CNS Neuroscience & Therapeutics最新文献

Background: Accelerated intermittent theta-burst stimulation (a-iTBS) is a novel rTMS protocol increasingly used for mental disorders, but its application in alcohol use disorder (AUD) remains early. This exploratory sham-controlled study evaluated a 50-session a-iTBS protocol for AUD.

Methods: Sixty-one male AUD inpatients were randomized to receive traditional iTBS (once daily, 600 pulse/session), a-iTBS (5 sessions/day, 3000 pulses/day), or sham iTBS. Treatments were administered on 10 weekdays (Monday to Friday over 2 weeks) and targeted the dorsolateral prefrontal cortex. The primary outcome was the change in craving. The alcohol relapse behavior, emotional symptoms, and sleep quality were evaluated pre-/post-intervention.

Results: Group showed no significant main effect on craving percentage change. The a-iTBS group showed a higher response rate and earlier response onset than the s-iTBS group, whereas no significant differences existed between a-iTBS and iTBS, or iTBS and s-iTBS. No intergroup differences were detected for mood and sleep indicators. At the 6-month follow-up, participants receiving a-iTBS achieved longer abstinence duration than those given s-iTBS. Exploratory logistic regression indicated that baseline GAD-7 scores and treatment group were associated with treatment response.

Conclusions: Although the primary craving outcome did not differ significantly among groups, a-iTBS showed preliminary signals of earlier response and longer time to first relapse than sham stimulation. These exploratory findings require confirmation in larger trials.

Trial design: This study aimed to explore the antiepileptic effect of Ganoderic acid A (GA-A) on pentylenetetrazol (PTZ)-induced epilepsy in mice and clarify its underlying mechanism, focusing on the KCNQ2 channel.

Methods: C57BL/6 mice and hippocampal-specific KCNQ2 knockout mice were used to establish PTZ-induced acute epilepsy models. GA-A was pretreated for 7 days. Epileptic seizures were evaluated by the Racine score and electroencephalogram (EEG). Neuronal injury was detected by HE and TUNEL staining. Neuroinflammation and oxidative stress were assessed by measuring inflammatory factors and oxidative markers. The target interaction between GA-A and KCNQ2 was verified by protein chip, molecular docking, surface plasmon resonance (SPR), and electrophysiological recording.

Results: GA-A dose-dependently reduced seizure severity, shortened epileptiform discharge duration, alleviated hippocampal neuronal loss and apoptosis, and inhibited neuroinflammation and oxidative stress in PTZ-treated mice. GA-A directly bound to KCNQ2 and activated KCNQ2/3 channels to generate M current. Hippocampal KCNQ2 knockout weakened the ameliorative effect of GA-A on EEG abnormalities and epilepsy-related anxiety- and depression-like behaviors, but did not affect its anti-inflammatory and antioxidant effects.

Conclusion: GA-A attenuates PTZ-induced epilepsy in mice via activating the KCNQ2 channel to suppress neuronal hyperexcitability and independently inhibiting neuroinflammation and oxidative stress. GA-A is a promising KCNQ2 activator and lead compound for antiepileptic drug development.

Background: Recent evidence suggests that the choroid plexus (ChP) serves as a gateway for neuroinflammation. Autoimmune encephalitis (AE) features a high inflammatory burden, yet the role of ChP in AE remains unclear. This study compared choroid plexus volume (CPV) at symptom onset between AE patients and healthy controls (HCs), and evaluated its association with prognosis.

Methods: This single-center study included 151 AE patients with definite autoantibodies. ChP volume (CPV) was segmented from baseline 3D-T1 MRI and normalized. Baseline CPV was compared between AE and age- and sex-matched HCs, and its associations with 12-month functional outcomes (mRS) and progression to autoimmune encephalitis-associated epilepsy (AEAE) were assessed. A logistic regression model based on ChP radiomic features was developed to predict AEAE. Exploratory cerebrospinal fluid (CSF) proteomics and metabolomics were performed in a small subset to generate hypotheses on underlying pathways.

