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

项目总结/摘要 目前抑郁症和焦虑症的治疗往往受到部分疗效和显著副作用的限制。 这些疾病构成了严重的公共卫生挑战，因为疾病负担沉重，而且缺乏有效的预防措施。 更有效的治疗方法会增加自杀的风险。为了满足这些未满足的需求，非侵入性 脑刺激是一种基于电路的治疗方法，副作用最小;临床上可用于主要的 抑郁症和强迫症，有证据表明对焦虑和创伤后应激障碍有效 disorder.杏仁核是参与这些疾病的核心大脑区域之一， 在显著性检测和情绪处理中起着关键作用。该区域显示了在 几乎所有的抑郁症和焦虑症，以及病理活动的变化与成功的治疗。然而， 因为杏仁核远离皮质表面，所以用当前技术不能直接接近它。我们 挑战是找到一种方法，以集中和非侵入性调节杏仁核，与更广泛的假设， 直接参与将产生具有上级临床结果的治疗。 低强度脉冲聚焦超声（LIFU）应用非侵入性声能， 调节翻译模型和非人灵长类动物的神经活动。不像经颅磁或 电刺激和相关技术，LIFU能够直接和集中地调节深层内的活动， 大脑结构LIFU可以安全地调节人类躯体感觉和运动皮层， 丘脑活动;最近的数据表明它可以抑制杏仁核活动。此外，MRI兼容 LIFU系统现已上市（Brainsonix，Inc. LA，USA），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，开发LIFU作为抑郁症和焦虑症的治疗， 测试它是否能安全地调节杏仁核。 为了给未来的临床试验做好准备，我们必须首先测试LIFU是如何与患者的杏仁核结合的 抑郁和焦虑根据U 01 RFA，我们提出了几个试点实验。我们将 系统地评估安全性（目标1），因为我们使用在线和 离线方法（目标2-3），使用随机、解剖学对照、实验设计，并探索 LIFU对临床症状的影响。我们从FDA获得了试验用器械豁免（IDE） 这份提案是这么写的 如果成功的话，这一首次在人类身上提出的建议将提供必要的数据，以支持一个广泛的， 项目研究重点是临床应用LIFU治疗抑郁和焦虑。结果数据将告知 未来的研究，包括改进LIFU的个体水平建模，为最佳靶点提供信息， 参与、改进LIFU假模，并评估不同LIFU参数或多次治疗的效果。

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.