Background and objectiveWithin the interdisciplinary field of cyberpsychology and mental health, trait mindfulness has been associated with lower levels of subclinical anomalous symptoms, such as Psychotic-Like Experiences (PLEs), has gained increasing attention. However, in the context of daily digital human-computer interactions (e.g., listening to AI-generated music), the specific pathways through which Mindfulness operates (the involvement with Presence and Perceived Interactivity) and the boundary conditions of physiological arousal, remain to be clarified. This study aims to explore the direct predictive relationship between mindfulness and individuals’ PLEs, and to investigate the multipath effect of brief AI-generated music listening context (with Presence and Perceived Interactivity), along with the moderating effect of Arousal.MethodsWith a cross-sectional survey design, self-reported multimodal data were collected from 527 Chinese participants. Structural equation modeling (SEM) was conducted using Mplus 8.3 to empirically test the main effects (path coefficients) of the theoretical hypotheses and the moderation model.ResultsBoth the measurement and structural models demonstrated good fit. The path analysis results indicated that: (1) trait trait mindfulness was significantly and negatively associated with PLEs (p < 0.001); (2) regarding the main effect paths of brief AI-generated music listening context, mindfulness significantly and positively predict individuals’ Presence and Perceived Interactivity, while both significantly and negatively predict PLEs; (3) Arousal played a significant moderating role in the relationship between mindfulness and brief AI-generated music listening context, exhibiting a synergistic enhancement effect. Higher levels of Arousal significantly amplified the positive prediction of Mindfulness on both Presence and Perceived Interactivity (p < 0.01).ConclusionsWith the help the SEM, this study maps out the underlying multipath network through which mindfulness is associated with lower PLEs within a brief AI-generated music listening context. The observed associations suggest that presence and perceived interactivity may function as pivotal correlational nodes relevant to mental health correlates, while these results also nuance classic cognitive load assumptions by indicating a potential synergistic association between trait mindfulness and emotional arousal. These results provide a solid empirical foundation and prospective insights, for the mental health-oriented design of AI music products, such as the immersive acoustic environment construction and dynamic, arousal-based interaction recommendations.
MapLight’s Schizophrenia Candidate Has Mixed Results at Phase II
MapLight Therapeutics announced this week that its candidate drug for treatment of schizophrenia had achieved its primary endpoint in a Phase II trial, but only at the twice daily dose tested in the trial.
As reported by the California-based company, while participants of the trial who were given the candidate drug, ML-007C-MA, once a day did show some signs of improvement it was not statistically significant.
ML-007C-MA is a combined muscarinic agonist (betovumeline) and peripherally acting anticholinergic (fesoterodine). It acts by turning on two receptors in the brain, M1 and M4.
M1 is the main receptor the drug is trying to stimulate in the brain cortex and hippocampus, where it is linked to cognition, attention, and possibly some aspects of psychosis. Turning on M4 also helps by acting like a brake on the overactive signaling that contributes to hallucinations and delusions. Betovumeline activates both M1 and M4 centrally, while fesoterodine is there mainly to block unwanted side effects outside the brain, like gastrointestinal issues.
In this study, MapLight randomized 307 adults with an acute exacerbation of schizophrenia to treatment with either a twice daily or once daily treatment with ML-007C-MA or placebo for five weeks.
At five weeks, patients given the twice daily dose had a statistically significant and clinically meaningful reduction in Positive and Negative Syndrome Scale (PANSS) total score of 4.5 points compared to placebo. Cognitive scores were also better in the twice daily group versus placebo.
While this result is positive overall, the non-statistically significant result for the once daily dose proved unpopular with investors and company shares on the Nasdaq fell 40% after the announcement.
In September 2024, Cobenfy, the first muscarinic M1/M4 agonist drug for treatment of schizophrenia was approved by the FDA. Now owned by BMS, Cobenfy will be the main competitor for ML-007C-MA if approved.
Cobenfy was groundbreaking because it was the first new mechanism of action for schizophrenia in decades, moving beyond dopamine blockade to a muscarinic approach and targeting both hallucinations and delusions as well as the more cognitive aspects of the disease, which are not well treated with other drugs.
Despite the approval of Cobenfy, a number of other competitors developing treatments for schizophrenia have failed in recent years. Whether MapLight can succeed at Phase III with ML-007C-MA—which is also being tested as a treatment for psychosis linked to Alzheimer’s disease—and compete with Cobenfy, remains to be seen.
