What is the pathophysiology of migraine headaches?

From the Guidelines

Migraine headaches are primarily caused by the activation of the trigeminovascular system, involving both peripheral and central mechanisms, with cortical spreading depression being the underlying neurophysiological substrate of migraine aura. The pathophysiology of migraine headaches is a complex process that involves the interplay of various neurological and vascular components 1. According to recent research, migraine manifests clinically as recurrent attacks of headache with accompanying symptoms, and in some cases, is preceded or accompanied by transient neurological disturbances known as migraine aura 1.

Key Pathophysiological Mechanisms

• Cortical spreading depression is thought to be the underlying neurophysiological substrate of migraine aura 1
• Activation of the trigeminovascular system, involving both peripheral and central mechanisms 1
• Release of inflammatory neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P from trigeminal nerve endings
• Neurotransmitter imbalances, particularly involving serotonin, dopamine, and glutamate, play crucial roles in this process

Triggers and Predisposing Factors

• Genetic factors predispose individuals to migraines by lowering the threshold for this cascade
• Environmental triggers like stress, certain foods, hormonal fluctuations, and sleep disturbances can initiate this neuroinflammatory cascade in susceptible individuals 1
• The accompanying symptoms such as nausea, light sensitivity, and sound sensitivity occur because the pain pathways interact with other brain regions controlling these functions

Current Understanding and Treatment

The current understanding of migraine pathophysiology has led to targeted treatments, including triptans and newer CGRP antagonists that block the inflammatory cascade at different points 1. Despite these treatment options, clinical care remains suboptimal, with misdiagnosis and under-treatment of migraine being substantial public health challenges 1. A comprehensive approach is needed to facilitate accurate diagnosis and evidence-based management of migraine 1.

From the Research

Pathophysiology of Migraine Headaches

The pathophysiology of migraine headaches is a complex process involving multiple phases and systems.

• The premonitory phase begins as early as 3 days before the headache phase and involves a complex interplay between various cortical and subcortical brain regions, including the hypothalamus and brainstem nuclei that modulate nociceptive signaling 2.
• The headache phase involves activation of the trigeminovascular system, a pathway that is well characterized, and in one-third of patients, an aura phase may occur during some attacks, likely correlating with a cortical spreading depression-like event 2.
• Neurogenic inflammation is also thought to play a role in the pathophysiology of migraine, characterized by the release of potent vasoactive neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A, from activated peripheral nociceptive sensory nerve terminals 3.

Key Mechanisms

Key mechanisms involved in the pathophysiology of migraine headaches include:

• Activation of the trigeminovascular system, leading to the release of vasoactive sensory neuropeptides, especially CGRP, which increases the pain response 4.
• Neurogenic inflammation, which contributes to a cascade of inflammatory tissue responses, including arteriolar vasodilation, plasma protein extravasation, and degranulation of mast cells in peripheral target tissue 3, 5.
• Sensitization of central neurons in the brain stem trigeminal sensory nuclei, which relay pain signals to higher centers where headache pain is perceived 4, 6.

Multiple Processes and Complex Pathophysiology

Migraine is a multifactorial, disabling, recurrent, hereditary neurovascular headache disorder, involving multiple processes and complex pathophysiology 6.

• The disease is characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities 5.
• Symptoms such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contribute to worsening pain 6, 5.
• Advances in understanding the genetic predisposition to migraine and the discovery of multiple susceptible gene variants define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain 6.