Our Evolving Understanding of What Causes Migraine

Alex

Mar 15

5 min read

Migraine has long been misunderstood as simply a severe headache or, at most, a disorder limited to the brain. However, modern research is revealing that migraine may involve far more than the nervous system alone. Emerging evidence suggests that migraine may be a systemic disease—a condition influenced by multiple systems throughout the body, including the vascular system, immune system, hormones, genetics, and even other medical conditions.

In this Migraine World Summit session, neurologist and headache specialist Dr. Vince Martin, director of the Headache and Facial Pain Center at the University of Cincinnati Gardner Neuroscience Institute, explains how scientific understanding of migraine has evolved over time and why this broader perspective may help improve treatment strategies for people living with migraine.

How Migraine Theories Have Changed Over Time

For decades, migraine was primarily viewed as a vascular disorder. Early theories suggested that migraine aura—the visual or neurological symptoms that sometimes occur before a headache—was caused by narrowing blood vessels in the brain. The subsequent headache phase was believed to result from dilation of those same blood vessels.

While this theory explained some migraine symptoms, it could not fully account for the wide range of neurological effects that migraine produces.

Later research shifted the focus toward the brain itself, leading to the idea that migraine is fundamentally a neuronal disease. Genetic studies of rare forms of migraine, such as familial hemiplegic migraine, identified mutations in genes that regulate ion channels in nerve cells. These discoveries suggested that abnormalities in neuronal signaling could trigger migraine attacks.

However, even this explanation proved incomplete.

Further research revealed that many genetic variations linked to migraine involve both nerve cells and blood vessels, leading scientists to adopt the concept of migraine as a neurovascular disorder—a condition involving both the nervous system and vascular system.

Today, scientists believe the picture may be even more complex.

Migraine as a Systemic Disease

Current research increasingly suggests that migraine may involve multiple body systems beyond the brain.

A systemic disease is one that affects the entire body or interacts with multiple organs and biological systems. Migraine appears to fit this definition because it is frequently associated with a wide range of other medical conditions.

These conditions include:

Depression
Anxiety
Autoimmune diseases such as lupus
Thyroid disorders
Gastrointestinal diseases
Vascular conditions
Chronic pain disorders such as fibromyalgia or back pain

These associations are not merely coincidental. New genetic research suggests that some of these conditions may actually contribute to the development of migraine in certain individuals.

What Happens During a Migraine Attack

One of the most important biological mechanisms involved in migraine is activation of the trigeminal nerve, the primary sensory nerve of the head.

The trigeminal nerve has three major branches that supply sensation to different regions of the face and head. During a migraine attack, this nerve becomes activated and releases a protein called calcitonin gene-related peptide (CGRP).

CGRP plays a central role in migraine because it triggers a cascade of events that affect both nerves and blood vessels. This process amplifies pain signaling and contributes to the characteristic symptoms of migraine, including throbbing head pain, nausea, and sensitivity to light or sound.

Many modern migraine medications specifically target this CGRP pathway, either by blocking the protein itself or preventing it from binding to receptors in the nervous system.

New Genetic Research Reveals Surprising Links

Recent studies using a method called Mendelian randomization are providing new insights into how other diseases may contribute to migraine.

These studies examine genetic variants associated with specific conditions and determine whether individuals carrying those genes are more likely to develop migraine. Because genetic traits are randomly distributed at birth, this method helps researchers identify potential cause-and-effect relationships.

Using this approach, scientists have discovered that several conditions appear to have a causal relationship with migraine, including:

Depression
Thyroid disorders (both hyperthyroidism and hypothyroidism)
Blood clotting conditions such as deep vein thrombosis
Gastrointestinal diseases such as peptic ulcer disease
Autoimmune diseases such as lupus

These findings suggest that migraine may sometimes arise as a downstream effect of other biological processes occurring in the body.

The Role of Inflammation and Immune Signaling

Many of the diseases associated with migraine involve inflammation.

Inflammatory conditions release signaling molecules called cytokines, which are proteins that regulate immune responses. These molecules can influence the nervous system and may increase susceptibility to migraine attacks.

Inflammation may therefore represent one pathway through which systemic diseases contribute to migraine activity.

For example, autoimmune diseases produce chronic inflammatory responses that could potentially activate migraine pathways in susceptible individuals.

Environmental Factors and Migraine Risk

While genetics play an important role in migraine, they do not explain the entire picture.

Research suggests that about half of migraine risk is genetic, meaning environmental factors likely contribute to the remaining risk.

These environmental influences may include:

Head injuries
Hormonal fluctuations
Sleep disorders
Stress
Air pollution or environmental exposures

For example, individuals who experience head trauma may develop post-traumatic headaches that share many characteristics with migraine. Over time, these headaches may evolve into chronic migraine-like patterns.

Understanding the Difference Between Causes and Triggers

One of the most important distinctions in migraine research is the difference between causes and triggers.

A cause refers to the underlying factors that make someone susceptible to migraine in the first place. These may include genetics, biological conditions, or systemic diseases.

A trigger, on the other hand, is something that provokes an individual migraine attack.

Common triggers include:

Hormonal changes
Weather shifts
Stress
Lack of sleep
Certain foods or environmental stimuli

Understanding this distinction is important because many conditions associated with migraine may influence both the development of migraine and the frequency of attacks.

Why Treating Other Conditions May Help Migraine

Because migraine interacts with many other medical conditions, addressing these conditions may help reduce migraine frequency.

For example:

Treating sleep apnea with continuous positive airway pressure (CPAP) can reduce morning headaches.
Managing sinus or allergy problems may reduce headaches triggered by sinus pressure.
Treating depression or anxiety may improve migraine severity and quality of life.
Addressing neck pain or TMJ disorders may reduce head pain originating from musculoskeletal sources.

This broader approach recognizes that migraine management may involve treating more than just the headache itself.

The Long-Term Effects of Migraine

Researchers have also observed long-term changes in the brains of some individuals with migraine.

Imaging studies sometimes show small white matter lesions, often called “white spots,” in people with migraine. These changes appear to be more common in individuals who experience frequent attacks.

Although these lesions are not typically associated with stroke, researchers are still investigating their exact cause and long-term significance.

Reducing migraine frequency through treatment may potentially help limit these changes, although more research is needed.

The Future of Migraine Research

One of the most exciting aspects of migraine science is the possibility that migraine may not have a single cause.

Instead, migraine may represent a common neurological response to many different biological pathways. In other words, there may be many different roads that ultimately lead to migraine attacks.

This concept could transform how migraine is treated in the future.

Rather than relying solely on broad therapies that affect the entire pain system, future treatments may focus on highly targeted interventions that address the specific pathway triggering migraine in each individual.

These therapies could include:

Personalized genetic treatments
Targeted hormonal therapies
Anti-inflammatory strategies
Treatments focused on specific comorbid conditions

As scientific understanding continues to evolve, this personalized approach may lead to more effective and individualized migraine care.

A Broader Way of Thinking About Migraine

The most important takeaway from this evolving science is that migraine should not be viewed in isolation.

Migraine is deeply interconnected with many aspects of human health, including genetics, immune function, hormonal systems, and other medical conditions.

By understanding migraine as a whole-body condition, clinicians may be better able to identify contributing factors and develop treatment strategies that address the full complexity of the disease.

For patients living with migraine, this broader perspective offers hope that future therapies will become increasingly precise, personalized, and effective.