Cortical pain modulatory functional enhancement after rTMS associated with durable headache improvement in mTBI patients

Background: Repetitive transcranial magnetic stimulation (rTMS) is able to alleviate mild traumatic brain injury-related headache (mTBI-HA). This functional magnetic resonance imaging (fMRI) study assessed the supraspinal correlates associated with the lasting analgesic effect of rTMS at the left dorsolateral prefrontal cortex (LDLPFC). Methods: Patients with mTBI-HA were randomized to receive either real or sham rTMS and subjected to pre- and post-treatment resting state and evoked heat pain fMRI consisting of 20 cycles of baseline temperature at 32°C for 30 seconds and 46°C for 10 seconds. Real rTMS consisted of 2000 pulses delivered at 10hz, 80% resting motor threshold at the LDLPFC. A follow-up fMRI was then performed one week after the treatment and headache clinical outcomes were assessed for one month. Results: 14 and 12 patients received real and sham treatments, respectively. The REAL group demonstrated significant (P<0.01) decreases in average daily headache intensity, debilitating headache exacerbation frequency and composite scores, and prevalence of persistent headache at one week following treatment. At one month, the REAL group demonstrated a significant decrease in daily headache intensity (P<0.01), a strong trend toward decreased debilitating headache frequency (P=0.057), and a trend toward decreased prevalence of persistent headaches (P=0.106). Correlated fMRI studies in the REAL group showed increase in evoked heat pain activity and resting functional connectivity at the LPFC after rTMS. This significant analgesic effect and correlated fMRI findings were not found in the sham group. Conclusions: This study correlates the durable analgesic effect of rTMS in alleviating mTBI-HA with enhanced supraspinal functional connectivity in the left prefrontal cortex, which is a brain area known to be involved in “top-down” pain inhibition along the descending midbrain-thalamic-cingulate pathway. Conflicts of Interests: None to report. Funding: This work was supported by VA Rehabilitation and Research Development SPIRE Awards (21RX001359, 21RX002366) and Department of Defense Congressionally Directed Medical Research Program Grant (W81XWH-16-1-0754).