Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain.

Differences in fMRI resting-state connectivity of the default mode network (DMN) seen in chronic pain patients are often interpreted as brain reorganization due to the chronic pain condition. Nevertheless, patients' pain at the time of fMRI might influence the DMN because pain, like cognitive stimuli, engages attentional mechanisms and cognitive engagement is known to alter DMN activity. Here, we aimed to dissociate the influence of chronic pain condition (trait) from the influence of current pain experience (state) on DMN connectivity in patients with fibromyalgia (FM). We performed resting-state fMRI scans to test DMN connectivity in FM patients and matched healthy controls in two separate cohorts: (1) in a cohort not experiencing pain during scanning (27 FM patients and 27 controls), (2) in a cohort with current clinical pain during scanning (16 FM patients and 16 controls). In FM patients without pain during scanning, the connectivity of the DMN did not differ significantly from controls. By contrast, FM patients with current clinical pain during the scan had significantly increased DMN connectivity to bilateral anterior insula (INS) similar to previous studies. Regression analysis showed a positive relationship between DMN-midINS connectivity and current pain. We therefore suggest that transient DMN disruptions due to current clinical pain during scanning (current pain state) may be a substantial contributor to DMN connectivity disruptions observed in chronic pain patients.

Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients.

OBJECTIVE: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. METHODS: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). RESULTS: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). CONCLUSIONS: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

The Role of PIEZO2 in Human Mechanosensation.

BACKGROUND: The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms. METHODS: We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation. RESULTS: Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception. CONCLUSIONS: Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.).

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Cognitive and emotional control of pain and its disruption in chronic pain.

Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states - important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. SIGNIFICANCE STATEMENT: We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks ["external-task positive" and "default-mode network" (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance.

Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.

We previously reported that effective treatment of chronic low back pain (CLBP) reversed abnormal brain structure and functional MRI (fMRI) activity during cognitive task performance, particularly in the left dorsolateral prefrontal cortex (DLPFC). Here, we used resting-state fMRI to examine how chronic pain affects connectivity of brain networks supporting cognitive functioning and the effect of treatment in 14 CLBP patients and 16 healthy, pain-free controls (scans were acquired at baseline for all subjects and at 6-months post-treatment for patients and a matched time-point for 10 controls). The main networks activated during cognitive task performance, task-positive network (TPN) and task-negative network (TNN) (aka default mode) network, were identified in subjects' task fMRI data and used to define matching networks in resting-state data. The connectivity of these cognitive resting-state networks was compared between groups, and before and after treatment. Our findings converged on the bilateral insula (INS) as the region of aberrant cognitive resting-state connectivity in patients pretreatment versus controls. These findings were complemented by an independent, data-driven approach showing altered global connectivity of the INS. Detailed investigation of the INS confirmed reduced connectivity to widespread TPN and TNN areas, which was partially restored post-treatment. Furthermore, analysis of diffusion-tensor imaging (DTI) data revealed structural changes in white matter supporting these findings. The left DLPFC also showed aberrant connectivity that was restored post-treatment. Altogether, our findings implicate the bilateral INS and left DLPFC as key nodes of disrupted cognition-related intrinsic connectivity in CLBP, and the resulting imbalance between TPN and TNN function is partially restored with treatment.

Insular cortex mediates increased pain tolerance in yoga practitioners.

Yoga, an increasingly popular discipline among Westerners, is frequently used to improve painful conditions. We investigated possible neuroanatomical underpinnings of the beneficial effects of yoga using sensory testing and magnetic resonance imaging techniques. North American yogis tolerated pain more than twice as long as individually matched controls and had more gray matter (GM) in multiple brain regions. Across subjects, insular GM uniquely correlated with pain tolerance. Insular GM volume in yogis positively correlated with yoga experience, suggesting a causal relationship between yoga and insular size. Yogis also had increased left intrainsular white matter integrity, consistent with a strengthened insular integration of nociceptive input and parasympathetic autonomic regulation. Yogis, as opposed to controls, used cognitive strategies involving parasympathetic activation and interoceptive awareness to tolerate pain, which could have led to use-dependent hypertrophy of insular cortex. Together, these findings suggest that regular and long-term yoga practice improves pain tolerance in typical North Americans by teaching different ways to deal with sensory inputs and the potential emotional reactions attached to those inputs leading to a change in insular brain anatomy and connectivity.

