What causes the different phases of migraine?

Migraine is a complex polygenic disease influenced by the internal factors and external environment

Activation of different brain regions appear to contribute to migraine-related symptoms¹

Migraine symptoms vary in severity and by phase, explained Professor David Dodick, Mayo Clinic College of Medicine, Scottsdale, Arizona, USA, and appear to result from activation of different brain regions with release of neuropeptides and altered brain connectivity.¹

Increasing disease severity correlates with structural and functional brain alterations, he added, and potential pathophysiological changes in the long term include:

• Altered neuropeptide levels²
• Structural brain changes (visualized by neuroimaging)³
• Changes in neuronal activation and function (visualized by neuroimaging)¹

Attack frequency, medication overuse, and severity of symptoms may act as indicators of increasing migraine severity and disease progression⁴ and facilitate optimal migraine management key to reduce the risk of disease progression.

The Prodromal phase is associated with hypothalamic activation, leptin, neuropeptide Y and orexins A and B

Migraine phases are not discrete and prodromal symptoms can persist throughout a migraine attack

The hypothalamus is involved in a number of physiological processes including nociceptive processing, control of the sleep-wake cycle, feeding, thirst, arousal, and autonomic and endocrine regulation.⁵ said Professor Andrew Charles, University of California and Los Angeles, California, USA. He commented that:

• activation of the hypothalamus occurs before onset of migraine pain⁶ and, together with neurotransmitters and neuromodulators that regulate hypothalamic function, may contribute to prodromal symptoms^5,7
• the hypothalamus may control non-headache symptoms such as nausea and vomiting, changes in appetite, and fatigue⁶

He also explained that neuropeptides involved in homeostatic functions may mediate the prodromal symptoms of migraine,⁷ for example:

• leptin, which reduces appetite, increases under normal sleep conditions, and is reduced interictally
• neuropeptide Y, which increases appetite, promotes sleep, and is increased in plasma and cerebrospinal fluid (CSF) during attacks
• orexin A and B, which increase appetite, contribute to the sleep/wakefulness cycle, and are increased in the CSF in chronic migraine and medication overuse headache

Aura is driven by cortical spreading depression (CSD)

CSD activates the trigeminovascular system, driving aura symptoms

CSD is considered to be primary pathophysiology behind the aura phase,⁷ said Professor Charles. It is hypothesized that CSD:

• activates the trigeminovascular system, driving aura symptoms
• causes a large wave of slow spreading depolarization within the gray matter, which inhibits cortical activity
• results in changes in synaptic activity, extracellular ion concentrations, blood flow, and metabolism

Sensitization of the central and peripheral trigeminal system can create a state of hypersensitivity and sustained pain,⁸ he added. Feedback from a sensitized brain may then potentiate pain signaling and contribute to photophobia, phonophobia, and cutaneous mechanical allodynia.⁸

Headache (ictal) phase is associated with brainstem abnormalities and CGRP, and PACAP activity

CGRP and PACAP are elevated during a migraine attack

Magnetic resonance imaging suggests that patients with migraine and greater symptoms of allodynia have structural abnormalities within the brainstem.⁹ In addition, sensitization of primary nociceptors and central trigeminovascular neurons may contribute to allodynia.¹⁰

The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are elevated during a migraine attack.¹¹ Both are implicated in the pathogenesis of headache pain and photophobia and may play a fundamental role in neurogenic inflammation and peripheral and central sensitization of the trigeminal and other systems,¹¹ said Professor Charles.

Postdromal and interictal phases are associated with ongoing brain hypoperfusion and activation

Bilateral posterior cortical hypoperfusion during migraine attacks persists following effective pain relief for 4–6 hours after the attack,¹² and functional imaging has demonstrated that multiple brain regions may remain active during the interictal period.¹³

Educational financial support for this Satellite symposium was provided by Amgen®/Novartis