210 results on '"Martien J. H. Kas"'
Search Results
2. CNTN4 modulates neural elongation through interplay with APP
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Rosemary A. Bamford, Amila Zuko, Madeline Eve, Jan J. Sprengers, Harm Post, Renske L. R. E. Taggenbrock, Dominique Fäβler, Annika Mehr, Owen J. R. Jones, Aurimas Kudzinskas, Josan Gandawijaya, Ulrike C. Müller, Martien J. H. Kas, J. Peter H. Burbach, and Asami Oguro-Ando
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CNTN4 ,APP ,cell ,cortex ,neuronal ,motor ,Biology (General) ,QH301-705.5 - Abstract
The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 −/− mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer’s disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.
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- 2024
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3. A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study
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Teuntje A. D. Pelgrim, Alexandra Philipsen, Allan H. Young, Mario Juruena, Ester Jimenez, Eduard Vieta, Marin Jukić, Erik Van der Eycken, Urs Heilbronner, Ramona Moldovan, Martien J. H. Kas, Raj R. Jagesar, Markus M. Nöthen, Per Hoffmann, Noam Shomron, Laura L. Kilarski, Thérèse van Amelsvoort, Bea Campforts, The PSY-PGx Consortium, and Roos van Westrhenen
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pharmacogenomics ,mental disorders ,personalized medicine ,psychopharmacology ,depressive disorders ,anxiety disorders ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.
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- 2024
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4. Models and methods: a perspective of the impact of six IMI translational data-centric initiatives for Alzheimer’s disease and other neuropsychiatric disorders
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Hilary North, Martin Hofmann-Apitius, Martien J. H. Kas, Hugh Marston, and Magali Haas
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innovative medicines initiative ,pharmaceutical industry ,public–private partnership ,European Union ,neuropsychiatric disorders ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The Innovative Medicines Initiative (IMI), was a European public–private partnership (PPP) undertaking intended to improve the drug development process, facilitate biomarker development, accelerate clinical trial timelines, improve success rates, and generally increase the competitiveness of European pharmaceutical sector research. Through the IMI, pharmaceutical research interests and the research agenda of the EU are supported by academic partnership and financed by both the pharmaceutical companies and public funds. Since its inception, the IMI has funded dozens of research partnerships focused on solving the core problems that have consistently obstructed the translation of research into clinical success. In this post-mortem review paper, we focus on six research initiatives that tackled foundational challenges of this nature: Aetionomy, EMIF, EPAD, EQIPD, eTRIKS, and PRISM. Several of these initiatives focused on neurodegenerative diseases; we therefore discuss the state of neurodegenerative research both at the start of the IMI and now, and the contributions that IMI partnerships made to progress in the field. Many of the initiatives we review had goals including, but not limited to, the establishment of translational, data-centric initiatives and the implementation of trans-diagnostic approaches that move beyond the candidate disease approach to assess symptom etiology without bias, challenging the construct of disease diagnosis. We discuss the successes of these initiatives, the challenges faced, and the merits and shortcomings of the IMI approach with participating senior scientists for each. Here, we distill their perspectives on the lessons learned, with an aim to positively impact funding policy and approaches in the future.
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- 2023
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5. A Study on REM Sleep Homeostasis in the Day-Active Tree Shrew (Tupaia belangeri): Cold-Induced Suppression of REM Sleep Is Not Followed by a Rebound
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Sjoerd J. van Hasselt, Luisa Epifani, Danique Zantinge, Kornelija Vitkute, Martien J. H. Kas, Giancarlo Allocca, and Peter Meerlo
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sleep homeostasis ,REM sleep ,sleep deprivation ,body temperature ,brain temperature ,cold exposure ,Biology (General) ,QH301-705.5 - Abstract
The function and regulation of rapid-eye-movement (REM) sleep is a topic of ongoing debate. It is often assumed that REM sleep is a homeostatically regulated process and that a need for REM sleep builds up, either during prior wakefulness or during preceding slow wave sleep. In the current study, we tested this hypothesis in six diurnal tree shrews (Tupaia belangeri), small mammals closely related to primates. All animals were individually housed and kept under a 12:12 light-dark cycle with an ambient temperature of 24 °C. We recorded sleep and temperature in the tree shrews for 3 consecutive 24 h days. During the second night, we exposed the animals to a low ambient temperature of 4 °C, a procedure that is known to suppress REM sleep. Cold exposure caused a significant drop in brain temperature and body temperature and also resulted in a strong and selective suppression of REM sleep by 64.9%. However, contrary to our expectation, the loss of REM sleep was not recovered during the subsequent day and night. These findings in a diurnal mammal confirm that the expression of REM sleep is highly sensitive to environmental temperature but do not support the view that REM sleep is homeostatically regulated in this species.
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- 2023
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6. Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
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Remco T. Molenhuis, Hilgo Bruining, Myrna J. V. Brandt, Petra E. van Soldt, Hanifa J. Abu-Toamih Atamni, J. Peter H. Burbach, Fuad A. Iraqi, Richard F. Mott, and Martien J. H. Kas
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Neurodevelopmental disorders ,Autism ,Animal models ,Quantitative genetics ,Genetic reference population ,Behavioral neuroscience ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with Autism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds.
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- 2018
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7. Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder
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Iris W. Riemersma, Robbert Havekes, and Martien J. H. Kas
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autism spectrum disorder ,animal models ,synaptopathology ,neurodevelopment ,sensory processing ,Genetics ,QH426-470 - Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.
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- 2021
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8. Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models
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Christopher Heise, Jonathan M. Preuss, Jan C. Schroeder, Chiara R. Battaglia, Jonas Kolibius, Rebecca Schmid, Michael R. Kreutz, Martien J. H. Kas, J. Peter H. Burbach, and Tobias M. Boeckers
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autism spectrum disorder ,autism mouse models ,Shank2 ,Shank3 ,Cntn4 ,synapse ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (Shank2−/−), Shank3 (Shank3αβ−/−), and Cntn4 (Cntn4−/−) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2−/− and Shank3αβ−/− mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions—especially in the striatum and thalamus—when compared to wildtype controls. Interestingly, even though Cntn4−/− mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4−/− mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.
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- 2018
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9. The aperiodic exponent of neural activity varies with vigilance state in mice and men.
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Freja Gam Østergaard, Brenda W J H Penninx, Neetha Das, Celso Arango, Nic van der Wee, Inge Winter-van Rossum, Jose Luis Ayuso-Mateos, Gerard R Dawson, Hugh Marston, and Martien J H Kas
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Medicine ,Science - Abstract
Recently the 1/f signal of human electroencephalography has attracted attention, as it could potentially reveal a quantitative measure of neural excitation and inhibition in the brain, that may be relevant in a clinical setting. The purpose of this short article is to show that the 1/f signal depends on the vigilance state of the brain in both humans and mice. Therefore, proper labelling of the EEG signal is important as improper labelling may obscure disease-related changes in the 1/f signal. We demonstrate this by comparing EEG results from a longitudinal study in a genetic mouse model for synaptic dysfunction in schizophrenia and autism spectrum disorders to results from a large European cohort study with schizophrenia and mild Alzheimer's disease patients. The comparison shows when the 1/f is corrected for vigilance state there is a difference between groups, and this effect disappears when vigilance state is not corrected for. In conclusion, more attention should be paid to the vigilance state during analysis of EEG signals regardless of the species.
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- 2024
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10. Influencing cognitive performance via social interactions
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Suzanne D. Lanooij, Ulrich L. M. Eisel, Wilhelmus H. I. M. Drinkenburg, Eddy A. van der Zee, and Martien J. H. Kas
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Molecular Biology - Abstract
Many psychiatric and neurological disorders present deficits in both the social and cognitive domain. In this perspectives article, we provide an overview and the potential of the existence of an extensive neurobiological substrate underlying the close relationship between these two domains. By mapping the rodent brain regions involved in the social and/or cognitive domain, we show that the vast majority of brain regions involved in the cognitive domain are also involved in the social domain. The identified neuroanatomical overlap has an evolutionary basis, as complex social behavior requires cognitive skills, and aligns with the reported functional interactions of processes underlying cognitive and social performance. Based on the neuroanatomical mapping, recent (pre-)clinical findings, and the evolutionary perspective, we emphasize that the social domain requires more focus as an important treatment target and/or biomarker, especially considering the presently limited treatment strategies for these disorders.
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- 2023
11. EEG-based visual deviance detection in freely behaving mice.
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Renate Kat, Berry van den Berg, Matthijs J. L. Perenboom, Maarten Schenke, Arn M. J. M. van den Maagdenberg, Hilgo Bruining, Else Tolner, and Martien J. H. Kas
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- 2021
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12. The continued need for animals to advance brain research
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Paul J. Lucassen, Kate Jeffrey, Antonis Asiminas, Heidi M. B. Lesscher, Jos Prickaerts, Gertjan van Dijk, Amanda J. Kiliaan, Daniela Jezova, Carlos P. Fitzsimons, Klaus-Peter Lesch, S. Mechiel Korte, Ulrich L. M. Eisel, Roger A.H. Adan, Tamas Kozicz, Liset Menendez de la Prida, Joanes Grandjean, Marloes J. A. G. Henckens, Corette J. Wierenga, Vladyslav V. Vyazovskiy, Cyriel M. A. Pennartz, Marten P. Smidt, Ype Elgersma, Anne S. Mallien, Sharon M. Kolk, Liya Ma, Kirk Leech, Ingo Willuhn, Jorge F. Mejias, Maximilian Wiesmann, Frank J. Meye, Louk J. M. J. Vanderschuren, Marilise Escobar Burger, Sidarta Ribeiro, August B. Smit, Peter Meerlo, Robbert Havekes, Eddy A. van der Zee, Rixt van der Veen, Regien G. Schoemaker, Massimo Pasqualetti, Andries Kalsbeek, Martien J H Kas, Michael Bader, Joram D. Mul, Bernhard Englitz, Janine I. Rossato, Denovan P. Begg, Tomonori Takeuchi, Markus Wöhr, Antonio Fernández-Ruiz, Bella Williams, Nael Nadif Kasri, Aniko Korosi, Judith R. Homberg, Tom Beckers, Maarten Kamermans, Piotr Popik, Peter Gass, Umberto Olcese, Anna S. Mitchell, Christiane Herden, Jocelien D A Olivier, Monique Wolvekamp, Arjan Blokland, Azahara Oliva González, Natalia Alenina, Lisa Genzel, Wendy Jarrett, Ali-Akbar Salari, Roelof A. Hut, Anne-Marie van Dam, Anita Lüthi, Benno Roozendaal, Steven A. Kushner, Medicinal chemistry, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Neurodegeneration, Netherlands Institute for Neuroscience (NIN), Clinical Genetics, Psychiatry, Afd Pharmacology, AISS Behaviour Neuroscience, dASS BW-1, Sub Cell Biology, Pharmacology, Celbiologie, Structural and Functional Plasticity of the nervous system (SILS, FNWI), Cognitive and Systems Neuroscience (SILS, FNWI), Molecular Neuroscience (SILS, FNWI), Section Psychopharmacology, RS: FPN NPPP II, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, University of Toronto, Endocrinology, Endocrinology Laboratory, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Biomedical Engineering and Physics, Paediatrics, Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, ANS - Systems & Network Neuroscience, Van Dijk lab, Eisel lab, Havekes lab, Hut lab, Kas lab, Meerlo lab, Olivier lab, Schoemaker lab, and Van der Zee lab
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Animal Experimentation ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Science & Technology ,Animals ,Brain ,Neurosciences ,General Neuroscience ,Neuroscience(all) ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,MEDLINE ,Neurophysiology ,Brain research ,Taverne ,Engineering ethics ,Neurosciences & Neurology ,Neuroscience research ,Animal testing ,Psychology ,Life Sciences & Biomedicine ,Value (mathematics) ,Molecular Neurobiology - Abstract
Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised., We would like to thank Loren Frank, UCSF, USA; Sheena Josselyn, Hospital for Sick Children, University of Toronto, Canada; Shantanu Jadhav, Brandeis University, USA; the European Animal Research Association (EARA); the Federation of European Neuroscience Societies Committee on Animals in Research (CARE); the Swiss Society for Neuroscience; the Society for Neuroscience Committee on Animals in Research (CAR); and Stichting Informatie Dierproeven (the Dutch foundation for public information on animal testing: SID) for input on and support for this article.
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- 2021
13. Author response for 'Largely unaffected auditory and visual sensory processing phenotypes in the evoked potentials of Fmr1 KO2 mice'
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null Renate Kat and null Martien J. H. Kas
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- 2022
14. Assessment of Social Behavior Using a Passive Monitoring App in Cognitively Normal and Cognitively Impaired Older Adults
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Marijn Muurling, Lianne M Reus, Casper de Boer, Sterre C Wessels, Raj R Jagesar, Jacob A S Vorstman, Martien J H Kas, Pieter Jelle Visser, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 6, Kas lab, Neurology, and Amsterdam Neuroscience - Neurodegeneration
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RISK ,DECLINE ,Health (social science) ,social withdrawal ,DEMENTIA ,Health Informatics ,FRAMEWORK ,social behavior ,NETWORK SIZE ,cognitive ,ALZHEIMERS-DISEASE ,smartphone app ,mHealth ,well-being ,PEOPLE ,mobile app ,passive monitoring ,Geriatrics and Gerontology ,Gerontology ,mental health ,cognitive impairment ,NEUROPSYCHIATRIC SYMPTOMS - Abstract
Background In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively. Objective This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms. Methods CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI. Results We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P Conclusions CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.
