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Background: and purpose: Speech entrainment therapy (SET) is a computerized therapeutic approach that involves mimicking an audiovisual speech model to improve speech production. In a pilot study using SET for treatment of post-stroke non-fluent aphasia, significant gains were achieved in verbs per minute (VPM) during discourse using untrained items 1 and 6 weeks after treatment, suggesting that SET may yield meaningful improvements in fluent spontaneous speech for individuals with non-fluent aphasia ., Methods: The Speech Entrainment for Aphasia Recovery (SpARc) trial is a prospective, randomized, assessor-blinded, multicenter phase II clinical trial studying persons with chronic post-stroke non-fluent aphasia. Participants will be randomized to 3 weeks, 4.5 weeks, or 6 weeks of SET delivered via telehealth or a no SET control condition for 6 weeks. 80 adults (ages 21-81) with history of left hemisphere ischemic or hemorrhagic stroke with residual chronic (>6 months post stroke) non-fluent aphasia diagnosed by the Western Aphasia Battery-Revised (WAB-R) will be randomized (1:1:1:1) over 4 years. The trial will be conducted at the clinical research facilities at three sites: the Medical University of South Carolina, the University of South Carolina, and the University of Utah., Conclusions: This paper details the trial design of the SpARc trial, which aims to determine the dose of SET that will generate the highest effect size on speech fluency, VPM, sustained at 3 months post-treatment compared to a no SET control arm, for individuals with chronic post-stroke non-fluent aphasia to permit a future definitive trial to test the clinical utility of SET., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier Inc.)

Background: Structural integrity of the ipsilesional corticospinal tract (CST) is important for upper limb motor recovery after stroke. However, additional neuromechanisms associated with motor function poststroke are less well understood, especially regarding the lower limb., Objective: To investigate the neural basis of upper/lower limb motor deficits poststroke by correlating measures of motor function with diffusion tensor imaging-derived indices of white matter integrity (fractional anisotropy (FA), mean diffusivity (MD)) in primary and secondary motor tracts/structures., Methods: Forty-three individuals with chronic stroke (time poststroke, 64.4 ± 58.8 months) underwent a comprehensive motor assessment and MRI scanning. Correlation and multiple regression analyses were performed to examine relationships between FA/MD in a priori motor tracts/structures and motor function., Results: FA in the ipsilesional CST and red nucleus (RN) was positively correlated with motor function of both the affected upper and lower limb ( r = 0.36-0.55, p ≤ 0.01), while only ipsilesional RN FA was associated with gait speed ( r = 0.50). Ipsilesional CST FA explained 37.3% of the variance in grip strength ( p < 0.001) and 31.5% of the variance in Arm Motricity Index ( p = 0.004). Measures of MD were not predictors of motor performance., Conclusions: Microstructural integrity of the ipsilesional CST is associated with both upper and lower limb motor function poststroke, but appears less important for gait speed. Integrity of the ipsilesional RN was also associated with motor performance, suggesting increased contributions from secondary motor areas may play a role in supporting chronic motor function and could become a target for interventions., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Denise M. Peters et al.)

The ability to string together words into a structured arrangement capable of conveying nuanced information is key to speech production. The assessment of the neural bases for structuring sentences has been challenged by the need of experts to delineate the aberrant morphosyntactic structures in aphasic speech. Most studies have relied on focused tasks with limited ecological validity. We characterized syntactic complexity during connected speech produced by patients with chronic post-stroke aphasia. We automated this process by employing Natural Language Processing (NLP). We conducted voxel-based and connectome-based lesion-symptom mapping to identify brain regions crucially associated with sentence production and syntactic complexity. Posterior-inferior aspects of left frontal and parietal lobes, as well as white matter tracts connecting these areas, were essential for syntactic complexity, particularly the posterior inferior frontal gyrus. These findings suggest that sentence structuring during word production depends on the integrity of Broca's area and the dorsal stream of language processing., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Topological signal processing is a novel approach for decoding multiscale features of signals recorded through electroencephalography (EEG) based on topological data analysis (TDA). New method: We establish stability properties of the TDA descriptor persistence landscape (PL) in event-related potential (ERP) across multi-trial EEG signals, state algorithms for computing PL, and propose an exact inference framework on persistence and PLs., Results: We apply the topological signal processing and inference framework to compare ERPs between individuals with post-stroke aphasia and healthy controls under a speech altered auditory feedback (AAF) paradigm. Results show significant PL difference in the ERP response of aphasic individuals and healthy controls over the parietal-occipital and occipital regions with respect to speech onset, and no significant PL difference in any regions with respect to the two pitch-shift stimuli. Comparison with existing methods: In comparison, spatial patterns of difference between aphasic individuals and healthy controls by persistence, local variance, and spectral powers are much more diffuse than the PL patterns. In simulation results, the exact test on persistence and PLs has more robust performance than the baseline tests on local variance and spectral powers., Conclusions: Persistence features provide a more robust EEG marker than local variance, and spectral powers. It could be a potentially powerful tool for comparing electrophysiological correlates in neurological disorders., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A critical concept in neurology is cortical disconnection, in which seemingly normal gray matter can have reduced function due to loss of white matter (WM) connections. White matter damage has been extensively described in temporal lobe epilepsy (TLE), but the anatomical distribution of cortical disconnection in TLE is not fully characterized. Here, we studied 221 participants (64 left-TLE, 55 right-TLE, 102 controls) from three different epilepsy treatment centers. We employed a group connectometry diffusion imaging tractography approach to identify WM fibers with reduced integrity in TLE. We then assessed the anatomical distribution of the gray matter endpoint projections of abnormal fibers to map the anatomical pattern of disconnections. As expected, left- and right-TLE were associated with multiple WM pathways with reduced integrity, which were associated with extensive cortical disconnection involving predominantly limbic structures. Controlling for medial temporal gray matter atrophy, cortical disconnection of the left cingulum and the thalamus as well as disconnection of the bilateral putamen and the amygdala was associated with lower verbal memory immediate recall. In conclusion, our results support that cortical disconnection is an underappreciated but pervasive phenomenon in TLE, and cortical disconnection of limbic structures beyond the medial temporal regions is related to verbal memory performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Substantial effort has been undertaken to improve the recruitment and retention of participants in stroke trials. African Americans are disproportionately under-represented in stroke clinical trials as well as clinical trials for other chronic disease conditions. To circumvent barriers to recruitment, clinical trial recruitment strategies used to recruit African Americans have focused on different aspects of community engagement., Purpose: This study examined a community-engaged, multi-phased tailored approach to recruiting African Americans with stroke. The recruitment approach described was designed to support the Community Based Intervention under Nurse Guidance after Stroke (CINGS) trial, part of the Wide Spectrum Investigation of Stroke Outcome Disparities on Multiple Levels (WISSDOM) Center established to explore stroke disparities., Methods: A multiple-phased recruitment approach was undertaken and involved a recruitment planning phase and a recruitment phase. The recruitment planning phase involved the use of focus groups designed to explore barriers and facilitators of stroke recovery. The active recruitment phase included multiple strategies with ongoing evaluation., Results: Information gained from focus groups offered insights into strategies critical to recruiting African Americans with stroke for behavioral research during the early recovery period. Strategies to enhance the identification of and recruitment of potential participants included use of: a) a hospital system stroke database, b) system-wide friendly visits/warm handoff approaches, c) electronic health record, d) associated external sites and e) protocol adjustments., Conclusions: Developing tailored approaches to curtail barriers to research participation is critical for increasing the probability of reaching African American study participant recruitment and retention goals. Research teams may require training in community-engagement research strategies essential for obtaining achieving target recruitment goals., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objectives: To investigate the hypothesis that language recovery in post-stroke aphasia is associated with structural brain changes., Methods: We evaluated whether treatment-induced improvement in naming is associated with reorganization of tissue microstructure within residual cortical regions. To this end, we performed a retrospective longitudinal treatment study using comprehensive language-linguistic assessments and diffusion MRI sequences optimized for the assessment of complex microstructure (diffusional kurtosis imaging) to evaluate the relationship between language treatment response and cortical changes in 26 individuals with chronic stroke-induced aphasia. We employed elastic net statistical models controlling for baseline factors including age, sex, and time since the stroke, as well as lesion volume., Results: We observed that improved naming accuracy (Philadelphia Naming Test) was statistically associated with increased post-treatment microstructural integrity in the left posterior superior temporal gyrus. Moreover, increase in microstructural integrity in the left middle temporal gyrus and left inferior temporal gyrus was specifically associated with a decrease in semantic paraphasias. This longitudinal relationship between brain tissue integrity and language improvement was not observed in other non-language related brain regions., Interpretation: Our findings provide evidence that structural brain changes in the preserved left hemisphere regions are associated with treatment-induced language recovery in aphasia and are part of the mechanisms supporting language and brain injury recovery., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Stroke can induce large-scale functional reorganization of the brain; however, the spatial patterns of this reorganization remain largely unknown. Methods: Using a large ( N  = 116) sample of participants who were in the chronic stages of stroke, we present a systematic study of the association between brain damage and functional connectivity (FC) within the intact hemisphere. We computed correlations between regional cortical damage and contralateral FC. Results: We identified left-hemisphere regions that had the most pronounced effect on the right-hemisphere FC, and, conversely, right-hemisphere connections where the effect of damage was particularly strong. Notably, the vast majority of significant correlations were positive: damage was associated with an increase in regional contralateral connectivity. Discussion: These findings lend evidence of the reorganization of contralateral cortical networks as a response to brain damage, which is more pronounced in a set of well-connected regions where connectivity increases with the amount of damage. Impact statement The relatively large sample size combined with our best-of-breed analysis methods provides us with sufficient statistical power and spatial sensitivity to identify a set of brain regions where damage has the strongest impact on contralateral networks, and a set of contralateral functional connections that increase in strength in response to brain damage. Our results demonstrate that the brain's ability to reorganize itself after extensive damage is not distributed equally in space, but is more likely to occur in specific core regions. We believe that the associations between brain damage and increased connectivity in the "intact" hemisphere provide novel, and important, insight into the plasticity of the adult brain.

