Assessment of tenecteplase target-associated pathogenic mechanisms underlying depression in acute ischemic stroke patients: insights from artificial intelligence-driven multi-omics analysis and in vitro validation

BackgroundAs a first-line treatment for acute ischemic stroke (AIS), tenecteplase (TNK) can cause adverse effects, such as depression, in AIS patients.ObjectiveThis study aims to elucidate the TNK target-related pathogenic mechanisms underlying major depressive disorder (MDD) in AIS patients.MethodsBy analyzing six public peripheral blood bulk datasets from AIS and MDD patients using integrative bioinformatics methods (limma, non-negative matrix factorization (NMF), and machine learning), we identified TNK target-associated molecular subgroups and diagnostic models for MDD and AIS patients, respectively. Next, a hub gene involved in the pathogenesis of both MDD and AIS was identified, and its corresponding molecular characteristics were analyzed in the peripheral blood bulk profiles of MDD and AIS patients. In addition, to gain a deeper understanding of the molecular implications of the hub gene involved in the pathogenesis of MDD in AIS, we performed disease ontology (DO) analysis and virtual cell knockout (KO) of the hub gene using public AIS mouse brain single-cell datasets. Furthermore, a deep learning pipeline (DrugReflector) model and molecular docking were used to identify MDD-preventive therapeutic agents for AIS patients based on MDD and AIS public blood bulk data. Finally, the expression pattern of the hub gene was also evaluated in MDD and AIS cell models.ResultsMyeloperoxidase (MPO) can be considered an upregulated TNK target-associated gene involved in the pathogenesis of MDD in AIS patients, and BRD-K11973162 can be considered an MDD-preventive therapeutic candidate for AIS patients after TNK treatment.ConclusionOur study is the first to identify MDD-associated diagnostic and therapeutic candidates for AIS patients after TNK treatment, providing a novel strategy for their clinical management.

Screening the optimal rTSMS frequency to orchestrate immune-fibrotic remodeling for adult spinal cord repair

IntroductionThe clinical translation of magnetic stimulation for central nervous system trauma is severely hindered by “parameter ambiguity”—the lack of evidence-based screen of stimulation protocol. Repetitive trans-spinal magnetic stimulation (rTSMS) holds therapeutic promise, yet its frequency-dependent effects on the complex spinal microenvironment remain poorly understood. To address this gap, this study aimed to decode the frequency-response relationship of rTSMS and establish an optimal, evidence-based frequency standard to orchestrate immune-fibrotic remodeling and promote functional recovery following spinal cord injury (SCI).MethodsUtilizing novel in vivo label-free second-harmonic generation (SHG) imaging to visualize the real-time microglia activation, we performed a high-fidelity close-loop screen of various rTSMS frequencies (10 Hz, 40 Hz, and 80 Hz). In an adult mice SCI model, we integrated transcriptomic profiling, morphological analysis, electrophysiological recordings, and behavioral assessments to comprehensively evaluate the neuroregenerative potential.ResultsWe identified 40 Hz as a privileged therapeutic frequency that specifically modulates microglia and the extracellular matrix. Unlike 10 Hz or 80 Hz regimens, 40 Hz rTSMS uniquely reprogrammed the transcriptomic landscape, driving microglia toward a restorative M2 phenotype, and most importantly, suppressing collagen fibrillogenesis. This targeted modulation effectively attenuated fibrotic scarring and preserved mitochondrial dynamics and axonal integrity. Consequently, the 40 Hz protocol significantly enhanced corticospinal tract conduction and drove robust, long term sensorimotor recovery.ConclusionOur findings define 40 Hz as the critical therapeutic standard for coupling immune modulation with fibrotic remodeling in SCI. By overcoming the barrier of inconsistent parameters, this study provides a precise, clinically translatable framework for the application of rTSMS in neurorestorative medicine.