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- 2022
15. Digital phenotyping and the COVID-19 pandemic
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Mila C. Roozen, Raj R. Jagesar, Henricus G. Ruhé, Iris E. C. Sommer, Nessa Ikani, Anna Tyborowska, Jacob A. S. Vorstman, Inge van der Heijden, Brenda W.J.H. Penninx, Martien J H Kas, Kas lab, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
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Gerontology ,Male ,Bipolar Disorder ,230 Affective Neuroscience ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Experimental Psychopathology and Treatment ,0302 clinical medicine ,Pandemic ,Medicine ,Pharmacology (medical) ,Netherlands ,Potential impact ,Communication ,Middle Aged ,Mobile Applications ,Psychiatry and Mental health ,Phenotype ,Neurology ,Schizophrenia ,Ambulatory ,Major depressive disorder ,Female ,Smartphone ,Adult ,Coronavirus disease 2019 (COVID-19) ,Physical Distancing ,Clinical Neurology ,Spatial Behavior ,Proof of Concept Study ,03 medical and health sciences ,Young Adult ,All institutes and research themes of the Radboud University Medical Center ,Humans ,In patient ,Bipolar disorder ,Biological Psychiatry ,Aged ,Pharmacology ,Behavior ,Depressive Disorder, Major ,business.industry ,SARS-CoV-2 ,COVID-19 ,medicine.disease ,030227 psychiatry ,Remote Sensing Technology ,Geographic Information Systems ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 227418.pdf (Publisher’s version ) (Closed access) The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor. 6 p.
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- 2021
16. Cross-site Reproducibility of Social Deficits in Group-housed BTBR Mice Using Automated Longitudinal Behavioural Monitoring
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Ingeborg Frentz, Bauke Buwalda, Bastian Hengerer, Kevin G. O. Ike, Tatiana Peleh, Sietse F. de Boer, Martien J H Kas, Kas lab, and Buwalda lab
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0301 basic medicine ,STRESS ,Social withdrawal ,PREFERENCE ,Mice, Inbred Strains ,C57BL/6J MICE ,PHENOTYPES ,Context (language use) ,Social behaviour ,Ethology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,INBRED MOUSE STRAINS ,medicine ,Animals ,AUTISM ,NOVELTY ,Social Behavior ,VISIBLE BURROW SYSTEM ,Reproducibility ,RELEVANT ,Behavior, Animal ,business.industry ,General Neuroscience ,Novelty ,Reproducibility of Results ,medicine.disease ,Social relation ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Autism ,business ,SOCIABILITY ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.
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- 2020
17. Relationships between social withdrawal and facial emotion recognition in neuropsychiatric disorders
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Gerard R. Dawson, Alba Viera-Campos, Alejandro de la Torre-Luque, Inge Winter van Rossum, Nic J.A. van der Wee, Jenna Clark, Bernd Sommer, Martien J H Kas, Jose Vivancos, Hugh Marston, Moji Aghajani, Celso Arango, Jose Luis Ayuso-Mateos, Asad Malik, Ilja M.J. Saris, Brenda W. J. H. Penninx, Amy C. Bilderbeck, Maria Teresa Carreras, Covadonga M. Díaz-Caneja, A. Raslescu, Kas lab, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Digital Health
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Adult ,Male ,Anxiety ,Social cognition ,Alzheimer Disease ,Surveys and Questionnaires ,Social functioning ,medicine ,Humans ,Disengagement theory ,Biological Psychiatry ,Pharmacology ,Facial expression ,Loneliness ,Social cue ,Hypervigilance ,Alzheimer's disease ,medicine.disease ,Mental illness ,Neuropsychiatric disorder ,Social Isolation ,Schizophrenia ,Female ,Self Report ,Emotion recognition ,medicine.symptom ,Cues ,Psychology ,Facial Recognition ,PRISM study ,Clinical psychology - Abstract
BACKGROUND: Emotion recognition constitutes a pivotal process of social cognition. It involves decoding social cues (e.g., facial expressions) to maximise social adjustment. Current theoretical models posit the relationship between social withdrawal factors (social disengagement, lack of social interactions and loneliness) and emotion decoding.OBJECTIVE: To investigate the role of social withdrawal in patients with schizophrenia (SZ) or probable Alzheimer's disease (AD), neuropsychiatric conditions associated with social dysfunction.METHODS: A sample of 156 participants was recruited: schizophrenia patients (SZ; n = 53), Alzheimer's disease patients (AD; n = 46), and two age-matched control groups (SZc, n = 29; ADc, n = 28). All participants provided self-report measures of loneliness and social functioning, and completed a facial emotion detection task.RESULTS: Neuropsychiatric patients (both groups) showed poorer performance in detecting both positive and negative emotions compared with their healthy counterparts (p CONCLUSIONS: Our findings help to detail the similarities and differences in social function and facial emotion recognition in two disorders rarely studied in parallel, AD and SZ. Transdiagnostic patterns in these results suggest that social withdrawal is associated with heightened sensitivity to negative emotion expressions, potentially reflecting hypervigilance to social threat. Across the neuropsychiatric groups specifically, this hypervigilance associated with social withdrawal extended to positive emotion expressions, an emotional-cognitive bias that may impact social functioning in people with severe mental illness.
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- 2022
18. Social withdrawal as a trans-diagnostic predictor of short-term remission: A meta-analysis of five clinical cohorts
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Alessandro Serretti, Diego Albani, Giuseppe Fanelli, Daniel Souery, Chiara Fabbri, Vincenzo Oliva, Martien J H Kas, Stuart Montgomery, Joseph Zohar, Siegfried Kasper, Diana De Ronchi, Dan Rujescu, Panagiotis Ferentinos, Julien Mendlewicz, Gianluigi Forloni, Kas lab, Oliva V., Fanelli G., Kasper S., Zohar J., Souery D., Montgomery S., Albani D., Forloni G., Ferentinos P., Rujescu D., Mendlewicz J., Kas M.J., de Ronchi D., Fabbri C., and Serretti A.
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medicine.medical_specialty ,Bipolar Disorder ,Social withdrawal ,Psychopharmacology ,Remission ,Major depressive disorder ,Disease ,Logistic regression ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Disengagement theory ,Transdiagnostic ,Depressive Disorder, Major ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Mental Disorders ,medicine.disease ,Psychiatry and Mental health ,Social Isolation ,Schizophrenia ,Meta-analysis ,business ,Psychopathology - Abstract
Social withdrawal is an early manifestation of several neuropsychiatric disorders, and it is characterised by a gradual disengagement from social interactions, potentially leading to complete isolation. This study investigated the association between social withdrawal at baseline and short-term symptom remission in five independent cohorts, including patients with major depressive disorder (MDD), bipolar spectrum disorders, and schizophrenia. Measures of social withdrawal were derived in each study, and clinical remission was estimated based on the psychopathological severity assessed after short-term psychopharmacological treatment (12weeks). Logistic regression was performed in each sample, adjusting for age and baseline psychopathological severity residualised for social withdrawal. Results were then meta-analysed across samples within a random-effect framework. A total of 4461 patients were included in the analyses (3195 patients with MDD, 655 with bipolar spectrum disorders and 611 with schizophrenia). The meta-analysis showed that higher baseline levels of social withdrawal were associated with a decreased likelihood of short-term remission (ORadj=0.67, 95% CI, 0.58-0.79, P=5.28×10−7), with the strongest effect in patients with schizophrenia. Overall, our study highlighted the need to address social withdrawal in the early phases of the disease to promote symptom remission in patients with major psychiatric disorders. Understanding the neurobiology underlying social withdrawal may aid the development of medications that can specifically reverse social impairment, thereby fostering clinical remission. Int Clin Psychopharmacol 37: 38-45 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
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- 2022
19. Sleep deprivation reduces the density of individual spine subtypes in a branch-specific fashion in CA1 neurons
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Martien J H Kas, Youri G Bolsius, Peter Meerlo, Robbert Havekes, Ted Abel, Havekes lab, Meerlo lab, and Kas lab
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Male ,Neurons ,Dendritic spine ,Adult male ,Cognitive Neuroscience ,Dendritic Spines ,Hippocampus ,General Medicine ,Biology ,Sleep in non-human animals ,Spine (zoology) ,Behavioral Neuroscience ,Sleep deprivation ,Basal (phylogenetics) ,Mice ,Cellular plasticity ,Synaptic plasticity ,medicine ,Animals ,Sleep Deprivation ,medicine.symptom ,Filopodia ,Neuroscience - Abstract
SummarySleep deprivation has a negative impact on hippocampus-dependent memory, which are thought to depend on cellular plasticity. We previously found that five hours of sleep deprivation robustly decreases dendritic spine density in the CA1 area of the hippocampus in adult male mice. However, recent work by others suggests that sleep deprivation increases the density of certain spine types on specific dendritic branches. Based on these recent findings and our previous work, we conducted a more in-depth analysis of different spine types on branches 1, 2 and 5 of both apical and basal dendrites to assess whether five hours of sleep deprivation may have previously unrecognized spine-type and branch-specific effects. This analysis shows no spine-type specific changes on branch 1 and 2 of apical dendrites after sleep deprivation. In contrast, sleep deprivation decreases the number of mushroom and branched spines on branch 5. Likewise, sleep deprivation reduces thin, mushroom, and filopodia spine density on branch 5 of the basal dendrites, without affecting spines on branch 1 and 2. Our findings indicate that sleep deprivation leads to local branch-specific reduction in the density of individual spine types, and that local effects might not reflect the overall impact of sleep deprivation on CA1 structural plasticity. Moreover, our analysis underscores that focusing on a subset of dendritic branches may lead to potential misinterpretation of the overall impact of in this case sleep deprivation on structural plasticity.
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- 2022
20. Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients
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Niels Jongs, Hugh Marston, Martien J H Kas, José Luis Ayuso-Mateos, Gerard R. Dawson, Ilja M.J. Saris, Amy C. Bilderbeck, Amber van Echteld, Sanne Koops, Jacob A. S. Vorstman, A. Raslescu, Marinus J.C. Eijkemans, Brenda W. J. H. Penninx, Nic J.A. van der Wee, Inge Winter van Rossum, Celso Arango, Bernd Sommer, Kas lab, UAM. Departamento de Psiquiatría, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
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Severity of cognitive ,Patients ,Medicina ,Schizophrenia (object-oriented programming) ,media_common.quotation_subject ,Social Interaction ,WHODAS ,Disease ,Public administration ,03 medical and health sciences ,0302 clinical medicine ,Bias ,Alzheimer Disease ,Political science ,Humans ,media_common.cataloged_instance ,European commission ,European union ,Biological Psychiatry ,media_common ,Social functioning ,Government ,030227 psychiatry ,Psychiatry and Mental health ,Caregivers ,Schizophrenia ,Christian ministry ,PRISM (surveillance program) ,Alzheimer’s disease ,030217 neurology & neurosurgery - Abstract
Background: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. Methods: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. Results: WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046). Conclusion: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases., The PRISM project (www.prism-project.eu) leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the authors’ views neither IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. Dr. Arango has also received funding support by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. Fundación Familia Alonso and Fundación Alicia Koplowitz
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- 2022
21. Social dysfunction is transdiagnostically associated with default mode network dysconnectivity in schizophrenia and Alzheimer’s disease
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Nic J.A. van der Wee, Gerard R. Dawson, Ilja M.J. Saris, Amy C. Bilderbeck, Martien J H Kas, Lianne M. Reus, Celso Arrango, Maarten Mennes, Asad Malik, Pieter Jelle Visser, Brenda W. J. H. Penninx, José Luis Ayuso-Mateos, Hugh Marston, Sanne Koops, Moji Aghajani, Yolande A.L. Pijnenburg, A. Raslescu, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Mental Health, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Neurology, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, UAM. Departamento de Psiquiatría, Centro Colaborador de la Organización Mundial de la Salud para Docencia e Investigación en Servicios de Salud Mental, and Kas lab
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medicine.medical_specialty ,Medicina ,Disease ,Alzheimer Disease ,Neural Pathways ,Humans ,Medicine ,DMN ,Psychiatry ,Biological Psychiatry ,Default mode network ,Brain Mapping ,business.industry ,Default Mode Network ,Brain ,medicine.disease ,Alzheimer's ,Magnetic Resonance Imaging ,schizophrenia ,Psychiatry and Mental health ,Schizophrenia ,transdiagnostic ,Social dysfunction ,Nerve Net ,business ,human activities ,Alzheimer’s ,Psychopathology - Abstract
Objectives: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. Methods: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N=48), Alzheimer disease (AD; N=47) patients and healthy controls (HC; N=55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). Results: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range=0.02–0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected =0.01). Conclusions: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour, The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s views and neither the IMI 2JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein
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- 2022
22. Histamine H3 receptor antagonism modulates autism-like hyperactivity but not repetitive behaviors in BTBR T+Itpr3tf/J inbred mice
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Martien J H Kas, Remco T. Molenhuis, Lianda Hutten, and Kas lab
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Male ,Agonist ,medicine.medical_specialty ,Repetitive behaviors ,Pitolisant ,Autism Spectrum Disorder ,medicine.drug_class ,autism spectrum disorders ,Clinical Biochemistry ,Striatum ,Hyperkinesis ,Toxicology ,Biochemistry ,Histamine Agonists ,Mice ,Behavioral Neuroscience ,chemistry.chemical_compound ,Histamine H3 receptor ,Piperidines ,Internal medicine ,Ciproxifan ,medicine ,Animals ,Humans ,Receptors, Histamine H3 ,Inverse agonist ,Behavioral pharmacology ,Social Behavior ,Biological Psychiatry ,Pharmacology ,BTBR T+Itpr3tf/J mice ,Behavior, Animal ,business.industry ,Imidazoles ,Histaminergic ,medicine.disease ,Grooming ,Corpus Striatum ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Autism ,Stereotyped Behavior ,business ,Locomotion ,Histamine H3 Antagonists ,medicine.drug - Abstract
Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain. Methods: Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts. Results: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereo-typic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors. Conclusions: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.
