title: Structural and functional hippocampal changes in multiple sclerosis patients with intact memory function.
abstract: OBJECTIVE
  To investigate changes in hippocampal functional connectivity and structural measures of hippocampal damage in multiple sclerosis (MS) patients with intact spatial memory, a cognitive domain frequently affected in progressive MS.
  
  
  METHODS
  The study protocol was approved by the institutional ethics review board; all subjects gave written informed consent prior to participation. Twenty-five MS patients with intact spatial memory function were compared with 30 age- and sex-matched controls. Hippocampal volume differences, based on manually drawn masks, were evaluated by using the Student t test. Additionally, focal hippocampal lesions and mean diffusivity were obtained as descriptive measures of structural hippocampal damage. Multiple regression analyses of the resting-state functional magnetic resonance (MR) imaging data were performed for each subject by using hippocampal time series. Between-group analyses were conducted with a mixed-effects model, corrected for multiple comparisons by a cluster defining threshold level of z = 2 and a corrected cluster size significance level of P < .05.
  
  
  RESULTS
  Right hippocampal volume was significantly lower in MS patients as compared with controls (P < .01). Left hippocampal volume was also lower in MS patients compared with controls, but not significantly so (P = .09). Resting-state functional connectivity between the hippocampus and its anatomic input or target areas, including the anterior cingulate gyrus, thalamus, and prefrontal cortex, were significantly decreased in MS patients. Decreased hippocampal functional connectivity was more pronounced in a subgroup of MS patients with hippocampal atrophy, although subtle decreases of functional connectivity were also found in patients with normal hippocampal volume.
  
  
  CONCLUSIONS
  In MS patients, substantial abnormalities of hippocampal functional connectivity are already present before spatial memory function is impaired, especially in those patients with more pronounced hippocampal atrophy. Longitudinal studies should now assess whether these functional connectivity and structural changes may precede memory impairment in MS.
authors.affiliation: Department of Radiology, MS Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1007 MB Amsterdam, the Netherlands. s.roosendaal@vumc.nl
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Roosendaal
authors.forename: Hanneke E
authors.initials: HE
authors.lastname: Hulst
authors.forename: Hugo
authors.initials: H
authors.lastname: Vrenken
authors.forename: Heleen E M
authors.initials: HE
authors.lastname: Feenstra
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Castelijns
authors.forename: Petra J W
authors.initials: PJ
authors.lastname: Pouwels
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
mesh_terms: D000328:Adult; D001931:Brain Mapping; D016022:Case-Control Studies; D005260:Female; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008568:Memory; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D009483:Neuropsychological Tests; D012044:Regression Analysis; D018709:Statistics, Nonparametric