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Multivariate time series (MTS) data exist in various fields of studies and MTS classification is an important research topic in the machine learning community. Researchers have proposed many MTS classification models over the years and the distance-based methods along with nearest neighbor classifier achieve good performance. However, the current methods mainly focus on defining distance metric on time-domain of MTS and ignore frequency information. Besides, these methods usually define the same linear distance metric for different datasets, which is not suitable for capturing the nonlinear relationship of MTS and degrades the discriminative power of the distance metric. In this paper, we propose a time–frequency deep metric learning (TFDM) approach for MTS classification. The multilevel discrete wavelet decomposition is first adopted to decompose an MTS into a group of sub-MTS so as to extract multilevel time–frequency representations. Then, a deep convolutional neural network is developed for each level to learn level-specific nonlinear features and a metric learning layer is added on the top of the network to learn the semantic similarity of MTS. Moreover, a cross-level consistency regularization term is designed to encourage the distance metrics of different levels to be consistent for capturing the correlations among different levels. Finally, we use 1-nearest neighbor to classify MTS according to the learned distance metrics. Extensive experiments on 18 benchmark datasets show the effectiveness of our approach.

Objective: Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood.Methods: In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. Results: The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. Conclusions: These findings suggested that as early as 1~4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01024-7.

Background. The clinical efficacy of temporal three-needle therapy for stroke dysfunction has been previously demonstrated in China. However, the central mechanism of temporal three-needle therapy remains unclear. Temporal three-needle projects the sensory cortex and the motor cortex, which may impact the cortex function. Current studies seldom focus on it. Hence, according to the “scalp-cortex corresponding theory,” the underlying mechanism of temporal three-needle remains a domain for further research. Methods. This trial is designed to provide objective and visual evidence for the neuromodulatory effect and neuroimaging mechanism of temporal three-needle therapy for stroke patients. This ongoing study is a prospective, randomized, controlled, patient-assessor blind, single-center, neuroimaging trial involving two-parallel patient groups and a healthy control group. Forty eligible patients will be recruited from Shenzhen Nanshan District People’s Hospital and randomized into either the experimental group or the control group. Twenty healthy volunteers will be recruited in the healthy control group and undergo baseline magnetic resonance imaging scans without any intervention. Patients in the control group will receive acupuncture at Dingnieqianxiexian (MS6), in addition to basic medicine and rehabilitative treatments. Patients in the experimental group will receive temporal three-needle therapy plus basic medicine and rehabilitative treatments 5 days per week, 10 sessions over two consecutive weeks. The primary outcome is resting-state functional connectivity, and the secondary outcomes are regional homogeneity, amplitude of low-frequency fluctuations, Fugl–Meyer assessment of the upper limb, and modified Barthel Index. All outcome measures will be assessed at baseline and after 2 weeks of intervention. Discussion. The results will explore the neuromodulatory effects and illustrate the central mechanism of temporal three-needle treatment from the network-level viewpoint of sensorimotor network functional plasticity and promote widespread application in real-world practice. This trial was registered at Chinese Clinical Trial Registry on 14 March 2018 with ChiCTR1800015209.

Background To evaluate whether electroacupuncture (EA) treatment at LI11 and ST36 could reduce motor impairments and enhance brain functional recovery in a rat model of ischemic stroke. Methods A rat model of middle cerebral artery occlusion (MCAO) was established. EA at LI11 and ST36 was started at 24 h (MCAO + EA group) after ischemic stroke modeling. Untreated model (MCAO) and sham-operated (Sham) groups were included as controls. The neurological deficits of all groups were assessed using modified neurologic severity scores (mNSS) at 24 h and 14 days after MCAO. To further investigate the effect of EA on infarct volume and brain function, functional magnetic resonance imaging was used to estimate the size of the brain lesions and neural activities of each group at 14 days after ischemic stroke. Results EA treatment of MCAO rats led to a significant reduction in the infarct volumes accompanied by functional recovery, reflected in improved mNSS outcomes and motor functional performances. Furthermore, functional connectivity between the left motor cortex and left cerebellum posterior lobe, right motor cortex, left striatum and bilateral sensory cortex were decreased in MCAO group but increased after EA treatment. Conclusion EA at LI11 and ST36 could enhance the functional connectivity between the left motor cortex and the motor function-related brain regions, including the motor cortex, sensory cortex and striatum, in rats. EA exhibits potential as a treatment for ischemic stroke.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Currently, the diagnosis of AD depends on clinical assessments and post-mortem neuropathology, which is unbenefited early diagnosis and progressive monitoring. In recent years, clinical studies have reported that the level of cerebrospinal fluid (CSF) and blood neurogranin (Ng) are closely related to the occurrence and subsequent progression of AD. Therefore, the study used meta-analysis to identify the CSF and blood Ng levels for the development of diagnosis biomarker of patients with AD and mild cognitive impairment (MCI). We searched the Pubmed, Embase, Cochrane Library, and Web of Science databases. A total of 24 articles eligible for inclusion and exclusion criteria were assessed, including 4661 individuals, consisting of 1518 AD patients, 1501 MCI patients, and 1642 healthy control subjects. The level of CSF Ng significantly increased in patients with AD and MCI compared with healthy control subjects (SMD: 0.84 [95% CI: 0.70–0.98], P P = 0.008), and higher in AD patients than in MCI patients (SMD: 0.18 [95% CI: 0.07–0.30], P = 0.002), and CSF Ng level of patients with MCI-AD who progressed from MCI to AD was significantly higher than that of patients with stable MCI (sMCI) (SMD: 0.71 [95% CI: 0.25–1.16], P = 0.002). Moreover, the concentration of Ng in blood plasma exosomes of patients with AD and MCI was lower than that of healthy control subjects (SMD: −6.657 [95% CI: −10.558 to −2.755], P = 0.001; and SMD: −3.64 [95% CI: −6.50 to −0.78], P = 0.013), and which in patients with AD and MCI-AD were also lower than those in patients with sMCI (P P = 0.047). Therefore, the Ng levels increased in CSF, but decreased in blood plasma exosomes of patients with AD and MCI-AD, and highly associated with cognitive declines. These findings provide the clinical evidence that CSF and blood exosomes Ng can be used as a cognitive biomarker for AD and MCI-AD, and further studies are needed to define the specific range of Ng values for diagnosis at the different stages of AD.

Background Knee osteoarthritis is a prevalent disorder with unsatisfactory treatment options. Both physical and mindful exercises may be able to relieve its pain symptoms. We compared the modulatory effects of different exercise modalities on the periaqueductal grey (PAG) and ventral tegmental area (VTA), which play important roles in descending opioidergic pathways and reward/motivation systems in patients with knee osteoarthritis. Methods We recruited and randomised 140 patients into Tai Chi, Baduanjin, stationary cycling, and health education control groups for 12 weeks. Knee injury and Osteoarthritis Outcome Score (KOOS), functional and structural MRI, and blood biomarkers were measured at the beginning and end of the experiment. We used the PAG and VTA as seeds in resting-state functional connectivity (rsFC) analysis. Results Compared with the control group: (i) all exercises significantly increased KOOS pain sub-scores (pain reduction) and serum programmed death 1 (PD-1) concentrations; (ii) all exercises decreased right PAG rsFC with the medial orbital prefrontal cortex, and the decreased rsFC was associated with improvements in knee pain; and (iii) grey matter volume in the medial orbital prefrontal cortex was significantly increased in all exercise groups. There was also significantly decreased rsFC between the left VTA and the medial orbital prefrontal cortex in the Tai Chi and Baduanjin groups. Conclusions Exercise can simultaneously modulate the rsFC of the descending opioidergic pathway and reward/motivation system and blood inflammation markers. Elucidating the shared and unique mechanisms of different exercise modalities may facilitate the development of exercise-based interventions for chronic pain. Clinical trial registration ChiCTR-IOR-16009308.

