Longitudinal Effects of Repetitive Transcranial Magnetic Stimulation on Persistent Post-traumatic Headaches and Post-concussion Symptoms in Mild Traumatic Brain Injury
DOI: Pending DOI
Synopsis
High-frequency rTMS over the left M1 was tested in a randomized controlled trial of 20 adults with persistent post-traumatic headaches and post-concussion symptoms after mTBI. Participants received 12 sessions of 10 Hz rTMS or sham rTMS and were followed for 6 months. rTMS produced large, sustained improvements in the impact of headaches, global post-concussion symptoms, reactions to pain, and pain-related restrictions on engagement in daily life, outperforming sham at 3 and 6 months. Treatment was safe and well-tolerated. Although TMS-derived cortical measures did not change longitudinally, baseline cortical excitability and interhemispheric inhibition predicted 6-month headache and symptom reductions, supporting their promise as mechanistic biomarkers for precision neurorehabilitation.
Background
Headache is one of the most prevalent chronic pain symptoms reported by individuals after a mild traumatic brain injury (mTBI).¹ Headaches can be challenging to manage clinically and adversely impact rehabilitation outcomes if poorly controlled.² Both early-manifesting and delayed-onset post-traumatic headaches (PTH) following a traumatic brain injury are predictive of persistent headaches and prolonged recovery.³ PTH is frequently accompanied by global post-concussion symptoms (PCS) that undermine rehabilitation outcomes and quality of life.¹ Conventional analgesics have not proven reliable in reducing persistent post-traumatic headaches (PTH), and common side effects (e.g., sedation, overdose) limit pharmacological benefits.⁴ Repetitive transcranial magnetic stimulation (rTMS) has demonstrated short-term efficacy for pain, depression, and cognitive dysfunction in mTBI.⁵ This non-invasive neuromodulation technique does not have the side effects commonly seen with pharmacotherapeutics and effectively modulates corticomotor excitation and inhibition. However, evidence for durable benefits and mechanistic biomarkers is limited. This study 1) examined the long-term efficacy of high-frequency rTMS (HF-rTMS) targeting the primary motor cortex (M1), a correlate known to induce analgesic effects with neuromodulation, on PTH and PCS in mTBI; and 2) explored biomarkers as mechanistic mediators of clinical benefits. We hypothesized that HF-rTMS at the M1 would demonstrate long-term benefits on PTH and PCS through modulation of cortical excitation and inhibition.
Methods
This was a randomized, double-blind, sham-controlled clinical trial. Twenty adults (active group: N = 10, 8 females; sham group: N = 10, 7 females) with mTBI were recruited. The participants were diagnosed with persistent PTH and PCS, which did not resolve after at least three months of standard care. The treatment included 12 sessions of 10 Hz rTMS at the left M1 (target muscle representation: abductor pollicis brevis, intensity: 80% resting motor threshold [RMT], 2000 pulses/session, 24000 pulses in total). The sham group received the same rTMS protocol delivered by a sham coil. The clinical outcomes were administered at baseline (pre), immediately (post), one month (1mFU), three months (3mFU), and six months (6mFU) following rTMS, including 1) the Headache Impact Test (HIT-6) to assess the impact of headaches on one’s ability to function in occupational and social lives; 2) Post-Concussion Symptom Scale (PCSS) to comprehensively address PCS in physical, cognitive, and emotional domains; and Patient-Reported Outcomes Measurement Information System (PROMIS) to assess 3) pain behavior and 4) pain interference, manifesting reactions to pain and impacts of pain on engagement with daily activities.
To uncover potential biomarkers of responsiveness to rTMS in mTBI, TMS-derived cortical measures (RMT, short- and long-interval intracortical inhibition, intracortical facilitation, cortical silent period, interhemispheric inhibition) were explored to predict symptom trajectories.⁶ Generalized estimating equations (GEE) were used to test group-by-time interactions on all outcomes.
