What causes migraines?

Migraine Pathophysiology: Understanding the Causes

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

Neurobiological Mechanisms

Primary Neurological Pathways

• Trigeminovascular System Activation: The core pathophysiological mechanism involves activation of trigeminal nerves that innervate meningeal blood vessels, with subsequent release of calcitonin gene-related peptide (CGRP) and other neuropeptides 2, 1
• Cortical Spreading Depression (CSD): This wave of neuronal and glial depolarization across the cerebral cortex is the neurophysiological substrate of migraine aura 1, 3
• Brainstem Involvement: PET studies have identified a "migraine active region" in the brainstem that modulates nociceptive signaling 3

Neurochemical Factors

• Calcitonin Gene-Related Peptide (CGRP): Released from the trigeminovascular system during attacks, causing vasodilation and pain transmission 3
• Substance P: A potent vasodilating peptide released from trigeminal nerve endings in response to stimulation 4
• Serotonin: Implicated in migraine pathogenesis, coexists with substance P in some terminals of the CNS and is present within trigeminal ganglia 4

Genetic and Environmental Factors

Genetic Predisposition

• Migraine is a complex familial disorder with multiple genetic factors affecting ion channels and neuronal excitability 3
• Three genes promoting familial hemiplegic migraine have been identified, each affecting a subunit of a different ion channel 2

Environmental Triggers

• Environmental factors interact with genetic predisposition to render individuals more sensitive to triggers 3
• Common triggers include:
  • Hormonal fluctuations
  • Stress
  • Sleep disturbances
  • Dietary factors
  • Sensory stimuli (bright lights, strong odors)

Migraine Progression and Manifestation

Four Phases of Migraine

1. Prodrome: Occurs hours to days before headache with symptoms like mood changes, food cravings, and fatigue
2. Aura: Occurs in approximately one-third of migraine sufferers, typically involving visual disturbances 2
3. Headache: Characterized by unilateral, pulsating pain with associated symptoms
4. Postdrome: Can last up to 48 hours after pain resolution, with symptoms including fatigue and concentration difficulties 1

Clinical Manifestations

• Pain Characteristics: Typically unilateral, pulsating, moderate to severe intensity, aggravated by routine physical activity 2
• Associated Symptoms: Nausea, vomiting, photophobia (sensitivity to light), and phonophobia (sensitivity to sound) 2
• Duration: Untreated attacks typically last 4-72 hours in adults 2

Comorbidities and Risk Factors

• Cardiovascular Risk: Migraine with aura significantly increases the risk of ischemic stroke (odds ratio 2.51), especially in individuals under 45, smokers, and those using oral contraceptives 1
• Patent Foramen Ovale: More common in patients with migraine (38.6% vs. 16.4% in those without migraine) 1
• Other Comorbidities: Higher prevalence of epilepsy, affective and anxiety disorders, and certain connective tissue disorders 2

Clinical Implications

• Understanding the pathophysiology of migraine has led to targeted treatments such as triptans (5-HT1B/1D receptor agonists) and CGRP receptor antagonists 3
• The complex neurobiological mechanisms explain why migraine is not just a vascular headache but a primary neurological disorder with multiple manifestations 1, 5
• Recognition of migraine as a neurovascular disorder with genetic underpinnings helps explain its chronic, recurrent nature and the need for both acute and preventive approaches 2

Understanding these pathophysiological mechanisms is crucial for developing effective treatment strategies and improving the quality of life for the more than one billion people worldwide affected by this disabling neurological disorder.