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- 2022
23. Social withdrawal and neurocognitive correlates in schizophrenia
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Domenico De Donatis, Martien J H Kas, Stefano Porcelli, Amy C. Bilderbeck, Emilio Merlo Pich, Diana De Ronchi, Alessandro Serretti, Domenico De Donati, Stefano Porcelli, Diana De Ronchi, Emilio Merlo Pich, Martien J. Ka, Amy Bilderbeck, Alessandro Serretti, and Kas lab
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medicine.medical_specialty ,Social withdrawal ,business.industry ,none ,Schizophrenia (object-oriented programming) ,Neuropsychological Tests ,Psychiatry and Mental health ,Cross-Sectional Studies ,Social Isolation ,Quality of Life ,Schizophrenia ,medicine ,Humans ,Pharmacology (medical) ,Cognition Disorders ,Psychiatry ,business ,Neurocognitive - Abstract
Background: Social withdrawal constitutes a clinical manifestation of social dysfunction in SCZ that has a high impact on the quality of life of patients. Poor neurocognitive performance has been associated with poor functional outcome in SCZ in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patients cross-sectional associations between neurocognitive domains and social withdrawal. Methods: The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in 5 domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Bivariate correlations, ANOVA and multiple regression analysis were conducted using STATISTICA software package (StatSoft, Inc. Tulsa, OK, USA). Statistical significance was tested at p value Results: Social withdrawal was associated with a lower score in the neurocognitive composite score and in “Verbal memory”, “Processing speed” and “Working memory” scores. “Verbal memory” score showed the strongest association with social withdrawal. 8% of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and socio-demographic factors (education years, PANSS positive symptoms score, employment). Conclusions: Our study showed that in a large and real-world representative sample of SCZ patients, social withdrawal was associated with neurocognitive deficits involving verbal memory, processing speed and working memory domains. Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal.
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- 2022
24. Social withdrawal
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Martien J H Kas, Sietse F. de Boer, Kevin G. O. Ike, and Bauke Buwalda
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Etiology ,Evolution ,Cognitive Neuroscience ,Context (language use) ,Disease ,DUTCH-HUNGER-WINTER ,NEGATIVE SYMPTOMS ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,INBRED MOUSE STRAINS ,QUALITY-OF-LIFE ,Adaptation, Psychological ,medicine ,Social decision making ,Animals ,Humans ,0501 psychology and cognitive sciences ,Social brain ,050102 behavioral science & comparative psychology ,Social Behavior ,VISIBLE BURROW SYSTEM ,Pathological ,Sociality ,Adaptive behavior ,MAJOR DEPRESSIVE DISORDER ,Behavior, Animal ,MEDIAL PREFRONTAL CORTEX ,Mental Disorders ,05 social sciences ,Translational ,Sociability ,RECEPTOR GENE OPRM1 ,medicine.disease ,Biological Evolution ,Social relation ,VENTRAL TEGMENTAL AREA ,Neuropsychology and Physiological Psychology ,INDUCED SICKNESS BEHAVIOR ,Social Isolation ,Quality of Life ,Major depressive disorder ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Neuropsychiatric disorders - Abstract
Social withdrawal is found across neuropsychiatric disorders and in numerous animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant target to obtain an understanding of the transition of normal social interaction into social withdrawal.
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- 2020
25. Influencing cognitive performance via social interactions: a novel therapeutic approach for brain disorders based on neuroanatomical mapping?
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Suzanne D, Lanooij, Ulrich L M, Eisel, Wilhelmus H I M, Drinkenburg, Eddy A, van der Zee, and Martien J H, Kas
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Brain Diseases ,Brain Mapping ,Cognition ,Humans ,Brain ,Social Behavior - Abstract
Many psychiatric and neurological disorders present deficits in both the social and cognitive domain. In this perspectives article, we provide an overview and the potential of the existence of an extensive neurobiological substrate underlying the close relationship between these two domains. By mapping the rodent brain regions involved in the social and/or cognitive domain, we show that the vast majority of brain regions involved in the cognitive domain are also involved in the social domain. The identified neuroanatomical overlap has an evolutionary basis, as complex social behavior requires cognitive skills, and aligns with the reported functional interactions of processes underlying cognitive and social performance. Based on the neuroanatomical mapping, recent (pre-)clinical findings, and the evolutionary perspective, we emphasize that the social domain requires more focus as an important treatment target and/or biomarker, especially considering the presently limited treatment strategies for these disorders.
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- 2021
26. Assessment of Social Behavior Using a Passive Monitoring App in Cognitively Normal and Cognitively Impaired Older Adults: Observational Study (Preprint)
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Marijn Muurling, Lianne M Reus, Casper de Boer, Sterre C Wessels, Raj R Jagesar, Jacob A S Vorstman, Martien J H Kas, and Pieter Jelle Visser
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BACKGROUND In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively. OBJECTIVE This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms. METHODS CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI. RESULTS We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (Pβ=–0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (β=0.8 [SE 0.25], P=.004). They also made less use of apps (β=–0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (β=0.042 [SE 0.015], P=.03). CONCLUSIONS CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.
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- 2021
27. The role of clock genes in sleep, stress and memory
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Peter Meerlo, Martien J H Kas, Robbert Havekes, Matias D. Zurbriggen, Youri G Bolsius, Sara J. Aton, and Jae Kyoung Kim
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0301 basic medicine ,Circadian clock ,CLOCK Proteins ,Biology ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Memory ,Circadian Clocks ,medicine ,Animals ,Humans ,Circadian rhythm ,Pharmacology ,Phenotype ,Circadian Rhythm ,CLOCK ,Sleep deprivation ,030104 developmental biology ,030220 oncology & carcinogenesis ,Synaptic plasticity ,Sleep Deprivation ,Wakefulness ,medicine.symptom ,Sleep ,Neuroscience ,Stress, Psychological - Abstract
Circadian clock genes serve as the molecular basis for animals' ~24-h internal timekeeping. Clock gene expression inside and outside of the mammalian brain's circadian pacemaker (i.e. the SCN) integrates temporal information into a wealth of physiological processes. Ample data suggests that in addition to canonical cellular timekeeping functions, clock proteins also interact with proteins involved in cellular processes not related to timekeeping, including protein regulation and the interaction with other signaling mechanisms not directly linked to the regulation of circadian rhythms. Indeed, recent data suggests that clock genes outside the SCN are involved in fundamental brain processes such as sleep/wakefulness, stress and memory. The role of clock genes in these brain processes are complex and divers, influencing many molecular pathways and phenotypes. In this review, we will discuss recent work on the involvement of clock genes in sleep, stress, and memory. Moreover, we raise the controversial possibility that these functions may be under certain circumstances independent of their circadian timekeeping function.
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- 2021
28. Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives
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Fabrizio Grieco, Briana J. Bernstein, Barbara Biemans, Lior Bikovski, C. Joseph Burnett, Jesse D. Cushman, Elsbeth A. van Dam, Sydney A. Fry, Bar Richmond-Hacham, Judith R. Homberg, Martien J. H. Kas, Helmut W. Kessels, Bastijn Koopmans, Michael J. Krashes, Vaishnav Krishnan, Sreemathi Logan, Maarten Loos, Katharine E. McCann, Qendresa Parduzi, Chaim G. Pick, Thomas D. Prevot, Gernot Riedel, Lianne Robinson, Mina Sadighi, August B. Smit, William Sonntag, Reinko F. Roelofs, Ruud A.J. Tegelenbosch, Lucas P.J.J. Noldus, and Cellular and Computational Neuroscience (SILS, FNWI)
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Computer science ,Cognitive Neuroscience ,Biophysics ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Review ,Behavioral neuroscience ,computer.software_genre ,Field (computer science) ,neuroscience ,Behavioral Neuroscience ,PhenoTyper ,video-tracking ,All institutes and research themes of the Radboud University Medical Center ,EthoVision XT ,Biotelemetry ,Replication crisis ,Cognition ,Variance (accounting) ,Cognitive artificial intelligence ,Data science ,home-cage ,Neuropsychology and Physiological Psychology ,Scripting language ,Video tracking ,rodent behavior ,computer ,RC321-571 - Abstract
Contains fulltext : 239279.pdf (Publisher’s version ) (Open Access) The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper® home-cages and the video-based tracking software, EthoVision® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a "home-cage", we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios. 26 p.
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- 2021
29. Author response: Introduction to the EQIPD quality system
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Björn Gerlach, Ernesto Prado Montes de Oca, Alexander Dityatev, Thomas Steckler, Merel Ritskes-Hoitinga, Gernot Riedel, Valerie Gailus-Durner, Patricia Kabitzke, Janko Samardzic, Claudia Stöger, Lior Bikovski, Raafat Fares, Martine C J Hofmann, Chantelle Ferland-Beckham, Sabine M. Hölter, Claudia Kurreck, Leonardo Restivo, Natasja de Bruin, Christoph H. Emmerich, Vootele Voikar, Michael Schunn, Małgorzata Pietraszek, Sandrine Bongiovanni, Heidrun Potschka, Piotr Popik, Kathleen Wuyts, Christelle Froger-Colléaux, Isabel A Lefevre, Fiona Ducrey, Malcolm R. Macleod, Jan Vollert, Kimberley E. Wever, Anja Gilis, Vincent Castagné, Javier Guillén, Anton Bespalov, Paul Moser, Esmeralda Castaños-Vélez, Martien J H Kas, René Bernard, María Arroyo-Araujo, Ulrich Dirnagl, Bruce Altevogt, and Lee Monk
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Engineering management ,Quality management system ,Computer science - Published
- 2021
30. Introduction to the EQIPD quality system
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Lior Bikovski, Raafat Fares, Anton Bespalov, Claudia Kurreck, Leonardo Restivo, Paul Moser, Chantelle Ferland-Beckham, Claudia Stöger, Patricia Kabitzke, Ernesto Prado Montes de Oca, Bruce Altevogt, Valerie Gailus-Durner, Sabine M. Hölter, Piotr Popik, Martine C J Hofmann, Vootele Voikar, Lee Monk, Michael Schunn, Alexander Dityatev, Janko Samardzic, Gernot Riedel, Thomas Steckler, Natasja de Bruin, Merel Ritskes-Hoitinga, Kathleen Wuyts, Christoph H. Emmerich, Heidrun Potschka, Vincent Castagné, Christelle Froger-Colléaux, Fiona Ducrey, Anja Gilis, Björn Gerlach, Jan Vollert, Kimberley E. Wever, Sandrine Bongiovanni, Esmeralda Castaños-Vélez, Martien J H Kas, René Bernard, Malcolm R. Macleod, Isabel A Lefevre, Javier Guillén, Małgorzata Pietraszek, María Arroyo-Araujo, Ulrich Dirnagl, Kas lab, Publica, Helsinki Institute of Life Science HiLIFE, Infra, and Neuroscience Center
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0301 basic medicine ,Life Sciences & Biomedicine - Other Topics ,Process management ,Biomedical Research ,Computer science ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Drug Evaluation, Preclinical ,0601 Biochemistry and Cell Biology ,neuroscience ,0302 clinical medicine ,Biology (General) ,Cooperative Behavior ,media_common ,General Neuroscience ,General Medicine ,Quality Improvement ,Tools and Resources ,3. Good health ,ddc ,Data Accuracy ,Europe ,Core (game theory) ,Research Design ,drug discovery ,nonregulated research ,research rigor ,Medicine ,Life Sciences & Biomedicine ,Quality Control ,QH301-705.5 ,Science ,standards [Biomedical Research] ,Context (language use) ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Stakeholder Participation ,media_common.cataloged_instance ,Humans ,European union ,Set (psychology) ,Biology ,Accreditation ,Science & Technology ,General Immunology and Microbiology ,3112 Neurosciences ,standards [Research Design] ,Private sector ,Preclinical data ,Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ,030104 developmental biology ,Quality management system ,Interdisciplinary Communication ,Other ,standards [Drug Evaluation, Preclinical] ,Diffusion of Innovation ,ddc:600 ,030217 neurology & neurosurgery - Abstract
While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e., performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.
