Optimized tDCS for fibromyalgia: targeting the endogenous pain control system

针对纤维肌痛的优化 tDCS：针对内源性疼痛控制系统

• 批准号: 10203831
• 负责人: Felipe Fregni
• 金额: $ 41.49万
• 依托单位: SPAULDING REHABILITATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203831
• 关键词: Adverse effects; Aerobic Exercise; Affect; Analgesics; Brief Pain Inventory; Chronic; Clinical; Combined Modality Therapy; Control Groups; Coupled; Data; Development; Diagnosis; Dose; Effectiveness; Electroencephalography; Electrophysiology (science); Evolution; Exercise; Fibromyalgia; Future; Goals; Hyperalgesia; Individual; Insula of Reil; Intervention; Lead; Life; Light; Measurement; Measures; Mediating; Motor; Motor Cortex; Neuronal Plasticity; Pain; Pain intensity; Pain management; Patients; Personal Satisfaction; Physiologic pulse; Prediction of Response to Therapy; Prefrontal Cortex; Quality of life; Questionnaires; Randomized; Reporting; Secondary to; Sensory; Societies; Somatosensory Cortex; System; Techniques; Testing; Thalamic structure; Therapeutic Intervention; Time; Transcranial magnetic stimulation; Unemployment; active control; allodynia; base; central sensitization; chronic pain; cingulate cortex; clinical effect; conditioned pain modulation; conditioning; cost; design; fibromyalgia pain; fibromyalgia patients; improved; indexing; insight; intervention effect; neural network; neuroregulation; new therapeutic target; novel; novel therapeutics; pain outcome; pain reduction; pain relief; pain score; primary outcome; relating to nervous system; response; restoration; secondary analysis; treatment effect; treatment optimization; treatment strategy

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.

1。摘要 纤维肌痛（FM）疼痛每年都会影响500万人，并且可能会对患者的社会生活质量和成本产生影响（例如治疗或失业成本）。鉴于大多数FM治疗干预措施的有限和可变作用，因此对FM中新型干预措施的发展尚无临床需求。最近的证据表明，FM疼痛可能与疼痛内源性调节控制中的定义有关。在这种情况下，我们的中心假设是，为了提高其效率，FM的新颖治疗方法需要针对与该内源性疼痛调节系统相关的特定神经元网络。我们的理由是基于研究表明，原发性运动皮层的经颅直流刺激（TDC）是一种强大的非侵入性神经调节技术，已知可显着调节神经元可塑性并减轻慢性疼痛。我们的小组报道了2006年TDC在FM中的第一个积极结果。为了优化运动皮层TDC的治疗效应，我们最近假设，将TDC与有氧运动（AE）相结合会增加其效果，鉴于其通过将两种治疗系统结合到内源性疼痛系统的调节作用增强了其对内源性疼痛的调节作用。我们进行了一项初步试验，对这一假设进行了检验，并显示了合并治疗的有益作用。该提案是根据此初步数据制定的。我们的具体目的是：（i）评估TDC和有氧运动对内源性疼痛控制的影响，如暂时的慢疼痛总和（TSP）和条件疼痛调节（CPM）评估； （ii）确定这些干预措施对FM中也受到影响的抑制性控制皮质标记的影响，例如通过经颅磁刺激（TMS）评估的皮质内抑制作用和丘脑皮质性运动障碍性的变化，如由EEG评估； （iii）评估本研究中测试的两个主要靶标（STS和CPM）是否与疼痛结果的变化有关（例如，短暂疼痛清单和其他临床量表）。我们的主要方法将使用94例被诊断为FM的患者进行随机2x2机械阶乘对照试验进行。受试者将被随机分为四组之一：TDC和AE； Sham TDCS和AE；主动TDC和NAE（非AE = AE的控制干预）；假TDC和NAE。这项研究的发现将是重要的，因为基于机械方法和目标参与的FM（尤其是非药理学）中新型疗法的开发未满足的临床需求。将通过条件疼痛调节和暂时的缓慢疼痛总和，单脉冲和配对的脉冲经颅磁刺激以及定量脑电表造影进行的广泛的感觉和电生理测量值将提供新型的机械见解，这些洞察力将与主要的临床目标相关，对研究新型止痛治疗的未来研究将是重要的。 FM的当前治疗方法要么有效，要么与全身不良反应有关。从临床角度来看，作为次要分析，我们将研究疼痛评分（即BPI）的时间演变，以了解治疗剂量反应，以便为设计TDC的镇痛作用的未来试验设计提供重要见解。最后，这项建议是新颖的，鉴于该治疗方法基于用于控制疼痛的神经靶标，内源性疼痛控制系统，并且该试验的结果不仅通过研究内源性疼痛控制来带来一种潜在的治疗FM的新方法，还将启动FM及其与主要调节仪的关系及其与主要调节器的关系：运动系统：运动系统。