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Aura and cortical spreading depolarization

TL;DR — Migraine aura is a fully reversible focal neurological syndrome, most often visual, that usually evolves over 5–60 minutes and may occur before, during or without headache (Charles 2018, PMID 30074546). Cortical spreading depolarization (CSD)—a slowly propagating wave of near-complete neuronal/glial depolarization followed by suppressed activity—is the leading physiological substrate because its speed, retinotopic progression and perfusion changes match human aura (Fraser 2019, PMID 31847045; Eikermann-Haerter 2010, PMID 20425031). The link is strong but not a routine diagnostic measurement: direct electrophysiology comes mainly from injured human cortex or experimental animals, while migraine evidence is indirect imaging and phenotype concordance (Major 2020, PMID 31820363). Aura is associated epidemiologically with ischemic stroke, but most strokes in people with aura are not migrainous infarctions and shared vascular/genetic factors remain plausible (Yemisci 2019, PMID 31142262). Persistent visual snow is usually distinct from persistent migraine aura and should not be collapsed into it (Schankin 2015, PMID 26021756).

Clinical phenotype

Aura occurs in roughly 15% to one third of people with migraine depending on population and definition (Lucas 2021, PMID 34384631). Visual symptoms dominate, followed by sensory and language symptoms; motor, brainstem and retinal subtypes are uncommon.

Aura domain Positive phenomena Negative phenomena Principal mimic
Visual Scintillation, fortification, flicker, geometric forms Scotoma, hemianopic loss Retinal ischemia, occipital seizure, visual snow
Sensory Pins-and-needles spreading along hand/arm/face Numbness TIA, focal seizure
Speech/language Paraphasia or language disturbance Inability to speak/understand TIA, seizure
Motor Weakness Hemiparesis Stroke, postictal paresis
Brainstem Vertigo, dysarthria, tinnitus, diplopia, ataxia Altered consciousness can occur Posterior-circulation ischemia, seizure
Retinal Monocular positive/negative visual event Monocular field loss Amaurosis fugax and ocular disease

Aura varies between people and between attacks in the same person, so a single canonical drawing is misleading (Charles 2018, PMID 30074546). Directed history should record monocular versus binocular perception, exact field, positive versus negative content, onset, spread, succession, duration, recovery and headache timing (Eren 2021, PMID 34636719).

The CSD event

CSD propagates across contiguous gray matter at approximately millimetres per minute. Extracellular potassium and glutamate rise; sodium, calcium and water enter cells; electrical activity is transiently suppressed after the depolarization (Smith 2006, PMID 16848916; Kitamura 2024, PMID 39456943).

Phase Cellular event Physiological readout
Initiation Local extracellular K+/glutamate exceeds recovery capacity Abrupt negative direct-current shift
Propagation Regenerative depolarization recruits adjacent cortex Wave moving a few mm/min
Hyperemia Initial neurovascular response Brief increased perfusion in many models
Oligemia/depression Suppressed activity and altered vascular coupling Longer reduced activity/perfusion
Recovery Ion gradients restored at high metabolic cost Function usually normalizes in healthy tissue

Neurovascular coupling during spreading depolarization depends on tissue state. Healthy cortex usually supplies hyperemia, while injured tissue can show inverse responses and worsening ischemia (Østergaard 2015, PMID 25882051). This continuum explains why the same electrophysiological class can accompany benign aura and acute brain injury without implying that aura is tissue-damaging.

Human evidence

Functional imaging during visual aura has shown a slowly spreading occipital blood-oxygen/perfusion change concordant with the perceived visual disturbance, a core bridge between Leão’s animal phenomenon and migraine (Aurora 2000, PMID 10871250). Structural/functional imaging overall supports abnormal cortical network excitability, but findings outside aura are heterogeneous and affected by attack timing, treatment and multiple comparisons (Tolner 2019, PMID 30922081).

Direct DC recordings demonstrate spreading depolarizations in injured human cortex, not in routine uncomplicated migraine. The electrophysiological identity is therefore established in human brain, while its occurrence during ordinary aura is inferred (Major 2020, PMID 31820363). This distinction matters when claims move from “best-supported substrate” to “measured cause in every aura.”

