title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan. Electronic address: sassanie@med.umich.edu.
authors.forename: Sawsan
authors.initials: S
authors.lastname: As-Sanie
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt-Wilcke
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pia C
authors.initials: PC
authors.lastname: Sundgren
authors.affiliation: Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Clauw
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Napadow
authors.affiliation: Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Harris
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D059350:Chronic Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D004715:Endometriosis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D009434:Neural Pathways; D017699:Pelvic Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D005973:Glutamine; D018698:Glutamic Acid
keywords: Endometriosis; chronic pelvic pain; functional connectivity; glutamate; neuroimaging