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Brain-behavior relationships are complex. For instance, one might know a brain region's function(s) but still be unable to accurately predict deficit type or severity after damage to that region. Here, I discuss the case of damage to the angular gyrus (AG) that can cause left-right confusion, finger agnosia, attention deficit, and lexical agraphia, as well as impairment in sentence processing, episodic memory, number processing, and gesture imitation. Some of these symptoms are grouped under AG syndrome or Gerstmann's syndrome, though its exact underlying neuronal systems remain elusive. This review applies recent frameworks of brain-behavior modes and principles from modern lesion-symptom mapping to explain symptomatology after AG damage. It highlights four major issues for future studies: (1) functionally heterogeneous symptoms after AG damage need to be considered in terms of the degree of damage to (i) different subdivisions of the AG, (ii) different AG connectivity profiles that disconnect AG from distant regions, and (iii) lesion extent into neighboring regions damaged by the same infarct. (2) To explain why similar symptoms can also be observed after damage to other regions, AG damage needs to be studied in terms of the networks of regions that AG functions with, and other independent networks that might subsume the same functions. (3) To explain inter-patient variability on AG symptomatology, the degree of recovery-related brain reorganisation needs to account for time post-stroke, demographics, therapy input, and pre-stroke differences in functional anatomy. (4) A better integration of the results from lesion and functional neuroimaging investigations of AG function is required, with only the latter so far considering AG function in terms of a hub within the default mode network. Overall, this review discusses why it is so difficult to fully characterize the AG syndrome from lesion data, and how this might be addressed with modern lesion-symptom mapping., Competing Interests: Declaration of competing interest The author declares that he has no conflict of interest., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

The detection of right temporal lobe dysfunction with nonverbal memory tests has remained difficult in the past. Reasons for this might be the potential influence of other biasing cognitive functions such as executive functions or the verbalisability of nonverbal material. The aim of this study was to investigate three classic nonverbal memory tests by identifying their neuroanatomical correlates with lesion-symptom mapping (LSM) and by probing their independence from verbal encoding abilities and executive functions. In a cohort of 119 patients with first-time cerebrovascular accident, memory performance was assessed in the Nonverbal Learning and Memory Test for Routes (NLMTR), the Rey Complex Figure Test (RCFT), and the Visual Design Learning Test (VDLT). Calculating multivariate LSM, we identified crucial brain structures for these three nonverbal memory tests. Behavioural analyses were performed to assess the impact of executive functions and verbal encoding abilities with regression analyses and likelihood-ratio tests. LSM revealed for the RCFT mainly right-hemispheric frontal, insular, subcortical, and white matter structures and for the NLMTR right-hemispheric temporal (hippocampus), insular, subcortical, and white matter structures. The VDLT did not reach significance in LSM analyses. Behavioural results showed that amongst the three nonverbal memory tests the impact of executive functions was most pronounced for RCFT, and the impact of verbal encoding abilities was most important in VDLT. Likelihood-ratio tests confirmed that only for NLMTR did the goodness of fit not significantly improve by adding executive functions or verbal encoding abilities. These results suggest that amongst the three nonverbal memory tests the NLMTR, as a spatial navigation test, could serve as the most suitable marker of right-hemispheric temporal lobe functioning, with the right hippocampus being involved only in this test. In addition, the behavioural results propose that only NLMTR seems mostly unaffected by executive functions and verbal encoding abilities., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Semantic processing is a central component of language and cognition. The anterior temporal lobe is postulated to be a key hub for semantic processing, but the posterior temporoparietal cortex is also involved in thematic associations during language. It is possible that these regions act in concert and depend on an anteroposterior network linking the temporal pole with posterior structures to support thematic semantic processing during language production. We employed connectome-based lesion-symptom mapping to examine the causal relationship between lesioned white matter pathways and thematic processing language deficits among individuals with post-stroke aphasia. Seventy-nine adults with chronic aphasia completed the Philadelphia Naming Test, and semantic errors were coded as either thematic or taxonomic to control for taxonomic errors. Controlling for nonverbal conceptual-semantic knowledge as measured by the Pyramids and Palm Trees Test, lesion size, and the taxonomic error rate, thematic error rate was associated with loss of white matter connections from the temporal pole traversing in peri-Sylvian regions to the posterior cingulate and the insula. These findings support the existence of a distributed network underlying thematic relationship processing in language as opposed to discrete cortical areas., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Memory disorders are a common consequence of cerebrovascular accident (CVA). However, uncertainties remain about the exact anatomical correlates of memory impairment and the material-specific lateralization of memory function in the brain. We used lesion-symptom mapping (LSM) in patients with first-time CVA to identify which brain structures are pivotal for verbal and nonverbal memory and to re-examine whether verbal and nonverbal memory functions are lateralized processes in the brain. The cognitive performance of a relatively large cohort of 114 patients in five classic episodic memory tests was analysed with factor analysis. Two factors were extracted that distinguished the verbal and nonverbal components of these memory tests, and their scores were subsequently tested for anatomical correlates by combining univariate and multivariate