Changes in brainstem habituation during onabotulinumtoxinA treatment in chronic migraine: A prospective case-control study.

Abstract

Objectives/background: Chronic migraine is a debilitating neurological disorder characterized by central sensitization and impaired brainstem habituation. OnabotulinumtoxinA is an established prophylactic treatment for chronic migraine, yet its effects on central trigeminal sensory processing remain incompletely understood. The nociceptive blink reflex (nBR) is a well-established neurophysiological tool for assessing brainstem excitability and central sensory processing within the trigeminal system. This prospective case-control study investigated longitudinal changes in brainstem neurophysiology following onabotulinumtoxinA treatment using the nBR.

Methods: Between November 2022 and April 2024, we assessed nBR habituation in 27 patients with chronic migraine and compared them with 27 age- and sex-matched healthy controls. Measurements were performed at peak efficacy (1 month postinjection, Month 1+) and prior to reinjection (3 months postinjection, Month 3+). Habituation of the polysynaptic R2 response was analyzed as the primary outcome.

Results: At Month 1+, R2 nBR habituation in patients was similar to that observed in healthy controls (4-s interstimulus interval, ipsilateral: β = 0.10, 95% confidence interval [CI] = -0.16 to 0.36, p = 0.457); however, by Month 3+, patients showed a significant impairment in R2 habituation compared to healthy controls (4-s interstimulus interval, ipsilateral: β = -0.29, 95% CI = -0.55 to -0.03, p = 0.029). Correlation analyses revealed that reduced habituation was associated with increased monthly migraine days (4-s interstimulus interval, contralateral: r = 0.41, 95% CI = 0.02 to 0.69, p = 0.039) and prolonged intervals since the last onabotulinumtoxinA treatment (4-s interstimulus interval, Month 3+, ipsilateral: r = 0.33, 95% CI = 0.06 to 0.55, p = 0.018), which aligns with the clinical observation of wearing off. Supporting this notion, patients with more prior treatment cycles exhibited sustained improvement in habituation deficits (4-s interstimulus interval, Month 3+, ipsilateral: r = -0.46, 95% CI = -0.71 to -0.09, p = 0.017). The monosynaptic R1 component remained unchanged between Month 1+ and 3+ (4-s interstimulus interval, ipsilateral: β = -0.028, 95% CI = -0.067 to 0.011, p = 0.164), emphasizing a specific treatment effect of trigeminal system-mediated pain processing at the brainstem level.

Conclusion: These findings indicate that onabotulinumtoxinA exerts a neuromodulatory effect on brainstem neurophysiology, with R2 habituation improving during peak treatment efficacy and declining as the effect wears off. The results underscore the time-dependent central effects of onabotulinumtoxinA on nociceptive processing within the trigeminal system. Future research should investigate the nBR as a potential biomarker for optimizing onabotulinumtoxinA treatment strategies in chronic migraine.