Posterior insular cortex hyperactivation drives vestibular migraine and comorbid anxiety

Vestibular migraine, a debilitating disorder characterized by recurrent episodes of headache and vertigo, is frequently comorbid with persistent anxiety and depression. The neural mechanisms that integrate these disparate sensory and affective symptoms remain elusive. Here, we combined clinical characterization with a translational mouse model to identify the posterior insular cortex (pIC) as a critical hub driving the pathophysiology of vestibular migraine. In patients, anxiety and depression scores remained elevated interictally, suggesting a trait-like affective disturbance. Using a validated mouse model combining nitroglycerin (NTG) administration and rotarod vestibular stimulation, which recapitulates vestibular migraine-like phenotypes (hyperalgesia, balance deficits, and anxiety-like behaviors), we observed hyperactivity within the pIC. This region responded to both nociceptive and vestibular challenges. Chemogenetic inhibition of the pIC reversed hyperalgesia and vestibular-motor deficits. Notably, while acute inhibition did not affect anxiety-like behaviors, chronic inhibition produced a full rescue, including the affective component, paralleling the clinical persistence of mood symptoms. Conversely, chronic chemogenetic activation of the pIC was sufficient to promote all core phenotypes under a subthreshold NTG regimen combined with rotarod vestibular stimulus. Furthermore, systemic administration of the NMDA receptor antagonist memantine alleviated vestibular migraine-like symptoms and normalized pIC hyperactivity. Our results establish pIC hyperactivation as a causal neural substrate that converges nociceptive, vestibular, and affective processing in vestibular migraine, and identify pIC suppression as a promising therapeutic strategy. Patients with vestibular migraine exhibit headache, vestibular dysfunction, and interictally persistent anxiety and depression. Hyperactivation of the posterior insular cortex drives vestibular migraine-like, balance deficits, and anxiety-like behaviors in a mouse model. The NMDA receptor antagonist memantine alleviates vestibular migraine-like symptoms and suppresses posterior insular cortex hyperactivity.