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- 2021
31. Requirements and operational guidelines for secure and sustainable digital phenotyping
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Jacob A. S. Vorstman, Martien J H Kas, Raj R. Jagesar, and Kas lab
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Process management ,Computer science ,Health Informatics ,lcsh:Computer applications to medicine. Medical informatics ,Field (computer science) ,passive behavioral monitoring ,smartphone-based behavioral monitoring ,mobile behavioral monitoring ,03 medical and health sciences ,0302 clinical medicine ,Software ,Health care ,Humans ,psychoinformatics ,030212 general & internal medicine ,digital phenotyping ,Original Paper ,mobile phone ,Data collection ,business.industry ,Communication ,Data Collection ,lcsh:Public aspects of medicine ,Reproducibility of Results ,lcsh:RA1-1270 ,Privacy ,Mobile phone ,Sustainability ,Key (cryptography) ,lcsh:R858-859.7 ,research data management ,Privacy law ,business ,030217 neurology & neurosurgery - Abstract
Background Digital phenotyping, the measurement of human behavioral phenotypes using personal devices, is rapidly gaining popularity. Novel initiatives, ranging from software prototypes to user-ready research platforms, are innovating the field of biomedical research and health care apps. One example is the BEHAPP project, which offers a fully managed digital phenotyping platform as a service. The innovative potential of digital phenotyping strategies resides among others in their capacity to objectively capture measurable and quantitative components of human behavior, such as diurnal rhythm, movement patterns, and communication, in a real-world setting. The rapid development of this field underscores the importance of reliability and safety of the platforms on which these novel tools are operated. Large-scale studies and regulated research spaces (eg, the pharmaceutical industry) have strict requirements for the software-based solutions they use. Security and sustainability are key to ensuring continuity and trust. However, the majority of behavioral monitoring initiatives have not originated primarily in these regulated research spaces, which may be why these components have been somewhat overlooked, impeding the further development and implementation of such platforms in a secure and sustainable way. Objective This study aims to provide a primer on the requirements and operational guidelines for the development and operation of a secure behavioral monitoring platform. Methods We draw from disciplines such as privacy law, information, and computer science to identify a set of requirements and operational guidelines focused on security and sustainability. Taken together, the requirements and guidelines form the foundation of the design and implementation of the BEHAPP behavioral monitoring platform. Results We present the base BEHAPP data collection and analysis flow and explain how the various concepts from security and sustainability are addressed in the design. Conclusions Digital phenotyping initiatives are steadily maturing. This study helps the field and surrounding stakeholders to reflect upon and progress toward secure and sustainable operation of digital phenotyping–driven research.
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- 2021
32. Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study
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Philippe Danjou, Andrew McCarthy, Simon Loiodice, Wilhelmus Drinkenburg, Marsel Mano, Bertrand Rion, Christophe Drieu La Rochelle, Valerie Bertaina-Anglade, Martien J H Kas, Abdallah Ahnaou, Emilie Cayre, Philippe L'Hostis, Geoffrey Viardot, and Kas lab
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0301 basic medicine ,Mismatch negativity ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Disease ,Electroencephalography ,behavioral disciplines and activities ,Article ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Animals ,Humans ,Phencyclidine ,Biological Psychiatry ,medicine.diagnostic_test ,business.industry ,Correction ,medicine.disease ,Precision medicine ,Rats ,Psychiatry and Mental health ,030104 developmental biology ,Pharmaceutical Preparations ,Drug development ,Schizophrenia ,Evoked Potentials, Auditory ,Biomarker (medicine) ,business ,Neuroscience ,030217 neurology & neurosurgery ,Biomarkers ,medicine.drug ,RC321-571 - Abstract
The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer’s disease (AD) patients, and age-matched healthy controls. To evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease evaluation of the MMN response. Our findings suggest further investigations to support the identification of neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and clinical stages of SZ drug development.
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- 2021
33. Overview of the clinical implementation of a study exploring social withdrawal in patients with schizophrenia and Alzheimer's disease
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Brenda W.J.H. Penninx, Inge van Rossum, René S. Kahn, Nic J.A. van der Wee, Gerard R. Dawson, Martien J H Kas, Amy C. Bilderbeck, Celso Arango, Anke Post, Anja Hayen, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, and Kas lab
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Research design ,Alzheimer Disease/diagnosis ,Cognitive Neuroscience ,Exploratory research ,Disease ,Behavioral neuroscience ,Epigenesis, Genetic ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Cognition ,Genetic ,Alzheimer Disease ,Schizophrenia/diagnosis ,medicine ,Journal Article ,Humans ,EEG ,Social isolation ,Social withdrawal ,Psychiatric Status Rating Scales ,Brain Mapping ,Brain/physiopathology ,Brain ,Electroencephalography ,Alzheimer's disease ,medicine.disease ,Magnetic Resonance Imaging ,3. Good health ,030227 psychiatry ,Neuropsychology and Physiological Psychology ,Social Isolation ,Schizophrenia ,Research Design ,RDOC ,Normative ,Schizophrenic Psychology ,medicine.symptom ,Psychology ,Biomarkers ,030217 neurology & neurosurgery ,Biomarkers/blood ,Epigenesis ,Clinical psychology ,MRI - Abstract
Trans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their potential. In this manuscript we describe the approach and protocol for an exploratory study, PRISM (Psychiatric Ratings using Intermediate Stratified Markers), that will be conducted to explore the biomarkers in schizophrenia (SZ) and Alzheimer's Disease (AD) that may be related to a common symptom, social withdrawal. Patient participants (N = 72 SZ and N = 72 AD study completers), will complete a series of fMRI, EEG, and behavioural paradigms, as well as contributing blood-derived (e.g. epigenetic) and smartphone data related to social behaviour. Self- as well as caregiver- and researcher-reported assessments will be provided to characterise social withdrawal. Normative data will also be collected from a group of healthy controls (N = 48 study completers), half of whom will be matched in terms of age and gender distribution to the SZ and AD group, respectively. Thus we will explore both differentiation and cross-diagnostic overlap in the biomarkers associated with different levels of social withdrawal in SZ and AD. In this way we aim to provide a deeper understanding of the biological underpinnings of symptomatology common to both disorders, and provide insights into novel treatment targets and future drug development approaches.
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- 2019
34. Multisensory cortical processing and dysfunction across the neuropsychiatric spectrum
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Martien J H Kas, Betty E Hornix, and Robbert Havekes
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Sensory processing ,Cognitive Neuroscience ,medicine.medical_treatment ,Sensory system ,Review ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Thalamus ,Neural Pathways ,Neuroplasticity ,Journal Article ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,0501 psychology and cognitive sciences ,050102 behavioral science & comparative psychology ,Cerebral Cortex ,Neurons ,Neuronal Plasticity ,Sensory stimulation therapy ,Mental Disorders ,05 social sciences ,Multisensory integration ,Sensory Gating ,medicine.disease ,Neuropsychology and Physiological Psychology ,Touch Perception ,Autism spectrum disorder ,Schizophrenia ,Auditory Perception ,Visual Perception ,Autism ,Perception ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Sensory processing is affected in multiple neuropsychiatric disorders like schizophrenia and autism spectrum disorders. Genetic and environmental factors guide the formation and fine-tuning of brain circuitry necessary to receive, organize, and respond to sensory input in order to behave in a meaningful and consistent manner. During certain developmental stages the brain is sensitive to intrinsic and external factors. For example, disturbed expression levels of certain risk genes during critical neurodevelopmental periods may lead to exaggerated brain plasticity processes within the sensory circuits, and sensory stimulation immediately after birth contributes to fine-tuning of these circuits. Here, the neurodevelopmental trajectory of sensory circuit development will be described and related to some example risk gene mutations that are found in neuropsychiatric disorders. Subsequently, the flow of sensory information through these circuits and the relationship to synaptic plasticity will be described. Research focusing on the combined analyses of neural circuit development and functioning are necessary to expand our understanding of sensory processing and behavioral deficits that are relevant across the neuropsychiatric spectrum.
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- 2019
35. Beter samen, de biologie van sociale gezondheid
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Martien J H Kas and Kas lab
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03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,media_common.quotation_subject ,Art ,Humanities ,030217 neurology & neurosurgery ,media_common - Abstract
Sociale interacties, de wijze waarop individuen met elkaar omgaan, zijn belangrijk voor mensen. Wie regelmatig sociale contacten heeft, is over het algemeen vaker gelukkiger dan iemand met weinig sociale interacties. Sociale terugtrekking blijkt zelfs een van de eerste symptomen van een groot scala aan hersenziekten, zoals depressie, autisme, schizofrenie en dementie. Het verminderd omgaan met vrienden, familie en collega’s, alsmede stoppen met deelname aan het arbeidsproces zijn bekende voorbeelden van sociale terugtrekking. Deze veranderingen in sociaal gedrag bij hersenziekten hebben grote gevolgen voor de patiënt zelf, zijn familie en vrienden, zijn verzorgers, voor de productiviteit van die persoon op de arbeidsmarkt en voor de gezondheidszorg in het algemeen. Sociale interacties zijn niet uniek voor mensen. Ook apen, orka’s, knaagdieren, vogels, fruitvliegen en vele andere soorten, kennen complexe vormen van sociaal gedrag die veel weg hebben van het gedrag zoals we dat bij mensen zien. Mijn onderzoek is erop gericht de biologische mechanismen die ten grondslag liggen aan sociale interacties en afwijkingen hierin te ontrafelen teneinde nieuwe inzichten te verkrijgen in de ontstaanswijze en behandeling van hersenziekten. Hierover ging mijn oratie bij de aanvaarding van mijn leerstoel ‘Neurobiologie van gedrag’ aan de Rijksuniversiteit Groningen op 24 oktober 2017, waarvan dit artikel een weergave is. Met de titel, ‘Beter samen’, geef ik u mijn visie op sociale gezondheid vanuit een biologisch oogpunt.
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- 2018
36. Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior
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Jan J. Sprengers, Asami Oguro-Ando, Wiedjai Sital, Marian Joëls, Angela Sarabdjitsingh, Rosemary A. Bamford, J. Peter H. Burbach, Martien J H Kas, Jolien M. Matser, H. Oppelaar, Amila Zuko, and Kas lab
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0301 basic medicine ,Long-Term Potentiation ,Hippocampus ,Pathogenesis ,Neurotransmission ,Biology ,Hippocampal formation ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Memory ,Neuroplasticity ,Animals ,Fear conditioning ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Gene knockout ,Molecular Neurobiology ,Mice, Knockout ,Neuronal Plasticity ,Long-term potentiation ,Fear ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,Synaptic plasticity ,Neuroscience, Pathogenesis ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons.
