Multivariate Lesion-symptom Mapping Research Articles

Multivariate mapping of low-resilient neurocognitive systems within and around low-grade gliomas.

Accumulating evidence suggests that the brain exhibits a remarkable capacity for functional compensation in response to neurological damage, a resilience potential that is deeply rooted in the malleable features of its underlying anatomo-functional architecture. This propensity is particularly exemplified by diffuse low-grade gliomas (DLGGs), a subtype of primary brain tumour. However, functional plasticity is not boundless, and surgical resections directed at structures with limited neuroplasticity may lead to incapacitating impairments. Yet, maximizing DLGG resections offers substantial oncological benefits, especially when the resection extends beyond the tumour margins (i.e., supra-tumour or supra-total resection). In this context, the primary objective of this study was to identify which cerebral structures were associated with less favourable cognitive outcomes after surgery, while accounting for intra-tumour and supra-tumour features of the surgical resections. To reach this objective, we leveraged a unique cohort of 400 DLGG patients who underwent surgery with awake cognitive mapping. Patients benefited from a neuropsychological assessment consisting of 18 subtests administered before and 3 months post-surgery. We analysed changes in performance and applied topography-focused and disconnection-focused multivariate lesion-symptom mapping (LSM) using support vector regressions with an attempt to capture resected cortico-subcortical structures less amenable to full cognitive compensations. The observed changes in performance were of a limited magnitude suggesting an overall recovery (13/18 tasks fully recovered despite a mean resection extent of 92.4%). Nevertheless, LSM analyses revealed that a lack of recovery in picture naming was linked to damage in the left inferior temporal gyrus and inferior longitudinal fasciculus. Similarly, for semantic fluency abilities, an association was established with damage to the left precuneus/posterior cingulate. For phonologic fluency abilities, the left dorso-medial frontal cortex and the frontal aslant tract were implicated. Moreover, difficulties in spatial exploration were associated with injury to the right dorsomedial prefrontal cortex and its underlying connectivity. An exploratory analysis suggested that supra-tumoral resections were associated with a less pronounced recovery following specific resection patterns, such as supra-tumour resections of the left uncinate fasciculus (picture naming), the left corticostriatal tract and the anterior corpus callosum (phonologic fluency), the hippocampus and para-hippocampus (episodic memory), and the right frontal-mesial areas (visuospatial exploration). Collectively, these patterns of results shed new light on both low-resilient neural systems and the prediction of cognitive recovery following glioma surgery. Furthermore, they indicate that supra-tumour resections were only occasionally less well-tolerated from a cognitive viewpoint. In doing so, they have deep implications for surgical planning and rehabilitation strategies.

Multivariate lesion symptom mapping for predicting trajectories of recovery from aphasia.

Individuals with post-stroke aphasia tend to recover their language to some extent; however, it remains challenging to reliably predict the nature and extent of recovery that will occur in the long term. The aim of this study was to quantitatively predict language outcomes in the first year of recovery from aphasia across multiple domains of language and at multiple timepoints post-stroke. We recruited 217 patients with aphasia following acute left hemisphere ischaemic or haemorrhagic stroke and evaluated their speech and language function using the Quick Aphasia Battery acutely and then acquired longitudinal follow-up data at up to three timepoints post-stroke: 1 month (n = 102), 3 months (n = 98) and 1 year (n = 74). We used support vector regression to predict language outcomes at each timepoint using acute clinical imaging data, demographic variables and initial aphasia severity as input. We found that ∼60% of the variance in long-term (1 year) aphasia severity could be predicted using these models, with detailed information about lesion location importantly contributing to these predictions. Predictions at the 1- and 3-month timepoints were somewhat less accurate based on lesion location alone, but reached comparable accuracy to predictions at the 1-year timepoint when initial aphasia severity was included in the models. Specific subdomains of language besides overall severity were predicted with varying but often similar degrees of accuracy. Our findings demonstrate the feasibility of using support vector regression models with leave-one-out cross-validation to make personalized predictions about long-term recovery from aphasia and provide a valuable neuroanatomical baseline upon which to build future models incorporating information beyond neuroanatomical and demographic predictors.

Impaired discourse content in aphasia is associated with frontal white matter damage.

