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. 2020 Jun 4:11:407.
doi: 10.3389/fneur.2020.00407. eCollection 2020.

Both Stationary and Dynamic Functional Interhemispheric Connectivity Are Strongly Associated With Performance on Cognitive Tests in Multiple Sclerosis

Sue-Jin Lin  1 , Shannon Kolind  2 , Aiping Liu  3 , Katrina McMullen  2 , Irene Vavasour  4 , Z Jane Wang  3 , Anthony Traboulsee  2 , Martin J McKeown  1   2
Affiliations

Both Stationary and Dynamic Functional Interhemispheric Connectivity Are Strongly Associated With Performance on Cognitive Tests in Multiple Sclerosis

Sue-Jin Lin et al. Front Neurol. .

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) (R 2 = 0.96) and paced auditory serial addition test (PASAT) (R 2 = 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.

Keywords: dynamic functional connectivity; multiple sclerosis; paced auditory serial addition test; resting state fMRI; static functional connectivity; symbol digit modalities test.

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Figures

Figure 1
Figure 1
Functional interhemispheric connectivity in healthy controls (HCs) and multiple sclerosis (MS). Upper left panel and lower left panel represent instantaneous and delayed interhemispheric connectivity in MS (red) and HC (black), respectively. The differences between Pearson's correlation and partial correlation represent the relative importance (connectivity values) of the brain regions of interest [conditional region of interest (ROI)] when it is included or excluded from the analysis. A larger difference reflects greater importance of that region. Black stars and red squares indicate the connection pairs, which significantly distinguish the two groups in instantaneous and delayed connectivity [p < 0.05, false discovery rate (FDR) corrected], respectively. Upper right and lower right panels show the altered connections on a brain template. The visualization was done in the BrainNet Viewer (50). Abbreviations are shown in Table 2.
Figure 2
Figure 2
Important brain regions for cognitive performances. With least absolute shrinkage and selection operator (LASSO) regression, the upper left and upper right panels express weights of important connectivity pairs in predicting SDMT and PASAT, respectively. The lower panel shows positive correlations between real scores and predicted scores of SDMT and PASAT with the limited number of pairs. Real and predicted SDMT scores especially demonstrate a good correlation with average R2 = 0.96 in leave-one-out calculation. Predicted and real PASAT scores also show a strong correlation with average R2 = 0.59. Abbreviations are shown in Table 2. PASAT3, Paced Auditory Serial Addition Test-3 s; SDMT, Symbol Digit Modalities Test.
Figure 3
Figure 3
Dynamic functional connectivity and cognition in multiple sclerosis (MS). FOCcs, which represent dynamic interhemispheric connectivity, are negatively correlated with Paced Auditory Serial Addition Test (PASAT) scores. FOCcs: flexibility of homologous connections. Each * represents each dataset.
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