title: Thalamic-hippocampal-prefrontal disruption in relapsing-remitting multiple sclerosis.
abstract: BACKGROUND
  Cortical, thalamic and hippocampal gray matter atrophy in relapsing-remitting MS (RRMS) is associated cognitive deficits. However, the role of interconnecting white matter pathways including the fornix, cingulum, and uncinate fasciculus (UF) is less well studied.
  
  
  OBJECTIVE
  To assess MS damage to a hippocampal-thalamic-prefrontal network and the relative contributions of its components to specific cognitive domains.
  
  
  METHODS
  We calculated diffusion tensor fractional anisotropy (FA) in the fornix, cingulum and UF as well as thalamic and hippocampal volumes in 27 RRMS patients and 20 healthy controls. A neuropsychological battery was administered and 4 core tests known to be sensitive to MS changes were used to assess cognitive impairment. To determine the relationships between structure and cognition, all tests were grouped into 4 domains: attention/executive function, processing speed, verbal memory, and spatial memory. Univariate correlations with structural measures and depressive symptoms identified potential contributors to cognitive performance and subsequent linear regression determined their relative effects on performance in each domain. For significant predictors, we also explored the effects of laterality and axial versus radial diffusivity.
  
  
  RESULTS
  RRMS patients had worse performance on the Symbol Digit Modalities Test, but no significant impairment in the 4 cognitive domains. RRMS had reduced mean FA of all 3 pathways and reduced thalamic and hippocampal volumes compared to controls. In RRMS we found that thalamic volume and BDI predicted attention/executive function, UF FA predicted processing speed, thalamic volume predicted verbal memory, and UF FA and BDI predicted spatial memory.
  
  
  CONCLUSIONS
  Hippocampal-thalamic-prefrontal disruption affects cognitive performance in early RRMS with mild to minimal cognitive impairment, confirming both white and gray matter involvement in MS and demonstrating utility in assessing functional networks to monitor cognition.
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Kern
authors.affiliation: Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gold
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Montag
authors.affiliation: Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Horsfall
authors.affiliation: Department of Psychology, University of Arizona, Tucson, AZ, USA.
authors.forename: Mary-Frances
authors.initials: MF
authors.lastname: O'Connor
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA ; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Sicotte
mesh_terms: D000328:Adult; D001284:Atrophy / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications / Q000473:pathology*; D009415:Nerve Net / Q000473:pathology*; D017397:Prefrontal Cortex / Q000473:pathology*; D013788:Thalamus / Q000473:pathology*
keywords: AD, axial diffusivity; BDI, Beck Depression Inventory; BSRT, Buschke Selective Reminding Test; BVMT, Brief Visuospatial Memory Test; BVRT, Benton Visual Retention Test; CVLT-II, California Verbal Learning Test II; Cognition; DTI, diffusion tensor imaging; Diffusion tensor imaging; EDSS, Expanded Disability Status Scale; FA, fractional anisotropy; FAST, FMRIB's Automated Segmentation Tool; FLAIR, Fluid Attenuated Inversion Recovery; FOV, field of view; FSL, Functional MRI of the Brain Software Library; GM, gray matter; Limbic system; MPRAGE, Magnetization Prepared Rapid Acquisition Gradient Echo; MRI; MRI, magnetic resonance image; Memory; Multiple sclerosis; NEX, number of excitations; PASAT, Paced Auditory Serial Addition Test; RAVLT, Rey Auditory Verbal Learning Test; RD, radial diffusivity; ROI, region of interest; RRMS, relapsing remitting multiple sclerosis; SDMT, Symbol Digit Modalities Test; TBSS, Tract-based Spatial Statistics; TE, echo time; TI, inversion time; TR, repetition time; UF, uncinate fasciculus; WAIS, Wechsler Adult Intelligence Scale; WM, white matter.