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ObjectiveChronic 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.MethodsWe 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.ResultsAfter 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.ConclusionLong-term opioid use may impact sensory processing in fibromyalgia via gray matter changes within the cervical spinal cord.

(title for manuscript(s) will be more specific depending on the results) Recent neuroimaging research has shown greater functional connectivity of nucleus accumbens (NAcc, within the ventral striatum) with medial prefrontal cortex (MPFC) in patients with chronic back pain as compared to healthy individuals (Baliki et al., 2010). Further, NAcc – MPFC functional connectivity predicts pain chronification (Baliki et al., 2012). As prior findings have demonstrated a critical role of NAcc in predicting reward and pain cues (e.g., Becerra & Borsook, 2008; Becerra et al., 2001; Carlezon et al., 2009), these findings suggest that chronic pain conditions may alter mesolimbic valuation circuitry. Martucci et al. (2018) also found that reward systems are altered in patients with chronic pain. More specifically, neural responses to monetary rewards were shown to be altered in fibromyalgia (FM) patients compared to healthy individuals, such that patients showed greater activation in the MPFC during a non-loss condition, and reduced MPFC activity was observed during the anticipation of reward. Evidently, patients with FM may experience reward differently compared to healthy individuals. Accordingly, it is essential to examine whether the previous findings of altered brain reward systems (ie, altered NAcc – MPFC functional connectivity) in patients with chronic low back pain extend also to patients with FM. Therefore, the aim of this study is to investigate the generalizability of previous findings in chronic back pain patients to another chronic pain patient population by looking at ventral striatum (VS) – MPFC functional connectivity in patients with FM. Using resting-state functional magnetic resonance imaging (fMRI), we will compare functional connectivity across groups of patients with FM and healthy individuals. We expect to identify significant group differences in VS – MPFC functional connectivity, with greater VS – MPFC functional connectivity in the patients with FM compared to the healthy controls. Additionally, we will examine within the patient group how VS - MPFC functional connectivity correlates with clinical and behavioral measures. We expect to find positive correlations between VS – MPFC functional connectivity and clinical measures of pain duration (as it may relate to pain chronification), as well as significant correlations with clinical/behavioral measures of pain intensity, affect, and fatigue. Moreover, we will further examine how emotional and behavioral consequences caused by pain (e.g., negative affect, fatigue) correlate with functional connectivity. This work has implications for expanding our understanding of chronic pain and its relation to the human mesolimbic valuation system, behaviorally and neurophysiologically.