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Synaptic mechanisms for differential severity of social preference deficits in male and female mice induced by diminished activity-dependent BDNF
Males are more commonly diagnosed with autism spectrum disorder (ASD) than females with a ratio of about 4–1. However, the neural mechanisms underlying the sex differences in ASD are unknown. Social deficits are the core symptoms of patients with ASD. Previous studies showed that diminished activity-dependent brain-derived neurotrophic factor (BDNF) signaling induced differential severity of autism-like social preference deficits in male and female mice by using a mouse model with genetic knock-in of human BDNF methionine (Met) allele, which significantly decreased activity-dependent BDNF release without affecting basal BDNF secretion. Here, we investigated the synaptic mechanisms for diminished activity-dependent BDNF-induced differential severity of social preference deficits in males and females. The prefrontal cortex (PFC) is a critical brain region for social behaviors. Whole-cell patch-clamp brain slice recordings showed that diminished activity-dependent BDNF signaling differentially increased the frequency of spontaneous action potentials (sAPs) of pyramidal neurons in the PFC of male and female BDNF+/Met mice. The frequency of sAPs in male BDNF+/Met mice was higher than in female BDNF+/Met mice. Diminished activity-dependent BDNF signaling differentially enhanced excitatory synaptic transmission and dampened inhibitory synaptic transmission of pyramidal neurons at pre- and post- synapses in males and females, which were mediated by dysregulated transcriptional levels of key synaptic genes. Chemogenetic inhibition of pyramidal neurons in the PFC of BDNF+/Met mice was sufficient to ameliorate autism-like social preference deficits in males and females. This study reveals synaptic mechanisms underlying the differential severity of social preference deficit in male and female BDNF+/Met mice, which provides a potential neural basis for sex differences in male and female ASD patients with and without the BDNF Val66Met SNP.
Immersive wearable virtual reality for autism: a systematic review of current evidence
IntroductionImmersive and wearable virtual reality (VR) is an emerging technology with growing potential to support assessment and intervention ifor autistic people. The methodological heterogeneity of existing studies limits the interpretation and generalization of current evidence.MethodsA systematic review with a narrative synthesis was conducted in accordance with the PRISMA guidelines. Electronic searches were performed in PubMed, Scopus, IEEE Xplore, Web of Science, and Google Scholar, identifying studies published between 2015 and August 2025. Twenty-two studies investigating wearable and immersive VR interventions in children and adults with ASD met the eligibility criteria.ResultsThe included studies demonstrated that wearable VR interventions may improve social communication, joint attention, emotional regulation, daily living skills, executive functioning, and user engagement. Innovative technologies, including eye-tracking and artificial intelligence-based systems, also enabled objective assessment of gaze behaviour, social interaction, and physiological responses. Nevertheless, the evidence was characterized by considerable methodological heterogeneity, predominantly small sample sizes, limited use of randomized controlled designs, and scarce long-term follow-up, reducing the generalizability of the findings.DiscussionWearable VR represents a promising tool for personalized assessment and intervention in ASD. Based on the current evidence, we propose a structured pre-intervention assessment integrating sensory, cognitive, emotional, and VR tolerance profiles to support individualized intervention planning. Future research should prioritize standardized outcome measures, rigorous study designs, and longitudinal investigations to strengthen the clinical translation of VR-based interventions in autism.
Resting-state functional connectivity of the sensorimotor network in medication-naïve Chinese children with ADHD: cross-sectional associations with hyperactivity/impulsivity and executive function
BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, often—but not always—characterized by inattention, hyperactivity/impulsivity, and deficits in executive functions (EFs); some individuals may also exhibit sensorimotor dysfunction. While SMN dysfunction has been implicated in ADHD, the patterns of SMN functional connectivity (FC) and their relationships with clinical symptoms and EFs remain inconsistent, partly due to methodological heterogeneity.MethodsThe study included 62 medication-naïve patients with ADHD (aged 6–15 years) and 46 healthy controls matched for age, sex, and IQ. Clinical symptoms and EFs were assessed using CPRS, IVA-CPT, and Stroop tests. Resting-state fMRI data were acquired, and ROIs within SMN, SN, DMN, and FPN were selected from the Dosenbach atlas. FC was analyzed using Network-Based Statistics (NBS). Partial correlations explored FC–behavior relationships in the ADHD group, controlling for age, sex, and IQ.ResultsThe ADHD group showed significantly higher CPRS hyperactivity/impulsivity scores and poorer IVA-CPT and Stroop performance. Compared to controls, ADHD showed increased FC within SMN (right posterior insula to left precentral gyrus/parietal lobe), between SMN–DMN (precentral gyrus, dorsal frontal cortex, temporal lobe, angular gyrus, posterior cingulate cortex, and precuneus), and SMN–SN (middle insula, superior parietal lobule, superior temporal gyrus, basal ganglia, and fusiform gyrus). Enhanced intra-SMN FC was negatively correlated with impulsivity/hyperactivity and hyperactivity index scores. Enhanced SMN–DMN FC was negatively correlated with hyperactivity symptoms and positively correlated with control quotients in IVA-CPT. Enhanced SMN–SN FC was negatively correlated with Stroop correct responses and positively correlated with omission errors.ConclusionsIn this medication-naïve pediatric sample, distinct SMN connectivity patterns differentially related to ADHD symptoms and executive function. However, given the cross-sectional design and modest sample size, these associations cannot establish causality; they require replication in longitudinal studies and larger cohorts to clarify whether they reflect developmental variation, neurobiological subtypes, or epiphenomena.