Anatomical and functional enhancements of the insula after loss of large primary somatosensory fibers.

Brain changes associated with the loss of a sensory modality such as vision and audition have previously been reported. Here, we examined the effect of loss of discriminative touch and proprioception on cortical thickness and functional connectivity. We performed structural magnetic resonance imaging and resting-state functional magnetic resonance imaging scans on a 60-year-old female who at age 31 suffered a selective loss of large-diameter myelinated primary afferents and, therefore, relies mainly on her intact thin-fiber senses (temperature, pain, itch, and C-fiber touch) and vision to negotiate her environment. The patient showed widespread cortical thinning compared with 12 age-matched female controls. In contrast, her right anterior insula was significantly thick. Seed-based resting-state analysis revealed that her right anterior insula had increased connectivity to bilateral posterior insula. A separate independent component analysis revealed the increased connectivity between the insula and visual cortex in the patient. As the insula is an important processing area for temperature and C-fiber tactile information, the increased intrainsular and insular-visual functional connectivity could be related to the patient's use of C-fiber (gentle) touch and temperature information in conjunction with visual information to navigate her environment. We, thus, demonstrated plasticity in networks involving the insular cortex following denervation of large-diameter somatosensory afferents.

The effects of virtual reality neuroscience-based therapy on clinical and neuroimaging outcomes in patients with chronic back pain: a randomized clinical trial.

ABSTRACT: Chronic pain remains poorly managed. The integration of immersive technologies (ie, virtual reality [VR]) with neuroscience-based principles may provide effective pain treatment by targeting cognitive and affective neural processes that maintain pain and therefore potentially changing neurobiological circuits associated with pain chronification and amplification. We tested the effectiveness of a novel VR neuroscience-based therapy (VRNT) to improve pain-related outcomes in n = 31 participants with chronic back pain, evaluated against usual care (waitlist control; n = 30) in a 2-arm randomized clinical trial (NCT04468074). We also conducted pre-treatment and post-treatment MRI to test whether VRNT affects brain networks previously linked to chronic pain and treatment effects. Compared with the control condition, VRNT led to significantly reduced pain intensity (g = 0.63) and pain interference (g = 0.84) at post-treatment vs pre-treatment, with effects persisting at 2-week follow-up. These improvements were partially mediated by reduced kinesiophobia and pain catastrophizing. Several secondary clinical outcomes were also improved by VRNT, including disability, quality of life, sleep, and fatigue. In addition, VRNT was associated with increases in dorsomedial prefrontal functional connectivity with the superior somatomotor, anterior prefrontal and visual cortices, and decreased white matter fractional anisotropy in the corpus callosum adjacent to the anterior cingulate, relative to the control condition. Thus, VRNT showed preliminary efficacy in significantly reducing pain and improving overall functioning, possibly through changes in somatosensory and prefrontal brain networks.

The Effects of Virtual Reality Neuroscience-based Therapy on Clinical and Neuroimaging Outcomes in Patients with Chronic Back Pain: A Randomized Clinical Trial.

Chronic pain remains poorly managed. The integration of innovative immersive technologies (i.e., virtual reality (VR)) with recent neuroscience-based principles that position the brain as the key organ of chronic pain may provide a more effective pain treatment than traditional behavioral therapies. By targeting cognitive and affective processes that maintain pain and potentially directly changing neurobiological circuits associated with pain chronification and amplification, VR-based pain treatment has the potential for significant and long-lasting pain relief. We tested the effectiveness of a novel VR neuroscience-based therapy (VRNT) to improve pain-related outcomes in n = 31 participants with chronic back pain, evaluated against usual care (n = 30) in a 2-arm randomized clinical trial ( NCT04468074) . We also conducted pre- and post-treatment MRI to test whether VRNT affects brain networks previously linked to chronic pain and treatment effects. Compared to the control condition, VRNT led to significantly reduced pain intensity (g = 0.63) and pain interference (g = 0.84) at post-treatment vs. pre-treatment, with effects persisting at 2-week follow-up. The improvements were partially mediated by reduced kinesiophobia and pain catastrophizing. Several secondary clinical outcomes were also improved, including disability, quality of life, sleep, and fatigue. In addition, VRNT was associated with modest increases in functional connectivity of the somatomotor and default mode networks and decreased white matter fractional anisotropy in the corpus callosum adjacent to anterior cingula, relative to the control condition. This, VRNT showed preliminary efficacy in significantly reducing pain and improving overall functioning, possibly via changes in somatosensory and prefrontal brain networks.

Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain.

Placebo analgesia is a replicable and well-studied phenomenon, yet it remains unclear to what degree it includes modulation of nociceptive processes. Some studies find effects consistent with nociceptive effects, but meta-analyses show that these effects are often small. We analyzed placebo analgesia in a large fMRI study (N = 392), including placebo effects on brain responses to noxious stimuli. Placebo treatment caused robust analgesia in both conditioned thermal and unconditioned mechanical pain. Placebo did not decrease fMRI activity in nociceptive pain regions, including the Neurologic Pain Signature (NPS) and pre-registered spinothalamic pathway regions, with strong support from Bayes Factor analyses. However, placebo treatment affected activity in pre-registered analyses of a second neuromarker, the Stimulus Intensity Independent Pain Signature (SIIPS), and several associated a priori brain regions related to motivation and value, in both thermal and mechanical pain. Individual differences in behavioral analgesia were correlated with neural changes in both thermal and mechanical pain. Our results indicate that processes related to affective and cognitive aspects of pain primarily drive placebo analgesia.

Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling.

ABSTRACT: Chronic pain conditions frequently co-occur, suggesting common risks and paths to prevention and treatment. Previous studies have reported genetic correlations among specific groups of pain conditions and reported genetic risk for within-individual multisite pain counts (≤7). Here, we identified genetic risk for multiple distinct pain disorders across individuals using 24 chronic pain conditions and genomic structural equation modeling (Genomic SEM). First, we ran individual genome-wide association studies (GWASs) on all 24 conditions in the UK Biobank ( N ≤ 436,000) and estimated their pairwise genetic correlations. Then we used these correlations to model their genetic factor structure in Genomic SEM, using both hypothesis- and data-driven exploratory approaches. A complementary network analysis enabled us to visualize these genetic relationships in an unstructured manner. Genomic SEM analysis revealed a general factor explaining most of the shared genetic variance across all pain conditions and a second, more specific factor explaining genetic covariance across musculoskeletal pain conditions. Network analysis revealed a large cluster of conditions and identified arthropathic, back, and neck pain as potential hubs for cross-condition chronic pain. Additionally, we ran GWASs on both factors extracted in Genomic SEM and annotated them functionally. Annotation identified pathways associated with organogenesis, metabolism, transcription, and DNA repair, with overrepresentation of strongly associated genes exclusively in brain tissues. Cross-reference with previous GWASs showed genetic overlap with cognition, mood, and brain structure. These results identify common genetic risks and suggest neurobiological and psychosocial mechanisms that should be targeted to prevent and treat cross-condition chronic pain.

Interdisciplinary views of fNIRS: Current advancements, equity challenges, and an agenda for future needs of a diverse fNIRS research community.

Functional Near-Infrared Spectroscopy (fNIRS) is an innovative and promising neuroimaging modality for studying brain activity in real-world environments. While fNIRS has seen rapid advancements in hardware, software, and research applications since its emergence nearly 30 years ago, limitations still exist regarding all three areas, where existing practices contribute to greater bias within the neuroscience research community. We spotlight fNIRS through the lens of different end-application users, including the unique perspective of a fNIRS manufacturer, and report the challenges of using this technology across several research disciplines and populations. Through the review of different research domains where fNIRS is utilized, we identify and address the presence of bias, specifically due to the restraints of current fNIRS technology, limited diversity among sample populations, and the societal prejudice that infiltrates today's research. Finally, we provide resources for minimizing bias in neuroscience research and an application agenda for the future use of fNIRS that is equitable, diverse, and inclusive.

Common and stimulus-type-specific brain representations of negative affect.