Attempts to personalize aphasia treatment to the extent where it is possible to reliably predict individual response to a particular treatment have yielded inconclusive results. The current study aimed to (i) compare the effects of phonologically versus semantically focussed naming treatment and (ii) examine biographical and neuropsychological baseline factors predictive of response to each treatment. One hundred and four individuals with chronic post-stroke aphasia underwent 3 weeks of phonologically focussed treatment and 3 weeks of semantically focussed treatment in an unblinded cross-over design. A linear mixed-effects model was used to compare the effects of treatment type on proportional change in correct naming across groups. Correlational analysis and stepwise regression models were used to examine biographical and neuropsychological predictors of response to phonological and semantic treatment across all participants. Last, chi-square tests were used to explore the association between treatment response and phonological and semantic deficit profiles. Semantically focussed treatment was found to be more effective at the group-level, independently of treatment order ( P = 0.041). Overall, milder speech and language impairment predicted good response to semantic treatment ( r range: 0.256-0.373) across neuropsychological tasks. The Western Aphasia Battery-Revised Spontaneous Speech score emerged as the strongest predictor of semantic treatment response ( R 2 = 0.188). Severity of stroke symptoms emerged as the strongest predictor of phonological treatment response ( R 2 = 0.103). Participants who showed a good response to semantic treatment were more likely to present with fluent speech compared to poor responders ( P = 0.005), whereas participants who showed a good response to phonological treatment were more likely to present with apraxia of speech ( P = 0.020). These results suggest that semantic treatment may be more beneficial to the improvement of naming performance in aphasia than phonological treatment, at the group-level. In terms of personalized predictors, participants with relatively mild impairments and fluent speech responded better to semantic treatment, while phonological treatment benefitted participants with more severe impairments and apraxia of speech., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: We performed a systematic review to evaluate available risk models to predict late seizure onset among stroke survivors., Methods: We searched major databases (PubMed, SCOPUS, and Cochrane Library) from inception to October 2020 for articles on the development and/or validation of risk models to predict late seizures after a stroke. The impact of models to predict late-onset seizures was also assessed. We included seven articles in the final analysis. For each of these studies, we evaluated the study design and scope of predictors analyzed to derive each model. We assessed the performance of the models during internal and external validation in terms of discrimination and calibration., Results: Three studies focused on ischemic stroke alone, with c-statistic values ranging from 0.73 to 0.77. The SeLECT model from Switzerland was externally validated in Italian, German, and Austrian cohorts where c-statistics ranged from 0.69 to 0.81. This model along with the PSEiCARe model, were internally validated and calibration performance was provided for both models. The CAVS and CAVE models reported on the risk of late-onset seizures in patients with hemorrhagic stroke. The CAVS model derivation cohort was racially diverse. The CAVS model's c-statistic was 0.76, while the CAVE model had a c-statistic of 0.81. Calibration and internal validation were not performed for either study. The CAVS model, created from a Finnish population, was externally validated in American and French cohorts, with c-statistics of 0.73 and 0.69, respectively. Finally, the two studies focusing on both types of stroke came from the PoSERS and INPOSE models. Neither model provided c-statistics, calibration metrics, internal or external validation information. We found no evidence of the presence of impact studies to assess the effect of adopting late-onset seizure risk models after stroke on clinical outcomes., Conclusion: The SeLECT model was the only model developed in line with proposed guidelines for appropriate model development. The model, which was externally validated in a very similar and homogeneous population, may need to be tested in a more racially/ethnic diverse and younger population; testing the SeLECT model, accounting for overall brain health is likely to improve the identification of high-risk patients for late post stroke seizures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Performance in verbal fluency tasks are widely used as a marker of cognitive impairment in Parkinson disease. However, the anatomical substrate of its impairment remains undetermined. Based on the dual-stream language model, we hypothesized cortical input to the subcortical circuitry would be a crucial determinant of fluency. We performed a retrospective study using individual whole-brain structural connectomes derived from 135 individuals with PD and assessed the relationship between white matter integrity and verbal fluency tasks. Controlling for multiple factors, including dysarthria, we observed higher integrity of dorsal stream-caudate connectivity was associated with better letter fluency. This preliminary study indicates the possible dissociation between dorsal and ventral stream connectivity and letter fluency in PD. In addition, it suggests a non-motor role of the frontostriatal fibers in letter fluency., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra-axonal and extra-axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra-axonal and extra-axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra-axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra-axonal diffusivity compared to those with nonrefractory epilepsy. The extra-axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Recent studies have combined multiple neuroimaging modalities to gain further understanding of the neurobiological substrates of aphasia. Following this line of work, the current study uses machine learning approaches to predict aphasia severity and specific language measures based on a multimodal neuroimaging dataset. A total of 116 individuals with chronic left-hemisphere stroke were included in the study. Neuroimaging data included task-based functional magnetic resonance imaging (fMRI), diffusion-based fractional anisotropy (FA)-values, cerebral blood flow (CBF), and lesion-load data. The Western Aphasia Battery was used to measure aphasia severity and specific language functions. As a primary analysis, we constructed support vector regression (SVR) models predicting language measures based on (i) each neuroimaging modality separately, (ii) lesion volume alone, and (iii) a combination of all modalities. Prediction accuracy across models was subsequently statistically compared. Prediction accuracy across modalities and language measures varied substantially (predicted vs. empirical correlation range: r = .00-.67). The multimodal prediction model yielded the most accurate prediction in all cases (r = .53-.67). Statistical superiority in favor of the multimodal model was achieved in 28/30 model comparisons (p-value range: <.001-.046). Our results indicate that different neuroimaging modalities carry complementary information that can be integrated to more accurately depict how brain damage and remaining functionality of intact brain tissue translate into language function in aphasia., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: White matter disconnection of language-specific brain regions associates with worse aphasia recovery. Despite a loss of direct connections, many stroke survivors may maintain indirect connections between brain regions., Objective: To determine (1) whether preserved direct connections between language-specific brain regions relate to better poststroke naming treatment outcomes compared to no direct connections and (2) whether for individuals with a loss of direct connections, preserved indirect connections are associated with better treatment outcomes compared to individuals with no connections., Methods: We computed structural whole-brain connectomes from 69 individuals with chronic left-hemisphere stroke and aphasia who completed a 3-week-long language treatment that was supplemented by either anodal transcranial direct current stimulation (A-tDCS) or sham stimulation (S-tDCS). We determined differences in naming improvement between individuals with direct, indirect, and no connections using 1-way analyses of covariance and multivariable linear regressions., Results: Independently of tDCS modality, direct or indirect connections between the inferior frontal gyrus pars opercularis and angular gyrus were both associated with a greater increase in correct naming compared to no connections ( P = .027 and P = .039, respectively). Participants with direct connections between the inferior frontal gyrus pars opercularis and middle temporal gyrus who received S-tDCS and participants with indirect connections who received A-tDCS significantly improved in naming accuracy., Conclusions: Poststroke preservation of indirect white matter connections is associated with better treated naming improvement in aphasia even when direct connections are damaged. This mechanistic information can be used to stratify and predict treated naming recovery in individuals with aphasia.

