Effect of transcranial direct current stimulation combined with transcutaneous auricular vagus nerve stimulation on poststroke cognitive impairment: a study protocol for a randomised controlled trial.

INTRODUCTION: Poststroke cognitive impairment is a common complication in stroke survivors, seriously affecting their quality of life. Therefore, it is crucial to improve cognitive function of patients who had a stroke. Transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) are non-invasive, safe treatments with great potential to improve cognitive function in poststroke patients. However, further improvements are needed in the effectiveness of a single non-invasive brain stimulation technique for cognitive rehabilitation. This study protocol aims to investigate the effect and neural mechanism of the combination of tDCS and taVNS on cognitive function in patients who had a stroke. METHODS AND ANALYSIS: In this single-centre, prospective, parallel, randomised controlled trial, a total of 66 patients with poststroke cognitive impairment will be recruited and randomly assigned (1:1:1) to the tDCS group, the taVNS group and the combination of tDCS and taVNS group. Each group will receive 30 min of treatment daily, five times weekly for 3 weeks. Primary clinical outcome is the Montreal Cognitive Assessment. Secondary clinical outcomes include the Mini-Mental State Examination, Stroop Colour Word Test, Trail Marking Test, Symbol Digit Modalities Test and Modified Barthel Index. All clinical outcomes, functional MRI and diffusion tensor imaging will be measured at preintervention and postintervention. ETHICS AND DISSEMINATION: The trial has been approved by the Ethics Committee of the First Affiliated Hospital of Yangtze University (approval no: KY202390). The results will be submitted for publication in peer-reviewed journals or at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300076632.

Enriched Environment Inhibits Neurotoxic Reactive Astrocytes via JAK2-STAT3 to Promote Glutamatergic Synaptogenesis and Cognitive Improvement in Chronic Cerebral Hypoperfusion Rats.

Chronic cerebral hypoperfusion (CCH) is a primary contributor to cognitive decline in the elderly. Enriched environment (EE) is proved to improve cognitive function. However, mechanisms involved remain unclear. The purpose of the study was exploring the mechanisms of EE in alleviating cognitive deficit in rats with CCH. To create a rat model of CCH, 2-vessel occlusion (2-VO) surgery was performed. All rats lived in standard or enriched environments for 4 weeks. Cognitive function was assessed using the novel object recognition test and Morris water maze test. The protein levels of glutamatergic synapses, neurotoxic reactive astrocytes, reactive microglia, and JAK2-STAT3 signaling pathway were measured using Western blot. The mRNA levels of synaptic regulatory factors, C1q, TNF-α, and IL-1α were identified using quantitative PCR. Immunofluorescence was used to detect glutamatergic synapses, neurotoxic reactive astrocytes, and reactive microglia, as well as the expression of p-STAT3 in astrocytes in the hippocampus. The results demonstrated that the EE mitigated cognitive impairment in rats with CCH and enhanced glutamatergic synaptogenesis. EE also inhibited the activation of neurotoxic reactive astrocytes. Moreover, EE downregulated microglial activation, levels of C1q, TNF-α and IL-1α and phosphorylation of JAK2 and STAT3. Our results suggest that inhibition of neurotoxic reactive astrocytes may be one of the mechanisms by which EE promotes glutamatergic synaptogenesis and improves cognitive function in rats with CCH. The downregulation of reactive microglia and JAK2-STAT3 signaling pathway may be involved in this process.

Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats.

A typical enriched environment (EE), which combines physical activity and social interaction, has been proven to mitigate cognitive impairment caused by chronic cerebral hypoperfusion (CCH). However, it remains unclear how the different components of EE promote cognitive recovery after CCH. This study stripped out the different components of EE into physical environmental enrichment (PE) and social environmental enrichment (SE), and compared the neuroprotective effects of PE, SE and typical EE (PSE) in CCH. The results of novel object recognition and Morris water maze tests showed that PE, SE, and PSE improved cognitive function in CCH rats. Additionally, Nissl and TUNEL staining revealed that three EEs reduced neuronal loss in the hippocampus. PSE exhibited superior neuroprotective and functional improvement effects compared to PE and SE, while there was no significant difference between PE and SE. Furthermore, three EEs reduced lipid peroxidation in the hippocampus with decreasing the levels of MDA and increasing the activities of SOD and GSH. The expression of SLC7A11 and GPX4 was increased, while the level of p53 was reduced in three EEs. This suggested that three EEs inhibited ferroptosis by maintaining the redox homeostasis in the hippocampus. Three EEs reduced the levels of IL-ß, TNF-α, and IL-6, thereby inhibiting neuroinflammation. Additionally, Western blotting and immunofluorescence results indicated that three EEs also inhibited the TLR4/MyD88/p38MAPK signaling pathway. These findings collectively demonstrated that the three EEs alleviated hippocampal ferroptosis and neuroinflammation in CCH rats, thereby reducing neuronal loss, which might be associated with the inhibition of the TLR4/MyD88/p38MAPK signaling pathway. Moreover, the study results supported that it is only through the combination of physical exercise and social interaction that the optimal neuroprotective effects can be achieved. These findings provided valuable insights for the prevention and treatment of vascular cognitive impairment.

