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Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort.We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis.Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25-2.81, p = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24-2.66, p = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33-4.31, p = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28-2.77, p = 0.001).Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.

Hydrogen evolution from electrochemical water splitting under alkaline conditions is an ongoing challenge for the requirement of a simultaneous balance to be achieved between the water dissociation step and the hydrogen adsorption on the catalysts. Herein, Bi2O3, an inactive catalyst for hydrogen evolution reaction (HER) aroused by its unfavourable hydrogen adsorption Gibbs free energy (ΔGH*), is activated by an in-situ phase engineering strategy for efficient HER electrocatalysis in alkaline media. Via this strategy, two-dimensional (2D) dual active Bi2O3 nanosheets with both BixNi alloy phases and α-Bi2O3 were fabricated to simultaneously catalyse the water dissociation step and the hydrogen formation step during the alkaline HER. In combining with the advantages of 2D nanomaterials and dual active catalytic sites, this phase engineered Bi2O3-based catalyst exhibited simultaneously accelerated water dissociation and optimized ΔGH* and thus excellent HER performance. The modulated catalyst demonstrated an overpotential of 127 mV (at j = 10 mA cm-2) and a Tafel slope of 92 mV dec-1 in 1 M KOH, which is exceptional compared with other Bi2O3-based HER electrocatalysts. This work not only provides an innovative way to activate HER-inferior bismuth oxide-based catalysts, but also offers new insights into the design of dual active catalysts for sluggish alkaline HER catalysis.

Background. Neuroimaging biomarkers are valuable predictors of motor improvement after stroke, but there is a gap between published evidence and clinical usage. Objective. In this work, we aimed to investigate whether machine learning techniques, when applied to a combination of baseline whole brain volumes and clinical data, can accurately predict individual motor outcome after stroke. Methods. Upper extremity Fugl-Meyer Assessments (FMA-UE) were conducted 1 week and 12 weeks, and structural MRI was performed 1 week, after onset in 56 patients with subcortical infarction. Proportional recovery model residuals were employed to assign patients to proportional and poor recovery groups (34 vs 22). A sophisticated machine learning scheme, consisting of conditional infomax feature extraction, synthetic minority over-sampling technique for nominal and continuous, and bagging classification, was employed to predict motor outcomes, with the input features being a combination of baseline whole brain volumes and clinical data (FMA-UE scores). Results. The proposed machine learning scheme yielded an overall balanced accuracy of 87.71% in predicting proportional vs poor recovery outcomes, a sensitivity of 93.77% in correctly identifying poor recovery outcomes, and a ROC AUC of 89.74%. Compared with only using clinical data, adding whole brain volumes can significantly improve the classification performance, especially in terms of the overall balanced accuracy (from 80.88% to 87.71%) and the sensitivity (from 92.23% to 93.77%). Conclusions. Experimental results suggest that a combination of baseline whole brain volumes and clinical data, when equipped with appropriate machine learning techniques, may provide valuable information for personalized rehabilitation planning after subcortical infarction.

The growing number of neuroimaging studies of cynomolgus macaques require extending existing templates to facilitate species-specific application of voxel-wise neuroimaging methodologies. This study aimed to create population-averaged structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) templates for the cynomolgus macaques and apply the templates in fully automated voxel-wise analyses. We presented the development of symmetric and asymmetric MRI and DTI templates from a sample of 63 young male cynomolgus monkeys with the use of optimized template creation approaches. We also generated the associated average tissue probability maps and Diffeomorphic Anatomical Registration using Exponentiated Lie Algebra templates for use with the Statistical Parametric Mapping (SPM), as well as the average fractional anisotropy/skeleton targets for incorporation into tract-based spatial statistics (TBSS) framework. Both asymmetric and symmetric templates in a standardized coordinate space demonstrated low bias and high contrast. Fully automated processing using SPM was accomplished for all native MRI datasets and demonstrated outstanding performance regarding skull-stripping, segmentation, and normalization when using the MRI templates. Automated normalization to the DTI template was excellently achieved for all native DTI images using the TBSS pipeline. The cynomolgus MRI and DTI templates are anticipated to provide a common platform for precise single-subject data analysis and facilitate comparison of neuroimaging findings in cynomolgus monkeys across studies and sites. It is also hoped that the procedures of template creation and fully-automated voxel-wise frameworks will provide a straightforward avenue for investigating brain function, development, and neuro-psychopathological disorders in non-human primate models.

Aims The risk of hemoglobin decline induced by low‐dose aspirin in glucose‐6‐phosphate dehydrogenase (G6PD) deficiency remains unknown, and its influence on stroke outcome remains to be investigated. This study aimed to evaluate the effect of G6PD deficiency on hemoglobin level during aspirin treatment and its association with outcome after acute ischemic stroke. Methods In total, 279 patients (40 G6PD‐deficient and 239 G6PD‐normal) with acute ischemic stroke treated with aspirin 100 mg/day from a cohort study were examined. The primary safety endpoint was a hemoglobin decline ≥25 g/L or 25% from baseline within 14 days after aspirin treatment. Poor outcomes were defined as a modified Rankin Scale score ≥2 at 3 months. The χ 2 test was used to compare stroke outcomes, and multivariate logistic regression analyses were performed to analyze the association between hemoglobin level and outcomes. Results The G6PD‐deficient group had lower baseline hemoglobin and tended to develop comorbid pulmonary infection more frequently (p, Hemoglobin decrease with bilirubin increase after aspirin treatment in patients with G6PD deficiency suggests hemolysis, which may influence stroke prognosis. The risk of hemoglobin decline should be carefully monitored in G6PD‐deficient stroke patients taking aspirin.