Background: Prior speech entrainment studies, where individuals with non-fluent aphasia mimic an audio-visual model, suggest speech entrainment improves speech fluency, as indexed by various linguistic measures (e.g., the total number of different words produced per minute). Here, more precise speech timing adjustments accompanying entrained speech were studied and compared to spontaneous speech to determine how these temporal variables relate to the fluency inducing effects of speech entrainment in aphasia., Methods: Thirty-one left hemisphere stroke survivors classified with fluent or non-fluent speech were audio-video recorded as they described a picture and during speech entrainment. Speech fluency was documented using the Western Aphasia Battery-Revised. Acoustic measures of speech timing included total number of syllables, speech rate, articulatory rate, silent pause frequency and duration. Standard descriptive statistics and a two-factor mixed model analysis of variance were used to investigate group, task, and 'group x task' interaction effects., Findings: All acoustic measures of speech timing differentiated the fluent and nonfluent groups except for silent pause frequency. Differences between speech entrainment and spontaneous speech were found for most acoustic measures of speech timing and speaker groups, yet the direction of the effect varied. Stroke survivors classified with non-fluent aphasia improved speech fluency such that speech entrainment elicited pause adjustments facilitating more typical speech timing in comparison to spontaneous speech., Conclusion: Overall, findings provide further evidence of the impact of speech entrainment on measures of speech timing to help individuals with non-fluent aphasia to practice speaking more fluently. Practicing speaking more fluently may ultimately impact perceptual judgments of speech naturalness and social acceptance for persons with aphasia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: It is commonly hypothesized that seizure spread patterns in patients with focal epilepsy are associated with structural brain pathways. However, this relationship is poorly understood and has not been fully demonstrated in patients with temporal lobe epilepsy. Here, we sought to determine whether directionality of seizure spread (DSS) is associated with specific cerebral white matter tracts in patients with temporal lobe epilepsy., Methods: Thirty-three adult patients with temporal lobe epilepsy who underwent stereoelectroencephalography (sEEG) and magnetic resonance diffusion tensor imaging (MR-DTI) as part of their standard-of-care clinical evaluation were included in the study. DSS was defined as anterior-posterior (AP) or medial-lateral (ML) spread based upon sEEG evaluation by two independent specialists who demonstrated excellent inter-rater agreement (Cohen's kappa = .92). DTI connectometry was used to assess differences between seizure spread pattern groups along major fiber pathways regarding fractional anisotropy (FA)., Results: Twenty-four participants showed seizures with AP spread and nine participants showed seizures with ML spread. There were no significant differences between the groups on their demographic and clinical profile. Patients with ML seizures had higher FA along the corpus callosum and, to a lesser degree, some portions of the bilateral cingulate tracts. In contrast, patients with AP seizures had higher FA along several anterior-posterior white matter projections bundles, including the cingulate fasciculus and the inferior longitudinal, with significantly less involvement of the corpus callosum compared with ML seizures., Significance: This study confirms the hypothesis that the anatomical pattern of electrophysiological ictal propagation is associated with the structural reinforcement of supporting pathways in temporal lobe epilepsy. This observation can help elucidate mechanisms of ictal propagation and may guide future translational approaches to curtail seizure spread., (Copyright © 2021 Elsevier B.V. All rights reserved.)

