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Objective Acupuncture is a complex multicomponent treatment that has shown promise in the treatment of fibromyalgia (FM). However, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. The present study was undertaken to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved. Methods Seventy-six patients with FM were randomized to receive either electroacupuncture (EA), with somatosensory afference, or mock laser acupuncture (ML), with no somatosensory afference, twice a week over 8 treatments. Patients with FM in each treatment group were assessed for pain severity levels, measured using Brief Pain Inventory (BPI) scores, and for levels of functional brain network connectivity, assessed using resting state functional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy in the right anterior insula, before and after treatment. Results Fibromyalgia patients who received EA therapy experienced a greater reduction in pain severity, as measured by the BPI, compared to patients who received ML therapy (mean difference in BPI from pre- to posttreatment was -1.14 in the EA group versus -0.46 in the ML group; P for group × time interaction = 0.036). Participants receiving EA treatment, as compared to ML treatment, also exhibited resting functional connectivity between the primary somatosensory cortical representation of the leg (S1leg ; i.e. primary somatosensory subregion activated by EA) and the anterior insula. Increased S1leg -anterior insula connectivity was associated with both reduced levels of pain severity as measured by the BPI (r = -0.44, P = 0.01) and increased levels of γ-aminobutyric acid (GABA+) in the anterior insula (r = 0.48, P = 0.046) following EA therapy. Moreover, increased levels of GABA+ in the anterior insula were associated with reduced levels of pain severity as measured by the BPI (r = -0.59, P = 0.01). Finally, post-EA treatment changes in levels of GABA+ in the anterior insula mediated the relationship between changes in S1leg -anterior insula connectivity and pain severity on the BPI (bootstrap confidence interval -0.533, -0.037). Conclusion The somatosensory component of acupuncture modulates primary somatosensory functional connectivity associated with insular neurochemistry to reduce pain severity in FM.

Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy ((1)H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting fMRI connectivity and (1)H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (p=0.03), with greater choline levels linked with worse pain interference (r=0.41, p=0.01). In addition, reduced resting functional connectivity between anterior insula and putamen was associated with both pain interference (whole brain analysis, p(corrected)

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

BACKGROUND: Despite its designation as a ‘dissociative anaesthetic,’ the dissociative and psychoactive effects of ketamine remain incompletely understood. The goal of this study was to characterise the subjective experiences and accompanying EEG changes with subanaesthetic doses of ketamine. METHODS: High-density EEG was recorded in 15 human volunteers before, during, and after subanaesthetic ketamine infusion (0.5 mg kg(−1) over 40 min), with self-reported measures of altered states of consciousness obtained after ketamine exposure. Sensor- and source-level EEG changes were analysed with a focus on spectral power and regional changes. RESULTS: Ketamine-induced altered states were characterised predominantly by dissociative experiences such as disembodiment and ego transcendence; sensory disturbances were also common. Ketamine broadly decreased low-frequency power, with mean reductions largest at alpha (8–12 Hz) in parietal (−0.94 dB, P

Objective Moderate alcohol consumption has been associated with improved health outcomes including reduced risk of heart disease; however, less is known regarding alcohol's effects on chronic pain. The aim of this study was to assess associations between pain, fibromyalgia symptoms, and moderate alcohol use in a large chronic pain sample. Methods A total of 2,583 new chronic pain patients presenting at a university pain clinic reported alcohol use and completed validated measures; 592 (23%) patients reported drinking, with 502 (85%) classified as moderate drinkers (females ≤7 and males ≤14 drinks/wk). General linear models (GLM) assessed the effects of moderate drinking on pain and symptom outcomes. The sample was stratified by gender and fibromyalgia (FM) status in secondary analyses. Results Moderate alcohol users reported significantly lower FM symptoms (widespread pain and symptom severity), pain severity, interference, anxiety, depression, and catastrophizing, and they reported higher physical function. Similar findings were observed in gender-stratified analysis, minus associations with FM symptom severity in females and anxiety in males. In patients meeting FM criteria, moderate drinking was associated with lower pain severity, interference, and depression, and higher physical function. Results in non-FM patients were similar to the total sample. Conclusions Moderate alcohol consumption in chronic pain patients was associated with decreased pain severity and interference, fewer painful body areas, lower somatic and mood symptoms, and increased physical function. A similar effect was observed in non-FM patients, but to a lesser extent in FM patients, suggesting chronic pain patients with less centralized forms of pain may benefit most from moderate alcohol consumption.

Kevin Boehnke and Richard E. Harris introduced a course in meditation, yoga and mindfulness to the neuroscience programme at their institution. Kevin Boehnke and Richard E. Harris introduced a course in meditation, yoga and mindfulness to the neuroscience programme at their institution.

Fibromyalgia (FM) is a chronic widespread pain condition characterized by augmented multi-modal sensory sensitivity. Although the mechanisms underlying this sensitivity are thought to involve an imbalance in excitatory and inhibitory activity throughout the brain, the underlying neural network properties associated with hypersensitivity to pain stimuli are largely unknown. In network science, explosive synchronization (ES) was introduced as a mechanism of hypersensitivity in diverse biological and physical systems that display explosive and global propagations with small perturbations. We hypothesized that ES may also be a mechanism of the hypersensitivity in FM brains. To test this hypothesis, we analyzed resting state electroencephalogram (EEG) of 10 FM patients. First, we examined theoretically well-known ES conditions within functional brain networks reconstructed from EEG, then tested whether a brain network model with ES conditions identified in the EEG data is sensitive to an external perturbation. We demonstrate for the first time that the FM brain displays characteristics of ES conditions, and that these factors significantly correlate with chronic pain intensity. The simulation data support the conclusion that networks with ES conditions are more sensitive to perturbation compared to non-ES network. The model and empirical data analysis provide convergent evidence that ES may be a network mechanism of FM hypersensitivity.

