Rapid auditory and phonemic processing relies on the left planum temporale.

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.

Rethinking Remapping: Circuit Mechanisms of Recovery after Stroke.

Stroke is one of the most common causes of disability, and there are few treatments that can improve recovery after stroke. Therapeutic development has been hindered because of a lack of understanding of precisely how neural circuits are affected by stroke, and how these circuits change to mediate recovery. Indeed, some of the hypotheses for how the CNS changes to mediate recovery, including remapping, redundancy, and diaschisis, date to more than a century ago. Recent technological advances have enabled the interrogation of neural circuits with ever greater temporal and spatial resolution. These techniques are increasingly being applied across animal models of stroke and to human stroke survivors, and are shedding light on the molecular, structural, and functional changes that neural circuits undergo after stroke. Here we review these studies and highlight important mechanisms that underlie impairment and recovery after stroke. We begin by summarizing knowledge about changes in neural activity that occur in the peri-infarct cortex, specifically considering evidence for the functional remapping hypothesis of recovery. Next, we describe the importance of neural population dynamics, disruptions in these dynamics after stroke, and how allocation of neurons into spared circuits can restore functionality. On a more global scale, we then discuss how effects on long-range pathways, including interhemispheric interactions and corticospinal tract transmission, contribute to post-stroke impairments. Finally, we look forward and consider how a deeper understanding of neural circuit mechanisms of recovery may lead to novel treatments to reduce disability and improve recovery after stroke.

Listening to Yourself and Watching Your Tongue: Distinct Abilities and Brain Regions for Monitoring Semantic and Phonological Speech Errors.

Despite the many mistakes we make while speaking, people can effectively communicate because we monitor our speech errors. However, the cognitive abilities and brain structures that support speech error monitoring are unclear. There may be different abilities and brain regions that support monitoring phonological speech errors versus monitoring semantic speech errors. We investigated speech, language, and cognitive control abilities that relate to detecting phonological and semantic speech errors in 41 individuals with aphasia who underwent detailed cognitive testing. Then, we used support vector regression lesion symptom mapping to identify brain regions supporting detection of phonological versus semantic errors in a group of 76 individuals with aphasia. The results revealed that motor speech deficits as well as lesions to the ventral motor cortex were related to reduced detection of phonological errors relative to semantic errors. Detection of semantic errors selectively related to auditory word comprehension deficits. Across all error types, poor cognitive control related to reduced detection. We conclude that monitoring of phonological and semantic errors relies on distinct cognitive abilities and brain regions. Furthermore, we identified cognitive control as a shared cognitive basis for monitoring all types of speech errors. These findings refine and expand our understanding of the neurocognitive basis of speech error monitoring.

Aphasia severity is modulated by race and lesion size in chronic survivors: A retrospective study.

INTRODUCTION: In stroke survivors with aphasia (SWA), differences in behavioral language performance have been observed between Black and White Americans. These racial differences in aphasia outcomes may reflect biological stroke severity, disparities in access to care, potential assessment bias, or interactions between these factors and race. Understanding the origin of disparities in aphasia outcomes is critical to any efforts to promote health equity among SWA. In this study, we explore aphasia outcomes by examining the relationship between race, socioeconomic status, and neurological factors in SWA. METHOD: Eighty-five chronic left-hemisphere SWA (31 Black, 54 White) participated in the study. The primary aphasia outcome measure was the Western Aphasia Battery-Revised (WAB-R). Lesion size was measured based on manual lesion segmentations. FLAIR and T2 images were scored for severity of white matter disease. Independent sample t-tests were used to determine differences by race in education, age, income, aphasia severity, white matter disease, and lesion size. A linear regression model was used to explore factors that predicted aphasia severity on the WAB-R. RESULT: Level of education and estimated income differed by race in our sample. For predictors of aphasia severity, the regression model revealed a significant effect of lesion size on WAB Aphasia Quotient and an interaction of race x lesion size, such that Black and White participants with small lesions had similar WAB scores, but in individuals with larger lesions, Black participants had lower WAB scores than White participants. CONCLUSION: We suggest two explanations for the difference between Black and White SWA in the relationship between lesion size and aphasia severity. First, the impact of disparities in access to rehabilitation after stroke may be more evident when a stroke is larger and causes significant aphasia. Additionally, an assessment bias in aphasia outcome measures may be more evident with increasing severity of aphasia. Future studies should further discern the drivers of observed disparities in aphasia outcomes in order to identify opportunities to improve equity in aphasia care.

