This study will evaluate a new form of non-invasive brain stimulation for individuals with depression. Personalized low-intensity transcranial focused ultrasound stimulation will first be delivered using a range of stimulation parameters during psychological and physiological monitoring. A well-tolerated stimulation protocol will then be selected for subsequent testing in a blinded randomized sham-controlled cross-over trial to evaluate brain target engagement using magnetic resonance imaging.

Inclusion Criteria:

1. Age 18-65, any gender
2. Primary diagnosis of major depressive disorder or bipolar disorder
3. Current moderate-to-severe depressive episode, without psychotic features, lasting at least 2 months
4. Self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS) total score > 10
5. Stated willingness to comply with all study procedures and avoid changes to psychiatric treatments (medications, psychotherapy) for the duration of the study
6. For females of reproductive potential: negative pregnancy test or use of highly effective contraception for at least 1 month prior to baseline; agreement to use such a method throughout the study
7. Capacity to provide informed consent; provision of a signed and dated consent form

Exclusion Criteria:

1. History of serious brain injury or other neurologic disorder
2. Poorly managed general medical condition
3. Pregnant or breast feeding
4. Implanted device in the head or neck
5. MRI intolerance or contraindication
6. Brain stimulation (e.g., ECT, TMS, VNS) in the past month
7. Suicidal ideation (Columbia Suicide Severity Rating Scale screen item #2, past month)
8. Lifetime history of a serious suicide attempt
9. Moderate-to-severe substance use disorder (past 3 months)
10. Obsessive compulsive disorder (past month)
11. Posttraumatic stress disorder (past month)
12. Schizophrenia-spectrum disorder (lifetime)
13. Neurocognitive disorder (past year)
14. Personality disorder as a current focus of treatment
15. Clinically inappropriate for participation in the study as determined by the study team