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Migraine Pathophysiology

Posted on May 22 2025, By: Cerebral Torque

Migraine Pathophysiology

A guide to the brain mechanisms underlying migraine
Updated May 2025

Beyond "Just a Headache"

Migraine is a complex neurological disorder affecting approximately 1 billion people worldwide. Far more than "just a headache," migraine is a multifaceted condition with genetic components, distinct phases, and complex brain changes that occur before, during, and after the migraine attack itself.

Key Facts About Migraine

  • Migraine is the 2nd leading cause of disability worldwide and the leading cause in people under 50
  • Women are 3 times more likely to experience migraine than men, with hormonal influences playing a significant role
  • Migraine has a strong genetic component with heritability estimated at 42-57%
  • Genome-wide association studies have identified over 100 genetic risk loci associated with migraine
  • Modern research shows migraine is a sensory processing disorder involving multiple brain regions
  • The condition costs the U.S. an estimated $36 billion annually in healthcare costs and lost productivity

For decades, scientists believed migraine was primarily a vascular disorder caused by abnormal dilation of blood vessels in the brain. This theory, popularized in the late 19th century, dominated scientific thinking for over a century. However, modern neuroscientific research has conclusively shown that migraine originates in the brain itself, with vascular changes being a consequence rather than the primary cause of attacks.

"Migraine is a fundamentally neuronal disorder." - Peter J. Goadsby, MD, PhD, a leading migraine researcher

Understanding the complex pathophysiology of migraine is crucial for both patients and healthcare providers. For patients, it validates their experience of a genuine neurological condition and explains the diverse symptoms beyond headache. For providers, it enables more targeted treatments based on the underlying mechanisms rather than just symptom management.

Historical Perspectives on Migraine Pathophysiology


Early Vascular Theory (1870s-1960s)

First proposed by researchers like Liveing (1873) and Gowers (1899), this theory suggested that migraine was caused by vasodilation of cranial blood vessels. The throbbing nature of migraine pain and the effect of ergotamine (a vasoconstrictor) in treating attacks seemed to support this theory.

The theory proposed that an initial vasoconstriction caused the aura phase (by reducing blood flow), followed by compensatory vasodilation that produced the headache.


Cortical Spreading Depression (1940s-1980s)

In 1944, Leão described cortical spreading depression (CSD) - a wave of depolarization that moves across the cerebral cortex, followed by a period of suppressed neural activity. By the 1980s, this was linked to the visual aura experienced by some migraine patients.

PET and MRI studies later confirmed that blood flow changes during migraine aura matched the pattern and timing of CSD, but this still didn't explain migraine without aura (maybe).


Neurogenic Inflammation (1980s-1990s)

Researchers like Moskowitz proposed that activation of trigeminal nerves caused the release of inflammatory neuropeptides (such as Substance P and CGRP) around brain blood vessels, leading to neurogenic inflammation, plasma protein leakage, and pain.

This theory connected neural activity with vascular changes and helped explain the pain of migraine attacks.


Brain Hyperexcitability and Networks (2000s-Present)

Modern functional neuroimaging has revolutionized our understanding of migraine, showing it to be a disorder of brain networks and sensory processing. Research has identified specific brain areas (hypothalamus, brainstem, thalamus, cortex) that show abnormal activity before, during, and between migraine attacks.

Current understanding views migraine as a complex neurological disorder with genetic underpinnings, environmental triggers, and dysfunction in multiple brain networks and neurotransmitter systems.

This evolution in understanding migraine pathophysiology has paralleled advances in treatment. From non-specific pain relievers to triptans (which affect both blood vessels and neural pathways) to modern CGRP-targeted therapies that specifically address neuronal mechanisms, treatments have become increasingly targeted as our understanding has improved.

The Four Phases of Migraine

Migraine is not just the headache itself but a complex, multi-phase neurological event that can span several days. Understanding these phases helps explain the diverse symptoms experienced before, during, and after the pain phase.

Phase 1: Prodrome (premonitary)

Timing: Up to 72 hours before headache onset

Prevalence: 70-77% of migraine patients

Key Symptoms:

  • Fatigue and yawning
  • Mood changes (irritability, depression)
  • Food cravings or loss of appetite
  • Neck stiffness
  • Concentration difficulties
  • Increased sensitivity to light, sound, smell
  • Sleep disturbances

Brain Activity: Hypothalamic activation, altered connections with spinal trigeminal nucleus, early changes in pain-modulating regions

Phase 2: Aura

Timing: Typically before headache onset, lasts 5-60 minutes

Prevalence: 20-30% of migraine patients

Key Symptoms:

  • Visual disturbances (zigzag lines, scotomas, flashing lights)
  • Sensory symptoms (numbness, tingling)
  • Speech disturbances
  • Motor weakness (in hemiplegic migraine)
  • Vertigo (in vestibular migraine)

Brain Activity: Cortical spreading depression - a wave of neuronal depolarization followed by inhibition that travels across the cortex at 3-5 mm/minute

Phase 3: Headache

Timing: 4-72 hours if untreated

Prevalence: Defining feature of migraine

Key Symptoms:

  • Moderate to severe pain, often throbbing
  • Typically one-sided (though can be bilateral)
  • Worsened by physical activity
  • Nausea and/or vomiting
  • Photophobia (light sensitivity)
  • Phonophobia (sound sensitivity)
  • Osmophobia (smell sensitivity)
  • Allodynia (normal touch causing pain)

Brain Activity: Activation of trigeminovascular system, release of inflammatory peptides, central sensitization in pain pathways

Phase 4: Postdrome

Timing: Up to 48 hours after headache resolution

Prevalence: Up to 80% of migraine patients

Key Symptoms:

  • Fatigue and weakness
  • "Brain fog" or cognitive difficulties
  • Mood changes (depression or euphoria)
  • Continued light and sound sensitivity
  • Neck pain
  • Decreased appetite

Brain Activity: Gradual normalization of brain function, though abnormal connectivity persists

Important Notes About Migraine Phases

  • Individual Variation: Not all people experience all phases, and symptoms can vary greatly between individuals and even between attacks in the same person.
  • Phase Overlap: Phases can overlap, with postdrome symptoms beginning before headache fully resolves, prodromal symptoms continuing into the headache phase, or aura occuring concomitantly with the headache phase. 
  • Aura Without Headache: Some people experience migraine aura without developing a headache (migraine aura without headache and formerly known as acephalgic or silent migraine).
  • Subtypes: Different migraine subtypes (chronic, episodic, hemiplegic, vestibular, etc.) may have variations in phase presentation.
  • Treatment Timing: Understanding the phases helps with timing of treatment interventions, as medications may work differently depending on the phase.

