This study will evaluate a new form of non-invasive brain stimulation for individuals with depression. Personalized low-intensity transcranial focused ultrasound stimulation will be delivered using a range of stimulation parameters during psychological and physiological monitoring. Individualized optimal targets will be selected using structural MRI and diffusion tractography. Brain target engagement will be evaluated using functional MRI.

This R61 project has 3 aims:

1. To determine whether stimulation engages the subcallosal cingulate (SCC) in an intensity-dependent manner
2. To examine the degree of specificity of neuromodulation by contrasting the neural effects of stimulating two spatially distinct targets versus sham
3. To evaluate safety, tolerability, and side effects

Inclusion Criteria:

1. Age 18-65, any gender.
2. Primary diagnosis of DMS-5 major depressive disorder (MINI).
3. Current moderate-to-severe depressive episode, without psychotic features, lasting at least 2 months (MINI).
4. Self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS) total score > 10.
5. History of at least 2 failed trials of evidence-based antidepressant medication and/or psychotherapy (at least one trial during the current depressive episode).
6. Stated willingness to comply with all study procedures and avoid changes to psychiatric treatments (medications, psychotherapy) for the duration of the study.
7. For participants 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.
8. Capacity to provide informed consent; provision of a signed and dated consent form
9. Currently are under the care of a licensed psychiatrist or other mental health care provider, or a licensed addiction medicine specialist and agrees to promptly inform the investigator or the study staff of any change in these providers.
10. Agrees to allow any and all forms of communication between the investigators/study staff and any healthcare provider who currently provides and/or has provided service to the patient/subject within at least two years of study enrollment for the purposes of eligibility confirmation or in case of a safety event.
11. Agrees to provide the name and verifiable contact information (email and mailing addresses, mobile and land-line phone numbers, as applicable) of at least two persons 22 years or older who reside within a 60-minute drive of the patient's residence. Subject agrees that in the event of a safety concern or event during study participation, research staff is at liberty to contact these individuals if the subject does not respond to contact attempts.

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 treatment such as ECT, TMS, or VNS (past month).
7. Recent change in antidepressant treatments (past month).
8. 8. Moderate-High Risk of Suicide according to the Columbia - Suicide Severity Rating Scale (C-SSRS) Screen Version - Recent (answers YES to Question 3 and NO to Question 6 (Moderate risk) or YES to Question 4, 5, or 6 (High risk)) and/or in the clinical judgement of the PI or a study psychiatrist
9. Suicidal behavior (past year).
10. Serious suicide attempt 33 (lifetime).
11. Moderate-to-severe substance use disorder (MINI, past 3 months).
12. Obsessive compulsive disorder, primary diagnosis (MINI, past month).
13. Posttraumatic stress disorder, primary diagnosis (MINI, past month).
14. Bipolar-spectrum disorder (MINI, lifetime).
15. Schizophrenia-spectrum disorder (MINI, lifetime).
16. Neurocognitive disorder (DSM-5, past year).
17. Severe personality disorder.
18. Clinically inappropriate for participation in the study as determined by the study team.

All individuals are masked except the device operator