Preliminary investigation of the interactive role of physiological arousal and insomnia complaints in gray matter volume alterations in chronic widespread pain.

STUDY OBJECTIVES: Brain regions involved in insomnia and chronic pain are overlapping and diffuse. The interactive role of physiological arousal in associations between insomnia symptoms and neural regions is unknown. This preliminary study examined whether arousal interacted with sleep in associations with gray matter volume of frontal (dorsolateral prefrontal cortex, anterior cingulate cortex) and temporal (right/left hippocampus) regions in adults with chronic widespread pain and insomnia complaints. METHODS: Forty-seven adults with chronic widespread pain and insomnia (mean age = 46.00, standard deviation = 13.88, 89% women) completed 14 daily diaries measuring sleep onset latency (SOL), wake time after sleep onset, and total sleep time (TST), as well as Holter monitor assessments of heart rate variability (measuring physiological arousal), and magnetic resonance imaging. Multiple regressions examined whether average SOL, wake time after sleep onset, or TST were independently or interactively (with arousal/heart rate variability) associated with dorsolateral prefrontal cortex, anterior cingulate cortex, and left/right hippocampus gray matter volumes. RESULTS: Shorter TST was associated with lower right hippocampus volume. TST also interacted with arousal in its association with right hippocampal volume, Specifically, shorter TST was associated with lower volume at highest and average arousal levels. SOL interacted with arousal in its association with anterior cingulate cortex volume, such that, among individuals with lowest arousal, longer SOL was associated with lower volume. CONCLUSIONS: Preliminary findings highlight the interactive roles of physiological arousal and insomnia symptoms in associations with neural structure in chronic widespread pain and insomnia. Individuals with the highest physiological arousal may be particularly vulnerable to the impact of shorter TST on hippocampal volume loss. Reducing SOL may only impact anterior cingulate cortex volume in those with lower physiological arousal. CITATION: Curtis AF, Nair N, Hayse B, et al. Preliminary investigation of the interactive role of physiological arousal and insomnia complaints in gray matter volume alterations in chronic widespread pain. J Clin Sleep Med. 2024;20(2):293-302.

Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study.

STUDY OBJECTIVES: To examine whether cognitive behavioral treatments for insomnia (CBT-I) and pain (CBT-P) lead to neural activation changes in response to pain in fibromyalgia. METHODS: Thirty-two patients with fibromyalgia (mean age = 55.9, standard deviation = 12.2) underwent an experimental pain protocol during functional magnetic resonance imaging and completed 14-day diaries assessing total wake time, total sleep time, and pain intensity before and after CBT-I, CBT-P, or waitlist control. Random effects analysis of covariance identified regions with significant group (CBT-I, CBT-P, waitlist control) by time (baseline, post-treatment) interactions in blood oxygen level-dependent response to pain. Linear regressions using residualized change scores examined how changes in total wake time, total sleep time, and pain intensity were related to activation (blood oxygen level-dependent) changes. RESULTS: Twelve regions exhibited small to moderate effects with significant interactions Ps < .00; right hemisphere: inferior frontal, middle occipital, and superior temporal gyri, insula, lentiform nucleus; left hemisphere: angular, superior temporal, midfrontal, inferior occipital, midtemporal, and inferior frontal gyri. Blood oxygen level-dependent response to pain decreased in 8 regions following CBT-I, and in 3 regions following CBT-P (CBT-I effects > CBT-P). Blood oxygen level-dependent response also increased in 3 regions following CBT-P and in 6 regions following waitlist control. Improved total wake time and/or total sleep time, not pain intensity, predicted decreased blood oxygen level-dependence in 7 regions (Ps < .05), accounting for 18%-47% of the variance. CONCLUSIONS: CBT-I prompted greater decreases in neural activation in response to pain across more regions associated with pain and sleep processing than CBT-P. Reported sleep improvements may underlie those decreases. Future research examining the longer-term impact of CBT-I and improved sleep on central pain and sleep mechanisms is warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep and Pain Interventions in Fibromyalgia (SPIN); Identifier: NCT02001077; URL: https://clinicaltrials.gov/ct2/show/NCT02001077. CITATION: McCrae CS, Craggs JG, Curtis AF, et al. Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study. J Clin Sleep Med. 2022;18(1):203-215.

Protocol for the impact of CBT for insomnia on pain symptoms and central sensitisation in fibromyalgia: a randomised controlled trial.

