Migraines are caused by waves of abnormal electrical activity in the brain that trigger inflammation and pain signaling along a major nerve network connecting the brain to the face and head. About 14% of the global population experiences migraines each year, affecting over one billion people worldwide. The process involves genetics, nerve chemistry, and a self-reinforcing cycle of inflammation that can sustain an attack for up to 72 hours.
The Electrical Wave That Starts It
Many migraines begin with an event called cortical spreading depression: a slow-moving wave of intense electrical activity that rolls across the surface of the brain, temporarily shutting down normal brain signaling in its wake. This wave depolarizes (essentially short-circuits) a large population of brain cells for about one minute and silences electrical activity in that region for several minutes afterward. In people who experience aura, the visual disturbances, tingling, or speech changes that precede the headache are a direct result of this wave passing through different brain regions.
Even in people who never experience aura, this wave can activate pain pathways deeper in the brain. The wave requires a specific chain of events at the cellular level: calcium channels on neurons must open first, which then activates a second set of receptors. Once both are engaged, a self-sustaining feedback loop kicks in, making the process all-or-none, like a domino chain that either falls completely or not at all.
How the Pain Signal Builds
The headache itself comes from a network called the trigeminovascular system, first identified as a key player in 1979. The trigeminal nerve, the largest nerve in the face and head, sends branches into the protective membranes surrounding the brain (the meninges) and their blood vessels. When these nerve fibers are activated, they release signaling molecules from their endings, most importantly one called CGRP (calcitonin gene-related peptide).
CGRP does several things at once. It dilates blood vessels in the brain and surrounding membranes, triggers immune cells called mast cells to release inflammatory chemicals, and transmits pain signals back to the brainstem. Those inflammatory chemicals, in turn, stimulate more nerve fibers, which release more CGRP. This creates a vicious cycle: inflammation drives more nerve activation, which drives more inflammation. The cycle ramps up CGRP production over hours to days, which lines up with the typical migraine duration of 4 to 72 hours.
The contents released by mast cells also activate a specific type of pain-sensing nerve fiber in the membranes around the brain. This is why migraine pain often starts as a dull ache and progressively worsens, and why physical movement or bending over can make it feel like your head is throbbing. The throbbing quality specifically reflects sensitized nerve endings around blood vessels responding to each pulse of blood flow.
Why Light and Sound Become Unbearable
The thalamus, a relay station deep in the brain, plays a central role in why migraines make you sensitive to light, sound, and even touch. Neurons in the thalamus that process sensory input from the skin and meninges overlap with neurons that process visual input from the eyes. During a migraine, when the pain-sensing neurons in the thalamus become sensitized, they amplify signals from light-sensitive pathways too. This is why bright light can intensify migraine pain even though light itself has nothing to do with the nerve inflammation happening around the brain.
The same convergence explains why touch on the face or scalp can become painful during an attack. Sensitized thalamic neurons respond to mechanical and thermal stimuli applied to both cranial and extracranial skin, meaning even brushing your hair or wearing a hat can feel painful once the system is ramped up.
Genetics Load the Gun
A landmark study of over 102,000 migraine cases identified 123 specific locations in the genome linked to migraine risk, 86 of which were previously unknown. These genetic variants don’t cause migraines on their own, but they lower the threshold for the electrical and chemical cascade described above.
Some of these genetic risk zones sit in or near genes that are already proven drug targets. One contains the genes that produce CGRP itself. Another encodes a serotonin receptor that newer acute migraine treatments target. Three risk variants appear specific to migraine with aura, including one in a calcium channel gene (CACNA1A) already known to cause a rare inherited form of severe migraine.
The genetic evidence also settled a long-running debate: migraine-associated variants are enriched in both vascular (blood vessel) and central nervous system tissues. Migraine is not purely a blood vessel problem or purely a brain problem. It is both.
Hormones and the Estrogen Drop
Women are roughly 1.7 times more likely to have migraines than men, with about 725 million women affected globally compared to 433 million men. Much of that gap traces to estrogen. The drop in estrogen that occurs just before menstruation reduces serotonin activity in the brain, and serotonin normally helps regulate pain signaling and blood vessel tone. When serotonin levels fall, the trigeminovascular system becomes easier to activate.
This is why menstrual migraines cluster in the two days before and the first three days of a period, precisely when estrogen levels plummet most sharply. The same mechanism helps explain why migraines often improve during pregnancy (when estrogen stays high) and can worsen during perimenopause (when estrogen fluctuates unpredictably).
How Episodic Migraines Become Chronic
In some people, migraines shift from occasional episodes to a chronic pattern of 15 or more headache days per month. This transition involves a process called central sensitization, where repeated activation of pain pathways physically changes how neurons in the brainstem process signals. Neurons in the trigeminal nucleus (the brainstem region that receives migraine pain signals) become hyperexcitable, responding to stimuli that would not normally register as painful.
One measurable sign of this process is cutaneous allodynia, where normal touch on the skin feels painful. Longitudinal data show that allodynia during migraine attacks is an independent risk factor for the progression from episodic to chronic migraine over a two-year period. CGRP contributes here too: it is secreted within the trigeminal ganglion (the cluster of nerve cell bodies outside the brain) and interacts with neighboring neurons and supporting cells, perpetuating the sensitization of downstream pain-processing neurons.
Repeated activation of a pain-modulating region in the brainstem called the periaqueductal gray also plays a role. This region normally helps suppress pain signals, but with repeated migraine attacks, its ability to dampen pain appears to degrade.
What Migraines Do to the Brain Over Time
Brain scans reveal that migraine patients have nearly four times the risk of developing small white matter lesions compared to people without migraines. These lesions show up as bright spots on MRI and represent areas of subtle structural change in the brain’s wiring. The risk increases with longer disease duration and higher attack frequency. In one study, 23% of patients with fewer than 20 years of migraines had these lesions, compared to 46% of those with more than 20 years. Patients averaging more than 8 attacks per month had lesions 43% of the time, compared to 19% of those with one attack or fewer per month.
The clinical significance of these lesions is still debated, as most migraine patients with white matter changes don’t show obvious cognitive symptoms. But the finding underscores that migraine is not just a pain disorder. It is a neurological condition with measurable effects on brain structure, particularly when attacks are frequent and span decades.