MS May Impair Cerebellar Regional Functional Connectivity

Impaired regional cerebellar functional connectivity in persons with multiple sclerosis (MS) is linked to overall disability and balance disturbance (ataxia), according to findings of a cross-sectional study published online November 27 and in the January 2014 issue of NeuroImage: Clinical.

"In addition to studying long-range connectivity within functional brain networks, resting-state fMRI (rs-fMRI) can also be used to assess local connectivity in a brain region," wrote Anne-Marie Dogonowski, from the Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital in Hvidovre, Denmark, and colleagues. "Here we employed regional homogeneity analysis of resting-state [blood-oxygen-level-dependent (BOLD)]-signal fluctuations to test for brain regions where MS patients express an abnormal pattern of local functional connectivity relative to healthy controls. Within the patient group, we were also interested to identify brain regions where the regional expression of local resting-state connectivity would predict clinical disability."

Using whole-brain rs-fMRI at 3 T and the Kendall's Coefficient of Concordance, the investigators calculated regional homogeneity of BOLD-signal fluctuations for each voxel. This allowed comparison of local functional connectivity in 42 persons with MS and 30 matched healthy control patients.

Compared with healthy control patients, patients with MS had decreased regional homogeneity in the upper left cerebellar hemisphere in lobules V and VI and similar trend changes in the right cerebellar hemisphere.

The investigators suggest these findings may reflect disintegration of regional processing in the cerebellum in MS. Reduction in cerebellar homogeneity was greater in patients with greater lesion volume in the left cerebellar peduncles, suggesting it might be caused by functional disruption of cortico-ponto-cerebellar and spino-cerebellar inputs.

The impairment of regional functional homogeneity in MS correlates well with previous research showing marked pathological changes in cerebellar cortex in MS and with positron emission tomography studies showing bilateral reductions in cerebellar resting-state glucose metabolism in early relapsing-remitting MS.

The investigators suggest this disrupted local cerebellar connectivity might be caused primarily by local cortical damage, or, more likely, that MS lesions in cerebellar white matter tracts cause a functional disruption of neurotransmission in these pathways.

Decreased Regional Homogeneity Linked to Disability

Among persons with MS, 2 clusters in the left posterior cerebellum showed a decrease in regional homogeneity with increasing global disability, as measured with the Expanded Disability Status Scale score or ataxia scores.

"These findings suggest a link between impaired regional integration in the cerebellum and general disability and ataxia," the study authors wrote.

There was little spatial overlap in the 2 identified clusters, which were primarily located in crus I and extended into crus II (both representing the "cognitive" cerebellum) and the dentate nucleus.

"The lesioned cerebellar peduncles in MS might become a bottleneck causing deficient parallel information transfer into the cerebellum reflected by a reduction in cerebellar local functional connectivity," the study authors conclude.

Key open questions

• Is disrupted local cerebellar connectivity in MS caused primarily by local cortical damage or by MS lesions in cerebellar white matter tracts resulting in functional disruption of neurotransmission in these pathways?
• Could rs-fMRI be useful in the diagnosis of early MS when disease-modifying therapy or preventive strategies might be most effective?

Disclosures

The Danish Multiple Sclerosis Society; Hvidovre Hospital; the University of Copenhagen, Faculty of Health Sciences; and the Lundbeck Foundation Mapping, Modulation & Modeling the Control of Actions supported this study. The Simon Spies Foundation donated the magnetic resonance scanner. Some of the study authors reported various financial disclosures involving Biogen Idec; Merck-Serono; Novartis; Genmab; TEVA; Elan; GSK; Bayer Schering; the European Journal of Neurology; the Multiple Sclerosis Journal; the European Journal of Neurology;  Therapeutic Advances in Neurological Disorders; sanofi-aventis; Genzyme; IBI Consulting (a division of Informa plc); Baxter; BioMS; RoFAR; Roche; the Danish Multiple Sclerosis Society; the Danish Medical Research Council; the European Union Sixth Framework Programme: Life Sciences, Genomics and Biotechnology; 7 T MR Tomographie/Hochfeld MR Zentrum; Swedish 7 TMR Steering Group; Elsass Foundation; Danish Governmental Department of Justice; Lundbeck Foundation; BKMedical; Danish Multiple Sclerosis Society; Solvay Pharma; NeuroImage; Springer Publishing; Forsknings-og Innovationsstyrelsen; and/or the John and Birthe Meyer Foundation.