Key Brain Regions in Migraine Pathophysiology

Key brain structures involved in migraine
Key brain structures involved in migraine. The hypothalamus activates early in attacks, triggering prodrome symptoms. The thalamus processes sensory information and becomes sensitized. The PAG (periaqueductal gray) is part of descending pain modulation pathways. The trigeminal nerve transmits pain signals from the face and head.

Hypothalamus

A small but critical structure deep in the brain that functions as:

  • Attack Initiator: Activates 24-48 hours before headache onset, generating prodrome symptoms
  • Biological Clock: Explains the cyclical nature of migraine and timing patterns (weekend migraine attacks, menstrual migraine)
  • Homeostatic Regulator: Controls hunger, thirst, sleep, and hormone cycles - all frequently change during a migraine attack
  • Connection Hub: Functionally connected to the spinal trigeminal nucleus and PAG early in attacks

Clinical Correlates: Explains why sleep disturbances, skipping meals, stress, and hormonal changes can trigger attacks. The hypothalamus's early activation explains why treating migraine during the prodrome phase might prevent headache development.

Trigeminovascular System

A key pain-signaling network consisting of:

  • Trigeminal Nerve: Provides sensory innervation to the face, scalp, and pain-sensitive structures in the head
  • Trigeminal Ganglion: Contains cell bodies of sensory neurons that detect head pain
  • Trigeminal Nucleus Caudalis: First central relay for pain signals, located in the brainstem
  • Blood Vessels: Trigeminal nerve fibers wrap around meningeal blood vessels

Clinical Correlates: The release of inflammatory neuropeptides (CGRP, substance P) from trigeminal nerve endings causes neurogenic inflammation and pain. The effectiveness of triptans and CGRP-targeted therapies stems from their action on this system.

Thalamus

The brain's major sensory relay station that becomes dysfunctional in migraine:

  • Sensory Gatekeeper: Processes and filters sensory information before it reaches the cortex
  • Central Sensitization: Becomes hyperexcitable during migraine, contributing to allodynia (normal touch causing pain)
  • Cross-Modality Effects: Explains why light can worsen migraine pain and why sound sensitivity occurs
  • Long-Term Changes: Shows altered connectivity even between migraine attacks

Clinical Correlates: Thalamic sensitization helps explain why migraine patients can experience pain from normal stimuli like gentle touch, brushing hair, or wearing glasses. It also explains widespread sensory hypersensitivity.

Brainstem

Contains several structures critical in migraine pathophysiology:

  • Periaqueductal Gray (PAG): Major pain modulation center that may be dysfunctional in migraine
  • Locus Coeruleus (LC): Produces norepinephrine and helps regulate arousal and stress responses
  • Rostral Ventromedial Medulla (RVM): Contains "on" and "off" cells that modulate pain signals
  • Nucleus Tractus Solitarius (NTS): Linked to nausea and autonomic symptoms

Clinical Correlates: Dysfunction in brainstem pain-modulating regions helps explain why migraine involves both increased pain perception and reduced ability to inhibit pain. Nausea, vomiting, and autonomic symptoms in migraine stem from brainstem involvement.

Cortex

The outer layer of the brain shows several abnormalities in migraine:

  • Cortical Spreading Depression (CSD): Wave of depolarization underlying aura, moving at 3-5mm/min across the cortex
  • Hyperexcitability: Enhanced responsiveness to sensory stimuli, even between attacks
  • Deficient Habituation: Failure to reduce response to repeated stimuli
  • Altered Metabolic Activity: Changes in metabolites and energy metabolism in visual and other cortical areas

Clinical Correlates: Cortical abnormalities explain visual, language, and sensory aura and the increased sensitivity to environmental stimuli. They also help explain why migraine patients often report difficulty with concentration and mental clarity.

Pain Matrix

A network of brain regions that collectively process pain signals:

  • Primary & Secondary Somatosensory Cortex: Process the sensory dimension of pain (location, intensity)
  • Anterior Cingulate Cortex: Processes the emotional aspects of pain
  • Insula: Integrates pain with emotional and autonomic responses
  • Prefrontal Cortex: Involved in cognitive aspects of pain and pain modulation

Clinical Correlates: Abnormal functioning in the pain matrix helps explain why migraine pain is often associated with emotional distress and cognitive difficulties. It also suggests why behavioral interventions targeting cognitive aspects of pain can be effective.

Evidence from Modern Neuroimaging

Advanced brain imaging techniques have revolutionized our understanding of migraine by allowing researchers to visualize brain structure and function:

  • Functional MRI (fMRI): Shows increased activity in the hypothalamus 24 hours before migraine headache onset
  • PET Scans: Reveal increased activity in the brainstem during migraine attacks that persists after pain relief with triptans
  • MR Spectroscopy: Shows metabolic abnormalities in the occipital cortex of migraine patients
  • Diffusion Tensor Imaging: Reveals structural connectivity differences in white matter tracts of migraine patients
  • Resting State fMRI: Shows altered connectivity in multiple brain networks, even between migraine attacks
  • MEG/EEG: Demonstrate cortical hyperexcitability and deficient habituation to repeated stimuli

These imaging findings support the concept of migraine as a brain network disorder rather than simply a vascular or pain condition.

The Trigeminovascular Pathway and CGRP

The trigeminovascular system is central to migraine pain generation. This system consists of neurons in the trigeminal ganglion that innervate cerebral blood vessels and dura mater (the outer membrane covering the brain), along with their connections to the brainstem and higher brain centers.

The Trigeminovascular Pathway diagram
The Trigeminovascular Pathway. Trigeminal nerve fibers innervate blood vessels in the meninges. When activated, they release CGRP and other inflammatory neuropeptides, causing neurogenic inflammation and pain. This signal is transmitted to the brainstem, thalamus, and ultimately the cortex.

Calcitonin Gene-Related Peptide (CGRP): The Migraine Molecule

CGRP has emerged as a critical neuropeptide in migraine pathophysiology and the target of the newest class of migraine medications. Here's why CGRP is so important:

  • Elevated in Migraine: CGRP levels increase during migraine attacks and normalize after effective treatment (in some studies)
  • Triggers Migraine: Intravenous CGRP can trigger migraine-like attacks in migraine-prone individuals
  • Vascular Effects: Causes potent vasodilation of cerebral and meningeal blood vessels
  • Inflammatory Actions: Initiates and maintains neurogenic inflammation
  • Sensitization: Contributes to both peripheral and central sensitization, making pain pathways more reactive
  • Expression: Found in 35-50% of trigeminal neurons, particularly in C-fibers and Aδ-fibers that transmit pain

Treatment Relevance: The development of CGRP-targeted treatments represents a significant breakthrough in migraine therapy. These include:

  • Monoclonal Antibodies: Erenumab targets the CGRP receptor while fremanezumab, galcanezumab, and eptinezumab target the CGRP peptide itself
  • Small Molecule Antagonists (Gepants): Ubrogepant, rimegepant, zavegepant, and atogepant block CGRP receptors

These medications have shown effectiveness even in patients who failed multiple traditional preventive and/or abortive treatments, confirming the central role of CGRP in migraine pathophysiology. Furthermore, CGRP has been found to be expressed more in female nerve cells. This correlates with the increased effectiveness of CGRP therapy in females with migraine vs men - especially when treating attacks. 