2022 analysis conducted by Morgan Rosser with Jason Bao. Using a data set of temporal summation (TS) (paper case report forms, electronic data entry) collected as part of an R00-funded study. Background: Affecting 2-8% of the population, fibromyalgia is a condition of chronic pain that coincides with widespread fatigue, forgetfulness, and disrupted mood and sleep states (Clauw, 2014). As the second most common rheumatic disorder, fibromyalgia is often comorbid with other disorders like irritable bowel syndrome and chronic fatigue syndrome and primarily impacts women (Sluka and Clauw, 2016). Diagnosis of the condition is based on the 2016 American College of Rheumatology standards. Specifically, patients with fibromyalgia must demonstrate generalized pain in at least 4 of 5 regions, present symptoms for at least 3 months, and a Widespread Pain Index (WPI) ≥ 7 and Symptom Severity Scale (SSS) ≥ 5 or WPI 4 – 6 and SSS ≥ 9 (Wolfe et al., 2016). Although the underlying pathology is unclear, as in other related pain conditions, fibromyalgia has been linked to altered central nervous system activity – specifically, enhanced response to afferent noxious and innocuous information and altered pain circuits (Sluka and Clauw, 2016; Gomez-Arguelles et al., 2018). Patients with fibromyalgia demonstrate altered cold pain tolerance and altered responses to pain and relief anticipation (Loggia et al., 2014; Jarrahi et al., 2018). Administration of exogenous opioids modulates these differences in pain processing. For example, patients with fibromyalgia who take opioids demonstrate different brain responses to reward anticipation and non-loss outcomes as healthy controls in comparison to pronounced differences in the responses of non-opioid patients (Martucci et al., 2019). In the context of patients with fibromyalgia, existing work, though very little, has offered conflicting findings about the impact of opioids on temporal summation levels. As shown by previous literature, compared to healthy controls, patients with fibromyalgia demonstrate enhanced temporal summation pain response to heat stimuli, with greater peak levels of pain, lower pain thresholds, greater after sensations (Staud et al., 2001; Price et al., 2002). Functional magnetic resonance imaging (fMRI) analyses attribute this greater summation and pain sensitivity to differences in descending control of activity in the spinal cord in fibromyalgia with greater activation in spinal cord and brainstem regions (Staud et al., 2021). In response to this hyperalgesia, recent efforts have focused on the administration of opioids, which have known hypoalgesic effects, to modulate temporal summation, though primarily in other chronic pain conditions. In the rodent model of chronic pain, opioids produce reversal of hyperalgesia and decreased magnitude of temporal summation (Lomas and Picker, 2005). Similarly, in a clinical trial of men with lumbar neuropathic pain, remifentanil administration of the opioid, remifentanil, produced significant reductions in temporal summation (Suzan et al., 2016). Thus, as acutely administered, opioids, in general, reduce temporal summation. However, though opioid administration does temporarily reduce temporal summation levels, patients with fibromyalgia interestingly demonstrate similar reductions in temporal summation and pain with both placebo and acute opioid treatments (Price et al., 2002; Hermans et al., 2018), therefore making it difficult to connect temporal summation reduction with drug administration or drug anticipation. More importantly, a comprehensive review suggests that opioid use contributes to opioid-induced hyperalgesia (OIH), an increased sensitivity to painful stimuli, which therefore complicates the understanding of opioid impact on central nervous system processing (Lee et al., 2011). Examples of OIH are as follows: (1) With short-term opioid administration, healthy male volunteers who received a high-dose of fentanyl exhibited increased areas of hyperalgesia within 4.5 to 6.5 hours of the opioid administration (Mauermann et al., 2016). (2) In patients with chronic pain who had received opioid therapy for at least three months, heat pain threshold decreased and temporal summation of second pain increased (Chen et al., 2009). (3) With continued use of opioids, patients can also develop opioid use disorder (OUD), which corresponds with greater central pain sensitization and temporal summation levels (Compton et al., 2020). To date, no studies have been conducted testing temporal summation in patients with fibromyalgia who are taking opioids long-term. Thus, it remains necessary to determine the impact of chronic opioid use on temporal summation in patients with fibromyalgia. As a result, we aimed to build upon previous findings regarding altered temporal summation responses in patients with fibromyalgia and quantify the impact of opioids on altered temporal summation in patients with fibromyalgia.

2021 analysis conducted by Eden Deng. Using CPT (paper, electronic data entry) and behavioral (REDCap) data from K99 and R00 studies. Background: The cold pressor test (CPT) has been used in clinical settings and in pain research to measure pain tolerance and sensitivity in a broad range of populations. However, in many studies CPT data have been inappropriately analyzed with parametric statistical methods (Treister et al., 2015). In particular, published analyses of pain tolerance in chronic pain research have rarely used survival analysis methods, despite this approach being more suitable for the type of data generated by pain tolerance tests. Several studies have utilized survival analysis for CPT data to study pain tolerance in adults with irritable bowel syndrome (IBS) (Stabell et al., 2013), to study psychological and genetic predictors of pain tolerance in healthy subjects (Patanwala et al., 2019), and to measure opioid-induced hyperalgesia (OIH) in opioid-dependent patients (Krishnan et al., 2012). However, regarding pain tolerance in the fibromyalgia patient population, to our knowledge, CPT responses have not been extensively studied with this approach. Various health and psychological factors may affect pain tolerance and chronic pain patients, including patients with fibromyalgia. Previous literature show that, compared to healthy individuals, fibromyalgia patients show less tolerance to cold pain (Brusselmans et al., 2015; Gormsen et al., 2012; Reyes del Paso et al., 2011), and CPT differences may be modulated by functional connectivity differences in sensorimotor networks and subcortical/brainstem areas (Jarrahi et al., 2018). In both pain-free individuals and chronic pain patients, state anxiety has been linked to greater pain sensitivity from a variety of noxious stimuli (Cimpean, 2019; Lauriola et al., 2019; Tang and Gibson, 2005; Zeidan et al., 2010). The number of pain areas across the body and negative affect have been found to related to levels of clinical pain intensity in fibromyalgia (Staud et al., 2004). More recently, there is evidence that positive affect (Finan and Garland, 2015; Thong et al., 2017) or affect balance (Sibille et al., 2012) may moderate the association between negative affect and pain intensity. Because opioid medications are broadly prescribed in the treatment of chronic pain, we also consider how opioid use may affect pain tolerance in patients with fibromyalgia. Opioid-dependence has been shown to correlate with greater sensitivity to cold pain (Doverty et al., 2001), and the CPT has been used as a measure of OIH in both fibromyalgia and other opioid-dependent patients (Krishnan et al., 2012; Oaks et al., 2018).

