Alterations of White Matter Microstructure in Migraine Patients Vary in the Peri-ictal Phases

Abstract

Alterations in white matter (WM) microstructure are commonly found in migraine patients. Here, we employ a longitudinal study of episodic migraine without aura using diffusion magnetic resonance imaging (dMRI) to investigate whether such WM microstructure alterations vary through the different phases of the pain cycle. Fourteen patients with episodic migraine without aura related with menstruation were scanned through four phases of their (spontaneous) migraine cycle (interictal, preictal, ictal, and postictal). Fifteen healthy controls were studied in the corresponding phases of the menstrual cycle. Multishell dMRI data were acquired and preprocessed to obtain maps of diffusion parameters reflecting WM microstructure. After a whole-brain analysis comparing patients with controls, a region-of-interest analysis was performed to determine whether the patients' microstructural changes varied across the migraine cycle in specific WM tracts. Compared with controls, patients showed reduced axial diffusivity (AD) in several WM tracts across the whole brain in the interictal phase and increased fractional anisotropy (FA) in commissural fibers in the ictal phase. Interestingly, AD returned to baseline levels during peri-ictal phases in specific projection and association fibers. In contrast, FA values decreased in the ictal phase away from normal values in a few commissural and projection tracts. Widespread WM fiber tracts suffer structural variations across the migraine cycle, suggesting microstructural changes potentially associated with limbic and salience functional networks and highlighting the importance of the cycle phase in imaging studies of migraine.

Keywords: diffusion MRI (dMRI); diffusion tensor imaging (DTI); diffusional kurtosis imaging (DKI); microstructure; migraine; white matter.

Figure 1.

Illustrative schematics of the study design. In our study, migraine patients (M) were assessed in four MRI sessions based on the migraine cycle phase: interictal (M-inter), pre-attack (M-pre), during the attack (M-ict), and postattack (M-post). In addition, HCs were scanned in corresponding periods of their menstrual cycle: perimenstrual phase (HC-pm) and postovulation phase (HC-postov). The total number of subjects per session is shown.

Figure 2.

Spatial distribution of the significant differences found in the voxelwise comparisons between patients and controls: AD for [M-inter] < [HC-postov] (top) and FA for [M-ict] < [HC-pm] (bottom). The p value maps are displayed for DTI (green) and DKI (blue), as well as their overlap (red). Interictally, patients showed lower AD compared with HCs (in postovulation) across multiple WM regions, more with DKI. Ictally, patients showed lower FA compared with HCs (in perimenstrual phases) across multiple WM regions, only with DKI.

Figure 3.

The percentage of voxels exhibiting significant changes in each ROI of the WM skeleton, for the two comparisons showing significant differences, [M-inter] versus [HC-postov] (left) and [M-ict] versus [HC-pm] (right), for each diffusion parameter (FA, MD, AD, RD, MK, AK, and RK), and both signal representations, DTI and DKI. Blue/red colors are used to represent decreased/increased values in comparison with controls.

Figure 4.

ROI analysis results are shown for AD exhibiting significant effects in multiple WM tracts across the migraine cycle estimated using the DKI signal representation. In the UNC, AD showed decreased values in the interictal phase, which tended to normalize during the peri-ictal phases. In addition, a reduction in AD was observed in the M-inter phase also in Ant_Cor, Post_thal, SLF, and cingulate, which also tended to normalize during the peri-ictal phases. Significant post hoc differences are shown and adjusted for multiple comparisons as indicated by *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 5.

ROI analysis results are shown for FA exhibiting significant effects in multiple WM tracts across the migraine cycle estimated using the DKI signal representation. In the UNC, FA showed decreased values in the interictal phase, which tended to normalize during the peri-ictal phases. In addition, FA in both the PLIC and CC_body showed normal values in the M-interictal phase, but these were significantly reduced specifically in the M-ictal phase. Significant post hoc differences are shown and adjusted for multiple comparisons as indicated by *p < 0.05; **p < 0.01; ***p < 0.001.