern, suggesting potential symptom-based biomarkers. Using these RSNs as predictors could enable personalised treatments and the identification of patients who would benefit most from MBCT.

Anatomical and functional overlap within the insula and anterior cingulate cortex during interoception and phobic symptom provocation.

The anterior insula and the dorsal anterior cingulate cortex (ACC) are regarded as key brain structures associated with the integration of perceived phobic characteristics of external stimuli and the perception of ones own body responses that leads to emotional feelings. To test to what extent the activity in these two brain structures anatomically and functionally overlap during phobic reactions and interoception, we submitted the same group of phobic participants (n = 29; either spider or blood-injection-injury (BII) phobics) and controls (n = 17) to both type of experimental paradigms. Results showed that there was a clear anatomical overlap in the Blood Oxygen Level-Dependent (BOLD) responses within the anterior insula and ACC elicited during phobic symptom provocation and during interoceptive awareness. The activity within these two brain structures also showed to be correlated in the spider phobia group, but not in the BII phobic participants. Our results seem to support the idea that the activity within these two brain areas would be associated with the integration of perceived stimuli characteristics and bodily responses that lead to what we label as "fear." However, that seems not to be the case in BII phobia, where more research is needed in order to clarify to what extent that could be associated with the idiosyncratic physiological response that these patients present in front of phobic stimuli (i.e., drop in heart rate and blood pressure).

Val66Met BDNF genotypes in melancholic depression: effects on brain structure and treatment outcome.

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.

Augmented pain-evoked primary sensorimotor cortex activation in adolescent girls with juvenile fibromyalgia.

ABSTRACT: Juvenile 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. Thirty-three adolescent girls with JFM and 33 healthy adolescent girls underwent functional magnetic resonance imaging scans involving noxious pressure applied to the left thumbnail at an intensity of 2.5 or 4 kg/cm 2 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. The JFM group reported significantly greater pain intensity and unpleasantness than the control group in response to noxious pressure stimuli at both intensities ( P < 0.05). The JFM group showed augmented right primary somatosensory cortex (S1) activation to 4 kg/cm 2 (Z > 3.1, cluster-corrected P < 0.05), and the peak S1 activation magnitudes significantly correlated with the scores on the Widespread Pain Index ( r = 0.35, P = 0.048) with higher activation associated with more widespread pain. We also found that greater primary sensorimotor cortex activation in response to 4 kg/cm 2 mediated the between-group differences in pain intensity ratings ( P < 0.001). In conclusion, we 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.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

Altered brain functional connectivity in relation to perception of scrutiny in social anxiety disorder.

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 functional 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 significantly 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 significantly greater task-induced functional connectivity in the thalamo-cortical and the fronto-striatal circuits. A statistically significant 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.

Common and stimulus-type-specific brain representations of negative affect.

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.

The neurologic pain signature responds to nonsteroidal anti-inflammatory treatment vs placebo in knee osteoarthritis.

INTRODUCTION: Many drug trials for chronic pain fail because of high placebo response rates in primary endpoints. Neurophysiological measures can help identify pain-linked pathophysiology and treatment mechanisms. They can also help guide early stop/go decisions, particularly if they respond to verum treatment but not placebo. The neurologic pain signature (NPS), an fMRI-based measure that tracks evoked pain in 40 published samples and is insensitive to placebo in healthy adults, provides a potentially useful neurophysiological measure linked to nociceptive pain. OBJECTIVES: This study aims to validate the NPS in knee osteoarthritis (OA) patients and test the effects of naproxen on this signature. METHODS: In 2 studies (50 patients, 64.6 years, 75% females), we (1) test the NPS and other control signatures related to negative emotion in knee OA pain patients; (2) test the effect of placebo treatments; and (3) test the effect of naproxen, a routinely prescribed nonsteroidal anti-inflammatory drug in OA. RESULTS: The NPS was activated during knee pain in OA (d = 1.51, P < 0.001) and did not respond to placebo (d = 0.12, P = 0.23). A single dose of naproxen reduced NPS responses (vs placebo, NPS d = 0.34, P = 0.03 and pronociceptive NPS component d = 0.38, P = 0.02). Naproxen effects were specific for the NPS and did not appear in other control signatures. CONCLUSION: This study provides preliminary evidence that fMRI-based measures, validated for nociceptive pain, respond to acute OA pain, do not appear sensitive to placebo, and are mild-to-moderately sensitive to naproxen.