Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.

Fibromyalgia (FM) is a functional chronic pain syndrome characterized by diffuse hyperalgesia and spontaneous widespread pain [1]. Multiple studies have described functional, structural and neurochemical brain changes in these patients [2]. Since most of these studies have been cross-sectional in nature they do not address whether these changes in brain structure, function, and neurochemistry are a cause of the pain, a consequence, or simply factors associated with chronic pain. Moreover most of the fMRI studies have assessed changes in response to pain stimuli and as such only provide information about hyperalgesia and not ongoing spontaneous pain. Recently we reported that a functional magnetic resonance imaging (fMRI) technique that assesses resting or intrinsic brain connectivity provides neurobiological correlates of spontaneous clinical pain report in FM [3]. FM patients displayed greater connectivity between the insula and the default mode network (DMN; see below) and the degree of connectivity was directly associated with the intensity of ongoing spontaneous pain. However this analysis was cross-sectional in nature and did not assess whether this marker could be a potential brain imaging marker reflecting dynamic longitudinal changes in pain in FM patients undergoing therapy. The field of FM and chronic pain in general is in great need of both effective analgesic therapies, as well as better understanding of the pathophysiology underlying chronic pain syndromes. Indeed these two factors are likely related: a better understating of the mechanistic pathways underlying specific pathology in sub-groups of individual patients could then be used to optimize and enhance therapy for specific individuals with FM. Subjective self-reports of pain symptoms most likely lack the specificity needed to phenotype specific pathologic factors in individuals patients; however, as FM is increasingly characterized as a disorder in central nervous system functioning [1], a non-invasive neuroimaging marker could greatly improve our ability to characterize and track pain symptoms in FM patients in longitudinal trials. Evaluation of intrinsic brain connectivity is a relatively recent approach in fMRI neuroimaging. Intrinsic connectivity assesses spontaneous neural and metabolic activity that occurs in a resting basal state since imaging is performed while subjects rest quietly in the scanner. We and others have proposed that this resting connectivity is related to the spontaneous chronic pain that these patients experience. It may reflect synaptic neurotransmission as inter-regional correlations in the fMRI signal follow known structural monosynaptic and polysynaptic pathways [4]. Thus, connectivity likely reflects neurophysiologically meaningful activity, and occurs within distinct networks of the brain. One such constellation is the Default Mode Network (DMN), an aggregate of brain structures which have been associated with self-referential cognition and autobiographical memory [5]. In addition to FM [3], altered intrinsic DMN connectivity has been detected in other chronic pain conditions [6]. We found that the DMN demonstrated greater connectivity to the insula in FM patients compared to healthy adults, and, perhaps even more importantly, increasing DMN/insula connectivity was associated with increasing levels of spontaneous pain [3]. These results suggested that intrinsic connectivity could serve as a brain biomarker for chronic pain - a hypothesis that would be bolstered if longitudinal changes in intrinsic DMN connectivity were associated with changes in the clinical pain state. Our current study was designed to evaluate longitudinal changes in intrinsic brain connectivity in FM patients treated with a non-pharmacological intervention known to modulate pain levels in this patient population [7]. Subjects were scanned before and after therapy and were evaluated for intrinsic connectivity. We hypothesized that DMN-insula connectivity, would be reduced following therapy and would be correlated with diminished pain.