Clinical Outcomes and Predictors of Improvement With Virtual Behavioral Health Care for Gambling Disorder: Retrospective Cohort Study
<strong>Background:</strong> Gambling disorder is associated with substantial psychiatric and functional burden, yet few individuals receive treatment. Limited real-world evidence exists evaluating outcomes of virtually delivered behavioral health care for gambling disorder, particularly among clinically complex patients. <strong>Objective:</strong> The purpose of this study was to evaluate gambling symptom severity outcomes among adults with gambling disorder receiving care from Birches Health. We aimed to (1) characterize the clinical profile of adults seeking treatment for gambling disorder; (2) quantify changes in gambling symptom severity over the initial 12 weeks of treatment and examine whether baseline clinical complexity, such as gambling symptom severity, depression severity, and psychiatric comorbidities, was associated with differences in gambling symptom severity improvement over time; and (3) estimate the timing and likelihood of achieving clinically meaningful improvement in gambling symptom severity. <strong>Methods:</strong> This retrospective cohort study included 1305 adults receiving virtual behavioral health treatment for gambling disorder through Birches Health between June 2024 and April 2026. Gambling symptom severity was assessed using the Gambling Symptom Assessment Scale (G-SAS) weekly. Linear mixed-effects models evaluated changes in gambling symptom severity over 12 weeks and associations with baseline clinical characteristics. Clinically meaningful improvement was defined as a reduction of 4 or more points in the G-SAS score. <strong>Results:</strong> Participants had a mean age of 41.5 (SD 13.1) years, 65.2% (851/1305) were male, and baseline gambling symptom severity was moderate (mean G-SAS score 20.5, SD 11.83). Over half (730/1305, 56%) of participants presented with at least one psychiatric comorbidity, most commonly anxiety disorder (351/1305, 26.9%) and depressive disorder (276/1305, 21.1%). Gambling symptom severity declined significantly over the first 12 weeks of treatment, with G-SAS scores decreasing by approximately 0.099 points per day (<i>P</i><.001), corresponding to an estimated 8.3-point reduction over 12 weeks. Higher baseline depressive symptom severity was associated with faster improvement in gambling symptoms (<i>P</i>=.01), whereas depressive disorder (<i>P</i>=.03) and attention-deficit/hyperactivity disorder (<i>P</i>=.008) diagnoses were associated with slower improvement trajectories. Among patients with routine follow-up assessments recorded during the initial 12 weeks of treatment (1071/1305, 82.1%), 71.7% (935/1305) achieved clinically meaningful improvement in gambling symptom severity, with a median time to improvement of 14 days. <strong>Conclusions:</strong> A clinically complex population of adults receiving care through a national virtual behavioral health care provider demonstrated rapid and clinically meaningful reductions in gambling symptom severity. These findings highlight the potential of specialized virtual care models to expand access to gambling treatment and support symptom improvement in routine care settings. Future research should evaluate longer-term recovery trajectories and identify factors associated with sustained improvement and ongoing engagement in care.
Drug Candidate Combats Age-Related Muscle Loss
Researchers in Japan have identified a compound that could help muscles stay strong as we age. Preclinical results published today in Scientific Reports uncover a promising new approach to treat conditions causing muscle loss and may help people preserve independence and quality of life in their later years.
Skeletal muscle is essential for movement, accounting for approximately 40% of an adult’s total body weight. Yet it is also one of the first tissues to decline with age, progressively leading to weakness, scarring, fat accumulation, and loss of fast-twitch muscle fibers.
The study focused on hepatocyte growth factor (HGF), a molecule that plays a crucial role in activating the repair of muscle fibers. In healthy muscle, this molecule is present in the tissue surrounding muscle fibers. When the muscle is injured or stimulated through exercise, HGF is released and binds to c-met receptors on stem cells within the skeletal muscle, known as satellite cells. This activates the satellite cells and enables them to proliferate and differentiate to repair muscle fibers.
