CNS Neuroscience & Therapeutics最新文献

Background

Hepatic ischemia–reperfusion injury (HIRI) is a pathologic process commonly encountered during liver surgery, which seriously threatens patient prognosis. Currently, effective interventions or preventive measures are still lacking. Notably, patients with liver disease commonly experience brief acute stress prior to surgery; however, the impact of acute stress on HIRI remains unclear.

Methods

A 30-min restraint stress was used to simulate acute restraint stress (ARS). Hematoxylin–eosin staining and ELISA were employed to assess HIRI. Immunofluorescence staining and electrophysiology were applied to evaluate neuronal activation. Chemogenetic manipulation was utilized to verify the role of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) in ARS-mediated attenuation of HIRI.

Results

The results showed that ARS significantly ameliorated liver injury, reduced the liver enzyme levels (ALT and AST), and down-regulated the inflammatory factors expression in HIRI mice. Furthermore, we found that ARS alleviated HIRI by activating the hypothalamic–pituitary–adrenal (HPA) axis to release corticosterone, rather than through the sympathetic nervous system. PVN^CRH represented a critical subpopulation responding to ARS. Chemogenetic activation of PVN^CRH neurons mimicked the protective effect of ARS against HIRI, whereas chemogenetic inhibition of these neurons abolished this protection.

Conclusion

Our findings demonstrate that PVN^CRH neurons mediate the protective effect of ARS against HIRI by activating the HPA axis to release corticosterone. This work may provide key insights for developing perioperative strategies to prevent HIRI.

Background and Aims

Wall shear stress (WSS) may govern the initiation and progression of atherosclerosis. We aimed to depict WSS distribution in symptomatic, atherosclerotic M1 middle cerebral artery (MCA-M1) stenosis, and its associations with adjacent vessel and plaque geometry.

Methods

Patients with symptomatic, atherosclerotic, 50%–99% MCA-M1 stenosis were analyzed. MCA-M1 vessel curve orientation and tortuosity, luminal stenosis, plaque length and longitudinal asymmetry were assessed on CT angiography (CTA). Relative WSS (rWSS) was calculated by the absolute WSS divided by mean WSS at the proximal, normal vessel segment, in a CTA-based computational fluid dynamics model. rWSS < 1.0, 1.0–3.0, and > 3.0 were respectively defined as low, normal, and high WSS; low- and high-WSS areas were measured. The vessel and plaque geometry was associated with the rWSS measures, across a plaque as a whole, and separately in upstream and downstream plaque segments divided at the stenotic throat.

Results

In 176 patients, rWSS increased progressively along the upstream plaque segment but highly varied downstream. rWSS was lower on the inner than on the outer wall of the MCA-M1 vessel curve. Patients with ventrally (than dorsally), inferiorly (than superiorly) oriented MCA-M1 vessel curves and higher tortuosity of the affected vessel segment exhibited lower rWSS and larger low-WSS areas at the downstream plaque segment. More severe luminal stenosis and upstream dominance in the plaque were associated with higher rWSS and larger high-WSS areas in the upstream and downstream plaque segments.

Conclusions

Wall shear stress (WSS) distribution across symptomatic MCA-M1 stenosis was variable and strongly associated with adjacent vessel and plaque geometry, independent of systemic factors.

Background

Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progression. Although ChREBP (key metabolic regulator) protects against NP, its specific mechanisms remain unclear.

Methods

NP rat model was established via spared nerve injury (SNI) surgery, and mechanical allodynia was evaluated using Von Frey tests. ChREBP expression in microglia was detected through immunofluorescence, RT-qPCR, and western blot. Functional studies involved ChREBP knockdown/overexpression to assess effects on microglial polarization, neuroinflammation, neuronal excitability, pain behaviors, and fatty acid metabolism. Mechanisms were explored via dual-luciferase reporter and chromatin immunoprecipitation assays.

Results

Mechanical pain thresholds were significantly decreased on the ipsilateral side after SNI. ChREBP was upregulated in SDH microglia after SNI and in LPS-stimulated microglia in vitro. ChREBP knockdown inhibited anti-inflammatory microglial polarization, exacerbated neuroinflammation, and aggravated pain. Conversely, ChREBP overexpression promoted the anti-inflammatory phenotype, suppressed neuroinflammation, and alleviated pain. ChREBP enhanced microglial fatty acid oxidation and energy metabolism. Mechanistically, ChREBP bound to the TFBS1 site on the PGC-1α promoter to activate its transcription. PGC-1α overexpression rescued the impairments caused by ChREBP knockdown, including reduced fatty acid oxidation, suppressed anti-inflammatory polarization, elevated inflammatory factors, and increased neuronal excitability. The protective effects of ChREBP were attenuated by the fatty acid oxidation inhibitor Etomoxir.