LSM. LSM analysis revealed for the verbal factor exclusively left-hemispheric insular, subcortical and adjacent white matter regions and for the nonverbal factor exclusively right-hemispheric temporal, occipital, insular, subcortical and adjacent white matter structures. These results corroborate the long-standing hypothesis of a material-specific lateralization of memory function in the brain and confirm a robust association between right temporal lobe lesions and nonverbal memory dysfunction. The right-hemispheric correlates for the nonverbal aspects of episodic memory include not only classic memory structures in the medial temporal lobe but also a more distributed network that includes cortical and subcortical structures also known for implicit memory processes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Naming and word retrieval deficits are two of the most persistent symptoms in chronic post-stroke aphasia. Naming success or failure on specific words can sometimes be predicted by the psycholinguistic properties of the word. Despite a wealth of literature investigating the influence of psycholinguistic properties in neuro-typical and clinical language processing, the underlying structure of these properties and their relation to the fundamental language components and neural correlates are unexplored. In this study, a multivariate data-decomposition approach was used to identify the underlying structure within a collection of psycholinguistic properties (word imageability, frequency, age-of-acquisition, familiarity, length, semantic diversity and phonological neighbourhood density) and their influence on naming accuracy was explored in a cohort of 42 participants with a diverse range of chronic post-stroke aphasia classifications and severities. The results extracted three principal psycholinguistic factors, which were best described as 'lexical usage', 'semantic clarity' and 'phonological complexity'. Furthermore, a novel approach was used to systematically relate the influence of these psycholinguistic properties to participants' neuropsychological and lesion profiles. The findings did not show a one-to-one mapping between psycholinguistic features and core language components. 'Lexical usage' was the only factor that showed a significant difference between fluent versus non-fluent aphasia groups in terms of the influence of this lexical factor on successful naming, and it was the only factor that was related to the pattern of patients' brain lesions. Voxel-wise whole brain lesion-symptom mapping identified left frontal regions, aligning with previous evidence that these regions are related to language production functions, including word retrieval and repetition. The evidence from the current study suggests that the functional locus of psycholinguistic properties is distributed across multiple language components rather than being localised to a single language element., (Copyright © 2019. Published by Elsevier Ltd.)

Impairments in executive functions are common in stroke survivors, both in the acute and in the chronic phase. However, little is known about the underlying lesion neuroanatomy of these deficits. This study aimed to elucidate the pattern of brain damage underlying executive dysfunction in a large and acute stroke cohort. Executive set-switching deficits were evaluated by a shape-based analogue of the Trail Making Test (from the Oxford Cognitive Screen) in a consecutive sample of 144 stroke patients (age: 70 ± 15 years, examination: 5 ± 4 days post-stroke; brain imaging: 1.7 ± 2.9 days post-stroke). A voxelwise lesion-symptom mapping analysis was performed by combining executive set-switching accuracy scores with manually delineated lesions on computerized tomography or magnetic resonance imaging scans. The analysis showed that lesions within the left insular cortex and adjacent white matter predicted poorer executive set-switching. Further analyses confirmed that the lesion effect in the left insula survived correction for the low-level visuospatial and motor component processes of executive set-switching. In conclusion, the study provides lesion-based evidence for the role of the left insular cortex in flexible switching of attention. The findings are consistent with emergent models of insular function postulating the role of this region in regulatory aspects of goal-directed behaviour., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Traditional neuropsychological approaches emphasize the specificity of behavioral deficits and the modular organization of the brain. At the population level, however, there is emerging evidence that deficits are correlated resulting in a low dimensional structure of post-stroke neurological impairments. Here we consider the implications of low dimensionality for the three-way mapping between structural damage, altered physiology, and behavioral deficits. Understanding this mapping will be aided by large-sample studies that apply multivariate models and focus on explained percentage of variance, as opposed to univariate lesion-symptom techniques that report statistical significance. The low dimensionality of behavioral deficits following stroke is paralleled by widespread, yet relatively consistent, changes in functional connectivity (FC), including a reduction in modularity. Both are related to the structural damage to white matter and subcortical grey commonly produced by stroke. We suggest that large-scale physiological abnormalities following a stroke reduce the variety of neural states visited during task processing and at rest, resulting in a limited repertoire of behavioral states., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The neural basis of speech processing is still a matter of great debate. Phonotactic knowledge-knowledge of the allowable sound combinations in a language-remains particularly understudied. The purpose of this study was to investigate the brain regions crucial to phonotactic knowledge in left-hemisphere stroke survivors. Results were compared to areas in which gray matter anatomy related to phonotactic knowledge in healthy controls. 