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.

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.

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.

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.

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.

Reward impacts visual statistical learning.

Humans automatically detect and remember regularities in the visual environment-a type of learning termed visual statistical learning (VSL). Many aspects of learning from reward resemble VSL in certain respects, yet whether and how reward learning impacts VSL is largely unexamined. In two studies, we found that reward contingencies affect VSL, with high-value associated with stronger behavioral and neural signatures of such learning than low-value images. In Experiment 1, participants learned values (high or low) of images through a trial-and-error risky choice task. Unbeknownst to them, images were paired as four types-High-High, High-Low, Low-High, and Low-Low. In subsequent recognition and reward memory tests, participants chose the more familiar of two pairs (a target and a foil) and recalled the value of images. We found better recognition when the first images of pairs have high-values, with High-High pairs showing the highest recognition rate. In Experiment 2, we provided evidence that both value and statistical contingencies affected brain responses. When we compared responses between the high-value first image and the low-value first image, greater activation in regions that included inferior frontal gyrus, anterior cingulate gyrus, hippocampus, among other regions, were found. These findings were driven by the interaction between statistically structured information and reward-the same value contrast yielded no regions for second-image contrasts and for singletons. Our results suggest that when reward information is embedded in stimulus-stimulus associations, it may alter the learning process; specifically, the higher-value first image potentially enables better memory for statistically learned pairs and reward information.

Visual statistical learning is modulated by arbitrary and natural categories.

Visual statistical learning (VSL) describes the unintentional extraction of statistical regularities from visual environments across time or space, and is typically studied using novel stimuli (e.g., symbols unfamiliar to participants) and using familiarization procedures that are passive or require only basic vigilance. The natural visual world, however, is rich with a variety of complex visual stimuli, and we experience that world in the presence of goal-driven behavior including overt learning of other kinds. To examine how VSL responds to such contexts, we exposed subjects to statistical contingencies as they learned arbitrary categorical mappings of unfamiliar stimuli (fractals, Experiment 1) or familiar stimuli with preexisting categorical boundaries (faces and scenes, Experiment 2). In a familiarization stage, subjects learned by trial and error the arbitrary mappings between stimuli and one of two responses. Unbeknownst to participants, items were paired such that they always appeared together in the stream. Pairs were equally likely to be of the same or different category. In a pair recognition stage to assess VSL, subjects chose between a target pair and a foil pair. In both experiments, subjects' VSL was shaped by arbitrary categories: same-category pairs were learned better than different-category pairs. Natural categories (Experiment 2) also played a role, with subjects learning same-natural-category pairs at higher rates than different-category pairs, an effect that did not interact with arbitrary mappings. We conclude that learning goals of the observer and preexisting knowledge about the structure of the world play powerful roles in the incidental learning of novel statistical information.

The roles of order, distance, and interstitial items in temporal visual statistical learning.

Humans are adept at learning regularities in a visual environment, even without explicit cues to structure and in the absence of instruction-this has been termed "visual statistical learning" (VSL). The nature of the representations resulting from VSL are still poorly understood. In five experiments, we examined the specificity of temporal VSL representations. In Experiments 1A, 1B, and 2, we compared recognition rates of triplets and all embedded pairs to chance. Robust learning of all structures was evident, and even pairs of non-adjacent items in a sequentially presented triplet (AC extracted from a triplet composed of ABC) were recognized at above-chance levels. In Experiment 3, we asked whether people could recognize rearranged pairs to examine the flexibility of learned representations. Recognition of all possible orders of target triplets and pairs was significantly higher than chance, and there were no differences between canonical orderings and their corresponding randomized orderings, suggesting that learners were not dependent upon originally experienced stimulus orderings to recognize co-occurrence. Experiment 4 demonstrates the essential role of an interstitial item in VSL representations. By comparing the learning of quadruplet sets (e.g., ABCD) and triplet sets (e.g., ABC), we found learning of AC and BD in ABCD (quadruplet) sets were better than the learning of AC in ABC (triplet) sets. This pattern of results might result from the critical role of interstitial items in statistical learning. In short, our work supports the idea of generalized representation in VSL and provides evidence about how this representation is structured.

Tasks determine what is learned in visual statistical learning.

Visual statistical learning (VSL), the unsupervised learning of statistical contingencies across time and space, may play a key role in efficient and predictive encoding of the perceptual world. How VSL capabilities vary as a function of ongoing task demands is still poorly understood. VSL is modulated by selective attention and faces interference from some secondary tasks, but there is little evidence that the types of contingencies learned in VSL are sensitive to task demands. We found a powerful effect of task on what is learned in VSL. Participants first completed a visual familiarization task requiring judgments of face gender (female/male) or scene location (interior/exterior). Statistical regularities were embedded between stimulus pairs. During a surprise recognition phase, participants showed less recognition for pairs that had required a change in response key (e.g., female followed by male) or task (e.g., female followed by indoor) during familiarization. When familiarization required detection of "flicker" or "jiggle" events unrelated to image content, there was weaker, but uniform, VSL across pair types. These results suggest that simple task manipulations play a strong role in modulating the distribution of learning over different pair combinations. Such variations may arise from task and response conflict or because the manner in which images are processed is altered.