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

Objectives Fatigue is a major burden among patients with RA, yet is poorly understood. We sought to conduct the first imaging study to investigate the neurobiological correlates of fatigue in RA and to improve upon the methodological limitations of previous neuroimaging studies that have investigated this symptom in other populations. Methods Chronically fatigued RA patients were clinically characterized before undertaking a combined functional and structural mode MRI brain scan. The functional sequences were acquired during a fatigue-evoking task, then network-to-whole-brain analyses were undertaken. The structural analyses employed voxel-based morphometry in order to quantify regional grey matter volume. The scan was repeated 6 months later to test reproducibility. Results Fifty-four participants attended both scans [n = 41 female; baseline mean (s.d.) age 54.94 (11.41) years]. A number of significant functional and structural neural imaging correlates of fatigue were identified. Notably, patients who reported higher levels of fatigue demonstrated higher levels of functional connectivity between the Dorsal Attention Network and medial prefrontal gyri, a finding that was reproduced in the repeat scans. Structurally, greater putamen grey matter volumes significantly correlated with greater levels of fatigue. Conclusion Fatigue in RA is associated with functional and structural MRI changes in the brain. The newly identified and reproduced neural imaging correlates provide a basis for future targeting and stratification of this key patient priority.

Editor's Note: This column takes our series from the Society for Acupuncture Research (SAR) in a new direction. Recently, the U.S. government's Center for Medicare and Medicaid Services (CMS) issued a call for public comment related to the government's exploration of inclusion of acupuncture and licensed acupuncturists in federal payment schemes. The decision of SAR's research leaders to engage with policymakers is forward thinking, especially as much dialogue and many research needs related to acupuncture and other integrative health practices and practitioners are shifting toward implementation concerns. SAR's engagement in this arena is also reflected in the organization's 2019 conference June 27–29, 2019 in Burlington, Vermont: “Acupuncture Research, Health Care Policy, & Community Health…Closing the Loop.” The author team includes the entire SAR Board, led by president-elect Jun J. Mao, MD, and current copresidents Robert T. Davis, MS, LAc, and Richard Harris, PhD. This is also a moment to congratulate Harris on his selection to the U.S. National Institutes of Health National Advisory Council on Complementary and Integrative Health.—John Weeks, Editor-in-Chief

Supplemental Digital Content is Available in the Text. Hub topology is altered in fibromyalgia, and disruption of the excitatory tone within the insula influences hub status and is associated with clinical pain intensity., A critical component of brain network architecture is a robust hub structure, wherein hub regions facilitate efficient information integration by occupying highly connected and functionally central roles in the network. Across a wide range of neurological disorders, hub brain regions seem to be disrupted, and the character of this disruption can yield insights into the pathophysiology of these disorders. We applied a brain network–based approach to examine hub topology in fibromyalgia, a chronic pain condition with prominent central nervous system involvement. Resting state functional magnetic resonance imaging data from 40 fibromyalgia patients and 46 healthy volunteers, and a small validation cohort of 11 fibromyalgia patients, were analyzed using graph theoretical techniques to model connections between 264 brain regions. In fibromyalgia, the anterior insulae functioned as hubs and were members of the rich club, a highly interconnected nexus of hubs. In fibromyalgia, rich-club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory, and motor cortices belonged to the rich club only in patients with the highest pain intensity. Furthermore, the eigenvector centrality (a measure of how connected a region is to other highly connected regions) of the posterior insula positively correlated with clinical pain and mediated the relationship between glutamate + glutamine (assessed by proton magnetic resonance spectroscopy) within this structure and the patient's clinical pain report. Together, these findings reveal altered hub topology in fibromyalgia and demonstrate, for the first time to our knowledge, a neurochemical basis for altered hub strength and its relationship to the perception of pain.

