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Classification of Major Depressive Disorder Using Vertex-Wise Brain Sulcal Depth, Curvature, and Thickness with a Deep and a Shallow Learning Model

arXiv

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arXiv 2023年

作者： Goya-Maldonado, Roberto Erwin-Grabner, Tracy Zeng, Ling-Li Ching, Christopher R.K. Aleman, Andre Amod, Alyssa R. Basgoze, Zeynep Benedetti, Francesco Besteher, Bianca Brosch, Katharina Bülow, Robin Colle, Romain Connolly, Colm G. Corruble, Emmanuelle Couvy-Duchesne, Baptiste Cullen, Kathryn Dannlowski, Udo Davey, Christopher G. Dols, Annemiek Ernsting, Jan Evans, Jennifer W. Fisch, Lukas Fuentes-Claramonte, Paola Gonul, Ali Saffet Gotlib, Ian H. Grabe, Hans J. Groenewold, Nynke A. Grotegerd, Dominik Hahn, Tim Hamilton, J. Paul Han, Laura K.M. Harrison, Ben J. Ho, Tiffany C. Jahanshad, Neda Jamieson, Alec J. Karuk, Andriana Kircher, Tilo Klimes-Dougan, Bonnie Koopowitz, Sheri-Michelle Lancaster, Thomas Leenings, Ramona Li, Meng Linden, David E.J. MacMaster, Frank P. Mehler, David M.A. Meinert, Susanne Melloni, Elisa Mueller, Bryon A. Mwangi, Benson Nenadić, Igor Ojha, Amar Okamoto, Yasumasa Oudega, Mardien L. Penninx, Brenda W.J.H. Poletti, Sara Pomarol-Clotet, Edith Portella, Maria J. Pozzi, Elena Radua, Joaquim Rodríguez-Cano, Elena Sacchet, Matthew D. Salvador, Raymond Schrantee, Anouk Sim, Kang Soares, Jair C. Solanes, Aleix Stein, Dan J. Stein, Frederike Stolicyn, Aleks Thomopoulos, Sophia I. Toenders, Yara J. Uyar-Demir, Aslihan Vieta, Eduard Vives-Gilabert, Yolanda Völzke, Henry Walter, Martin Whalley, Heather C. Whittle, Sarah Winter, Nils Wittfeld, Katharina Wright, Margaret J. Wu, Mon-Ju Yang, Tony T. Zarate, Carlos Veltman, Dick J. Schmaal, Lianne Thompson, Paul M. Georg-August University Göttingen Germany College of Intelligence Science and Technology National University of Defense Technology Changsha410073 China Imaging Genetics Center Mark & Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del ReyCA90274 United States Department of Biomedical Sciences of Cells and Systems University Medical Center Groningen University of Groningen Groningen Netherlands Department of Psychiatry & Mental Health Neuroscience Institute University of Cape Town Cape Town South Africa Department of Psychiatry and Behavioral Science University of Minnesota Medical School MinneapolisMN United States Division of Neuroscience IRCCS Scientific Institute Ospedale San Raffaele Milano Italy Department of Psychiatry and Psychotherapy Jena University Hospital Jena Germany Department of Psychiatry and Psychotherapy University of Marburg Rudolf Bultmann Str. 8 Marburg35039 Germany Institute for Radiology and Neuroradiology University Medicine Greifswald Greifswald Germany MOODS Team CESP INSERM U1018 Faculté de Médecine Univ Paris-Saclay Le Kremlin Bicêtre94275 France Service Hospitalo Universitaire de Psychiatrie de Bicêtre Hôpitaux Universitaires Paris-Saclay Assistance Publique-Hôpitaux deParis Hôpital de Bicêtre Le Kremlin BicêtreF-94275 France Department of Biomedical Sciences Florida State University TallahasseeFL United States Sorbonne University Paris Brain Institute - ICM CNRS Inria Inserm AP-HP Hôpital de la Pitié Salpêtrière ParisF-75013 France Institute for Molecular Bioscience the University of Queensland St LuciaQLD Australia Institute for Translational Psychiatry University of Münster Münster Germany Melbourne Neuropsychiatry Centre Department of Psychiatry the University of Melbourne ParkvilleVIC Australia Department of Psychiatry Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam Neuroscience Amsterdam Public Health Research Institute Am

Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. In this study, we used globally representative data from the ENIGMA-MDD working group containing 7,012 participants from 30 sites (N=2,772 MDD and N=4,240 HC), which allows a comprehensive analysis with generalizable results. Based on the hypothesis that integration of vertex-wise cortical features can improve classification performance, we evaluated the classification of a DenseNet and a Support Vector Machine (SVM), with the expectation that the former would outperform the latter. As we analyzed a multi-site sample, we additionally applied the ComBat harmonization tool to remove potential nuisance effects of site. We found that both classifiers exhibited close to chance performance (balanced accuracy DenseNet: 51%;SVM: 53%), when estimated on unseen sites. Slightly higher classification performance (balanced accuracy DenseNet: 58%;SVM: 55%) was found when the cross-validation folds contained subjects from all sites, indicating site effect. In conclusion, the integration of vertex-wise morphometric features and the use of the non-linear classifier did not lead to the differentiability between MDD and HC. Our results support the notion that MDD classification on this combination of features and classifiers is unfeasible. Future studies are needed to determine whether more sophisticated integration of information from ot

关键词： Support vector machines

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Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures

arXiv

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arXiv 2022年

作者： Belov, Vladimir Erwin-Grabner, Tracy Gonul, Ali Saffet Amod, Alyssa R. Ojha, Amar Aleman, Andre Dols, Annemiek Schrantee, Anouk Uyar-Demir, Aslihan Harrison, Ben J. Mwangi, Benson Besteher, Bianca Klimes-Dougan, Bonnie Penninx, Brenda W.J.H. Mueller, Bryon A. Zarate, Carlos Davey, Christopher G. Ching, Christopher R.K. Connolly, Colm G. Fu, Cynthia H.Y. Stein, Dan J. Dima, Danai Linden, David E.J. Mehler, David M.A. Pomarol-Clotet, Edith Pozzi, Elena Melloni, Elisa Benedetti, Francesco MacMaster, Frank P. Grabe, Hans J. Völzke, Henry Gotlib, Ian H. Soares, Jair C. Evans, Jennifer W. Sim, Kang Wittfeld, Katharina Cullen, Kathryn Reneman, Liesbeth Oudega, Mardien L. Wright, Margaret J. Portella, Maria J. Sacchet, Matthew D. Li, Meng Aghajani, Moji Wu, Mon-Ju Jaworska, Natalia Jahanshad, Neda van der Wee, Nic J.A. Groenewold, Nynke Hamilton, Paul J. Sämann, Philipp G. Bülow, Robin Poletti, Sara Whittle, Sarah Thomopoulos, Sophia I. van der Werff, Steven J.A. Koopowitz, Sheri-Michelle Lancaster, Thomas Ho, Tiffany C. Yang, Tony T. Basgoze, Zeynep Veltman, Dick J. Schmaal, Lianne Thompson, Paul M. Goya-Maldonado, Roberto Georg-August University Von-Siebold-Str. 5 Goettingen37075 Germany SoCAT Lab Department of Psychiatry School of Medicine Ege University Izmir Turkey Department of Psychiatry & Mental Health University of Cape Town Cape Town South Africa Center for Neuroscience University of Pittsburgh PittsburghPA United States Center for Neural Basis of Cognition University of Pittsburgh PittsburghPA United States Department of Biomedical Sciences of Cells and Systems University Medical Center Groningen University of Groningen Groningen Netherlands Department of Psychiatry Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam Neuroscience Amsterdam Public Health Research Institute Amsterdam Netherlands Amsterdam University Medical Centers Location AMC Department of Radiology and Nuclear Medicine Amsterdam Netherlands Melbourne Neuropsychiatry Centre Department of Psychiatry The University of Melbourne ParkvilleVIC Australia Louis A. Faillace MD Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston HoustonTX United States Center of Excellence On Mood Disorders Louis A. Faillace MD Department of Psychiatry and Behavioral Sciences McGovern Medical School The University of Texas Health Science Center HoustonTX United States Department of Psychiatry and Psychotherapy Jena University Hospital Jena Germany Department of Psychology University of Minnesota MinneapolisMN United States Department of Psychiatry and Behavioral Science University of Minnesota Medical School MinneapolisMN United States Section on the Neurobiology and Treatment of Mood Disorders National Institute of Mental Health BethesdaMD United States Imaging Genetics Center Mark & Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del ReyCA90274 United States Department of Biomedical Sciences Florida Stateu University TallahasseeFL United States School of Psychology University

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (n=5,356) to provide a generalizable ML classification benchmark of major depressive disorder (MDD). Using brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD vs healthy controls (HC) with around 62% balanced accuracy, but when harmonizing the data using ComBat balanced accuracy dropped to approximately 52%. Similar results were observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may achieve more encouraging prospects. © 2022, CC BY-NC-ND.

