Investigations of functional and structural changes in migraine with aura by magnetic resonance imaging

Migraine sufferers with aura often report visual discomfort outside of attacks and many consider bright or flickering light an attack-precipitating factor. The nature of this visual hypersensitivity and its relation to the underlying pathophysiology of the migraine aura is unknown. A useful technology to study these features of migraine with aura (MA) is functional magnetic resonance imaging (fMRI), which has the potential not only to detect, but also to localize hypersensitive cortex. The main objective of this thesis was to investigate the cortical responsivity of patients with MA during visual stimulation using fMRI. To optimize sensitivity, we applied a within-patient design by assessing functional interhemispheric differences in patients consistently experiencing visual aura in the same visual hemifield. To validate our data analysis methods, we initially studied healthy volunteers using single hemifield visual stimulation and compared the "stimulated" hemispheres (i.e. hemispheres contralateral to the visual stimulation) to the "non-stimulated" hemispheres. We then applied this validated method of interhemispheric comparison of fMRI-blood oxygenation level dependent (BOLD) activation to compare left versus right hemisphere responses to symmetric full-field visual stimulation in 54 healthy subjects (study I). This study concluded that, a) the applied visual stimulation is effective in activating large expanses of visual cortex, b) interhemispheric differences in fMRI-BOLD activation can be determined using the proposed method, and c) visual responses to symmetric full-field visual stimulation are asymmetrically distributed between the cerebral hemispheres. We investigated the effects of migraine aura, by including 20 patients with frequent side-fixed visual aura attacks, i.e. ≥= 90% of auras occurring in the same visual hemifield (study II). To circumvent bias relating to differences between right and left hemispheres (e.g. caused by physiological left/right bias, asymmetry of the visual stimulation or magnetic field inhomogeneity of the scanner), we included an equal number of patients with right- and left-sided symptoms. Further, we included 20 individually matched healthy controls with no history (including family history) of migraine. We compared the fMRI-BOLD responses to visual stimulation between symptomatic and asymptomatic hemispheres during the interictal phase and between migraine patients and controls. BOLD responses were selectively increased in the symptomatic hemispheres and localized in the inferior parietal lobule, the inferior frontal gyrus and the superior parietal lobule. The affected cortical areas comprise a visually driven functional network involved in oculomotor control, guidance of movement, motion perception, visual attention, and visual spatial memory. The patients also had significantly increased response in the same cortical areas when compared to controls. Since these findings theoretically could depend on aura-related differences in brain structure, we performed additional analyses (study III) to determine the relation between migraine aura and structural, cortical and subcortical, grey matter abnormalities. We analyzed structural MRI data from the same 20 patients and applied voxel-based morphometry and surface-based morphometry on a whole-hemisphere level and for specific anatomical regions of interest. Within-subject comparisons were made with regard to aura symptoms (N = 20 vs 20) and with regard to headache (N = 13 vs 13). We found no differences in grey matter structure with regard to aura symptoms in MA patients. Comparing the typical migraine headache side of the patients to the contralateral side revealed a difference in cortical thickness in the inferior frontal gyrus, which correlated significantly with the migraine attack frequency. In conclusion, we validated a method of interhemispheric comparison of fMRI-BOLD responses to visual stimulation. By using this method we discovered a lateralized alteration of a visually driven functional network in patients with side-fixed aura. These findings suggest a hyperexcitability of the visual system in the interictal phase of migraine with visual aura. Further, this abnormal function is not dependent on lateralized abnormalities of gray matter structure. However, alteration of the inferior frontal cortex related to headache lateralization could indicate structural reorganization of pain inhibitory circuits in response to the repeated intense nociceptive input due to the headache attacks.