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In this study we explore the spatio‐temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free‐water imaging. Twenty‐seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3–7) received diffusion MRI 3–5 days, 1 month, 3 months, and 12 months after symptom‐onset. Extracellular free‐water and fractional anisotropy of the tissue (FAT) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free‐water and decreased FAT in the white matter of patients with subcortical stroke (lesion [free‐water/FAT, mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3–5 days, 1 month, 3 months, and 12 months after symptom‐onset]: +41/−34, +111/−37, +208/−26, +251/−18; perilesional tissue [range in %]: +[5–24]/−[0.2–7], +[2–20]/−[3–16], +[5–43]/−[2–16], +[10–110]/−[2–12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free‐water elevations continuously increased over time and peaked after 12 months, FAT decreases were most evident 1 month post‐stroke, gradually returning to baseline values thereafter. Higher perilesional free‐water and higher lesional FAT at baseline were correlated with greater reductions in lesion size (rho = −0.51, p =.03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio‐temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy. [ABSTRACT FROM AUTHOR]

• Levels of T cell-derived EVs and the size of those from neurons correlate with disease activity while oligodendrocyte-derived EVs size is associated with cognitive and motor dysfunction in the MS group. • Protein content of extracelular vesicles of MS patients participates in B-cell activation, inflammation and p53 pathway. • High levels of AMPB and FIBB from T cell-derived EVs are MS-associated proteins and correlates with disease activity in MS patients. • Low levels of GELS from B cell-derived EVs and IGHG4 from EV released from neurons are also MS-specific proteins and are associated with active disease in MS patients. • AMPB, FIBB, GELS, IGHG4 and MBP are involved in non-canonical functions of EVs in MS with a focus on regulation of complement system, extracellular matrix remodeling, brain repair and antigen tolerance. Multiple sclerosis (MS) is an immune-mediated central nervous system disease whose course is unpredictable. Finding biomarkers that help to better comprehend the disease's pathogenesis is crucial for supporting clinical decision-making. Blood extracellular vesicles (EVs) are membrane-bound particles secreted by all cell types that contain information on the disease's pathological processes. To identify the immune and nervous system-derived EV profile from blood that could have a specific role as biomarker in MS and assess its possible correlation with disease state. Higher levels of T cell-derived EVs and smaller size of neuron-derived EVs were associated with clinical relapse. The smaller size of the oligodendrocyte-derived EVs was related with motor and cognitive impairment. The proteomic analysis identified mannose-binding lectin serine protease 1 and complement factor H from immune system cell-derived EVs as autoimmune disease-associated proteins. We observed hepatocyte growth factor-like protein in EVs from T cells and inter-alpha-trypsin inhibitor heavy chain 2 from neurons as white matter injury-related proteins. In patients with MS, a specific protein profile was found in the EVs, higher levels of alpha-1-microglobulin and fibrinogen β chain, lower levels of C1S and gelsolin in the immune system-released vesicles, and Talin-1 overexpression in oligodendrocyte EVs. These specific MS-associated proteins, as well as myelin basic protein in oligodendrocyte EVs, correlated with disease activity in the patients with MS. Neural-derived and immune-derived EVs found in blood appear to be good specific biomarkers in MS for reflecting the disease state. [ABSTRACT FROM AUTHOR]

Ischemic injury to white matter tracts is increasingly recognized to play a key role in age-related cognitive decline, vascular dementia, and Alzheimer's disease. Knowledge of the effects of ischemic axonal injury on cortical neurons is limited yet critical to identifying molecular pathways that link neurodegeneration and ischemia. Using a mouse model of subcortical white matter ischemic injury coupled with retrograde neuronal tracing, we employed magnetic affinity cell sorting with fluorescence-activated cell sorting to capture layer-specific cortical neurons and performed RNA-sequencing. With this approach, we identified a role for microtubule reorganization within stroke-injured neurons acting through the regulation of tau. We find that subcortical stroke-injured Layer 5 cortical neurons up-regulate the microtubule affinity-regulating kinase, Mark4, in response to axonal injury. Stroke-induced up-regulation of Mark4 is associated with selective remodeling of the apical dendrite after stroke and the phosphorylation of tau in vivo. In a cell-based tau biosensor assay, Mark4 promotes the aggregation of human tau in vitro. Increased expression of Mark4 after ischemic axonal injury in deep layer cortical neurons provides new evidence for synergism between axonal and neurodegenerative pathologies by priming of tau phosphorylation and aggregation.

Purpose: The purpose of the present study was to explore the longitudinal changes in functional homotopy in the default mode network (DMN) and motor network and its relationships with clinical characteristics in patients with stroke. Methods: Resting-state functional magnetic resonance imaging was performed in stroke patients with subcortical ischemic lesions and healthy controls. The voxel-mirrored homotopic connectivity (VMHC) method was used to examine the differences in functional homotopy in patients with stroke between the two time points. Support vector machine (SVM) and correlation analyses were also applied to investigate whether the detected significant changes in VMHC were the specific feature in patients with stroke. Results: The patients with stroke had significantly lower VMHC in the DMN and motor-related regions than the controls, including in the precuneus, parahippocampus, precentral gyrus, supplementary motor area, and middle frontal gyrus. Longitudinal analysis revealed that the impaired VMHC of the superior precuneus showed a significant increase at the second time point, which was no longer significantly different fromthe controls. Between the two time points, the changes in VMHC in the superior precuneus were significantly correlated with the changes in clinical scores. SVM analysis revealed that the VMHC of the superior precuneus could be used to correctly identify the patients with stroke from the controls with a statistically significant accuracy of 81.25% (P = 0.003). Conclusions: Our findings indicated that the increased VMHC in the superior precuneus could be regarded as the neuroimaging manifestation of functional recovery. The significant correlation and the discriminative power in classification results might provide novel evidence to understand the neural mechanisms responsible for brain reorganization after stroke. [ABSTRACT FROM AUTHOR]

