Lisa Röhrig

One of the most pressing questions after a stroke is whether an individual patient will recover in the long term. Previous studies demonstrated that spatial neglect—a common cognitive deficit after right hemispheric stroke—is a strong predictor for poor performance on a wide range of everyday tasks and for resistance to rehabilitation. The possibility of predicting long-term prognosis of spatial neglect is therefore of great relevance. The aim of the present study was to test the prognostic value of different imaging and non-imaging features from right hemispheric stroke patients: individual demographics (age, sex), initial neglect severity and acute lesion information (size, location). Patients’ behaviour was tested twice in the acute and the chronic phases of stroke and prediction models were built using machine learning-based algorithms with repeated nested cross-validation and feature selection. Model performances indicate that demographic information seemed less beneficial. The best variable combination comprised individual neglect severity in the acute phase of stroke, together with lesion location and size. The latter were based on individual lesion overlaps with a previously proposed chronic neglect region of interest that covers anterior parts of the superior and middle temporal gyri and the basal ganglia. These variables achieved a remarkably high level of accuracy by explaining 66% of the total variance of neglect patients, making them promising features in the prediction of individual outcome prognosis. An online tool is provided with which our algorithm can be used for individual outcome predictions (https://niivue.github.io/niivue-neglect/).

Pusher syndrome is a disorder of postural control after stroke. Patients show a mismatch in their perception of (almost preserved) visual and (pathologically tilted) postural verticality. In order to reduce this mismatch, we developed a novel head-mounted Tilted Reality Device (TRD). It presents patients visual footage of their actual surroundings but tilted to one side rather than upright. We investigated its usability and possible limitations in its use for the treatment of pusher patients in two samples of healthy participants with an average age of 26.4 years and 63.9 years respectively. Individuals from both age groups showed similar levels of tolerance to prolonged exposure to the tilted visual environment for an average of 40.4 min while walking around in the hospital. The TRD was found to be comfortable and not frustrating whilst wearing, but somewhat challenging in terms of technical handling, particularly for older participants. At the end of the maximally tolerated exposure time participants of both groups experienced some feelings of discomfort, like dizziness or increased stomach awareness, which disappeared rapidly after terminating TRD exposure. Our TRD appears to be a practical device especially for an older population, like pusher patients. While users must be aware of the possibility of side effects, these should be balanced against the benefits of future use for rehabilitation purposes.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, affect a wide range of cognitive dysfunctions, including spatial neglect. The latter is a disorder of spatial attention and exploration typically after right hemisphere brain damage. To explore the impact of WMH on neglect‐related structural disconnections, the present study investigated the indirectly quantified structural disconnectome induced by either stroke lesion alone, WMH alone, or their combination. Furthermore, we compared different measures of structural disconnection—voxel‐wise, pairwise, tract‐wise, and parcel‐wise—to identify neural correlates and predict acute neglect severity. We observed that WMH‐derived disconnections alone were not associated with neglect behavior. However, when combined with disconnections derived from individual stroke lesions, pre‐stroke WMH contributed to post‐stroke neglect severity by affecting right frontal and subcortical substrates, like the middle frontal gyrus, basal ganglia, thalamus, and the fronto‐pontine tract. Predictive modeling demonstrated that voxel‐wise disconnection data outperformed other measures of structural disconnection, explaining 42% of the total variance; interestingly, the best model used predictors of stroke‐based disconnections only. We conclude that prestroke alterations in the white matter microstructure due to WMH contribute to poststroke deficits in spatial attention, likely by impairing the integrity of human attention networks.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, affect a wide range of cognitive dysfunctions, including spatial neglect. The latter is a disorder of spatial attention and exploration typically after right hemisphere brain damage. To explore the impact of WMH on neglect-related structural disconnections, the present study investigated the indirectly quantified structural disconnectome induced by either stroke lesion alone, WMH alone, or their combination. Further, we compared different measures of structural disconnections – voxel-wise, pairwise, tract-wise, and parcel-wise – to identify neural correlates and predict acute neglect severity. We observed that WMH-derived disconnections alone were not associated to neglect behavior. However, when combined with disconnections derived from individual stroke lesions, pre-stroke WMH contributed to post-stroke neglect severity by affecting right frontal and subcortical substrates, like the middle frontal gyrus, basal ganglia, thalamus, and the fronto-pontine tract. Predictive modeling demonstrated that voxel-wise disconnection data outperformed other measures of structural disconnection, explaining 42% of the total variance. Compared to using stroke lesion anatomy, prediction performance can be improved by either estimating stroke-based structural disconnections or delineating the combined anatomy of stroke lesion and WMH. We conclude that pre-stroke alterations in the white matter microstructure due to WMH contribute to post-stroke deficits in spatial attention, likely by impairing the integrity of human attention networks.

Introduction For limb apraxia ‒ a heterogeneous disorder of higher motor cognition following stroke ‒ an enduring debate has arisen regarding the existence of dissociating neural correlates for finger and hand gestures in the left hemisphere. We re-assessed this question asking whether previous attempts analysing pooled samples of patients with deficits in only one and patients with deficits in both imitation types might have led to systematically biased results. Methods We conducted frequentist and Bayesian, voxelwise and regionwise lesion symptom mappings on a pooled sample (N=96) and subsamples containing only shared and only isolated hand and finger imitation deficits and respective controls. Results Anatomical analyses on the isolated sample reinforced a cortical dissociation of finger deficits (located more anteriorly) and hand deficits (located more posteriorly). The presence of patients with shared deficits did indeed dilute associations that appeared stronger in the respective isolated samples. Also, brain regions truly associated with hand imitation deficits showed a positive bias for finger imitation deficits, when the sample contained patients with shared deficits. In addition, our frequentist parameters uncovered that some of our Bayesian evidence supported reverse associations (damage protecting from rather than increasing the deficit). Discussion Joint analyses of patients with shared and isolated imitation deficits do indeed lead to biases, which may explain why some previous studies have failed to detect the actual neural dissociation between hand and finger imitation deficits.

