Background:Genetic polymorphisms in drug metabolism play an important role in the wide inter-individual variability in antidepressant efficacy. This study aimed to determine whether cytochrome P450 2C19 (CYP2C19) and cytochrome P450 2D6 (CYP2D6) genotypes predict treatment response to escitalopram (ESC) and venlafaxine (VEN), respectively, in patients with post-stroke depression (PSD). Methods:In this single-center prospective observational study, 313 acute stroke patients with PSD were consecutively enrolled and received ESC or VEN for 8 weeks. Efficacy was assessed using the 17-item Hamilton Depression Scale (HAMD-17). The primary outcome was the change in HAMD-17 score from baseline to week 8; secondary outcomes were response (≥50% reduction) and remission (score ≤7). Patients were stratified by CYP2C19 and CYP2D6 genotypes into fast- and slow-metabolizer subgroups. Subgroup comparisons utilized χ2 -tests and Mann-Whitney U-tests. Results:At week 8, among 148 ESC-treated patients, CYP2C19 genotypes were distributed as poor/intermediate metabolizers (PM/IM) 82 (55.4%) and normal/rapid metabolizers (NM/RM) 64 (43.2%); among 113 VEN-treated patients, CYP2D6 genotypes showed marked imbalance (only 2 IM, 111 NM). No significant difference was found between ESC PM/IM and NM/RM subgroups in HAMD‑17 reduction (median: 10 vs 11, P=0.434), response (61.0% vs 69.7%, P=0.269), or remission (48.8% vs 51.5%, P=0.741). For patients treated with VEN, there was a significant imbalance in the distribution of CYP2D6 genotypes, which prevented us from further analyzing the association between CYP2D6 gene polymorphisms and the efficacy of VEN. Conclusion:No significant effect of CYP2C19 genetic polymorphism on ESC efficacy was observed in this study. These findings underscore the need for further exploration into the clinical utility of pharmacogenetics. Future antidepressant treatment should prioritize cost-effective, pragmatic approaches over costly genetic testing alone.

Depression has been increasingly recognized as a disorder involving structural and functional abnormalities of the white matter, with myelin pathology emerging as a consistent feature observed across multiple studies. This review aimed to synthesize evidence from neuroimaging, postmortem, transcriptomic, and experimental studies to elucidate the relationship between myelin damage and depressive pathophysiology. Major depressive disorder is consistently associated with reduced white matter integrity in emotion-related brain regions, including the medial prefrontal cortex, hippocampus, amygdala, and corpus callosum. Histopathological analyses reveal decreased oligodendrocyte density, impaired differentiation of oligodendrocyte progenitor cells, and downregulation of critical myelin-associated genes, alongside microglial activation and astrocytic dysfunction that exacerbate demyelination. Animal models demonstrate that demyelination correlates with depression-like behaviors and that depression interventions-such as clemastine, venlafaxine, or enriched environments-can partially restore myelin structure and alleviate behavioral deficits. These findings suggest that myelin impairment is not solely a downstream consequence of depression but may play an active role in its onset and progression. Targeting myelin protection and repair represents a promising therapeutic avenue. Future clinical studies are urgently needed to determine causal mechanisms and evaluate the efficacy of remyelination-based strategies in patients with depression.

Vascular cognitive impairment (VCI) is a devastating clinical endpoint of microvascular senescence. However, the mechanisms by which age-related focal vascular insults cause systemic brain network failure and molecular vulnerability remain unknown. To decode the multi-scale neurobiology of VCI, we conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with VCI and healthy controls. We used coordinate-based network mapping on a normative functional connectome to identify convergent structural atrophy networks. To decode multi-scale biological substrates, we checked the resulting macroscopic topography against the Allen Human Brain Atlas and 28 positron emission tomography-derived neurotransmitter maps. 18 studies contributed to the analysis, including 682 VCI patients and 643 healthy controls. VCI-related atrophy, despite appearing disparate, functionally converges onto a robust macroscopic architecture that is anchored predominantly in the somatomotor and salience networks. Transcriptomic profiling further showed that this network colocalizes significantly with Layer 6 corticothalamic and subcortical projection neurons. These neuron populations feature exceptionally long axonal projections, a property that heightens their metabolic susceptibility to chronic hypoperfusion. At the neurochemical level, this structural degradation exhibited profound spatial coherence with the macroscopic distribution of dopamine transporter (DAT) and 5-hydroxytryptamine transporter (5‑HTT). These findings suggest that VCI may represent a quintessential “disconnection syndrome” associated with the vulnerability of long-range projection pathways to vascular aging, providing a novel multi-scale neurobiological template to identify network-level targets for intervention.

