Lesion-symptom studies in persons with aphasia showed that left temporoparietal damage, but surprisingly not prefrontal damage, correlates with impaired ability to process thematic roles in the comprehension of semantically reversible sentences (The child is hugged by the mother). This result has led to challenge the time-honored view that left prefrontal regions are critical for sentence comprehension. However, most studies focused on thematic role assignment and failed to consider morphosyntactic processes that are also critical for sentence processing. We reviewed and meta-analyzed lesion-symptom studies on the neurofunctional correlates of thematic role assignment and morphosyntactic processing in comprehension and production in persons with aphasia. Following the PRISMA checklist, we selected 43 papers for the review and 27 for the meta-analysis, identifying a set of potential bias risks. Both the review and the meta-analysis confirmed the correlation between thematic role processing and temporoparietal regions but also clearly showed the involvement of prefrontal regions in sentence processing. Exploratory meta-analyses suggested that both thematic role and morphosyntactic processing correlate with left prefrontal and temporoparietal regions, that morphosyntactic processing correlates with prefrontal structures more than with temporoparietal regions, and that thematic role assignment displays the opposite trend. We discuss current limitations in the literature and propose a set of recommendations for clarifying unresolved issues.

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.

OBJECTIVE: The few voxel-wise lesion-symptom mapping (VLSM) studies aimed at identifying the anatomy of executive function are limited by the absence of a model and by small populations. Using Trail Making Test (TMT) and verbal fluency and a model of their architectures, our objective was to identify the key structures underlying two major executive processes, set-shifting and strategic word search.
METHODS: We applied a validated VLSM analysis to harmonized cognitive and imaging data from 2009 ischemic stroke patients as a part of the Meta VCI Map consortium. All contrast analyses used an adjusted threshold with 2000 Freedman-Lane permutations (p ≤ 0.05).
RESULTS: The TMT parts A and B were associated with structures involved in visual-spatial processing, the motor system, the frontal lobes, and their subcortical connections. Set-shifting depended on the left dorsomedial frontal region. Both semantic and phonemic fluency tests depended on verbal output abilities and processing speed with similar slopes in different languages. The strategic search process depended on Broca\'s area, F2 and related tracts, temporal and deep regions. Lastly, the lesion map of set-shifting did not overlap with those of strategic word search processes.
CONCLUSIONS: Our results identify the anatomical substrates of two main executive processes, revealing that they represent only a specific subpart of previously reported structures. Finally, our results indicate that executive functions depend on several specific, anatomically separable executive processes mainly operating in various parts of the frontal lobes.

An influential model of spatial attention postulates three main attention-orienting mechanisms: disengagement, shifting, and engagement. Early research linked disengagement deficits with superior parietal damage, regardless of hemisphere or presence of spatial neglect. Subsequent studies supported the involvement of more ventral parietal regions, especially in the right hemisphere, and linked spatial neglect to deficient disengagement from ipsilateral cues. However, previous lesion studies faced serious limitations, such as small sample sizes and the lack of brain-injured controls without neglect. Additionally, some studies employed symbolic cues or used long cue-target intervals, which may fail to reveal impaired disengagement. We here used a machine-learning approach to conduct lesion-symptom mapping (LSM) on 89 patients with focal cerebral lesions to the left (LH) or right (RH) cerebral hemisphere. A group of 54 healthy participants served as controls. The paradigm used to uncover disengagement deficits employed non-predictive cues presented in the visual periphery and at short cue-target intervals, targeting exogenous attention. The main factors of interest were group (healthy participants, LH, RH), target position (left, right hemifield) and cue validity (valid, invalid). LSM-analyses were performed on two indices: the validity effect, computed as the absolute difference between reaction times (RTs) following invalid compared to valid cues, and the disengagement deficit, determined by the difference between contralesional and ipsilesional validity effects. While LH patients showed general slowing of RTs to contralesional targets, only RH patients exhibited a disengagement deficit from ipsilesional cues. LSM associated the validity effect with a right lateral frontal cluster, which additionally affected subcortical white matter of the right arcuate fasciculus, the corticothalamic pathway, and the superior longitudinal fasciculus. In contrast, the disengagement deficit was related to damage involving the right temporoparietal junction. Thus, our results support the crucial role of right inferior parietal and posterior temporal regions for attentional disengagement, but also emphasize the importance of lateral frontal regions, for the reorienting of attention.

