Cerebral Thiamine-Dependent Metabolic Constraint in Migraine Aura: A Dynamic-Reserve Hypothesis for Time-Locked Parenteral Intervention

Recurrent stereotyped visual aura offers a recognizable clinical clock for testing whether an intervention alters progression to migraine headache. Cortical spreading depolarization imposes substantial ionic and metabolic restoration demands; thiamine-dependent oxidative metabolism is one candidate contributor to the capacity available to meet them. Small randomized oral thiamine trials provide a preventive-treatment signal, while observational evidence is mixed. Neither this evidence nor the intravenous case reports answers the acute aura-onset question. We propose that, in a prospectively defined subgroup, reduced effective thiamine-dependent cerebral metabolic capacity narrows the functional margin available to tolerate or recover from the aura-associated disturbance. A Dynamic-Reserve model expresses that margin as capacity minus contemporaneous demand, not as a blood concentration or literal thiamine store. The primary experiment is one 200 mg/2 mL intramuscular thiamine hydrochloride dose at the first recognizable qualifying aura, evaluated against progression to customary moderate-to-severe headache within a prespecified window. Increasing treatment latency is predicted to diminish benefit if the early-transition mechanism is correct. State-2 intravenous escalation and changes in activation or sleep remain subordinate hypotheses. Etiologic contribution, intervention efficacy, latency dependence, and incremental intravenous benefit require separate adjudication. An adequately powered randomized blinded trial showing no clinically meaningful primary benefit, with a confidence interval excluding the prospectively defined minimum worthwhile effect, defeats the State-1 intervention as tested. Reproducibly absent state and latency dependence together with comparable efficacy after established moderate-to-severe headache defeats the timing mechanism despite treatment benefit. Prespecified failure rules prevent either unmeasured cerebral dysfunction or an asserted earlier biological onset from rescuing those results.