Enriched environment attenuates ferroptosis after cerebral ischemia/reperfusion injury by regulating iron metabolism.

Preventing neuronal death after ischemic stroke (IS) is crucial for neuroprotective treatment, yet current management options are limited. Enriched environment (EE) is an effective intervention strategy that promotes the recovery of neurological function after cerebral ischemia/reperfusion (I/R) injury. Ferroptosis has been identified as one of the mechanisms of neuronal death during IS, and inhibiting ferroptosis can reduce cerebral I/R injury. Our previous research has demonstrated that EE reduced ferroptosis by inhibiting lipid peroxidation, but the underlying mechanism still needs to be investigated. This study aims to explore the potential molecular mechanisms by which EE modulates iron metabolism to reduce ferroptosis. The experimental animals were randomly divided into four groups based on the housing environment and the procedure the animals received: the sham-operated + standard environment (SSE) group, the sham-operated + enriched environment (SEE) group, the ischemia/reperfusion + standard environment (ISE) group, and the ischemia/reperfusion + enriched environment (IEE) group. The results showed that EE reduced IL-6 expression during cerebral I/R injury, hence reducing JAK2-STAT3 pathway activation and hepcidin expression. Reduced hepcidin expression led to decreased DMT1 expression and increased FPN1 expression in neurons, resulting in lower neuronal iron levels and alleviated ferroptosis. In addition, EE also reduced the expression of TfR1 in neurons. Our research suggested that EE played a neuroprotective role by modulating iron metabolism and reducing neuronal ferroptosis after cerebral I/R injury, which might be achieved by inhibiting inflammatory response and down-regulating hepcidin expression.

Disturbed functional connectivity and topological properties of the frontal lobe in minimally conscious state based on resting-state fNIRS.

Background: Patients in minimally conscious state (MCS) exist measurable evidence of consciousness. The frontal lobe is a crucial part of the brain that encodes abstract information and is closely related to the conscious state. We hypothesized that the disturbance of the frontal functional network exists in MCS patients. Methods: We collected the resting-state functional near-infrared spectroscopy (fNIRS) data of fifteen MCS patients and sixteen age- and gender-matched healthy controls (HC). The Coma Recovery Scale-Revised (CRS-R) scale of MCS patients was also composed. The topology of the frontal functional network was analyzed in two groups. Results: Compared with HC, the MCS patients showed widely disrupted functional connectivity in the frontal lobe, especially in the frontopolar area and right dorsolateral prefrontal cortex. Moreover, the MCS patients displayed lower clustering coefficient, global efficiency, local efficiency, and higher characteristic path length. In addition, the nodal clustering coefficient and nodal local efficiency in the left frontopolar area and right dorsolateral prefrontal cortex were significantly reduced in MCS patients. Furthermore, the nodal clustering coefficient and nodal local efficiency in the right dorsolateral prefrontal cortex were positively correlated to auditory subscale scores. Conclusion: This study reveals that MCS patients' frontal functional network is synergistically dysfunctional. And the balance between information separation and integration in the frontal lobe is broken, especially the local information transmission in the prefrontal cortex. These findings help us to understand the pathological mechanism of MCS patients better.

Clinical phase I/II trial of SVF therapy for cartilage regeneration: A cellular therapy with novel 3D MRI imaging for evaluating chondral defect of knee osteoarthritis.