Aphasia is a common consequence of stroke with severe impacts on employability, social interactions and quality of life. Producing discourse-relevant information in a real-world setting is the most important aspect of recovery because it is critical to successful communication. This study sought to identify the lesion correlates of impaired production of relevant information in spoken discourse in a large, unselected sample of participants with post-stroke aphasia. Spoken discourse (n = 80) and structural brain scans (n = 66) from participants with aphasia following left hemisphere stroke were analysed. Each participant provided 10 samples of spoken discourse elicited in three different genres, and 'correct information unit' analysis was used to quantify the informativeness of speech samples. The lesion correlates were identified using multivariate lesion-symptom mapping, voxel-wise disconnection and tract-wise analyses. Amount and speed of relevant information were highly correlated across different genres and with total lesion size. The analyses of lesion correlates converged on the same pattern: impaired production of relevant information was associated with damage to anterior dorsal white matter pathways, specifically the arcuate fasciculus, frontal aslant tract and superior longitudinal fasciculus. Damage to these pathways may be a useful biomarker for impaired informative spoken discourse and informs development of neurorehabilitation strategies.

Localization of a Medial Temporal Lobe-Precuneus Network for Time Orientation.

Time orientation is a fundamental cognitive process in which one's personal sense of time is matched with a universal reference. Time orientation is commonly assessed through mental status examination, yet its neural correlates remain unclear. Large lesions have been associated with deficits in time orientation, but the regional anatomy implicated in time disorientation is not well established. The current study investigates the anatomy of time disorientation and its network correlates in patients with focal brain lesions. Time orientation was assessed 3 months or more after lesion onset using the Benton Temporal Orientation Test (BTOT) in 550 patients with acquired, focal brain lesions, 39 of whom were impaired. Multivariate lesion-symptom mapping and lesion network mapping were used to evaluate the anatomy and networks associated with time disorientation. Performance on a variety of neuropsychological tests was compared between the time oriented and time disoriented group. Lesion-symptom mapping showed that lesions of the precuneus, medial temporal lobes (MTL), and occipito-temporal cortex were associated with time disorientation (r = 0.264, p < 0.001). Lesion network mapping using normative connectome data demonstrated that these regional findings occurred along a network that includes white and gray matter connecting the precuneus and MTL. There was a strong behavioral and anatomical association of time disorientation with memory impairment, such that the 2 processes could not be fully disentangled. We interpret these findings as novel evidence for a network involving the precuneus and the medial temporal lobe in supporting time orientation. ANN NEUROL 2023;94:421-433.

Benefit of visual speech information for word comprehension in post-stroke aphasia

Aphasia is a language disorder that often involves speech comprehension impairments affecting communication. In face-to-face settings, speech is accompanied by mouth and facial movements, but little is known about the extent to which they benefit aphasic comprehension. This study investigated the benefit of visual information accompanying speech for word comprehension in people with aphasia (PWA) and the neuroanatomic substrates of any benefit. Thirty-six PWA and 13 neurotypical matched control participants performed a picture-word verification task in which they indicated whether a picture of an animate/inanimate object matched a subsequent word produced by an actress in a video. Stimuli were either audiovisual (with visible mouth and facial movements) or auditory-only (still picture of a silhouette) with audio being clear (unedited) or degraded (6-band noise-vocoding). We found that visual speech information was more beneficial for neurotypical participants than PWA, and more beneficial for both groups when speech was degraded. A multivariate lesion-symptom mapping analysis for the degraded speech condition showed that lesions to superior temporal gyrus, underlying insula, primary and secondary somatosensory cortices, and inferior frontal gyrus were associated with reduced benefit of audiovisual compared to auditory-only speech, suggesting that the integrity of these fronto-temporo-parietal regions may facilitate cross-modal mapping. These findings provide initial insights into our understanding of the impact of audiovisual information on comprehension in aphasia and the brain regions mediating any benefit.

Network Architecture of Verticality Processing in the Human Thalamus.

Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023.

Reduced likelihood of the Poggendorff illusion in cerebellar strokes: a clinical and neuroimaging study.