Stroke can be viewed as an acute disruption of an individual's connectome caused by a focal or widespread loss of blood flow. Although individuals exhibit connectivity changes in multiple functional networks after stroke, the neural mechanisms that underlie the longitudinal reorganization of the connectivity patterns are still unclear. The study aimed to determine whether brain network connectivity patterns after stroke can predict longitudinal behavioral outcomes. Nineteen patients with stroke with subcortical lesions underwent two sessions of resting-state functional magnetic resonance imaging scanning at a 1-month interval. By independent component analysis, the functional connectivity within and between multiple brain networks (including the default mode network, the dorsal attention network, the limbic network, the visual network, and the frontoparietal network) was disrupted after stroke and partial recovery at the second time point. Additionally, regression analyses revealed that the connectivity between the limbic and dorsal attention networks at the first time point showed sufficient reliability in predicting the clinical scores (Fugl-Meyer Assessment and Neurological Deficit Scores) at the second time point. The overall findings suggest that functional coupling between the dorsal attention and limbic networks after stroke can be regarded as a biomarker to predict longitudinal clinical outcomes in motor function and the degree of neurological functional deficit. Overall, the present study provided a novel opportunity to improve prognostic ability after subcortical strokes. [ABSTRACT FROM AUTHOR]

Objective: Subcortical stroke can cause a variety of language deficits. However, the neural mechanisms underlying subcortical aphasia after stroke remain incompletely elucidated. We aimed to determine the effects of distant cortical structures on aphasia outcomes and examine the correlation of cortical thickness measures with connecting tracts integrity after chronic left subcortical stroke. Methods: Thirty-two patients and 30 healthy control subjects underwent MRI scanning and language assessment with the Western Aphasia Battery-Revised (WAB-R) subtests. Among patients, the cortical thickness in brain regions that related to language performance were assessed by the FreeSurfer software. Fiber tracts connecting the identified cortical regions to stroke lesions were reconstructed to determine its correlations with the cortical thickness measures across individual patient. Results: Cortical thickness in different parts of the left frontotemporo-parietal (FTP) regions were positively related to auditory-verbal comprehension, spontaneous speech and naming/word finding abilities when controlling for key demographic variables and lesion size. Cortical thickness decline in the identified cortical regions was positively correlated with integrity loss of fiber tracts connected to stroke lesions. Additionally, no significant difference in cortical thickness was found across the left hemisphere between the subgroup of patients with hypoperfusion (HP) and those without HP at stroke onset. Conclusions: These findings suggest that remote cortical atrophy independently predicts language outcomes in patients with chronic left subcortical stroke and aphasia and that cortical thinning in these regions might relate to integrity loss of fiber tracts connected to stroke lesions. [ABSTRACT FROM AUTHOR]

Abstract Introduction Stroke is one of the leading causes of substantial disability worldwide. Previous studies have shown brain functional and structural alterations in adults with stroke. However, few studies have examined the longitudinal reorganization in whole-brain structural networks in stroke. Methods Here, we applied graph theoretical analysis to investigate the longitudinal topological organization of white matter networks in 20 ischemic stroke patients with a one-month interval between two timepoints. Two sets of clinical scores, Fugl-Meyer motor assessment (FMA) and neurological deficit scores (NDS), were assessed for all patients on the day the image data were collected. Results The stroke patients exhibited significant increases in FMA scores and significant reductions in DNS between the two timepoints. All groups exhibited small-world organization (σ > 1) in the brain structural network, including a high clustering coefficient (γ > 1) and a low normalized characteristic path length (λ ≈ 1). However, compared to healthy controls, stroke patients showed significant decrease in nodal characteristics at the first timepoint, primarily in the right supplementary motor area, right middle temporal gyrus, right inferior parietal lobe, right postcentral gyrus and left posterior cingulate gyrus. Longitudinal results demonstrated that altered nodal characteristics were partially restored one month later. Additionally, significant correlations between the nodal characteristics of the right supplementary motor area and the clinical scale scores (FMA and NDS) were observed in stroke patients. Similar behavioral-neuroimaging correlations were found in the right inferior parietal lobe. Conclusion Altered topological properties may be an effect of stroke, which can be modulated during recovery. The longitudinal results and the neuroimaging-behavioral relationship may provide information for understanding brain recovery from stroke. Future studies should detect whether observed changes in structural topological properties can predict the recovery of daily cognitive function in stroke.

[Display omitted] • Examining brain structure or function alone can't fully capture brain operation mechanisms. • Brain structural-functional coupling weakens in patients with post-stroke cognitive impairment. • Decoupling in brain structural-functional coupling is linked to cognitive impairment. • Increased brain structural-functional coupling three months post-stroke may be a compensatory mechanism. Stroke can lead to significant restructuring of brain structure and function. However, the precise changes in the coordination between brain structure and function in subcortical stroke patients remain unclear. We investigated alterations in brain structural–functional coupling (SC-FC coupling) and their impact on cognitive function in subcortical basal ganglia infarction patients. The study comprised 40 patients with mild stroke with basal ganglia region infarcts and 29 healthy controls (HC) who underwent multidimensional neuroimaging examination and neuropsychological testing. The subcortical stroke patients were divided into post-stroke cognitive impairment (PSCI) and stroke with no cognitive impairment (NPSCI) groups based on cognitive performance, with 22 individuals undergoing follow-up examination after three months. We investigated differences in brain structural–functional coupling across three groups, and their associations with cognitive functions. Compared to both HC participants and NPSCI, PSCI exhibited significantly reduced structural–functional coupling strength in specific brain regions. After a three-month period, there was observed an increase in structural–functional coupling strength within the frontal lobe (precentral gyrus and paracentral lobule). The strength of SC-FC coupling within the precentral gyrus, precuneus, and paracentral lobule regions demonstrated a decline correlating with the deterioration of cognitive function (MoCA, memory and visual motor speed functions). After subcortical basal ganglia stroke, PSCI patients demonstrated decreased SC-FC coupling in the frontal lobe region, correlating with multidimensional cognitive impairment. Three months later, there was an increase in SC-FC coupling in the frontal lobe, suggesting a compensatory mechanism during the recovery phase of cognitive impairment following stroke. [ABSTRACT FROM AUTHOR]

