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Abstract Sharing neuroimaging datasets enables reproducibility, education, tool development, and new discoveries. Neuroimaging from many studies are publicly available, providing a glimpse into progressive disorders and human development. In contrast, few stroke studies are shared, and these datasets lack longitudinal sampling of functional imaging, diffusion imaging, as well as the behavioral and demographic data that encourage novel applications. This is surprising, as stroke is a leading cause of disability, and acquiring brain imaging is considered standard of care. The first release of the Aphasia Recovery Cohort includes imaging data, demographics and behavioral measures from 230 chronic stroke survivors who experienced aphasia. We also share scripts to illustrate how the imaging data can predict impairment. In conclusion, recent advances in machine learning thrive on large, diverse datasets. Clinical data sharing can contribute to improvements in automated detection of brain injury, identification of white matter hyperintensities, measures of brain health, and prognostic abilities to guide care.

Background Unfavorable clinical outcomes in patients with acute ischemic stroke caused by large‐vessel occlusions despite successful reperfusion have been associated with poor venous outflow. The objective of this study is to assess the relationship between prolonged venous transit (PVT), a novel perfusion imaging surrogate for poor venous outflow, and likelihood of favorable clinical recovery. Methods In this retrospective review of prospectively collected data of consecutive patients (2017–2022) with successfully reperfused, anterior circulation acute ischemic stroke caused by large‐vessel occlusions, we assessed the association between PVT+, defined as time to maximum ≧10‐second timing delays within either the posterior superior sagittal sinus, torcula, or both regions on pretreatment perfusion imaging, and favorable clinical outcomes defined as 90‐day modified Rankin Scale score of 0 to 2. Patients were dichotomized into PVT+ and PVT− for analysis. Multivariable logistic regression analyses for favorable recovery were performed with demographic variables and stroke characteristics. Results A total of 127 consecutive patients (median age, 71 [interquartile range 61—77] years; 59.1% women) were included, and 40 of 127 (31.5%) were PVT+. PVT+ (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07–0.81]; P = 0.02) and advanced age (aOR, 0.92 [95% CI, 0.88–0.97]; P = 0.01) were significantly associated with the primary outcome. Conclusion PVT+ was associated with a lower likelihood of achieving favorable clinical recovery in successfully reperfused patients with acute ischemic stroke caused by large vessel occlusion. PVT may serve as a clinically useful adjunctive imaging parameter.

Background Hemorrhagic transformation (HT) is a major complication in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy. However, HT in patients with AIS due to medium‐vessel occlusions has still not been well researched. In large‐vessel occlusions, collateral status is an important determinant of postprocedural HT, and the cerebral blood volume (CBV) index is a reliable surrogate of collateral status. The aim of our study is to identify an optimal CBV index threshold associated with HT in patients with AIS due to medium‐vessel occlusion and evaluate additional parameters that are independently associated with HT in this group. Methods This retrospective analysis of our prospectively collected database from 2 comprehensive stroke centers consisted of patients presenting with AIS due to medium‐vessel occlusion from 2019 to 2023. The primary outcome was the presence of HT on follow‐up imaging. Optimal CBV index cutoff for HT was derived from a univariate logistic regression analysis. Multivariable logistic regression analysis for HT was derived from the dichotomized CBV index and other covariates. The receiver operator characteristic curve yielded area under the curve. Statistical significance was P≤$ \le $0.05. Results Of 111 patients (median age, 70 years; 43.2% women) included, 26 (23.4%) patients had HT. The optimal CBV index cutoff was 0.7. From multivariable regression analysis, significant variables included prior stroke (adjusted odds ratio [aOR], 7.18 [95% CI, 1.60–32.16]; P = 0.01), endovascular thrombectomy attempt (aOR, 7.86 [95% CI, 1.78–34.68]; P = 0.01), and CBV index (≤$ \le $ 0.7; aOR, 4.23 [95% CI, 1.02–17.59]; P = 0.04). The area under the curve was 0.82 (95% CI, 0.69–0.91). Conclusion A CBV index ≤$ \le $ 0.7 was independently associated with HT in patients with AIS due to medium‐vessel occlusion. Endovascular thrombectomy attempt and prior stroke history were also independently associated with HT in this population.

Abstract Objective To examine changes to connectivity after aphasia treatment in the first 3 months after stroke. Methods Twenty people experiencing aphasia within the first 3 months of stroke completed MRI before and immediately following 15 hours of language treatment. They were classified based on their response to treatment on a naming test of nouns as either high responders (10% improvement or more), or low responders (

Abstract To extract meaningful and reproducible models of brain function from stroke images, for both clinical and research proposes, is a daunting task severely hindered by the great variability of lesion frequency and patterns. Large datasets are therefore imperative, as well as fully automated image post-processing tools to analyze them. The development of such tools, particularly with artificial intelligence, is highly dependent on the availability of large datasets to model training and testing. We present a public dataset of 2,888 multimodal clinical MRIs of patients with acute and early subacute stroke, with manual lesion segmentation, and metadata. The dataset provides high quality, large scale, human-supervised knowledge to feed artificial intelligence models and enable further development of tools to automate several tasks that currently rely on human labor, such as lesion segmentation, labeling, calculation of disease-relevant scores, and lesion-based studies relating function to frequency lesion maps.

