Severity-Dependent Interhemispheric White Matter Connectivity Predicts Poststroke Neglect Recovery.

Left-sided spatial neglect is a very common and challenging issue after right-hemispheric stroke, which strongly and negatively affects daily living behavior and recovery of stroke survivors. The mechanisms underlying recovery of spatial neglect remain controversial, particularly regarding the involvement of the intact, contralesional hemisphere, with potential contributions ranging from maladaptive to compensatory. In the present prospective, observational study, we assessed neglect severity in 54 right-hemispheric stroke patients (32 male; 22 female) at admission to and discharge from inpatient neurorehabilitation. We demonstrate that the interaction of initial neglect severity and spared white matter (dis)connectivity resulting from individual lesions (as assessed by diffusion tensor imaging, DTI) explains a significant portion of the variability of poststroke neglect recovery. In mildly impaired patients, spared structural connectivity within the lesioned hemisphere is sufficient to attain good recovery. Conversely, in patients with severe impairment, successful recovery critically depends on structural connectivity within the intact hemisphere and between hemispheres. These distinct patterns, mediated by their respective white matter connections, may help to reconcile the dichotomous perspectives regarding the role of the contralesional hemisphere as exclusively compensatory or not. Instead, they suggest a unified viewpoint wherein the contralesional hemisphere can - but must not necessarily - assume a compensatory role. This would depend on initial impairment severity and on the available, spared structural connectivity. In the future, our findings could serve as a prognostic biomarker for neglect recovery and guide patient-tailored therapeutic approaches.

Joint impact on attention, alertness and inhibition of lesions at a frontal white matter crossroad.

In everyday life, information from different cognitive domains-such as visuospatial attention, alertness and inhibition-needs to be integrated between different brain regions. Early models suggested that completely segregated brain networks control these three cognitive domains. However, more recent accounts, mainly based on neuroimaging data in healthy participants, indicate that different tasks lead to specific patterns of activation within the same, higher-order and 'multiple-demand' network. If so, then a lesion to critical substrates of this common network should determine a concomitant impairment in all three cognitive domains. The aim of the present study was to critically investigate this hypothesis, i.e. to identify focal stroke lesions within the network that can concomitantly affect visuospatial attention, alertness and inhibition. We studied an unselected sample of 60 first-ever right-hemispheric, subacute stroke patients using a data-driven, bottom-up approach. Patients performed 12 standardized neuropsychological and oculomotor tests, four per cognitive domain. A principal component analysis revealed a strong relationship between all three cognitive domains: 10 of 12 tests loaded on a first, common component. Analysis of the neuroanatomical lesion correlates using different approaches (i.e. voxel-based and tractwise lesion-symptom mapping, disconnectome maps) provided convergent evidence on the association between severe impairment of this common component and lesions at the intersection of superior longitudinal fasciculus II and III, frontal aslant tract and, to a lesser extent, the putamen and inferior fronto-occipital fasciculus. Moreover, patients with a lesion involving this region were significantly more impaired in daily living cognition, which provides an ecological validation of our results. A probabilistic functional atlas of the multiple-demand network was performed to confirm the potential relationship between patients' lesion substrates and observed cognitive impairments as a function of the multiple-demand network connectivity disruption. These findings show, for the first time, that a lesion to a specific white matter crossroad can determine a concurrent breakdown in all three considered cognitive domains. Our results support the multiple-demand network model, proposing that different cognitive operations depend on specific collaborators and their interaction, within the same underlying neural network. Our findings also extend this hypothesis by showing (i) the contribution of superior longitudinal fasciculus and frontal aslant tract to the multiple-demand network; and (ii) a critical neuroanatomical intersection, crossed by a vast amount of long-range white matter tracts, many of which interconnect cortical areas of the multiple-demand network. The vulnerability of this crossroad to stroke has specific cognitive and clinical consequences; this has the potential to influence future rehabilitative approaches.

A case study of left visual neglect after right pontine lesion: pathophysiological evidence for the infratentorial involvement in human visual attention.