INTRODUCTION: Approximately 50% of individuals with fibromyalgia (a chronic widespread pain condition) have comorbid insomnia. Treatment for these comorbid cases typically target pain, but growing research supports direct interventions for insomnia (eg, cognitive behavioural treatment for insomnia (CBT-I)) in these patients. Previous research suggests sustained hyperarousal mediated by a neural central sensitisation mechanism may underlie insomnia and chronic pain symptoms in fibromyalgia. We hypothesise CBT-I will improve insomnia symptoms, improve clinical pain and reduce central sensitisation. The trial will be the first to evaluate the short-term and long-term neural mechanisms underlying insomnia and pain improvements in fibromyalgia. Knowledge obtained from this trial might allow us to develop new or modify current treatments to better target pain mechanisms, perhaps reversing chronic pain or preventing it. METHODS AND ANALYSIS: Female participants (n=130) 18 years of age and older with comorbid fibromyalgia (with pain severity of at least 50/100) and insomnia will be recruited from the University of Missouri in Columbia, Missouri, and surrounding areas. Participants will be randomised to 8 weeks (plus 4 bimonthly booster sessions) of CBT-I or a sleep hygiene control group (SH). Participants will be assessed at baseline, post-treatment, 6 and 12 months follow-ups. The following assessments will be completed: 2 weeks of daily diaries measuring sleep and pain, daily actigraphy, insomnia severity index, pain-related disability, single night of polysomnography recording, arousal (heart rate variability, cognitive affective arousal), structural and functional MRI to examine pain-related neural activity and plasticity and mood (depression, anxiety). ETHICS AND DISSEMINATION: Ethics approval was obtained in July 2018 from the University of Missouri. All data are expected to be collected by 2022. Full trial results are planned to be published by 2024. Secondary analyses of baseline data will be subsequently published. TRIAL REGISTRATION NUMBER: NCT03744156.

Gray Matter Changes Following Cognitive Behavioral Therapy for Patients With Comorbid Fibromyalgia and Insomnia: A Pilot Study.

STUDY OBJECTIVES: Insomnia frequently co-occurs with fibromyalgia, which is associated with gray matter atrophy. We examined the effect of cognitive behavioral therapy for insomnia (CBT-I) and pain (CBT-P) on cortical thickness. METHODS: Patients with fibromyalgia and insomnia underwent MRI before and after random assignment to CBT-I (n = 14), CBT-P (n = 16), or waitlist control (WLC; n = 7). RESULTS: Repeated-measures analyses of variance revealed significant interactions for two regions (left lateral orbitofrontal cortex, left rostral middle frontal, Ps < .05) and trends for four regions (right medial orbitofrontal cortex, right posterior cingulate, left caudal middle frontal, left transverse temporal; Ps < .10). Cortical thickness increased in all regions for CBT-I and decreased in five regions for CBT-P and WLC. Hierarchical regressions revealed that for the CBT-I group, reductions in wake after sleep onset were associated with an increase in cortical thickness. CONCLUSIONS: Our pilot study presents novel evidence suggesting that CBT-I may slow or reverse cortical gray matter atrophy in patients with fibromyalgia and insomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Identifier: NCT02001077, Title: Sleep and Pain Interventions in Fibromyalgia (SPIN), URL: https://clinicaltrials.gov/ct2/show/NCT02001077.

Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study.

PURPOSE: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial. METHODS: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT). RESULTS: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC. CONCLUSIONS: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC.

Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems.

Alcohol use disorder (AUD) is highly comorbid with chronic pain (CP). Evidence has suggested that neuroadaptive processes characterized by reward deficit and stress surfeit are involved in the development of AUD and pain chronification. Neurological data suggest that shared genetic architecture associated with the reward and stress systems may contribute to the comorbidity of AUD and CP. This monograph first delineates the prevailing theories of the development of AUD and pain chronification focusing on the reward and stress systems. It then provides a brief summary of relevant neurological findings followed by an evaluation of evidence documented by molecular genetic studies. Candidate gene association studies have provided some initial support for the genetic overlap between AUD and CP; however, these results must be interpreted with caution until studies with sufficient statistical power are conducted and replications obtained. Genomewide association studies have suggested a number of genes (e.g., TBX19, HTR7, and ADRA1A) that are either directly or indirectly related to the reward and stress systems in the AUD and CP literature. Evidence reviewed in this monograph suggests that shared genetic liability underlying the comorbidity between AUD and CP, if present, is likely to be complex. As the advancement in molecular genetic methods continues, future studies may show broader central nervous system involvement in AUD-CP comorbidity.