Other Key Neuropeptides

Pituitary Adenylate Cyclase-Activating Peptide (PACAP)

  • Similar to CGRP in structure and function
  • Induces migraine-like attacks when infused
  • Levels increase during spontaneous migraine
  • Vasodilatory effects via multiple receptor types
  • Several anti-PACAP treatments are in development

Other Relevant Neuropeptides

  • Substance P: Released with CGRP from trigeminal fibers, causes plasma protein extravasation
  • Vasoactive Intestinal Peptide (VIP): Elevated in cluster headache and migraine
  • Neuropeptide Y: May be involved in pain modulation
  • Amylin: Related to CGRP, can activate CGRP receptors
  • Orexins: Hypothalamic peptides involved in sleep-wake regulation. Male nociceptors are sensitized by orexin B

Sensitization: Why Migraine Pain Persists and Worsens

A key aspect of migraine pathophysiology is sensitization - the process by which pain pathways become increasingly reactive during an attack. Sensitization occurs at multiple levels of the nervous system and helps explain many clinical features of migraine.

Peripheral Sensitization

Occurs in the peripheral branches of the trigeminal nerve outside the central nervous system:

  • Mechanism: Inflammatory mediators (CGRP, substance P, bradykinin, prostaglandins) sensitize nociceptors in the meninges
  • Cellular Changes: Phosphorylation of ion channels, increased membrane excitability, reduced activation threshold
  • Timing: Develops within 10-20 minutes after activation of the trigeminovascular system
  • Clinical Signs: Throbbing pain that worsens with physical activity, coughing, or bending over

Molecular Details: Involves activation of TRP channels, sodium channels (Nav1.7, Nav1.8), and modulation of potassium channels. Sustained by neurogenic inflammation in the dura mater, with mast cell degranulation playing a supporting role.

Central Sensitization

Affects central pain-processing neurons in the trigeminal nucleus, thalamus, and cortex:

  • Mechanism: Repeated inputs from sensitized peripheral neurons cause hyperexcitability of second-order and third-order neurons
  • Cellular Changes: Increased synaptic efficacy, reduced inhibitory control, expanded receptive fields
  • Timing: Develops 60-120 minutes into a migraine attack
  • Clinical Signs: Cutaneous allodynia (pain from normal touch), spread of pain beyond the initial area

Molecular Details: Involves activation of NMDA receptors, calcium influx, wind-up phenomenon, and changes in gene expression. Maintained by deficient descending pain inhibition from brainstem centers.

Clinical Implications of Sensitization

  • Treatment Timing: Early treatment (before central sensitization develops) is more effective for aborting migraine attacks
  • Treatment Resistance: Once central sensitization is established, triptans and other medications become less effective
  • Medication Overuse/Adaptation: Frequent use of acute medications can perpetuate and worsen central sensitization, leading to chronic migraine
  • Preventive Treatment: Many preventive medications work by reducing sensitization and restoring normal excitability
  • Allodynia as Marker: The presence of allodynia (pain from normal touch) indicates central sensitization has occurred and may guide treatment decisions

Chronification of Migraine

Repeated episodes of sensitization can lead to long-term changes in pain processing - a process called chronification. This helps explain the progression from episodic to chronic migraine (≥15 headache days per month).

1

Repeated Attacks

Frequent migraine attacks cause repeated cycles of sensitization in pain pathways

2

Neuroplastic Changes

Persistent central sensitization leads to lasting changes in synaptic connections and gene expression

3

Reduced Pain Threshold

Pain thresholds decrease, making it easier to trigger attacks with lesser stimuli

4

Impaired Pain Modulation

Dysfunction develops in descending pain modulatory systems that normally inhibit pain

5

Chronic Migraine

Attacks become more frequent and may eventually blend together, with persistent symptoms between attacks

Risk factors for chronification include medication overuse/adaptation, obesity, sleep disorders, depression, anxiety, and high-frequency episodic migraine. Understanding this process has led to more aggressive early intervention strategies aimed at preventing chronification.

Cortical Spreading Depression and Migraine Aura

Approximately 20-30% of migraine patients experience aura - a reversible neurological symptoms that typically precede the headache phase. The neurobiological basis of migraine aura is cortical spreading depression (CSD).

What is Cortical Spreading Depression?

CSD is a wave of intense neuronal and glial depolarization that spreads across the cerebral cortex at a rate of 3-5 mm per minute, followed by a period of suppressed neural activity. Key characteristics include:

  • Electrophysiological Changes: Initial brief hyperexcitation followed by prolonged neuronal silence
  • Ionic Shifts: Dramatic changes in ion concentrations (increases in extracellular K+, decreases in extracellular Ca2+, Na+, and Cl-)
  • Metabolic Demands: High energy requirements with increased oxygen consumption but paradoxical decreased blood flow
  • Propagation: Self-propagating wave that matches the timing and progression of visual aura symptoms
  • Recovery: Requires active restoration of ion gradients through ATP-dependent membrane pumps
YouTube Video on Cortical Spreading Depression (CSD) underlying migraine aura. This wave of depolarization travels across the visual cortex at 3-5 mm/minute, matching the progression of visual aura symptoms in the visual field. As CSD spreads across the occipital cortex, patients experience expanding visual disturbances.

The Link Between CSD and Migraine Pain

While CSD clearly underlies aura symptoms, its connection to migraine headache has been debated. Current evidence suggests several mechanisms by which CSD may trigger the pain phase:

Trigeminovascular Activation
CSD can activate meningeal nociceptors by releasing potassium, hydrogen ions, nitric oxide, and glutamate into the extracellular space
Blood-Brain Barrier
CSD temporarily opens the blood-brain barrier, allowing inflammatory mediators to access pain-sensitive structures
Pannexin Channels
CSD activates pannexin 1 channels, releasing pro-inflammatory molecules that can sensitize trigeminal nerve endings
Central Sensitization
CSD may directly enhance the excitability of central trigeminovascular neurons in the thalamus and brainstem

Clinical Aspects of Migraine Aura

  • Types of Aura:
    • Visual (most common): Scintillating scotoma, zigzag lines, blind spots, flashing lights
    • Sensory: Numbness or tingling, typically starting in the hand and progressing to the arm and face
    • Language: Difficulty finding words, confusion, transient aphasia
    • Motor (atypical): Weakness on one side of the body (hemiplegic migraine)
    • Brainstem (atypical): Vertigo, tinnitus, double vision, ataxia (migraine with brainstem aura)
  • Timing and Duration: Aura typically develops over 5-20 minutes, lasts less than 60 minutes, and usually occurs before headache but can occur during or without headache
  • Genetics: Certain genetic forms of migraine with aura (like familial hemiplegic migraine) have identified mutations in ion channel genes (CACNA1A, ATP1A2, SCN1A)
  • Treatment Considerations: Triptans were traditionally avoided during aura due to theoretical vascular concerns, but this practice is changing. Some treatments specifically target CSD (lamotrigine, ketamine, intranasal ketamine)

Neurotransmitter Systems in Migraine

Multiple neurotransmitter systems play important roles in migraine pathophysiology. Understanding these systems helps explain both migraine symptoms and the mechanisms of many migraine treatments.