Background: The clinical applications of stromal vascular fraction (SVF) therapy for osteoarthritis (OA) have attracted academic and clinical attention. However, data of the effects of stromal vascular fraction therapy on regeneration of degenerated cartilage are limited in the literature. Meanwhile, there is a great need for a simple and non-invasive evaluation method to analyze the changes of joint cartilage qualitatively and quantitatively in clinical trials. This study entitled "stromal vascular fraction Therapy for Human Knee Osteoarthritis" was registered in ClinicalTrial.gov # NCT05019378. Materials and Methods: We designed and conducted a single center, open labeled clinical phase I/II study, and 6 osteoarthritis patients with both knee cartilage defect I-II were enrolled in this study. The two knees of each patient were randomly assigned to autologous stromal vascular fraction treatment group or non-treatment control group to evaluate the safety and therapeutic effect of stromal vascular fraction therapy for human knee osteoarthritis. We have also established a novel protocol to provide 3D MRI imaging for human knee cartilage enabling us to qualitatively and quantitatively evaluate cartilage degeneration and regeneration in this study. Results: The qualitative and quantitative evaluation of 3D Magnetic Resonance Imaging (MRI) imaging of knee cartilage demonstrated that the stromal vascular fraction therapy reduced the cartilage defects; and significant increase of cartilage value both in defect cartilage area and whole cartilage area of treated group and significant increase of thickness and area of both femoral and tibia cartilage in vertical sections of the stromal vascular fraction treated Group at 12 and 24 W post treatment in cartilage defect I-II osteoarthritis patients. Conclusion: This clinical phase I/II study indicated that stromal vascular fraction therapy is a safe clinical procedure and provided evidence that the stromal vascular fraction therapy significantly facilitated cartilage regeneration, opening the opportunity to a phase III trial investigating authentic efficacy of the procedure. This study is the first qualitative and quantitative evaluation of the efficacy of autologous stromal vascular fraction cellular therapy on cartilage regeneration. Through early and definite diagnosis of knee osteoarthritis patients, and providing safe and efficient therapy to facilitate cartilage regeneration, we will be able to control or reverse cartilage degeneration and completely change the epidemiology of osteoarthritis worldwide.

Enriched Environment Attenuates Ferroptosis after Cerebral Ischemia/Reperfusion Injury via the HIF-1α-ACSL4 Pathway.

Enriched environment (EE) has been proven to be an effective intervention strategy which can improve neurofunctional recovery following cerebral ischemia/reperfusion (I/R) injury. However, it still needs further investigation for the underlying mechanisms. Recently, it has been shown that ferroptosis played an essential role in the pathophysiological development of ischemic stroke (IS). This study is aimed at investigating whether EE plays a neuroprotective role by attenuating ferroptosis after cerebral I/R injury. We used middle cerebral artery occlusion/reperfusion (MCAO/R) to build a model of cerebral I/R injury. To evaluate the effect of EE on neurological recovery, we used the modified neurological severity score (mNSS) and the Morris water maze (MWM). We used the western blot to detect the protein levels of glutathione peroxidase 4 (GPX4), hypoxia-inducible factor-1α (HIF-1α), and acyl-CoA synthetase long-chain family member 4 (ACSL4). We used the quantitative real-time PCR (qRT-PCR) to measure the mRNA levels of ACSL4 and inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and interleukin 1 beta (IL-1ß). The occurrence of ferroptosis was detected by TdT-mediated dUTP nick-end labeling (TUNEL) assay, diaminobenzidine- (DAB-) enhanced Perls' staining, iron level assays, and malondialdehyde (MDA) level assays. The results verified that EE enhanced functional recovery and attenuated ferroptosis and neuroinflammation after cerebral I/R injury. EE increased the expression of HIF-1α while inhibited the expression of ACSL4. Our research indicated that EE improved functional recovery after cerebral I/R injury through attenuating ferroptosis, and this might be related to its regulation of the neuroinflammation and HIF-1α-ACSL4 pathway.

Short-term effects of Kinesio taping combined with cervical muscles multi-angle isometric training in patients with cervical spondylosis.

OBJECTIVE: The purpose of this study was to investigate the efficacy of Kinesio taping (KT) combined with multi-angle isometric resistance training for cervical spondylosis. METHODS: Sixty-one patients were divided into two groups by random number table method. Both groups were given multi-angle isometric training, the patients in the observation group were supplemented with Kinesio taping. Before and after treatment, the symptoms of cervical spine function were evaluated in two groups by visual analogue scale (VAS), cervical dysfunction index (NDI), cervical range of motion and muscle stiffness. RESULTS: After 3 weeks of treatment, VAS, NDI scores and the cervical range of motion were significantly better than before (P < 0.05). The range of anterior flexion and extension was significantly larger than the control group (P < 0.05), but the range of other motions were not certain. The muscle stiffness in KT group were significantly lower than the control group. CONCLUSION: Kinesio taping combined with multi-angle isometric resistance training can further alleviate the clinical symptoms and correct the neck abnormal posture. But its effects on the range of cervical motion remain uncertain.