Low-to-Moderate Alcohol Consumption is Associated With Hippocampal Volume in Fibromyalgia and Insomnia.

Fibromyalgia and chronic insomnia are frequently comorbid conditions with heightened sensitivity to painful stimuli, potentially subserved by the hippocampus. Recent evidence suggests moderate alcohol consumption is associated with reduced fibromyalgia symptom severity. We examined the relationship among alcohol use, hippocampal morphology, fibromyalgia, and insomnia symptom severity in 41 fibromyalgia patients (19 with insomnia). A 14-day diary of sleep, pain, and alcohol consumption was followed by structural MRI. Analyses indicated greater bilateral hippocampal volume, lower clinical pain intensity, and better sleep quality in moderate drinkers versus abstainers. Underlying mechanisms may include gamma-amino butyric acid (GABA) receptor agonism, n-methyl d-aspartate (NMDA) receptor antagonism, and psychosocial factors. Further study of the relationship between alcohol use and fibromyalgia and insomnia symptom severity is warranted.

Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses.

Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue.

Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by severe fatigue and neurocognitive dysfunction. Recent work from our laboratory and others utilizing arterial spin labeling functional magnetic resonance imaging (ASL) indicated that ME/CFS patients have lower resting state regional cerebral blood flow (rCBF) in several brain areas associated with memory, cognitive, affective, and motor function. This hypoperfusion may underlie ME/CFS pathogenesis and may result in alterations of functional relationships between brain regions. The current report used ASL to compare functional connectivity of regions implicated in ME/CFS between patients and healthy controls (HC). METHODS: Participants were 17 ME/CFS patients (Mage=48.88years, SD=12) fulfilling the 1994 CDC criteria and 17 age/sex matched HC (Mage=49.82years, SD=11.32). All participants underwent T1-weighted structural MRI as well as a 6-min pseudo-continuous arterial spin labeling (pCASL) sequence, which quantifies CBF by magnetically labeling blood as it enters the brain. Imaging data were preprocessed using SPM 12 and ASL tbx, and seed-to-voxel functional connectivity analysis was conducted using the CONN toolbox. All effects noted below are significant at p<0.05 with cluster-wise FDR correction for multiple comparisons. RESULTS: ME/CFS patients demonstrated greater functional connectivity relative to HC in bilateral superior frontal gyrus, ACC, precuneus, and right angular gyrus to regions including precuneus, right postcentral gyrus, supplementary motor area, posterior cingulate gyrus, and thalamus. In contrast, HC patients had greater functional connectivity than ME/CFS in ACC, left parahippocampal gyrus, and bilateral pallidum to regions including right insula, right precentral gyrus, and hippocampus. Connectivity of the left parahippocampal gyrus correlated strongly with overall clinical fatigue of ME/CFS patients. CONCLUSION: This is the first ASL based connectivity analysis of patients with ME/CFS. Our results demonstrate altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS patients. Connectivity to memory related brain areas (parahippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

Sleep is associated with task-negative brain activity in fibromyalgia participants with comorbid chronic insomnia.

Patients with chronic pain exhibit altered default mode network (DMN) activity. This preliminary project questioned whether comorbid disease states are associated with further brain alterations. Thirteen women with fibromyalgia (FM) only and 26 women with fibromyalgia with comorbid chronic insomnia (FMI) underwent a single night of ambulatory polysomnography and completed a sleep diary each morning for 14 days prior to performing a neuroimaging protocol. Novel imaging analyses were utilized to identify regions associated with significantly disordered sleep that were more active in task-negative periods than task-oriented periods in participants with FMI, when compared to participants with FM. It was hypothesized that core DMN areas (ie, cingulate cortex, inferior parietal lobule, medial prefrontal cortex, medial temporal cortex, precuneus) would exhibit increased activity during task-negative periods. Analyses revealed that significantly disordered sleep significantly contributed to group differences in the right cingulate gyrus, left lentiform nucleus, left anterior cingulate, left superior gyrus, medial frontal gyrus, right caudate, and the left inferior parietal lobules. Results suggest that FMI may alter some brain areas of the DMN, above and beyond FM. However, future work will need to investigate these results further by controlling for chronic insomnia only before conclusions can be made regarding the effect of FMI comorbidity on the DMN.

Placebo analgesia enhances descending pain-related effective connectivity: a dynamic causal modeling study of endogenous pain modulation.

