Biological Psychiatry最新文献

{"title":"The Orbitofrontal Cortex to Striatal Cholinergic Interneuron Circuit Controls Cognitive Flexibility Shaping Alcohol-Seeking Behavior.","authors":"Jiaxin Li, Yao Zhou, Fangyuan Yin, Yanfeng Du, Jiancheng Xu, Shuyuan Fan, Ziyi Li, Xiaojie Wang, Qingfeng Shen, Yongsheng Zhu, Tengfei Ma","doi":"10.1016/j.biopsych.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.10.005","url":null,"abstract":"<p><strong>Background: </strong>A top-down neuronal circuit from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) appears to be critical for cognitive flexibility. However, how OFC projections to different types of neurons in the DMS control cognitive flexibility and contribute to substance seeking and use, which are relatively inflexible behaviors, remains unclear.</p><p><strong>Methods: </strong>Mice were trained on two-bottle choice and operant alcohol self-administration procedures. The cognitive flexibility of the mice was tested through a place discrimination task. Electrophysiology and in vivo optogenetics were used to test the function of neural circuits in alcohol-seeking behavior.</p><p><strong>Results: </strong>We depicted a connection from the OFC to striatal neurons and found that OFC afferents could elicit functional flexibility in striatal cholinergic interneurons (CINs). A mouse model of chronic alcohol consumption showed impaired cognitive flexibility and reduced burst-pause firing. The impairment of the OFC-DMS circuit resulted in a reduction in glutamatergic transmission in OFC-medium spiny neurons (MSNs) through a CIN-mediated pre-inhibition mechanism. Importantly, remodeling the OFC-DMS circuit by inducing LTP restored cognitive flexibility. Furthermore, CINs were responsible for the impact of remodeling of the OFC-DMS circuit on cognitive flexibility. This regulatory role of CINs preferentially facilitated the potentiation of glutamatergic transmission in D2 receptor-expressing medium spiny neurons (D2-MSNs) but not in D1-MSNs. Finally, activation of the OFC-CIN-D2-MSN circuit decreased alcohol-seeking behavior.</p><p><strong>Conclusions: </strong>Improving OFC-CIN circuit-mediated cognitive flexibility may provide a novel strategy for treating uncontrolled alcohol-seeking behavior.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of allostatic load with depression, anxiety, and suicide: a prospective cohort study.","authors":"Yifan Gou, Shiqiang Cheng, Meijuan Kang, Ruixue Zhou, Chen Liu, Jingni Hui, Ye Liu, Bingyi Wang, Panxing Shi, Feng Zhang","doi":"10.1016/j.biopsych.2024.09.026","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.09.026","url":null,"abstract":"<p><strong>Background: </strong>Allostatic load (AL) is an objective measure of the biological components of chronic stress within clinical practice, potentially influencing depression, anxiety, and suicide. This study investigates the association between AL and these mental disorders.</p><p><strong>Methods: </strong>In this cohort study of 333,017 adults, participants without prior diagnoses of depression, anxiety, or suicide were observed from March 13, 2006, to October 31, 2022. AL was estimated using 10 biomarkers reflecting metabolic, cardiovascular, and inflammatory dysregulation. Diagnoses were based on the International Classification of Diseases 10th Revision (ICD-10). We performed Cox proportional hazards models to assess the relationship between AL and these mental disorders. Additionally, we conducted subgroup analyses for sex, age, and Townsend Deprivation Index (TDI), along with sensitivity analyses.</p><p><strong>Results: </strong>The median follow-up period was 12.99 years. Over the follow-up period, 13,441 (4.04%) participants developed depression, 13,903 (4.17%) developed anxiety and 796 (0.24%) committed suicide. In fully adjusted model, individuals with high AL had an increased risk of depression (HR = 1.389, P = 8.38 ×10^-27), anxiety (HR = 1.304, P = 5.82 ×10^-19) and suicide (HR = 1.433, P = 4.46 ×10^-3). Women and younger individuals with high AL were vulnerable to depression and anxiety, while moderate AL levels were significantly associated with suicide in men and younger participants. Moreover, individuals with middle and high AL had an elevated risk of comorbid depression and anxiety.</p><p><strong>Conclusions: </strong>High AL is positively associated with increased risks of depression, anxiety, and suicide, highlighting its potential as a predictive tool in mental health.