Ascertaining Neurocircuitry to Enhance Neuromodulation Development ASCEND

项目摘要 重性抑郁症（MDD）在全球范围内的所有疾病中排名第二。不幸的是很多 患者患有难治性MDD（TRD），最有效的抗抑郁治疗选择是 电休克疗法（ECT）。然而，神经认知不良反应（例如，顺行和 逆行性遗忘症）减轻了所需临床结果的实现。因此， 开发新的和安全的神经调节性抗抑郁干预是非常必要的。一个新 一种具有抗抑郁特性并正在积极开发的神经调节治疗方法， 磁惊厥治疗（MST）。MST在神经认知方面比ECT更安全，因为它使用的是磁性而不是 电场诱导癫痫发作，其具有较浅的穿透，因此避免了不期望的侧面， 对内侧颞叶进行强电刺激的效果。到目前为止，还没有任何研究 MST的抗抑郁和神经认知作用的神经机制。系统地 发现这些机制，我们正在建立一个国际，NIMH资助（R 01 MH 112815），美国食品 和药品监督管理局试验用器械豁免（IDE; #G170127）批准的临床研究， 比较ECT和MST的临床和神经认知结果。R 01的目标是 开展研究确定神经回路，以加强神经调节发展（ASCEND）。在 在拟议的研究中，我们将利用该项目，通过增加先进的磁共振成像（MRI）， ECT和MST（刺激大脑区域的电场）的个性化三维计算头部建模，以及 神经生理学建模的活动传播和可塑性，从每种治疗类型。这 创新的5年项目有两个目标：1）确定共同的和不同的神经回路相关的 RUL-UB-ECT和MST之间的抗抑郁治疗反应，以及2）确定共同和 RUL-UB-ECT和MST之间记忆副作用的明显神经回路相关性。拟定研究 将利用来自不同背景的跨学科团队，包括翻译神经认知 科学、神经心理学、计算神经科学、精神病学、神经成像、生物工程和 生物统计学物理（电场）和生理（神经活动和动力学）计算的综合 目前NIMH资助的临床试验的临床和神经认知指标的建模和MRI将 使我们能够确定神经调节引起的神经回路变化，以及它们相应的 关系到行为。这些知识将阐明抗抑郁剂癫痫发作的神经机制 治疗（ECT，MST），为最佳靶向与症状相关的神经回路的新治疗方法提供信息 改善，同时确保神经认知安全。这些发展将对 改善许多TRD患者的生活，并产生实质性的积极公共卫生影响。

PROJECT ABSTRACT Major depressive disorder (MDD) is ranked second among all diseases in global impact. Unfortunately, many patients have treatment-resistant MDD (TRD), for which the most effective antidepressant treatment option is electroconvulsive therapy (ECT). However, the neurocognitive adverse effects (e.g., anterograde and retrograde amnesia) induced by ECT mitigate the attainment of desired clinical outcomes. As such, the development of new and safe neuromodulatory antidepressant interventions is strongly warranted. One new type of neuromodulation treatment that has antidepressant properties and is under active development is magnetic seizure therapy (MST). MST is neurocognitively safer than ECT because it uses magnetic rather than electrical fields to induce seizures, which have shallower penetration and therefore avoid the undesired side- effect of delivering intense electrical stimulation to the medial temporal lobe. As yet there has been no research into the neuromechanisms underlying MST’s antidepressant and neurocognitive effects. To systematically uncover these mechanisms, we are building upon an international, NIMH funded (R01 MH112815), US Food and Drug Administration Investigational Device Exemption (IDE; #G170127) approved clinical study that will compare and contrast clinical and neurocognitive outcomes of ECT and MST. The goal of this R01 is to conduct research Ascertaining Neurocircuitry to Enhance Neuromodulation Development (ASCEND). In the proposed study, we will capitalize on that project by adding advanced magnetic resonance imaging (MRI), individualized 3-D computational head modeling of ECT and MST (E-fields in stimulated brain regions), and neurophysiological modeling of activity propagation and plasticity resulting from each treatment type. This innovative 5-year project has two aims: 1) Determine the common and distinct neural circuit correlates of antidepressant treatment response between RUL-UB-ECT and MST, and 2) Determine the common and distinct neural circuit correlates of memory side effects between RUL-UB-ECT and MST. The proposed study will draw upon an interdisciplinary team from diverse backgrounds including translational neurocognitive science, neuropsychology, computational neuroscience, psychiatry, neuroimaging, bioengineering, and biostatistics. The synthesis of physical (E-field) and physiological (neural activity and dynamics) computational modeling and MRI with the clinical and neurocognitive metrics from the current NIMH-funded clinical trial will allow us to determine neuromodulation-induced changes in neurocircuitry, and their corresponding relationships to behavior. Such knowledge will elucidate the neural mechanisms of antidepressant seizure therapy (ECT, MST) to inform new treatment methods that optimally target neurocircuitry related to symptom improvement, while ensuring neurocognitive safety. These developments will make a major contribution to improving the lives of the many patients with TRD and yield a substantial positive public health impact.