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1. Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents (the TECTO trial): a statistical analysis plan for the randomised clinical trial

Author

Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Janus Engstrøm, Jane Lindschou, Hartwig Roman Siebner, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Per Hove Thomsen, Katja Hybel, Line Katrine Harder Clemmesen, Christian Gluud, Kerstin Jessica Plessen, Anne Katrine Pagsberg, and Janus Christian Jakobsen

Subjects
Obsessive-compulsive disorder, Cognitive behavioural therapy, Family-based psychoeducation/relaxation training, Randomised clinical trial, Statistical analysis plan, Medicine (General), R5-920
Abstract

Abstract Background Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder which affects up to 3% of children and adolescents. OCD in children and adolescents is generally treated with cognitive behavioural therapy (CBT), which, in more severely affected patients, can be combined with antidepressant medication. The TECTO trial aims to compare the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation/relaxation training (FPRT) in children and adolescents aged 8 to 17 years. This statistical analysis plan outlines the planned statistical analyses for the TECTO trial. Methods The TECTO trial is an investigator-initiated, independently funded, single-centre, parallel-group, superiority randomised clinical trial. Both groups undergo 14 sessions of 75 min each during a period of 16 weeks with either FCBT or FPRT depending on the allocation. Participants are randomised stratified by age and baseline Children’s Yale–Brown Obsessive-Compulsive Scale (CY-BOCS) score. The primary outcome is the CY-BOCS score. Secondary outcomes are health-related quality of life assessed using KIDSCREEN-10 and adverse events assessed by the Negative Effects Questionnaire (NEQ). Primary and secondary outcomes are assessed at the end of the intervention. Continuous outcomes will be analysed using linear regression adjusted for the stratification variables and baseline value of the continuous outcome. Dichotomous outcomes will be analysed using logistic regression adjusted for the stratification variables. The statistical analyses will be carried out by two independent blinded statisticians. Discussion This statistical analysis plan includes a detailed predefined description of how data will be analysed and presented in the main publication before unblinding of study data. Statistical analysis plans limit selective reporting bias. This statistical analysis plan will increase the validity of the final trial results. Trial registration ClinicalTrials.gov NCT03595098. July 23, 2018

Published
2022
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2. Adverse events in cognitive behavioral therapy and relaxation training for children and adolescents with obsessive-compulsive disorder: A mixed methods study and analysis plan for the TECTO trial

Author

Linea Pretzmann, Sofie Heidenheim Christensen, Anne Bryde Christensen, Camilla Funch Uhre, Valdemar Uhre, Christine Lykke Thoustrup, Iben Thiemer Clemmesen, Tin Aaen Gudmandsen, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Markus Harboe Olsen, Line Katrine Harder Clemmensen, Jane Lindschou, Christian Gluud, Per Hove Thomsen, Signe Vangkilde, Julie Hagstrøm, Alexander Rozental, Pia Jeppesen, Frank Verhulst, Katja Anna Hybel, Nicole Nadine Lønfeldt, Kerstin Jessica Plessen, Stig Poulsen, and Anne Katrine Pagsberg

Subjects
Adverse effects, Obsessive-compulsive disorder, Cognitive behavioral therapy, Randomized clinical trial, Child, Adolescent, Medicine (General), R5-920
Abstract

Background: Knowledge on adverse events in psychotherapy for youth with OCD is sparse. No official guidelines exist for defining or monitoring adverse events in psychotherapy. Recent recommendations call for more qualitative and quantitative assessment of adverse events in psychotherapy trials. This mixed methods study aims to expand knowledge on adverse events in psychotherapy for youth with OCD. Methods: This is an analysis plan for a convergent mixed methods study within a randomized clinical trial (the TECTO trial). We include at least 128 youth aged 8–17 years with obsessive-compulsive disorder (OCD). Participants are randomized to either family-based cognitive behavioral therapy (FCBT) or family-based psychoeducation and relaxation training (FPRT). Adverse events are monitored quantitatively with the Negative Effects Questionnaire. Furthermore, we assess psychiatric symptoms, global functioning, quality of life, and family factors to investigate predictors for adverse events. We conduct semi-structured qualitative interviews with all youths and their parents on their experience of adverse events in FCBT or FPRT. For the mixed methods analysis, we will merge 1) a qualitative content analysis with descriptive statistics comparing the types, frequencies, and severity of adverse events; 2) a qualitative content analysis of the perceived causes for adverse events with prediction models for adverse events; and 3) a thematic analysis of the participants’ treatment evaluation with a correlational analysis of adverse events and OCD severity. Discussion: The in-depth mixed methods analysis can inform 1) safer and more effective psychotherapy for OCD; 2) instruments and guidelines for monitoring adverse events; and 3) patient information on potential adverse events. The main limitation is risk of missing data. Trial registration: ClinicalTrials.gov identifier: NCT03595098. Registered on July 23, 2018.

Published
2023
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3. Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents: protocol for a randomised clinical trial (the TECTO trial)

Author

Anne Katrine Pagsberg, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Iben Clemmesen, Amanda Aaen Gudmandsen, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Emilie D. Thorsen, Klara Sofie Vangstrup Halberg, Birgitte Bugge, Nina Staal, Helga Kristensen Ingstrup, Birgitte Borgbjerg Moltke, Anne Murphy Kloster, Pernille Juul Zoega, Marie Sommer Mikkelsen, Gitte Sommer Harboe, Katrin Frimann Larsen, Line Katrine Harder Clemmesen, Jane Lindschou, Janus Christian Jakobsen, Janus Engstrøm, Christian Gluud, Hartwig Roman Siebner, Per Hove Thomsen, Katja Hybel, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, and Kerstin Jessica Plessen

Subjects
Obsessive-compulsive disorder, Children, Adolescents, Youth, Cognitive behavioural therapy, Psycho-education and relaxation training, Psychiatry, RC435-571
Abstract

Abstract Background Cognitive behavioural therapy (CBT) is the recommended first-line treatment for children and adolescents with obsessive-compulsive disorder (OCD), but evidence concerning treatment-specific benefits and harms compared with other interventions is limited. Furthermore, high risk-of-bias in most trials prevent firm conclusions regarding the efficacy of CBT. We investigate the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation and relaxation training (FPRT) in youth with OCD in a trial designed to reduce risk-of-bias. Methods This is an investigator-initiated, independently funded, single-centre, parallel group superiority randomised clinical trial (RCT). Outcome assessors, data managers, statisticians, and conclusion drawers are blinded. From child and adolescent mental health services we include patients aged 8–17 years with a primary OCD diagnosis and an entry score of ≥16 on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We exclude patients with comorbid illness contraindicating trial participation; intelligence quotient

Published
2022
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4. Associations Between the Severity of Obsessive-Compulsive Disorder and Vocal Features in Children and Adolescents: Protocol for a Statistical and Machine Learning Analysis

Author

Line Katrine Harder Clemmensen, Nicole Nadine Lønfeldt, Sneha Das, Nicklas Leander Lund, Valdemar Funch Uhre, Anna-Rosa Cecilie Mora-Jensen, Linea Pretzmann, Camilla Funch Uhre, Melanie Ritter, Nicoline Løcke Jepsen Korsbjerg, Julie Hagstrøm, Christine Lykke Thoustrup, Iben Thiemer Clemmesen, Kersten Jessica Plessen, and Anne Katrine Pagsberg

Subjects
Medicine, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

BackgroundArtificial intelligence tools have the potential to objectively identify youth in need of mental health care. Speech signals have shown promise as a source for predicting various psychiatric conditions and transdiagnostic symptoms. ObjectiveWe designed a study testing the association between obsessive-compulsive disorder (OCD) diagnosis and symptom severity on vocal features in children and adolescents. Here, we present an analysis plan and statistical report for the study to document our a priori hypotheses and increase the robustness of the findings of our planned study. MethodsAudio recordings of clinical interviews of 47 children and adolescents with OCD and 17 children and adolescents without a psychiatric diagnosis will be analyzed. Youths were between 8 and 17 years old. We will test the effect of OCD diagnosis on computationally derived scores of vocal activation using ANOVA. To test the effect of OCD severity classifications on the same computationally derived vocal scores, we will perform a logistic regression. Finally, we will attempt to create an improved indicator of OCD severity by refining the model with more relevant labels. Models will be adjusted for age and gender. Model validation strategies are outlined. ResultsSimulated results are presented. The actual results using real data will be presented in future publications. ConclusionsA major strength of this study is that we will include age and gender in our models to increase classification accuracy. A major challenge is the suboptimal quality of the audio recordings, which are representative of in-the-wild data and a large body of recordings collected during other clinical trials. This preregistered analysis plan and statistical report will increase the validity of the interpretations of the upcoming results. International Registered Report Identifier (IRRID)DERR1-10.2196/39613

Published
2022
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5. Synaptic processes and immune-related pathways implicated in Tourette syndrome

