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MS Functional Connectivity Abnormalities Not Defined by One Brain Region

Disease Spotlight | <b>Disease Spotlight: Multiple Sclerosis</b>

In cognitively impaired vs unimpaired patients, investigators found functional connectivity decreases in DMNa and DMNp and increases in the right and left frontoparietal networks.

Recently published findings in Neurology provide the first evidence that abnormal functional connectivity (FC) co-occurs with altered structured connectivity and cerebral blood flow (CBF) in cognitively impaired (CI) patients with multiple sclerosis (MS) in resting state network (RSN) regions. The findings also revealed that the exact location of abnormalities differed between metrics.

To test the hypothesis that functional network regions may be susceptible to disease-related "wear and tear," lead author Danka Jandric, PhD student, University of Manchester, and colleagues conducted a cross-sectional study in 102 patients with relapsing-remitting MS (RRMS) and 27 healthy controls (HC).

Each patient underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological tests and multimodal 3T MRI to assess whether FC abnormalities in CI patients with MS coincide with overlapping, local, or distal changes in anatomic connectivity and CBF abnormalities. Patients who scored at least 1.5 standard deviations (SDs) below the control mean on at least 2 tests were considered CI (n = 55), a medium-stringency definition of cognitive impairment. The remaining (n = 47) were considered cognitively preserved (CP).

Compared with HC, patients with RRMS had FC abnormalities in all RSNs investigated. CI patients had areas of decreased FC in the anterior part of the default mode network (DMNa), DMN, posterior part of DMN (DMNp), left frontoparietal network (LFPN), and primary visual network and increased FC in the areas of the DMN, salience network, right frontoparietal network (RFPN), LFPN, and primary visual network relative to CP patients. Among these locations, the DMNa, DMNp, LFPN, and RFPN showed the largest proportion of abnormal voxels between groups and therefore were used for subsequent analysis (threshold-free cluster enhancement corrected at P ≤.05; 2-sided).

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After applying Bonferroni correction, local changes in median atomic connectivity map (ACM), fractional anisotropy (FA), and CBF values were not significantly different between CI and CP patients (corrected P threshold = .0125).

In CI compared to CP patients, the ACM, FA, and CBF regions demonstrated abnormalities in all 4 RSNs. A closer look showed reduction of ACM in DMNa regions that correspond to the forceps minor, left cingulum, left anterior thalamic radiation, and right anterior corona radiata; DMNp regions, including parts of the splenium of the corpus callosum, left and right cingulum, forceps major, and forceps minor; RFPN WM corresponding to parts of the right inferior longitudinal fasciculus and the right inferior fronto-occipital fasciculus; and LFPN regions corresponding to parts of the left superior longitudinal fasciculus, left ILF, and left side of forceps major.

Reduced CBF was found in all 4 networks for CI patients compared with CP. Reductions were seen in several locations, including the bilateral cingulate gyrus and precuneus in the DMNa; bilateral precuneus, left cuneal cortex, right lateral occipital cortex, left lingual gyrus, and left posterior cingulate gyrus in the DMNp; and the right occipital cortex, right angular gyrus, right superior supramarginal gyrus, and right cingulate gyrus in the RFPN. Notably, some individual CBF voxel increases were observed in CI patients in the DMNa, DMNp, and RFPN.

"This highlights the possibility of a common underlying pathologic change in RSNs such as altered metabolic state in CI patients," the study authors concluded. "The metabolic state of functional networks affected by MS should be further investigated with more direct methods of metabolic brain function to determine the pathologic basis of FC abnormalities and potentially lead to their use as effective biomarkers of disease."

Comparisons of extracted median values only found reduced ACM in CI patients (median, 0.0039) compared to CP patients (median, 0.0043) in the anterior DMN (U = 897; P = .008) but no other RSNs. Notably, investigators documented no differences in median FA or CBF values in RSN regions.

At the conclusion of the study, widespread ACM and FC reductions were observed throughout the brain in those with CI compared to those with CP. Some small areas of increased ACM and FC were found at the edge of the brain as well and all patients showed decreased CBF throughout the brain.

Jandric D, Lipp L, Paling D, et al. Mechanisms of network changes in cognitive impairment in multiple sclerosis. Neurology. 2021;97(19). doi:10.1212/WNL.00000000000012834