Purpose: To explore the changes of cerebral blood flow (CBF) and fractional anisotropy (FA) in stroke patients with motor dysfunction after repetitive transcranial magnetic stimulation (rTMS) treatment, and to better understand the role of rTMS on motor rehabilitation of subcortical stroke patients from the perfusion and structural level. Materials and Methods: In total, 23 first-episode acute ischemic stroke patients and sixteen healthy controls (HCs) were included. The patients were divided into the rTMS and sham group. The rehabilitation assessments and examination of perfusion and structural MRI were performed before and after rTMS therapy for each patient. Voxel-based analysis was used to detect the difference in CBF and FA among all three groups. The Pearson correlation analysis was conducted to evaluate the relationship between the CBF/FA value and the motor scales. Results: After rTMS, significantly increased CBF was found in the ipsilesional supplementary motor area, postcentral gyrus, precentral gyrus, pons, medulla oblongata, contralesional midbrain, superior cerebellar peduncle, and middle cerebellar peduncle compared to that during the prestimulation and in the sham group, these fasciculi comprise the cortex-pontine-cerebellum-cortex (CPC) loop. Besides, altered CBF in the ipsilesional precentral gyrus, postcentral gyrus, and pons was positively associated with the improved Fugl-Meyer assessment (FMA) scores. Significantly decreased FA was found in the contralesional precentral gyrus, increased FA was found in the ipsilesional postcentral gyrus, precentral gyrus, contralesional supplementary motor area, and bilateral cerebellum, these fasciculi comprise the corticospinal tract (CST). The change of FMA score was positively correlated with altered FA value in the ipsilesional postcentral gyrus and negatively correlated with altered FA value in the contralesional precentral gyrus. Conclusion: Our results suggested that rTMS could facilitate the motor recovery of stroke patients. High frequency could promote the improvement of functional activity of ipsilesional CPC loop and the recovery of the microstructure of CST. [ABSTRACT FROM AUTHOR]

PurposeTo explore the changes of cerebral blood flow (CBF) and fractional anisotropy (FA) in stroke patients with motor dysfunction after repetitive transcranial magnetic stimulation (rTMS) treatment, and to better understand the role of rTMS on motor rehabilitation of subcortical stroke patients from the perfusion and structural level.Materials and MethodsIn total, 23 first-episode acute ischemic stroke patients and sixteen healthy controls (HCs) were included. The patients were divided into the rTMS and sham group. The rehabilitation assessments and examination of perfusion and structural MRI were performed before and after rTMS therapy for each patient. Voxel-based analysis was used to detect the difference in CBF and FA among all three groups. The Pearson correlation analysis was conducted to evaluate the relationship between the CBF/FA value and the motor scales.ResultsAfter rTMS, significantly increased CBF was found in the ipsilesional supplementary motor area, postcentral gyrus, precentral gyrus, pons, medulla oblongata, contralesional midbrain, superior cerebellar peduncle, and middle cerebellar peduncle compared to that during the prestimulation and in the sham group, these fasciculi comprise the cortex-pontine-cerebellum-cortex (CPC) loop. Besides, altered CBF in the ipsilesional precentral gyrus, postcentral gyrus, and pons was positively associated with the improved Fugl-Meyer assessment (FMA) scores. Significantly decreased FA was found in the contralesional precentral gyrus, increased FA was found in the ipsilesional postcentral gyrus, precentral gyrus, contralesional supplementary motor area, and bilateral cerebellum, these fasciculi comprise the corticospinal tract (CST). The change of FMA score was positively correlated with altered FA value in the ipsilesional postcentral gyrus and negatively correlated with altered FA value in the contralesional precentral gyrus.ConclusionOur results suggested that rTMS could facilitate the motor recovery of stroke patients. High frequency could promote the improvement of functional activity of ipsilesional CPC loop and the recovery of the microstructure of CST.

Context: In the elderly stroke or stroke-related injury often results in cortical dysfunction termed as aphasia. This affects language usage and multiple aspects of communication. Comparative studies between cortical and subcortical lesions in aphasia are lacking. Aim: To study the type of aphasia in cortical and subcortical strokes. Settings and Design: Prospective observational. Subjects and Methods: Subjects with cortical and subcortical strokes of the dominant cerebral hemisphere were included in the study and divided into various aphasia types. Bedside language tests and distribution according to educational qualifications were performed. The subjects were assessed for aphasia scores and its association was performed with other baseline characteristics. Statistical Analysis Used: Data was expressed as a percentage and mean ± standard deviation. Kolmogorov-Smirnov analysis and Fischer's exact test or Chi-square test were used. Results: Significant difference was noted between the type of aphasia and age group in study subjects (P < 0.001). A severe form of language dysfunction like global aphasia was noted in subjects with a comparatively low level of education, with subcortical bleed, or those with left perisylvian infarcts. Subjects with diabetes and dyslipidemia had a higher risk of developing anomic aphasia (P = 0.02). Conclusions: This study showed the type of aphasia in subjects with cortical and subcortical strokes and it revealed that age at onset, level of education, and site of the lesion were associated with the outcome of patients of aphasia. [ABSTRACT FROM AUTHOR]