关键词： Brain mapping

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Study protocol for a randomized, placebo-controlled, double-masked mechanistic clinical trial of transdermal estrogen replacement in hypoestrogenic eating disorders to explore the role of estrogen on cognitive flexibility and reward processing

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Contemporary Clinical Trials 2025年 154卷 107924-107924页

作者： Breithaupt, Lauren Slattery, Meghan Lauze, Meghan Petterway, Felicia Lindman, Lauren Cravitz, Mia Naticchia, Sarah Seenivasa, Siddarth Powers, Macy Javaras, Kristin N. Alperovitz, David J. Halperin, Judith Dechant, Esther Thomas, Jennifer J. Lawson, Elizabeth A. Lee, Hang Pizzagalli, Diego A. Romer, Adrienne L. Kumar, Poornima Plessow, Franziska Misra, Madhusmita Eddy, Kamryn T. Department of Psychiatry Massachusetts General Hospital Boston MA United States Eating Disorders Clinical and Research Program Massachusetts General Hospital MA United States Mass General Brigham Multidisciplinary Eating Disorders Research Collaborative Mass General Brigham Boston MA United States Psychiatry Neuroimaging Laboratory Department of Psychiatry Brigham and Women's Hospital Harvard Medical School Boston MA United States Department of Psychiatry Harvard Medical School Boston MA United States Neuroendocrine Unit Massachusetts General Hospital Harvard Medical School MA United States Harvard University Department of Neuroscience Cambridge MA United States Division of Women's Mental Health McLean Hospital Belmont MA United States Klarman Eating Disorders Center McLean Hospital Belmont MA United States Department of Medicine Harvard Medical School Boston MA United States Division of Biostatistics Massachusetts General Hospital Boston MA United States Center for Depression Anxiety and Stress Research McLean Hospital Belmont MA United States McLean Imaging Center McLean Hospital Belmont MA United States Department of Psychology Virginia Polytechnic Institute and State University Blacksburg VA United States Department of Psychiatry and Behavioral Sciences Weill Institute for Neurosciences University of California San Francisco San Francisco CA United States Department of Pediatrics University of Virginia School of Medicine Charlottesville VA United States

Background: Restrictive eating disorders (EDs) are associated with cognitive inflexibility, reduced reward responsiveness, and tendency to favor delayed rewards, which contribute to illness maintenance and poor outcomes. Low estrogen is common in EDs and has been linked to poor cognitive flexibility and reward processing in other conditions. We describe a randomized controlled double-masked trial of short-term (12 weeks) transdermal estrogen (100 μg 17-β) replacement versus placebo to test estrogen-effects on cognitive flexibility, reward responsiveness, delay discounting, and ED pathology in females with EDs and low estrogen (ED-LE). Methods: Participants will include N = 120 females with ED-LE (14–35 years) with clinical, neuropsychological, and neural assessments occurring at baseline, eight weeks, and 12 weeks. Results: Primary outcomes will include between-group differences in 8-week change in cognitive flexibility, reward responsiveness, and delay discounting, and between-group differences in 12-week change in ED pathology. Secondary outcomes will include between-group differences in 8-week change in neural activation during cognitive flexibility and reward-related functional magnetic resonance imaging paradigms and mediation effects of 8-week change in cognitive flexibility, reward responsiveness, and delay discounting on 12-week change in ED pathology. Conclusion: We hypothesize that estrogen replacement will (1) increase cognitive flexibility, reward responsiveness, and delay discounting, and (2) reduce ED pathology;and (3) 8-week changes in cognitive flexibility, reward responsiveness, and delay discounting will mediate 12-week changes in ED pathology. These data will systematically probe the role of estrogen in key neurocognitive features associated with poor ED outcomes to guide development of novel interventions for this population. © 2024

关键词： Anorexia nervosa Atypical anorexia nervosa Cognitive flexibility Delay discounting Eating disorder Estrogen Reward responsiveness

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Vasopressin and oxytocin excite BNST neurons via oxytocin receptors, which reduce anxious arousal

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Cell reports 2025年第6期44卷 115768页