High on-treatment platelet reactivity (HTPR) determined by platelet function assays is present in certain patients with ischemic stroke or transient ischemic attack (TIA). However, it is unclear whether HTPR is associated with poor clinical outcomes. Our study aimed to investigate the relationship of HTPR with recurrent vascular events in ischemic stroke or TIA.Pubmed (MEDLINE), EMBASE, and Cochrane Library were searched for eligible studies from inception to January 1, 2022. Stata 17.0 software was used to calculate the risk ratio (RR). Subgroup and sensitivity analyses were conducted to assess the source of heterogeneity. A random-effects model was used when heterogeneity was present. Primary endpoint of the meta-analysis was the risk ratio of recurrent vascular events in HTPR Patients. While stroke and TIA, all-cause death, early neurological deterioration, early new ischemic lesions, and stroke severity measured by National Institute of Health Stroke Scale (NIHSS) scores at admission were also pooled.Thirty articles (7995 patients) were eligible including 28 cohort studies and 2 prospective case-control studies. The prevalence of HTPR varied from 5.9% to 60%. HTPR was associated with an increased risk of recurrent vascular events (RR = 2.94, 95% CI 2.04-4.23), stroke recurrence (RR = 2.05; 95% CI 1.43-2.95), and all-cause mortality (RR = 2.43; 95% CI 1.83-3.22). Subgroup analysis showed that HTPR determined by optical aggregometry, Verify-Now system and 11dh TXB2 is related to a higher risk of recurrent vascular events (RR = 3.53, 95% CI 1.51-9.40; RR = 2.16, 95% CI 1.02-4.56; RR = 3.76, 95% CI 1.51-9.40, respectively). Moreover, patients with HTPR had an increased incidence of early neurological deterioration (RR = 2.75; 95% CI 1.76-4.30) and higher NIHSS scores at admission (Mean difference 0.19, 95% CI 0.01-0.36).This meta-analysis demonstrates HTPR is associated with higher risk of recurrent vascular events, early neurological deterioration and increased severity in patients with ischemic stroke and TIA. HTPR measured by platelet function assays may guide the use of antiplatelet agents in ischemic stroke and TIA.

Unfavorable venous outflow (VO) is associated with cerebral edema, which represents microvascular dysfunction. This study estimated the relationship between VO and microvascular function in acute ischemic stroke patients. We retrospectively included 102 MCA/ICA occluded patients with anterior circulation infarction who underwent reperfusion therapy between July 2017 and April 2022. Unfavorable VO was defined as a cortical vein opacification score of 0–3 and favorable VO as that of 4–6. The clinical characteristics, collateral status, microvascular integrity, and outcomes were compared between patients with favorable and unfavorable VO. Multivariate analysis and receiver operator characteristic (ROC) analysis were used. The patients with unfavorable VO had higher extravascular-extracellular volume fraction (Ve) in the infarct core and a lower percentage of robust arterial collateral circulation. ROC analysis revealed that Ve in the infarct core predicts unfavorable VO (AUC = 0.67, sensitivity = 65.08%, specificity = 69.23%). The higher Ve in the infarct core (odds ratio = 1.011, 95% CI = 1.000–1.021, P = 0.046) and poor arterial collateral flow (odds ratio = 0.102, 95% CI = 0.032–0.327, P

ObjectiveTo assess the risk of glucose-6-phosphate dehydrogenase (G6PD) on stroke prognosis, we compared outcomes between patients with stroke with and without G6PD deficiency.MethodsThe study recruited 1,251 patients with acute ischemic stroke. Patients were individually categorized into G6PD-deficiency and non-G6PD-deficiency groups according to G6PD activity upon admission. The primary endpoint was poor outcome at 3 months defined by a modified Rankin Scale (mRS) score ≥2 (including disability and death). Secondary outcomes included the overall mRS score at 3 months and in-hospital death and all death within 3 months. Logistic regression and Cox models, adjusted for potential confounders, were fitted to estimate the association of G6PD deficiency with the outcomes.ResultsAmong 1,251 patients, 150 (12.0%) were G6PD-deficient. Patients with G6PD deficiency had higher proportions of large-artery atherosclerosis (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09–2.17) and stroke history (OR 1.93, 95% CI 1.26–2.90) compared to the non-G6PD-deficient group. The 2 groups differed significantly in the overall mRS score distribution (adjusted common OR 1.57, 95% CI 1.14–2.17). Patients with G6PD deficiency had higher rates of poor outcome at 3 months (adjusted OR 1.73, 95% CI 1.08–2.76; adjusted absolute risk increase 13.0%, 95% CI 2.4%–23.6%). The hazard ratio of in-hospital death for patients with G6PD-deficiency was 1.46 (95% CI 1.37–1.84).ConclusionsG6PD deficiency is associated with the risk of poor outcome at 3 months after ischemic stroke and may increase the risk of in-hospital death. These findings suggest the rationality of G6PD screening in patients with stroke.