This study aimed to test our hypothesis that the cerebellum plays an important role in the generation of the optical-geometric illusion known as the Poggendorff illusion, the mechanism of which has been explained by accumulated experience with natural scene geometry. A total of 79 participants, comprising 28 patients with isolated cerebellar stroke, 27 patients with isolated cerebral stroke and 24 healthy controls, performed Poggendorff illusion tasks and 2 different control tasks. We also investigated core brain regions underpinning changes in the experience of the illusion effect using multivariate lesion-symptom mapping. Our results indicate that patients with isolated cerebellar stroke were significantly less likely to experience the Poggendorff illusion effect than patients with isolated cerebral stroke or healthy controls (74.6, 90.5 and 89.8%, respectively; F(2,76) = 6.675, P = 0.002). However, there were no inter-group differences in the control tasks. Lesion-symptom mapping analysis revealed that the brain lesions associated with the reduced frequency of the Poggendorff illusion effect were mainly centred on the right posteromedial cerebellar region, including the right lobules VI, VII, VIII, IX and Crus II. Our findings demonstrated, for the first time, that patients with cerebellar damage were significantly less likely to experience the Poggendorff illusion effect and that right posteromedial cerebellar lesions played an important role in this effect. These results provide new insight into alterations of a geometric illusion effect in patients with cerebellar disorders and pave the way for future clinical use of the illusion task to detect cerebellar abnormalities.

Amygdala lesions are associated with improved mood after epilepsy surgery.

Neuroimaging studies in healthy and clinical populations strongly associate the amygdala with emotion, especially negative emotions. The consequences of surgical resection of the amygdala on mood are not well characterized. We tested the hypothesis that amygdala resection would result in mood improvement. In this study, we evaluated a cohort of 52 individuals with medial temporal lobectomy for intractable epilepsy who had resections variably involving the amygdala. All individuals achieved good post-surgical seizure control and had pre- and post-surgery mood assessment with the Beck Depression Inventory (BDI) ratings. We manually segmented the surgical resection cavities and performed multivariate lesion-symptom mapping of change in BDI. Our results showed a significant improvement in average mood ratings from pre- to post-surgery across all patients. In partial support of our hypothesis, resection of the right amygdala was significantly associated with mood improvement (r = 0.5, p = 0.008). The lesion-symptom map also showed that resection of the right hippocampus and para-hippocampal gyrus was associated with worsened post-surgical mood. Future studies could evaluate this finding prospectively in larger samples while including other neuropsychological outcome measures.

Behavioural and neural structure of fluent speech production deficits in aphasia.

Deficits in fluent speech production following left hemisphere stroke are a central concern because of their impact on patients' lives and the insight they provide about the neural organization of language processing. Fluent speech production requires the rapid coordination of phonological, semantic, and syntactic processing, so this study examined how deficits in connected speech relate to these language sub-systems. Behavioural data (N = 69 participants with aphasia following left hemisphere stroke) consisted of a diverse and comprehensive set of narrative speech production measures and measures of overall severity, semantic deficits, and phonological deficits. These measures were entered into a principal component analysis with bifactor rotation-a latent structure model where each item loads on a general factor that reflects what is common among the items, and orthogonal factors that explain variance not accounted for by the general factor. Lesion data were available for 58 of the participants, and each factor score was analysed with multivariate lesion-symptom mapping. Effects of connectivity disruption were evaluated using robust regression with tract disconnection or graph theoretic measures of connectivity as predictors. The principal component analysis produced a four-factor solution that accounted for 70.6% of the variance in the data, with a general factor corresponding to the overall severity and length and complexity of speech output (complexity factor), a lexical syntax factor, and independent factors for Semantics and Phonology. Deficits in the complexity of speech output were associated with a large temporo-parietal region, similar to overall aphasia severity. The lexical syntax factor was associated with damage in a relatively small set of fronto-parietal regions which may reflect the recruitment of control systems to support retrieval and correct usage of lexical items that primarily serve a syntactic rather than semantic function. Tract-based measures of connectivity disruption were not statistically associated with the deficit scores after controlling for overall lesion volume. Language network efficiency and average clustering coefficient within the language network were significantly associated with deficit scores after controlling for overall lesion volume. These results highlight overall severity as the critical contributor to fluent speech in post-stroke aphasia, with a dissociable factor corresponding to lexical syntax.

Poststroke action slowing: Motor and attentional impairments and their imaging determinants. Evidence from lesion-symptom mapping, disconnection and fMRI activation studies

