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 sessi...