Focal cerebral infarction leads to autophagic activation, which contributes to secondary neuronal damage in the ipsilateral thalamus. Although Nogo-A deactivation enhances neuronal plasticity, its role in autophagic activation in the thalamus after ischemic stroke remains unclear. This study aimed to investigate the potential roles of Nogo-A/Nogo-66 receptor 1 (NgR1) in autophagic activation in the ipsilateral thalamus after cerebral infarction. Focal neocortical infarction was established using the middle cerebral artery occlusion (MCAO) method. Secondary damage in the ipsilateral thalamus was assessed by Nissl staining and immunostaining. The expression of Nogo-A, NgR1, Rho-A and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as well as autophagic flux were evaluated by immunofluorescence and immunoblotting. The roles of Nogo-A–NgR1 signaling in autophagic activation were determined by intraventricular delivery of an NgR1 antagonist peptide, NEP1–40, at 24 h after MCAO. The results showed that Nogo-A and NgR1 overexpression temporally coincided with marked increases in the levels of Beclin1, LC3-II and sequestosome 1 (SQSTM1)/p62 in the ipsilateral thalamus at seven and fourteen days after MCAO. In contrast, NEP1–40 treatment significantly reduced the expression of Rho-A and ROCK1 which was accompanied by marked reductions of LC3-II conversion as well as the levels of Beclin1 and SQSTM1/p62. Furthermore, NEP1–40 treatment significantly reduced neuronal loss and gliosis in the ipsilateral thalamus, and accelerated somatosensory recovery at the observed time-points after MCAO. These results suggest that blockade of Nogo-A–NgR1 signaling inhibits autophagic activation, attenuates secondary neuronal damage in the ipsilateral thalamus, and promotes functional recovery after focal cerebral cortical infarction.

Cerebral infarction induces angiogenesis in the thalamus and influences functional recovery. The mechanisms underlying angiogenesis remain unclear. This study aimed to investigate the role of RTN4/Nogo-A in mediating macroautophagy/autophagy and angiogenesis in the thalamus following middle cerebral artery occlusion (MCAO). We assessed secondary neuronal damage, angiogenesis, vascular autophagy, RTN4 and S1PR2 signaling in the thalamus. The effects of RTN4-S1PR2 on vascular autophagy and angiogenesis were evaluated using lentiviral and pharmacological approaches. The results showed that RTN4 and S1PR2 signaling molecules were upregulated in parallel with angiogenesis in the ipsilateral thalamus after MCAO. Knockdown of Rtn4 by siRNA markedly reduced MAP1LC3B-II conversion and levels of BECN1 and SQSTM1 in vessels, coinciding with enhanced angiogenesis in the ipsilateral thalamus. This effect coincided with rescued neuronal loss of the thalamus and improved cognitive function. Conversely, activating S1PR2 augmented vascular autophagy, along with suppressed angiogenesis and aggravated neuronal damage of the thalamus. Further inhibition of autophagic initiation with 3-methyladenine or spautin-1 enhanced angiogenesis while blockade of lysosomal degradation by bafilomycin A1 suppressed angiogenesis in the ipsilateral thalamus. The control of autophagic flux by RTN4-S1PR2 was verified in vitro. Additionally, ROCK1-BECN1 interaction along with phosphorylation of BECN1 (Thr119) was identified in the thalamic vessels after MCAO. Knockdown of Rtn4 markedly reduced BECN1 phosphorylation whereas activating S1PR2 increased its phosphorylation in vessels. These results suggest that blockade of RTN4-S1PR2 interaction promotes angiogenesis and secondary neural repair in the thalamus by suppressing autophagic activation and alleviating dysfunction of lysosomal degradation in vessels after cerebral infarction. Abbreviations: 3-MA: 3-methyladenine; ACTA2/ɑ-SMA: actin alpha 2, smooth muscle, aorta; AIF1/Iba1: allograft inflammatory factor 1; BafA1: bafilomycin A1; BMVECs: brain microvascular endothelial cells; BrdU: 5-bromo-2’-deoxyuridine; CLDN11/OSP: claudin 11; GFAP: glial fibrillary acidic protein; HUVECs: human umbilical vein endothelial cells; LAMA1: laminin, alpha 1; MAP2: microtubule-associated protein 2; MBP2: myelin basic protein 2; MCAO: middle cerebral artery occlusion; PDGFRB/PDGFRβ: platelet derived growth factor receptor, beta polypeptide; RECA-1: rat endothelial cell antigen-1; RHOA: ras homolog family member A; RHRSP: stroke-prone renovascular hypertensive rats; ROCK1: Rho-associated coiled-coil containing protein kinase 1; RTN4/Nogo-A: reticulon 4; RTN4R/NgR1: reticulon 4 receptor; S1PR2: sphingosine-1-phosphate receptor 2; SQSTM1: sequestosome 1.

Background The cerebellum receives afferent signals from spinocerebellar pathways regulating lower limb movements. However, the longitudinal changes in the spinocerebellar pathway in the early stage of unilateral supratentorial stroke and their potential clinical significance have received little attention. Methods Diffusion tensor imaging and Fugl-Meyer assessment of lower limb were performed 1, 4, and 12 weeks after onset in 33 patients with acute subcortical infarction involving the supratentorial areas, and in 33 healthy subjects. We evaluated group differences in diffusion metrics in the bilateral inferior cerebellar peduncle (ICP) and analyzed the correlation between ICP diffusion metrics and changes to the Fugl-Meyer scores of the affected lower limb within 12 weeks after stroke. Results Significantly decreased fractional anisotropy and increased mean diffusivity were found in the contralesional ICP at week 12 after stroke compared to controls (all P P P = 0.008) and week 12 (P = 0.004) compared to controls. Both fractional anisotropy (rs = 0.416, P = 0.025) and mean diffusivity (rs = -0.507, P = 0.005) changes in the contralesional ICP correlated with changes in Fugl-Meyer scores of the affected lower limb in all patients. Conclusions Bilateral ICP degeneration occurs in the early phase of supratentorial stroke, and diffusion metric values of the contralesional ICP are useful indicators of affected lower limb function after supratentorial stroke.