Conclusions

ChREBP alleviates NP by enhancing microglial fatty acid oxidation and anti-inflammatory phenotype via PGC-1α transcriptional activation, revealing a novel metabolic-immune axis for potential NP therapy.

Aims

To summarize the anatomo-electro-clinical characteristics of parietal lobe epilepsy (PLE) subgroups using unsupervised cluster analysis.

Methods

This retrospective cohort study included patients with drug-resistant PLE with seizure freedom after surgery and evaluated scalp video-electroencephalography (EEG) recordings from three epilepsy centers. Hierarchical cluster analysis associated interictal/ictal patterns and initial ictal semiology with anatomical subgroups.

Results

We analyzed 79 interictal EEG, 141 ictal EEG, and 141 semiological patterns in 47 patients. Cluster analysis associated interictal and ictal discharges from lateral superior parietal lobule epilepsy with centroparietal region distributions on scalp EEG, whereas discharges from other subgroups involved broader regions. Cluster heatmaps of the initial ictal semiology showed: Chapeau de gendarme, affective phenomena, and forced eye deviation in intraparietal sulcus; contralateral limb tonic/clonic or akinetic, affective phenomena, and visual illusions in SPL-lateral; Chapeau de gendarme, behavioral arrest, and vestibular in parieto-occipital sulcus; behavioral arrest in angular gyrus; distal gestural automatisms and cephalic sensations in posterior cingulate; body-perception illusion and contralateral versive in supramarginal gyrus; contralateral facial tonic/clonic in parietal operculum.

Conclusion

PLE subgroups exhibited distinct scalp EEG features and ictal semiology, reflecting unique propagation networks and highlighting the importance of detailed video-EEG for identifying the epileptogenic zone and guiding intracranial electrode placement.

Background

Depression is associated with adverse effects in patients with autoimmune hepatitis (AIH). However, the underlying mechanism remains unclear. This study explores the impact of depression and related intestinal microbiota on immune-mediated hepatitis.

Methods

We assessed depression in 260 AIH patients receiving 2-year standardized treatment and 173 healthy controls. In mice, depressive-like behaviors were induced by chronic unpredictable mild stress (CUMS), and immune-mediated hepatitis was induced by intravenous injection of concanavalin A (ConA). Fecal microbiota transplantation (FMT) was performed using samples from patients with major depressive disorder (MDD) and controls.

Results

Depression was common in patients with AIH (106/260, 40.8%) and was associated with cirrhosis. Compared with nondepressed AIH patients, those with depression showed exacerbated intestinal barrier dysfunction and hepatic NLR family pyrin domain containing 3 (NLRP3) inflammasome overactivation. In the ConA-induced hepatitis model, CUMS exposure aggravated these abnormalities, which were then attenuated by mirtazapine. Furthermore, mice colonized with MDD microbiota exhibited greater intestinal barrier disruption and hepatic NLRP3 inflammasome overactivation than those colonized with control microbiota. Notably, gut-derived Lactococcus formosensis, isolated from the livers of MDD microbiota-colonized mice, could translocate to the liver and induce hepatic NLRP3 inflammasome overactivation. In addition, vaccination against L. formosensis prevented translocation and alleviated liver injury in monocolonized mice.

Conclusion

Depression aggravates immune-mediated hepatitis through disruption of intestinal barrier integrity and overactivation of hepatic NLRP3 inflammasome. Gut-derived L. formosensis could translocate to the liver and induce liver injury in mice. This study provides the necessity of screening for depression in patients with AIH.

Background

Post-stroke cognitive impairment (PSCI) is a common yet frequently overlooked complication that adversely affects recovery and long-term outcomes in stroke survivors. Early identification of individuals at risk is essential for timely cognitive rehabilitation.

Objective

This study aimed to investigate the association between carotid atherosclerosis indicators—specifically, carotid plaque burden and degree of carotid artery stenosis—and the occurrence of PSCI in patients with mild acute ischemic stroke (AIS), using carotid ultrasound as a cost-effective, widely accessible diagnostic modality.

Methods

A prospective cohort of 181 patients diagnosed with AIS within 7 days of onset was enrolled. Baseline demographics, clinical characteristics, and carotid ultrasound parameters were collected. PSCI was assessed at 6 months using the Montreal Cognitive Assessment (MoCA). Binary logistic regression was used to identify independent predictors of PSCI. The predictive accuracy of individual and combined markers was evaluated using receiver operating characteristic (ROC) curve analysis.