Serotonin molecule
Serotonin (5-HT)

Central to migraine pathophysiology, with multiple receptor subtypes involved. Low levels associated with migraine attacks. Triptans work by activating 5-HT1B/1D receptors.

Glutamate molecule
Glutamate

Primary excitatory neurotransmitter that increases during migraine attacks. Contributes to cortical spreading depression and sensitization. Targeted by some anticonvulsant migraine preventives.

GABA molecule
GABA

Primary inhibitory neurotransmitter that decreases during migraine attacks. Imbalance with glutamate creates neuronal hyperexcitability. Targeted by gabapentin, topiramate, and valproate.

Dopamine molecule
Dopamine

Dysregulation during prodrome explains yawning, food cravings, mood changes. Activation during attacks contributes to nausea and vomiting. Anti-dopaminergic drugs can help with migraine-associated nausea.

Norepinephrine molecule
Norepinephrine

Released during stress and migraine attacks. Implicated in sympathetic symptoms and pain modulation. Targeted by some preventive medications like beta-blockers and SNRIs.

Serotonin System in Detail

The serotonergic system has been central to migraine theories for decades:

  • 5-HT Release: During early migraine phases, serotonin is released from platelets and brainstem nuclei, followed by depletion
  • 5-HT1B/1D Receptors: Located on trigeminal nerve endings and blood vessels; activation inhibits CGRP release and causes vasoconstriction
  • 5-HT1F Receptors: Located in trigeminal ganglion and CNS; activation inhibits trigeminal activation without vascular effects
  • 5-HT7 Receptors: Involved in pain processing and vasodilation
  • Raphe Nuclei: Brainstem serotonergic centers show altered activity in migraine patients

Clinical Connections:

  • Triptans work as 5-HT1B/1D agonists
  • Lasmiditan is a 5-HT1F agonist without vascular effects
  • SSRIs/SNRIs can prevent migraine in some patients
  • The serotonin syndrome risk with triptans and antidepressants

Glutamate-GABA Balance

The balance between excitatory glutamate and inhibitory GABA is disrupted in migraine:

  • Glutamate Excess: Increased glutamate levels in migraine patients, particularly during attacks
  • GABA Deficiency: Reduced GABA levels contribute to cortical hyperexcitability
  • NMDA Receptors: Glutamate activation of NMDA receptors promotes central sensitization
  • Metabotropic Glutamate Receptors: Various subtypes involved in pain transmission and modulation
  • GABA Receptor Subtypes: GABA-A (ionotropic) and GABA-B (metabotropic) both contribute to inhibitory tone

Clinical Connections:

  • Topiramate enhances GABA function and blocks glutamate receptors
  • Valproate increases GABA synthesis and release
  • Memantine blocks NMDA receptors
  • Ketamine's effect on refractory migraine related to NMDA antagonism

Other Neurotransmitters and Modulators

  • Acetylcholine: Involved in cortical activation and vasodilation; may play a role in symptoms like photophobia
  • Histamine: Released during neurogenic inflammation; contributes to headache, itch, and vasodilation
  • Orexins: Hypothalamic peptides that regulate sleep-wake cycles and feeding; abnormalities linked to cluster headache and migraine chronification
  • Endocannabinoids: Modulate pain and inflammation; deficiency may contribute to migraine susceptibility
  • Melatonin: Regulates sleep and has anti-inflammatory properties; effective as migraine preventive in clinical trials
  • Nitric Oxide (NO): Vasodilator that can trigger migraine attacks; produced by NO synthase in response to various stimuli

The complex interplay of these neurotransmitter systems explains why migraine involves such diverse symptoms - from pain to autonomic disturbances to sensory hypersensitivity. It also helps explain why medications that target different neurotransmitter systems can be effective in treating or preventing migraine attacks.

Genetic Factors in Migraine Pathophysiology

Migraine has a strong genetic component, with heritability estimated at 42-57%. Family studies show that first-degree relatives of migraine patients have a 1.5-4 times higher risk of developing migraine compared to the general population.

50%
Risk if One Parent Has Migraine
Children with one migraine-affected parent have approximately a 50% chance of developing migraine
75%
Risk if Both Parents Have Migraine
When both parents are affected, the risk for their children increases to approximately 75%
100+
Risk Loci Identified
Genome-wide association studies have identified over 100 genetic risk loci associated with migraine

Monogenic Migraine Syndromes

Certain rare migraine subtypes follow Mendelian inheritance patterns and have identified causative gene mutations:

Familial Hemiplegic Migraine Type 1 (FHM1)

Gene: CACNA1A on chromosome 19p13

Protein: CaV2.1 (P/Q-type voltage-gated calcium channel α1 subunit)

Function: Controls calcium influx into neurons and neurotransmitter release at synapses

Mechanism: Gain-of-function mutations lead to increased glutamate release and enhanced cortical excitability

Familial Hemiplegic Migraine Type 2 (FHM2)

Gene: ATP1A2 on chromosome 1q23

Protein: Na+/K+ ATPase α2 subunit

Function: Maintains ion gradients across neuronal and glial cell membranes

Mechanism: Loss-of-function mutations impair glutamate clearance from synapses and destabilize resting membrane potential

Familial Hemiplegic Migraine Type 3 (FHM3)

Gene: SCN1A on chromosome 2q24

Protein: Nav1.1 (voltage-gated sodium channel α1 subunit)

Function: Controls sodium influx during action potential generation, especially in inhibitory interneurons

Mechanism: Mutations affect neuronal firing patterns and cortical excitability

Familial Hemiplegic Migraine Type 4 (FHM4)

Gene: PRRT2 on chromosome 16p11.2

Protein: Proline-rich transmembrane protein 2

Function: Regulates synaptic vesicle release and SNARE complex function

Mechanism: Mutations affect neurotransmitter release and synaptic function

Common Migraine Genetics

Unlike the rare monogenic forms above, common migraine (with and without aura) has a polygenic inheritance pattern involving many genes with small individual effects. Genome-wide association studies have identified over 100 risk loci, clustered in several biological pathways:

  • Vascular Function: Genes involved in vascular development, integrity, and regulation
  • Neuronal Function: Ion channels, synaptic signaling, axon guidance
  • Pain Signaling: Nociceptive pathways and modulators
  • Metal Ion Homeostasis: Genes regulating iron, copper, and other metal ions
  • Hormonal Pathways: Estrogen signaling and metabolism
  • Nitric Oxide Signaling: NO production and signaling cascade
  • Glutamatergic Pathways: Glutamate receptors and transporters

Many of these genetic variants affect gene expression rather than protein structure, and often show tissue-specific effects in brain, vascular, or immune cells.