Background. Subcortical infarcts can result in verbal memory impairment, but the potential underlying mechanisms remain unknown. Objective. We investigated the spatiotemporal deterioration patterns of brain structures in patients with subcortical infarction and identified the regions that contributed to verbal memory impairment. Methods. Cognitive assessment and structural magnetic resonance imaging were performed 1, 4, and 12 weeks after stroke onset in 28 left-hemisphere and 22 right-hemisphere stroke patients with subcortical infarction. Whole-brain volumetric analysis combined with a further-refined shape analysis was conducted to analyze longitudinal morphometric changes in brain structures and their relationship to verbal memory performance. Results. Between weeks 1 and 12, significant volume decreases in the ipsilesional basal ganglia, inferior white matter, and thalamus were found in the left-hemisphere stroke group. Among those 3 structures, only the change rate of the thalamus volume was significantly correlated with that in immediate recall. For the right-hemisphere stroke group, only the ipsilesional basal ganglia survived the week 1 to week 12 group comparison, but its change rate was not significantly correlated with the verbal memory change rate. Shape analysis of the thalamus revealed atrophies of the ipsilesional thalamic subregions connected to the prefrontal, temporal, and premotor cortices in the left-hemisphere stroke group and positive correlations between the rates of those atrophies and the change rate in immediate recall. Conclusions. Secondary damage to the thalamus, especially to the left subregions connected to specific cortices, may be associated with early verbal memory impairment following an acute subcortical infarct.

Background and purpose Aspirin is the first recommended antiplatelet agent to prevention secondary stroke, but its safety and efficacy in stroke patients with glucose-6-phosphate dehydrogenase deficiency remain unclear. We sought to evaluate its safety and efficacy in ischemic stroke patients with and without glucose-6-phosphate dehydrogenase deficiency. Methods Patients with ischemic stroke receiving aspirin (100 mg/day) for three months were recruited for a multicenter, prospective, cohort study. Blood glucose-6-phosphate dehydrogenase activity was examined after stroke. Safety outcomes including acute hemolysis, moderate-to-severe bleeding, and death (vascular, all-cause), and efficacy outcome indicated as stroke recurrence were evaluated at three months. Risk factors associated with moderate-to-severe bleeding and all-cause death were determined using multivariate or Cox regression analysis. Results Among the included 1121 patients, 81 of 130 glucose-6-phosphate dehydrogenase deficient and 576 of 991 glucose-6-phosphate dehydrogenase normal patients received aspirin for three months. Acute hemolysis was observed in one of the glucose-6-phosphate dehydrogenase deficient and in none of the glucose-6-phosphate dehydrogenase normal patients ( p = 0.876). The rates of moderate-to-severe bleeding were 2.5% and 0.3% ( p = 0.045), and the percentages of all-cause death were 6.2% and 1.4% ( p = 0.008) in the glucose-6-phosphate dehydrogenase deficient and glucose-6-phosphate dehydrogenase normal patients. Stroke recurrence rate was similar in the two groups (2.5% vs. 1.7%; p = 0.608). Glucose-6-phosphate dehydrogenase deficiency was significantly associated with increased risk of moderate-to-severe bleeding (adjust p = 0.048) and all-cause death during aspirin use (adjust p = 0.008). Conclusions Long-term low-dose aspirin therapy might relate to worse safety outcomes in patients with glucose-6-phosphate dehydrogenase deficiency and large clinical trials are needed to further confirm these findings.

Supplemental material, sj-pdf-1-wso-10.1177_1747493020950903 for Safety and efficacy of low-dose aspirin in ischemic stroke patients with different G6PD conditions by Yicong Chen, Jianle Li, Zilin Ou, Yusheng Zhang, Zhijian Liang, Weisheng Deng, Weixian Huang, Zhengdong Wu, Haihong Jiang, Qinghua Liu, Fubing Ouyang, Shihui Xing and Jinsheng Zeng in International Journal of Stroke

Background. In functional magnetic resonance imaging studies, picture naming engages widely distributed brain regions in the parietal, frontal, and temporal cortices. However, it remains unknown whether those activated areas, along with white matter pathways between them, are actually crucial for naming. Objective. We aimed to identify nodes and pathways implicated in naming in healthy older adults and test the impact of lesions to the connectome on naming ability. Methods. We first identified 24 cortical nodes activated by a naming task and reconstructed anatomical connections between these nodes using probabilistic tractography in healthy adults. We then used structural scans and fractional anisotropy (FA) maps in 45 patients with left hemisphere stroke to assess the relationships of node and pathway integrity to naming, phonology, and nonverbal semantic ability. Results. We found that mean FA values in 13 left hemisphere white matter tracts within the dorsal and ventral streams and 1 interhemispheric tract significantly related to naming scores after controlling for lesion size and demographic factors. In contrast, lesion loads in the cortical nodes were not related to naming performance after controlling for the same variables. Among the identified tracts, the integrity of 4 left hemisphere ventral stream tracts related to nonverbal semantic processing and 1 left hemisphere dorsal stream tract related to phonological processing. Conclusions. Our findings reveal white matter structures vital for naming and its subprocesses. These findings demonstrate the value of multimodal methods that integrate functional imaging, structural connectivity, and lesion data to understand relationships between brain networks and behavior.

Cerebral infarction causes secondary neurodegeneration and angiogenesis in thalamus, which impacts functional recovery after stroke. Here, we hypothesize that activation of ephrinB2 could stimulate angiogenesis and restore the secondary neurodegeneration in thalamus after cerebral infarction. Focal cerebral infarction was induced by middle cerebral artery occlusion (MCAO). Secondary damage, angiogenesis, amyloid-β (Aβ) deposits, levels of ephrinB2 and receptor for advanced glycation end product (RAGE) in the ipsilateral thalamus were determined by immunofluorescence and immunoblot. The contribution of ephrinB2 to angiogenesis was determined by siRNA-mediated knockdown of ephrinB2 and pharmacological activation of ephrinB2. The results showed that formation of new vessels and ephrinB2 expression was markedly increased in the ipsilateral thalamus at seven days after MCAO. EphrinB2 knockdown markedly suppressed angiogenesis coinciding with increased Aβ accumulation, neuronal loss and gliosis in the ipsilateral thalamus. In contrast, clustered EphB2-Fc significantly enhanced angiogenesis, alleviated Aβ accumulation and the secondary thalamic damage, which was accompanied by accelerated function recovery. Additionally, activation of ephrinB2 significantly reduced RAGE levels in the ipsilateral thalamus. Our findings suggest that activation of ephrinB2 promotes angiogenesis, ameliorates Aβ accumulation and the secondary thalamic damage after cerebral infarction. Additionally, RAGE might be involved in Aβ clearance by activating ephrinB2 in the thalamus.