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- 2021
37. Genetic underpinnings of sociability in the general population
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S.E.E.C. Bauduin, Alessandro Serretti, Geert Poelmans, Brenda W.J.H. Penninx, David A. Collier, Nina Roth Mota, Hilde de Kluiver, Celso Arango, Nic J.A. van der Wee, Barbara Franke, José Luis Ayuso-Mateos, Cornelius J. H. M. Klemann, Emma Laing, Ward De Witte, Janita Bralten, Chiara Fabbri, Martien J H Kas, Bralten J., Mota N.R., Klemann C.J.H.M., De Witte W., Laing E., Collier D.A., de Kluiver H., Bauduin S.E.E.C., Arango C., Ayuso-Mateos J.L., Fabbri C., Kas M.J., van der Wee N., Penninx B.W.J.H., Serretti A., Franke B., Poelmans G., Kas lab, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Digital Health
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Adult ,Bipolar Disorder ,Population ,Genome-wide association study ,Disease ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Bipolar disorder ,education ,030304 developmental biology ,Pharmacology ,0303 health sciences ,education.field_of_study ,Depressive Disorder, Major ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Depression ,Autism spectrum disorders ,medicine.disease ,Psychiatry and Mental health ,Schizophrenia ,Behavioural genetics ,Major depressive disorder ,Autism ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology ,Genome-Wide Association Study ,Human - Abstract
Contains fulltext : 237832.pdf (Publisher’s version ) (Open Access) Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h(2) of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
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- 2021
38. Common Genetic Variation And Age at Onset Of Anorexia Nervosa
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Marion Leboyer, Martin A. Kennedy, Yiran Guo, Stephan Ripke, Roger D. Cone, Nadia Micali, Allan S. Kaplan, Jonathan R. I. Coleman, Michael Strober, Dan Rujescu, Roland Burghardt, Pierre J. Magistretti, John F. Pearson, Stephan Zipfel, Ian Jones, Paul Lichtenstein, Leonid Padyukov, Jurjen J. Luykx, Wade H. Berrettini, Nicolas Ramoz, James I. Hudson, Ulrike Schmidt, Anke Hinney, Tõnu Esko, Johanna Giuranna, Sara Marsal, Johan G. Eriksson, Richard Parker, Roger A.H. Adan, George Dedoussis, Lars Klareskog, Cynthia M. Bulik, Liselotte Petersen, Stephanie Le Hellard, P. Eline Slagboom, Jochen Seitz, Ilka Boehm, Anna Keski-Rahkonen, Joseph M. Boden, Sébastien Guillaume, Xavier Estivill, Yasmina Silén, Elisabeth Widen, Josef Bulant, Marta Tyszkiewicz-Nwafor, Vladimir Janout, Janne Tidselbak Larsen, Artemis Tsitsika, Kirsty Kiezebrink, James E. Mitchell, Lenka Slachtova, Andreas J. Forstner, Harry Brandt, Nicholas G. Martin, James L. Kennedy, Wolfgang Herzog, Jennifer Jordan, Ionna Ntalla, Marie Navratilova, Gun Peggy Knudsen, Stephanie Zerwas, Steven Crawford, Oleksandr Frei, Sven Cichon, Katherine A. Halmi, Scott D. Gordon, Sietske G. Helder, Marion Roberts, Esther Walton, Beate Herpertz-Dahlmann, Martina de Zwaan, Federica Tozzi, Bochao Lin, Beata Świątkowska, Konstantinos Tziouvas, Mikael Landén, Lenka Foretova, Richard M. Myers, Annemarie A. van Elburg, Martien J H Kas, Antonio Julià, Pamela K. Keel, Susana Jiménez-Murcia, Karin Egberts, Alessandro Rotondo, Lars Alfredsson, Hartmut Imgart, L. John Horwood, Margarita Ct. Slof-Op 't Landt, Maria La Via, Dalila Pinto, Danielle M. Dick, Craig Johnson, Xiao Chang, Julie K. O'Toole, Philip Gorwood, Christian R. Marshall, Preben Bo Mortensen, Srdjan Djurovic, Mònica Gratacòs, Laura M. Thornton, Elisa Docampo-Martinez, Jessica H. Baker, Walter H. Kaye, Sandro Sorbi, Catherine M. Olsen, Hakon Hakonarson, Helga Ask, Franziska Ritschel, Agnieszka Słopień, Steven Gallinger, Dong Li, Roel A. Ophoff, Ole A. Andreassen, Andreas Birgegård, Philibert Duriez, Monika Dmitrzak-Weglarz, Alexandra Havdahl, Andrew W. Bergen, Fragiskos Gonidakis, André Scherag, Scott J. Crow, Filip Rybakowski, Tracey D. Wade, Karen S. Mitchell, Claudette Boni, Hunna J. Watson, David C. Whiteman, Ina Giegling, Samuli Ripatti, Palmiero Monteleone, James J. Crowley, Manuel Föcker, Zeynep Yilmaz, Dimitris Dikeos, Stefan Herms, Thomas Werge, Eric F. van Furth, Christian Dina, Nancy L. Pedersen, Mario Maj, Philippe Courtet, Stephanie Jamain, Janet Treasure, Johannes Hebebrand, Hana Papežová, Michael Boehnke, Katharina Buehren, Joanna Hauser, Jacques Pantel, Manfred M. Fichter, Stephen W. Scherer, Gerome Breen, Fernando Fernández-Aranda, Leila Karhunen, Gursharan Kalsi, Geòrgia Escaramís, Anne Farmer, Ingrid Meulenbelt, Janiece E. DeSocio, Valdo Ricca, Lisa Lilenfeld, Laura J. Scott, Stefan Ehrlich, Jolanta Lissowska, Unna N. Danner, Morten Mattingsdal, D. Blake Woodside, Alfonso Tortorella, Anu Raevuori, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Deborah Kaminská, Jaakko Kaprio, Sarah Maguire, Kelly L. Klump, Watson, Hunna J., Thornton, Laura M., Yilmaz, Zeynep, Baker, Jessica H., Coleman, Jonathan RI., Adan, Roger AH., Alfredsson, Lar, Andreassen, Ole A., Ask, Helga, Berrettini, Wade H., Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., de Zwaan, Martina, Dedoussis, George, Desocio, Janiece E., Dick, Danielle M., Dikeos, Dimitri, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G., Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M., Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragisko, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johanne, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hudson, James I., Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R., Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien JH., Keel, Pamela K., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lar, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S., Monteleone, Alessio Maria, Monteleone, Palmiero, Myers, Richard, Navratilova, Marie, Ntalla, Ionna, O'Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Pantel, Jacque, Papežová, Hana, Pinto, Dalila, Raevuori, Anu, Ramoz, Nicola, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ripke, Stephan, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Scott, Laura J., Seitz, Jochen, Silén, Yasmina, Šlachtová, Lenka, Slagboom, P. Eline, Slof-Op 't Landt, Margarita CT., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemi, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantino, van Elburg, Annemarie A., van Furth, Eric F., Walton, Esther, Widen, Elisabeth, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James E., Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thoma, Whiteman, David C., Woodside, D Blake, Gordon, Scott, Maguire, Sarah, Larsen, Janne T., Parker, Richard, Petersen, Liselotte V., Jordan, Jennifer, Kennedy, Martin, Wade, Tracey D., Birgegård, Andrea, Lichtenstein, Paul, Landén, Mikael, Martin, Nicholas G., Mortensen, Preben Bo, Breen, Gerome, Bulik, Cynthia M., Clinicum, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Anna Keski-Rahkonen / Principal Investigator, Department of Public Health, HUS Psychiatry, Nuorisopsykiatria, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Faculty Common Matters (Faculty of Social Sciences), Biostatistics Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, and Psychiatry
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Age of onset ,Anorexia nervosa ,Early-onset ,GWAS ,Genetic risk score ,Genetics ,Menarche ,Mendelian randomization ,Puberty ,Genome-wide association study ,Biology ,Genetic correlation ,3124 Neurology and psychiatry ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Genetic variation ,030304 developmental biology ,0303 health sciences ,Mendelian Randomization Analysis ,General Medicine ,Heritability ,3. Good health ,Anorexia nervosa (differential diagnoses) ,age at onset ,030217 neurology & neurosurgery ,Demography - Abstract
BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (ResultsTwo loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.ConclusionsOur results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction. Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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- 2021
39. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
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Samuel Kuperman, Leila Karhunen, Geòrgia Escaramís, Sébastien Guillaume, Kelly L. Klump, David C. Whiteman, Colin A. Hodgkinson, Stephanie H. Witt, Artemis Tsitsika, Hana Papezova, Renato Polimanti, P. Eline Slagboom, Peter Zill, Jakob Grove, Toni-Kim Clarke, Michael Soyka, Jennifer Jordan, Steven Gallinger, Philip Gorwood, Preben Bo Mortensen, Yuri Milaneschi, Ingrid Meulenbelt, Jen Chyong Wang, Markus M. Nöthen, Katrin Männik, Henry R. Kranzler, Michael M. Vanyukov, Anna Keski-Rahkonen, William G. Iacono, Raymond K. Walters, Stephanie Le Hellard, Bochao Danae Lin, Vesna Boraska Perica, Marion Roberts, Patrick F. Sullivan, Steven Crawford, Mark A. Frye, Melissa A. Munn-Chernoff, Hakon Hakonarson, Andreas Birgegård, Robert Culverhouse, Alexis C. Edwards, Jerome C. Foo, Alessandro Rotondo, Brenda W.J.H. Penninx, Laura M. Hack, Michael T. Lynskey, Mario Maj, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Julie K. O'Toole, Marta Tyszkiewicz-Nwafor, Matt McGue, Julien Bryois, Martina de Zwaan, Norbert Dahmen, Stefanie Heilmann-Heimbach, Deborah Kaminská, Benedetta Nacmias, Nicholas G. Martin, Anna R. Docherty, Christopher Hübel, Nancy L. Pedersen, Janet Treasure, William E. Copeland, Roger A.H. Adan, Jaakko Kaprio, Aarno Palotie, L. John Horwood, Maria La Via, Philippe Courtet, Virpi M. Leppä, Judy L. Silberg, Jason D. Boardman, Fazil Aliev, Wade H. Berrettini, Doo Sup Choi, Youl-Ri Kim, Konstantinos Hatzikotoulas, Harriet de Wit, Sandra A. Brown, Elisabeth Widen, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Ralph E. Tarter, Jana Strohmaier, Allan S. Kaplan, Richard A. Grucza, Bradley T. Webb, Angela Favaro, Dalila Pinto, Helena Gaspar, Andrew W. Bergen, Beate Herpertz-Dahlmann, Robert Levitan, Wolfgang Gäbel, Xavier Estivill, Emma C. Johnson, Konstantinos Tziouvas, Lindsay A. Farrer, Lenka Foretova, Marc A. Schuckit, Joanna M. Biernacka, André Scherag, Robbee Wedow, Abraham A. Palmer, Amy E. Adkins, Franziska Degenhardt, Louisa Degenhardt, Jurjen J. Luykx, Marius Lahti-Pulkkinen, Brien P. Riley, Monika Ridinger, Matteo Cassina, Harry Brandt, Yiran Guo, Stephan Ripke, Palmiero Monteleone, Katri Räikkönen, Jonathan R. I. Coleman, Martin A. Kennedy, Stephen W. Scherer, Ioanna Tachmazidou, Catherine M. Olsen, Bernice Porjesz, Esther Walton, Yi-Ling Chou, Nicolas Ramoz, Tetsuya Ando, Andres Metspalu, Bertram Müller-Myhsok, Brion S. Maher, Sarah Bertelsen, Melanie L. Schwandt, Janiece E. DeSocio, Margaret Keyes, John F. Pearson, Dongbing Lai, Paul Lichtenstein, James MacKillop, George Dedoussis, Jari Lahti, Ulrike Schmidt, Stefan Ehrlich, Amanda G. Wills, Teemu Palviainen, David Goldman, Elena Tenconi, Dimitris Dikeos, Scott I. Vrieze, Sietske G. Helder, Katharina Buehren, Hongyu Zhao, Sara McDevitt, Jolanta Lissowska, Joseph M. Boden, Li-Shiun Chen, Susanne Lucae, Sara Marsal, Dan Rujescu, Claes Norring, Howard J. Edenberg, Victor M. Karpyak, Fragiskos Gonidakis, Per Hoffmann, Christopher S. Franklin, Karin Egberts, Johanna Giuranna, Stefan Herms, Leah Wetherill, Stephanie Zerwas, Anthony Batzler, Elliot C. Nelson, Jouke-Jan Hottenga, Marcella Rietschel, Ioanna Ntalla, Victor Hesselbrock, Sarah M. Hartz, Marie Navratilova, Falk Kiefer, Martien J H Kas, Richard J. Rose, Andrew C. Heath, Jin P. Szatkiewicz, Lenka Slachtova, Lisa Lilenfeld, Katherine A. Halmi, John P. Rice, Anjali K. Henders, Christian Dina, Norbert Wodarz, Satu Männistö, Hamdi Mbarek, Shuyang Yao, Vladimir Janout, Alison Goate, Bettina Konte, Alexandra Schosser, Danfeng Chen, Kirsty Kiezebrink, Euijung Ryu, Dana B. Hancock, James Mitchell, Sarah E. Medland, Ina Giegling, Valdo Ricca, Scott D. Gordon, Gabrielle Koller, Samuli Ripatti, Laura M. Thornton, Alison D. Murray, Morten Mattingsdal, Zeynep Yilmaz, Jens Treutlein, Kathleen K. Bucholz, Tim B. Bigdeli, Eric F. van Furth, Hermine H. Maes, Ken B. Hanscombe, Sandra Sanchez-Roige, Daniela Degortes, Monica Forzan, Manuel Mattheisen, Richard Sherva, Scott J. Crow, Mikael Landén, Wolfgang Herzog, Jeanette N. McClintick, Tõnu Esko, Louis Fox, Wolfgang Maier, Liselotte Petersen, Laura J. Bierut, Roseann E. Peterson, Gursharan Kalsi, Kathleen Mullan Harris, Margarita C T Slof-Op 't Landt, Tamara L. Wall, Patrik K. E. Magnusson, Unna N. Danner, Stephan Zipfel, Ulrich W. Preuss, Elisa Docampo, D. Blake Woodside, Alfonso Tortorella, Benjamin W. Domingue, Franziska Ritschel, Johan G. Eriksson, Anu Raevuori, Benjamin M. Neale, Marcus Ising, Annemarie A. van Elburg, Filip Rybakowski, Maureen Reynolds, Tracey D. Wade, Manfred M. Fichter, Monica Gratacos Mayora, Claudette Boni, Andreas J. Forstner, John Whitfield, Silviu Alin Bacanu, Matthew B. McQueen, Andrew M. McIntosh, Norbert Scherbaum, Tatiana Foroud, Gun Peggy Knudsen, Sven Cichon, Christian J. Hopfer, Josef Frank, Eleftheria Zeggini, Federica Tozzi, Nadia Micali, Danielle M. Dick, Pamela A. F. Madden, Christian R. Marshall, Johannes Hebebrand, Fernando Fernández-Aranda, Roel A. Ophoff, Roland Burghardt, Nathaniel Thomas, Leonid Padyukov, Nancy L. Saccone, Anu Loukola, Fabian Streit, James L. Kennedy, Jessica H. Baker, Peter McGuffin, Walter H. Kaye, Pei Hong Shen, Anne Farmer, Roger D. Cone, Ilka Boehm, Jacquelyn L. Meyers, Paolo Santonastaso, Maurizio Clementi, Susana Jiménez-Murcia, Gudrun Wagner, Anke Hinney, Richard Parker, James I. Hudson, Nathan A. Gillespie, Michael Strober, John I. Nurnberger, Sandro Sorbi, Dorret I. Boomsma, Beata Świątkowska, Janne Tidselbak Larsen, Kenneth S. Kendler, Hidetoshi Inoko, Jessica E. Salvatore, Hunna J. Watson, Jochen Seitz, Jacques Pantel, Karl Mann, Hang Zhou, Antonio Julià, Oliver S. P. Davis, Nancy