Annalisa Lella, Linda A Antonucci, Roberta Passiatore, Loredana Bellantuono, Pierluigi Selvaggi, Teresa Popolizio, Guido Di Sciascio, Alessandro Saponaro, Patrizia Ricci, Mario Altamura, Giuseppe Blasi, Antonio Rampino, Chris Vriend, Vince D Calhoun, Kelly Rootes-Murdy, Aaron L Goldman, Inmaculada Baeza, Josefina Castro-Fornieles, Gisela Sugranyes, Elena De la Serna, Edith Pomarol-Clotet, Mar Fatjó-Vilas, Raymond Salvador, Andriana Karuk, Paola Fuentes-Claramonte, David C Glahn, Amanda L Rodrigue, John Blangero, Lei Wang, Taeyoung Lee, Karolin E Einenkel, Saskia Hamers, Oliver Gruber, Adrian Preda, Young-Chul Chung, Soyolsaikhan Odkhuu, Corentin Vallée, Paola Dazzan, Machteld Marcelis, Stijn Michielse, Katharina Brosch, Frederike Stein, Igor Nenadić, Benjamin Straube, Florian Thomas-Odenthal, Tilo Kircher, Sean Carruthers, Susan L Rossell, Phillip J Sumner, Tamsyn E Van Rheenen, Caroline Demro, Ian S Ramsay, Scott R Sponheim, Rebekka Lencer, Susanne Meinert, Tim Hahn, Udo Dannlowski, Dominik Grotegerd, Mariateresa Ciccarelli, Felice Iasevoli, Giuseppe Pontillo, Godfrey D Pearlson, Derin Cobia, Fabrizio Piras, Nerisa Banaj, Daniela Vecchio, Marjolein E A Barendse, Neeltje E M van Haren, Hang Joon Jo, Kang Sim, Yann Quidé, Melissa J Green, Rachael Slate, Giacomo Cecere, Wolfgang Omlor, Stephanie Homan, Philipp Homan, Sophia I Thomopoulos, Jessica A Turner, Theo G M van Erp, Paul M Thompson, Alessandro Bertolino, Giulio Pergola
{"title":"Thalamo-cortical structural co-variation networks are related to familial risk for schizophrenia in the context of lower nuclei volume estimates in patients: an ENIGMA study.","authors":"Annalisa Lella, Linda A Antonucci, Roberta Passiatore, Loredana Bellantuono, Pierluigi Selvaggi, Teresa Popolizio, Guido Di Sciascio, Alessandro Saponaro, Patrizia Ricci, Mario Altamura, Giuseppe Blasi, Antonio Rampino, Chris Vriend, Vince D Calhoun, Kelly Rootes-Murdy, Aaron L Goldman, Inmaculada Baeza, Josefina Castro-Fornieles, Gisela Sugranyes, Elena De la Serna, Edith Pomarol-Clotet, Mar Fatjó-Vilas, Raymond Salvador, Andriana Karuk, Paola Fuentes-Claramonte, David C Glahn, Amanda L Rodrigue, John Blangero, Lei Wang, Taeyoung Lee, Karolin E Einenkel, Saskia Hamers, Oliver Gruber, Adrian Preda, Young-Chul Chung, Soyolsaikhan Odkhuu, Corentin Vallée, Paola Dazzan, Machteld Marcelis, Stijn Michielse, Katharina Brosch, Frederike Stein, Igor Nenadić, Benjamin Straube, Florian Thomas-Odenthal, Tilo Kircher, Sean Carruthers, Susan L Rossell, Phillip J Sumner, Tamsyn E Van Rheenen, Caroline Demro, Ian S Ramsay, Scott R Sponheim, Rebekka Lencer, Susanne Meinert, Tim Hahn, Udo Dannlowski, Dominik Grotegerd, Mariateresa Ciccarelli, Felice Iasevoli, Giuseppe Pontillo, Godfrey D Pearlson, Derin Cobia, Fabrizio Piras, Nerisa Banaj, Daniela Vecchio, Marjolein E A Barendse, Neeltje E M van Haren, Hang Joon Jo, Kang Sim, Yann Quidé, Melissa J Green, Rachael Slate, Giacomo Cecere, Wolfgang Omlor, Stephanie Homan, Philipp Homan, Sophia I Thomopoulos, Jessica A Turner, Theo G M van Erp, Paul M Thompson, Alessandro Bertolino, Giulio Pergola","doi":"10.1016/j.biopsych.2025.03.027","DOIUrl":"https://doi.org/10.1016/j.biopsych.2025.03.027","url":null,"abstract":"<p><strong>Background: </strong>Structural brain differences in the thalamus and the cortex have been widely reported in schizophrenia (SCZ) relative to neurotypical controls (NC). Most prior studies examined the thalamus as a whole, single region-of-interest. Additionally, findings in individuals at familial high-risk for schizophrenia (FHR) remain inconclusive. Here, we investigated whether local and network-wide thalamic-related structural alterations vary as a function of familial risk for schizophrenia.</p><p><strong>Methods: </strong>Structural MRI scans were obtained from 5,197 participants (3,409 NC, 257 FHR, 1,531 SCZ) across 32 cross-sectional samples within the ENIGMA Consortium. Random-effects meta-analyses, and network analyses were conducted on (i) local thalamic alterations (volume estimates of seven thalamic subdivisions), and (ii) network-wide thalamic alterations (thickness and surface-related thalamo-cortical/cortico-cortical co-variation patterns) across groups (NC, FHR, SCZ).