Stronger prediction of motor recovery and outcome post-stroke by cortico-spinal tract integrity than functional connectivity.

OBJECTIVES: To examine longitudinal changes in structural and functional connectivity post-stroke in patients with motor impairment, and define their importance for recovery and outcome at 12 months. METHODS: First-time stroke patients (N = 31) were studied at 1-2 weeks, 3 months, and 12 months post-injury with a validated motor battery and resting-state fMRI to measure inter-hemispheric functional connectivity (FC). Fractional anisotropy (FA) of the cortico-spinal tract (CST) was derived from diffusion tensor imaging as a measure of white matter organization. ANOVAs were used to test for changes in FC, FA, and motor performance scores over time, and regression analysis related motor outcome to clinical and neuroimaging variables. RESULTS: FA of the ipsilesional CST improved significantly from 3 to 12 months and was strongly correlated with motor performance. FA improved even in the absence of direct damage to the CST. Inter-hemispheric FC also improved over time, but did not correlate with motor performance at 12 months. Clinical variables (early motor score, education level, and age) predicted 80.4% of the variation of motor outcome, and FA increased the predictability to 84.6%. FC did not contribute to the prediction of motor outcome. CONCLUSIONS: Stroke causes changes to the CST microstructure that can account for behavioral variability even in the absence of demonstrable lesion. Ipsilesional CST undergoes remodeling post-stroke, even past the three-month window when most of the motor recovery happens. FA of the CST, but not inter-hemispheric FC, can improve to the prediction of motor outcome based on early motor scores.

Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke.

Visuospatial attention depends on the integration of multiple processes, and people with right hemisphere lesions after a stroke may exhibit severe or no visuospatial deficits. The anatomy of core components of visuospatial attention is an area of intense interest. Here we examine the relationship between the disruption of core components of attention and lesion distribution in a heterogeneous group (N = 70) of patients with right hemisphere strokes regardless of the presence of clinical neglect. Deficits of lateralized spatial orienting, measured as the difference in reaction times for responding to visual targets in the contralesional or ipsilesional visual field, and deficits in re-orienting attention, as measured by the difference in reaction times for invalidly versus validly cued targets, were measured using a computerized spatial orienting task. Both measures were related through logistic regression and a novel ridge regression method to anatomical damage measured with magnetic resonance imaging. While many regions were common to both deficit maps, a deficit in lateralized spatial orienting was more associated with lesions in the white matter underlying the posterior parietal cortex, and middle and inferior frontal gyri. A deficit in re-orienting of attention toward unattended locations was associated with lesions in the white matter of the posterior parietal cortex, insular cortex and less so with white matter involvement of the anterior frontal lobe. An hodological analysis also supports this partial dissociation between the white matter tracts that are damaged in lateralized spatial biases versus impaired re-orienting. Our results underscore that the integrity of fronto-parietal white matter tracts is crucial for visuospatial attention and that different attention components are mediated by partially distinct neuronal substrates.

Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke.

Strokes often cause multiple behavioural deficits that are correlated at the population level. Here, we show that motor and attention deficits are selectively associated with abnormal patterns of resting state functional connectivity in the dorsal attention and motor networks. We measured attention and motor deficits in 44 right hemisphere-damaged patients with a first-time stroke at 1-2 weeks post-onset. The motor battery included tests that evaluated deficits in both upper and lower extremities. The attention battery assessed both spatial and non-spatial attention deficits. Summary measures for motor and attention deficits were identified through principal component analyses on the raw behavioural scores. Functional connectivity in structurally normal cortex was estimated based on the temporal correlation of blood oxygenation level-dependent signals measured at rest with functional magnetic resonance imaging. Any correlation between motor and attention deficits and between functional connectivity in the dorsal attention network and motor networks that might spuriously affect the relationship between each deficit and functional connectivity was statistically removed. We report a double dissociation between abnormal functional connectivity patterns and attention and motor deficits, respectively. Attention deficits were significantly more correlated with abnormal interhemispheric functional connectivity within the dorsal attention network than motor networks, while motor deficits were significantly more correlated with abnormal interhemispheric functional connectivity patterns within the motor networks than dorsal attention network. These findings indicate that functional connectivity patterns in structurally normal cortex following a stroke link abnormal physiology in brain networks to the corresponding behavioural deficits.