Diazgranados, Krista Fischer, John K. Hewitt, Karen S. Mitchell, Joanna Hauser, Eric O. Johnson, Craig Johnson, E. Jane Costello, Agnieszka Słopień, Dong Li, Laramie E. Duncan, Arpana Agrawal, Grant W. Montgomery, Manuel Föcker, Thomas Werge, Lannie Ligthart, Andreas Karwautz, Raquel Rabionet, Kenneth Krauter, Joel Gelernter, James J. Crowley, Cynthia M. Bulik, Paola Giusti-Rodríguez, Laura M. Huckins, Gerome Breen, Michael C. Stallings, Daniel E. Adkins, Pierre J. Magistretti, John Kramer, Lars Alfredsson, Hartmut Imgart, Annette M. Hartmann, Ole A. Andreassen, Monika Dmitrzak-Weglarz, Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], QIMR Berghofer Medical Research Institute, Karolinska Institutet [Stockholm], University Children's Hospital of Essen [Essen, Germany], University of Duisburg-Essen, Aarhus University [Aarhus], Stockholm County Council, University of Würzburg, Guy's Hospital [London], University Medical Center [Utrecht], University of Gothenburg (GU), Altrecht Center for Eating Disorders Rintveld [Zeist, The Netherlands] (Mental Health Institute), National Institute of Mental Health [Tokyo, Japan] (NIMH), National Center of Neurology and Psychiatry [Tokyo, Japan], University of Oslo (UiO), Norwegian Centre for Mental Disorders Research [Oslo] (NORMENT), University of Oslo (UiO)-Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB)-Oslo University Hospital [Oslo], Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Perelman School of Medicine, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Split, The Wellcome Trust Sanger Institute [Cambridge], RWTH Aachen University, Universitätsklinikum Frankfurt, Universita degli Studi di Padova, University Hospital Basel [Basel], Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota System, University of Bristol [Bristol], Hannover Medical School [Hannover] (MHH), Harokopio University of Athens, Seattle University [Seattle], Virginia Commonwealth University (VCU), University of Athens Medical School [Athens], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Poznan University of Medical Sciences [Poland] (PUMS), Institute of Environmental Science and Technology [Barcelona] (ICTA), Universitat Autònoma de Barcelona (UAB), Massachusetts General Hospital [Boston], Stanford University, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Estonian Genome and Medicine, University of Tartu, Universitat Pompeu Fabra [Barcelona] (UPF), MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Ludwig-Maximilians-Universität München (LMU), Infectious diseases division, Department of internal medicine, University of Münster, Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Universitätsklinikum Bonn (UKB), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Medstar Research Institute, Universität Duisburg-Essen [Essen], National and Kapodistrian University of Athens (NKUA), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Heidelberg University Hospital [Heidelberg], Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Parkland-Klinik [Bad Wildungen-Reinhardshausen, Germany], Tokai University, Department of Epidemiology and Public Health [university of Ostrava], Lékařská fakulta / Faculty of Medicine [University of Ostrava], Ostravská univerzita / University of Ostrava-Ostravská univerzita / University of Ostrava, Vall d'Hebron University Hospital [Barcelona], Charles University [Prague] (CU), University of Eastern Finland, Medizinische Universität Wien = Medical University of Vienna, Centre de toxicomanie et de santé mentale [Toronto, ON, Canada], University of Helsinki, University of Aberdeen, Faculty of Science, J.E. Purkinje University, J. E. Purkinje University, Michigan State University System, Norwegian Institute of Public Health [Oslo] (NIPH), Haukeland University Hospital, University of Bergen (UiB), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), The Chicago School of Professional Psychology [Washington, District of Columbia, USA] (Washington DC Campus), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Department of Psychiatry, University of Napoli, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], University College Cork (UCC), Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, VA Boston Healthcare System, Università degli studi della Campania 'Luigi Vanvitelli', Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Kartini Clinic [Portland, Oregon, USA], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Vanderbilt University School of Medicine [Nashville], The Hospital for sick children [Toronto] (SickKids), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Medical Epidemiology and Biostatistics (MEB), University of Pisa - Università di Pisa, Division of Psychiatric Genomics, Institute of Medical Informatics, Biometry and Epidemiology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Leiden University Medical Center (LUMC), Center for Eating Disorders Ursula [Leiden, The Netherlands] (Rivierduinen), Medical University of Łódź (MUL), The Jackson Laboratory [Bar Harbor] (JAX), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Human Genetics, Internal Medicine [Tuebingen, Germany], Tuebingen University [Germany], Oregon Research Institute (ORI), University of Otago [Dunedin, Nouvelle-Zélande], The Center for Eating Disorders at Sheppard Pratt [Baltimore, MD, USA], Weill Medical College of Cornell University [New York], Eating Recovery Center [Denver, CO, USA], Centre for Addiction and Mental Health [Toronto, ON, Canada], University of California [San Diego] (UC San Diego), University of California, Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Institute of Medical Science [Toronto], University of Toronto, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Genomics, Yale University School of Medicine, Indiana University School of Medicine, Indiana University System, Mayo Clinic [Rochester], Mayo Clinic, SUNY Downstate Medical Center, State University of New York (SUNY), University of Edinburgh, Department of Genomics, Life and Brain Center, University of Bonn, University of Utah School of Medicine [Salt Lake City], University of Heidelberg, Medical Faculty, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], National Institutes of Health [Bethesda] (NIH), National Institute on Alcohol Abuse and Alcoholism [Bethesda, MD, USA] (NIAAA), Martin-Luther-University Halle-Wittenberg, Helsinki Institute of Life Science (HiLIFE), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Vrije Universiteit Amsterdam [Amsterdam] (VU), Mathematical Sciences Institute (MSI), Australian National University (ANU), University of Colorado [Boulder], VU University Medical Center [Amsterdam], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Universität Heidelberg [Heidelberg], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Harvard University [Cambridge], University of Colorado Anschutz [Aurora], University of Vermont [Burlington], University of New South Wales [Sydney] (UNSW), University of Dusseldorf, Genetics and Pathology, Center for Human Genetic Research, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Heidelberg University, University of Iowa [Iowa City], Vienna University of Technology (TU Wien), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Indiana University System-Indiana University System, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Regensburg, Rush University Medical Center [Chicago], University of Utah, Duke University Medical Center, University of Illinois [Chicago] (UIC), University of Illinois System, Department of Medical and Molecular Genetics, Dpt of Neuroscience [New York], Laboratory of Neurogenetics, National Institutes of Health [Bethesda] (NIH)-National Institute on Alcohol Abuse and Alcoholism, Department of Health and Human Services, University of Connecticut (UCONN), University of Colorado [Denver], Research Triangle Institute International (RTI International), McMaster University [Hamilton, Ontario], CLinical Psychology, Department of Electrical and Computer Engineering [Montréal], McGill University = Université McGill [Montréal, Canada], Yale School of Public Health (YSPH), Analytic and Translational Genetics Unit, Flinders University [Adelaide, Australia], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Department of Public Health, Indiana University - Purdue University Indianapolis (IUPUI), National Institute of Mental Health (NIMH), University of Pennsylvania, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Università degli Studi di Padova = University of Padua (Unipd), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), King‘s College London-The Institute of Psychiatry, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Masaryk Memorial Cancer Institute (MMCI), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Medical Research Council-Cardiff University, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Martinez Rico, Clara, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Kas lab, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Munn-Chernoff, M. A., Johnson, E. C., Chou, Y. -L., Coleman, J. R. I., Thornton, L. M., Walters, R. K., Yilmaz, Z., Baker, J. H., Hubel, C., Gordon, S., Medland, S. E., Watson, H. J., Gaspar, H. A., Bryois, J., Hinney, A., Leppa, V. M., Mattheisen, M., Ripke, S., Yao, S., Giusti-Rodriguez, P., Hanscombe, K. B., Adan, R. A. H., Alfredsson, L., Ando, T., Andreassen, O. A., Berrettini, W. H., Boehm, I., Boni, C., Boraska Perica, V., Buehren, K., Burghardt, R., Cassina, M., Cichon, S., Clementi, M., Cone, R. D., Courtet, P., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J. E., Dick, D. M., Dikeos, D., Dina, C., Dmitrzak-Weglarz, M., Docampo, E., Duncan, L. E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Farmer, A., Favaro, A., Fernandez-Aranda, F., Fichter, M. M., Fischer, K., Focker, M., Foretova, L., Forstner, A. J., Forzan, M., Franklin, C. S., Gallinger, S., Giegling, I., Giuranna, J., Gonidakis, F., Gorwood, P., Gratacos Mayora, M., Guillaume, S., Guo, Y., Hakonarson, H., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S. G., Herms, S., Herpertz-Dahlmann, B., Herzog, W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jimenez-Murcia, S., Julia, A., Kalsi, G., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, J. L., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K. L., Knudsen, G. P. S., La Via, M. C., Le Hellard, S., Levitan, R. D., Li, D., Lilenfeld, L., Lin, B. D., Lissowska, J., Luykx, J., Magistretti, P. J., Maj, M., Mannik, K., Marsal, S., Marshall, C. R., Mattingsdal, M., Mcdevitt, S., Mcguffin, P., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, K., Monteleone, A. M., Monteleone, P., Nacmias, B., Navratilova, M., Ntalla, I., O'Toole, J. K., Ophoff, R. A., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Pinto, D., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rotondo, A., Rujescu, D., Rybakowski, F., Santonastaso, P., Scherag, A., Scherer, S. W., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M. C. T., Slopien, A., Sorbi, S., Swiatkowska, B., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wagner, G., Walton, E., Widen, E., Zeggini, E., Zerwas, S., Zipfel, S., Bergen, A. W., Boden, J. M., Brandt, H., Crawford, S., Halmi, K. A., Horwood, L. J., Johnson, C., Kaplan, A. S., Kaye, W. H., Mitchell, J., Olsen, C. M., Pearson, J. F., Pedersen, N. L., Strober, M., Werge, T., Whiteman, D. C., Woodside, D. B., Grove, J., Henders, A. K., Larsen, J. T., Parker, R., Petersen, L. V., Jordan, J., Kennedy, M. A., Birgegard, A., Lichtenstein, P., Norring, C., Landen, M., Mortensen, P. B., Polimanti, R., Mcclintick, J. N., Adkins, A. E., Aliev, F., Bacanu, S. -A., Batzler, A., Bertelsen, S., Biernacka, J. M., Bigdeli, T. B., Chen, L. -S., Clarke, T. -K., Degenhardt, F., Docherty, A. R., Edwards, A. C., Foo, J. C., Fox, L., Frank, J., Hack, L. M., Hartmann, A. M., Hartz, S. M., Heilmann-Heimbach, S., Hodgkinson, C., Hoffmann, P., Hottenga, J. -J., Konte, B., Lahti, J., Lahti-Pulkkinen, M., Lai, D., Ligthart, L., Loukola, A., Maher, B. S., Mbarek, H., Mcintosh, A. M., Mcqueen, M. B., Meyers, J. L., Milaneschi, Y., Palviainen, T., Peterson, R. E., Ryu, E., Saccone, N. L., Salvatore, J. E., Sanchez-Roige, S., Schwandt, M., Sherva, R., Streit, F., Strohmaier, J., Thomas, N., Wang, J. -C., Webb, B. T., Wedow, R., Wetherill, L., Wills, A. G., Zhou, H., Boardman, J. D., Chen, D., Choi, D. -S., Copeland, W. E., Culverhouse, R. C., Dahmen, N., Degenhardt, L., Domingue, B. W., Frye, M. A., Gaebel, W., Hayward, C., Ising, M., Keyes, M., Kiefer, F., Koller, G., Kramer, J., Kuperman, S., Lucae, S., Lynskey, M. T., Maier, W., Mann, K., Mannisto, S., Muller-Myhsok, B., Murray, A. D., Nurnberger, J. I., Preuss, U., Raikkonen, K., Reynolds, M. D., Ridinger, M., Scherbaum, N., Schuckit, M. A., Soyka, M., Treutlein, J., Witt, S. H., Wodarz, N., Zill, P., Adkins, D. E., Boomsma, D. I., Bierut, L. J., Brown, S. A., Bucholz, K. K., Costello, E. J., de Wit, H., Diazgranados, N., Eriksson, J. G., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Goate, A. M., Goldman, D., Grucza, R. A., Hancock, D. B., Harris, K. M., Hesselbrock, V., Hewitt, J. K., Hopfer, C. J., Iacono, W. G., Johnson, E. O., Karpyak, V. M., Kendler, K. S., Kranzler, H. R., Krauter, K., Lind, P. A., Mcgue, M., Mackillop, J., Madden, P. A. F., Maes, H. H., Magnusson, P. K. E., Nelson, E. C., Nothen, M. M., Palmer, A. A., Penninx, B. W. J. H., Porjesz, B., Rice, J. P., Rietschel, M., Riley, B. P., Rose, R. J., Shen, P. -H., Silberg, J., Stallings, M. C., Tarter, R. E., Vanyukov, M. M., Vrieze, S., Wall, T. L., Whitfield, J. B., Zhao, H., Neale, B. M., Wade, T. D., Heath, A. C., Montgomery, G. W., Martin, N. G., Sullivan, P. F., Kaprio, J., Breen, G., Gelernter, J., Edenberg, H. J., Bulik, C. M., and Agrawal, A.
