Translational Psychiatry最新文献

{"title":"Changes in resting-state functional connectivity between large-scale brain networks after an intensive arts intervention for adolescents with depression.","authors":"Kathryn R Cullen, Donovan Roediger, Zeynep Başgöze, Laura Padilla, Shanze Hayee, Bonnie Klimes-Dougan, Mark Fiecas, Wilma Koutstaal, Yuko Taniguchi, Bryon A Mueller","doi":"10.1038/s41398-026-04352-4","DOIUrl":"https://doi.org/10.1038/s41398-026-04352-4","url":null,"abstract":"<p><p>Emerging data support the benefits of creative arts interventions for addressing depression in adolescents, but the neural mechanisms are poorly understood. This study examined changes in connectivity among large-scale brain networks implicated in both depression and creativity, before and after an arts intervention for adolescents with depression. Thirty-nine adolescents with depression completed resting-state functional magnetic resonance imaging scans before and after completing a two-week arts intervention called Creativity Camp. To approximate a \"waitlist\" control, half the sample also completed scanning 2 weeks before camp. Using a graph theory approach, we calculated the strength of connectivity between four networks at the \"nexus\" of mood and creativity: Default, Control, Salience, and Limbic. For these between-network connection strength indices, we (1) measured pre- to post-camp changes across the whole sample; (2) compared changes during waitlist versus during camp for the rest of the sample; and (3) explored correlations between changes in connectivity and changes in depression. In the whole sample, the strength of connectivity between three network pairs increased significantly from pre- to post-camp: Default-Control, Limbic-Control, and Salience-Default (all p < 0.05, corrected). The waitlist control comparison revealed that pre-to-post camp changes were greater than those observed during the waitlist for two of these network pairs (uncorrected). Connectivity changes did not significantly correlate with changes in depressive symptoms. Intensive engagement in creative arts may contribute to increases in connections between large-scale neural networks that are implicated in both mood and creative thinking. Future research is needed with larger samples using randomized control trials to further understand how creative arts engagement confers its mental health benefits for adolescents.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic characteristics of plasma from Chinese ethnic minority patients with major depressive disorder.","authors":"Jun Ye, Jiang Huang, Chongwei Zhou, Zhijin Yuan, Haiping Guan, Zhiyou Long, Haini Chen, Wenfeng Li","doi":"10.1038/s41398-026-04342-6","DOIUrl":"10.1038/s41398-026-04342-6","url":null,"abstract":"<p><p>Ethnic and regional disparities have been observed in the diagnosis and treatment of psychiatric disorders. Our previous research revealed metabolic heterogeneity in plasma samples from ethnic minority patients with schizophrenia in Qiandongnan, China. In this study, individuals of Han, Miao, and Dong ethnicities with major depressive disorder (MDD) from Qiandongnan, China, were enrolled. Peripheral blood samples were collected from both the MDD groups of these ethnicities and their corresponding healthy control (HC) groups for transcriptomic analysis. Ethnicity-specific genes and signaling pathways were identified. Specifically, the genes B3GNTL1, DNASE2, and OAS3 may distinguish individuals of Han ethnicity. The gene ELANE may distinguish individuals of Miao ethnicity. The gene SETSIP may distinguish individuals of Dong ethnicity. Transcriptomic heterogeneity in peripheral blood was observed among Han, Miao, and Dong ethnic groups with MDD from Qiandongnan, China. Furthermore trans-ethnically consistent genes and pathways may uncover the core mechanisms of depression. These findings may provide novel insights into diagnosis and treatment strategies for depression.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between lifestyle, genetic liability for severe mental illness and risk of incident somatic illnesses.","authors":"Ulker Isayeva, Sinan Guloksuz, Bochao Danae Lin, Nini de Boer, Bart P F Rutten, David E J Linden, Mirko Manchia, Jurjen J Luykx","doi":"10.1038/s41398-026-04332-8","DOIUrl":"10.1038/s41398-026-04332-8","url":null,"abstract":"<p><p>People with severe mental illness (SMI), including schizophrenia (SCZ) and bipolar disorder (BD), show elevated risk for somatic conditions and premature mortality. Both genetic liability and modifiable lifestyle factors have been implicated in this comorbidity, yet large-scale studies examining their independent and combined effects across multiple somatic conditions are lacking. We therefore examined whether modifiable lifestyle factors (i.e. smoking, alcohol intake, diet, and exercise) and polygenic risk scores (PRS) for SCZ and BD are associated with the risk of developing somatic illnesses. Data were drawn from 315,313 unrelated individuals in the UK Biobank cohort, with a median follow up of 14 years. Cox proportional hazards models were used to estimate the independent, joint, and interaction effects of PRS-SCZ and PRS-BD and lifestyle factors on the incidence of nine chronic somatic illnesses. Healthy lifestyle was associated with lower risks