From cortex to headache

CSD can activate meningeal/trigeminovascular pathways in experimental systems through parenchymal-to-meningeal signaling, potassium, nitric oxide, inflammatory mediators and vascular/immune interfaces (Erdener 2021, PMID 34794382; Christensen 2024, PMID 39304416). However:

  • aura can occur without headache;
  • headache can begin before or during aura;
  • most migraine occurs without reported aura;
  • some experimental CSD-to-trigeminal links are model-dependent.

Thus CSD is a compelling aura mechanism but cannot be the universal initiator of migraine pain (Cui 2014, PMID 25260797). Animal models expose cortex, induce CSD mechanically/chemically/electrically and measure nociceptive proxies; they are essential mechanistic tools but not complete attacks (Erdener 2014, PMID 24611635).

Genetics and excitability

Familial hemiplegic migraine demonstrates that altered ion transport can lower the CSD threshold. CACNA1A, ATP1A2 and SCN1A variants change glutamatergic release, ion clearance or neuronal excitability; transgenic models generally show enhanced CSD susceptibility (Gandini 2012, PMID 22991044). These rare monogenic forms illuminate a mechanism but do not explain most typical aura, whose genetic architecture is polygenic (Charles 2018, PMID 30074546).

Inference Strength Boundary
CSD can generate an aura-like propagating cortical dysfunction Strong Direct routine migraine recordings absent
Rare ion-channel/transport variants alter CSD susceptibility Strong for monogenic models Low population contribution
Typical aura is simply “cortical hyperexcitability” Incomplete Excitability tests are inconsistent and state-dependent
CSD always activates headache pathways False as a universal claim Aura can be painless
Suppressing CSD will prevent clinical aura Plausible, not established broadly Few aura-specific randomized endpoints

Aura, TIA and seizure

Gradual spread, positive phenomena and symptom succession favour aura; sudden maximal negative deficit favours ischemia; seconds-long highly stereotyped events favour seizure. But all are probabilistic. Imaging-confirmed stroke can contain migraine-like positive or spreading symptoms, and aura can start abruptly (Yemisci 2019, PMID 31142262).

Migraine and epilepsy share episodicity, triggers, family aggregation and excitability biology, but “migralepsy” is rare and diagnostic overlap frequently reflects misclassification (Zarcone 2017, PMID 28527083). A first motor aura, prolonged deficit, isolated monocular loss or materially changed event deserves exclusion of stroke, seizure and structural disease rather than retrospective reassurance.

Persistent and atypical visual phenomena

Persistent aura without infarction is an ICHD complication in which aura symptoms last at least one week and imaging shows no infarction. Evidence consists mainly of case reports/series; a prolonged symptom should not receive this label until vascular, epileptic, ophthalmic, toxic and structural causes are considered (Robertson 2024, PMID 38307662).

Visual snow is continuous tiny flickering dots across the entire visual field, usually bilateral and present for months or years, often with palinopsia, photophobia, enhanced entoptic phenomena or nyctalopia. It is phenotypically distinct from a time-limited spreading scotoma (Schankin 2015, PMID 26021756; Metzler 2018, PMID 29934719).

Persistent symptom Temporal signature Key distinction
Persistent aura Previous aura-like symptom continues ≥1 week Resembles the person’s prior aura
Visual snow syndrome Continuous full-field static plus associated visual symptoms Not a spreading 5–60-min event
Retinal disease Monocular or anatomically retinal defect Ophthalmic signs/testing may localize
Occipital epilepsy Brief recurrent positive phenomena Often seconds; EEG/history may support
Hallucinogen-persisting perception Exposure-linked persistent perceptual symptoms Exposure chronology is central
Cerebral ischemia Sudden negative deficit, often persistent Diffusion/vascular evaluation may identify lesion

Ophthalmological series find normal routine examinations in primary visual snow, but that normality is part of an exclusion process rather than proof of mechanism (Tegetmeyer 2017, PMID 27508888). Pediatric cases exist, and prolonged adolescent visual aura has been reported, so age alone does not decide the diagnosis (Bruen 2013, PMID 23871134).

Stroke relationship

Meta-analytic and population evidence associates migraine with aura with approximately doubled relative ischemic-stroke risk in many analyses, with stronger signals in younger women, smokers and estrogen-containing contraceptive users (de Falco 2015, PMID 26017513). Absolute risk can remain low when baseline risk is low; relative and absolute risk should always be separated.

