White matter changes after stroke in rats as studied by serial diffusion tensor imaging and manganese-enhanced MRI

Background and Aims: Restoration of lost function after stroke is often associated with alterations in neuronal circuitry in the brain. However, the exact pattern of neural reorganization after stroke has not been fully characterized. Changes in neuronal connectivity may be assessed in vivo with diffusion tensor imaging (DTI)1,2 or manganese-enhanced MRI (MEMRI).3 The aim of this study was to characterize the temporal pattern of white matter changes with DTI and MEMRI after stroke in rats. Methods: Transient focal cerebral ischemia was induced in four male Wistar rats by 30-minutes intraluminal occlusion of the right middle cerebral artery.4 Repetitive T2 mapping and DTI were performed at 3 hours, 3 days, 3 weeks and 9 weeks after ischemia induction. T2 maps were used for lesion assessment. From DTI data we calculated mean diffusivity (ADCav) and fractional anisotropy (FA) maps. MEMRI was performed at 10 weeks after stroke, four days after injection of 0.2 ml 1M MnCl2 into spared ipsilesional sensorimotor cortex. Manganese enhancement was calculated from changes in R1 (1/T1).5 To assess temporal white matter changes after stroke, we selected three white matter structures as regions-of-interest (ROIs) for data analysis: ipsilesional internal capsule (ICipsi); ipsilesional external capsule (ECipsi); and contralateral internal capsule (ICcontra). Results and Conclusions: In ICcontra, no significant changes in T2, ADCav and FA were observed over time. ICipsi and ECipsi were both part of the T2-defined lesion area at 3 days after stroke. However, while T2 in ECipsi remained prolonged, in ICipsi T2 was normalized after 3 and 9 weeks. As compared to ICcontra (0.44 ± 0.04), FA was significantly decreased in ICipsi (0.22 ± 0.02, P < 0.05) and ECipsi (0.21 ± 0.02, P < 0.05) at 3 days after stroke. After 9 weeks, FA in ECipsi remained significantly reduced as compared to ICcontra (0.32 ± 0.04 vs. 0.44 ± 0.03, P < 0.05). FA in ICipsi, however, was significantly increased (0.58 ± 0.03, P < 0.05) at this time-point. In addition, at 10 weeks after stroke, there was significant manganese-induced R1 increase in ICipsi, suggestive of intact connectivity with the ipsilesional sensorimotor cortex. This study demonstrates that early ischemia-induced changes in white matter structures that are reflective of tissue degeneration (i.e., increased T2 and decreased FA), may recover at chronic time-points. The observed T2 normalization, elevated FA, and significant manganese enhancement in ICipsi at 9 weeks after stroke, may indicate reorganization of white matter including axonal sprouting and/or remyelination. In conclusion, combining DTI and MEMRI can provide unique in vivo information on changes in tissue architecture and connectivity, and may give important insights in mechanisms underlying functional recovery after stroke.