This study investigated the effects of Tai Chi compared with no exercise control on the cerebral hemodynamic parameters and other health-related factors in community older adults at risk of ischemic stroke. A total of 170 eligible participants were randomly allocated to Tai Chi or control group. The cerebral hemodynamic parameters and physical fitness risk factors of cardiovascular disease were measured at baseline, 12 weeks, and 24 weeks. After the 12-week intervention, Tai Chi significantly improved the minimum of blood flow velocity (BFVmin); BFVmean; pulsatility index and resistance index of the right anterior cerebral artery; and BFVmax, BFVmin, and BFVmean parameters of the right middle cerebral artery. Tai Chi training also decreased triglyceride, fasting blood glucose, and homocysteine levels, and improved balance ability. Therefore, the supervised 12-week Tai Chi exercise had potential beneficial effects on cerebral hemodynamics, plasma risk factors, and balance ability in older community adults at risk of ischemic stroke.

Objective: Stand-to-sit task is an important daily function, but there is a lack of research evidence on whether knee osteoarthritis (knee OA) affects the postural balance during the task. This study aimed to compare individuals with knee OA and asymptomatic controls in postural balance and identify kinematic and lower extremity muscle activity characteristics in individuals with knee OA during the stand-to-sit task.Methods: In total, 30 individuals with knee OA and 30 age-matched asymptomatic controls performed the 30-s Chair Stand Test (30sCST) at self-selected speeds. Motion analysis data and surface electromyography (sEMG) were collected while participants performed the 30sCST. To quantify postural balance, the displacement of the center of mass (CoM) and the peak instantaneous velocity of the CoM were calculated. The kinematic data included forward lean angles of the trunk and pelvic, range of motion (RoM) of the hip, knee, and ankle joints in the sagittal plane. The averaged activation levels of gluteus maximus, vastus lateralis, vastus medialis, rectus femoris, biceps femoris (BF), tibialis anterior (TA), and medial head of gastrocnemius muscles were indicated by the normalized root mean square amplitudes.Results: Compared with the asymptomatic control group, the knee OA group prolonged the duration of the stand-to-sit task, demonstrated significantly larger CoM displacement and peak instantaneous CoM velocity in the anterior-posterior direction, reduced ankle dorsiflexion RoM, greater anterior pelvic tilt RoM, and lower quadriceps femoris and muscles activation level coupled with higher BF muscle activation level during the stand-to-sit task.Conclusion: This study indicates that individuals with knee OA adopt greater pelvic forward lean RoM and higher BF muscle activation level during the stand-to-sit task. However, these individuals exist greater CoM excursion in the anterior-posterior direction and take more time to complete the task. This daily functional activity should be added to the rehabilitation goals for individuals with knee OA. The knee OA group performs reduced ankle dorsiflexion RoM, quadriceps femoris, and TA activation deficit. In the future, the rehabilitation programs targeting these impairments could be beneficial for restoring the functional transfer in individuals with knee OA.

Background: Oxidative stress (OS) plays an important role in the progression of many aging-related diseases. Exercises can delay this kind of progress, but aerobic exercise is the most commonly used type of training among older adults; therefore, its influence needs to be further verified.Methods: A literature search was conducted in eight electronic databases, including Cochrane, EMBASE, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Date, and SinoMed from their inception to April 2020. Methodological quality was assessed using Cochrane RoB tool v2.0 for individual studies, and RevMan 5.3 software was used to perform the meta-analysis.Results: The meta-analysis included 20 studies, involving 1,170 older adults. The results showed that regular aerobic exercise could reduce blood oxidant markers, including malondialdehyde (MDA; SMD=−1.80, 95% CI −2.46 to −1.14, pp=0.02), and increase the levels of antioxidant factors, such as nitric oxide (NO; SMD=0.89, 95% CI 0.37–1.41, pp=0.001), and total antioxidant capacity (TAC; SMD=1.22, 95% CI 0.45–1.98, p=0.002), with clear statistical significance. It may also improve the levels of other OS markers, such as 8-OHdG, 8-isoPGF2, VE, and reduced glutathione/oxidized glutathione (GSH/GSSG).Conclusion: Regular aerobic exercise may have a positive effect on the OS levels of older adults by reducing some oxidant markers and increasing antioxidant marker levels.

Mild cognitive impairment (MCI) is a common global health problem. Recently, the potential of mind-body intervention for MCI has drawn the interest of investigators. This study aims to comparatively explore the modulation effect of Baduanjin, a popular mind-body exercise, and physical exercise on the cognitive function, as well as the norepinephrine and dopamine systems using the resting state functional connectivity (rsFC) method in patients with MCI. 69 patients were randomized to the Baduanjin, brisk walking, or healthy education control group for 6 months. The Montreal Cognitive Assessment (MoCA) and magnetic resonance imaging (MRI) scans were applied at baseline and at the end of the experiment. Results showed that (1) compared to the brisk walking, the Baduanjin significantly increased MoCA scores; (2) Baduanjin significantly increased the right locus coeruleus (LC) and left ventral tegmental area (VTA) rsFC with the right insula and right amygdala compared to that of the control group; and the right anterior cingulate cortex (ACC) compared to that of the brisk walking group; (3) the increased right LC-right insula rsFC and right LC-right ACC rsFC were significantly associated with the corresponding MoCA score after 6-months of intervention; (4) both exercise groups experienced an increased effective connectivity from the right ACC to the left VTA compared to the control group; and (5) Baduanjin group experienced an increase in gray matter volume in the right ACC compared to the control group. Our results suggest that Baduanjin can significantly modulate intrinsic functional connectivity and the influence of the norepinephrine (LC) and dopamine (VTA) systems. These findings may shed light on the mechanisms of mind-body intervention and aid the development of new treatments for MCI.

To determine the mechanism(s) involved in electroacupuncture (EA)-mediated improvements in synaptic plasticity in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R)-induced cognitive deficits.Focal cerebral ischemic stroke was induced by (MCAO/R) surgery. Rats were randomly split into 4 groups: control group (sham operation control), MCAO group, Baihui (GV 20) and Shenting (GV 24) acupoint EA group (verum acupuncture, MCAO + VA), and nonacupoint EA group (control acupuncture, MCAO + CA). EA treatment was administered for 14 consecutive days in MCAO + VA and MCAO + CA groups. Neurological assessment, behavioral performance testing, and molecular biology assays were used to evaluate the MCAO/R model, EA therapeutic effect and potential therapeutic mechanism(s) of EA.Significant amelioration of neurological deficits was found in MCAO + VA rats compared with MCAO rats (P.01). Moreover, learning and memory significantly improved in EA-treated rats compared with MCAO or MCAO + CA rats (P.05) together with an increase in the number of PSD-95EA at GV 20 and GV 24 acupoints improved cognitive deficits in cerebral ischemic rats via the JAK2/STAT3 signaling pathway and mediated synaptic plasticity in the peri-infarct hippocampal CA1 region of rats following ischemic stroke.

Numerous previous studies have suggested that physical activity or exercise may play an important role in both structural integrity of the brain and cognitive function. However, it is unclear what effect exercise has on cognitive related brain structure. The present study comprehensively reviews the effect of exercise on cognitive related brain regions of the healthy elderly by using activation likelihood estimation (ALE).Seven electronic databases were searched for randomized controlled trials published up to September 2017. The quality of the selected studies was evaluated using the Cochrane Collaboration's tool for assessing the risk of bias. GingerALE version 2.3.6 was used to perform the coordinate-based ALE meta-analysis.Nine randomized controlled trials (RCTs) with 50 distinct foci were analyzed for structural changes, containing 412 healthy older subjects. ALE showed significant regional increases in regions including the left superior temporal gyrus, left medial temporal gyrus, left inferior frontal gyrus, right medial frontal gyrus, right and left superior frontal gyrus, left cingulate gyrus, right anterior cingulate and left lentiform nucleus in subjects with the exercise intervention compared to controls. However, considering the quantity and limitations of the included studies, the conclusion could not yet be drawn. Additional randomized controlled trials with rigorous designs and longer intervention periods are needed in the future.