Epigenetic Factors

Beyond fixed genetic variants, epigenetic modifications - changes that affect gene expression without altering DNA sequence - also play a role in migraine:

  • DNA Methylation: Altered methylation patterns in genes related to neuroinflammation and pain processing
  • Histone Modifications: Changes in chromatin structure affecting gene accessibility
  • MicroRNAs: Small non-coding RNAs that regulate gene expression; several miRNAs show altered levels in migraine patients
  • Environmental Triggers: Stress, hormonal fluctuations, and inflammation can induce epigenetic changes that affect migraine susceptibility

Epigenetic changes may help explain why migraine patterns can change over a lifetime and may account for some environmental effects on migraine expression.

Sex Hormones and Migraine

The striking sex difference in migraine prevalence - affecting women three times more often than men - points to the important role of sex hormones in migraine pathophysiology. Hormonal influences help explain why migraine often begins at puberty, changes during pregnancy, and frequently improves after menopause.


Estrogen Effects

Fluctuations vs. Levels: It's the change in estrogen levels, particularly the rapid drop before menstruation, that triggers migraine in susceptible women.

Neurobiological Effects:

  • Modulates serotonin and dopamine systems
  • Upregulates prolactin which in turn sensitizes nociceptors
  • Increases neuronal excitability
  • Enhances NMDA receptor activity and glutamatergic transmission
  • Affects opioid receptor sensitivity
  • Potentiates neurogenic inflammation
  • Influences CGRP expression and release
  • Alters pain perception thresholds

Clinical Patterns: Explains menstrual migraine, periovulatory migraine, and pregnancy/menopause transitions


Progesterone Effects

Progesterone's role is more complex and often counterbalances estrogen:

  • Has inhibitory effects on neuronal excitability via metabolites that enhance GABA function
  • Decreases during the late luteal phase before menstruation, removing this inhibitory effect
  • High levels during pregnancy may contribute to migraine improvement
  • Synthetic progestins in hormonal contraceptives may have different effects than natural progesterone

Testosterone

Emerging research suggests testosterone may be protective against migraine:

  • Men with migraine show lower testosterone levels than healthy controls
  • Women with chronic migraine have lower free testosterone levels
  • May explain part of the sex difference in migraine prevalence
  • Acts via anti-inflammatory mechanisms and modulation of CGRP release
  • May influence the effectiveness of pain inhibitory systems

Hormonal Migraine Patterns

  • Pure Menstrual Migraine: Attacks occur exclusively on days -2 to +3 of menstruation in at least 2/3 of cycles
  • Menstrually-Related Migraine: Attacks occur predictably around menstruation but also at other times of the cycle
  • Periovulatory Migraine: Attacks triggered by the estrogen surge or drop around ovulation
  • Pregnancy Effects: 50-80% of migraine patients improve during pregnancy, especially in the 2nd and 3rd trimesters when estrogen levels are high and stable
  • Perimenopause: Often a time of worsening migraine due to erratic hormone fluctuations
  • Postmenopause: Many women experience improvement after natural menopause when hormones stabilize at lower levels
  • Hormonal Contraceptive Effects: Variable. Can improve, worsen, or have no effect on migraine depending on formulation and individual factors

Mechanistic Studies on Hormonal Effects

Research has revealed several specific mechanisms by which sex hormones influence migraine:

  • Brain Excitability: Estrogen increases cortical excitability and reduces the threshold for cortical spreading depression in animal models
  • Trigeminal System: Estrogen receptors are expressed in trigeminal ganglia neurons and influence their sensitivity
  • CGRP Regulation: Estrogen upregulates CGRP expression in trigeminal ganglia and enhances CGRP release
  • Trigeminovascular Vasodilation: Estrogen potentiates vasodilatory responses to CGRP in the dura mater
  • Mast Cell Activation: Estrogen can promote mast cell degranulation, contributing to neurogenic inflammation
  • Nitric Oxide Production: Estrogen increases nitric oxide synthase activity, increasing NO-mediated vasodilation
  • Blood-Brain Barrier: Estrogen affects blood-brain barrier permeability, potentially allowing inflammatory mediators greater access to pain-sensitive structures

Migraine Triggers and Pathophysiological Mechanisms

Migraine triggers are factors that can precipitate attacks in susceptible individuals (people without migraine do not have migraine triggers. These do not cause migraine, but can contribute to progression and/or attacks). Understanding how triggers activate underlying migraine mechanisms provides insights into both pathophysiology and management strategies.

Stress

Mechanisms:

  • Activates hypothalamic-pituitary-adrenal axis
  • Causes cortisol and catecholamine release
  • Disrupts sleep and other homeostatic mechanisms
  • Creates neuroinflammation via glial activation
  • Often triggers attacks during the "let-down" phase after stress resolves

Neurobiological Pathway: HPA axis → autonomic nervous system → altered neurotransmitter release → lowered migraine threshold

Sleep Disruption

Mechanisms:

  • Affects hypothalamic function and circadian rhythms
  • Alters serotonin and dopamine levels
  • Increases cortical excitability
  • Disrupts glymphatic clearance of metabolic waste
  • Enhances pain processing (both too much and too little sleep can trigger)

Neurobiological Pathway: Altered hypothalamic activity → neurotransmitter imbalance → increased neural excitability → lowered migraine threshold

Environmental Triggers

Mechanisms:

  • Bright/Flickering Light: Activates photosensitive retinal cells → trigeminal activation
  • Loud Sounds: Cochlear activations → brainstem nuclei → trigeminal system
  • Strong Odors: Direct trigeminal nerve stimulation + emotional/autonomic response
  • Weather Changes: Barometric pressure effects on sinuses and inner ear; possible influence on ion channels

Neurobiological Pathway: Sensory overload → thalamic processing → cortical hyperexcitability and/or direct trigeminovascular activation

The Migraine Threshold Theory

The "migraine threshold" concept helps explain how triggers and underlying pathophysiology interact:

  • Individual Thresholds: Each person with migraine has a genetically influenced threshold for attacks
  • Fluctuating Threshold: This threshold is not fixed but fluctuates based on internal and external factors
  • Trigger Accumulation: Multiple mild triggers can combine to cross the threshold, explaining why the same trigger doesn't always cause an attack
  • Preventive Strategies: Raise the threshold through medications, lifestyle modifications, and trigger avoidance

Factors that lower the migraine threshold include:

  • Hormonal fluctuations (especially estrogen withdrawal)
  • Stress and stress let-down
  • Sleep disruption
  • Dehydration and fasting
  • Environmental triggers (bright lights, strong odors, weather changes)
  • Previous migraine attacks (leading to sensitization)

Factors that raise the threshold include preventive medications, regular sleep and meal patterns, stress management, and consistent exercise.

