What causes migraines?

Causes 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

Pathophysiological Mechanisms

The pathophysiology of migraine involves several key mechanisms:

• Trigeminovascular System Activation:

  • Activation of trigeminal nerves that innervate meningeal blood vessels
  • Release of calcitonin gene-related peptide (CGRP) and other neuropeptides 1
  • This process leads to neurogenic inflammation, vasodilation, and pain transmission

• Cortical Spreading Depression (CSD):

  • Represents the neurophysiological substrate of migraine aura 1
  • Manifests as a wave of neuronal depolarization followed by inhibition
  • Visual aura occurs in over 90% of cases with aura, while sensory symptoms occur in approximately 31% 1

• Genetic Factors:

  • Three genes promoting familial hemiplegic migraine have been identified, each affecting different ion channel subunits 1
  • Complex genetic inheritance pattern in common migraine types 2
  • Genetic variations affect neuronal excitability and vascular function 3

• Brainstem Involvement:

  • PET studies have identified a "migraine active region" in the brainstem 4
  • Abnormal brainstem processing of pain signals contributes to migraine attacks

Clinical Manifestations and Triggers

Migraine attacks typically present with:

• Unilateral, pulsating, moderate to severe headache
• Pain aggravated by routine physical activity
• Associated symptoms including nausea, vomiting, photophobia, and phonophobia 1
• Attacks typically last 4-72 hours if untreated 1

Common triggers include:

• Environmental factors (weather changes, odors like perfume or chemicals) 5
• Dietary factors (certain foods, missed meals) 5
• Hormonal fluctuations (menstrual cycle) 5
• Stress and sleep disturbances 5

Genetic and Molecular Insights

Recent research has expanded our understanding of migraine genetics:

• Genome-wide association studies have identified multiple susceptibility variants 6
• These variants belong to several "pro-migraine" molecular networks that are mainly neuronal or vascular 7
• Gene co-expression analysis has identified specific brain regions involved in migraine pathophysiology:
  • Cortical areas related to neurotransmission and mitochondrial function
  • Subcortical areas involving oligodendrocytes 6

Comorbidities and Risk Factors

Migraine is associated with several comorbidities:

• Higher prevalence of epilepsy, affective disorders, and anxiety disorders 5
• Increased risk of ischemic stroke, especially in migraine with aura (odds ratio 2.51) 1
• Additional risk factors include age under 45, smoking, and oral contraceptive use 1
• Patent foramen ovale is more common in migraine patients (38.6% vs 16.4% in non-migraine) 1

Clinical Implications

Understanding migraine pathophysiology has led to targeted treatments:

• Triptans (5-HT1B/1D receptor agonists) that inhibit CGRP release 4
• CGRP receptor antagonists that block the action of this key neuropeptide 4
• Glutamate receptor antagonists that may reduce cortical spreading depression 4

The postdromal phase can last up to 48 hours after pain resolution, with symptoms including fatigue, concentration difficulties, and neck stiffness 1.