Targeting Functional Improvement in rTMS Therapy

对药物和心理治疗反应不充分的抑郁症患者经常患有严重的 心理社会功能障碍；因此，重复经颅磁刺激(RTMS)是一种重要的 FDA批准的替代疗法。在典型的rTMS治疗中，临床医生将刺激线圈放置在 患者的头皮集中调节下面的皮质区。左侧背外侧前额叶皮质区 (DLPFC)是治疗抑郁症最确定的目标；然而，三分之一的临床医生没有达到这一目标 患者和治疗失败，可能是导致31%的相对较低缓解率的原因之一。错误的原因 在以DLPFC为目标的情况下，临床医生通常无法使用MR图像指导来识别 它们的目标是潜在的大脑区域。相反，他们使用当前的护理标准方法来识别 使用头皮地标并在头皮上移动固定距离的刺激位置。一个新的，有希望的 另一种基于脑电电极放置的头皮靶向方法，束流F3准确地靶向 92%的退伍军人DLPFC来自我们的飞行员数据(n=12)。我们的合作者采用了光束F3作为他的 临床标准，并显示抑郁严重程度和相关功能磁图的变化 磁共振成像(FMRI)数据。其他实验室也有间接证据表明光束F3头皮靶向 该方法将rTMS刺激线圈放置在DLPFC内fMRI确定的最佳分区附近， 包括对情绪分散和反应性的控制。目前提案的总体目标是测试 利用波束F3头皮定位准确达到基于fMRI的最佳分区的可行性 接近。我们进一步假设，由于心理社会功能与认知控制有关， 准确刺激这一fMRI区域也可能导致心理社会功能的改善(即减少 功能限制和生活质量的提高)。我们的计划是收集功能性核磁共振和核磁共振的标记物 临床医生将BEAM F3放置在抑郁症退伍军人身上。我们的策略是测试波束是否 F3规则将线圈放置得足够近(即在rTMS的空间分辨率内)以达到最佳的DLPFC 在95%的退伍军人中。在目标1中，我们建议使用图像引导来高精度地测试 准确地说，波束F3的目标是这个最佳的、功能磁共振定义的大脑区域。在目标2中，我们演示了该方法的准确性 在rTMS临床患者中，治疗者通常偏离头皮规则以适应 患者舒适度，因为额部刺激会导致面部抽搐和部分患者的脑神经疼痛刺激 头皮位置。为了解决我们选择大脑靶点的临床重要性，在我们基于临床的样本中，我们将 评估与最佳大脑目标的空间偏差是否与心理社会改善相关 根据世界卫生组织残疾评估附表2.0和 退伍军人兰德12项健康生活质量调查。我们将执行几个额外的分析 获取的数据。我们将使用精确的图像引导，并在相同的患者中直接比较 BEAM F3头皮定位于临床标准，为临床医生提供了令人信服的证据 哪种方法更准确。如果我们发现光束F3规则中的系统性偏差，我们可以确定 如何调整它以提高精确度。这项提案的结果将改善RTMS的实施情况 抑郁症退伍军人的治疗。我们将通过我们的临床rTMS VA培训来传播我们的发现 提高全国退伍军人管理局诊所的目标精确度。我们的愿景是，这种图像制导方法可以 基于头皮的靶点的验证将作为开发新的大脑信息头皮靶点的模型 并将指导创新的大规模临床试验，以研究大脑预测因素、变化、 和临床上有意义的结果。因此，本提案中开发的工具可以实现大规模的 退伍军人rTMS诊所之间可以识别大脑和头皮靶点的合作治疗退伍军人功能障碍 他们发现这在临床上有意义。

Depressed patients inadequately responsive to medication and psychotherapy often live with serious difficulties in psychosocial functioning; thus, repetitive transcranial magnetic stimulation (rTMS) is an important, alternative, FDA approved therapy. During typical rTMS therapy, clinicians place a stimulation coil on the patient's scalp that focally modulates the underlying cortical areas. The left dorsolateral prefrontal cortex region (DLPFC) is the most established target for treating depression; however, clinicians miss this target in a third of patients and treatment fails, likely contributing to the relatively low remission rate of 31%. The reason for errors in targeting the DLPFC is that clinicians typically do not have access to MR image-guidance to identify the underlying brain regions they target. Instead they use the current standard-of-care method to identify the stimulation location that uses scalp landmarks and moves a fixed distance over the scalp. A new, promising alternative scalp targeting approach based on EEG electrode placement, the Beam F3 accurately targeted the DLPFC in 92% of Veterans from our pilot data (n=12). Our collaborator has adopted the Beam F3 as his clinical standard and showed improved depression severity and changes in associated functional Magnetic Resonance Imaging (fMRI) data. Other labs also, have indirect evidence that the Beam F3 scalp targeting approach places the rTMS stimulation coil near an fMRI identified optimal subregion within the DLPFC that involves control over emotional distraction and reactivity. The overall aim of the current proposal is to test the feasibility of accurately reaching this fMRI based optimal subregion using the Beam F3 scalp-based targeting approach. We further hypothesize that, since psychosocial functioning is related to cognitive control that accurate stimulation of this fMRI region could also lead to improved psychosocial functioning (i.e. reduced functional limitations and improved quality of life). Our plan is to collect fMRI and MRI's with markers identifying where clinicians place the Beam F3 location in depressed Veterans. Our strategy is to test whether the Beam F3 rule places the coil close enough (i.e. within the spatial resolution of rTMS) to reach an optimal DLPFC subregion in 95% of Veterans. In Aim 1 we propose to use image-guidance to test with high precision how accurately the Beam F3 targets this optimal, fMRI defined, brain region. In Aim 2 we demonstrate the accuracy of the Beam F3 in rTMS clinic patients where treaters typically deviate from scalp rules to accommodate patient comfort since frontal stimulation causes facial twitches and painful cranial nerve stimulation in some scalp locations. To address clinical importance of our choice of brain targets, in our clinic-based sample we will evaluate whether spatial deviations from the optimal brain target correlate with improvements in psychosocial functioning on a composite score of the World Health Organization Disability Assessment Schedule 2.0 and the Veterans RAND 12-item health survey of quality of life. We will perform several additional analyses on the acquired data. We will use precise image-guidance and directly compare in the same patients the accuracy of the Beam F3 scalp targeting to that of the clinical standard to provide clinicians with compelling evidence of which approach is more accurate. If we discover a systematic deviation in the Beam F3 rule, we can identify how to adapt it to improve accuracy. Results from this proposal will improve the implementation of rTMS therapy for depressed Veterans. We will disseminate our findings through our clinical rTMS VA training to improve targeting accuracy at VA clinics nationwide. Our vision is that this image-guidance approach to validation of scalp-based targets will serve as a model for the development of new brain-informed scalp targets and will guide innovative large scale clinical trials to study the relationship between brain predictors, changes, and clinically meaningful outcomes. The tools developed in this proposal can thus enable large-scale collaborations between VA rTMS clinics that can identify brain and scalp targets treat dysfunction in Veterans they find clinically meaningful.