Author

Fotis Tsetsos, Dongmei Yu, Jae Hoon Sul, Alden Y. Huang, Cornelia Illmann, Lisa Osiecki, Sabrina M. Darrow, Matthew E. Hirschtritt, Erica Greenberg, Kirsten R. Muller-Vahl, Manfred Stuhrmann, Yves Dion, Guy A. Rouleau, Harald Aschauer, Mara Stamenkovic, Monika Schlögelhofer, Paul Sandor, Cathy L. Barr, Marco A. Grados, Harvey S. Singer, Markus M. Nöthen, Johannes Hebebrand, Anke Hinney, Robert A. King, Thomas V. Fernandez, Csaba Barta, Zsanett Tarnok, Peter Nagy, Christel Depienne, Yulia Worbe, Andreas Hartmann, Cathy L. Budman, Renata Rizzo, Gholson J. Lyon, William M. McMahon, James R. Batterson, Danielle C. Cath, Irene A. Malaty, Michael S. Okun, Cheston Berlin, Douglas W. Woods, Paul C. Lee, Joseph Jankovic, Mary M. Robertson, Donald L. Gilbert, Lawrence W. Brown, Barbara J. Coffey, Andrea Dietrich, Pieter J. Hoekstra, Samuel Kuperman, Samuel H. Zinner, Michael Wagner, James A. Knowles, A. Jeremy Willsey, Jay A. Tischfield, Gary A. Heiman, Nancy J. Cox, Nelson B. Freimer, Benjamin M. Neale, Lea K. Davis, Giovanni Coppola, Carol A. Mathews, Jeremiah M. Scharf, Peristera Paschou, on behalf of the Tourette Association of America International Consortium for Genetics, Sabrina Darrow, Roger Kurlan, James F. Leckman, Jan H. Smit, the Gilles de la Tourette GWAS Replication Initiative, Harald Aschauer Harald Aschauer, Anastasios Konstantinidis, Kirsten Müller-Vahl, Tomasz Wolanczyk, the Tourette International Collaborative Genetics Study, Lawrence Brown, Keun-Ah Cheon, Blanca Garcia-Delgar, Donald Gilbert, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Bennett L. Leventhal, Marcos Madruga-Garrido, Pablo Mir, Astrid Morer, Alexander Münchau, Kerstin J. Plessen, Veit Roessner, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Samuel Zinner, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group, Thomas Fernandez, Gary Heiman, Pieter Hoekstra, Jay Tischfield, and Douglas Woods

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Published
2021
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6. Correction: Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents: protocol for a randomised clinical trial (the TECTO trial)

Author

Anne Katrine Pagsberg, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Iben Clemmesen, Amanda Aaen Gudmandsen, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Emilie D. Thorsen, Klara Sofie Vangstrup Halberg, Birgitte Bugge, Nina Staal, Helga Kristensen Ingstrup, Birgitte Borgbjerg Moltke, Anne Murphy Kloster, Pernille Juul Zoega, Marie Sommer Mikkelsen, Gitte Sommer Harboe, Katrin Frimann Larsen, Line Katrine Harder Clemmensen, Jane Lindschou, Janus Christian Jakobsen, Janus Engstrøm, Christian Gluud, Hartwig Roman Siebner, Per Hove Thomsen, Katja Hybel, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, and Kerstin Jessica Plessen

Subjects
Psychiatry, RC435-571
Published
2022
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7. Yale Global Tic Severity Scale (YGTSS): Psychometric Quality of the Gold Standard for Tic Assessment Based on the Large-Scale EMTICS Study

Author

Martina Haas, Ewgeni Jakubovski, Carolin Fremer, Andrea Dietrich, Pieter J. Hoekstra, Burkard Jäger, Kirsten R. Müller-Vahl, The EMTICS Collaborative Group, Alan Apter, Valentina Baglioni, Juliane Ball, Noa Benaroya-Milshtein, Benjamin Bodmer, Emese Bognar, Bianka Burger, Judith Buse, Francesco Cardona, Marta Correa Vela, Nanette M. Debes, Maria Cristina Ferro, Blanca Garcia-Delgar, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Tammy J. Hedderly, Isobel Heyman, Chaim Huyser, Marcos Madruga-Garrido, Anna Marotta, Davide Martino, Pablo Mir, Astrid Morer, Norbert Müller, Alexander Münchau, Peter Nagy, Valeria Neri, Thaïra J.C. Openneer, Alessandra Pellico, Ángela Periañez Vasco, Kerstin J. Plessen, Cesare Porcelli, Marina Redondo, Renata Rizzo, Veit Roessner, Daphna Ruhrman, Jaana M.L. Schnell, Anette Schrag, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Friederike Tagwerker Gloor, Zsanett Tarnok, Jennifer Tübing, Victoria L. Turner, Susanne Walitza, and Elif Weidinger

Subjects
Tourette's syndrome (TS), YGTSS = Yale Global Tic Severity Scale, psychometric properties, internal consistency, confirmatory factor analysis, Psychiatry, RC435-571
Abstract

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Published
2021
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8. The Puzzle of Emotion Regulation: Development and Evaluation of the Tangram Emotion Coding Manual for Children

Author

Julie Hagstrøm, Katrine S. Spang, Bianca Munkebo Christiansen, Katrine Maigaard, Signe Vangkilde, Barbara Hoff Esbjørn, Jens Richardt Møllegaard Jepsen, and Kerstin Jessica Plessen

Subjects
emotion regulation, development, interrater reliability, intrarater reliability, construct validity, convergent validity, Psychiatry, RC435-571
Abstract

The ability to regulate one’s emotions is crucial to engaging successfully in social contexts. Difficulties in emotion regulation are seen in multiple psychiatric disorders, prompting an increased interest in the concept. Suitable methods for assessing emotion regulation, however, are lacking. In this study, we investigated the interrater and intrarater reliability, construct validity, and content validity of a new observational method for evaluating children’s emotion regulation abilities (a complex puzzle task) in a sample of 62 children without psychiatric disorders and 23 children with attention-deficit/hyperactivity disorder (ADHD) aged 7–12, using intra-class correlation coefficients for the reliability analyses and Spearman’s rank-order correlations for analyses of convergent and discriminant validity. A panel of experts examined the content validity of the test, and Mann–Whitney U-tests were used to investigate the ability of the test to differentiate the non-clinical group from the ADHD group. Results showed a high level of interrater and intrarater reliability of the test. There was mixed evidence for convergent and discriminant validity as expected due to the novelty and experimental nature of the test, making it difficult to compare with questionnaire-based measures. Content validity analysis was satisfactory, and the group comparison showed that the test differentiated the groups on the primary outcome measure. Overall, the measure demonstrated high feasibility and satisfactory psychometric properties. The generic nature of the test makes it suitable for use across psychiatric disorders and age groups with potential relevance in both research and clinical settings

Published
2019
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10. Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author

Fotis Tsetsos, Apostolia Topaloudi, Pritesh Jain, Zhiyu Yang, Dongmei Yu, Petros Kolovos, Zeynep Tumer, Renata Rizzo, Andreas Hartmann, Christel Depienne, Yulia Worbe, Kirsten R. Müller-Vahl, Danielle C. Cath, Dorret I. Boomsma, Tomasz Wolanczyk, Cezary Zekanowski, Csaba Barta, Zsofia Nemoda, Zsanett Tarnok, Shanmukha S. Padmanabhuni, Joseph D. Buxbaum, Dorothy Grice, Jeffrey Glennon, Hreinn Stefansson, Bastian Hengerer, Evangelia Yannaki, John A. Stamatoyannopoulos, Noa Benaroya-Milshtein, Francesco Cardona, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Pablo Mir, Astrid Morer, Norbert Mueller, Alexander Munchau, Kerstin J. Plessen, Cesare Porcelli, Veit Roessner, Susanne Walitza, Anette Schrag, Davide Martino, Jay A. Tischfield, Gary A. Heiman, A. Jeremy Willsey, Andrea Dietrich, Lea K. Davis, James J. Crowley, Carol A. Mathews, Jeremiah M. Scharf, Marianthi Georgitsi, Pieter J. Hoekstra, Peristera Paschou, Cathy L. Barr, James R. Batterson, Cheston Berlin, Cathy L. Budman, Giovanni Coppola, Nancy J. Cox, Sabrina Darrow, Yves Dion, Nelson B. Freimer, Marco A. Grados, Erica Greenberg, Matthew E. Hirschtritt, Alden Y. Huang, Cornelia Illmann, Robert A. King, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. McMahon, Benjamin M. Neale, Michael S. Okun, Lisa Osiecki, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan H. Smit, Jae Hoon Sul, Christos Androutsos, Entela Basha, Luca Farkas, Jakub Fichna, Piotr Janik, Mira Kapisyzi, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Joanna Puchala, Natalia Szejko, Urszula Szymanska, Vaia Tsironi, Alan Apter, Juliane Ball, Benjamin Bodmer, Emese Bognar, Judith Buse, Marta Correa Vela, Carolin Fremer, Blanca Garcia-Delgar, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Marcos Madruga-Garrido, Alessandra Pellico, Daphna Ruhrman, Jaana Schnell, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Friederike Tagwerker Gloor, Victoria L. Turner, Elif Weidinger, John Alexander, Tamas Aranyi, Wim R. Buisman, Jan K. Buitelaar, Nicole Driessen, Petros Drineas, Siyan Fan, Natalie J. Forde, Sarah Gerasch, Odile A. van den Heuvel, Cathrine Jespersgaard, Ahmad S. Kanaan, Harald E. Möller, Muhammad S. Nawaz, Ester Nespoli, Luca Pagliaroli, Geert Poelmans, Petra J.W. Pouwels, Francesca Rizzo, Dick J. Veltman, Ysbrand D. van der Werf, Joanna Widomska, Nuno R. Zilhäo, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Thomas V. Fernandez, Donald L. Gilbert, Hyun Ju Hong, Laura Ibanez-Gomez, Eun-Joo Kim, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L. Leventhal, Athanasios Maras, Tara L. Murphy, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Matthew W. State, Frank Visscher, Sheng Wang, Samuel H. Zinner, Psychiatry, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Systems & Network Neuroscience, Biological Psychology, and Amsterdam Reproduction & Development