Post-stroke depression (PSD) follows a dynamic remission-relapse course, yet predictors of state transitions remain unclear. Here, we applied a continuous-time multi-state Markov model to 536 ischemic stroke patients with 1,441 longitudinal assessments. We quantified transition intensities between non-PSD, mild-PSD, and severe-PSD states and identified baseline predictors of deterioration and recovery. The transition intensity from mild to non-PSD was 5.5-fold higher than progression to severe-PSD. Education ≥10 years reduced deterioration risk (HR = 0.63), while functional independence (Barthel index >60) and social support predicted remission. Severe-PSD exhibited an apparent short sojourn time (estimated mean 2.7 months) and frequent observed transitions toward milder states; however, in the absence of mortality data, this estimate may be biased by unobserved competing events and should be interpreted as hypothesis-generating rather than definitive. These findings enable early risk stratification and targeted intervention for PSD management.

BACKGROUND:Post-stroke depression (PSD) is common after acute ischemic stroke, yet its neural substrates remain unclear. This study identified structural disconnection subnetworks associated with PSD and evaluated their association with depression severity and topology. METHODS:We retrospectively analyzed 615 first-ever acute ischemic stroke patients. Depressive symptoms were assessed with HAMD-17 at baseline and 3 months. Individual 135 × 135 structural disconnection matrices were constructed from acute DWI lesions (MRI median 3 days post-stroke [1-4]) and HCP-842 normative connectome. Network-Based Statistic (NBS) identified PSD-associated subnetworks; graph theory characterized their topological properties. Partial correlation and linear regression evaluated the association between subnetwork disconnection burden and depression severity. RESULTS:NBS detected no significant subnetwork in the acute phase. Using identical acute-phase matrices, a cross-hemispheric subnetwork was associated with subacute PSD, centered on the left middle temporal gyrus, bridging the left DMN/limbic system with the right attention, visual, and default mode networks. Total subnetwork disconnection strength independently associated with 3-month HAMD scores (β = 0.001, P = 0.005) after adjusting for baseline depression, neurological deficit, cognition, and lesion volume. The left middle temporal gyrus exhibited the highest degree and betweenness centrality. CONCLUSIONS:This cross-hemispheric disconnection subnetwork is specifically associated with subacute PSD. The acute-phase negative finding may reflect time-specific phenotypic heterogeneity, where acute-phase PSD represents a mixed syndrome encompassing stress reactions and adjustment disorders, whereas subacute PSD more closely reflects stable structural network injury. This subnetwork provides a connectomic coordinate for understanding PSD-related network disruption and offers a reference for future strategies.

Neuroinflammation plays a pivotal role in the pathogenesis of secondary brain injury (SBI) after intracerebral hemorrhage (ICH). TREK-1 is a background potassium channel, and its role in regulating neuroinflammation after ICH remains unclear. In this study, ICH models were induced in wide-type (WT) and TREK knockout mice via intra-striatal administration of collagenase. Additionally, WT ICH mice were treated with the TREK-1 agonist ML67-33. Immunofluorescence, western blot, quantitative real-time PCR, enzyme-linked immunosorbent assay, and RNA-sequencing were performed to determine the role and the mechanism of TREK-1 in regulating neuroinflammation after ICH. The results indicate that TREK-1 deficiency exacerbated microglia/macrophages activation and pro-inflammatory polarization, as well as the influx of inflammatory cytokines and peripheral inflammatory cells compared to WT ICH mice. Conversely, activation of TREK-1 attenuated the inflammatory response and SBI post-ICH. These effects may be mediated through the CX3CL1-CX3CR1 pathway, as validated by specific inhibitors AZD8797. This study identified TREK-1 as a crucial modulator in alleviating SBI by regulating the inflammatory microenvironment via the CX3CL1-CX3CR1 pathway.