Background To prevent and control dementia, many scholars have focused on the transition stage between normal ageing and dementia, mild cognitive impairment (MCI) which is a key interventional target for dementia. Studies have shown that non-invasive brain stimulation (NIBS) is beneficial to improve cognitive function of MCI patients. However, whether NIBS is conducive to the protection of cognitive ability in MCI patients remains unknown due to limited evidence. The aim of the study was to systematically evaluate the modulation effect of NIBS on cognitive function (global cognitive ability and specific domains of cognition) in patients with MCI. Results A total of 11 RCTs comprising a total of 367 MCI participants. Meta-analysis showed that NIBS can significantly improve global cognition (n = 271, SMD = 0.94, 95% CI 0.47–1.41, p

To evaluate the effect of tai chi exercise on cardiac and static lung function for older community-dwelling adults at risk of ischemic stroke. A total of 170 older community-dwelling adults (aged 55–75 years old) at risk of ischemic stroke were allocated to either tai chi training group (85 cases, five 60-min sessions of tai chi training per week for 12 weeks) or control group (85 cases, usual pbysical activity for 12 weeks) using a computer-generated randomization. The echocardiographic parameters of cardiac structure, cardiac function and static lung function were measured at baseline, after 12 weeks of intervention and additional 12-week follow-up period by a blinded professional staffmember using a color Doppler ultrasound imaging device or a cardiopulmonary function instrument. The t test and linear mixed model based on the intentionto-treat analysis principle was used to calculate the effect. The adverse effect was observed. Most of echocardiographic parameters on the cardiac structure, cardiac function and static lung function between the tai chi group and control group did not have a significant difference either post 12-week intervention or additional 12-week follow-up period. Only three parameters involving in right ventricular diameter (P=0.024), main pulmonary artery diameter (P=0.002) and vital capacity maximum (P=0.036) were beneficial to be improved in the tai chi group compared to the control group by the analysis of mixed linear model. No adverse effects were found during the intervention period. The 12-week tai chi exercise did not have an obvious beneficial effect on cardiac structure, cardiac function and static lung function in older community-dwelling adults at risk of ischemic stroke. The study with a longer duration of intervention should be necessary. (Trial registration No. ChiCTR-TRC-13003601)

BackgroundCognitive frailty is a particular state of cognitive vulnerability toward dementia with neuropathological hallmarks. The hippocampus is a complex, heterogeneous structure closely relates to the cognitive impairment in elderly which is composed of 12 subregions. Atrophy of these subregions has been implicated in a variety of neurodegenerative diseases. The aim of this study was to explore the changes in hippocampal subregions in older adults with cognitive frailty and the relationship between subregions and cognitive impairment as well as physical frailty.MethodsTwenty-six older adults with cognitive frailty and 26 matched healthy controls were included in this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and Wechsler Memory Scale-Revised Chinese version (WMS-RC), while physical frailty was tested with the Chinese version of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out between the volumes of hippocampal subregions and MoCA scores, Wechsler’s Memory Quotient and physical frailty indexes.ResultsA significant volume decrease was found in six hippocampal subregions, including the bilateral presubiculum, the left parasubiculum, molecular layer of the hippocampus proper (molecular layer of the HP), and hippocampal amygdala transition area (HATA), and the right cornu ammonis subfield 1 (CA1) area, in older adults with cognitive frailty, while the proportion of brain parenchyma and total number of white matter fibers were lower than those in the healthy controls. Positive correlations were found between Wechsler’s Memory Quotient and the size of the left molecular layer of the HP and HATA and the right presubiculum. The sizes of the left presubiculum, molecular of the layer HP, and HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score. The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively correlated with the physical frailty index.ConclusionSignificant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive impairment and physical frailty. Therefore, the atrophy of hippocampal subregions could participate in the pathological progression of cognitive frailty.

BackgroundType 2 diabetes mellitus (T2DM) is a worldwide public health concern with high morbidity and various progressive diabetes complications that result in serious economic expenditure and social burden. This systematic review aims to evaluate the effect of Tai Chi on improving quality of life (QoL), body mass index (BMI) and waist-hip ratio (WHR) in patients with T2DM.MethodA systematic review and meta-analysis was performed following PRISMA recommendation. Four English databases and three Chinese databases were searched. The PEDro scale was used to assess the methodological quality of including studies. Study inclusion criteria: randomized controlled trials (RCTs) and quasi-experimental studies were included, patients with T2DM that adopted Tai Chi as intervention and QoL, BMI and/or WHR as outcome measurements.ResultsEighteen trials were included. The aggregated results of seven trials showed that Tai Chi statistically significantly improved QoL measured by the SF-36 on every domains (physical function: MD = 7.73, 95% confidence interval (CI) = 1.76 to 13.71, p = 0.01; role-physical function: MD = 9.76, 95% CI = 6.05 to 13.47, p < 0.001; body pain: MD = 8.49, 95% CI = 1.18 to 15.8, p = 0.02; general health: MD = 9.80, 95% CI = 5.77 to 13.82, p < 0.001; vitality: MD = 6.70, 95% CI = 0.45 to 12.94, p = 0.04; social function: MD = 9.1, 95% CI = 4.75 to 13.45, p < 0.001; role-emotional function: MD = 7.88, 95% CI = 4.03 to 11.72, p < 0.001; mental health: MD = 5.62, 95% CI = 1.57 to 9.67, p = 0.006) and BMI (MD = −1.53, 95% CI = −2.71 to −0.36, p < 0.001) compared with control group (wait list; no intervention; usual care; sham exercise).ConclusionTai Chi could improve QoL and decrease BMI for patients with T2DM, more studies are needed to be conducted in accordance with suggestions mentioned in this review.

Background: Minimally invasive diagnostic biomarkers of neurodegenerative diseases such as Alzheimer’s disease (AD) facilitate patient selection and cognitive progressive decline monitoring. However, the diagnostic value of circulating microRNAs (miRNAs) for early cognitive impairment and progression to dementia is currently under debate. Thus, this study aimed to assess the diagnostic performance of circulating, cerebrospinal fluid (CSF) and exosomal miRNAs in the detection of clinical cognitive impairment in mild cognitive impairment (MCI), AD, and MCI-AD. Methods: We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), VIP Chinese Science and Technology Journals Database (CQVIP), and Chinese Medicine Premier (Wanfang) to identify potentially eligible studies related to noncoding RNAs and cognitive dysfunction biomarkers published before November 2018. The quality assessment of the studies was performed according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Meta-analysis of the literature data was performed using Stata/MP 14.0 software. The corresponding effects models were selected to calculate the summary sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), and diagnostic odds ratio (DOR) and to plot the summary receiver operating characteristic curves (SROCs) and calculate the areas under the curves (AUCs). Results: A total of 18 studies involving 729 patients with AD, 283 patients with MCI, and 15 patients with MCI-AD were pooled. The results revealed that the sensitivity and specificity of miRNAs in the diagnosis of AD were 0.78 and 0.79, respectively, and the area under the summary receiver operating characteristic curve (AUSROC) was 0.90. The sensitivity and specificity of miRNAs in the diagnosis of MCI were 0.89 and 0.85, respectively, and the AUSROC was 0.94. The sensitivity and specificity of microRNAs in the diagnosis of MCI-AD were 0.87 and 0.84, respectively, and the AUSROC was 0.92. Conclusion: Our study found that miRNAs have certain diagnostic value for cognitive impairment, with high sensitivity and specificity, especially in diagnostics with multiple miRNAs and serum-based miRNA assays.

Background: Cognitive frailty (CF) is defined as the simultaneous presence of physical frailty and cognitive impairment among older adults without dementia. Previous studies have revealed that neuropathological changes may contribute to the degeneration of subcortical nuclei in the process of cognitive impairment. However, it is unclear in CF. The aim of this study is to investigate the changes in subcortical nuclei in older adults with CF and their relationship with cognitive decline and physical frailty.Methods: A total of 26 older adults with CF and 26 matched healthy subjects were enrolled. Cognitive function and physical frailty were assessed with the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and the Chinese version of the Edmonton Frailty Scale (EFS). Volumetric and diffusion tensor imaging (DTI) parameters of subcortical nuclei were measured with structural and DTI brain magnetic resonance imaging (MRI) and compared between groups. Partial correlation analysis was conducted between subcortical nuclei volumes, MoCA scores, and physical frailty indexes.Results: Significant volume reductions were found in five subcortical nuclei, including the bilateral thalami, left caudate, right pallidum, and accumbens area, in older adults with CF (P < 0.05), and the bilateral thalami was most obvious. Decreased fractional anisotropy and relative anisotropy values were observed only in the left thalamus in the CF group (P < 0.05). No group differences were found in apparent diffusion coefficient (ADC) values. The MoCA scores were positively correlated with the volumes of the bilateral thalami, right pallidum, and accumbens area (P < 0.05). Negative correlations were found between the physical frailty index and the volumes of the bilateral thalami, caudate, pallidum, and right accumbens area (P < 0.05).Conclusion: Microstructural changes occur in the subcortical nuclei of older adults with CF, and these changes are correlated with cognitive decline and physical frailty. Therefore, microstructural atrophy of the subcortical nuclei may be involved in the pathological progression of CF.