Four relationships must not be conflated (Eikermann-Haerter 2014, PMID 24913618):

  1. migraine and stroke share a cause or susceptibility;
  2. ischemia triggers a migraine-like headache/aura;
  3. a typical aura persists and infarction appears in the relevant territory (migrainous infarction);
  4. CSD alters tissue vulnerability during ischemia.

Preclinical models suggest enhanced CSD susceptibility can increase vulnerability to ischemic depolarizations, but translation to spontaneous stroke risk is unresolved (Yemisci 2019, PMID 31142262). Mechanisms proposed include endothelial dysfunction, prothrombotic state, patent foramen ovale, shared genetics and medication/exposure confounding; none explains all associations (Harriott 2015, PMID 25652090; Pezzini 2009, PMID 19275630).

Treatment evidence

Most acute and preventive migraine trials do not use aura frequency as a primary outcome. Triptans are generally less reliable when taken during aura before pain than after headache begins; this does not establish that all acute agents fail against aura (Fraser 2019, PMID 31847045). A 2026 retrospective cohort of 81 people selected for burdensome aura found mean monthly aura days fell from 6.9 to 1.4 after lamotrigine, but the uncontrolled, selected design cannot separate treatment effect from regression, co-intervention or ascertainment (Uzun 2026, PMID 42591364). The live PubMed search through 2026-08-30 identified no controlled trial with aura-day reduction as the primary outcome, so broad aura-specific recommendations remain unsupported.

CGRP literature is much richer for headache than aura. A systematic review found limited and inconsistent CGRP evidence specific to migraine with aura (Hansen 2014, PMID 24452423). Preventive trials should report aura days and aura phenotype separately rather than assuming reduction in headache days equals suppression of CSD.

Open questions

  • Can non-invasive electrophysiology or ultrafast imaging directly capture CSD during spontaneous human aura? (Major 2020, PMID 31820363)
  • Why does CSD produce headache in some attacks but remain painless in others? (Cui 2014, PMID 25260797; Erdener 2021, PMID 34794382)
  • Does lowering aura frequency alter stroke risk, or are both downstream of shared susceptibility? (Yemisci 2019, PMID 31142262)
  • Which persistent visual syndromes share biology with migraine and which are coincidental comorbidities? (Robertson 2024, PMID 38307662; Schankin 2015, PMID 26021756)
  • Can aura-specific randomized endpoints identify a preventive that suppresses CSD rather than only headache expression? (Fraser 2019, PMID 31847045)

References

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  17. Zarcone D, et al. Shared mechanisms of epilepsy, migraine and affective disorders. Neurol Sci. 2017. PMID 28527083
  18. Robertson CE, et al. Persistent aura, visual snow, and other visual symptoms. Handb Clin Neurol. 2024. PMID 38307662
  19. Schankin CJ, et al. Visual snow—persistent positive visual phenomenon distinct from migraine aura. Curr Pain Headache Rep. 2015. PMID 26021756
  20. Metzler AI, Robertson CE. Visual snow syndrome: proposed criteria, clinical implications, and pathophysiology. Curr Neurol Neurosci Rep. 2018. PMID 29934719
  21. Tegetmeyer H. Visual snow syndrome: symptoms and ophthalmological findings. Klin Monbl Augenheilkd. 2017. PMID 27508888
  22. Bruen R, et al. Persistent migraine aura in an adolescent girl. J AAPOS. 2013. PMID 23871134
  23. Yemisci M, et al. Aura and stroke: relationship and lessons from preclinical models. J Headache Pain. 2019. PMID 31142262
  24. de Falco FA, et al. Migraine with aura: which patients are most at risk of stroke? Neurol Sci. 2015. PMID 26017513
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  26. Harriott AM, et al. Dissecting the association between migraine and stroke. Curr Neurol Neurosci Rep. 2015. PMID 25652090
  27. Pezzini A, et al. The migraine-ischemic stroke connection: potential pathogenic mechanisms. Curr Mol Med. 2009. PMID 19275630
  28. Hansen JM, et al. CGRP and migraine with aura: a systematic review. Cephalalgia. 2014. PMID 24452423
  29. Uzun N, et al. Lamotrigine prophylaxis and aura frequency in burdensome migraine aura: retrospective observational study. Front Neurol. 2026. PMID 42591364