Biological psychiatry global open science最新文献

{"title":"High Baseline Plasma Anthranilic Acid Predicts Remission Upon Acute-Series Ketamine Infusion for Treatment-Resistant Depression","authors":"Stephen A. Murata ,&nbsp;Zachary B. Madaj ,&nbsp;Colt D. Capan ,&nbsp;Ryan D. Sheldon ,&nbsp;Rif S. El-Mallakh ,&nbsp;Sagar V. Parikh ,&nbsp;William V. Bobo ,&nbsp;Fernando S. Goes ,&nbsp;Owen M. Wolkowitz ,&nbsp;Jennifer L. Vande Voort ,&nbsp;Louis J. Nykamp ,&nbsp;Balwinder Singh ,&nbsp;Gustavo C. Medeiros ,&nbsp;Erik B. Nelson ,&nbsp;Michael E. Thase ,&nbsp;Gregory F. Oxenkrug ,&nbsp;Mark A. Frye ,&nbsp;John F. Greden ,&nbsp;Eric D. Achtyes ,&nbsp;Lena C. Brundin","doi":"10.1016/j.bpsgos.2025.100503","DOIUrl":"10.1016/j.bpsgos.2025.100503","url":null,"abstract":"<div><h3>Background</h3><div>Treatment-resistant depression (TRD) remains a challenge, but intravenous racemic ketamine offers rapid antidepressant effects. Reliable biomarkers are needed. In this study, we examined kynurenine pathway metabolites and inflammatory cytokines as predictors of ketamine response.</div></div><div><h3>Methods</h3><div>The Bio-K study was a multicenter, open-label trial of 74 patients with TRD who received 3 ketamine infusions over 11 days. Remission (Montgomery–Åsberg Depression Rating Scale [MADRS] score ≤9) was assessed 24 hours post infusion 3, with a subset of study participants continuing weekly infusions. Plasma biomarkers (9 kynurenines, 14 cytokines) were measured at baseline and post infusion. Mixed-effects models and logistic regression analyses were used, adjusting for sex, age, body mass index, benzodiazepine use, and baseline MADRS scores. Second-generation <em>p</em> values were used to determine significance.</div></div><div><h3>Results</h3><div>Of the 74 participants, 52% (<em>n</em> = 38) achieved remission. Higher baseline anthranilic acid (AA) levels predicted remission (β = −0.93, <em>p</em> = .02). Composite ratios, including AA:intercellular adhesion molecule-1 (ICAM-1) (β = −1.15, <em>p</em> = .002) and AA:tryptophan (TRP) (β = −0.98, <em>p</em> = .007), significantly improved predictive accuracy (area under the receiver operating characteristic curve = 0.75 vs. 0.64, <em>p</em> = .03). The findings were independent of demographic and clinical covariates.</div></div><div><h3>Conclusions</h3><div>Elevated AA levels and AA-based biomarker ratios predicted ketamine remission in patients with TRD, supporting biomarker-driven personalized treatment. These findings highlight immunometabolic mechanisms in ketamine response.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100503"},"PeriodicalIF":4.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidepressant Switching as a Proxy Phenotype for Drug Nonresponse: Investigating Clinical, Demographic, and Genetic Characteristics","authors":"Chris Wai Hang Lo ,&nbsp;Alexandra C. Gillett ,&nbsp;Matthew H. Iveson ,&nbsp;Michelle Kamp ,&nbsp;Chiara Fabbri ,&nbsp;Win Lee Edwin Wong ,&nbsp;Dale Handley ,&nbsp;Oliver Pain ,&nbsp;Evangelos Vassos ,&nbsp;Naomi R. Wray ,&nbsp;Heather C. Whalley ,&nbsp;Danyang Li ,&nbsp;Allan H. Young ,&nbsp;Andrew M. McIntosh ,&nbsp;Cathryn M. Lewis","doi":"10.1016/j.bpsgos.2025.100502","DOIUrl":"10.1016/j.bpsgos.2025.100502","url":null,"abstract":"<div><h3>Background</h3><div>Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI nonresponders.</div></div><div><h3>Methods</h3><div>In the UK Biobank (UKB) (<em>N</em> = 38,813) and Generation Scotland (<em>N</em> = 1777) datasets, SSRI switching was defined using ≤90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Nonswitchers were participants with ≥3 consecutive prescriptions for an SSRI. In the UKB, clinical, demographic, and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated.</div></div><div><h3>Results</h3><div>In the UKB, 5133 (13.2%) SSRI switchers and 33,680 nonswitchers were defined. The mean time to switch was 28 days (interquartile range, 17–49). Switching patterns were consistent across the UKB and Generation Scotland (<em>n</em> = 498 switchers). Higher annual income and educational levels (odds ratio [OR] [95% CI] for a university degree, 0.73 [0.67–0.79] compared with no qualifications) were associated with lower levels of switching. PGSs for nonremission, based on clinical studies, were associated with increased risk of switching (OR, 1.07 [1.02–1.12], <em>p</em> = .007). MDD PGSs and family history of depression were not significantly associated with switching. Using genome-wide complex trait Bayesian, the single nucleotide polymorphism–based heritability was approximately 4% (SE 0.016) on the observed scale.</div></div><div><h3>Conclusions</h3><div>This study identified SSRI switching as a proxy for nonresponse, scalable across biobanks with electronic health records, capturing demographics and genetics of treatment nonresponse, and independent of MDD genetics.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100502"},"PeriodicalIF":4.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grin2a Hypofunction Impairs Spatial Working Memory and Disrupts Hippocampal Network Oscillations and Excitatory-Inhibitory Balance","authors":"Hassan Hosseini ,&nbsp;Sky Evans-Martin ,&nbsp;Emma Bogomilsky ,&nbsp;Dominique L. Pritchett ,&nbsp;Kevin S. Jones","doi":"10.1016/j.bpsgos.2025.100500","DOIUrl":"10.1016/j.bpsgos.2025.100500","url":null,"abstract":"<div><h3>Background</h3><div>NMDA receptors, particularly those containing the GluN2A subunit, are critical for hippocampal-dependent learning and memory. The GluN2A subunit is encoded by the <em>GRIN2A</em> gene and is essential for maintaining cognitive function, including working memory. In this study, we explored how full or partial ablation of the mouse <em>Grin2a</em> gene impairs working memory and disrupts hippocampal network oscillations and excitatory/inhibitory (E/I) balance.</div></div><div><h3>Methods</h3><div>Male <em>Grin2a</em> mutant mice were assessed for spatial working memory deficits using the 8-arm radial maze. We utilized multielectrode arrays and whole-cell patch-clamp electrophysiology to evaluate network oscillations and synaptic inputs to pyramidal cells in ex vivo hippocampal slices. We performed an immunohistochemical analysis of hippocampal slices to evaluate changes in the abundance of GABAergic (gamma-aminobutyric acidergic) neurons.</div></div><div><h3>Results</h3><div><em>Grin2a</em> deficiency impaired spatial working memory and disrupted coupling of theta-gamma oscillations in the hippocampus. Moreover, <em>Grin2a</em> mutants expressed an overabundance of parvalbumin-expressing interneurons that integrated into hippocampal circuits and destabilized E/I input to CA1 pyramidal neurons.</div></div><div><h3>Conclusions</h3><div>This study highlights the critical role of GluN2A-containing NMDA receptors in maintaining hippocampal network synchrony. Impairments in network synchrony and E/I balance within the hippocampus may contribute to cognitive deficits observed in <em>Grin2a</em>-related disorders such as schizophrenia, epilepsy, and intellectual disability.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100500"},"PeriodicalIF":4.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac and Electrodermal Responses to Threats: Modulation by Childhood Sexual Abuse History","authors":"Mariana Xavier ,&nbsp;Arthur V. Machado ,&nbsp;Eliane Volchan ,&nbsp;Letícia Oliveira ,&nbsp;Liana Catarina L. Portugal ,&nbsp;Gabriela G.L. Souza ,&nbsp;Fátima S. Erthal ,&nbsp;Raquel M. Gonçalves ,&nbsp;Camila M.F. Gama ,&nbsp;Rita de Cássia S. Alves ,&nbsp;Izabela Mocaiber ,&nbsp;Mirtes G. Pereira","doi":"10.1016/j.bpsgos.2025.100499","DOIUrl":"10.1016/j.bpsgos.2025.100499","url":null,"abstract":"<div><h3>Background</h3><div>Childhood sexual abuse (CSA) is associated with significant negative lifelong consequences for physical and mental health. However, the impact of CSA history on danger perception and response has been understudied. In this study, we explored how autonomic reactivity to threat<del>s</del> is influenced by the history of CSA in a nonclinical sample.