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.

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.

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.

Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents.

ABSTRACT: Accumulating evidence suggests hippocampal impairment under the chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here, we enhanced hippocampal activity by pharmacological, optogenetic, and chemogenetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH) hippocampus induces analgesia in 2 rodent models of neuropathic pain (SNI and SNL) and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by N-Methyl-D-aspartate and µ-opioid receptors. In addition to analgesia, optogenetic stimulation of the DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where the DH was activated, a finding consistent with pain relief. Similar manipulations in the VH were ineffective. Using chemo-functional magnetic resonance imaging (fMRI), where awake resting-state fMRI was combined with viral vector-mediated chemogenetic activation (PSAM/PSEM89s) of DH neurons, we demonstrated changes of functional connectivity between the DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic back pain. Altogether, these results imply that downregulation of the DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of the DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, this study exhibits a novel causal role for the DH but not the VH in controlling neuropathic pain-related behaviors.

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.

Neural and Genetic Bases for Human Ability Traits.

The judgement of human ability is ubiquitous, from school admissions to job performance reviews. The exact make-up of ability traits, however, is often narrowly defined and lacks a comprehensive basis. We attempt to simplify the spectrum of human ability, similar to how five personality traits are widely believed to describe most personalities. Finding such a basis for human ability would be invaluable since neuropsychiatric disease diagnoses and symptom severity are commonly related to such differences in performance. Here, we identified four underlying ability traits within the National Institutes of Health Toolbox normative data (n = 1, 369): (1) Motor-endurance, (2) Emotional processing, (3) Executive and cognitive function, and (4) Social interaction. We used the Human Connectome Project young adult dataset (n = 778) to show that Motor-endurance and Executive and cognitive function were reliably associated with specific brain functional networks (r 2 = 0.305 ± 0.021), and the biological nature of these ability traits was also shown by calculating their heritability (31 and 49%, respectively) from twin data.

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.

A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis.

The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments.

Inflammatory and neuropathic pain animals exhibit distinct responses to innocuous thermal and motoric challenges.

Most current methods for assessing pain in animals are based on reflexive measures and require constant interaction between the observer and the animal. Here we explore two new fully automated methods to quantify the impact of pain on the overall behavior of the organism. Both methods take advantage of the animals' natural preference for a dark environment. We used a box divided into two compartments: dark and bright. In the motoric operant task, "AngleTrack", one end of the box was raised so that the animals had to climb uphill to go from the light to the dark compartment. In the thermal operant task, "ThermalTrack", the floor of the dark compartment was heated to a given temperature, while the light compartment remained at 25 degrees C. Rats were individually placed in the light box and their crossing between chambers monitored automatically for 30 minutes. The angle of the box, or the temperature of the dark compartment, was altered to challenge the animals' natural preference. We test the hypothesis that different models of pain (inflammatory or neuropathic) can be differentiated based on performance on these devices. Three groups of rats were tested at five different challenge levels on both tasks: 1) normal, 2) neuropathic injury pain (Spared Nerve Injury), and 3) inflammatory pain (intraplantar injection of Carrageenan). We monitored the position of the animals as well as their rate of switching between compartments. We find significant differences between the three groups and between the challenge levels both in their average position with respect to time, and in their switching rates. This suggests that the angle-track and thermal-track may be useful in assessing automatically the global impact of different types of pain on behavior.