This is the first demonstration, to our knowledge, of interictal cortical abnormalities in migraine. Migraine remains an enigmatic disease. The presence of transient neurological signs (aura) in a subgroup of migraineurs has long raised a question that, perhaps surprisingly, still remains controversial: Are MWA and MWoA two separate entities, or are they different manifestations of a similar underlying mechanism? Although the two forms of migraine may be distinct disorders [51
], similarities between them are remarkable. Pure MWA is comparatively rare, and most MWA patients suffer also from attacks without aura, clearly suggesting a connection between the two forms [53
MWA and MWoA share a number of characteristics: they both have a strong genetic component; they can be triggered by the same substances (usually serotonin releasers such as reserpin or fenfluramine, NO releasers, or high-tyramine foods); both are at higher risks for WM lesions in the cerebellar region of the posterior circulation [54
]; and both share the same clinical picture with regard to the pain and related symptoms during the headache phase. In addition, a number of similarities in the therapeutic approach also suggest that a similar pathophysiological phenomenon underlies both disorders—namely, an altered excitability of the cortex. Preventive treatments for both types that have been validated for efficacy in double-blind, placebo-controlled studies include anticonvulsants (divalproex sodium, topiramate); calcium channel antagonists (flunarizine); antidepressants (amitriptyline); beta-blockers (propranolol); and serotonin blocking agents (pizotifen). The two first classes (anticonvulsants, calcium channel antagonists) are likely to reduce cortical excitability, whereas the mechanism of action of three others (antidepressants, beta-blockers, and serotonin blocking agents) is less clear. However, recent data show that migraine prophylactic agents may act by increasing the CSD threshold [55
]. A common pathophysiology remains a valid hypothesis, and several recent functional studies have underlined the importance of neuronal hyperexcitability in both types of migraine [25
Our data show that both MWA and MWoA present anatomical changes in precortical and cortical areas involved in motion perception and confirm that these abnormalities are detectable outside the acute phase.
Reduction of anisotropy can be due to several conditions. In the most commonly referred cases, a loss of myelin (as is the case in MS [56
], stroke [61
], or in the cerebral arteriopathy CADASIL [64
]) is accompanied by a loss of barriers to diffusion, and by an increase in mean diffusivity and a decrease in fractional anisotropy. In these patients, decreased performance is correlated with increased mean diffusivity [64
], reflecting damage to specific tracts.
Paradoxically, however, a reduced FA can be due to opposite patterns of myelin fiber conditions: loss of myelin, as described above, or increased axonal diameter with increased myelin [67
]. In healthy individuals, positive correlations have been described between reaction time in a visuospatial task and visual WM pathways [68
]. The faster the individuals were, the lower the FA was. In addition, two studies have shown that intensive training results in lower FA values in the motor pathways of piano players [69
]. Abnormal white matter maturation processes could result in the alteration observed in motion-processing areas and their subjacent WM, as MT+ is an area that undergoes myelination in an early phase during development [71
]. This hypothesis cannot be excluded for area V3A, for which no specific developmental data are available presently. Supporting evidence for this interpretation is provided by the early visual processing abnormalities observed in migraineurs, and the close association between motion sickness in childhood and later appearance of migraine [18
]. FA changes observed in the WM beneath areas V3A and MT+ may correspond to “thicker” and faster axons, a hypothesis that would be corroborated by the psychophysical findings in migraineurs. Prospective studies in migraineurs' children may help to resolve this question.
An increased thickness of areas V3A and MT+ could be the result of a focal dysplasia leading to exaggerated excitability of neurons in these regions [25
] and to the classical aura percept. In this context, the role of area V3A is particularly intriguing, since it has been suggested as the source of CSD during the aura phase. Our results show that this region is abnormally thickened in both hemispheres in migraine patients, without distinction between subgroups. These findings, as well as the FA abnormalities in V3A supporting white matter, suggest the importance of this area in migraine during the interictal period, as hyperexcitability of the V3A area could contribute to the alteration of motion processing frequently observed in MWA and MWoA.
Most migraine headaches are not preceded by any obvious neurological symptoms, and their origin remains a mystery. Should CSD be of pivotal importance in migraine and aura symptoms reflect a CSD-like phenomenon in the human brain, there is no clear reason that only some migraine patients experience aura. Two imaging studies suggest that MWoA could be the result of a “silent” CSD-like event occurring in the brain: Occipitally originating cortical spreading hypoperfusion was observed by Woods et al. [74
] during MWoA; and spreading suppression of neuronal activity in the occipital cortex in MWoA before headache onset was reported by Cao et al. [28
]. These data suggest that CSD occurs without being necessarily expressed as aura symptoms and that it could be an underlying phenomenon in both MWA and MWoA.
Alternatively, or in addition, the changes observed may also develop as the consequence of repetitive migraine attacks on the integrity of the cortical layers in V3A and MT+ and the subjacent white matter. The increase in cortical thickness observed in both MWA and MWoA could be due to repeated glial activation following repeated episodes of CSD [75
] and/or hypoperfusion [76
], known to play a role in migraine pathophysiology [38
Neuronal abnormalities in areas MT+ and V3A could explain the common interictal motion-processing deficits observed in both groups (differences in sensitivity to temporal and spatial contrast, color, and orientation; and abnormal visual discomfort when viewing striped patterns [7
]. Following this hypothesis, in addition to these chronic symptoms, migraineurs with aura may present acute episodes of CSD originating from these regions that translate into visual scintillations.
A number of recent studies in migraineurs [54
] show subclinical structural brain changes, going from progressive cellular damage in nociceptive systems to diffuse WM loss, multifocal WM lesions, and ischemic stroke. However, these changes were present in only a small subset of patients. DTI is more sensitive than conventional T1 and T2 imaging, and can detect subtle white matter changes that are not necessarily ischemic. We did not observe any macroscopic lesions in our participants, but did observe significant FA changes common to all individuals in the migraineurs group that were specifically located in the WM subjacent to areas V3A and MT+ as well as in the superior colliculus and in the lateral geniculate nucleus. We cannot conclude from the present data whether these changes are due to a loss of WM, or to an increase in axonal diameter in these functionally organized areas.
In conclusion, we demonstrate that cortical and subcortical structures involved in motion perception differ between migraineurs and persons without migraine. Chronic dysfunction of these areas may explain interictal findings of motion-processing deficits in migraineurs, whereas episodic dysfunction might contribute to the initiation of an attack. The present data indicate that structural changes are present in at least two cortical regions in migraine patients, even outside attacks; that MWA and MWoA share the same abnormalities; and that the changes are present in areas where CSD most probably develops. It seems likely that MWA and MWoA are two phenotypes sharing a common pathophysiological substrate, and that asymptomatic CSD may occur in some patients.
The finding of morphometric changes in the brains of migraineurs may be of fundamental importance because migraine has so far been considered a condition with abnormal brain function but completely normal brain structure. Further characterization of the histological and chemical properties of V3A, MT+, and the subjacent WM, both prospectively and developmentally, will tell us more about the precise nature of and the mechanisms underlying cortical and subcortical changes in migraineurs.
This study presents the limitation inherent to all question-driven reports, as it voluntary restricted itself to the examination of areas of the brain involved in vision and specifically visual motion processing.
Although our data are experimental and represent the result of a group analysis, the present findings of specific alteration in migraineurs, e.g., cortical thickness increases in specific areas, may open the possibility of a new noninvasive diagnostic tool in migraine.