Dynamic structural connectivity changes in cortical and cortico-striatal strokes in mice

Abstract Stroke is a primary global health concern, leading to significant mortality and long-term disability. Beyond immediate neuronal damage, functional and structural connectivity is altered brain-wide with implications for functional deficits and recovery. It remains unclear, however, if the level of degeneration, i.e. reduced myelination and axonal damage, as well as compensatory plasticity, i.e., axonal sprouting and remyelination, depend on the lesion size and topology. This study compares for the first time two different stroke models in adult male mice, with the aim of uncovering the dynamics in white matter changes. Repetitive diffusion magnetic resonance imaging (dMRI) over four weeks post photothrombotic cortical (1.41±0.92% of brain volume), and middle cerebral artery occlusion (MCAO) cortico-striatal (11.53±2.8% of brain volume), strokes were used to map structural connectivity changes at the whole-brain level. We quantified inter- and intra-hemispheric seed strength changes over time, with seed strength reflecting how strongly each region is connected to the rest of the brain. Differences between groups and time points were assessed using a mixed model corrected for multiple comparisons. In conclusion, large cortico-striatal lesions led to increased structural connectivity in sensorimotor regions, whereas small cortical lesions induced asymmetric connectivity changes: an increase extending globally from the ischemic hemisphere and a decrease expanding globally from the healthy hemisphere. These findings highlight that stroke severity and lesion size significantly affect the temporal dynamics and spatial distribution of connectivity disruptions, emphasizing the need for targeted monitoring of neural changes post-stroke. Significance statement Pathophysiological changes close to an ischemic lesion are well understood. But structurally connected regions also undergo stroke-related changes potentially contributing to functional deficits. Animal studies using in vivo diffusion MRI to quantify white matter changes have been limited to single connections, time points after stroke, and basic diffusion measures. We provide the first in-depth characterization of whole-brain fiber tracking to compare small cortical and large cortico-striatal strokes. We found a complex dynamic of decreasing and increasing structural connectivity in single sensorimotor-related brain regions within the brain network - even remote areas from the stroke lesion. This study provides a better understanding of the interactions of regions during stroke recovery, which may help in developing therapies targeting localized white matter repair.