Changes in brain structure and function during early aging in patients with chronic low back pain.

Objective: To explore the structural and functional changes in cognition-related brain regions in patients with chronic low back pain (CLBP) at earlier ages, and explore the impact of the interaction between CLBP and age on the brain. Methods: Seventy-six patients with CLBP were recruited and divided into "younger" age group (20-29 years, YA), "middle" age group (30-39 years, MA), and "older" age group (40-49 years, OA). All patients underwent functional magnetic resonance imaging (fMRI) as well as clinical psychological and pain-related symptoms assessments. Results: Structural analysis showed that patients in OA group had lower gray matter (GM) volumes in the orbitofrontal cortex (OFC) bilaterally and the right superior frontal gyrus (SFG) compared to YA group. The resting-state brain activity analysis showed that amplitude of low-frequency fluctuation (ALFF) values in the bilateral postcentral gyrus and left ventral medial prefrontal cortex (mPFC) were significantly different in the OA group. The functional connectivity (FC) in the right ventral dorsolateral prefrontal cortex (DLPFC) and the right insula was significantly decreased in the OA group compared to the YA and MA groups. Likewise, the FC in the left caudal parahippocampal gyrus (PHG) and left inferior parietal lobule (IPL) were significantly lower in the MA and OA groups compared to the YA group. In addition, both the structural properties and the FC values of these brain regions were significantly correlated with age. Conclusion: This preliminary study concludes that CLBP affects the aging process. The synergistic effects of CLBP and aging accelerate the functional and structural decline of certain areas of the brain, which not only affects pain processing, but are also may be associated with cognitive declines.

Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys.

BACKGROUND: Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). METHODS: Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. RESULTS: Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). CONCLUSIONS: Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.

Risk Factors and Prognostic Implications of New-Onset Paroxysmal Atrial Fibrillation in Patients Hospitalized with Intracerebral Hemorrhage.

Objective: We aimed to assess the prevalence and risk factors of new-onset paroxysmal atrial fibrillation (PAF) in patients hospitalized with ICH and determine whether the new-onset PAF had influenced functional outcomes. Methods: We analyzed a database of all consecutive patients with ICH from October 2013 to May 2022. Univariate and multivariable regression analyses were performed to identify risk factors for new-onset PAF in patients with ICH. Multivariate models were also constructed to assess whether the new-onset PAF was an independent predictor of poor functional outcome, as measured using the modified Rankin scale. Results: This study included 650 patients with ICH, among whom 24 patients had new-onset PAF. In the multivariable model, older age (OR per 10-y increase, 2.26 [95% CI, 1.52-3.35]; P<0.001), hematoma volume (OR per 10-mL increase, 1.80 [95% CI, 1.26-2.57]; P=0.001), and heart failure (OR, 21.77 [95% CI, 5.52-85.91]; P<0.001) were independent risk factors for new-onset PAF. In a sensitivity analysis restricted to 428 patients with N-terminal pro-B-type natriuretic peptide (NT-proBNP), older age, larger hematoma volume, heart failure, and increased NT-proBNP were associated with new-onset PAF. After adjusting for baseline variables, new-onset PAF was an independent predictor of poor functional outcome (OR, 10.35 [95% CI, 1.08-98.80]; P=0.042). Conclusion: Older age, larger hematoma volume, and heart failure were independent risk factors for new-onset PAF after ICH. Increased NT-proBNP is correlated with higher risks for new-onset PAF when their information is available at admission. Furthermore, new-onset PAF is a significant predictor of poor functional outcome.

Network Pharmacology Prediction and Experimental Verification for Anti-Ferroptosis of Edaravone After Experimental Intracerebral Hemorrhage.