The resting-state topological organization damage of language-related brain regions in post-stroke cognitive impairment.

The topology of brain networks is the foundation of cognition. We hypothesized that stroke damaged topological organization resulting in cognitive impairment. The aim was to explore the damage pattern of the resting-state topology in post-stroke cognitive impairment (PSCI) patients. Thirty-seven patients with PSCI and thirty-seven gender- and age-matched healthy controls (HC) were recruited. The structural and functional data were collected from all subjects. The degree centrality (DC), betweenness centrality (BC), and global properties of brain networks were analyzed between groups. Spearman correlation analysis was performed between topological properties that changed significantly and clinical cognitive function scale scores. Compared with HC, the PSCI patients had significantly reduced DC in language-related brain regions and significantly higher DC in the right frontal lobe, hippocampus, and paracentral lobule. The decreased BC was located in the left caudate, thalamus, temporal, and frontal lobes. The increased BC was detected in the left cuneus and right precuneus. In addition, PSCI exhibited increased characteristic path length and decreased small-worldness. PSCI patients had impaired functional topology of the language-related brain regions, mainly in the left hemisphere. The enhanced processing and relaying information of some right high-order cognitive brain regions may be a compensatory mechanism. However, the whole brain's function integration was reduced, and there was an imbalance between efficiency and consumption.

Suboptimal states and frontoparietal network-centered incomplete compensation revealed by dynamic functional network connectivity in patients with post-stroke cognitive impairment.

Background: Neural reorganization occurs after a stroke, and dynamic functional network connectivity (dFNC) pattern is associated with cognition. We hypothesized that dFNC alterations resulted from neural reorganization in post-stroke cognitive impairment (PSCI) patients, and specific dFNC patterns characterized different pathological types of PSCI. Methods: Resting-state fMRI data were collected from 16 PSCI patients with hemorrhagic stroke (hPSCI group), 21 PSCI patients with ischemic stroke (iPSCI group), and 21 healthy controls (HC). We performed the dFNC analysis for the dynamic connectivity states, together with their topological and temporal features. Results: We identified 10 resting-state networks (RSNs), and the dFNCs could be clustered into four reoccurring states (modular, regional, sparse, and strong). Compared with HC, the hPSCI and iPSCI patients showed lower standard deviation (SD) and coefficient of variation (CV) in the regional and modular states, respectively (p < 0.05). Reduced connectivities within the primary network (visual, auditory, and sensorimotor networks) and between the primary and high-order cognitive control domains were observed (p < 0.01). Conclusion: The transition trend to suboptimal states may play a compensatory role in patients with PSCI through redundancy networks. The reduced exploratory capacity (SD and CV) in different suboptimal states characterized cognitive impairment and pathological types of PSCI. The functional disconnection between the primary and high-order cognitive control network and the frontoparietal network centered (FPN-centered) incomplete compensation may be the pathological mechanism of PSCI. These results emphasize the flexibility of neural reorganization during self-repair.

Physical Exercise-Induced Astrocytic Neuroprotection and Cognitive Improvement Through Primary Cilia and Mitogen-Activated Protein Kinases Pathway in Rats With Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is closely related to vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). The neuroinflammation involving astrocytes is an important pathogenic mechanism. Along with the advancement of the concept and technology of astrocytic biology, the astrocytes have been increasingly regarded as the key contributors to neurological diseases. It is well known that physical exercise can improve cognitive function. As a safe and effective non-drug treatment, physical exercise has attracted continuous interests in neurological research. In this study, we explored the effects of physical exercise on the response of reactive astrocytes, and its role and mechanism in CCH-induced cognitive impairment. A rat CCH model was established by 2 vessel occlusion (2VO) and the wheel running exercise was used as the intervention. The cognitive function of rats was evaluated by morris water maze and novel object recognition test. The phenotypic polarization and the primary cilia expression of astrocytes were detected by immunofluorescence staining. The activation of MAPKs cascades, including ERK, JNK, and P38 signaling pathways, were detected by western blot. The results showed that physical exercise improved cognitive function of rats 2 months after 2VO, reduced the number of C3/GFAP-positive neurotoxic astrocytes, promoted the expression of S100A10/GFAP-positive neuroprotective astrocytes, and enhanced primary ciliogenesis. Additionally, physical exercise also alleviated the phosphorylation of ERK and JNK proteins induced by CCH. These results indicate that physical exercise can improve the cognitive function of rats with CCH possible by promoting primary ciliogenesis and neuroprotective function of astrocytes. The MAPKs signaling cascade, especially ERK and JNK signaling pathways may be involved in this process.

Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury.

Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1ß and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1ß and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.

Using Fractional Amplitude of Low-Frequency Fluctuations and Functional Connectivity in Patients With Post-stroke Cognitive Impairment for a Simulated Stimulation Program.

Stroke causes alterations in local spontaneous neuronal activity and related networks functional connectivity. We hypothesized that these changes occur in patients with post-stroke cognitive impairment (PSCI). Fractional amplitude of low-frequency fluctuations (fALFF) was calculated in 36 patients with cognitive impairment, including 16 patients with hemorrhagic stroke (hPSCI group), 20 patients with ischemic stroke (iPSCI group). Twenty healthy volunteers closely matched to the patient groups with respect to age and gender were selected as the healthy control group (HC group). Regions with significant alteration were regarded as regions of interest (ROIs) using the one-way analysis of variance, and then the seed-based functional connectivity (FC) with other regions in the brain was analyzed. Pearson correlation analyses were performed to investigate the correlation between functional indexes and cognitive performance in patients with PSCI. Our results showed that fALFF values of bilateral posterior cingulate cortex (PCC)/precuneus and bilateral anterior cingulate cortex in the hPSCI group were lower than those in the HC group. Compared with the HC group, fALFF values were lower in the superior frontal gyrus and basal ganglia in the iPSCI group. Correlation analysis showed that the fALFF value of left PCC was positively correlated with MMSE scores and MoCA scores in hPSCI. Besides, the reduction of seed-based FC values was reported, especially in regions of the default-mode network (DMN) and the salience network (SN). Abnormalities of spontaneous brain activity and functional connectivity are observed in PSCI patients. The decreased fALFF and FC values in DMN of patients with hemorrhagic and SN of patients with ischemic stroke may be the pathological mechanism of cognitive impairment. Besides, we showed how to use fALFF values and functional connectivity maps to specify a target map on the cortical surface for repetitive transcranial magnetic stimulation (rTMS).

Differential Effects of Physical and Social Enriched Environment on Angiogenesis in Male Rats After Cerebral Ischemia/Reperfusion Injury.

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits.

Effect of Tetramethylpyrazine on Neuroplasticity after Transient Focal Cerebral Ischemia Reperfusion in Rats.

Tetramethylpyrazine (TMP) has been widely used in ischemic stroke in China. The regulation of neuroplasticity may underlie the recovery of some neurological functions in ischemic stroke. Middle cerebral artery occlusion (MCAO) model was established in this study. Rats were divided into three groups: sham group, model group, and TMP group. The neurological function was evaluated using modified neurological severity score (mNSS). Following the neurological function test, expression of synaptophysin (SYP) and growth-associated protein 43 (GAP-43) were analyzed through immunohistochemistry at 3 d, 7 d, 14 d, and 28 d after MCAO. Finally, the synaptic structural plasticity was investigated using transmission electron microscopy (TEM). The TMP group showed better neurological function comparing to the model group. SYP levels increased gradually in ischemic penumbra (IP) in the model group and could be enhanced by TMP treatment at 7 d, 14 d, and 28 d, whereas GAP-43 levels increased from 3 d to 7 d and thereafter decreased gradually from 14 d to 28 d in the model group, which showed no significant improvement in the TMP group. The results of TEM showed a flatter synaptic interface, a thinner postsynaptic density (PSD), and a wider synaptic cleft in the model group, and the first two alterations could be ameliorated by TMP. Then, a Pearson's correlation test revealed mNSS markedly correlated with SYP and synaptic ultrastructures. Taken together, TMP is capable of promoting functional outcome after ischemic stroke, and the mechanisms may be partially associated with regulation of neuroplasticity.