Hemispatial neglect, the inability to attend to the contralesional side of space, is the most common disturbance of visuospatial attention. Both hemispatial neglect and visuospatial attention are typically associated with extended cortical networks. Nevertheless, recent accounts challenge this so-called corticocentric view and postulate the participation of structures well beyond the telencephalic cortex, in particular advocating the role of the brainstem. However, to the best of our knowledge, hemispatial neglect after a brainstem lesion has not yet been described. We describe, for the first time in a human, the occurrence and remission of contralesional visual hemispatial neglect after a focal lesion in the right pons. Hemispatial neglect was assessed by means of video-oculography during free visual exploration, a very sensitive and established method, and its remission was followed up until 3 wk after stroke. Moreover, by means of a lesion-deficit approach complemented by imaging, we identify a pathophysiological mechanism involving the disconnection of cortico-ponto-cerebellar and/or tecto-cerebellar-tectal pathways passing through the pons. Our findings offer, for the first time in a human, causal, lesion-based support for recent seminal accounts postulating the role of infratentorial structures participating in the activity of cerebral cortical attentional networks mediating attentional processes.NEW & NOTEWORTHY Visuospatial attention and its most common disturbance, hemispatial neglect, are typically associated with extended cortical networks. However, recent accounts challenge this corticocentric view and advocate the role of infratentorial structures. We describe, for the first time in a human, the occurrence of contralesional visual hemispatial neglect after a focal lesion in the right pons. We provide causal, lesion-based evidence for a pathophysiological mechanism involving the disconnection of cortico-ponto-cerebellar and/or tecto-cerebellar-tectal pathways passing through the pons.

Feasibility of a combined intermittent theta-burst stimulation and video game-based dexterity training in Parkinson's disease.

BACKGROUND: Persons with Parkinson's disease (PD) often exhibit difficulties with dexterity during the performance of activities of daily living (ADL), inter alia due to dysfunctional supplementary motor area (SMA). Combined intermittent theta-burst stimulation (iTBS) over the SMA followed by video game-based training (VBT) may therefore improve dexterity related ADL. The VBT may induce high flow levels related to high performance during the training. The aim of this study is to evaluate the feasibility of a combined iTBS-VBT intervention in persons with PD. METHODS: A total of nine persons with PD (mean age 63.3 ± 8.76 years) with self-reported difficulties with dexterity related ADL were included in this pilot iTBS-VBT study. All participants received either iTBS or sham stimulation over the SMA followed by a 45-min VBT, three times a week for a total of three weeks. Feasibility was measured by means of the adherence rate and the system usability (System Usability Scale). Moreover, flow was measured after the last VBT session. RESULTS: Adherence rate was excellent with 100%. High system usability scores (i.e., mean 80%, range 55-97.5) and a significant Spearman's correlation with the Flow State Scale (r = .762, p = .017) further point to the high feasibility of the VBT. Neither demographic variables nor difficulties in dexterity related ADL affected the usability of the VBT. CONCLUSION: This study demonstrates the high feasibility of a combined iTBS-VBT intervention. Moreover, the level of self-reported usability was related to flow experience. Whether this kind of combined iTBS-VBT intervention improves dexterity will be evaluated in a randomized controlled trial. Trial registration clincaltrials.gov NCT04699149, date of registration 1. June 2021.

Theta burst stimulation in neglect after stroke: functional outcome and response variability origins.

Spatial neglect is a strong and negative predictor of general functional outcome after stroke, and its therapy remains a challenge. Whereas inhibitory non-invasive brain stimulation over the contralesional, intact hemisphere has generally been shown to ameliorate neglect on a group level, a conspicuous variability of the effects at the individual level is typically observed. We aimed to assess the characteristics and determinants of the effects of inhibitory non-invasive brain stimulation in neglect, identifying which patients would respond to this therapeutic approach and which not. To this end, we prospectively included 60 patients with a subacute right-hemispheric stroke. In 30 patients with spatial neglect, continuous theta burst stimulation (cTBS) was applied over the left posterior parietal cortex in a randomized clinical trial, either in eight or 16 trains, or as sham stimulation. Thirty patients without neglect served as a control group. Neglect severity was measured with a neuropsychological test battery and the Catherine Bergego Scale, at admission to and at discharge from inpatient neurorehabilitation, as well as at 3 months follow-up. General functional outcome was assessed by means of the Functional Independence Measure and the Lucerne ICF-based Multidisciplinary Observation Scale. The impact of clinical and demographic factors was evaluated, and the influence of lesion location and extension was assessed by means of voxel-based lesion-symptom mapping. On a group level, both cTBS protocols (i.e. eight and 16 trains) significantly reduced neglect severity in both the Catherine Bergego Scale and the neuropsychological tests, at discharge and 3 months later. Furthermore, cTBS significantly improved general functional outcome. On an individual level, hierarchical cluster and voxel-based lesion-symptom mapping analyses revealed that the variability in the responses to cTBS is determined by the integrity of interhemispheric connections within the corpus callosum, in particular parieto-parietal connections. In cTBS responders, in whom neglect and general functional outcome were significantly improved, the corpus callosum was intact, whereas this was not the case in cTBS non-responders. Moreover, analyses based on the proportional recovery rule and the Maugeri predictive stroke recovery model showed that the recovery of neglect and of the activities of daily living was accelerated only in cTBS responders. Furthermore, the level of activities of daily living recovery of these neglect patients was brought close to the one of right-hemispheric control patients without neglect. Hence, in neglect patients with intact interhemispheric connectivity, cTBS over the contralesional posterior parietal cortex significantly improves and accelerates neglect recovery and, associated with it, general functional outcome.

