Migraines are caused by abnormal activity in the brain’s pain-signaling networks, not simply by blood vessels expanding in the skull. For decades, scientists believed dilating blood vessels were the primary culprit, but brain imaging studies have shown no significant blood vessel changes during spontaneous migraine attacks. The current understanding points to a dysfunctional nervous system that becomes hypersensitive to normal stimuli, setting off a cascade of chemical and electrical events that produce throbbing pain, nausea, and sensitivity to light and sound. Globally, headache disorders affect roughly 2.9 billion people, and migraine consistently ranks among the top causes of disability worldwide.
The Trigeminal Nerve and Pain Signaling
The trigeminal nerve is the main pain highway for your head and face. During a migraine, nerve fibers in this system release a signaling molecule called CGRP from their endings. CGRP itself doesn’t directly cause pain. Instead, it kicks off a chain reaction: it triggers the production of nitric oxide, which sensitizes nearby nerve endings so they fire more easily. Once those nerve endings become sensitized, ordinary signals that wouldn’t normally register as painful start producing intense pain.
What makes this process so hard to shut down is that it feeds on itself. CGRP released from one set of nerve fibers can sensitize neighboring fibers that don’t even produce CGRP on their own. Meanwhile, support cells surrounding the nerve cluster respond to CGRP by releasing inflammatory molecules, which further ramp up nerve activity. The nerve cells, in turn, produce even more CGRP. This self-reinforcing loop helps explain why migraines can last hours or even days once they get going, and why early treatment tends to work better than waiting.
Serotonin’s Role in the Cascade
Serotonin, a chemical messenger involved in mood and blood vessel tone, plays a pivotal role in migraine. Most of the neurons where the trigeminal nerve originates are serotonin-producing cells, and when serotonin levels drop, blood vessels lose one of their main signals to stay constricted. That leaves nitric oxide, a powerful vessel-dilating molecule, unopposed. The resulting shift in blood flow and nerve signaling contributes to pain.
This connection is the reason one of the most effective classes of migraine medication, triptans, works by mimicking serotonin. Triptans bind to serotonin receptors on trigeminal nerve endings and blood vessels, reducing the release of CGRP and substance P (another pain-amplifying molecule). That dual action, calming the nerve and restoring vessel tone, is what stops a migraine attack in progress. Newer medications called gepants take a different approach by blocking CGRP receptors directly, while another class called ditans activate a specific serotonin receptor subtype without affecting blood vessels at all.
What Happens During an Aura
About one in four people with migraine experience aura, the visual disturbances, tingling, or speech difficulties that can precede the headache. Aura is caused by a phenomenon called cortical spreading depression: a slow-moving wave of intense electrical activity that rolls across the brain’s surface, followed by a period of silence where those brain cells essentially go quiet for several minutes. The wave travels at roughly 3 to 5 millimeters per minute, which matches the gradual spread of visual symptoms across a person’s field of vision.
This wave requires a buildup of the brain’s main excitatory chemical, glutamate, beyond a critical threshold. Once that threshold is crossed, a positive feedback cycle begins where each phase of the electrical event creates the conditions for the next, making the wave self-sustaining. The wave of depression is thought to activate the trigeminal pain system, linking aura to the headache phase. People who have migraine without aura may still experience similar brain activity at a lower intensity or in regions that don’t produce noticeable symptoms.
The Brain’s Internal Clock
The hypothalamus, a small region at the base of the brain that regulates sleep, appetite, and hormone cycles, activates early in a migraine attack, often before any pain begins. This is why many people experience food cravings, yawning, or mood changes hours before a headache starts.
The hypothalamus houses the body’s master clock, which synchronizes your sleep-wake cycle. People with migraine tend to have lower melatonin levels and delayed circadian rhythms compared to people without migraine. Research using dim-light melatonin testing has shown that circadian misalignment and delayed sleep timing are associated with more frequent and severe attacks, independent of how many hours a person sleeps. In at least two families studied, a single gene mutation affecting the speed of the internal clock co-segregated with both migraine with aura and abnormally early sleep timing, linking the two conditions at a molecular level.
The hypothalamus also produces orexins, signaling molecules that help regulate wakefulness and appetite. People with episodic migraine tend to have lower orexin levels, while those with chronic migraine who overuse pain medication show higher levels. This dysregulation helps explain why both too little and too much sleep can trigger attacks.
Genetics and Inherited Risk
Migraine runs in families, and researchers have identified several genes that increase susceptibility. Changes in a gene called KCNK18, which helps control the excitability of trigeminal nerve cells, can make those neurons fire too easily, lowering the threshold for a migraine to begin. Mutations in sodium channel genes (SCN1A and SCN2A) that are also linked to epilepsy appear in people with both familial and sporadic migraine, reinforcing the idea that migraine is fundamentally a disorder of brain excitability.
Another gene, STX1A, involved in how nerve cells release chemical signals, has shown a statistically significant association with migraine in meta-analyses. And the TRPA1 gene, which encodes a receptor on trigeminal nerve fibers, may explain why certain environmental irritants like strong perfumes or cigarette smoke can set off attacks in some people. No single gene causes migraine on its own. Instead, combinations of genetic variants make some brains more reactive to triggers that wouldn’t bother someone without that inherited vulnerability.
Common Triggers and Why They Matter
Triggers don’t cause migraine in the way a virus causes a cold. They’re more like the final push that tips an already-sensitive brain past its threshold. The most commonly reported triggers include:
- Stress. The most frequently cited trigger. Interestingly, many people report attacks not during peak stress but during the letdown period afterward, such as the first day of a vacation or a weekend after a demanding work week.
- Hormonal changes. The drop in estrogen that occurs just before menstruation is a well-established trigger. Estrogen modulates pain processing in the trigeminal system, so when levels fall, the pain network loses a protective buffer.
- Sleep disruption. Both too little sleep and oversleeping can provoke attacks, likely through the hypothalamic and circadian mechanisms described above.
- Diet. Fermented or pickled foods, aged cheeses, processed meats, and certain preservatives are reported triggers. Skipping meals can also provoke attacks, possibly through blood sugar shifts.
- Sensory overload. Bright or flickering lights, loud sounds, and strong odors can trigger attacks and worsen symptoms once an attack has started.
Not every person with migraine has the same triggers, and a given trigger won’t necessarily cause an attack every time. Whether a trigger pushes someone into an attack often depends on how many other factors are stacking up at the same time: how well they slept, where they are in their hormonal cycle, how much stress they’re carrying, and how recently they last had an attack.
Why the Old “Blood Vessel” Theory Fell Apart
For most of the 20th century, migraine was considered a vascular disorder. The logic seemed straightforward: ergotamine, a drug that constricts blood vessels, relieved migraine pain, and other vasoconstrictors like noradrenaline also helped abort attacks. But this theory couldn’t explain why some potent vasodilators don’t trigger migraines at all, or why neurological symptoms like aura, brain fog, and mood changes occur long before any headache begins.
The decisive evidence came from imaging studies showing that people in the middle of a spontaneous migraine attack had no significant changes in blood vessel diameter. The field has since shifted to a neurovascular model, which recognizes that while blood vessels play a role, they’re responding to signals from a dysfunctional nervous system rather than driving the process. The brain’s pain networks, its internal clock, its chemical signaling, and its genetic wiring are the primary players. Blood vessel changes, when they occur, are a downstream consequence rather than the root cause.