Neuroimaging of opioid effects in humans across conditions of acute administration, chronic pain therapy, and opioid use disorder.

Evidence of central nervous system (CNS) exogenous opioid effects in humans has been primarily gained through neuroimaging of three participant populations: individuals after acute opioid administration, those with opioid use disorder (OUD), and those with chronic pain receiving opioid therapy. In both the brain and spinal cord, opioids alter processes of pain, cognition, and reward. Opioid-related CNS effects may persist and accumulate with longer opioid use duration. Meanwhile, opioid-induced benefits versus risks to brain health remain unclear. This review article highlights recent accumulating evidence for how exogenous opioids impact the CNS in humans. While investigation of CNS opioid effects has remained largely disparate across contexts of opioid acute administration, OUD, and chronic pain opioid therapy, integration across these contexts may enable advancement toward effective interventions.

Enhanced motor network engagement during reward gain anticipation in fibromyalgia.

Reward motivation is essential in shaping human behavior and cognition. Both reward motivation and reward brain circuits are altered in chronic pain conditions, including fibromyalgia. In this study of fibromyalgia patients, we used a data-driven independent component analysis (ICA) approach to investigate how brain networks contribute to altered reward processing. From females with fibromyalgia (N = 24) and female healthy controls (N = 24), we acquired fMRI data while participants performed a monetary incentive delay (MID) reward task. After analyzing the task-based fMRI data using ICA to identify networks, we analyzed 3 networks of interest: motor network (left), value-driven attention network, and basal ganglia network. Then, we evaluated correlation coefficients between each network timecourse versus a task-based timecourse which modeled gain anticipation. Compared to controls, the fibromyalgia cohort demonstrated significantly stronger correlation between the left motor network timecourse and the gain anticipation timecourse, indicating the left motor network was more engaged with gain anticipation in fibromyalgia. In an exploratory analysis, we compared motor network engagement during early versus late phases of gain anticipation. Across cohorts, greater motor network engagement (i.e., stronger correlation between network and gain anticipation) occurred during the late timepoint, which reflected enhanced motor preparation immediately prior to response. Consistent with the main results, patients exhibited greater engagement of the motor network during both early and late phases compared with healthy controls. Visual-attention and basal ganglia networks revealed similar engagement in the task across groups. As indicated by post-hoc analyses, motor network engagement was positively related to anxiety and negatively related to reward responsiveness. In summary, we identified enhanced reward-task related engagement of the motor network in fibromyalgia using a novel data-driven ICA approach. Enhanced motor network engagement in fibromyalgia may relate to impaired reward motivation, heightened anxiety, and possibly to altered motor processing, such as restricted movement or dysregulated motor planning.

Interplay between noxious heat sensitivity and temporal summation magnitude in patients with fibromyalgia and long-term opioid use.

Introduction: In chronic pain conditions such as fibromyalgia (FM), pain amplification within the central nervous system, or "central sensitization," may contribute to the development and maintenance of chronic pain. Chronic pain treatments include opioid therapy, and opioid therapy may maladaptively increase central sensitization, particularly in patients who take opioids long-term. However, it has remained unknown how central sensitization is impacted in patients who use opioids long-term. Methods: To investigate how long-term opioid therapy affects central sensitization, we used the validated measure of temporal summation. The temporal summation measurement consists of applying a series of noxious stimuli to a patient's skin and then calculating changes in the patient's pain rating to each stimulus. Using this measurement, we evaluated temporal summation in study participants with fibromyalgia who take opioids long-term (i.e., greater than 90 days duration; n = 24, opioid-FM). We compared opioid-FM responses to 2 control groups: participants with fibromyalgia who do not take opioids (n = 33, non-opioid FM), and healthy controls (n = 31). For the temporal summation measurement, we applied a series of 10 noxious heat stimuli (sensitivity-adjusted temperatures) to the ventral forearm (2s duration of each stimulus, applied once every 3 s). Additionally, we collected responses to standard pain and cognitive-affective questionnaires to assess pain severity and other factors. Results and discussion: Group differences in sensitivity-adjusted stimulus temperatures were observed, with only the non-opioid FM group requiring significantly lower stimulus temperatures (The opioid-FM group also required lower temperatures, but not significantly different from the control group). However, all 3 groups exhibited similar magnitudes of temporal summation. Across combined FM groups, temporal summation negatively correlated with pain severity (r = -0.31, p = 0.021). Within the opioid-FM group, higher pain sensitivity to heat (i.e., lower sensitivity-adjusted temperatures) showed a trend relationship with higher opioid dosage (r = -0.45, p = 0.036), potentially reflective of opioid-related hyperalgesia. Our findings also indicated that heightened pain severity may skew sensitivity-adjusted temporal summation, thereby limiting its utility for measuring central sensitization. Overall, in participants taking opioids, temporal summation may be influenced by hypersensitivity to heat pain, which appeared to vary with opioid dosage.