While the structural integrity of the corticospinal tract (CST) has been shown to support motor performance after stroke, the neural correlates of within-session practice effects are not known. The purpose of this preliminary investigation was to examine the structural brain correlates of within-session practice effects on a functional motor task completed with the more impaired arm after stroke. Eleven individuals with mild motor impairment (mean age 57.0 ± 9.4 years, mean months post-stroke 37.0 ± 66.1, able to move ≥ 26 blocks on the Box and Blocks Test) due to left hemisphere stroke completed structural MRI and practiced a functional motor task that involved spooning beans from a start cup to three distal targets. Performance on the motor task improved with practice (p = 0.004), although response was variable. Baseline motor performance (Block 1) correlated with integrity of the CST (r = - 0.696) while within-session practice effects (change from Block 1 to Block 3) did not. Instead, practice effects correlated with degree of lesion to the superior longitudinal fasciculus (r = 0.606), a pathway that connects frontal and parietal brain regions previously shown to support motor learning. This difference between white matter tracts associated with baseline motor performance and within-session practice effects may have implications for understanding response to motor practice and the application of brain-focused intervention approaches aimed at improving hand function after stroke.

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : In this pilot study, we examined the effects of ipsilesional high-frequency rTMS (iHF-rTMS) and contralesional low-frequency rTMS (cLF-rTMS) applied via a double-cone coil on neurophysiological and gait variables in patients with chronic stroke. Objective/Hypothesis : To determine the group and individual level effects of two types of stimulation to better individualize neuromodulation for rehabilitation. Methods : Using a randomized, within-subject, double-blind, sham-controlled trial with 14 chronic stroke participants iHF-rTMS and cLF-rTMS were applied via a double-cone coil to the tibialis anterior cortical representation. Neurophysiological and gait variables were compared pre-post rTMS. Results : A small effect of cLF-rTMS indicated increased MEP amplitudes (Cohen's D; cLF-rTMS, d = -0.30). Group-level analysis via RMANOVA showed no significant group effects of stimulation ( P > 0.099). However, secondary analyses of individual data showed a high degree of response variability to rTMS. Individual percent changes in resting motor threshold and normalized MEP latency correlated with changes in gait propulsive forces and walking speed (iHF-rTMS, nLAT:Pp, R = 0.632 P = 0.015; cLF-rTMS, rMT:SSWS, R = -0.557, P = 0.039; rMT:Pp, R = 0.718, P = 0.004). Conclusions : Changes in propulsive forces and walking speed were seen in some individuals that showed neurophysiological changes in response to rTMS. The neurological consequences of stroke are heterogeneous making a "one type fits all" approach to neuromodulation for rehabilitation unlikely. This pilot study suggests that an individual's unique response to rTMS should be considered before the application/selection of neuromodulatory therapies. Before neuromodulatory therapies can be incorporated into standard clinical practice, additional work is needed to identify biomarkers of response and how best to prescribe neuromodulation for rehabilitation for post-stroke gait., (Copyright © 2020 Kindred, Wonsetler, Charalambous, Srivastava, Marebwa, Bonilha, Kautz and Bowden.)

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Objective: Medial temporal lobe epilepsy (TLE) is the most common form of medication-resistant focal epilepsy in adults. Despite removal of medial temporal structures, more than one-third of patients continue to have disabling seizures postoperatively. Seizure refractoriness implies that extramedial regions are capable of influencing the brain network and generating seizures. We tested whether abnormalities of structural network integration could be associated with surgical outcomes., Methods: Presurgical magnetic resonance images from 121 patients with drug-resistant TLE across 3 independent epilepsy centers were used to train feed-forward neural network models based on tissue volume or graph-theory measures from whole-brain diffusion tensor imaging structural connectomes. An independent dataset of 47 patients with TLE from 3 other epilepsy centers was used to assess the predictive values of each model and regional anatomical contributions toward surgical treatment results., Results: The receiver operating characteristic area under the curve based on regional betweenness centrality was 0.88, significantly higher than a random model or models based on gray matter volumes, degree, strength, and clustering coefficient. Nodes most strongly contributing to the predictive models involved the bilateral parahippocampal gyri, as well as the superior temporal gyri., Interpretation: Network integration in the medial and lateral temporal regions was related to surgical outcomes. Patients with abnormally integrated structural network nodes were less likely to achieve seizure freedom. These findings are in line with previous observations related to network abnormalities in TLE and expand on the notion of underlying aberrant plasticity. Our findings provide additional information on the mechanisms of surgical refractoriness. ANN NEUROL 2020;88:970-983., (© 2020 American Neurological Association.)

Background: Prefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia., Objective: /Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity., Methods: We enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10 Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition., Results: Of the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p = 0.0157; max z-score = 4.7) and neighboring BA46 (p = 0.019; max z-score = 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p = 0.02; max z-score = 3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p = 0.004)., Conclusions: Subjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To define left temporal lobe regions where surgical resection produces a persistent postoperative decline in naming visual objects., Methods: Pre- and postoperative brain magnetic resonance imaging data and picture naming (Boston Naming Test) scores were obtained prospectively from 59 people with drug-resistant left temporal lobe epilepsy. All patients had left hemisphere language dominance at baseline and underwent surgical resection or ablation in the left temporal lobe. Postoperative naming assessment occurred approximately 7 months after surgery. Surgical lesions were mapped to a standard template, and the relationship between presence or absence of a lesion and the degree of naming decline was tested at each template voxel while controlling for effects of overall lesion size., Results: Patients declined by an average of 15% in their naming score, with wide variation across individuals. Decline was significantly related to damage in a cluster of voxels in the ventral temporal lobe, located mainly in the fusiform gyrus approximately 4-6 cm posterior to the temporal tip. Extent of damage to this region explained roughly 50% of the variance in outcome. Picture naming decline was not related to hippocampal or temporal pole damage., Significance: The results provide the first statistical map relating lesion location in left temporal lobe epilepsy surgery to picture naming decline, and they support previous observations of transient naming deficits from electrical stimulation in the basal temporal cortex. The critical lesion is relatively posterior and could be avoided in many patients undergoing left temporal lobe surgery for intractable epilepsy., (© 2020 International League Against Epilepsy.)