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Netherlands Twin Register (NTR) ,Alcoholism/genetics ,Schizophrenia/genetics ,[SDV]Life Sciences [q-bio] ,[SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,Medizin ,Medicine (miscellaneous) ,Genome-wide association study ,Alcohol use disorder ,Anorexia nervosa ,Linkage Disequilibrium ,ddc:616.89 ,[SCCO]Cognitive science ,0302 clinical medicine ,Risk Factors ,Tobacco Use Disorder/genetics ,Substance-Related Disorders/genetics ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Factors de risc en les malalties ,Bulimia nervosa ,Feeding and Eating Disorders/genetics ,eating disorders ,genetic correlation ,substance use ,Tobacco Use Disorder ,3. Good health ,Fenotip ,[SDV] Life Sciences [q-bio] ,Psychiatry and Mental health ,Alcoholism ,Eating disorders ,Phenotype ,Schizophrenia ,Drinking of alcoholic beverages ,eating disorder ,Consum d'alcohol ,Major depressive disorder ,medicine.symptom ,Depressive Disorder, Major/genetics ,eating disorders, genetic correlation, substance use ,Clinical psychology ,Substance abuse ,Risk factors in diseases ,Substance-Related Disorders ,Polymorphism, Single Nucleotide ,Article ,Feeding and Eating Disorders ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,mental disorders ,Genetics ,medicine ,Humans ,Trastorns de la conducta alimentària ,030304 developmental biology ,Genetic association ,Pharmacology ,Depressive Disorder, Major ,Binge eating ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SCCO.NEUR] Cognitive science/Neuroscience ,[SCCO] Cognitive science ,medicine.disease ,Comorbidity ,Twin study ,030227 psychiatry ,Abús de substàncies ,[SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,business ,Genètica ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genome-Wide Association Study - Abstract
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; qwith binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to −0.23; qs
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- 2021
40. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
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Stephan Zipfel, Hidetoshi Inoko, K. Fischer, Laramie E. Duncan, Jochen Seitz, Lars Klareskog, Ina Giegling, Grant W. Montgomery, Manuel Föcker, Colin A. Johnson, Agnieszka Słopień, Dong Li, M. C. T. Slof-Op 't Landt, Thomas Werge, Janiece E. DeSocio, Stefan Ehrlich, Joseph M. Boden, Patrick F. Sullivan, M. La Via, Bochao Danae Lin, Andreas Karwautz, Ilka Boehm, Lenka Foretová, Stephen W. Scherer, Anders Juréus, Jolanta Lissowska, Janne Tidselbak Larsen, Antonio Julià, A. Metspalu, Roger A.H. Adan, George Dedoussis, Stefan Herms, Franziska Ritschel, Martin A. Kennedy, Vesna Boraska Perica, S.D. Gordon, Johanna Giuranna, Janet Treasure, Youl-Ri Kim, Joanna Hauser, Manfred M. Fichter, P.E. Slagboom, Wade H. Berrettini, Kirstin L. Purves, Fernando Fernández-Aranda, Eleftheria Zeggini, Nadia Micali, Anne Farmer, Beata Swiatkowska, Tracey D. Wade, Claudette Boni, Fragiskos Gonidakis, Ioanna Ntalla, Johannes Pantel, Raquel Rabionet, Pierre J. Magistretti, Johannes Hebebrand, Mario Maj, Sietske G. Helder, Roland Burghardt, Sarah E. Medland, Maurizio Clementi, John F. Pearson, Gerd Wagner, V. Janout, Susana Jiménez-Murcia, Mikael Landén, Samuli Ripatti, Sandro Sorbi, Martien J H Kas, Leonid Padyukov, Zeynep Yilmaz, Kelly L. Klump, Paul Lichtenstein, Shuyang Yao, Dan Rujescu, James J. Crowley, Valdo Ricca, Palmiero Monteleone, Steve Crawford, Sébastien Guillaume, Liselotte Petersen, Yiran Guo, Stephan Ripke, Beate Herpertz-Dahlmann, Marie Navratilova, S. Gallinger, Anjali K. Henders, Cynthia M. Bulik, Wolfgang Herzog, Alfonso Tortorella, Christian Dina, Garret D. Stuber, A. A. van Elburg, Manuel Mattheisen, Harry Brandt, Hunna J. Watson, Alessandro Rotondo, Roel A. Ophoff, Artemis Tsitsika, Nicholas G. Martin, Sara Marsal, Konstantinos Tziouvas, Ken B. Hanscombe, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Anu Raevuori, Lars Alfredsson, E. F. van Furth, Hartmut Imgart, Esther Walton, Julie K. O'Toole, Katharina Buehren, Unna N. Danner, Hana Papezova, Katherine M. Kirk, Deborah Kaminská, Lisa R. Lilenfeld, Aarno Palotie, Paola Giusti-Rodríguez, Jennifer Jordan, Gun Peggy Knudsen, L. Slachtova, Ole A. Andreassen, Monica Gratacos Mayora, Elisabeth Widen, Benedetta Nacmias, Nicholas J. Schork, Monika Dmitrzak-Weglarz, Jurjen J. Luykx, André Scherag, Christopher Hübel, Laura M. Thornton, Marion Roberts, Angela Favaro, Catherine M. Olsen, Jaakko Kaprio, S Le Hellard, Federica Tozzi, Monica Forzan, Claes Norring, Leila Karhunen, Karin Egberts, Dalila Pinto, Geòrgia Escaramís, Nicolas Ramoz, Robert D. Levitan, Laura M. Huckins, Ulrike Schmidt, Gerome Breen, Kirsty Kiezebrink, Andreas J. Forstner, Scott J. Crow, Ingrid Meulenbelt, Dimitris Dikeos, Sven Cichon, Daniela Degortes, L. J. Horwood, Tetsuya Ando, Jonathan R. I. Coleman, Stephanie Zerwas, Katherine A. Halmi, Helena Gaspar, Andrew W. Bergen, Elena Tenconi, Katrin Männik, Christopher S. Franklin, Anna Keski-Rahkonen, Sara McDevitt, Marta Tyszkiewicz-Nwafor, Jakob Grove, Philip Gorwood, Christian R. Marshall, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Hakon Hakonarson, Roger D. Cone, Allan S. Kaplan, Paolo Santonastaso, James I. Hudson, M. de Zwaan, Xavier Estivill, James E. Mitchell, Danielle M. Dick, Jessica H. Baker, Peter McGuffin, Walter H. Kaye, Michael Strober, D. B. Woodside, Oliver S. P. Davis, Karen S. Mitchell, David C. Whiteman, Julien Bryois, Nancy L. Pedersen, Philippe Courtet, Virpi M. Leppä, Konstantinos Hatzikotoulas, T Esko, Matteo Cassina, Andreas Birgegård, Anke Hinney, Richard Parker, James L. Kennedy, Elisa Docampo, Ioanna Tachmazidou, Jin P. Szatkiewicz, Alexandra Schosser, Filip Rybakowski, Morten Mattingsdal, and Gursharan Kalsi
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medicine.medical_specialty ,Anorexia nervosa (differential diagnoses) ,business.industry ,medicine ,Genome-wide association study ,Psychiatry ,business - Published
- 2020
41. Basic mechanisms, genetics, targets, and animal models for anxiety disorders
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Berend Olivier and Martien J H Kas
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medicine ,Anxiety ,medicine.symptom ,Psychology ,Clinical psychology - Abstract
Historically, two extensively studied neurotransmitter systems have been studied in anxiety and anxiety disorders, namely the gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT, serotonin) systems. Here, the chapter illuminates the various targets within these systems that have led to treatment or are potentially targets for the treatment of anxiety disorders. Human genome-wide association studies have offered potentially novel candidate genes for anxiety disorders, although replication often failed to confirm the original findings. A complicating factor is the heterogenous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) and the complex translational operationalization of anxiety—preclinical and clinical studies use diverging definitions and models of anxiety. Stratification of patient populations based on quantitative biological parameters (rather than diagnosis), as well as functional studies in mice mutant for risk genes using homologous endpoints, might optimize our understanding of the relationships between risk genetic variations and core features of anxiety disorders.
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- 2020
42. Reproducibility of animal research in light of biological variation
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Martien J H Kas, Hanno Würbel, Jessica Gurevitch, Ivana Jaric, Wolfgang Forstmeier, Anders Forsman, Tom Van de Casteele, Natasha A. Karp, Naomi Altman, Holger Schielzeth, and Bernhard Voelkl
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Animal Experimentation ,0301 basic medicine ,SEX-DIFFERENCES ,Standardization ,Computer science ,MOUSE ,03 medical and health sciences ,0302 clinical medicine ,Biological variation ,Animals ,Road map ,Biological sciences ,NIH ,Reproducibility ,ENVIRONMENT ,630 Agriculture ,CEREBRAL-ISCHEMIA ,General Neuroscience ,Reproducibility of Results ,SCIENCE ,STANDARDIZATION ,Data science ,Experimental animal ,MICE ,030104 developmental biology ,Biological Variation, Population ,Research Design ,13. Climate action ,Paradigm shift ,INBRED STRAINS ,030217 neurology & neurosurgery ,BEHAVIOR - Abstract
Context-dependent biological variation presents a unique challenge to the reproducibility of results in experimental animal research, because organisms’ responses to experimental treatments can vary with both genotype and environmental conditions. In March 2019, experts in animal biology, experimental design and statistics convened in Blonay, Switzerland, to discuss strategies addressing this challenge. In contrast to the current gold standard of rigorous standardization in experimental animal research, we recommend the use of systematic heterogenization of study samples and conditions by actively incorporating biological variation into study design through diversifying study samples and conditions. Here we provide the scientific rationale for this approach in the hope that researchers, regulators, funders and editors can embrace this paradigm shift. We also present a road map towards better practices in view of improving the reproducibility of animal research. In this Perspective, Hanno Wurbel and colleagues argue that a disregard for incorporating biological variation in study design is an important cause of poor reproducibility in animal research. They put the case for the use of systematic heterogenization of study samples and conditions in studies to improve reproducibility.
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- 2020
43. A framework for assessing neuropsychiatric phenotypes by using smartphone-based location data
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Martien J H Kas, Niels Jongs, Celso Arango, Pieter Jelle Visser, Jacob A. S. Vorstman, Lianne M. Reus, Iris E. C. Sommer, Brenda W.J.H. Penninx, Ina M. Koning, Nic J.A. van der Wee, Marinus J.C. Eijkemans, Raj R. Jagesar, Neeltje E.M. van Haren, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, Neurology, APH - Digital Health, APH - Mental Health, Child and Adolescent Psychiatry / Psychology, Kas lab, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), and Movement Disorder (MD)
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Behavioral phenotypes ,Geospatial analysis ,020205 medical informatics ,Computer science ,Schizophrenia (object-oriented programming) ,Context (language use) ,02 engineering and technology ,Machine learning ,computer.software_genre ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,0202 electrical engineering, electronic engineering, information engineering ,Preprocessor ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Location data ,business.industry ,Psychiatry and Mental health ,Phenotype ,Schizophrenia ,Artificial intelligence ,HEALTH ,Smartphone ,business ,computer ,030217 neurology & neurosurgery ,Biomarkers ,Neuroscience - Abstract
The use of smartphone-based location data to quantify behavior longitudinally and passively is rapidly gaining traction in neuropsychiatric research. However, a standardized and validated preprocessing framework for deriving behavioral phenotypes from smartphone-based location data is currently lacking. Here, we present a preprocessing framework consisting of methods that are validated in the context of geospatial data. This framework aims to generate context-enriched location data by identifying stationary, non-stationary, and recurrent stationary states in movement patterns. Subsequently, this context-enriched data is used to derive a series of behavioral phenotypes that are related to movement. By using smartphone-based location data collected from 245 subjects, including patients with schizophrenia, we show that the proposed framework is effective and accurate in generating context-enriched location data. This data was subsequently used to derive behavioral readouts that were sensitive in detecting behavioral nuances related to schizophrenia and aging, such as the time spent at home and the number of unique places visited. Overall, our results indicate that the proposed framework reliably preprocesses raw smartphone-based location data in such a manner that relevant behavioral phenotypes of interest can be derived.