作者： Walter Francesconi Valentina Olivera-Pasilio Fulvia Berton Susan L Olson Rachel Chudoba Lorena M Monroy Quirin Krabichler Valery Grinevich Joanna Dabrowska Center for Neurobiology of Stress Resilience and Psychiatric Disorders Discipline of Cellular and Molecular Pharmacology The Chicago Medical School Rosalind Franklin University of Medicine and Science 3333 Green Bay Road North Chicago IL 60064 USA. Center for Neurobiology of Stress Resilience and Psychiatric Disorders Discipline of Cellular and Molecular Pharmacology The Chicago Medical School Rosalind Franklin University of Medicine and Science 3333 Green Bay Road North Chicago IL 60064 USA School of Graduate and Postdoctoral Studies Rosalind Franklin University of Medicine and Science 3333 Green Bay Road North Chicago IL 60064 USA Center for Psychiatric Neuroscience Department of Psychiatry and Behavioral Sciences Northwestern University Chicago IL 60611 USA. School of Graduate and Postdoctoral Studies Rosalind Franklin University of Medicine and Science 3333 Green Bay Road North Chicago IL 60064 USA. Neuroscience Program Lake Forest College Lake Forest IL 60045 USA. Department of Neuropeptide Research in Psychiatry German Center for Mental Health (DZPG) Medical Faculty Mannheim Heidelberg University 68159 Mannheim Germany. School of Graduate and Postdoctoral Studies Rosalind Franklin University of Medicine and Science 3333 Green Bay Road North Chicago IL 60064 USA. Electronic address: joanna.dabrowska@rosalindfranklin.edu.

Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to the bed nucleus of stria terminalis (BNST), which expresses OT receptors (OTRs) and vasopressin receptors, and governs fear responses. However, understanding the integrated role of AVP and OT is complicated by their cross-reactivity and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by cell-type-specific receptor selectivity and input specificity. We show that OTR-expressing BNST neurons, excited by hypothalamic AVP and OT inputs via OTR, play a major role in regulating BNST excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNST neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs.

关键词： CP: neuroscience CRF DREADDs arousal bed nucleus of the stria terminalis fear hypothalamus optogenetics patch-clamp rat startle

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Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments

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American Journal of Human Genetics 2025年第5期112卷 975-983页

作者： Cheerie, David Meserve, Margaret M. Beijer, Danique Kaiwar, Charu Newton, Logan Taylor Tavares, Ana Lisa Verran, Aubrie Soucy Sherrill, Emma Leonard, Stefanie Sanders, Stephan J. Blake, Emily Elkhateeb, Nour Gandhi, Aastha Liang, Nicole S.Y. Morgan, Jack T. Verwillow, Anna Verheijen, Jan Giles, Andrew Williams, Sean Chopra, Maya Croft, Laura Dafsari, Hormos Salimi Davidson, Alice E. Friedman, Jennifer Gregor, Anne Haque, Bushra Lechner, Rosan Montgomery, Kylie-Ann Ryten, Mina Schober, Emil Siegel, Gabriele Sullivan, Patricia J. Whittle, Ella F. Zardetto, Bianca Yu, Timothy W. Synofzik, Matthis Aartsma-Rus, Annemieke Costain, Gregory Lauffer, Marlen C. Program in Genetics & Genome Biology SickKids Research Institute Toronto M5G 0A4 ON Canada Department of Molecular Genetics University of Toronto Toronto M5S 1A8 ON Canada Division of Genetics and Genomics Boston Children's Hospital Boston 02115 MA United States Division of Translational Genomics of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research and Center of Neurology University of Tübingen Tübingen 72076 Germany German Center of Neurodegenerative Diseases (DZNE) Tübingen 72076 Germany Clinical Molecular Geneticist Department of Pathology and Laboratory Medicine Precision Diagnostics Laboratory Children's Hospital Colorado Aurora 80045 CO United States Genomics England London E14 5AB United Kingdom Department of Clinical Genetics Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire CB2 0QQ United Kingdom N=1 Collaborative 7 Carole Place Somerville 02143 MA United States Institute of Developmental and Regenerative Medicine Department of Pediatrics University of Oxford Oxford OX3 7TY United Kingdom Department of Psychiatry and Behavioral Sciences UCSF Weill Institute for Neurosciences University of California San Francisco San Francisco 94158 CA United States New York Genome Center New York 10013 NY United States Department of Quantitative Health Sciences Mayo Clinic Rochester 55902 MN United States Division of Clinical & Metabolic Genetics Hospital for Sick Children Toronto M5G 1X8 ON Canada Department of Genetic Counselling Hospital for Sick Children Toronto M5G 1X8 ON Canada Dutch Center for RNA Therapeutics Department of Human Genetics Leiden University Medical Center Leiden 2333 ZA Netherlands Center for Genomic Medicine Massachusetts General Hospital 55 Fruit Street Boston 02114 MA United States Department of Pathology University of Utah School of Medicine Salt Lake City 84112 UT United States ARUP Laboratories Salt Lake City 84108 UT United States Ambry Genetics 1 E

Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The patient identification working group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic DNA variants for ASO treatments. We herein present the N1C VARIANT (variant assessments toward eligibility for antisense oligonucleotide treatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different approaches or as “unable to assess.” We also review key considerations related to assessing the upregulation of transcripts from the wild-type allele, an emerging ASO therapeutic strategy. We provide additional tools and training materials to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice. © 2025 The Authors

关键词： antisense oligonucleotides consensus guidelines individualized genetic therapies personalized medicine rare genetic diseases

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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

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Molecular psychiatry 2023年第12期28卷 5251-5261页

作者： Azmeraw T Amare Anbupalam Thalamuthu Klaus Oliver Schubert Janice M Fullerton Muktar Ahmed Simon Hartmann Sergi Papiol Urs Heilbronner Franziska Degenhardt Fasil Tekola-Ayele Liping Hou Yi-Hsiang Hsu Tatyana Shekhtman Mazda Adli Nirmala Akula Kazufumi Akiyama Raffaella Ardau Bárbara Arias Jean-Michel Aubry Roland Hasler Hélène Richard-Lepouriel Nader Perroud Lena Backlund Abesh Kumar Bhattacharjee Frank Bellivier Antonio Benabarre Susanne Bengesser Joanna M Biernacka Armin Birner Cynthia Marie-Claire Pablo Cervantes Hsi-Chung Chen Caterina Chillotti Sven Cichon Cristiana Cruceanu Piotr M Czerski Nina Dalkner Maria Del Zompo J Raymond DePaulo Bruno Étain Stephane Jamain Peter Falkai Andreas J Forstner Louise Frisen Mark A Frye Sébastien Gard Julie S Garnham Fernando S Goes Maria Grigoroiu-Serbanescu Andreas J Fallgatter Sophia Stegmaier Thomas Ethofer Silvia Biere Kristiyana Petrova Ceylan Schuster Kristina Adorjan Monika Budde Maria Heilbronner Janos L Kalman Mojtaba Oraki Kohshour Daniela Reich-Erkelenz Sabrina K Schaupp Eva C Schulte Fanny Senner Thomas Vogl Ion-George Anghelescu Volker Arolt Udo Dannlowski Detlef Dietrich Christian Figge Markus Jäger Fabian U Lang Georg Juckel Carsten Konrad Jens Reimer Max Schmauß Andrea Schmitt Carsten Spitzer Martin von Hagen Jens Wiltfang Jörg Zimmermann Till F M Andlauer Andre Fischer Felix Bermpohl Philipp Ritter Silke Matura Anna Gryaznova Irina Falkenberg Cüneyt Yildiz Tilo Kircher Julia Schmidt Marius Koch Kathrin Gade Sarah Trost Ida S Haussleiter Martin Lambert Anja C Rohenkohl Vivien Kraft Paul Grof Ryota Hashimoto Joanna Hauser Stefan Herms Per Hoffmann Esther Jiménez Jean-Pierre Kahn Layla Kassem Po-Hsiu Kuo Tadafumi Kato John Kelsoe Sarah Kittel-Schneider Ewa Ferensztajn-Rochowiak Barbara König Ichiro Kusumi Gonzalo Laje Mikael Landén Catharina Lavebratt Marion Leboyer Susan G Leckband Alfonso Tortorella Mirko Manchia Lina Martinsson Michael J McCarthy Susan McElroy Francesc Colom Vincent Millischer Marina Mitjans Francis M Mondimore Palmiero Monteleone Caroline Discipline of Psychiatry School of Medicine University of Adelaide Adelaide SA Australia. azmeraw.amare@adelaide.edu.au. Centre for Healthy Brain Ageing (CHeBA) Discipline of Psychiatry and Mental Health UNSW Medicine & Health University of New South Wales Sydney Australia. Discipline of Psychiatry School of Medicine University of Adelaide Adelaide SA Australia. Northern Adelaide Local Health Network Mental Health Services Adelaide SA Australia. Neuroscience Research Australia Sydney NSW Australia. School of Medical Sciences University of New South Wales Sydney NSW Australia. Institute of Psychiatric Phenomics and Genomics (IPPG) University Hospital LMU Munich Munich Germany. Department of Psychiatry and Psychotherapy University Hospital Ludwig-Maximilian-University Munich Munich Germany. Institute of Human Genetics University of Bonn School of Medicine & University Hospital Bonn Bonn Germany. Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy LVR Klinikum Essen University of Duisburg-Essen Rheinische Kliniken Essen Germany. Epidemiology Branch Division of Population Health Research Division of Intramural Research Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA. Intramural Research Program National Institute of Mental Health National Institutes of Health US Department of Health & Human Services Bethesda MD USA. HSL Institute for Aging Research Harvard Medical School Boston MA USA. Program for Quantitative Genomics Harvard School of Public Health Boston MA USA. Department of Psychiatry University of California San Diego San Diego CA USA. Department of Psychiatry and Psychotherapy Charité - Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany. Department of Biological Psychiatry and Neuroscience Dokkyo Medical University School of Medicine Mibu Tochigi Japan. Unit of Clinical Pharmacology Hospital University Agency of Caglia