Purpose The objectives of this study are to (a) identify speech-language pathologists' (SLPs') familiarity with transcranial direct current stimulation (tDCS), (b) quantify what SLPs consider necessary tDCS-related improvement in aphasia severity (i.e., tDCS enhancement; desired improvement above and beyond traditional behavioral therapy) to implement this adjuvant therapy for the clinical management of aphasia, and (c) identify concerns that could potentially hinder the clinical adoption of tDCS. Method A brief (14-question) survey was disseminated via e-mail and social media outlets targeting SLPs working with individuals with aphasia. Results Two hundred twenty-one individuals responded, and 155 valid surveys were analyzed. Seventy-one percent of participants reported familiarity with tDCS prior to taking the survey. Clinicians reported a desired mean enhancement of 22.9% additional points on the Western Aphasia Battery-Revised Aphasia Quotient. Importantly, 94.2% of SLPs reported concerns regarding the implementation of tDCS in clinical settings (i.e., safety, cost, administrative approval, reimbursement and training). Conclusions This is the first study to identify SLPs' perspectives regarding the clinical adoption of tDCS. Results suggest the majority of queried SLPs were familiar with tDCS prior to taking the survey. Although SLPs report a desired improvement of approximately 23% additional points on the Western Aphasia Battery-Revised Aphasia Quotient to consider adopting tDCS into practice, many SLPs reported concerns regarding clinical adoption. Responses from the current survey offer important preliminary evidence to begin bridging the research-to-practice gap as it relates to the clinical implementation of tDCS. Relatedly, these results will inform future clinical trials.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine the predictive power of white matter neuronal networks (i.e., structural connectomes [SCs]) in discriminating memory-impaired patients with temporal lobe epilepsy (TLE) from those with normal memory., Methods: T1- and diffusion MRI (dMRI), clinical variables, and neuropsychological measures of verbal memory were available for 81 patients with TLE. Prediction of memory impairment was performed with a tree-based classifier (XGBoost) for 4 models: (1) a clinical model including demographic and clinical features, (2) a hippocampal volume (HCV) model, (3) a tract model including 5 temporal lobe white matter association tracts derived from a dMRI atlas, and (4) an SC model based on dMRI. SCs were derived by extracting cortical-cortical connections from a temporal lobe subnetwork with probabilistic tractography. Principal component (PC) analysis was then applied to reduce the dimensionality of the SC, yielding 10 PCs. Multimodal models were also tested combining SCs and tracts with HCV. Each model was trained on 48 patients from 1 epilepsy center and tested on 33 patients from a different center., Results: Multimodal models that included the SC + HCV model yielded the highest classification accuracy (81%; 0.90 sensitivity; 0.67 specificity), outperforming the clinical model (61%; p < 0.001) and HCV model (66%; p < 0.001). In addition, the unimodal SC model (76% accuracy) and tract model (73% accuracy) outperformed the clinical model ( p < 0.001) and HCV model ( p < 0.001) for classifying patients with TLE with and without memory impairment. Furthermore, the SC identified that short-range temporal-temporal connections were important contributors to memory performance., Conclusion: SCs and tract-based models are stronger predictors of memory impairment in TLE than HCVs and clinical variables. However, SCs may provide additional information about local cortical-cortical connectivity contributing to memory that is not captured in large association tracts., (© 2020 American Academy of Neurology.)

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Numerous studies have shown that surgical resection of the left anterior temporal lobe (ATL) is associated with a decline in object naming ability (Hermann et al., 1999). In contrast, few studies have examined the effects of left ATL surgery on auditory description naming (ADN) or category-specific naming. Compared with object naming, which loads heavily on visual recognition processes, ADN provides a more specific measure of concept retrieval. The present study examined ADN declines in a large group of patients who were tested before and after left ATL surgery, using a 2 × 2 × 2 factorial manipulation of uniqueness (common vs. proper nouns), taxonomic category (living vs. nonliving things), and time (pre- vs. postsurgery). Significant declines occurred across all categories but were substantially larger for proper living (PL) concepts, i.e., famous individuals. The disproportionate decline in PL noun naming relative to other conditions is consistent with the notion that the left ATL is specialized not only for retrieval of unique entity concepts, but also plays a role in processing social concepts and person-specific features., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Left-hemisphere brain damage commonly affects patients' abilities to produce and comprehend syntactic structures, a condition typically referred to as "agrammatism." The neural correlates of agrammatism remain disputed in the literature, and distributed areas have been implicated as important predictors of performance, for example, Broca's area, anterior temporal areas, and temporo-parietal areas. We examined the association between damage to specific language-related ROIs and impaired syntactic processing in acute aphasia. We hypothesized that damage to the posterior middle temporal gyrus, and not Broca's area, would predict syntactic processing abilities. One hundred four individuals with acute aphasia (<20 days poststroke) were included in the study. Structural MRI scans were obtained, and all participants completed a 45-item sentence-picture matching task. We performed an ROI-based stepwise regression analyses to examine the relation between cortical brain damage and impaired comprehension of canonical and noncanonical sentences. Damage to the posterior middle temporal gyrus was the strongest predictor for overall task performance and performance on noncanonical sentences. Damage to the angular gyrus was the strongest predictor for performance on canonical sentences, and damage to the posterior superior temporal gyrus predicted noncanonical scores when performance on canonical sentences was included as a cofactor. Overall, our models showed that damage to temporo-parietal and posterior temporal areas was associated with impaired syntactic comprehension. Our results indicate that the temporo-parietal area is crucially implicated in complex syntactic processing, whereas the role of Broca's area may be complementary.

Local field potentials (LFPs) encode visual information via variations in power at many frequencies. These variations are complex and depend on stimulus and cognitive state in ways that have yet to be fully characterized. Specifically, the frequencies (or combinations of frequencies) that most robustly encode specific types of visual information are not fully known. To address this knowledge gap, we used intracranial EEG to record LFPs at 858 widely distributed recording sites as human subjects (six males, five females) indicated whether briefly presented natural scenes depicted one of three attended object categories. Principal component analysis applied to power spectra of the LFPs near stimulus onset revealed a broadband component (1-100 Hz) and two narrowband components (1-8 and 8-30 Hz, respectively) that encoded information about both seen and attended categories. Interestingly, we found that seen and attended categories were not encoded with the same fidelity by these distinct spectral components. Model-based tuning and decoding analyses revealed that power variations along the broadband component were most sharply tuned and offered more accurate decoding for seen than for attended categories. Power along the narrowband delta-theta (1-8 Hz) component robustly decoded information about both seen and attended categories, while the alpha-beta (8-30 Hz) component was specialized for attention. We conclude that, when viewing natural scenes, information about the seen category is encoded via broadband and sub-gamma (<30 Hz) power variations, while the attended category is most robustly encoded in the sub-gamma range. More generally, these results suggest that power variation along different spectral components can encode qualitatively different kinds of visual information. SIGNIFICANCE STATEMENT In this article, we characterize how changes in visual stimuli depicting specific objects (cars, faces, and buildings) and changes in attention to those objects affect the frequency content of local field potentials in the human brain. In contrast to many previous studies that have investigated encoding by variations in power at high (>30 Hz) frequencies, we find that the most important variation patterns are broadband (i.e., distributed across multiple frequencies) and narrowband, but in lower frequencies (<30 Hz). Interestingly, we find that seen and attended categories are not encoded with the same fidelity by these distinct spectral encoding patterns, suggesting that power at different frequencies can encode qualitatively different kinds of information., (Copyright © 2020 the authors.)

