Concurrent anatomical, physiological and network changes in cognitively impaired multiple sclerosis patients

AbstractCognitive impairment in multiple sclerosis is associated with functional connectivity abnormalities, but the pathological substrates of these abnormalities are not well understood. It has been proposed that resting-state network nodes that integrate information from disparate regions are susceptible to metabolic stress, which may impact functional connectivity. In multiple sclerosis, pathology could increase metabolic stress within axons, damaging the anatomical connections of network regions, and leading to functional connectivity changes. We tested this hypothesis by assessing whether resting state network regions that show functional connectivity abnormalities in people with cognitive impairment also show anatomical connectivity abnormalities.Multimodal MRI and neuropsychological assessments were performed in 102 relapsing remitting multiple sclerosis patients and 27 healthy controls. Patients were considered cognitively impaired if they obtained a z-score of ≤1.5 on ≥2 tests of the Brief Repeatable Battery of Neuropsychological Tests (n=55). Functional connectivity was assessed with Independent Component Analysis of resting state fMRI images, and anatomical connectivity with Anatomical Connectivity Mapping of diffusion-weighted MRI. Exploratory analyses of fractional anisotropy and cerebral blood flow changes were conducted to assess local tissue characteristics.We found significantly decreased functional connectivity in the anterior and posterior default mode networks and significant increases in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved patients. Networks showing functional abnormalities also showed reduced anatomical connectivity and white matter microstructure integrity as well as reduced local tissue cerebral blood flow.Our results identify key pathological correlates of functional connectivity abnormalities associated with impaired cognitive function in multiple sclerosis, consistent with metabolic dysfunction in functional network regions.

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Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000012834 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012834

Author(s):

Danka Jandric ◽

Ilona Lipp ◽

David Paling ◽

David Rog ◽

Gloria Castellazzi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Impairment ◽

Functional Connectivity ◽

Resting State ◽

Structural Connectivity ◽

Cognitively Impaired ◽

Anatomical Connectivity ◽

Cross Sectional

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.

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Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity Strength in Cervical Spondylotic Myelopathy Patients

Frontiers in Neurology ◽

10.3389/fneur.2021.713520 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wuzeng Wei ◽

Tao Wang ◽

Tuersong Abulizi ◽

Bing Li ◽

Jun Liu

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Functional Connectivity ◽

Resting State ◽

Cervical Spondylotic Myelopathy ◽

Cortical Level ◽

Functional Connectivity Strength ◽

Visual Cortices ◽

Connectivity Strength ◽

Bilateral Thalamus

Background: Changes in regional neural activity and functional connectivity in cervical spondylotic myelopathy (CSM) patients have been reported. However, resting-state cerebral blood flow (CBF) changes and coupling between CBF and functional connectivity in CSM patients are largely unknown.Methods: Twenty-seven CSM patients and 24 sex/age-matched healthy participants underwent resting-state functional MRI and arterial spin labeling imaging to compare functional connectivity strength (FCS) and CBF between the two groups. The CBF–FCS coupling of the whole gray matter and specific regions of interest was also compared between the groups.Results: Compared with healthy individuals, CBF–FCS coupling was significantly lower in CSM patients. The decrease in CBF–FCS coupling in CSM patients was observed in the superior frontal gyrus, bilateral thalamus, and right calcarine cortex, whereas the increase in CBF–FCS coupling was observed in the middle frontal gyrus. Moreover, low CBF and high FCS were observed in sensorimotor cortices and visual cortices, respectively.Conclusion: In general, neurovascular decoupling at cortical level may be a potential neuropathological mechanism of CSM.

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Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity in Schizophrenia

Schizophrenia Bulletin ◽

10.1093/schbul/sbx051 ◽

2017 ◽

Vol 43 (6) ◽

pp. 1363-1374 ◽

Cited By ~ 32

Author(s):

Jiajia Zhu ◽

Chuanjun Zhuo ◽

Lixue Xu ◽

Feng Liu ◽

Wen Qin ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Functional Connectivity ◽

Resting State

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Classifying multiple sclerosis patients on the basis of SDMT performance using machine learning

Multiple Sclerosis Journal ◽

10.1177/1352458520958362 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107-116

Author(s):

Korhan Buyukturkoglu ◽

Dana Zeng ◽

Srinidhi Bharadwaj ◽

Ceren Tozlu ◽

Enricomaria Mormina ◽

...

Keyword(s):

Multiple Sclerosis ◽

Functional Connectivity ◽

Resting State ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Cognitive Status ◽

Lesion Volume ◽

Cognitive Changes ◽

Final Model ◽

Multiple Sclerosis Patients

Objective: To build a model to predict cognitive status reflecting structural, functional, and white matter integrity changes in early multiple sclerosis (MS). Methods: Based on Symbol Digit Modalities Test (SDMT) performance, 183 early MS patients were assigned “lower” or “higher” performance groups. Three-dimensional (3D)-T2, T1, diffusion weighted, and resting-state magnetic resonance imaging (MRI) data were acquired in 3T. Using Random Forest, five models were trained to classify patients into two groups based on 1—demographic/clinical, 2—lesion volume/location, 3—local/global tissue volume, 4—local/global diffusion tensor imaging, and 5—whole-brain resting-state-functional-connectivity measures. In a final model, all important features from previous models were concatenated. Area under the receiver operating characteristic curve (AUC) values were calculated to evaluate classifier performance. Results: The highest AUC value (0.90) was achieved by concatenating all important features from neuroimaging models. The top 10 contributing variables included volumes of bilateral nucleus accumbens and right thalamus, mean diffusivity of left cingulum-angular bundle, and functional connectivity among hubs of seven large-scale networks. Conclusion: These results provide an indication of a non-random brain pattern mostly compromising areas involved in attentional processes specific to patients who perform worse in SDMT. High accuracy of the final model supports this pattern as a potential neuroimaging biomarker of subtle cognitive changes in early MS.