The neural basis of speech processing is still a matter of great debate. Phonotactic knowledge—knowledge of the allowable sound combinations in a language—remains particularly understudied. The purpose of this study was to investigate the brain regions crucial to phonotactic knowledge in left-hemisphere stroke survivors. Results were compared to areas in which gray matter anatomy related to phonotactic knowledge in healthy controls. 44 patients with chronic left-hemisphere stroke, and 32 controls performed an English-likeness rating task on 60 auditory non-words of varying phonotactic regularities. They were asked to rate on a 1–5 scale, how close each non-word sounded to English. Patients' performance was compared to that of healthy controls, using mixed effects modeling. Multivariate lesion-symptom mapping and voxel-based morphometry were used to find the brain regions important for phonotactic processing in patients and controls respectively. The results showed that compared to controls, stroke survivors were less sensitive to phonotactic regularity differences. Lesion-symptom mapping demonstrated that a loss of sensitivity to phonotactic regularities was associated with lesions in left angular gyrus and posterior middle temporal gyrus. Voxel-based morphometry also revealed a positive correlation between gray matter density in left angular gyrus and sensitivity to phonotactic regularities in controls. We suggest that the angular gyrus is used to compare the incoming speech stream to internal predictions based on the frequency of sound sequences in the language derived from stored lexical representations in the posterior middle temporal gyrus.

Background and Purpose— Initial clinical assessment or conventional diffusion tensor imaging parameters alone do not reliably predict poststroke recovery of motor function. Recently, local diffusion homogeneity (LDH) has been proposed to represent the local coherence of water molecule diffusion and can serve as a complementary marker for investigating white matter alterations of the brain. We aimed to determine whether a combination of initial clinical assessment and LDH could predict motor recovery after acute subcortical infarction. Methods— Standard upper extremity Fugl-Meyer assessment and diffusion tensor imaging were performed 1, 4, and 12 weeks after onset in 50 patients with subcortical infarction. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Tract-based spatial statistics analysis was used to compare diffusion differences between proportional and poor recovery outcomes. Multivariate logistic regression model was used to identify the predictors of motor improvement within 12 weeks after stroke. Results— The poor recovery group had lower LDH than the proportional recovery group, mainly in the ipsilesional corticospinal tract in the superior corona radiate and posterior limb of internal capsule 1 week after stroke ( P P P Conclusions— These results suggest that a combination of clinical assessment and LDH in the ipsilesional corticospinal tract in the acute phase can accurately predict resolution of upper limb impairment within 12 weeks after subcortical infarction.

Neuroimaging studies have implicated left temporal lobe regions in audiovisual integration of speech, and inferior parietal regions in temporal binding of incoming signals. However, it remains unclear which regions are necessary for audiovisual integration, especially when the auditory and visual signals are offset in time. Aging also influences integration, but the nature of this influence is unresolved. We used a McGurk task to test audiovisual integration and sensitivity to the timing of audiovisual signals in two older adult groups: left hemisphere stroke survivors and controls. We observed a positive relationship between age and audiovisual speech integration in both groups, and an interaction indicating that lesions reduce sensitivity to timing offsets between signals. Lesion-symptom mapping demonstrated that damage to the left supramarginal gyrus and planum temporale reduces temporal acuity in audiovisual speech perception. This suggests that a process mediated by these structures identifies asynchronous audiovisual signals that should not be integrated.

Supplemental material, Supplementary_materials for Regional Shape Abnormalities in Thalamus and Verbal Memory Impairment After Subcortical Infarction by Gang Liu, Xiaoqing Tan, Chao Dang, Shuangquan Tan, Shihui Xing, Nianwei Huang, Kangqiang Peng, Chuanmiao Xie, Xiaoying Tang and Jinsheng Zeng in Neurorehabilitation and Neural Repair

Damage to the brain's mood regulation systems may contribute to poststroke depression. This study examines relationships between depression symptoms and psychosocial factors and then uses multivariate lesion-symptom mapping to localize depression symptoms in people with chronic left hemisphere stroke. Depression symptoms relate inversely to education and directly to physical disability. Damage in the left dorsolateral prefrontal cortex is associated with greater depression symptoms. These results demonstrate a neurological contribution to depression symptoms in chronic left hemisphere stroke and provide evidence of convergent biological mechanisms for poststroke depression symptoms and major depression with regard to left dorsolateral prefrontal cortex dysfunction.