Abstract Background Although artificial intelligence systems that diagnosis among different conditions from medical images are long term aims, specific goals for automation of human-labor, time-consuming tasks are not only feasible but equally important. Acute conditions that require quantitative metrics, such as acute ischemic strokes, can greatly benefit by the consistency, objectiveness, and accessibility of automated radiological reports. Methods We used 1,878 annotated brain MRIs to generate a fully automated system that outputs radiological reports in addition to the infarct volume, 3D digital infarct mask, and the feature vector of anatomical regions affected by the acute infarct. This system is associated to a deep-learning algorithm for segmentation of the ischemic core and to parcellation schemes defining arterial territories and classically-identified anatomical brain structures. Results Here we show that the performance of our system to generate radiological reports was comparable to that of an expert evaluator. The weight of the components of the feature vectors that supported the prediction of the reports, as well as the prediction probabilities are outputted, making the pre-trained models behind our system interpretable. The system is publicly available, runs in real time, in local computers, with minimal computational requirements, and it is readily useful for non-expert users. It supports large-scale processing of new and legacy data, enabling clinical and translational research. Conclusion: The generation of reports indicates that our fully automated system is able to extract quantitative, objective, structured, and personalized information from stroke MRIs.

Abstract Cerebrovascular disease is a leading cause of death globally. Prevention and early intervention are known to be the most effective forms of its management. Non-invasive imaging methods hold great promises for early stratification, but at present lack the sensitivity for personalized prognosis. Resting-state functional magnetic resonance imaging (rs-fMRI), a powerful tool previously used for mapping neural activity, is available in most hospitals. Here we show that rs-fMRI can be used to map cerebral hemodynamic function and delineate impairment. By exploiting time variations in breathing pattern during rs-fMRI, deep learning enables reproducible mapping of cerebrovascular reactivity (CVR) and bolus arrival time (BAT) of the human brain using resting-state CO2 fluctuations as a natural “contrast media”. The deep-learning network is trained with CVR and BAT maps obtained with a reference method of CO2-inhalation MRI, which includes data from young and older healthy subjects and patients with Moyamoya disease and brain tumors. We demonstrate the performance of deep-learning cerebrovascular mapping in the detection of vascular abnormalities, evaluation of revascularization effects, and vascular alterations in normal aging. In addition, cerebrovascular maps obtained with the proposed method exhibit excellent reproducibility in both healthy volunteers and stroke patients. Deep-learning resting-state vascular imaging has the potential to become a useful tool in clinical cerebrovascular imaging.

Individuals with Mild Cognitive Impairment (MCI), a transitional stage between cognitively healthy aging and dementia, are characterized by subtle neurocognitive changes. Clinically, they can be grouped into two main variants, namely patients with amnestic MCI (aMCI) and non-amnestic MCI (naMCI). The distinction of the two variants is known to be clinically significant as they exhibit different progression rates to dementia. However, it has been particularly challenging to classify the two variants robustly. Recent research indicates that linguistic changes may manifest as one of the early indicators of pathology. Therefore, we focused on MCI’s discourse-level writing samples in this study. We hypothesized that a written picture description task can provide information that can be used as an ecological, cost-effective classification system between the two variants. We included one hundred sixty-nine individuals diagnosed with either aMCI or naMCI who received neurophysiological evaluations in addition to a short, written picture description task. Natural Language Processing (NLP) and a BERT pre-trained language model were utilized to analyze the writing samples. We showed that the written picture description task provided 90% overall classification accuracy for the best classification models, which performed better than cognitive measures. Written discourses analyzed by AI models can automatically assess individuals with aMCI and naMCI and facilitate diagnosis, prognosis, therapy planning, and evaluation.

Here, we review the literature on neurotypical individuals and individuals with post-stroke aphasia showing that right-hemisphere regions homologous to language network and other regions, like the right cerebellum, are activated in language tasks and support language even in healthy people. We propose that language recovery in post-stroke aphasia occurs largely by potentiating the right hemisphere network homologous to the language network and other networks that previously supported language to a lesser degree and by modulating connection strength between nodes of the right-hemisphere language network and undamaged nodes of the left-hemisphere language network. Based on this premise (supported by evidence we review), we propose that interventions should be aimed at potentiating the right-hemisphere language network through Hebbian learning or by augmenting connections between network nodes through neuroplasticity, such as non-invasive brain stimulation and perhaps modulation of neurotransmitters involved in neuroplasticity. We review aphasia treatment studies that have taken this approach. We conclude that further aphasia rehabilitation with this aim is justified.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman’s rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = −0.214, p < 0.01), mTICI (beta = −0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

IntroductionDespite a growing emphasis on discourse processing in clinical neuroscience, relatively little is known about the neurobiology of discourse production impairments. Individuals with a history of left or right hemisphere stroke can exhibit difficulty with communicating meaningful discourse content, which implies both cerebral hemispheres play a role in this skill. However, the extent to which successful production of discourse content relies on network connections within domain-specific vs. domain-general networks in either hemisphere is unknown.MethodsIn this study, 45 individuals with a history of either left or right hemisphere stroke completed resting state fMRI and the Cookie Theft picture description task.ResultsParticipants did not differ in the total number of content units or the percentage of interpretative content units they produced. Stroke survivors with left hemisphere damage produced significantly fewer content units per second than individuals with right hemisphere stroke. Intrinsic connectivity of the left language network was significantly weaker in the left compared to the right hemisphere stroke group for specific connections. Greater efficiency of communication of picture scene content was associated with stronger left but weaker right frontotemporal connectivity of the language network in patients with a history of left hemisphere (but not right hemisphere) stroke. No significant relationships were found between picture description measures and connectivity of the dorsal attention, default mode, or salience networks or with connections between language and other network regions.DiscussionThese findings add to prior behavioral studies of picture description skills in stroke survivors and provide insight into the role of the language network vs. other intrinsic networks during discourse production.

