The trigeminovascular system is recognized as the anatomical and physiological substrate of migraine.1 Within this system, migraine-inducing and vasodilatory substances are thought to initially cause the activation of pain-sensitive first-order neurons that innervate meningeal blood vessels. The cell bodies of these neurons reside in the trigeminal ganglion, from which pain signals are transmitted unto second-order neurons of the spinal trigeminal nucleus (SpV) in the brainstem that relay to third-order neurons in the thalamus. From there, signals are sent to numerous cortical and subcortical sites to ultimately yield a migraine attack.
The initial substrate for migraine is thought to differ between attacks of migraine with and without aura. In attacks of migraine with aura, cortical spreading depolarization (the neural substrate of aura) might produce the initial stimulus for activation of first order neurons. In attacks of migraine without aura, migraine-inducing substances are thought to be released from the trigeminal system itself. Moreover, activation of the parasympathetic system from the superior salivatory nucleus (SSN) can cause the release of migraine inducing neuropeptides, such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), to trigger meningeal vasodilation and activation of first order neurons.
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