Objective-Focal brain lesions can have important remote effects on the function of distant brain regions. The resulting network dysfunction may contribute significantly to behavioral deficits observed after stroke. This study investigates the behavioral significance of changes in the coherence of spontaneous activity in distributed networks after stroke by measuring resting state functional connectivity (FC) using functional MRI.Methods-In acute stroke patients we measured FC in a dorsal attention and an arm somatomotor network, and determined the correlation of FC with performance (behavioral correlation) obtained in a separate session on tests of attention (n=23) and motor function (n=16). In particular we compared the behavioral correlation with intra-hemispheric FC to the behavioral correlation with inter-hemispheric FC.Results-In the attention network disruption of inter-hemispheric FC was significantly correlated with abnormal detection of visual stimuli (Pearson's r with Field Effect = −0.624, p =0.002). In the somatomotor network disruption of inter-hemispheric FC was significantly Correspondence should be addressed to M.C. (mau@npg.wustl.edu). * Drs Shulman and Corbetta contributed equally to this study.Author ContributionsA.R.C. performed the analysis of most imaging data (BOLD functional connectivity analysis and stroke lesion segmentation analysis), imaging-behavior correlations, statistical analysis, assisted in the recruitment and scanning of subjects and wrote the paper. S.V.A. assisted in the scanning of subjects, image analysis, ROI creation, encoding of behavioral data, and developed the composite functional connectivity scores. C.E.L. contributed to the experimental design and development of an appropriate battery for testing motor behavior. L.T.C. contributed to the experimental design, behavioral battery and helped with the statistical analysis. J.R. recruited and consented patients, assisted in the scanning, administered the behavioral battery and analyzed the behavioral data. M.J.S. instructed the authors in statistical methods for comparing non-independent correlations. D.L.P. assisted in scanning and behavioral testing. G.L.S. and M.C. designed the study, oversaw data acquisition and analysis, and were principal editors of the paper. All authors discussed the results and commented on the paper. DisclosuresThe authors declare no competing financial interests. Interpretation-These results suggest that lesions cause 'state' changes in the spontaneous functional architecture of the brain, and constrain behavioral output. Clinically, these results validate using FC for assessing the health of brain networks, with implications for prognosis and recovery from stroke, and underscore the importance of inter-hemispheric interactions. NIH Public Access

SUMMARY A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1–2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.

The relationship between spontaneous brain activity and behaviour following focal injury is not well understood. Here, we report a large-scale study of resting state functional connectivity MRI and spatial neglect following stroke in a large (n=84) heterogeneous sample of first-ever stroke patients (within 1-2 weeks). Spatial neglect, which is typically more severe after right than left hemisphere injury, includes deficits of spatial attention and motor actions contralateral to the lesion, and low general attention due to impaired vigilance/arousal. Patients underwent structural and resting state functional MRI scans, and spatial neglect was measured using the Posner spatial cueing task, and Mesulam and Behavioural Inattention Test cancellation tests. A principal component analysis of the behavioural tests revealed a main factor accounting for 34% of variance that captured three correlated behavioural deficits: visual neglect of the contralesional visual field, visuomotor neglect of the contralesional field, and low overall performance. In an independent sample (21 healthy subjects), we defined 10 resting state networks consisting of 169 brain regions: visual-fovea and visual-periphery, sensory-motor, auditory, dorsal attention, ventral attention, language, fronto-parietal control, cingulo-opercular control, and default mode. We correlated the neglect factor score with the strength of resting state functional connectivity within and across the 10 resting state networks. All damaged brain voxels were removed from the functional connectivity:behaviour correlational analysis. We found that the correlated behavioural deficits summarized by the factor score were associated with correlated multi-network patterns of abnormal functional connectivity involving large swaths of cortex. Specifically, dorsal attention and sensory-motor networks showed: (i) reduced interhemispheric functional connectivity; (ii) reduced anti-correlation with fronto-parietal and default mode networks in the right hemisphere; and (iii) increased intrahemispheric connectivity with the basal ganglia. These patterns of functional connectivity:behaviour correlations were stronger in patients with right- as compared to left-hemisphere damage and were independent of lesion volume. Our findings identify large-scale changes in resting state network interactions that are a physiological signature of spatial neglect and may relate to its right hemisphere lateralization.

Background Recent studies have shown that focal injuries can have remote effects on network function that impact behavior but these network-wide repercussions are poorly understood. Objective This study tested the hypothesis that lesions specifically to the outflow tract of a distributed network can result in upstream dysfunction in structurally intact portions of the network. In the somatomotor system this upstream dysfunction hypothesis predicted that lesions of the corticospinal tract might be associated with functional disruption within the system. Motor impairment might then reflect the dual contribution of corticospinal damage and altered network functional connectivity. Methods Twenty-three subacute stroke patients and thirteen healthy controls participated in the study. Corticospinal tract damage was quantified using a template of the tract generated from diffusion tensor imaging in healthy controls. Somatomotor network functional integrity was determined by resting state functional connectivity magnetic resonance imaging. Results The extent of corticospinal damage was negatively correlated with inter-hemispheric resting functional connectivity, in particular with connectivity between the left and right central sulcus. While corticospinal damage accounted for much of the variance in motor performance, the behavioral impact of resting connectivity was greater in subjects with mild or moderate corticospinal damage, and less in those with severe corticospinal damage. Conclusions Our results demonstrated that dysfunction of cortical functional connectivity can occur after interruption of corticospinal outflow tracts, and can contribute to impaired motor performance. Recognition of these secondary effects from a focal lesion is essential for understanding brain-behavior relationships after injury, and may have important implications for neurorehabilitation.

In a longitudinal study of recovery of left neglect following stroke using reaction time computerized assessment, we find that lateralized spatial deficits of attention and perception to be more severe than disturbance of action. Perceptual-attention deficits also show the most variability in the course of recovery, making them prime candidates for intervention. In an anatomical analysis of MRI findings, ventral frontal cortex damage was correlated with the most severe neglect, reflecting impaired fronto-parietal communication.