BACKGROUND AND PURPOSE Patients with acute pontine infarcts generally have good short-term motor outcomes; however, the mechanisms underlying this recovery of function remain unclear. METHODS Twenty well-recovered patients with acute pontine infarcts and 20 well-recovered patients with acute striato-capsular infarcts were recruited. Fugl-Meyer assessment and resting-state functional magnetic resonance imaging were performed 1, 4 and 12 weeks after onset. Patients were further assigned to better and worse recovery subgroups according to the degree of motor recovery at the twelfth week after stroke. Voxel-wise degree centrality (DC)-behavior correlation analysis was used to identify brain regions related to changes in motor function within 12 weeks after stroke. RESULTS A significant correlation was found between DC and Fugl-Meyer scores within 12 weeks in the ipsilesional cerebellar crus I and crus II in patients with pontine infarction and in the ipsilesional middle temporal gyrus in patients with striato-capsular infarction (all P

Background: Orthostatic hypotension (OH) is the key manifestation of autonomic dysfunction with many causes. Systemic neurological causes such as paraneoplastic syndrome are usually ignored. Methods: We retrospectively analyzed clinical and examination data of 2 patients who were hospitalized, with onset symptom of OH and who were diagnosed as paraneoplastic syndrome. Results: The patients were characteristic of an initial symptom of OH, positive anti-Hu antibody and albuminocytologic dissociation in the cerebrospinal fluid. Patient 2 died and Patient 1 worsened during follow-up. Conclusions: The diagnosis of paraneoplastic syndrome is usually neglected when the onset symptoms are autonomic dysfunctions such as OH. Neurologists should improve their knowledge to diagnose accurately.

BACKGROUND Secondary degeneration of the fiber tract of the motor pathway below infarct foci and functional recovery after stroke have been well demonstrated, but the role of the fiber tract above stroke foci remains unclear. OBJECTIVE This study aimed to investigate diffusion changes in motor fibers above the lesion and identify predictors of motor improvement within 12 weeks after subcortical infarction. METHODS Diffusion tensor imaging and the Fugl-Meyer (FM) scale were conducted 1, 4, and 12 weeks (W) after a subcortical infarct. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Region of interest analysis was used to assess diffusion changes in the motor pathway above and below a stroke lesion. Multivariable linear regression was employed to identify predictors of motor improvement within 12 weeks after stroke. RESULTS Axial diffusivity (AD) in the underlying white matter of the ipsilesional primary motor area (PMA) and cerebral peduncle (CP) in both proportional and poor recovery groups was lower at W1 compared to the controls and values in the contralesional PMA and CP (all P

Supplemental material, Supplemental_Table for Behavioral Effects of Chronic Gray and White Matter Stroke Lesions in a Functionally Defined Connectome for Naming by Shihui Xing, Ayan Mandal, Elizabeth H. Lacey, Laura M. Skipper-Kallal, Jinsheng Zeng and Peter E. Turkeltaub in Neurorehabilitation and Neural Repair

The neural mechanisms underlying recovery of language after left hemisphere stroke remain elusive. Although older evidence suggested that right hemisphere language homologues compensate for damage in left hemisphere language areas, the current prevailing theory suggests that right hemisphere engagement is ineffective or even maladaptive. Using a novel combination of support vector regression-based lesion-symptom mapping and voxel-based morphometry, we aimed to determine whether local grey matter volume in the right hemisphere independently contributes to aphasia outcomes after chronic left hemisphere stroke. Thirty-two left hemisphere stroke survivors with aphasia underwent language assessment with the Western Aphasia Battery-Revised and tests of other cognitive domains. High-resolution T1-weighted images were obtained in aphasia patients and 30 demographically matched healthy controls. Support vector regression-based multivariate lesion-symptom mapping was used to identify critical language areas in the left hemisphere and then to quantify each stroke survivor’s lesion burden in these areas. After controlling for these direct effects of the stroke on language, voxel-based morphometry was then used to determine whether local grey matter volumes in the right hemisphere explained additional variance in language outcomes. In brain areas in which grey matter volumes related to language outcomes, we then compared grey matter volumes in patients and healthy controls to assess post-stroke plasticity. Lesion–symptom mapping showed that specific left hemisphere regions related to different language abilities. After controlling for lesion burden in these areas, lesion size, and demographic factors, grey matter volumes in parts of the right temporoparietal cortex positively related to spontaneous speech, naming, and repetition scores. Examining whether domain general cognitive functions might explain these relationships, partial correlations demonstrated that grey matter volumes in these clusters related to verbal working memory capacity, but not other cognitive functions. Further, grey matter volumes in these areas were greater in stroke survivors than healthy control subjects. To confirm this result, 10 chronic left hemisphere stroke survivors with no history of aphasia were identified. Grey matter volumes in right temporoparietal clusters were greater in stroke survivors with aphasia compared to those without history of aphasia. These findings suggest that the grey matter structure of right hemisphere posterior dorsal stream language homologues independently contributes to language production abilities in chronic left hemisphere stroke, and that these areas may undergo hypertrophy after a stroke causing aphasia. * Abbreviations : AQ : aphasia quotient PCAD : proportion of critical area damaged SVR-LSM : support vector regression-based lesion–symptom mapping VBM : voxel-based morphometry WAB-R : Western Aphasia Battery-Revised

Previous studies have demonstrated that both oxidative stress and autophagy play important roles in secondary neuronal degeneration in the ipsilateral thalamus after distal middle cerebral artery occlusion (MCAO). This study aimed to investigate whether oxidative stress is associated with autophagy activation within the ipsilateral thalamus after distal MCAO. Sixty stroke-prone renovascular hypertensive rats were subjected to distal MCAO or sham operation, and were killed at 14 days after MCAO. Mn-SOD, LC3-II, Beclin-1 and p62 expression were evaluated by immunostaining and immunoblotting. Secondary damage in the thalamus was assessed with Nissl staining and immunostaining. The association of oxidative stress with autophagy activation was investigated by the antioxidant, ebselen. We found that treatment with ebselen at 24h after MCAO significantly reduced the expression of Mn-SOD in the ipsilateral thalamus at 14 days following focal cerebral infarction. In parallel, it prevented the elevation of LC3-II and Beclin-1, and the reduction of p62. Furthermore, ebselen attenuated the neuronal loss and gliosis in the ipsilateral thalamus. These results suggested that ebselen reduced oxidative stress, autophagy activation and secondary damage in the ipsilateral thalamus following MCAO. There are associations between oxidative stress, autophagy activation and secondary damage in the thalamus after MCAO.