CEST MRI reveals nicotine-induced alterations in glutamate-associated molecular connectivity in the mouse brain

IntroductionUnderstanding how neurotransmitter systems organize into large-scale networks is essential for elucidating the mechanisms through which drugs, diseases, and behavioral states alter brain function. Existing imaging modalities such as functional MRI (fMRI) and positron emission tomography (PET) provide measures of hemodynamic and metabolic connectivity, but cannot noninvasively map neurotransmitter-associated networks with high spatial resolution. Herein, we introduce a chemical exchange saturation transfer (CEST) MRI-based framework for mapping glutamate-associated molecular connectivity and apply it to characterize nicotine-induced network reorganization in the mouse brain.MethodsMale C57BL/6 mice underwent dynamic glutamate-weighted CEST (gluCEST) MRI before and after seven days of nicotine exposure. Regional glutamate-weighted CEST time series were extracted from 51 brain regions, and connectivity was evaluated using within-subject temporal correlation and inter-subject covariance analyses.ResultsGraph theory analyses identified four baseline glutamate-associated modules involving frontal-sensorimotor, cortico-hippocampal, intra-hippocampal, and cortico-striatal circuits. Nicotine exposure attenuated these baseline networks in analyses performed without global signal regression (GSR) and with conditional GSR, whereas full GSR reduced the apparent magnitude of these effects. Nicotine also reduced nodal strength in the CA1 and insular cortex. In contrast, nicotine selectively strengthened a thalamo-striato-motor circuit involving the motor cortex, mediodorsal and ventral thalamic nuclei, and caudoputamen. This pattern remained evident even under full GSR. Subject-level covariance analysis confirmed widespread nicotine-induced attenuation of glutamate-associated connectivity and revealed a distinct sensory-limbic module involving the lateral geniculate nucleus, amygdala, and piriform cortex that was selectively disrupted following nicotine exposure.DiscussionThese results demonstrate the feasibility of dynamic gluCEST MRI for mapping glutamate-associated molecular connectivity in vivo and detecting pharmacologically induced network remodeling. This approach provides a noninvasive platform for investigating glutamatergic dysregulation in addiction, neuropsychiatric disorders, and therapeutic response.

Brain protein burden is related to intravoxel incoherent motion: PET-MR imaging study

IntroductionDysfunction in brain protein clearance mechanisms is thought to contribute to many neurodegenerative diseases, yet non-invasive assessment of these mechanisms in humans remains challenging. This study is the first to examine whether intravoxel incoherent motion (IVIM) diffusion MRI metrics, measures of water diffusion and fluid dynamics, are associated with pathological protein accumulation and cognition in aging individuals, and hence whether they serve as a proxy for brain waste clearance function.MethodsWe analyzed data from 94 participants (n = 45 β-amyloid positive) who underwent simultaneous PET/MRI scans to calculate three key IVIM metrics: D (true diffusion coefficient), D* (pseudo-diffusion coefficient reflecting perfusion), and f (perfusion fraction) within 98 regions of interest. A machine learning model was trained to identify the most informative IVIM features for predicting β-amyloid (Aβ) status. Selected features were then evaluated for correlations with protein burden (Aβ and tau) and cognitive performance.ResultsThe model identified a subset of 25 key features that effectively predicted Aβ status, achieving a predictive accuracy of 80.0% on unseen data. Regions with important IVIM features aligned with previously identified Aβ-affected regions and showed significant correlations with Aβ burden (r = 0.53, p < 0.0001) and tau burden (r = 0.61, p < 0.0001). A significant negative correlation was observed between IVIM features and cognitive decline (r = −0.60, p < 0.0001). When stratified by Aβ status, this correlation remained significant only in the Aβ-positive group (r = −0.61, p < 0.0001), but not in the Aβ-negative group.ConclusionIVIM-derived metrics (D, D*, and f), which measure water diffusion and perfusion dynamics in the brain, may be valuable non-invasive biomarkers of protein accumulation and associated cognitive decline in the aging human brain.