Background and Purpose: Strokes consistently result in brain network dysfunction. Previous studies have focused on the resting-state characteristics over the study period, while dynamic recombination remains largely unknown. Thus, we explored differences in dynamics between brain networks in patients who experienced subcortical stroke and the effects of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) on dynamic functional connectivity (dFC). Methods: A total of 41 patients with subcortical stroke were randomly divided into the LF-rTMS (n = 23) and the sham stimulation groups (n = 18). Resting-state functional MRI data were collected before (1 month after stroke) and after (3 months after stroke) treatment; a total of 20 age- and sex-matched healthy controls were also included. An independent component analysis, sliding window approach, and k-means clustering were used to identify different functional networks, estimate dFC matrices, and analyze dFC states before treatment. We further assessed the effect of LF-rTMS on dFCs in patients with subcortical stroke. Results: Compared to healthy controls, patients with stroke spent significantly more time in state I [ p = 0.043, effect size (ES) = 0.64] and exhibited shortened stay in state II (p = 0.015, ES = 0.78); the dwell time gradually returned to normal after LF-rTMS treatment (p = 0.015, ES = 0.55). Changes in dwell time before and after LF-rTMS treatment were positively correlated with changes in the Fugl–Meyer Assessment for Upper Extremity (pr = 0.48, p = 0.028). Moreover, patients with stroke had decreased dFCs between the sensorimotor and cognitive control domains, yet connectivity within the cognitive control network increased. These abnormalities were partially improved after LF-rTMS treatment. Conclusion: Abnormal changes were noted in temporal and spatial characteristics of sensorimotor domains and cognitive control domains of patients who experience subcortical stroke; LF-rTMS can promote the partial recovery of dFC. These findings offer new insight into the dynamic neural mechanisms underlying effect of functional recombination and rTMS in subcortical stroke. Registration: http://www.chictr.org.cn/index.aspx, Unique.identifier: ChiCTR1800019452. [ABSTRACT FROM AUTHOR]

Abstract Background Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. Materials and methods For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 μg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 μg, 100 μg, or 200 μg) of EVs were intravenously administered after 24 h. Results All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 μg and 100 μg doses. Only the 50-μg dose was associated with significant increases in brain-derived neurotrophic factor expression. Conclusion In conclusion, 50 μg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.

Background and Purpose: Strokes consistently result in brain network dysfunction. Previous studies have focused on the resting-state characteristics over the study period, while dynamic recombination remains largely unknown. Thus, we explored differences in dynamics between brain networks in patients who experienced subcortical stroke and the effects of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) on dynamic functional connectivity (dFC).Methods: A total of 41 patients with subcortical stroke were randomly divided into the LF-rTMS (n = 23) and the sham stimulation groups (n = 18). Resting-state functional MRI data were collected before (1 month after stroke) and after (3 months after stroke) treatment; a total of 20 age- and sex-matched healthy controls were also included. An independent component analysis, sliding window approach, and k-means clustering were used to identify different functional networks, estimate dFC matrices, and analyze dFC states before treatment. We further assessed the effect of LF-rTMS on dFCs in patients with subcortical stroke.Results: Compared to healthy controls, patients with stroke spent significantly more time in state I [p = 0.043, effect size (ES) = 0.64] and exhibited shortened stay in state II (p = 0.015, ES = 0.78); the dwell time gradually returned to normal after LF-rTMS treatment (p = 0.015, ES = 0.55). Changes in dwell time before and after LF-rTMS treatment were positively correlated with changes in the Fugl–Meyer Assessment for Upper Extremity (pr = 0.48, p = 0.028). Moreover, patients with stroke had decreased dFCs between the sensorimotor and cognitive control domains, yet connectivity within the cognitive control network increased. These abnormalities were partially improved after LF-rTMS treatment.Conclusion: Abnormal changes were noted in temporal and spatial characteristics of sensorimotor domains and cognitive control domains of patients who experience subcortical stroke; LF-rTMS can promote the partial recovery of dFC. These findings offer new insight into the dynamic neural mechanisms underlying effect of functional recombination and rTMS in subcortical stroke.Registration:http://www.chictr.org.cn/index.aspx, Unique.identifier: ChiCTR1800019452.

Introduction: Stroke is one of the leading causes of substantial disability worldwide. Previous studies have shown brain functional and structural alterations in adults with stroke. However, few studies have examined the longitudinal reorganization in whole-brain structural networks in stroke.Methods: Here, we applied graph theoretical analysis to investigate the longitudinal topological organization of white matter networks in 20 ischemic stroke patients with a one-month interval between two timepoints. Two sets of clinical scores, Fugl-Meyer motor assessment (FMA) and neurological deficit scores (NDS), were assessed for all patients on the day the image data were collected.Results: The stroke patients exhibited significant increases in FMA scores and significant reductions in DNS between the two timepoints. All groups exhibited small-world organization (σ  >  1) in the brain structural network, including a high clustering coefficient (γ  >  1) and a low normalized characteristic path length (λ ≈ 1). However, compared to healthy controls, stroke patients showed significant decrease in nodal characteristics at the first timepoint, primarily in the right supplementary motor area, right middle temporal gyrus, right inferior parietal lobe, right postcentral gyrus and left posterior cingulate gyrus. Longitudinal results demonstrated that altered nodal characteristics were partially restored one month later. Additionally, significant correlations between the nodal characteristics of the right supplementary motor area and the clinical scale scores (FMA and NDS) were observed in stroke patients. Similar behavioral-neuroimaging correlations were found in the right inferior parietal lobe.Conclusion: Altered topological properties may be an effect of stroke, which can be modulated during recovery. The longitudinal results and the neuroimaging-behavioral relationship may provide information for understanding brain recovery from stroke. Future studies should detect whether observed changes in structural topological properties can predict the recovery of daily cognitive function in stroke. [ABSTRACT FROM AUTHOR]

