Personalized Ultrasonic Brain Stimulation for Depression (R61)

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, lastingat least 2 months (MINI).

4. Self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS) total score >

6. History of at least 2 failed trials of evidence-based antidepressant medicationand/or psychotherapy (at least one trial during the current depressive episode).

7. Stated willingness to comply with all study procedures and avoid changes topsychiatric treatments (medications, psychotherapy) for the duration of the study.

8. For participants of reproductive potential: negative pregnancy test or use of highlyeffective contraception for at least 1 month prior to baseline; agreement to usesuch a method throughout the study.

9. Capacity to provide informed consent; provision of a signed and dated consent form

10. Currently are under the care of a licensed psychiatrist or other mental health careprovider, or a licensed addiction medicine specialist and agrees to promptly informthe investigator or the study staff of any change in these providers.

11. Agrees to allow any and all forms of communication between the investigators/studystaff and any healthcare provider who currently provides and/or has provided serviceto the patient/subject within at least two years of study enrollment for thepurposes of eligibility confirmation or in case of a safety event.

12. Agrees to provide the name and verifiable contact information (email and mailingaddresses, mobile and land-line phone numbers, as applicable) of at least twopersons 22 years or older who reside within a 60-minute drive of the patient'sresidence. Subject agrees that in the event of a safety concern or event duringstudy participation, research staff is at liberty to contact these individuals ifthe 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).

9. Moderate-High Risk of Suicide according to the Columbia - Suicide SeverityRating Scale (C-SSRS) Screen Version - Recent (answers YES to Question 3 and NOto Question 6 (Moderate risk) or YES to Question 4, 5, or 6 (High risk)) and/orin the clinical judgement of the PI or a study psychiatrist

10. Suicidal behavior (past year).

11. Serious suicide attempt 33 (lifetime).

12. Moderate-to-severe substance use disorder (MINI, past 3 months).

13. Obsessive compulsive disorder, primary diagnosis (MINI, past month).

14. Posttraumatic stress disorder, primary diagnosis (MINI, past month).

15. Bipolar-spectrum disorder (MINI, lifetime).

16. Schizophrenia-spectrum disorder (MINI, lifetime).

17. Neurocognitive disorder (DSM-5, past year).

18. Severe personality disorder.

19. Clinically inappropriate for participation in the study as determined by the studyteam.