Background The aim of this study was to investigate the central mechanism underlying the putative beneficial effects of electroacupuncture (EA) on learning and memory ability of rats with ischemic stroke-induced cognitive deficits by resting-state functional magnetic resonance imaging (fMRI). Methods A rat model of middle cerebral artery occlusion (MCAO)-induced cognitive deficit (MICD) was established. Rats were randomly assigned into a sham-operated control group (SC group, n = 12), untreated MICD model group (MICD group, n = 12), and MICD group receiving EA treatment at GV20 and GV24 (MICD + EA group, n = 12). Results Compared to the MICD group, rats in the MICD + EA group receiving EA at GV20 and GV24 exhibited significantly shortened escape latency times and crossed the position of the platform a significantly increased number of times during the Morris water maze test on the 14th day after EA, which suggested EA could significantly improve spatial learning and memory ability. Furthermore, compared to the MICD group, functional connectivity of the left retrosplenial cortex (RSC) with the left hippocampus, left RSC, right RSC, left cingulate gyrus, right cingulate gyrus, right tegmentum of midbrain, and right visual cortex was increased in the MICD + EA group; the MICD group showed decreased functional connectivity of the left RSC with the left hippocampus, right hippocampus, left RSC, right RSC, right amygdaloid body, left visual cortex, and right visual cortex. Conclusion These findings suggest that EA at GV20 and GV24 might improve the learning and memory ability of MICD rats by increasing the functional connectivity between the RSC and hippocampus, cingulate gyrus and midbrain, which is encouraging for the potential treatment for cognitive impairment secondary to ischemia stroke.

IntroductionCognitive frailty (CF) is a clinical manifestation characterised by the simultaneous presence of both physical frailty and cognitive impairment among older adults without dementia and has become a new target for healthy ageing. Increasing evidence shows that regular Baduanjin (a traditional Chinese mind–body exercise) training is beneficial in improving physical function and cognitive ability in the older adults. The primary aim of this trial is to observe the effect of Baduanjin on physical and cognitive functions in older adults with CF.Methods and analysisIn this prospective, outcome assessor-blind, two-arm randomised controlled trial, a total of 102 participants with CF will be recruited and randomly allocated (1:1) into the Baduanjin training or usual physical activity control group. The control group will receive health education for 30 min at least once a month. Based on health education, participants in the Baduanjin exercise group will receive a 24-week Baduanjin training with 60 min per session and 3 sessions per week, while those in the usual physical activity control group will maintain their original lifestyle. Primary outcomes (frailty index and global cognitive ability), body composition, grip force, balance, fatigue, specific cognitive domain, including memory, execution and visual spatial abilities, and life quality of secondary outcomes will be measured at baseline, and at 13 and 25 weeks after randomisation, while the structural and functional MRI will be measured at baseline and 25 weeks after randomisation. The mixed linear model will be conducted to observe the intervention effects.Ethics and disseminationThe study has been approved by the ethics committee of the second people’s hospital of Fujian province (Approval no. 2018-KL015). Results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences.Trial registration numberChiCTR1800020341; Pre-results.

Microglia are the primary cells that exert immune function in the central nervous system, and accumulating evidence suggests that microglia act as critical players in the initiation of neurodegenerative disorders, such as Alzheimer’s disease (AD). Microglia seemingly demonstrate two contradictory phenotypes in response to different microenvironmental cues, the M1 phenotype and the M2 phenotype, which are detrimental and beneficial to pathogenesis, respectively. Inhibiting the M1 phenotype with simultaneous promoting the M2 phenotype has been suggested as a potential therapeutic approach for cure AD. In this study, we demonstrated that electroacupuncture at the Shenting and Baihui acupoints for 16 weeks could improve learning and memory in the Morris water maze test and reduce amyloid β-protein in the parietal association cortex and entorhinal cortex in mice with mild and moderate AD. Besides, electroacupuncture at the Shenting and Baihui acupoints not only suppressed M1 marker (iNOS/IL-1β) expression but also increased the M2 marker (CD206/Arg1) expression in those regions. We propose that electroacupuncture at the Shenting and Baihui acupoints could regulate microglial polarization and decrease Aβ plaques to improve learning and memory in mild AD mice.

Vascular cognitive impairment no dementia (VCIND) is likely to develop into vascular dementia (VD) without intervention. The clinical efficacy of electroacupuncture (EA) for VCIND has been previously demonstrated. However, the neuroimaging mechanism of EA for VCIND has not been elucidated clearly. This trial is designed to provide solid evidence for the efficacy and neuroimaging mechanism of EA treatment for patients with VCIND. This ongoing study is an assessor-blind, parallel-group, randomized controlled trial. 140 eligible subjects will be recruited from the General Hospital of Ningxia Medical University and randomized into either the electroacupuncture (EA) group or the control group (CG). All subjects will receive basic treatment, and participants in the CG will receive health education performed weekly. Except for basic treatment and health education, participants in the EA group will receive treatment 5 times per week for a total of 40 sessions over 8 weeks. The primary outcome in this study is Montreal Cognitive Assessment (MoCA), and the secondary outcomes are Auditory Verbal Learning Test (AVLT), Stroop color-naming condition (STROOP), Rey–Osterrieth Complex Graphics Testing, and resting-state functional magnetic resonance imaging (rs-fMRI). All of the outcome measures will be assessed at baseline and 8 weeks of intervention. The medical abstraction of adverse events will be done at each visit. The results of this trial will demonstrate the efficacy and neuroimaging mechanism of EA treatment for VCIND, thus supporting EA treatment as an ideal choice for VCIND treatment. The trial was registered at the Chinese Clinical Trial Registry on 28 July 2018 (ChiCTR1800017398).

The primary objective of this review article was to summarize comprehensive information related to the neuropharmacological activity, mechanisms of action, toxicity, and safety of salidroside in medicine. A number of studies have revealed that salidroside exhibits neuroprotective activities, including anti-Alzheimer’s disease, anti-Parkinson’s disease, anti-Huntington’s disease, anti-stroke, anti-depressive effects, and anti-traumatic brain injury; it is also useful for improving cognitive function, treating addiction, and preventing epilepsy. The mechanisms underlying the potential protective effects of salidroside involvement are the regulation of oxidative stress response, inflammation, apoptosis, hypothalamus-pituitary-adrenal axis, neurotransmission, neural regeneration, and the cholinergic system. Being free of side effects makes salidroside potentially attractive as a candidate drug for the treatment of neurological disorders. It is evident from the available published literature that salidroside has potential use as a beneficial therapeutic medicine with high efficacy and low toxicity to the central nervous system. However, the definite target protein molecules remain unclear, and clinical trials regarding this are currently insufficient; thus, guidance for further research on the molecular mechanisms and clinical applications of salidroside is urgent.

Recovery following stroke involves neurogenesis and axonal remodeling within the ischemic brain. Gualou Guizhi decoction (GLGZD) is a Chinese traditional medicine used for the treatment of post-stroke limb spasm. GLGZD has been reported to have neuroprotective effects in cerebral ischemic injury. However, the effects of GLGZD on neurogenesis and axonal remodeling following cerebral ischemia remain unknown. In this study, a rat model of focal cerebral ischemia/reperfusion was established by middle cerebral artery occlusion. Neurological function was assessed immediately after reperfusion using Longa's 5-point scoring system. The rats were randomly divided into vehicle and GLGZD groups. Rats in the sham group were given sham operation. The rats in the GLGZD group were intragastrically administered GLGZD, once daily, for 14 consecutive days. The rats in the vehicle and sham groups were intragastrically administered distilled water. Modified neurological severity score test, balance beam test and foot fault test were used to assess motor functional changes. Nissl staining was performed to evaluate histopathological changes in the brain. Immunofluorescence staining was used to examine cell proliferation using the marker 5-bromo-2'-deoxyuridine (BrdU) as well as expression of the neural precursor marker doublecortin (DCX), the astrocyte marker glial fibrillary acidic protein (GFAP) and the axon regeneration marker growth associated protein-43 (GAP-43). GLGZD substantially mitigated pathological injury, increased the number of BrdU, DCX and GFAP-immunoreactive cells in the subventricular zone of the ischemic hemisphere, increased GAP-43 expression in the cortical peri-infarct region, and improved motor function. These findings suggest that GLGZD promotes neurological functional recovery by increasing cell proliferation, enhancing axonal regeneration, and increasing the numbers of neuronal precursors and astrocytes in the peri-infarct area.

Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca2+]i in cortex and striatum neurone of MCAO rats. GLGZD contains Trichosanthin and various small molecular that they are the potential active ingredients directed against NR2A, NR2B, FKBP12 and Calnodulin target proteins/enzyme have been screened by computer simulation. “Multicomponent systems” is capable to create pharmacological superposition effects. The Chinese medicine compound prescriptions could be considered as promising sources of candidates for discovery new agents.

Background During ischemic stroke (IS), adenosine 5′-triphosphate (ATP) is released from damaged nerve cells of the infract core region to the extracellular space, invoking peri-infarct glial cellular P2 purinoceptors singling, and causing pro-inflammatory cytokine secretion, which is likely to initiate or aggravate motor and cognitive impairment. It has been proved that electroacupuncture (EA) is an effective and safe strategy used in anti-inflammation. However, EA for the role of purine receptors in the central nervous system has not yet been reported. Methods Ischemia-reperfusion injured rat model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). EA treatment at the DU 20 and DU 24 acupoints treatment were conducted to rats from the 12 h after MCAO/R injury for consecutive 7 days. The neurological outcomes, infarction volumes and the level of astroglial and microglial/macrophage hyperplasia, inflammatory cytokine and P2X7R and P2Y1R expression in the peri-infarct hippocampal CA1and sensorimotor cortex were investigated after IS to evaluate the MCAO/R model and therapeutic mechanism of EA treatment. Results EA effectively reduced the level of pro-inflammatory cytokine interleukin-1β (IL-1β) as evidenced by reduction in astroglial and microglial/macrophage hyperplasia and the levels of P2X7R and ED1, P2X7R and GFAP, P2Y1R and ED1, P2Y1R and GFAP co-expression in peri-infarct hippocampal CA1 and sensorimotor cortex compared with that of MCAO/R model and Non-EA treatment, accompanied by the improved neurological deficit and the motor and memory impairment outcomes. Therefore, our data support the hypothesis that EA could exert its anti-inflammatory effect via inhibiting the astroglial and microglial/macrophage P2 purinoceptors (P2X7R and P2Y1R)-mediated neuroinflammation after MCAO/R injury. Conclusion Astroglial and microglial/macrophage P2 purinoceptors-mediated neuroinflammation and hyperplasia in peri-infarct hippocampal CA1 and sensorimotor cortex were attenuated by EA treatment after ischemic stroke accompanied by the improved motor and memory behavior performance. Electronic supplementary material The online version of this article (10.1186/s12906-017-1974-y) contains supplementary material, which is available to authorized users.

Background Amnestic mild cognitive impairment (aMCI) is characterized by cognitive functional decline, especially in memory. Resting-state functional magnetic resonance imaging (fMRI) has been widely used in neuroimaging studies that explore alterations between patients and normal individuals to elucidate the pathological mechanisms of different diseases. The current study was performed to investigate alterations in the functional connectivity of the default mode network (DMN) in aMCI patients compared to healthy elderly controls, as well as further define the association between neurological alterations and memory function. Methods Twenty-five aMCI patients and 25 healthy individuals were recruited and underwent both fMRI and neuropsychological examinations. fMRI data was analyzed by independent component analysis. Results Compared to healthy individuals, aMCI patients exhibited a significant increase in functional connectivity between the DMN and right-middle and right-superior frontal gyri, left-middle occipital gyrus, and left-middle temporal gyrus, but reduced functional connectivity between the DMN and left-middle and left-inferior frontal gyri and left insula. These alterations were found to be associated with reduced memory function. Conclusions aMCI patients exhibited abnormal functional connectivity between the DMN and certain brain regions which is associated with changes in memory function associated with aMCI. Electronic supplementary material The online version of this article (doi:10.1186/s12880-017-0221-9) contains supplementary material, which is available to authorized users.

Studies have reported that electroacupuncture (EA) may reduce learning and memory impairment following cerebral ischemic injury. However, the precise mechanism of action remains unclear. In the present study, the attenuation of focal cerebral ischemia/reperfusion injury by EA in rats was investigated. EA at the Baihui (DU 20) and Shenting (DU 24) acupoints was demonstrated to significantly improve performance in the Morris water maze task, with shortened latency time and increased frequency of passing the platform. Molecular analysis revealed that EA activated the expression of α7 nicotinic acetylcholine receptors (α7nAChR) in the hippocampus. In addition, EA led to a decreased expression of the microglia/macrophage marker Iba1 and the astrocyte marker glial fibrillary acidic protein in the hippocampus. EA treatment also led to decreased production of the inflammatory cytokines tumor necrosis factor-α and interleukin-1β. Treatment with methyllycaconitine, an α7nAChR antagonist, attenuated the improvement of learning and memory following EA treatment and the inhibitory effects of EA on glial cell activation and inflammatory cytokine production. In conclusion, the findings of the present study demonstrate that EA is able to improve learning and memory function following cerebral ischemic injury via activation of α7nAChR, which significantly decreases the neuroinflammatory response.

The quality of life in neurological disorders (Neuro-QoL) is a U.S. National Institutes of Health initiative that produced a set of self-report measures of physical, mental, and social health experienced by adults or children who have a neurological condition or disorder. To describe the content of the Neuro-QoL at the item level using the World Health Organization’s international classification of functioning, disability and health (ICF). We assessed the Neuro-QoL for its content coverage of functioning and disability relative to each of the four ICF domains (i.e., body functions, body structures, activities and participation, and environment). We used second-level ICF three-digit codes to classify items into categories within each ICF domain and computed the percentage of categories within each ICF domain that were represented in the Neuro-QoL items. All items of Neuro-QoL could be mapped to the ICF categories at the second-level classification codes. The activities and participation domain and the mental functions category of the body functions domain were the areas most often represented by Neuro-QoL. Neuro-QoL provides limited coverage of the environmental factors and body structure domains. Neuro-QoL measures map well to the ICF. The Neuro-QoL–ICF-mapped items provide a blueprint for users to select appropriate measures in ICF-based measurement applications.

ObjectiveThe aim of this study was to identify the clinical efficacy of acupuncture in combination with RehaCom cognitive training in poststroke patients with cognitive dysfunction.Methods/DesignThis study was a 2 × 2 factorial design randomized controlled trial comparing acupuncture, computer-assisted cognitive rehabilitation, and the usual treatment by per-protocol analysis. The trial was completed by 204 stroke patients, including 49 patients in a control group, 52 patients in an acupuncture treatment group, 51 patients in a RehaCom training group, and 52 patients in an acupuncture combined with RehaCom group. All of the patients accepted basic treatment and health education. The interventions continued for 12 weeks (30 minutes per day, 5 days per week). The relative cognitive and functional outcomes were measured at baseline and 12 weeks (at the end of intervention) using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Functional Independence Measure (FIM) scales.ResultsAfter 12 weeks of treatment, the functional statuses of the patients in each of the 4 groups showed varying degrees of improvement. Multiple comparisons of the changes in the MMSE, MoCA, and FIM scores indicated that acupuncture combined with RehaCom cognitive training (ACR) had enhanced therapeutic effects on the functional statuses of the stroke patients (P

Ischemic stroke is a common cause of death due to obstructed blood supply of the brain. Despite growing numbers of research, etiology underlying ischemic stroke remains complex and elusive. Elevated plasma homocysteine has been known as a risk factor for ischemic stroke. Recently, a genome-wide association study reported association between rs548987 of SLC17A3 and homocysteine. Given existing relation between homocysteine and ischemic stroke, SLC17A3 was believed to be a promising candidate gene of ischemic stroke. Indeed, its association with ischemic stroke was previously reported in a western population. Herein, we used rs548987 as a candidate genetic variant of ischemic stroke and performed association analysis in a Chinese population with 918 ischemic stroke cases and 979 controls. Although rs548987 failed to show significant association with total ischemic stroke and large vessel disease subtype, the C allele of rs548987 showed significant association with small vessel disease subtype of ischemic stroke (OR=0.68, p=0.004). Our preliminary results suggested different genetic etiology underlying the two most common subtypes of ischemic stroke and provided additional evidence to understand contribution of homocysteine to the disease.