Abstract Ischemic injury to white matter tracts is increasingly recognized to play a key role in age-related cognitive decline, vascular dementia, and Alzheimer’s disease. Knowledge of the effects of ischemic axonal injury on cortical neurons is limited yet critical to identifying molecular pathways that link neurodegeneration and ischemia. Using a mouse model of subcortical white matter ischemic injury coupled with retrograde neuronal tracing, we employed magnetic affinity cell sorting with fluorescence-activated cell sorting to capture layer-specific cortical neurons and performed RNA-sequencing. With this approach, we identified a role for microtubule reorganization within stroke-injured neurons acting through the regulation of tau. We find that subcortical stroke-injured Layer 5 cortical neurons up-regulate the microtubule affinity-regulating kinase, Mark4, in response to axonal injury. Stroke-induced up-regulation of Mark4 is associated with selective remodeling of the apical dendrite after stroke and the phosphorylation of tau in vivo. In a cell-based tau biosensor assay, Mark4 promotes the aggregation of human tau in vitro. Increased expression of Mark4 after ischemic axonal injury in deep layer cortical neurons provides new evidence for synergism between axonal and neurodegenerative pathologies by priming of tau phosphorylation and aggregation.

Aphasia, one of the most common cognitive impairments after stroke, is commonly considered to be a cortical deficit. However, many studies have reported cases of post subcortical stroke aphasia (PSSA). The pathology and recovery mechanism of PSSA remain unclear. This study aimed to investigate PSSA mechanism through a multimodal magnetic resonance imaging (MRI) approach and a two-session study design (baseline and one month after treatment). Thirty-six PSSA patients and twenty-four matched healthy controls (HC) were included. All patients had subcortical infarctions involving left subcortical white matter for 1 to 6 months. The patients underwent MRI scan and Western Aphasia Battery (WAB) examination before and after one month’s comprehensive treatment. Region-wise lesion-symptom mapping (RLSM), tractography, fractional anisotropy (FA), and amplitude of low-frequency fluctuations (ALFF) analysis were conducted. After MRI preprocessing and exclusion, FA analysis included 35 patients pre-treatment and 16 patients post-treatment. ALFF analysis included 30 patients pre-treatment and 14 patients post-treatment. We found: 1) the amount of damage in the left uncinate fasciculus (UF) was associated with WAB aphasia quotient (AQ); 2) the left UF FA and left temporal pole (TP) ALFF were decreased and positively correlated with WAB-AQ, spontaneous speech, and naming in PSSA patients; and 3) PSSA patients showed increased left TP ALFF when their language ability recovered after treatment. The left TP ALFF change was positively correlated with AQ change. Our results demonstrate the importance of left UF and left TP (one of the cortical terminals of the left UF) in PSSA pathology and recovery. These results may further provide support for the disconnection theory in the mechanism of PSSA.

Background: Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. Materials and methods: For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 μg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 μg, 100 μg, or 200 μg) of EVs were intravenously administered after 24 h. Results: All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 μg and 100 μg doses. Only the 50-μg dose was associated with significant increases in brain-derived neurotrophic factor expression. Conclusion: In conclusion, 50 μg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke. [ABSTRACT FROM AUTHOR]

Arm motor recovery after stroke is mainly attributed to reorganization of the primary motor cortex (M1). While M1 contralateral to the paretic arm (cM1) is critical for recovery, the role of ipsilateral M1 (iM1) is still inconclusive. Whether iM1 activity is related to recovery, behavioral compensation, or both is still far from settled. We hypothesized that the magnitude of iM1 activity in chronic stroke survivors will increase or decrease in direct proportion to the degree that movements of the paretic arm are compensated. Movement kinematics (VICON, Oxford Metrics) and functional MRI data (3T MR system) were collected in 11 patients before and after a 4-week training designed to improve motor control of the paretic arm and decrease compensatory trunk recruitment. Twelve matched controls underwent similar evaluations and training. Relationships between iM1 activity and trunk motion were analyzed. At baseline, patients exhibited increased iM1 activity (p = 0.001) and relied more on trunk movement (p = 0.02) than controls. These two variables were directly and significantly related in patients (r = 0.74, p = 0.01) but not in controls (r = 0.28, p = 0.4). After training, patients displayed a significant reduction in iM1 activity (p = 0.008) and a trend toward decreased trunk use (p = 0.1). The relationship between these two variables remained significant (r = 0.66, p = 0.03) and different from controls (r = 0.26, p = 0.4). Our preliminary results suggest that iM1 may play a role in compensating for brain damage rather than directly gaining control of the paretic arm. However, we recommend caution in interpreting these results until more work is completed. [ABSTRACT FROM AUTHOR]