</p><p><strong>Results: </strong>Individuals with SCZ showed significantly lower gray matter volume estimates in the anterior, pulvinar, medial, posterior, and ventral thalamic subdivisions compared to NC (q<sub>FDR</sub><0.05). FHR did not differ from NC. At the network-wide level, thalamo-cortical co-variations discriminated FHR from NC (q<sub>FDR</sub><0.05), with FHR showing intermediate co-variation between SCZ and NC. Cortico-cortical co-variation patterns revealed that SCZ and FHR shared similarly disconnected clustering configurations, distinct from NC (q<sub>FDR</sub><0.05).</p><p><strong>Conclusions: </strong>Results revealed lower thalamic volume estimates in SCZ but not in FHR, hence yielding no evidence of a familial risk trait, whereas thalamo-cortical and cortico-cortical co-variation estimates were associated with familial risk for SCZ These findings suggest that, once the thalamus is parsed into subdivisions, network-wide thalamo-cortical features may identify trait-dependent, neurobiological correlates of genetic risk for SCZ.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958189","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}
Stephane A De Brito, Jack C Rogers, Ruth Pauli, Gregor Kohls, Nora M Raschle, Anne Martinelli, Areti Smaragdi, Karen Gonzalez-Madruga, Harriet Cornwell, Christina Stadler, Kerstin Konrad, Christine M Freitag, Graeme Fairchild
{"title":"Brain Responses During Face Processing in Conduct Disorder: Considering Sex and Callous-Unemotional Traits.","authors":"Stephane A De Brito, Jack C Rogers, Ruth Pauli, Gregor Kohls, Nora M Raschle, Anne Martinelli, Areti Smaragdi, Karen Gonzalez-Madruga, Harriet Cornwell, Christina Stadler, Kerstin Konrad, Christine M Freitag, Graeme Fairchild","doi":"10.1016/j.biopsych.2025.04.023","DOIUrl":"https://doi.org/10.1016/j.biopsych.2025.04.023","url":null,"abstract":"<p><p>Functional magnetic resonance imaging (fMRI) studies of conduct disorder (CD) have mostly been limited to males. Here, we examined whether male and female youth with CD showed similar or distinct alterations in brain responses to emotional faces, using a large, mixed-sex sample of youths with CD. We also investigated the influence of callous-unemotional (CU) traits. Brain responses to angry, fearful, and neutral faces were assessed in 161 CD youths (74 females) and 241 typically-developing (TD) youths (139 females) aged 9-18 years. Categorical analyses tested for diagnosis effects (CD vs. TD and CD with high [CD/HCU] vs. low [CD/LCU] levels of CU traits vs. TD) and sex-by-diagnosis interactions. When processing faces in general (all faces versus baseline), youths with CD exhibited lower amygdala responses compared to TD youths, which appeared driven by the CD/HCU subgroup. Sex-by-CU subgroups interactions were identified in the amygdala (CD/LCU females<TD females; CD/LCU males>TD males) and insula (CD/HCU females>CD/LCU females; CD/HCU males<CD/LCU males). The findings for males support an influential neurocognitive model of CD. However, the association between CU traits and brain response to facial expressions differed in females and males with CD, suggesting distinct pathophysiological processes.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962770","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}
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach, Daniel Ryskamp Rijsketic, Austen B Casey, Nicholas Gregory, Wesley Zhao, Tyler E Girard, Kathryn T Mattox, Juliana S Salgado, Robert C Malenka, Boris D Heifets
