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Background: Analyzing distance-dependent functional connectivity density (FCD) yields valuable insights into patterns of brain activity. Nevertheless, whether alterations of FCD in non-acute stroke patients are associated with the anatomical distance between brain regions remains unclear. This study aimed to explore the distance-related functional reorganization in non-acute stroke patients following left and right hemisphere subcortical lesions, and its relationship with clinical assessments., Methods: In this study, we used resting-state fMRI to calculate distance-dependent (i.e., short- and long-range) FCD in 25 left subcortical stroke (LSS) patients, 22 right subcortical stroke (RSS) patients, and 39 well-matched healthy controls (HCs). Then, we compared FCD differences among the three groups and assessed the correlation between FCD alterations and paralyzed motor function using linear regression analysis., Results: Our findings demonstrated that the left inferior frontal gyrus displayed distance-independent FCD changes, while the bilateral supplementary motor area, cerebellum, and left middle occipital gyrus exhibited distance-dependent FCD alterations in two patient subgroups compared with HCs. Furthermore, we observed a positive correlation between increased FCD in the bilateral supplementary motor area and the motor function of lower limbs, and a negative correlation between increased FCD in the left inferior frontal gyrus and the motor function of both upper and lower limbs across all stroke patients. These associations were validated by using a longitudinal dataset., Conclusions: The FCD in the cerebral and cerebellar cortices shows distance-related changes in non-acute stroke patients with motor dysfunction, which may serve as potential biomarkers for predicting motor outcomes after stroke. These findings enhance our comprehension of the neurobiological mechanisms driving non-acute stroke., Trial Registration: All data used in the present study were obtained from a research trial registered with the ClinicalTrials.gov database (NCT05648552, registered 05 December 2022, starting from 01 January 2022)., (© 2024. The Author(s).)

Background: It is unclear which cortical regions are specific to or commonly associated with the impairments of the upper/lower limbs and the activities of daily life (ADL) in stroke patients., Purpose: To investigate the relationships between MRI-assessed surface-based morphometry (SBM) features and motor function as well as ADL in participants with chronic stroke., Study Type: Prospective., Subjects: Thirty-five participants with subcortical stroke more than 3 months from the first-onset (age: 56.44 ± 9.56 years; 32 male)., Field Strength/sequence: T 1 -weighted images, 3.0 T, three-dimensional fast field-echo sequence., Assessment: FreeSurfer (6.0) was used to parcellate each hemisphere into 34 regions based on the Desikan-Killiany atlas and to extract the surface area, volume, thickness, and curvature. The motor function and ADL were assessed by the Fugl-Meyer Assessment for the Upper/Lower Extremity (FMA-UE/FMA-LE) and the Chinese version of the Modified Barthel Index (MBI-C), respectively., Statistical Tests: A linear mixed-effect model was applied to evaluate the relationship between the morphological features and the FMA-UE, FMA-LE, and MBI-C. A false discovery rate corrected P value < 0.05 was considered statistically significant., Results: Correlations between the size of stroke lesion and MRI measurements did not pass the FDR correction (adjusted P > 0.05). SBM features in motor-related and high-order cognitive cortical regions showed significant correlations with FMA-UE and FMA-LE, respectively. Moreover, the thickness in the prefrontal cortex significantly positively correlated, while the surface area in the right supramarginal gyrus significantly negatively correlated, with both FMA-UE, FMA-LE, and MBI-C. The thickness in the left frontal lobe significantly positively correlated with both FMA-UE and MBI-C., Data Conclusion: This study's findings suggest that different hemiparetic motor-related outcomes in participants with subcortical stroke which suffered a corticospinal tract-related injury show specific, but also share common, associations with several cortical regions., Evidence Level: 2 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Aim: To investigate the directional and selective disconnection of the sensorimotor cortex (SMC) subregions in chronic stroke patients with hand dysfunction., Methods: We mapped the resting-state fMRI effective connectivity (EC) patterns for seven SMC subregions in each hemisphere of 65 chronic stroke patients and 40 healthy participants and correlated these patterns with paretic hand performance., Results: Compared with controls, patients demonstrated disrupted EC in the ipsilesional primary motor cortex&#95;4p, ipsilesional primary somatosensory cortex&#95;2 (PSC&#95;2), and contralesional PSC&#95;3a. Moreover, we found that EC values of the contralesional PSC&#95;1 to contralesional precuneus, the ipsilesional inferior temporal gyrus to ipsilesional PSC&#95;1, and the ipsilesional PSC&#95;1 to contralesional postcentral gyrus were correlated with paretic hand performance across all patients. We further divided patients into partially (PPH) and completely (CPH) paretic hand subgroups. Compared with CPH patients, PPH patients demonstrated decreased EC in the ipsilesional premotor&#95;6 and ipsilesional PSC&#95;1. Interestingly, we found that paretic hand performance was positively correlated with seven sensorimotor circuits in PPH patients, while it was negatively correlated with five sensorimotor circuits in CPH patients., Conclusion: SMC neurocircuitry was selectively disrupted after chronic stroke and associated with diverse hand outcomes, which deepens the understanding of SMC reorganization., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Although many neuroimaging studies have reported structural and functional abnormalities in the brains of patients with cognitive impairments following stroke, little is known about the pattern of such brain reorganization in poststroke dementia (PSD). The present study was aimed at investigating alterations in spontaneous brain activity and gray matter volume (GMV) in PSD patients. We collected T1-weighted and resting-state functional magnetic resonance imaging data from 20 PSD patients, 24 poststroke nondementia (PSND) patients, and 21 well-matched normal controls (NCs). We compared the differences among the groups in GMV and the fractional amplitude of low-frequency fluctuations (fALFF). Then, we evaluated the relationship between these brain measures and cognitive assessments and explored the possible distinguisher for PSD by receiver operating characteristic (ROC) curve analysis. PSD patients showed smaller GMV in the right superior temporal gyrus and lower fALFF values in the right inferior frontal gyrus than both PSND patients and NCs, but such differences were not observed between PSND patients and NCs. Moreover, GMV in the left medial prefrontal cortex showed a significant positive correlation with the Mini-Cog assessment in PSD patients, and GMV in the left CPL displayed the highest area under the ROC curve among all the features for classifying PSD versus PSND patients. Our findings suggest that PSD patients show dementia-specific structural and functional alteration patterns, which may help elucidate the pathophysiological mechanisms underlying PSD., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2021 Huaying Cai et al.)