Highlights • BS patients exhibited functional damage primarily in ipsilesional sensorimotor cortex and contralesional cerebellum. • PS patients showed functional impairment primarily in cerebellum. • Different patterns of secondary brain damage in different types of infarction. Abstract We investigated the influence of lesion location on cerebral blood flow (CBF) in chronic subcortical stroke patients. Three-dimensional pseudocontinuous arterial spin labeling was employed to obtain CBF images in normal controls (NC) and patients with left hemisphere subcortical infarctions involving motor pathways. Stroke patients were divided into two subgroups based on the infarction location (basal ganglia (BS) or pontine (PS). We mapped CBF alterations in a voxel-wise manner and compared them to detect differences among groups with height-level false discovery rate correction. Regions with significant group differences were extracted to perform post hoc analyses among the BS, PS and NC groups using a general linear model with age, gender, years of education, and interval after stroke as covariates. The BS group displayed significantly increased CBF in the contralesional putamen relative to NC and significantly decreased CBF in the ipsilesional sensorimotor cortex, ipsilesional thalamus and contralesional cerebellum. The PS group displayed significantly increased CBF in the contralesional inferior frontal gyrus relative to both the NC and BS groups. Nevertheless, the PS group showed significantly decreased CBF mainly in the cerebellum. Our results suggest different alteration patterns of CBF in chronic stroke patients with different infarct locations within subcortical motor pathways, potentially providing important information for the initiation of individualized rehabilitation strategies for subcortical stroke patients involving different infarct types. [ABSTRACT FROM AUTHOR]

Exosomes are gaining importance because they show great promise in therapeutic applications for several diseases. Particularly in stroke, exosomes derived from mesenchymal stem cell (MSC) therapy work as paracrine effectors responsible for promoting neurovascular remodeling and functional recovery. Adult male rats were subjected to intracerebral hemorrhage (ICH) by intrastriatal injection of collagenase type IV; 24 h after surgery, MSC-derived exosomes were administered through the tail vein. The rats were euthanized at 7 or 28 days after treatment. Functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers, biodistribution of exosomes and secretome proteomics were analyzed. DiI-labeled exosomes were found in the brains of the ICH-treated group and in the liver, lung and spleen. Animals receiving treatment with exosomes showed significantly better results in terms of functional recovery, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group 28 days after stroke. Proteomics analysis of the exosomes identified more than 2000 proteins that could be implicated in brain repair function. In conclusion, white matter integrity was partly restored by exosome administration mediated by molecular repair factors. Exosomes as a treatment could be a heterogeneous process by nature and presents many factors that can influence brain plasticity in an adaptable and versatile manner. [ABSTRACT FROM AUTHOR]

The mechanism of motor recovery after stroke may involve reorganization of the surviving networks. However, details of adaptive changes in structural connectivity are not well understood. Here, we show long-term changes in white matter microstructure that relate to motor recovery in stroke patients. We studied ten subcortical ischemic stroke patients who showed motor hemiparesis at the initial clinical examination and an infarcted lesion centered in the posterior limb of internal capsule of the unilateral hemisphere at the initial diffusion-weighted magnetic resonance imaging scan. The participants underwent serial diffusion tensor imaging and motor function assessments at three consecutive time points; within 2 weeks, and at 1 and 3 months after the onset. Fractional anisotropy (FA) was analyzed for regional differences between hemispheres and time points, as well as for correlation with motor recovery using a tract-based spatial statistics analysis. The results showed significantly increased FA in the red nucleus and dorsal pons in the ipsi-lesional side at 3 months, and significantly decreased FA in the ipsi-lesional internal capsule at all time points, and in the cerebral peduncle, corona radiata, and corpus callosum at 3 months. In the correlation analysis, FA values of clusters in the red nucleus, dorsal pons, midbody of corpus callosum, and cingulum were positively correlated with recovery of motor function. Our study suggests that changes in white matter microstructure in alternative descending motor tracts including the rubro-spinal pathway, and interhemispheric callosal connections may play a key role in compensating for motor impairment after subcortical stroke.

The authors' purpose was to evaluate bilateral ankle intrinsic stiffness in subcortical poststroke subjects. Ten subcortical poststroke subjects and 10 healthy controls participated in this study. The ankle passive stiffness at 3 different speeds and the electromyographic activity of the soleus, the gastrocnemius, and the tibialis anterior muscles of poststroke contralesional (CONTRA) and ipsilesional (IPSI) limbs and of one limb of healthy subjects were assessed. Ankle electromyographic activity was collected to ensure that reflexive or voluntary muscle activity was not being elicited during the passive movements. A significant interaction was observed between the effects of the limb (IPSI vs. CONTRA vs. control) and ankle position, F(4, 28) = 3.285, p = .025, and between the effects of the limb and the velocity of stretch, F(2, 14) = 4.209, p = .037. While increased intrinsic stiffness was observed in the CONTRA limb of poststroke subjects at ankle neutral position when the passive stretch was applied with a velocity of 1°/s (p = .021), the IPSI limb of poststroke subjects presented increased stiffness at 20º of plantar flexion when the stretch was applied with a velocity of 5°/s (p = .009) when compared to healthy group. Subcortical poststroke subjects present increased intrinsic stiffness in both the CONTRA and IPSI limbs in specific ankle amplitudes. [ABSTRACT FROM AUTHOR]