{"title":"Ketamine Evokes Acute Behavioral Effects Via μ Opioid Receptor-Expressing Neurons of the Central Amygdala.","authors":"Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach, Daniel Ryskamp Rijsketic, Austen B Casey, Nicholas Gregory, Wesley Zhao, Tyler E Girard, Kathryn T Mattox, Juliana S Salgado, Robert C Malenka, Boris D Heifets","doi":"10.1016/j.biopsych.2025.04.020","DOIUrl":"10.1016/j.biopsych.2025.04.020","url":null,"abstract":"<p><strong>Background: </strong>Ketamine has anesthetic, analgesic, and antidepressant properties, which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the brain regions and circuits that contribute to ketamine's antidepressant mechanism in humans.</p><p><strong>Methods: </strong>We screened male and female wild-type mice for a behavioral response to ketamine that could be reversed by OR antagonists in several assays, including locomotor activation, analgesia, and the forced swim test. Whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, was used to identify brain areas that mediated ketamine/OR interactions. Region-specific pharmacological and genetic interference with μ OR (MOR) signaling was used to test predictions of whole-brain imaging results in a subset of behavioral assays.</p><p><strong>Results: </strong>Among a series of behavioral assays, only locomotor activation was sensitive to ketamine and blocked by an MOR-selective antagonist. Locomotor activation produced by the NMDA receptor antagonist MK-801 was not OR dependent. Whole-brain imaging revealed that cFos expression in neurons of the central amygdala (CeA) showed the greatest difference between ketamine in the presence versus absence of naltrexone. CeA neurons expressing both MOR and PKCδ were strongly activated by naltrexone, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine.</p><p><strong>Conclusions: </strong>These data suggest that ketamine acts at MORs expressed in CeA neurons to produce acute hyperlocomotion.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973313","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":"Insomnia and Inflammation Conspire to Heighten Depression Risk: Implications for Treatment and Prevention of Mood Disorders.","authors":"Michael R Irwin","doi":"10.1016/j.biopsych.2025.04.018","DOIUrl":"10.1016/j.biopsych.2025.04.018","url":null,"abstract":"<p><p>Insomnia is ubiquitous, is comorbid with all major mental disorders, increases the risk of depression, and contributes to inflammatory morbidity and all-cause mortality. This review examines the relationships between insomnia and inflammation in the pathophysiology of depression. The unique role of insomnia on depression risk is examined with interrogation of what aspects of sleep disturbance contribute to depressed mood. Furthermore, the influence of insomnia and its specific aspects (i.e., short sleep duration, disturbance of sleep maintenance) on affective mechanisms are considered, with a focus on reward activation and emotion processing. Given that inflammation contributes to some types of depression, the bidirectional interactions between sleep and inflammation are examined with consideration of how sleep deprivation induces activation of systemic, cellular, and genomic inflammatory outcomes and the causal role of inflammation in precipitating depressed mood and depressive symptoms. Key gaps in the literature linking insomnia and inflammation to depression risk are identified, and maps for future research are proposed. In particular, this review considers how the components of insomnia and inflammation conspire together to exaggerate deficits in reward activation and recognition of emotion, which underlie depression risk and adverse depression outcomes. Finally, informed by this two-hit model of insomnia and inflammation on depression risk, this review examines the efficacy of behavioral interventions that target insomnia and reverse related inflammation and discusses their potential to refine therapeutic approaches for depression treatment and prevention in individuals with insomnia.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962977","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}
Julia R Plank, Elveda Gozdas, Jennifer Bruno, Chloe A McGhee, Hua Wu, Mira M Raman, Manish Saggar, Tamar Green
