Developing a Novel rTMS Intervention for Transdiagnostic Psychosocial Rehabilitation: ADose-finding Study

对左背外侧前额叶皮质（dlPFC）进行高频重复经颅磁刺激（rTMS） 被FDA批准用于治疗重度抑郁症通常用rTMS靶向的左侧dlPFC位点是 位于与完整的高级认知（即，执行功能）。主要研究者有 研究表明，这个左前额叶皮层区域通常在认知任务中处于低激活状态， 神经精神障碍因此，认知改善已被报告为辅助益处， rTMS治疗和rTMS改善轻度至中度认知障碍的认知。 我们认为，由于dlPFC的rTMS针对的是适应性认知不可或缺的认知神经回路， 功能，促进神经可塑性在这个网络与rTMS可以更精确地优化，以改善 生活质量跨越心理社会领域和跨神经精神表现。我们推测 通过rTMS上调认知控制电路，个体将具有1）增强的能力 成功应对日常生活中不断变化的突发事件; 2）提高调节能力 侵入性的影响和冲动。作为这些过程的一个功能，个人预计将经历减少 社会心理障碍因此，我们建议，而不是针对具体的症状减少， 在某些疾病中，rTMS可以用于增强心理社会功能的功效。这种方法具有 有可能为更多患有一系列神经精神疾病的退伍军人提供康复服务。 rTMS的治疗过程通常由大约30-40分钟的高频（即，10 Hz） 每个工作日治疗，持续4至6周。这个时间表可能是繁重的，并降低依从性。 最近，共同研究者马克乔治，医学博士。和同事们证明， 连续三天每天对退伍军人进行的会议是安全的，可行的，并提示快速 抗抑郁作用这些患者在三天内接受了等效剂量（即，脉冲总数） 传统的4到6周的课程。我们建议，建立一个有效的加速协议， 在1周内交付将大大增加在VA医疗保健系统中实施的可能性。 此外，rTMS的加速过程，增强了心理功能的障碍， 成为VA医疗保健系统中已使用的其他康复方式的现成辅助手段，包括 药物治疗和认知行为治疗以及职业和物理治疗。 鉴于利用加速rTMS减少心理社会功能障碍的目标， 建立相关的剂量反应曲线，作为为这一工作奠定基础的第一步。之前 rTMS研究依赖于合理的决策树来确定TMS剂量，通常基于 非退伍军人样本中抑郁症的rTMS结果。例如，加速协议通常 最终适合用于抑郁症的常规rTMS剂量（即，总共54，000个脉冲）转换成截断时间 期我们认为SPiRE机制是经验性确定剂量-反应曲线的理想机制 针对左侧dlPFC的加速rTMS，以改善心理社会功能障碍。 在目前的研究中，我们建议随机化一个转诊断的退伍军人样本[（n=40）]， 严重的社会心理障碍参与者将随机接受10种不同剂量的加速rTMS。 为了在本初步研究中对不同剂量进行适当的随机化，受试者将被限制为 符合焦虑和/或抑郁障碍的标准。尖端的基于神经导航的靶向技术， 将进行结构MRI以确保左侧dlPFC的个体化放置。总之，我们建议 通过1）实施为期1周的加速rTMS方案，2） 建立剂量-反应曲线，3）优化治疗以增强转诊断 心理社会功能

High frequency repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex (dlPFC) is FDA-approved for the treatment of major depression. The left dlPFC site typically targeted with rTMS is seated in an area of cortex integral to intact higher order cognition (i.e., executive function). The PI has demonstrated that this left dlPFC region is commonly hypoactivated during cognitive tasks across neuropsychiatric disorders. Accordingly, cognitive improvements have been reported as ancillary benefits to rTMS treatment and that rTMS improves cognition in mild to moderate cognitive impairment. We propose that because rTMS to dlPFC is targeting cognitive neurocircuitry integral to adaptive cognitive functioning, promoting neuroplasticity in this network with rTMS could be more precisely optimized to improve quality of life across psychosocial domains and across neuropsychiatric presentations. We postulate that through up-regulating cognitive control circuitry with rTMS that an individual would have 1) enhanced capacity for successfully contending with the shifting contingencies of daily life and 2) improved ability to regulate intrusive affect and impulses. As a function of these processes an individual is expected to experience reduced psychosocial impairment. Thus, we propose that rather than targeting specific symptom reductions in specific disorders, rTMS could be dosed for efficacy in enhancing psychosocial functioning. Such an approach has the potential to enhance rehabilitation for far more veterans suffering a range of neuropsychiatric conditions. A therapeutic course of rTMS typically consists of approximately 30-40 minutes of high-frequency (i.e., 10 Hz) treatment on each weekday, for 4 to 6 weeks. This schedule can be burdensome and reduce adherence. Recently, Co-investigator Mark George, M.D. and colleagues demonstrated that delivering multiple high-dose sessions to veterans on each of three consecutive days was safe, feasible, and suggestive of rapid antidepressant effects. These patients received in three days, the equivalent dose (i.e., total number of pulses) of a conventional 4- to 6-week course. We propose that establishing an efficacious accelerated protocol delivered within 1 week would greatly increase the likelihood of implementation in the VA healthcare system. Furthermore, an accelerated course of rTMS that enhances psychosocial functioning across disorders, would be a ready adjunct for other modalities of rehabilitation already utilized in the VA healthcare system including pharmacotherapy and cognitive-behavioral therapy as well as occupational and physical therapy. In light of the goal to utilize accelerated rTMS to reduce psychosocial functional impairment, it is essential to establish the associated dose-response curve as a first step in laying the foundation for this line of work. Prior rTMS investigations have relied upon rational decision trees in determining TMS dose, typically founded upon the rTMS outcomes for depression in non-veteran samples. For example, accelerated protocols have typically endeavored to fit the conventional rTMS dose for depression (i.e., 54,000 total pulses) into a truncated time period. We propose that the SPiRE mechanism is ideal for empirically determining the dose-response curve specific to accelerated rTMS to left dlPFC for improving psychosocial functional impairment. In the current study we propose to randomize a transdiagnostic sample of veterans [ (n=40) ] with moderate to severe psychosocial impairment. Participants would be randomized to 10 different doses of accelerated rTMS. For appropriate randomization across different doses in this pilot study, participants would be restricted to meeting criteria for an anxiety and/or depressive disorder. Cutting-edge neuronavigation-based targeting with structural MRI would be performed to ensure individualized placement at left dlPFC. In summary, we propose to innovate veteran care with this SPiRE proposal by 1) implementing a 1-week accelerated rTMS protocol, 2) establishing the dose-response curve, and 3) optimizing the treatment to enhance transdiagnostic psychosocial functioning.