Given the rising incidence of stroke, several technology-driven methods for rehabilitation have recently been developed. Virtual reality (VR) is a promising therapeutic technology among them. We recently developed a neuroscientifically grounded VR system to aid recovery of motor function poststroke. The developed system provides unilateral and bilateral upper extremity (UE) training in a fully immersive virtual environment that may stimulate and activate mirror neurons (MNs) in the brain necessary for UE rehabilitation. Twenty-three participants were randomized to a VR group (n = 12) to receive VR intervention (8 h within 2 weeks) plus 8-h occupational therapy (OT) or a control group (n = 11) to receive time-matched OT alone. Treatment effects on motor recovery and cortical reorganization were investigated using the Barthel Index (BI), Fugl-Meyer Upper Extremity (FM-UE), and resting-state fMRI. Both groups significantly improved BI (P < 0.05), reflecting the recovery of UE motor function. The VR group revealed significant improvements on FM-UE scores (P < 0.05) than the control group. Neural activity increased after the intervention, particularly in the brain areas implicating MNs, such as in the primary motor cortex. Overall, results suggested that using a neuroscientifically grounded VR system might offer additional benefits for UE rehabilitation in patients receiving OT., (© 2021 New York Academy of Sciences.)

Virtual reality (VR) is considered to be a promising therapeutic technology for the rehabilitation of upper extremities (UEs) post-stroke. Recently, we designed and then implemented a neuroscientifically grounded VR protocol for the rehabilitation of patients with stroke. The system provides unilateral and bilateral limb mirroring exercises in a fully immersive virtual environment that may stimulate and activate the mirror neuron system in the brain to help patients for their rehabilitation. Twelve patients with subacute stroke underwent the newly implemented VR treatment in addition to conventional rehabilitation for 8 consecutive weekdays. The treatment effect on brain reorganization and motor function was investigated using resting-state fMRI (rs-fMRI) and the Fugl-Meyer assessment for Upper Extremity (FM-UE), respectively. Fifteen healthy controls (HCs) also underwent rs-fMRI scanning one time. The study finally obtained usable data from 8 patients and 13 HCs. After the intervention, patients demonstrated significant improvement in their FM-UE scores (p values < 0.042). Voxel-wise functional connectivity (FC) analysis based on the rs-fMRI data found that HCs showed widespread bilateral FC patterns associated with the dominant hemispheric primary motor cortex (M1). However, the FC patterns in patients revealed intra-hemispheric association with the ipsilesional M1 seed and this association became visible in the contra-hemisphere after the intervention. Moreover, the change of FC values between the bilateral M1 was significantly correlated with the changes in FM-UE scores (p values < 0.037). We conclude that unilateral and bilateral limb mirroring exercise in an immersive virtual environment may enhance cortical reorganization and lead to improved motor function.