Links between brain neuroimaging and blood inflammatory markers in urological chronic pelvic pain syndrome.

Urological chronic pelvic pain syndrome (UCPPS) is a debilitating painful condition with unclear etiology. Prior researchers have indicated that compared to healthy controls, patients with UCPPS demonstrated altered brain activity. Researchers have also shown that in UCPPS, several blood inflammatory markers relate to clinical variables of pain, fatigue, and pain widespreadness. However, how altered brain function in patients with UCPPS relates to blood inflammation remains unknown. To extend and connect prior findings of altered brain function and inflammatory factors in UCPPS, we conducted a secondary analysis of data from a cohort of UCPPS patients (N = 29) and healthy controls (N = 31) who provided both neuroimaging and blood data (National Institute of Health MAPP Research Network publicly available dataset). In our present study, we aimed to evaluate relationships between a priori-defined brain neuroimaging markers and inflammatory factors of interest and their relationships to pain-psychological variables. We hypothesized that two brain alterations of interest (i.e., PCC - left hippocampus functional connectivity and PCC - bilateral amygdala functional connectivity) would be correlated with four cytokine markers of interest: interleukin (IL) - 6, tumor necrosis factor-alpha (TNF-a), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the UCPPS cohort, we identified a significant PCC - left hippocampus functional connectivity relationship with IL-6 (p = 0.0044). Additionally, in the UCPPS cohort, we identified a PCC - amygdala functional connectivity relationship with GM-CSF which did not meet our model's threshold for statistical significance (p = 0.0665). While these data are preliminary and cross-sectional, our findings suggest connections between brain function and levels of low-grade systemic inflammation in UCPPS. Thus, while further study is needed, our data indicate the potential for advancing the understanding of how brain functional circuits may relate to clinical symptoms and systemic inflammation.

Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance.

BACKGROUND: Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans. METHODS: This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively. RESULTS: There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aß), tau, or phospho-tau181p levels, or on the tau/Aß or p-tau181p/Aß ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses. CONCLUSIONS: Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults. CLINICAL TRIAL REGISTRATION: NCT01993836.

Altered Functional Networks during Gain Anticipation in Fibromyalgia.

Reward motivation is essential in shaping human behavior and cognition. Previous studies have shown altered reward motivation and reward brain circuitry in chronic pain conditions, including fibromyalgia. Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, cognitive problems, and mood-related symptoms. In this study, we analyzed brain reward networks in patients with fibromyalgia by using a data-driven approach with task-based fMRI data. fMRI data from 24 patients with fibromyalgia and 24 healthy controls were acquired while subjects performed a monetary incentive delay (MID) reward task. Functional networks were derived using independent component analysis (ICA) focused on the gain anticipation phase of the reward task. Functional activity in the motor, value-driven attention, and basal ganglia networks was evaluated during gain anticipation in both patient and healthy control groups. Compared to controls, the motor network was more engaged during gain anticipation in patients with fibromyalgia. Our findings suggest that reward motivation may lead to hyperactivity in the motor network, possibly related to altered motor processing, such as restricted movement or dysregulated motor planning in fibromyalgia. As an exploratory analysis, we compared levels of motor network engagement during early and late timepoints of the gain anticipation phase. Both groups showed greater motor network engagement during the late timepoint (i.e., closer to response), which reflected motor preparation prior to target response. Importantly, compared to controls and consistent with the initial findings described above, patients exhibited greater engagement of the motor network during both early and late timepoints. In summary, by using a novel data-driven ICA approach to analyze task-based fMRI data, we identified elevated motor network engagement during gain anticipation in fibromyalgia.

Reduced Spinal Cord Gray Matter in Patients with Fibromyalgia Using Opioids Long-term.