Pusher syndrome is a disorder of postural control after stroke. Patients show a mismatch in their perception of (almost preserved) visual and (pathologically tilted) postural verticality. In order to reduce this mismatch, we developed a novel head-mounted ‘Tilted Reality Device (TRD)’. It presents patients visual footage of their actual surroundings but tilted to one side rather than upright. We investigated its usability and possible limitations in its use for the treatment of pusher patients in two samples of healthy participants with an average age of 26.4 years and 63.9 years respectively. Individuals from both age groups showed similar levels of tolerance to prolonged exposure to the tilted visual environment for an average of 40.4 minutes while walking around in the hospital. The TRD was found to be comfortable and not frustrating whilst wearing, but somewhat challenging in terms of technical handling, particularly for older participants. At the end of the maximally tolerated exposure time participants of both groups experienced some feelings of discomfort, like dizziness or increased stomach awareness, which disappeared rapidly after terminating TRD exposure. Our TRD appears to be a practical device especially for an older population, like pusher patients. While users must be aware of the possibility of side effects, these should be balanced against the benefits of future use for rehabilitation purposes.

One of the most pressing questions after a stroke is whether an individual patient will recover in the long-term. Previous studies demonstrated that spatial neglect – a common behavioral deficit after right hemispheric stroke – is a strong predictor for poor performance on a wide range of everyday tasks and for resistance to rehabilitation. The possibility of predicting long-term prognosis of spatial neglect is therefore of great relevance. The aim of the present study was to test the prognostic value of different imaging and non-imaging features from right hemispheric stroke patients: individual demographics (age, sex), initial neglect severity, and acute lesion information (size, location). Patients’ behavior was tested twice in the acute and the chronic phases of stroke and prediction models were built using machine learning-based algorithms with repeated nested cross-validation and feature selection. Model performances indicate that demographic information seemed less beneficial. The best variable combination comprised individual neglect severity in the acute phase of stroke, together with lesion location and size. The latter were based on individual lesion overlaps with a previously proposed chronic neglect region-of-interest (ROI) that covers anterior parts of the superior and middle temporal gyri and the basal ganglia. These variables achieved a remarkably high level of accuracy by explaining 66% of the total variance of neglect patients, making them promising features in the prediction of individual outcome prognosis.

The development of new approaches indirectly measuring the structural disconnectome has recently led to an increase in studies investigating pairwise structural disconnections following brain damage. Previous studies jointly analyzed patients with left hemispheric and patients with right hemispheric lesions when investigating a behavior of interest. An alternative approach would be to perform analyses separated by hemisphere, which has been applied in only a minority of studies to date. The present simulation study investigated whether joint or separate analyses (or both equally) are appropriate to reveal the ground truth disconnections. In fact, both approaches resulted in very different patterns of disconnection. In contrast to analyses separated by hemisphere, joint analyses introduced a bias to the disadvantage of intra‐hemispheric disconnections. Intra‐hemispheric disconnections were statistically underpowered in the joint analysis and thus surpassed the significance threshold with more difficulty compared to inter‐hemispheric disconnections. This statistical imbalance was also shown by a greater number of significant inter‐hemispheric than significant intra‐hemispheric disconnections. This bias from joint analyses is based on mechanisms similar to those underlying the “partial injury problem.” We therefore conclude that pairwise structural disconnections in patients with unilateral left hemispheric and with unilateral right hemispheric lesions exhibiting a specific behavior (or disorder) of interest should be studied separately by hemisphere rather than in a joint analysis.

The development of new approaches indirectly measuring the structural disconnectome has recently led to an increase in studies investigating pairwise structural disconnections following brain damage. Previous studies jointly analyzed patients with left hemispheric and patients with right hemispheric lesions when investigating a behavior of interest. An alternative approach would be to perform analyses separated by hemisphere, which has been applied in only a minority of studies to date. The present simulation study investigated whether joint or separate analyses (or both equally) are appropriate to reveal the ground truth disconnections. In fact, both approaches resulted in very different patterns of disconnection. In contrast to analyses separated by hemisphere, joint analyses introduced a bias to the disadvantage of intra-hemispheric disconnections. Intra-hemispheric disconnections were statistically underpowered in the joint analysis and thus surpassed the significance threshold with more difficulty compared to inter-hemispheric disconnections. This statistical imbalance was also shown by a greater number of significant inter-hemispheric than significant intra-hemispheric disconnections. This bias from joint analyses is based on mechanisms similar to those underlying the ‘partial injury problem’. We therefore conclude that pairwise structural disconnections in patients with unilateral left hemispheric and with unilateral right hemispheric lesions exhibiting a specific behavior (or disorder) of interest should be studied separately by hemisphere rather than in a joint analysis.

The presence of both isolated thalamic and isolated cortical lesions have been reported in the context of pusher syndrome—a disorder characterized by a disturbed perception of one’s own upright body posture, following unilateral left- or right-sided stroke. In recent times, indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one’s own postural upright. Lesion network symptom mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in pusher patients with cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnection mapping identified posterior thalamic disconnection to temporal, pre-, post- and paracentral regions. Fibre tracking between the thalamic and cortical pusher lesion hotspots indicated that in cortical lesions of patients with pusher syndrome, it is disconnectivity to the posterior thalamus caused by accompanying white matter damage, rather than the direct cortical lesions themselves, that lead to the emergence of pusher syndrome. Our analyses thus offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections. Pusher syndrome seems to be a consequence of direct damage or of disconnection of the posterior thalamus.