Recent advances in treatment of spatial neglect: networks and neuropsychology.

INTRODUCTION: Spatial neglect remains an underdiagnosed and undertreated consequence of stroke that imposes significant disability. A growing appreciation of brain networks involved in spatial cognition is helping us to develop a mechanistic understanding of different therapies under development. AREAS COVERED: This review focuses on neuromodulation of brain networks for the treatment of spatial neglect after stroke, using evidence-based approaches including 1) Cognitive strategies that are more likely to impact frontal lobe executive function networks; 2) Visuomotor adaptation, which may depend on the integrity of parietal and parieto- and subcortical-frontal connections and the presence of a particular subtype of neglect labeled Aiming neglect; 3) Non-invasive brain stimulation that may modulate relative levels of activity of the two hemispheres and depend on corpus callosum connectivity; and 4) Pharmacological modulation that may exert its effect primarily via right-lateralized networks more closely involved in arousal. EXPERT OPINION: Despite promising results from individual studies, significant methodological heterogeneity between trials weakened conclusions drawn from meta-analyses. Improved classification of spatial neglect subtypes will benefit research and clinical care. Understanding the brain network mechanisms of different treatments and different types of spatial neglect will make possible a precision medicine treatment approach.

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.

High-Intensity, Unilateral Resistance Training of a Non-Paretic Muscle Group Increases Active Range of Motion in a Severely Paretic Upper Extremity Muscle Group after Stroke.

Limited rehabilitation strategies are available for movement restoration when paresis is too severe following stroke. Previous research has shown that high-intensity resistance training of one muscle group enhances strength of the homologous, contralateral muscle group in neurologically intact adults. How this "cross education" phenomenon might be exploited to moderate severe weakness in an upper extremity muscle group after stroke is not well understood. The primary aim of this study was to examine adaptations in force-generating capacity of severely paretic wrist extensors resulting from high intensity, dynamic contractions of the non-paretic wrist extensors. A secondary, exploratory aim was to probe neural adaptations in a subset of participants from each sample using a single-pulse, transcranial magnetic stimulation (TMS) protocol. Separate samples of neurologically intact controls (n = 7) and individuals ≥4 months post stroke (n = 6) underwent 16 sessions of training. Following training, one-repetition maximum of the untrained wrist extensors in the control group and active range of motion of the untrained, paretic wrist extensors in the stroke group were significantly increased. No changes in corticospinal excitability, intracortical inhibition, or interhemispheric inhibition were observed in control participants. Both stroke participants who underwent TMS testing, however, exhibited increased voluntary muscle activation following the intervention. In addition, motor-evoked potentials that were unobtainable prior to the intervention were readily elicited afterwards in a stroke participant. Results of this study demonstrate that high-intensity resistance training of a non-paretic upper extremity muscle group can enhance voluntary muscle activation and force-generating capacity of a severely paretic muscle group after stroke. There is also preliminary evidence that corticospinal adaptations may accompany these gains.

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.

Resting-state functional connectivity and its association with multiple domains of upper-extremity function in chronic stroke.

BACKGROUND: Recent work has shown that resting-state functional connectivity (rsFC) between homotopic, motor-related brain regions is associated with upper-extremity control early after stroke. OBJECTIVES: This study examined various patterns of rsFC in chronic stroke, a time at which extensive neural reorganization has occurred. Associations between homotopic somatomotor connectivity and clinical measures, representing separate domains of upper-extremity function, were determined. METHODS: A total of 19 persons ≥6 months poststroke participated. Four connectivity patterns within a somatomotor network were quantified using functional magnetic resonance imaging. Upper-extremity gross muscle activation, control, and real-world use were evaluated with the Motricity Index, Action Research Arm Test, and accelerometry, respectively. RESULTS: Connectivity between homotopic regions was stronger than that in the contralesional and ipsilesional hemispheres. No differences in connectivity strength were noted between homotopic pairs, indicating that a specific brain structure was not driving somatomotor network connectivity. Homotopic connectivity was significantly associated with both upper-extremity control (r = 0.53; P= .02) and real-world use (r = 0.54; P= .02); however, there was no association with gross muscle activation (r = 0.23; P=.34). The combination of clinical measures accounted for 40% of the variance in rsFC (= .05). CONCLUSIONS: The results reported here expand on previous findings, indicating that homotopic rsFC persists in chronic stroke and discriminates between varying levels of upper-extremity control and real-world use. Further work is needed to evaluate its adequacy as a biomarker of motor recovery following stroke.

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

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.

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.

Rehabilitation after stroke: current state of the science.

Stroke rehabilitation is evolving into a clinical field based on the neuroscience of recovery and restoration. There has been substantial growth in the number and quality of clinical trials performed. Much effort now is directed toward motor restoration and is being led by trials of constraint-induced movement therapy. Although the results do not necessarily support that constraint-induced movement therapy is superior to other training methods, this treatment has become an important vehicle for developing clinical trial methods and studying the physiology underlying activity-based rehabilitation strategies. Other promising interventions include robotic therapy delivery, magnetic and electrical cortical stimulation, visualization, and constraint-driven aphasia therapies. Amphetamine has not been demonstrated to be effective, and studies of other pharmacologic agents are still preliminary. Future studies will incorporate refinements in clinical trial methods and improved activity- and technology-based interventions.

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.