Abstract The Alberta Stroke Program Early CT Score (ASPECTS) is a simple visual system to assess the extent and location of ischemic stroke core. The capability of ASPECTS for selecting patients’ treatment, however, is affected by the variability in human evaluation. In this study, we developed a fully automatic system to calculate ASPECTS comparable with consensus expert readings. Our system was trained in 400 clinical diffusion weighted images of patients with acute infarcts and evaluated with an external testing set of 100 cases. The models are interpretable, and the results are comprehensive, evidencing the features that lead to the classification. This system adds to our automated pipeline for acute stroke detection, segmentation, and quantification in MRIs (ADS), which outputs digital infarct masks and the proportion of diverse brain regions injured, in addition to the predicted ASPECTS, the prediction probability and the explanatory features. ADS is public, free, accessible to non-experts, has very few computational requirements, and run in real time in local CPUs with a single command line, fulfilling the conditions to perform large-scale, reproducible clinical and translational research.

Measurement(s) brain arterial territories Technology Type(s) Magnetic Resonance Imaging Factor Type(s) location Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location United States of America

Velocity-selective inversion (VSI) based velocity-selective arterial spin labeling (VSASL) has been developed to measure cerebral blood flow (CBF) with low susceptibility to the prolonged arterial transit time and high sensitivity to brain perfusion signal. The purpose of this magnetic resonance imaging study is to evaluate the test-retest reliability of a VSI-prepared 3D VSASL protocol with whole-brain coverage to detect baseline CBF variations among cognitively normal participants in different brain regions. Coefficients of variation (CoV) of both absolute and relative CBF across scans or sessions, subjects, and gray matter regions were calculated, and corresponding intraclass correlation coefficients (ICC) were computed. The higher between-subject CoV of absolute CBF (13.4 ± 2.0%) over within-subject CoV (within-session: 3.8 ± 1.1%; between-session: 4.9 ± 0.9%) yielded moderate to excellent ICC (within-session: 0.88±0.08; between-session: 0.77±0.14) to detect normal variations of individual CBF. The higher between-region CoV of relative CBF (11.4 ± 3.0%) over within-region CoV (within-session: 2.3 ± 0.9%; between-session: 3.3 ± 1.0%) yielded excellent ICC (within-session: 0.92±0.06; between-session: 0.85±0.12) to detect normal variations of regional CBF. Age, blood pressure, end-tidal CO2, and hematocrit partially explained the variability of CBF across subjects. Together these results show excellent test-retest reliability of VSASL to detect both between-subject and between-region variations supporting its clinical utility.

Background and Aim: Considering the anatomical features of Middle Cerebral Artery (MCA) bifurcation, larger emboli are more likely to enter the inferior division over the superior division. Since emboli of cardiac origin are larger on average than emboli of arterial origin, we hypothesize that the infarcts in temporal and parietal lobes are more likely associated to atrial fibrillation than those in the frontal lobes, therefore occurring more often in populations with higher incidence of atrial fibrillation, such as male (compared to women) and white (compared to black) patients.Methods: We included 197 patients with MCA “temporoparietal predominant” infarcts and 105 with “frontal predominant” infarcts. Variations between stroke location (frontal or temporoparietal), sex, and race were examined via Chi-square test.Results: Male patients were more likely than female patients to be afflicted by temporoparietal strokes versus frontal strokes, while white patients had greater likelihood than black patients to be afflicted by temporoparietal strokes versus frontal strokes. Patients with confirmed diagnosis of atrial fibrillation display more temporoparietal strokes compared to frontal strokes.Conclusion: Temporoparietal MCA ischemic strokes occur more frequently in male and white patients: populations with known increased incidence of atrial fibrillation. In addition, population-specific anatomical characteristics of the MCA bifurcation might favor the larger cardiac emboli to enter the inferior division and cause temporoparietal infarcts. This association can help guide search for the most likely etiology of infarcts.