Subjects
meta-analysis, Medizin, GWAS, Biological Psychiatry, NR2F1, Tourette Syndrome
Abstract

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Published
2023

11. Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents (the TECTO trial):a statistical analysis plan for the randomised clinical trial

Author

Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Janus Engstrøm, Jane Lindschou, Hartwig Roman Siebner, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Per Hove Thomsen, Katja Hybel, Line Katrine Harder Clemmesen, Christian Gluud, Kerstin Jessica Plessen, Anne Katrine Pagsberg, and Janus Christian Jakobsen

Subjects
Obsessive-Compulsive Disorder, Statistical analysis plan, Adolescent, Cognitive Behavioral Therapy, Family-based psychoeducation/relaxation training, Medicine (miscellaneous), Cognitive behavioural therapy, Relaxation Therapy, Randomised clinical trial, Treatment Outcome, Quality of Life, Obsessive-compulsive disorder, Humans, Pharmacology (medical), Family Therapy, Child
Abstract

Background Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder which affects up to 3% of children and adolescents. OCD in children and adolescents is generally treated with cognitive behavioural therapy (CBT), which, in more severely affected patients, can be combined with antidepressant medication. The TECTO trial aims to compare the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation/relaxation training (FPRT) in children and adolescents aged 8 to 17 years. This statistical analysis plan outlines the planned statistical analyses for the TECTO trial. Methods The TECTO trial is an investigator-initiated, independently funded, single-centre, parallel-group, superiority randomised clinical trial. Both groups undergo 14 sessions of 75 min each during a period of 16 weeks with either FCBT or FPRT depending on the allocation. Participants are randomised stratified by age and baseline Children’s Yale–Brown Obsessive-Compulsive Scale (CY-BOCS) score. The primary outcome is the CY-BOCS score. Secondary outcomes are health-related quality of life assessed using KIDSCREEN-10 and adverse events assessed by the Negative Effects Questionnaire (NEQ). Primary and secondary outcomes are assessed at the end of the intervention. Continuous outcomes will be analysed using linear regression adjusted for the stratification variables and baseline value of the continuous outcome. Dichotomous outcomes will be analysed using logistic regression adjusted for the stratification variables. The statistical analyses will be carried out by two independent blinded statisticians. Discussion This statistical analysis plan includes a detailed predefined description of how data will be analysed and presented in the main publication before unblinding of study data. Statistical analysis plans limit selective reporting bias. This statistical analysis plan will increase the validity of the final trial results. Trial registration ClinicalTrials.gov NCT03595098. July 23, 2018

Published
2022

12. Investigation of gene-environment interactions in relation to tic severity

Author

Frank Visscher, Kerstin J. Plessen, Tammy Hedderly, Jungeun Song, Bennett L. Leventhal, Eun-Young Shin, Lawrence W. Brown, Alexander Münchau, Robert A. King, Young Key Kim, Young Shin Kim, Veit Roessner, Andrea Dietrich, Samuel Kuperman, Thomas V. Fernandez, Keun-Ah Cheon, Carol A. Mathews, Athanasios Maras, Donald L. Gilbert, Yun-Joo Koh, Laura Ibanez-Gomez, Dongmei Yu, Astrid Morer, Sodahm Kook, Marcos Madruga-Garrido, Julie Hagstrøm, Dorothy E. Grice, Jay A. Tischfield, Lisa Osiecki, Mohamed Abdulkadir, Blanca Garcia-Delgar, Samuel H. Zinner, Chaim Huyser, Barbara J. Coffey, Dong-Ho Song, Gary A. Heiman, Pieter J. Hoekstra, Hyun Ju Hong, Pablo Mir, Isobel Heyman, Jeremiah M. Scharf, National Institute of Mental Health (US), Tourette Syndrome Association of New Jersey, Judah Foundation, Tourette Association of America, National Institutes of Health (US), Instituto de Salud Carlos III, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Jacques and Gloria Gossweiler Foundation, Generalitat de Catalunya, German Research Foundation, National Institute of Environmental Health Sciences (US), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Child Psychiatry, Paediatric Psychosocial Care, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
Candidate gene, Tic severity, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), Single-nucleotide polymorphism, Genome-wide association study, Neurodegenerative, Tourette syndrome, Severity of Illness Index, Attention Deficit Disorder with Hyperactivity/genetics, Autism Spectrum Disorder/genetics, Female, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Pregnancy, Tics, Tourette Syndrome, Gene–environment interaction, Pre- and perinatal complications, mental disorders, medicine, Genetics, SNP, 2.1 Biological and endogenous factors, Psychology, Aetiology, Biological Psychiatry, Genetic association, Pediatric, Neurology & Neurosurgery, business.industry, Psychiatry and Preclinical Psychiatric Studies - Original Article, Human Genome, Neurosciences, medicine.disease, Serious Mental Illness, Gene-environment interaction, Brain Disorders, Psychiatry and Mental health, Mental Health, Neurology, Autism spectrum disorder, Attention Deficit Disorder with Hyperactivity, Neurology (clinical), business
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies., This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462).

Published
2021

13. Vitamin D levels in children and adolescents with chronic tic disorders: a multicentre study

Author

Molly, Bond, Natalie, Moll, Alicia, Rosello, Rod, Bond, Jaana, Schnell, Bianka, Burger, Pieter, J Hoekstra, Andrea, Dietrich, Anette, Schrag, Eva, Kocovska, Martino, Davide, Norbert, Mueller, Markus, Schwarz, Ute-Christiane, Meier, EMTICS Collaborative Group: Alan Apter, Baglioni, Valentina, Juliane, Ball, Noa, Benaroya-Milshtein, Benjamin, Bodmer, Emese, Bognar, Judith, Buse, Cardona, Francesco Carmelo Giovanni, Marta Correa Vela, Nanette, M Debes, Maria Cristina Ferro, Carolin, Fremer, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Tammy, J Hedderly, Isobel, Heyman, Chaim, Huyser, Marcos, Madruga-Garrido, Anna, Marotta, Pablo, Mir, Astrid, Morer, Norbert, Müller, Kirsten, R Müller-Vahl, Alexander, Münchau, Peter, Nagy, Neri, Valeria, Thaïra Jc Openneer, Pellico, Alessandra, Ángela Periañez Vasco, Kerstin, J Plessen, Cesare, Porcelli, Marina, Redondo, Rizzo, Renata, Veit, Roessner, Daphna, Ruhrman, Jaana Ml Schnell, Silvestri, PAOLA ROSARIA, Liselotte, Skov, Tamar, Steinberg, Friederike Tagwerker Gloor, Zsanett, Tarnok, Jennifer, Tübing, Victoria, L Turner, Susanne, Walitza, Elif, Weidinger, Clinical Cognitive Neuropsychiatry Research Program (CCNP), EMTICS Collaborative Group, Bruun, J.E., Grejsen, J., Ommundsen, C.L., Rubæk, M., Enghardt, S., Bokemeyer, S., Driedger-Garbe, C., Reichert, C., Schmalfeld, J., Duffield, T., Gergye, F., Kovacs, M., Vidomusz, R., Carmel, M., Fennig, S., Gev, E., Keller, N., Michaelovsky, E., Nahon, M., Regev, C., Simcha, T., Smollan, G., Weizman, A., Gagliardi, G., Tallon, M., Roazzi, P., van den Ban, E., de Bruijn, SFTM, Driessen, N., Lamerz, A., Messchendorp, M., Rath, JJG, Sival, NSD, Tromp, N., Visscher, F., de la Tourettes, S.G., Cáceres, M.T., Carrillo, F., Gómez-Garre, P., Vargas, L., Gariup, M., Stöber, S., Apter, A., Baglioni, V., Ball, J., Benaroya-Milshtein, N., Bodmer, B., Bond, M., Bognar, E., Burger, B., Buse, J., Cardona, F., Vela, M.C., Dietrich, A., Debes, N.M., Ferro, M.C., Fremer, C., Garcia-Delgar, B., Gulisano, M., Hagen, A., Hagstrøm, J., Hedderly, T.J., Heyman, I., Hoekstra, P.J., Huyser, C., Madruga-Garrido, M., Marotta, A., Martino, D., Meier, U.C., Mir, P., Moll, N., Morer, A., Mueller, N., Müller-Vahl, K., Münchau, A., Nagy, P., Neri, V., Openneer, TJC, Pellico, A., Vasco, Á.P., Plessen, K.J., Porcelli, C., Redondo, M., Rizzo, R., Roessner, V., Ruhrman, D., Schnell, JML, Schrag, A., Schwarz, M.J., Silvestri, P.R., Skov, L., Steinberg, T., Gloor, F.T., Tarnok, Z., Tübing, J., Turner, V.L., Walitza, S., Weidinger, E., and Woods, M.L.

