Table 1 Overview of key arguments for a peripheral or central origin of migraine attacks

Prodromal symptoms and central dysfunction

• Methodological uncertainties limits inferences from reports on prodromal symptoms in migraine

• The hypothesis of a hypothalamic or brainstem generator of migraine attacks does not explain specificity to migraine headache in humans

• Rather than before or at onset, allodynia typically takes 1 h or longer for development after onset of a migraine attack

• Some individuals with migraine are able to accurately predict their migraine attacks based on prodromal symptoms

• Common migraine prodromal symptoms such as yawning, cravings, and mood changes likely have a central, not peripheral, origin

• Advanced neuroimaging studies support activation of brain structures including the hypothalamus and brainstem, prior to onset of migraine attacks

Migraine aura

• Migraine aura does not provide an explanation for the most common phenotype, migraine without aura

• Migraine aura is not a prerequisite of migraine attacks. Only a minority of patients experience migraine aura

• “Silent” cortical spreading depression has never been demonstrated in humans

• Observations of migraine aura without headache suggests that cortical spreading depression is but a potent potential trigger of migraine attacks without aura

• Symptoms in monogenic subtypes of migraine (e.g., hemiplegia during aura, progressive ataxia, attacks triggered by mild head trauma; brain edema, mental retardation, and progressive ataxia) are not found in common migraine subtypes

• Migraine aura symptoms precede the headache in nearly all cases of migraine with aura

• Migraine aura symptoms clearly originate from the cerebral cortex

• Preclinical studies have demonstrated that cortical spreading depression, the underlying mechanism of aura, can lead to activation of meningeal nociceptors

• In familial hemiplegic migraine, attack initiation is understood on the molecular level and is explained by ion transport dysfunction leading to neuronal depolarization

• A recent meta-analysis of genetic studies supports that migraine with typical aura may involve dysfunction of similar ion transporters in the cerebral cortex

Migraine pain

• Pain-sensitive structures are limited to the surrounding structures of the brain, e.g., dura mater, pia mater and their feeding vessels, and not the brain parenchyma itself

• Peripheral administration of neuropeptides, e.g., calcitonin gene-related peptide (CGRP), provokes migraine attacks in susceptible individuals. These compounds do not cross the blood–brain barrier

• There is no increased permeability of the blood–brain barrier in individuals with migraine without aura or migraine with aura

• Migraine headache (and relief) is associated with changes in the circumference of intracranial arteries

• Monoclonal antibodies targeting the CGRP signaling pathway are highly effective for migraine prevention and these molecules do not cross the blood–brain barrier

• Epidemiological (association with cardiovascular disease) and genetic data suggest an association between migraine and vascular dysfunction

• Although the pain perceived during migraine attacks may originate peripheral structures, the primary events of migraine may well occur in the central nervous system (CNS), as suggested by the early symptoms of migraine, i.e., prodromal symptoms and migraine aura

• In spontaneous migraine attacks, primary CNS activity may in turn lead to downstream activation of peripheral nociceptors

• Hypothetically, peripheral administration of neuropeptides may initiate migraine attacks by mimicking downstream effects of the CNS in spontaneous migraine attacks. Administration of CGRP generally triggers migraine headache, not migraine aura, even in patients who always experience aura symptoms before the headache phase in the course of their spontaneous migraine attacks

• Genetic data suggest an association between migraine and central dysfunction