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

iTBS 的频率和电场增强治疗抑郁症（免费）

• 批准号: 10645423
• 负责人: Zafiris J. Daskalakis
• 金额: $ 80.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645423
• 关键词: Anatomy; Biological; Brain; Clinical; Clinical Trials; Clinical assessments; Coupled; Coupling; Data; Diagnosis; Disease; Disease remission; Dose; Double-Blind Method; Effectiveness; Electroencephalography; Ensure; Frequencies; Goals; Individual; Investigation; Left; Link; Location; Major Depressive Disorder; Measures; Mental Depression; Methods; Modeling; Moods; Neuronal Plasticity; Outcome; Parietal; Patients; Pattern; Performance; Phase; Physiologic pulse; Population; Prefrontal Cortex; Randomized; Randomized, Controlled Trials; Reporting; Research; Resistance; Rest; Safety; Severities; Short-Term Memory; Site; Testing; Time; Treatment Cost; Treatment Efficacy; arm; clinical efficacy; clinical practice; cognitive function; comparative efficacy; cost effectiveness; depressive symptoms; effective therapy; electric field; improved; individual patient; individualized medicine; interest; neuroimaging; novel; novel strategies; programs; repetitive transcranial magnetic stimulation; response; societal costs; symptomatic improvement; treatment response; treatment-resistant depression; trial comparing

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.

摘要 难治性抑郁症（TRD）存在于约2.5%的人群中，并与 巨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 在世界各地的临床实践中越来越多地使用。然而，在这方面， 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 在患者中通常显著低于50%。再加上一个rTMS课程需要相当长的时间 给药时间（长达6周），这种有限的功效显著影响临床效用。间歇性θ爆发 刺激（iTBS）是一种新形式的TMS，它涉及在两个组织中模式化地应用刺激脉冲。 θ和γ频率iTBS最近已被证明不劣于标准rTMS，但可以 应用时间大大缩短，通常每天3分钟，而不是20-40分钟。但 与rTMS相比，iTBS的使用并未显示出增强总体治疗功效。几种方法 正在研究试图提高iTBS治疗的疗效，部分是通过个体化治疗， 治疗参数在这项研究中，个性化的iTBS将包括频率和位置优化。 频率个体化包括刺激每个患者的内源性脑节律， 工作记忆任务中的伽马耦合我们的研究结果表明，这种频率的个性化， iTBS对健康受试者的神经可塑性、认知功能和情绪增强产生更大的影响。 接下来，我们已经开发了使用电场（E场）建模来限制线圈放置的方法。 解剖变异性和最大化每个患者的剂量。我们的目标是将TMS的电子场单独定位到 对应于左侧背外侧前额叶Talairach坐标（-45，45，35）的特定皮质区域 皮质（DLPFC）。我们以前也报道过，靶向该区域与rTMS产生上级疗效 与传统的瞄准相比。我们现在建议进行两阶段计划，以确定是否 基于频率和电场建模的个体化iTBS将增强其在TRD患者中的疗效。在 在本申请的R61阶段，我们将测试这种新方法是否通过随机化 75例TRD患者接受频率和位置个体化iTBS，仅位置个体化iTBS， 或标准iTBS刺激。我们的目标是确定个性化的频率/位置iTBS是否产生 θ连接性的更大变化，证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，我们将达到我们的行动标准，并将要求继续进行三项- R33阶段。在此阶段，我们将进行一项更大规模的随机对照试验， 在144名TRD患者中将个体化频率/位置iTBS与标准iTBS进行比较，并比较对 目标参与（额顶叶θ连接）和临床结果（抑郁严重程度）。的 本研究的总体目标是为TRD患者开发更有效的iTBS治疗形式。