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li was developed in the International Consortium of Lithium Genetics cohort (ConLiGen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li was positively associated with lithium treatment response in the ConLiGen cohort, in both the categorical (P = 9.8 × 10, R = 1.9%) and continuous (P = 6.4 × 10, R = 2.6%) outcomes. Compared to bipolar patients in the 1 decile of the risk distribution, individuals in the 10 decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10, R = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li may be useful in the development of pharmacog

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Effects of the KCNQ (Kv7) Channel Opener Ezogabine on Resting-State Functional Connectivity of Striatal Brain Reward Regions, Depression, and Anhedonia in Major Depressive Disorder: Results From a Randomized Controlled Trial

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Biological Psychiatry 2025年

作者： Chowdhury, Avijit Boukezzi, Sarah Costi, Sara Hameed, Sara Jacob, Yael Salas, Ramiro Iosifescu, Dan V. Han, Ming-Hu Swann, Alan Mathew, Sanjay J. Morris, Laurel Murrough, James W. Depression and Anxiety Center for Discovery and Treatment Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York United States Psychopharmacology and Emotion Research Laboratory Department of Psychiatry Warneford Hospital University of Oxford Oxford United Kingdom Warneford Hospital Oxford Health NHS Foundation Trust Oxford United Kingdom Mood and Anxiety Disorders Program Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston Texas United States Michael E. DeBakey VA Medical Center Houston Texas United States Menninger Clinic Houston Texas United States Department of Psychiatry New York University School of Medicine New York New York United States Nathan Kline Institute for Psychiatric Research Orangeburg NY United States Brain Cognition and Brain Disease Institute Shenzhen Institute of Advanced Technology Shenzhen China Faculty of Life and Health Sciences Shenzhen University of Advanced Technology Shenzhen China Department of Pharmacological Sciences Icahn School of Medicine at Mount Sinai New York New York United States Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai New York New York United States VISN 2 Mental Illness Research Education and Clinical Center James J. Peters VA Medical Center Bronx NY United States

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD. Methods: A double-blind, randomized, placebo-controlled clinical trial in individuals with MDD ages 18 to 65 years compared daily dosing with ezogabine (n = 19) with placebo (n = 21) for 5 weeks. Functional magnetic resonance imaging assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and posttreatment. Clinical symptoms were measured using the Snaith-Hamilton Pleasure Scale (SHAPS), Montgomery–Åsberg Depression Rating Scale (MADRS), and other clinical symptom scales. Results: Ezogabine significantly reduced RSFC between the reward seeds and the posterior cingulate cortex (PCC)/precuneus compared with placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared with placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (midcingulate cortex, PCC, precuneus). Conclusions: The findings suggest that ezogabine's antidepressant effects are mediated through modulation of striatal–mid/posterior cingulate connectivity, indicating a potential therapeutic mechanism for KCNQ-targeted drugs for MDD and anhedonia. Future studies should validate these results in larger trials. © 2025

关键词： Anhedonia Depression Ezogabine KCNQ (Kv7) potassium channel opener Neuroimaging Reward

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Publisher Correction: Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo

Nature Mental Health

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Nature Mental Health 2024年 1120页

