Frontal-pole Neuromodulation for Impulsivity and Suicidality in Veterans with Mild Traumatic Brain Injury and Common Co-Occurring Mental Health Conditions: Protocol for a Pilot Randomized Controlled Trial (Preprint)

BACKGROUND Suicide remains a leading cause of death among Veterans, and mild traumatic brain injury (mTBI) increases the risk of suicidal ideation and suicide attempts (SI/SA). mTBI worsens impulsivity and contributes to poor social and occupational functioning, which further increasing the risk of SI/SA. Repetitive transcranial magnetic stimulation (TMS) is a neuromodulation treatment approach designed to mimic endogenous brain rhythms. Intermittent theta burst stimulation (iTBS) is a "second-generation" form of TMS that is safe, shorter in duration, displays a minimal side effect profile, and is a promising treatment approach for impulsivity in mTBI. Our novel treatment uses frontal pole stimulation to target the ventromedial prefrontal cortex (VMPFC) and may reduce impulsivity by strengthening functional connectivity between the limbic system and frontal cortex, potentially saving lives. OBJECTIVE The objectives of this study are to (1) develop an iTBS intervention for individuals with mTBI and SI, (2) assess the feasibility and tolerability of the intervention, and (3) gather preliminary clinical outcome data on SI, impulsivity, and functioning that will guide future studies. METHODS This is a pilot, double-blinded, randomized controlled trial. In developing this protocol, we referenced SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials). We will enroll 50 subjects (25 active iTBS and 25 sham iTBS). The iTBS intervention will be performed daily, five days a week, for two weeks. We will collect quantitative outcome measures before and after the intervention. Measures included will assess functioning (Social and Occupational Functioning Assessment Scale (SOFAS), Veteran RAND-36), impulsivity (Urgency, Premeditation (lack of), Preservation (lack of), Sensation Seeking, Positive Urgency Impulsive Behavior Scale – Negative Urgency subscale (UPPS-P)), SI (Beck Suicide Scale (BSS), Columbia Suicide Severity Rating Scale (C-SSRS)), PTSD symptoms (PTSD Checklist for DSM-5 (CAPS-5) (PCL-5)), and depressive symptoms (Patient Health Questionnaire-9 (PHQ-9), Inventory for Depressive Symptoms – Self-Report (IDSSR)). We will collect qualitative data through semi-structured interviews to elicit feedback on the subject’s experience and symptoms. RESULTS This study protocol was approved by the Edward Hines Jr Veterans Administration Hospital Institutional Review Board (Hines IRB#14-003) and registered on ClinicalTrials.gov (NCT05647044). This novel treatment is a 5-year research project (04/01/2023 – 03/31/2028) funded by the VA Rehabilitation Research & Development (RR&D) service (CDA2 grant IK2 RX002938). Study results will be disseminated at or before the project’s end date in March 2028. CONCLUSIONS We will provide preliminary evidence of the safety, feasibility, and acceptability of a novel frontal pole iTBS treatment for mTBI, impulsivity, SI/SA, and functional deficits. CLINICALTRIAL ClinicalTrials.gov (NCT05647044); https://clinicaltrials.gov/study/NCT05647044