Neuronal ferroptosis plays an important role in secondary brain injuries after intracerebral hemorrhage (ICH). Edaravone (Eda) is a promising free radical scavenger that inhibits ferroptosis in neurological diseases. However, its protective effects and underlying mechanisms in ameliorating post-ICH ferroptosis remain unclear. We employed a network pharmacology approach to determine the core targets of Eda against ICH. Forty-two rats were subjected to successful striatal autologous whole blood injection (n=28) or sham operation (n=14). The 28 blood-injected rats were randomly assigned to either the Eda or vehicle group (n=14) for immediate administration and then for 3 consecutive days. Hemin-induced HT22 cells were used for in vitro studies. The effects of Eda in ICH on ferroptosis and the MEK/ERK pathway were investigated in vivo and in vitro. Network pharmacology-based analysis revealed that candidate targets of Eda-treated ICH might be related to ferroptosis; among which prostaglandin G/H synthase 2 (PTGS2) was a ferroptosis marker. In vivo experiments showed that Eda alleviated sensorimotor deficits and decreased PTGS2 expression (all p<0.05) after ICH. Eda rescued neuron pathological changes after ICH (increased NeuN+ cells and decreased FJC+ cells, all p<0.01). In vitro experiments showed that Eda reduced intracellular reactive oxygen species and reversed mitochondria damage. Eda repressed ferroptosis by decreasing malondialdehyde and iron deposition and by influencing ferroptosis-related protein expression (all p<0.05) in ICH rats and hemin-induced HT22 cells. Mechanically, Eda significantly suppressed phosphorylated-MEK and phosphorylated-ERK1/2 expression. These results indicate that Eda has protective effects on ICH injury through ferroptosis and MEK/ERK pathway suppression.

Altered excitability of motor neuron pathways after stroke: more than upper motor neuron impairments.

BACKGROUND: Previous studies have suggested that impairment occurs in the lower motor neuron (LMN) pathway after stroke, but more research remains to be supported. OBJECTIVE: In this study, we tested the hypotheses: (1) both motor cortex and peripheral nerve pathways have decreased excitability and structural damage after stroke; (2) parameters of transcranial magnetic stimulation motor evoked potentials (TMS-MEP) can be used as predictors of motor function and stroke prognosis. METHODS: We studied five male cynomolgus monkeys with ischaemic stroke. TMS-MEP, cranial MRI, behavioural assessment, neurological scales and pathology were applied. RESULTS: Elevated resting motor threshold (RMT) (p<0.05), decreased TMS-MEP amplitudes (p<0.05) and negative RMT lateralisation were detected in both the affected motor cortex (AMC) and the paretic side median nerve (PMN) at 2 weeks poststroke. Disturbed structure and loose arrangement of myelin sheaths were observed in the PMN through H&E staining and LFB staining at 12 weeks poststroke. The primate Rankin Scale (used for assess the stroke prognosis) scores at 2-12 weeks after middle cerebral artery occlusion were [1, (1; 3)], [1, (1;2)], [1, (1; 1.5)] and [1, (1; 1.5)], respectively. The RMT and RMT lateralisation (AMC) were predictors of stroke prognosis, and the RMT lateralisation of PMN and latency of AMC were predictors of motor impairment. CONCLUSIONS: Both upper motor neuron (UMN) and LMN pathway excitability is reduced after stroke, and structural damage in median nerve 12 weeks after stroke occur. In addition, RMT and RMT lateralisation are predictors of stroke prognosis and motor impairment.

Population-Average Brain Templates and Application to Automated Voxel-Wise Analysis Pipelines for Cynomolgus Macaque.

The growing number of neuroimaging studies of cynomolgus macaques require extending existing templates to facilitate species-specific application of voxel-wise neuroimaging methodologies. This study aimed to create population-averaged structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) templates for the cynomolgus macaques and apply the templates in fully automated voxel-wise analyses. We presented the development of symmetric and asymmetric MRI and DTI templates from a sample of 63 young male cynomolgus monkeys with the use of optimized template creation approaches. We also generated the associated average tissue probability maps and Diffeomorphic Anatomical Registration using Exponentiated Lie Algebra templates for use with the Statistical Parametric Mapping (SPM), as well as the average fractional anisotropy/skeleton targets for incorporation into tract-based spatial statistics (TBSS) framework. Both asymmetric and symmetric templates in a standardized coordinate space demonstrated low bias and high contrast. Fully automated processing using SPM was accomplished for all native MRI datasets and demonstrated outstanding performance regarding skull-stripping, segmentation, and normalization when using the MRI templates. Automated normalization to the DTI template was excellently achieved for all native DTI images using the TBSS pipeline. The cynomolgus MRI and DTI templates are anticipated to provide a common platform for precise single-subject data analysis and facilitate comparison of neuroimaging findings in cynomolgus monkeys across studies and sites. It is also hoped that the procedures of template creation and fully-automated voxel-wise frameworks will provide a straightforward avenue for investigating brain function, development, and neuro-psychopathological disorders in non-human primate models.