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- 2020
44. The reduction of astrocytes and brain volume loss in anorexia nervosa—the impact of starvation and refeeding in a rodent model
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Stefanie Trinh, Julia Kempermann, Beate Herpertz-Dahlmann, Cordian Beyer, Fabian Kiessling, Jochen Seitz, Martien J H Kas, Serhat Etdöger, Johanna Liesbrock, Joseph Neulen, Rene Tolba, Vera Päfgen, Kerstin Konrad, Christina Leunissen, Nicole Heussen, Linda Frintrop, and Kas lab
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0301 basic medicine ,Anorexia Nervosa ,ADOLESCENT ,Corpus callosum ,Corpus Callosum ,MORPHOLOGICAL-CHANGES ,0302 clinical medicine ,MARKERS ,Medicine ,NEURONS ,Cerebral Cortex ,RISK ,FOCUS ,Neuropsychology ,Brain ,Magnetic Resonance Imaging ,Pathophysiology ,Psychiatry and Mental health ,medicine.anatomical_structure ,Cerebral cortex ,Brain size ,Female ,medicine.symptom ,Astrocyte ,medicine.medical_specialty ,Anorexia ,Motor Activity ,ILLNESS ,Molecular neuroscience ,Article ,lcsh:RC321-571 ,White matter ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,Animals ,ddc:610 ,Rats, Wistar ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,business.industry ,EATING-DISORDERS ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Starvation ,Astrocytes ,RAT ,Psychiatric disorders ,business ,030217 neurology & neurosurgery ,WEIGHT-RECOVERED PATIENTS - Abstract
Translational Psychiatry 9(1), 159 (2019). doi:10.1038/s41398-019-0493-7, Published by Nature Publishing Group, London
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- 2019
45. Reproducibility via coordinated standardization : a multi-center study in a S hank2 genetic rat model for Autism Spectrum Disorders
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Bastijn Koopmans, Sietse F. de Boer, Radka Graf, Barbara Biemans, Wilhelmus Drinkenburg, Wil van Dommelen, Esther Schenker, Martien J H Kas, Derek L. Buhl, Michaela Cullum-Doyle, Elsbeth van Dam, María Arroyo-Araujo, Will Spooren, Martine Maco, Lucas P. J. J. Noldus, Maarten Loos, Kas lab, and Neurobiology
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Male ,0301 basic medicine ,Standardization ,Autism Spectrum Disorder ,Rat model ,lcsh:Medicine ,Nerve Tissue Proteins ,Article ,Rats, Sprague-Dawley ,External validity ,03 medical and health sciences ,0302 clinical medicine ,ADULT ,medicine ,Animals ,lcsh:Science ,General ,Pharmacology ,Reproducibility ,Cross-Over Studies ,Multidisciplinary ,business.industry ,lcsh:R ,Reproducibility of Results ,Autism spectrum disorders ,medicine.disease ,Rats ,3. Good health ,SHANK2 ,Disease Models, Animal ,MICE ,030104 developmental biology ,Gene Knockdown Techniques ,Multi center study ,Autism ,lcsh:Q ,Test protocol ,business ,Neuroscience ,030217 neurology & neurosurgery ,GLUTAMATE-RECEPTOR MGLUR1 ,BEHAVIOR - Abstract
Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers. All three sites reliably observed a hyperactive and repetitive behavioral phenotype in KO rats compared to their wild-type littermates as well as a dose-dependent phenotype attenuation following acute injections of a selective mGluR1 antagonist. These results show that reproducibility in preclinical studies can be obtained and emphasizes the need for high quality and rigorous methodologies in scientific research. Considering the observed external validity, the present study also suggests mGluR1 as potential target for the treatment of autism spectrum disorders.
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- 2019
46. Genetic underpinnings of sociability in the UK Biobank
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van der Wee N, Barbara Franke, Nina Roth Mota, Martien J H Kas, Brenda W.J.H. Penninx, C. Arango, Chiara Fabbri, Janita Bralten, Cornelius J. H. M. Klemann, Alessandro Serretti, Geert Poelmans, and De Witte W
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0303 health sciences ,education.field_of_study ,business.industry ,Population ,Social anxiety ,Loneliness ,Genome-wide association study ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Schizophrenia ,mental disorders ,medicine ,Autism ,Major depressive disorder ,Bipolar disorder ,medicine.symptom ,education ,business ,030217 neurology & neurosurgery ,030304 developmental biology ,Clinical psychology - Abstract
Difficulties with sociability include a tendency to avoid social contacts and activities, and to prefer being alone rather than being with others. While sociability is a continuously distributed trait in the population, decreased sociability represent a common early manifestation of multiple neuropsychiatric disorders such as Schizophrenia (SCZ), Bipolar Disorder (BP), Major Depressive Disorder (MDD), Autism Spectrum Disorders (ASDs), and Alzheimer’s disease (AD). We aimed to investigate the genetic underpinnings of sociability as a continuous trait in the general population. In this respect, we performed a genome-wide association study (GWAS) using a sociability score based on 4 social functioning-related self-report questions in the UK Biobank sample (n=342,461) to test the effect of individual genetic variants. This was followed by LD score analyses to investigate the genetic correlation with psychiatric disorders (SCZ, BP, MDD, ASDs) and a neurological disorder (AD) as well as related phenotypes (Loneliness and Social Anxiety). The phenotypic data indeed showed that the sociability score was decreased in individuals with ASD, (probable) MDD, BP and SCZ, but not in individuals with AD. Our GWAS showed 604 genome-wide significant SNPs, coming from 18 independent loci (SNP-based h2=0.06). Genetic correlation analyses showed significant correlations with SCZ (rg=0.15, p=9.8e-23), MDD (rg=0.68, p=6.6e-248) and ASDs (rg=0.27, p=4.5e-28), but no correlation with BP (rg=0.01, p=0.45) or AD (rg=0.04, p=0.55). Our sociability trait was also genetically correlated with Loneliness (rg=0.45, p=2.4e-8) and Social Anxiety (rg=0.48, p=0.002). Our study shows that there is a significant genetic component to variation in population levels of sociability, which is relevant to some psychiatric disorders (SCZ, MDD, ASDs), but not to BP and AD.
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- 2019
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47. The Visible Burrow System: A behavioral paradigm to assess sociability and social withdrawal in BTBR and C57BL/6J mice strains
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Martien J H Kas, Maria Bove, Sietse F. de Boer, Luigia Trabace, Maria Grazia Morgese, Vincenzo Cuomo, Bauke Buwalda, Stefania Schiavone, Kevin G. O. Ike, Adriaan Eldering, Kas lab, and Buwalda lab
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Male ,0301 basic medicine ,STRESS ,AUTISM SPECTRUM DISORDERS ,Disease ,Behavioral Neuroscience ,0302 clinical medicine ,MOUSE MODELS ,SCHIZOPHRENIA ,T PLUS TF/J ,BRAIN ,Prefrontal cortex ,Chromatography, High Pressure Liquid ,gamma-Aminobutyric Acid ,MEDIAL PREFRONTAL CORTEX ,Equipment Design ,Amygdala ,Housing, Animal ,medicine.anatomical_structure ,Schizophrenia ,Models, Animal ,Female ,Psychology ,Social withdrawal ,Glutamic Acid ,Prefrontal Cortex ,Mice, Inbred Strains ,Motor Activity ,03 medical and health sciences ,Species Specificity ,C57BL/6J mice ,medicine ,Animals ,Social Behavior ,Psychological Tests ,Sociability ,BTBR mice ,medicine.disease ,Burrow ,Grooming ,030104 developmental biology ,Exploratory Behavior ,Autism ,Visible burrow system ,INBRED STRAINS ,Neuroscience ,030217 neurology & neurosurgery ,RESPONSES ,Social behavior - Abstract
Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases.
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- 2018
48. Establishment of a chronic activity-based anorexia rat model
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Jochen Seitz, Johanna Liesbrock, Stefanie Trinh, Rene Tolba, Beate Herpertz-Dahlmann, Martien J H Kas, Kerstin Konrad, Linda Frintrop, Lisa Paulukat, Cordian Beyer, and Kas lab
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0301 basic medicine ,Anorexia Nervosa ,Medizin ,Acute vs. chronic starvation ,Anorexia nervosa ,CALORIC RESTRICTION ,Running ,0302 clinical medicine ,Weight loss ,Sexual Maturation ,Amenorrhea ,media_common ,Starvation ,DEHYDRATION-ANOREXIA ,General Neuroscience ,Activity-based anorexia rat model ,Eating disorders ,ESTROUS-CYCLE ,Acute Disease ,Female ,NERVOSA ,medicine.symptom ,Psychology ,EXPRESSION ,CHRONIC FOOD RESTRICTION ,medicine.medical_specialty ,media_common.quotation_subject ,Estrous Cycle ,Anorexia ,03 medical and health sciences ,FEMALE RATS ,Stress, Physiological ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Menstrual cycle ,Estrous cycle ,Body Weight ,EATING-DISORDERS ,Feeding Behavior ,medicine.disease ,Disease Models, Animal ,PHYSICAL-ACTIVITY ,030104 developmental biology ,Endocrinology ,Amenorrhoea ,Chronic Disease ,WEIGHT ,030217 neurology & neurosurgery - Abstract
Background Anorexia nervosa (AN) is often a chronic eating disorder characterised by body image disturbance and low body weight often associated with starvation-induced amenorrhoea and excessive exercise. Activity-based anorexia (ABA) is an animal model representing many somatic aspects of this psychiatric illness. We systematically manipulated the extent and length of starvation and animal age to find the optimal parameters to study chronic starvation. New methods Wistar rats had 24 h/day running wheel access and received 40% of their baseline food intake until a 20% or 25% weight reduction was reached (acute starvation). This body weight was then maintained for two weeks (chronic starvation). The rats of different ages of 4 or 8 weeks were used to represent early and late adolescent animals, respectively. The complete absence of a menstrual cycle was defined as the primary outcome parameter. Results Acute starvation caused a disruption of the oestrous cycle in 58% of the animals. During chronic starvation, a complete loss of the oestrous cycle could be found. Furthermore, 4-week-old rats exhibited higher levels of hyperactivity and amenorrhoea than 8-week-old animals. A 20% starvation level led to 90% loss of cycle, while a 25% starvation level triggered complete loss. Comparison with existing methods Most current ABA models focus on acute starvation, while most patients are chronically ill. Conclusions The optimal parameters to achieve complete amenorrhoea included early adolescence, chronic starvation and 25% weight loss. The new ABA model allows studying the effects of chronic AN on underlying behavioural, hormonal and brain pathobiology.
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- 2018
49. P.389 Social withdrawal levels influence cerebellar activity during consumption of monetary rewards – fMRI results from the PRISM clinical study
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Anja Hayen, N. van der Wee, Asad Malik, J. R. Clark, Bernd Sommer, Amy C. Bilderbeck, Brenda W. J. H. Penninx, Gerard R. Dawson, C. Arango, A. Raslescu, Hugh Marston, Martien J H Kas, and I. Winter van Rossum
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Pharmacology ,Consumption (economics) ,medicine.medical_specialty ,Social withdrawal ,05 social sciences ,Clinical study ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Physical medicine and rehabilitation ,Neurology ,medicine ,0501 psychology and cognitive sciences ,Pharmacology (medical) ,050102 behavioral science & comparative psychology ,Neurology (clinical) ,Prism ,Psychology ,030217 neurology & neurosurgery ,Biological Psychiatry - Published
- 2020
50. P.228 The role of Protocadherin 9 in layer 6 of the cortex in sensory-related behavioural tasks
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Martien J H Kas, Betty E Hornix, and Robbert Havekes
- Subjects
Pharmacology ,Chemistry ,Protocadherin ,Sensory system ,Psychiatry and Mental health ,medicine.anatomical_structure ,Neurology ,Cortex (anatomy) ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Layer (object-oriented design) ,Neuroscience ,Biological Psychiatry - Published
- 2020
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