Increasing neuroimaging researches in stroke rehabilitation had revealed the neural mechanisms of rehabilitation therapy. However, little was known about the neural mechanisms of acupuncture therapy in subcortical stroke patients. The aim of this study was to investigate the changes of functional connectivity (FC) between the bilateral primary motor cortices (M1s) after acupuncture intervention in right subcortical stroke patients. Twenty right-hemispheric subcortical stroke patients and 20 healthy subjects were recruited to undergo one functional magnetic resonance imaging (fMRI) scanning. The scanning consisted of resting-state fMRI before and after needling at Yanglinquan (GB34), and task-evoked fMRI. The most significant active point during the left passive thumb-to-index task was chosen as the seed point. The seed-based FC analysis of the bilateral M1s was performed. Stroke patients revealed decreased FC between the bilateral M1s compared with healthy subjects, and the decreased FC was significantly enhanced after acupuncture at GB34. Acupuncture could increase the intrinsically decreased FC between the bilateral M1s which provided further insight into the neural mechanisms of acupuncture for motor function recovery in stroke patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • We first time applied DC analysis to investigate the intrinsic dysconnectivity pattern of the brain in PSCI patients, and explore the relationship between DC values and cognitive function. • We put forward a new explanation and extends previous findings for the potential mechanism of cognitive dysfunction in PSCI patients at the acute stage. • The results from our study provide a more objective imaging basis for the prediction and evaluation of cognitive dysfunction in stroke patients. Patients with post stroke cognitive impairment (PSCI) frequently show changes in brain functional connectivity (FC). However, the underlying neurobiological mechanism of PSCI remains unclear. This study first applied degree centrality (DC) analysis to investigate the intrinsic dysconnectivity pattern of the brain in PSCI patients, as well as to explore the relationship between these changes and cognitive function. Resting-state functional magnetic resonance imaging (rs-fMRI) scanning was performed on all participants, including those with PSCI (n = 20), stroke with no cognitive impairment (NPSCI, n = 15), and healthy controls (HC, n = 29). DC values were used to identify differences in FC among the three groups. The relationship between abnormal DC values and cognitive function was examined. PSCI and NPSCI had significantly higher DC values in the right parahippocampal gyrus (PhG) in comparison with HC (p＜0.05). In addition, DC values of the right PhG showed a negative correlation with MoCA scores (r = − 0.405, p = 0.001), the Auditory Verbal Learning Test (AVLT; r = − 0.278, p = 0.026), Rey-Osterrieth Complex Figure Test-Delayed Recall (RCFT-DR; r = − 0.250, p = 0.046), Symbol Digit Modality Test (SDMT; r = − 0.385, p = 0.002), Boston Naming Test (BNT; r = − 0.402, p = 0.001) and Animal Fluency Test (AFT; r = − 0.395, p = 0.001). However, DC was significantly positively correlated with the Trail Making Test (TMT-A; r = 0.347, p = 0.005) and TMT-B (r = 0.294, p = 0.019). DC values were increased in the right PhG following a mild subcortical stroke. DC values in the PhG were negatively correlated with cognitive function, which may indicate brain nodes reorganization. [ABSTRACT FROM AUTHOR]

Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury. [ABSTRACT FROM AUTHOR]

Objectives Early neurological worsening is common in minor subcortical strokes ( SS) and may lead to a poor outcome. We aimed to describe clinical and imaging features associated with progression. Material and methods Consecutive patients with SS were divided into progressive and non-progressive. Progression was defined as an increase of NIHSS motor score ≥1 point within 72 h from onset. Vascular risk factors and imaging features (vascular territory, size and number of slices in which the lesion was visible, the presence of leukoaraiosis) were compared in the two groups. We investigated potential independent determinants of progression using stepwise logistic regression. Results Thirty of 94 patients (31.9%) underwent progression. The distribution of vascular risk factors did not differ significantly between the two groups. Increasing number of risk factors was associated with a higher risk of progression ( OR 2.2; 95% CI 1.1-4.5). Patients who progressed were more likely to have a lesion ≥15 mm in diameter ( P = 0.004) or a lesion visible ≥3 slices ( P = 0.007). After logistic regression stepwise adjustment for all the considered potential determinants, diameter ≥15 mm and severe leukoaraiosis proved to be independently associated with neurological worsening ( OR = 6.3, 95% CI 2.0-19.6 and OR = 5.9, 95% CI 1.3-25.7, respectively). Conclusion In a series of consecutive SS, early neurological worsening was associated with a high vascular risk profile, a larger infarct size and the presence of severe leukoaraiosis. Based on the knowledge that extensive microvascular changes are a feature of severe leukoaraiosis, we hypothesize that stroke progression could be promoted through an impaired compensatory flow in the penumbral area. [ABSTRACT FROM AUTHOR]

The left putamen is known to be important for speech production, but some patients with left putamen damage can produce speech remarkably well. We investigated the neural mechanisms that support this recovery by using a combination of techniques to identify the neural regions and pathways that compensate for loss of the left putamen during speech production. First, we used fMRI to identify the brain regions that were activated during reading aloud and picture naming in a patient with left putamen damage. This revealed that the patient had abnormally high activity in the left premotor cortex. Second, we used dynamic causal modeling of the patient's fMRI data to understand how this premotor activity influenced other speech production regions and whether the same neural pathway was used by our 24 neurologically normal control subjects. Third, we validated the compensatory relationship between putamen and premotor cortex by showing, in the control subjects, that lower connectivity through the putamen increased connectivity through premotor cortex. Finally, in a lesion-deficit analysis, we demonstrate the explanatory power of our fMRI results in new patients who had damage to the left putamen, left premotor cortex, or both. Those with damage to both had worse reading and naming scores. The results of our four-pronged approach therefore have clinical implications for predicting which patients are more or less likely to recover their speech after left putaminal damage. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to explore the longitudinal changes in functional homotopy in the default mode network (DMN) and motor network and its relationships with clinical characteristics in patients with stroke., Methods: Resting-state functional magnetic resonance imaging was performed in stroke patients with subcortical ischemic lesions and healthy controls. The voxel-mirrored homotopic connectivity (VMHC) method was used to examine the differences in functional homotopy in patients with stroke between the two time points. Support vector machine (SVM) and correlation analyses were also applied to investigate whether the detected significant changes in VMHC were the specific feature in patients with stroke., Results: The patients with stroke had significantly lower VMHC in the DMN and motor-related regions than the controls, including in the precuneus, parahippocampus, precentral gyrus, supplementary motor area, and middle frontal gyrus. Longitudinal analysis revealed that the impaired VMHC of the superior precuneus showed a significant increase at the second time point, which was no longer significantly different from the controls. Between the two time points, the changes in VMHC in the superior precuneus were significantly correlated with the changes in clinical scores. SVM analysis revealed that the VMHC of the superior precuneus could be used to correctly identify the patients with stroke from the controls with a statistically significant accuracy of 81.25% ( P ≤ 0.003)., Conclusions: Our findings indicated that the increased VMHC in the superior precuneus could be regarded as the neuroimaging manifestation of functional recovery. The significant correlation and the discriminative power in classification results might provide novel evidence to understand the neural mechanisms responsible for brain reorganization after stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Yu, Zhou, Wu and Chen.)

