Defining Trajectories of Linguistic, Cognitive-Communicative, and Quality of Life Outcomes in Aphasia: Longitudinal Observational Study Protocol.

Objective: To describe the trajectories of linguistic, cognitive-communicative, and health-related quality of life (HRQOL) outcomes after stroke in persons with aphasia. Design: Longitudinal observational study from inpatient rehabilitation to 18 months after stroke. Setting: Four US mid-west inpatient rehabilitation facilities (IRFs). Participants: We plan to recruit 400 adult (older than 21 years) English speakers who meet the following inclusion criteria: (1) Diagnosis of aphasia after a left-hemisphere infarct confirmed by CT scan or magnetic resonance imaging (MRI); (2) first admission for inpatient rehabilitation due to a neurologic event; and (3) sufficient cognitive capacity to provide informed consent and participate in testing. Exclusion criteria include any neurologic condition other than stroke that could affect language, cognition or speech, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, or the presence of right-hemisphere lesions. Interventions: Not applicable. Main Outcome Measures: Subjects are administered a test battery of linguistic, cognitive-communicative, and HRQOL measures. Linguistic measures include the Western Aphasia Battery-Revised and the Apraxia of Speech Rating Scale. Cognitive-communicative measures include the Communication Participation Item Bank, Connor's Continuous Performance Test-3, the Communication Confidence Rating Scale for Aphasia, the Communication Effectiveness Index, the Neurological Quality of Life measurement system (Neuro-QoL) Communication short form, and the Neuro-QoL Cognitive Function short form. HRQOL measures include the 39-item Stroke & Aphasia Quality of Life Scale, Neuro-QoL Fatigue, Sleep Disturbance, Depression, Ability to Participate in Social Roles & Activities, and Satisfaction with Social Roles & Activities tests, and the Patient-Reported Outcome Measurement and Information System 10-item Global Health short form. The test battery is administered initially during inpatient rehabilitation, and at 3-, 6-, 12-, and 18-months post-IRF discharge. Biomarker samples are collected via saliva samples at admission and a subgroup of participants also undergo resting state fMRI scans. Results: Not applicable. Conclusions: This longitudinal observational study will develop trajectory models for recovery of clinically relevant linguistic, cognitive-communicative, and quality of life outcomes over 18 months after inpatient rehabilitation. Models will identify individual differences in the patterns of recovery based on variations in personal, genetic, imaging, and therapy characteristics. The resulting models will provide an unparalleled representation of recovery from aphasia resulting from stroke. This improved understanding of recovery will enable clinicians to better tailor and plan rehabilitation therapies to individual patient's needs.

Exercise effect on pain is associated with negative and positive affective components: A large-scale internet-based cross-sectional study in Japan.

Pain is a global health problem that leads to sedentary behavior and tends to cause negative emotion. In contrast, exercise is widely recommended for a health promotion, while pain often worsens with physical activity. Although exercise therapy is often prescribed to people with pain, the mechanisms of exercise effect on pain remains unclear. In this study, we tried to identify a universal association factor between regular exercise and pain intensity utilizing a cross-sectional web-based survey involving 52,353 adult participants from a large national study conducted in Japan. Using principal component analysis, we uncovered a mediation model of exercise effect on pain through psychological components. Analyses were performed in half of the population with pain (n = 20,330) and validated in the other half (n = 20,330), and showed that high-frequency exercise had a significant association with reduction in pain intensity. We also found Negative Affect and Vigor, two psychological components, are fully associating the exercise effect on pain (indirect effect = - 0.032, p < 0.001; association proportion = 0.99) with a dose-dependent response corresponding to the frequency of exercise. These findings were successfully validated (indirect effect of high-frequency exercise = - 0.028, p < 0.001; association proportion = 0.85). Moreover, these findings were also identified in subpopulation analyses of people with low back, neck, knee pain, and the tendency of the exercise effect on pain was increased with older people. In conclusion, the effect of exercise on pain is associated with psychological components and these association effects increased in parallel with the frequency of exercise habit regardless pain location.

Neuropsychology of chronic back pain managed with long-term opioid use.

Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits' dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.

Influence of exercise on pain is associated with resting-state functional connections: A cross-sectional functional brain imaging study.