作者： Cynthia H. Y. Fu Danilo Arnone Roland Zahn Allan H. Young Mathilde Antoniades Guray Erus Jose A. Garcia Yong Fan Haochang Shou Ashish Singh Christos Davatzikos Stephen R. Arnott Stephen C. Strother Taolin Chen Kun Qin Qiyong Gong Ki Sueng Choi Helen S. Mayberg Cherise Chin Fatt Madhukar H. Trivedi Benicio N. Frey Vibe G. Frokjaer Melanie Ganz Gitte M. Knudsen Beata R. Godlewska Catherine J. Harmer Stefanie Hassel Keith Ho Susan Rotzinger Sidney H. Kennedy Andrew M. McIntosh Aleks Stolicyn Heather C. Whalley Matthew D. Sacchet Jonathan Savitz Teresa A. Victor Martin P. Paulus Irina Strigo Duygu Tosun Dongtao Wei Jiang Qiu Toby Wise Ian M. Anderson J. F. William Deakin Rebecca Elliott W. Edward Craighead Boadie W. Dunlop Ian H. Gotlib Chao-Gan Yan School of Psychology University of East London London UK Centre for Affective Disorders Department of Psychological Medicine Institute of Psychiatry Psychology and Neuroscience King’s College London London UK South London and Maudsley NHS Foundation Trust Bethlem Royal Hospital London UK Center for Biomedical Image Computing and Analytics Perelman School of Medicine University of Pennsylvania Philadelphia PA USA Penn Statistics in Imaging and Visualization Endeavor (PennSIVE) Center Department of Biostatistics Epidemiology and Informatics University of Pennsylvania Philadelphia PA USA Rotman Research Institute Baycrest Centre Toronto Ontario Canada Department of Medical Biophysics University of Toronto Toronto Ontario Canada Huaxi MR Research Center Department of Radiology West China Hospital Sichuan University Chengdu China Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu China Department of Radiology Taihe Hospital Hubei University of Medicine Shiyan China Nash Family Center for Advanced Circuit Therapeutics Icahn School of Medicine at Mount Sinai New York NY USA Department of Psychiatry Center for Depression Research and Clinical Care University of Texas Southwestern Medical Center Dallas TX USA Department of Psychiatry and Behavioural Neurosciences McMaster University Hamilton Ontario Canada Mood Disorders Treatment and Research Centre and Women’s Health Concerns Clinic St Joseph’s Healthcare Hamilton Hamilton Ontario Canada Neurobiology Research Unit University Hospital Rigshospitalet Copenhagen Denmark Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark Department of Psychiatry Psychiatric Centre Copenhagen Copenhagen Denmark Department of Computer Science University of Copenhagen Copenhagen Denmark Department of Psychiatry University of Oxford Oxford UK Oxford Health NHS Foundation Trust Warneford Hospital Oxford UK Mathison Centre for Me

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Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

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Movement disorders : official journal of the Movement Disorder Society 2023年第2期38卷 286-303页