Subjects
Obsessive-Compulsive Disorder, Tic disorder, medicine.medical_specialty, Adolescent, Tics, Comorbidity, Severity of Illness Index, Pediatrics, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, Developmental and Educational Psychology, medicine, Child and adolescent psychiatry, Vitamin D and neurology, Humans, ADHD, Vitamin D, Child, OCD, business.industry, Tourette, Symptom severity, General Medicine, Attention Deficit Disorder with Hyperactivity/psychology, Cross-Sectional Studies, Obsessive-Compulsive Disorder/epidemiology, Obsessive-Compulsive Disorder/psychology, Tic Disorders/metabolism, Tic Disorders/psychology, Tics/complications, Tics/metabolism, Tourette Syndrome/psychology, Vitamin D/metabolism, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, Tic Disorders, Pediatrics, Perinatology and Child Health, Cohort, CTD, business, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3–16 years) with CTD (n = 327); first-degree relatives (3–10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive–compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27–3.42, p p = 0.01) and was inversely associated with ADHD symptom severity (β = − 2.52, 95% CI − 4.16–0.88, p

Published
2022

14. Hair cortisol-a stress marker in children and adolescents with chronic tic disorders? A large European cross-sectional study

Author

Judith, Buse, Josefine, Rothe, Anne, Uhlmann, Benjamin, Bodmer, Clemens, Kirschbaum, Hoekstra, Pieter J., Andrea, Dietrich, Veit, Roessner, EMTICS collaborative group: Alan Apter, Baglioni, Valentina, Juliane, Ball, Noa, Benaroya-Milshtein, Emese, Bognar, Bianka, Burger, Cardona, Francesco Carmelo Giovanni, Marta Correa Vela, Maria Cristina Ferro, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Hedderly, Tammy J., Isobel, Heyman, Chaim, Huyser, Marcos, Madruga-Garrido, Martino, Davide, Pablo, Mir, Astrid, Morer, Kirsten, Müller-Vahl, Alexander, Münchau, Peter, Nagy, Neri, Valeria, Openneer, Thaïra J. C., Pellico, Alessandra, Plessen, Kerstin J., Cesare, Porcelli, Rizzo, Renata, Daphna, Ruhrman, Schnell, Jaana M. L., Anette, Schrag, Silvestri, PAOLA ROSARIA, Liselotte, Skov, Tamar, Steinberg, Friederike Tagwerker Gloor, Zsanett Tarnok &amp, Elif, Weidinger, EMTICS collaborative group, Apter, A., Baglioni, V., Ball, J., Benaroya-Milshtein, N., Bodmer, B., Bognar, E., Burger, B., Buse, J., Cardona, F., Vela, M.C., Dietrich, A., Ferro, M.C., Garcia-Delgar, B., Gulisano, M., Hagen, A., Hagstrøm, J., Hedderly, T.J., Heyman, I., Hoekstra, P.J., Huyser, C., Madruga-Garrido, M., Martino, D., Mir, P., Morer, A., Müller-Vahl, K., Münchau, A., Nagy, P., Neri, V., Openneer, TJC, Pellico, A., Plessen, K.J., Porcelli, C., Rizzo, R., Roessner, V., Ruhrman, D., Schnell, JML, Schrag, A., Silvestri, P.R., Skov, L., Steinberg, T., Gloor, F.T., Tarnok, Z., Weidinger, E., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
BIOMARKER, medicine.medical_specialty, Adolescent, Hydrocortisone, GENETICS, Tics, RESPONSIVITY, Cross-sectional study, Chronic tic disorders, Emotional and behavioral problems, Physiological stress marker, Psychosocial stress, Tourette, Tourette syndrome, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Child, Cross-Sectional Studies, Hair, Humans, Tic Disorders/diagnosis, Developmental and Educational Psychology, Child and adolescent psychiatry, Medicine, ASSOCIATIONS, business.industry, TOURETTE-SYNDROME, Stressor, OBSESSIVE-COMPULSIVE DISORDER, General Medicine, medicine.disease, PREVALENCE, 030227 psychiatry, INDIVIDUALS, Psychiatry and Mental health, PSYCHOMETRIC PROPERTIES, Tic Disorders, Pediatrics, Perinatology and Child Health, Cohort, Biomarker (medicine), STRENGTHS, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Background There is clear evidence that tic disorders (TDs) are associated with psychosocial stress as well as emotional and behavioral problems. Studies have shown that individuals with TDs have higher acute physiological stress responses to external, single stressors (as reflected by saliva cortisol). The aim of the present study was to examine a physiological marker of longer-term stress (as reflected by hair cortisol concentration) in children and adolescents with TDs and unaffected siblings of individuals with TDs. Methods Two samples of a European cohort were included in this study. In the COURSE sample, 412 children and adolescents aged 3–16 years with a chronic TD including Tourette syndrome according to DSM IV-TR criteria were included. The ONSET sample included 131 3–10 years old siblings of individuals with TDs, who themselves had no tics. Differences in hair cortisol concentration (HCC) between the two samples were examined. Within the COURSE sample, relations of HCC with tic severity and perceived psychosocial stress as well as potential effects and interaction effects of comorbid emotional and behavioral problems and psychotropic medication on HCC were investigated. Results There were no differences in HCC between the two samples. In participants with TDs, there were no associations between HCC and tic severity or perceived psychosocial stress. No main effects of sex, psychotropic medication status and comorbid emotional and behavioral problems on HCC were found in participants with TDs. Conclusion A link between HCC and TDs is not supported by the present results.

Published
2021

15. Associations between OCD severity and vocal features in children and adolescents: A statistical and machine learning analysis plan (Preprint)

Author

Line K. H. Clemmensen, Nicole Lønfeldt, Sneha Das, Nicklas Leander Lund, Valdemar Uhre, A.R. Cecilie Mora-Jensen, Linea Pretzman, Camilla Funch Uhre, Melanie Ritter, Nicoline Løcke Jepsen Korsbjerg, Julie Hagstrøm, Christine Lykke Thoustrup, Iben Clemmensen, Kersten Jessica Plessen, and Anne Pagsberg

Abstract

UNSTRUCTURED Artificial intelligence (AI) tools have the potential to objectively identify youth in need of mental health care. Speech signals have demonstrated promise as a source for predicting various psychiatric conditions and transdiagnostic symptoms. Thus, we designed a study testing the association between obsessive compulsive disorder (OCD) diagnosis and symptom severity on vocal features in children and adolescents. Here, we present an analysis plan and statistical report for the study. Audio recordings of clinical interviews of 15 children and adolescents with OCD and 15 children and adolescents without a psychiatric diagnosis will be analyzed. Youth were between 8 and 17 years old. We will test the effect of OCD diagnosis on computationally-derived scores of vocal activation and valence using an analysis of variance. To test the effect of OCD severity classifications on the same computationally-derived vocal scores, we will use logistic regression. Finally, we attempt to create an improved indicator of OCD severity by refining the model with more relevant labels. Models will be adjusted for age and gender. Model validation strategies are outlined. A major strength is that we include age and gender in our models to increase classification accuracy. A major challenge is the suboptimal quality of the audio recordings, which are representative of in-the-wild data and a large body of recordings collected during other clinical trials. This pre-registered analysis plan and statistical report will increase validity of the interpretations of the coming results.