UNLABELLED: The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia remains incomplete. This study used functional magnetic resonance imaging data from 30 healthy individuals and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, participants were conditioned to expect less thermal pain at 2 of 4 sites on their feet. Visual analog scale pain ratings revealed a significant but small difference between the baseline and placebo sites (mean difference = 6.63, t(29) = 3.91, P ≤ .001, d = .97), confirming an analgesic effect. However, no significant differences in the magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. Dynamic causal modeling was then used to investigate changes in effective connectivity during placebo analgesia. The results indicate that during placebo analgesia but not baseline condition, couplings between brain regions, including those involved in cognitive processes (eg, attention, expectation, evaluation), were significantly enhanced. Specifically, a significantly consistent decrease in the dorsolateral prefrontal cortex → periaqueductal gray coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions than only via changes in the magnitude of blood oxygenation level dependent activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as dynamic causal modeling are necessary to better understand the neural mechanisms underlying pain processing in patient populations. PERSPECTIVE: Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than are changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation.

Effective connectivity predicts future placebo analgesic response: A dynamic causal modeling study of pain processing in healthy controls.

A better understanding of the neural mechanisms underlying pain processing and analgesia may aid in the development and personalization of effective treatments for chronic pain. Clarification of the neural predictors of individual variability in placebo analgesia (PA) could aid in this process. The present study examined whether the strength of effective connectivity (EC) among pain-related brain regions could predict future placebo analgesic response in healthy individuals. In Visit 1, fMRI data were collected from 24 healthy subjects (13 females, mean age=22.56, SD=2.94) while experiencing painful thermal stimuli. During Visit 2, subjects were conditioned to expect less pain via a surreptitiously lowered temperature applied at two of the four sites on their feet. They were subsequently scanned again using the Visit 1 (painful) temperature. Subjects used an electronic VAS to rate their pain following each stimulus. Differences in ratings at conditioned and unconditioned sites were used to measure placebo response (PA scores). Dynamic causal modeling was used to estimate the EC among a set of brain regions related to pain processing at Visit 1 (periaqueductal gray, thalamus, rostral anterior cingulate cortex, dorsolateral prefrontal cortex). Individual PA scores from Visit 2 were regressed on salient EC parameter estimates from Visit 1. Results indicate that both greater left hemisphere modulatory DLPFC➔PAG connectivity and right hemisphere, endogenous thalamus➔DLPFC connectivity were significantly predictive of future placebo response (R(2)=0.82). To our knowledge, this is the first study to identify the value of EC in understanding individual differences in PA, and may suggest the potential modifiability of endogenous pain modulation.

Comparison of machine classification algorithms for fibromyalgia: neuroimages versus self-report.

UNLABELLED: Recent studies have posited that machine learning (ML) techniques accurately classify individuals with and without pain solely based on neuroimaging data. These studies claim that self-report is unreliable, making "objective" neuroimaging classification methods imperative. However, the relative performance of ML on neuroimaging and self-report data have not been compared. This study used commonly reported ML algorithms to measure differences between "objective" neuroimaging data and "subjective" self-report (ie, mood and pain intensity) in their ability to discriminate between individuals with and without chronic pain. Structural magnetic resonance imaging data from 26 individuals (14 individuals with fibromyalgia and 12 healthy controls) were processed to derive volumes from 56 brain regions per person. Self-report data included visual analog scale ratings for pain intensity and mood (ie, anger, anxiety, depression, frustration, and fear). Separate models representing brain volumes, mood ratings, and pain intensity ratings were estimated across several ML algorithms. Classification accuracy of brain volumes ranged from 53 to 76%, whereas mood and pain intensity ratings ranged from 79 to 96% and 83 to 96%, respectively. Overall, models derived from self-report data outperformed neuroimaging models by an average of 22%. Although neuroimaging clearly provides useful insights for understanding neural mechanisms underlying pain processing, self-report is reliable and accurate and continues to be clinically vital. PERSPECTIVE: The present study compares neuroimaging, self-reported mood, and self-reported pain intensity data in their ability to classify individuals with and without fibromyalgia using ML algorithms. Overall, models derived from self-reported mood and pain intensity data outperformed structural neuroimaging models.

Fibromyalgia patients have reduced hippocampal volume compared with healthy controls.