Exercise is associated with lower prevalence and severity of pain, and is widely recommended for pain management. However, the mechanisms the exercise effect on pain remain unclear. In this study, we examined the association of exercise with pain and aimed to identify its neurobiological mediators. We utilized a baseline data of a clinical trial for people with low back pain. Participants reported pain intensity and exercise habit, as well as pain-related psychological and emotional assessments. We also obtained brain imaging data using a resting-state functional MRI and performed mediation analyses to identify brain regions mediating the exercise effect on pain. Forty-five people with low back pain (mean pain intensity = 59.6 and mean duration = 9.9 weeks) were included in this study. Participants with an exercise habit (n = 29) showed significant less pain compared to those without an exercise habit (n = 16). Mediation analysis using resting-state functional connectivity identified the left thalamus, right amygdala, and medial prefrontal cortex as statistical mediators of the exercise effect on pain (indirect effect = -0.460, 95% confidence interval = -0.767 to -0.153). In conclusion, our findings suggest that brain function of the specific regions is probably a neuro-mechanism of exercise alleviating pain.

Limits of decoding mental states with fMRI.

A growing number of studies claim to decode mental states using multi-voxel decoders of brain activity. It has been proposed that the fixed, fine-grained, multi-voxel patterns in these decoders are necessary for discriminating between and identifying mental states. Here, we present evidence that the efficacy of these decoders might be overstated. Across various tasks, decoder patterns were spatially imprecise, as decoder performance was unaffected by spatial smoothing; 90% redundant, as selecting a random 10% of a decoder's constituent voxels recovered full decoder performance; and performed similarly to brain activity maps used as decoders. We distinguish decoder performance in discriminating between mental states from performance in identifying a given mental state, and show that even when discrimination performance is adequate, identification can be poor. Finally, we demonstrate that simple and intuitive similarity metrics explain 91% and 62% of discrimination performance within- and across-subjects, respectively. These findings indicate that currently used across-subject decoders of mental states are superfluous and inappropriate for decision-making.

Reversal of neuropathic pain is associated with corticostriatal functional reorganization after nerve repair in the spared nerve injury model.

ABSTRACT: Following surgical repair after peripheral nerve injury, neuropathic pain diminishes in most patients but can persist in a small proportion of cases, the mechanism of which remains poorly understood. Based on the spared nerve injury (SNI), we developed a rat nerve repair (NR) model, where a delayed reconstruction of the SNI-injured nerves resulted in alleviating chronic pain-like behavior only in a subpopulation of rats. Multiple behavioral measures were assayed over 11-week presurgery and postsurgery periods (tactile allodynia, pain prick responses, sucrose preference, motor coordination, and cold allodynia) in SNI (n = 10), sham (n = 8), and NR (n = 12) rats. All rats also underwent resting-state functional magnetic resonance imaging under anesthesia at multiple time points postsurgery, and at 10 weeks, histology and retrograde labeling were used to calculate peripheral reinnervation. Behavioral measures indicated that at approximately 5 weeks postsurgery, the NR group separated to pain persisting (NR persisting, n = 5) and recovering (NR recovering, n = 7) groups. Counts of afferent nerves and dorsal root ganglion cells were not different between NR groups. Therefore, NR group differences could not be explained by peripheral reorganization. By contrast, large brain functional connectivity differences were observed between NR groups, where corticolimbic reorganization paralleled with pain recovery (repeated-measures analysis of variance, false discovery rate, P < 0.05), and functional connectivity between accumbens and medial frontal cortex was related both to tactile allodynia (nociception) and to sucrose preference (anhedonia) in the NR group. Our study highlights the importance of brain circuitry in the reversal of neuropathic pain as a natural pain-relieving mechanism. Further studies regarding the therapeutic potentials of these processes are warranted.

Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BACKGROUND: Preventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent. METHODS: A total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months. RESULTS: Both treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration. CONCLUSIONS: These results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.

Momentary pain assessments reveal benefits of endoscopic discectomy: a prospective cohort study.