Background and objectivesAlthough action slowing is the main cognitive impairment in stroke survivors, its mechanisms and determinants are still poorly understood. The objectives of the present study were to determine the mechanisms of post-stroke action slowing (using validated, highly specific simple reaction time (SRT) and tapping tests) and identify its imaging determinants (using multivariate lesion-symptom mapping (mLSM)). MethodsAction speed in the GRECogVASC cohort was assessed using finger tapping and SRT tests performed with both hands and analyzed using previously validated indices. Imaging determinants were identified using validated mLSM analyses and disconnection analysis and compared to those of an fMRI activation meta-analytic database. ResultsBoth the tapping time and SRT were 10.7% slower for the 394 patients (p = 0.0001) than for the 786 controls, without a group × test interaction (p = 0.2). The intra-individual distribution curve was characterized by a rightward shift with an unaltered attentional peak. The mLSM analyses showed tapping to be associated with lesions in the frontostriatal tract (p = 0.0007). The SRT was associated with lesions in the frontostriatal tract (p = 0.04) and the orbital part of F3 (p = 0.0001). The SRT-tapping index was associated with lesions in the orbital part of F3 (p = 0.0001). All lesions were located in the right hemisphere only and were responsible for the disconnection of several structures involved in motor preparation, initiation, and speed. A comparison with fMRI activation meta-analytic data highlighted mostly the same regions, including the orbital part of F3, the ventral and dorsal parts of F1, and the premotor and cingulate regions in the right hemisphere. DiscussionOur results confirm the marked impairment of action speed in stroke and show that the primary mechanism is motor slowing and that it is related to lesions in the right frontostriatal tract. A deficit in sustained alertness accounted for action slowing in the subgroup with lesions in the right orbital part of F3. Our SRT and mLSM results were in accordance with the fMRI activation data. Thus, stroke induces slowing in the broad network associated with SRT tasks by disrupting the frontostriatal tract and, to a lesser extent, other sites involved in attention.

Use of multi-perturbation Shapley analysis in lesion studies of functional networks: The case of upper limb paresis.

Understanding the impact of variation in lesion topography on the expression of functional impairments following stroke is important, as it may pave the way to modeling structure-function relations in statistical terms while pointing to constraints for adaptive remapping and functional recovery. Multi-perturbation Shapley-value analysis (MSA) is a relatively novel game-theoretical approach for multivariate lesion-symptom mapping. In this methodological paper, we provide a comprehensive explanation of MSA. We use synthetic data to assess the method's accuracy and perform parameter optimization. We then demonstrate its application using a cohort of 107 first-event subacute stroke patients, assessed for upper limb (UL) motor impairment (Fugl-Meyer Assessment scale). Under the conditions tested, MSA could correctly detect simulated ground-truth lesion-symptom relationships with a sensitivity of 75% and specificity of ~90%. For real behavioral data, MSA disclosed a strong hemispheric effect in the relative contribution of specific regions-of-interest (ROIs): poststroke UL motor function was mostly contributed by damage to ROIs associated with movement planning (supplementary motor cortex and superior frontal gyrus) following left-hemispheric damage (LHD) and by ROIs associated with movement execution (primary motor and somatosensory cortices and the ventral brainstem) following right-hemispheric damage (RHD). Residual UL motor ability following LHD was found to depend on a wider array of brain structures compared to the residual motor ability of RHD patients. The results demonstrate that MSA can provide a unique insight into the relative importance of different hubs in neural networks, which is difficult to obtain using standard univariate methods.

Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience.

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion-symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as 'risk' versus 'resilience' regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion-symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak 'risk' regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these 'risk' regions localized to nodes of the salience network. Peak 'resilience' regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as 'risk' tracts and ventral prefrontal white matter tracts as 'resilience' tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.

Central precuneus lesions are associated with impaired executive function.

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.

Efficient and effective assessment of deficits and their neural bases in stroke aphasia

ObjectiveMulti-assessment batteries are necessary for diagnosing and quantifying the multifaceted deficits observed post-stroke. Extensive batteries are thorough but impractically long for clinical settings or large-scale research studies. Clinically-targeted “shallow” batteries superficially cover a wide range of language skills relatively quickly but can struggle to identify mild deficits or quantify the impairment level. Our aim was to compare these batteries across a large group of chronic stroke aphasia and to test a novel data-driven reduced version of an extensive battery that maintained sensitivity to mild impairment, ability to grade deficits and the underlying component structure. MethodsWe tested 75 chronic left-sided stroke participants, spanning global to mild aphasia. The underlying structure of these three batteries was analysed using cross-validation and principal component analysis, in addition to univariate and multivariate lesion-symptom mapping. ResultsThis revealed a four-factor solution for the extensive and data-reduced batteries, identifying phonology, semantic skills, fluency and executive function in contrast to a two-factor solution using the shallow battery (language severity and cognitive severity). Lesion symptom mapping using participants’ factor scores identified convergent neural structures for phonology (superior temporal gyrus), semantics (inferior temporal gyrus), speech fluency (precentral gyrus) and executive function (lateral occipitotemporal cortex). The two shallow battery components converged with the phonology and executive function clusters. In addition, we show that multivariate models could predict the component scores using neural data, however not for every component. ConclusionsOverall, the data-driven battery appears to be an effective way to save time yet retain maintained sensitivity to mild impairment, ability to grade deficits and the underlying component structure observed in post-stroke aphasia.