This study investigated the neural mechanisms behind high-frequency heart rate variability (HF-HRV), a marker of cardiac parasympathetic tone, which is crucial for understanding the interplay between physiological and emotional regulation. Previous neuroimaging studies have yielded inconsistent results, making it challenging to identify the specific brain networks involved in cardiac vagal control. To address this issue, we conducted a systematic search of PubMed, Web of Science, and Scopus for studies linking HF-HRV with brain activation coordinates. An Activation Likelihood Estimation (ALE) meta-analysis was performed to identify convergence in brain activation associated with HF-HRV. We subsequently used coordinate-based network mapping to investigate the functional connectivity of brain regions related to HF-HRV, via a database of resting-state functional connectivity from 1000 healthy volunteers. Despite the high heterogeneity among studies, which prevented the ALE meta-analysis from identifying significant voxels or clusters, coordinate-based network mapping revealed consistent network overlap in the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC), both of which were positively correlated with HF-HRV. No significantly correlated areas were detected in the brain networks that were negatively correlated with HF-HRV. These findings suggest that HF-HRV is associated with a distributed network of brain regions, with the sgACC and the vmPFC playing crucial roles in cardiac vagal control. This study introduces an innovative approach to understanding the role of the brain in HF-HRV control and provides a foundation for future research into the neural mechanisms underlying cardiac autonomic regulation.

Microglia are major resident immune cells in the central nervous system and are actively involved in the pathogenesis of ischemic stroke. Histone lactylation confers macrophage homeostatic gene expressions and regulates physiological and immune-related pathological conditions. However, the spatiotemporal expression and functional role of histone lactylation in microglial reprogramming and neurological injuries after ischemic stroke remain elusive. In this study, we observed increased levels of histone lactylation in peri-infarct areas after the middle cerebral artery occlusion-induced focal cerebral ischemia in mice. The enhanced histone lactylation favored an anti-inflammatory micro-environment and provided neuroprotective effects after ischemia, which might be mediated by histone H3 lysine 18 lactylation (H3K18la)-regulated plxnb2 expression in microglia. Microglia-specific inhibition of plxnb2 abrogated the neuroprotective effects of lactate after ischemic stroke. These findings suggest that interventions aimed at the lactate/lactylation(H3K18la)/plxnb2 axis may represent a promising therapeutic strategy for ischemic stroke treatment.

Purpose:Post-stroke depression (PSD) is the most common psychiatric complication after stroke, and its persistent form carries greater symptom burden and poorer long-term outcomes. The mechanisms of persistent PSD remain unclear. We investigated genetic variants associated with persistent PSD and evaluated prespecified gene-environment (G×E) interactions with modifiable stroke risk factors (lifestyle, diet, and common biomarkers) to test whether genotype modifies susceptibility across different environmental exposures. Patients and Methods:Patients with first-onset acute ischemic stroke who met the inclusion criteria were recruited from three hospitals in Central China between May 2018 and October 2023. A nested case-control study from May 2018 to December 2020 was conducted for initial screening of PSD-associated single nucleotide polymorphisms (SNPs) via whole-exome sequencing (WES). Validation of risk SNPs was performed in a subsequent cohort enrolled between December 2020 and October 2023. Further, risk SNPs for persistent PSD were identified, and a G×E interaction model was applied to explore how environmental exposures modulate genetic risk in persistent PSD pathogenesis. Sensitivity analyses confirmed the robustness of the results. Results:Through WES association analysis and validation, nine SNPs potentially related to PSD onset were identified: rs1055851, rs12647814, rs11108643, rs2481880, rs9965081, rs846791, rs4434123, rs1390318, and rs824695. Among these, rs9965081 showed a significant correlation with persistent PSD. This variant interacts with serum low-density lipoprotein cholesterol (LDL-C) levels in the development of persistent PSD and was validated by subgroup analysis. Conclusion:rs9965081 may be a persistent PSD-associated SNP that interacts with serum LDL-C levels. Carriers of the rs9965081 risk allele are more sensitive to LDL-C fluctuations and therefore have greater susceptibility to persistent PSD.

