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

项目总结/摘要 纤维肌痛综合征是一种令人不安的特发性疼痛状况，它因周期性的身心关系而复杂化，涉及生理和心理过程。一种有可能减轻纤维肌痛疼痛的疗法是催眠镇痛-一种可以调节对有害刺激的感知的技术。对催眠的敏感性是一种可量化的特征，被描述为可催眠性，但只有一部分人是可催眠的。已发现催眠与L-DLPFC和dACC之间的较高静息状态功能连接相关。然而，作为默认模式网络和（L-DLPFC）之间改变的功能连接的基础的神经化学特征是未知的，但可以提供治疗效果的关键指标。通过经颅磁刺激（TMS）对L-DLPFC进行靶向神经调节可能被证明是调节催眠能力的有用工具，扩大了纤维肌痛疼痛催眠镇痛的临床范围。这导致我们假设纤维肌痛疼痛中改变的功能连接与L-DLPFC GABA和Glx浓度相关。经颅磁刺激（TMS）调节L-DLPFC GABA和GLX浓度可以改变对催眠的敏感性，从而改变催眠减轻纤维肌痛症状的疗效。 在目标1中，我们将描述纤维肌痛综合征受试者的行为指标（临床疼痛/催眠能力）与L-DLPFC中GABA、Glx和肌醇浓度之间的基线相关性。为了验证这一点，我们将通过功能性磁共振成像（fMRI）确定的L-DLPFC目标进行磁共振波谱（MRS），非侵入性地测量脑神经化学。在目标2中，我们将收集试验数据，以测试靶向L-DLPFC的TMS对a）GABA/Glx浓度和连接性的影响，以及B）确定催眠镇痛的疗效是否与L-DLPFC神经化学的变化相关。 这些目标将在斯坦福大学由医学博士大卫斯皮格尔赞助的培训计划的背景下完成，精神病学教授和催眠专家，由丹尼尔斯皮尔曼博士共同赞助，放射学教授和光谱成像的主要研究人员，以及医学博士诺兰威廉姆斯，他是一位受过双重训练的神经学家-心理学家，也是包括TMS在内的神经调节领域的领导者。该培训计划将包括研究，技术熟练程度和专业发展的申请人和博士后研究员，詹姆斯主教，博士。这项研究将集中在纤维肌痛疼痛和TMS的脑神经化学改变之间的关系，目的是增加催眠和催眠镇痛。詹姆斯将通过与他的赞助商一起直接培训，并完成外部课程，研讨会和讲习班，发展与TMS和MRS相关的技能。职业发展将包括在负责任的研究行为，出版同行评议的手稿，参加国际会议，并授予写作，除了在斯坦福大学的专业发展办公室提供的资源培训。詹姆斯和他的赞助商之间的每周讨论和个性化发展计划（IDP）的形成将确保他接受必要的培训，以追求他作为一个独立的学术科学家的目标。

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.