Chronic pain is characterized by hyperalgesia and heightened temporal summation of pain, however, the brain mechanisms underlying these phenomena remain understudied. We sought to understand the relationship of hyperalgesia and temporal summation with the balance between basal excitatory and inhibitory neurotransmission (E-I balance) and brain functional connectivity during sustained pressure pain. Sixty-four females with Fibromyalgia (FM, age=43±11, M±SD) and 19 controls (age=42±16) were recruited for the study. Brain imaging included proton magnetic resonance spectroscopy (1H-MRS) to measure Glutamate+Glutamine (Glx) and gamma-Aminobutyric acid (GABA) in the right anterior insula (aINS), followed by individually calibrated 6-minute tonic pressure pain (PAIN) over the left leg (40/100 pain). Pain ratings were obtained for initial, middle, and final 2-minutes of PAIN. Temporal Summation Index (TSI) was calculated as ((Final/Initial Rating)/mmHg) x 100. aINS E-I balance was calculated as Glx/GABA ratio. Functional connectivity amplification of the primary somatosensory cortical representation of the leg (S1leg) was calculated as the contrast between the final 2 minutes of PAIN versus the initial 2 minutes of PAIN (final-initial). FM patients required lower pressure (p=0.0002) but reported higher TSI (p=0.0031) relative to controls. In FM, TSI was associated with clinical pain (r=0.47). During PAIN, FM showed amplified S1leg-aINS connectivity, and this amplification was associated with clinical pain (r=0.44), TSI (r=0.34), and cuff pressure (r=-0.37). aINS E-I balance was also associated with cuff pressure (r=-0.34) and S1leg-aINS connectivity (r=0.29) in FM. Mediation analysis showed that the effect of aINS E-I balance on clinical pain was serially mediated by cuff pressure and amplification of S1leg-aINS connectivity (indirect effect, β=0.053, BootSE=0.027, BootCI=[0.005, 0.114]). Mechanistically, in chronic pain, greater basal aINS excitability (E-I balance) necessitates lower pressure to achieve target experimental pain, resulting in greater amplification of S1leg and aINS communication during tonic experimental pain. This project was supported by R01AT007550 (NIH-NCCIH) awarded to R. E. Harris and V. Napadow and F99DK126121 (NIH-NIDDK) training grant awarded to I. Mawla.

Purpose Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25–70% of SLE patients. Using diffusion tensor imaging, various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate if changes can be detected in the individual white matter tracts in SLE patients regardless if neuropsychiatric symptoms are present or not. Materials and Methods Magnetic resonance diffusion tractography in several individual white matter tracts that are involved in language and memory tasks, including tracts to cortical association areas, was applied in 21 patients with NPSLE (mean age: 40.7 ± 12.8 years; range: 22–67 years), 18 patients with non-neurologic systemic lupus erythematosus (non-NPSLE) (mean age: 40.6 ± 12 years; range: 22–67 years), and 20 healthy control (HC) individuals (mean age: 40.64 ± 12.7 years; range: 19–60 years). Additional patients were evaluated; however, because of the inability to complete the scans required, they were excluded from the study. The fractional anisotropy of individual fiber tracts was measured and correlated with cognitive function and lupus disease severity index (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]) to assess predictability and diagnostic value of these measures for NPSLE. Results Analyses of variance of the tractography data from the analysis of 21 tracts revealed decreased fractional anisotropy in uncinate fasciculus in the NPSLE patients when compared to non-NPSLE lupus patients and HC individuals (P = 0.002). Non-NPSLE patients also demonstrated decreased fractional anisotropy when compared to healthy patients (P = 0.03). Decreased fractional anisotropy was also identified in the corpus callosum and corona radiata in NPSLE patients when compared to HC individuals; however, these tracts did not show a significant difference between NPSLE and non-NPSLE patients. Decreased fractional anisotropy in the uncinate fasciculus correlated with low SLEDAI score (R2 = 0.32). Conclusions Diffusion tensor tractography corroborates findings of decreased white matter integrity within the anterior corona radiate as well as the corpus callosum as previously described. Specifically, our study identified changes in the uncinate fasciculus in NPSLE and non-NPSLE patients that correlate with clinical changes (SLEDAI scores) and are independent of conventional T2 lesion burden. (Less)

Clinical phenotyping of urological chronic pelvic pain syndromes (UCPPSs) in men and women have focused on end organ abnormalities to identify putative clinical subtypes. Initial evidence of abnormal brain function and structure in male pelvic pain has necessitated large-scale, multisite investigations into potential UCPPS brain biomarkers. We present the first evidence of regional white matter (axonal) abnormalities in men and women with UCPPS, compared with positive (irritable bowel syndrome, IBS) and healthy controls. Epidemiological and neuroimaging data were collected from participants with UCPPS (n = 52), IBS (n = 39), and healthy sex- and age-matched controls (n = 61). White matter microstructure, measured as fractional anisotropy (FA), was examined by diffusion tensor imaging. Group differences in regional FA positively correlated with pain severity, including segments of the right corticospinal tract and right anterior thalamic radiation. Increased corticospinal FA was specific and sensitive to UCPPS, positively correlated with pain severity, and reflected sensory (not affective) features of pain. Reduced anterior thalamic radiation FA distinguished patients with IBS from those with UCPPS and controls, suggesting greater microstructural divergence from normal tract organization. Findings confirm that regional white matter abnormalities characterize UCPPS and can distinguish between visceral diagnoses, suggesting that regional axonal microstructure is either altered with ongoing pain or predisposes its development.

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Objective Pregabalin (PGB) is an α2δ calcium-channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down-regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation, and recent clinical findings support the notion that PGB modulates glutamatergic activity and functional brain connectivity in order to produce analgesia. The present study was undertaken to examine concurrent changes in brain gray matter volume (GMV) or evoked-pain connectivity in humans receiving PGB. Methods Sixteen female fibromyalgia patients participated in a randomized double-blind 2-period crossover study of PGB versus placebo. Before and after each period, patients underwent high-resolution structural and evoked pressure–pain functional brain imaging. GMV was analyzed using voxel-based morphometry, and functional connectivity during evoked pressure–pain was assessed. Results PGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following placebo treatment. GMV reductions in the medial frontal gyrus were also observed when comparing PGB versus placebo treatment, and were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network, which was also associated with reduced clinical pain. Conclusion Short-term PGB treatment altered brain structure and evoked-pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown whether these effects are generalizable to other chronic pain states.