For the past decade, brain health has been an emerging line of scientific inquiry assessing the impact of age-related neurostructural changes on cognitive decline and recovery from brain injury. Typically, compromised brain health is attributed to the presence of small vessel disease (SVD) and brain tissue atrophy, which are represented by various neuroimaging features. However, to date, the relationship between brain health markers and chronic aphasia severity remains unclear. Thus, the goal of this scoping review was to assess the current body of evidence regarding the relationship between SVD-related brain health biomarkers and post-stroke aphasia and cognition. In all, 187 articles were identified from 3 databases, of which 16 articles met the criteria for inclusion. Among these studies, 11 focused on cognition rather than aphasia, while 2 investigated both. Of the 10 studies that used white matter hyperintensities (WMHs) as an indicator of SVD severity, 8 studies (80%) demonstrated a relationship between WMH load and worse cognition in stroke patients. Interestingly, among the studies that specifically investigated aphasia, all 5 studies (100%) demonstrated a relationship between SVD and worse language performance. They also indicated that factors other than brain health (e.g., lesion, age, time post onset) played an important role in determining aphasia severity at a single timepoint. These findings suggest that brain health is likely a crucial factor in the context of aphasia recovery, possibly indicating the necessity of cognitive reserve thresholds for the multimodal cognitive demands associated with language recovery. While SVD and structural brain health are not commonly considered as predictors of aphasia severity, more comprehensive models incorporating brain health have the potential to improve prognosis of post-stroke cognitive and language deficits. Given the variability in the existing literature, a uniform grading system for overall SVD would be beneficial for future research on the mechanisms related to brain networks and neuroplasticity, and their translational impact.

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language functions. Neuromodulatory techniques (e.g., transcranial direct current stimulation, active-tDCS) and behavioral (speech-language) therapy have shown promising results in treating speech and language deficits in PPA patients. One mechanism of active-tDCS efficacy is through modulation of network functional connectivity (FC). It remains unknown how biological sex influences FC and active-tDCS or language treatment(s). In the current study, we compared sex differences, induced by active-tDCS and language therapy alone, in the default mode and language networks, acquired during resting-state fMRI in 36 PPA patients. Using a novel statistical method, the covariate-assisted-principal-regression (CAPs) technique, we found sex and age differences in FC changes following active-tDCS. In the default mode network (DMN): (1) men (in both conditions) showed greater FC in DMN than women. (2) men who received active-tDCS showed greater FC in the DMN than men who received language-treatment only. In the language network: (1) women who received active-tDCS showed significantly greater FC across the language network than women who received sham-tDCS. As age increases, regardless of sex and treatment condition, FC in language regions decreases. The current findings suggest active-tDCS treatment in PPA alters network-specific FC in a sex-dependent manner.

Liu et al. develop a deep learning-based tool to detect and segment diffusion abnormalities seen on magnetic resonance imaging (MRI) in acute ischemic stroke. The tool is tested in two clinical MRI datasets and outperforms existing algorithms in the detection of small lesions, potentially allowing clinicians and clinical researchers to more quickly and accurately diagnose and assess ischemic strokes.

The differences in mental health outcomes of right and left hemisphere strokes are well studied; however, there is a long-standing controversy surrounding whether depression is associated with lateralization of stroke or not. In this investigation, we examined the effect of lesion location on post-stroke depression controlling for lesion size and hemiparesis in a longitudinal sample assessed at acute, subacute, and chronic timepoints. As a secondary aim, we further examined the effect of lesion location on self-reported difficulties across a wide array of domains. A series of 134 patients with left hemisphere strokes and 79 with right hemisphere strokes completed the Patient Health Questionnaire-9 and an inventory of post-stroke abilities at within acute, subacute, and chronic windows following stroke. When controlling for hemiparesis and overall lesion volume, we found no difference in depression between groups at any timepoint. Additional exploratory analyses provided a further look at differing challenges associated with depression in each group.

AbstractAltered functional connectivity is related to severity of language impairment in poststroke aphasia. However, it is not clear whether this finding specifically reflects loss of functional coherence, or more generally, is related to decreased structural connectivity due to cortical necrosis. The aim of the current study was to investigate this issue by factoring out structural connectivity from functional connectivity measures and then relating the residual data to language performance poststroke. Ninety-seven participants with a history of stroke were assessed using language impairment measures (Auditory Verbal Comprehension and Spontaneous Speech scores from the Western Aphasia Battery–Revised) and MRI (structural, diffusion tensor imaging, and resting-state functional connectivity). We analyzed the association between functional connectivity and language and controlled for multiple potential neuroanatomical confounders, namely structural connectivity. We identified functional connections within the left hemisphere ventral stream where decreased functional connectivity, independent of structural connectivity, was associated with speech comprehension impairment. These connections exist in frontotemporal and temporoparietal regions. Our results suggest poor speech comprehension in aphasia is at least partially caused by loss of cortical synchrony in a left hemisphere ventral stream network and is not only reflective of localized necrosis or structural connectivity.

NIHSS score is higher for left vs. right hemisphere strokes of equal volumes. However, differences in each vascular territory have not been evaluated yet. We hypothesized that left vs. right differences are driven by the middle cerebral artery (MCA) territory, and there is no difference between hemispheres for other vascular territories. This study is based on data from 802 patients with evidence of acute ischemic stroke in one major arterial territory (MCA, n = 437; PCA, n = 209; ACA, n = 21; vertebrobasilar, n = 46). We examined differences in patients with left or right strokes regarding to lesion volume, NIHSS, and other covariates (age, sex, race). We used linear models to test the effects of these covariates on NIHSS. We looked at the whole sample as well as in the sample stratified by NIHSS (≤5 or >5) and by lesion location (MCA or PCA). Patients with left MCA strokes had significantly higher NIHSS than those with right strokes. Only patients with MCA strokes showed NIHSS score affected by the hemisphere when controlling for stroke volume and patient's age. This difference was driven by the more severe strokes (NIHSS>5). It is important to consider this systematic bias in the NIHSS when using the score for inclusion criteria for treatment or trials. Patients with right MCA stroke may be under-treated and left with disabling deficits that are not captured by the NIHSS.