Stroke survivors are known to suffer from post-stroke depression (PSD). However, the likelihood of structural changes in the brains of PSD patients has not been explored. This study aims to extract changes in the gray matter of these patients and test how these changes account for the PSD symptoms. High-resolution T1 weighted images were collected from 23 PSD patients diagnosed with subcortical stroke. Voxel-based morphometry and support vector machine analyses were used to analyze the data. The results were compared with those collected from 33 non-PSD patients. PSD group showed decreased gray matter volume (GMV) in the left middle frontal gyrus (MFG) when compared to the non-PSD patients. Together with the clinical and demographic variables, the MFG's GMV predictive model was able to distinguish PSD from the non-PSD patients (0•70 sensitivity and 0•88 specificity). The changes in the left inferior frontal gyrus (61%) and dorsolateral prefrontal cortex (39%) suggest that the somatic/affective symptoms in PSD is likely to be due to patients' problems with understanding and appraising negative emotional stimuli. The impact brought by the reduced prefrontal to limbic system connectivity needs further exploration. These findings indicate possible systemic involvement of the frontolimbic network resulting in PSD after brain lesions which is likely to be independent from the location of the lesion. The results inform specific clinical interventions to be provided for treating depressive symptoms in post-stroke patients., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stroke has a large physical, psychological, and financial burden on patients, their families, and society. Based on functional networks (FNs) constructed from resting state fMRI data, network connectivity after stroke is commonly conjectured to be more randomly reconfigured. We find that this hypothesis depends on the severity of stroke. Head movement-corrected, resting-state fMRI data were acquired from 32 patients after stroke, and 37 healthy volunteers. We constructed anomaly FNs, which combine time series information of a patient with the healthy control group. We propose data-driven techniques to automatically identify regions of interest that are stroke relevant. Graph analysis based on anomaly FNs suggests consistently that strong connections in healthy controls are broken down specifically and characteristically for brain areas that are related to sensorimotor functions and frontoparietal control systems, but new links in stroke patients are rebuilt randomly from all possible areas. Entropic measures of complexity are proposed for characterizing the functional connectivity reorganization patterns, which are correlated with hand and wrist function assessments of stroke patients and show high potential for clinical use.

Motor functions are supported through functional integration across the extended motor system network. Individuals following stroke often show deficits on motor performance requiring coordination of multiple brain networks; however, the assessment of connectivity patterns after stroke was still unclear. This study aimed to investigate the changes in intra- and inter-network functional connectivity (FC) of multiple networks following stroke and further correlate FC with motor performance. Thirty-three left subcortical chronic stroke patients and 34 healthy controls underwent resting-state functional magnetic resonance imaging. Eleven resting-state networks were identified via independent component analysis (ICA). Compared with healthy controls, the stroke group showed abnormal FC within the motor network (MN), visual network (VN), dorsal attention network (DAN), and executive control network (ECN). Additionally, the FC values of the ipsilesional inferior parietal lobule (IPL) within the ECN were negatively correlated with the Fugl-Meyer Assessment (FMA) scores (hand + wrist). With respect to inter-network interactions, the ipsilesional frontoparietal network (FPN) decreased FC with the MN and DAN; the contralesional FPN decreased FC with the ECN, but it increased FC with the default mode network (DMN); and the posterior DMN decreased FC with the VN. In sum, this study demonstrated the coexistence of intra- and inter-network alterations associated with motor-visual attention and high-order cognitive control function in chronic stroke, which might provide insights into brain network plasticity following stroke., (© 2018 Wiley Periodicals, Inc.)