Results: Of 151 AE patients, 141 completed 12-month follow-up; 26 (18.4%) developed AEAE. AE patients had significantly larger CPV than controls (1.235 ± 0.274 vs. 1.035 ± 0.264, p < 0.001). Larger baseline CPV was significantly associated with AEAE and mRS (p < 0.05). A two-feature radiomic model (RunEntropy and original volume) predicted AEAE with AUCs of 0.766 (training) and 0.851 (test). Exploratory proteomics in a subset suggested CPV-correlated downregulation of glutamatergic synapse pathways and upregulation of PI3K-Akt/integrin pathways.

Conclusions: Baseline CPV was greater in AE patients than in HCs, and larger baseline CPV was associated with progression to AEAE and poor one-year functional outcomes. ChP imaging may aid in early risk stratification for AE patients.

Introduction: The efficacy of awake craniotomy (AC) with intraoperative mapping for glioblastoma (GBM) in eloquent regions remains debated. This study aims to evaluate functional and survival outcomes of GBM patients undergoing AC stratified by tumor locations.

Methods: A combined retrospective (2015-2023, n = 114: 43 AC vs. 71 standard craniotomy) and prospective cohort (2023-2025, n = 28: 13 AC vs. 15 standard craniotomy) of GBM patients with motor/language-eloquent tumors was analyzed. Tumors were classified into motor subtypes (I: precentral gyrus; II: premotor/supplementary motor; III: internal capsule posterior limb; IV: other) and language subtypes (I: Broca's/precentral; II: postcentral/supramarginal gyrus; III: Wernicke's; IV: insular; V: other). Outcomes included extent of resection (EOR), postoperative motor/language recovery, overall survival (OS), and progression-free survival (PFS).

Results: The retrospective cohort demonstrated that AC has advantages in functional preservation across various motor/language subtypes. However, AC was associated with significantly deteriorated survival outcomes specifically in precentral gyrus GBMs. A prospective cohort study, enrolling only precentral gyrus GBMs for validation, yielded results consistent with the retrospective findings: worsened OS and PFS (OS: HR = 3.223, p = 0.0450; PFS: HR = 2.374, p = 0.0476); reduced EOR (AC: 74.3% ± 5.3%; standard craniotomy: 86.9% ± 12.3%, p = 0.0470); and better motor recovery.

Conclusions: Functional preservation and survival outcomes of AC in GBM exhibited subtype-specific correlations with tumor locations. AC with intraoperative mapping effectively preserves neurological function in GBM patients. However, for tumors involving the precentral gyrus, the AC approach carries greater risks than benefits and should be considered with caution.

Trial registration: Strategic Intervention on Preserving Motor Function During Awake Craniotomy: NCT05143788. Strategic Intervention on Preserving Language Function During Awake Craniotomy: NCT05143775.

Aims: Melatonin has shown neuroprotective potential in various models of cerebrovascular diseases, but its effects on mitophagy in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH) remain unclear.

Methods: Eighteen adult male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) to induce CCH. Animals were randomly assigned to three groups (n = 6 per group): sham-operated controls, BCCAO model animals receiving vehicle injection, and BCCAO animals treated with daily melatonin (10 mg/kg, intraperitoneally for 14 days). Cognitive performance was evaluated using the Morris water maze. Regional cerebral blood flow (rCBF) was measured with high-resolution laser Doppler imaging. Mitophagy was assessed via Western blot analysis of LC3BII/I, TOMM20, COX IV, caspase-3, and immunofluorescence colocalization of LC3B with TOMM20 in the hippocampal CA1 subfield.

