Clinical and preclinical investigation of the mechanism promoting aura in post-traumatic headache and inhibition of pain-related behavior in mice by onabotulinumtoxinA.

Authors

Colin Bader, Kaitlyn E Haskie, Guohui Li, Robson Cristiano Lillo Vizin, Catherine Chong, Gina Dumkrieger, Caroline Koprusinski, David W Dodick, Edita Navratilova, Frank Porreca, Todd J Schwedt, Trent Anderson

Published in

Pain. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Post-traumatic headache (PTH) is the most common consequence of mild traumatic brain injury (mTBI) and often resembles migraine. In 20% to 30% of migraine patients, headaches are preceded by aura, transient visual or sensory disturbances, which are caused by cortical spreading depression (CSD) that can induce headache pain. However, whether mTBI promotes the development of aura and CSD and their possible contributions to PTH remains unclear. We examined the incidence of new-onset aura in individuals with PTH who had no history of aura. Thirty-two percent (35/108) developed new aura symptoms within 60 days of injury, suggesting that mTBI can sensitize the cortex to the induction of CSD. To test this, we combined electrophysiology, neuroimaging, and behavioral assays in a mouse model of mTBI-induced PTH. After closed-head mTBI, injured mice exhibited a 160% increase in CSD induction probability (ie, lowered threshold) and became sensitized to CSD induction by brief exposure to stress, a common headache trigger. When evoked optogenetically, CSD produced prolonged periorbital and hind paw allodynia, consistent with headache-like pain. Subcutaneous onabotulinumtoxinA administered to the scalp after mTBI did not alter CSD susceptibility but completely abolished optogenetic CSD-induced allodynia. These findings suggest that mTBI elicits sensitization to CSD induction and promotes the emergence of aura in humans, likely contributing to PTH. It is important that, even after mTBI-induced sensitization, onabotulinumtoxinA decoupled CSD from pain behaviors, suggesting efficacy in treating PTH associated with aura.

PMID:
42775980
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.

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