The organization of individually mapped structural and functional semantic networks in aging adults.

Language function in the brain, once thought to be highly localized, is now appreciated as relying on a connected but distributed network. The semantic system is of particular interest in the language domain because of its hypothesized integration of information across multiple cortical regions. Previous work in healthy individuals has focused on group-level functional connectivity (FC) analyses of the semantic system, which may obscure interindividual differences driving variance in performance. These studies also overlook the contributions of white matter networks to semantic function. Here, we identified semantic network nodes at the individual level with a semantic decision fMRI task in 53 typically aging adults, characterized network organization using structural connectivity (SC), and quantified the segregation and integration of the network using FC. Hub regions were identified in left inferior frontal gyrus. The individualized semantic network was composed of three interacting modules: (1) default-mode module characterized by bilateral medial prefrontal and posterior cingulate regions and also including right-hemisphere homotopes of language regions; (2) left frontal module extending dorsally from inferior frontal gyrus to pre-motor area; and (3) left temporoparietal module extending from temporal pole to inferior parietal lobule. FC within Module3 and integration of the entire network related to a semantic verbal fluency task, but not a matched phonological task. These results support and extend the tri-network semantic model (Xu in Front Psychol 8: 1538 1538, 2017) and the controlled semantic cognition model (Chiou in Cortex 103: 100 116, 2018) of semantic function.

Simulated Attack Reveals How Lesions Affect Network Properties in Poststroke Aphasia.

Aphasia is a prevalent cognitive syndrome caused by stroke. The rarity of premorbid imaging and heterogeneity of lesion obscures the links between the local effects of the lesion, global anatomic network organization, and aphasia symptoms. We applied a simulated attack approach in humans to examine the effects of 39 stroke lesions (16 females) on anatomic network topology by simulating their effects in a control sample of 36 healthy (15 females) brain networks. We focused on measures of global network organization thought to support overall brain function and resilience in the whole brain and within the left hemisphere. After removing lesion volume from the network topology measures and behavioral scores [the Western Aphasia Battery Aphasia Quotient (WAB-AQ), four behavioral factor scores obtained from a neuropsychological battery, and a factor sum], we compared the behavioral variance accounted for by simulated poststroke connectomes to that observed in the randomly permuted data. Global measures of anatomic network topology in the whole brain and left hemisphere accounted for 10% variance or more of the WAB-AQ and the lexical factor score beyond lesion volume and null permutations. Streamline networks provided more reliable point estimates than FA networks. Edge weights and network efficiency were weighted most highly in predicting the WAB-AQ for FA networks. Overall, our results suggest that global network measures provide modest statistical value beyond lesion volume when predicting overall aphasia severity, but less value in predicting specific behaviors. Variability in estimates could be induced by premorbid ability, deafferentation and diaschisis, and neuroplasticity following stroke.SIGNIFICANCE STATEMENT Poststroke, the remaining neuroanatomy maintains cognition and supports recovery. However, studies often use small, cross-sectional samples that cannot fully model the interactions between lesions and other variables that affect networks in stroke. Alternate methods are required to account for these effects. "Simulated attack" models are computational approaches that apply virtual damage to the brain and measure their putative consequences. Using a simulated attack model, we estimated how simulated damage to anatomic networks could account for language performance. Overall, our results reveal that global network measures can provide modest statistical value predicting overall aphasia severity, but less value in predicting specific behaviors. These findings suggest that more theoretically precise network models could be necessary to robustly predict individual outcomes in aphasia.

Structural disconnection of the posterior medial frontal cortex reduces speech error monitoring.

Optimal performance in any task relies on the ability to detect and correct errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production, comprehension, and executive function. Interactions between pMFC and other task-relevant processors may similarly be critical for error monitoring in other task contexts.

Two types of phonological reading impairment in stroke aphasia.