After initial bilateral acoustic processing of the speech signal, much of the subsequent language processing is left-lateralized. The reason for this lateralization remains an open question. Prevailing hypotheses describe a left hemisphere (LH) advantage for rapidly unfolding information-such as the segmental (e.g., phonetic and phonemic) components of speech. Here we investigated whether and where damage to the LH predicted impaired performance on judging the directionality of frequency modulated (FM) sweep stimuli that changed within short (25ms) or longer (250ms) temporal windows. Performance was significantly lower for stroke survivors (n = 50; 18 female) than controls (n = 61; 34 female) on FM Sweeps judgments, particularly on the short sweeps. Support vector regression lesion-symptom mapping (SVR-LSM) revealed that part of the left planum temporale (PT) was related to worse performance on judging the short FM sweeps, controlling for performance on the long sweeps. We then investigated whether damage to this particular area related to diminished performance on two levels of linguistic processing that theoretically depend on rapid auditory processing: stop consonant identification and pseudoword repetition. We separated stroke participants into subgroups based on whether their LH lesion included the part of the left PT that related to diminished short sweeps judgments. Participants with PT lesions (PT lesion+, n = 24) performed significantly worse than those without (PT lesion-, n = 26) on stop consonant identification and pseudoword repetition, controlling for lesion size and hearing ability. Interestingly, PT lesions impacted pseudoword repetition more than real word repetition (PT lesion-by-repetition trial type interaction), which is of interest because pseudowords rely solely on sound perception and sequencing, whereas words can also rely on lexical-semantic knowledge. We conclude that the left PT is a critical region for processing auditory information in short temporal windows, and it may also be an essential transfer point in auditory-to-linguistic processing.

Language comprehension is often affected in individuals with post-stroke aphasia. However, deficits in auditory comprehension are not fully correlated with deficits in reading comprehension and the mechanisms underlying this dissociation remain unclear. This distinction is important for understanding language mechanisms, predicting long-term impairments and future development of treatment interventions. Using comprehensive auditory and reading measures from a large cohort of individuals with aphasia, we evaluated the relationship between aphasia type and reading comprehension impairments, the relationship between auditory versus reading comprehension deficits and the crucial neuroanatomy supporting the dissociation between post-stroke reading and auditory deficits. Scores from the Western Aphasia Battery-Revised from 70 participants with aphasia after a left-hemisphere stroke were utilized to evaluate both reading and auditory comprehension of linguistically equivalent stimuli. Repeated-measures and univariate ANOVA were used to assess the relationship between auditory comprehension and aphasia types and correlations were employed to test the relationship between reading and auditory comprehension deficits. Lesion-symptom mapping was used to determine the dissociation of crucial brain structures supporting reading comprehension deficits controlling for auditory deficits and vice versa. Participants with Broca\'s or global aphasia had the worst performance on reading comprehension. Auditory comprehension explained 26% of the variance in reading comprehension for sentence completion and 44% for following sequential commands. Controlling for auditory comprehension, worse reading comprehension performance was independently associated with damage to the inferior temporal gyrus, fusiform gyrus, posterior inferior temporal gyrus, inferior occipital gyrus, lingual gyrus and posterior thalamic radiation. Auditory and reading comprehension are only partly correlated in aphasia. Reading is an integral part of daily life and directly associated with quality of life and functional outcomes. This study demonstrated that reading performance is directly related to lesioned areas in the boundaries between visual association regions and ventral stream language areas. This behavioural and neuroanatomical dissociation provides information about the neurobiology of language and mechanisms for potential future treatment interventions.

Mental rotation (MR) is widely regarded as a quintessential example of an embodied cognitive process. This viewpoint stems from the functional parallels between MR and the physical rotation of tangible objects, as well as participants\' inclination to employ motor-based strategies when tackling MR tasks involving bodily stimuli. These commonalities imply that MR may depend on brain regions crucial for the planning and execution of motor programs. However, there is disagreement regarding the anatomy of MR between findings from functional imaging and lesion studies involving brain-injured patients. The former indicate the involvement of the right-hemispheric parietal cortex, while the latter underscore the significance of posterior areas in the left hemisphere. In this study, we aimed to discern the neural underpinnings of MR using lesion-symptom mapping (LSM) for both bodily (hands) and non-bodily (letters) stimuli. Behavioral results from the two MR tasks revealed impaired MR of bodily stimuli in patients with left hemisphere damage. LSM results pinpointed the left primary motor and somatosensory cortices, along with the superior parietal lobule, as the anatomical substrates of MR for both bodily and non-bodily stimuli. Furthermore, damage to the left angular gyrus, supramarginal gyrus, supplementary motor area, and retrosplenial cortex was associated with MR of non-bodily stimuli. These findings support the causal involvement of the left hemisphere in MR and underscore the existence of a common anatomical substrate in brain regions pertinent to motor planning and execution.

