What Actually Causes Chronic Migraine? A Mechanistic Reading of Treatment-Resistant Migraine — Why the standard migraine model produces variable results

The dominant current model of migraine pathophysiology centers on neurovascular activation involving the trigeminovascular system. Cortical spreading depression (CSD) is a wave of depolarization across the cortex. The CSD activates trigeminal afferents. Trigeminal activation releases neuropeptides including CGRP, substance P, and PACAP. These produce vasodilation, plasma protein extravasation, mast cell degranulation in the dura, and sensitization of pain pathways. What the model does not adequately describe is the upstream question: what determines whether a given patient develops cortical spreading depression in the first place? What lowers the threshold over time, transforming episodic migraine into chronic migraine? What determines which patients respond well to CGRP blockade and which do not?