Supplemental Digital Content is Available in the Text. Sensitivity to visual stimuli is increased in patients with fibromyalgia and improved with administration of pregabalin., Pain can be elicited through all mammalian sensory pathways yet cross-modal sensory integration, and its relationship to clinical pain, is largely unexplored. Centralized chronic pain conditions such as fibromyalgia are often associated with symptoms of multisensory hypersensitivity. In this study, female patients with fibromyalgia demonstrated cross-modal hypersensitivity to visual and pressure stimuli compared with age- and sex-matched healthy controls. Functional magnetic resonance imaging revealed that insular activity evoked by an aversive level of visual stimulation was associated with the intensity of fibromyalgia pain. Moreover, attenuation of this insular activity by the analgesic pregabalin was accompanied by concomitant reductions in clinical pain. A multivariate classification method using support vector machines (SVM) applied to visual-evoked brain activity distinguished patients with fibromyalgia from healthy controls with 82% accuracy. A separate SVM classification of treatment effects on visual-evoked activity reliably identified when patients were administered pregabalin as compared with placebo. Both SVM analyses identified significant weights within the insular cortex during aversive visual stimulation. These data suggest that abnormal integration of multisensory and pain pathways within the insula may represent a pathophysiological mechanism in some chronic pain conditions and that insular response to aversive visual stimulation may have utility as a marker for analgesic drug development.

There are an increasing number of neuroimaging studies that allow a better understanding of symptoms, neural correlates and associated conditions of fibromyalgia. However, the results of these studies are difficult to compare, as they include a heterogeneous group of patients, use different stimulation paradigms, tasks, and the statistical evaluation of neuroimaging data shows high variability. Therefore, this meta-analytic approach aimed at evaluating potential alterations in neuronal brain activity or structure related to pain processing in fibromyalgia syndrome (FMS) patients, using quantitative coordinate-based "activation likelihood estimation" (ALE) meta-analysis. 37 FMS papers met the inclusion criteria for an ALE analysis (1,264 subjects, 274 activation foci). A pooled ALE analysis of different modalities of neuroimaging and additional analyses according functional and structural changes indicated differences between FMS patients and controls in the insula, amygdala, anterior/mid cingulate cortex, superior temporal gyrus, the primary and secondary somatosensory cortex, and lingual gyrus. Our analysis showed consistent results across FMS studies with potential abnormalities especially in pain-related brain areas. Given that similar alterations have already been demonstrated in patients with other chronic pain conditions and the lack of adequate control groups of chronic pain subjects in most FMS studies, it is not clear however, whether these findings are associated with chronic pain in general or are unique features of patients with FMS. Hum Brain Mapp 37:1749-1758, 2016. © 2016 Wiley Periodicals, Inc.

Pain is a complex phenomenon that may involve both peripheral and central neurobiological processes. Nociception is the unconscious registration of a noxious stimulus by the nervous system, while pain is a conscious experience. Neurobiological correlates of pain perception have been characterized from the initial point of tissue damage to its realization in the brain. Importantly, various pharmacological and psychological interventions exist that can target various points along this pathway. Evidence shows the nervous system remodels in response to chronic pain. More evidence-based treatments showing efficacy for chronic pain conditions are needed. Finally, an individualized and multidisciplinary approach in concordance with the biopsychosocial model of illness is often advocated. The neuroanaesthetist requires a nuanced understanding of pain, since many patients presenting for neurosurgical procedures suffer chronic pain.

BackgroundCancer survivors with fatigue often experience depressive symptoms, anxiety, and pain. Previously, we reported that self-acupressure improved fatigue; however, its impact on other co-occurring symptoms and their involvement in treatment action has not been explored.MethodsChanges in depressive symptoms, anxiety, and pain were examined prior to and following two formulas of self-acupressure and usual care using linear mixed models in 288 women from a previously reported clinical trial. Participants were categorized by random assignment into one of three groups: 1) relaxing acupressure, 2) stimulating acupressure, or 3) usual care. Moderators investigated were body mass index, age, depressive symptoms, anxiety, sleep and pain, and mediators were change in these symptoms.ResultsFollowing treatment, depressive symptoms improved statistically significantly for the relaxing acupressure group (41.5%) compared with stimulating acupressure (25%) and usual care (7.7%). Both acupressure groups were associated with greater improvements in anxiety than usual care, but only relaxing acupressure was associated with greater reductions in pain severity, and only stimulating acupressure was associated with greater reductions in pain interference. There were no statistically significant moderators of sleep quality, anxiety, or depressive symptoms. Fatigue statistically significantly moderated pain, and age statistically significantly modified fatigue. Changes in depressive symptoms and sleep quality statistically significantly mediated the relationship between relaxing acupressure and usual care on fatigue; however, the effect was small.ConclusionsAcupressure was associated with greater improvements than usual care in anxiety, pain, and symptoms of depression in breast cancer survivors with troublesome fatigue. These findings warrant further evaluation in suitably controlled randomized trials.