Alexia is common in the context of aphasia. It is widely agreed that damage to phonological and semantic systems not specific to reading causes co-morbid alexia and aphasia. Studies of alexia to date have only examined phonology and semantics as singular processes or axes of impairment, typically in the context of stereotyped alexia syndromes. However, phonology, in particular, is known to rely on subprocesses, including sensory-phonological processing, motor-phonological processing, and sensory-motor integration. Moreover, many people with stroke aphasia demonstrate mild or mixed patterns of reading impairment that do not fit neatly with one syndrome. This cross-sectional study tested whether the hallmark symptom of phonological reading impairment, the lexicality effect, emerges from damage to a specific subprocess of phonology in stroke patients not selected for alexia syndromes. Participants were 30 subjects with left-hemispheric stroke and 37 age- and education-matched controls. A logistic mixed-effects model tested whether post-stroke impairments in sensory phonology, motor phonology, or sensory-motor integration modulated the effect of item lexicality on patient accuracy in reading aloud. Support vector regression voxel-based lesion-symptom mapping localized brain regions necessary for reading and non-orthographic phonological processing. Additionally, a novel support vector regression structural connectome-symptom mapping method identified the contribution of both lesioned and spared but disconnected, brain regions to reading accuracy and non-orthographic phonological processing. Specifically, we derived whole-brain structural connectomes using constrained spherical deconvolution-based probabilistic tractography and identified lesioned connections based on comparisons between patients and controls. Logistic mixed-effects regression revealed that only greater motor-phonological impairment related to lower accuracy reading aloud pseudowords versus words. Impaired sensory-motor integration was related to lower overall accuracy in reading aloud. No relationship was identified between sensory-phonological impairment and reading accuracy. Voxel-based and structural connectome lesion-symptom mapping revealed that lesioned and disconnected left ventral precentral gyrus related to both greater motor-phonological impairment and lower sublexical reading accuracy. In contrast, lesioned and disconnected left temporoparietal cortex is related to both impaired sensory-motor integration and reduced overall reading accuracy. These results clarify that at least two dissociable phonological processes contribute to the pattern of reading impairment in aphasia. First, impaired sensory-motor integration, caused by lesions disrupting the left temporoparietal cortex and its structural connections, non-selectively reduces accuracy in reading aloud. Second, impaired motor-phonological processing, caused at least partially by lesions disrupting left ventral premotor cortex and structural connections, selectively reduces sublexical reading accuracy. These results motivate a revised cognitive model of reading aloud that incorporates a sensory-motor phonological circuit.

Influence of stroke infarct location on quality of life assessed in a multivariate lesion-symptom mapping study.

Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22-36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4-9; median EQ-5D score 90 days after stroke 1, IQR 0-4, median lesion volume 3.3 ml, IQR 1.1-16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.

An Exploratory Study of Cerebellar Transcranial Direct Current Stimulation in Individuals With Chronic Stroke Aphasia.

BACKGROUND: Aphasia is a common, debilitating consequence of stroke, and speech therapy is often inadequate to achieve a satisfactory outcome. Neuromodulation techniques have emerged as a potential augmentative treatment for improving aphasia outcomes. Most studies have targeted the cerebrum, but there are theoretical and practical reasons that stimulation over the cerebral hemispheres might not be ideal. On the other hand, the right cerebellum is functionally and anatomically linked to major language areas in the left hemisphere, making it a promising alternative target site for stimulation. OBJECTIVE: To provide preliminary effect sizes for the ability of a short course of anodal transcranial direct current stimulation (tDCS) targeted over the right cerebellum to enhance language processing in individuals with chronic poststroke aphasia. METHOD: Ten individuals received five sessions of open-label anodal tDCS targeting the right cerebellum. The effects of the tDCS were compared with the effects of sham tDCS on 14 controls from a previous clinical trial. In total, 24 individuals with chronic poststroke aphasia participated in the study. Behavioral testing was conducted before treatment, immediately following treatment, and at the 3-month follow-up. RESULTS: Cerebellar tDCS did not significantly enhance language processing measured either immediately following treatment or at the 3-month follow-up. The effect sizes of tDCS over sham treatment were generally nil or small, except for the mean length of utterance on the picture description task, for which medium to large effects were observed. CONCLUSION: These results may provide guidance for investigators who are planning larger trials of tDCS for individuals with chronic poststroke aphasia.

Domains of Health-Related Quality of Life Are Associated With Specific Deficits and Lesion Locations in Chronic Aphasia.