44 patients with chronic left-hemisphere stroke, and 32 controls performed an English-likeness rating task on 60 auditory non-words of varying phonotactic regularities. They were asked to rate on a 1-5 scale, how close each non-word sounded to English. Patients' performance was compared to that of healthy controls, using mixed effects modeling. Multivariate lesion-symptom mapping and voxel-based morphometry were used to find the brain regions important for phonotactic processing in patients and controls respectively. The results showed that compared to controls, stroke survivors were less sensitive to phonotactic regularity differences. Lesion-symptom mapping demonstrated that a loss of sensitivity to phonotactic regularities was associated with lesions in left angular gyrus and posterior middle temporal gyrus. Voxel-based morphometry also revealed a positive correlation between gray matter density in left angular gyrus and sensitivity to phonotactic regularities in controls. We suggest that the angular gyrus is used to compare the incoming speech stream to internal predictions based on the frequency of sound sequences in the language derived from stored lexical representations in the posterior middle temporal gyrus., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Behavioural impairment post-stroke is a consequence of structural damage and altered functional network dynamics. Hypoperfusion of intact neural tissue is frequently observed in acute stroke, indicating reduced functional capacity of regions outside the lesion. However, cerebral blood flow (CBF) is rarely investigated in chronic stroke. This study investigated CBF in individuals with chronic Wernicke's aphasia (WA) and examined the relationship between lesion, CBF and neuropsychological impairment. Arterial spin labelling CBF imaging and structural MRIs were collected in 12 individuals with chronic WA and 13 age-matched control participants. Joint independent component analysis (jICA) investigated the relationship between structural lesion and hypoperfusion. Partial correlations explored the relationship between lesion, hypoperfusion and language measures. Joint ICA revealed significant differences between the control and WA groups reflecting a large area of structural lesion in the left posterior hemisphere and an associated area of hypoperfusion extending into grey matter surrounding the lesion. Small regions of remote cortical hypoperfusion were observed, ipsilateral and contralateral to the lesion. Significant correlations were observed between the neuropsychological measures (naming, repetition, reading and semantic association) and the jICA component of interest in the WA group. Additional ROI analyses found a relationship between perfusion surrounding the core lesion and the same neuropsychological measures. This study found that core language impairments in chronic WA are associated with a combination of structural lesion and abnormal perfusion in non-lesioned tissue. This indicates that post-stroke impairments are due to a wider disruption of neural function than observable on structural T1w MRI., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Naming pictures and matching words to pictures belonging to the same semantic category negatively affects language production and comprehension. By most accounts, semantic interference arises when accessing lexical representations in naming (e.g., Damian, Vigliocco, & Levelt, 2001) and semantic representations in comprehension (e.g., Forde & Humphreys, 1997). Further, damage to the left inferior frontal gyrus (LIFG), a region implicated in cognitive control, results in increasing semantic interference when items repeat across cycles in both language production and comprehension (Jefferies, Baker, Doran, & Lambon Ralph, 2007). This generates the prediction that the LIFG via white matter connections supports resolution of semantic interference arising from different loci (lexical vs semantic) in the temporal lobe. However, it remains unclear whether the cognitive and neural mechanisms that resolve semantic interference are the same across tasks. Thus, we examined which gray matter structures [using whole brain and region of interest (ROI) approaches] and white matter connections (using deterministic tractography) when damaged impact semantic interference and its increase across cycles when repeatedly producing and understanding words in 15 speakers with varying lexical-semantic deficits from left hemisphere stroke. We found that damage to distinct brain regions, the posterior versus anterior temporal lobe, was associated with semantic interference (collapsed across cycles) in naming and comprehension, respectively. Further, those with LIFG damage compared to those without exhibited marginally larger increases in semantic interference across cycles in naming but not comprehension. Lastly, the inferior fronto-occipital fasciculus, connecting the LIFG with posterior temporal lobe, related to semantic interference in naming, whereas the inferior longitudinal fasciculus (ILF), connecting posterior with anterior temporal regions related to semantic interference in comprehension. These neuroanatomical-behavioral findings have implications for models of the lexical-semantic language network by demonstrating that semantic interference in language production and comprehension involves different representations which differentially recruit a cognitive control mechanism for interference resolution., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Neuropsychological deficits after occipital infarction are most often described in case studies and only a small sample of studies has attempted to exactly correlate the anatomical localization of lesions with associated neuropsychological symptoms. The present study investigated a large number of patients (N = 128) in order to provide an overview of neurological and neuropsychological deficits after occipital, occipito-temporal and occipito-parietal infarction. A particular approach of the study was to define exact anatomical correlates of neuropsychological dysfunction by using voxel-based lesion-symptom mapping (VLSM) in 61 patients. In addition to a visual field defect and phosphenes, patients often reported anomia, difficulties in reading and memory deficits. Visual disorders, such as achromatopsia, akinetopsia or prosopagnosia, were rarely reported by the patients. Memory and visual disorders were diagnosed efficiently using simple clinical screening tests, such as the Rey-Osterrieth Complex Figure Test for immediate recall, the Demtect and the Lang Stereo Test. Visual field defects, reading disorders and the perception of phosphenes were associated primarily with lesions of the calcarine sulcus. Anomia and memory deficits were related to lesions of the occipital inferior gyrus, the lingual gyrus and hippocampus, as well as to lesions of principal white matter tracts., (Copyright © 2012 Elsevier Ltd. All rights reserved.)