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biased information routing through the basolateral amygdala, altered valence processing, and impaired affective states associated with psychiatric illnesses.","authors":"Pantelis Antonoudiou, Eric Teboul, Kenneth A Amaya, Bradly T Stone, Kaitlyn E Dorst, Jamie L Maguire","doi":"10.1016/j.biopsych.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.10.003","url":null,"abstract":"<p><p>Accumulating evidence supports a role for altered circuit function in impaired valence processing and altered affective states as a core feature of psychiatric illnesses. We review the circuit mechanisms underlying normal valence processing and highlight evidence supporting altered function of the basolateral amygdala (BLA), valence processing and affective states across psychiatric illnesses. The mechanisms controlling network activity which governs valence processing will be reviewed in the context of potential pathophysiological mechanisms mediating circuit dysfunction and impaired valence processing in psychiatric illnesses. Finally, we review emerging data demonstrating experience-dependent, biased information routing through the BLA promoting negative valence processing and discuss the potential relevance to impaired affective states and psychiatric illnesses.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D's Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [¹¹C]-PHNO Positron Emission Tomography Study.","authors":"Patrick D Worhunsky, Marcella M Mignosa, Jean-Dominique Gallezot, Brian Pittman, Nabeel B Nabulsi, Adam Stryjewski, Laya Jalilian-Khave, Richard Trinko, Ralph J DiLeone, Richard E Carson, Robert T Malison, Marc N Potenza, Gustavo A Angarita","doi":"10.1016/j.biopsych.2024.09.028","DOIUrl":"10.1016/j.biopsych.2024.09.028","url":null,"abstract":"<p><strong>Background: </strong>Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans.</p><p><strong>Methods: </strong>Healthy, vitamin-D-sufficient adults (N=18; 32.8 ±6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving four total scans over two visits consisting of same-day pre-amphetamine and post-amphetamine (0.3 mg/kg) ¹¹C-PHNO positron emission tomography (PET) scanning to examine D2/3 receptor availability (BP_ND) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least six days apart. Parametric images of ¹¹C-PHNO PET BP_ND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra.</p><p><strong>Results: </strong>For pre-amphetamine scans, there was a medication-by-region-of-interest interaction (F_4,153=2.59, p=0.039) and a main effect of medication (F_1,153=4.88, p=0.029) on BP_ND, with higher BP_ND values on calcitriol in the ventral striatum (t=2.89, p=0.004) and dorsal putamen (t=2.15, p=0.033). There was a main effect of medication on post-amphetamine change in BP_ND (F_4,153=5.93, p=0.016), with greater decreases on calcitriol in the ventral striatum (t=3.00, p=0.003), substantia nigra (t=2.49, p=0.014), and dorsal caudate (t=2.29, p=0.023).</p><p><strong>Conclusions: </strong>Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders involving dysregulated dopamine function.</p><p><strong>Clinical trial registration: </strong>Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD; https://clinicaltrials.gov/study/NCT03103750; ClinicalTrials.gov ID: NCT03103750.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study.","authors":"Antoine Lefrere, Ophélia Godin, Stéphane Jamain, Yecodji Dansou, Ludovic Samalin, Martin Alda, Bruno Aouizerate, Valérie Aubin, Romain Rey, Martina Contu, Philippe Courtet, Caroline Dubertret, Emmanuel Haffen, Dominique Januel, Marion Leboyer, Pierre Michel Llorca, Emeline Marlinge, Mirko Manchia, Samantha Neilson, Emilie Olié, Pasquale Paribello, Marco Pinna, Mircea Polosan, Paul Roux, Raymund Schwan, Leonardo Tondo, Michel Walter, Eleni Tzavara, Guillaume Auzias, Christine Deruelle, Bruno Etain, Raoul Belzeaux","doi":"10.1016/j.biopsych.2024.09.025","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.09.025","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses.</p><p><strong>Method: </strong>We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications.</p><p><strong>Results: </strong>Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD.</p><p><strong>Conclusions: </strong>The proposed NDP constitutes a promising clinical tool for patient stratification in BD.