Decreased Functional Connectivities of Low-Degree Level Rich Club Organization and Caudate in Post-stroke Cognitive Impairment Based on Resting-State fMRI and Radiomics Features.

BACKGROUND: Stroke is an important cause of cognitive impairment. Rich club organization, a highly interconnected network brain core region, is closely related to cognition. We hypothesized that the disturbance of rich club organization exists in patients with post-stroke cognitive impairment (PSCI). METHODS: We collected data on resting-state functional magnetic resonance imaging (rs-fMRI) with 21 healthy controls (HC), 16 hemorrhagic stroke (hPSCI), and 21 infarct stroke (iPSCI). 3D shape features and first-order statistics of stroke lesions were extracted using 3D slicer software. Additionally, we assessed cognitive function using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). RESULTS: Normalized rich club coefficients were higher in hPSCI and iPSCI than HC at low-degree k-levels (k = 1-8 in iPSCI, k = 2-8 in hPSCI). Feeder and local connections were significantly decreased in PSCI patients versus HC, mainly distributed in salience network (SN), default-mode network (DMN), cerebellum network (CN), and orbitofrontal cortex (ORB), especially involving the right and left caudate with changed nodal efficiency. The feeder and local connections of significantly between-group difference were positively related to MMSE and MoCA scores, primarily distributed in the sensorimotor network (SMN) and visual network (VN) in hPSCI, SN, and DMN in iPSCI. Additionally, decreased local connections and low-degree ϕnorm(k) were correlated to 3D shape features and first-order statistics of stroke lesions. CONCLUSION: This study reveals the disrupted low-degree level rich club organization and relatively preserved functional core network in PSCI patients. Decreased feeder and local connections in cognition-related networks (DMN, SN, CN, and ORB), particularly involving the caudate nucleus, may offer insight into pathological mechanism of PSCI patients. The shape and signal features of stroke lesions may provide an essential clue for the damage of functional connectivity and the whole brain networks.

miR-142-3p suppresses apoptosis in spinal cord-injured rats.

INTRODUCTION: Spinal cord injury (SCI) leads to abnormal expression of miRs, leading to secondary responses such as oxidative stress, inflammation and apoptosis. In the present work, we screened the miRs involved and the associated pathway. METHODS: In a rat model of SCI, the microarray analysis for expression of miRs at various time points post-SCI was done. The locomotor analysis was done by Basso, Beattie and Bresnahan score, and Cresyl violet staining was done for lesion volume and TUNEL assay was done for apoptosis in neuronal cells. The expression of apoptotic proteins was done by the western blot study. RESULTS: It was evidenced that the expression of the number of miRs was altered on the 14th day post-SCI, and miR-142-3p was found to be the most significantly suppressed miR. The results suggested that overexpression of miR-142-3p by its agomir-attenuated functional recovery decreased lesion size and apoptosis of neuronal cells in rats subjected to SCI. The luciferase assay indicated that miR-142-3p blocked the levels of Bax, which is a significant activator of the mitochondrial apoptotic pathway (MAP) via targeting the 3'UTR region of BV-2 cells, and in addition, pc-DNA-Bax restored Bax and inhibited the correcting role of miR-142-3p in hydrogen peroxide-treated BV-2 cells. The findings suggested that miR-142-3p may inhibit the MAP by inhibiting the expression of cleaved-caspase-3/-9 and Bax in SCI rats. CONCLUSION: This study concludes that miR-142-3p may attenuate the functional recovery and decrease apoptosis in neuronal cells via inhibiting the MAP in the spinal cord-injured rats, confirming miR-142-3p as a potential therapeutic target in treating SCI.

Environmental enrichment rescues cognitive impairment with suppression of TLR4-p38MAPK signaling pathway in vascular dementia rats.

