🧠 Migraine

🌩️ Pathophysiology of Migraine (High-Performance Summary)

Migraine = a complex neurovascular network disorder driven by brain hyperexcitability, trigeminovascular activation, and defective pain modulation.

❄️1. Genetic & Neural Hyperexcitability

• ✔️ Migraine brains show increased cortical excitability, especially in the occipital cortex.
• ✔️ Mutations affecting ion channels, glutamate signaling, & inhibitory circuits lower the firing threshold.
• ✔️ FHM gene mutations:
  • CACNA1A, ATP1A2, SCN1A → ↑ glutamate, impaired neuronal homeostasis.
• ✔️ Clinical pearl: Hyperexcitability explains sensitivity to light, stress, hormones, sleep loss and why visual aura starts in the occipital cortex.

❄️2. Cortical Spreading Depression (CSD) → Aura

• ✔️ A slow depolarization wave moves across cortex at ~3 mm/min.
• CSD produces aura depending on the region it crosses:
  • 👁️ Occipital cortex → visual aura
  • ✋ Parietal cortex → sensory aura
  • 🗣️ Temporal cortex → language/aphasic aura
• ✔️ CSD also activates trigeminovascular pathways, causing headache—even without visible aura (subclinical CSD).

❄️3. Trigeminovascular Activation (Core Pain Generator)

• ✔️ Brainstem dysfunction triggers trigeminal nerve activation.
• ✔️ Release of CGRP, Substance P, Neurokinin A →
  • 🩸 Meningeal vasodilation
  • 🔥 Neurogenic inflammation
  • 📈 Peripheral sensitization → throbbing, movement-worsened pain
• ✔️ CGRP is the dominant pathway, explaining the efficacy of:
  • Anti-CGRP monoclonal antibodies
  • CGRP receptor antagonists (gepants)

❄️4. Central Sensitization (Pain Becomes Diffuse & Persistent)

• ✔️ Continued attack → hyperactivity in trigeminal nucleus caudalis.
• Leads to:
  • Spread of pain
  • Persistence of symptoms
  • Allodynia: pain from brushing hair, touching face
• ✔️ Explains:
  • Why late triptan use is less effective
  • How episodic migraine becomes chronic

❄️5. Brainstem Dysfunction

Functional imaging shows abnormal activation in:

• 🧠 Dorsal pons
• 🎯 Periaqueductal gray (PAG)
• 🔵 Locus coeruleus

These regulate:

• 🔽 Descending pain inhibition
• 🤢 Nausea/vomiting
• 🌡️ Autonomic symptoms
• 🌞 Photophobia & phono­phobia

Prodrome features: yawning, food cravings, fatigue → explained by brainstem dysregulation.

❄️6. Vascular Mechanisms (Now Secondary)

• Old theory: migraine = primary vasodilation (❌ outdated).
• Current view: vascular changes are consequences, not the root cause.
• Still relevant because:
  • CGRP → vasodilation → throbbing pain
  • Triptans → cranial vasoconstriction + ↓ presynaptic CGRP release

❄️7. Hormonal Influences

• Estrogen fluctuations: ↑ glutamate, ↓ GABA → lower migraine threshold.
• Explains:
  • Menstrual migraines
  • Perimenopausal worsening

❄️8. Inflammation & Immune System

• Meningeal cells release histamine and prostaglandins.
• Microglial activation contributes to chronic migraine.
• Connects migraine with co-morbidities:
  • IBS
  • Fibromyalgia
  • Anxiety & depression

❄️ High-Performance Clinical Recap

Migraines are driven by:

1. Genetic cortical hyperexcitability
2. Cortical spreading depression → aura
3. Trigeminovascular activation → CGRP release → inflammation
4. Brainstem dysfunction → pain modulation failure + autonomic symptoms
5. Central sensitization → chronic migraine + allodynia
6. Hormonal & immune factors lowering threshold