The neuroanatomy of visual extinction following right hemisphere brain damage: Insights from multivariate and Bayesian lesion analyses in acute stroke.

Multi-target attention, that is, the ability to attend and respond to multiple visual targets presented simultaneously on the horizontal meridian across both visual fields, is essential for everyday real-world behaviour. Given the close link between the neuropsychological deficit of extinction and attentional limits in healthy subjects, investigating the anatomy that underlies extinction is uniquely capable of providing important insights concerning the anatomy critical for normal multi-target attention. Previous studies into the brain areas critical for multi-target attention and its failure in extinction patients have, however, produced heterogeneous results. In the current study, we used multivariate and Bayesian lesion analysis approaches to investigate the anatomical substrate of visual extinction in a large sample of 108 acute right hemisphere stroke patients. The use of acute stroke patient data and multivariate/Bayesian lesion analysis approaches allowed us to address limitations associated with previous studies and so obtain a more complete picture of the functional network associated with visual extinction. Our results demonstrate that the right temporo-parietal junction (TPJ) is critically associated with visual extinction. The Bayesian lesion analysis additionally implicated the right intraparietal sulcus (IPS), in line with the results of studies in neurologically healthy participants that highlighted the IPS as the area critical for multi-target attention. Our findings resolve the seemingly conflicting previous findings, and emphasise the urgent need for further research to clarify the precise cognitive role of the right TPJ in multi-target attention and its failure in extinction patients.

Beyond visual integration: sensitivity of the temporal-parietal junction for objects, places, and faces.

One important role of the TPJ is the contribution to perception of the global gist in hierarchically organized stimuli where individual elements create a global visual percept. However, the link between clinical findings in simultanagnosia and neuroimaging in healthy subjects is missing for real-world global stimuli, like visual scenes. It is well-known that hierarchical, global stimuli activate TPJ regions and that simultanagnosia patients show deficits during the recognition of hierarchical stimuli and real-world visual scenes. However, the role of the TPJ in real-world scene processing is entirely unexplored. In the present study, we first localized TPJ regions significantly responding to the global gist of hierarchical stimuli and then investigated the responses to visual scenes, as well as single objects and faces as control stimuli. All three stimulus classes evoked significantly positive univariate responses in the previously localized TPJ regions. In a multivariate analysis, we were able to demonstrate that voxel patterns of the TPJ were classified significantly above chance level for all three stimulus classes. These results demonstrate a significant involvement of the TPJ in processing of complex visual stimuli that is not restricted to visual scenes and that the TPJ is sensitive to different classes of visual stimuli with a specific signature of neuronal activations.

Reducing alertness does not affect line bisection bias in neurotypical participants.

Alertness, or one's general readiness to respond to stimulation, has previously been shown to affect spatial attention. However, most of this previous research focused on speeded, laboratory-based reaction tasks, as opposed to the classical line bisection task typically used to diagnose deficits of spatial attention in clinical settings. McIntosh et al. (Cogn Brain Res 25:833-850, 2005) provide a form of line bisection task which they argue can more sensitively assess spatial attention. Ninety-eight participants were presented with this line bisection task, once with and once without spatial cues, and both before and after a 50-min vigilance task that aimed to decrease alertness. A single participant was excluded due to potentially inconsistent behaviour in the task, leaving 97 participants for the full analyses. While participants were, on a group level, less alert after the 50-min vigilance task, they showed none of the hypothesised effects of reduced alertness on spatial attention in the line bisection task, regardless of with or without spatial cues. Yet, they did show the proposed effect of decreased alertness leading to a lower level of general attention. This suggests that alertness has no effect on spatial attention, as measured by a line bisection task, in neurotypical participants. We thus conclude that, in neurotypical participants, the effect of alertness on spatial attention can be examined more sensitively with tasks requiring a speeded response compared to unspeeded tasks.

Thalamocortical disconnection involved in pusher syndrome.

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.

The need for hemispheric separation in pairwise structural disconnection studies.

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.

Spatial neglect in the digital age: Influence of presentation format on patients' test behavior.

