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While several prior studies have identified altered brain reward systems in chronic pain, other aspects of cognitive function may relate to reward circuit alterations in chronic pain and opioid use. In this study, we focused on the representation of attentional processing in the brain while participants anticipated a monetary reward. Using functional magnetic resonance imaging (fMRI) combined with a well-established monetary incentive delay task, we collected data across three groups: healthy controls (N=35), patients with fibromyalgia who were not taking opioids (non-opioid FM; N=36), and patients with fibromyalgia who were taking opioids long-term (i.e., greater than 90 days opioid use, opioid FM; N=26). For the group fMRI analyses, we focused on activity in two predetermined regions of interest which are highly relevant for attentional processing, the lateral occipital cortex (LOC) and inferior frontal gyrus (IFG). Despite no group effect in the LOC, as compared to controls, both patient groups demonstrated a trend of decreased gain anticipation response within the IFG (one-way ANOVA, main effect of group, P = 0.057). Interestingly, LOC-IFG functional connectivity differed across groups (ANOVA, main effect of group, P = 0.02), with decreased connectivity in non-opioid FM vs. controls (post-hoc t-test, Pbonf = 0.018) despite similar LOC-IFG functional connectivity between opioid FM and control groups. Together, these results provide novel evidence of the relationship between altered brain reward systems and dysregulated attentional processing in chronic pain, especially in patients with fibromyalgia, and suggest a potential impact of opioid use on this relationship. K99/R00 DA040154, R01 DA055850.

The purpose of this study was to evaluate cervical spinal cord dorsal and ventral horn gray matter volume (GMV) in patients with fibromyalgia on long-term opioid therapy. To do this, we analyzed average C5-C7 dorsal and ventral horn GMV in separate cohorts of healthy controls (n = 30), fibromyalgia patients not using opioids (n = 31), and fibromyalgia patients using opioids long-term (n = 27). To assess the effect of group on average dorsal and ventral horn GMV, we conducted a one-way multivariate analysis of covariance (MANCOVA). After controlling for age, we observed a significant effect of group on ventral horn GMV (p = 0.03, h2 = 0.09), and on dorsal horn GMV (p = 0.05, h2 = 0.08). We examined post-hoc pairwise comparisons with Tukey's multiple comparisons test. Pairwise comparisons showed that, compared to healthy controls, FMO participants had significantly lower ventral (p = 0.01, 95% CI [-588.81, -97.14]) and dorsal (p = 0.02, 95% CI [55.94, 527.27]) horn GMVs. Further, we examined bivariate associations—stratified by group—between average dorsal and ventral horn GMV, quantitative sensory testing measures, and clinical measures of pain. Among opioid-using patients only, ventral horn GMV was significantly positively associated with pain severity, pain interference, and cold pressor test (CPT) submersion time. Dorsal horn GMV was also significantly positively associated with CPT submersion time. All analyses were corrected for multiple comparisons. As suggested by these results, long-term opioid use may impact sensory processing in fibromyalgia via structural mechanisms within the cervical spinal cord. Funding: K99/R00DA0405154, R01DA055850 National Institutes of Health, National Institute on Drug Abuse: K99/R00DA0405154, R01DA055850.

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.

The challenges and understanding of acute and chronic pain have been illuminated through the advancement of central neuroimaging. Through neuroimaging research, new technology and findings have allowed us to identify and understand the neural mechanisms contributing to chronic pain. Several regions of the brain are known to be of particular importance for the maintenance and amplification of chronic pain, and this knowledge provides novel targets for future research and treatment. This article reviews neuroimaging for the study of chronic pain, and in particular, the rapidly advancing and popular research tools of structural and functional MRI.

Fibromyalgia is a prevalent chronic pain condition characterized by widespread pain and sensory hypersensitivity. While much remains to be learned about the neurobiological underpinnings of this condition, alterations to the central nervous system appear to be heavily implicated in fibromyalgia's pathophysiology. Previous research examining brain structural abnormalities among fibromyalgia patients has yielded inconsistent findings. Thus, we followed previous voxel-based morphometry methods in magnetic resonance imaging to examine brain gray matter differences in females (n=17) with fibromyalgia and female healthy controls (n=17). We hypothesized that, relative to healthy control participants, fibromyalgia participants would exhibit lower gray matter volume in regions consistently implicated in pain processing and, specifically, fibromyalgia: the anterior cingulate cortex and the medial prefrontal cortex. Previously reported peak coordinates are located in both the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC), but interpretation of these locations is varied. Therefore, we first examined a large region of interest that encompassed both the mPFC and ACC, followed by a whole brain analysis. Group differences were analyzed with two-sample t-tests, controlling for total intracranial volume. No significant differences in regional or whole brain gray matter volumes were detected between fibromyalgia patients and healthy controls. These results add to an existing body of disparate findings regarding brain gray matter volume differences in fibromyalgia, and suggest structural differences previously detected among fibromyalgia patients should be rigorously examined for reproducibility and support the need for additional meta-analyses. Absent significant differences may also suggest that individual differences, rather than methodological variability, account for contradictory results. Grant support from K99DA040154.

Highly relevant to both pain and reward, corticostriatal circuits are important for understanding chronic pain. Previous research has demonstrated importance of the nucleus accumbens (NAcc) - medial prefrontal cortex (MPFC) circuit in predicting localized pain chronification in chronic back pain (CBP). The aims of our study were to extend prior evidence of brain reward/value circuit alterations to new cohorts of chronic pain patients and further evaluate activity within reward/value networks in chronic pain. As outlined in our pre-registered plan on the Open Science Framework (OSF, https://osf.io/cj9u8), we hypothesized that resting-state brain reward circuits (i.e., fMRI-indicated NAcc-MPFC resting-state functional connectivity [rsFC] measurements) are altered in patients with fibromyalgia (FM). In a first study, we examined corticostriatal rsFC strength of the NAcc-MPFC circuit in patients with FM (N=17) compared to healthy controls (HC, N=17). Robust NAcc-MPFC functional connectivity was found among patients with FM and HCs, but no significant group differences were observed, indicating intact NAcc-MPFC rsFC in FM. Because previous resting-state studies in patients with CBP involved a pain-monitoring/rating task, in a second study, we compared our results from FM and HC cohorts to a separate cohort of patients with CBP (publicly available dataset, N=31) during resting-state fMRI with no rating task. We again found no significant group differences in NAcc-MPFC rsFC. In a third study, we conducted an expanded analysis of NAcc rsFC to mesolimbic (i.e., subcortical) circuit regions in chronic pain. We found reduced rsFC of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in FM vs. HC, and additional NAcc-mesolimbic alterations across FM and CBP vs. HC groups. Together, our results expand upon prior observed alterations in brain reward circuits, providing novel evidence of intact corticostriatal but altered subcortical-striatal circuits in chronic pain. This project was funded by the National Institutes of Health, National Institute of Drug Abuse (NIDA), K99/R00 DA040154 (awarded to K.T.M.), K24 NS126781 (awarded to S.C.M.), and the Redlich Pain Research Endowment (S.C.M.). Data used in this project from the Open Pain Project (OPP; Principal Investigator: A. Vania Apkarian, PhD, Northwestern University) was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Drug Abuse (NIDA).