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

Objectives: Oncology providers are often confronted by patients who use complementary or alternative therapies, but have limited knowledge or confidence on how to advise patients on appropriate use. Despite this, there are few opportunities for oncology providers to learn about complementary or alternative therapies, while at the same time there is a high demand for integrative oncology (IO) training. To address a gap in IO educational opportunities, and particularly for nonphysicians, we created the Integrative Oncology Scholars (IOS) Program. The program's goal is to train 100 IO leaders and facilitate partnerships between them and complementary practitioners. Design: Four iterations of a year-long National Cancer Institute-funded educational program that combines in-person team-based learning and eLearning to teach the evidence, application, and philosophy supporting IO. Settings: In-person sessions take place at the University of Michigan, and eLearning is implemented using a Canvas website (Instructure, Inc., Salt Lake City, UT). Subjects: Nurses, social workers, physician assistants, psychologists, physicians, pharmacists, and physical/occupational therapists with active oncology practices. Educational intervention: Four cohorts of 25 oncology providers per year will learn the evidence base for complementary and alternative approaches to a wide number of oncology topics, including symptom control, dietary supplements commonly used by cancer patients, diet, and the utility of specific integrative approaches for common oncology side-effects such as fatigue. Outcome measures: A mixed methods approach will be used to evaluate overall IOS Program progress and individual scholar's impact on IO research, education, and clinical endeavors. Results: The first cohort of 25 IOS has been recruited and their education will begin in Summer 2018. Scholars come from 13 states and represent 23 different healthcare systems. Conclusions: The IOS Program has the potential to increase the number of trained IO providers, educators, and researchers in the United States.

Detecting covert consciousness in behaviorally unresponsive patients by brain imaging is of great interest, but a reproducible model and evidence from independent sources is still lacking. Here we demonstrate the possibility of using general anesthetics in a within-subjects study design to test methods or statistical paradigms of assessing covert consciousness. Using noninvasive neuroimaging in healthy volunteers, we identified a healthy study participant who was able to exhibit the specific fMRI signatures of volitional mental imagery while behaviorally unresponsive due to sedation with propofol. Our findings reveal a novel model that may accelerate the development of new approaches to reproducibly detect covert consciousness, which is difficult to achieve in patients with heterogeneous and sometimes clinically unstable neuropathology.

Objective The physiological mechanisms behind the therapeutic effects of spinal cord stimulation (SCS) are only partially understood. Our aim was to perform a literature review of studies that used objective measures to characterize mechanisms of action of SCS in neuropathic pain patients. Materials and methods We searched the PubMed data base to identify clinical studies that used objective measures to assess the effects of SCS in neuropathic pain. We extracted the study factors (e.g., type of measure, diagnoses, painful area[s], and SCS parameters) and outcomes from the included studies. Results We included 67 studies. Of these, 24 studies used neurophysiological measures, 14 studies used functional neuroimaging techniques, three studies used a combination of neurophysiological and functional neuroimaging techniques, 14 studies used quantitative sensory testing, and 12 studies used proteomic, vascular, and/or pedometric measures. Our findings suggest that SCS largely inhibits somatosensory processing and/or spinal nociceptive activity. Our findings also suggest that SCS modulates activity across specific regions of the central nervous system that play a prominent role in the sensory and emotional functions of pain. Conclusions SCS appears to modulate pain via spinal and/or supraspinal mechanisms of action (e.g., pain gating, descending pain inhibition). However, to better understand the mechanisms of action of SCS, we believe that it is necessary to carry out systematic, controlled, and well-powered studies using objective patient measures. To optimize the clinical effectiveness of SCS for neuropathic pain, we also believe that it is necessary to develop and implement patient-specific approaches.

Background: Acupuncture has a long history of relieving many forms of pain. However, many of acupuncture's mechanisms are still unknown and/or misunderstood. Objective: This review looks a...

In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis. Perspective Similar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.

Research into acupuncture has had ripple effects beyond the field of acupuncture. This paper identifies five exemplars to illustrate that there is tangible evidence of the way insights gleaned from acupuncture research have informed biomedical research, practice, or policy. The first exemplar documents how early research into acupuncture analgesia has expanded into neuroimaging research, broadening physiologic understanding and treatment of chronic pain. The second describes how the acupuncture needle has become a tool to enhance biomedical knowledge of connective tissue. The third exemplar, which illustrates use of a modified acupuncture needle as a sham device, focuses on emergent understanding of placebo effects and, in turn, on insights into therapeutic encounters in treatments unrelated to acupuncture. The fourth exemplar documents that two medical devices now in widespread use were inspired by acupuncture: transcutaneous electrical nerve stimulators for pain control and antinausea wrist bands. The final exemplar describes how pragmatic clinical trial designs applied in acupuncture research have informed current general interest in comparative effectiveness research. In conclusion, these exemplars of unanticipated outcomes of acupuncture research comprise an additional rationale for continued support of basic and clinical research evaluating acupuncture and other under-researched therapies.