OBJECTIVE: Computerized neglect tests could significantly deepen our disorder-specific knowledge by effortlessly providing additional behavioral markers that are hardly or not extractable from existing paper-and-pencil versions. This study investigated how testing format (paper versus digital), and screen size (small, medium, large) affect the Center of cancelation (CoC) in right-hemispheric stroke patients in the Letters and the Bells cancelation task. Our second objective was to determine whether a machine learning approach could reliably classify patients with and without neglect based on their search speed, search distance, and search strategy. METHOD: We compared the CoC measure of right hemisphere stroke patients with neglect in two cancelation tasks across different formats and display sizes. In addition, we evaluated whether three additional parameters of search behavior that became available through digitization are neglect-specific behavioral markers. RESULTS: Patients' CoC was not affected by test format or screen size. Additional search parameters demonstrated lower search speed, increased search distance, and a more strategic search for neglect patients than for control patients without neglect. CONCLUSION: The CoC seems robust to both test digitization and display size adaptations. Machine learning classification based on the additional variables derived from computerized tests succeeded in distinguishing stroke patients with spatial neglect from those without. The investigated additional variables have the potential to aid in neglect diagnosis, in particular when the CoC cannot be validly assessed (e.g., when the test is not performed to completion).

Spatial Neglect Therapy With the Augmented Reality App "Negami" for Active Exploration Training: A Randomized Controlled Trial on 20 Stroke Patients With Spatial Neglect.

OBJECTIVE: To investigate the efficacy of the augmented reality (AR) app "Negami" as an active exploration training for the treatment of spatial neglect. Improvements of the ipsilesional attention and orientation bias (and resulting contralesional neglect) will be examined in stroke patients with spatial neglect and compared with a control group. DESIGN: Randomized controlled trial with an experimental Negami group, consisting of patients with spatial neglect, and a group of neglect patients receiving standard neglect therapy. SETTING: Three rehabilitation hospitals. PARTICIPANTS: Twenty right hemispheric stroke patients with spatial neglect (N=20). INTERVENTION: Over a period of 2 weeks, both groups received 5 training sessions per week (à 25 minutes). Neglect behavior was assessed weekly over a 5-week period, with the Negami therapy group receiving a second follow-up assessment at 1-to-2-month intervals after completion of training. MAIN OUTCOME MEASURES: Letter Cancellation, Bells Test, Copying Task, Line Bisection Task, and a self-developed "Exploration Test". RESULTS: Both groups improved significantly. While the Negami therapy group improved in 4 of 5 neglect tests used, the standard therapy group improved in only 1 of these tests. We observed significantly better improvement in the Negami group already after the first week of training. This difference was also significant after the end of the training as well as 1 week after the end of training and remained stable 1-2 months after the end of treatment. CONCLUSION: Negami can be used as an effective alternative or addition to current standard neglect therapy, and may even be superior to it.

[Clinical examination of spatial neglect and other disorders of spatial cognition]. / Klinische Untersuchung des unilateralen Neglects und weiterer Störungen der Raumkognition.

Neglect occurring after stroke, neoplasms or degenerative processes can lead to considerable disability in everyday life as can other disorders of spatial orientation. Therefore, a dedicated examination and early diagnostic classification are obligatory. Behavioral tests are helpful in this respect, enabling the clinician to obtain an initial overview of the existing deficits even at the patient's bedside. The clinical (bedside) examination of spatial neglect as well as the corresponding differential diagnostic procedure for the clarification of (possibly additionally or exclusively existing) hemianopia and extinction, as well as the examination of disorders of visuospatial perception, visuoconstructive disorders, topographic disorders, Bálint's syndrome, simultanagnosia, and optic ataxia are presented. The presentation is based on the newly revised (year 2023) guidelines of the Association of the Scientific Medical Societies in Germany (AWMF) on this subject area.

The role of ventral stream areas for viewpoint-invariant object recognition.