Brain takes up approximately 20% of the total body oxygen and glucose consumption due to its relatively high energy demand. Glucose is one of the major sources to generate ATP, the process of which can be realized via glycolysis, oxidative phosphorylation, pentose phosphate pathways and others. Lactate serves as a hub molecule amid these metabolic pathways, as it may function as product of glycolysis, substrate of a variety of enzymes and signal molecule. Thus, the roles of lactate in central nervous system (CNS) diseases need to be comprehensively elucidated. Histone lactylation is a novel lactate-dependent epigenetic modification that plays an important role in immune regulation and maintaining homeostasis. However, there's still a lack of studies unveiling the functions of histone lactylation in the CNS. In this review, we first comprehensively reviewed the roles lactate plays in the CNS under both physiological and pathological conditions. Subsequently, we've further discussed the functions of histone lactylation in various neurological diseases. Furthermore, future perspectives regarding histone lactylation and its therapeutic potentials in stroke are also elucidated, which may possess potential clinical applications.

Scedosporium apiospermum species complex are widely distributed fungi that can be found in a variety of polluted environments, including soil, sewage, and decaying vegetation. Those opportunistic pathogens with strong potential of invasion commonly affect immunosuppressed populations However, few cases of scedosporiosis are reported in immunocompetent individuals, who might be misdiagnosed, leading to a high mortality rate. Here, we reported an immunocompetent case of systemtic infection involved in lung, brain and spine, caused by S. apiospermum species complex ( S. apiospermum and S. boydii ). The patient was an elderly male with persistent fever and systemtic infection after near-drowning. In the two tertiary hospitals he visited, definite diagnosis was extremely difficult. After being admitted to our hospital, he was misdiagnosed as tuberculosis infection, before diagnosis of S. apiospermum species complex infection by the metagenomic next-generation sequencing. His symptoms were alleviated after voriconazole treatment. In the present case, the details associated with its course were reported and published studies on Scedosporium spp. infection were also reviewed, for a better understanding of this disease and reducing the misdiagnosis rate.

OBJECTIVE:Post-stroke depression (PSD) is one of the most common and severe neuropsychological sequelae after stroke. Using a prediction model composed of multiple predictors may be more beneficial than verifying the predictive performance of any single predictor. The primary objective of this study was to construct practical prediction tools for PSD at discharge utilizing a decision tree (DT) algorithm. METHODS:A multi-center prospective cohort study was conducted from May 2018 to October 2019 and stroke patients within seven days of onset were consecutively recruited. The independent predictors of PSD at discharge were identified through multivariate logistic regression with backward elimination. Classification and regression tree (CART) algorithm was employed as the DT model's splitting method. RESULTS:A total of 876 stroke patients who were discharged from the neurology departments of three large general Class A tertiary hospitals in Wuhan were eligible for analysis. Firstly, we divided these 876 patients into PSD and non-PSD groups, history of coronary heart disease (OR = 1.835; 95 % CI, 1.106-3.046; P = 0.019), length of hospital stay (OR = 1.040; 95 % CI, 1.013-1.069; P = 0.001), NIHSS score (OR = 1.124; 95 % CI, 1.052-1.201; P = 0.001), and Mini mental state examination (MMSE) score (OR = 0.935; 95 % CI, 0.893-0.978; P = 0.004) were significant predictors. The subgroup analysis results have shown that hemorrhagic stroke, history of hypertension and higher modified Rankin Scale score (mRS) score were associated with PSD at discharge in the young adult stroke patients. CONCLUSIONS:Several predictors of PSD at discharge were identified and convenient DT models were constructed to facilitate clinical decision-making.

