Neurology
Migraine Mechanism
Cortical spreading depression, trigeminovascular CGRP release, and the new antibody era
A migraine starts in the brain — a slow wave of cortical depression activates the trigeminal system, which floods the meninges with CGRP. Anti-CGRP antibodies cut monthly attacks by 50%+ in trials.
- Global prevalence~14% of adults; ~1 billion people
- Aura speed3-5 mm/min across cortex (CSD)
- Key peptideCGRP — released by trigeminal afferents
- Anti-CGRP mAbs~50% reduction in monthly migraine days
- Chronic migraine≥15 headache days/month, ≥3 months
- F:M ratio3:1 (estrogen withdrawal trigger)
Interactive visualization
Press play, or step through manually. Watch a cortical depression wave march across the brain, activate the trigeminal system, and release CGRP onto dilating meningeal vessels.
Watch the 60-second explainer
A condensed visual walkthrough — narrated, captioned, under a minute.
How it works
Migraine is not a vascular headache and it is not a tension headache — it is a brain disorder that engages the vasculature only secondarily. The modern model has four sequential layers:
- Premonitory phase (up to 48 hours before pain). Hypothalamic dysfunction generates yawning, food cravings, mood change, and neck stiffness. Functional MRI shows hypothalamic activation hours before the headache begins.
- Aura phase (when present, ~15-30 min). A wave of cortical spreading depression — intense depolarization followed by prolonged neuronal silencing — propagates across the cortex at 3-5 mm/min. The visual scintillating fortification spectrum maps perfectly onto a CSD wave starting at the occipital pole and sweeping forward.
- Headache phase (4-72 hours). CSD and other triggers activate trigeminal sensory afferents that innervate the meninges. These terminals release CGRP, substance P, and PACAP. CGRP dilates dural arteries, increases plasma protein extravasation, and degranulates mast cells. The trigeminal nucleus caudalis in the brainstem becomes hyperexcitable — central sensitization.
- Postdrome (the "migraine hangover," 24-48 hours). Fatigue, cognitive slowing, mood depression as the brain recovers.
Worked clinical example
A 32-year-old graphic designer presents with recurrent severe headaches starting in her early teens. She describes the pattern: every 2-3 weeks, often around her menses, a 20-minute period of seeing a "shimmering zigzag" that starts as a dot and slowly expands across her left visual field. As the zigzag fades, a throbbing right-sided headache builds over 30 minutes, accompanied by nausea, intense light sensitivity, and a "tender scalp" so bad that brushing her hair hurts. She lies in a dark room. Untreated attacks last 12-24 hours. She averages 5 migraine days per month — episodic but disabling. Her examination and brain MRI are normal. Diagnosis: migraine with typical aura. She starts a triptan (sumatriptan 100 mg early in attack), which aborts ~60% of attacks when taken in the first 30 minutes. After 6 months, attacks rise to 8 days/month and she begins erenumab 70 mg monthly subcutaneous; over 12 weeks her monthly migraine days fall from 8 to 3, and triptan use drops accordingly. Six months later she has tapered triptan use to occasional and is on minimum-effective-dose erenumab.
Treatment landscape
- Acute (abortive). NSAIDs early; triptans (sumatriptan, rizatriptan, eletriptan); gepants (rimegepant, ubrogepant); ditans (lasmiditan — no vasoconstriction, safe in CV disease but requires no driving for 8 hours); intranasal/SC routes for nausea-dominant attacks.
- Preventive — oral. Propranolol, topiramate, amitriptyline, candesartan, flunarizine. Cheap but side-effect burden (cognitive slowing on topiramate, weight gain on amitriptyline).
- Preventive — biologics. Anti-CGRP monoclonal antibodies: erenumab (anti-receptor), fremanezumab, galcanezumab, eptinezumab (IV every 3 months). Monthly or quarterly dosing; ~50% of patients achieve ≥50% reduction in monthly migraine days.
- Preventive — chronic migraine. OnabotulinumtoxinA every 12 weeks via the PREEMPT 31-site protocol; effective for chronic (≥15 headache days/month) but not episodic.
- Neuromodulation. sTMS (single-pulse transcranial magnetic stimulation), supraorbital nerve stimulation, remote electrical neuromodulation devices.
Common pitfalls
- Medication-overuse headache. The single biggest avoidable cause of chronification. Simple analgesics ≥15 days/month, or triptans/opioids/combination analgesics ≥10 days/month, transforms episodic migraine into chronic daily headache. Withdrawal is essential first; new preventives won't work over the top.
- Calling it "sinus headache." Studies of self-diagnosed sinus headache show ~80% meet criteria for migraine. The sinus distribution comes from V1 trigeminal innervation, not infection. CT scans are usually normal.
- Opioids and butalbital combinations. Both cause severe medication-overuse headache and don't work as well as migraine-specific drugs. Avoid as first-line.
- Missing secondary headache red flags. SNOOP4 mnemonic: Systemic symptoms (fever, weight loss), Neurologic signs (papilledema, focal deficit), Onset sudden (thunderclap — SAH until proven otherwise), Older age >50 new-onset (giant cell arteritis), Pattern change. Any of these requires imaging.
