Is canonical SD a clinically relevant model of migraine? Argument con.

Cortical spreading depolarization (CSD) is a unique brain response to a neuronal insult, manifested by a massive exchange of intra- and extracellular compartments, loss of ionic gradients, and membrane potential, where neurons are caged in this pathological state for minutes with no activity. This electrochemical tsunami propagates slowly by invading the neighboring intact cortex in the whole hemisphere in rodents, and it is transient in metabolically uncompromised brains. Vascular reactivity of brief hyperemia, prolonged oligemia, increased inhibitory synaptic tonus, intracellular edema, and blood-brain barrier disruption are the typical features of canonical CSD. The translation of canonical CSD to migraine aura symptoms in humans presents significant inconsistencies. These include positive symptomatology of aura and the temporal discrepancy between the multisensory manifestation of aura and allegedly affected cortical areas, the limited march of CSD in the intact human brain, laterality of aura and headache, and the lack of CSD-inducing capability of migraine-triggering substances. No study showed direct evidence of canonical CSD during migraine aura. Reported findings depend on vascular reactivity changes that are spatially and temporally discordant with clinical symptoms. Given these limitations, canonical CSD, as the underlying cause of migraine aura and headache, oversimplifies a more complex system and raises doubts about its sufficiency as a sole explanatory model and as a therapeutic target. We argue that while CSD may play a role in migraine pathophysiology, it is unlikely to propagate in the same manner as the canonical CSD observed in rodents. CSD in higher-order cortical areas may disrupt the cortico-thalamo-cortical loop in the sensory or pain network. This perspective better accommodates the complex sensory phenomena observed in migraine aura and may lead to more effective and targeted patient treatments by broadening the conceptual framework of migraine pathophysiology.