Objective: Chronic pain involves alterations in brain gray matter volume (GMV). Moreover, opioid medications are known to reduce GMV in numerous brain regions involved in pain processing. However, no research has evaluated (1) chronic pain-related GMV alterations in the spinal cord or (2) the effect of opioids on spinal cord GMV. Accordingly, this study evaluated spinal cord GMV in health controls and patients with fibromyalgia who were using and not using opioids long-term. Methods: We analyzed average C5 - C7 GMV of the spinal cord dorsal and ventral horns in separate female cohorts of healthy controls (HC, n = 30), fibromyalgia patients not using opioids (FMN, n = 31), and fibromyalgia patients using opioids long-term (FMO, n = 27). To assess the effect of group on average dorsal and ventral horn GMV, we conducted a one-way multivariate analysis of covariance. Results: After controlling for age, we observed a significant effect of group on ventral horn GMV (p = 0.03, η2 = 0.09), and on dorsal horn GMV (p = 0.05, η2 = 0.08). Tukey's posthoc comparisons showed that, compared to HC participants, FMOs had significantly lower ventral (p = 0.01) and dorsal (p = 0.02) GMVs. Among FMOs only, ventral horn GMV was significantly positively associated with pain severity and interference, and both dorsal and ventral GMVs were significantly positively associated with cold pain tolerance. Conclusion: Long-term opioid use may impact sensory processing in fibromyalgia via gray matter changes within the cervical spinal cord.

Evaluation by Survival Analysis of Cold Pain Tolerance in Patients with Fibromyalgia and Opioid Use.

Purpose: The cold pressor test (CPT) is a clinical pain research method used to measure cold pain tolerance. During this test, participants immerse an extremity (ie, hand or foot) into cold water for as long as tolerable. The duration of the test (traditionally up to an experimentally imposed cut-off at 2 minutes) indicates the amount of cold pain tolerance by the participant. Prior research studies have investigated cold pain tolerance in patients with chronic pain. However, few of these studies have used survival analysis, which allows for proper handling of data censoring and is therefore, an optimal statistical method for CPT data analysis. The goal of the present study was to use survival analysis to evaluate cold pain tolerance in patients with fibromyalgia. Furthermore, we aimed to model relationships between psychological and clinical variables as well as opioid medication use and cold pain tolerance. Patients and Methods: A total of 85 patients with fibromyalgia (42 who were taking opioids) and 47 healthy pain-free controls provided CPT and questionnaire data (collected across 2 study sites) for a case-control study. We used survival analysis using Cox regression to evaluate group differences (patients vs controls) in cold pain tolerance and to evaluate cold pain tolerance relationships with psychological, clinical, and medication use. Results: As compared to healthy controls, patients with fibromyalgia exhibited significantly lower CPT survival (HR = 2.17, 95% CI: [1.42, 3.31], p = 0.00035). As indicated by Cox regression models, the significant group difference in CPT survival did not relate to our selected psychological and clinical measures (p > 0.05). The groups of non-opioid-taking patients and healthy controls showed consistent CPT survival across study sites. However, patients taking opioid pain medications showed differences in CPT survival across study sites. Conclusion: By using survival analysis, an optimal method for time-to-event pain measures such as the CPT, we confirmed previously identified reductions in cold pain tolerance in patients with fibromyalgia. While our selected psychological and clinical measures were not significantly associated with cold pain tolerance, our data suggest that opioid medication use may impart greater cold pain tolerance in some patients.

Altered resting-state functional connectivity within corticostriatal and subcortical-striatal circuits in chronic pain.

Brain corticostriatal circuits are important for understanding chronic pain and highly relevant to motivation and cognitive processes. It has been demonstrated that in patients with chronic back pain, altered nucleus accumbens (NAcc)-medial prefrontal cortex (MPFC) circuit fMRI-based activity is predictive of patient outcome. We evaluated the NAcc-MPFC circuit in patients with another chronic pain condition, fibromyalgia, to extend these important findings. First, we compared fMRI-based NAcc-MPFC resting-state functional connectivity in patients with fibromyalgia (N = 32) vs. healthy controls (N = 37). Compared to controls, the NAcc-MPFC circuit's connectivity was significantly reduced in fibromyalgia. In addition, within the fibromyalgia group, NAcc-MPFC connectivity was significantly correlated with trait anxiety. Our expanded connectivity analysis of the NAcc to subcortical brain regions showed reduced connectivity of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in fibromyalgia. Lastly, in an exploratory analysis comparing our fibromyalgia and healthy control cohorts to a separate publicly available dataset from patients with chronic back pain, we identified reduced NAcc-MPFC connectivity across both the patient groups with unique alterations in NAcc-mesolimbic connectivity. Together, expanding upon prior observed alterations in brain corticostriatal circuits, our results provide novel evidence of altered corticostriatal and mesolimbic circuits in chronic pain.