Results: BCCAO rats exhibited significant cognitive deficits in the Morris water maze, along with persistently reduced rCBF. BCCAO also induced a significant upregulation of hippocampal mitophagy, as indicated by an elevated LC3BII/I, decreased TOMM20 and COX IV levels, and increased colocalization of TOMM20 and LC3B immunofluorescence signals. Caspase-3 expression was markedly higher in the BCCAO group. Melatonin treatment improved rCBF recovery at day 14, mitigated the spatial learning and memory impairments, decreased the LC3BII/I, increased mitochondrial protein markers (TOMM20, COX IV), reduced the colocalization of TOMM20 and LC3B puncta, and attenuated caspase-3 levels.

Conclusion: These findings indicate that CCH in the VaD model induces excessive hippocampal mitophagy and cognitive impairment. The cognitive improvement observed with melatonin treatment is closely correlated with restored cerebral perfusion and attenuated mitophagic activity.

Aims: Absence seizures, characterized by spike-and-wave discharges (SWDs), are mediated by reciprocal thalamocortical interactions; however, the contribution of developing inhibitory networks to SWDs remains unclear. We investigated the developmental trajectory of inhibitory interneurons in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) by analyzing their distribution across postnatal development in the somatosensory (S1) and motor (M1) cortices, the hippocampus, and striatum.

Methods: The neurodevelopmental trajectory of parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons was quantified at three critical stages: postnatal day 14 (P14), when SWDs were not yet observed, P21 when immature SWDs appear, and adulthood (P90), when mature SWDs are established. Wistar rats served as controls. Brain sections were processed immunohistochemically to quantify interneuron density.

Results: PV+ interneuron density across S1 and M1 was significantly higher in GAERS at P14 than control. However, this difference was not maintained at P21 and adults. Conversely, SST+ interneurons exhibited a delayed increase in M1. GAERS displayed higher PV+ interneuron density in the dentate gyrus and CA1 at P14, whereas SST+ interneuron density remained unchanged across hippocampal subfields. Striatal PV+ and SST+ interneurons increased at later developmental stages, suggesting altered inhibition in basal ganglia.

Conclusion: These findings demonstrate a temporally dynamic and region-specific reorganization of interneurons in GAERS that may underlie absence epileptogenesis.

Aims: To characterize the clinical, electrophysiological, and genetic spectrum of pediatric CMS and evaluate genotype-informed outcomes using an integrated phenotype-electrophysiology-genomics approach.

Methods: We retrospectively reviewed 36 pediatric CMS patients evaluated at a single center between 2015 and 2025. Clinical features, RNS, targeted NGS/WES variants, ventilator use, treatments, ACMG/AMP classifications, and MG-ADL outcomes were analyzed.

Results: Of 36 patients, 28 (77.8%) developed symptoms in the neonatal period or infancy. Biallelic variants involved 17 CMS genes; postsynaptic CMS was most common (55.6%, 20/36). COLQ and CHRNE were the most frequent genes (13.9%, 5/36 each), followed by CHAT (11.1%, 4/36). VUS were detected in 19 patients (52.8%, 19/36), including 8 with biallelic VUS supported by phenotype, neuromuscular transmission findings, treatment response, and follow-up. RNS showed a ≥ 10% decrement in 16/21 tested patients (76.2%). CHAT-CMS was associated with higher ventilator use (3/4 vs. 6/32; p = 0.041) and early mortality (3/4 vs. 1/32; p = 0.002). Median MG-ADL improved from 5 to 3 after genotype-informed therapy.

Conclusion: Pediatric CMS shows marked genetic heterogeneity and frequent VUS-related uncertainty. Integrating phenotype, electrophysiology, and genomics supports diagnosis and mechanism-guided therapy. CHAT-CMS is high risk for early respiratory failure and mortality.

Aims: To evaluate the frequency and characteristics of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) accompanied by fever.

Methods: This retrospective study was conducted from April 2019 to December 2025 at Beijing Tiantan Hospital in China. Patients who met the 2023 international MOGAD panel diagnostic criteria and had a disease duration of at least 6 months were included. Febrile and afebrile groups were compared using Mann-Whitney U, χ², and log-rank tests pre- and post-propensity score matching. Logistic regression identified factors associated with fever.

