Altered Functional Connectivity in White and Gray Matter in Patients With Multiple Sclerosis

Abstract

Background: Functional magnetic resonance imaging (fMRI) has been widely used to assess neural activity changes in gray matter (GM) in patients with multiple sclerosis (MS); however, brain function alterations in white matter (WM) relatively remain under-explored. Purpose: This work aims to identify the functional connectivity in both the WM and the GM of patients with MS using fMRI and the correlations between these functional changes and cumulative disability as well as the lesion ratio. Materials and Methods: For this retrospective study, 37 patients with clinically definite MS and 43 age-matched healthy controls were included between 2010 and 2014. Resting-state fMRI was performed. The WFU Pick and JHU Eve atlases were used to define 82 GM and 48 WM regions in common spaces, respectively. The time courses of blood oxygen level-dependent (BOLD) signals were averaged over each GM or WM region. The averaged time courses for each pair of GM and WM regions were correlated. All 82 × 48 correlations for each subject formed a functional correlation matrix. Results: Compared with the healthy controls, the MS patients had a decreased temporal correlation between the WM and the GM regions. Five WM bundles and four GM regions had significantly decreased mean correlation coefficients (CCs). More specifically, the WM functional alterations were negatively correlated with the lesion volume in the bilateral fornix, and the mean GM-averaged CCs of the WM bundles were inversely correlated with the lesion ratio (r = -0.36, P = 0.012). No significant correlation was found between WM functional alterations and the paced auditory serial addition test score, Expanded Disease Severity Scale score, and Multiple Sclerosis Severity Score (MSSS) in MS. Conclusions: These findings highlight current gaps in our knowledge of the WM functional alterations in patients with MS and may link WM function with pathological mechanisms.

Keywords: MRI; functional connectivity; multiple sclerosis; resting-state; white matter.

Figure 1

Maps of temporal correlations between blood oxygen level-dependent (BOLD) signals in white matter (WM) bundles (ordinate) and gray matter (GM) regions (abscissa). Top to bottom maps (A–D) show the data for multiple sclerosis (MS) patients, healthy controls, MS patients—healthy controls, and healthy controls—MS patients, respectively.

Figure 1

Maps of temporal correlations between blood oxygen level-dependent (BOLD) signals in white matter (WM) bundles (ordinate) and gray matter (GM) regions (abscissa). Top to bottom maps (A–D) show the data for multiple sclerosis (MS) patients, healthy controls, MS patients—healthy controls, and healthy controls—MS patients, respectively.

Figure 2

GM-averaged correlation coefficients (CCs) of WM (A) and WM-averaged CCs of GM (B). Five of 48 WM bundles displayed a significantly decreased mean correlation coefficient [using two-sample t-test with a false positive-corrected *P < (1/48) = 0.021], while four of the 82 GM regions exhibited decreased mean CCs [using two-sample t-test with a false positive-corrected *P < (1/82) = 0.012].

Figure 3

Correlations between WM functional alterations and T₂ lesion volume. Negative correlations between the T₂-LV and WM functional alterations in bilateral fornix (cres)/stria terminalis are presented in the graphs.

Figure 4

The T₂WI lesion probability map in patients with multiple sclerosis. The color overlay was created on the ICBM152 T₁ template in the Montreal Neurological Institute (MNI) standard brain. The mean lesion probability distribution thresholded at 50% is shown in dark red, and the probability distribution thresholded at 20% is shown in blue.

Figure 5

Map showing the comparison of WM bundle function and lesion ratio. The X axis depicts the 48 WM bundles, the positive longitudinal coordinate is the WM function of these bundles, and the negative longitudinal coordinate is the lesion ratio of the corresponding bundles. *P < (1/48) = 0.021.

Figure 6

Correlation between WM functional alterations and the lesion ratio. The mean GM-averaged correlation coefficients of WM bundles were inversely correlated with the lesion ratio (r = −0.36, P = 0.012).