Inclusion Criteria:
1. Persons 18-65 years old, with sex and ethnicity recruitment targets including a M:F proportion of 1:2 and White:Black:Hispanic:Native American proportion as close as possible to 8:2:2:1 to reflect the regional epidemiology of TRD (63% White American; 16% African American; 14% Hispanic of any race; 5% Native American),
2. DSM-5-TR diagnosis of MDD as confirmed by MINI structured interview followed by consultation with a board-certified psychiatrist,
3. Evidence of treatment resistance defined as continued MDD symptoms despite any of the following:
1. two or more adequate (6 week) trials of antidepressants with different mechanisms,
2. evidence-based psychotherapy,
3. augmentation agent (lithium, atypical antipsychotic, or T3), or
4. consideration of ECT or prior ECT nonresponse or intolerance,
4. at least moderate symptoms as indicated by MADRS≥20 upon screening
5. stable treatments including psychotherapy and medication for at least six weeks prior to participation.
6. Fluent English speaker, capable of written consent
7. Consent that random observations of pathology are possible (e.g., brain abnormality seen during imaging)
Exclusion Criteria:
1. Clinical history of at least minor neurocognitive disorder of neurodegenerative origin,
2. PROMIS (Cognitive Function scale) score ≤40 (i.e., mean - 1SD), collected at baseline
3. clinical history of relevant structural pathology of the central nervous system, including Parkinson's disease, multiple sclerosis, and brain malignant neoplasia,
4. uncontrolled diabetes mellitus (as evidenced by a fasting glycemia ≥ 120 mg/dL or hemoglobin A1c ≥ 6.5%) or hypertension (as evidenced by two consecutive readings ≥ 140/90 mmHg) to ensure medical stability, collected at baseline
5. pregnancy or lactation,
6. Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, amphetamine/methamphetamine, and ecstasy), or substance use disorder including alcohol, stimulants, sedatives, and cannabis exceeding mild severity in the last 6 months,
7. active suicidal ideation (as measured by Suicide-Risk-Assessment-C-SSRS75 "Yes" answers to items 3, 4 or 5 of Suicidal Ideation-Past 1 month section, or any "Yes" answer to any of the items of Suicidal Behavior-Past 3 months section), or any suicide attempt in the last 3 months, collected at baseline
8. MRI contraindications as detected by the MRI Safety Screen, including unwillingness/unable to complete MRI scans
9. medical history indicative of moderate to severe traumatic brain injury as evidenced by history of \> 5 minutes of loss of consciousness, or of skull fractures, which in theory could distort LIFU tissue propagation, and
10. a current diagnosis of a psychotic disorder (e.g. schizophrenia, bipolar disorder), an eating disorder (e.g. anorexia or bulimia nervosa), learning disability, or a personality disorder that is considered by the investigator to interfere with the ability of the subject to adhere to the protocol (e.g., narcissistic personality disorder, borderline personality disorder).
11. Has a history of moderate or severe substance or alcohol use disorder according to DSM-5-TR
12. Use of benzodiazepines or anticonvulsants in the 7 days prior ot screening
13. Medical, psychiatric, or other conditions that restrict the patient's following abilities: to interpret the study information, to give informed consent, to adhere to the rules of the protocol, or to complete the study.
14. No reliable method of communication (i.e., no access to internet or phone connection)
15. Prescription of a medication outside of the accepted range, as determined by best clinical practices and current research
16. Unwilligness or inability to complete any of the major aspects of the study protocol
17. Non-correctable vision or hearing problems
