Ascertaining Neurocircuitry to Enhance Neuromodulation Development ASCEND

项目摘要 在全球影响方面，严重抑郁障碍(MDD)在所有疾病中排名第二。不幸的是，许多人 患者患有难治性MDD(TRD)，对于这种疾病，最有效的抗抑郁治疗选择是 电休克治疗(ECT)。然而，神经认知的不良影响(如顺行和 ECT引起的逆行性遗忘症)减轻了预期临床结果的实现。因此， 开发新的、安全的神经调节性抗抑郁药物干预措施是非常必要的。一个新的 一种具有抗抑郁特性并正在积极开发的神经调节疗法是 磁癫痫疗法(MST)。MST在神经认知方面比ECT更安全，因为它使用磁性而不是 诱发癫痫发作的电场，具有较浅的穿透性，因此避免了不受欢迎的一面- 对内侧颞叶进行强烈电刺激的效果。到目前为止，还没有研究 研究MST抗抑郁和神经认知作用的神经机制。有系统地 发现这些机制，我们正在建立一个国际，NIMH资助(R01 MH112815)，美国食品 和药品监督管理局研究设备豁免(IDE；#G170127)批准的临床研究将 比较和对比ECT和MST的临床和神经认知结果。这款R01的目标是 进行研究以确定神经回路以促进神经调节发育(ASCEND)。在……里面 在拟议的研究中，我们将利用该项目，增加先进的磁共振成像(MRI)， ECT和MST(刺激脑区的电场)的个性化三维计算头部建模，以及 每种治疗类型所产生的活动、繁殖和可塑性的神经生理学模型。这 创新的5年计划有两个目标：1)确定共同的和不同的神经回路关联 RUL-UB-ECT和MST的抗抑郁治疗反应，2)测定常见和 RUL-UB-ECT和MST之间不同的神经回路与记忆副作用相关。建议进行的研究 将利用一个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 使用NIMH资助的当前临床试验的临床和神经认知指标进行建模和磁共振成像将 使我们能够确定神经调节诱导的神经回路的变化，以及它们相应的 与行为的关系。这些知识将阐明抗抑郁药癫痫发作的神经机制。 治疗(ECT、MST)提供新的治疗方法，最佳地针对与症状相关的神经回路 改善，同时确保神经认知安全。这些发展将对以下方面做出重大贡献 改善许多TRD患者的生活，并产生重大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.