The primary motor cortex (M1) is often abnormally recruited in stroke patients with motor disabilities. However, little is known about the alterations in the causal connectivity of M1 following stroke. The purpose of the present study was to investigate whether the effective connectivity of the ipsilesional M1 is disturbed in stroke patients who show different outcomes in hand motor function. 23 patients with left-hemisphere subcortical stroke were selected and divided into two subgroups: partially paralyzed hands (PPH) and completely paralyzed hands (CPH). Further, 24 matched healthy controls (HCs) were recruited. A voxel-wise Granger causality analysis (GCA) on the resting-state fMRI data between the ipsilesional M1 and the whole brain was performed to explore differences between the three groups. Our results showed that the influence from the frontoparietal cortices to ipsilesional M1 was diminished in both stroke subgroups and the influence from ipsilesional M1 to the sensorimotor cortices decreased greater in the CPH group than in the PPH group. Moreover, compared with the PPH group, the decreased influence from ipsilesional M1 to the contralesional cerebellum and from the contralesional superior parietal lobe to ipsilesional M1 were observed in the CPH group, and their GCA values were positively correlated with the FMA scores; Conversely, the increased influence from ipsilesional M1 to the ipsilesional middle frontal gyrus and middle temporal gyrus were observed, whose GCA values were negatively correlated with the FMA scores. This study suggests that the abnormalities of casual flow in the ipsilesional M1 are related to the severity of stroke-hand dysfunction, providing valuable information to understand the deficits in resting-state effective connectivity of motor execution and the frontoparietal motor control network during brain plasticity following stroke., Competing Interests: The authors have declared that no competing interests exist.

The recovery of motor functions is accompanied by brain reorganization, and identifying the inter-hemispheric interaction post stroke will conduce to more targeted treatments. However, the alterations of bi-hemispheric coordination pattern between homologous areas in the whole brain for chronic stroke patients were still unclear. The present study focuses on the functional connectivity (FC) of mirror regions of the whole brain to investigate the inter-hemispheric interaction using a new fMRI method named voxel-mirrored homotopic connectivity (VMHC). Thirty left subcortical chronic stroke patients with pure motor deficits and 37 well-matched healthy controls (HCs) underwent resting-state fMRI scans. We employed a VMHC analysis to determine the brain areas showed significant differences between groups in FC between homologous regions, and we explored the relationships between the mean VMHC of each survived area and clinical tests within patient group using Pearson correlation. In addition, the brain areas showed significant correlations between the mean VMHC and clinical tests were defined as the seed regions for whole brain FC analysis. Relative to HCs, patients group displayed lower VMHC in the precentral gyrus, postcentral gyrus, inferior frontal gyrus, middle temporal gyrus, calcarine gyrus, thalamus, cerebellum anterior lobe, and cerebellum posterior lobe (CPL). Moreover, the VMHC of CPL was positively correlated with the Fugl-Meyer Score of hand (FMA-H), while a negative correlation between illness duration and the VMHC of this region was also detected. Furthermore, we found that when compared with HCs, the right CPL exhibited reduced FC with the left precentral gyrus, inferior frontal gyrus, inferior parietal lobule, middle temporal gyrus, thalamus and hippocampus. Our results suggest that the functional coordination across hemispheres is impaired in chronic stroke patients, and increased VMHC of the CPL is significantly associated with higher FMA-H scores. These findings may be helpful in understanding the mechanism of hand deficit after stroke, and the CPL may serve as a target region for hand rehabilitation following stroke.

Introduction: It has been demonstrated that rehabilitative interventions can promote motor function recovery in stroke patients. However, little is known regarding the neural mechanisms that underlie the rehabilitation treatments. The aim of this study was to investigate the plasticity of intrinsic functional connectivity patterns that are associated with rehabilitation intervention in chronic stroke patients., Methods: Twelve chronic stroke patients with subcortical lesions in the left motor pathway participated in a 4-week rehabilitation intervention and underwent resting-state functional magnetic resonance imaging (fMRI) scanning before and after the intervention. Both functional connectivity analyses of the ipsilesional (left) primary motor cortex (M1) and measurements of the lateralization index of the connectivity patterns were performed in both the stroke patients and healthy controls (HC)., Results: Compared with the HC, the decreased connectivity of the ipsilesional M1 with the contralesional sensorimotor cortex (SMC), bilateral supplementary motor areas, and inferior parietal lobule due to stroke were remarkably restored after the intervention. More specifically, the lateralization index of the bilateral SMC tends to be the normal level. Moreover, comparing post- with pre-intervention, we observed significantly increased connectivity of ipsilesional M1 with the contralesional M1 and medial superior frontal gyrus (mSFG). Additionally, the index of pre-intervention connectivity with the contralesional mSFG was positively correlated with motor improvement., Conclusion: The impact of rehabilitation intervention on intrinsic functional connectivity patterns throughout the brain was measurable on resting-state fMRI, and systematic assessment of resting-state functional connectivity can provide prognostic insight for later motor improvement.