</div></div><div><h3>Methods</h3><div>Participants were undergraduate students with no current diagnosis of cardiovascular disease or mental disorders. After exclusion criteria were applied, the sample consisted of 135 participants. Among these 135 participants, 48 (mean age, 20.43 years; SD, 3.07; 9 men) reported having experienced significant CSA (CSA group), and 87 (mean age, 20.89 years; SD, 4.99; 30 men) reported not having had such experiences (non-CSA group). The participants viewed trauma-unrelated threatening or neutral pictures while their skin conductance response and heart rate data were collected.</div></div><div><h3>Results</h3><div>Compared with the neutral pictures, when viewing trauma-unrelated threatening pictures, the non-CSA group presented bradycardia, which is a typical cardiac response upon exposure to negative images. In contrast, the CSA group presented a blunted cardiac response. Furthermore, we observed an overrepresentation of skin conductance nonresponders in the CSA group.</div></div><div><h3>Conclusions</h3><div>Taken together, these findings suggest that youth who are exposed to CSA seem to have blunted autonomic responsiveness to threats. This blunted responsiveness is an atypical pattern that may represent a biomarker of many unfavorable physiological and psychological outcomes.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100499"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Leukocyte Telomere Length With Trait Resilience, Adverse Childhood Experiences, and Psychological Distress Among Expecting Parents in the FinnBrain Birth Cohort","authors":"Viivi Mondolin ,&nbsp;Hasse Karlsson ,&nbsp;Laura Perasto ,&nbsp;Tiina Paunio ,&nbsp;Emma Vitikainen ,&nbsp;Dries S. Martens ,&nbsp;Linnea Karlsson ,&nbsp;Jetro J. Tuulari ,&nbsp;Eeva-Leena Kataja","doi":"10.1016/j.bpsgos.2025.100498","DOIUrl":"10.1016/j.bpsgos.2025.100498","url":null,"abstract":"<div><h3>Background</h3><div>Telomere attrition has previously been associated with mental health problems and adverse childhood experiences (ACEs). Resilience has been shown to protect against mental health problems even in the context of ACEs. In this study, we examined the associations between leukocyte telomere length (LTL), symptoms of psychological distress, ACEs, and trait resilience. We examined whether LTL mediates the negative effects of ACEs and whether trait resilience moderates the association between LTL and distress.</div></div><div><h3>Methods</h3><div>The study population was drawn from the ongoing FinnBrain Birth Cohort Study and included 342 mothers and 339 fathers who had provided blood samples and questionnaire data during pregnancy. Questionnaire data included the Connor-Davidson Resilience Scale 10, Edinburgh Postnatal Depression Scale, Symptom Checklist-90, and Trauma and Distress Scale. Data analysis included regression analysis, mixed-methods models, and statistical evaluation.</div></div><div><h3>Results</h3><div>ACEs were associated with depressive and anxiety symptoms. However, contrary to the initial hypothesis, LTL was not associated with ACEs or distress symptoms and thus did not mediate their association. Furthermore, resilience was not associated with LTL and did not moderate the possible association between LTL and distress symptoms.</div></div><div><h3>Conclusions</h3><div>We found no association between TL and ACEs, psychological distress, or trait resilience. The mild distress symptoms, limited exposure to high ACEs, and the predominantly moderate to high socioeconomic status in the sample may be relevant to interpreting these findings. Encouragingly, not all ACEs necessarily lead to telomere attrition.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100498"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare Copy Number Variants Reveal Critical Cell Types and Periods of Brain Development in Neurodevelopmental Disorders","authors":"Susmita Malwade ,&nbsp;Carl M. Sellgren ,&nbsp;Navneet A. Vasistha ,&nbsp;Konstantin Khodosevich","doi":"10.1016/j.bpsgos.2025.100495","DOIUrl":"10.1016/j.bpsgos.2025.100495","url":null,"abstract":"<div><h3>Background</h3><div>Multiple copy number variations (CNVs) in the human genome are associated with neurodevelopmental disorders (NDDs). Their markedly larger effect sizes and penetrance than common risk variants make them invaluable for investigating the etiology of NDDs.