Background and PurposeHydration at the time of stroke may impact functional outcomes. We sought to investigate the relationship between blood pressure, hydration status, and stroke severity in patients with acute ischemic stroke (AIS).MethodsWe evaluated hydration status, determined by blood urea nitrogen (BUN)/creatinine ratio, in consecutive patients with AIS from a single comprehensive stroke center. Baseline mean arterial pressure (MAP) was analyzed using a linear spline with a knot at 90 mmHg. Baseline stroke severity was defined based on admission NIH Stroke Scale scores (NIHSSS) and MRI diffusion-weighted imaging.ResultsAmong 108 eligible subjects, 55 (51%) presented in a volume contracted state. In adjusted models, in the total sample, for every 10 mmHg higher MAP up to 90 mmHg, NIHSSS was 2.8 points lower (p = 0.053), without further statistically significant association between MAP above 90 and NIHSSS. This relationship was entirely driven by the individuals in a volume contracted state: MAP was not associated with NIHSSS in individuals who were euvolemic. For individuals in a volume contracted state, each 10 mmHg higher MAP, up to 90 mmHg, was associated with 6.9 points lower NIHSSS (95% CI −11.1, −2.6). MAP values above 90 mmHg were not related to NIHSSS in either dehydrated or euvolemic patients.ConclusionsLower MAP contributes to more severe stroke in patients who are volume contracted, but not those who are euvolemic, suggesting that hydration status and blood pressure may jointly contribute to the outcome. Hydration status should be considered when setting blood pressure goals for patients with AIS.

In acute ischemic stroke, reported relationships between lesion metrics and behavior have largely focused on lesion volume and location. However, hypoperfusion has been shown to correlate with deficits in the acute stage. Hypoperfusion is typically identified using perfusion imaging in clinical settings, which requires contrast. Unfortunately, contrast is contraindicated for some individuals. An alternative method has been proposed to identify hypoperfusion using hyperintense vessels on fluid-attenuated inversion recovery (FLAIR) imaging. This study aimed to validate the clinical importance of considering hypoperfusion when accounting for behavior in acute stroke and demonstrate the clinical utility of scoring the presence of hyperintense vessels to quantify it.One hundred and fifty-three participants with acute ischemic stroke completed a battery of commonly-used neurological and behavioral measures. Clinical MRIs were used to determine lesion volume and to score the presence of hyperintense vessels seen on FLAIR images to estimate severity of hypoperfusion in six different vascular regions. National Institutes of Health Stroke Scale (NIHSS) scores, naming accuracy (left hemisphere strokes), and language content produced during picture description were examined in relation to lesion volume, hypoperfusion, and demographic variables using correlational analyses and multivariable linear regression.Results showed that lesion volume and hypoperfusion, in addition to demographic variables, were independently associated with performance on NIHSS, naming, and content production. Specifically, hypoperfusion in the frontal lobe independently correlated with NIHSS scores, while hypoperfusion in parietal areas independently correlated with naming accuracy and content production.These results correspond to previous reports associating hypoperfusion with function, confirming that hypoperfusion is an important consideration—beyond lesion volume—when accounting for behavior in acute ischemic stroke. Quantifying hypoperfusion using FLAIR hyperintense vessels can be an essential clinical tool when other methods of identifying hypoperfusion are unavailable or time prohibitive.

Cerebrovascular Reactivity (CVR) provides an assessment of the brain’s vascular reserve and has been postulated to be a sensitive marker in cerebrovascular diseases. MRI-based CVR measurement typically employs alterations in arterial carbon dioxide (CO2) level while continuously acquiring Blood-Oxygenation-Level-Dependent (BOLD) images. CO2-inhalation and resting-state methods are two commonly used approaches for CVR MRI. However, processing of CVR MRI data often requires special expertise and may become an obstacle in broad utilization of this promising technique. The aim of this work was to develop CVR-MRICloud, a cloud-based CVR processing pipeline, to enable automated processing of CVR MRI data. The CVR-MRICloud consists of several major steps including extraction of end-tidal CO2 (EtCO2) curve from raw CO2 recording, alignment of EtCO2 curve with BOLD time course, computation of CVR value on a whole-brain, regional, and voxel-wise basis. The pipeline also includes standard BOLD image processing steps such as motion correction, registration between functional and anatomic images, and transformation of the CVR images to canonical space. This paper describes these algorithms and demonstrates the performance of the CVR-MRICloud in lifespan healthy subjects and patients with clinical conditions such as stroke, brain tumor, and Moyamoya disease. CVR-MRICloud has potential to be used as a data processing tool for a variety of basic science and clinical applications.

