Optimized tDCS for fibromyalgia: targeting the endogenous pain control system

1.摘要 纤维肌痛(FM)疼痛每年影响美国500多万人，并会对患者的生活质量和社会成本(如治疗或失业成本)产生相当大的影响。鉴于大多数治疗FM的干预措施的效果有限且多变，开发FM的新干预措施的临床需求尚未得到满足。最近的证据表明，FM疼痛可能与疼痛内源性调节控制缺陷有关。在此背景下，我们的中心假设是，为了提高疗效，FM的新疗法需要针对与这种内源性疼痛调节系统相关的特定神经网络。我们的理论基础是基于研究表明，经颅直流电刺激初级运动皮质是一种强大的非侵入性神经调节技术，已知可以显着调节神经可塑性和缓解慢性疼痛。我们小组于2006年在FM报告了第一批tdcs阳性结果。为了优化运动皮质tdcs的治疗效果，我们最近假设tdcs与有氧运动(AE)相结合将增加其作用，因为tdcs与有氧运动联合使用可增强运动系统参与对内源性疼痛系统的调节作用。我们对这一假说进行了初步试验，并显示了联合治疗的有益效果。这项建议是在这一初步数据的基础上制定的。我们的具体目标是：(I)通过时间缓慢疼痛总和(TSP)和条件性疼痛调制(CPM)来评估TDC和有氧运动对内源性疼痛控制的影响；(Ii)确定这些干预措施对FM中也受影响的抑制控制皮质标志物的影响，例如经颅磁刺激(TMS)评估的皮质内抑制和EEG评估的丘脑皮质心律失常的变化；(Iii)评估在本研究中测试的两个主要目标-STS和CPM-的参与是否与疼痛结果的变化(例如简短的痛量表和其他临床评分)有关。我们的主要方法将在94名被诊断为FM的患者中使用随机2x2机械因素对照试验进行。受试者将被随机分为四组：TDC和AE组；假TDC组和AE组；活动TDC组和NAE组(非AE=AE的控制干预组)；假TDC组和NAE组。这项研究的结果将是重要的，因为在FM中开发新的治疗方法，特别是基于机械方法和靶向参与的非药物治疗的临床需求尚未得到满足。广泛的感觉和电生理测量将通过条件性疼痛调制和暂时性缓慢疼痛总和、单脉冲和双脉冲经颅磁刺激以及定量脑电图法进行，将提供新的机制见解，与主要临床目标无关，将对未来研究新的疼痛疗法具有重要意义。目前治疗FM的方法要么疗效有限，要么与全身不良反应有关。从临床的角度来看，作为二次分析，我们将研究疼痛评分(即BPI)的时间演变，以了解治疗的剂量-反应，以便为未来研究tDCs的镇痛效果的试验设计提供重要的见解。最后，这一建议是新颖的，因为这种治疗是基于疼痛控制的神经靶点-内源性疼痛控制系统，本试验的结果不仅将通过研究内源性疼痛控制带来一种潜在的治疗FM的新方法，而且还将揭示FM的疼痛机制及其与主要调节器：运动系统的关系。

1. ABSTRACT Fibromyalgia (FM) pain affects upwards of 5 million people in US annually and can have a considerable impact on patients’ quality of life and costs for the society (e.g., treatments or unemployment costs). Given the limited and variable effects of most of the therapeutic interventions for FM, there is an unmet clinical need for the development of novel interventions in FM. Recent evidence has suggested that FM pain can be related to deficits in pain endogenous regulatory control. In this context, our central hypothesis is that, to improve their efficacy, novel treatments of FM need to target specific neural networks associated with this endogenous pain regulatory system. Our rationale is based on studies showing that transcranial direct current stimulation (tDCS) of primary motor cortex is a powerful non-invasive neuromodulation technique of known to significantly modulate neural plasticity and alleviate chronic pain. Our group reported the first positive results of tDCS in FM in 2006. In order to optimize the treatment effects of motor cortex tDCS, we recently hypothesized that combining tDCS with aerobic exercise (AE) would increase its effects, given its enhanced modulatory effect of motor system engagement on endogenous pain system by combining two therapies. We conducted a preliminary trial testing this hypothesis and showed a beneficial effect of the combined treatment. This proposal was developed based on this preliminary data. Our specific aims are: (i) evaluate the effects of tDCS and aerobic exercise on endogenous pain control as assessed by temporal slow pain summation (TSPS) and conditioned pain modulation (CPM); (ii) determine the effect of these interventions on cortical markers of inhibitory control that are also affected in FM, such as intracortical inhibition as assessed by transcranial magnetic stimulation (TMS) and changes in thalamocortical dysrhythmia as assessed by EEG; (iii) assess whether engagement of the two main targets tested in this study – STS and CPM – are associated with changes in pain outcomes (e.g., Brief Pain Inventory and other clinical scales). Our main approach will be carried out using a randomized 2x2 mechanistic factorial controlled trial in 94 patients diagnosed with FM. Subjects will be randomized to one of four groups: tDCS and AE; sham tDCS and AE; active tDCS and nAE (non-AE= control intervention for AE); sham tDCS and nAE. The findings from this study will be significant as there is an unmet clinical need for the development of novel therapies in FM, particularly non-pharmacological ones, based on mechanistic approaches and target engagement. The extensive sensory and electrophysiological measurements that will be conducted with conditioned pain modulation and temporal slow pain summation, single- and paired-pulse transcranial magnetic stimulation, and quantitative electroencephalography will provide novel mechanistic insights that, independently of the main clinical aim, will be significant to future studies investigating novel pain therapies. Current treatments for FM have either limited efficacy or are associated with systemic adverse effects. From a clinical perspective, as secondary analysis, we will investigate the time evolution of pain scores (i.e., BPI) to understand the treatment dose-response in order to provide important insights for the design of future trials investigating the analgesic effects of tDCS. Finally, this proposal is novel given that this treatment is based on a neural target for pain control, the endogenous pain control system, and the results of this trial will not only bring a potential novel way of treating FM, by looking into the endogenous pain control, but will also shed light into pain mechanisms of FM and its relationship to a major modulator: the motor system.