作者： Eva-Juliane Vollstedt Susen Schaake Katja Lohmann Shalini Padmanabhan Alexis Brice Suzanne Lesage Christelle Tesson Marie Vidailhet Isabel Wurster Faycel Hentati Anat Mirelman Nir Giladi Karen Marder Cheryl Waters Stanley Fahn Meike Kasten Norbert Brüggemann Max Borsche Tatiana Foroud Eduardo Tolosa Alicia Garrido Grazia Annesi Monica Gagliardi Maria Bozi Leonidas Stefanis Joaquim J Ferreira Leonor Correia Guedes Micol Avenali Simona Petrucci Lorraine Clark Ekaterina Y Fedotova Natalya Y Abramycheva Victoria Alvarez Manuel Menéndez-González Silvia Jesús Maestre Pilar Gómez-Garre Pablo Mir Andrea Carmine Belin Caroline Ran Chin-Hsien Lin Ming-Che Kuo David Crosiers Zbigniew K Wszolek Owen A Ross Joseph Jankovic Kenya Nishioka Manabu Funayama Jordi Clarimon Caroline H Williams-Gray Marta Camacho Mario Cornejo-Olivas Luis Torres-Ramirez Yih-Ru Wu Guey-Jen Lee-Chen Ana Morgadinho Teeratorn Pulkes Pichet Termsarasab Daniela Berg Gregor Kuhlenbäumer Andrea A Kühn Friederike Borngräber Giuseppe de Michele Anna De Rosa Alexander Zimprich Andreas Puschmann George D Mellick Jolanta Dorszewska Jonathan Carr Rosangela Ferese Stefano Gambardella Bruce Chase Katerina Markopoulou Wataru Satake Tatsushi Toda Malco Rossi Marcelo Merello Timothy Lynch Diana A Olszewska Shen-Yang Lim Azlina Ahmad-Annuar Ai Huey Tan Bashayer Al-Mubarak Hasmet Hanagasi Dariusz Koziorowski Sibel Ertan Gençer Genç Patricia de Carvalho Aguiar Melinda Barkhuizen Marcia M G Pimentel Rachel Saunders-Pullman Bart van de Warrenburg Susan Bressman Mathias Toft Silke Appel-Cresswell Anthony E Lang Matej Skorvanek Agnita J W Boon Rejko Krüger Esther M Sammler Vitor Tumas Bao-Rong Zhang Gaetan Garraux Sun Ju Chung Yun Joong Kim Juliane Winkelmann Carolyn M Sue Eng-King Tan Joana Damásio Péter Klivényi Vladimir S Kostic David Arkadir Mika Martikainen Vanderci Borges Jens Michael Hertz Laura Brighina Mariana Spitz Oksana Suchowersky Olaf Riess Parimal Das Brit Mollenhauer Emilia M Gatto Maria Skaalum Petersen Nobutaka Hattori Ruey-Meei Wu Sergey N Illarioshkin Enz Institute of Neurogenetics University of Lübeck Lübeck Germany. Research Programs The Michael J. Fox Foundation for Parkinson's Research New York New York USA. Department of Neurology Sorbonne University Paris Brain Institute - ICM Inserm CNRS Assistance Publique Hôpitaux de Paris Pitié-Salpêtrière Hospital Paris France. Sorbonne University Paris Brain Institute - ICM Inserm CNRS Paris France. Department of Neurodegenerative Diseases University of Tuebingen Tuebingen Baden Wuerttemberg Germany Hertie Institute for Clinical Brain Research and German Centre for Neurodegenerative Diseases Tuebingen Germany. Mongi Ben Hmida National Institute of Neurology Tunis Tunisia. Laboratory of Early Markers of Neurodegeneration Neurological Institute Tel-Aviv Medical Center Tel-Aviv Israel Sackler School of Medicine Tel-Aviv University Tel-Aviv Israel Sagol School of Neuroscience Tel-Aviv University Tel-Aviv Israel. Neurological Institute Tel-Aviv Medical Center Tel-Aviv Israel Sackler School of Medicine Sagol School of Neuroscience Tel-Aviv University Tel-Aviv Israel. Department of Neurology Taub Institute for Alzheimer's Disease and the Aging Brain Columbia University New York New York USA. Department of Neurology Columbia University New York New York USA. Department of Psychiatry and Psychotherapy and Institute of Neurogenetics University of Lübeck Lübeck Germany. Department of Neurology and Institute of Neurogenetics University of Lübeck Lübeck Germany. Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA. Parkinson Disease and Movement Disorders Unit Neurology Service Hospital Clínic de Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB) Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona Spain. Institute of Biomedical Research and Innovation National Research Council Cosenza

BACKGROUND:As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE:The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS:We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS:We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS:Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clini

关键词： Parkinson's disease monogenic PD

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Corrigendum to "Associations of circulating cell-free DNA, C-reactive protein, and cardiometabolic risk among low-active smokers with elevated depressive symptoms" [Brain Behav. Immun. - Health 25 (2022) 100519]

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Brain, behavior, & immunity - health 2023年 27卷 100583页

作者： Teresa E Daniels Emily K Zitkovsky Zachary J Kunicki Destiny J Price Abigail L Peterson Phyllis A Dennery Hung-Teh Kao Lawrence H Price Audrey R Tyrka Ana M Abrantes Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience Butler Hospital 345 Blackstone Boulevard Providence RI 02906 USA. Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University 345 Blackstone Boulevard Providence RI 02906 USA. Initiative on Stress Trauma and Resilience (STAR) Department of Psychiatry and Human Behavior Warren Alpert Medical School Brown University Providence RI USA. Warren Alpert Medical School of Brown University Providence RI USA. Department of Psychiatry New York State Psychiatric Institute and Columbia University Irving Medical Center 1051 Riverside Dr New York NY 10032 USA. Department of Molecular Biology Cell Biology and Biochemistry Brown University Providence RI USA. Department of Pediatrics Warren Alpert Medical School of Brown University 593 Eddy St Providence RI 02903 USA. Behavioral Medicine and Addictions Research Department Butler Hospital 345 Blackstone Boulevard Providence RI 02906 USA.

[This corrects the article DOI: 10.1016/***.2022.100519.].

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