Sickle cell disease (SCD) is a hemoglobinopathy that affects more than 100,000 individuals in the United States. The disease is characterized by the presence of sickle hemoglobin and recurrent episodes of pain. Some individuals with SCD experience frequent hospitalizations and a high burden of pain. The role of central mechanisms in SCD pain has not been explored. Twenty-five adolescents and young adults with SCD underwent functional magnetic resonance imaging. Participants were stratified into groups with high pain or low pain based on the number of hospitalizations for pain in the preceding 12 months. Resting state functional connectivity was analyzed using seed-based and dual regression independent component analysis. Intrinsic brain connectivity was compared between the high pain and low pain groups, and association with fetal hemoglobin, a known modifier of SCD, was explored. Patients in the high pain group displayed an excess of pronociceptive connectivity such as between anterior cingulate and default mode network structures, such as the precuneus, whereas patients in the low pain group showed more connectivity to antinociceptive structures such as the perigenual and subgenual cingulate. Although a similar proportion of patients in both groups reported that they were on hydroxyurea, the fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to antinociceptive structures. These findings support the role of central mechanisms in SCD pain. Intrinsic brain connectivity should be explored as a complementary and objective outcome measure in SCD pain research. Perspective Altered connectivity patterns associated with high pain experience in patients with sickle cell disease suggest a possible role of central mechanisms in sickle cell pain. Resting state brain connectivity studies should be explored as an effective methodology to investigate pain in SCD.

© 2015 American Urological Association Education and Research, Inc. Purpose: Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network. Materials and Methods: We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood anddaily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence. Results: Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi. Conclusions: To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.

Chronic pain patients feel pain as a primarily somatosensory sensation, although it is well understood that clinical pain is much more than somatic and encompasses multiple affective and cognitive domains. Fibromyalgia (FM) is a prototypical functional pain syndrome characterized by multi-dimensional symptomatology. Symptoms include widespread pain, mood disturbance with significant pain catastrophizing, cognitive and physical fatigue, dysfunction of autonomic activity, and amplified sensitivity and temporal summation to experimental pain stimuli (1).Multiple neuroimaging studies have supported the theory that FM is primarily a multi-system disorder of central nervous system (e.g. brain) processing. However, the precise linkage between the circuitries processing somatic sensation with those underlying broader affective and cognitive domains remains unknown. Functional connectivity magnetic resonance imaging (fcMRI) is an adaptation of fMRI that may help assess brain circuitry supporting spontaneous clinical pain. While spontaneous clinical pain(2), and negative affect (3) components of FM have been linked to altered resting (or intrinsic)functional brain connectivity, previous studies have not systematically probed the primary somatosensory cortex (S1) – a potentially integral brain area for somatic symptomatology such as pain. In FM, decreased secondary somatosensory (S2) connectivity to primary motor cortex (3), and reduced connectivity between S2 and S1 (4) were also recently reported. Interestingly, S1 connectivity is also sensitive to sustained experimental pain stimulation in healthy adults (5), suggesting malleable state-like properties for S1 connectivity networks. This view is consistent with generalized reports that functional brain connectivity can reflect both state and trait processes (6). Such state processes may even underlie the hyperalgesia, allodynia, and temporal summation commonly noted in chronic pain patients, as region-specific changes in S1 connectivity may support maladaptive changes in central processing of somatosensory afference. Our current study investigated evoked-pain state induced alterations in S1 connectivity in chronic pain patients suffering from FM. We also explored how altered S1 connectivity is associated with clinically-relevant variables such as pain intensity and pain-related catastrophizing, key determinants of FM morbidity. Furthermore, we linked evoked deep-tissue pain modulated S1 connectivity with temporal summation of pain and core non-somatic aspects of FM pathophysiology including altered autonomic modulation. The latter investigation follows past studies that have noted autonomic dysfunction in FM patients (7), linking such dysfunction with clinically-relevant parameters (7, 8). We hypothesized that multi-system pathology, common to FM, is supported by altered functional S1 connectivity at rest and/or in response to evoked nociceptive stimuli highly relevant to FM patients – i.e. deep-tissue pain.

In the field of acupuncture research there is an implicit yet unexplored assumption that the evidence on manual and electrical stimulation techniques, derived from basic science studies, clinical trials, systematic reviews, and meta-analyses, is generally interchangeable. Such interchangeability would justify a bidirectional approach to acupuncture research, where basic science studies and clinical trials each inform the other. This article examines the validity of this fundamental assumption by critically reviewing the literature and comparing manual to electrical acupuncture in basic science studies, clinical trials, and meta-analyses. The evidence from this study does not support the assumption that these techniques are interchangeable. This article also identifies endemic methodologic limitations that have impaired progress in the field. For example, basic science studies have not matched the frequency and duration of manual needle stimulation to the frequency and duration of electrical stimulation. Further, most clinical trials purporting to compare the two types of stimulation have instead tested electroacupuncture as an adjunct to manual acupuncture. The current findings reveal fundamental gaps in the understanding of the mechanisms and relative effectiveness of manual versus electrical acupuncture. Finally, future research directions are suggested to better differentiate electrical from manual simulation, and implications for clinical practice are discussed.