Background: Hemispatial neglect is a debilitating consequence of right hemispheric ischemic stroke (RIS), with evidence that patient-level factors influence neglect severity. Study objective: Determine if cardiac function is associated with presence and severity of neglect, independent of infarct size.Methods: Two hundred and eighteen non-demented, RIS with cerebral MRI and echocardiography who completed ≥1 of 4 tests evaluating neglect were included. Age- and sex- adjusted Z-scores defined neglect with severity categorized as no neglect, neglect on one or neglect on ≥2 tests. The dependent variable was presence of neglect (multivariable logistic regression), or neglect severity (multinomial logistic regression). The association with left ventricular (LV) structure/function (independent variable) was evaluated using separate nested adjustment models.Results: Patients were on average 61 yo (21–95), female (50%), black (53%), with an ejection fraction of 60% (IQR 20–75%). Fifty eight (27%) had neglect. Each 1 cm increase in LV systolic diameter was associated with a higher relative risk of having neglect on two tests compared to those with no neglect (RRR = 1.83, 95% CI 1.01–3.32), but not after adjusting for education and DWI volume (RRR = 1.68, 95% CI 0.89–3.19). Per 1 cm increase in left atrial (LA) diameter, the relative risk of having neglect on 2 tests vs. no neglect was over two times higher (95% CI 1.04–4.77), but lost significance in the final model (RRR = 1.73, 95% CI 0.76–3.94).Conclusions: We found an association between markers of diastolic dysfunction (enlarging LV, compensatory enlarging LA) and severity of neglect, suggesting that cardiac structure, and function affects not only lesion volume, but also the functional consequences of infarct volume.

Abstract Introduction The Frontotemporal Lobar Degeneration Module (FTLD‐MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD‐MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 185), non‐fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data. Results Among PPAs, the FTLD‐MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change. Discussion The FTLD‐MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network.We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming).Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy.These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions. Keywords: Primary progressive aphasia (PPA), Transcranial direct current stimulation (tDCS), Resting-state fMRI (rsfMRI), Functional connectivity, Neurodegenerative diseases

Verbal fluency (VF) is an informative cognitive task. Lesion and functional imaging studies implicate distinct cerebral areas that support letter versus semantic fluency and the understanding of neural and cognitive mechanisms underlying task performance. Most lesion studies include chronic stroke patients. People with primary progressive aphasia (PPA) provide complementary evidence for lesion-deficit associations, as different brain areas are affected in stroke versus PPA. In the present study we sought to determine imaging, clinical and demographic correlates of VF in PPA. Thirty-five patients with PPA underwent an assessment with letter and category VF tasks, evaluation of clinical features and an MRI scan for volumetric analysis. We used stepwise regression models to determine which brain areas are associated with VF performance while acknowledging the independent contribution of clinical and demographic factors. Letter fluency was predominantly associated with language severity (R2 = 38%), and correlated with the volume of the left superior temporal regions (R2 = 12%) and the right dorsolateral prefrontal area (R2 = 5%). Semantic fluency was predominantly associated with dementia severity (R2 = 47%) and correlated with the volume of the left inferior temporal gyrus (R2 = 7%). No other variables were significantly associated with performance in the two VF tasks. We concluded that, independently of disease severity, letter fluency is significantly associated with the volume of frontal and temporal areas whereas semantic fluency is associated mainly with the volume of temporal areas. Furthermore, our findings indicated that clinical severity plays a critical role in explaining VF performance in PPA, compared to the other clinical and demographic factors.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network.We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming).Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy.These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions. Keywords: Primary progressive aphasia (PPA), Transcranial direct current stimulation (tDCS), Resting-state fMRI (rsfMRI), Functional connectivity, Neurodegenerative diseases

Deficits in lexical retrieval are commonly observed in individuals with post-stroke aphasia. Successful lexical retrieval is related to lexical diversity, lexical sophistication, and phonological word properties; however, the crucial brain regions supporting these different features are not fully understood. We performed MRI-based lesion symptom mapping in 58 individuals with a chronic left hemisphere stroke to assess how regional damage relates to spoken discourse-extracted measures of lexical diversity, lexical sophistication, and phonological word properties. For discourse transcription and word feature analysis, we used the Computerized Language Analysis (CLAN) program, Stanford Core Natural Language Processing, Irvine Phonotactic Online Dictionary, Lexical Complexity Analyzer, and Gramulator. Lesions involving the left posterior insula and supramarginal gyri and inferior fronto-occipital fasciculus were significant predictors of utterances with, on average, lower lexical diversity. Low lexical sophistication was associated with damage to the left pole of the superior temporal gyrus. Production of words with lower phonological complexity (fewer phonemes, higher phonological similarity) was associated with damage to the left supramarginal gyrus. Our findings indicate that discourse-extracted features of lexical retrieval depend on the integrity of specific brain regions involving insular and peri-Sylvian areas. The identified regions provide insight into potentially underlying mechanisms of lexically diverse, sophisticated and phonologically complex words produced during discourse. Keywords: Stroke, Aphasia, Speech production, Brain lesions, Magnetic resonance imaging

Difficulty recognizing affective prosody (receptive aprosodia) can occur following right hemisphere damage (RHD). Not all individuals spontaneously recover their ability to recognize affective prosody, warranting behavioral intervention. However, there is a dearth of evidence-based receptive aprosodia treatment research in this clinical population. The purpose of the current study was to investigate an explicit training protocol targeting affective prosody recognition in adults with RHD and receptive aprosodia. Eighteen adults with receptive aprosodia due to acute RHD completed affective prosody recognition before and after a short training session that targeted proposed underlying perceptual and conceptual processes. Behavioral impairment and lesion characteristics were investigated as possible influences on training effectiveness. Affective prosody recognition improved following training, and recognition accuracy was higher for pseudo- vs. real-word sentences. Perceptual deficits were associated with the most posterior infarcts, conceptual deficits were associated with frontal infarcts, and a combination of perceptual-conceptual deficits were related to temporoparietal and subcortical infarcts. Several right hemisphere ventral stream regions and pathways along with frontal and parietal hypoperfusion predicted training effectiveness. Explicit acoustic-prosodic-emotion training improves affective prosody recognition, but it may not be appropriate for everyone. Factors such as linguistic context and lesion location should be considered when planning prosody training.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value