We will examine how attentional processes might be involved and/or altered in processing reward information in patients with fibromyalgia (FM) by investigating brain regions within which activity scales with attentional processing (lateral occipital cortex [LOC], inferior frontal gyrus [IFG], and precentral gyrus; Anderson, 2017; Corbetta, 1998; Corbetta & Shulman, 2002). Additionally, we will examine within the patient group how the BOLD responses of our primary regions of interest (ROIs) during reward anticipation correlate with behavioral and clinical measures. First, we expect to find a negative correlation between the beta values of our primary ROIs and participants’ reaction time on the monetary incentive delay (MID) task. Prior research showed a critical role of an individual’s current affective state, fatigue, and depression in modulating attentional processes (Farrin et al., 2003; Jefferies et al., 2008; Rowe et al., 2007; Vermeulen, 2010). Thus, we will further examine how emotional and behavioral consequences related to the experience of chronic pain (e.g., negative affect, fatigue, depression) correlate with brain activity.

Fibromyalgia (FM) is a common chronic pain condition (Walitt et al., 2015). While the mechanistic underpinnings of FM have yet to be fully elucidated, the presence of central sensitization appears to be a defining feature; this involves increased neuronal activity in the central nervous system (CNS) and exaggerated responses to incoming sensory input (Latremloeire and Woolf, 2009). In addition to functional CNS alterations, structural abnormalities may yield insight into CNS mechanisms undergirding the development and maintenance of FM. Neuroanatomical distinctions have been broadly observed in chronic pain conditions (e.g., Apkarian et al., 2004; Kim et al., 2008), including fibromyalgia (Shi et al., 2016; McCrae et al., 2015). A recent meta-analysis of studies utilizing voxel-based morphometry (VBM) to assess gray matter (GM) abnormalities associated with fibromyalgia reported significantly lower GM among FM patients relative to healthy controls in several brain regions, including 1) the bilateral anterior cingulate cortex (ACC) extending to the medial prefrontal cortex and paracingulate cortex, 2) the bilateral posterior cingulate cortex (PCC), and 3) the bilateral parahippocampal gyri extending to the fusiform cortex and hippocampus (Shi et al., 2016). Another seminal paper demonstrated similar results in the left ACC, right PCC, and right mPFC, as well as in the bilateral thalamus and several other regions (Pomares et al., 2017). While meta-analytic and ancillary findings largely report decreased regional GM volumes associated with FM, others have reported increased GM in the striatum (Schmidt-Wilcke et al., 2007) and left angular gyrus, right cuneus, and right postcentral gyrus (Pomares et al., 2017). And still others have reported no GM differences when controlling for affective dysregulation (Hsu et al., 2009). As Baliki et al. (2011) have noted, it is improbable these discrepant findings are a function of differences among patients; rather, they point to variability in methods. Thus, in an effort to substantiate the reproducibility of previous results, the present study aims to utilize VBM to closely follow previous methods (Burgmer et al., 2009, Ceko et al., 2013) and replicate previous findings of altered gray matter volumes in a sample of women with fibromyalgia (n=17) relative to sex-matched healthy controls (n=17). In order to conserve statistical power, we have elected to limit our analyses to regions consistently implicated in pain processing and, specifically, FM: the anterior cingulate cortex and the medial prefrontal cortex. Previous peak coordinates reported by Burgmer et al. (2009) and Ceko et al. (2013) are located in both the ACC and mPFC, but interpretation of these locations is varied. Therefore, we will restrict our analyses to examine within a large region of interest (ROI) that encompasses both the mPFC and ACC.