BACKGROUND: Health-related quality of life (HRQL) in stroke survivors is related to numerous factors, but more research is needed to delineate factors related to HRQL in people with aphasia. OBJECTIVE: To examine the relationship between HRQL and demographic factors, impairment-based measures, and lesion characteristics in chronic aphasia. METHODS: A total of 41 left-hemisphere stroke survivors with aphasia underwent cognitive testing and magnetic resonance imaging. To address relationships with demographic and impairment-based measures, test scores were entered into a principal component analysis (PCA) and multiple linear regression was performed for overall and domain (physical, communication, psychosocial) scores of the Stroke and Aphasia Quality of Life Scale (SAQOL-39g). Independent variables included factor scores from the PCA, motricity, lesion volume, depressed mood, and demographic variables. To address relationships with lesion location, multivariate support vector regression lesion-symptom mapping (SVR-LSM) was used to localize lesions associated with SAQOL-39g scores. RESULTS: The PCA yielded 3 factors, which were labeled Language Production, Nonlinguistic Cognition, and Language Comprehension. Multiple linear regression revealed that depression symptoms predicted lower SAQOL-39g average and domain scores. Lower motricity scores predicted lower SAQOL-39g average and physical scores, and lower Language Production factor scores predicted lower communication scores. SVR-LSM demonstrated that basal ganglia lesions were associated with lower physical scores, and inferior frontal lesions were associated with lower psychosocial scores. CONCLUSIONS: HRQL in chronic left-hemisphere stroke survivors with aphasia relates to lesion location, depression symptoms, and impairment-based measures. This information may help identify individuals at risk for specific aspects of low HRQL and facilitate targeted interventions to improve well-being.

Assessing Methods for Evaluating the Number of Components in Non-Negative Matrix Factorization.

Non-negative matrix factorization is a relatively new method of matrix decomposition which factors an m×n data matrix X into an m×k matrix W and a k×n matrix H, so that X≈W×H. Importantly, all values in X, W, and H are constrained to be non-negative. NMF can be used for dimensionality reduction, since the k columns of W can be considered components into which X has been decomposed. The question arises: how does one choose k? In this paper, we first assess methods for estimating k in the context of NMF in synthetic data. Second, we examine the effect of normalization on this estimate's accuracy in empirical data. In synthetic data with orthogonal underlying components, methods based on PCA and Brunet's Cophenetic Correlation Coefficient achieved the highest accuracy. When evaluated on a well-known real dataset, normalization had an unpredictable effect on the estimate. For any given normalization method, the methods for estimating k gave widely varying results. We conclude that when estimating k, it is best not to apply normalization. If underlying components are known to be orthogonal, then Velicer's MAP or Minka's Laplace-PCA method might be best. However, when orthogonality of the underlying components is unknown, none of the methods seemed preferable.

Functional anomaly mapping reveals local and distant dysfunction caused by brain lesions.

The lesion method has been important for understanding brain-behavior relationships in humans, but has previously used maps based on structural damage. Lesion measurement based on structural damage may label partly damaged but functional tissue as abnormal, and moreover, ignores distant dysfunction in structurally intact tissue caused by deafferentation, diaschisis, and other processes. A reliable method to map functional integrity of tissue throughout the brain would provide a valuable new approach to measuring lesions. Here, we use machine learning on four dimensional resting state fMRI data obtained from left-hemisphere stroke survivors in the chronic period of recovery and control subjects to generate graded maps of functional anomaly throughout the brain in individual patients. These functional anomaly maps identify areas of obvious structural lesions and are stable across multiple measurements taken months and even years apart. Moreover, the maps identify functionally anomalous regions in structurally intact tissue, providing a direct measure of remote effects of lesions on the function of distant brain structures. Multivariate lesion-behavior mapping using functional anomaly maps replicates classic behavioral localization, identifying inferior frontal regions related to speech fluency, lateral temporal regions related to auditory comprehension, parietal regions related to phonology, and the hand area of motor cortex and descending corticospinal pathways for hand motor function. Further, this approach identifies relationships between tissue function and behavior distant from the structural lesions, including right premotor dysfunction related to ipsilateral hand movement, and right cerebellar regions known to contribute to speech fluency. Brain-wide maps of the functional effects of focal lesions could have wide implications for lesion-behavior association studies and studies of recovery after brain injury.

Brain structures and cognitive abilities important for the self-monitoring of speech errors.

The brain structures and cognitive abilities necessary for successful monitoring of one's own speech errors remain unknown. We aimed to inform self-monitoring models by examining the neural and behavioral correlates of phonological and semantic error detection in individuals with post-stroke aphasia. First, we determined whether detection related to other abilities proposed to contribute to monitoring according to various theories, including naming ability, fluency, word-level auditory comprehension, sentence-level auditory comprehension, and executive function. Regression analyses revealed that fluency and executive scores were independent predictors of phonological error detection, while a measure of word-level comprehension related to semantic error detection. Next, we used multivariate lesion-symptom mapping to determine lesion locations associated with reduced error detection. Reduced overall error detection related to damage to a region of frontal white matter extending into dorsolateral prefrontal cortex (DLPFC). Detection of phonological errors related to damage to the same areas, but the lesion-behavior association was stronger, suggesting the localization for overall error detection was driven primarily by phonological error detection. These findings demonstrate that monitoring of different error types relies on distinct cognitive functions, and provide causal evidence for the importance of frontal white matter tracts and DLPFC for self-monitoring of speech.