Background: Persistent fatigue is a common and debilitating symptom in breast cancer survivors (BCS), yet treatments remain limited. The purpose of this study was to examine the effect of two types of self-administered acupressure on fatigue versus usual care in BCS. Methods: This was a 10-week randomized trial that enrolled adult female BCS (stage 0-III), who had completed cancer treatments at least 12 months previously and who reported persistent mild-moderate fatigue (≥ 4 on the Brief Fatigue Inventory [BFI]). BCS were randomized equally into relaxation acupressure (RA), stimulating acupressure (SA) or usual care (UC). The primary endpoint was change in BFI from baseline to week 6 when acupressure was stopped and at week 10 to assess carryover effects of acupressure. Secondary analyses were conducted on sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and 14-day sleep diaries; quality of life was assessed with the Long-Term Quality of Life in BCS (LTQL). Intent-to-treat analyses were conducted using linear mixed models. Results: 288 BCS were randomized (98 RA, 94 SA, and 96 UC). 228 BCS completed the 6-week visit and 223 the 10-week visit (71 RA, 69 SA, and 83 UC). There were no significant group differences on baseline sociodemographic, clinical characteristics, BFI, PSQI, sleep diary parameters, or LTQL. At week 6 the mean change in BFI from baseline was significantly lower in the RA and SA arms than UC (RA = -2.57 ± 1.5, SA = -1.98 ± 1.5, and UC = -1.07 ± 1.6; p < 0.001 for both RA and SA vs. UC), but there was no significant difference between acupressure arms (p = 0.29). At week 10 the mean change in BFI from baseline ± SD was maintained and continued to be lower in RA and SA arms than UC (RA = -2.27 ± 1.4, SA = -1.96 ± 1.5, and UC = -0.99 ± 1.5; p < 0.001 for both RA and SA vs. UC), but no significant difference between acupressure arms (p >0.99). At week 6 the mean change in PSQI from baseline mean ± SD for RA = -1.93 ± 3.3 was significantly different from UC = -0.46 ± 3.1 (p = 0.03) but not SA = -1.34 ± 3.2 (p = 0.96). At week10 there was no significant difference on the PSQI between arms (RA vs. UC, p = 0.40; SA vs. UC, p Conclusions: Both acupressure arms significantly reduced fatigue compared to UC, but only RA had a significant effect on improving sleep quality and quality of life in BCS. Improvements in fatigue, sleep, and quality of life continued to persist for 4 weeks after cessation of acupressure. Self-administered RA offers an inexpensive easy to learn method to manage fatigue, sleep quality and overall quality of life in BCS with persistent fatigue. Citation Format: Zick SM, Wyatt GK, Murphy SL, Arnedt JT, Sen A, Harris RE. Acupressure for persistent fatigue in breast cancer survivors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD4-06.

Chronic pain impacts approximately 100 million people in the United States with annual costs more than $635 billion [1]. Fibromyalgia (FM) is considered the prototypical central pain syndrome and emerging data suggests that there are central nervous system alterations in FM patients [2-4]. Despite the presence of multiple treatments for this condition, many FM patients still report significant unresolved pain and disability. A significant limitation to evaluating potential interventions for chronic pain syndromes, including FM, is the lack of an objective marker of pain. There has been significant interest in using neuroimaging methods to develop an objective test of pain such as proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS is able to measure brain metabolite levels including γ–aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter, Glx, a combined marker of glutamine and glutamate (the latter being the brain’s major excitatory neurotransmitter), and N-acetylaspartate (NAA), thought to be a measure of neuronal integrity. Our group has reported increased levels of Glx in FM subjects in the posterior insula which is responsible for the graded sensory processing of pain [5, 6]. Our group has also reported decreased levels of GABA in FM subjects in the anterior insula which is important in the emotional processing and affective aspects of pain [6, 7]. Lower NAA levels within the hippocampus has also been reported in the setting of FM [8]. One potential treatment for FM is transcranial direct current stimulation (tDCS). tDCS is a brain stimulating procedure that uses noninvasive weak direct current applied to the scalp. tDCS in FM, as well as other pain conditions, has been shown to modulate experimental and clinical pain measures. Specifically, tDCS has been shown to improve pain symptomatology in FM [9, 10]. Anodal stimulation from tDCS has been shown to increase cortical excitability which is postulated to mitigate pain symptoms through indirect effects on pain processing regions in the brain [9]. However, the mechanisms underlying tDCS efficacy in chronic pain are not well understood, and chronic pain trials using tDCS have not reported consistent results [11]. Our objective was to explore the underlying neurochemical action of tDCS in the FM brain using 1H-MRS.

Objective:\ud Many patients with rheumatoid arthritis (RA) report pain despite excellent control of inflammation with immunotherapies. Variable degrees of coexisting fibromyalgia (FM) may explain this disparity. FM has been characterized by aberrant brain functional connectivity, especially between the default mode network (DMN) and insula. We undertook this study to test the hypothesis that RA patients with the highest 2011 American College of Rheumatology FM survey criteria scores—a continuous measure of the degree of FM also known as “fibromyalgianess” (FMness)—would demonstrate functional connectivity abnormalities similar to those in FM.\ud \ud Methods:\ud RA patients underwent an 11‐minute functional connectivity magnetic resonance imaging (MRI) brain scan and a clinical evaluation which included a measure of FMness. Brain networks were isolated from functional connectivity MRI data. Individual patient network‐to–whole brain connectivity analyses were then conducted, followed by group‐level regression, which correlated the connectivity of each network with FMness. Results were significant on the cluster level with a family‐wise error (FWE) rate P value less than 0.05 derived from an uncorrected voxel‐level P value less than 0.001.\ud \ud Results:\ud A total of 54 patients participated (mean age 54.9 years, 75.9% women, mean FMness score 13.2 [range 1–29]). From the whole brain analyses, a single significant positive correlation between DMN connectivity to the left mid/posterior insula and FMness (r = 0.58, FWE‐corrected P = 0.001) was demonstrated.\ud \ud Conclusion:\ud RA patients who have increased levels of FMness appear to share neurobiologic features consistently observed in FM patients. This study is the first to provide neuroimaging evidence that RA is a mixed pain state, with many patients’ symptoms being related to the central nervous system rather than to classic inflammatory mechanisms.