</div></div><div><h3>Methods</h3><div>We integrated &gt;1 million single-cell transcriptomes from multiple datasets, capturing major brain regions and the entire timeline of human brain development. We performed expression-weighted cell-type enrichment analysis of genes contained in 127 CNVs associated with NDDs to identify human brain cell types, brain regions, and periods of development most susceptible to variations in gene dosage.</div></div><div><h3>Results</h3><div>We identified 3 groups of CNVs differentially enriched in developing cell types. Two groups of CNVs were preferentially expressed during early fetal brain development. While group A could be defined as developing neuron CNVs, group B was precursor CNVs, which were highly enriched in radial glia. Group A CNVs were associated with synaptic signaling, suggesting that synaptic dysfunction observed in NDDs may originate very early during fetal brain development. Group B CNVs were related to cell cycle and suggest dysfunction in proliferation and differentiation of precursor cells. Postnatally, expression of groups A and B genes was enriched in intratelencephalic neurons that integrate cortical information.</div></div><div><h3>Conclusions</h3><div>Overall, we showed that although NDDs are only diagnosed during childhood or adolescence, the actual effect of genetic mutations on embryonic progenitor cells or early neurons may be strongest during fetal brain development, which could program the cascade for subsequent developmental changes and, together with further postnatal dysfunction, impair brain function.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100495"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Putative Mechanisms of Electroconvulsive Therapy in Treatment-Resistant Schizophrenia Examined Using Magnetic Resonance Imaging","authors":"Neelabja Roy ,&nbsp;Dhruva Ithal ,&nbsp;Urvakhsh Meherwan Mehta ,&nbsp;Rakshathi Basavaraju ,&nbsp;Rose Dawn Bharath ,&nbsp;Nicolas R. Bolo ,&nbsp;Jagadisha Thirthalli ,&nbsp;Bangalore N. Gangadhar ,&nbsp;Matcheri S. Keshavan","doi":"10.1016/j.bpsgos.2025.100494","DOIUrl":"10.1016/j.bpsgos.2025.100494","url":null,"abstract":"<div><h3>Background</h3><div>The neural mechanisms of electroconvulsive therapy (ECT) in refractory schizophrenia remain elusive. In the current study, we aimed to identify magnetic resonance imaging (MRI)–derived structural (cortical/subcortical volumes) and functional (resting-state connectivity) brain changes after ECT and their associations with clinical response.</div></div><div><h3>Methods</h3><div>We used an inductive (whole-brain, hypothesis-free) approach to examine structural and functional brain changes and their association with clinical response (positive symptom reduction) in clozapine-refractory schizophrenia (<em>n</em> = 30) after ECT (median 8 sessions). Furthermore, a deductive approach was used to compare baseline whole-brain MRI data from clozapine-refractory patients (<em>n</em> = 31) to data from clozapine responders (<em>n</em> = 23), thereby identifying regions of interest unique to clozapine-refractory schizophrenia. Changes in these regions of interest post-ECT and their association with clinical response were then examined.</div></div><div><h3>Results</h3><div>The inductive approach identified volumetric enhancement in the bilateral amygdalae (Cohen’s <em>d</em> = 0.4), which was significantly associated with clinical response (β = −0.01, <em>p</em> = .003). The deductive approach identified posterior cerebellar hyperconnectivity as being unique to clozapine-refractory schizophrenia (<em>d</em> = 1.57), which was associated with baseline positive symptoms (<em>r</em> = 0.36, <em>p</em> = .04). Following ECT, there was a significant reduction in posterior cerebellar hyperconnectivity (<em>d</em> = −0.86), and this reduction was significantly associated with clinical response (β = 0.42, <em>p</em> = .002). Increased hippocampal and frontal volumes, frontoparietal connectivity, and reduced sensorimotor connectivity were also observed but were unrelated to clinical response.