Objective: The distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment., Methods: T1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results., Results: The SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p < .001; accuracy: 70%, p < .001) and the CV-model (AUC: .59, p < .001; accuracy: 64%, p < .001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance., Conclusion: The SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-fluent speech is one of the most common impairments in post-stroke aphasia. The rehabilitation of non-fluent speech in aphasia is particularly challenging as patients are rarely able to produce and practice fluent speech production. Speech entrainment is a behavioural technique that enables patients with non-fluent aphasia to speak fluently. However, its mechanisms are not well understood and the level of improved fluency with speech entrainment varies among individuals with non-fluent aphasia. In this study, we evaluated the behavioural and neuroanatomical factors associated with better speech fluency with the aid of speech entrainment during the training phase of speech entrainment. We used a lesion-symptom mapping approach to define the relationship between chronic stroke location on MRI and the number of different words per second produced during speech entrainment versus picture description spontaneous speech. The behavioural variable of interest was the speech entrainment/picture description ratio, which, if ≥1, indicated an increase in speech output during speech entrainment compared to picture description. We used machine learning (shallow neural network) to assess the statistical significance and out-of-sample predictive accuracy of the neuroanatomical model, and its regional contributors. We observed that better assisted speech (higher speech entrainment/picture description ratio) was achieved by individuals who had preservation of the posterior middle temporal gyrus, inferior fronto-occipital fasciculus and uncinate fasciculus, while exhibiting lesions in areas typically associated with non-fluent aphasia, such as the superior longitudinal fasciculus, precentral, inferior frontal, supramarginal and insular cortices. Our findings suggest that individuals with dorsal stream damage but preservation of ventral stream structures are more likely to achieve more fluent speech with the aid of speech entrainment compared to spontaneous speech. This observation provides insight into the mechanisms of non-fluent speech in aphasia and has potential implications for future research using speech entrainment for rehabilitation of non-fluent aphasia., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose The brain-derived neurotrophic factor (BDNF) gene has been shown to be important for synaptic plasticity in animal models. Human research has suggested that BDNF genotype may influence stroke recovery. Some studies have suggested a genotype-specific motor-related brain activation in stroke recovery. However, recovery from aphasia in relation to BDNF genotype and language-related brain activation has received limited attention. We aimed to explore functional brain activation by BDNF genotype in individuals with chronic aphasia. Consistent with findings in healthy individuals and individuals with poststroke motor impairment, we hypothesized that, among individuals with aphasia, the presence of the Met allele of the BDNF gene is associated with reduced functional brain activation compared to noncarriers of the Met allele. Method Eighty-seven individuals with chronic stroke-induced aphasia performed a naming task during functional magnetic resonance imaging scanning and submitted blood or saliva samples for BDNF genotyping. The mean number of activated voxels was compared between groups, and group-based activation maps were directly compared. Neuropsychological testing was conducted to compare language impairment between BDNF genotype groups. The Western Aphasia Battery Aphasia Quotient (Kertesz, 2007) was included as a covariate in all analyses. Results While lesion size was comparable between groups, the amount of activation, quantified as the number of activated voxels, was significantly greater in noncarriers of the Met allele (whole brain: 98,500 vs. 28,630, p < .001; left hemisphere only: 37,209 vs. 7,000, p < .001; right hemisphere only: 74,830 vs. 30,630, p < .001). This difference was most strongly expressed in the right hemisphere posterior temporal area, pre- and postcentral gyrus, and frontal lobe, extending into the white matter. Correspondingly, the atypical BDNF genotype group was found to have significantly less severe aphasia (Western Aphasia Battery Aphasia Quotient of 64.2 vs. 54.3, p = .033) and performed better on a naming task (Philadelphia Naming Test [Roach, Schwartz, Martin, Grewal, & Brecher, 1996] score of 74.7 vs. 52.8, p = .047). A region of interest analysis of intensity of activation revealed no group differences, and a direct comparison of average activation maps across groups similarly yielded null results. Conclusion BDNF genotype mediates cortical brain activation in individuals with chronic aphasia. Correspondingly, individuals carrying the Met allele present with more severe aphasia compared to noncarriers. These findings warrant further study into the effects of BDNF genotype in aphasia. Supplemental Material https://doi.org/10.23641/asha.10073147 Presentation Video https://doi.org/10.23641/asha.10257581.

Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1β (IL-1β), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1β induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1β. N -acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1β by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes. SIGNIFICANCE STATEMENT In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1β release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke., (Copyright © 2019 the authors.)

Objective: To investigate whether pre-articulatory neural activity could be used to predict correct vs. incorrect naming responses in individuals with post-stroke aphasia., Methods: We collected 64-channel high density electroencephalography (hdEEG) data from 5 individuals with chronic post-stroke aphasia (2 female/3 male, median age: 54 years) during naming of 80 concrete images. We applied machine learning on continuous wavelet transformed hdEEG data separately for alpha and beta energy bands (200 ms pre-stimulus to 1500 ms post-stimulus, but before articulation), and determined whether electrode/time-range/energy (ETE) combinations were predictive of correct vs incorrect responses for each participant., Results: The five participants correctly named between 30% and 70% of the 80 stimuli correctly. We observed that pre-articulatory scalp EEG ETE combinations could predict correct vs incorrect responses with accuracies ranging from 63% to 80%. For all but one participant, the prediction accuracies were statistically better than chance., Conclusions: Our findings indicate that pre-articulatory neural activity may be used to predict correct vs incorrect naming responses for some individuals with aphasia., Significance: The individualized pre-articulatory neural pattern associated with correct naming responses could be used to both predict naming problems in aphasia and lead to the development of brain stimulation strategies for treatment., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Introduction: Epilepsy is one of the most common serious brain disorders, characterised by seizures that severely affect a person's quality of life and, frequently, their cognitive and mental health. Although most existing work has examined chronic epilepsy, newly diagnosed patients present a unique opportunity to understand the underlying biology of epilepsy and predict effective treatment pathways. The objective of this prospective cohort study is to examine whether cognitive dysfunction is associated with measurable brain architectural and connectivity impairments at diagnosis and whether the outcome of antiepileptic drug treatment can be predicted using these measures., Methods and Analysis: 107 patients with newly diagnosed focal epilepsy from two National Health Service Trusts and 48 healthy controls (aged 16-65 years) will be recruited over a period of 30 months. Baseline assessments will include neuropsychological evaluation, structural and functional Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), and a blood and saliva sample. Patients will be followed up every 6 months for a 24-month period to assess treatment outcomes. Connectivity- and network-based analyses of EEG and MRI data will be carried out and examined in relation to neuropsychological evaluation and patient treatment outcomes. Patient outcomes will also be investigated with respect to analysis of molecular isoforms of high mobility group box-1 from blood and saliva samples., Ethics and Dissemination: This study was approved by the North West, Liverpool East Research Ethics Committee (19/NW/0384) through the Integrated Research Application System (Project ID 260623). Health Research Authority (HRA) approval was provided on 22 August 2019. The project is sponsored by the UoL (UoL001449) and funded by a UK Medical Research Council (MRC) research grant (MR/S00355X/1). Findings will be presented at national and international meetings and conferences and published in peer-reviewed journals., Trial Registration Number: IRAS Project ID 260623., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

