Dose-dependent effects of neuromodulation on headaches in mild traumatic brain injury

The National Institute of Child Health and Human Development awarded The Research Foundation For The State University Of New York $326,000 on September 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate dose-dependent effects of repetitive transcranial magnetic stimulation (rTMS) on post-traumatic headaches in mild traumatic brain injury.

The project expands an ongoing clinical trial that demonstrated moderate-dose rTMS outperformed sham-rTMS in reducing persistent post-traumatic headaches and post-concussion symptoms. This award adds high-dose and low-dose rTMS arms to define the dose-response relationship and identify the optimal balance between therapeutic benefit and treatment burden. The research addresses a critical gap in managing persistent post-traumatic headaches, which conventional analgesic medications have not effectively treated and which impair attention, memory, sleep, and physical activity—factors that reduce rehabilitation responsiveness in mild traumatic brain injury patients.

Work is performed in Syracuse, New York, with a period of performance from September 1, 2026, through August 31, 2028. The recipient organization, The Research Foundation For The State University Of New York (operating as Upstate Medical Center), serves as the sponsored programs administrator and fiscal agent for the State University of New York system.

Abstract

Headache is one of the most common symptoms in people experiencing mild traumatic brain injury (MTBI) as a result of a concussion. Persistent post-traumatic headaches (PTH) following a concussion are crucial determinants of prolonged recovery and poor rehabilitation outcomes, which lead to physical and emotional burdens. Although rehabilitation for individuals with MTBI emphasizes post-concussion symptoms (PCS), such as cognitive, psychological, and vestibular deficits, PTH is often not a targeted symptom in rehabilitation. This is because persistent PTH is challenging to manage. Conventional analgesic medications have not been shown to be effective in managing persistent headaches and often lead to side effects such as sedation and complications of abuse or misuse (e.g., opioid overdose). Given that PTH adversely impacts attention, memory, sleep, and physical activity, which are risk factors associated with poor responsiveness to rehabilitation, there is an urgent need to find an alternative treatment option for persistent PTH in MTBI. Repetitive transcranial magnetic stimulation (RTMS) is an emerging and safe non-pharmacological treatment for lingering symptoms following MTBI with heterogeneous benefits for PTH and PCS. Although RTMS appears to be a promising treatment for the sequelae of MTBI, we know virtually nothing about the mechanism underlying the neuromodulatory effects of RTMS. Building on our ongoing clinical trial with demonstrated long- term efficacy (moderate-dose RTMS outperformed sham-RTMS in reducing PTH and PCS), this project adds two new doses (high-dose and low-dose RTMS) to define the RTMS dose-response relationship and pinpoint the optimal balance between therapeutic benefit and treatment burden. Therefore, the overarching goals of this project are to: 1) determine the dose effects of RTMS applied to the primary motor cortex on persistent PTH and global PCS in MTBI with four RTMS dosages (high-dose, moderate-dose, low-dose, and sham); 2) characterize RTMS-induced neuroplasticity by integrating TMS-derived neurophysiological measures with blood-based molecular data using the brain gene expression and network imputation engine (BRAINGENIE); and 3) develop a predictive model integrating central and imputed brain biomarkers to identify and characterize responders and guide individualized RTMS dosing. This is the first study to illustrate mechanisms of action by providing in vivo neurophysiological and molecular data of RTMS-induced plasticity in the human brain through transcriptomic and proteomic imputation. Neuromodulation-sensitive biomarkers will be the steppingstone to generate mechanistic hypotheses for future MTBI research. Specifically, subsequent work will drive neuroplasticity with tailored RTMS dosages and probe pragmatic outcomes such as return to work. This randomized controlled trial harnesses an interdisciplinary team to carry out a translational research project using RTMS as an alternative long-term solution for persistent PTH and global PCS in MTBI.