Nearly 49,000 Americans die by suicide each year, while many more make attempts and live with distressing ideations. This heartbreaking reality requires urgent and innovative solutions beyond currently available interventions. Previous research has found that deficits in a psychological factor called cognitive flexibility—the capacity to adapt new thoughts and behaviors—are associated with a higher suicide risk in some individuals. The Suicide-related Experience Reduction via Enhancement of Neuroplasticity (SERENE) project aims to reduce suicidality by developing a new therapeutic protocol to improve cognitive flexibility. This protocol will include a combination of reversible, non-invasive Low Intensity Focused Ultrasound (LIFU) for deep brain and regional circuit neuromodulation and scalable Neuroplasticity-informed computerized cognitive training (NICCT).