OBJECTIVE: Fibromyalgia patients frequently report cognitive abnormalities. As the hippocampus plays an important role in learning and memory, we determined whether individuals with fibromyalgia had smaller hippocampal volume compared with healthy control participants. METHODS: T1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 40 female participants with fibromyalgia and 22 female healthy controls. The volume of the hippocampus was estimated using the software FreeSurfer. An analysis of covariance model controlling for potentially confounding factors of age, whole brain size, MRI signal quality, and Beck Depression Inventory scores were used to determine significant group differences. RESULTS: Fibromyalgia participants had significantly smaller hippocampi in both left (F[1,56]=4.55, P=0.037, η (2) p=0.08) and right hemispheres (F[1,56]=5.89, P=0.019, η (2) p=0.10). No significant effect of depression was observed in either left or right hemisphere hippocampal volume (P=0.813 and P=0.811, respectively). DISCUSSION: Potential mechanisms for reduced hippocampal volume in fibromyalgia include abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction; these factors can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus. Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients.

Test-retest reliability of pain-related brain activity in healthy controls undergoing experimental thermal pain.

UNLABELLED: Although functional magnetic resonance imaging (fMRI) has been proposed as a method to elucidate pain-related biomarkers, little information exists related to psychometric properties of fMRI findings. This knowledge is essential for potential translation of this technology to clinical settings. The purpose of this study was to assess the test-retest reliability of pain-related brain activity and how it compares to the reliability of self-report. Twenty-two healthy controls (mean age = 22.6 years, standard deviation = 2.9) underwent 3 runs of an fMRI paradigm that used thermal stimuli to elicit experimental pain. Functional MRI summary statistics related to brain activity during thermal stimulation periods were extracted from bilateral anterior cingulate cortices and anterior insula. Intraclass correlations (ICCs) were conducted on these summary statistics and generally showed "good" test-retest reliability in all regions of interest (ICC range = .32-.88; mean = .71); however, these results did not surpass ICC values from pain ratings, which fell within the "excellent" range (ICC range = .93-.96; mean = .94). Findings suggest that fMRI is a valuable tool for measuring pain mechanisms but did not show an adequate level of test-retest reliability for fMRI to potentially act as a surrogate for individuals' self-report of pain. PERSPECTIVE: This study is one of the first reports to demonstrate the test-retest reliability of fMRI findings related to pain processing and provides a comparison to the reliability of subjective reports of pain. This information is essential for determining whether fMRI technology should be potentially translated for clinical use.

Enhancing the placebo response: functional magnetic resonance imaging evidence of memory and semantic processing in placebo analgesia.

UNLABELLED: Two groups of patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension (20 seconds, 7 stimuli). Group 1 was tested under baseline (natural history [NH]) and a verbally induced placebo condition, whereas Group 2 was tested under baseline and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group 2. Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects. PERSPECTIVE: Expectations for pain can be verbally manipulated to produce placebo analgesia. Placebo analgesia is accompanied by decreased brain activity related to processing pain and increased brain activity that generates placebo analgesia, including semantic and memory regions. Placebo suggestions may enhance placebo analgesia by engaging a feedback mechanism triggered by the painful stimulus itself and related to brain mechanisms involved in memory and semantic processing.

Functional connectivity of the default mode network and its association with pain networks in irritable bowel patients assessed via lidocaine treatment.

UNLABELLED: The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the DMN's internal connectivity and its temporal relationship (ie, functional network connectivity) with pain-related neural networks in chronic pain conditions is poorly understood, as is the DMN's sensitivity to analgesic effects. The current study assessed how DMN functional connectivity and its temporal association with 3 pain-related networks changed after rectal lidocaine treatment in irritable bowel syndrome patients. Eleven females with irritable bowel syndrome underwent a rectal balloon distension paradigm during functional magnetic resonance imaging in 2 conditions: natural history (ie, baseline) and lidocaine. Results showed increased DMN connectivity with pain-related regions during natural history and increased within-network connectivity of DMN structures under lidocaine. Further, there was a significantly greater lag time between 2 of the pain networks, those involved in cognitive and in affective pain processes, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects, and 2) reduced pain ratings via analgesia reflect DMN connectivity more similar to pain-free individuals. Findings show potential implications of this network as an approach for understanding clinical pain management techniques. PERSPECTIVE: This study shows that lidocaine, a peripheral analgesic, significantly altered DMN connectivity and affected its relationship with pain-related networks. These findings suggest that the DMN, which is hypothesized to represent non-goal-oriented activity, is sensitive to analgesic effects and could be useful to understand pain treatment mechanisms.

Effective connectivity among brain regions associated with slow temporal summation of C-fiber-evoked pain in fibromyalgia patients and healthy controls.