The present study aimed to investigate the inhibitory effects, and underlying mechanisms, of Gua Lou Gui Zhi decoction (GLGZD) in a rat model of neuroinflammation. Sprague-Dawley rats were treated with GLGZD following middle cerebral artery occlusion (MCAO). Neurological function and infarct volume were evaluated to confirm successful generation of the rat model. Subsequently, brain tissues and blood samples were collected for further analysis. Nitric oxide (NO) and prostaglandin E2 (PGE2) were evaluated in peripheral blood samples using the Griess reagent assay and an ELISA, respectively. The relative expression levels of inducible nitric oxide synthase (iNOS) and cylooxygenase‑2 (COX‑2) were detected by quantitative polymerase chain reaction and immunohistochemistry. The associated pathways, including nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinases (MAPK) signaling pathways, were detected by electrophoretic mobility shift assay and western blotting. The results demonstrated that treatment with GLGZD significantly inhibited MCAO-induced inflammation; GLGZD suppressed the production of NO and PGE2, and the expression of iNOS and COX‑2, by inhibiting NF‑κB activation and MAPK phosphorylation. These findings suggest that GLGZD, a potential agent for post‑stroke treatment, may exert anti‑inflammatory effects, thus providing neuroprotection.

Brain ischemia leads to insufficient oxygen supply or hypoxia and thus to ischemic stroke or chronic hypoperfusion, which results in neuronal death and white matter damage is irreversible or partially recoverable under the interruption of blood flow more than a few minutes. The present study investigated the abnormal characteristics of white matter integrity after the chronic cerebral ischemia in a mouse model of bilateral carotid artery stenosis and the acute cerebral ischemia in a mouse model of middle cerebral artery occlusion via longitudinal diffusion tensor imaging, which revealed that the mean diffusivity of corpus callosum (cc) was decreased as early as the 1 st day after chronic cerebral ischemia, and then the damage gradually aggravated and lasted to the 28th day. Moreover, the brain regions, including cingulum (cg), dorsal hippocampal commissure (dhc), forceps major of the corpus callosum (fmj), alveus of the hippocampus (alv) and medial lemniscus (ml), were damaged in duration of 7∼28 days after chronic cerebral ischemia. Oppositely, white matter signals in the contralateral hemisphere appeared compensatory increase in the internal capsule (ic) at the 1 st day after acute cerebral ischemia, simultaneously the ipsilateral hemisphere signals were decreased in alv, cerebral peduncle (cp), external capsule (ec), ml, fimbria of the hippocampus (fi), ic, forceps minor of the corpus callosum (fmi) and dhc. While these regional white matter signals were decreased in the bilateral hemisphere at the 7th day after acute cerebral ischemia. In addition, the motor function was impaired after acute cerebral ischemia, and cognitive function were impaired after chronic and acute cerebral ischemia. Furthermore, voxel-wise analysis revealed the obvious differences of white matter integrity in these two models of ischemia. The chronic cerebral ischemia showed better white matter integrity in the ipsilateral hemisphere of acute cerebral ischemic model at the 1 st day after surgery, but worse in the contralateral hemisphere. Subsequently, these differences were reduced significantly and just only the ipsilateral cp and bilateral ml signals were higher in chronic cerebral ischemia. Taken together, the present study demonstrates that the chronic and acute cerebral ischemia cause progressive damages of white matter that are irreversible in a relatively long time, of which the contralateral white matter present transient compensation in acute cerebral ischemia but not in chronic cerebral ischemia. These might be helpful to better diagnosis of clinical different cerebral ischemia.

Stroke is a significant cause of morbidity and long-term disability globally. Detection of injured neuron is a prerequisite for defining the degree of focal ischemic brain injury, which can be used to guide further therapy. Here, we demonstrate the capability of two-photon microscopy (TPM) to label-freely identify injured neurons on unstained thin section and fresh tissue of rat cerebral ischemia-reperfusion model, revealing definite diagnostic features compared with conventional staining images. Moreover, a deep learning model based on convolutional neural network is developed to automatically detect the location of injured neurons on TPM images. We then apply deep learning-assisted TPM to evaluate the ischemic regions based on tissue edema, two-photon excited fluorescence signal intensity, as well as neuronal injury, presenting a novel manner for identifying the infarct core, peri-infarct area, and remote area. These results propose an automated and label-free method that could provide supplementary information to augment the diagnostic accuracy, as well as hold the potential to be used as an intravital diagnostic tool for evaluating the effectiveness of drug interventions and predicting potential therapeutics.

Objectives Knee osteoarthritis (KOA) is a common degenerative joint disease with no satisfactory intervention. Recently, both physical and mindfulness exercises have received considerable attention for their implications in KOA pain management, and the dorsolateral prefrontal cortex (DLPFC) has displayed a critical role in pain modulation. This study aimed to comparatively investigate the modulation effects of different exercises using multidisciplinary measurements. Methods 140 KOA patients were randomized into Tai Chi, Baduanjin, stationary cycling, or health education control groups for 12 weeks. Knee Injury and Osteoarthritis Outcome Score (KOOS), resting state functional magnetic resonance imaging (fMRI), structural MRI, and serum biomarkers were measured at baseline and at the end of the study. Results We found: 1) increased KOOS pain subscores (pain reduction) and serum programmed cell death protein 1 (PD-1) levels in the three exercise groups compared to the control group; 2) decreased resting state functional connectivity (rsFC) of the DLPFC-supplementary motor area (SMA) and increased rsFC between the DLPFC and anterior cingulate cortex in all exercise groups compared to the control group; 3) significant associations between DLPFC-SMA rsFC with KOOS pain subscores and serum PD-1 levels at baseline; 4) significantly increased grey matter volume in the SMA in the Tai Chi and stationary cycling groups, and a trend toward significant increase in the Baduanjin group compared to the control group; 5) significant DLPFC rsFC differences among different exercise groups; and 6) that baseline DLPFC-SMA rsFC can predict the effect of mind-body exercise on pain improvement in KOA. Conclusion Our results suggest that different exercises can modulate both common and unique DLPFC (cognitive control) pathways, and altered DLPFC-SMA rsFC is associated with serum biomarker levels. Our findings also highlight the potentials of neuroimaging biomarkers in predicting the therapeutic effect of mind-body exercises on KOA pain.

Mild cognitive impairment (MCI) is a common neurological disorder. This study aims to investigate the modulation effect of Baduanjin (a popular mind-body exercise) on MCI. 69 patients were randomized to Baduanjin, brisk walking, or an education control group for 24 weeks. The Montreal Cognitive Assessment (MoCA) and Magnetic Resonance Imaging scans were applied at baseline and at the end of the experiment. Compared to the brisk walking and control groups, the Baduanjin group experienced significantly increased MoCA scores. Amplitude of low-frequency fluctuations (ALFF) analysis showed significantly decreased ALFF values in the right hippocampus (classic low-freqency band, 0.01‐0.08 Hz) in the Baduanjin group compared to the brisk walking group and increased ALFF values in the bilateral anterior cingulate cortex (ACC, slow-5 band, 0.01-0.027 Hz) in the Baduanjin group compared to the control group. Further, ALFF value changes in the right hippocampus and bilateral ACC were significantly associated with corresponding MoCA score changes across all groups. We also found increased gray matter volume in the Baduanjin group in the right hippocampus compared to the brisk walking group and in the bilateral ACC compared to the control group. In addition, there was an increased resting state functional connectivity between the hippocampus and right angular gyrus in the Baduanjin group compared to the control group. Our results demonstrate the potential of Baduanjin for the treatment of MCI. Keywords: Mind-body intervention, Baduanjin, Resting state functional connectivity, Voxel-based morphometry, Mild cognitive impairment, Hippocampus, Anterior cingulate cortex