The insula has been implicated in many sequelae of stroke. It is the area most commonly infarcted in people with post-stroke arrhythmias, loss of thermal sensation, hospital acquired pneumonia, and apraxia of speech. We hypothesized that some of these results reflect the fact that: (1) ischemic strokes that involve the insula are larger than strokes that exclude the insula (and therefore are associated with more common and persistent deficits); and (2) insular involvement is a marker of middle cerebral artery (MCA) occlusion. We analyzed MRI scans of 861 patients with acute ischemic hemispheric strokes unselected for functional deficits, and compared infarcts involving the insula to infarcts not involving the insula using t-tests for continuous variables and chi square tests for dichotomous variables. Mean infarct volume was larger for infarcts including the insula (n = 232) versus excluding the insula (n = 629): 65.8 ± 78.8 versus 10.2 ± 15.9 cm3 (p

Impaired expression of emotion through pitch, loudness, rate, and rhythm of speech (affective prosody) is common and disabling after right hemisphere (RH) stroke. These deficits impede all social interactions. Previous studies have identified cortical areas associated with impairments of expression, recognition, or repetition of affective prosody, but have not identified critical white matter tracts. We hypothesized that: (1) differences across patients in specific acoustic features correlate with listener judgment of affective prosody and (2) these differences are associated with infarcts of specific RH gray and white matter regions. To test these hypotheses, 41 acute ischemic RH stroke patients had MRI diffusion weighted imaging and described a picture. Affective prosody of picture descriptions was rated by 21 healthy volunteers. We identified percent damage (lesion load) to each of seven regions of interest previously associated with expression of affective prosody and two control areas that have been associated with recognition but not expression of prosody. We identified acoustic features that correlated with listener ratings of prosody (hereafter “prosody acoustic measures”) with Spearman correlations and linear regression. We then identified demographic variables and brain regions where lesion load independently predicted the lowest quartile of each of the “prosody acoustic measures” using logistic regression. We found that listener ratings of prosody positively correlated with four acoustic measures. Furthermore, the lowest quartile of each of these four “prosody acoustic measures” was predicted by sex, age, lesion volume, and percent damage to the seven regions of interest. Lesion load in pars opercularis, supramarginal gyrus, or associated white matter tracts (and not control regions) predicted lowest quartile of the four “prosody acoustic measures” in logistic regression. Results indicate that listener perception of reduced affective prosody after RH stroke is due to reduction in specific acoustic features caused by infarct in right pars opercularis or supramarginal gyrus, or associated white matter tracts.

The sequelae of post-stroke aphasia are considerable, necessitating an understanding of the functional neuroanatomy of language, cognitive processes underlying various language tasks, and the mechanisms of recovery after stroke. This knowledge is vital in providing optimal care of individuals with aphasia and counseling to their families and caregivers. The standard of care in the rehabilitation of aphasia dictates that treatment be evidence-based and person-centered. Promising techniques, such as cortical stimulation as an adjunct to behavioral therapy, are just beginning to be explored. These topics are discussed in this review.

Spelling–a core language skill–is commonly affected in neurological diseases such as stroke and Primary Progressive Aphasia (PPA). We present two case studies of the same spelling therapy (learning of phoneme-to-grapheme correspondences with help from key words) in two participants: one who had a stroke and one with PPA (logopenic variant). Our study highlights similarities and differences in the time course of each indivdual's therapy. The study evaluates the effectiveness and generalization of treatment in each case, i.e. whether the treatment affected the trained items and/or untrained items, and whether or not the treatment gains were maintained after the end of therapy. Both participants were able to learn associations between phonemes and graphemes as well as between phonemes and words. Reliable generalization to untrained words was shown only for the participant with post-stroke aphasia, but we were not able to test generalization to untrained words in the individual with PPA. The same spelling therapy followed a different time course in each case. The participant with post-stroke aphasia showed a lasting effect of improved spelling, but we were unable to assess maintenance of improvement in the participant with PPA. We discuss these differences in light of the underlying nature of each disease.

We report patterns of dysgraphia in participants with primary progressive aphasia that can be explained by assuming disruption of one or more cognitive processes or representations in the complex process of spelling. These patterns are compared to those described in participants with focal lesions (stroke). Using structural imaging techniques, we found that damage to the left extrasylvian regions, including the uncinate, inferior fronto-occipital fasciculus, and sagittal stratum (including geniculostriate pathway and inferior longitudinal fasciculus), as well as other deep white and grey matter structures, was significantly associated with impairments in access to orthographic word forms and semantics (with reliance on phonology-to-orthography to produce a plausible spelling in the spelling to dictation task). These results contribute not only to our understanding of the patterns of dysgraphia following acquired brain damage but also the neural substrates underlying spelling.

Objective: Test the hypothesis that right hemisphere stroke can cause extinction of left hand movements or movements of either hand held in left space, when both are used simultaneously, possibly depending on lesion site.

