Development of Low-Intensity Focused Ultrasound for Post Traumatic Brain Injury Depression

Inclusion Criteria:

1. Adult Veteran, male or female, 22 to 55 years of age at the time of screening.
2. Able to read, understand, and provide written, dated informed consent before initiation of formal study screening procedures. A brief IRB-approved telephone pre-screen may be conducted prior to written informed consent as described in Section 8.1. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and LIFU interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
3. History of non-penetrating mild to moderate TBI confirmed by medical records and adjudicated by the study investigator using established TBI criteria (e.g., ACRM/VA-DoD criteria). If contemporaneous records are incomplete, a structured lifetime TBI interview may be used to support classification.
4. The TBI must have occurred at least 3 months before the occurrence of depression
5. Current depressive disorder defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
6. Medical records confirming a history of moderate to severe treatment-resistance as defined by a score of 7-14 on the Maudsley Staging Method (MSM3).
7. MADRS score of ≥20 at screening.
8. Total duration of current depressive episode is less than 2 years
9. LIFU naive.
10. Access to ongoing psychiatric care before and after completion of the study.
11. The dose of the primary antidepressant medication must be stable for 6 weeks prior to baseline , and participants must agree to continue at this dose throughout the study period.
12. In good general health, as evidenced by medical history.
13. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to baseline and agreement to use such a method during study participation.
14. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration.

Exclusion Criteria:

1. Any lifetime DSM-5 depressive disorder or clinically significant depressive episode with onset prior to the qualifying index TBI, including major depressive disorder, persistent depressive disorder, or other specified/unspecified depressive disorder, or any antidepressant treatment initiated for depression prior to the index TBI.
2. Pregnancy
3. Primary psychiatric condition other than MDD requiring treatment except stable comorbid anxiety disorder
4. History of or current psychotic disorder or bipolar disorder
5. Severe borderline personality disorder.
6. Diagnosis of Intellectual Disability or Autism Spectrum Disorder
7. Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
8. Urine screening test positive for illicit substances
9. Active suicidal ideation (defined as an MSSI > 8) or a suicide attempt (as defined by the C-SSRS) within the past one year
10. Cognitive impairment (defined as MoCA < 23)

10. Any history of ECT without meeting responder criteria 11. Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT) 12. History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, or multiple sclerosis 13. Untreated or insufficiently treated endocrine disorder. 14. Contraindication to receiving LIFU 15. Contraindication to MRI (ferromagnetic metal in their body) 16. Treatment with another investigational drug or other intervention within the study period 17. Unstable symptoms between screening and baseline as defined by a > 30% change in MADRS-S score.

18. Any other condition deemed by the PD to interfere with the study or increase risk to the participant