Adaptive Trial for the Treatment of Depressive Symptoms Associated with Concussion using Accelerated Intermittent Theta Burst Stimulation (ADEPT): Rationale, Design and Methods

Lindsay M Oberman^1*Adriana I. Penafiel²Rachel Dieterich³Cuong T. Phan²Yiyu Chou²Dzung L Pham⁴Maheen Mausoof Adamson^5,6Christopher E. Hines⁷Zeynab Rezaee¹Zhi-De Deng¹Hemant Pal⁸Sarah H. Lisanby^10,9David L. Brody^11,4

• ¹National Institute of Mental Health (NIH), Bethesda, United States
• ²Henry M Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, Maryland, United States
• ³Palo Alto Veterans Institute for Research, Palo Alto, California, United States
• ⁴Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, Bethesda, Illinois, United States
• ⁵VA Palo Alto Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Palo Alto, California, United States
• ⁶Department of Neurosurgery, School of Medicine, Stanford University, Stanford, California, United States
• ⁷Walter Reed National Military Medical Center, Bethesda, Maryland, United States
• ⁸William Beaumont Army Medical Center, El Paso, Texas, United States
• ⁹Arizona State University School of Medicine and Advanced Medical Engineering, Phoenix, Arizona, United States
• ¹⁰Department of Psychiatry & Behavioral Sciences, School of Medicine, Duke University, Durham, North Carolina, United States
• ¹¹Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Illinois, United States

Military service members (SMs) and veterans who have sustained one or more concussions during their service have significantly higher rates of persistent depressive symptoms and suicidality compared to non-injured peers. Despite over 500,000 SMs who have sustained concussions, there are currently no Level I evidence-based treatments for improving depressive symptoms associated with concussion. Accelerated intermittent theta burst stimulation (aiTBS), a specific repetitive transcranial magnetic stimulation (rTMS) protocol, targeted at the dorsolateral prefrontal cortex (DLPFC) has demonstrated efficacy and is cleared for the treatment of Major Depressive Disorder (MDD) by the United States Food and Drug Administration (FDA). The mechanism of action of aiTBS is thought to be via the modulation of functional networks. Herein we outline the design of a multisite, double-blind, randomized, sham-controlled trial of aiTBS for the treatment of depressive symptoms in SMs and veterans with a history of concussion. We present the rationale for this specific design and highlight the potential for personalized neuroimaging-informed parameter determination in this population where brain injuries have resulted in variable structural and functional brain circuitry disruptions.If successful, this project will accelerate solutions to improve the health, well-being, and healthcare of SMs and veterans with depressive symptoms following concussion.