Transcranial focused ultrasound neuromodulation for post-traumatic stress disorder: Emerging evidence and outstanding challenges.

Post-traumatic stress disorder (PTSD) is a psychiatric condition precipitated by exposure to severe, threatening, or catastrophic events and is characterized by core symptoms including intrusion symptoms, avoidance behaviours, altered mood, and altered reactivity. Although evidence-based treatments, including trauma-focused psychotherapy and selective serotonin reuptake inhibitors, provide benefit for some patients, a substantial proportion exhibit incomplete response, relapse, or treatment resistance, underscoring an urgent need for novel therapeutic strategies. Transcranial focused ultrasound stimulation (tFUS) is an emerging non-invasive neuromodulation technique distinguished by its superior cranial penetrability and millimeter-scale spatial resolution. These properties enable relatively precise modulation of deep brain structures implicated in PTSD pathophysiology. In this review, we systematically examine the core neural circuitry implicated in PTSD. We place particular emphasis on the molecular and circuit-level mechanisms through which tFUS modulates neuronal excitability, synaptic plasticity, and large-scale network dynamics via mechanotransduction. We further synthesize emerging evidence from preclinical models and early-stage clinical studies suggesting that tFUS may reduce fear-related behaviours and improve PTSD-related symptoms. Finally, we critically discuss key challenges hindering clinical translation, including correcting transcranial acoustic aberrations, standardizing stimulation parameters, and achieving precise, individualized targeting. Collectively, this review highlights the potential of tFUS as an emerging neuromodulatory approach for PTSD, while underscoring several important mechanistic, technical, and translational challenges that remain to be addressed before broader clinical implementation.