Treatment of Persisting Symptoms after Concussion with Repetitive Transcranial Magnetic Stimulation: A Double-Blinded, Randomized, Controlled Trial

Following a mild traumatic brain injury (mTBI), up to 30% of individuals will experience persisting symptoms beyond 3 months. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has shown promise as an intervention for persisting symptoms after concussion (PSaC); however, to determine efficacy, larger clinical trials are required. The objective of this study was to investigate the efficacy of high-frequency rTMS targeting the left dorsolateral prefrontal cortex as an intervention for PSaC. This randomized, double-blinded, sham-controlled study recruited adults (aged 18-75 years) experiencing PSaC for at least 3 months and up to 5 years post-mTBI. Participants were randomized 1:1 to receive 20 sessions of rTMS (10 Hz, 10 trains of 60 pulses with 45 s inter-train intervals, 100-120% resting motor threshold) using either an active or sham coil. The primary outcome was the Rivermead Postconcussion Symptoms Questionnaire (RPQ). The primary end-point was the difference in total RPQ score change from baseline at post-rTMS and 1- and 3-month follow-ups in active compared with sham rTMS. Secondary exploratory outcomes included anxiety, depression, quality of life, headache, post-traumatic stress disorder (PTSD), and cognition. To determine the effects of rTMS, a difference-in-differences approach was adopted using linear mixed models, which controlled for age, sex, and baseline stress (life stress questionnaire LSQ). One hundred and forty individuals were screened, and 91 participants were enrolled (mean age 41.3 ± 11.3; 61% female). For our primary end-point, there was no significant difference in differences in total RPQ score between the active and sham groups at post-rTMS (β = 1.07, 95% CI -3.01, 5.1, p = 0.607), 1 month (β = 3.81, 95% CI -0.72, 8.3, p = 0.099), or 3 months (β = -3.18, 95% CI -7.1, 0.70, p = 0.108). However, both active and sham groups demonstrated a significant improvement in total RPQ scores from baseline at post-rTMS, 1 month, and 3 months. The secondary outcomes (depression, anxiety, quality of life, headache impact, cognition, post-traumatic stress) demonstrated a significant effect of time, but no significant effect of group. Age and sex did not influence the model; however, higher baseline LSQ (>300) was associated with higher scores in both active and sham groups at all timepoints for every outcome measure other than headache impact. Lower LSQ significantly influenced response to active rTMS treatment with regard to PTSD symptoms at post-rTMS timepoint only but not in the sham group. In conclusion, there was no significant difference between active and sham rTMS when evaluating symptom severity scores. However, both treatment groups significantly improved following intervention, which was maintained up to 3 months. Lower baseline LSQ significantly influenced PTSD symptom response in the active group at post-rTMS only. Alternative neuromodulation approaches should be considered in this patient population.