Altered Reward Processing and Sex Differences in Chronic Pain.

Chronic pain and reward processing are understood to be reciprocally related to one another. Previous studies of reward processing in chronic pain patients have reported incongruent findings. While several factors likely contribute to these disparate findings, these previous studies did not stratify their analyses by sex-a factor previously shown to robustly impact reward-related responses. Thus, we examined sex as a factor of interest in level of striatal activation during anticipation of monetary incentives among patients with chronic non-specific back pain and healthy controls (HC). This study utilized functional magnetic resonance imaging during a monetary incentive delay task to evaluate reward and loss responsivity in the striatum among males and females with and without chronic pain (N = 90). Group, sex, and group-by-sex interactions were analyzed via repeated measures analysis of variance. Among HC, males exhibited significantly greater blood oxygen level dependent (BOLD) signal in the striatum during reward anticipation, particularly during large reward trials. By contrast, no significant sex differences were observed among patients. A significant group-by-sex interaction was also observed, revealing diminished BOLD responses among males with chronic pain relative to control males. These results provide novel evidence of sex-specific reductions in anticipatory responses to reward in patients with chronic pain. Altered striatal reward responsivity among males, but not females, suggests that the reward systems of males and females are uniquely disrupted by chronic pain, and highlights the value of including sex as a factor of interest in future studies of reward responsivity in the context of persistent pain.

Replication of neural responses to monetary incentives and exploration of reward-influenced network connectivity in fibromyalgia.

Neuroimaging research has begun to implicate alterations of brain reward systems in chronic pain. Previously, using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in fibromyalgia. In the present study, we aimed to test the replicability of these altered neural responses to reward in a separate fibromyalgia cohort. In addition, the present study was conducted at a distinct U.S. location but involved a similar study design. For the present study, 20 patients with fibromyalgia and 20 healthy controls participated in MID task fMRI scan procedures and completed clinical/psychological questionnaires. fMRI analyses comparing patient and control groups revealed a consistent trend of main results which were largely similar to the prior reported results. Specifically, in the replication fibromyalgia cohort, medial prefrontal cortex (MPFC) response was reduced during gain anticipation and was increased during no-loss (non-punishment) outcome compared to controls. Also consistent with previous findings, the nucleus accumbens response to gain anticipation did not differ in patients vs. controls. Further, results from similarly-designed behavioral, correlational, and exploratory analyses were complementary to previous findings. Finally, a novel network-based functional connectivity analysis of the MID task fMRI data across patients vs. controls implied enhanced connectivity within the default mode network in participants with fibromyalgia. Together, based on replicating prior univariate results and new network-based functional connectivity analyses of MID task fMRI data, we provide further evidence of altered brain reward responses, particularly in the MPFC response to reward outcomes, in patients with fibromyalgia.

Spinal Cord Resting State Activity in Individuals With Fibromyalgia Who Take Opioids.

Chronic pain coincides with myriad functional alterations throughout the brain and spinal cord. While spinal cord mechanisms of chronic pain have been extensively characterized in animal models and in vitro, to date, research in patients with chronic pain has focused only very minimally on the spinal cord. Previously, spinal cord functional magnetic resonance imaging (fMRI) identified regional alterations in spinal cord activity in patients (who were not taking opioids) with fibromyalgia, a chronic pain condition. Here, in patients with fibromyalgia who take opioids (N = 15), we compared spinal cord resting-state fMRI data vs. patients with fibromyalgia not taking opioids (N = 15) and healthy controls (N = 14). We hypothesized that the opioid (vs. non-opioid) patient group would show greater regional alterations in spinal cord activity (i.e., the amplitude of low frequency fluctuations or ALFF, a measure of regional spinal cord activity). However, we found that regional spinal cord activity in the opioid group was more similar to healthy controls, while regional spinal cord activity in the non-opioid group showed more pronounced differences (i.e., ventral increases and dorsal decreases in regional ALFF) vs. healthy controls. Across patient groups, self-reported fatigue correlated with regional differences in spinal cord activity. Additionally, spinal cord functional connectivity and graph metrics did not differ among groups. Our findings suggest that, contrary to our main hypothesis, patients with fibromyalgia who take opioids do not have greater alterations in regional spinal cord activity. Thus, regional spinal cord activity may be less imbalanced in patients taking opioids compared to patients not taking opioids.