Re-fixation and perseveration patterns in neglect patients during free visual exploration.

The literature suggests that neglect patients not only show impairments in directing attention toward the left, contralesional space, but also present with perseverative behavior. Moreover, previous studies described re-fixations during visual search tasks, and interpreted this finding as an impairment of spatial working memory. The aim of the present study was to study re-fixations and perseverations (i.e., recurrent re-fixations to same locations) during free visual exploration, a task with high ecological validity. We hypothesized that: (1) neglect patient would perform re-fixations more frequently than healthy controls within the right hemispace; and, (2) the re-fixation behavior of neglect patients would be characterized by perseverative fixations. To test these hypotheses, we assessed 22 neglect patients and 23 healthy controls, measuring their eye movements during free exploration of naturalistic pictures. The results showed that neglect patients tend to re-fixate locations within the ipsilesional hemispace when they freely explore naturalistic pictures. Importantly, the saliency of discrete locations within the pictures has a stronger influence on fixation behavior within the contralesional than within the ipsilesional hemispace in neglect patients. Finally, the results indicated that, for re-fixations, saliency plays a more important role within the contralesional than the ipsilesional hemispace. Moreover, we found evidence that re-fixation behavior of neglect patients is characterized by frequent recurrent re-fixations back to the same spatial locations which may be interpreted as perseverations. Hence, with the present study, we could better elucidate the mechanism leading to re-fixations and perseverative behavior during free visual exploration in neglect patients.

Intracortical recordings reveal vision-to-action cortical gradients driving human exogenous attention.

Exogenous attention, the process that makes external salient stimuli pop-out of a visual scene, is essential for survival. How attention-capturing events modulate human brain processing remains unclear. Here we show how the psychological construct of exogenous attention gradually emerges over large-scale gradients in the human cortex, by analyzing activity from 1,403 intracortical contacts implanted in 28 individuals, while they performed an exogenous attention task. The timing, location and task-relevance of attentional events defined a spatiotemporal gradient of three neural clusters, which mapped onto cortical gradients and presented a hierarchy of timescales. Visual attributes modulated neural activity at one end of the gradient, while at the other end it reflected the upcoming response timing, with attentional effects occurring at the intersection of visual and response signals. These findings challenge multi-step models of attention, and suggest that frontoparietal networks, which process sequential stimuli as separate events sharing the same location, drive exogenous attention phenomena such as inhibition of return.

The connectional anatomy of visual mental imagery: evidence from a patient with left occipito-temporal damage.

Most of us can use our "mind's eye" to mentally visualize things that are not in our direct line of sight, an ability known as visual mental imagery. Extensive left temporal damage can impair patients' visual mental imagery experience, but the critical locus of lesion is unknown. Our recent meta-analysis of 27 fMRI studies of visual mental imagery highlighted a well-delimited region in the left lateral midfusiform gyrus, which was consistently activated during visual mental imagery, and which we called the Fusiform Imagery Node (FIN). Here, we describe the connectional anatomy of FIN in neurotypical participants and in RDS, a right-handed patient with an extensive occipito-temporal stroke in the left hemisphere. The stroke provoked right homonymous hemianopia, alexia without agraphia, and color anomia. Despite these deficits, RDS had normal subjective experience of visual mental imagery and reasonably preserved behavioral performance on tests of visual mental imagery of object shape, object color, letters, faces, and spatial relationships. We found that the FIN was spared by the lesion. We then assessed the connectional anatomy of the FIN in the MNI space and in the patient's native space, by visualizing the fibers of the inferior longitudinal fasciculus (ILF) and of the arcuate fasciculus (AF) passing through the FIN. In both spaces, the ILF connected the FIN with the anterior temporal lobe, and the AF linked it with frontal regions. Our evidence is consistent with the hypothesis that the FIN is a node of a brain network dedicated to voluntary visual mental imagery. The FIN could act as a bridge between visual information and semantic knowledge processed in the anterior temporal lobe and in the language circuits.