Object constancy is one of the most crucial mechanisms of the human visual system enabling viewpoint invariant object recognition. However, the neuronal foundations of object constancy are widely unknown. Research has shown that the ventral visual stream is involved in processing of various kinds of object stimuli and that several regions along the ventral stream are possibly sensitive to the orientation of an object in space. To systematically address the question of viewpoint sensitive object perception, we conducted a study with stroke patients as well as an fMRI experiment with healthy participants applying object stimuli in several spatial orientations, for example in typical and atypical viewing conditions. In the fMRI experiment, we found stronger BOLD signals and above-chance classification accuracies for objects presented in atypical viewing conditions in fusiform face sensitive and lateral occipito-temporal object preferring areas. In the behavioral patient study, we observed that lesions of the right fusiform gyrus were associated with lower performance in object recognition for atypical views. The complementary results from both experiments emphasize the contributions of fusiform and lateral-occipital areas to visual object constancy and indicate that visual object constancy is particularly enabled through increased neuronal activity and specific activation patterns for objects in demanding viewing conditions.

The amnestic syndrome of posterior cerebral artery infarction.

BACKGROUND AND PURPOSE: Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized. METHODS: Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory-impaired and memory-intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures. RESULTS: Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left- or right-sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito-temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment. CONCLUSIONS: Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.

Temporo-parietal brain regions are involved in higher order object perception.

Lesions to posterior temporo-parietal brain regions are associated with deficits in perception of global, hierarchical shapes, but also with impairments in the processing of objects presented under demanding viewing conditions. Evidence from neuroimaging studies and lesion patterns observed in patients with simultanagnosia and agnosia for object orientation suggest similar brain regions to be involved in perception of global shapes and processing of objects in atypical ('non-canonical') orientation. In a localizer experiment, we identified individual temporo-parietal brain areas involved in global shape perception and found significantly higher BOLD signals during the processing of non-canonical compared to canonical objects. In a multivariate approach, we demonstrated that posterior temporo-parietal brain areas show distinct voxel patterns for non-canonical and canonical objects and that voxel patterns of global shapes are more similar to those of objects in non-canonical compared to canonical viewing conditions. These results suggest that temporo-parietal brain areas are not only involved in global shape perception but might serve a more general mechanism of complex object perception. Our results challenge a strict attribution of object processing to the ventral visual stream by suggesting specific dorsal contributions in more demanding viewing conditions.

Strategies for feature extraction from structural brain imaging in lesion-deficit modelling.

High-dimensional modelling of post-stroke deficits from structural brain imaging is highly relevant to basic cognitive neuroscience and bears the potential to be translationally used to guide individual rehabilitation measures. One strategy to optimise model performance is well-informed feature selection and representation. However, different feature representation strategies were so far used, and it is not known what strategy is best for modelling purposes. The present study compared the three common main strategies: voxel-wise representation, lesion-anatomical componential feature reduction and region-wise atlas-based feature representation. We used multivariate, machine-learning-based lesion-deficit models to predict post-stroke deficits based on structural lesion data. Support vector regression was tuned by nested cross-validation techniques and tested on held-out validation data to estimate model performance. While we consistently found the numerically best models for lower-dimensional, featurised data and almost always for principal components extracted from lesion maps, our results indicate only minor, non-significant differences between different feature representation styles. Hence, our findings demonstrate the general suitability of all three commonly applied feature representations in lesion-deficit modelling. Likewise, model performance between qualitatively different popular brain atlases was not significantly different. Our findings also highlight potential minor benefits in individual fine-tuning of feature representations and the challenge posed by the high, multifaceted complexity of lesion data, where lesion-anatomical and functional criteria might suggest opposing solutions to feature reduction.

Hippocampal diaschisis contributes to anosognosia for hemiplegia: Evidence from lesion network-symptom-mapping.

