Functional Connectivity is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain

Abstract

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.

Keywords: Endometriosis; chronic pelvic pain; functional connectivity; glutamate; neuroimaging.

Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Anterior and posterior insula regions of interest (ROIs) and resulting spectrum. A. Sagittal T1- weighted images showing single-voxel placement for right anterior insula (ant) and right posterior insula (post). B. Representative proton magnetic resonance spectroscopy spectrum from the posterior insula fit with LCModel (red trace; * = resonance from 2 glutamate proton resonances at 2.35 parts per million). LCModel uses linear combination of individual spectra obtained from pure molecular species to fit the experimental spectra. Absolute concentrations of Glx (glutamine and glutamate) and NAA were calculated in arbitrary units using water as an internal scaling factor.

Figure 2

Combined glutamine and glutamate (Glx) levels are elevated within the anterior insula in women with chronic pelvic pain (CPP), regardless of endometriosis status.

Figure 3

Greater connectivity between anterior insula and medial prefrontal cortex (mPFC) in women with endometriosis and chronic pelvic pain (⊕Endo⊕CPP, n=16).

Figure 4

Anterior insula connectivity to medial prefrontal cortex (mPFC) is correlated with Glx levels in anterior insula in women with endometriosis and chronic pelvic pain (⊕Endo⊕CPP, n=14), p

Figure 5

Anterior insula connectivity to medial prefrontal cortex (mPFC) is correlated with anxiety (STPIDA-A), depression (STPIDA-D), and pain intensity (BPI) scores in women with endometriosis and chronic pelvic pain (⊕Endo⊕CPP, n=14).