Aging can interfere with this process, making it a key driver of age-related muscle wasting. In an earlier study, the same team found that aging causes HGF to undergo nitration, a chemical modification that prevents it from binding to c-met receptors.
“HGF is not necessarily missing as we age,” said Ryuichi Tatsumi, PhD, professor at Kyushu University. “Rather, it can be chemically altered after it is made. That led us to wonder whether a compound with strong antioxidant capacity might protect HGF, either by preventing nitration or by compensating for the functional loss it causes.”
Tatsumi’s team then identified two compounds with strong antioxidant activity that could potentially interfere with HGF nitration: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS). Both belong to a drug class known as trisulfides that has been gaining attention in preclinical research for their protective and anti-inflammatory properties across a wide range of indications.
While both drugs were able to suppress HGF nitration, only LASSS restored its ability to bind to c-met receptors. In fact, the drug candidate more than doubled HGF’s binding affinity while simultaneously preventing nitration.
“This exceeded our expectations,” said Tatsumi. “We knew trisulfides had diverse biological functions, but we never expected that simply mixing HGF with LASSS would produce such a striking effect. What this tells us is that LASSS does more than simply neutralize reactive molecules. It may interact directly with HGF and induce a subtle structural change, creating an enhanced ‘Super HGF’ form that binds c-met more strongly and resists nitration.”
The researchers then tested these effects in a mouse model of muscle atrophy. Compared to untreated animals, mice receiving LASSS showed a significant reduction in HGF nitration. Although further preclinical studies are needed before this approach can be tested in humans, these early findings point toward a promising strategy to preserve the muscle’s natural regenerative capacity and support healthy aging.
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Single-Cell Maps Reveal Genome Reorganization in Alzheimer’s Brain Cells
While Alzheimer’s disease is the most common cause of dementia, many of the molecular mechanisms that drive its progression remain poorly understood. While researchers have cataloged changes in gene activity across different brain cell types, a key unanswered question has been how the genome’s 3D organization influences those changes. Now, researchers have linked alterations in genome folding to disrupted gene regulation in Alzheimer’s disease, providing a new layer of insight into the biology of neurodegeneration.
The findings, published in Science in the paper “Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease,” were reported by researchers from Carnegie Mellon University’s School of Computer Science, the University of Pittsburgh School of Medicine, the University of Washington, and collaborating institutions. Using single-cell multiomics, spatial transcriptomics, and artificial intelligence (AI), the team generated a multiscale view connecting genome structure, gene expression, and tissue organization in Alzheimer’s disease.
To investigate the role of genome architecture in Alzheimer’s disease, the researchers analyzed postmortem prefrontal cortex tissue from individuals with and without the disease. They used GAGE-seq (genome architecture and gene expression by sequencing), a technique that measures both gene expression and physical genome contacts in the same single cell. The team combined those data with chromatin accessibility data, spatial transcriptomic maps, and a transformer-based AI model called Hicformer, which integrates DNA sequence and 3D genome features to predict cell-type-specific gene activity.
The study revealed widespread changes in chromatin organization across major brain cell types. According to the paper, Alzheimer’s disease was associated with “reduced short-range interactions and increased longer-range interactions” within the genome. Active and inactive genomic regions also exhibited increased mixing, consistent with weaker compartment segregation. The researchers linked these structural changes to cell type–specific alterations in gene expression programs involved in disease-relevant pathways.
Researchers also observed weakening of promoter-proximal interactions and changes in regulatory elements, alongside evidence of senescence-related activation in microglia and sex-dependent dysregulation of X-linked genes in females. Integrating the molecular data with spatial transcriptomics revealed altered cellular neighborhoods and disrupted coordination of gene programs within diseased brain tissue. The authors wrote that the results connect “genome structure, gene regulation, and tissue organization through a unified multimodal analysis.”
Their predictive model Hicformer also demonstrated that “3D genome features provide information beyond DNA sequence alone for explaining AD-relevant gene expression, enabling prioritization of distal regulatory elements whose effects are mediated through chromatin contacts,” the authors wrote.
“Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure with disease-related gene programs,” said Yang Zhang, PhD, a project scientist in Carnegie Mellon’s Computational Biology Department and co-lead author. “Across several kinds of brain cells, this paired view revealed a consistent signature of 3D genome reorganization in Alzheimer’s disease and helped us prioritize regulatory regions for future mechanistic and therapeutic investigation.”
The researchers concluded that genome folding represents a previously underappreciated regulatory layer associated with Alzheimer’s pathology. By creating a detailed map linking 3D genome remodeling to gene expression and tissue organization, the study provides a framework for future experiments aimed at determining which structural changes contribute directly to disease progression. This may also provide clues to future therapeutic focuses.
