Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography. Attention and language deficits were well predicted by both. Next, we identified a general pattern of physiological network dysfunction consisting of decrease of interhemispheric integration and intrahemispheric segregation, which strongly related to behavioral impairment in multiple domains. Network-specific patterns of dysfunction predicted specific behavioral deficits, and loss of interhemispheric communication across a set of regions was associated with impairment across multiple behavioral domains. These results link key organizational features of brain networks to brainbehavior relationships in stroke.stroke | functional connectivity | interhemispheric | memory | language A lthough structural damage from stroke is focal, remote dysfunction can occur in regions of the brain distant from the area of damage (1, 2). The set of regions that are directly damaged or indirectly affected is embedded within a larger functional network that is in dynamic balance with other networks in the brain. This framework posits that a lesion in a single location in the brain has the ability to disrupt brain functions far beyond the lesion boundaries (3-5).Numerous correlates of remote physiological dysfunction have been proposed, including abnormal task recruitment of contralesional brain areas (6-8), disruption of metabolism (9) or regional cerebral blood flow (10, 11), and more recently disruption of signal coherence (12-15).However, there is only a limited understanding of how remote physiological dysfunction is related to lesion topography (14, 16). Moreover, the behavioral relevance of reported physiological changes is unclear. Although some studies have reported significant correlation with behavioral impairment, the total amount of behavioral variance explained is unknown. Finally, because mechanisms of remote dysfunction have typically been examined in relatively small groups of individuals, their generalization at the population level is unknown. As a result, physiological measures of brain function are not used in the evaluation and treatment of stroke victims.More traditional lesion-symptom mapping studies have also used statistical methods to relate lesion topography to the severity of different behavioral deficits (17,18). An implicit assumption of these studies is that the strength of association between structural damage and behavior is the same irrespective of the behavior that is measured. However, it is also possi...
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.
Highlights d White matter structural disconnections explain brain network dysfunction after stroke d Damage to the gray matter, including ''hub'' regions, provides less explanatory power d Interhemispheric disconnections are linked to widespread functional disruptions d Disconnection and disruption are topographically linked within functional networks
Objective We recently reported that spatial and non-spatial attention deficits in stroke patients with hemi-spatial neglect are correlated at 2 weeks post-onset with widespread alterations of inter-hemispheric and intra-hemispheric functional connectivity (FC) measured with resting state fMRI (R-fMRI) across multiple brain networks. The mechanisms underlying neglect recovery are largely unknown. In this study we test the hypothesis that recovery of hemi-spatial neglect correlates with a return of network connectivity toward a normal pattern, herein defined as ‘network normalization’. Methods We measured attention deficits with a neuropsychological battery, and FC in a large cohort of stroke patients at, on average, 2 weeks (n=99), 3 months (n=77), and 12 (n=64) months post onset. The relationship between behavioral improvement and changes in FC was analyzed both in terms of a priori regions and networks known to be abnormal sub-acutely, and in a data driven manner. Results Attention deficit recovery was mostly complete by 3 months, and was significantly correlated with a normalization of abnormal FC across many networks. Improvement of attention deficits, independent of initial severity, was correlated with improvements of previously depressed inter-hemispheric FC across attention, sensory, and motor networks, and a restoration of the normal anti-correlation between dorsal attention/motor regions and default-mode/frontoparietal regions, particularly in the damaged hemisphere. Interpretation These results demonstrate that abnormal network connectivity in hemi-spatial neglect is behaviorally relevant. A return toward normal network interactions, and presumably optimal information processing, is therefore a systems level mechanism that is associated with improvements of attention over time after focal injury.
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