Low intensity focused ultrasound: a new paradigm for depression and anxiety

项目摘要/摘要 目前治疗抑郁症和焦虑症的方法往往受到部分疗效和显著副作用的限制。 由于严重的疾病负担，这些疾病构成了严重的公共卫生挑战，而且缺乏 更有效的治疗方法会增加大量的自杀风险。为了解决这些未得到满足的需求，非侵入性 脑刺激是一种以电路为基础的治疗方法，副作用最小；临床上可用于 抑郁症和强迫症，以及对焦虑和创伤后应激有效的证据 无序。与这些疾病有关的核心大脑区域之一是杏仁核，它的 在显著检测和情绪处理中的关键作用。这一区域表现出病理性的激活 治疗成功后，几乎所有的抑郁症和焦虑症以及病理活动都会发生变化。然而， 由于杏仁核位于皮质表面的远端，因此目前的技术无法直接接触到它。我们的 挑战是找到一种方法，在更广泛的假设下，有针对性地、非侵入性地调节杏仁核 这种直接参与将产生具有卓越临床结果的治疗方法。 低强度脉冲聚焦超声(LIFU)将无创声能量应用于安全 调节翻译模型和非人类灵长类动物的神经活动。不同于经颅磁或 电刺激和相关技术，利福能够直接和焦点调制深部的活动 大脑结构。利福可以安全地调节人体躯体感觉和运动皮质，并安全地抑制 丘脑活动；最近的数据表明，它可以抑制杏仁核的活动。此外，与MRI兼容的 LIFU系统现已可用(美国洛杉矶Brainsonix公司)，从而允许同时进行fMRI-LIFU实验。 这些因素创造了一个令人信服的论点，将理府发展为一种治疗抑郁症和焦虑症的方法 测试它是否可以安全地调节杏仁核。 为了为未来的临床试验奠定基础，我们必须首先测试利福是如何与患者的杏仁核接合的 带着抑郁和焦虑。根据U01RFA，我们提出了几个中试实验。我们会 系统评估安全性(目标1)，因为我们评估目标交战的空间特性，使用在线和 离线方法(目标2-3)使用随机、解剖控制的实验设计，并探索 利福对临床症状的影响。我们获得了FDA的调查设备豁免(IDE) 对于这项提案，就像它写的那样。 如果成功，这项人类第一提案将提供必要的数据，以支持广泛的和 程序性研究侧重于临床应用利福治疗抑郁症和焦虑症。由此产生的数据将通知 未来的研究，包括改进利福的个人水平建模，通知最优目标 参与、改进利福骗局，以及评估各种利福参数或多个会话的效果。

PROJECT SUMMARY/ABSTRACT Current treatments for depression and anxiety are often limited by partial efficacy and significant side effects. These disorders constitute serious public health challenges due to significant burden of illness, and the lack of more effective treatments contributes to substantial suicide risks. To address these unmet needs, non-invasive brain stimulation is a circuit-based treatment with minimal side effects; it is clinically available for major depression and obsessive-compulsive disorder, with evidence for efficacy in anxiety and posttraumatic stress disorder. One of the core brain regions involved in these disorders, among others, is the amygdala, with its critical role in salience detection and emotion processing. This region demonstrates pathological activation in nearly all depressive and anxiety disorders, and pathological activity changes with successful treatment. Yet, because the amygdala is distal to the cortical surface it is not directly accessible with current technologies. Our challenge is to find a way to focally and non-invasively modulate the amygdala, with the broader hypothesis that direct engagement will yield treatments with superior clinical outcomes. Low intensity pulsed focused ultrasound (LIFU) applies non-invasive acoustic energy to safely modulate neural activity in translational models and non-human primates. Unlike transcranial magnetic or electrical stimulation and related technologies, LIFU is able to directly and focally modulate activity within deep brain structures. LIFU can safely modulate human somatosensory and motor cortex and safely suppress thalamic activity; recent data indicates it can suppress amygdala activity. Furthermore, an MRI-compatible LIFU system is now available (Brainsonix, Inc. LA, USA), thus permitting simultaneous fMRI-LIFU experiments. These factors create a compelling argument to develop LIFU as a treatment for depression and anxiety by testing whether it can safely modulate the amygdala. To set the stage for future clinical trials, we must first test how LIFU engages the amygdala in patients with depression and anxiety. In accordance with the U01 RFA, we propose several pilot experiments. We will systematically assess safety (Aim 1) as we evaluate spatial specificity of target engagement, using online and offline approaches (Aims 2-3) using a randomized, anatomically controlled, experimental design, and explore the impact of LIFU on clinical symptoms. We obtained an Investigational Device Exemption (IDE) from the FDA for this proposal as it is written. If successful, this first-in-human proposal will provide the necessary data to support a broad and programmatic research focus on clinically applied LIFU for depression and anxiety. Resulting data will inform future studies, including improvement of individual-level modeling for LIFU, informing optimal targets to engage, refinement of LIFU shams, and evaluating effects of varied LIFU parameters or multiple sessions.