• This study is a close replication of Martucci et al. (2018): Martucci KT, Borg N, MacNiven KH, Knutson B, Mackey SC. Altered prefrontal correlates of monetary anticipation and outcome in chronic pain. Pain. 2018;159(8):1494-1507. doi:10.1097/j.pain.0000000000001232. Using functional magnetic resonance imaging (fMRI), Martucci et al. found that brain reward systems are altered for patients with chronic pain. Specifically, neural responses to monetary rewards are altered in patients with fibromyalgia (FM), such that patients showed greater activation in the medial prefrontal cortex (MPFC) during a non-loss condition, and reduced MPFC activity was observed during the anticipation of reward compared to a healthy population. Moreover, nucleus accumbens (NAcc) activity during reward anticipation showed no significant group differences, and patients with FM showed slightly reduced activity in the ventral tegmental area (VTA), anterior insular cortex (aINS), and anterior cingulate cortex (ACC) during reward anticipation compared to healthy controls. The aim of this study is to examine the reproducibility of these results in a separate cohort of patients with FM. • Additionally, we will further examine how attentional processes might be involved and/or altered in processing reward information in FM by investigating brain regions whose activity is known to scale with attentional processing (lateral occipital cortex (LOC), inferior frontal gyrus (IFG), and precentral gyrus; Anderson, 2017; Corbetta, 1998; Corbetta & Shulman, 2002).

Structural differences in brain gray matter density and volume have been broadly observed in a wide array of chronic pain conditions (Apkarian et al., 2004; Bagarinao et al., 2014; Barad et al., 2014; Kairys et al., 2015), including fibromyalgia (Shi et al., 2016; McCrae et al., 2015; Pomares et al., 2017). Although the mechanistic underpinnings of these differences remain unclear (Martucci et al., 2018), at the very least structural abnormalities yield insight into adaptations occurring within the central nervous system (CNS) in the context of persistent pain. No previous research has similarly evaluated gray matter differences in the spinal cord among fibromyalgia patients. Numerous opportunities for modulation of both ascending and descending nociceptive signaling exist within the spinal cord; accordingly, examination of this part of the CNS is essential for building understanding of chronic pain. Less gray matter volume (GMV) in the cervical spinal cord has been associated with disability and disease progression in multiple sclerosis (Agosta et al., 2007; Schlaeger et al., 2014) and with clinical disability in amyotrophic lateral sclerosis (ALS; Paquin et al., 2018). Moreover, dorsal and ventral horn gray matter atrophy following injury to the spinal cord have been associated with clinical outcomes (Huber et al., 2018). Specifically, sensory disturbances were associated with dorsal horn atrophy and motor impairments were associated with ventral horn atrophy. Among others, these studies provide a foundation of research implicating gray matter alterations in the dorsal and ventral horns of the cervical spine in disease processes, particularly with regard to pathologies involving disruptions in sensory processing. Compounding research implicating altered cervical spinal cord gray matter in disease processes, opioid medications are known to reduce gray matter volumes in numerous brain regions involved in pain processing (Upadhyay et al., 2010; Younger et al., 2011; Lin et al., 2015). To our knowledge, the effect of opioids on dorsal and ventral horn GMV in FM remains to be evaluated. Previous fMRI research has demonstrated unbalanced activity between the ventral and dorsal horns of the cervical spine among fibromyalgia patients (Martucci et al., 2019), with patients exhibiting greater ventral and lesser dorsal resting state activity compared to healthy controls. Additionally, comparatively less activity in the dorsal horn during experimental heat stimulation has been observed in FM patients during fMRI (Bosma et al., 2016). Together, these findings suggest that functional imbalances between the ventral and dorsal horns of the cervical spinal cord may be implicated in the development and maintenance of FM. In particular, central sensitization—a persistent state of heightened CNS activity and reactivity—may be, in part, a function of increased ventral and decreased dorsal activity. Expanding from these findings, we aim to examine gray matter differences in the dorsal and ventral horns of the cervical spinal cord among FM patients both taking and not taking opioids, relative to pain-free controls. Due to the dearth of research examining spinal cord gray matter volume differences in fibromyalgia or chronic pain, we have elected to posit exploratory hypotheses without directionality.