Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity

Abstract

Background: Nabiximols (Sativex®) is a cannabinoid approved for multiple sclerosis (MS)-related spasticity. Its mechanism of action is partially understood, and efficacy is variable.

Objective: To conduct an exploratory analysis of brain networks connectivity changes on resting state (RS) functional MRI (fMRI) of MS patients treated with nabiximols.

Methods: We identified a group of MS patients treated with Sativex® at Verona University Hospital, who underwent RS brain fMRI in the 4 weeks before (T0) and 4-8 weeks after (T1) treatment start. Sativex® response was defined as ≥ 20% spasticity Numerical Rating Scale score reduction at T1 vs. T0. Connectivity changes on fMRI were compared between T0 and T1 in the whole group and according to response status. ROI-to-ROI and seed-to-voxel connectivity were evaluated.

Results: Twelve MS patients (7 males) were eligible for the study. Seven patients (58.3%) resulted Sativex® responders at T1. On fMRI analysis, Sativex® exposure was associated with global brain connectivity increase (particularly in responders), decreased connectivity of motor areas, and bidirectional connectivity changes of the left cerebellum with a number of cortical areas.

Conclusions: Nabiximols administration is associated with brain connectivity increase of MS patients with spasticity. Modulation of sensorimotor cortical areas and cerebellum connectivity could play a role in nabiximols effect.

Keywords: Cannabinoid; Functional MRI; Multiple sclerosis; Nabiximols; Spasticity; Symptomatic therapy.

Fig. 1

Region of interest (ROI)-to-ROI connectome ring maps of all selected ROI seeds in Post vs. Pre nabiximols exposure (all patients). Increased connectivity (a). Decreased connectivity (b). The colour links are obtained at a ROI-to-ROI connections height threshold (FDR) of P < 0.05, seed ROI height threshold (uncorrected) of P < 0.05, with one-sided positive seed level correction and permutation tests. The colour bar indicates the statistical T value. Abbreviations: ROI (region of interest), FDR (false discovery rate), ICC l (Intracalcarine Cortex left), aMTG r (Middle Temporal Gyrus, anterior division Right), pSTG l (Superior Temporal Gyrus, posterior division Left), MidFG r (Middle Frontal Gyrus Right), Ver6 (Vermis 6), Cereb45 r (Cerebellum 4 5 Right), OP r (Occipital Pole Right), pTFusC r (Temporal Fusiform Cortex, posterior division Right), aTFusC r (Temporal Fusiform Cortex, anterior division Right), FO r (Frontal Operculum Cortex Right)

Fig. 2

ROI-to-ROI connectome ring maps, Post- vs. Pre- condition, Sativex® responders. Increased connectivity (a). Decreased connectivity (b). The colour links are obtained at a ROI-to-ROI connections height threshold (FDR) of P < 0.05, seed ROI height threshold (uncorrected) of P < 0.05, with one-sided positive seed level correction and permutation tests. The colour bar indicates the statistical T value. HG l (Heschl's Gyrus Left), pPaHC r (Parahippocampal Gyrus, posterior division Right), PaCiG l (Paracingulate Gyrus Left), pITG r (Inferior Temporal Gyrus, posterior division Right), FP r (Frontal Pole Right), FP l (Frontal Pole Left)

Fig. 3

ROI-to-ROI connectome ring maps, Post- vs. Pre- condition, Sativex® non-responders. Increased connectivity (a). Decreased connectivity (b). The colour links are obtained at a ROI-to-ROI connections height threshold (FDR) of P < 0.05, seed ROI height threshold (uncorrected) of P < 0.05, with one-sided positive seed level correction and permutation tests. The colour bar indicates the statistical T value. Cereb45 r (Cerebellum 4 5 Right), Cereb6 r (Cerebellum 6 Right), TOFusC l (Temporal Occipital Fusiform Cortex Left), pTFusC r (Temporal Fusiform Cortex, posterior division Right), pTFusC l (Temporal Fusiform Cortex, posterior division Left), FOrb l (Frontal Orbital Cortex Left), ICC r (Intracalcarine Cortex Right), pITG r (Inferior Temporal Gyrus, posterior division Right), aMTG r (Middle Temporal Gyrus, anterior division Right), aMTG l (Middle Temporal Gyrus, anterior division Left), PreCG r (Precentral Gyrus Right), PreCG l (Precentral Gyrus Left), Cereb1 l (Cerebellum Crus1 Left), Cereb7 r (Cerebellum 7b Right), SCC l (Supracalcarine Cortex Left), aTFusC l (Temporal Fusiform Cortex, anterior division Left)

Fig. 4

Seed-to-Voxel statistically significant clusters maps using precentral and postcentral gyrus as a seed ROIs, all patients. Pre- (a) and Post- (b) Sativex exposure. Results are visualized as clusters on inflated brain (p < 0.05, FDR corrected). In post-condition (b), there is an increase in connectivity in pre and post central gyrus compared to the pre-condition (a)

Fig. 5

Seed-to-Voxel statistically significant clusters maps using precentral and postcentral gyrus as a seed ROIs, according to responder status. Pre (a) and Post (b) condition in Sativex® non responders and Pre (c) and Post (d) condition in responders. Results are visualized as clusters on inflated brain (p < 0.05, FDR corrected). In post condition (b), there is an increase in connectivity in pre and post central gyrus compared to the pre-condition in non-responders. Same condition is evident in responders (c, d), despite in pre-condition (c) there are no significant clusters