To compare the clinical and radiologic characteristics, possible stroke mechanisms, and prognosis of intracranial artery dissections (IADs) with those of extracranial artery dissections (EADs) presenting with cerebral infarction.Among 3250 adult patients with acute ischemic stroke (cerebral infarction), we prospectively recruited and categorized patients with cerebral infarction secondary to spontaneous cerebral artery dissection into IAD or EAD groups. The clinical and radiologic characteristics, possible stroke mechanisms according to the distributions of the infarctions based on diffusion-weighted imaging, and prognosis were analyzed for both groups.There were 48 and 50 patients experiencing IAD and EAD, accounting for 1.5% and 1.5% of all ischemic stroke patients, respectively. Compression of the perforating artery was the most common possible stroke mechanism (33.3%) in IADs; thromboembolism was more common in EADs than that in IADs (36 of 50 versus 12 of 48; P .001). Magnetic resonance imaging and angiography were used to investigate the arterial dissections in all IAD patients and 46 EAD patients. Based on magnetic resonance imaging and angiography, the IADs more frequently displayed dissecting aneurysm (6 of 48 versus 0 of 46; P = .027) and intimal flap or double lumen (21 of 48 versus 4 of 46; P .001) than EADs. For the clinical characteristics and prognosis, there was no significant difference between the 2 groups.These results indicate that IAD is an important cause of ischemic stroke, and it displays unique radiologic characteristics and specific stroke mechanisms compared with EAD.

Objective: Primary amyloidosis is a disease with a poor prognosis and multi-organ involvement. Here, we report the clinical and pathological features of a patient with primary amyloidosis featuring autonomic neuropathy as the initial symptom and albuminocytologic dissociation in the cerebralspinal fluid (CSF). Methods: The patient was a 60-year-old Chinese male patient with numbness, orthostatic hypotension and gastrointestinal symptoms. For diagnosis, we performed an electromyogram, lumbar puncture, Bence Jones protein urine test, serum electrophoresis blood test, sural nerve and rectal membrane biopsies, transthyretin (TTR) gene sequencing and bone marrow puncture. Results: Congo red staining of sural nerve and rectal membrane biopsies showed amyloid deposition and apple-green birefringence was visualized under polarized light microscopy. TTR gene sequencing showed no causative mutation. Following lumbar puncture, normal CSF cell counts and elevated CSF protein concentration (1680 mg/L) were detected. Bone marrow puncture showed that out of the total number of whole blood cells, 0.56% were abnormal plasma cells, and that 87.4% of the total number of plasma cells were abnormal. Electromyogram results showed mixed peripheral nerve damage predominately in the sensory nerve fibers. Conclusions:Obvious symptoms of neuropathy, particularly autonomic neuropathy, albuminocytologic dissociationand organ function damage suggested a diagnosis of amyloidosis. In such patients, neurologists should use caution to differentiate between chronic inflammatory demyelinating polyneuropathy, primary amyloidosis and familial amyloid neuropathy.

Neuroimaging studies have shown that speech comprehension involves a number of widely distributed regions within the frontal and temporal lobes. We aimed to examine the differential contributions of white matter connectivity to auditory word and sentence comprehension in chronic post-stroke aphasia. Structural and diffusion MRI data were acquired on 40 patients with chronic post-stroke aphasia. A battery of auditory word and sentence comprehension tests were administered to all the patients. Tract-based spatial statistics were used to identify areas in which white matter integrity related to specific comprehension deficits. Relevant tracts were reconstructed using probabilistic tractography in healthy older participants, and the mean values of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of the entire tracts were examined in relation to comprehension scores. Anterior temporal white matter integrity loss and involvement of the uncinate fasciculus related to word-level comprehension deficits (RFA = 0.408, P = 0.012; RMD = −0.429, P = 0.008; RAD = −0.424, P = 0.009; RRD = −0.439, P = 0.007). Posterior temporal white matter integrity loss and involvement of the inferior longitudinal fasciculus related to sentence-level comprehension deficits (RFA = 0.382, P = 0.02; RMD = −0.461, P = 0.004; RAD = −0.457, P = 0.004; RRD = −0.453, P = 0.005). Loss of white matter integrity in the inferior fronto-occipital fasciculus related to both word- and sentence-level comprehension (word-level scores: RFA = 0.41, P = 0.012; RMD = −0.447, P = 0.006; RAD = −0.489, P = 0.002; RRD = −0.432, P = 0.008; sentence-level scores: RFA = 0.409, P = 0.012; RMD = −0.413, P = 0.011; RAD = −0.408, P = 0.012; RRD = −0.413, P = 0.011). Lesion overlap, but not white matter integrity, in the arcuate fasciculus related to sentence-level comprehension deficits. These findings suggest that word-level comprehension outcomes in chronic post-stroke aphasia rely primarily on anterior temporal lobe pathways, whereas sentence-level comprehension relies on more widespread pathways including the posterior temporal lobe.