- Triptans in vascular disease. 5-HT1B vasoconstriction makes triptans contraindicated in established coronary or peripheral arterial disease; use ditans or gepants instead.
| Class | Mechanism | Route | Acute or preventive | Key caveat |
|---|---|---|---|---|
| Triptans | 5-HT1B/1D agonist; vasoconstriction + ↓CGRP release | Oral, nasal, SC | Acute | Avoid in CV disease; take early |
| Gepants | CGRP receptor small-molecule antagonist | Oral | Both (rimegepant) | Safe in CV disease; expensive |
| Anti-CGRP mAbs | Antibody against CGRP or its receptor | SC or IV | Preventive | ~50% responders; cost |
| Ditans | 5-HT1F selective; no vasoconstriction | Oral | Acute | Driving restriction 8 h post-dose |
| OnabotulinumtoxinA | Block sensory peptide release at peripheral terminals | IM (PREEMPT) | Preventive (chronic only) | Every 12 weeks; chronic migraine label |
| Topiramate / propranolol | Multiple (ion channels, β-blockade) | Oral | Preventive | Side effects; cheap |
Frequently asked questions
What is cortical spreading depression?
Cortical spreading depression (CSD) is a slow-moving wave of intense neuronal and glial depolarization, followed by prolonged suppression of activity, that propagates across the cortex at 3-5 mm per minute. Extracellular K⁺ rises to 30-60 mM, glutamate is released, and the wave engages neighboring neurons in turn. CSD is the most likely substrate of the migraine aura — and the speed of its march matches the speed at which a scintillating scotoma expands across the visual field over 15-30 minutes. Animal data show CSD activates trigeminal nociceptors on the pial surface, linking aura to subsequent headache.
What is CGRP and why does it matter?
Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide released from activated trigeminal sensory neurons. During a migraine attack, jugular venous CGRP rises measurably; triptans normalize it. CGRP causes potent vasodilation of meningeal arteries, plasma protein extravasation in the dura, mast cell degranulation, and sensitization of trigeminal afferents. Two drug classes target it: monoclonal antibodies against CGRP or its receptor (erenumab, fremanezumab, galcanezumab, eptinezumab) for prevention, and small-molecule receptor antagonists 'gepants' (rimegepant, ubrogepant, atogepant) for acute and preventive use. Both work in roughly 50% of patients.
How do triptans work?
Triptans (sumatriptan and successors) are agonists of 5-HT1B and 5-HT1D serotonin receptors. 5-HT1B activation constricts dilated meningeal vessels; 5-HT1D presynaptically blocks CGRP release from trigeminal terminals; central 5-HT1F (newer ditans like lasmiditan) blocks pain transmission without vasoconstriction. Triptans should be taken early in the headache phase — efficacy falls once central sensitization has set in (about two hours). Cardiovascular caution: avoid in established coronary or cerebrovascular disease because of vasoconstriction.
What is migraine aura?
Aura is a transient focal neurological symptom that precedes or accompanies the headache in about a third of migraineurs. Most common: visual scintillating zig-zag (fortification spectrum) expanding from a small spot to fill a hemifield over 15-30 minutes, leaving a scotoma. Other auras: sensory tingling that marches up the arm to the face, transient aphasia, brainstem symptoms (vertigo, diplopia, dysarthria — migraine with brainstem aura), and hemiplegic aura (rare, familial channelopathies). Aura without subsequent headache is common with age and is sometimes called 'acephalgic migraine.' Pure visual aura over age 50, especially without prior history, deserves a workup for TIA.
Why is migraine throbbing and one-sided?
Throbbing reflects the pulsation of dilated meningeal arteries against sensitized trigeminal nociceptors — each systolic pulse stretches the vessel wall and re-activates the nerve. Unilateral pain follows the unilateral distribution of trigeminal afferents to the dura: V1 (ophthalmic) provides most coverage, so periorbital, frontal, and temporal locations dominate. Photophobia and phonophobia come from convergent sensitization in the thalamus and brainstem. Cutaneous allodynia ('my hair hurts') signals central sensitization — once present, triptan efficacy drops sharply.
What are common migraine triggers?
Sleep change (too little or too much), missed meals, dehydration, menstruation (estrogen withdrawal), stress let-down (the post-stressor 'weekend migraine'), red wine and aged cheese (tyramine), MSG, nitrates, weather pressure shifts, bright lights, and strong smells. Identifying triggers is helpful but rarely the whole story — chronic migraine is driven more by central sensitization than by single triggers. Diary apps and a behavior-change focus on sleep, hydration, regular meals, and aerobic exercise reduce frequency in many patients.
Who needs preventive therapy?
Guidelines recommend prevention for ≥4 migraine days per month, disabling attacks, contraindications to acute therapy, or medication-overuse headache risk. Tiered options: oral preventives (propranolol, topiramate, amitriptyline, candesartan, flunarizine) at low cost but with side-effect burden; anti-CGRP monoclonal antibodies (~50% responders gain ≥50% reduction); onabotulinumtoxinA every 12 weeks (PREEMPT protocol — for chronic migraine, ≥15 headache days/month); and gepants (atogepant, rimegepant). Stop medication-overuse first: simple analgesics ≥15 days/month, triptans or combination analgesics ≥10 days/month transforms episodic to chronic migraine.