We considered pineal displacement as an index of lateralization defect during embryogenesis [11
]. We found a significant difference between migraineurs and controls in the amount of pineal displacement from the midline, supporting our hypothesis of a common developmental origin for migraine and PFO. Our second prediction, that the pineal displacement should be greater in MWA than MWoA, however, was not fulfilled and needs to be addressed in further studies.
A number of disorders, including bipolar disorders and cluster headache, exhibit seasonal behavior, and the role of the pineal gland in the chronobiology of our organism is well known. Bipolar disorders are frequently associated with migraine. Cluster headache is noteworthily accompanied by a higher prevalence of PFO [12
Pineal dysfunction may contribute to migraine. Migraine has a strong chronobiological component: attacks usually take place between 4 AM and 9 AM, and migraine is linked to impaired sleep quality and disturbances in the sleep-wake cycle in children. In Arctic areas, migraine with aura has been reported to be more prevalent in the light season than in the dark.
The circadian clockwork, which generates endogenous rhythmic phenomena, relies on light-dark transitions. Light itself may play a role in migraine chronobiology because migraineurs have a different sensitivity of S-cones, the detectors of short wavelength as blue [13
]. Short-wavelength visible or blue light is the most efficient to suppress melatonin production by the pineal gland [14
The pineal produces melatonin from serotonin, itself a derivative from tryptophan. A disturbance in the process of tryptophan to melatonin biosynthesis could lead to an imbalance of the two substances, leading to abnormal levels of both melatonin and serotonin. Serotonin production is increased by light [15
], while melatonin secretion is inhibited by light [16
Serotoninergic neurotransmission seems to be altered in migraine [17
], and low serotonin may facilitate the activation of the trigeminovascular nociceptive pathway [17
]; levels of melatonin on the other hand are pronouncedly reduced in migraineurs [19
]. These observations suggest that the control of serotonin-melatonin axis is disturbed both in migraine and bipolar disorder and may explain their co-morbidity.
Phosphatidylinositol 3-kinase (PI3K) is an enzyme mediating the effects of serotonin through 5-HT1A receptor activation. During embryogenesis, PI3K inhibits Nodal-induced cell differentiation [20
], and abnormal levels of PI3K could lead to lateralization defect including PFO and pineal displacement. This in turn could later in life result the abnormal serotonin-melatonin pattern observed in migraine.
Serotonin receptors are the target of numerous anti-migraine drugs. Selective serotonin 1B/1D receptor agonists triptans act in the dorsal raphe, the periacqueductal gray, and the trigeminal nucleus caudalis [21
]. In addition, new data suggest a potential effect of triptans in the ventroposteromedial nucleus of the thalamus acting through 5-HT(1A/1B/1D) mechanisms [22
Cortical spreading depression if the probable mechanism of migraine aura [23
]. The blockade of cortical spreading depression can be achieved by the action on inhibitory 5-HT1A receptors [24
]. In addition to stopping migraine attacks, dihydroergotamine is an efficient drug for migraine prophylaxis. Through their actions at 5-HT1A autoreceptors (in the dorsal raphe nucleus) and heteroreceptors (notably in the hippocampus), dihydroergotamine and its metabolite can exert an inhibitory influence on neuronal excitability which might contribute to their antimigraine prophylactic efficiency [25
In conclusion, our study indicates that there might be a common embryologic origin between PFO and migraine, and these two ailments may not have a causal relationship. It is not known yet whether the abnormal serotonin or melatonin levels can induce the migrainous attacks directly or whether they are surrogate rather than specific markers of a deeper underlying pathology. Further studies should address our hypothesis of PI3K abnormalities in migraine and other chronobiological disorders.