</div></div><div><h3>Conclusions</h3><div>ECT may drive clinical improvement in refractory schizophrenia by increasing amygdala volumes and reducing posterior cerebellar connectivity. Randomized sham-controlled trials can confirm these findings in the future.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100494"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment","authors":"Yalin Sun ,&nbsp;Meenalochani Sivasubramanian ,&nbsp;Marija Milenkovic ,&nbsp;Andrew Gumbert ,&nbsp;Jack Bergman ,&nbsp;Preston Ge ,&nbsp;Myriam Heiman ,&nbsp;Marie-Eve Di Raddo ,&nbsp;Sarah L. Withey ,&nbsp;Bertha K. Madras ,&nbsp;Susan R. George","doi":"10.1016/j.bpsgos.2025.100496","DOIUrl":"10.1016/j.bpsgos.2025.100496","url":null,"abstract":"<div><h3>Background</h3><div>Adolescent-onset cannabis use confers higher risk for neuropsychiatric disorders, implicating amygdala dysfunction. However, the mechanisms that mediate Δ⁹-tetrahydrocannabinol (THC)–triggered neuroadaptive changes in the maturing amygdala remain unclear.</div></div><div><h3>Methods</h3><div>Proteomic analysis of amygdala tissue from male adolescent <em>Saimiri boliviensis</em> nonhuman primates chronically treated with THC provided leads for targeted analyses of glial fibrillary acidic protein (GFAP), stathmin-1, and neuronal cell adhesion molecule (NrCAM) in a second species of male adolescent (postnatal day [P]35) and adult (P70) Sprague-Dawley rats. Primate activity monitoring and rat behavioral testing revealed THC-disrupted sleep architecture and anxiety-related behavior, respectively. Primary rat astrocyte cultures provided mechanistic insight into THC activation of astrocyte inflammatory function.</div></div><div><h3>Results</h3><div>THC-induced upregulation of GFAP and complement factor-B (CF-B) signified proinflammatory glial activation exclusively in the adolescent amygdala, an effect absent in other brain regions and in adults. THC attenuated synaptic plasticity enhancers, stathmin-1 and NrCAM, effects not recapitulated in adults. Co-administered cannabidiol (CBD) prevented astrogliosis but did not restore synaptic plasticity marker levels. Astrogliosis was correlated with fragmented sleep, and attenuated plasticity markers were correlated with anxiety. THC-induced GFAP and CF-B upregulation with attenuation by CBD were replicated in cultured astrocytes, requiring cannabinoid type 1 receptor (CB1R)-activated calcium signaling. Elevated CB1R expression in the maturing brain was astrocyte-localized in the amygdala, but neuronal in the cortex and striatum.</div></div><div><h3>Conclusions</h3><div>Brain region- and age-specific regulation of CB1R in astrocytes critically links THC and unique adolescent amygdala vulnerability to inflammatory gliosis, impairing behaviors implicated in neuropsychiatric disorders. Mitigation of specific THC-induced changes by CBD offers leads for attenuating some adverse effects of THC.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100496"},"PeriodicalIF":4.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical Neural Activation During Emotional but Not Nonemotional Response Inhibition in Healthy Young People Exposed to Childhood Maltreatment and Peer Victimization","authors":"Lena Lim ,&nbsp;Keith M. Shafritz","doi":"10.1016/j.bpsgos.2025.100497","DOIUrl":"10.1016/j.bpsgos.2025.100497","url":null,"abstract":"<div><h3>Background</h3><div>Early-life interpersonal stress, particularly childhood maltreatment (CM), is associated with neurobiological abnormalities and atypical emotion regulation. However, few studies have investigated the neural effects of peer victimization (PV). We examined neural alterations in emotional and nonemotional response inhibition in carefully matched healthy CM and PV groups.</div></div><div><h3>Methods</h3><div>Functional magnetic resonance imaging data were collected from 113 age- and sex-matched nonclinical/community youths (38 CM, 39 PV, and 36 control) during an emotional (fearful/happy) and nonemotional (letter) Go/NoGo task.