Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis

Abstract

Background and Objectives:Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers there remains to be a full understanding of why they are affected in MS. In this cross-sectional study we tested the hypothesis that functional network regions may be susceptible to disease-related ‘wear-and-tear’ and that this can be observable on co-occuring abnormalities on other MR metrics. We tested whether functional connectivity abnormalities in cognitively impaired MS patients co-occur with either 1) overlapping, 2) local, or 3) distal changes in anatomical connectivity and cerebral blood flow abnormalities.Methods:Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests was performed in 102 relapsing-remitting MS patients and 27 healthy controls. MS patients were classified as cognitively impaired if they scored ≥1.5 standard deviations below the control mean on ≥2 tests (n=55), or else cognitively preserved (n=47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated and anatomical connectivity was assessed with anatomical connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomical connectivity were assessed within resting state networks that showed functional connectivity abnormalities in cognitively impaired MS patients.Results:Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved MS patients (TFCE-corrected at p≤0.05, two-sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomical connectivity locally and distally but not in overlapping locations.Discussion:We provide the first evidence that FC abnormalities are accompanied with local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathological mechanism for altered functional connectivity in brain networks in MS.

Diffusion Tensor Imaging Revealed Microstructural Changes in Normal-Appearing White Matter Regions in Relapsing–Remitting Multiple Sclerosis

“…Although the relationship between the DTI metrics and the blood-oxygenation-level-dependent (BOLD) signal is complex, it is generally accepted that the microstructural integrity of WM is a prerequisite for normal BOLD activation and functional connectivity ( Duerden et al, 2019 ; Huang et al, 2019 ; Jandric et al, 2021 ). Both increasing ( Chiaravalloti et al, 2005 ) and decreasing ( Sweet et al, 2006 ) BOLD activations were observed for MS patients in previous studies.…”

A tractometry principal component analysis of white matter tract network structure and relationships with cognitive function in relapsing-remitting multiple sclerosis

“…Given the prior evidence showing connectivity changes associated with cognition in MS (reviewed in Chard et al, 2021 , Jandric et al, 2021a , Jandric et al, 2021b a ) and the possibility that they are driven by WM degeneration ( Catani and ffytche, 2005 , Dineen et al, 2009 , Schoonheim et al, 2015 ), we aimed to assess whether WM tracts can be decomposed based on shared pathological or other features, and whether the resulting components reflect known functional network structures.…”

“…A second possible reason for the lack of several principal components is that patterns of WM pathology may only emerge at later stages of the disease. While network changes measured by rs-fMRI are common in RRMS and occur even in clinically isolated syndrome (CIS, reviewed in Jandric et al, 2021a , Jandric et al, 2021b ), they have been shown to be more pronounced in progressive MS ( Meijer et al, 2018 , Rocca et al, 2018 ), and the severity of brain pathology is generally related to disease duration ( Reynolds et al, 2011 ). It is therefore feasible that if there is shared susceptibility to MS pathology in the WM, like in the grey matter, it comes more pronounced as the disease advances.…”

“…Demographic, clinical and MRI data was collected in one study session from 102 RRMS patients and 27 healthy controls. This cohort has also been investigated and described in previous work ( Jandric et al, 2021b ). All participants were between 18 and 60 years of age, right-handed and had no contraindications for MR scanning.…”

“…Cognitive symptoms in MS have been associated with functional network connectivity abnormalities (reviewed in Chard et al, 2021 , Jandric et al, 2021a , Jandric et al, 2021b ), but the mechanisms causing these functional connectivity changes are not known. White matter (WM) damage can influence functional connectivity ( Schoonheim et al, 2015 , Patel et al, 2018 , Tewarie et al, 2018 ), possibly through alteration of anatomical connections between functionally connected regions ( Catani and ffytche, 2005 , Dineen et al, 2009 ).…”