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients. Perspective These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.

Objective Fibromyalgia is a chronic pain condition with few effective treatments. Many fibromyalgia patients seek acupuncture for analgesia; however, its efficacy is limited and not fully understood. This may be due to heterogeneous pathologies among participants in acupuncture clinical trials. We hypothesized that pressure pain tenderness would differentially classify treatment response to verum and sham acupuncture in fibromyalgia patients. Design Baseline pressure pain sensitivity at the thumbnail at baseline was used in linear mixed models as a modifier of differential treatment response to sham versus verum acupuncture. Similarly, needle-induced sensation was also analyzed to determine its differential effect of treatment on clinical pain. Methods and Patients A cohort of 114 fibromyalgia patients received baseline pressure pain testing and were randomized to either verum (N = 59) or sham (N = 55) acupuncture. Participants received treatments from once a week to three times a week, increasing in three-week blocks for a total of 18 treatments. Clinical pain was measured on a 101-point visual analog scale, and needle sensation was measured by questionnaire throughout the trial. Results Participants who had higher pain pressure thresholds had greater reduction in clinical pain following verum acupuncture while participants who had lower pain pressure thresholds showed better analgesic response to sham acupuncture. Moreover, patients with lower pressure pain thresholds had exacerbated clinical pain following verum acupuncture. Similar relationships were observed for sensitivity to acupuncture needling. Conclusions These findings suggest that acupuncture efficacy in fibromyalgia may be underestimated and a more personalized treatment for fibromyalgia may also be possible.

Background Diamond-Blackfan anemia (DBA), an inherited marrow failure syndrome, has severe hypoplastic anemia in infancy and association with aplastic anemia, MDS/leukemia, and other malignancies. Short stature is present in most patients. Isolated cases have demonstrated improved growth on growth hormone (GH) therapy. Procedures GH treatment data were obtained from 19 children with DBA (6 at our site and 13 from Genentech). Control data from 44 non-GH treated children were provided by Diamond Blackfan Anemia Registry. Annual growth velocity (GV) and height-for-age Z-scores (HAZ) were compared between groups and for up to 4y of GH treatment. Results Constructed DBA-specific male and female height-for-age charts for non-GH treated patients revealed short stature compared to CDC norms. GH-treated patients had significantly lower HAZ prior to treatment initiation compared to non-GH-treated controls. Among GH-treated patients, GV significantly improved in the first two years relative to pre-treatment. HAZ significantly improved in each of 4y of GH therapy compared to baseline. After 2y of therapy, HAZ for GH-treated patients were not significantly different from controls, demonstrating successful catch-up growth. Conclusions GH treatment in children with DBA improves both GV and HAZ during treatment sustained for up to 4y. Very short children with DBA can be treated successfully with GH to restore stature to levels comparable to less affected patients. DBA height charts are useful tools for assessing age-specific growth in this typically short population. Careful consideration of individualized benefit of GH therapy versus risk is important in view of long-term underlying ∼5% malignancy risk in DBA. Pediatr Blood Cancer 2015;62:402–408. © 2014 Wiley Periodicals, Inc.

Sickle cell disease (SCD) is a hemoglobinopathy affecting more than 100,000 individuals in the USA. Pain is the most common symptom experienced by patients with SCD. Understanding the central mechanisms underlying SCD pain is essential for developing future treatment strategies for these patients. Our recent studies in SCD using functional magnetic resonance imaging (fMRI) demonstrated the differential brain connectivity in pro- and anti-nociceptive structures in SCD patients with higher- and lower- frequency of hospitalization for pain. In the present study, we investigated whether regional brain grey matter (GM) volume is associated with the number of parent-reported pain crises over the past 12 months in SCD patients. Thirty-four subjects (mean age=11.1years; 62% females) were included in this voxel-based morphometry study. Each subject underwent a high-resolution T1 structural scan. Structural scans were segmented to GM, white matter, and cerebral spinal fluid, and were preprocessed using the DARTEL toolbox in SPM12. In SPM, a whole brain multiple regression analysis comparing GM volume and pain crises with age, gender, presence of silent infarct, and total intracranial brain volume as covariates with no interest was performed. We also performed a priori region of interest (ROI) analyses with 5mm radius spheres from 4 regions from our previous study: left and right precuneus, right primary somatosensory cortex and middle cingulate cortex. GM volumes were extracted and correlated with pain crises in SPSS. There was a negative correlation between perigenual anterior cingulate cortex GM volume and pain crises (r=-0.5622, PFWE=0.033). The ROI analysis identified a negative correlation between middle cingulate cortex GM volume and pain crises (r=-0.465, P=0.006). These brain structural alterations may be involved with the accentuated acute pain experience in SCD, and could be used as an objective parameter to facilitate clinical assessment of pain and therapeutic effect in a subset of these patients. (Darbari, J Pain, 2015)

Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response., Highlights • Resting brain connectivity predicts clinical pain response to milnacipran. • Different brain connectivity patterns predicted response to placebo treatment. • Personalized analgesic therapy may be facilitated by brain imaging.