Background: Chronic inflammation plays a significant role in accelerating the aging process and is closely associated with the initiation and progression of a broad range of age-related diseases. Physical exercise is considered beneficial in alleviating these conditions, but the effects of aerobic exercise on inflammatory markers in a healthy population should be furtherly clarified. Objective: The purpose of this systematic review and meta-analysis was to evaluate the effect of aerobic exercise on inflammatory markers in middle-aged and older adults. Methods: The literature search was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library from their inception through April 2018, and the reference lists were screened to identify appropriate studies. Only randomized controlled trials that investigated the effect of aerobic exercise on inflammatory markers in middle-aged and older adults were eligible for this review. Results: Eleven studies involving 1,250 participants were retrieved from the databases for analysis. The pooled results showed that aerobic exercise significantly reduced inflammatory markers (C-reactive protein (CRP): SMD = 0.53, 95% CI 0.26-0.11, p = 0.0002; tumor necrosis factor-alpha (TNF-α): SMD = 0.75, 95% CI 0.31-1.19, p = 0.0007; interleukin 6 (IL-6): SMD = 0.75, 95% CI 0.31-1.19, p = 0.0007). No significant improvement was found in relation to interleukin 4 (IL-4). Conclusions: Aerobic exercise may have a positive effect on reduction of CRP, TNF-α, and IL-6 in middle-aged and older adults. Further randomized controlled trials (RCTs) need to be conducted to determine the effect of aerobic exercise on additional inflammatory markers in the population of middle-aged and older adults.

The aim of current study was to assess the effects of Baduanjin exercise on cerebrovascular function, cardiac structure and cardiac function, static pulmonary function, traditional risk factors of CVD and the related psychological outcomes in older community adults at risk for ischaemic stroke. A randomized controlled trial was conducted in three community between November 2013 and October 2015. Older community-dwelling adults (N = 170) were randomly allocated into either a Baduanjin training (5 × 60 min/weekly) or control group who kept their unaltered lifestyle during a 12-week intervention period. Primary (cerebral haemodynamic parameters) and secondary outcomes (cardiac structure, cardiac function, static pulmonary function, traditional risk factors and the related psychological outcomes) were measured at baseline, after a 12-week intervention period and after an additional 12-week follow-up period. After the 12-week intervention period and additional 12-week follow-up period, the Baduanjin exercise group displayed significant changes in most cerebral haemodynamic parameters compared to the control group: lower systolic blood pressure, diastolic blood pressure, plasma total cholesterol levels, waist circumference, hip circumference and waist/hip ratio; and improved mood, self-confidence, self-esteem, quality of life and sleep quality. A supervised 12-week Baduanjin exercise intervention was effective and safe in modulating cerebral haemodynamics, reducing blood pressure and improving anthropometric parameters and related psychological outcomes in older community adults at risk for ischaemic stroke.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Currently, the diagnosis of AD depends on clinical assessments and post-mortem neuropathology, which is unbenefited early diagnosis and progressive monitoring. In recent years, clinical studies have reported that the level of cerebrospinal fluid (CSF) and blood neurogranin (Ng) are closely related to the occurrence and subsequent progression of AD. Therefore, the study used meta-analysis to identify the CSF and blood Ng levels for the development of diagnosis biomarker of patients with AD and mild cognitive impairment (MCI). Methods: We did a systematic review and meta-analysis, in which we searched the Pubmed, Embase, Cochrane Library and Web of Science databases from database inception to June 1, 2019, to identify comparative studies to analysis the association of cerebrospinal fluid and blood plasma exosomes Ng with cognitive impairment in patients with AD and MCI. Findings: A total of 24 articles eligible for inclusion and exclusion criteria were assessed, including 4661 individuals, consisting of 1518 AD patients, 1501 MCI patients, and 1642 healthy control subjects. The level of CSF Ng significantly increased in patients with AD and MCI compared with healthy control subjects (SMD: 0.84 [95% CI: 0.70 to 0.98], P

Backgroud Tai Chi Chuan was used for stroke survivors with balance impairments. However, even a short-form of Tai Chi Chuan includes forms that make the exercise challenging for the stroke survivors. Tai Chi Yunshou (wave hands in the cloud) is the “mother” form and the fundamental form of all Tai Chi Chuan styles, which is considered more suitable and feasible for stroke survivors with balance impairments. So this study was designed to evaluate the effects of Tai Chi Yunshou exercise on community-based stroke patients with balance dysfunctions. Methods A total of 250 participants from 10 community health centers (5 per arm) were selected and randomly allocated into Tai Chi Yunshou exercise group (TC group) or a balance rehabilitation training group (control group) in an equal ratio. Participants in the TC group were received Tai Chi Yunshou exercise training five times per week for 12 weeks and those in control group were received balance rehabilitation training five times per week for 12 weeks. Outcome assessments including Berg Balance Scale (BBS), Time up to go test (TUGT), Modified Barthel Index (MBI) were measured at baseline, 4 weeks, 8 weeks, 12 weeks and followed-up 6 weeks (18 weeks), 12 weeks (24 weeks). Intention-to-treat analysis was performed. Analysis of variance of repeated measures was used to assess between-group differences. Results A total of 244 participants, 120 in the TC group and 124 in the rehabilitation group, were included in final analysis. There was no siginificant difference in Tai Chi Yunshou and balance rehabilitation training on the improvement of balance ability and mobility (P = 0.531 and P = 0.839, respectively) after adjustment for baseline. However, there was significant difference between two groups on improvement of motor funtion (P = 0.022), fear of falling (P

The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)‑2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP‑2/MMP‑9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury.

Rheumatoid arthritis is considered a serious public health problem, which is commonly treated with traditional Chinese or herbal medicine. The present study evaluated the effects of Bauhinia championii (Benth.) Benth. extraction (BCBE) on a type II collagen-induced arthritis (CIA) rat model. Wistar rats with CIA received either 125 or 500 mg/kg BCBE, after which, paw swelling was markedly suppressed compared with in the model group. In addition, BCBE significantly ameliorated pathological joint alterations, including synovial hyperplasia, and cartilage and bone destruction. The protein and mRNA expression levels of interleukin (IL)‑6, IL‑8, tumor necrosis factor‑α and nuclear factor‑κB in synovial tissue were determined by immunohistochemical staining, western blot analysis and reverse transcription‑polymerase chain reaction. The results demonstrated that the expression levels of these factors were significantly downregulated in the BCBE‑treated group compared with in the model group. These results indicated that BCBE may exert an inhibitory effect on the CIA rat model, and its therapeutic potential is associated with its anti-inflammatory action.

The aim of the present study was to investigate whether the cyclic adenosine 3',5'‑monophosphate (cAMP)/protein kinase A(PKA)/cAMP‑responsive element binding protein (CREB) signal transduction pathway triggered by γ‑aminobutyric acid class B (GABA(B)) receptor activation is involved in neuroprotection against ischemia and behavioral recovery induced by opposing needling (ON). A total of 80 rats were randomly divided into four groups: A sham operation group, an ischemia group, an ON group and an ON group effectively inhibited by the GABA(B) receptor antagonist, CGP35384 (n=20/group). The behavior of the rats was assessed by their neurological deficit score, whereas the impairment of gait was examined using the CatWalk system. The volume of cerebral infarction was examined upon treatment with 2,3,5‑triphenyltetrazolium chloride. The expression levels of CREB, GABA(B1) and GABA(B2) were examined by western blotting and reverse transcription‑quantitative polymerase chain reaction, and the activity of adenylyl cyclase (AC), cAMP and PKA in the serum was detected using an enzyme‑linked immunosorbent assay. In the present study, in comparison with other groups, the ON group exhibited a reduced score for the neurological deficit, the stride length and swing speed were improved, and the volume of infarction was reduced. However, these effects were reversed upon administration of CGP35384. Additionally, the expression levels of CREB, GABA(B1) and GABA(B2) were increased in the ON group. The levels of AC, cAMP and PKA in the serum were also increased in the ON group, whereas the addition of CGP35384 reversed these effects. The results of the present study demonstrated that ON markedly protected the brain against transient cerebral ischemic injury, and this effect was possibly mediated by the activation of the GABAB/cAMP/PKA/CREB signal transduction pathway. These findings implied that ON may be a potential therapeutic method for treating stroke.