Is Cerebral Amyloid-ß Deposition Related to Post-stroke Cognitive Impairment?

Approximately two-thirds of ischemic stroke patients suffer from different levels of post-stroke cognitive impairment (PSCI), but the underlying mechanisms of PSCI remain unclear. Cerebral amyloid-ß (Aß) deposition, a pathological hallmark of Alzheimer's disease, has been discovered in the brains of stroke patients in some autopsy studies. However, less is known about the role of Aß pathology in the development of PSCI. It is hypothesized that cerebral ischemic injury may lead to neurotoxic Aß accumulation in the brain, which further induces secondary neurodegeneration and progressive cognitive decline after stroke onset. In this review, we summarized available evidence from pre-clinical and clinical studies relevant to the aforementioned hypothesis. We found inconsistency in the results obtained from studies in rodents, nonhuman primates, and stroke patients. Moreover, the causal relationship between post-stroke cerebral Aß deposition and PSCI has been uncertain and controversial. Taken together, evidence supporting the hypothesis that brain ischemia induces cerebral Aß deposition has been insufficient so far. And, there is still no consensus regarding the contribution of cerebral amyloid pathology to PSCI. Other non-amyloid neurodegenerative mechanisms might be involved and remain to be fully elucidated.

Aspirin Therapy in Cardiovascular Disease with Glucose-6-Phosphate Dehydrogenase Deficiency, Safe or Not?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, which may present as acute hemolysis, neonatal jaundice, or chronic hemolysis. Ingestion of fava beans, as well as infection and certain drugs, are the most typical causes of acute hemolysis in people with G6PD deficiency. Aspirin, the cornerstone in current therapies for the prevention of cardiovascular disease (CVD), is occasionally reported to induce acute hemolysis in G6PD-deficient individuals. G6PD deficiency is typically asymptomatic and many CVD patients with this enzyme defect start to take long-term aspirin therapy without G6PD activity examination; however, no consensus on the safety of aspirin in this population has been reached. A few studies have reported on this issue and produced contradictory results. In this review, we discuss the possible mechanisms of aspirin-induced hemolysis, and summarize clinical evidence regarding the safety of aspirin in subjects with G6PD deficiency.

Graphene Quantum Dot Reinforced Electrospun Carbon Nanofiber Fabrics with High Surface Area for Ultrahigh Rate Supercapacitors.

High surface area, good conductivity, and high mechanical strength are important for carbon nanofiber fabrics (CNFs) as high-performance supercapacitor electrodes. However, it remains a big challenge because of the trade-off between the strong and continuous conductive network and a well-developed porous structure. Herein, we report a simple strategy to integrate these properties into the electrospun CNFs by adding graphene quantum dots (GQDs). The uniformly embedded GQDs play a crucial bifunctional role in constructing an entire reinforcing phase and conductive network. Compared with the pure CNF, the GQD-reinforced activated CNF exhibits a greatly enlarged surface area from 140 to 2032 m2 g-1 as well as a significantly improved conductivity and strength of 5.5 and 2.5 times, respectively. The mechanism of the robust reinforcing effect is deeply investigated. As a freestanding supercapacitor electrode, the fabric performs a high capacitance of 335 F g-1 at 1 A g-1 and extremely high capacitance retentions of 77% at 100 A g-1 and 45% at 500 A g-1. Importantly, the symmetric device can be charged to 80% capacitance within only 2.2 s, showing great potential for high-power startup supplies.

Sandwiching Sulfur into the Dents Between N, O Co-Doped Graphene Layered Blocks with Strong Physicochemical Confinements for Stable and High-Rate Li-S Batteries.