Background: The hippocampus (HP) plays a critical role in memory and orientational functions and is functionally heterogeneous along the longitudinal anterior–posterior axis. Although the previous study has reported volumetric atrophy in hippocampal subfields of patients with poststroke dementia (PSD), how the functional connectivity (FC) is altered in these subfields remains unclear. Purpose: To examine the FC changes of the HP subfields in patients with PSD. Study Type: Prospective. Population: Seventeen normal controls, 20 PSD, and 24 nondemented poststroke (PSND) patients. Field Strength/Sequence: A 3.0 T/ T1‐weighted imaging, resting‐state functional and diffusion tensor imaging. Assessment: We first segmented the HP using independent component analysis, and then used granger causality analysis to calculate the directed FCs (dFCs) between the subfields and the whole brain, and compared the dFCs among PSD, PSND, and controls. Statistical Tests: Student's t‐test, chi‐square test, one‐way ANCOVA, multiple regression, support vector machine, multiple comparison correction, and reproducibility analysis. A P value < 0.05 was considered statistically significant. Results: Our results showed HP was functionally divided into HPhead, HPbody, and HPtail bilaterally along the longitudinal axis. PSD patients showed significant dementia‐specific decreases in the inward information flow and increases in the outward information flow associated with the bilateral entire HP/HPhead and left HPbody (P < 0.05). Moreover, we observed significant correlations (P < 0.05) between the cognition score and the dFCs related to the bilateral entire HP and left HPhead in the PSD group. Furthermore, dFCs of the HP and its subfields improved the classification between the PSD and PSND patients (accuracy/sensitivity/specificity: 94%/95%/93%) compared to the clinical and demographic parameters alone. Data Conclusion: These findings suggest that altered transmission and reception of information in the HP. These alternations were specific to individual subfields in PSD patients and may offer insight into the neurophysiological mechanisms underlying PSD. Evidence Level: 1 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that hippocampal atrophy is a hallmark of dementia and can be used to predict the outcome of post-stroke demented (PSD) patients. The hippocampus consists of several subfields but their involvement in the pathophysiology of the PSD remains unclear.Objective: The present study aimed to investigate volumetric alterations of hippocampal subfields in patients with PSD.Methods: High-resolution T1-weighted images were collected from 27 PSD and 28 post-stroke nondemented (PSND) patients who recovered from ischemic stroke, and 17 age-matched normal control (NC). We estimated the volumes of the hippocampal subfields using FreeSurfer 6.0 which segmented the hippocampus into 12 subfields in each hemisphere. The volumetric differences between the groups were evaluated by the two-sample tests after regressing out the age, sex, education, and total intracranial volume.Results: Compared with NC group, PSD group showed smaller volumes in the entire hippocampus and its subfields, and such differences were not found in PSND group. Moreover, we found the dementia-specific atrophy in the left granule cell layer of dentate gyrus (GC-DG) and CA4 in the PSD patients compared with NC and PSND. Regression analysis showed positive correlations between the changes of cognitive performance and the asymmetry index in the CA3/4 and GC-DG of the PSD group. Furthermore, we found that the volumes of hippocampal subfields provided a better classification performance than the entire hippocampus.Conclusion: Our findings suggest that the hippocampus is reduced in the PSD patients and it presents a selective subfield involvement. [ABSTRACT FROM AUTHOR]

Emerging evidence has suggested that abnormalities in regional spontaneous brain activity following stroke may be detected by intrinsic low‐frequency oscillations (LFO) in resting‐state functional MRI (R‐fMRI). However, the relationship between hand function outcomes following stroke and local LFO synchronization in different frequency bands is poorly understood. In this study, we performed R‐fMRI to examine the regional homogeneity (ReHo) at three different frequency bands (slow‐5:.01–.027 Hz; slow‐4:.027–.08 Hz; and typical band:.01–.1 Hz) in 26 stroke patients with completely paralyzed hands (CPH) and 26 matched patients with partially paralyzed hands (PPH). Compared to the PPH group, decreased ReHo in the bilateral cerebellum posterior lobes and the contralesional cerebellum anterior lobe was observed in the slow‐5 band and the slow‐4 band in the CPH group, respectively. The mean ReHo values in these regions were positively correlated with the Fugl‐Meyer assessment (FMA) scores. In contrast, increased ReHo in the contralesional supplementary motor area and the contralesional superior temporal gyrus was observed in the slow‐4 band and the slow‐5 band, respectively. The mean ReHo values in these regions were negatively correlated with the FMA scores. Importantly, significant interactions were identified between the frequency bands and the subgroups of patients in the contralesional precentral gyrus and middle frontal gyrus. These findings indicate that frequency‐dependent R‐fMRI patterns may serve as potential biomarkers of the neural substrates associated with hand function outcomes following stroke. [ABSTRACT FROM AUTHOR]