Anterior insula and inferior frontal gyrus: where ventral and dorsal visual attention systems meet.

The clinical link between spatial and non-spatial attentional aspects in patients with hemispatial neglect is well known; in particular, an increase in alerting can transitorily help to allocate attention towards the contralesional side. In models of attention, this phenomenon is postulated to rely on an interaction between ventral and dorsal cortical networks, subtending non-spatial and spatial attentional aspects, respectively. However, the exact neural underpinnings of the interaction between these two networks are still poorly understood. In the present study, we included 80 right-hemispheric patients with subacute stroke (50% women; age range: 24-96), 33 with and 47 without neglect, as assessed by paper-pencil cancellation tests. The patients performed a computerized task in which they were asked to respond as quickly as possible by button-press to central targets, which were either preceded or not preceded by non-spatial, auditory warning tones. Reaction times in the two different conditions were measured. In neglect patients, a warning tone, enhancing activity within the ventral attentional 'alerting' network, could boost the reaction (in terms of shorter reaction times) of the dorsal attentional network to a visual stimulus up to the level of patients without neglect. Critically, using voxel-based lesion-symptom mapping analyses, we show that this effect significantly depends on the integrity of the right anterior insula and adjacent inferior frontal gyrus, i.e., right-hemispheric patients with lesions involving these areas were significantly less likely to show shorter reaction times when a warning tone was presented prior to visual target appearance. We propose that the right anterior insula and inferior frontal gyrus are a critical hub through which the ventral attentional network can 'alert' and increase the efficiency of the activity of the dorsal attentional network.

Video-Oculography During Free Visual Exploration to Detect Right Spatial Neglect in Left-Hemispheric Stroke Patients With Aphasia: A Feasibility Study.

Spatial neglect has been shown to occur in 17-65% of patients after acute left-hemispheric stroke. One reason for this varying incidence values might be that left-hemispheric stroke is often accompanied by aphasia, which raises difficulties in assessing attention deficits with conventional neuropsychological tests entailing verbal instructions. Video-oculography during free visual exploration (FVE) requires only little understanding of simple non-verbal instruction and has been shown to be a sensitive and reliable tool to detect spatial neglect in patients with right-hemispheric stroke. In the present study, we aimed to investigate the feasibility of FVE to detect neglect in 10 left-hemispheric stroke patients with mild to severe aphasia as assessed by means of the Token Test, Boston Naming Test and Aachener Aphasie Test. The patient's individual deviation between eye movement calibration and validation was recorded and compared to 20 age-matched healthy controls. Furthermore, typical FVE parameters such as the landing point of the first fixation, the mean gaze position (in ° of visual angle), the number and duration of visual fixations and the mean visual exploration area were compared between groups. In addition, to evaluate for neglect, the Bells cancellation test was performed and neglect severity in daily living was measured by means of the Catherine Bergego Scale (CBS). Our results showed that the deviation between calibration and validation did not differ between aphasia patients and healthy controls highlighting its feasibility. Furthermore, FVE revealed the typical neglect pattern with a significant leftward shift in visual exploration bahaviour, which highly correlated with neglect severity as assessed with CBS. The present study provides evidence that FVE has the potential to be used as a neglect screening tool in left-hemispheric stroke patients with aphasia in which compliance with verbal test instructions may be compromised by language deficits.

The right anterior temporal lobe critically contributes to magnitude knowledge.

Cognitive estimation is a mental ability applied to solve numerical problems when precise facts are unknown, unavailable or impractical to calculate. It has been associated with several underlying cognitive components, most often with executive functions and semantic memory. Little is known about the neural correlates of cognitive estimation. To address this issue, the present cross-sectional study applied lesion-symptom mapping in a group of 55 patients with left hemineglect due to right-hemisphere stroke. Previous evidence suggests a high prevalence of cognitive estimation impairment in these patients, as they might show a general bias towards large magnitudes. Compared to 55 age- and gender-matched healthy controls, the patient group demonstrated impaired cognitive estimation. However, the expected large magnitude bias was not found. Lesion-symptom mapping related their general estimation impairment predominantly to brain damage in the right anterior temporal lobe. Also critically involved were the right uncinate fasciculus, the anterior commissure and the right inferior frontal gyrus. The main findings of this study emphasize the role of semantic memory in cognitive estimation, with reference to a growing body of neuroscientific literature postulating a transmodal hub for semantic cognition situated in the bilateral anterior temporal lobe. That such semantic hub function may also apply to numerical knowledge is not undisputed. We here propose a critical contribution of the right anterior temporal lobe to at least one aspect of number processing, i.e. the knowledge about real-world numerical magnitudes.

