Involvement of the cerebellum in structural connectivity enhancement in episodic migraine

Abstract

Background: The pathophysiology of migraine remains poorly understood, yet a growing number of studies have shown structural connectivity disruptions across large-scale brain networks. Although both structural and functional changes have been found in the cerebellum of migraine patients, the cerebellum has barely been assessed in previous structural connectivity studies of migraine. Our objective is to investigate the structural connectivity of the entire brain, including the cerebellum, in individuals diagnosed with episodic migraine without aura during the interictal phase, compared with healthy controls.

Methods: To that end, 14 migraine patients and 15 healthy controls were recruited (all female), and diffusion-weighted and T1-weighted MRI data were acquired. The structural connectome was estimated for each participant based on two different whole-brain parcellations, including cortical and subcortical regions as well as the cerebellum. The structural connectivity patterns, as well as global and local graph theory metrics, were compared between patients and controls, for each of the two parcellations, using network-based statistics and a generalized linear model (GLM), respectively. We also compared the number of connectome streamlines within specific white matter tracts using a GLM.

Results: We found increased structural connectivity in migraine patients relative to healthy controls with a distinct involvement of cerebellar regions, using both parcellations. Specifically, the node degree of the posterior lobe of the cerebellum was greater in patients than in controls and patients presented a higher number of streamlines within the anterior limb of the internal capsule. Moreover, the connectomes of patients exhibited greater global efficiency and shorter characteristic path length, which correlated with the age onset of migraine.

Conclusions: A distinctive pattern of heightened structural connectivity and enhanced global efficiency in migraine patients compared to controls was identified, which distinctively involves the cerebellum. These findings provide evidence for increased integration within structural brain networks in migraine and underscore the significance of the cerebellum in migraine pathophysiology.

Keywords: Cerebellum; MRI; Migraine; Structural connectivity; Tractography.

Fig. 1

Overview of the data processing pipeline, from the acquisition of the images to the connectome generation, including the different analyses performed

Fig. 2

Connectograms of connections exhibiting significantly increased connectivity in patients (M) vs. controls (HC), detected by NBS using both the Schaefer + SC + CB parcellation (M > HC, p = 0.03) and the AAL116 parcellation (M > HC, p = 0.04). The edges represent the sum of connections with significant differences within each region (node aggregate). L = Left, R = Right, VN = Visual Network, SMN = Somatossensory Network, FPN = Fronto-Parietal Network, DAN = Dorsal Attention Network, VAN = Ventral Attention Network, DMN = Default Mode Network, LN = Limbic Network, Occ = Occipital, Frt = Frontal, Par = Parietal, Tmp = Temporal, SC = Subcortical, PLC = Posterior Lobe of the Cerebellum

Fig. 3

Local graph metrics that show significant differences between patients and controls for both parcellations. The boxplots represent distributions of the metrics across subjects. Significant differences between groups are indicated (*p < 0.05, **p < 0.01 corrected for multiple comparisons). The node degree of the right and left Posterior Lobes of the Cerebellum (PLC) is increased in migraine patients relative to healthy controls (M > HC)

Fig. 4

Global graph metrics in patients and controls for both parcellations. The boxplots represent distributions across subjects. Significant differences between groups are indicated (*p < 0.05, **p < 0.01, ***p < 0.001). The characteristic path length was decreased in patients relative to controls in both parcellations, whilst the global efficiency and the average degree were increased. No significant changes were found in the clustering coefficient and the small-worldness

Fig. 5

Correlation between the characteristic path length (from the connectome obtained with the Schaefer + SC + CB parcellation) and the age onset of migraine for the patients (Spearman rank correlation r² = 0.26 with p = 0.038)

Fig. 6

Number of reconstructed streamlines in the left and right anterior limb of the internal capsule (ALIC) (from the ICBM-DTI-81 white-matter labels atlas) for patients (M) and controls (HC). The boxplots represent distributions of the metrics across subjects. No significant differences between groups are indicated. In both ROIs, there was a slight increase in the number of reconstructed streamlines in patients