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Neurological diseases

Neurobiology of migraine

Nature Reviews Neuroscience volume 4, pages 386–398 (2003)Cite this article

Key Points

  • Migraine — an episodic headache — is caused by the activation of the so-called trigeminovascular system (TGVS): trigeminal afferents lead to the activation of structures that are involved in the transmission and perception of pain, and to the release of vasoactive peptides (presumably causing neurogenic inflammation).

  • The two main open issues in the neurobiology of migraine headache are the primary cause of activation of the TGVS and the mechanism of pain generation after activation of the TGVS.

  • Two ideas have dominated the field regarding the primary cause of TGVS activation: cortical spreading depression (a slowly moving wave of cortical depolarization) and the existence of a brainstem generator (dysfunctional brainstem nuclei involved in antinociception as a primary cause of migraine). In any case, alterations in cortical excitability seem to be related to migraine attacks.

  • Regarding the pain mechanisms in migraine, two main ideas have been considered: neurogenic inflammation of the meninges, and sensitization of the trigeminal nerve and nucleus.

  • Migraine has a strong genetic component. So far, the only two genes that have been identified, both causing a rare form of migraine, are CACNA1A (which encodes a subunit of the voltage-gated Ca2+ channel CaV2.1) and ATP1A2 (which encodes a subunit of the Na+/K+ ATPase).

  • Migraine-linked mutations in CACNA1A alter the biophysical properties and density of CaV2.1, but how this phenotype translates into the neurological condition remains unclear. Similarly, the mutations in ATP1A2 lead to a loss of ATPase function, but it remains to be established how this phenotype leads to the onset of migraine.

  • The identification of the most probable primary cause of TGVS activation, the increased understanding of the pain mechanisms in migraine, and the discovery of migraine-linked mutations provide us with new targets for the development of anti-migraine compounds. This is an area of paramount importance owing to the prevalence of the condition and to the fact that currently available drugs are not always effective.

Abstract

Migraine — an episodic headache — affects more than 10% of the general population. Despite recent progress, drug therapy for preventing and treating migraine remains unsatisfactory for many patients. One problem that slows the development of new therapeutic approaches is our limited understanding of migraine neurobiology. Activation of the trigeminovascular system is a central step in the development of migraine. However, two main issues remain incompletely understood: the primary cause of migraine, leading to activation of the trigeminovascular system, and the mechanisms of pain generation after its activation.

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Figure 1: Neuronal pathways involved in trigeminovascular activation and pain processing.
Figure 2: Spreading suppression of cortical activation during migraine aura.
Figure 3: Proposed pathophysiological mechanisms in the generation of migraine headache.
Figure 4: Functional effects of type 1 familial hemiplegic migraine (FHM1) mutations on neuronal Cav2.1 channels.

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Acknowledgements

Our work is funded by the Austrian Science Fund, Telethon-Italia, the Italian Ministry of University and Research, and the European Community.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, via G. Colombo 3, Padova, 35121, Italy

    Daniela Pietrobon

  2. Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Peter-Mayr-Str. 1, Innsbruck, A-6020, Austria

    Jörg Striessnig

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  1. Daniela Pietrobon
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Correspondence to Daniela Pietrobon.

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DATABASES

LocusLink

ATP1A2

CACNA1A

Cav2.2

OMIM

FHM

MA

MO

FURTHER INFORMATION

Encyclopedia of Life Sciences

headache

migraine

Glossary

POLYGENIC

A characteristic controlled by different genes, each of which has only a small role in the phenotype.

EXTRAVASATION

The exit of fluid from a blood vessel.

SCOTOMA

An area of lost vision that is surrounded by an area of less depressed or normal vision.

MAGNETOENCEPHALOGRAPHY

A non-invasive technique that allows the detection of the changing magnetic fields that are associated with brain activity. As the magnetic fields of the brain are very weak, extremely sensitive magnetic detectors known as superconducting quantum interference devices, which work at very low, superconducting temperatures (−269 °C), are used to pick up the signal.

FOS

An immediate early gene that is rapidly turned on when many types of neuron increase their activity. It can therefore be used to identify responsive neurons.

PERFUSION-WEIGHTED IMAGING

Imaging technique in which the magnetic resonance signal is intrinsically sensitive to the presence and rate of blood perfusion. It commonly involves the intravenous injection of a bolus of a contrast agent, and the subsequent imaging of the changes in signal intensity as the contrast agent first passes through the brain.

TRANSCRANIAL MAGNETIC STIMULATION

A technique that is used to induce a transient interruption of normal activity in a relatively restricted area of the brain. It is based on the generation of a strong magnetic field near the area of interest, which, if changed rapidly enough, will induce an electric field that is sufficient to stimulate neurons.

PHOSPHENES

Luminous perceptions that are elicited by excitation of the retina by means other than light itself, as when the eyeballs are pressed through closed lids.

INTERICTAL

Refers to events that occur between attacks or paroxysms.

EVENT-RELATED POTENTIALS

Electrical potentials that are generated in the brain as a consequence of the synchronized activation of neuronal networks by external stimuli. These evoked potentials are recorded at the scalp and consist of precisely timed sequences of waves or 'components'.

CONTINGENT NEGATIVE VARIATION

A small electroencephalographic potential that is often recorded as subjects perform expectation- or attention-dependent tasks. It is also known as the expectation or E wave.

P300 POTENTIAL

A positive waveform in the electroencephalogram that occurs about 300 ms after the onset of a stimulus, and is related to the attentional and working memory demands of a task.

PAIRED-PULSE DEPRESSION

When two depolarizing stimuli are delivered in close succession to a group of axons, their average response to the second one is sometimes smaller than to the first. This form of short-term plasticity is more common at inhibitory than at excitatory synapses.

ALLODYNIA

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

ATAXIA

Lack of movement coordination that is commonly associated with cerebellar damage.

NYSTAGMUS

An involuntary, rapid and rhythmic movement of the eyeball.

MISSENSE MUTATIONS

Mutations that result in the substitution of an amino acid in a protein.

LINKAGE ANALYSIS

An analysis of the frequency of co-inheritance of a pair of genetic markers to obtain an index of their physical proximity on a chromosome.

SIB-PAIRS ANALYSIS

A means to establish whether affected siblings have the same allele at a particular locus.

SNARE PROTEINS

A family of membrane-tethered coiled-coil proteins that are required for membrane fusion in exocytosis (such as during neurotransmitter release) and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes close together, presumably causing them to fuse.

DYSTONIA

The occurrence of dyskinetic movements due to alterations of muscle tone.

SPIKE-FREQUENCY ADAPTATION

A decrease in the rate of action potentials fired by a neuron under prolonged depolarization.

LEANER MICE

Mice with mutations in Cacna1a. They are characterized by marked cerebellar atrophy that is accompanied by ataxia, wobbly gait and dyskinesia.

PENETRANCE

The probability that an individual with a particular genotype will manifest a given phenotype. Complete penetrance corresponds to the situation in which every individual with the same specific genotype manifests the phenotype in question.

ACTIVE ZONE

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.

KNOCK-IN

The insertion of a mutant gene at the exact site in the genome where the corresponding wild-type gene is located. This approach is used to ensure that the effect of the mutant gene is not affected by the activity of the endogenous locus.

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Pietrobon, D., Striessnig, J. Neurobiology of migraine. Nat Rev Neurosci 4, 386–398 (2003). https://doi.org/10.1038/nrn1102

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