Lumbar disc herniation (LDH) is a common back disorder that evokes back and/or leg pain. Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive surgery for patients with LDH. However, there is little evidence of effectiveness of PELD compared with conservative treatments. OBJECTIVE: The goal of this study was to quantify the efficacy of PELD compared with conservative treatments. METHODS: Here, we conducted a prospective observational cohort study using momentary pain assessments via a smartphone app during 3 months following surgery. The trajectories of daily ecological momentary pain assessments were fitted with an exponential model containing two parameters: a pain reduction coefficient and the percentage of persistent pain. To control for selection bias between PELD and Conservative groups (N = 167 and 34), we used inverse probability (IP) of treatment weighting for statistical comparisons. RESULTS: Compared with conservative treatments, both momentary pain rating and the exponential model showed statistically significant pain recovery following PELD (p < 0.001). In addition, PELD had a faster pain recovery rate (hazard ratio (95% confidence interval): 1.75 (1.40, 2.20), p < 0.001), greater overall pain recovery rate (odds ratio (95%CI): 2.35 (2.01, 5.26), p < 0.001), faster pain reduction (t199 = 3.32, p = 0.001), and lower estimated persistent pain (Z = 2.53, p = 0.011). Greater pain intensity and lower anxiety before the surgery were predictors of faster pain reduction in the recovery subgroup following PELD. CONCLUSIONS: In conclusion, momentary pain rating and the model fitting revealed that PELD provided rapid pain recovery that lasted for at least three months. Greater pain intensity and lower anxiety before the surgery were predictors of faster pain reduction in the recovery subgroup following PELD. Daily momentary pain rating on a smartphone may be able to provide more informative data to evaluate effect of an intervention than pain assessment on hospital visits.

Psychosocial, Functional, and Emotional Correlates of Long-Term Opioid Use in Patients with Chronic Back Pain: A Cross-Sectional Case-Control Study.

INTRODUCTION: The opiate epidemic has severe medical and social consequences. Opioids are commonly prescribed in patients with chronic pain, and are a main contributor to the opiate epidemic. The adverse effects of long-term opioid usage have been studied primarily in dependence/addiction disorders, but not in chronic pain. Here, we examine the added iatrogenic effects, psychology, and brain morphology of long-term opioid use in matched patients with chronic pain with and without opioid use (case-controlled design). METHODS: We compared psychosocial, functional, and psychological measures between patients with chronic back pain (CBP) who were managing their pain with or without opioids, thereby controlling for the effect of pain on these outcomes. In addition, we investigated brain morphological differences associated with long-term opioid usage. We recruited 58 patients with CBP, 29 of them on long-term opioids and 29 who did not use opioids, and who were matched in terms of age, sex, pain intensity, and pain duration. Questionnaires were used to assess pain quality, pain psychology, negative and positive emotions, physical, cognitive, sensory, and motor functions, quality of life, and personality traits. RESULTS: Patients with CBP on opioids displayed more negative emotion, poorer physical function, and more pain interference (p < 0.001), whereas there were no statistical differences in cognitive and motor functions and personality traits. Voxel-based morphometry using structural brain imaging data identified decreased gray matter density of the dorsal paracingulate cortex (family-wise error-corrected p < 0.05) in patients with opioids, which was associated with negative emotion (p = 0.03). Finally, a volumetric analysis of hippocampal subfields identified lower volume of the left presubiculum in patients on opioids (p < 0.001). CONCLUSION: Long-term opioid use in chronic pain is associated with adverse negative emotion and disabilities, as well as decreased gray matter volumes of specific brain regions.

Contribution of extracellular matrix components to the stiffness of skeletal muscle contractures in patients with cerebral palsy.

Purpose: Joint contractures in children with cerebral palsy contain muscle tissue that is mechanically stiffer with higher collagen content than typically developing children. Interestingly, the correlation between collagen content and stiffness is weak. To date, no data are available on collagen types or other extracellular matrix proteins in these muscles, nor any information regarding their function. Thus, our purpose was to measure specific extracellular protein composition in cerebral palsy and typically developing human muscles along with structural aspects of extracellular matrix architecture to determine the extent to which these explain mechanical properties. Materials and Methods: Biopsies were collected from children with cerebral palsy undergoing muscle lengthening procedures and typically developing children undergoing anterior cruciate ligament reconstruction. Tissue was prepared for the determination of collagen types I, III, IV, and VI, proteoglycan, biglycan, decorin, hyaluronic acid/uronic acid and collagen crosslinking. Results: All collagen types increased in cerebral palsy along with pyridinoline crosslinks, total proteoglycan, and uronic acid. In all cases, type I or total collagen and total proteoglycan were positive predictors, while biglycan was a negative predictor of stiffness. Together these parameters accounted for a greater degree of variance within groups than across groups, demonstrating an altered relationship between extracellular matrix and stiffness with cerebral palsy. Further, stereological analysis revealed a significant increase in collagen fibrils organized in cables and an increased volume fraction of fibroblasts in CP muscle. Conclusions: These data demonstrate a novel adaptation of muscle extracellular matrix in children with cerebral palsy that includes alterations in extracellular matrix protein composition and structure related to mechanical function.

Reorganization of functional brain network architecture in chronic osteoarthritis pain.

Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by subdividing the KOA data into discovery and testing groups and tested the generalizability of our findings in HOA. Despite brain global topological properties being conserved in OA, we show there is a network wide pattern of reorganization that can be captured at the subject-level by a single measure, the hub disruption index. We localized reorganization patterns and uncovered a shift in the hierarchy of network hubs in OA: primary sensory and motor regions and parahippocampal gyrus behave as hubs and insular cortex loses its central placement. At an intermediate level of network structure, frontoparietal and cingulo-opercular modules showed preferential reorganization. We examined the association between network properties and clinical correlates: global disruption indices and isolated degree properties did not reflect clinical parameters; however, by modeling whole brain nodal degree properties, we identified a distributed set of regions that reliably predicted pain intensity in KOA and generalized to hip OA. Together, our findings reveal that while conserving global topological properties, brain network architecture reorganizes in OA, at both global and local scale. Network connectivity related to OA pain intensity is dissociated from the major hub disruptions, challenging the extent of dependence of OA pain on nociceptive signaling.

Dissimilarity of functional connectivity uncovers the influence of participant's motion in functional magnetic resonance imaging studies.

Head motion is a major confounding factor impairing the quality of functional magnetic resonance imaging (fMRI) data. In particular, head motion can reduce analytical efficiency, and its effects are still present even after preprocessing. To examine the validity of motion removal and to evaluate the remaining effects of motion on the quality of the preprocessed fMRI data, a new metric of group quality control (QC), dissimilarity of functional connectivity, is introduced. Here, we investigate the association between head motion, represented by mean framewise displacement, and dissimilarity of functional connectivity by applying four preprocessing methods in two independent resting-state fMRI datasets: one consisting of healthy participants (N = 167) scanned in a 3T GE-Discovery 750 with longer TR (2.5 s), and the other of chronic back pain patients (N = 143) in a 3T Siemens Magnetom Prisma scanner with shorter TR (0.555 s). We found that dissimilarity of functional connectivity uncovers the influence of participant's motion, and this relationship is independent of population, scanner, and preprocessing method. The association between motion and dissimilarity of functional connectivity, and how the removal of high-motion participants affects this association, is a new strategy for group-level QC following preprocessing.

Structural MRI Analysis of Chronic Pain Patients Following Interdisciplinary Treatment Shows Changes in Brain Volume and Opiate-Dependent Reorganization of the Amygdala and Hippocampus.

OBJECTIVE: The present study examined pre- to post-treatment changes in volumes for brain structures known to be associated with pain processing (thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens) following an interdisciplinary pain management program. DESIGN: Twenty-one patients participating in a four-week interdisciplinary pain management program completed the study. The program consisted of individual and group therapies with the following disciplines: physical therapy, occupational therapy, pain psychology, biofeedback/relaxation training, nursing lectures, and medical management. All patients underwent functional magnetic resonance imaging of the brain before the start and at completion of the program. They also completed standard outcome measures assessing pain, symptoms of central sensitization, disability, mood, coping, pain acceptance, and impressions of change. RESULTS: Our results showed a significant increase in total brain volume, as well as increased volumes in the thalamus, hippocampus, and amygdala. As expected, we also found significant improvements in our standard outcome measures. The majority of patients rated themselves as much or very much improved. The increase in volume in the hippocampus was significantly associated with patient perceptions of change. However, the correlations were in the unexpected direction, such that greater increases in hippocampal volume were associated with perceptions of less improvement. Further exploratory analyses comparing patients by their opioid use status (use vs no use) showed differential program effects on volume increases in the hippocampus and amygdala. CONCLUSIONS: These findings show that a four-week interdisciplinary pain management program resulted in changes in the brain, which adds objective findings further demonstrating program efficacy.

Whole-brain functional network disruption in chronic pain with disk herniation.

