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

The goal of this clinical trial is to learn about evaluate the safety, tolerability, and feasibility of MRI-guided LIFU targeting the sgACC in Veterans with post-traumatic brain injury depression. The main questions it aims to answer are:

1. the safety, tolerability, and feasibility of MRI-guided LIFU.
2. Evaluate preliminary antidepressant efficacy.
3. Characterize target engagement using multimodal neuroimaging and electrophysiology.
4. Identify imaging and electrophysiological biomarkers that predict treatment response.
5. Generate preliminary effect size estimates to support future multicenter clinical trials.

Study Overview

• Status: Not yet recruiting
• Conditions: Veteran Health; Post-traumatic Brain Injury Depression
• Intervention / Treatment: Device: Active Low-Intensity Focused Ultrasound (LIFU); Other: Sham Low-Intensity Focused Ultrasound (LIFU)

Detailed Description

The study is a single-site, randomized (3:2 to active LIFU or sham), rater- and participant-blinded mechanistic study of MRI-guided low-intensity focused ultrasound (LI-FUS) targeting the subgenual anterior cingulate cortex (sgACC) in adult Veterans with post traumatic brain injury depression (PTD). The purpose of this study is to evaluate the safety and tolerability of repeated sgACC-targeted LI-FUS stimulation in adult Veterans with PTD. To evaluate the preliminary antidepressant efficacy of repeated sgACC-targeted LI-FUS in adult Veterans with PTD. To characterize the relationship between delivered LI-FUS dose and clinical response in adult Veterans with PTD. To characterize changes in neuroimaging and electrophysiologic measures associated with LI-FUS, including fMRI- and EEG-based indices of target engagement and network modulation, in adult Veterans with PTD. (b) To evaluate whether baseline fMRI and EEG features predict clinical response to LI-FUS in adult Veterans with PTD.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Masataka Wada, MD; Phone Number: 650-434-7844; Email: mwada@stanford.edu
• Study Contact Backup: Name: John P Coetzee, PhD; Email: jpcoetzee@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine
      • Contact: Nick Bassano, MSW; Phone Number: 6504973933; Email: nbassano@stanford.edu
      • Principal Investigator: Mahendra Bhati, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Low-Intensity Focused Ultrasound (LIFU); Participants receive active LIFU over 5 consecutive treatment days, with 5 sessions per day and 20 minutes per session	Device: Active Low-Intensity Focused Ultrasound (LIFU); MRI-guided Low-Intensity Focused Ultrasound (LIFU) neuromodulation targeting the sgACC delivered over a brief, intensive course (20-minute sessions; 5 sessions/day for 5 consecutive days).
Sham Comparator: Sham Low-Intensity Focused Ultrasound (LIFU); Participants receive sham LIFU over 5 consecutive treatment days, with 5 sessions per day and 20 minutes per session	Other: Sham Low-Intensity Focused Ultrasound (LIFU); Non-active MRI-guided Low-Intensity Focused Ultrasound (LIFU) neuromodulation targeting the sgACC delivered over a brief, intensive course (20-minute sessions; 5 sessions/day for 5 consecutive days).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the safety and tolerability of repeated sgACC-targeted LIFU stimulation in adult Veterans with PTD.	Cumulative incidence of treatment-emergent adverse events and serious adverse events.	Baseline, Treatment Days 1 through 5, 1-Week, 1-2:4-week follow up visits.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the preliminary antidepressant efficacy of repeated sgACC-targeted LIFU in adult Veterans with PTD.	Absolute change from baseline in the MADRS total score.	Baseline, 1-week follow up, 4-week follow up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterize changes in neuroimaging measures associated with LIFU.	Change from baseline in prespecified resting-state fMRI measures of sgACC-centered functional connectivity and depression-related network connectivity.	Baseline and 1-week follow-up
To characterize changes in electrophysiologic measures associated with LIFU.	Change from baseline in prespecified resting-state and LIFU-associated EEG measures of neural activity and functional connectivity.	Baseline, treatment days 1 through 5 and 1-week follow-up
To evaluate whether baseline fMRI feature predict clinical response to LIFU.	Associations between baseline fMRI features and absolute change from baseline in MADRS total score.	Baseline, 1-week follow up and 4-week follow up visits
To evaluate whether baseline EEG features predict clinical response to LIFU.	Associations between baseline EEG features and absolute change from baseline in MADRS total score.	Baseline, 1-week follow up and 4-week follow up visits

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: VA Palo Alto Health Care System
• Investigators: Principal Investigator: Mahendra Bhati, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: September 14, 2026
• First Submitted That Met QC Criteria: September 14, 2026
• First Posted (Actual): September 18, 2026

Study Record Updates

• Last Update Posted (Actual): September 18, 2026
• Last Update Submitted That Met QC Criteria: September 14, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: depression; veteran; post-traumatic brain injury
• Additional Relevant MeSH Terms: Behavioral Symptoms; Behavior; Depression
• Other Study ID Numbers: 85834 (Hillman)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No