Neural Substrates of Poststroke Depression: Current Opinions and Methodology Trends.

Poststroke depression (PSD), affecting about one-third of stroke survivors, exerts significant impact on patients’ functional outcome and mortality. Great efforts have been made since the 1970s to unravel the neuroanatomical substrate and the brain-behavior mechanism of PSD. Thanks to advances in neuroimaging and computational neuroscience in the past two decades, new techniques for uncovering the neural basis of symptoms or behavioral deficits caused by focal brain damage have been emerging. From the time of lesion analysis to the era of brain networks, our knowledge and understanding of the neural substrates for PSD are increasing. Pooled evidence from traditional lesion analysis, univariate or multivariate lesion-symptom mapping, regional structural and functional analyses, direct or indirect connectome analysis, and neuromodulation clinical trials for PSD, to some extent, echoes the frontal-limbic theory of depression. The neural substrates of PSD may be used for risk stratification and personalized therapeutic target identification in the future. In this review, we provide an update on the recent advances about the neural basis of PSD with the clinical implications and trends of methodology as the main features of interest.

Lesion correlates of auditory sentence comprehension deficits in post-stroke aphasia

Auditory sentence comprehension requires coordination of multiple levels of processing: auditory-phonological perception, lexical-semantic comprehension, syntactic parsing and discourse construction, as well as executive functions such as verbal working memory (WM) and cognitive control. This study examined the lesion correlates of sentence comprehension deficits in post-stroke aphasia, building on prior work on this topic by using a different and clinically-relevant measure of sentence comprehension (the Token Test) and multivariate (SCCAN) and connectome-based lesion-symptom mapping methods. The key findings were that lesions in the posterior superior temporal lobe and inferior frontal gyrus (pars triangularis) were associated with sentence comprehension deficits, which was observed in both mass univariate and multivariate lesion-symptom mapping. Graph theoretic measures of connectome disruption were not statistically significantly associated with sentence comprehension deficits after accounting for overall lesion size.

Neuroanatomical correlates of speech and singing production in chronic post-stroke aphasia.

A classical observation in neurology is that aphasic stroke patients with impairments in speech production can nonetheless sing the same utterances. This preserved ability suggests a distinctive neural architecture for singing that could contribute to speech recovery. However, to date, these structural correlates remain unknown. Here, we combined a multivariate lesion–symptom mapping and voxel-based morphometry approach to analyse the relationship between lesion patterns and grey matter volume and production rate in speech and singing tasks. Lesion patterns for spontaneous speech and cued repetition extended into frontal, temporal and parietal areas typically reported within the speech production network. Impairment in spontaneous singing was associated with damage to the left anterior–posterior superior and middle temporal gyri. Preservation of grey matter volume in the same regions where damage led to poor speech and singing production supported better performance in these tasks. When dividing the patients into fluent and dysfluent singers based on the singing performance from demographically matched controls, we found that the preservation of the left middle temporal gyrus was related to better spontaneous singing. These findings provide insights into the structural correlates of singing in chronic aphasia and may serve as biomarkers to predict treatment response in clinical trials using singing-based interventions for speech rehabilitation.

Stimulation of frontal pathways disrupts hand muscle control during object manipulation.