Anosognosia for hemiplegia (AHP) is known to be associated with lesions to the motor system combined with varying lesions to the right insula, premotor cortex, parietal lobe or hippocampus. Due to this widespread cortical lesion distribution, AHP can be understood best as a network disorder. We used lesion maps and behavioral data (n â€‹= â€‹49) from two previous studies on AHP and performed a lesion network-symptom-mapping (LNSM) analysis. This new approach permits the identification of relationships between behavior and regions connected to the lesion site based on normative functional connectome data. In a first step, using ordinary voxel-based lesion-symptom mapping, we found an association of AHP with lesions in the right posterior insula. This is in accordance with previous studies. Applying LNSM, we were able to additionally identify a region in the right posterior hippocampus where AHP was associated with significantly higher normative lesion connectivity. Notably, this region was spared by infarction in all patients. We therefore argue that remote neuronal dysfunction caused by disrupted functional connections between the lesion site and the hippocampus (i.e. diaschisis) contributed to the phenotype of AHP. An indirect affection of the hippocampus may lead to memory deficits which, in turn, impair the stable encoding of updated beliefs on the bodily state thus contributing to the multifactorial phenomenon of AHP.

Post-stroke cognitive deficits rarely come alone: Handling co-morbidity in lesion-behaviour mapping.

Post-stroke behavioural symptoms often correlate and systematically co-occur with each other, either because they share cognitive processes, or because their neural correlates are often damaged together. Thus, neuropsychological symptoms often share variance. Many previous lesion-behaviour mapping studies aimed to methodologically consider this shared variance between neuropsychological variables. A first group of studies controlled the behavioural target variable for the variance explained by one or multiple other variables to obtain a more precise mapping of the target variable. A second group of studies focused on the shared variance of multiple variables itself with the aim to map neural correlates of cognitive processes that are shared between the original variables. In the present study, we tested the validity of these methods by using real lesion data and both real and simulated data sets. We show that the variance that is shared between post-stroke behavioural variables is ambiguous, and that mapping procedures that consider this variance are prone to biases and artefacts. We discuss under which conditions such procedures could still be used and what alternative approaches exist.

Reprint of: Mapping human brain lesions and their functional consequences.

Neuroscience has a long history of inferring brain function by examining the relationship between brain injury and subsequent behavioral impairments. The primary advantage of this method over correlative methods is that it can tell us if a certain brain region is necessary for a given cognitive function. In addition, lesion-based analyses provide unique insights into clinical deficits. In the last decade, statistical voxel-based lesion behavior mapping (VLBM) emerged as a powerful method for understanding the architecture of the human brain. This review illustrates how VLBM improves our knowledge of functional brain architecture, as well as how it is inherently limited by its mass-univariate approach. A wide array of recently developed methods appear to supplement traditional VLBM. This paper provides an overview of these new methods, including the use of specialized imaging modalities, the combination of structural imaging with normative connectome data, as well as multivariate analyses of structural imaging data. We see these new methods as complementing rather than replacing traditional VLBM, providing synergistic tools to answer related questions. Finally, we discuss the potential for these methods to become established in cognitive neuroscience and in clinical applications.

Using machine learning-based lesion behavior mapping to identify anatomical networks of cognitive dysfunction: Spatial neglect and attention.

Previous lesion behavior studies primarily used univariate lesion behavior mapping techniques to map the anatomical basis of spatial neglect after right brain damage. These studies led to inconsistent results and lively controversies. Given these inconsistencies, the idea of a wide-spread network that might underlie spatial orientation and neglect has been pushed forward. In such case, univariate lesion behavior mapping methods might have been inherently limited in detecting the presumed network due to limited statistical power. By comparing various univariate analyses with multivariate lesion-mapping based on support vector regression, we aimed to validate the network hypothesis directly in a large sample of 203 newly recruited right brain damaged patients. If the exact same correction factors and parameter combinations (FDR correction and dTLVC for lesion size control) were used, both univariate as well as multivariate approaches uncovered the same complex network pattern underlying spatial neglect. At the cortical level, lesion location dominantly affected the temporal cortex and its borders into inferior parietal and occipital cortices. Beyond, frontal and subcortical gray matter regions as well as white matter tracts connecting these regions were affected. Our findings underline the importance of a right network in spatial exploration and attention and specifically in the emergence of the core symptoms of spatial neglect.

An empirical evaluation of multivariate lesion behaviour mapping using support vector regression.