“Alzheimer’s disease cannot be understood one layer at a time,” said senior author Jian Ma, PhD, the Ray and Stephanie Lane Professor of Computational Biology at Carnegie Mellon University. “The genome’s 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity. By integrating genome folding, cell state, and tissue context, we can move beyond cataloging disease-associated changes toward understanding how they fit together and which mechanisms to test next,” said Ma. “Alzheimer’s disease cannot be understood one layer at a time.”
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Vagus nerve–driven microbiota homeostasis: a promising integrative add-on therapy for neurodevelopmental disorders
Over the past two decades, the conceptualization of neurodevelopmental disorders (NDDs) has undergone a profound transformation, shifting from a primarily brain-centric framework toward a systems-level perspective that integrates peripheral physiological processes. Among these, the gut microbiota has emerged as a critical determinant of neurodevelopmental trajectories. Through its involvement in immune modulation, metabolic signaling, and neural communication, the microbiota–gut–brain axis (MGBA) exerts a pervasive influence on brain maturation and function. A growing body of evidence indicates that early-life disruptions of microbiota composition—commonly referred to as dysbiosis—are associated with an increased risk of NDDs, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and epilepsy. These disruptions are frequently driven by environmental exposures such as antibiotic use, cesarean delivery, dietary patterns, and psychosocial stress. Despite the expanding recognition of these associations, current therapeutic strategies aimed at restoring microbiota balance, including probiotics and fecal microbiota transplantation, have yielded inconsistent and often transient results. In this context, Vagus Nerve Stimulation (VNS), particularly in its non-invasive forms (nVNS), has emerged as a promising approach capable of modulating environmental exposures through the host-centered regulatory mechanisms of the MGBA. By influencing autonomic tone, activating the cholinergic anti-inflammatory pathway, and modulating neurotransmitter systems, nVNS may restore microbiota homeostasis while simultaneously improving neurodevelopmental outcomes. This article provides a comprehensive and integrative review of the mechanistic, preclinical, and clinical evidence supporting the role of nVNS as a microbiota-modulating intervention. We further discuss its potential as a safe, cost-effective and promising therapeutic strategy for neurodevelopmental disorders, with a particular emphasis on pediatric populations.
A comparison between seven scales of neuropsychological assessments for cognitive impairment screening in Chinese older population: a cross-sectional study in Chongqing, China
BackgroundThe Clinical Dementia Rating Scale (CDR), the Ascertain Dementia 8 (AD8), the Mini-Cog, the Verbal Fluency Test (VFT), the Community Screener for Dementia (CSI-D), the Rey Auditory Verbal Learning Test (RAVLT), and the Activities of Daily Living Scale (ADL) represent seven commonly employed methods for community cognitive impairment screening in China that have garnered limited attention. This study aimed to assess the discriminatory power of these seven tests when administered concurrently in a single screening to detect cognitive impairment in the absence of a gold standard.MethodsWe conducted a cross-sectional survey among 1,506 elderly people aged 60 and above in the community. The cognitive and social functions of the elderly population were evaluated by using the Seven scales. The characteristics related to demographics and health were collected through questionnaire surveys, and the correlations and consistencies of the Seven scales with cognitive impairment were analyzed respectively. Multifactor logistic regression model was used to analyze the risk factors of cognitive impairment in each scale.ResultsThe positive screening proportions for the seven scales—CDR, ADL, AD8, CSI-D, Mini-Cog, VFT, and RAVLT—were 61.1%, 33.7%, 38.0%, 37.1%, 53.7%, 39.3%, and 52.9%, respectively. Agreement on cognitive impairment risk between each pair of scales was fair-to-moderate (Kappa: 0.32–0.645, all p < 0.001). Screening results differed significantly across the seven scales by age, educational, marital status, epilepsy, cerebral infarction, brain atrophy, and depression (all P < 0.001). Notably, Screen-positive proportions for cognitive impairment rose significantly with increasing age (p < 0.001); the ≥ 80-year-old group showed the highest proportions across scales. Conversely, higher educational attainment was associated with lower risk of screening positive for cognitive impairment (p < 0.001).ConclusionsOur study identified a relatively high screening positivity proportion for cognitive impairment in Chongqing, Age, Sex, Education, Marital status, Brain atrophy, Anxiety, and Depression are risk factors for screening positivity. The identified screening positivity for cognitive impairment varied across different neuropsychological assessment methods, indicating that assessment choice should be tailored to population characteristics rather than applying a one-size-fits-all approach. Selecting the appropriate tool can improve sensitivity and reduce missed diagnoses.