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Visuospatial neglect is a common, post-stroke cognitive impairment which is widely considered to be a disconnection syndrome. However, the patterns of disconnectivity associated with visuospatial neglect remain unclear. Here, we had 480 acute stroke survivors [age = 72.8 (SD = 13.3), 44.3% female, 7.5 days post-stroke (SD = 11.3)] undertake routine clinical imaging and standardised visuospatial neglect testing. The data were used to conduct voxel-wise, tract-level, and network-level lesion-mapping analyses aimed at localising the neural correlates of left and right egocentric (body-centred) and allocentric (object-centred) visuospatial neglect. Only minimal anatomical homogeneity was present between the correlates of right and left egocentric neglect across all analysis types. This finding challenges previous work suggesting that right and left visuospatial neglect are anatomically homologous, and instead suggests that egocentric neglect may involve damage to a shared, but hemispherically asymmetric attention network. By contrast, egocentric and allocentric neglect was associated with disconnectivity in a distinct but overlapping set of network edges, with both deficits related to damage across the dorsal and ventral attention networks. Critically, this finding suggests that the distinction between egocentric and allocentric neglect is unlikely to reflect a simple dichotomy between dorsal versus ventral networks dysfunction, as is commonly asserted. Taken together, the current findings provide a fresh perspective on the neural circuitry involved in regulating visuospatial attention, and provide important clues to understanding the cognitive and perceptual processes involved in this common and debilitating neuropsychological syndrome.

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 ​= ​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. •In VLSM, right insular lesions are associated with anosognosia for hemiplegia (AHP).•Lesion-network symptom-mapping can locate remote dysfunction after brain lesions.•In LNSM, higher lesion connectivity of the right hippocampus is associated with AHP.•Thus direct and indirect (e.g. diaschisis) lesion effects contribute to AHP.

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.

The functional roles of the precuneus are unclear. Focal precuneus lesions are rare, making it difficult to identify robust brain–behavior relationships. Distinct functional subdivisions of the precuneus have been proposed based on unique connectivity profiles. This includes an association of the anterior division with bodily awareness, the central region with complex cognition, and the posterior division with visual processing. Our goal was to test the hypothesis that the central precuneus is preferentially involved (compared to the other sectors of the precuneus) in executive function, as estimated from performance on the trail-making test (TMT). 35 patients with focal brain lesions involving the precuneus were included from the University of Iowa and Montpellier University. Multivariate lesion symptom mapping of TMT performance was performed to evaluate whether lesion location was associated with impaired task performance. Lesion symptom mapping revealed a statistically significant association of central precuneus lesions with impaired TMT performance (r = 0.43, p < 0.01). Further, a functional network derived from this precuneus region showed connectivity to other cortical areas implicated in executive function, including the dorsolateral prefrontal cortex and inferior parietal lobe. This analysis provides support for the role of the central precuneus in executive function, consistent with the unique connectivity pattern of the central precuneus with a broader network implicated in cognitive control and executive function.

Background: We aimed to evaluate the resected area of endonasal endoscopic approach (EEA) and transcranial approach (TCA) for skull base meningiomas (SBMs) using voxel-based-lesion mapping and visualized the appropriate tumor location in each approach. Methods: We retrospectively examined 182 patients with SBMs who underwent tumor resection in our hospital between 2014 and 2019. Pre- and post-operative SBMs were manually delineated on MRI to create the voxels-of-interest (VOIpre and VOIpost) and were registered onto the normalized brain (normalized VOIpre and normalized VOIpost). The resected map was created by subtracting normalized VOIpost from the normalized VOIpre divided by the number of cases. The resected maps of TCA and EEA were compared by subtracting them. Results: Twenty patients underwent EEA and 135 patients underwent TCA. The tumor resected map demonstrated that the resected area of EEA frequently accumulated on the central skull base, while that of TCA accumulated near the central skull base. The border of both approaches matched the circle that connects neural foramens at the skull base. Conclusions: The resected area of SBMs by EEA and TCA was well visualized by voxel-based-lesion mapping. The circle connecting the neural foramens was the border of EEA and TCA.

Several neurophysiologic and neuroimaging studies suggested that motor and perceptual systems are tightly linked along a continuum rather than providing segregated mechanisms supporting different functions. Using correlational approaches, these studies demonstrated that action observation activates not only visual but also motor brain regions. On the other hand, brain stimulation and brain lesion evidence allows tackling the critical question of whether our action representations are necessary to perceive and understand others' actions. In particular, recent neuropsychological studies have shown that patients with temporal, parietal, and frontal lesions exhibit a number of possible deficits in the visual perception and the understanding of others' actions. The specific anatomical substrates of such neuropsychological deficits however, are still a matter of debate. Here we review the existing literature on this issue and perform an anatomic likelihood estimation meta-analysis of studies using lesion-symptom mapping methods on the causal relation between brain lesions and non-linguistic action perception and understanding deficits. The meta-analysis encompassed data from 361 patients tested in 11 studies and identified regions in the inferior frontal cortex, the inferior parietal cortex and the middle/superior temporal cortex, whose damage is consistently associated with poor performance in action perception and understanding tasks across studies. Interestingly, these areas correspond to the three nodes of the action observation network that are strongly activated in response to visual action perception in neuroimaging research and that have been targeted in previous brain stimulation studies. Thus, brain lesion mapping research provides converging causal evidence that premotor, parietal and temporal regions play a crucial role in action recognition and understanding.

