Why use a connectivity-based approach to study stroke and recovery of function?

Abstract

The brain is organized into a set of widely distributed networks. Therefore, although structural damage from stroke is focal, remote dysfunction can occur in regions connected to the area of lesion. Historically, neuroscience has focused on local processing due in part to the absence of tools to study the function of distributed networks. In this article we discuss how a more comprehensive understanding of the effects of stroke can be attained using resting state functional connectivity BOLD magnetic resonance imaging (resting state fcMRI). Resting state fcMRI has a number of advantages over task-evoked fMRI for studying brain network reorganization in response to stroke, including the ability to image subjects with a broad range of impairments and the ability to study multiple networks simultaneously. We describe our rationale for using resting state connectivity as a tool for investigating the neural substrates of stroke recovery in a heterogeneous population of stroke patients and discuss the main questions we hope to answer, in particular whether resting state fcMRI measures in the acute phase of stroke can predict subsequent recovery. Early results suggest that disruption of inter-hemispheric connectivity in the somatomotor network and the dorsal attention network is more strongly associated with behavioral impairment in those domains than is intra-hemispheric connectivity within either the lesioned or unaffected hemisphere. We also observe in the somatomotor network an interesting interaction between corticospinal tract damage and decreased inter-hemispheric connectivity that suggests that both processes combine to contribute to neuromotor impairment after stroke. A connectivity-based approach will provide greater insight into network reorganization in the acute and chronic phases after stroke and will contribute to improving prognostic ability and the development of therapeutic interventions.

Fig. 1

Correlation of motor function with large scale patterns of resting state functional connectivity in the somatomotor network. In a study of 23 subacute stroke patients, grip strength (in kg) was significantly correlated with inter-hemispheric connectivity (left panel) but not with intra-hemispheric connectivity either within the lesioned hemisphere (middle panel) or the unaffected hemisphere (right panel). Inter-hemispheric connectivity represents the average of the connectivity scores between homologous regions in the left and right hemispheres (e.g. average of the Fisher z score for the temporal correlation between left and right hemisphere ROIs in the network). Ipsilesional intra-hemispheric rsFC represents the average of the connectivity scores between each ROI in the damaged hemisphere and all other ROIs in the same network within the damaged hemisphere. Contralesional intra-hemispheric FC is the same as the ipsilesional score but all ROI pairs are in the unaffected hemisphere. rsFC: resting state functional connectivity.

Fig. 2

A model for how interactions between structural damage and network dysfunction contribute to behavioral impairment. A template of the corticospinal tract (CST) was developed based on diffusion tensor imaging in 12 healthy controls (colored in pink in top panel). Each stroke patient's lesion was segmented out (colored in green in top panel) and overlaid on the CST template to obtain the % CST damage. Structural damage to the CST had a direct effect on behavior (arrow A to right panel), as illustrated by the scatter plot (top panel) demonstrating that as % CST damage increased grip strength decreased. In addition, CST damage affected inter-hemispheric resting connectivity (arrow B to bottom panel). As % CST damage increased, inter-hemispheric functional connectivity decreased as shown in the scatter plot and functional connectivity maps from 4 subjects with increasing amounts of CST damage (note the decreased connectivity with the hemisphere contralateral to the hemisphere that was seeded (*) for the analysis). Effects of structural damage and altered connectivity (arrows A and C respectively) converge to impact motor behavior (right panel). In this three dimensional representation, black circles in the foreground have severe CST damage; white circles in the midground have moderate CST damage; red circles in the background have little or no CST damage. When CST damage is severe, grip performance is not correlated with functional connectivity. However, when CST damage is moderate or mild, then grip performance improves with higher inter-hemispheric connectivity (white and red circles). FC: inter-hemispheric resting state functional connectivity in somatomotor network.