The activity of frontal motor areas during hand-object interaction is coordinated by dense communication along specific white matter pathways. This architecture allows the continuous shaping of voluntary motor output but, despite extensive investigation in non-human primate studies, remains poorly understood in humans. Disclosure of this system is crucial for predicting and treatment of motor deficits after brain lesions.For this purpose, we investigated the effect of direct electrical stimulation on white matter pathways within the frontal lobe on hand-object manipulation. This was tested in 34 patients (15 left hemisphere, mean age 42 years, 17 male, 15 with tractography) undergoing awake neurosurgery for frontal lobe tumour removal with the aid of the brain mapping technique. The stimulation outcome was quantified based on hand-muscle activity required by task execution. The white matter pathways responsive to stimulation with an interference on muscles were identified by means of probabilistic density estimation of stimulated sites, tract-based lesion-symptom (disconnectome) analysis and diffusion tractography on the single patient level. Finally, we assessed the effect of permanent tract disconnection on motor outcome in the immediate postoperative period using a multivariate lesion-symptom mapping approach.The analysis showed that stimulation disrupted hand-muscle activity during task execution at 66 sites within the white matter below dorsal and ventral premotor regions. Two different EMG interference patterns associated with different structural architectures emerged: (i) an ‘arrest’ pattern, characterized by complete impairment of muscle activity associated with an abrupt task interruption, occurred when stimulating a white matter area below the dorsal premotor region. Local middle U-shaped fibres, superior fronto-striatal, corticospinal and dorsal fronto-parietal fibres intersected with this region. (ii) a ‘clumsy’ pattern, characterized by partial disruption of muscle activity associated with movement slowdown and/or uncoordinated finger movements, occurred when stimulating a white matter area below the ventral premotor region. Ventral fronto-parietal and inferior fronto-striatal tracts intersected with this region. Finally, only resections partially including the dorsal white matter region surrounding the supplementary motor area were associated with transient upper-limb deficit (P = 0.05; 5000 permutations).Overall, the results identify two distinct frontal white matter regions possibly mediating different aspects of hand-object interaction via distinct sets of structural connectivity. We suggest the dorsal region, associated with arrest pattern and postoperative immediate motor deficits, to be functionally proximal to motor output implementation, while the ventral region may be involved in sensorimotor integration required for task execution.

Auditory Comprehension Deficits in Post-stroke Aphasia: Neurologic and Demographic Correlates of Outcome and Recovery.

Introduction: One of the most challenging symptoms of aphasia is an impairment in auditory comprehension. The inability to understand others has a direct impact on a person's quality of life and ability to benefit from treatment. Despite its importance, limited research has examined the recovery pattern of auditory comprehension and instead has focused on aphasia recovery more generally. Thus, little is known about the time frame for auditory comprehension recovery following stroke, and whether specific neurologic and demographic variables contribute to recovery and outcome.Methods: This study included 168 left hemisphere chronic stroke patients stroke patients with auditory comprehension impairments ranging from mild to severe. Univariate and multivariate lesion-symptom mapping (LSM) was used to identify brain regions associated with auditory comprehension outcomes on three different tasks: Single-word comprehension, yes/no sentence comprehension, and comprehension of sequential commands. Demographic variables (age, gender, and education) were also examined for their role in these outcomes. In a subset of patients who completed language testing at two or more time points, we also analyzed the trajectory of recovery in auditory comprehension using survival curve-based time compression.Results: LSM analyses revealed that poor single-word auditory comprehension was associated with lesions involving the left mid- to posterior middle temporal gyrus, and portions of the angular and inferior-middle occipital gyri. Poor yes/no sentence comprehension was associated almost exclusively with the left mid-posterior middle temporal gyrus. Poor comprehension of sequential commands was associated with lesions in the left posterior middle temporal gyrus. There was a small region of convergence between the three comprehension tasks, in the very posterior portion of the left middle temporal gyrus. The recovery analysis revealed that auditory comprehension scores continued to improve beyond the first year post-stroke. Higher education was associated with better outcome on all auditory comprehension tasks. Age and gender were not associated with outcome or recovery slopes.Conclusions: The current findings suggest a critical role for the posterior left middle temporal gyrus in the recovery of auditory comprehension following stroke, and that spontaneous recovery of auditory comprehension can continue well beyond the first year post-stroke.

Distinct Neural Substrates Support Phonological and Orthographic Working Memory: Implications for Theories of Working Memory.

Prior behavioral and neuroimaging evidence supports a separation between working memory capacities in the phonological and orthographic domains. Although these data indicate distinct buffers for orthographic and phonological information, prior neural evidence does indicate that nearby left inferior parietal regions support both of these working memory capacities. Given that no study has directly compared their neural substrates based on data from the same individuals, it is possible that there is a common left inferior parietal region shared by both working memory capacities. In fact, those endorsing an embedded processes account of working memory might suggest that parietal involvement reflects a domain-general attentional system that directs attention to long-term memory representations in the two domains, implying that the same neural region supports the two capacities. Thus, in this work, a multivariate lesion-symptom mapping approach was used to assess the neural basis of phonological and orthographic working memory using behavioral and lesion data from the same set of 37 individuals. The results showed a separation of the neural substrates, with regions in the angular gyrus supporting orthographic working memory and with regions primarily in the supramarginal gyrus supporting phonological working memory. The results thus argue against the parietal involvement as supporting a domain-general attentional mechanism and support a domain-specific buffer account of working memory.