What is the pathology of migraine?

Pathophysiology of Migraine

Migraine is a complex neurological disorder involving sequential activation of multiple brain regions, beginning with hypothalamic and brainstem dysfunction during the premonitory phase, followed by cortical spreading depression (in aura), and culminating in trigeminovascular system activation that generates the headache through calcitonin gene-related peptide (CGRP) release.

Multi-Phase Pathophysiological Process

Migraine progresses through distinct phases, each with specific underlying mechanisms 1:

Premonitory Phase (Pre-Headache)

• Begins up to 3 days before headache onset, involving complex interactions between cortical and subcortical brain regions 1
• Hypothalamic activation plays a central role, explaining prodromal symptoms like yawning, fatigue, mood changes, and food cravings 2
• Brainstem nuclei that modulate nociceptive signaling become activated during this early phase 1

Aura Phase (When Present)

• Occurs in approximately one-third of patients and involves cortical spreading depression—a slowly propagating wave of neuronal and glial cell depolarization followed by hyperpolarization 1, 3
• Fully reversible neurological symptoms develop gradually over ≥5 minutes and last 5-60 minutes, including visual, sensory, speech, motor, brainstem, or retinal manifestations 4
• This cortical spreading depression may also trigger subsequent trigeminal sensory activation 3

Headache Phase (Core Attack)

• Trigeminovascular system activation is the primary mechanism generating migraine pain 1, 5
• CGRP release from trigeminal nerve terminals occurs during attacks, with levels normalizing when headache resolves 5
• The trigeminal system contains CGRP receptors and 5-HT₁B/₁D receptors that modulate pain transmission 5
• Contrary to earlier theories, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for the headache mechanism 3

Postdromal Phase

• Can last up to 48 hours after headache resolution, with symptoms including tiredness, concentration difficulties, and neck stiffness 2

Underlying Neurobiology

Genetic Component

• Multifactorial etiology with rare monogenic variants in some cases 3
• Complex familial disorder where severity and susceptibility are governed by multiple genes that vary between families 5, 6
• Genetic vulnerability combined with environmental triggers influences the migraine phenotype 6

Central Nervous System Involvement

• Primary event originates in the CNS, involving genetic changes in ion channels and environmental factors that increase sensitivity to triggers 5
• Brainstem regions have been identified through PET studies as migraine-active areas 5
• Multiple cortical and subcortical networks are involved throughout the attack phases 7

Clinical Implications of Pathophysiology

Why Certain Treatments Work

• Triptans (5-HT₁B/₁D receptor agonists) abort headaches by inhibiting CGRP action in pain transmission 5
• CGRP receptor antagonists (gepants) and monoclonal antibodies targeting CGRP directly address the core pathophysiological mechanism 3, 7
• Lasmiditan (5-HT₁F receptor agonist) provides an alternative serotonin receptor target without cardiovascular effects 3

Common Pitfall to Avoid

Do not conceptualize migraine as primarily a vascular disorder—this outdated theory has been superseded by understanding migraine as a neurological disorder with secondary vascular phenomena 3. Treatment selection should target neural mechanisms rather than focusing on vascular effects.