Salience–limbic–cerebellar network reconfiguration during nitroglycerin-triggered cluster headache attacks

Cluster headache is one of the most painful known disorders. Cluster headache sufferers compare the extreme unilateral pain to labour pains and gunshot wounds. Given the many logistical challenges of capturing spontaneous cluster headache attacks, only a handful of neuroimaging studies have successfully captured such attacks. Intravenous nitroglycerin (NTG) reliably induces cluster headache attacks in a controlled setting, thereby enabling investigation of resting-state functional connectivity during the attack stage. Cluster headache patients aged 18–60 years were recruited from both the population and tertiary headache clinics. Consented participants received either 0.5 µg/kg/min NTG or placebo infusion for 20 min. Structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependent contrast (BOLD) time series were obtained at baseline (pre-infusion) and during headache. A total of 16 paired headache (NTG-infusion) and placebo scans were analysed. The functional connectivity was assessed for three pre-determined seeds: thalamus, ACC and insula. A two-factor (time and treatment), repeated measures 2 × 2 ANOVA model was used to assess main effects and interactions. Significant changes in functional connectivity between the contralateral amygdala ( T = 3.47, peak connectivity change at 30, 0, -20, P < 0.001), and hippocampus ( T = 4.33, peak connectivity change at 28, -8, -20, P < 0.001) and ipsilateral cerebellum culmen ( T = 5.13, peak connectivity change at -14, -30, -18, P < 0.001), with respect to the anterior insula ipsilateral to the pain side. These findings suggest reconfiguration of salience, limbic, cerebellar and default mode networks during the cluster headache attack state and implicate the cerebellum in trigeminal nociceptive processing.