{"title":"Quantitative T1 mapping indicates elevated white matter myelin in children with RASopathies.","authors":"Julia R Plank, Elveda Gozdas, Jennifer Bruno, Chloe A McGhee, Hua Wu, Mira M Raman, Manish Saggar, Tamar Green","doi":"10.1016/j.biopsych.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.biopsych.2025.04.014","url":null,"abstract":"<p><strong>Background: </strong>Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in prior clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).</p><p><strong>Methods: </strong>We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal components analysis captured cortical myelination patterns across 360 regions, followed by a MANOVA. A support vector machine (SVM) identified the most discriminative features between-groups.</p><p><strong>Results: </strong>Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD (p<sub>FDR</sub><.05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p=.002, η<sup>2</sup>=.028), suggesting cortical myelination differences between-groups. The SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.</p><p><strong>Conclusions: </strong>We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models showing oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965189","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":"Social Homeostasis: A New Paradigm for Mental Health Diagnosis and Treatment","authors":"AZA Stephen Allsop , Kay M. Tye , John H. Krystal","doi":"10.1016/j.biopsych.2025.03.007","DOIUrl":"10.1016/j.biopsych.2025.03.007","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"97 10","pages":"Pages 932-935"},"PeriodicalIF":9.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887707","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}
Daniel P Moriarity, Emily R Perkins, Keanan J Joyner
{"title":"Hierarchical Phenotyping of Psychopathology: Implications and Opportunities for Precision Psychiatry When Biology Could Be Associated With Both Symptoms and Syndromes.","authors":"Daniel P Moriarity, Emily R Perkins, Keanan J Joyner","doi":"10.1016/j.biopsych.2025.04.015","DOIUrl":"10.1016/j.biopsych.2025.04.015","url":null,"abstract":"<p><p>As psychiatry increasingly embraces precision medicine principles, there have been efforts to characterize the specificity of biology-psychopathology associations (e.g., is biology associated with syndromes or symptoms?). Unfortunately, the vast majority of research is designed to test syndromes (e.g., case-control, symptom total/average scores) or individual symptoms a priori based on untested assumptions. Alternatively, most studies that attempt to empirically compare these options test biology as a predictor of 1) syndromes and 2) symptoms in separate models that are unable to directly falsify the specificity of observed associations because these options are not directly competing for the same variance. In this review, we will 1) discuss the historical tension between symptom- and syndrome-focused psychiatry; 2) introduce hierarchical phenotyping as an approach to determining the specificity of biology-psychopathology associations; 3) highlight how hierarchical phenotyping approaches are complementary to leading nosological movements in psychopathology research; 4) illustrate how a hierarchical phenotyping lens can generate promising future directions for precision psychiatry using immunopsychiatric, genetic, and neurophysiological examples; 5) highlight clinical implications of hierarchical phenotyping approaches to psychiatry; 6) discuss methodological implications of hierarchical phenotyping for best practices in measuring and modeling psychopathology; and 7) introduce methodological resources for readers interested in investigating hierarchical phenotyping in their own work. In doing so, we seek to build the case for hierarchical phenotyping approaches while simultaneously preparing motivated readers to use these methods in their own work to advance precision psychopathology research.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960898","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}