Results

Among 181 participants, 75 (41.4%) were diagnosed with PSCI at the 6-month follow-up. Multivariate analysis revealed that the carotid plaque Crouse score (OR = 1.157, 95% CI: 1.055–1.269) and severe carotid artery stenosis (OR = 3.733, 95% CI: 1.582–8.811) were independently associated with PSCI. ROC analysis demonstrated modest predictive performance for the Crouse score (AUC = 0.667) and stenosis (AUC = 0.596), while a multivariable model incorporating clinical and ultrasound parameters achieved an AUC of 0.818 (95% CI: 0.758–0.877). Significant between-group differences were observed in AVLT-I, AVLT-II, VFT, TMT-B, CDT, and MoCA subdomains (p < 0.05).

Conclusion

Carotid plaque burden and severe carotid stenosis are independently associated with the development of PSCI in patients with mild AIS. Carotid ultrasound, combined with clinical risk factors, may provide a practical approach for early identification and risk stratification of PSCI.

Trial Registration: Chinese Clinical Trial Registry (ChiCTR1900022675); URL: https://www.chictr.org.cn/

Aims

This study aimed to investigate the association between autonomic activity, assessed by 24-hour heart rate variability (HRV), and the development of perihematomal edema (PHE) as well as 3-month functional outcomes following intracerebral hemorrhage (ICH).

Methods

We retrospectively included patients with ICH who underwent 24-hour electrocardiographic (ECG) monitoring within 14 days of onset from a prospective cohort. HRV parameters were calculated from ECG data. A poor functional outcome at 3 months was defined as a modified Rankin Scale (mRS) score ≥ 3. PHE volume was measured on 7-day computed tomography scans using 3D Slicer software, and adverse PHE was defined as relative PHE (edema volume/hematoma volume) ≥ 2. Univariate and multivariate logistic regression analyses were performed to identify predictors of adverse PHE and poor outcomes. Partial correlation analysis was conducted to examine the association between HRV parameters and adverse PHE. Five machine-learning algorithms were applied to develop predictive models for 3-month poor outcomes.

Results

A total of 312 patients were included, of whom 45.2% (141/312) had poor outcomes at 3 months and 48.6% (122/251) had adverse PHE. Parasympathetic hypoactivity, indicated by low high-frequency power, was independently associated with poor 3-month outcomes. In addition, parasympathetic hypoactivity (measured by the root mean square of successive differences between adjacent NN intervals) and relative sympathetic hyperactivity (measured by the ratio of low-frequency to high-frequency power) independently predicted adverse PHE. Among the machine-learning models, the eXtreme Gradient Boosting (XGBoost) algorithm achieved the highest predictive performance for poor 3-month outcomes, with an AUC of 0.883.

Conclusions

Twenty-four–hour parasympathetic hypoactivity is associated with adverse PHE and poor functional outcomes following ICH.

Background

Previous studies have reported functional alterations in the brains of patients with rhegmatogenous retinal detachment (RRD). However, it remains largely unclear whether RRD affects hemispheric specialization and interhemispheric coordination, and how these alterations relate to underlying gene expression patterns and neurotransmitter receptor distributions.

Methods

We employed the Autonomy Index (AI) and Connectivity between Functionally Homotopic Voxels (CFH) to quantify alterations in hemispheric specialization and interhemispheric cooperation in patients with RRD. Transcriptome–neuroimaging spatial correlation analysis was performed by integrating gene expression data from the Allen Human Brain Atlas (AHBA) to identify genes associated with AI and CFH alterations. Enrichment and protein–protein interaction analyses were conducted to characterize the biological processes and molecular features of these genes. Furthermore, we explored the spatial associations between AI/CFH abnormalities and neurotransmitter receptor distributions. Finally, a support vector machine (SVM) classifier combined with Shapley additive explanations (SHAP) was implemented to distinguish RRD patients from healthy controls (HCs) and to determine the most discriminative brain regions.

Results

RRD patients exhibited significant alterations in AI and CFH within the frontal lobe, occipital lobe, and thalamus. Transcriptome–neuroimaging integration revealed gene sets closely associated with these abnormalities. These genes were primarily enriched in key biological processes including synaptic signaling, sensory organ development, Notch signaling, and structural neuroplasticity. The spatial pattern of CFH changes showed strong alignment with the regional distributions of multiple neurotransmitter systems, particularly serotonergic, dopaminergic, glutamatergic, and cholinergic pathways. Finally, the SVM–SHAP classification framework identified CFH in the right thalamus as the most discriminative feature for differentiating RRD patients from HCs.

Conclusion

These findings deepen our neurobiological understanding of RRD-induced brain functional remodeling and provide theoretical support and a methodological foundation for developing central intervention strategies and potential discriminative imaging tools for retinal diseases.