Alzheimer's disease (AD) is a common human neurodegenerative disorder characterized by progressive deterioration of cognition and memory. Acupuncture at the Baihui (DU20) acupoint has long been used in China to clinically treat cognitive impairment. However, the precise mechanism underlying its neuroprotective effects remains to be elucidated. In the present study, electroacupuncture (EA) at the Baihui (DU20) acupoint was observed to markedly ameliorate cognitive impairments, reduce the aberrant overexpression of β-amyloid(1-42), and inhibit neuronal apoptosis in APP/PS1 mice. As brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of AD, the expression and processing of BDNF in APP/PS1 mice was investigated. EA at the Baihui (DU20) acupoint was indicated to significantly enhance the expression levels of mature BDNF and proBDNF in APP/PS1 mice. Furthermore, an increase in the BDNF/proBDNF ratio, upregulation of the expression levels of phosphorylated tropomyosin receptor kinase B and a decrease in the expression level of p75 neurotrophin receptor were also observed in the APP/PS1 mice. The present study demonstrates the efficacy of EA at the Baihui (DU20) acupoint in the treatment of cognitive impairments in APP/PS1 transgenic mice. The present study hypothesized that modulation of BDNF expression and processing may be the underlying mechanism by which stimulation of the Baihui (DU20) acupoint exerts its neuroprotective effect.

The aim of the present study was to investigate the neuroprotective mechanism of the miR-9-mediated activation of the nuclear factor (NF)-κB signaling pathway by electroacupuncture (EA) stimulation of the Quchi (LI11) and Zusanli (ST36) acupoints in a rat model of middle cerebral artery occlusion (MCAO). The present study demonstrated that EA alleviated the symptoms of neurological deficits and reduced the infarct volume in the rat brains. The expression of miR-9 in the peri-infarct cortex was increased in the EA group compared with the MCAO group, and the expression of NF-κB signaling pathway-associated factors, NF-κB p65, tumor necrosis factor (TNF)-α and interleukin (IL)-1β were reduced. Notably, miR-9 inhibitors were revealed to have the ability to suppress EA-alleviated cerebral inflammation and the expression of NF-κB downstream-related factors, NF-κB p65, TNF-α and IL-1β, and caused no alteration on the level of NF-κB upstream-related protein inhibitor of κBα, suggesting that the cerebral protective efficacy of EA targets miR-9-mediated NF-κB downstream pathway following ischemic stroke.

In a previous study by our group, we demonstrated that electroacupuncture (EA) activates the class I phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. There is considerable evidence that the downstream mammalian target of rapamycin complex 1 (mTORC1) plays an important role in autophagy following ischemic stroke. The aim of the present study was to determine whether EA exerts a neuroprotective effect through mTORC1-mediated autophagy following ischemia/reperfusion injury. Our results revealed that EA at the LI11 and ST36 acupoints attenuated motor dysfunction, improved neurological deficit outcomes and decreased the infarct volumes. The number of autophagosomes, autolysosomes and lysosomes was decreased following treatment with EA. Simultaneously, the levels of the autophagosome membrane maker, microtubule-associated protein 1 light chain 3 beta (LC3B)II/I, Unc-51-like kinase 1 (ULK1), autophagy related gene 13 Atg13) and Beclin1 (ser14) were decreased, whereas mTORC1 expression was increased in the peri-infarct cortex. These results suggest that EA protects against ischemic stroke through the inhibition of autophagosome formation and autophagy, which is mediated through the mTORC1-ULK complex-Beclin1 pathway.

BackgroundMonitoring the functional status of poststroke patients after they transition home is significant for rehabilitation. Mobile health (mHealth) technologies may provide an opportunity to reach and follow patients post discharge. However, the feasibility and validity of functional assessments administered by mHealth technologies are unknown.ObjectiveThis study aimed to evaluate the feasibility, validity, and reliability of functional assessments administered through the videoconference function of a mobile phone–based app compared with administration through the telephone function in poststroke patients after rehabilitation hospitalization.MethodsA randomized controlled trial was conducted in a rehabilitation hospital in Southeast China. Participants were randomly assigned to either a videoconference follow-up (n=60) or a telephone follow-up (n=60) group. We measured the functional status of participants in each group at 2-week and 3-month follow-up periods. Half the participants in each group were followed by face-to-face home visit assessments as the gold standard. Validity was assessed by comparing any score differences between videoconference follow-up and home visit assessments, as well as telephone follow-up and home visit assessments. Reliability was assessed by computing agreements between videoconference follow-up and home visit assessments, as well as telephone follow-up and home visit assessments. Feasibility was evaluated by the levels of completion, satisfaction, comfort, and confidence in the 2 groups.ResultsScores obtained from the videoconference follow-up were similar to those of the home visit assessment. However, most scores collected from telephone administration were higher than those of the home visit assessment. The agreement between videoconference follow-up and home visit assessments was higher than that between telephone follow-up and home visit assessments at all follow-up periods. In the telephone follow-up group, completion rates were 95% and 82% at 2-week and 3-month follow-up points, respectively. In the videoconference follow-up group, completion rates were 95% and 80% at 2-week and 3-month follow-up points, respectively. There were no differences in the completion rates between the 2 groups at all follow-up periods (X21=1.6, P=.21 for 2-week follow-up; X21=1.9, P=.17 for 3-month follow-up). Patients in the videoconference follow-up group perceived higher confidence than those in the telephone follow-up group at both 2-week and 3-month follow-up periods (X23=6.7, P=.04 for 2-week follow-up; X23=8.0, P=.04 for 3-month follow-up). The videoconference follow-up group demonstrated higher satisfaction than the telephone follow-up group at 3-month follow-up (X23=13.9; P=.03).ConclusionsThe videoconference follow-up assessment of functional status demonstrates higher validity and reliability, as well as higher confidence and satisfaction perceived by patients, than the telephone assessment. The videoconference assessment provides an efficient means of assessing functional outcomes of patients after hospital discharge. This method provides a novel solution for clinical trials requiring longitudinal assessments.Trial Registrationchictr.org.cn: ChiCTR1900027626; http://www.chictr.org.cn/edit.aspx?pid=44831&htm=4.

Stroke at the acute stage is a major cause of disability in adults, and is associated with dysfunction of brain networks. However, the mechanisms underlying changes in brain connectivity in stroke are far from fully elucidated. In the present study, we investigated brain metabolism and metabolic connectivity in a rat ischemic stroke model of middle cerebral artery occlusion (MCAO) at the acute stage using (18)F-fluorodeoxyglucose positron emission tomography. Voxel-wise analysis showed decreased metabolism mainly in the ipsilesional hemisphere, and increased metabolism mainly in the contralesional cerebellum. We used further metabolic connectivity analysis to explore the brain metabolic network in MCAO. Compared to sham controls, rats with MCAO showed most significantly reduced nodal and local efficiency in the ipsilesional striatum. In addition, the MCAO group showed decreased metabolic central connection of the ipsilesional striatum with the ipsilesional cerebellum, ipsilesional hippocampus, and bilateral hypothalamus. Taken together, the present study demonstrated abnormal metabolic connectivity in rats at the acute stage of ischemic stroke, which might provide insight into clinical research.

Objective To explore the precise mechanism of electroacupuncture (EA) to delay cognitive impairment in Alzheimer disease. Methods N -Acetylaspartate (NAA), glutamate (Glu) and myoinositol (mI) metabolism were measured by magnetic resonance spectroscopy, learning and memory of APP/PS1 mouse was evaluated by the Morris water maze test and the step-down avoidance test, neuron survival number and neuronal structure in the hippocampus were observed by Nissl staining, and BDNF and phosphorylated TrkB detected by Western blot. Results EA at DU20 acupuncture significantly improve learning and memory in behavioral tests, up-regulate NAA, Glu and mI metabolism, increase the surviving neurons in hippocampus, and promote the expression of BDNF and TrkB in the APP/PS1 transgenic mice. Conclusion These findings suggested that EA is a potential therapeutic for ameliorate cognitive dysfunction, and it might be due to EA could improve NAA and Glu metabolism by upregulation of BDNF in APP/PS1 mice.