Published
2022

16. Emotion regulation in 7-year-old children with familial high risk for schizophrenia or bipolar disorder compared to controls - The Danish High Risk and Resilience Study - VIA 7, a population-based cohort study

Author

Katrine Søborg Spang, Julie Hagstrøm, Ditte Ellersgaard, Camilla Christiani, Nicoline Hemager, Birgitte Klee Burton, Aja Neergaard Greve, Kirsten Rohr, Ditte Gantriis, Signe Vangkilde, Ole Mors, Merete Nordentoft, Carsten Obel, Kerstin Jessica Plessen, Jens Richardt Møllegaard Jepsen, and Anne A. E. Thorup

Subjects
bipolar disorder, emotion regulation, familial high risk, Bipolar Disorder, offspring, Denmark, General Medicine, schizophrenia spectrum psychosis, Emotional Regulation, Cohort Studies, Clinical Psychology, Schizophrenia, Humans, Child
Abstract

OBJECTIVES: Emotion regulation is a predictor of overall life outcome. Problems of emotion regulation are associated with multiple psychiatric disorders and could be a potential treatment target for improving well-being and functioning. Children at familial high risk of severe mental illness have a markedly increased risk of various psychopathology and constitute a group at significant risk of emotion regulation problems. Investigations of emotion regulation in children at familial high risk of severe mental illness are sparse.METHODS: We applied an instrument for assessing emotion regulation, the Tangram Emotion Coding Manual (TEC-M), to a population-based cohort of 522 7-year-old children born to parents diagnosed with either schizophrenia or bipolar disorder and matched controls. The TEC-M is an ecologically valid, clinician-rated observational test measure of spontaneous emotion regulation. We aimed to compare emotion regulation between risk groups and to investigate associations between emotion regulation and psychopathology and daily life functioning, and between emotion regulation and an acknowledged questionnaire-based dysregulation profile.RESULTS: In this early developmental phase, we found no between group differences in emotion regulation. We found a significant but weak negative association between emotion regulation and both child psychopathology and the presence of a dysregulation profile on the Child Behavior Checklist and a weak positive association between emotion regulation and current level of functioning.CONCLUSIONS: These findings contribute to the understanding of emotion regulation in familial high-risk children and further studies of emotion regulation in children at familial high risk of severe mental illness are warranted.

Published
2022

17. Transforming Motivation for Exercise in a Safe and Kind Environment—A Qualitative Study of Experiences among Individuals with Type 2 Diabetes

Author

Nielsen, Susanne Grøn, Danielsen, Julie Hagstrøm, Grønbæk, Helle Nergaard, Molsted, Stig, Jacobsen, Sandra Schade, Vilsbøll, Tina, Varming, Annemarie Reinhardt, Nielsen, Susanne Grøn, Danielsen, Julie Hagstrøm, Grønbæk, Helle Nergaard, Molsted, Stig, Jacobsen, Sandra Schade, Vilsbøll, Tina, and Varming, Annemarie Reinhardt

Abstract

Exercise is a cornerstone in diabetes care; however, adherence is low and sustaining physical activity remains a challenge. Patient-centered diabetes self-management education and support are recommended; however, sparse literature exists on how to design exercise interventions that improve self-management in individuals with complications of type 2 diabetes mellitus (T2D). We aimed to gain insights into needs, barriers, and motivation based on experiences with exercise participation among individuals with T2D and complications to adjust and develop new types of tailored, supervised exercise classes in specialized care at three hospitals in Denmark. In keeping with a constructivist research paradigm, a qualitative hermeneutic approach using focus group interviews was applied to explore perspectives among different participants in terms of disease severity. Seven interviews with 30 participants (aged 49–88) representing seven different exercise classes, were conducted over three years. Reflective thematic analysis was used. Four themes were generated: People like us, Getting started with exercise, Game changers, and Moving forward. An overarching theme ‘The transformation of motivation when exercising in a safe and kind environment’ links the themes together, resembling the participants’ development of physical literacy encompassing motivation, confidence, physical competence as well as an ability to value physical activity. Supportive patient-centered exercise classes promoted a transformation of motivation grounded in the development of physical literacy among participants in specialized diabetes care. However, participants were concerned with continuing to exercise on their own after the intervention, as they experienced a lack of continuous, supervised exercise opportunities in local communities.

Published
2022

18. Effectiveness and acceptability of a pragmatic exercise intervention for patients with type 2 diabetes in specialized care

Author

Nielsen, Susanne Grøn, Danielsen, Julie Hagstrøm, Jacobsen, Sandra Schade, Kristensen, Peter Lommer, Storgaard, Heidi, Mølsted, Stig, Vilsbøll, Tina, Nielsen, Susanne Grøn, Danielsen, Julie Hagstrøm, Jacobsen, Sandra Schade, Kristensen, Peter Lommer, Storgaard, Heidi, Mølsted, Stig, and Vilsbøll, Tina

Abstract

Aims: Physical activity improves glycaemic control in type 2 diabetes (T2D), but adherence is low, and diabetes complications are barriers towards adopting physical activity. We investigated adherence and effects of individualized supervised exercise. Methods: Patients with intermediate (level 2) to high (level 3) risk of complications to T2D (stratified by Danish risk stratification model) were offered 12 weeks of exercise. Primary outcomes were working capacity assessed with the Åstrand-Rhyming cycling test (Åstrand), functional capacity assessed with the 30-second chair-stand test (30 s-CST) and health-related quality of life assessed with EuroQoL-5D-5L (EQ-5D-5L). Associations between stratification levels (2 vs 3) and drop-out, changes in 30 s-CST and EQ-5D-5L were analysed using multiple regression. Results: In total 350 patients accepted participation and 254 (73%) completed with 26 patients experiencing an adverse event. Odds ratio (OR) for non-completion were 1.82 [1.02–3.23] (p = 0.043) for patients stratified level 3 vs 2. Improvements were seen in Åstrand 2.71 [1.59; 3.83] ml O2/kg/min (p < 0.001), in 30 s-CST 2.34 [2.01; 2.67] repetitions (p < 0.001) and in EQ-5D-5L 0.01 (−0.05 to 0.11) (p = 0.002). There were no associations between changes and risk-stratification levels. Conclusions: Clinically relevant changes were seen after exercising regardless of the stratification levels in patients with intermediate to high risk of complications to T2D.

Published
2022

19. Anti‐dopamine D2 receptor antibodies in chronic tic disorders

Author

Jennifer Tübing, Thaïra J.C. Openneer, Juliane Ball, Erika Bartolini, Anna Marotta, Giovanni Laviola, Peter Nagy, Marco Tallon, Zsanett Tarnok, Renata Rizzo, Alexander Münchau, Davide Martino, Nanette Mol Debes, Paolo Roazzi, Noa Benaroya-Milshtein, Isobel Heyman, Maria Cristina Ferro, Marianthi Georgitsi, Mariangela Gulisano, Julie Hagstrøm, Angela Periañez, Alan Apter, Liselotte Skov, Benjamin Bodmer, Zacharias Anastasiou, Daphna Ruhrman, Veit Roessner, Vasco Alessandra Pellico, Androulla Efstratiou, Annelieke Hagen, Francesco Addabbo, Kerstin J. Plessen, Immaculada Margarit, Carolin Fremer, Anette Schrag, Marta Correa Vela, Bianka Burger, Marcos Madruga-Garrido, Elif Weidinger, Onofrio Petruzzelli, Ute C. Meier, Friederike Tagwerker Gloor, Blanca Garcia-Delgar, Jaana M. L. Schnell, Marina Redondo, Sara Stöber, Francesco Cardona, Simone Macrì, Valeria Neri, Natalie Moll, Paola R. Silvestri, Pablo Mir, Graziella Orefici, Maura Buttiglione, Pieter J. Hoekstra, Cesare Porcelli, Emese Bognar, Astrid Morer, Susanne Walitza, Iordanis Karagiannidis, Monica Imperi, Markus J. Schwarz, Judith Buse, Valentina Baglioni, Chaim Huyser, Roberta Creti, Andrea Dietrich, Gregor A. Schütze, Tamar Steinberg, Peristera Paschou, Maria Gariup, Tammy Hedderly, Kirsten R. Müller-Vahl, Victoria Turner, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Child Psychiatry, and ANS - Cellular & Molecular Mechanisms

Subjects
tourette syndrome, Male, 030506 rehabilitation, medicine.medical_specialty, Adolescent, Tics, Exacerbation, antiD2R antibodies, Logistic regression, Tourette syndrome, MOVEMENT, 03 medical and health sciences, GPCR, 0302 clinical medicine, McNemar's test, Developmental Neuroscience, tic exacerbations, Internal medicine, medicine, Humans, Child, Autoantibodies, Receptors, Dopamine D2, business.industry, Confounding, Autoantibody, Odds ratio, medicine.disease, tourette syndrome, antiD2R antibodies, tic exacerbations, Child, Preschool, Tic Disorders, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract

AIM To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). METHOD One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. RESULTS At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p

Published
2020

20. Inhibitory Control in Children with Tourette Syndrome Is Impaired in Everyday Life but Intact during a Stop Signal Task

Author

Melanie Ritter, Signe Allerup Vangkilde, Katrine Maigaard, Anne Katrine Pagsberg, Kerstin Jessica Plessen, and Julie Hagstrøm

Subjects
inhibitory control, mental disorders, Tourette Syndrome, ADHD, stop signal task, Medicine, General Medicine, Inhibitory control, Stop signal task, behavioral disciplines and activities, Article
Abstract

Tourette Syndrome (TS) has previously been associated with deficits in inhibitory control (IC). However, studies on IC in individuals with TS have produced conflicting results. In the present study, we investigated IC, comparing the Stop Signal Reaction Time (SSRT) measure with parent and teacher ratings of daily life IC in 169 children aged 8–12 (60 with TS, 60 typically developing controls, 27 with attention-deficit/hyperactivity disorder (ADHD), and 22 with TS + ADHD). We further investigated associations of IC with TS and ADHD symptom severity. Children with TS showed intact SSRT performance, but impairments in daily life IC, as reported by parents and teachers. For the latter, we observed a staircase distribution of groups, with the healthy controls presenting with the best IC, followed by TS, TS + ADHD, and finally ADHD. Dimensional analyses indicated a strong association between ADHD severity and both measures of IC. Our results indicate that children with TS are not impaired in a laboratory-based measure of IC, although some difficulties were evident from measures of everyday behaviour, which may in part be due to parents and teachers interpreting tics as disinhibited behaviour. Comorbid ADHD or the severity of subthreshold ADHD symptomatology appeared to account for IC deficits.

