Schwedt, Todd J.

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.

Abstract Objectives/Background This narrative review summarizes evidence implicating a role for the hypothalamus in the prodrome phase of a migraine attack. Prodrome is the earliest phase of the migraine attack. Understanding the migraine prodrome could lead to a better description of how migraine attacks are initiated and identification of targets for acute and preventive migraine treatment. The hypothalamus has been implicated in migraine prodrome via (1) localization of common prodrome symptoms to the hypothalamus; (2) identification of neurotransmitters, peptides, and hormones important in migraine pathophysiology for which the hypothalamus influences their production or release; and (3) brain neuroimaging studies identifying changes in hypothalamic activity and functional connectivity during the prodrome and preheadache phases of the migraine attack. Methods For this narrative review, PubMed was searched for relevant English language articles using the terms “hypothalamus, prodrome,” “hypothalamus, premonitory,” “hypothalamus, migraine,” “migraine, prodrome,” and “migraine, premonitory.” The PubMed search was performed on October 29, 2025. Full articles were chosen for review based on their relevance to the three areas defined just above: symptom localization, neuropeptide/neurotransmitter release, and brain imaging. Results Those with migraine commonly, and often consistently, experience prodrome symptoms, including hypersensitivities to visual and auditory stimuli, neck pain, fatigue, sleep–wake disturbances, changes in appetite, mood changes, and alterations in thermoregulation perception. Many of these symptoms can be localized to functions of hypothalamic subregions and nuclei. Several neuropeptides, neurotransmitters, and hormones that contribute to prodrome and other migraine attack symptoms, including calcitonin gene‐related peptide, dopamine, orexins, and pituitary adenylate cyclase‐activating polypeptide, are either produced by the hypothalamus or their release is mediated by the hypothalamus. Functional neuroimaging studies of spontaneous and triggered migraine attacks have identified increased hypothalamic activity and altered hypothalamic functional connectivity before migraine headache onset, including during the prodrome. Conclusion There is compelling evidence that the hypothalamus plays a role in the migraine prodrome and likely in migraine attack initiation. This is supported by many migraine prodrome symptoms localizing to hypothalamic function and functional neuroimaging studies demonstrating increased activity and altered connectivity of the hypothalamus during the prodrome phase. Further evidence and research are required to understand the hypothalamus' contribution relative to other brain regions.

Abstract Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.