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

Abstract

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.

Figure 1

Selection criteria for participants used in analysis. Participants were selected from a study sample of 1079 participants. 427 participants did not meet the criteria for analysis in this study (e.g. did not have neuroimaging data or were not UCPPS patients). 334 UCPPS patients were identified with self-reported symptoms but no neuroimaging data and were called the non-neuroimaging UCPPS cohort. These UCPPS patients completed the Brief Pain Inventory questionnaire (including body map of pain and pain severity questions) as well as the SF-12 questionnaire about daily function. These 334 were used for the analysis shown in Figures 2 and 5. A separate set of 318 participants were identified with both self-reported symptoms and neuroimaging data. 280 of these participants had high-quality structural and resting-state functional neuroimaging determined independently of the investigators [3]. 110 of these participants had a diagnosis of UCPPS and constituted the UCPPS neuroimaging discovery cohort (localized n=33, intermediate n=37, and widespread n=40) analyzed in Figures 3 and 4. In order to validate a neural signature related to widespread pain in fibromyalgia patients, we constructed a set independent of the UCPPS neuroimaging discovery cohort that contained individuals with very widespread pain (fibromyalgia) and individuals without widespread pain (healthy controls). This neuroimaging validation cohort was constructed by creating a sex-matched (all female) set of every healthy female with no self-reported pain anywhere on the body map (healthy controls n=49) and every female participant with a clinical diagnosis of fibromyalgia (but no diagnosis of UCPPS; n=23).

Figure 2. Distribution of painful body locations in three independent cohorts

Panel A shows data from 334 participants in the UCPPS non-neuroimaging cohort. Histogram of number of painful body regions (out of 45) was divided into 3 tertiles (localized n=109, intermediate n=115, widespread n=110). The body maps show the percentage of patients in each tertile reporting pain in each body region with P being the number of body locations with pain. Panel B shows the same data analysis arising from a separate smaller group of 110 participants in the UCPPS neuroimaging discovery cohort (localized n=33, intermediate n=37, widespread n=40). Panel C shows similar data in the neuroimaging validation cohort of pain-free controls (n=49) and patients diagnosed with fibromyalgia (n=23).

Figure 3. Structural and functional brain signature of widespread pain

Panel A shows increases in gray matter volume (GMV) in right supplementary motor area/cingulate cortex (SMA/CC) and bilateral primary sensory/motor cortex (S1/M1) regions among UCPPS patients with widespread pain as compared to localized pain. Panel B shows an increase in brain connectivity between salience network (SLN) and a left S1/M1 region among UCPPS with widespread pain as compared to localized pain. Panel C shows overlap of the S1/M1 cluster from structural (Panel A) and functional connectivity (Panel B) analyses. Panel D shows box plots of median and inter-quartile range (25–75%), highlighting significant SMA/CC GMV increases from localized (local. - blue), to intermediate (inter. – yellow), to widespread (wide. - red) tertiles. This same region is validated by displaying increased GMV in patients diagnosed with fibromyalgia (FM - red) as compared to pain-free healthy controls (HC - gray; Panel D inset). Panel E shows box plots of median and inter-quartile range (25 – 75%), highlighting a significant increase in functional connectivity between SLN to left S1/M1 region from localized (local. – blue), to intermediate (inter. – yellow), to widespread (wide. - red) pain groups. This result is validated by FM patients (red) having greater connectivity in this same region as compared to HCs (gray; Panel E inset).

Figure 4. Functional connectivity associated with widespread pain

Panel A shows 165 anatomically-defined brain regions, arranged around a circle for visualization, with red lines indicating the 37 pairs of regions for which functional connectivity increased in the UCPPS neuroimaging discovery cohort (UCPPS patients with widespread pain compared to UCPPS patients with localized pain) as well as in the neuroimaging validation cohort (patients with fibromyalgia compared to pain-free controls). Panel B shows these same connections spatially in the brain. Panel C shows that the number of connections identified to increase in both cohorts exceeds what would be expected by chance (p = 0.033, 50000 iterations, see Materials and Methods).

Figure 5. Functional impact of widespread pain on physical and mental function is independent of overall pain severity

UCPPS patients divided into tertiles according to pain spread were independently divided into tertiles according to overall pain severity to provide a classification as mild, moderate (mod.) or severe (sev.). Each grouping shows the average physical (Panel A) and mental (Panel B) function scores across pain widespread and severity tertiles. A decline in physical (p < 0.001) and mental function (p < 0.001) scores as a function of pain spread is observed even after controlling for pain severity. * Denotes post hoc p < 0.05 significant relationships between decline in function (physical or mental) and pain spread, within individual pain severity tertiles.