Defining the Neuromolecular Signature of TMS-Augmented Hypnotic Analgesia in Fibromyalgia Syndrome

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Project Summary / Abstract Fibromyalgia syndrome is a troubling idiopathic pain condition that is complicated by a cyclical mind-body relationship, involving both physiological and psychological processes. One therapy with potential to mitigate fibromyalgia pain is hypnotic analgesia – a technique that can modulate perception of noxious stimuli. Susceptibility to hypnosis is a quantifiable trait described as hypnotizability, but only a subset of the population is hypnotizable. Hypnotizability has been found to be associated with higher resting state functional connectivity between the L-DLPFC and the dACC. However, the neurochemical signature that underlies altered functional connectivity between the default mode network and (L-DLPFC) is unknown, but could provide critical indications of therapeutic efficacy. Targeted neuromodulation of the L-DLPFC by transcranial magnetic stimulation (TMS) may prove a useful tool to modulate hypnotizability, expanding the clinical reach of hypnotic analgesia in fibromyalgia pain. This leads us to the hypothesis that altered functional connectivity in fibromyalgia pain is associated with L-DLPFC GABA and Glx concentrations. Transcranial Magnetic Stimulation (TMS) modulation of L-DLPFC GABA and GLx concentrations can alter susceptibility to hypnosis and therefore the efficacy of hypnosis in reducing fibromyalgia symptoms. In Aim 1, we will characterize baseline associations between behavioral measures (clinical pain / hypnotizability) and GABA, Glx, and myo-inositol concentrations in the L-DLPFC in subjects with fibromyalgia syndrome. To test this, we will measure brain neurochemistry non-invasively by performing magnetic resonance spectroscopy (MRS) in an L-DLPFC target identified through functional magnetic resonance imaging (fMRI). In Aim 2, we will collect pilot data to test the effect of L-DLPFC targeted TMS on a) GABA/Glx concentrations and connectivity and b) determine whether efficacy of hypnotic analgesia is associated with a change in L-DLPFC neurochemistry. These aims will be completed in the context of a training plan at Stanford University sponsored by David Spiegel, M.D., a professor of psychiatry and expert hypnosis practitioner, and co-sponsored by Daniel Spielman, Ph.D., a professor of radiology and leading researcher in spectroscopy imaging, and Nolan Williams, M.D., a dually trained neurologist-psychologist and leader in the field of neuromodulation including TMS. The training plan will include research, technical proficiency, and professional development for the applicant and postdoctoral fellow, James Bishop, Ph.D. The research will focus on the relationship between altered brain neurochemistry in fibromyalgia pain and TMS, with the goal of increasing hypnotizability and hypnotic analgesia. James will develop skills related to TMS, and MRS through directly training alongside his sponsors, and completing external coursework, seminars, and workshops. Career development will include training in the responsible conduct in research, publishing peer-reviewed manuscripts, attending international conferences, and grant writing, in addition to resources provided by professional development offices at Stanford University. Weekly discussions between James and his sponsors and formation of individualized development plan (IDP) will ensure that he receives the training necessary to pursue his objective as an independent academic scientist.