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrogliosis marker [11C]SL25.1188 After COVID-19 With Ongoing Depressive and Cognitive Symptoms.","authors":"Joeffre Braga, Emily J Y Kuik, Mariel Lepra, Pablo M Rusjan, Stephen J Kish, Erica L Vieira, Zahra Nasser, Natasha Verhoeff, Neil Vasdev, Thomas Chao, Michael Bagby, Isabelle Boileau, Stefan Kloiber, M Ishrat Husain, Nathan Kolla, Yuko Koshimori, Khunsa Faiz, Wei Wang, Jeffrey H Meyer","doi":"10.1016/j.biopsych.2024.09.027","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.09.027","url":null,"abstract":"<p><strong>Background: </strong>After acute COVID-19, five percent of people experience persistent depressive symptoms and reduced cognitive function (COVID-DC). Theoretical models propose that astrogliosis is important in long COVID but measures primarily indicative of astrogliosis have not been studied in the brain of long COVID or COVID-DC. The objective is to measure [¹¹C]SL25.1188 total distribution volume ([¹¹C]SL25.1188 V_T), index of monoamine oxidase B (MAO-B) density and marker of astrogliosis with PET in COVID-DC and compare to healthy controls.</p><p><strong>Methods: </strong>In 21 COVID-DC cases and 21 healthy controls, [¹¹C]SL25.1188 V_T was measured in prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum. Depressive symptoms were measured with the Beck Depression Inventory-II and cognitive symptoms were measured with neuropsychological tests.</p><p><strong>Results: </strong>[¹¹C]SL25.1188 V_T was higher in COVID-DC in prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum compared to healthy controls. Depressive symptom severity correlated negatively with [¹¹C]SL25.1188 V_T across prioritized brain regions. More recent acute COVID-19 correlated positively with [¹¹C]SL25.1188 V_T, reflecting higher values since predominance of the omicron variant. Exploratory analyses found greater [¹¹C]SL25.1188 V_T in hippocampus, dorsal putamen, and ventral striatum compared to major depressive episode controls with no history of COVID-19; and no relationship to cognitive testing in prioritized regions.</p><p><strong>Conclusions: </strong>Results strongly support the presence of MAO-B labelled astrogliosis in COVID-DC throughout the regions assessed although the association of greater astrogliosis with less symptoms raises the possibility of a protective role. Magnitude of astrogliosis in COVID-DC is greater since emergence of omicron variant.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders.","authors":"Janine Knauer-Arloth, Anastasiia Hryhorzhevska, Elisabeth B Binder","doi":"10.1016/j.biopsych.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.10.004","url":null,"abstract":"<p><strong>Background: </strong>Alterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk.</p><p><strong>Methods: </strong>We measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation.</p><p><strong>Results: </strong>We identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP.</p><p><strong>Conclusions: </strong>Genetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prophylactic (R,S)-ketamine and (2S,6S)-HNK decrease fear expression by differentially modulating fear neural ensembles.","authors":"Alessia Mastrodonato, Michelle Jin, Noelle Kee, Marcos Lanio, Juliana Tapia, Liliette Quintana, Andrea Muñoz Zamora, Shi-Xian Deng, Xiaoming Xu, Donald W Landry, Christine A Denny","doi":"10.1016/j.biopsych.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.09.024","url":null,"abstract":"<p><strong>Background: </strong>We previously reported that a single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) prior to stress attenuates learned fear. However, whether these drugs attenuate learned fear through divergent or convergent effects on neural activity remains to be determined.</p><p><strong>Methods: </strong>129S6/SvEv male mice were injected with saline, (R,S)-ketamine, or (2S,6S)-HNK one week before a 3-shock contextual fear conditioning (CFC) paradigm. Five days later, mice were re-exposed to the aversive context, and euthanized one hour later to quantify active cells. Brains were processed for c-fos immunoreactivity, and neural networks were built with a novel, wide-scale imaging pipeline.</p><p><strong>Results: </strong>We found that (R,S)-ketamine and (2S,6S)-HNK attenuate learned fear. Fear-related neural activity was altered in: dorsal CA3 following (2S,6S)-HNK; ventral CA3 and CA1, infralimbic (IL) and prelimbic (PL) regions, insular cortex (IC), retrosplenial cortex (RSP), piriform cortex (PIR), nucleus reuniens (RE), and periaqueductal grey (PAG) following both (R,S)-ketamine and (2S,6S)-HNK; and in the paraventricular nucleus of thalamus (PVT) following (R,S)-ketamine. Dorsal CA3 and ventral hippocampus activation correlated with freezing in the (R,S)-ketamine group, and RSP activation correlated with freezing in both (R,S)-ketamine and (2S,6S)-HNK groups. (R,S)-ketamine increased connectivity between cortical and subcortical regions while (2S,6S)-HNK increased connectivity within these regions.