Results
No adverse events were reported in this study. There were no between-group differences in age (43.3 ± 13.0 years) and injury chronicity (3.5 ± 3.4 years). Injury mechanisms included motor vehicle accident (N = 6), fall (N = 5), sports injury (N = 1), hit by a falling object (N = 6), and assault (N = 2). Mild side effects occurring during the rTMS treatments, including headaches (10%), dizziness (10%), tingling sensations in the scalp (10%), and ringing in the ear (5%), were observed, which were tolerable and resolved within minutes after the completion of rTMS and removal of the coil from the participants.
The group data of the HIT-6 and PCSS at the five time points are shown in Figures 1A and 1C, respectively (active group: light green, sham group: light red). The percentage changes of the HIT-6 and PCSS in comparison to the baseline are shown in Figures 1B and 1D, respectively (active group: dark green, sham group: dark red). The GEE demonstrated group-by-time interactions for HIT-6 (p < 0.001) and PCSS (p < 0.001). Initially, both groups demonstrated symptom reduction in the HIT-6 and PCSS at the post-intervention and 1-month follow-up assessments. At the 3-month follow-up, the active group demonstrated greater reductions in HIT-6 (active: -26.3 ± 21.5% vs. sham: -0.3 ± 9.3%, p < 0.001, Cohen’s d = 0.9) and PCSS (active: -20.0 ± 32.6% vs. sham: -7.6 ± 35.0%, p < 0.001, Cohen’s d = 0.9) compared to the sham. The active group maintained the improvement in HIT-6 (active: -34.4 ± 21.4% vs. sham: 4.6 ± 13.7%, p < 0.001, Cohen’s d = 1.4) and PCSS (active: -29.8 ± 37.8% vs. sham: -7.3 ± 42.7%, p < 0.001, Cohen’s d = 1.6) at the 6-month follow-up, significantly outperforming the sham group.
Similarly, there were significant group-by-time interactions for PROMIS-pain behavior and PROMIS-pain interference, as the active group sustained the improvement at the 6-month follow-up while the sham group did not (pain behavior: active: -9.1 ± 13.2% vs. sham: -1.1 ± 12.4%, p < 0.001, Cohen’s d = 0.9; pain interference: active: -10.2 ± 14.4% vs. sham: -5.7 ± 12.5%, p < 0.001, Cohen’s d = 0.8). Half of the participants in the active group achieved a minimal clinically important difference in at least one of the four clinical outcome measures.
There were no group-by-time interactions in any of the TMS-derived cortical excitation and inhibition measures. Among these baseline TMS-derived assessments, RMT was a predictor of PTH (R² = 0.89, p = 0.01) at the 6-month follow-up. The interhemispheric inhibition of the M1 was a predictor of PCS reduction (R² = 0.83, p = 0.03) at the 6-month follow-up. Overall, higher motor threshold (i.e., lower corticospinal excitability) and greater interhemispheric communication at baseline were indicative of more symptom reduction after receiving rTMS intervention in mTBI.
Discussion
The protocol implemented in the current study was safe and well-tolerated. The treatment burden was reasonable as there were no dropouts from participation. The amount of PTH reduction at 6-month follow-up in our preliminary data was superior to the previously reported data at 1-month (18%).⁷ Also, there was approximately 40% greater headache reduction in the active (-34.4%) versus sham (4.6%) groups. Thus, our rTMS protocol exceeded the efficacy shown in the literature and demonstrated long-term efficacy.
To date, there are limited studies investigating the neuroplastic effects following rTMS in mTBI.⁸ We demonstrated that baseline TMS-derived measures were sensitive to symptom improvements. Assessing neuromodulation-induced changes in M1 fills the gap in the relationship between neurophysiological changes and clinical symptom resolution in mTBI.
The initial improvements in the sham group possibly resulted from placebo effects, although only one participant accurately reported receiving sham rTMS in the exit interview. However, placebo effects did not maintain, and the benefits dissipated after 3 months (see Figure 1), indicating it is the neuromodulatory effects of rTMS that lead to long-term efficacy.
In summary, HF-rTMS applied at the M1 induced large, clinically meaningful, and sustained improvements in persistent PTH and global PCS following mTBI. TMS-derived cortical excitation and inhibition may predict treatment responsiveness, supporting the use of mechanistic biomarkers for precision neurorehabilitation strategies.
Disclosures
This study was funded by the Hendricks Intramural Seed Grant, SUNY Upstate Medical University.
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