Altered intersubject variability of functional connectivity in gray and white matter underlying neurocognition and genetic profiles in neuromyelitis optica spectrum disorder

Abstract Neuromyelitis optica spectrum disorder is an autoimmune disease that causes inflammatory damage to the central nervous system. While alterations in functional connectivity have been reported in neuromyelitis optica spectrum disorder, changes in intersubject variability of functional connectivity within gray matter and white matter are not yet understood. A total of 66 patients with neuromyelitis optica spectrum disorder and 71 healthy controls were recruited. We compared intersubject variability of functional connectivity between patients with neuromyelitis optica spectrum disorder and healthy controls and performed subgroup analyses comparing neuromyelitis optica spectrum disorder patients with and without a history of optic neuritis. We also examined the associations between intersubject variability of functional connectivity alterations and disease duration, clinical disability, and cognitive scores. We combined our imaging results with those of the Allen Human Brain Atlas to conduct transcriptome–neuroimaging association analyses, identified gene expression profiles linked to intersubject variability of functional connectivity alterations and characterized their potential biological functions. Compared with healthy controls, patients with neuromyelitis optica spectrum disorder showed widespread increases in intersubject variability of functional connectivity. Notable gray matter alterations included the precentral and postcentral gyri; extensive occipital areas; and the insula, putamen, and thalamus. The corresponding white matter changes involved the fornix, corticospinal tract, widespread corona radiata, cingulum, and uncinate fasciculus. Compared with patients without optic neuritis, the optic neuritis subgroup exhibited distinct intersubject variability of functional connectivity alterations in specific regions, such as the inferior parietal lobule, angular gyrus, thalamus, fornix, and internal capsule. Clinically, only white matter-intersubject variability of functional connectivity correlated significantly with physical disability and cognitive processing speed and was not significantly associated with disease duration. Transcriptomic analysis revealed that genes positively associated with white matter-intersubject variability of functional connectivity were enriched in synaptic plasticity and cognition, while negatively associated genes were enriched in oxidative stress. Additionally, genes positively associated with the gray matter-intersubject variability of functional connectivity were enriched in myelination and lipid biosynthesis, whereas genes negatively associated with the gray matter-intersubject variability of functional connectivity were involved in synapse organization. In conclusion, our study revealed alterations in gray matter- and white matter-intersubject variability of functional connectivity across neuromyelitis optica spectrum disorder and clinical subtypes. We demonstrate that changes in white matter-intersubject variability of functional connectivity correlate with clinical disability and neurocognition. Linking these connectivity patterns with gene expression profiles may provide insights into the underlying pathophysiology of neuromyelitis optica spectrum disorder.