Migraine Comorbidities and Shared Pathophysiology

Migraine frequently co-occurs with other medical conditions at rates higher than would be expected by chance. These comorbidities often share underlying pathophysiological mechanisms, suggesting common biological pathways.

Psychiatric Comorbidities
Depression: 2-4x higher risk
Anxiety Disorders: 2-5x higher risk
PTSD: 2-3x higher risk
Shared mechanisms: Serotonin dysfunction, inflammation, HPA axis abnormalities
Other Pain Disorders
Fibromyalgia: 2-3x higher risk
Irritable Bowel Syndrome: 2-3x higher risk
Chronic Low Back Pain: 1.5-2x higher risk
Shared mechanisms: Central sensitization, deficient pain inhibition
Cardiovascular & Stroke Risk
Ischemic Stroke: 2x higher risk, especially in migraine with aura
Patent Foramen Ovale: 2-4x more common
Shared mechanisms: Endothelial dysfunction, platelet abnormalities, inherited thrombophilias
Neurological Comorbidities
Epilepsy: 2-3x higher risk
Restless Legs Syndrome: 2-3x higher risk
Essential Tremor: 1.5-2x higher risk
Shared mechanisms: Neuronal hyperexcitability, ion channel dysfunction

Shared Pathophysiological Mechanisms

Migraine & Psychiatric Disorders

  • Neurotransmitter Abnormalities: Both involve serotonin, dopamine, and glutamate dysregulation
  • HPA Axis: Abnormal stress responses in both conditions
  • Inflammation: Elevated inflammatory markers in both depression and migraine
  • Genetics: Shared genetic risk factors in serotonergic and dopaminergic pathways
  • Treatment Response: Similar response to antidepressants, especially SNRIs and TCAs

Bidirectional relationship: Each condition increases risk for the other, suggesting true biological connection rather than just comorbidity.

Migraine & Cardiovascular Disorders

  • Endothelial Dysfunction: Abnormal vascular reactivity in both conditions
  • Platelet Activation: Hypercoagulability and platelet reactivity
  • CGRP Function: Involved in both migraine and cardiovascular regulation
  • Patent Foramen Ovale (PFO): Right-to-left cardiac shunt more common in migraine with aura
  • Shared Risk Factors: Obesity, smoking, and inflammation

Clinical Implications: Higher stroke risk in migraine patients, especially women with aura who smoke and use estrogen-containing contraceptives.

Clinical Significance of Comorbidities

  • Diagnosis Implications: Presence of comorbidities should prompt consideration of migraine in patients with unexplained symptoms
  • Treatment Selection: Choose medications that can address multiple comorbid conditions (e.g., SNRIs for migraine and depression/anxiety)
  • Treatment Limitations: Some comorbidities limit treatment options (e.g., cardiovascular disease may limit triptan use)
  • Treatment Resistance: Unrecognized comorbidities can lead to poorer migraine treatment outcomes if not addressed
  • Disease Progression: Comorbidities may increase the risk of migraine chronification
  • Preventive Opportunities: Treating one condition may improve the other (e.g., treating sleep disorders may reduce migraine frequency)

The Concept of Central Sensitivity Syndromes

Many migraine comorbidities fall into the category of "central sensitivity syndromes" (CSS) - disorders characterized by central sensitization and amplified pain processing:

  • Examples: Fibromyalgia, irritable bowel syndrome, temporomandibular disorders, chronic fatigue syndrome, and interstitial cystitis
  • Shared Features: Pain amplification, sensory hypersensitivity, fatigue, sleep disturbances, and cognitive difficulties
  • Neurobiological Basis: Altered central processing in pain pathways, neuroinflammation, and deficient descending pain inhibition
  • Genetic Factors: Polymorphisms in genes related to catecholamines, serotonin transport, and inflammatory mediators
  • Treatment Approach: CSS often respond to similar interventions (SNRIs, anticonvulsants, CBT, exercise) regardless of the specific syndrome

This shared pathophysiology suggests that migraine is not just a headache disorder but part of a spectrum of disorders involving sensitization of the central nervous system.

How Understanding Pathophysiology Guides Treatment

Our improved understanding of migraine pathophysiology has led to more targeted and effective treatments. This section explains how specific migraine mechanisms are targeted by different treatment approaches.

1

CGRP Pathway Treatments

Mechanism Targeted: CGRP release and receptor activation in the trigeminovascular system

Treatments:

  • Monoclonal Antibodies:
    • Anti-CGRP Ligand: Fremanezumab, galcanezumab, eptinezumab bind and neutralize CGRP peptide
    • Anti-CGRP Receptor: Erenumab blocks the CGRP receptor
  • Small Molecule Antagonists (Gepants):
    • Acute Treatment: Ubrogepant, rimegepant, zavegepant block CGRP receptors during attacks
    • Prevention: Atogepant, rimegepant when taken regularly prevent CGRP signaling

Efficacy Evidence: Effective even in patients who failed traditional preventives; 50% responder rates of 30-60% for prevention; 2-hour pain freedom rates of 20-25% for acute treatment

2

Serotonergic Agents

Mechanism Targeted: Serotonergic transmission in pain pathways and trigeminal system

Treatments:

  • Triptans (5-HT1B/1D agonists): Sumatriptan, rizatriptan, zolmitriptan, etc.
    • Inhibit release of inflammatory neuropeptides
    • Cause cranial vasoconstriction
    • Inhibit transmission in trigeminal pain pathways
  • Ditans (5-HT1F agonists): Lasmiditan
    • Inhibits CGRP release from trigeminal neurons
    • No vasoconstrictor activity (safer for cardiovascular risk patients)
  • Antidepressants: Amitriptyline (TCA), venlafaxine (SNRI)
    • Enhance serotonergic and noradrenergic transmission
    • Modulate pain processing in central pathways

Efficacy Evidence: Triptans provide 2-hour pain freedom in 30-40% of attacks; antidepressants reduce migraine frequency by 30-50% in responsive patients

3

Neuromodulation Approaches

Mechanism Targeted: Electrical activity in key neural circuits involved in migraine

Full neuromodulation table here

Treatments:

  • Supraorbital Nerve Stimulation: Cefaly, HeadaTerm device stimulates branches of the trigeminal nerve
  • Vagus Nerve Stimulation: gammaCore device modulates pain pathways through vagal afferents
  • Single-Pulse Transcranial Magnetic Stimulation: sTMS mini device disrupts cortical spreading depression
  • Remote Electrical Neurostimulation: Nerivio device activates conditioned pain modulation
  • Occipital Nerve Stimulation: Invasive approach for refractory chronic migraine

Efficacy Evidence: Generally modest efficacy (20-40% response rates) but excellent safety profile; particularly useful for patients with contraindications to medications or medication overuse

4

Membrane Stabilizers & Ion Channel Modulators

Mechanism Targeted: Neuronal hyperexcitability and abnormal ion channel function

Treatments:

  • Anticonvulsants:
    • Topiramate: Blocks sodium channels, enhances GABA, inhibits glutamate receptors
    • Valproate: Enhances GABA function, blocks sodium channels, inhibits trigeminal firing
    • Gabapentin/Pregabalin: Modulate calcium channels and decrease glutamate release
  • Lamotrigine: Sodium channel blocker particularly effective for migraine aura
  • Memantine: NMDA receptor antagonist that prevents glutamate excitotoxicity

Efficacy Evidence: Topiramate and valproate reduce migraine frequency by 40-50% in responders; others show more variable response

5

Botulinum Toxin

Mechanism Targeted: Peripheral sensitization and neuropeptide release

Treatment: OnabotulinumtoxinA (Botox) injections using the PREEMPT protocol

Mechanisms of Action:

  • Inhibits release of CGRP, substance P, and glutamate from peripheral nerve terminals
  • Reduces mechanical sensitivity in peripheral nociceptors
  • Indirectly decreases central sensitization by reducing afferent input
  • May have direct central effects via retrograde axonal transport
  • Relaxes pericranial muscles, reducing nociceptive input

Efficacy Evidence: FDA-approved for chronic migraine; reduces headache days by 8-9 days/month compared to 6-7 for placebo in clinical trials; effects build over multiple treatment cycles

6

Emerging Therapeutic Targets

PACAP Pathway: Antibodies targeting PACAP or its receptors in development

Glutamate Modulation: Novel glutamate receptor antagonists showing promise

Orexin Antagonists: Targeting hypothalamic orexin system for sleep-related migraine

ATP-Sensitive Potassium Channel Openers: Modulating neuronal excitability

Acid-Sensing Ion Channel (ASIC) Blockers: Targeting pH-sensitive channels in pain pathways

Glial Modulators: Reducing neuroinflammation by targeting support cells

Non-Pharmacological Approaches: Mechanism-Based Explanations

  • Cognitive Behavioral Therapy:
    • Modulates pain processing in the anterior cingulate cortex and prefrontal regions
    • Reduces catastrophizing, which is associated with increased pain signaling
    • Enhances descending pain inhibition through cognitive reappraisal
  • Biofeedback/Relaxation:
    • Reduces sympathetic arousal and stress hormones that sensitize pain pathways
    • Modulates cortical excitability, potentially raising the threshold for cortical spreading depression
    • Enhances vagal tone, which can inhibit pain transmission
  • Regular Exercise:
    • Releases endogenous opioids and endocannabinoids that modulate pain
    • Improves sleep quality, reducing this common trigger
    • Reduces inflammation through multiple mechanisms
    • Enhances stress resilience through HPA axis modulation
  • Sleep Hygiene:
    • Normalizes hypothalamic function and circadian rhythm
    • Enhances glymphatic clearance of metabolic waste during deep sleep
    • Reduces cortical excitability through balanced GABA/glutamate function
  • Dietary Interventions:
    • Ketogenic diets may reduce cortical excitability through GABA enhancement. Difficult to maintain long-term and may increase cardiovascular disease (CVD) risk in susceptible individuals. Individuals with migraine have a naturally increased CVD risk although not via the traditional atherosclerotic pathology. 
    • Mediterranean diets decrease CVD risk, reduces obesity which decreases migraine progression risk, is low-inflammatory, and may be maintained long-term. 
    • Low inflammatory diets reduce CGRP and other inflammatory mediators
    • Regular eating prevents hypoglycemia-triggered hypothalamic activation

Future Directions in Migraine Research

Our understanding of migraine pathophysiology continues to evolve, with several exciting areas of ongoing research that promise to further refine our understanding and treatment approaches.

Precision Medicine Approaches

Moving beyond one-size-fits-all treatment to personalized approaches:

  • Biomarker Development: CGRP levels, neuroimaging patterns, and genetic profiles to predict treatment response
  • Endophenotyping: Identifying subgroups of migraine patients based on pathophysiological patterns
  • Pharmacogenomics: Using genetic information to predict medication response and side effects
  • Migraine Subtypes: Better characterization of mechanistically distinct migraine types

Impact: May allow clinicians to match patients with the most effective treatment based on their specific migraine mechanisms, rather than through trial and error.

Novel Therapeutic Targets

Beyond CGRP, several promising targets are under investigation:

  • PACAP Pathway: PACAP (Pituitary Adenylate Cyclase-Activating Peptide) and its receptors (PAC1, VPAC1, VPAC2)
  • Glutamate Receptors: More selective antagonists with fewer side effects
  • Orexin System: Dual orexin receptor antagonists for sleep-related migraine
  • Nitric Oxide Synthesis: NOS inhibitors with improved selectivity
  • ATP-Sensitive Potassium Channels: K+ channel modulators to stabilize neuronal excitability

Impact: Expands treatment options beyond current classes, potentially addressing treatment-resistant cases.

Advanced Neuroimaging

New imaging techniques to visualize migraine processes in real-time:

  • High-Field MRI: Ultra-high-resolution imaging of brainstem nuclei
  • PET Ligands: Visualization of specific receptors and neurotransmitters
  • Advanced fMRI: Real-time monitoring of brain activity during attacks
  • Artificial Intelligence: Pattern recognition in complex imaging datasets
  • Combined EEG-fMRI: Integrating temporal and spatial information

Impact: Allows direct visualization of migraine mechanisms in humans, potentially identifying new therapeutic targets.

Neuromodulation Advances

More precise, non-invasive methods to modify brain activity:

  • Focused Ultrasound: Non-invasive deep brain stimulation
  • Closed-Loop Systems: Devices that detect early attack signatures and deliver treatment
  • Transcranial Alternating Current Stimulation: Modulating brain oscillations
  • Targeted Vagus Nerve Stimulation Protocols: More specific parameters for migraine
  • Wearable Long-Term Neuromodulation: Continuous treatment for chronic migraine

Impact: Provides non-pharmacological options with potentially fewer side effects and more targeted action.

