Cortical spreading depression and migraine
Comprehensive Overview
Published in Nature Reviews Neurology in 2013, this review by two neurologists at the University of California, Los Angeles set out to answer a question migraine researchers have debated since the 1940s: does a slow-moving wave of altered brain activity called cortical spreading depression (CSD), first described in animal experiments by physiologist Aristides Leão, actually explain the visual and sensory disturbances known as migraine aura? Rather than reporting one new experiment, the authors synthesized decades of research, systematically searching the PubMed database from 1940 onward alongside findings from major international headache conferences. They weighed evidence from genetically engineered mice carrying migraine-linked mutations, direct brain-surface recordings from patients with strokes, brain injuries, and hemorrhages, and blood-flow imaging studies, using techniques such as PET and MRI, in people experiencing actual migraine attacks. As expected given decades of accumulated indirect support, the review found that CSD remains the leading explanation for migraine aura, sharing strikingly similar timing and spread patterns with brain activity recorded directly in humans with brain injury. However, the authors noted that the classic electrical signature of CSD has never actually been captured in a living migraine patient, leaving a widely accepted theory formally unproven at its core.
Outcomes and Implications
The single most striking finding running through this review is that no one has ever directly recorded the electrical signature of cortical spreading depression (CSD) in a person having a migraine, despite nearly seventy years of assuming it causes the aura. Animal studies offer strong circumstantial support: mice engineered with migraine-linked mutations, including those causing familial hemiplegic migraine (a rare inherited migraine with weakness), show a far lower threshold for triggering CSD, and female mice are more susceptible than males, mirroring migraine's higher prevalence in women. Medications already used to prevent migraines, such as topiramate and valproate, reliably suppress CSD in animals, while drugs known not to work against migraine fail to suppress it. Yet the link between CSD and headache pain is far shakier: some animal studies show CSD activating pain-signaling pathways, while others find inconsistent pain responses, and many patients experience aura with no headache at all, or report headache before the aura even begins. This timing problem challenges the assumption that CSD directly triggers pain, suggesting it may instead be one parallel feature of a broader abnormal brain state rather than its direct cause. Current migraine treatment largely targets pain and blood vessels without addressing this mechanism. The authors conclude that pinning down how CSD is triggered, how far it spreads in the human brain, and why it produces such varied or absent symptoms is essential to developing genuinely new migraine therapies, rather than simply refining existing ones.