We aimed to identify neural regions where ischemia acutely after stroke is associated with impairment in phoneme discrimination, and to determine whether such deficits are associated with impairment of spoken word comprehension. We evaluated 33 patients within 48 h of left hemisphere ischemic stroke onset with tests of phoneme discrimination and word-picture matching. We identified Pearson correlations between accuracy in phoneme discrimination and accuracy of word comprehension and identified areas where the percentage of infarcted tissue was associated with severity of phoneme discrimination deficit. We found that 54% had deficits in phoneme discrimination relative to healthy controls. Accuracy in phoneme discrimination correlated with accuracy on word comprehension tests. Damage to left intraparietal sulcus and hypoperfusion and/or infarct of left superior temporal gyrus were associated with phoneme discrimination deficits acutely, although patients with these lesions showed improvement or resolution of the deficit by six months., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We sought to determine the underlying pathophysiology relating white matter hyperintensities to chronic aphasia severity. We hypothesized that: (i) white matter hyperintensities are associated with damage to fibres of any length, but to a higher percentage of long-range compared to mid- and short-range intracerebral white matter fibres; and (ii) the number of long-range fibres mediates the relationship between white matter hyperintensities and chronic post-stroke aphasia severity. We measured the severity of periventricular and deep white matter hyperintensities and calculated the number and percentages of short-, mid- and long-range white matter fibres in 48 individuals with chronic post-stroke aphasia. Correlation and mediation analyses were performed to assess the relationship between white matter hyperintensities, connectome fibre-length measures and aphasia severity as measured with the aphasia quotient of the Western Aphasia Battery-Revised (WAB-AQ). We found that more severe periventricular and deep white matter hyperintensities correlated with a lower proportion of long-range fibres (r = -0.423, P = 0.003 and r = -0.315, P = 0.029, respectively), counterbalanced by a higher proportion of short-range fibres (r = 0.427, P = 0.002 and r = 0.285, P = 0.050, respectively). More severe periventricular white matter hyperintensities also correlated with a lower proportion of mid-range fibres (r = -0.334, P = 0.020), while deep white matter hyperintensities did not correlate with mid-range fibres (r = -0.169, P = 0.250). Mediation analyses revealed: (i) a significant total effect of periventricular white matter hyperintensities on WAB-AQ (standardized beta = -0.348, P = 0.008); (ii) a non-significant direct effect of periventricular white matter hyperintensities on WAB-AQ (P > 0.05); (iii) significant indirect effects of more severe periventricular white matter hyperintensities on worse aphasia severity mediated in parallel by fewer long-range fibres (effect = -6.23, bootstrapping: standard error = 2.64, 95%CI: -11.82 to -1.56) and more short-range fibres (effect = 4.50, bootstrapping: standard error = 2.59, 95%CI: 0.16 to 10.29). We conclude that small vessel brain disease seems to affect chronic aphasia severity through a change of the proportions of long- and short-range fibres. This observation provides insight into the pathophysiology of small vessel brain disease, and its relationship with brain health and chronic aphasia severity., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Neuromodulation of the cerebello-thalamo-cortical (CTC) circuit via thalamic stimulation is an effective therapy for essential tremor (ET). In order to develop non-invasive neuromodulation approaches, clinically relevant thalamo-cortical connections must be elucidated., Methods: Twenty-eight subjects (18 ET patients and 10 controls) underwent MRI diffusional kurtosis imaging (DKI). A deterministic fiber-tracking algorithm based on DKI was used, with a seeding region placed at the ventral intermediate nucleus (Vim-located based on intraoperative physiology) to the ending regions at the supplementary motor area (SMA), pre-SMA, or primary motor cortex. One-tailed t -tests were performed to compare groups, and associations with tremor severity were determined by Pearson correlations. All p-values were adjusted for multiple comparisons using Bonferroni correction., Results: There was a decrease in the mean diffusivity (MD) in patients compared to controls in all three tracts: Vim-M1 (ET 0.87, control 0.96, p < 0.01), Vim-SMA (ET 0.86, control 0.96, p < 0.05), and Vim-pre-SMA (ET 0.87, control 0.95, p < 0.05). There was a significant positive correlation between Tremor Rating Scale score and MK ( r = 0.471, p = 0.033) and mean FA ( r = 0.438, p = 0.045) for the Vim-SMA tract, and no significant correlation for the Vim-pre-SMA or Vim-M1 tracts was found., Discussion: Patients with ET demonstrated a reinforcement of Vim-cortical connectivity, with higher Vim-SMA connectivity being associated with greater tremor severity. This finding suggests that the Vim-SMA connection is relevant to the underlying pathophysiology of ET, and inhibition of the SMA may be an effective therapeutic approach., Competing Interests: Funding: This study was supported by NIH Grants 1K23NS091391-01A1, R01DC014021, RF1AG057602, R01NS097775, R01AG054159, and R01AG055132. Conflict of Interest: Jens Jensen is a co-inventor on US patents 8,811,706, 9,478,026, and 9,965,962, which are related to the MRI techniques utilized in this work; the other authors do not report any conflict of interest related to the research reported in this article. Ethics Statement: This study was reviewed by the authors’ institutional ethics committee and was considered exempted from further review.

Background . A fraction of stroke survivors with chronic aphasia experience declines in language abilities over time, but the reason for this remains unclear. Objective . To evaluate the effect of leukoaraiosis on baseline aphasia severity and long-term changes in aphasia severity. This study directly compares the predictive capacity of leukoaraiosis severity to that of lesion damage, a factor known to account for a substantial proportion of variance in the degree of language impairment and recovery. Methods . Using a longitudinal database of behavioral and neuroimaging data from 35 individuals in the chronic stage of recovery after a single-event left-hemisphere stroke (9 females, mean stroke age = 55.8 ± 9.1 years, mean months poststroke at initial evaluation = 36.3 ± 40.8), we examined 2 lines of inquiry: (1) to what extent does leukoaraiosis severity at initial evaluation predict aphasia severity and (2) to what extent does leukoaraiosis severity at initial evaluation predict longitudinal change in aphasia severity. Participants underwent high-resolution magnetic resonance imaging for the purpose of lesion volume analysis and leukoaraiosis severity rating. Biographical information was also considered. Results . Lesion volume and time poststroke at initial assessment best predicted initial aphasia severity (adjusted R 2 = 0.37). Leukoaraiosis severity and initial aphasia severity significantly predicted decline in language abilities at follow-up, accounting for approximately one-third of the variance (adjusted R 2 = 0.33). More severe leukoaraiosis was associated with a 4.3 odds increase of decline. Conclusions . Leukoaraiosis is a significant risk factor for declining language abilities in aphasia and should be considered for better identification of individuals at risk for long-term decline, which can guide clinical decision making.