Background. Understanding the relationships between clinical tests, the processes they measure, and the brain networks underlying them, is critical in order for clinicians to move beyond aphasia syndrome classification toward specification of individual language process impairments. Objective. To understand the cognitive, language, and neuroanatomical factors underlying scores of commonly used aphasia tests. Methods. Twenty-five behavioral tests were administered to a group of 38 chronic left hemisphere stroke survivors and a high-resolution magnetic resonance image was obtained. Test scores were entered into a principal components analysis to extract the latent variables (factors) measured by the tests. Multivariate lesion-symptom mapping was used to localize lesions associated with the factor scores. Results. The principal components analysis yielded 4 dissociable factors, which we labeled Word Finding/Fluency, Comprehension, Phonology/Working Memory Capacity, and Executive Function. While many tests loaded onto the factors in predictable ways, some relied heavily on factors not commonly associated with the tests. Lesion symptom mapping demonstrated discrete brain structures associated with each factor, including frontal, temporal, and parietal areas extending beyond the classical language network. Specific functions mapped onto brain anatomy largely in correspondence with modern neural models of language processing. Conclusions. An extensive clinical aphasia assessment identifies 4 independent language functions, relying on discrete parts of the left middle cerebral artery territory. A better understanding of the processes underlying cognitive tests and the link between lesion and behavior may lead to improved aphasia diagnosis, and may yield treatments better targeted to an individual’s specific pattern of deficits and preserved abilities.

The study of language network plasticity following left hemisphere stroke is foundational to the understanding of aphasia recovery and neural plasticity in general. Damage in different language nodes may influence whether local plasticity is possible and whether right hemisphere recruitment is beneficial. However, the relationships of both lesion size and location to patterns of remapping are poorly understood. In the context of a picture naming fMRI task, we tested whether lesion size and location relate to activity in surviving left hemisphere language nodes, as well as homotopic activity in the right hemisphere during covert name retrieval and overt name production. We found that lesion size was positively associated with greater right hemisphere activity during both phases of naming, a pattern that has frequently been suggested but has not previously been clearly demonstrated. During overt naming, lesions in the inferior frontal gyrus led to deactivation of contralateral frontal areas, while lesions in motor cortex led to increased right motor cortex activity. Furthermore, increased right motor activity related to better naming performance only when left motor cortex was lesioned, suggesting compensatory takeover of speech or language function by the homotopic node. These findings demonstrate that reorganization of language function, and the degree to which reorganization facilitates aphasia recovery, is dependent on the size and site of the lesion.

Purpose: Tongxinluo, a well-known traditional Chinese medicine complex, has been widely used for the treatment of cerebrovascular diseases in China. The present study was to explore whether treatment with tongxinluo could improve neurological function and alleviate secondary damage in the ipsilateral thalamus after focal cortical infarction in hypertensive rats. Methods: Tongxinluo was given through oral gavage starting 24 h after distal middle cerebral artery occlusion (MCAO). Neurological function was assessed and then rats were sacrificed 7 and 14 days after MCAO. Brains were harvested for examining infarction volume, Nissl staining and immunofluorescence analysis. Results: Compared with vehicle treatment, tongxinluo remarkably improved neurological function without reducing infarction volume, attenuated neuronal loss and astrocyte activation in the ipsilateral thalamus 7 and 14 days after MCAO (all p < 0.05). Also, tongxinluo markedly increased the number of BrdU+/nestin+ and BrdU+/NeuN+ cells 14 days after MCAO. Moreover, vascular density, the number of BrdU+ vascular endothelial cells, and vascular perimeter in the ipsilateral thalamus were markedly increased in the tongxinluo group relative to that of the vehicle group (all p < 0.05). Conclusion: Administration of tongxinluo 24 h after cortical infarction may promote neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological function after cortical infarction in rats.

Background and Purpose— Secondary changes in the volume of motor-related cortical regions and the relationship with functional recovery during the acute stage after cerebral infarction have not been determined. In the present study, we quantified changes in gray matter (GM) volume in motor-related cortical regions and analyzed their correlations to clinical scores in patients with focal cerebral infarct. Methods— Fifteen patients with acute subcortical infarct underwent longitudinal high-resolution structural MRI and clinical assessment 3 times during a 12-week period (weeks 1, 4, and 12). Fourteen age- and sex-matched controls underwent MRI examination. Voxel-based morphometry was used to quantify changes in global GM volume; in addition, relationships between GM volume changes in volumes of interest and clinical scores were analyzed. Results— In patients with cerebral infarction, GM volumes detected by voxel-based morphometry both decreased and increased significantly in diffuse cortical regions during the observation period ( P P r s =0.52; P =0.048; contralesional, r s =0.74; P =0.002) and Barthel Index (ipsilesional, r s =0.56; P =0.030; contralesional, r s =0.65; P =0.009). Conclusions— These results suggest that secondary GM changes occur in diffuse areas and structural changes in some specific motor-related cortex may inhibit or promote functional recovery after an acute subcortical cerebral infarct.

Focal cerebral cortical infarction causes secondary neurodegeneration in the remote regions, such as the ventroposterior nucleus of the thalamus. Retrograde degeneration of thalamocortical fibers is considered as the principle mechanism, but the exact molecular events remain to be elucidated. This study aimed to investigate whether unfolded protein response (UPR) is activated in thalamic neurons following distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats. Immunostaining and immunoblotting were performed to evaluate the expression of Grp78 and its downstream effectors in the thalamus at 3, 7, and 14 days after MCAO. Secondary thalamic degeneration was assessed with Nissl staining and NeuN immunostaining. Neuronal death was not apparent at 3 days post-ischemia but was evident in the thalamus at 7 and 14 days after MCAO. Grp78 level was reduced in the ipsilateral thalamus at 3 and 7 days after MCAO. In parallel, phosphorylated eIF2α and ATF4 levels were elevated, indicating the activation of UPR. In contrast, ATF6α and CHOP levels were not changed. These results suggest that UPR is activated before neuronal death in the ipsilateral thalamus after MCAO and may represent a key early event in the secondary thalamic degeneration. This article is protected by copyright. All rights reserved.