Multimodal behavioral phenotyping for depressive-spectrum classification and severity estimation using eye tracking, facial behavior, and transcript-derived language

IntroductionDepression assessment remains largely dependent on symptom reports and clinician judgment, while objective tools for depressive-spectrum stratification and severity estimation remain limited. Existing digital and multimodal depression-detection studies often focus on binary case-control classification, handle missing modalities incompletely, provide limited calibration assessment, and rarely combine depressive-spectrum classification with continuous symptom-severity estimation. We therefore developed a quality-aware multimodal framework integrating eye tracking, facial behavior, and transcript-derived language for classification across normal control (NC), subthreshold depression (SD), and major depressive disorder (MDD), together with prediction of 17-item Hamilton Depression Rating Scale (HAMD-17) severity.MethodsA total of 186 participants completed a controlled task battery including interview, emotional reading, free viewing with verbal description, fixation, gaze orienting, smooth pursuit, prosaccade, and antisaccade tasks. Eye-tracking, facial-video, and transcript-derived language data were converted into modality-specific features. Baseline-3 combined modality-specific encoders, quality-aware gated fusion, and joint classification-regression learning under a nested repeated-resampling framework with explicit missing-modality handling. Baseline-3+ further incorporated Transformer-based cross-modal interaction and uncertainty-based dynamic task weighting. Performance was evaluated on held-out outer-loop test sets after temperature scaling. Interpretability analyses included gate profiling, selective prediction, SHAP, Integrated Gradients, and counterfactual analysis.ResultsBaseline-3+ showed the most favorable classification and calibration profile, with accuracy, balanced accuracy, and F1-macro approaching 0.90 across both classification routes and lower expected calibration error than Baseline-3. For severity estimation, the improvement was route-dependent and mainly reduced the regression disadvantage observed under the hierarchical route. Misclassification was concentrated near the SD boundary. Interpretability analyses showed stable quality-aware modality reweighting, with facial features providing the dominant signal, complemented by eye tracking and smaller but meaningful language contributions.DiscussionThis framework addresses key limitations of prior binary and incompletely calibrated depression-detection models by jointly supporting depressive-spectrum classification, severity estimation, missing-modality handling, calibrated prediction, and individual-level interpretation. Its most plausible role is to augment clinical assessment, particularly for boundary states such as SD.

Generative AI as interactional infrastructure for meaning-centered care in later life

Generative artificial intelligence (GenAI) and large language models are rapidly entering mental health research and service delivery, yet their dominant use remains symptom-centric, emphasizing screening, classification, triage, and risk detection. For older adults, mental health is often inseparable from existential concerns: loss of social role, disrupted continuity of self, loneliness, diminished dignity, and questions of legacy. This perspective argues that GenAI should not be conceptualized as an autonomous substitute for clinicians, nurses, social workers, or family caregivers. Instead, it may be better understood as an interactional infrastructure for meaning-centered care in later life. Drawing on meaning-centered psychotherapy, dignity therapy, life review, gerotranscendence theory, care ethics, and implementation science, we propose a Sensing-Narrating-Connecting-Governing framework. In this model, multimodal AI systems help detect existential and relational cues, support life-review conversations, co-construct dignity-preserving narratives, connect older adults with human care networks, and operate under explicit safeguards for privacy, hallucination, dependency, crisis escalation, and cultural adaptation. The proposed framework shifts evaluation from model performance alone toward existential well-being, dignity, continuity of self, therapeutic alliance, equity, and workflow integration. We conclude that GenAI may contribute to public mental health only when deployed as a bounded, human-supervised, culturally responsive layer of relational augmentation rather than as a replacement for human presence.

Generative AI for pre-consultation mental health triage in disorders of gut-brain interaction