</div></div><div><h3>Results</h3><div>There were no significant group differences in behavioral performance. However, during fearful face inhibition, the CM group exhibited hyperactivation compared with the PV group in a cluster comprising the bilateral calcarine, cuneus, and lingual gyri, which was related to higher parental antipathy in the CM group. Hyperactivation also occurred in limbic-striatal, middle temporal, and cerebellar regions, although at a more liberal threshold. Additionally, there was a trend of PV-specific underactivation in the left middle temporal gyrus during happy inhibition. Despite no significant group differences in nonemotional response inhibition, both the CM and PV groups exhibited greater activation than the control group in default mode network regions during the cognitively low-load LetterGo condition.</div></div><div><h3>Conclusions</h3><div>These findings suggest that early-life interpersonal stress is associated with atypical neural activation during emotionally driven decision making but not during nonemotional response inhibition, underscoring the importance of examining both “hot” and “cold” decision-making processes. The atypical activation of key emotion-visual processing regions may be a potential mechanism to cope with aversive experiences and may reflect the brain’s attempt to facilitate emotional inhibitory control, particularly in resilient maltreated youths.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100497"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autism-Associated PTCHD1 Missense Variants Bind to the SNARE-Associated Protein SNAPIN but Exhibit Impaired Subcellular Trafficking","authors":"Stephen F. Pastore ,&nbsp;Connie T.Y. Xie ,&nbsp;Roya Derwish ,&nbsp;Tahir Muhammad ,&nbsp;Tereza Blahova ,&nbsp;Sierra C. El-masri ,&nbsp;Paul W. Frankland ,&nbsp;Paul A. Hamel ,&nbsp;John B. Vincent","doi":"10.1016/j.bpsgos.2025.100492","DOIUrl":"10.1016/j.bpsgos.2025.100492","url":null,"abstract":"<div><h3>Background</h3><div><em>PTCHD1</em> is a susceptibility gene for autism spectrum disorder and intellectual disability. Its function in brain development and neurotransmission remains elusive. Studies have sought to characterize PTCHD1 function by elucidating its neural network of interacting proteins. However, given the current paucity of functional information, many PTCHD1 missense variants in clinical databases are classified as variants of uncertain significance (VUSs), severely limiting the health care resources available to patients and families.</div></div><div><h3>Methods</h3><div>A yeast 2-hybrid assay was used to identify synaptic PTCHD1-interacting proteins. Candidate binding partners were validated by cloning; transient overexpression in human embryonic kidney (HEK) 293T cells, followed by co-immunoprecipitation and immunoblotting; and immunocytochemistry in differentiated P19 cells. Site-directed mutagenesis was used to evaluate the pathogenicity of clinical missense variants, followed by transient overexpression and immunocytochemistry in non-neuronal (HEK293T) and neuronal (Neuro-2a cells) systems.</div></div><div><h3>Results</h3><div>A novel interaction was identified between the first lumenal loop of PTCHD1 and the SNARE-associated protein SNAPIN, which is implicated in synaptic vesicle exocytosis. Clinically associated missense variants within this region did not disrupt SNAPIN binding, indicating that the pathoetiology of these variants is unrelated to this interaction. However, 6 of the 12 missense variants tested exhibited pronounced retention within the endoplasmic reticulum and impaired neuronal and non-neuronal trafficking to the plasma membrane.</div></div><div><h3>Conclusions</h3><div>These data yield insights into the role of PTCHD1 in neurodevelopment and neurotransmission and suggest a neuropathological mechanism for missense variants. These findings provide a platform for diagnostic assay and VUS interpretation, allowing for clinical reclassification of these variants.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 4","pages":"Article 100492"},"PeriodicalIF":4.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}