Increasing evidence demonstrated the promising effects of environmental enrichment (EE) on brain recovery and cognitive performance in animal models of various diseases. However, the effect and molecular mechanisms of EE on vascular dementia (VD) remain to be studied. The aim of this study was to explore the effect of EE on cognitive decline and its mechanism. Sprague-Dawley rats underwent 2-vessel occlusion (2-VO) surgery or sham operation. Subsequently, rats were kept in EE for 4 weeks. In Morris water maze (MWM) test, we demonstrated that EE significantly improved cognitive function in rats with VD. HE staining exhibited morphological changes of neurons and quantitative analysis of TUNEL showed increased apoptotic neurons in hippocampal CA1 region following 2-VO. Results from RT-qPCR showed up-regulation of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) after 2-VO. Western blotting analysis revealed enhanced toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MYD88) and phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK) in 2-VO rats. Whereas administration of EE reduced apoptotic neurons, down-regulated inflammatory factors. Moreover, EE suppressed protein expression of TLR4-p38MAPK pathway. Spearman correlation analysis showed that improved cognitive function was associated with decreased expression of TLR4 and p-p38MAPK proteins. Thus, our study proved that EE has a prominent effect on cognitive impairment and neuronal damage following 2-VO by attenuating inflammation and apoptosis, which may be realized via inhibiting the TLR4-P38MAPK signaling pathway.

Impact of blood-brain barrier disruption on newly diagnosed neuromyelitis optica spectrum disorder symptoms and prognosis.

BACKGROUND: Blood-brain barrier (BBB) disruption and ensuing immune activation are central to the pathogenesis of central nervous system (CNS) inflammatory diseases. However, the influence of BBB permeability on the clinical signs and prognosis of newly diagnosed neuromyelitis optica spectrum disorder (NMOSD) has not been examined. We investigate the relationships between BBB permeability as showed by the albumin quotient (qalb) and clinical features of NMOSD. METHODS: Demographic and clinical data of 46 patients, including peripheral blood (PB) measures (serum albumin concentration and total leukocyte, neutrophil, total lymphocyte, CD4+ T cell, and CD8+ T cell counts, complement C3 and C4 concentrations, AQP4-IgG titer),autoimmune antibody titers (ANA/SSA/SSB/Ro-52), and cerebrospinal fluid (CSF) parameters (total leukocyte count, total protein and albumin concentrations, AQP4-IgG titer), were compared between qalb(BBB permeability) increased and normal groups. Complete measures were not obtained from 9 patients, but all other measures were included in the analysis. RESULTS: According to the calculated qalb, 15 patients with albumin quotient (qalb) > (4 + age/15) × 10-3 were assigned to the qalb increased (high BBB permeability) group (33%) and the remainder to the qalb normal group. Compared to the qalb normal group, the qalb increased group exhibited significantly lower serum albumin (P=0.001) and CD4+ T cell count (P=0.044), CD8+ T cell count (P=0.014), and total T lymphocyte count (P=0.016). The qalb increased group proved higher CSF albumin, total protein, leukocyte count, and IgG titer (all P=0.000). Optic neuritis and optic nerve abnormalities on magnetic resonance images were also more frequent in the qalb increased group (P=0.037 and 0.038, respectively). Patients in the qalb increased group showed significantly poorer treatment response as indicated by the lower post-treatment change in Expanded Disability Status Scale (EDSS) score compared to the qalb normal group. CONCLUSIONS: BBB permeability is strongly associated with the clinical features and treatment response of newly diagnosed NMOSD. The qalb is a potentially valuable indicator of disease severity and an index to guide personalized treatment.

The effect of combined scalp acupuncture and cognitive training in patients with stroke on cognitive and motor functions.

OBJECTIVE: To investigate the effect of combined scalp acupuncture and cognitive training on cognitive and motor functioning in patients with stroke during the recovery stage. METHODS: Seventy patients with post-stroke cognitive impairment were randomly divided into an experimental group and a control group. Patients in the experimental group additionally received scalp acupuncture and cognitive training, while the control group received sham scalp acupuncture and cognitive training. The cognitive and motor functioning of all patients were assessed using MMSE, LOTCA, and FMA, before and 12 weeks after treatment. In addition, the plasma BDNF and NGF levels were measured from peripheral blood samples using ELISA kits. RESULTS: After 12 weeks, the MMSE, LOTCA and FMA scores were significantly higher in the experimental group than in the control group. In the experimental group, there was an improvement in the total MMSE score, orientation, spatial executive function, the total LOTCA score, and the score of command of language orientation post-treatment. Significant improvements of BDNF and NGF were found in the experimental group after treatment, while only significant improvements of NGF was found in the control group after treatment. Both BDNF and NGF in the experiment group were higher than those in the control group at the last day of treatment. CONCLUSIONS: Combined scalp acupuncture and cognitive training can efficiently enhance cognitive and motor functions in patients with stroke during the recovery stage, which may be a more effective rehabilitation treatment after stroke than routine therapy and rehabilitation training alone.