Frequency and E-field Enhancement of iTBS for Depression (FREED)

摘要 治疗难治性抑郁症(TRD)存在于约2.5%的人群中，并与 相当大的个人痛苦和社会代价。重复经颅磁刺激(RTMS)是一种安全的 以及对TRD的有效治疗，这种治疗在世界各地的临床实践中越来越多地使用。然而， 虽然有令人信服的证据表明rTMS治疗的有效性，但总体缓解率达到 在患者中的比例通常远低于50%。再加上一个疗程的rtms需要相当长的时间 给药时间(长达6周)，这种有限的疗效极大地影响了临床应用。间歇性theta爆发 刺激(ITBS)是一种新形式的TMS，它涉及刺激脉冲在两个部位的模式应用 西塔和伽马频率。ITBS最近被证明不逊于标准的rtms，但可以 使用时间大大缩短，通常为每天3分钟，而不是20-40分钟。然而， 与rTMS相比，ITBS的使用并未显示出提高总体治疗效果的作用。有几种方法 正在调查中，试图通过部分通过个体化治疗来提高ITBS的疗效 治疗参数。在本研究中，ITBS的个性化将包括频率和位置的优化。 频率个体化涉及到刺激每个患者的内源性大脑节律，这些节律来自于 在工作记忆任务中的伽马耦合。我们的发现表明，这种频率个体化 ITBS对健康受试者的神经可塑性、认知功能和情绪改善有更大的影响。 接下来，我们开发了使用电场(电场)建模来限制线圈位置的个性化方法 解剖可变性，并最大限度地增加每个患者的剂量。我们的目标是将TMS e-field单独定位为 左侧额叶背外侧的Talairach坐标(-45，45，35)对应的特定皮质区域 皮质(DLPFC)。我们之前也曾报道过，使用rTMS靶向该地区会产生更好的疗效 与传统的目标定位相比。我们现在建议进行一个分两个阶段的计划，以确定 基于频率和电场模型的个体化ITBS将提高TRD患者的疗效。在……里面 在本应用程序的R61阶段，我们将测试这种新方法是否通过随机化来产生目标交战 75例TRD患者以频率和位置个体化ITBS为一个疗程，仅用位置个体化ITBS， 或标准的ITBS刺激。我们的目标是确定个性化的频率/位置ITBS是否会产生 Theta连接性的更大变化，以表明其改变相关额顶叶活动的能力 电路。如果这一点得到确立，我们将达到我们的GO标准，并将要求继续进行以下三项工作： R33年阶段。在这一阶段，我们将进行更大规模的随机对照试验 144例TRD患者个体化频率/位置ITBS与标准ITBS的疗效比较 目标参与(额叶至顶叶的连接)和临床结果(抑郁症的严重程度)。这个 这项研究的总体目标是为TRD患者开发一种更有效的ITBS治疗形式。

Abstract Treatment resistant depression (TRD) is present in about 2.5 percent of the population and is associated with considerable personal suffering and societal costs. Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for TRD that is increasingly being used in clinical practice across the world. However, while there is convincing evidence for the effectiveness of rTMS treatment, the overall remission rate achieved in patients is typically considerably less than 50%. Coupled with the fact that a course of rTMS takes considerable time to administer (up to 6 weeks), this limited efficacy substantially impacts clinical utility. Intermittent theta burst stimulation (iTBS) is a new form of TMS that involves the patterned application of stimulation pulses in both the theta and gamma frequencies. iTBS has recently been shown to be non-inferior to standard rTMS but can be applied in a dramatically shorter time, typically three minutes per day compared to 20-40 minutes. However, the use of iTBS has not been shown to enhance overall treatment efficacy compared to rTMS. Several methods are under investigation to try to improve the efficacy of iTBS treatment, in part through the individualization of treatment parameters. In this study, individualization of iTBS will include frequency and location optimization. Frequency individualization involves stimulating at each patient’s endogenous brain rhythms derived from theta- gamma coupling during a working memory task. Our findings suggest that such frequency individualization of iTBS produces greater effects on neuroplasticity, cognitive function, and mood enhancement in healthy subjects. Next, we have developed methods to individualize coil placement using electric field (E-field) modelling to limit anatomic variability and maximize dosing for each patient. We will aim to individually target the TMS e-field to a specific cortical region corresponding to Talairach coordinate (–45, 45, 35) in the left dorsolateral prefrontal cortex (DLPFC). We also previously reported that targeting this region with rTMS produces superior efficacy compared to conventional targeting. We now propose to undertake a 2-phase program to determine if individualized iTBS based on frequency and E-field modelling will enhance its efficacy in patients with TRD. In the R61 phase of this application, we will test if this novel approach produces target engagement by randomizing 75 patients with TRD to a course of frequency and location individualized iTBS, location individualized iTBS only, or standard iTBS stimulation. We aim to establish whether individualized frequency/location iTBS produces a greater change in theta connectivity as a demonstration of its capacity to alter activity in relevant frontal–parietal circuitry. If this is established, we will have achieved our go-criterion and will request to proceed with the three- year R33 phase. During this phase, we will conduct a larger scale randomized controlled trial comparing individualized frequency/location iTBS to standard iTBS in 144 patients with TRD and compare the effects on both target engagement (fronto-parietal theta connectivity) and clinical outcomes (depression severity). The overall goal of this research is to develop a more effective form of iTBS treatment for patients with TRD.