Published
2022

21. Tic disorders in children and adolescents: does the clinical presentation differ in males and females? A report by the EMTICS group

Author

Blanca, Garcia‐delgar, Mateu, Servera, Coffey, Barbara J., Luisa, Lázaro, Thaïra, Openneer, Noa, Benaroya‐milshtein, Tami, Steinberg, Hoekstra, Pieter J., Andrea, Dietrich, Astrid Morer EMTICS collaborative group Alan Apter, Baglioni, Valentina, Juliane, Ball, Noa, Benaroya-Milshtein, Emese, Bognar, Bianka, Burger, Judith, Buse, Cardona, Francesco Carmelo Giovanni, Marta Correa Vela, Debes, Nanette M., Maria Cristina Ferro, Carolin, Fremer, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Hedderly, Tammy J., Isobel, Heyman, Chaim, Huyser, Marcos, Madruga-Garrido, Anna, Marotta, Martino, Davide, Pablo, Mir, Astrid, Morer, Norbert, Müller, Kirsten, Müller-Vahl, Alexander, Münchau, Peter, Nagy, Neri, Valeria, Openneer, Thaïra J. C., Pellico, Alessandra, Plessen, Kerstin J., Cesare, Porcelli, Rizzo, Renata, Veit, Roessner, Daphna, Ruhrman, Schnell, Jaana M. L., Silvestri, PAOLA ROSARIA, Liselotte, Skov, Tamar, Steinberg, Friederike Tagwerker Gloor, Zsanett, Tarnok, Susanne Walitza &amp, Elif, Weidinger, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Child Psychiatry, Child and Adolescent Psychiatry & Psychosocial Care, and ANS - Cellular & Molecular Mechanisms

Subjects
Male, Pediatrics, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Younger age, Tics, Adolescent, Autism Spectrum Disorder, Comorbidity, Adolescents, Tourette syndrome, Severity of Illness Index, Limited access, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Sex differences, Developmental and Educational Psychology, Child and adolescent psychiatry, Medicine, Humans, 0501 psychology and cognitive sciences, 10. No inequality, Child, Children, business.industry, 05 social sciences, General Medicine, medicine.disease, 030227 psychiatry, body regions, Psychiatry and Mental health, Autism spectrum disorder, Attention Deficit Disorder with Hyperactivity, Tic Disorders, Pediatrics, Perinatology and Child Health, Female, Presentation (obstetrics), business, human activities, 050104 developmental & child psychology, Male predominance
Abstract

Tic disorders have a strong male predominance, with a male-to-female ratio of 4:1 in Tourette syndrome (TS) and 2:1 in persistent tic disorders. In other neurodevelopmental conditions, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), the disparity in sex distribution has been partially related to differences in symptom presentation between males and females. In tic disorders, however, little research has been conducted on this topic, probably due to the limited access to large samples with a significant proportion of females. The aim of this study was to describe sex differences in the clinical presentation of tic disorders in children and adolescents in one of the largest pediatric samples with TS/persistent tic disorders (n = 709, 23.3% females) recruited as part of the European Multicenter Tics in Children Study (EMTICS). Validated measures assessed the severity of tics and comorbid psychiatric symptoms. Using mixed-effect models, we found that sex had a significant influence on the severity of tics, ADHD symptoms, ASD symptoms, and emotional problems. Males had more severe symptoms than females, except for emotional problems. We also observed a statistically significant interaction between sex and age on the severity of tics and compulsions, with females showing higher symptom severity with increasing age than males. These findings indicate that the clinical presentation of TS/persistent tic disorders varies with sex. Males seem to exhibit a more noticeable pattern of clinical symptoms at a younger age that may contribute to their earlier detection in comparison to females.

Published
2022

22. Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study

Author

Anette-Eleonore, Schrag, Martino, Davide, Hanyuying, Wang, Gareth, Ambler, Noa, Benaroya-Milstein, Maura, Buttiglione, Cardona, Francesco Carmelo Giovanni, Roberta, Creti, Androulla, Efstratiou, Tammy, Hedderly, Isobel, Heyman, Chaim, Huyser, Pablo, Mir, Astrid, Morer, Natalie, Moll, Norbert, E Müller, Kirsten, R Müller-Vahl, Kerstin, J Plessen, Cesare, Porcelli, Rizzo, Renata, Veit, Roessner, Markus, Schwarz, Zsanett, Tarnok, Susanne, Walitza, Andrea, Dietrich, Pieter, J Hoekstra Alan Apter, Baglioni, Valentina, Juliane, Ball, Noa, Benaroya-Milshtein, Benjamin, Bodmer, Emese, Bognar, Bianka, Burger, Judith, Buse, Marta Correa Vela, Nanette, M Debes, Maria Cristina Ferro, Carolin, Fremer, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Tammy, J Hedderly, Pieter, J Hoekstra, Marcos, Madruga-Garrido, Anna, Marotta, Norbert, Müller, Alexander, Münchau, Peter, Nagy, Neri, Valeria, Thaïra Jc Openneer, Pellico, Alessandra, Ángela Periañez Vasco, Marina, Redondo, Daphna, Ruhrman, Jaana Ml Schnell, Anette, Schrag, Silvestri, PAOLA ROSARIA, Liselotte, Skov, Tamar, Steinberg, Friederike Tagwerker Gloor, Jennifer, Tübing, Victoria, L Turner, and Elif, Weidinger

Subjects
Neuroimmunity, Neuroinflammation, Tic Disorders, Streptococcal infections
Published
2022

23. Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents:protocol for a randomised clinical trial (the TECTO trial)

Author

Anne Katrine Pagsberg, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Iben Clemmesen, Amanda Aaen Gudmandsen, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Emilie D. Thorsen, Klara Sofie Vangstrup Halberg, Birgitte Bugge, Nina Staal, Helga Kristensen Ingstrup, Birgitte Borgbjerg Moltke, Anne Murphy Kloster, Pernille Juul Zoega, Marie Sommer Mikkelsen, Gitte Sommer Harboe, Katrin Frimann Larsen, Line Katrine Harder Clemmensen, Jane Lindschou, Janus Christian Jakobsen, Janus Engstrøm, Christian Gluud, Hartwig Roman Siebner, Per Hove Thomsen, Katja Hybel, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, and Kerstin Jessica Plessen

Subjects
Obsessive-Compulsive Disorder, Youth, Cognitive Behavioral Therapy, Adolescent, Obsessive-Compulsive Disorder/psychology, Cognitive Behavioral Therapy/methods, Cognitive behavioural therapy, Relaxation Therapy, Adolescents, behavioral disciplines and activities, Randomised clinical trial, Treatment effects, Psychiatry and Mental health, Treatment Outcome, SDG 3 - Good Health and Well-being, Psycho-education and relaxation training, mental disorders, Outcome Assessment, Health Care, Obsessive-compulsive disorder, Humans, Family Therapy, Child, Children, Randomized Controlled Trials as Topic
Abstract

Background Cognitive behavioural therapy (CBT) is the recommended first-line treatment for children and adolescents with obsessive-compulsive disorder (OCD), but evidence concerning treatment-specific benefits and harms compared with other interventions is limited. Furthermore, high risk-of-bias in most trials prevent firm conclusions regarding the efficacy of CBT. We investigate the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation and relaxation training (FPRT) in youth with OCD in a trial designed to reduce risk-of-bias. Methods This is an investigator-initiated, independently funded, single-centre, parallel group superiority randomised clinical trial (RCT). Outcome assessors, data managers, statisticians, and conclusion drawers are blinded. From child and adolescent mental health services we include patients aged 8–17 years with a primary OCD diagnosis and an entry score of ≥16 on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We exclude patients with comorbid illness contraindicating trial participation; intelligence quotient Discussion In our trial design we aim to reduce risk-of-bias, enhance generalisability, and broaden the outcome measures by: 1) conducting an investigator-initiated, independently funded RCT; 2) blinding investigators; 3) investigating a representative sample of OCD patients; 3) using an active control intervention (FPRT) to tease apart general and specific therapy effects; 4) using equal dosing of interventions and therapist supervision in both intervention groups; 5) having therapists perform both interventions decided by randomisation; 6) rating fidelity of both interventions; 7) assessing a broad range of benefits and harms with repeated measures. The primary study limitations are the risk of missing data and the inability to blind participants and therapists to the intervention. Trial registration ClinicalTrials.gov: NCT03595098, registered July 23, 2018.