OBJECTIVE:To explore the clinical features and genetic etiology of a patient with Adult-onset globoid cell leukodystrophy/Krabbe disease (KD).METHODS:A patient who was admitted to the Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology on February 15, 2022 due to exacerbation of right leg weakness for over 4 years was selected as the study subject. Clinical data and results of medical imaging and genetic analysis were analyzed. Candidate variants were verified by family analysis.RESULTS:The patient, a 36-year-old woman, had spasmodic gait as the primary presentation. Cranial magnetic resonance imaging (MRI) revealed symmetrical abnormalities in the bilateral corticospinal tracts, and the activity of β-galactocerebrosidase (GALC) in her white blood cells was significantly decreased. The patient was found to harbor compound heterozygous variants of the GALC gene, namely c.461C>A (p.Pro154His) and c.1901T>C (p.Leu634Ser). Her mother, sister and nephew were heterozygous carriers of the c.461C>A (p.Pro154His) variant, whilst her father was heterozygous for the c.1901T>C (p.Leu634Ser) variant.CONCLUSION:The patient was ultimately diagnosed with adult-onset KD, for which the compound heterozygous variants of the GALC gene may be accountable.

Background Post-stroke depression (PSD) can be conceptualized as a complex network where PSD symptoms (PSDS) interact with each other. The neural mechanism of PSD and interactions among PSDS remain to be elucidated. This study aimed to investigate the neuroanatomical substrates of, as well as the interactions between, individual PSDS to better understand the pathogenesis of early-onset PSD. Methods A total of 861 first-ever stroke patients admitted within 7 days poststroke were consecutively recruited from three independent hospitals in China. Sociodemographic, clinical and neuroimaging data were collected upon admission. PSDS assessment with Hamilton Depression Rating Scale was performed at 2 weeks after stroke. Thirteen PSDS were included to develop a psychopathological network in which central symptoms (i.e. symptoms most strongly correlated with other PSDS) were identified. Voxel-based lesion-symptom mapping (VLSM) was performed to uncover the lesion locations associated with overall PSDS severity and severities of individual PSDS, in order to test the hypothesis that strategic lesion locations for central symptoms could significantly contribute to higher overall PSDS severity. Results Depressed mood , Psychiatric anxiety and Loss of interest in work and activities were identified as central PSDS at the early stage of stroke in our relatively stable PSDS network. Lesions in bilateral (especially the right) basal ganglia and capsular regions were found significantly associated with higher overall PSDS severity. Most of the above regions were also correlated with higher severities of 3 central PSDS. The other 10 PSDS could not be mapped to any certain brain region. Conclusions There are stable interactions among early-onset PSDS with Depressed mood , Psychiatric anxiety and Loss of interest as central symptoms. The strategic lesion locations for central symptoms may indirectly induce other PSDS via the symptom network, resulting in higher overall PSDS severity. Trial registration URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

Objective: Repetitive transcranial magnetic stimulation (rTMS) has attracted considerable attention because of its non-invasiveness, minimal side effects, and treatment efficacy. Despite an adequate duration of rTMS treatment, some patients with post-stroke depression (PSD) do not achieve full symptom response or remission. Methods: This was a prospective randomized controlled trial. Participants receiving rTMS were randomly assigned to the ventromedial prefrontal cortex (VMPFC), left dorsolateral prefrontal cortex (DLPFC), or contralateral motor area (M1) groups in a ratio of 1:1:1. Enrollment assessments and data collection were performed in weeks 0, 2, 4, and 8. The impact of depressive symptom dimensions on treatment outcomes were tested using a linear mixed-effects model fitted with maximum likelihood. Univariate analysis of variance (ANOVA) and back-testing were used to analyze the differences between the groups. Results: In total, 276 patients were included in the analysis. Comparisons across groups showed that 17-item Hamilton Rating Scale for Depression (HAMD-17) scores of the DLPFC group significantly differed from those of the VMPFC and M1 groups at 2, 4, and 8 weeks after treatment (p < 0.05). A higher observed mood score (I3 = -0.44, 95% confidence interval [CI]: - 0.85-0.04, p = 0.030) could predict a greater improvement in depressive symptoms in the DLPFC group. Higher neurovegetative scores (I3 = 0.60, 95% CI: 0.25-0.96, p = 0.001) could predict less improvement of depressive symptoms in the DLPFC group. Conclusion: Stimulation of the left DLPFC by high-frequency rTMS (HF-rTMS) could significantly improve depressive symptoms in the subacute period of subcortical ischemic stroke, and the dimension of depressive symptoms at admission might predict the treatment effect.