Stroke can be viewed as an acute disruption of an individual's connectome caused by a focal or widespread loss of blood flow. Although individuals exhibit connectivity changes in multiple functional networks after stroke, the neural mechanisms that underlie the longitudinal reorganization of the connectivity patterns are still unclear. The study aimed to determine whether brain network connectivity patterns after stroke can predict longitudinal behavioral outcomes. Nineteen patients with stroke with subcortical lesions underwent two sessions of resting-state functional magnetic resonance imaging scanning at a 1-month interval. By independent component analysis, the functional connectivity within and between multiple brain networks (including the default mode network, the dorsal attention network, the limbic network, the visual network, and the frontoparietal network) was disrupted after stroke and partial recovery at the second time point. Additionally, regression analyses revealed that the connectivity between the limbic and dorsal attention networks at the first time point showed sufficient reliability in predicting the clinical scores (Fugl-Meyer Assessment and Neurological Deficit Scores) at the second time point. The overall findings suggest that functional coupling between the dorsal attention and limbic networks after stroke can be regarded as a biomarker to predict longitudinal clinical outcomes in motor function and the degree of neurological functional deficit. Overall, the present study provided a novel opportunity to improve prognostic ability after subcortical strokes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Yu, Wu and Chen.)

Background. Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies. Objective. We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons. Methods. In 20 participants at >6 months postonset of a subcortical ischemic stroke and 16 age- and sex-matched healthy controls, the concentrations of N-acetylaspartate and myo-inositol were quantified by proton magnetic resonance spectroscopy. Regions of interest identified by functional magnetic resonance imaging included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored. Results. N-Acetylaspartate was lower in M1 (P = .04) and SMA (P = .004) and myo-inositol was higher in M1 (P = .003) and PMd (P = .03) in the injured (ipsilesional) hemisphere after stroke compared with the left hemisphere in controls. N-Acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores (P = .04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores (P = .02, .01, .02, and .02, respectively). Conclusions. Our preliminary results demonstrated that proton magnetic resonance spectroscopy is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke and consequently increase our knowledge of the factors leading from these changes to arm motor impairment. [ABSTRACT FROM AUTHOR]

Objective: Subcortical stroke can cause a variety of language deficits. However, the neural mechanisms underlying subcortical aphasia after stroke remain incompletely elucidated. We aimed to determine the effects of distant cortical structures on aphasia outcomes and examine the correlation of cortical thickness measures with connecting tracts integrity after chronic left subcortical stroke., Methods: Thirty-two patients and 30 healthy control subjects underwent MRI scanning and language assessment with the Western Aphasia Battery-Revised (WAB-R) subtests. Among patients, the cortical thickness in brain regions that related to language performance were assessed by the FreeSurfer software. Fiber tracts connecting the identified cortical regions to stroke lesions were reconstructed to determine its correlations with the cortical thickness measures across individual patient., Results: Cortical thickness in different parts of the left fronto-temporo-parietal (FTP) regions were positively related to auditory-verbal comprehension, spontaneous speech and naming/word finding abilities when controlling for key demographic variables and lesion size. Cortical thickness decline in the identified cortical regions was positively correlated with integrity loss of fiber tracts connected to stroke lesions. Additionally, no significant difference in cortical thickness was found across the left hemisphere between the subgroup of patients with hypoperfusion (HP) and those without HP at stroke onset., Conclusions: These findings suggest that remote cortical atrophy independently predicts language outcomes in patients with chronic left subcortical stroke and aphasia and that cortical thinning in these regions might relate to integrity loss of fiber tracts connected to stroke lesions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tang, Fan, Niu, Li, Xiao, Zeng and Xing.)

Abstract: Whether functional changes of the non-primary motor areas, e.g., dorsal premotor (PMd) and supplementary motor (SMA) areas, after stroke, reflect reorganization phenomena or recruitment of a pre-existing motor network remains to be clarified. We hypothesized that cellular changes in these areas would be consistent with their involvement in post-stroke reorganization. Specifically, we expected that neuronal and glial compartments would be altered in radiologically normal-appearing, i.e., spared, PMd and SMA in patients with arm paresis. Twenty survivors of a single ischemic subcortical stroke and 16 age-matched healthy controls were included. At more than six months after stroke, metabolites related to neuronal and glial compartments: N-acetylaspartate, myo-inositol, and glutamate/glutamine, were quantified by proton magnetic resonance spectroscopy in PMd and SMA in both injured (ipsilesional) and un-injured (contralesional) hemispheres. Correlations between metabolites were also calculated. Finally, relationships between metabolite concentrations and arm motor impairment (total and proximal Fugl-Meyer Upper Extremity, FMUE, scores) were analyzed. Compared to controls, stroke survivors showed significantly higher ipsilesional PMd myo-inositol and lower SMA N-acetylaspartate. Significantly lower metabolite correlations were found between ipsilesional and contralesional SMA. Ipsilesional N-acetylaspartate was significantly related to proximal FMUE scores. This study provides evidence of abnormalities in metabolites, specific to neuronal and glial compartments, across spared non-primary motor areas. Ipsilesional alterations were related to proximal arm motor impairment. Our results suggest the involvement of these areas in post-stroke reorganization. [Copyright &y& Elsevier]