Distributional changes in myelin-specific MRI markers uncover dynamics in the fornix following spatial navigation training

Abstract

Increasing evidence implicates white matter (WM) dynamics supporting learning in the mature brain. Recent MRI studies, mostly using diffusion tensor MRI (DT-MRI), have demonstrated learning-induced WM changes at the microstructural level. However, while DT-MRI-derived measures have sensitivity to general WM microstructural changes, they lack compartmental specificity, making them difficult to relate to underlying cellular mechanisms, stymying deeper understanding of mechanisms supporting training-induced gains in performance. Gaining a deeper understanding demands a more detailed characterization of changes in specific WM sub-components. To this end, four microstructural MRI techniques were employed to study alterations in rat brains after 5-days of water maze training: DT-MRI; Composite Hindered and Restricted Model of Diffusion (CHARMED); magnetization transfer (MT) imaging; quantitative susceptibility mapping and R2*. The hypothesis tested here was that microstructural changes would be: (i) observed in tracts supporting spatial navigation, i.e., fornix and corpus callosum (CC); and (ii) more pronounced in the myelin-specific measures. Medians and distributions of microstructural parameters were derived along the fornix, CC and cingulum (as a comparison tract) using the tractometry approach. Summary measures were derived from different metrics using unsupervised data reduction. Significant pre-vs-post training differences were found in the medians of two principal components loading on: (i) anisotropy indices; and (ii) MT ratio. The most striking effect, however, was seen in the distributions of pre-vs-post training MT ratio in the fornix, consistent with the primary hypothesis, and highlighting the value of this alternative to the standard approach (i.e., comparing means/medians of DT-MRI parameters) for studying neuroplasticity in vivo. Significance statementRecent MRI-studies have demonstrated that white matter (WM) dynamics support learning, even in the mature brain. However, most studies are based on diffusion tensor MRI (DT-MRI) measures, which although providing sensitivity to WM microstructural changes, do not provide a direct translation to the underlying cellular mechanisms making interpretation difficult. Using alternative quantitative MRI approaches, this study provided more specific subcomponent microstructural insights into the brains WM response to water-maze training. We show that myelin-specific MR measures show more marked changes than axonal-specific and DT-MRI measures, in WM tracts responsible for spatial navigation. The results promote adoption of these alternative approaches to DT-MRI for studying neuroplasticity in vivo.