Objective: Preliminary studies show that low intensity focused ultrasound (LIFU), a new type of non invasive brain stimulation, may be able to reach deep structures of the brain involved with depression and anxiety, that remain inaccessible using current forms of non-invasive brain stimulation with precision. In this study, the investigators will test if this technique can be used to change brain activity in areas that are connected to depression and anxiety symptoms. The primary objectives of this study are to test the safety and tolerability of LIFU, evaluate the feasibility of using LIFU to reduce brain activity, and evaluate the feasibility of simultaneous fMRI-LIFU. If the results of this study are positive, what the investigators learn will serve as a strong foundation for the future development of innovative treatments for a variety of psychiatric disorders.

Research Procedures: 25 veterans will be recruited. Visits will take place at the VA Providence Healthcare System. During some visits, healthy and patient participants may undergo clinical and research neuroimaging, neuropsychological testing, complete questionnaires, and participate in clinical/neurological assessments. Healthy veterans will not receive LIFU and will only attend 2 study visits. Patients are expected to attend up to 8 visits over 6 weeks. However, some may require up to 6 extended follow-ups after visits 5 or 8, in which case they would attend a total of 11 or 14 visits over 6 months. Two patient visits will include the LIFU application, following FDA safety guidelines. Patients will be assigned either to an experiment in which LIFU stimulation will be delivered immediately prior to a task or to an experiment in which stimulation will be delivered during the task. Within each experiment, patients will be assigned to first receive either LIFU stimulation to the study target or anatomical control. Study staff, but not participants will know which location is being targeted in case safety concerns arise. Safety assessments will be conducted at follow-up visits. A clinician will be available during LIFU administration /follow-up visits. Assuming no injury or other concerns are present, patients will then repeat this process again, receiving stimulation targeting other brain area not previously selected.

US military Veterans

Inclusion Criteria:

• Patients must meet DSM-5 criteria for major depressive disorder with and without anxiety symptoms
• Patients must also be symptomatic (i.e. symptom severity above clinical thresholds using standard rating scales) and, if relevant, stable treatment(s) for >6 weeks.

Exclusion Criteria:

• history of seizure disorder or serious neurologic illness including dementia
• structural or neurologic abnormalities present or in close proximity to sonication site for patients (e.g., clinically significant calcification as might be observed in Fahr disease)
• history of brain surgery, iv) pacemaker or implanted central nervous system device
• greater than mild traumatic brain injury, or any head injury within sixty days of participation
• greater than moderate alcohol or substance use disorders (last six months; excluding nicotine/caffeine)
• active use or withdrawal from alcohol or substances (assessed via breathalyzer/urine testing as indicated)
• metal in the head
• impediment to vision, hearing and/or hand use likely to interfere with assessments
• pregnant or lactating (assessed via pregnancy test)
• unable to follow protocols
• acute suicidality, defined as "Yes" on item 4 of the Columbia Suicide Severity Rating Scale (C-SSRS), (i.e., active suicidal ideation with some intent to act on thoughts), or any endorsement of item 5 (active ideation with specific plan and intent) or any actual, interrupted, aborted attempt or preparatory behavior within the past month.
• symptom threshold considered in the "very severe" range using standard rating scales will be excluded.

data may be available via the NIMH Data Archive

Single blind administration