Cortical spreading depolarization activates the trigeminal system and upregulates CGRP peptide expression, connecting migraine aura to migraine pain and validating CGRP-targeted therapies.
CSD → CGRP upregulation → migraine painCortical spreading depolarization directly activates the trigeminal system and increases CGRP expression, providing the mechanistic bridge between migraine aura and headache pain.
What the researchers found
CSD triggers activation of the trigeminal nervous system and upregulates calcitonin gene-related peptide (CGRP) expression, establishing a direct mechanistic link between migraine aura and migraine pain. The review synthesizes evidence showing that CSD causes ionic changes and excitotoxicity in neurons and glia, which then propagate signals to the trigeminal system. Factors including genetics, obesity, and environmental conditions influence the threshold for CSD, representing potential therapeutic targets. Current CGRP-targeting drugs are evaluated for their expected ability to suppress CSD-related activity, and emerging therapies including intranasal insulin-like growth factor 1 and vagus nerve stimulation show promise in reducing CSD susceptibility.
Why it matters
Migraine affects over 1 billion people worldwide, yet its underlying mechanisms have long been debated. This review connects the dots between the visual aura that many migraine sufferers experience and the subsequent headache pain through the CGRP peptide pathway. This mechanistic understanding validates the growing class of CGRP-targeted drugs and helps identify who might benefit most from these therapies.
How the study worked
Narrative review synthesizing historical and contemporary studies on cortical spreading depolarization and its relationship to migraine, including imaging studies in humans, animal models, cellular and molecular mechanisms, and evaluation of current and emerging therapeutic approaches.
What this study cannot tell us
As a narrative review, the paper selectively summarizes existing literature without systematic methodology. Much of the CSD-CGRP evidence comes from animal models, and direct confirmation of CSD in all migraine patients (especially those without aura) remains challenging. The review discusses emerging therapies whose clinical evidence is still limited.
How to read the evidence
This is a narrative review summarizing decades of research from imaging studies, animal models, and clinical evidence. It provides a comprehensive mechanistic framework but does not present new experimental data.
When this study was published
Published in 2024, this review incorporates the latest understanding of CSD and CGRP biology, including recently approved CGRP-targeting medications and emerging therapeutic approaches.
The bigger picture
The success of CGRP-targeted drugs (monoclonal antibodies like erenumab and small molecules like ubrogepant) has validated the peptide hypothesis of migraine. This review provides the mechanistic foundation explaining why these drugs work: by blocking the CGRP peptide that is released when CSD activates the trigeminal system. Understanding this pathway also opens doors for next-generation treatments that target earlier steps in the cascade — preventing CSD itself rather than blocking its downstream peptide effects.
Questions still open
- Does CSD occur in migraine patients who don't experience visual aura, and does CGRP still play a role in those cases?
- Could therapies that prevent CSD be more effective than blocking CGRP after it's already released?
- How do genetic variations in CSD threshold relate to individual responses to CGRP-targeting drugs?
Common questions
What is cortical spreading depolarization and how does it relate to migraine aura?
How does this explain why CGRP drugs work for migraine?
Read the original research
Molecular and Cellular Neurobiology of Spreading Depolarization/Depression and Migraine: A Narrative Review.
International journal of molecular sciences, 25(20)
Citation
Kitamura, Eiji; Imai, Noboru. (2024). Molecular and Cellular Neurobiology of Spreading Depolarization/Depression and Migraine: A Narrative Review.. International journal of molecular sciences, 25(20). https://doi.org/10.3390/ijms252011163