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Cerebral Blood Flow-Based Resting State Functional Connectivity of the Human Brain using Optical Diffuse Correlation Spectroscopy

Journal of Visualized Experiments ◽

10.3791/60765 ◽

2020 ◽

Cited By ~ 2

Author(s):

Chien Poon ◽

Ben Rinehart ◽

Jun Li ◽

Ulas Sunar

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Functional Connectivity ◽

Human Brain ◽

Resting State ◽

Correlation Spectroscopy ◽

Resting State Functional Connectivity ◽

Diffuse Correlation Spectroscopy

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Disruptions in Resting State Functional Connectivity and Cerebral Blood Flow in Mild Traumatic Brain Injury Patients

PLoS ONE ◽

10.1371/journal.pone.0134019 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0134019 ◽

Cited By ~ 36

Author(s):

Chandler Sours ◽

Jiachen Zhuo ◽

Steven Roys ◽

Kathirkamanthan Shanmuganathan ◽

Rao P. Gullapalli

Keyword(s):

Traumatic Brain Injury ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Injury ◽

Functional Connectivity ◽

Mild Traumatic Brain Injury ◽

Resting State ◽

Resting State Functional Connectivity

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Cerebral blood flow modulation insufficiency in brain networks in multiple sclerosis: A hypercapnia MRI study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16654922 ◽

2016 ◽

Vol 36 (12) ◽

pp. 2087-2095 ◽

Cited By ~ 16

Author(s):

Olga Marshall ◽

Sanjeev Chawla ◽

Hanzhang Lu ◽

Louise Pape ◽

Yulin Ge

Keyword(s):

Multiple Sclerosis ◽

Carbon Dioxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Networks ◽

Cerebrovascular Reactivity ◽

Functional Networks ◽

Attention Networks ◽

Default Mode ◽

Multiple Sclerosis Patients

Cerebrovascular reactivity measures vascular regulation of cerebral blood flow and is responsible for maintaining healthy neurovascular coupling. Multiple sclerosis exhibits progressive neurodegeneration and global cerebrovascular reactivity deficits. This study investigates varied degrees of cerebrovascular reactivity impairment in different brain networks, which may be an underlying cause for functional changes in the brain, affecting long-distance projection integrity and cognitive function; 28 multiple sclerosis and 28 control subjects underwent pseudocontinuous arterial spin labeling perfusion MRI to measure cerebral blood flow under normocapnia (room air) and hypercapnia (5% carbon dioxide gas mixture) breathing. Cerebrovascular reactivity, measured as normocapnic to hypercapnic cerebral blood flow percent increase normalized by end-tidal carbon dioxide change, was determined from seven functional networks (default mode, frontoparietal, somatomotor, visual, limbic, dorsal, and ventral attention networks). Group analysis showed significantly decreased cerebrovascular reactivity in patients compared to controls within the default mode, frontoparietal, somatomotor, and ventral attention networks after multiple comparison correction. Regression analysis showed a significant correlation of cerebrovascular reactivity with lesion load in the default mode and ventral attention networks and with gray matter atrophy in the default mode network. Functional networks in multiple sclerosis patients exhibit varied amounts of cerebrovascular reactivity deficits. Such blood flow regulation abnormalities may contribute to functional communication disruption in multiple sclerosis.

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Changes of brain resting state functional connectivity predict the persistence of cognitive rehabilitation effects in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458513505692 ◽

2013 ◽

Vol 20 (6) ◽

pp. 686-694 ◽

Cited By ~ 46

Author(s):

Laura Parisi ◽

Maria A Rocca ◽

Flavia Mattioli ◽

Massimiliano Copetti ◽

Ruggero Capra ◽

...

Keyword(s):

Multiple Sclerosis ◽

Functional Connectivity ◽

Resting State ◽

Cognitive Rehabilitation ◽

Severe Depression ◽

Control Group ◽

Neuropsychological Performance ◽

Resting State Functional Connectivity ◽

Multiple Sclerosis Patients

Objective: We investigated whether the efficacy of 12-week cognitive rehabilitation in MS patients persists six months after treatment termination and, together with resting state (RS) functional connectivity (FC), changes on neuropsychological performance at follow-up. Methods: Eighteen MS patients with cognitive deficits, assigned randomly either to undergo treatment ( n=9) or not ( n=9), underwent neuropsychological evaluation at baseline (t0), after 12 weeks of rehabilitation (t1) and at six-month follow-up (t2). RS fMRI was obtained at t0 and t1. Changes in neuropsychological performance and their correlations with RS FC modifications were assessed using longitudinal linear models. Results: At t2 vs. t0, compared with the control group, treated group patients improved in tests of attention, executive function, depression and quality of life (QoL). Neuropsychological scores in these tests at t2 were significantly correlated with RS FC changes in cognitive-related networks and RS FC of the anterior cingulum. RS FC changes in the default mode network predicted cognitive performance and less severe depression, whereas RS FC changes of the executive network predicted better QoL. Discussion: Changes in RS FC of cognitive-related networks helps to explain the persistence of the effects of cognitive rehabilitation after several months in relapsing–remitting multiple sclerosis patients and their improvement on depression and QoL scales.

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