Fornix damage limits verbal memory functional compensation in multiple sclerosis

Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.