Migraine: a disorder of brain excitatory–inhibitory balance?

Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache and interictal hypersensitivity to sensory stimuli. Migraine arises from a primary brain dysfunction that leads to episodic activation and sensitization of the trigeminovascular pain pathway and as a consequence to headache. Major open issues concern the molecular and cellular mechanisms of the primary brain dysfunction(s) and of migraine pain. We review here our current understanding of these mechanisms, focusing on recent advances regarding migraine genetics, headache mechanisms, and the primary brain dysfunction(s) underlying migraine onset and susceptibility to cortical spreading depression, the neurophysiological correlate of migraine aura. We also discuss insights obtained from the functional analysis of familial hemiplegic migraine mouse models.

Introduction

Migraine is a common episodic neurological disorder with complex pathophysiology that manifests itself as recurrent attacks of typically throbbing and unilateral, often severe, headache with associated features such as nausea, phonophobia and/or photophobia; in a third of patients the headache is preceded by transient neurological symptoms that are most frequently visual but may involve other senses (migraine with aura: MA) [1] (Table 1). Migraine is a public health problem of great impact upon both the individual and society. It is one of the 20 most disabling diseases (according to World Health Organization ranking [2]). Furthermore, it is remarkably common (e.g., it affects 17% of females and 8% of males in the European population [3]) and very costly (EUR 18.5 billion/year in Europe [4]).

It is generally believed that migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway 5, 6, 7 (Figure 1), and that cortical spreading depression (CSD)-like events underlie migraine aura 5, 8, 9. CSD can be induced in animals by focal stimulation of the cerebral cortex and consists of a slowly propagating (2–6 mm/min) wave of strong neuronal and glial depolarization whose mechanisms of initiation and propagation remain unclear 10, 11. It is also generally recognized that most migraine attacks start in the brain. This is suggested by the premonitory symptoms (such as difficulty with speech and reading, increased emotionality, sensory hypersensitivity) – which in many patients are highly predictive of the attack although occurring up to 12 h before it [12] – as well as by the nature of some typical migraine triggers (e.g., stress, sleep deprivation, oversleeping, hunger and/or prolonged sensory stimulation) [13]. Psychophysical and neurophysiological studies have provided clear evidence that in the period between attacks migraineurs show hypersensitivity to sensory stimuli and abnormal processing of sensory information, characterized by increased amplitudes and reduced habituation of evoked and event-related potentials 14, 15.

The nature and mechanisms of the primary brain dysfunction(s) leading to the onset of a migraine attack, to CSD susceptibility, and to episodic activation of the trigeminovascular pain pathway remain largely unknown and are major outstanding issues to be addressed in furthering our understanding of the neurobiology of migraine. Other important open questions concern the mechanisms of migraine pain.

Here, we review recent advances regarding (i) the genetics of migraine; (ii) the mechanisms of migraine headache, focusing on the roles of meningeal inflammation, calcitonin gene-related peptide (CGRP), central sensitization, and dysfunctional central control of pain; and (iii) the mechanisms of the primary brain dysfunction(s) leading to episodic activation of the trigeminovascular pain pathway. We also discuss insights into these mechanisms obtained from the functional analysis of mouse models of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of MA.