Increased default-mode network centrality in cognitively impaired multiple sclerosis patients.
OBJECTIVE
To investigate how changes in functional network hierarchy determine cognitive impairment in multiple sclerosis (MS).


METHODS
A cohort consisting of 332 patients with MS (age 48.1 ± 11.0 years, symptom duration 14.6 ± 8.4 years) and 96 healthy controls (HCs; age 45.9 ± 10.4 years) underwent structural MRI, fMRI, and extensive neuropsychological testing. Patients were divided into 3 groups: cognitively impaired (CI; n = 87), mildly cognitively impaired (MCI; n = 65), and cognitively preserved (CP; n = 180). The functional importance of brain regions was quantified with degree centrality, the average strength of the functional connections of a brain region with the rest of the brain, and eigenvector centrality, which adds to this concept by adding additional weight to connections with brain hubs because these are known to be especially important. Centrality values were calculated for each gray matter voxel based on resting-state fMRI data, registered to standard space. Group differences were assessed with a cluster-wise permutation-based method corrected for age, sex, and education.


RESULTS
CI patients demonstrated widespread centrality increases compared to both HCs and CP patients, mainly in regions making up the default-mode network. Centrality decreases were similar in all patient groups compared to HCs, mainly in occipital and sensorimotor areas. Results were robust across centrality measures.


CONCLUSIONS
Patients with MS with cognitive impairment show hallmark alterations in functional network hierarchy with increased relative importance (centrality) of the default-mode network.
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK. a.eijlers@vumc.nl.
Anand J C
AJ
Eijlers
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Kim A
KA
Meijer
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Thomas M
TM
Wassenaar
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Martijn D
MD
Steenwijk
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Bernard M J
BM
Uitdehaag
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Frederik
F
Barkhof
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Alle M
AM
Wink
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Jeroen J G
JJ
Geurts
Departments of Anatomy and Neurosciences (A.J.C.E., K.A.M., T.M.W., M.D.S., J.J.G.G., M.M.S.), Neurology (M.D.S., B.M.J.U.), and Radiology and Nuclear Medicine (F.B., A.M.W.), Neuroscience Campus Amsterdam, MS Center Amsterdam, VU University Medical Center, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), UCL, London, UK.
Menno M
MM
Schoonheim
D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications*; D016571:Neural Networks, Computer; D009434:Neural Pathways / Q000000981:diagnostic imaging; D009483:Neuropsychological Tests