Abnormal White Matter Blood-Oxygen-Level-Dependent Signals in Chronic Mild Traumatic Brain Injury.

Concussion, or mild traumatic brain injury (mTBI), can cause persistent behavioral symptoms and cognitive impairment, but it is unclear if this condition is associated with detectable structural or functional brain changes. At two sites, chronic mTBI human subjects with persistent post-concussive symptoms (three months to five years after injury) and age- and education-matched healthy human control subjects underwent extensive neuropsychological and visual tracking eye movement tests. At one site, patients and controls also performed the visual tracking tasks while blood-oxygen-level-dependent (BOLD) signals were measured with functional magnetic resonance imaging. Although neither neuropsychological nor visual tracking measures distinguished patients from controls at the level of individual subjects, abnormal BOLD signals were reliably detected in patients. The most consistent changes were localized in white matter regions: anterior internal capsule and superior longitudinal fasciculus. In contrast, BOLD signals were normal in cortical regions, such as the frontal eye field and intraparietal sulcus, that mediate oculomotor and attention functions necessary for visual tracking. The abnormal BOLD signals accurately differentiated chronic mTBI patients from healthy controls at the single-subject level, although they did not correlate with symptoms or neuropsychological performance. We conclude that subjects with persistent post-concussive symptoms can be identified years after their TBI using fMRI and an eye movement task despite showing normal structural MRI and DTI.

Common behavioral clusters and subcortical anatomy in stroke.

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.

Large-scale changes in network interactions as a physiological signature of spatial neglect.

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.

Upstream dysfunction of somatomotor functional connectivity after corticospinal damage in stroke.

BACKGROUND: Recent studies have shown that focal injuries can have remote effects on network function that affect 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: A total of 23 subacute stroke patients and 13 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 interhemispheric resting functional connectivity, in particular with connectivity between the left and right central sulcus. Although 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 they may have important implications for neurorehabilitation.

A behavioral analysis of spatial neglect and its recovery after stroke.

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.

Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke.

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 magnetic resonance imaging. METHODS: In acute stroke patients, we measured FC in a dorsal attention network and an arm somatomotor network, and determined the correlation of FC with performance obtained in a separate session on tests of attention and motor function. In particular, we compared the behavioral correlation with intrahemispheric FC to the behavioral correlation with interhemispheric FC. RESULTS: In the attention network, disruption of interhemispheric FC was significantly correlated with abnormal detection of visual stimuli (Pearson r with field effect = -0.624, p = 0.002). In the somatomotor network, disruption of interhemispheric FC was significantly correlated with upper extremity impairment (Pearson r with contralesional Action Research Arm Test = 0.527, p = 0.036). In contrast, intrahemispheric FC within the normal or damaged hemispheres was not correlated with performance in either network. Quantitative lesion analysis demonstrated that our results could not be explained by structural damage alone. 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 interhemispheric interactions.

Is the posner reaction time test more accurate than clinical tests in detecting left neglect in acute and chronic stroke?

UNLABELLED: Rengachary J, d'Avossa G, Sapir A, Shulman GL, Corbetta M. Is the Posner Reaction Time Test more accurate than clinical tests in detecting left neglect in acute and chronic stroke? OBJECTIVE: To compare the accuracy of common clinical tests for left neglect with that of a computerized reaction time Posner test in a stroke population. DESIGN: Neglect measures were collected longitudinally in patients with stroke at the acute ( approximately 2wk) and chronic ( approximately 9mo) stages. Identical measures were collected in a healthy control group. SETTING: Inpatient and outpatient rehabilitation. PARTICIPANTS: Patients with acute stroke (n=59) with left neglect, 30 of whom were tested longitudinally; healthy age-matched controls (n=30). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A receiver operating characteristic analysis ranking the measures' sensitivity and specificity using a single summary statistic. RESULTS: Most clinical tests were adequately accurate at the acute stage, but many were near chance at the chronic stage. The Posner test was the most sensitive test at both stages. The most sensitive variable was the reaction time difference for detecting targets appearing on the left compared with the right side. CONCLUSIONS: Computerized reaction time tests can be used to screen for subtle but potentially clinically relevant left neglect, which may not be detectable by conventional clinical tests, especially at the chronic stage. Such tests may be useful to assess the severity of the patients' deficits and provide more accurate measures of the degree of recovery in clinical trials than established clinical measures.