Abstract
Although functional connectivity has been extensively studied in MS, robust estimates of both stationary (static connectivity at the time) and dynamic (connectivity variation across time) functional connectivity has not been commonly evaluated and neither has its association to cognition. In this study, we focused on interhemispheric connections as previous research has shown links between anatomical homologous connections and cognition. We examined functional interhemispheric connectivity (IC) in MS during resting-state functional MRI using both stationary and dynamic strategies and related connectivity measures to processing speed performance. Twenty-five patients with relapsing-remitting MS and 41 controls were recruited. Stationary functional IC was assessed between homologous Regions of Interest (ROIs) using correlation. For dynamic IC, a sliding window approach was used to quantify changes between homologous ROIs across time. We related IC measures to cognitive performance with correlation and regression. Compared to control subjects, MS demonstrated increased IC across homologous regions, which accurately predicted performance on the symbol digit modalities test (SDMT) (R2 = 0.96) and paced auditory serial addition test (PASAT) (R2 = 0.59). Dynamic measures were not different between the 2 groups, but dynamic IC was related to PASAT scores. The associations between stationary/dynamic connectivity and cognitive tests demonstrated that different aspects of functional IC were associated with cognitive processes. Processing speed measured in SDMT was associated with static interhemispheric connections and better PASAT performance, which requires working memory, sustain attention, and processing speed, was more related to rigid IC, underlining the neurophysiological mechanism of cognition in MS.
Highlights
As multiple sclerosis (MS) is characterized by discrete lesions visible on standard T2-weighted MRI images, there has been traditional emphasis on establishing the clinical–pathologic correlation between lesion location and symptomatology, including cognitive functioning [1, 2]
This indicated that most subjects had cognitive decline on both tests especially symbol digit modalities test (SDMT), but they did not reach the standard of impairments
We show that interhemispheric connectivity (IC) of the frontal pole, temporal pole, insula, amygdala, superior temporal cortex, parietal and occipital regions, anterior cingulate cortex, and posterior parietal cortex is important for SDMT performance (Figure 2), which is partially consistent with previous studies showing that parietal areas play a role in SDMT as well as frontal areas and occipital regions [61], which are considered to be long-range connections
Summary
As multiple sclerosis (MS) is characterized by discrete lesions visible on standard T2-weighted MRI images, there has been traditional emphasis on establishing the clinical–pathologic correlation between lesion location and symptomatology, including cognitive functioning [1, 2]. Resting-state functional MRI (rs-fMRI) has been used to explore the more spatially distributed aspects of neural correlates of cognitive dysfunction, which can affect up to 70% of patients with MS and contribute to an impaired quality of life [3]. Linking processing speed deficits and functional connectivity has been a trend to further understand cognitive disease sequelae. Structural neuroimaging suggests that white matter lesions involving callosal connections predict disability in MS [7]. Abnormal callosal fractional anisotropy is correlated with impairment in several behavioral measures such as functional composite scores, processing speed, and performance of upper extremity function [13]
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