Published
2022

24. Effectiveness and acceptability of a pragmatic exercise intervention for patients with type 2 diabetes in specialized care

Author

Susanne Grøn Nielsen, Julie Hagstrøm Danielsen, Sandra Schade Jacobsen, Peter Lommer Kristensen, Heidi Storgaard, Stig Molsted, and Tina Vilsbøll

Subjects
Endocrinology, Diabetes Mellitus, Type 2, Psychometrics, Endocrinology, Diabetes and Metabolism, Surveys and Questionnaires, Internal Medicine, Quality of Life, Humans, General Medicine, Exercise, Exercise Therapy
Abstract

Physical activity improves glycaemic control in type 2 diabetes (T2D), but adherence is low, and diabetes complications are barriers towards adopting physical activity. We investigated adherence and effects of individualized supervised exercise.Patients with intermediate (level 2) to high (level 3) risk of complications to T2D (stratified by Danish risk stratification model) were offered 12 weeks of exercise. Primary outcomes were working capacity assessed with the Åstrand-Rhyming cycling test (Åstrand), functional capacity assessed with the 30-second chair-stand test(30 s-CST) and health-related quality of life assessed with EuroQoL-5D-5L (EQ-5D-5L). Associations between stratification levels (2vs3) and drop-out, changes in 30 s-CST and EQ-5D-5L were analysed using multiple regression.In total 350 patients accepted participation and 254 (73%) completed with 26 patients experiencing an adverse event. Odds ratio (OR) for non-completion were 1.82 [1.02-3.23] (p = 0.043) for patients stratified level 3 vs 2.Improvements were seen in Åstrand 2.71 [1.59; 3.83] ml OClinically relevant changes were seen after exercising regardless of the stratification levels in patients with intermediate to high risk of complications to T2D.

Published
2021

25. European Multicentre Tics in Children Studies (EMTICS)

Author

Schrag, A, Martino, D, Apter, A, Ball, J, Bartolini, E, Benaroya-Milshtein, N, Buttiglione, M, Cardona, F, Creti, R, Efstratiou, A, Gariup, M, Georgitsi, M, Hedderly, T, Heyman, I, Margarit, I, Mir, P, Moll, N, Morer, A, Müller, N, Müller-Vahl, K, Münchau, A, Orefici, G, Plessen, Kj, Porcelli, C, Paschou, P, Rizzo, R, Roessner, V, Schwarz, Mj, Steinberg, T, Tagwerker Gloor, F, Tarnok, Z, Walitza, S, Dietrich, A, Hoekstra, Pj, Zacharias, Anastasiou, Isobel, Heyman, Chaim, Huyser, Marcos, Madruga, Pablo, Mir, Astrid, Morer, Nanette Mol Debes, Natalie, Moll, Norbert Mu ̈ller, Peter, Nagy, Kerstin Jessica Plessen, Cesare, Porcelli, Renata, Rizzo, Veit, Roessner, Jaana, Schnell, Liselotte, Skov, Zsanett, Tarnok, Susanne, Walitza, Andrea, Dietrich, Baglioni, Valentina, Juliane, Ball, Emese, Bognar, Bianka, Burger, Judith, Buse, Marta Correa Vela, Maria Cristina Ferro, Carolin, Fremer, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Anna, Marotta, Neri, Valeria, Thaïra J, C Openneer, Pellico, Alessandra, Kerstin, J Plessen, Daphna, Ruhrman, Jaana M, L Schnell, Silvestri, PAOLA ROSARIA, Tamar, Steinberg, Friederike Tagwerker Gloor, Elif, Weidinger, EMTICS Collaborative Group, Anastasiou, Z., Apter, A., Baglioni, V., Ball, J., Bartolini, E., Benaroya-Milshtein, N., Bodmer, B., Bognar, E., Burger, B., Buse, J., Buttiglione, M., Cardona, F., Correa Vela, M., Creti, R., Dietrich, A., Debes, N.M., Efstratiou, A., Ferro, M.C., Fremer, C., Garcia-Delgar, B., Gariup, M., Georgitsi, M., Gulisano, M., Hagen, A., Hagstrøm, J., Hedderly, T.J., Heyman, I., Hoekstra, P.J., Huyser, C., Imperi, M., Karagiannidis, I., Laviola, G., Macri, S., Madruga-Garrido, M., Margarit, I., Marotta, A., Martino, D., Meier, U.C., Mir, P., Moll, N., Morer, A., Müller, N., Müller-Vahl, K., Münchau, A., Nagy, P., Neri, V., Openneer, TJC, Orefici, G., Paschou, P., Pellico, A., Petruzzelli, O., Plessen, K.J., Porcelli, C., Redondo, M., Rizzo, R., Roazzi, P., Roessner, V., Ruhrman, D., Schnell, JML, Schrag, A., Schütze, G.A., Schwarz, M.J., Silvestri, P.R., Skov, L., Steinberg, T., Stöber, S., Gloor, F.T., Tallon, M., Tarnok, Z., Turner, V.L., Walitza, S., Weidinger, E., Woods, M.L., European Commission, National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), University College London, NHS Foundation Trust, GlaxoSmithKline, German Research Foundation, Instituto de Biomedicina de Sevilla (IBIS), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Pediatrics, Tic disorder, BLOOD, Tourette syndrome, Obsessive–compulsive disorder, Cohort Studies, 0302 clinical medicine, Risk Factors, QUALITY-OF-LIFE, Obsessive-compulsive disorder, Developmental and Educational Psychology, Genetics, Longitudinal, Streptococcal infection, Stress, Prospective cohort study, Child, GENE-EXPRESSION, education.field_of_study, HAIR CORTISOL, 05 social sciences, A STREPTOCOCCAL INFECTIONS, Original Contribution, General Medicine, 3. Good health, Europe, Psychiatry and Mental health, LA-TOURETTE SYNDROME, Child, Preschool, NEUROPSYCHIATRIC DISORDERS, Cohort, Female, 050104 developmental & child psychology, Cohort study, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Tics, Adolescent, PSYCHOSOCIAL STRESS, Population, 03 medical and health sciences, mental disorders, medicine, Humans, 0501 psychology and cognitive sciences, Genetic Predisposition to Disease, education, Tic Disorders/complications, Tic Disorders/diagnosis, Tic Disorders/pathology, business.industry, OBSESSIVE-COMPULSIVE DISORDER, medicine.disease, 030227 psychiatry, nervous system diseases, body regions, PSYCHOMETRIC PROPERTIES, Tic Disorders, Pediatrics, Perinatology and Child Health, Chronic Tic Disorder, business, human activities
Abstract

EMTICS Collaborative Group., Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host’s immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant agreement no. 278367. Schrag was supported by the National Institute for Health Research UCLH Biomedical Research Centre, and Müller, Burger, Schnell and Weidinger by Stiftung Immunität und Seele. This research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (Heyman); partially sponsored by GSK Vaccines (Margarit, Bartolini); and Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1 (Münchau).

