Neurobiology of migraine.

Migraine is a public health problem of great impact on both the patient and society. The overall migraine prevalence in western countries is 6–8% in men and 15–25% in women. It has been calculated that about 5% of the general population have at least 18 days of migraine per year, and that at least 1% — that is, more than 2.5 million people in North America — have at least one day of migraine per week. Severe migraine is rated as one of the most disabling chronic disorders. The annual cost of migraine-related lost productivity is enormous. Migraine attacks are typically characterized by unilateral and pulsating severe headache, lasting 4–72 hours, and are often accompanied by nausea, phonoand photophobia (migraine without aura; MO). In at least 20% of patients, the attacks are preceded by transient (usually less than 60 min duration) neurological symptoms (migraine with aura; MA). Auras are most frequently visual, but can involve other senses, or occasionally cause motor or speech deficits. Migraine has a strong (up to 50%) genetic component, which is higher in MA than MO, with a probable multifactorial POLYGENIC inheritance. Genetic load can be seen as determining an inherent migraine threshold that is modulated by external and internal factors (migraine triggers). Although several susceptibility loci have been reported in chromosomes 1q, 4q24, Xq24-28 and 19p13 (REF. 1), causative genes have not yet been identified, except for familial hemiplegic migraine (FHM) — a rare, autosomal dominant subtype of MA. Here we review recent experimental evidence mainly from brain imaging and neurophysiological studies that, despite leaving many open questions, have advanced our understanding of migraine towards a unifying pathophysiological hypothesis to explain this disease. Convincing mechanistic explanations for some of the migraine symptoms have been discovered. So, activation of the trigeminovascular system (TGVS) is thought to be responsible for the pain itself, and cortical spreading depression (CSD) seems to underlie the aura symptoms. Important questions that remain include the primary cause of migraine, leading to activation of the TGVS, and the mechanisms of pain generation after its activation. We will discuss these questions in the context of the discovery that Ca v 2.1 Ca channel dysfunction causes FHM.