Challenges in Migraine Research

  • Heterogeneity: Migraine likely represents several distinct disorders with shared clinical features
  • Biomarker Development: Lack of reliable, accessible biomarkers hampers diagnosis and treatment selection
  • Animal Models: Limitations in modeling complex human experiences like headache and associated symptoms
  • Disease Modification: Current treatments are largely symptomatic rather than addressing underlying progression
  • Comorbidities: The complex relationship between migraine and its many comorbidities complicates research
  • Funding: Despite its enormous disease burden, migraine research remains underfunded relative to other neurological conditions
As research continues to unravel the complex mechanisms of migraine, we move closer to more effective, targeted treatments that could potentially prevent or even cure this disabling condition. The transformation of migraine from a poorly understood "vascular headache" to a complex neurological disorder with well-characterized pathophysiology represents one of the great success stories in modern neuroscience. - Cerebral Torque

The Complex Brain of Migraine

Our understanding of migraine pathophysiology has evolved dramatically over the past few decades. What was once considered simply a vascular headache is now recognized as a complex neurological disorder involving multiple brain regions, networks, and systems.

Brain-Based Disorder
Migraine originates in the brain, not blood vessels. The hypothalamus, brainstem, thalamus, and cortex all play crucial roles in attack initiation, progression, and termination.
Sensory Processing Disorder
The migraine brain processes sensory information differently, showing hyperexcitability, deficient habituation, and altered connectivity between sensory processing regions.
Complex Cascade
Migraine involves a cascade of neurobiological events with multiple phases and diverse symptoms beyond headache—from prodromal symptoms to postdrome effects.
Genetic Foundation
Genetic factors create susceptibility, while environmental factors trigger individual attacks. Over 100 genetic risk loci have been identified, affecting multiple biological pathways.

Key insights from modern migraine research include:

  • Cyclic Nature: Migraine is not just an episodic pain disorder but a cyclic brain disorder with interictal (between-attack) abnormalities that predispose to attacks
  • Multifactorial Pathogenesis: No single "migraine generator" exists, but rather a complex interaction of genetic vulnerability, environmental triggers, and neurobiological cascades
  • Phases and Networks: Different brain regions and networks become activated or deactivated during different phases of the migraine cycle
  • Neurochemical Complexity: Multiple neurotransmitters, neuropeptides, and inflammatory mediators contribute to migraine, with CGRP playing a particularly central role
  • Treatment Implications: Understanding these mechanisms has led to more targeted treatments, from triptans to CGRP antagonists to neuromodulation approaches

For patients, understanding migraine as a neurological disorder with complex pathophysiology helps validate their experiences and explains the diverse symptoms beyond headache. For clinicians, this knowledge enables more informed treatment decisions based on underlying mechanisms rather than just symptomatic approaches.

Clinical Takeaways for Patients and Providers

  • Early Intervention: Treating migraine attacks before central sensitization develops improves outcomes
  • Multifaceted Approach: The complex pathophysiology often requires multimodal treatment addressing different mechanisms
  • Prevention Focus: Raising the migraine threshold through preventive treatments can reduce attack frequency and severity
  • Comorbidity Awareness: Recognizing and addressing comorbid conditions improves overall management
  • Trigger Management: Understanding how triggers activate underlying neurobiological mechanisms helps with prevention
  • Patient Education: Knowledge of migraine pathophysiology empowers patients to participate in treatment decisions and adhere to management plans
The migraine brain is not "broken" - it's different, with both vulnerabilities and potentially adaptive features that we are just beginning to understand. As research continues to unravel these complex mechanisms, we move closer to more effective, personalized approaches to managing this common and disabling neurological disorder. - Cerebral Torque

References

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  2. Ashina, M., Benítsvegna, E., Martelletti, P., & Eikermann-Haerter, K. Structural and functional brain changes in migraine. Pain and Therapy. 2021; 10:211-223.
  3. Dodick, D. W. A phase-by-phase review of migraine pathophysiology. Headache. 2018; 58(Suppl. 1):4-16.
  4. Karsan, N., & Goadsby, P. J. Biological insights from the premonitory symptoms of migraine. Nature Reviews Neurology. 2018; 14:699-710.
  5. Karsan, N., & Goadsby, P. J. Imaging the premonitory phase of migraine. Frontiers in Neurology. 2020; 11:140.
  6. Burstein, R., Noseda, R., & Borsook, D. Migraine: Multiple processes, complex pathophysiology. Journal of Neuroscience. 2015; 35:6619-6629.
  7. Charles, A. C., & Baca, S. M. Cortical spreading depression and migraine. Nature Reviews Neurology. 2013; 9:637-644.
  8. Edvinsson, L., Haanes, K. A., Warfvinge, K., & Krause, D. N. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nature Reviews Neurology. 2018; 14:338-350.
  9. Schulte, L. H., & May, A. The migraine generator revisited: Continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016; 139:1987-1993.
  10. Schulte, L. H., Menz, M. M., Haaker, J., & May, A. The migraineur's brain networks: Continuous resting state fMRI over 30 days. Cephalalgia. 2020; 40:1614-1621.
  11. Eftekhari, S., & Edvinsson, L. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neuroscience. 2011; 12:112.
  12. Hendrikse, E. R., Bower, R. L., Hay, D. L., & Walker, C. S. Molecular studies of CGRP and the CGRP family of peptides in the central nervous system. Cephalalgia. 2019; 39:403-419.
  13. Iyengar, S., Johnson, K. W., Ossipov, M. H., & Aurora, S. K. CGRP and the trigeminal system in migraine. Headache. 2019; 59:659-681.
  14. Maniyar, F. H., Sprenger, T., Monteith, T., et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014; 137:232-241.
  15. Marciszewski, K. K., Meylakh, N., Pietro, F. D., et al. Changes in brainstem pain modulation circuitry function over the migraine cycle. Journal of Neuroscience. 2018; 38:10479-10488.
  16. Kaushal, R., Taylor, B. K., Jamal, A. B., et al. GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat: contribution of NAA1 receptors in the medial prefrontal cortex. Neuroscience. 2016; 334:148-159.
  17. Raffaelli, B., Do, T. P., Chaudhry, B. A., et al. Menstrual migraine is caused by estrogen withdrawal: Revisiting the evidence. The Journal of Headache and Pain. 2023; 24:131.
  18. Hautakangas, H., Winsvold, B. S., Ruotsalainen, S. E., et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nature Genetics. 2022; 54:152-160.
  19. Huang, T., Zhang, Y., Zhou, Y., et al. Glymphatic dysfunction in migraine mice model. Neuroscience. 2023; 528:64-74.
  20. Bigal, M. E., Ashina, S., Burstein, R., et al. Prevalence and characteristics of allodynia in headache sufferers: A population study. Neurology. 2008; 70:1525-1533.
  21. Schwedt, T. J. Multisensory integration in migraine. Current Opinion in Neurology. 2013; 26:248-253.
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This information is provided for educational purposes only and does not constitute medical advice. Always consult with your healthcare provider for diagnosis and treatment of medical conditions.

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