Longitudinal microstructural alterations surrounding subcortical ischemic stroke lesions detected by free-water imaging.

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.

Brain and immune system-derived extracellular vesicles mediate regulation of complement system, extracellular matrix remodeling, brain repair and antigen tolerance in Multiple sclerosis.

BACKGROUND: 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. PURPOSE: 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. RESULTS: 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 ß 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. CONCLUSION: Neural-derived and immune-derived EVs found in blood appear to be good specific biomarkers in MS for reflecting the disease state.

The disrupted topological properties of structural networks showed recovery in ischemic stroke patients: a longitudinal design study.

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.

Ipsilateral primary motor cortex and behavioral compensation after stroke: a case series study.

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.

The importance of premotor cortex for supporting speech production after left capsular-putaminal damage.

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.

Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.

BACKGROUND AND PURPOSE: Translational research is beginning to reveal the importance of trophic factors as a therapy for cellular brain repair. The purpose of this study was to analyze whether brain-derived neurotrophic factor (BDNF) administration could mediate oligodendrogenesis and remyelination after white matter injury in subcortical stroke. METHODS: Ischemia was induced in rats by injection of endothelin-1. At 24 hours, 0.4 µg/kg of BDNF or saline was intravenously administered to the treatment and control groups, respectively. Functional evaluation, MRI, and fiber tract integrity on tractography images were analyzed. Proliferation (KI-67) and white matter repair markers (A2B5, 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase], adenomatous polyposis coli [APC], platelet-derived growth factor receptor alpha [PDGFR-α], oligodendrocyte marker O4 [O4], oligodendrocyte transcription factor [Olig-2], and myelin basic protein [MBP]) were analyzed at 7 and 28 days. RESULTS: The BDNF-treated animals showed less functional deficit at 28 days after treatment than the controls (P<0.05). Although T2-MRI did not show differences in lesion size at 7 and 28 days between groups, diffusion tensor imaging tractography analysis revealed significantly better tract connectivity at 28 days in the BDNF group than in the controls (P<0.05). Increased proliferation of oligodendrocyte progenitors was observed in treated animals at 7 days (P<0.05). Finally, the levels of white matter repair markers (A2B5, CNPase, and O4 at 7 days; Olig-2 and MBP at 28 days) were higher in the BDNF group than in the controls (P<0.05). CONCLUSIONS: BDNF administration exerted better functional outcome, oligodendrogenesis, remyelination, and fiber connectivity than controls in rats subjected to subcortical damage in ischemic stroke.

Predictors of progression in patients presenting with minor subcortical stroke.

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.

Brain structural-functional coupling mechanism in mild subcortical stroke and its relationship with cognition.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The relationship between altered degree centrality and cognitive function in mild subcortical stroke: A resting-state fMRI study.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Corrigendum: Low-frequency repetitive transcranial magnetic stimulation restores dynamic functional connectivity in subcortical stroke.

[This corrects the article DOI: 10.3389/fneur.2021.771034.].

Remote cortical atrophy and language outcomes after chronic left subcortical stroke with aphasia.

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.

Repetitive Transcranial Magnetic Stimulation Induces Quantified Functional and Structural Changes in Subcortical Stroke: A Combined Arterial Spin Labeling Perfusion and Diffusion Tensor Imaging Study.

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.

Aberrant interhemispheric functional reciprocities of the default mode network and motor network in subcortical ischemic stroke patients with motor impairment: A longitudinal study.

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.

Ability of an altered functional coupling between resting-state networks to predict behavioral outcomes in subcortical ischemic stroke: A longitudinal study.

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.

Uncinate fasciculus and its cortical terminals in aphasia after subcortical stroke: A multi-modal MRI study.

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.

N-Acetylaspartate Biomarker of Stroke Recovery: A Case Series Study.

BACKGROUND AND PURPOSE: Strong experimental neurobehavioral evidence suggests that intensive training improves arm motor disability after stroke. Yet, we still have only limited understanding why some patients recover more completely and others do not. This is in part due to our limited knowledge of the neurobiological principles of recovery from stroke. Mounting evidence suggests that functional and structural remapping of the primary motor cortex (M1) plays a major role in arm recovery after stroke. We used MR Spectroscopy to test the hypothesis that therapy-related arm improvement is associated with changes in levels of a putative marker of neuronal integrity (N-acetylaspartate, NAA) in M1 controlling the paretic arm (ipsilesional M1) in chronic stroke patients (n=5). METHODS: Patients (1 female, age, mean ± SD, 58.4 ± 5.8 years) underwent 4-week arm-focused motor training (1080 repetitions of a reach-to-grasp task) at 13.6 ± 5.3 months after stroke onset. NAA levels in the ipsilesional M1 and arm impairment (Fugl-Meyer, FM, 66=normal; proximal FM, FMp, 30=normal) were assessed prior to and immediately after training. RESULTS: At baseline, patients exhibited moderate-to-mild arm impairment (FM, 47.2 ± 18.8, FMp, 22.2 ± 8.6) and showed lower levels of NAA compared with age/sex-matched healthy controls (10.2 ± 0.9 mM in patients vs. 11.6 ± 1.6 mM in controls, p=0.03). After training, arm impairment improved (FM by 7%, 50.6 ± 17.5, p=0.01; FMp, by 5%, 23.4 ± 8.2, p=0.2) and NAA levels increased by 10.5% (11.2 ± 1.2 mM, p=0.1). Changes in NAA positively correlated with changes in FM (r=0.63, p=0.2) and FMp (r=0.93, p=0.03), suggesting that patients who show greater neuronal changes have a better chance of recovery. CONCLUSIONS: Our data suggest the potential use of M1 NAA as a biomarker of motor recovery after stroke. However, because of our small sample, these preliminary results should be interpreted cautiously. Further work with larger sample sizes is warranted.

Low-Frequency Repetitive Transcranial Magnetic Stimulation Restores Dynamic Functional Connectivity in Subcortical 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.

Enhanced positive functional connectivity strength in left-sided chronic subcortical stroke.

Patients with stroke often exhibit evidence of abnormal functional connectivity (FC). However, whether and how anatomical distance affects FC at rest remains unclear in patients with chronic subcortical stroke. Eighty-six patients with chronic (more than six months post-onset) subcortical stroke (44 left-sided patients and 42 right-sided patients) with different degrees of functional recovery, and 75 matched healthy controls underwent resting-state functional magnetic resonance imaging scanning. Positive functional connectivity strength (FCS) was computed for each voxel in the brain using a data-driven whole-brain resting state FCS method, which was further divided into short- and long-range FCS. Compared with healthy controls, patients with left-sided infarctions exhibited stronger global- and long-range FCS in the left sensorimotor cortex (SMC), and no significant intergroup difference was found for short-range FCS. No significant differences were found between the patients with right-sided infarctions and healthy controls for global, long- and short-range FCS. These findings suggested that the positive FCS alteration was connection-distance dependent within patients with left-sided chronic subcortical stroke. Also, a positive correlation was found between the FCS in the left SMC and the accuracy of the Flanker test, reflecting a compensatory FCS alteration for altered attention and executive function abilities exhibited by those with left-sided stroke.

Low dose of extracellular vesicles identified that promote recovery after ischemic stroke.

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.

Cerebral blood flow features in chronic subcortical stroke: Lesion location-dependent study.

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.