Dissociable Mechanisms of Verbal Working Memory Revealed through Multivariate Lesion Mapping.

Two maintenance mechanisms with separate neural systems have been suggested for verbal working memory: articulatory-rehearsal and non-articulatory maintenance. Although lesion data would be key to understanding the essential neural substrates of these systems, there is little evidence from lesion studies that the two proposed mechanisms crucially rely on different neuroanatomical substrates. We examined 39 healthy adults and 71 individuals with chronic left-hemisphere stroke to determine if verbal working memory tasks with varying demands would rely on dissociable brain structures. Multivariate lesion-symptom mapping was used to identify the brain regions involved in each task, controlling for spatial working memory scores. Maintenance of verbal information relied on distinct brain regions depending on task demands: sensorimotor cortex under higher demands and superior temporal gyrus (STG) under lower demands. Inferior parietal cortex and posterior STG were involved under both low and high demands. These results suggest that maintenance of auditory information preferentially relies on auditory-phonological storage in the STG via a nonarticulatory maintenance when demands are low. Under higher demands, sensorimotor regions are crucial for the articulatory rehearsal process, which reduces the reliance on STG for maintenance. Lesions to either of these regions impair maintenance of verbal information preferentially under the appropriate task conditions.

Language Mapping in Aphasia.

Purpose Recovery from aphasia is thought to depend on neural plasticity, that is, functional reorganization of surviving brain regions such that they take on new or expanded roles in language processing. To make progress in characterizing the nature of this process, we need feasible, reliable, and valid methods for identifying language regions of the brain in individuals with aphasia. This article reviews 3 recent studies from our lab in which we have developed and validated several novel functional magnetic resonance imaging paradigms for language mapping in aphasia. Method In the 1st study, we investigated the reliability and validity of 4 language mapping paradigms in neurologically normal older adults. In the 2nd study, we developed a novel adaptive semantic matching paradigm and assessed its feasibility, reliability, and validity in individuals with and without aphasia. In the 3rd study, we developed and evaluated 2 additional adaptive paradigms-rhyme judgment and syllable counting-for mapping phonological encoding regions. Results We found that the adaptive semantic matching paradigm could be performed by most individuals with aphasia and yielded reliable and valid maps of core perisylvian language regions in each individual participant. The psychometric properties of this paradigm were superior to those of other commonly used paradigms such as narrative comprehension and picture naming. The adaptive rhyme judgment paradigm was capable of identifying fronto-parietal phonological encoding regions in individual participants. Conclusion Adaptive language mapping paradigms offer a promising approach for future research on the neural basis of recovery from aphasia. Presentation Video https://doi.org/10.23641/asha.10257584.

Localization of Phonological and Semantic Contributions to Reading.

Reading involves the rapid extraction of sound and meaning from print through a cooperative division of labor between phonological and lexical-semantic processes. Whereas lesion studies of patients with stereotyped acquired reading deficits contributed to the notion of a dissociation between phonological and lexical-semantic reading, the neuroanatomical basis for effects of lexicality (word vs pseudoword), orthographic regularity (regular vs irregular spelling-sound correspondences), and concreteness (concrete vs abstract meaning) on reading is underspecified, particularly outside the context of strong behavioral dissociations. Support vector regression lesion-symptom mapping (LSM) of 73 left hemisphere stroke survivors (male and female human subjects) not preselected for stereotyped dissociations revealed the differential contributions of specific cortical regions to reading pseudowords (ventral precentral gyrus), regular words (planum temporale, supramarginal gyrus, ventral precentral and postcentral gyrus, and insula), and concrete words (pars orbitalis and pars triangularis). Consistent with the primary systems view of reading being parasitic on language-general circuitry, our multivariate LSM analyses revealed that phonological decoding depends on perisylvian areas subserving sound-motor integration and that semantic effects on reading depend on frontal cortex subserving control over concrete semantic representations that aid phonological access from print. As the first study to localize the differential cortical contributions to reading pseudowords, regular words, and concrete words in stroke survivors with variable reading abilities, our results provide important information on the neurobiological basis of reading and highlight the insights attainable through multivariate, process-based approaches to alexia.SIGNIFICANCE STATEMENT Whereas fMRI evidence for neuroanatomical dissociations between phonological and lexical-semantic reading is abundant, evidence from modern lesion studies establishing the differential contributions of specific brain regions to specific reading processes is lacking. Our application of multivariate lesion-symptom mapping revealed that effects of lexicality, orthographic regularity, and concreteness on reading differentially depend on areas subserving auditory-motor integration and semantic control. Phonological decoding of print relies on a dorsal perisylvian network supporting auditory and articulatory representations, with unfamiliar words relying especially on articulatory mapping. In tandem with this dorsal decoding system, anterior inferior frontal gyrus may coordinate control over concrete semantic representations that support mapping of print to sound, which is a novel potential mechanism for semantic influences on reading.

