• GABA levels may decrease in patients with RRMS. • Lower GABA levels correlated with worse cognitive performance in patients with RRMS. • Dysfunctional GABAergic neurotransmission may have a role in cognitive impairment in RRMS.

There is growing evidence for dysfunctional glutamatergic excitation and/or gamma-aminobutyric acid (GABA)ergic inhibition in patients with multiple sclerosis (MS). Cognitive impairment may occur during the early stages of MS and hippocampal abnormalities have been suggested as biomarkers. However, researchers have not clearly determined whether changes in hippocampal GABA and glutamate (Glu) levels are associated with cognitive impairment and aberrant neural activity in patients with MS. We used magnetic resonance spectroscopy to measure GABA+ and Glu levels in the left hippocampal region of 29 patients with relapsing-remitting MS and 29 healthy controls (HCs). Resting-state functional connectivity (FC) with the hippocampus was also examined. Compared to HCs, patients exhibited significantly lower GABA+ and Glu levels, which were associated with verbal and visuospatial memory deficits, respectively. Patients also showed decreased FC strengths between the hippocampus and several cortical regions, which are located within the default mode network. Moreover, hippocampal GABA+ levels and Glu/GABA+ ratios correlated with the FC strengths in HCs but not in patients with MS. This study describes a novel method for investigating the complex relationships among excitatory/inhibitory neurotransmitters, brain connectivity and cognition in health and disease. Strategies that modulate Glu and GABA neurotransmission may represent new therapeutic treatments for patients with MS.

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Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC ( p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS ( p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS ( R = −0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.