Multivariate lesion behaviour mapping based on machine learning algorithms has recently been suggested to complement the methods of anatomo-behavioural approaches in cognitive neuroscience. Several studies applied and validated support vector regression-based lesion symptom mapping (SVR-LSM) to map anatomo-behavioural relations. However, this promising method, as well as the multivariate approach per se, still bears many open questions. By using large lesion samples in three simulation experiments, the present study empirically tested the validity of several methodological aspects. We found that (i) correction for multiple comparisons is required in the current implementation of SVR-LSM, (ii) that sample sizes of at least 100-120 subjects are required to optimally model voxel-wise lesion location in SVR-LSM, and (iii) that SVR-LSM is susceptible to misplacement of statistical topographies along the brain's vasculature to a similar extent as mass-univariate analyses.

Preserved Expert Object Recognition in a Case of Visual Hemiagnosia.

We examined a stroke patient (HWS) with a unilateral lesion of the right medial ventral visual stream, involving the right fusiform and parahippocampal gyri. In a number of object recognition tests with lateralized presentations of target stimuli, HWS showed significant symptoms of hemiagnosia with contralesional recognition deficits for everyday objects. We further explored the patient's capacities of visual expertise that were acquired before the current perceptual impairment became effective. We confronted him with objects he was an expert for already before stroke onset and compared this performance with the recognition of familiar everyday objects. HWS was able to identify significantly more of the specific ("expert") than of the everyday objects on the affected contralesional side. This observation of better expert object recognition in visual hemiagnosia allows for several interpretations. The results may be caused by enhanced information processing for expert objects in the ventral system in the affected or the intact hemisphere. Expert knowledge could trigger top-down mechanisms supporting object recognition despite of impaired basic functions of object processing. More importantly, the current work demonstrates that top-down mechanisms of visual expertise influence object recognition at an early stage, probably before visual object information propagates to modules of higher object recognition. Because HWS showed a lesion to the fusiform gyrus and spared capacities of expert object recognition, the current study emphasizes possible contributions of areas outside the ventral stream to visual expertise.

Mapping human brain lesions and their functional consequences.

Neuroscience has a long history of inferring brain function by examining the relationship between brain injury and subsequent behavioral impairments. The primary advantage of this method over correlative methods is that it can tell us if a certain brain region is necessary for a given cognitive function. In addition, lesion-based analyses provide unique insights into clinical deficits. In the last decade, statistical voxel-based lesion behavior mapping (VLBM) emerged as a powerful method for understanding the architecture of the human brain. This review illustrates how VLBM improves our knowledge of functional brain architecture, as well as how it is inherently limited by its mass-univariate approach. A wide array of recently developed methods appear to supplement traditional VLBM. This paper provides an overview of these new methods, including the use of specialized imaging modalities, the combination of structural imaging with normative connectome data, as well as multivariate analyses of structural imaging data. We see these new methods as complementing rather than replacing traditional VLBM, providing synergistic tools to answer related questions. Finally, we discuss the potential for these methods to become established in cognitive neuroscience and in clinical applications.

Body-relative horizontal-vertical anisotropy in human representations of traveled distances.

A growing number of studies investigated anisotropies in representations of horizontal and vertical spaces. In humans, compelling evidence for such anisotropies exists for representations of multi-floor buildings. In contrast, evidence regarding open spaces is indecisive. Our study aimed at further enhancing the understanding of horizontal and vertical spatial representations in open spaces utilizing a simple traveled distance estimation paradigm. Blindfolded participants were moved along various directions in the sagittal plane. Subsequently, participants passively reproduced the traveled distance from memory. Participants performed this task in an upright and in a 30° backward-pitch orientation. The accuracy of distance estimates in the upright orientation showed a horizontal-vertical anisotropy, with higher accuracy along the horizontal axis compared with the vertical axis. The backward-pitch orientation enabled us to investigate whether this anisotropy was body or earth-centered. The accuracy patterns of the upright condition were positively correlated with the body-relative (not the earth-relative) coordinate mapping of the backward-pitch condition, suggesting a body-centered anisotropy. Overall, this is consistent with findings on motion perception. It suggests that the distance estimation sub-process of path integration is subject to horizontal-vertical anisotropy. Based on the previous studies that showed isotropy in open spaces, we speculate that real physical self-movements or categorical versus isometric encoding are crucial factors for (an)isotropies in spatial representations.