Dysregulated Cerebellar-Subcortical-Cortical Interactions in Cluster Headache: Evidence From Edge Analysis Across Three Independent Datasets.

OBJECTIVE

The objective of this study was to apply edge-centric functional connectivity and motif analyses to capture co-fluctuation communication patterns and test whether altered dynamic network integration underlies clinical manifestations of cluster headache (CH).

METHODS

This cross-sectional study included 100 participants with episodic CH imaged during the in-bout period outside acute attacks and 116 healthy controls (HCs) using functional magnetic resonance imaging (MRI). Robustness of the findings was assessed via pooled and separate analyses of 3 independent datasets using brain parcellation, edge graph construction, k-means clustering, community entropy calculations, motif, and clinical correlation analyses.

RESULTS

Participants with CH showed lower entropy in the cerebellar vermis (β = -0.493, 95% confidence interval [CI] = -0.683 to -0.302, p false discovery rate [pFDR] = 3.02 × 10-6) and cerebellar network (mean difference = -0.043, 95% CI = -0.068 to -0.018, t = -3.361, pFDR = 0.009) compared with HCs. In individuals with CH, longer disease duration was accompanied by a greater reduction in entropy of the cerebellar vermis (r = -0.390, 95% CI = -0.550 to -0.196, pFDR = 0.004). Motif analysis revealed that participants with CH exhibited (i) higher fractions of forked triads with vermis coordinating subcortical and cortical nodes belonging to sensorimotor, visual, default-mode, and cerebellar networks; and (ii) lower fractions of diverse triads linking vermis to both sensorimotor and cognitive- control networks and to both sensorimotor and default-mode networks (all pFDR < 0.05).

INTERPRETATION: We identified reorganization of the cerebellar-subcortical-cortical network in CH. The cerebellar vermis exhibited a paradoxical pattern: retaining hub-like connectivity while losing flexible network integration. This pattern worsened with disease duration, supporting its role in symptomatology and potential as a candidate region for future neuromodulation studies. ANN NEUROL 2026.