The goal of this clinical trial is to test a new type of magnetic brain stimulation in patients with persistent post-concussive symptoms. Participants will undergo detailed MRI scans before and after 30 treatment sessions (of 3-10 minutes each). The main questions the study aims to answer are:

• Will this new type of treatment result in fewer symptoms and better daily functioning?
• What are the effects of this treatment on brain functioning?

Repetitive transcranial magnetic stimulation (rTMS) seems a promising treatment option for patients with persistent post-concussive symptoms (PPCS). Traditional rTMS sessions are relatively long in duration and can be exhaustive for patients with PPCS. Intermittent theta-burst stimulation (iTBS) is a newer and more rapid form of rTMS, which only takes up to 10 minutes per session. However, little is known about the effects of iTBS in patients with PPCS. Furthermore, there is a pressing need for methods that reliably measure the effects of TMS treatments in-vivo. Using diffusion magnetic resonance spectroscopy (dMRS) changes in neural and glial cell morphology can be quantified, which makes it possible to disentangle neurometabolic changes related to neural injury and neuroinflammation, two key elements in the pathophysiology of mTBI.

In the current study, 15 patients with chronic (>3 months after mTBI) PPCS will undergo a total of 30 iTBS sessions. After a baseline scan, patients will enter a 2-week control waitlist period. Following the waitlist control, a pre-treatment scan is acquired, followed by the stimulation sessions, and final post-treatment scan. The scanning protocol includes T1 and T2 imaging, dMRS, multi-shell diffusion MRI (dMRI), as well as a demanding executive function fMRI task, and resting-state fMRI (rs-fMRI). A comprehensive battery of clinical tests will be administered at all time points, which includes cognitive testing, self-report of symptoms and emotional distress. Long-term outcome is determined three months after start of the study.

Specific study aims are:

Aim 1: To determine the effects of a precision-medicine iTBS guided approach applied to the left dorsolateral prefrontal cortex (DLPFC) on clinical recovery in patients with PPCS relative to waitlist control.

Aim 2: To determine the neurometabolic effects of iTBS in both the left and right DLPFC as measured with dMRS in patients with PPS, and to untangle differential effects on pathophysiological processes (e.g., neural plasticity vs. anti-inflammatory effects).

Aim 3: To determine the relationship of these neurometabolic effects and the integrity of major frontoparietal white matter tracts (as measured with dMRI), as well as activation and functional connectivity of key large-scale cognitive and emotional networks (i.e., executive, default mode, and salience network), measured using task-based and resting-state fMRI.

Inclusion Criteria:

• Adult age at inclusion 18-64 years.
• mTBI as defined by an altered mental status at time of injury, and LOC of max 30 min, GCS 13-15 (after 30 min), and PTA max 24 hrs.
• Persistent post-traumatic symptoms in chronic phase (>3 months post-injury).

Exclusion Criteria:

• History of developmental, neurological (e.g., epilepsy) or serious mental health disorders (e.g., schizophrenia, bipolar disorder) prior to TBI onset.
• History of a previous substance use disorder except for alcohol, or a currently active substance use disorder (within last 6 months.)
• Contraindications for MRI (e.g., any implanted ferromagnetic materials, claustrophobia, pregnancy) or iTBS (e.g., history of seizures).

Demographic, clinical, structural MRI, functional MRI, diffusion MRI, and diffusion MRS data will de-identified, linked to a global unique identifier (GUID) and uploaded to The Federal Interagency Traumatic Brain Injury Research (FITBIR) system. These data will be collected on 15 patients with mild traumatic brain injury. All data are exported in industry-specific, but standardized, formats to promote future research endeavors based on FAIR (Findable, Accessible, Interoperable, and Reusable) Data Principles.