The brain contains both generalized and stimulus-type-specific representations of aversive events, but models of how these are integrated and related to subjective experience are lacking. We combined functional magnetic resonance imaging with predictive modeling to identify representations of generalized (common) and stimulus-type-specific negative affect across mechanical pain, thermal pain, aversive sounds and aversive images of four intensity levels each. This allowed us to examine how generalized and stimulus-specific representations jointly contribute to aversive experience. Stimulus-type-specific negative affect was largely encoded in early sensory pathways, whereas generalized negative affect was encoded in a distributed set of midline, forebrain, insular and somatosensory regions. All models specifically predicted negative affect rather than general salience or arousal and accurately predicted negative affect in independent samples, demonstrating robustness and generalizability. Common and stimulus-type-specific models were jointly important for predicting subjective experience. Together, these findings offer an integrated account of how negative affect is constructed in the brain and provide predictive neuromarkers for future studies.

Neural effects of placebo analgesia in fibromyalgia patients and healthy individuals.

ABSTRACT: Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the neurologic pain signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opioidergic prefrontal modulatory networks.

A neuroimaging biomarker for sustained experimental and clinical pain.

Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation.

A human colliculus-pulvinar-amygdala pathway encodes negative emotion.

Animals must rapidly respond to threats to survive. In rodents, threat-related signals are processed through a subcortical pathway from the superior colliculus to the amygdala, a putative "low road" to affective behavior. This pathway has not been well characterized in humans. We developed a novel pathway identification framework that uses pattern recognition to identify connected neural populations and optimize measurement of inter-region connectivity. We first verified that the model identifies known thalamocortical pathways with high sensitivity and specificity in 7 T (n = 56) and 3 T (n = 48) fMRI experiments. Then we identified a human functional superior colliculus-pulvinar-amygdala pathway. Activity in this pathway encodes the intensity of normative emotional responses to negative images and sounds but not pleasant images or painful stimuli. These results provide a functional description of a human "low road" pathway selective for negative exteroceptive events and demonstrate a promising method for characterizing human functional brain pathways.

Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.

Fibromyalgia patients and healthy volunteers express difficulties and variability in rating experimental pain: a qualitative study.

Background and aims Despite the enormous body of literature spanning more than 50 years describing results of pain experiments, very few have used qualitative methods to explore subjects' thoughts while scoring experimental painful stimuli, and none in the available literature have used qualitative interviews to do so. The current study examined how participants in experimental pain research delineate pain ratings to better understand the unique influences of the experimental setting on pain scores. An additional aim was to highlight how individuals with fibromyalgia and healthy volunteers are differently influenced by characteristics of the experimental setting. Methods This was an inductive, qualitative study in which individual, semi-structured interviews were performed with 31 fibromyalgia patients and 44 healthy volunteers. Participants had taken part in a pain experiment during which a thermode was used to induce painful heat stimuli on two skin areas. There were two primary interview questions analyzed for this report: (1) "Thinking back to when you were getting the heat pain on your leg, what were you thinking about when deciding on your pain score?" and (2) Participants who said that it was difficult to decide on a pain score were asked to, "Describe what made it difficult to choose a number." Thematic analysis was used to generate conceptual categories from textual data and find common themes. Results Three notable differences were found between fibromyalgia patients and healthy volunteers: (1) using current daily pain as a benchmark was seen more in patients, (2) wanting to appear strong in front of the study investigators was more common in healthy volunteers, and (3) becoming mentally fatigued from rating many stimuli was more common for fibromyalgia patients. Thoughts while scoring pain included: (1) comparing with previous or current pain, (2) self-monitoring of one's ability to endure the pain, (3) focusing on the physical aspects of the pain, (4) knowing the experimental setting is safe, (5) focusing on the pain scale as an anchor, and (6) desire to appear strong. Additionally, five difficulties in scoring experimental pain were identified: (1) falling asleep, (2) mentally fatigued, (3) feeling as though they were guessing, (4) having to make a quick decision, and (5) difficulty in being consistent. Conclusions This study provides insights into the thoughts of participants in experimental pain research studies. Participants were distracted and influenced by the experimental setting and some factors differed for fibromyalgia patients versus healthy volunteers. Implications Understanding the ways in which the experimental setting influences pain ratings may help pain researchers better design and interpret studies. Researchers can use these findings to mitigate difficulties for participants in experimental research to add to its validity.