Results: A total of 123 patients were included. Fever occurred during 43 acute attacks in 38 (30.9%) patients, with the majority (33 attacks) representing the initial episode. The median maximal temperature was 38.6°C. Cerebral cortical encephalitis was the leading phenotype in febrile attacks (48.8%). Compared to the afebrile group, the febrile group exhibited a significantly higher median cerebrospinal fluid (CSF) leukocyte count (56/μL vs. 11.5/μL; p < 0.001) and CSF protein (52.65 mg/dL vs. 39.76 mg/dL; p = 0.001). Cerebral cortical encephalitis and CSF pleocytosis were independently associated with fever in the multivariable model.

Conclusions: Fever was relatively common in our MOGAD cohort, occurring in approximately one-third of patients and across all clinical phenotypes. Both cerebral cortical encephalitis and CSF pleocytosis were independently associated with fever.

Background: P7C3 compounds are aminopropyl carbazole derivatives identified through phenotypic screening for proneurogenic activity. They directly activate nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway. However, a comprehensive synthesis of their mechanisms and therapeutic potential across neurological disorders is currently lacking.

Methods: A systematic literature review was conducted in PubMed, Web of Science, and Scopus to synthesize the discovery trajectory, structure-activity relationships, molecular mechanisms, and preclinical efficacy of P7C3 compounds. The following keyword combinations were used: ("P7C3" OR "P7C3 compound") AND ("NAMPT" OR "NAD+" OR "sirtuin" OR "mitochondria") AND ("neuroprotection" OR "neurodegenerative").

Results: P7C3 elevates intracellular NAD⁺ levels, engages SIRT1 and SIRT3 deacetylase cascades, enhances mitochondrial quality control and attenuates oxidative stress. This review discusses the discovery, structure-activity relationships, and molecular mechanisms of P7C3, with a particular emphasis on mitochondrial dynamics and redox homeostasis. The efficacy of P7C3 in preclinical studies was evaluated across Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), ischemic stroke, depression, and chemotherapy-induced neuropathy. These neuroprotective effects occur independently of disease-specific aggregates. Challenges hindering clinical application include the on-target safety of NAMPT activation given the concurrent development of NAMPT inhibitors for tumorigenesis, the absence of validated predictive biomarkers, and the failure of prior NAMPT-targeting trials.

Conclusions: P7C3 illustrates how phenotypic screening coupled with target deconvolution can yield therapeutic candidates with potential applications across a broad spectrum of neurological disorders.

Introduction: Cerebral small vessel disease (CSVD) is associated with altered spontaneous brain activity on resting-state functional magnetic resonance imaging (rs-fMRI). However, MRI studies usually overlook the potential effects of postural change. This study characterized posture-related alterations in spontaneous brain activity in CSVD patients.

Materials and methods: Forty-one CSVD patients and 30 normal controls (NCs) underwent multi-position MRI, including upright and supine rs-fMRI. Amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) were calculated, and supine-upright differences (Δ) were derived. Mixed-design ANOVA assessed group, position, and interaction effects. Within-group and between-group differences were examined, followed by cognition-related analyses.

Results: The main effect of posture on ReHo was observed in frontal, temporal, and parietal cortices and deep gray nuclei. In the upright position, CSVD patients had higher ReHo in the right anterior cingulate gyrus than NCs, which was associated with worse global cognitive function and a higher composite CSVD score. CSVD patients also exhibited widespread posture-related ReHo alterations. Regression analyses demonstrated that ΔReHo in the left hippocampus was positively associated with memory function, whereas ΔReHo in the right putamen and left calcarine cortex was associated with the composite CSVD score.

Conclusion: Upright imaging and upright-supine comparison may help unmask latent posture-related ReHo abnormalities in patients with CSVD.