UNLABELLED: Temporal summation of "second pain" (TSSP) or "windup" results from the summation of C-fiber-evoked responses of dorsal-horn neurons. This phenomenon is dependent on stimulus frequency (≥.33 Hz) and relevant to central sensitization and chronic pain. Our previous neuroimaging studies characterized brain regions associated with TSSP in normal control (NC) and fibromyalgia (FM) groups. During an fMRI scan, subjects received sensitivity-adjusted repetitive heat pulses at .33 on the right foot. FM subjects required significantly lower stimulus intensities than NC to achieve similar TSSP and no significant group differences in the pain-related brain activity were detected. In our current study, we asked whether the effective connectivity among a set of TSSP-related brain regions identified in our previous work differs amongst FM and NC groups. Structural equation modeling was used to characterize the effective connectivity amongst a priori selected brain areas, including the thalamus, S1, S2, posterior insula, and the anterior midcingulate cortex (aMCC) within the left and right hemispheres. This analysis confirmed our a priori models of effective connectivity among these regions mainly confirmed those hypothesized, yet some unpredicted connections were additionally identified (thalamus to aMCC and aMCC to S1). While the models of effective connectivity were not identical in the FM and NC groups, they were very similar. Additionally, the TSSP related effective connectivity of right and left hemisphere regions was very similar. These results provide evidence for significant overlap of the fundamental brain mechanisms that process sensory and affective information related to TSSP in NC and FM groups. PERSPECTIVE: Models of effective connectivity involving pain-related processes were estimated with fMRI data from chronic pain and healthy populations. Models were estimated in both hemispheres, and although similar, fibromyalgia was associated with unique models of pain-related processes. Group differences involved the left hemisphere and S1, S2, and posterior insula.

Psychometric properties of the community integration questionnaire in a heterogeneous sample of adults with physical disability.

OBJECTIVE: To investigate the psychometric properties of the Community Integration Questionnaire (CIQ) in a mixed sample of adults with physical disabilities. DESIGN: Cross-sectional, survey study. SETTING: Academic and community medical clinics, national registry, and self-referral. PARTICIPANTS: Community-dwelling adults with spinal cord injury (n=146), multiple sclerosis (n=174), limb loss (n=158), or muscular dystrophy (n=273). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CIQ, General Health item from the Medical Outcomes Study 36-Item Short-Form Health Survey, and Mental Health Scale from the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: Based on the original scoring procedures, the CIQ Total scale and Home Integration subscale demonstrated acceptable internal consistency; however, reliability indices for the Social Integration and Productive Activities subscales were suboptimal. The exploratory factor analysis yielded a 4-factor solution (accounting for approximately 63% of the variance) that did not replicate the original factor structure of the CIQ. The results of the confirmatory factor analyses indicated that a modified 3-factor solution provided the best fit to the data from our samples. Using a revised scoring system based on these findings, the CIQ demonstrated improved reliability relative to the original scoring and good concurrent validity. CONCLUSIONS: The results provide general support for the validity of the CIQ as a measure of participation in adults with physical disabilities. However, our results indicate that some small modifications to the original scoring system are needed to optimize its use in this patient group. Additional research is needed to refine the measurement of participation in these and other populations.

Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome.

UNLABELLED: Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain disorder that is very prevalent in the general population (approximately 5%). Accumulating evidence suggests that FM is associated with central pain processing abnormalities, ie, central sensitization. Several previous studies of chronic pain patients, including FM, have shown gray matter atrophy of brain areas associated with sensory and affective pain processing. These findings, however, have not been confirmed in all FM studies. In this study, we investigated gray matter volumes of brain areas associated with pain-related areas of FM patients identified by functional brain imaging. Using voxel-based morphometric (VBM) analysis of magnetic resonance brain images, we compared 19 pain-related brain areas of 14 female FM patients and 11 healthy controls (NC). We found that FM patients had significantly less gray matter volumes than NC in 3 of these brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Importantly, FM patients demonstrated neither global gray matter atrophy nor gray matter changes associated with depression, as shown in some studies. Using a more stringent analysis than other VBM studies, we provide evidence for decreased gray matter volumes in a number of pain-related brain areas in FM. Although the mechanisms for these gray matter changes are presently unclear, they may contribute to some of the core features of this chronic disorder including affective disturbances and chronic widespread pain. PERSPECTIVE: Increasing evidence supports the association of chronic pain with accelerated gray matter atrophy in pain disorders like low back pain, IBS, and FM syndrome. However, cause-effect relationships between chronic pain and decreased gray matter volumes have not been established yet and will require future prospective studies.