of type 2 diabetes (T2D), cardiovascular disease (CVD), dementia, rheumatoid arthritis, asthma, chronic liver disease (CLD), and cancer (HRs ranging from 0.43 to 0.80). In addition, higher PRS for SCZ was associated with increased risks of asthma and dementia and lower risk of T2D, while higher PRS for BD was associated with increased risk of T2D. Moreover, likelihood ratio tests confirmed that PRS-SCZ and PRS-BD each contribute independent information to the joint Cox model for T2D, indicating that the opposing directions of their associations with T2D risk are not driven by shared genetic variance between the two scores. Finally, individuals with a healthy lifestyle consistently showed lower risks of CLD, T2D, CVD, and dementia across genetic risk strata; however, no significant additive interaction was observed between genetic risk and lifestyle factors. In conclusion, these findings indicate that genetic liabilities for SCZ and BD show outcome-specific associations with somatic illnesses, while a healthy lifestyle is associated with lower somatic illness risk regardless of genetic risk level.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of comprehensive genetic factors, pathways, and shared genetic architecture of putamen volume in adolescent cohort.","authors":"Abanish Singh, Jonathan Posner","doi":"10.1038/s41398-026-04299-6","DOIUrl":"https://doi.org/10.1038/s41398-026-04299-6","url":null,"abstract":"<p><p>The putamen plays a key role in motor control, learning, and cognition, with abnormal putamen volumes associated with neuropsychiatric disorders. Using data from the ABCD study, we performed a genome wide association study (GWAS) of putamen volumes, followed by replication and pathway enrichment analyses. We next evaluated the shared genetic architecture of putamen volume and neuropsychiatric disorders-including depression, schizophrenia, Parkinson's, ADHD, bipolar, and OCD- using SNP associations from this and prior GWASs. We identified 142 genome-wide significant SNP associations in White participants. Most identified SNPs were in gene regulatory regions and in the neuronal growth-linked genes, DCC and DSCAM. Sixteen of the seventeen most significant associations observed in White participants were also observed in non-White participants. Seventeen known SNPs from prior GWASs of putamen volume were also replicated in our ABCD analysis, including five of the eight most significant GWAS SNPs. There was considerable genetic heterogeneity between White and non-White participants in putamen-linked SNPs with significant differences between the minor allele frequencies across the two groups (Wilcoxon rank-sum test Exact prob < 0.0001). We identified a key pathway (REACTOME_DSCAM_INTERACTIONS) associated with putamen volume that involves DSCAM gene, netrin-1 protein and/or DCC gene. In addition, 28 unique SNPs from prior GWASs of neuropsychiatric disorders were strongly associated with putamen volume at Bonferroni-corrected significance, while 41 SNPs shared by at least three disorders were associated with putamen volume at a 0.05 threshold. Our findings provide deeper insights into the shared genetic architecture and cross-population differences in genetic associations of putamen volume.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-strain probiotic intervention in adults with depressive and anxiety symptoms: A 12-Week pilot study.","authors":"Yaniv S Ovadia, Tamer Okal, Dov Gefel, Amit Shama, Pnina Nir, Milena Pitashny, Daniela Amital","doi":"10.1038/s41398-026-04334-6","DOIUrl":"10.1038/s41398-026-04334-6","url":null,"abstract":"<p><p>Depressive and anxiety symptoms prevalent in major depressive disorder (MDD), that affects millions globally, with many patients showing incomplete response to standard treatments. This open-label pilot study evaluated the effects of a 12-week multi-strain probiotic supplementation on depressive and anxiety symptoms in 30 adults with depressive and anxiety symptoms (e.g., MDD, adjustment disorder, anxiety disorders). Participants received a daily capsule for eight weeks containing 11 bacterial strains (9.8 billion CFU), including Bifidobacterium animalis ssp. Lactis Lafti B94 (5 billion CFU) and Lactobacillus rhamnosus RO-11 (1.9 billion CFU). Outcomes were assessed using the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A), Generalized Anxiety Disorder 7-item scale (GAD-7), and Clinical Global Impression (CGI) scale at baseline, 4, 8, and 12 weeks following treatment. The intervention was well-tolerated, with minor gastrointestinal side effects in 10% of participants. Significant reductions were observed in HDRS (22.47 ± 6.95 to 8.83 ± 5.32, p < 0.01), HAM-A (32.27 ± 11.18 to 13.09 ± 10.49, p < 0.01), GAD-7 (15.33 ± 4.21 to 6.87 ± 5.37, p < 0.01), and CGI (4.53 ± 0.94 to 3.00 ± 1.65, p < 0.01) scores. Of note, females, participants with tertiary education, and married individuals showed greater improvements. The substantial reductions in these scores suggest probiotics may contribute in the reduction of depressive and anxiety symptoms, potentially via the microbiota-gut-brain axis, supporting further investigation in larger, controlled trials.