Brain functional network properties are globally disrupted in multiple musculoskeletal chronic pain conditions. Back pain with lumbar disk herniation (LDH) is highly prevalent and a major route for progression to chronic back pain. However, brain functional network properties remain unknown in such patients. Here, we examined resting-state functional magnetic resonance imaging-based functional connectivity networks in chronic back pain patients with clear evidence for LDH (LDH-chronic pain n = 146), in comparison to healthy controls (HCs, n = 165). The study was conducted in China, thus providing the opportunity to also examine the influence of culture on brain functional reorganization with chronic pain. The data were equally subdivided into discovery and validation subgroups (n = 68 LDH-chronic pain and n = 68 HC, for each subgroup), and contrasted to an off-site data set (n = 272, NITRC 1000). Graph disruption indices derived from 3 network topological measurements, degree, clustering coefficient, and efficiency, which respectively represent network hubness, segregation, and integration, were significantly decreased compared with HC, across all predefined link densities, in both discovery and validation groups. However, global mean clustering coefficient and betweenness centrality were decreased in the discovery group and showed trend in the validation group. The relationship between pain and graph disruption indices was limited to males with high education. These results deviate somewhat from recent similar analysis for other musculoskeletal chronic pain conditions, yet we cannot determine whether the differences are due to types of pain or also to cultural differences between patients studied in China and the United States.

Altered functional connectivity associated with time discounting in chronic pain.

Chronic pain (CP) is a global problem extensively associated with an unhealthy lifestyle. Time discounting (TD), a tendency to assign less value to future gains than to present gains, is an indicator of the unhealthy behaviors. While, recent neuroimaging studies implied overlapping neuro mechanisms underlying CP and TD, little is known about the specific relationship between CP and TD in behavior or neuroscience. As such, we investigated the association of TD with behavioral measures in CP and resting-state brain functional network in both CP patients and healthy subjects. Behaviorally, TD showed a significant correlation with meaningfulness in healthy subjects, whereas TD in patients only correlated with pain intensity. We identified a specific network including medial and dorsolateral prefrontal cortex (PFC) in default mode network (DMN) associated with TD in healthy subjects that showed significant indirect mediation effect of meaningfulness on TD. In contrast, TD in patients was correlated with functional connectivity between dorsolateral PFC (DLPFC) and temporal lobe that mediated the effect of pain intensity on TD in patients. These results imply that TD is modulated by pain intensity in CP patients, and the brain function associated to TD is shifted from a medial to lateral representation within the frontal regions.

Deconstructing biomarkers for chronic pain: context- and hypothesis-dependent biomarker types in relation to chronic pain.

This review expounds on types and properties of biomarkers for chronic pain, given a mechanistic model of processes underlying development of chronic pain. It covers advances in the field of developing biomarkers for chronic pain, while outlining the general principles of categorizing types of biomarkers driven by specific hypotheses regarding underlying mechanisms. Within this theoretical construct, example biomarkers are described and their properties expounded. We conclude that the field is advancing in important directions and the developed biomarkers have the potential of impacting both the science and the clinical practice regarding chronic pain.

Brain network topology influences response to intensive comprehensive aphasia treatment.

BACKGROUND: Recent imaging studies indicate that aphasia is associated with large-scale reorganization of brain networks. Today, neuroimaging studies show that various brain connectivity properties, as measured by resting state fMRI, can partially explain different behavioral symptoms in and across various patient groups. Despite these observations, the neural networks underlying the progress and recovery of aphasia following intensive treatment remains relatively obscure. OBJECTIVE: To examine the role of brain network properties in determining recovery of aphasia following intensive therapy in stroke patients. METHODS: We studied eight patients with left hemispheric lesions who completed an intensive comprehensive aphasia program (ICAP). Language and cognition were assessed before and after four weeks of intensive treatment. In addition, all patients underwent resting state fMRI prior to and after treatment. We used graph theory analysis to evaluate relationships of baseline brain network properties, such as efficiency, modularity, and connectivity to clinical improvements. RESULTS: We found global properties such as efficiency and interhemispheric connectivity could partially explain recovery. More importantly, we identified two unique brain networks that are significantly associated with improvement in language and attention related behavior. CONCLUSIONS: These results suggest baseline brain functional properties play a key role in determining responsiveness of patients with aphasia to intensive comprehensive aphasia treatment. Furthermore, these results indicate that brain mechanisms underlying language comprehension and processes are different from those involved in spatial attention.

Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations.

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.

Global disruption of degree rank order: a hallmark of chronic pain.

Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic pain conditions. We used resting-state functional MRI data to analyze the brain connectome at varying scales and densities. In three chronic pain conditions, we observe disrupted kD, in proportion to individuals' pain intensity, and associated with community membership disruption. Additionally, we observe regional degree changes, some of which were unique to each type of chronic pain. Subjects with recent onset of back pain exhibited emergence of kD only when the pain became chronic. Similarly, in neuropathic rats kD emerged weeks after injury, in proportion to pain-like behavior. Thus, we found comprehensive cross-species evidence for chronic pain being a state of global randomization of functional connectivity.

Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials.

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo's effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700.