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 non-pelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. While 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 MRI 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 elevated 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=0.87), as well as clinical anxiety (r=0.61,p=0.02), depression (r=0.60,p=0.03), and pain intensity (r=0.55,p=0.05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis without CPP subjects 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.

OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study

“…In support of this hypothesis, it has been demonstrated that inactivation of cervical trigger points by anesthetic infiltrations or manual therapy resulted in reduced migraine number and intensity [18, 19, 32–34]. The present study is to our knowledge the first to use OnaA injections targeted to pericranial muscle pain in CM patients.…”

“…Since the pivotal PREEMPT studies, a variety of injection techniques have been proposed, with modification of doses or sites of injections. Negro et al [32] have demonstrated a dose-depending effect of OnaA in patients with CM and medication overuse headache, with a superior efficacy of OnaA 195 U compared to 155 U. Our results suggest that parameters others than the global injected dosage may be of relevance, such as the selection of a limited number of muscles using an individualized follow-the-pain approach, as well as an adequate dosage per muscle.…”

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

“…1 H-MRS has been used to show increased levels of the excitatory neurotransmitter Glx and decreased concentrations of the inhibitory neurotransmitter GABA in the insula of FM patients compared to healthy controls [62, 74], implying that this may be an “overactive” pain promoting region within the brain. Heightened activity in the insula may in turn influence its connectivity to networks such as the DMN [7]. Indeed, there is a striking association between the magnitude of self-reported clinical pain and connectivity between the insula and the DMN across multiple chronic pain conditions (e.g., FM, CLBP, pelvic pain) [7, 121, 136].…”

“…Heightened activity in the insula may in turn influence its connectivity to networks such as the DMN [7]. Indeed, there is a striking association between the magnitude of self-reported clinical pain and connectivity between the insula and the DMN across multiple chronic pain conditions (e.g., FM, CLBP, pelvic pain) [7, 121, 136]. Emerging work has also begun to explore the relationship between connectivity in different brain networks and chronic pain expression (e.g., [79].…”

A modest proposal to investigate chronic uterine pain

“…Yet, there are frequent counterexamples where pain symptoms persist postoperatively despite removal of pelvic pathology. 9 Similar to fibromyalgia, decreased grey matter volume (GMV) in key pain regulatory regions such as the thalamus, cingulate gyrus, putamen, and insula, as well as increased concentrations of excitatory neurotransmitters in the insula, have been shown in women with CPP, again, both in those with and without endometriosis. Validated clinical assessments for the presence of uterine pain on examination, and physiological studies of abnormal patterns of uterine blood flow or myometrial contractility could prove helpful but would need systematic study in larger cohorts of women.…”