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant insula activity to negative and reduced learning from positive feedback underlie maladaptive self-beliefs in depression.","authors":"Nora Czekalla, Alexander Schröder, Annalina V Mayer, Janine Stierand, David S Stolz, Tobias Kube, Christoph W Korn, Ines Wilhelm, Jan Philipp Klein, Frieder M Paulus, Sören Krach, Laura Müller-Pinzler","doi":"10.1038/s41398-026-04341-7","DOIUrl":"10.1038/s41398-026-04341-7","url":null,"abstract":"<p><strong>Background: </strong>Maladaptive self-beliefs are a core symptom of major depressive disorder. These beliefs are perpetuated by a negatively biased integration of self-related feedback. Understanding the neurocomputational mechanisms of biased belief updating may help to counteract maladaptive beliefs and the maintenance of depression.</p><p><strong>Methods: </strong>The present study uses a belief-updating task and functional neuroimaging to examine the neurocomputational mechanisms associated with self-related feedback processing in individuals with major depression (n = 35) and matched healthy controls (n = 32). We hypothesized that increased symptom burden in depression is associated with negatively biased self-belief updating and altered hemodynamic responses to social feedback.</p><p><strong>Results: </strong>Our findings show that, in the clinical sample, the incorporation of unexpected positive feedback was reduced with greater symptom burden, and that insula reactivity was generally elevated to unexpected negative feedback.</p><p><strong>Conclusion: </strong>The interplay of increased hemodynamic responsiveness to negative feedback and the reduced learning from positive feedback provide new insights into cognitive distortions in depression and may explain the persistence of maladaptive self-beliefs and, thus, the maintenance of depression.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.","authors":"Tetyana Voloshyna, Øyvind V Svendsen, Karolina Szafranska, Jakub Pospíšil, Eike C Struck, Elisabet Størset, Robert L Smith, Espen Molden, David G Le Couteur, Victoria C Cogger, Peter A G McCourt, Erik S Dietrichs","doi":"10.1038/s41398-026-04328-4","DOIUrl":"10.1038/s41398-026-04328-4","url":null,"abstract":"<p><p>Clozapine is the most effective antipsychotic drug, while also causing the most severe metabolic side effects. The underlying mechanisms of these side effects appear multifactorial and are not entirely understood. We hypothesized that liver sinusoidal endothelial cells (LSEC) dysfunction is linked to the metabolic side effects of clozapine, based on known association between reduced LSEC porosity, hypertriglyceridemia and insulin resistance. Accordingly, we conducted a translational study by assessing the porosity of murine LSECs following clozapine exposure in vitro and correlating serum clozapine concentrations with metabolic parameters in routine human blood samples. The patient data showed a correlation for clozapine serum concentrations with both triglycerides (Spearman's ρ = 0.47, P = 0.00024) and glucose levels (ρ = 0.24, P = 0.034), but no correlation with LDL cholesterol (ρ = -0.04, P = 0.82) or HDL cholesterol (ρ = -0.22, P = 0.088). The in vitro experiments showed a concentration-dependent reduction in murine LSEC porosity (P for trend = 0.00036). Together, these findings support a link between clozapine exposure and reduced LSEC porosity. This represents a promising point of intervention that potentially could expand safe access to clozapine as a highly effective antipsychotic treatment for a broader population, also in individuals at high risk for metabolic and cardiovascular side effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13683405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating biological pathway polygenic scores and trauma in psychosis: findings from the EU-GEI study.","authors":"Giulia Trotta, Isabelle Austin-Zimmerman, Edoardo Spinazzola, Lucia Sideli, Monica Aas, Victoria Rodriguez, Senta Haussler, Zhikun Li, Perry Bm Leung, Qiang Li, Diego Quattrone, Teya Petrova, Craig Morgan, Michael O'Donovan, Pak C Sham, Evangelos Vassos, Chloe Cy Wong, Richard Bentall, Robin M Murray, Luis Alameda, Marta Di Forti","doi":"10.1038/s41398-026-04317-7","DOIUrl":"10.1038/s41398-026-04317-7","url":null,"abstract":"<p><p>Psychotic disorders are complex, multifactorial conditions influenced by both genetic liability and early environmental adversity. Polygenic risk scores (PRSs) derived from genome-wide association studies have shown utility in capturing genetic predisposition, but their biological interpretability remains limited. In this study, we evaluated whether biologically informed pathway-specific polygenic scores (pPGSs) for psychosis, restricted to neurotransmitter-related pathways, could help clarify gene-environment interplay. Using data from 1 192 individuals in the EU-GEI multi-site case-control study, we constructed pPGSs for dopamine, glutamate, GABA, and serotonin systems. We investigated associations between pPGSs and childhood trauma (rGE), their interactions on psychosis risk (GxE), and the influence of the genome-wide psychosis PRS on these relationships. Serotonin, dopamine, and glutamate pPGSs were positively associated with a composite trauma exposure (i.e., abuse and neglect), suggesting shared genetic factors contributing to both psychosis liability and early adversity. Significant negative GxE effects were observed for both dopamine and serotonin pPGSs, indicating that higher trauma exposure diminished the relative influence of genetic liability on psychosis risk. Adjustment for the genome-wide psychosis PRS attenuated most effects, but serotonergic and dopaminergic associations remained robust, supporting pathway-specific contributions beyond general polygenic risk. These findings provide proof-of-concept for the utility of pPGSs in psychiatric research, suggesting both genetic contributions to trauma exposure and GxE effects on psychosis risk. Further research incorporating epigenetic data and longitudinal designs may enhance mechanistic insight and translational potential.