Associations between pain catastrophizing and resting-state functional brain connectivity: Ethnic/race group differences in persons with chronic knee pain.

Chronic pain is a significant public health problem, and the prevalence and societal impact continues to worsen annually. Multiple cognitive and emotional factors are known to modulate pain, including pain catastrophizing, which contributes to pain facilitation and is associated with altered resting-state functional connectivity in pain-related cortical and subcortical circuitry. Pain and catastrophizing levels are reported to be higher in non-Hispanic black (NHB) compared with non-Hispanic White (NHW) individuals. The current study, a substudy of a larger ongoing observational cohort investigation, investigated the pathways by which ethnicity/race influences the relationship between pain catastrophizing, clinical pain, and resting-state functional connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), insula, and primary somatosensory cortex (S1). Participants included 136 (66 NHBs and 70 NHWs) community-dwelling adults with knee osteoarthritis. Participants completed the Coping Strategies Questionnaire-Revised Pain Catastrophizing subscale and Western Ontario and McMaster Universities Osteoarthritis Index. Magnetic resonance imaging data were obtained, and resting-state functional connectivity was analyzed. Relative to NHW, the NHB participants were younger, reported lower income, were less likely to be married, and self-reported greater clinical pain and pain catastrophizing (ps < 0.05). Ethnicity/race moderated the mediation effects of catastrophizing on the relationship between clinical pain and resting-state functional connectivity between the ACC, dlPFC, insula, and S1. These results indicate the NHB and NHW groups demonstrated different relationships between pain, catastrophizing, and functional connectivity. These results provide evidence for a potentially important role of ethnicity/race in the interrelationships among pain, catastrophizing, and resting-state functional connectivity.

Cerebral Perfusion and Sensory Testing Results Differ in Interstitial Cystitis/Bladder Pain Syndrome Patients with and without Fibromyalgia: A Site-Specific MAPP Network Study.

PURPOSE: Fibromyalgia is a common co-morbidity in patients with interstitial cystitis/bladder pain syndrome. Quantitative sensory testing measures and regional cerebral blood flow measures have been noted to differ from healthy controls in both subjects with fibromyalgia and those with interstitial cystitis when studied independently. The present study examined such measures in subjects with the diagnosis of interstitial cystitis both with and without the co-diagnosis of fibromyalgia to determine whether differences in these measures may be associated with co-morbidity. PATIENTS AND METHODS: Female subjects with the diagnosis of interstitial cystitis with (n = 15) and without (n = 19) the co-diagnosis of fibromyalgia as well as healthy control subjects (n = 41) underwent quantitative sensory testing. A subset of these patients (9 with and 9 without fibromyalgia) underwent brain perfusion studies using arterial spin labeled functional magnetic resonance imaging. An analysis was performed of absolute regional cerebral blood flow of regions-of-interest when experiencing a full bladder compared with an empty bladder. RESULTS: Subjects with both interstitial cystitis and fibromyalgia were more hypersensitive than those without fibromyalgia as well as healthy controls in most sensory measures except heat. Subjects with interstitial cystitis, but no fibromyalgia, differed from healthy controls only in toleration of the ischemic forearm task. Other co-morbidities were more common in those subjects with both interstitial cystitis and fibromyalgia. Bladder fullness was associated with significantly greater whole brain gray matter blood flow in subjects with interstitial cystitis and fibromyalgia when compared with that of subjects with interstitial cystitis without fibromyalgia. Examination of regional cerebral blood flow in individual regions-of-interest demonstrated statistically significant differences between the subjects with interstitial cystitis with and those without fibromyalgia bilaterally in the thalamus, amygdala and hippocampus, as well as the right prefrontal cortex and greater responsiveness to changes in bladder fullness in the insula. CONCLUSION: Quantitative sensory testing and brain perfusion data support that there are two phenotypes of interstitial cystitis patients, which can be differentiated by a co-diagnosis of fibromyalgia. This may affect responsiveness to treatment and suggest the utility of stratifying interstitial cystitis patients according to their co-morbidities.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

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.

Bladder Distension Increases Blood Flow in Pain Related Brain Structures in Subjects with Interstitial Cystitis.

PURPOSE: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis. MATERIALS AND METHODS: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition. RESULTS: Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis. CONCLUSIONS: Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral blood flow increases in the full bladder state in regions of interest typically associated with pain, emotion and/or motor control, indicating altered processing of bladder related sensations.

Unique Microstructural Changes in the Brain Associated with Urological Chronic Pelvic Pain Syndrome (UCPPS) Revealed by Diffusion Tensor MRI, Super-Resolution Track Density Imaging, and Statistical Parameter Mapping: A MAPP Network Neuroimaging Study.

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome.

PURPOSE: Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants. MATERIALS AND METHODS: We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States. RESULTS: Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS). CONCLUSIONS: These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.

Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome.