Adaptive paradigms for mapping phonological regions in individual participants.

Phonological encoding depends on left-lateralized regions in the supramarginal gyrus and the ventral precentral gyrus. Localization of these phonological regions in individual participants-including individuals with language impairments-is important in several research and clinical contexts. To localize these regions, we developed two paradigms that load on phonological encoding: a rhyme judgment task and a syllable counting task. Both paradigms relied on an adaptive staircase design to ensure that each individual performed each task at a similarly challenging level. The goal of this study was to assess the validity and reliability of the two paradigms, in terms of their ability to consistently produce left-lateralized activations of the supramarginal gyrus and ventral precentral gyrus in neurologically normal individuals with presumptively normal language localization. Sixteen participants were scanned with fMRI as they performed the rhyme judgment paradigm, the syllable counting paradigm, and an adaptive semantic paradigm that we have described previously. We found that the rhyme and syllable paradigms both yielded left-lateralized supramarginal and ventral precentral activations in the majority of participants. The rhyme paradigm produced more lateralized and more reliable activations, and so should be favored in future applications. In contrast, the semantic paradigm did not reveal supramarginal or precentral activations in most participants, suggesting that the recruitment of these regions is indeed driven by phonological encoding, not language processing in general. In sum, the adaptive rhyme judgment paradigm was effective in localizing left-lateralized phonological encoding regions in individual participants, and, in conjunction with the adaptive semantic paradigm, can be used to map individual language networks.

A multivariate lesion symptom mapping toolbox and examination of lesion-volume biases and correction methods in lesion-symptom mapping.

Lesion-symptom mapping has become a cornerstone of neuroscience research seeking to localize cognitive function in the brain by examining the sequelae of brain lesions. Recently, multivariate lesion-symptom mapping methods have emerged, such as support vector regression, which simultaneously consider many voxels at once when determining whether damaged regions contribute to behavioral deficits (Zhang, Kimberg, Coslett, Schwartz, & Wang, ). Such multivariate approaches are capable of identifying complex dependences that traditional mass-univariate approach cannot. Here, we provide a new toolbox for support vector regression lesion-symptom mapping (SVR-LSM) that provides a graphical interface and enhances the flexibility and rigor of analyses that can be conducted using this method. Specifically, the toolbox provides cluster-level family-wise error correction via permutation testing, the capacity to incorporate arbitrary nuisance models for behavioral data and lesion data and makes available a range of lesion volume correction methods including a new approach that regresses lesion volume out of each voxel in the lesion maps. We demonstrate these new tools in a cohort of chronic left-hemisphere stroke survivors and examine the difference between results achieved with various lesion volume control methods. A strong bias was found toward brain wide lesion-deficit associations in both SVR-LSM and traditional mass-univariate voxel-based lesion symptom mapping when lesion volume was not adequately controlled. This bias was corrected using three different regression approaches; among these, regressing lesion volume out of both the behavioral score and the lesion maps provided the greatest sensitivity in analyses.

The neural substrates of improved phonological processing following successful treatment in a case of phonological alexia and agraphia.

Phonological deficits are common in aphasia after left-hemisphere stroke, and can have significant functional consequences for spoken and written language. While many individuals improve through treatment, the neural substrates supporting improvements are poorly understood. We measured brain activation during pseudoword reading in an individual through two treatment phases. Improvements were associated with greater activation in residual left dorsal language regions and bilateral regions supporting attention and effort. Gains were maintained, while activation returned to pre-treatment levels. This case demonstrates the neural support for improved phonology after damage to critical regions and that improvements may be maintained without markedly increased effort.