Post-traumatic Brain Injury Depression, Veteran Health
Conditions
Keywords
post-traumatic brain injury, depression, veteran
Brief summary
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.
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.
Interventions
DEVICEActive 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).
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).
Sponsors
Stanford University
VA Palo Alto Health Care System
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
The rater and participant will be blinded. Participants will be randomized 3:2 to Active LIFU or sham delivered.
Eligibility
Sex/Gender
ALL
Age
22 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the safety and tolerability of repeated sgACC-targeted LIFU stimulation in adult Veterans with PTD. | Baseline, Treatment Days 1 through 5, 1-Week, 1-2:4-week follow up visits. | Cumulative incidence of treatment-emergent adverse events and serious adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the preliminary antidepressant efficacy of repeated sgACC-targeted LIFU in adult Veterans with PTD. | Baseline, 1-week follow up, 4-week follow up | Absolute change from baseline in the MADRS total score. |
Countries
United States
Contacts
CONTACTMasataka Wada, MD
CONTACTJohn P Coetzee, PhD
PRINCIPAL_INVESTIGATORMahendra Bhati, MD
Stanford University
Outcome results
None listed