Sentence structure, or syntax, is potentially a uniquely creative aspect of the human mind. Neuropsychological experiments in the 1970s suggested parallel syntactic production and comprehension deficits in agrammatic Broca\'s aphasia, thought to result from damage to syntactic mechanisms in Broca\'s area in the left frontal lobe. This hypothesis was sometimes termed overarching agrammatism, converging with developments in linguistic theory concerning central syntactic mechanisms supporting language production and comprehension. However, the evidence supporting an association among receptive syntactic deficits, expressive agrammatism, and damage to frontal cortex is equivocal. In addition, the relationship among a distinct grammatical production deficit in aphasia, paragrammatism, and receptive syntax has not been assessed. We used lesion-symptom mapping in three partially overlapping groups of left-hemisphere stroke patients to investigate these issues: grammatical production deficits in a primary group of 53 subjects and syntactic comprehension in larger sample sizes (N = 130, 218) that overlapped with the primary group. Paragrammatic production deficits were significantly associated with multiple analyses of syntactic comprehension, particularly when incorporating lesion volume as a covariate, but agrammatic production deficits were not. The lesion correlates of impaired performance of syntactic comprehension were significantly associated with damage to temporal lobe regions, which were also implicated in paragrammatism, but not with the inferior and middle frontal regions implicated in expressive agrammatism. Our results provide strong evidence against the overarching agrammatism hypothesis. By contrast, our results suggest the possibility of an alternative grammatical parallelism hypothesis rooted in paragrammatism and a central syntactic system in the posterior temporal lobe.

This paper considers the steps needed to generate pragmatic and interpretable lesion-symptom mappings that can be used for clinically reliable prognoses. The novel contributions are 3-fold. We first define and inter-relate five neurobiological and five methodological constraints that need to be accounted for when interpreting lesion-symptom associations and generating synthetic lesion data. The first implication is that, because of these constraints, lesion-symptom mapping needs to focus on probabilistic relationships between Lesion and Symptom, with Lesion as a multivariate spatial pattern, Symptom as a time-dependent behavioural profile and evidence that Lesion raises the probability of Symptom. The second implication is that in order to assess the strength of probabilistic causality, we need to distinguish between causal lesion sites, incidental lesion sites, spared but dysfunctional sites and intact sites, all of which might affect the accuracy of the predictions and prognoses generated. We then formulate lesion-symptom mappings in logical notations, including combinatorial rules, that are then used to evaluate and better understand complex brain-behaviour relationships. The logical and theoretical framework presented applies to any type of neurological disorder but is primarily discussed in relationship to stroke damage. Accommodating the identified constraints, we discuss how the 1965 Bradford Hill criteria for inferring probabilistic causality, post hoc, from observed correlations in epidemiology-can be applied to lesion-symptom mapping in stroke survivors. Finally, we propose that rather than rely on post hoc evaluation of how well the causality criteria have been met, the neurobiological and methodological constraints should be addressed, a priori, by changing the experimental design of lesion-symptom mappings and setting up an open platform to share and validate the discovery of reliable and accurate lesion rules that are clinically useful.

Aphasia is an acquired disorder caused by damage, most commonly due to stroke, to brain regions involved in speech and language. While language impairment is the defining symptom of aphasia, the co-occurrence of non-language cognitive deficits and their importance in predicting rehabilitation and recovery outcomes is well documented. However, people with aphasia (PWA) are rarely tested on higher-order cognitive functions, making it difficult for studies to associate these functions with a consistent lesion correlate. Broca\'s area is a particular brain region of interest that has long been implicated in speech and language production. Contrary to classic models of speech and language, cumulative evidence shows that Broca\'s area and surrounding regions in the left inferior frontal cortex (LIFC) are involved in, but not specific to, speech production. In this study we aimed to explore the brain-behaviour relationships between tests of cognitive skill and language abilities in thirty-six adults with long-term speech production deficits caused by post-stroke aphasia. Our findings suggest that non-linguistic cognitive functions, namely executive functions and verbal working memory, explain more of the behavioural variance in PWA than classical language models imply. Additionally, lesions to the LIFC, including Broca\'s area, were associated with non-linguistic executive (dys)function, suggesting that lesions to this area are associated with non-language-specific higher-order cognitive deficits in aphasia. Whether executive (dys)function - and its neural correlate in Broca\'s area - contributes directly to PWA\'s language production deficits or simply co-occurs with it, adding to communication difficulties, remains unclear. These findings support contemporary models of speech production that place language processing within the context of domain-general perception, action and conceptual knowledge. An understanding of the covariance between language and non-language deficits and their underlying neural correlates will inform better targeted aphasia treatment and outcomes.