The development of lithium-sulfur batteries (LSBs) is restricted by their poor cycle stability and rate performance due to the low conductivity of sulfur and severe shuttle effect. Herein, an N, O co-doped graphene layered block (NOGB) with many dents on the graphene sheets is designed as effective sulfur host for high-performance LSBs. The sulfur platelets are physically confined into the dents and closely contacted with the graphene scaffold, ensuring structural stability and high conductivity. The highly doped N and O atoms can prevent the shuttle effect of sulfur species by strong chemical adsorption. Moreover, the micropores on the graphene sheets enable fast Li+ transport through the blocks. As a result, the obtained NOGB/S composite with 76 wt% sulfur content shows a high capacity of 1413 mAh g-1 at 0.1 C, good rate performance of 433 mAh g-1 at 10 C, and remarkable stability with 526 mAh g-1 at after 1000 cycles at 1 C (average decay rate: 0.038% per cycle). Our design provides a comprehensive route for simultaneously improving the conductivity, ion transport kinetics, and preventing the shuttle effect in LSBs.

Persistence of Gut Microbiota Dysbiosis and Chronic Systemic Inflammation After Cerebral Infarction in Cynomolgus Monkeys.

Background: The bidirectional interaction between the gut and brain after stroke through the immune-mediated pathway has been studied. However, the long-term effects of gut microbiota and systemic immune homeostasis after cerebral ischemia remain unclear. We examined long-term changes in the gut microbiota and systemic inflammatory cytokines after cerebral infarction in cynomolgus monkeys. Methods: Twelve monkeys underwent successful distal M1 segment of the left middle cerebral artery occlusion (MCAO) and were randomly and equally assigned to the MCAO-1.5 m, MCAO-6 m, and MCAO-12 m groups, which were sacrificed 1.5, 6, and 12 months after cerebral infarction induction, respectively. Four monkeys that underwent a sham operation were sacrificed 12 months later. The gut microbiota and short-chain fatty acids (SCFAs) were analyzed by 16S rDNA sequencing and gas chromatography mass spectrometry, respectively. Histological examinations of the transverse colon were performed. Plasma D-lactate, zonulin, lipopolysaccharide (LPS), tumor necrosis factor (TNF-α), interferon (IFN)-γ, and interleukin (IL)-6 were detected by immunoassay kits. Results: The levels of the Bacteroidetes phylum and Prevotella genus were significantly increased, while the Firmicutes phylum as well as the Faecalibacterium, Oscillospira, and Lactobacillus genera were decreased after cerebral infarction. Gut-originating SCFAs were significantly decreased 6 and 12 months after cerebral infarction (P < 0.05). We observed intestinal mucosal damage, evaluated by Chiu's score. Plasma D-lactate, zonulin, LPS, TNF-α, IFN-γ, and IL-6 were significantly increased after cerebral infarction (P < 0.05). Additionally, the increases in plasma LPS, TNF-α, IFN-γ, and IL-6 after cerebral infarction coincided with overgrowth of the Bacteroidetes phylum (P < 0.001). Conclusion: Cerebral infarction induces persistent host gut microbiota dysbiosis, intestinal mucosal damage, and chronic systemic inflammation in cynomolgus monkeys.

Advanced Li-Ion Batteries with High Rate, Stability, and Mass Loading Based on Graphene Ribbon Hybrid Networks.

To optimize the cycle life and rate performance of lithium-ion batteries (LIBs), ultra-fine Fe2 O3 nanowires with a diameter of approximately 2 nm uniformly anchored on a cross-linked graphene ribbon network are fabricated. The unique three-dimensional structure can effectively improve the electrical conductivity and facilitate ion diffusion, especially cross-plane diffusion. Moreover, Fe2 O3 nanowires on graphene ribbons (Fe2 O3 /GR) are easily accessible for lithium ions compared with the traditional graphene sheets (Fe2 O3 /GS). In addition, the well-developed elastic network can not only undergo the drastic volume expansion during repetitive cycling, but also protect the bulk electrode from further pulverization. As a result, the Fe2 O3 /GR hybrid exhibits high rate and long cycle life Li storage performance (632 mAh g-1 at 5 A g-1 , and 471 mAh g-1 capacity maintained even after 3000 cycles). Especially at high mass loading (≈4 mg cm-2 ), the Fe2 O3 /GR can still deliver higher reversible capacity (223 mAh g-1 even at 2 A g-1 ) compared with the Fe2 O3 /GS (37 mAh g-1 ) for LIBs.