Disorders of gut-brain interaction (DGBI) are common, disabling, and frequently accompanied by anxiety, depressive symptoms, sleep disturbance, symptom-related fear, and repeated health care use. In routine gastroenterology practice, these problems are often recognized late, after fragmented histories, multiple visits, and avoidable investigations. Recent work on generative artificial intelligence (GenAI) and conversational systems suggests a narrower and more practical clinical use case than autonomous diagnosis: supervised pre-consultation triage. We propose that DGBI is a suitable setting for this approach because triage depends on integrating symptom narratives, prior investigations, alarm features, and psychosocial context rather than on a single test result. A GenAI-enabled intake tool could summarize patient-entered histories, incorporate brief distress screening and symptom diaries, flag possible medical or psychiatric escalation, and help route patients toward standard gastroenterology review, integrated psychogastroenterology, dietetic input, or urgent assessment. Its value would lie in making the first consultation more efficient and more clinically informed, not in replacing specialist judgment. For such systems to be acceptable, five conditions are essential: a narrowly defined triage task, multidomain but proportionate data collection, explicit rules for medical and psychiatric escalation, clinician review before action, and prospective evaluation across workflow, safety, equity, and patient acceptability. DGBI offers a realistic opportunity to develop GenAI tools that are useful precisely because they are constrained, auditable, and embedded in multidisciplinary care.

From digital access to social connectedness: the digital divide, bonding social capital, and depressive symptoms among older adults in China

IntroductionAs population aging and digital transformation continue simultaneously in China, the digital divide among older adults has become an increasingly important social issue. This study examines the associations between multiple dimensions of the digital divide and depressive symptoms among older adults, as well as the potential role of bonding social capital.MethodsDrawing on three waves of data from the China Family Panel Studies (CFPS, 2018–2022), this study employs two-way fixed effects models and mediation analyses to examine the relationships between digital access, digital usage, digital outcomes, and depressive symptoms among older adults. Robustness checks were further conducted using propensity score matching (PSM), sample restriction adjustments, and replacement of the dependent variable.ResultsInternet access was significantly associated with lower levels of depressive symptoms among older adults (p < 0.05). Compared with non-Internet users, entertainment-oriented, instrument-oriented, and mixed Internet use were all significantly associated with lower depressive symptoms (all p < 0.05). Digital outcomes were also negatively associated with depressive symptoms (p < 0.01). Bonding social capital showed significant indirect pathways linking all dimensions of the digital divide and depressive symptoms, with mediating proportions ranging from 5.95% to 26.67%. Period heterogeneity analyses further indicated that the associations remained generally stable before and during the COVID-19 period, although mixed Internet use exhibited a significant structural difference across periods (p = 0.036).DiscussionThe findings suggest that the digital divide is closely associated with the mental well-being of older adults, while bonding social capital constitutes an important social pathway linking digital engagement and psychological health. Policy efforts should move beyond technological access toward broader digital empowerment and the construction of a more inclusive digital society for aging populations.

Experiences and wellbeing of family members and carers, regarding PARCS across Victoria

IntroductionWhen consumers experience mental health crises, carers are often key supporters and are also impacted significantly themselves. The Prevention and Recovery Care (PARC) model offers a community-based residential program for consumers, in times of mental health crisis. The potential of PARC services to engage carers is under-examined. This study addresses two questions: How do carers experience the PARC service; and what are carers’ experiences of their own wellbeing, during and after engagement with PARC?MethodsThis is a mixed-methods convergent study of carer experience, whereby quantitative survey data and qualitative survey and interview data were gathered, analysed concurrently, and integrated to report carers perspectives of PARC services. Carers reported their wellbeing across 4 timepoints (n = 71) and also their experience of PARC services in a Carer Exit Survey (n = 50). An independent sample of six family members, each from a different PARC service, engaged in semi-structured telephone interviews.ResultsFor service experience, carers rated the PARC service as highly satisfactory. Interviewees reported a sense of relief, gratitude, and period of regrouping, while valuing the PARC service and feeling positive about accessing PARC services in the future. Positive experience was defined in contrast with distressing experiences of acute wards; concerns were expressed about limits to timely access of PARC services in future if needed. Regarding carer wellbeing, time 1 levels varied across participants, and all measures showed improvement for carers over time. They reported experience of respite, with confidence to entrust their family member to the team, and learning from PARC service staff ways to cope and interact with their family member.DiscussionCarers considered the PARC service a positive environment for the person to receive treatment and support and also experienced PARC services as supporting their own quality of life and wellbeing. This study contributes evidence about how highly valued these recovery oriented sub acute residential services are for carer service users; however, there is potential to further enhance the engagement of carers in PARC service delivery, including through inclusion of carers in co-design.