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Pathophysiology of Migraine

Reviewed by: HU Medical Review Board | Last reviewed: October 2020

Pathophysiology is the medical term for any changes in the body that occur because of a disease. These changes can be physical, such as how a joint works, or biochemical, such as how a protein is processed. So, when doctors talk about the pathophysiology of migraine, they are referring to changes in the brain and body that take place before, during, and after a migraine attack.

Past theories on migraine disease

In ancient times, doctors thought migraine disease was caused by vapors rising from the stomach to the head, and vomiting would relieve some of the pain.1

Between the 1600s and 1900s, many doctors thought that migraine disease was caused by the dilation of blood vessels. Aura was thought to be caused by vasoconstriction, or narrowing of the blood vessels.1

By the Victorian era, some doctors had begun to think that “megrims” were caused by “nerve storms” in the brain. Others believed in the same vasodilation theory that lasted until the late 20th century. However, in the early 1900s, science had evolved enough to explain new, more accurate ideas about changes in the brain and body that lead to migraine.1

What is the pathophysiology today?

Functional magnetic resonance imaging (fMRI) tests from the 1980s and 90s showed that migraine symptoms appeared before, not after, vasodilation, or widening of the blood vessels. That meant widening or narrowing of the blood vessels were physical changes that occurred because of migraine. In other words, changes in the human brain lead to migraine attacks, not caused them.2-4

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More research lead doctors to believe that the physical and biochemical changes that caused migraine attacks were:5

  • Cortical spreading depression
  • Triggers to the trigeminovascular system
  • Nerve cell sensitization
  • How the body processes calcitonin gene-related peptide (CGRP)

Other possible physical and biochemical changes that may cause migraine are:5

  • How the body processes the brain chemical serotonin
  • Changes to the heart muscle

What role does cortical spreading depression play?

Cortical spreading depression is the medical term for a slow wave of electrical activity that takes place in the neurons of the brain. Neurons are specialized brain cells that send signals to other types of cells.4,5

Cortical spreading depression may be the cause of migraine auras. In addition, these slow electrical waves can activate the nerves responsible for sensing pain in the covering surrounding the brain (called the “meninges”) and also change the function of blood vessels, both of which can lead to migraine pain.4,5

How is the trigeminovascular system related?

The trigeminovascular system is a group of nerve cells that sense pain in the face and covering of the brain. These nerves send signals to blood vessels in the brain and spinal cord. In people who have migraine, this system releases brain chemicals that cause inflammation in the brain, vasodilation, and leaks of plasma protein. The trigeminovascular system is thought to play a role in how long and how intense a migraine is. This inflammation may
lead to nerve cell sensitization.5

What role does nerve cell sensitization play?

Sensitization is exactly what it sounds like. Nerve cells (neurons) in the brain become increasingly sensitive to stimulation. This sensitivity leads to a person being more easily triggered, having a stronger response to known triggers, and reacting to new and different triggers than before. Doctors believe sensitization may be caused by changes in tissues and blood flow in the brain.5

Sensitization is thought to be one of the reasons behind occasional migraine turning into chronic migraine. It may also be responsible for many of the symptoms of migraine, such as throbbing pain, pain that gets worse with a cough or movement, sensitivity to light or sound, and sensitivity to things that do not normally cause pain.5

How is calcitonin gene-related peptide (CGRP) related?

CGRP is a brain chemical found in nerve cells. CGRP appears to control how the trigeminovascular system transmits pain signals. If the brain of a person with migraine releases too much CGRP, it can trigger a migraine attack. CGRP levels also play a role in the severity of a migraine.5

What role does serotonin play?

Serotonin lives in tissues in the brain, gut, and blood. It has many jobs in the body, like sending signals between nerve cells and helping the body control how the blood vessels contract. It also plays a role in controlling moods, sleeping, eating, and digestion. Too little serotonin may lead to depression. Too much serotonin may play a role in migraine by causing too much activity in the brain’s neurons and triggering cortical spreading depression. It may also cause blood vessels in the brain to react and lead to migraine symptoms.5,6

Doctors believe this may be why tricyclic antidepressants, which block serotonin levels in the brain, can help prevent migraine attacks, but selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels, do not.5

How are changes in the heart muscle related?

Studies have found that certain changes to the heart muscle may trigger migraine with aura. This includes some people who have a right-to-left shunt installed and those living with certain other heart conditions.5