</p><p><strong>Conclusions: </strong>This work identifies novel nodes in fear networks, involving the RE, PIR, IC, PAG and RSP, that can be targeted with neuromodulatory strategies or pharmaceutical compounds to treat fear-induced disorders. This approach could be used to optimize target engagement and dosing strategies of existing medications.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study meta-analysis of 9,619 cases with tic disorders.","authors":"Nora I Strom, Matthew W Halvorsen, Jakob Grove, Bergrún Ásbjörnsdóttir, Pétur Luðvígsson, Ólafur Thorarensen, Elles de Schipper, Julia Boberg, Per Andrén, Chao Tian, Thomas Damm Als, Judith Becker Nissen, Sandra M Meier, Jonas Bybjerg-Grauholm, David M Hougaard, Thomas Werge, Anders D Børglum, David A Hinds, Christian Rück, David Mataix-Cols, Hreinn Stefánsson, Kari Stefansson, James J Crowley, Manuel Mattheisen","doi":"10.1016/j.biopsych.2024.07.025","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.07.025","url":null,"abstract":"<p><strong>Background: </strong>Despite the significant personal and societal burden of tic disorders (TD), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor and identifying risk genes could accelerate progress in the field.</p><p><strong>Methods: </strong>Expanding upon previous sample size limitations, we added 4,800 new TD cases and 971,560 controls, conducting a GWAS meta-analysis with 9,619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE Genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses.</p><p><strong>Results: </strong>A genome-wide significant hit (rs79244681, p=2.27x10^-08) within MCHR2-AS1 was identified, though it was not replicated. Post-GWAS analyses revealed a 13.8% SNP-heritability and three significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodman area 9) and five brain cell types (excitatory and inhibitory telencephalon-, inhibitory- di- and mesencephalon, hindbrain-, and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p=0.0017) and high-confidence neurodevelopmental disorder genes (p=0.0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the two SNPs previously associated with TD, one (rs2453763) replicated in an independent sub-sample of our GWAS (p=0.00018).</p><p><strong>Conclusions: </strong>This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TD.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping lesion-related human aggression to a common brain network.","authors":"Shaoling Peng, Frederic L W V J Schaper, Shira Cohen-Zimerman, Gillian N Miller, Jing Jiang, Rob P W Rouhl, Yasin Temel, Shan H Siddiqi, Jordan Grafman, Michael D Fox, Alexander L Cohen","doi":"10.1016/j.biopsych.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.biopsych.2024.09.022","url":null,"abstract":"<p><strong>Background: </strong>Aggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients for which neural mechanisms are unclear and treatment options are limited.</p><p><strong>Methods: </strong>Using recently validated lesion network mapping technique, we derived an aggression associated network by analyzing 182 patients who had suffered penetrating head injuries during their service in the Vietnam War. To test whether damage to this lesion-derived network would increase the risk of aggression related neuropsychiatric symptoms, we used the Harvard Lesion Repository (N = 928). To explore potential therapeutic relevance of this network, we used an independent Deep brain stimulation dataset of 25 patients with epilepsy, in which irritability and aggression are known potential side effects.</p><p><strong>Results: </strong>We found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific brain network defined by functional connectivity to a hub region in the right prefrontal cortex (PFC). This network involves positive connectivity to the ventromedial PFC, dorsolateral PFC, frontal pole, posterior cingulate cortex, anterior cingulate cortex, temporal-parietal junction, and lateral temporal lobe and negative connectivity to the amygdala, hippocampus, insula, and visual cortex. Among all 25 neuropsychiatric symptoms included in the Harvard Lesion Repository, criminality demonstrated the most alignment with our aggression associated network. DBS site connectivity to this same network was associated with increased irritability.</p><p><strong>Conclusions: </strong>We conclude that brain lesions associated with aggression map to a specific human brain circuit, and the functionally connected regions in this circuit provide testable targets for therapeutic neuromodulation.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}