What Actually Causes Chronic Migraine? A Mechanistic Reading of Treatment-Resistant Migraine — The four mechanistic drivers of chronic migraine

Driver 1: Mitochondrial bioenergetic failure The migraine brain is bioenergetically compromised. Magnetic resonance spectroscopy studies have documented reduced phosphocreatine levels, slowed phosphocreatine recovery after exercise, and elevated lactate-to-creatine ratios in the brains of migraine patients compared to controls. CSD is energetically expensive. It involves massive ion-pumping demand to restore neuronal membrane potential after the depolarization wave. A brain with adequate ATP capacity can recover without producing sustained dysfunction. A brain with compromised ATP capacity cannot. The CSD threshold falls. This mechanism is supported by evidence for mitochondrial-targeted prophylactic supplements. High-dose riboflavin (400 mg daily) reduces migraine frequency in multiple randomized controlled trials. CoQ10 supplementation reduces migraine frequency. Magnesium is essential for ATP synthase function and is the most well-established prophylactic supplement in migraine. The framework predicts that patients with dominant Driver 1 will respond particularly well to mitochondrial support: riboflavin, CoQ10 (ubiquinol form), magnesium glycinate. They will also respond well to addressing the upstream causes of their mitochondrial compromise, which include the CD38-NAD+-SIRT3 cascade and iron-sulfur cluster damage . The clinical signature of Driver 1 migraine includes wors