Exploring the predictive value of lesion topology on motor function outcomes in a porcine ischemic stroke model

Abstract

Harnessing the maximum diagnostic potential of magnetic resonance imaging (MRI) by including stroke lesion location in relation to specific structures that are associated with particular functions will likely increase the potential to predict functional deficit type, severity, and recovery in stroke patients. This exploratory study aims to identify key structures lesioned by a middle cerebral artery occlusion (MCAO) that impact stroke recovery and to strengthen the predictive capacity of neuroimaging techniques that characterize stroke outcomes in a translational porcine model. Clinically relevant MRI measures showed significant lesion volumes, midline shifts, and decreased white matter integrity post-MCAO. Using a pig brain atlas, damaged brain structures included the insular cortex, somatosensory cortices, temporal gyri, claustrum, and visual cortices, among others. MCAO resulted in severely impaired spatiotemporal gait parameters, decreased voluntary movement in open field testing, and higher modified Rankin Scale scores at acute timepoints. Pearson correlation analyses at acute timepoints between standard MRI metrics (e.g., lesion volume) and functional outcomes displayed moderate R values to functional gait outcomes. Moreover, Pearson correlation analyses showed higher R values between functional gait deficits and increased lesioning of structures associated with motor function, such as the putamen, globus pallidus, and primary somatosensory cortex. This correlation analysis approach helped identify neuroanatomical structures predictive of stroke outcomes and may lead to the translation of this topological analysis approach from preclinical stroke assessment to a clinical biomarker.

Prediction of Stroke Outcome in Mice Based on Non-Invasive MRI and Behavioral Testing

“…This indicates that for functional recovery, lesion topology is more relevant than lesion volume, which again is in line with clinical data. 12,28 It should be noted, that in the 45 minutes MCAO model, lesion volume and lesion topology are not fully independent predictors. Larger ischemic lesions typically include cortical regions while smaller lesions are restricted to subcortical structures.…”

“…[2][3][4][5][6]8 While one pre-clinical study on predictors of stroke outcome in a porcine MCAO model exists, evidence on prediction of stroke outcome in mice is scarce, despite rodents being used most commonly as model animals in stroke studies. 12,24 We modified previously published protocols for the staircase test of skilled reaching in mice, which enabled us to daily monitor motor function and to detect both subacute and long-term functional deficits. 18,25 Training the mice over a period of 21 days prior to the MCAO surgery and implementing separation during feeding hours enabled us to detect a side-specific disability of the forepaw over a period of three weeks post stroke.…”

“…2–6,8 While one pre-clinical study on predictors of stroke outcome in a porcine MCAO model exists, evidence on prediction of stroke outcome in mice is scarce, despite rodents being used most commonly as model animals in stroke studies. 12,24…”

“…[5][6][7][8][9][10][11] This was also shown in an exploratory preclinical study using a porcine stroke model. 12 Additionally, the degree of the subacute deficit has been shown to be a reliable predictor of long-term outcome, especially for mild functional deficits. 13,14 In contrast to humans, little is known about predictors of functional outcome after stroke in mice, although they are commonly used in preclinical research.…”

Regional homogeneity alterations in multifrequency bands in patients with basal ganglia stroke: A resting-state functional magnetic resonance imaging study

“…Damage to the corticospinal tract in the putamen would affect lower limb motor function of patients with stroke ( Frenkel-Toledo et al, 2021 ). And ischemic impairment of the putamen was found to be associated with the motor dysfunction in animal ischemic stroke models ( Scheulin et al, 2021 ). In addition, a previous study showed that the low variability of dynamic connectivity between bilateral putamen and the supplementary motor area was related to a better motor recovery of patients with stroke ( Bonkhoff et al, 2021 ).…”