Targeting Functional Improvement in rTMS Therapy

对药物和心理治疗反应不足的抑郁症患者往往生活在严重的 心理社会功能的困难;因此，重复经颅磁刺激（rTMS）是一个重要的， FDA批准的替代疗法在典型的rTMS治疗期间，临床医生将刺激线圈放置在 患者头皮局部调节下层皮层区域。左背外侧前额叶皮层区域 （DLPFC）是治疗抑郁症最确定的目标;然而，临床医生在三分之一的患者中错过了这一目标。 患者和治疗失败，可能导致相对较低的缓解率31%。错误的原因 在瞄准DLPFC方面，临床医生通常无法使用MR图像引导来识别DLPFC 它们所针对的潜在大脑区域相反，他们使用当前的标准治疗方法来识别 刺激位置使用头皮界标并在头皮上移动固定距离。一个新的，有前途的 基于EEG电极放置的替代头皮靶向方法，Beam F3准确地靶向 来自我们的试点数据（n=12）的92%退伍军人的DLPFC。我们的合作者采用了Beam F3作为他的 临床标准，并显示改善抑郁症的严重程度和相关的功能磁 共振成像（fMRI）数据。其他实验室也有间接证据表明Beam F3头皮靶向 该方法将rTMS刺激线圈放置在DLPFC内fMRI识别的最佳子区域附近， 包括控制情绪上的分心和反应。目前提案的总体目标是测试 使用Beam F3基于头皮的靶向准确达到该基于fMRI的最佳子区域的可行性 approach.我们进一步假设，由于心理社会功能与认知控制有关， 对该功能磁共振成像区域的精确刺激也可以导致改善的心理社会功能（即， 功能限制和改善生活质量）。我们的计划是收集功能磁共振成像和磁共振成像的标记， 临床医生将Beam F3定位在抑郁的退伍军人中。我们的策略是测试光束 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DLPFC 95%的退伍军人。在目标1中，我们建议使用图像制导来高精度地测试如何 射束F3精确地瞄准了这个最佳的、功能磁共振成像定义的大脑区域。在目标2中，我们证明了 在rTMS临床患者中的射束F3，其中植入者通常偏离头皮规则以适应 患者舒适度，因为在某些情况下，额叶刺激会导致面部抽搐和疼痛的颅神经刺激 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的改善相关 根据世界卫生组织残疾评估表2.0的综合评分， 退伍军人兰德12项生活质量健康调查。我们将对这些数据进行一些额外的分析。 获得的数据。我们将使用精确的图像引导，并直接比较相同患者的准确性， Beam F3头皮瞄准临床标准，为临床医生提供令人信服的证据， 哪种方法更准确。如果我们发现Beam F3规则中存在系统偏差，我们可以确定 如何调整它以提高准确性。该提案的结果将改善rTMS的实施 治疗抑郁的退伍军人。我们将通过临床rTMS VA培训传播我们的研究结果， 提高了全国退伍军人事务部诊所的定位准确性。我们的愿景是，这种图像引导的方法， 基于头皮的目标的验证将作为开发新的大脑通知头皮目标的模型 并将指导创新的大规模临床试验，以研究大脑预测因子，变化， 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 VA rTMS诊所之间的合作可以识别大脑和头皮目标，治疗退伍军人的功能障碍 他们认为有临床意义。

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.