Relationship Between Blood Cytokine Levels, Psychological Comorbidity, and Widespreadness of Pain in Chronic Pelvic Pain.

Background: Low-grade inflammation has been implicated in the etiology of depression, long-term fatigue and chronic pain. TNFα and IL-6 are perhaps the most studied pro-inflammatory cytokines in the field of psychoneuroimmunology. The purpose of our study was to further investigate these relationships in patients with chronic pelvic pain specifically. Using plasma samples from a large, well-described cohort of patients with pelvic pain and healthy controls via the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network, we examined the relationship between TNFα and IL-6 and comorbid psychological symptoms. We also investigated the relationship between IL-8 and GM-CSF, and widespreadness of pain. Methods: We included baseline blood samples in the analyses, 261 patients (148 women) and 110 healthy controls (74 women). Fourteen pro- and anti-inflammatory or regulatory cytokines were analyzed in a Luminex® xMAP® high-sensitivity assay. We used regression models that accounted for known factors associated with the outcome variables to determine the relationship between cytokine levels and clinical measures. Results: There were no statistical differences in cytokine levels between patients and healthy controls when controlling for age. In patients, TNFα was significantly associated with levels of fatigue (p = 0.026), but not with pain intensity or depression. IL-6 was not significantly related to any of the outcome variables. Women with pelvic pain showed a negative relationship between IL-8 and widespreadness of pain, while men did not (p = 0.003). For both sexes, GM-CSF was positively related to widespreadness of pain (p = 0.039). Conclusion: Our results do not suggest low-grade systemic inflammation in chronic pelvic pain. Higher TNFα blood levels were related to higher fatigue ratings, while higher systemic GM-CSF levels predicted more widespread pain. Our study further suggests a potentially protective role of IL-8 with regard to with regard to the widepreadness of pain in the body, at least for women.

Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine.

One of the key ambitions of neuroimaging-based pain biomarker research is to augment patient and clinician reporting of clinically relevant phenomena with neural measures for prediction, prognosis, and detection of pain. Despite years of productive research on the neuroimaging of pain, such applications have seen little advancement. However, recent developments in identifying brain-based biomarkers of pain through advances in technology and multivariate pattern analysis provide some optimism. Here, we (1) define and review the different types of potential neuroimaging-based biomarkers, their clinical and research applications, and their limitations and (2) describe frameworks for evaluation of pain biomarkers used in other fields (eg, genetics, cancer, cardiovascular disease, immune system disorders, and rare diseases) to achieve broad clinical and research utility and minimize the risks of misapplication of this emerging technology. To conclude, we discuss future directions for neuroimaging-based biomarker research to achieve the goal of personalized pain medicine.

Apparent Effects of Opioid Use on Neural Responses to Reward in Chronic Pain.

Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively "normalized" neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.

Altered Cervical Spinal Cord Resting-State Activity in Fibromyalgia.