PURPOSE: The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance in the processing of pain and viscerosensory signals. We identified differences in brain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands. RESULTS: Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest in patients who reported pain during bladder filling. CONCLUSIONS: Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations and connectivity in a cortico-cerebellar network previously associated with bladder function.

Lessons from fibromyalgia: abnormal pain sensitivity in knee osteoarthritis.

Fibromyalgia (FM) is a disorder that is characterized by widespread, musculoskeletal pain and abnormal pain sensitivity at multiple anatomic sites. Laboratory studies involving psychophysical and neuroimaging methods suggest that central augmentation of low intensity stimulation may contribute to abnormal pain sensitivity in FM. Recently, several investigators, using similar laboratory methods, have shown that patients with knee or hip osteoarthritis (OA) exhibit abnormal pain sensitivity or abnormal pain inhibition at anatomic sites distal to affected joints. Consistent with animal models of central sensitization, differences between patients and healthy controls in pain processing and pain inhibition at these distal sites are eliminated after nociceptive input is eliminated following total joint replacement surgery. This paper reviews these findings from our laboratory and those of independent investigators. It also presents verbal, psychophysical and neuroimaging data concerning ethnic group differences in affective and cognitive pain responses among patients with knee OA. We suggest that central sensitization as well as centrally-mediated cognitive and affective factors influence the pain responses of patients with knee OA. In addition, ethnic group differences in pain cognition and affect may contribute to differences among these groups in preferences for healthcare interventions such as total joint replacement.

Neuroimaging in cerebrovascular disorders: measurement of cerebral physiology after stroke and assessment of stroke recovery.

Nuclear medicine imaging can play an important role in the diagnosis of stroke risk, the differential diagnosis of vascular and parenchymal cerebral abnormalities, and the understanding and management of poststroke recovery. Radionuclide brain-imaging methods can assess hemodynamic, vascular, and metabolic status before and after stroke. Several techniques, including vasodilatory stress imaging with regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT), oxygen extraction methods with positron emission tomography (PET), and spectroscopic imaging with magnetic resonance spectroscopic imaging, offer ways to distinguish vascular from parenchymal dysfunction and to determine whether any observed abnormalities in cerebral blood flow are primary or secondary disease manifestations. The value of radionuclide imaging in assessing the efficacy of several interventional surgical procedures is presented. Data from several imaging modalities bearing on the controversial issue of luxury perfusion and reperfusion injury are analyzed, including some of the discrepancies between animal and human clinical data. Imaging evidence for white matter disease and microangiopathy is analyzed, including a quantitative rCBF pattern analysis that distinguishes between typical Alzheimer's disease and microangiopathy by using multivariate analysis of variance curve profile analysis, which shows results of significant differences in the circumferential cortical blood flow profiles at P =.01. Microangiopathy showed rCBF reduction in the frontal and frontotemporal regions as compared with the more typical reduction in posterior temporal-parietal rCBF diminution characteristic of Alzheimer's disease. Several functional neuroimaging approaches to the study of cerebral poststroke reorganization are analyzed in the context of 2 major models of recovery: the resolution of diaschisis and reorganization in spared brain. Research on these issues is presented with SPECT, PET, magnetic resonance imaging, and magnetic resonance spectroscopy. Data show how standard structural magnetic resonance imaging, (99m)Tc hexamethylpropylene amine oxime SPECT, PET imaging, and magnetic resonance spectroscopy can be used to identify the extent of permanent damage versus penumbral and remote effects of a stroke. The results of the analysis of the pure-diaschisis model show a high correlation between the rCBF brain SPECT defect volume in the cortex and the magnetic resonance spectroscopic imaging (MRSI) change in the white matter. There is a statistically significant positive correlation between the 2 (P <.01; r(2) = 0.94). The increased creatine/N-acetyl aspartate and reduced rCBF are proposed to be due to an increase in the white matter creatine component due to diaschisis and the repair mechanisms associated with increased astrocytosis, in addition to a reduction of N-acetyl aspartate in diaschitic white matter. Xenon-133 dynamic SPECT is shown to be a quantitative and sensitive measure of cerebrovascular status and hemodynamic constraints in both spared and affected brain, providing evidence for reorganization and cerebral plasticity. Fluorine-18 PET and (31)P spectroscopic imaging data show reorganizational changes in the contralesional hemisphere after stroke. The phosphocreatine-adenosine triphosphate ratio in the contralesional hemisphere was 38% +/- 17% higher than in the ipsilateral hemisphere. The phosphocreatine-adenosine triphosphate ratio was highly correlated (r = 0.88, P <.05) with increasing (18)F-fluorodeoxyglucose uptake. These results showed that there is a parallel change in glucose metabolism and high-energy phosphate metabolism associated with poststroke recovery that is proposed to be due to cerebral reorganization in the contralateral premotor cortex. The value of these results on rehabilitation strategy, including possible criteria for the use of facilitatory versus compensatory approaches, is analyzed.