Studies in patients with brain lesions play a fundamental role in unraveling the brain's functional anatomy. Lesion‐symptom mapping (LSM) techniques can relate lesion location to cognitive performance. However, a limitation of current LSM approaches is that they can only evaluate one cognitive outcome at a time, without considering interdependencies between different cognitive tests. To overcome this challenge, we implemented canonical correlation analysis (CCA) as combined multivariable and multioutcome LSM approach. We performed a proof‐of‐concept study on 1075 patients with acute ischemic stroke to explore whether addition of CCA to a multivariable single‐outcome LSM approach (support vector regression) could identify infarct locations associated with deficits in three well‐defined verbal memory functions (encoding, consolidation, retrieval) based on four verbal memory subscores derived from the Seoul Verbal Learning Test (immediate recall, delayed recall, recognition, learning ability). We evaluated whether CCA could extract cognitive score patterns that matched prior knowledge of these verbal memory functions, and if these patterns could be linked to more specific infarct locations than through single‐outcome LSM alone. Two of the canonical modes identified with CCA showed distinct cognitive patterns that matched prior knowledge on encoding and consolidation. In addition, CCA revealed that each canonical mode was linked to a distinct infarct pattern, while with multivariable single‐outcome LSM individual verbal memory subscores were associated with largely overlapping patterns. In conclusion, our findings demonstrate that CCA can complement single‐outcome LSM techniques to help disentangle cognitive functions and their neuroanatomical correlates.

Lesion‐behavior mapping (LBM) provides a statistical map of the association between voxel‐wise brain damage and individual differences in behavior. To understand whether two behaviors are mediated by damage to distinct regions, researchers often compare LBM weight outputs by either the Overlap method or the Correlation method. However, these methods lack statistical criteria to determine whether two LBM are distinct versus the same and are disconnected from a major goal of LBMs: predicting behavior from brain damage. Without such criteria, researchers may draw conclusions from numeric differences between LBMs that are irrelevant to predicting behavior. We developed and validated a predictive validity comparison method (PVC) that establishes a statistical criterion for comparing two LBMs using predictive accuracy: two LBMs are distinct if and only if they provide unique predictive power for the behaviors being assessed. We applied PVC to two lesion‐behavior stroke data sets, demonstrating its utility for determining when behaviors arise from the same versus different lesion patterns. Using region‐of‐interest‐based simulations derived from proportion damage from a large data set (n = 131), PVC accurately detected when behaviors were mediated by different regions (high sensitivity) versus the same region (high specificity). Both the Overlap method and Correlation method performed poorly on the simulated data. By objectively determining whether two behavioral deficits can be explained by single versus distinct patterns of brain damage, PVC provides a critical advance in establishing the brain bases of behavior. We have developed and released a GUI‐driven web app to encourage widespread adoption. Multivariate lesion behavior mapping (LBM) is often used to summarize brain behavior relationships but there is no principled approach to determine whether two behaviors are mediated by damage to distinct brain regions. We developed a predictive validity comparison method that establishes such a criterion by directly comparing two LBMs based on the difference in predictive accuracy. We released a GUI‐driven, open‐access web app to encourage widespread adoption.

Subcortical ischemic stroke can lead to persistent structural changes in the cerebral cortex. The evolution of cortical structural changes after subcortical stroke is largely unknown, as are their relations with motor recovery, lesion location, and early impairment of specific subsets of fibers in the corticospinal tract (CST). In this observational study, cortical structural changes were compared between 181 chronic patients with subcortical stroke involving the motor pathway and 113 healthy controls. The impacts of acute lesion location and early impairments of specific CSTs on cortical structural changes were investigated in the patients by combining voxel‐based correlation analysis with an association study that compared CST damage and cortical structural changes. Longitudinal patterns of cortical structural change were explored in a group of 81 patients with subcortical stroke using a linear mixed‐effects model. In the cross‐sectional analyses, patients with partial recovery showed more significant reductions in cortical thickness, surface area, or gray matter volume in the sensorimotor cortex, cingulate gyrus, and gyrus rectus than did patients with complete recovery; however, patients with complete recovery demonstrated more significant increases in the cortical structural measures in frontal, temporal, and occipital regions than did patients with partial recovery. Voxel‐based correlation analysis in these patients showed that acute stroke lesions involving the CST fibers originating from the primary motor cortex were associated with cortical thickness reductions in the ipsilesional motor cortex in the chronic stage. Acute stroke lesions in the putamen were correlated with increased surface area in the temporal pole in the chronic stage. The early impairment of the CST fibers originating from the primary sensory area was associated with increased cortical thickness in the occipital cortex. In the longitudinal analyses, patients with partial recovery showed gradually reduced cortical thickness, surface area, and gray matter volume in brain regions with significant structural damage in the chronic stage. Patients with complete recovery demonstrated gradually increasing cortical thickness, surface area, and gray‐matter volume in the frontal, temporal, and occipital regions. The directions of slow structural changes in the frontal, occipital, and cingulate cortices were completely different between patients with partial and complete recovery. Complex cortical structural changes and their dynamic evolution patterns were different, even contrasting, in patients with partial and complete recovery, and were associated with lesion location and with impairment of specific CST fiber subsets. Complex cortical structural changes and their dynamic evolution patterns were different, even contrasting, in stroke patients with partial and complete recovery, and were associated with lesion location and with impairment of specific corticospinal tract fiber subsets.

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.