Background Paraneoplastic peripheral neuropathy (PPN) caused by olfactory neuroblastoma (ONB) has not yet been reported. Case report We present a rare case of an adult who hospitalized repeatedly over the past 9 months for persistent pain and numbness in the limbs. This patient was initially diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) and treated accordingly, but neurological symptoms did not improve significantly. After this admission, FDG-PET/CT showed focal hypermetabolism of a soft-tissue mass in the nasal cavity, and further lesion biopsy suggested ONB. Combined with positive serum anti-Hu antibody, the diagnosis of PPN associated with ONB was eventually made. Furthermore, the patient's neurological symptoms were relieved after removal of the primary tumor, confirming the accuracy of the diagnosis. Conclusion Our case not only expanded the clinical characteristics of ONB but also highlighted the importance of early and comprehensive tumor screening for the diagnosis of PPN.

Background: Poststroke cognitive impairment (PSCI) is highly prevalent in stroke survivors and correlated with unfavorable clinical outcomes. This study aimed to identify the neural substrate of PSCI using atlas-based disconnectome analysis and assess the value of disconnection score, a baseline measure for stroke-induced structural disconnection, in PSCI prediction. Methods: A multicenter prospective cohort of 676 first-ever patients with acute ischemic stroke was enrolled from 3 independent hospitals in China. Sociodemographic, clinical, and neuroimaging data were collected at acute stage of stroke. Cognitive assessment was performed at 3 months after stroke. Voxel-wise and tract-wise disconnectome analysis were performed to uncover the strategic structural disconnection pattern for global PSCI. Disconnection score was calculated for each participant in leave-one-dataset-out cross-validation. Multivariable logistic regression was performed for the association between disconnection score and PSCI. Prediction models with and without disconnection score were developed, cross-validated, and compared in terms of discrimination and goodness-of-fit. Results: Compared with lesions of non-PSCI, those of PSCI were more likely to have fiber connections with left prefrontal cortex and left deep structures (thalamus and basal ganglia). Disconnection score could predict the risk and severity of PSCI during cross-validation, and was independently associated with PSCI after controlling for all baseline covariates (odds ratio, 1.38 [95% CI, 1.17–1.64]; P <0.001). Incorporating disconnection score into a reference model with 6 known predictors resulted in significant improvement in both discrimination and goodness-of-fit throughout cross-validation. Conclusions: A strategic structural disconnection pattern centered on left prefrontal cortex, thalamus, and basal ganglia is identified for global PSCI using indirect disconnectome analysis. The baseline disconnection score is independently predictive of PSCI and has significant incremental value to preexisting sociodemographic, clinical, and neuroimaging predictors. Registration: URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

Objective: Stroke is a leading cause of mortality and disability. This study aimed to investigate the temporal and directional relationships between post-stroke depressive symptoms and cognitive impairment using a crosslagged panel design. Depressive symptoms and cognitive impairment are two common post-stroke complications. However, the precise underlying mechanism remains unclear despite their close relationship. Therefore, elucidating the causal relationship between these two issues is of great clinical significance for improving the poor prognosis of stroke.Methods: This study employed a hospital-based multicenter prospective cohort design. A total of 610 patients with ischemic stroke were eligible. Depressive symptoms (measured using the seventeen-item Hamilton Rating Scale for Depression) and cognitive function (measured using the Montreal Cognitive Assessment) were assessed at baseline and the 12-month follow-up. Spearman's correlation was used to examine the correlation between cognitive function and depressive symptoms. Additionally, a cross-lagged panel analysis was employed to elucidate the causal relationship between these factors after adjusting for potential covariates. Results: The results of a four-iteration cross-lagged panel analysis substantiated a bidirectional relationship between post-stroke depressive symptoms and cognitive function over time. Specifically, higher scores for early depressive symptoms were associated with lower scores for later cognitive function; additionally, higher baseline cognitive function scores were associated with lower depressive symptom scores at a later point.Conclusion: This study establishes a reciprocally causal long-term relationship between depressive symptoms and cognitive function after an ischemic stroke. Therefore, interventions aimed at improving cognitive function and ameliorating depressive symptoms may positively affect both cognition and mood.Trial registration: ChiCTR-ROC-17013993.