While numerous studies have explored single-word naming, few have evaluated the behavioral and neural correlates of more naturalistic language, like connected speech, which we produce every day. Here, in a retrospective analysis of 120 participants at least six months following left hemisphere stroke, we evaluated the distribution of word errors (paraphasias) and associated brain damage during connected speech (picture description) and object naming. While paraphasias in connected speech and naming shared underlying neural substrates, analysis of the distribution of paraphasias suggested that lexical-semantic load is likely reduced during connected speech. Using voxelwise lesion-symptom mapping (VLSM), we demonstrated that verbal (real word: semantically related and unrelated) and sound (phonemic and neologistic) paraphasias during both connected speech and naming loaded onto the left hemisphere ventral and dorsal streams of language, respectively. Furthermore, for the first time using both connected speech and naming data, we localized semantically related paraphasias to more anterior left hemisphere temporal cortex and unrelated paraphasias to more posterior left temporal and temporoparietal cortex. The connected speech results, in particular, highlight a gradient of specificity as one translates visual recognition from left temporo-occipital cortex to posterior and subsequently anterior temporal cortex. The robustness of VLSM results for sound paraphasias derived during connected speech was notable, in that analyses performed on sound paraphasias from the connected speech task, and not the naming task, demonstrated significant results following removal of lesion volume variance and related apraxia of speech variance. Therefore, connected speech may be a particularly sensitive task on which to evaluate further lexical-phonological processing in the brain. The results presented here demonstrate the related, though different, distribution of paraphasias during connected speech, confirm that paraphasias arising in connected speech and single-word naming likely share neural origins, and endorse the need for continued evaluation of the neural substrates of connected speech processes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To assess ischemic stroke patients regarding the relationship between lesion locations, swallowing impairment, medical and demographic factors and (1) oral intake improvement and (2) feeding tube dependency at discharge from their acute hospital stay., Methods: We conducted an exploratory, retrospective observational longitudinal cohort study of acute, first-ever, ischemic stroke patients. Patients who had an initial nonoral feeding recommendation from a speech and language pathologist and who underwent a modified barium swallow study within their hospital stay were included. Oral intake status was measured with the Functional Oral Intake Scale (FOIS) as the change in FOIS during the hospital stay and as feeding tube dependency at hospital discharge. Associations were assessed with multiple linear regression modeling controlling for age, comorbidities, and hospital length of stay., Results: We included 44 stroke patients. At hospital discharge, 93% of patients had oral intake restrictions and 30% were feeding tube dependent. Following multiple linear regression modeling, age, damage to the left superior frontal gyrus, dorsal anterior cingulate gyrus, hypothalamus, and nucleus accumbens were significant predictors for FOIS change. Feeding tube dependency showed no significant associations with any prognostic variables when controlling for confounders., Conclusions: The vast majority of patients with an initial nonoral feeding recommendation are discharged with oral intake restrictions indicating a continued need for swallowing assessments and treatment after discharge. Lesion locations associated with motivation, reward, and drive to consume food as well as swallowing impairment, higher age, and more comorbidities were related to less oral intake improvement., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose The severity of aphasic impairment in chronic stroke survivors is typically thought to be stable by 6 months postonset. However, a recent study showed that stroke survivors with aphasia experience language improvement or decline in the chronic phase, years beyond onset. Little is known about why some individuals improve whereas others remain stable or decline. Additionally, no study has tracked changes in aphasia from assessments completed at multiple time points across many years. The current study offers a comprehensive analysis of potential predictive demographic and health information to determine which factors predict dynamic changes in aphasia severity in chronic stroke. Methods Individuals in the chronic stage of a single-event, left-hemisphere ischemic stroke were identified from an archival database and included for study ( N = 39). Participants were included if they had undergone 2 or more standardized language assessments acquired at time points at least 6 months apart, with the 1st assessment at least 6 months postinjury. A linear mixed-effects model was used to determine the impact of treatment and a variety of demographic and health factors on language change. Results Over time, half of the participants improved (51%), whereas approximately a quarter (26%) decreased, and a quarter (23%) remained stable. A greater number of aphasia treatment hours significantly predicted language improvement ( p = .03), whereas older stroke age was associated with long-term decline ( p = .04). Two interactions were found to be significant in predicting improvement in individuals with diabetes: Increased exercise and younger age at stroke were significant in predicting outcomes ( p < .05). Conclusions Factors that significantly influence language recovery in chronic aphasia include stroke age and receiving aphasia treatment. For those with diabetes, increased exercise was shown to improve outcomes. Results from this study offer clinicians greater insight into the influence of patient factors on long-term recovery from stroke aphasia while suggesting a potential adjunct to language therapy: exercise. Supplemental Material https://doi.org/10.23641/asha.7849304.

Background: Population-wide reductions in cardiovascular disease (CVD) have not been equally shared in the African American community due to a higher burden of CVD risk factors such as metabolic disorders and obesity. Differential concentrations of sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) has been associated with the development of CVD, metabolic disorders (MetD), and obesity. Whether African Americans have disparate expression levels of sphingolipids that explain higher burdens of CVD remains unknown., Methods: A cross sectional analysis of plasma concentrations of ceramides, sphingosine, and S1P were measured from 8 whites and 7 African Americans without metabolic disorders and 7 whites and 8 African Americans with metabolic disorders using high performance liquid chromatography/tandem mass spectrometry methodology (HPLC/MS-MS). Subjects were stratified by both race and metabolic status. Subjects with one or more of the following physician confirmed diagnosis: diabetes, hypertension, hypercholesterolemia, or dyslipidemia were classified as having metabolic disease (MetD). Data was analyzed using a Two-Way ANOVA and Tukey's post hoc test., Results: Total ceramide levels were increased in African Americans compared to African Americans with MetD. Ceramide C16 levels were higher in whites with MetD compared to African Americans with MetD (p<0.05). Ceramide C20 levels were higher in whites with MetD compared to whites. Ceramide C20 levels were higher in African Americans compared to African Americans with MetD. Furthermore, whites with MetD had higher levels of C20 compared to African Americans with MetD (p<0.0001). Ceramide C24:0 and C24:1 in African Americans was higher compared to African Americans with MetD (p<0.05). The plasma concentration of Sph-1P ceramide was higher in African Americans vs whites (p = 0.01). Lastly, ceramide C20 negatively correlated with hemoglobin A1c (HbA1c) levels in our study cohort., Conclusions: Plasma ceramide concentration patterns are distinct in African Americans with MetD. Further research with larger samples sizes are needed to confirm these findings and to understand whether racial disparities in sphingolipid concentrations have potential therapeutic implications for CVD-related health outcomes., Competing Interests: The authors have declared that no competing interests exist.

Agrammatism in aphasia is not a homogeneous syndrome, but a characterization of a nonuniform set of language behaviors in which grammatical markers and complex syntactic structures are omitted, simplified, or misinterpreted. In a sample of 71 left-hemisphere stroke survivors, syntactic processing was quantified with the Northwestern Assessment of Verbs and Sentences (NAVS). Classification analyses were used to assess the relation between NAVS performance and morphosyntactically reduced speech in picture descriptions. Voxel-based and connectivity-based lesion-symptom mapping were applied to investigate neural correlates of impaired syntactic processing. Despite a nonrandom correspondence between NAVS performance and morphosyntactic production deficits, there was variation in individual patterns of syntactic processing. Morphosyntactically reduced production was predicted by lesions to left-hemisphere inferior frontal cortex. Impaired verb argument structure production was predicted by damage to left-hemisphere posterior superior temporal and angular gyrus, as well as to a ventral pathway between temporal and frontal cortex. Damage to this pathway was also predictive of impaired sentence comprehension and production, particularly of noncanonical sentences. Although agrammatic speech production is primarily predicted by lesions to inferior frontal cortex, other aspects of syntactic processing rely rather on regional integrity in temporoparietal cortex and the ventral stream., (© 2019 Wiley Periodicals, Inc.)