Functional imaging studies consistently find that older adults recruit bilateral brain regions in cognitive tasks that are strongly lateralized in younger adults, a characterization known as the Hemispheric Asymmetry Reduction in Older Adults model. While functional imaging displays what brain areas are active during tasks, it cannot demonstrate what brain regions are necessary for task performance. We used behavioral data from acute stroke patients to test the hypothesis that older adults need both hemispheres for a verbal working memory task that is predominantly left-lateralized in younger adults. Right-handed younger (age ≥ 50, n = 7) and older adults (age > 50, n = 21) with acute unilateral stroke, as well as younger (n = 6) and older (n = 13) transient ischemic attack (TIA) patients, performed a self-paced verbal item-recognition task. Older patients with stroke to either hemisphere had a higher frequency of deficits in the verbal working memory task compared to older TIA patients. Additionally, the deficits in older stroke patients were mainly in retrieval time while the deficits in younger stroke patients were mainly in accuracy. These data suggest that bihemispheric activity is necessary for older adults to successfully perform a verbal working memory task.

Background: The National Institutes of Health Stroke Scale (NIHSS) has been criticized for limited representation of cognitive dysfunction and bias towards dominant hemisphere functions. Patients may therefore receive a low NIHSS score despite a fairly large stroke. A broader scale including simple cognitive tests would improve the clinical and research utility of the NIHSS.

One of the main sources of information regarding the underlying processes involved in both normal and impaired reading has been the study of reading deficits that occur as a result of brain damage. However, patterns of reading deficits found acutely after brain injury have been little explored. The observed patterns of performance in chronic stroke patients might reflect reorganization of the cognitive processes underlying reading or development of compensatory strategies that are not normally used to read. Method: 112 acute left hemisphere stroke patients were administered a task of oral reading of words and pseudowords within 1–2 days of hospital admission; performance was examined for error rate and type, and compared to that on tasks involving visual lexical decision, visual/auditory comprehension, and naming. Results: Several distinct patterns of performance were identified. Although similarities were found between the patterns of reading performance observed acutely and the classical acquired dyslexias generally identified more chronically, some notable differences were observed. Of interest was the finding that no patient produced any pure semantic errors in reading, despite finding such errors in comprehension and naming.

Background: Impairments in oral word production are common at the onset of stroke. The identification of factors that predict early recovery has important implications for identifying those at greater risk of continued impaired functioning, and the management of the patient's care following discharge.

Studies of the cognitive outcome after shunt insertion for treatment of Normal Pressure Hydrocephalus have reported widely mixed results. We prospectively studied performance of 60 patients with Normal Pressure Hydrocephalus on a comprehensive battery of neuropsychological tests before and after shunt surgery to determine which cognitive functions improve with shunt insertion. We also administered a subset of cognitive tests before and after temporary controlled drainage of cerebrospinal fluid to determine if change on this brief subset of tests after drainage could predict which patients would show cognitive improvement three to six months after shunt insertion. There was a significant improvement in learning, retention, and delayed recall of verbal memory three to six months after surgery (using paired t-tests). The majority (74%) of patients showed significant improvement (by at least one standard deviation) on at least one of the memory tests. Absence of improvement on verbal memory after temporary drainage of cerebrospinal fluid had a high negative predictive value for improvement on memory tests at 3–6 months after surgery (96%; p = 0.0005). Also, the magnitude of improvement from Baseline to Post-Drainage on few specific tests of learning and recall significantly predicted the magnitude of improvement after shunt surgery on the same tests (r2 = 0.32–0.58; p = 0.04–0.001). Results indicate that testing before and after temporary drainage may be useful in predicting which patients are less likely to improve in memory with shunting.

Functional imaging studies indicate that the left hemisphere mediates verbal working memory, while the right hemisphere mediates both verbal and spatial working memory. We evaluated acute stroke patients with working memory tests and imaging to identify whether unilateral dysfunction causes deficits in spatial and/or verbal working memory deficits. While left cortical stroke patients had verbal working memory impairments (p < 0.003), right cortical stroke patients had both verbal (p < 0.007) and spatial working memory (p < 0.03) impairments, confirming functional imaging results. Patients with transient ischemic stroke and patients with non-cortical stroke did not have significant deficits in working memory in either modality.

Objective: There has been controversy over whether diffusion-perfusion mismatch provides a biomarker for the ischemic penumbra. Regions of the diffusion-perfusion mismatch that do not progress to infarct in the absence of reperfusion are considered to represent benign oligemia. However, at least in some cases (particularly large vessel stenosis), some of this hypoperfused tissue may remain dysfunctional for a prolonged period without progressing to infarct and may recover function if eventually reperfused. We hypothesized that patients with persistent diffusion-perfusion mismatch using a hypoperfusion threshold of 4-5.9 seconds delay on time-to-peak maps at least sometimes have persistent cognitive deficits relative to those who show some reperfusion. Methods: We tested this hypothesis in 38 patients with acute ischemic stroke who had simple cognitive tests and MRI with diffusion and perfusion imaging within 24 hours of onset and again within 10 days, most of whom had large vessel stenosis. Results: When we evaluated all patients or only patients who did not have infarct growth, persistent hypoperfusion was associated with a lack of cognitive improvement compared with those who had reperfused (p