OBJECTIVE: Altered afferent input and central neural modulation are thought to contribute to fibromyalgia symptoms, and these processes converge within the spinal cord. We undertook this study to investigate the hypothesis that, using resting-state functional magnetic resonance imaging (rs-fMRI) of the cervical spinal cord, we would observe altered frequency-dependent activity in fibromyalgia. METHODS: Cervical spinal cord rs-fMRI was conducted in fibromyalgia patients (n = 16) and healthy controls (n = 17). We analyzed the amplitude of low-frequency fluctuations (ALFF), a measure of low-frequency oscillatory power, for frequencies of 0.01-0.198 Hz and frequency sub-bands to determine regional and frequency-specific alterations in fibromyalgia. Functional connectivity and graph metrics were also analyzed. RESULTS: As compared to healthy controls (n = 14), greater ventral and lesser dorsal mean ALFF of the cervical spinal cord was observed in fibromyalgia patients ( n = 15) (uncorrected P < 0.05) for frequencies of 0.01-0.198 Hz and all sub-bands. Additionally, lesser mean ALFF within the right dorsal quadrant (corrected P < 0.05) for frequencies of 0.01-0.198 Hz and sub-band frequencies of 0.073-0.198 Hz was observed in fibromyalgia. Regional mean ALFF was not correlated with pain; however, regional lesser mean ALFF was correlated with fatigue in patients (r = 0.763, P = 0.001). Functional connectivity and graph metrics were similar between groups. CONCLUSION: Our results indicate unbalanced activity between the ventral and dorsal cervical spinal cord in fibromyalgia. Increased ventral neural processes and decreased dorsal neural processes may reflect the presence of central sensitization and contribute to fatigue and other bodily symptoms in fibromyalgia.

Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network.

Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, is characterized by chronic pain in the pelvic region or genitalia that is often accompanied by urinary frequency and urgency. Despite considerable research, no definite aetiological risk factors or effective treatments have been identified. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network uses a novel integrated strategy to characterize UCPPS as a systemic disorder that potentially involves multiple aetiologies. The first phase, MAPP I, included >1,000 participants who completed an intensive baseline assessment followed by a 12-month observational follow-up period. MAPP I studies showed that UCPPS pain and urinary symptoms co-vary, with only moderate correlation, and should be evaluated separately and that symptom flares are common and can differ considerably in intensity, duration and influence on quality of life. Longitudinal clinical changes in UCPPS correlated with structural and functional brain changes, and many patients experienced global multisensory hypersensitivity. Additionally, UCPPS symptom profiles were distinguishable by biological correlates, such as immune factors. These findings indicate that patients with UCPPS have objective phenotypic abnormalities and distinct biological characteristics, providing a new foundation for the study and clinical management of UCPPS.

Cold Water Pressor Test Differentially Modulates Functional Network Connectivity in Fibromyalgia Patients Compared with Healthy Controls.

Fibromyalgia is a multifaceted chronic pain condition of unknown etiology. Conditioned pain modulation (CPM) such as cold water pressor test of the foot, is widely documented as being disrupted in patients with fibromyalgia. To date, the mechanisms underlying such dysregulation of the descending control of pain in fibromyalgia remain poorly understood. In this study, we used ICA-based network analysis to comprehensively compare differences in functional network connectivity among relevant (nonartifactual) intrinsic connectivity brain networks during the resting state before and after cold pressor test in patients with fibromyalgia and healthy controls. The results revealed significant differences in functional connectivity between the two groups that included the networks that integrate cognitive control and attention systems with memory, emotion and brainstem regions. Specifically, functional connectivity involving central executive network was absent in patients with fibromyalgia compared with controls. Patients showed significant functional connectivity changes involving subcortical and brainstem networks with the sensorimotor and dorsal attention networks. Accordingly, aberrant CPM in patients with fibromyalgia may be due to the differences in functional connectivity involving the subcortical/brainstem regions, and is facilitated by the recruitment of the dorsal attention network in lieu of the central executive network. Future research replicating the present findings with larger sample size can shed more light on neurobiology of endogenous pain modulation in fibromyalgia.

Altered prefrontal correlates of monetary anticipation and outcome in chronic pain.

Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

Neuroimaging of Pain: Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation.

Neuroimaging research has demonstrated definitive involvement of the central nervous system in the development, maintenance, and experience of chronic pain. Structural and functional neuroimaging has helped elucidate central nervous system contributors to chronic pain in humans. Neuroimaging of pain has provided a tool for increasing our understanding of how pharmacologic and psychologic therapies improve chronic pain. To date, findings from neuroimaging pain research have benefitted clinical practice by providing clinicians with an educational framework to discuss the biopsychosocial nature of pain with patients. Future advances in neuroimaging-based therapeutics (e.g., transcranial magnetic stimulation, real-time functional magnetic resonance imaging neurofeedback) may provide additional benefits for clinical practice. In the future, with standardization and validation, brain imaging could provide objective biomarkers of chronic pain, and guide treatment for personalized pain management. Similarly, brain-based biomarkers may provide an additional predictor of perioperative prognoses.