What is the pathogenesis of migraine?

Pathogenesis of Migraine

Migraine is primarily caused by the activation of the trigeminovascular system and cortical spreading depression, involving complex interactions between genetic factors, neuronal hyperexcitability, and environmental triggers. 1

Core Pathophysiological Mechanisms

Trigeminovascular System Activation

• The trigeminovascular system plays a central role in migraine pathogenesis 2
• Activation of trigeminal nerves that innervate meningeal blood vessels leads to the release of calcitonin gene-related peptide (CGRP) and other neuropeptides 1
• This release causes neurogenic inflammation, including vasodilation, plasma extravasation, edema, and mast cell degranulation 3
• The inflammatory cascade contributes to pain transmission and sensitization of pain pathways 3

Cortical Spreading Depression

• Cortical spreading depression (CSD) is the neurophysiological substrate of migraine aura 2, 1
• CSD manifests as a wave of neuronal and glial depolarization followed by prolonged inhibition, spreading across the cerebral cortex at 2-5 mm/min 4
• In approximately one-third of migraine sufferers, CSD produces aura symptoms, typically visual disturbances 1
• CSD can activate meningeal nociceptors and trigger headache even in migraine without aura 5

Genetic Factors

• Migraine has a strong genetic component with higher prevalence among people with affected first-degree relatives 2
• Three genes promoting familial hemiplegic migraine have been identified, each affecting different ion channel subunits 1
• These genetic changes in ion channels contribute to neuronal hyperexcitability, rendering individuals more sensitive to environmental triggers 6

Brain Regions and Networks Involved

Brainstem and Diencephalic Systems

• Early PET studies identified a "migraine active region" in the brainstem 6
• Dysfunction in brainstem and diencephalic systems that modulate sensory processing precedes the headache phase 4
• These regions play a critical role in controlling sensory inputs and pain modulation 5

Central and Peripheral Nervous System

• Migraine involves a series of central and peripheral nervous system areas and networks 5
• The disorder represents a complex neurobiology that manifests as a cycle of altered brain sensory processing 4
• This cycling is influenced by both genetic predisposition and environmental factors 4

Neurotransmitters and Neuropeptides

Calcitonin Gene-Related Peptide (CGRP)

• CGRP release from the trigeminovascular system is a key component of migraine pathophysiology 2, 6
• Administration of triptans (5-HT1B/1D receptor agonists) causes headache to subside and normalizes CGRP levels 6
• CGRP receptor antagonists (gepants) and monoclonal antibodies targeting CGRP have proven effective in migraine treatment 5

Serotonin

• Serotonergic pathways play an important role in migraine pathophysiology 6
• 5-HT1B/1D receptors inhibit the action of CGRP in pain transmission when activated 6
• Novel treatments targeting serotonin 5-HT1F receptors (ditans) have emerged as effective therapies 5

Phases of Migraine Attack

Premonitory Phase

• Precedes the headache phase and involves dysfunction in brain stem and diencephalic systems 4
• Characterized by altered sensory processing, including sensitivity to light, sound, and other stimuli 4

Headache Phase

• Involves activation and sensitization of the trigeminovascular system 3
• Characterized by unilateral, throbbing, pulsating pain that worsens with physical activity 3
• Associated with nausea, vomiting, photophobia, and phonophobia 2

Postdromal Phase

• Can last up to 48 hours after pain resolution 1
• Common symptoms include fatigue, concentration difficulties, and neck stiffness 1

Clinical Implications and Complications

Stroke Risk

• Migraine with aura significantly increases the risk of ischemic stroke, with an odds ratio of 2.51 1
• Additional risk factors include age under 45, smoking, and oral contraceptive use 1
• Women with migraine with aura have an increased risk for late-life ischemic lesions as seen on brain MRI 2

Patent Foramen Ovale Association

• Patent foramen ovale is more common in patients with migraine (38.6% vs. 16.4% in those without migraine) 1
• This association is particularly strong in patients under 50 with cerebral infarcts and migraine with aura 1

Understanding the complex pathophysiology of migraine has led to targeted treatments such as triptans, CGRP antagonists, and neuromodulation devices, significantly improving management options for this highly disabling neurological disorder 2, 1.