Immersive 3D Virtual Reality Cancellation Task for Visual Neglect Assessment: A Pilot Study.

Background: Unilateral spatial neglectis an attention disorder frequently occurring after a right-hemispheric stroke. Neglect results in a reduction in qualityof life and performance in activities of daily living. With current technical improvements in virtual reality (VR) technology, trainingwith stereoscopic head-mounted displays (HMD) has become a promising new approach for the assessment and the rehabilitation of neglect. The focus of this pilot study was to develop and evaluate a simple visual search task in VR for HMD. The VR system was tested regarding feasibility, acceptance, and potential adverse effects in healthy controls and right-hemispheric stroke patients with and without neglect. Methods: The VR system consisted of two main components, a head-mounted display to present the virtual environment, and a hand-held controller for the interaction with the latter. The task followed the rationale of diagnostic paper-pencil cancellation tasks; i.e., the participants were asked to search targets among distractors. However, instead of a two-dimensional setup, the targets and distractors were arranged in three dimensions, in a sphere around the subject inside its field of view. Usability and acceptance of the task, as well as the performance in the latter, were tested in 15 right-hemispheric subacute stroke patients (10 of whom with and five of whom without unilateral spatial neglect; mean age: 67.1 ± 10.5 years) and 35 age-matched healthy controls. Results: System usability and acceptance were rated as high both in stroke patients and healthy controls, close to the maximum score of the questionnaire scale. No relevant adverse effects occurred. There was a high correlation (r = 0.854, p = 0.002) between the Center of Cancellation [an objective neglect measure) calculated from a paper-pencil cancellation task (Sensitive Neglect Test (SNT)] and the newly developed VR cancellation task. Conclusion: Overall, the developed visual search task in the tested VR system is feasible, well-accepted, enjoyable, and does not evoke any significant negative effects, both for healthy controls and for stroke patients. Findings for task performance show that the ability of the VR cancellation to detect neglect in stroke patients is similar to paper-pencil cancellation tasks.

Eyetracking during free visual exploration detects neglect more reliably than paper-pencil tests.

Neglect after stroke is most accurately diagnosed by a systematic, ecological observation during everyday behaviour using the Catherine Bergego Scale (CBS). However, the CBS is time-consuming and often omitted in clinical settings, especially stroke units. In this study, we aimed to explore if video-oculography during free visual exploration (FVE), which can be performed in few minutes, is sensitive in mirroring neglect in everyday behaviour and whether it is more sensitive than conventional neuropsychological paper-pencil tests. In this retrospective, observational, multicentre study, we identified 78 patients in our database with subacute right-hemispheric stroke, with and without neglect in everyday behaviour, diagnosed by the CBS, who also performed FVE. 40 age-matched healthy participants served as controls. The sensitivity to detect neglect was compared between FVE (i.e., mean gaze position on the horizontal axis) and conventional neuropsychological paper-pencil tests, i.e., Random Shape Cancellation, Line Bisection, Two-Part Picture, Bells, Star Cancellation, Letter Cancellation, Sensitive Neglect, and Five-Point. FVE correctly identified neglect in 85%of patients, with an AUC-value of .922 in ROC-analysis. Conventional neuropsychological paper-pencil tests, considered alone or in combination, showed heterogeneous results, and identified neglect significantly less often (21.74%-68.75%). Moreover, there was a significant correlation between mean gaze position and CBS scores, providing evidence for the relationship between FVE and neglect in everyday behaviour. Furthermore, VLSM analyses suggested that the absence of a pathological rightward bias in FVE might depend on the integrity of the second branch of the right Superior Longitudinal Fascicle (SLF II), a white-matter tract connecting cortical areas critical for visual attention. Video-oculography during FVE has a high sensitivity and specificity to diagnose neglect after stroke and it is more sensitive than conventional neuropsychological paper-pencil tests. It can be performed in short time and has the potential to be used as a fast and accurate screening tool that allows the initiation of comprehensive neuropsychological diagnostics and therapy from early on.