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13470413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency of therapeutic drug monitoring in inpatient precision depression care and duration of hospitalization.","authors":"Chantal Hampf, Jürgen Deckert, Sebastian Walther, Heike Weber, Stefan Unterecker, Maike Scherf-Clavel","doi":"10.1038/s41398-026-04316-8","DOIUrl":"10.1038/s41398-026-04316-8","url":null,"abstract":"<p><p>In psychiatry, therapeutic drug monitoring (TDM) is routinely used to improve treatment safety and efficacy, yet its association with hospitalization duration and cost-effectiveness remains unclear. We hypothesized that the frequency of routinely requested TDM is associated with hospitalization duration. In this retrospective study, patients with major depressive disorder receiving TDM of antidepressants between 2015 and 2021 (N = 383) were analyzed. Inclusion criteria were a hospital stay ≥7 days and a first TDM request at admission. Regression analyses assessed associations between TDM frequency and hospitalization duration. Receiver operating characteristic analysis identified a minimum effective TDM frequency of 0.66/week, which was associated with a mean reduction in hospitalization duration of 21 days (p < 2.2*10^-¹⁶). The upper effective threshold was approximated at 1.3/week. Higher TDM frequency was associated with more therapy adjustments within 7 days after TDM, including dose adaptations (p = 3.07*10^-¹⁶) and drug initiation/discontinuation (p = 6.70*10^-6). Drug-specific analyses for amitriptyline, venlafaxine, and mirtazapine confirmed these associations. Cost-effectiveness analysis demonstrated a 37% cost reduction for patients with TDM frequencies ≥0.66/week. In conclusion, frequent, clinically integrated TDM of antidepressants and timely treatment adaptations were associated with shorter hospitalization and reduced hospitalization costs. These findings suggest that at least biweekly TDM combined with subsequent treatment adaptations may represent a previously underappreciated strategy to improve clinical and economic outcomes in a tertiary referral center for severe major depression. Whether these findings are transferable to other inpatient and outpatient settings of depression care requires further studies.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148649312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac vagal activity during in-vivo threat exposure is associated with within-session inhibition of fear and avoidance.","authors":"Christoph Szeska, Kai Klepzig, Alfons O Hamm, Mathias Weymar","doi":"10.1038/s41398-026-04333-7","DOIUrl":"10.1038/s41398-026-04333-7","url":null,"abstract":"<p><p>Laboratory research suggests that the attenuation of defensive responses during threat exposure relies on the inhibition of subcortical defense circuits orchestrated by the prefrontal cortex. This process may be reflected by increased vagal efferent activity on the autonomic nervous system. Here, we tested whether cardiac vagal efferent activity, indicated by vagally-mediated heart rate variability (vmHRV), is associated with reduced defensive responses during in-vivo threat exposure and whether it may serve as a physiological index of multi-level exposure responding. Thirty-three women with excessive fear of spiders underwent standardized exposure, where they first approached a living tarantula (approach phase) and subsequently progressed through stages of increasingly direct interactions with the spider (threat imminence task). Indices of cardiac vagal activity (vmHRV) and overall cardiac autonomic arousal (heart rate) were measured alongside self-reported fear and avoidance behavior (distance to spider, performance in threat imminence task). During approach, self-reported fear increased until it reached a stable ceiling. Concurrent vmHRV leveled accordingly, with greater activity being related to lower fear and reduced avoidance during the subsequent threat imminence task. From the very first minute, cardiac vagal activity was associated with the participants' ability to physically engage with the fear cue during threat imminence task, irrespective of covariations in self-reported fear. Our results suggest that cardiac vagal activity may represent inhibition of fear and avoidance during exposure to perceived threat. Cardiac vagal activity, indexed by vmHRV, could therefore represent an index of within-session multi-level responding to exposure and a promising target for adjuncts to promote fear reduction.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148654059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}