Published
2019

26. Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders

Author

Martino, Davide, Anette, Schrag, Zacharias, Anastasiou, Alan, Apter, Noa, Benaroya-Milstein, Maura, Buttiglione, Cardona, Francesco Carmelo Giovanni, Roberta, Creti, Androulla, Efstratiou, Tammy, Hedderly, Isobel, Heyman, Chaim, Huyser, Marcos, Madruga, Pablo, Mir, Astrid, Morer, Nanette Mol Debes, Natalie, Moll, Norbert Mu ̈ller, Kirsten Mu ̈ller-Vahl, Alexander, Munchau, Peter, Nagy, Kerstin Jessica Plessen, Cesare, Porcelli, Rizzo, Renata, Veit, Roessner, Jaana, Schnell, Markus, Schwarz, Liselotte, Skov, Tamar, Steinberg, Zsanett, Tarnok, Susanne, Walitza, Andrea, Dietrich, Hoekstra, Pieter J., Baglioni, Valentina, Juliane, Ball, Emese, Bognar, Bianka, Burger, Judith, Buse, Marta Correa Vela, Maria Cristina Ferro, Carolin, Fremer, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Anna, Marotta, Neri, Valeria, Thaïra J, C Openneer, Pellico, Alessandra, Kerstin, J Plessen, Daphna, Ruhrman, Jaana M, L Schnell, Silvestri, PAOLA ROSARIA, Friederike Tagwerker Gloor, and Susanne Walitza, Elif Weidinger

Subjects
neuroimmunity, Tourette syndrome, tic disorders, neuroimmunity, tic disorders
Published
2021

27. Clinical precursors of tics: an EMTICS study

Author

Openneer, Tha€ıra J. C., Chaim, Huyser, Martino, Davide, Anette, Schrag, Alan, Apter, Baglioni, Valentina, Juliane, Ball, Noa, Benaroya-Milshtein, Emese, Bognar, Bianka, Burger, Judith, Buse, Cardona, Francesco Carmelo Giovanni, Marta Correa Vela, Nanette, M Debes, Andrea, Dietrich, Maria Cristina Ferro, Carolin, Fremer, Blanca, Garcia-Delgar, Mariangela, Gulisano, Annelieke, Hagen, Julie, Hagstrøm, Tammy, J Hedderly, Isobel, Heyman, Marcos, Madruga-Garrido, Pablo, Mir, Astrid, Morer, Norbert, Müller, Kirsten, Müller-Vahl, Alexander, Münchau, Peter, Nagy, Neri, Valeria, Thaïra J, C Openneer, Pellico, Alessandra, Kerstin, J Plessen, Cesare, Porcelli, Rizzo, Renata, Veit, Roessner, Daphna, Ruhrman, Jaana M, L Schnell, Silvestri, PAOLA ROSARIA, Liselotte, Skov, Tamar, Steinberg, Friederike Tagwerker Gloor, Zsanett, Tarnok, Susanne, Walitza, Elif, Weidinger, Hoekstra, Pieter J., Child Psychiatry, Child and Adolescent Psychiatry & Psychosocial Care, ANS - Cellular & Molecular Mechanisms, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, sex differences, Pediatrics, Longitudinal study, SYMPTOMS, Autism Spectrum Disorder, Comorbidity, Logistic regression, Tourette syndrome, 0302 clinical medicine, Developmental and Educational Psychology, Obsessive compulsive scale, Spectrum disorder, Longitudinal Studies, Child, 05 social sciences, PSYCHIATRIC-DISORDERS, clinical precursors, PREVALENCE, Psychiatry and Mental health, Autism spectrum disorder, Child, Preschool, Compulsions, Tics, Female, Psychology, 050104 developmental & child psychology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, conduct problems, 03 medical and health sciences, OBSESSIVE-COMPULSIVE SCALE, mental disorders, medicine, Humans, ADHD, 0501 psychology and cognitive sciences, tic onset, SPECTRUM DISORDER, TOURETTE-SYNDROME, medicine.disease, nervous system diseases, body regions, PSYCHOMETRIC PROPERTIES, SEVERITY, Attention Deficit Disorder with Hyperactivity, Tic Disorders, Pediatrics, Perinatology and Child Health, Selection operator, human activities, 030217 neurology & neurosurgery, DISRUPTIVE BEHAVIOR, Tourette Syndrome
Abstract

Background: Children with Tourette syndrome (TS) often have comorbid disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). While subtle premorbid symptoms have been described in various psychiatric disorders, the presence of clinical precursors that may exist before the onset of tics is unknown. This longitudinal study aimed to find clinical precursors of tics by assessing a range of clinical characteristics prior to tic onset in comparison with children without onset of tics.Methods: A sample of 187 3- to 10-year-old first-degree unaffected relatives of children with TS were followed up to 7 years in the European Multicentre Tics in Children Study (EMTICS). We investigated whether clinical characteristics assessed at baseline predicted tic onset, comparing 126 children without tic onset to 61 children who developed tics. We used the least absolute shrinkage and selection operator (LASSO) method, a penalised logistic regression approach. We also explored sex differences and repeated our analyses in an age- and sex-matched subsample.Results: Children with tic onset were more frequently male (beta = -0.36), had higher baseline severity of conduct problems (beta = 0.23), autism spectrum disorder symptoms (ASD; beta = 0.08), compulsions (beta = 0.02) and emotional problems (beta = 0.03) compared to children without tic onset. Conduct and ASD problems were male-specific predictors, whereas severity of compulsions and oppositional (beta = 0.39) and emotional problems were female-specific predictors.Conclusion: This study supports the presence of clinical precursors prior to tic onset and highlights the need of sex-specific monitoring of children at risk of developing tics. This may aid in the earlier detection of tics, particularly in females. We moreover found that tics most often persisted one year after tic onset, in contrast to the common belief that tics are mostly transient.

Published
2021

28. Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families

Author

Gary A. Heiman, Samuel Kuperman, Andrea Dietrich, Li Deng, Julie Hagstrøm, Yeting Zhang, Jinchuan Xing, Xiaolong Cao, Lisheng Zhou, Pieter J. Hoekstra, Cara Nasello, Astrid Morer, Jay A. Tischfield, Mohamed Abdulkadir, Blanca Garcia-Delgar, Joshua K. Thackray, Kerstin J. Plessen, Justin Koesterich, Thomas V. Fernandez, Robert A. King, Clinical Cognitive Neuropsychiatry Research Program (CCNP), National Institute of Mental Health (US), Tourette Syndrome Association of New Jersey, National Institute of Environmental Health Sciences (US), Instituto de Salud Carlos III, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Jacques and Gloria Gossweiler Foundation, German Research Foundation, Tourette Association of America, National Institute for Health and Care Research (US), Tourette International Collaborative Genetics Study (TIC Genetics), Brown, L.W., Cao, X., Coffey, B.J., Gilbert, D.L., Hedderly, T., Heyman, I., Huyser, C., Kim, E., Kim, Y.S., Koh, Y.J., Leventhal, B.L., Madruga-Garrido, M., Maras, A., Mir, P., Münchau, A., Roessner, V., Song, D.H., State, M.W., Willsey, A.J., Zinner, S.H., Child Psychiatry, Paediatric Psychosocial Care, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
0301 basic medicine, Candidate gene, Population, Cadherin Related Proteins, Nerve Tissue Proteins, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neurodevelopmental disorder, Exome Sequencing, medicine, Humans, Family, Genetic Predisposition to Disease, education, Molecular Biology, Gene, Genotyping, Exome sequencing, Zinc finger, Genetics, education.field_of_study, Genetic heterogeneity, Serine Endopeptidases, medicine.disease, Pedigree, Genetic Predisposition to Disease/genetics, Nerve Tissue Proteins/genetics, Tourette Syndrome/genetics, Whole Exome Sequencing, Psychiatry and Mental health, 030104 developmental biology, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies., This study was supported by a grant from the National Institute of Mental Health (R01MH092293 to GAH and JAT) and by a grant from the New Jersey Center for Tourette Syndrome (to GAH and JAT). This study was also supported by grants from the National Institute of Mental Health (K08MH099424 to TVF) and the National Institute for Environmental Health Science (R01 ES021462 for YSK and BLL). PM has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña, and the Jaques and Gloria Gossweiler Foundation. AM has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. AM has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1, and FOR 2698). AJW received a Young Investigator Award from Tourette Association of America. IH declares that all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

Published
2020

29. An observational study of emotion regulation in children with Tourette syndrome

Author

Signe Vangkilde, Katrine Søborg Spang, Anne Katrine Pagsberg, Katrine Maigaard, Liselotte Skov, Kerstin J. Plessen, Jens Richardt Møllegaard Jepsen, and Julie Hagstrøm

Subjects
Tics, Comorbidity, Tourette syndrome, 03 medical and health sciences, 0302 clinical medicine, Group differences, mental disorders, Developmental and Educational Psychology, medicine, Attention deficit hyperactivity disorder, Humans, 0501 psychology and cognitive sciences, 05 social sciences, Emotional dysregulation, medicine.disease, Emotional Regulation, Psychiatry and Mental health, Distress, Attention Deficit Disorder with Hyperactivity, Tic Disorders, Pediatrics, Perinatology and Child Health, Observational study, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology, Tourette Syndrome
Abstract

Background Explosive outbursts occur in 25%-70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent-reported questionnaires. Methods We examined emotion regulation (ER) with an observational measure in 150 medication-naive children aged 7-12 allocated to four groups: Forty-nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent-child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC-M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD. Results Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD. Conclusions This study is the first to evaluate ER with an observational, clinician-rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire-based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders.

Published
2020

30. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Author

Sheng Wang, Jeffrey D. Mandell, Yogesh Kumar, Nawei Sun, Montana T. Morris, Juan Arbelaez, Cara Nasello, Shan Dong, Clif Duhn, Xin Zhao, Zhiyu Yang, Shanmukha S. Padmanabhuni, Dongmei Yu, Robert A. King, Andrea Dietrich, Najah Khalifa, Niklas Dahl, Alden Y. Huang, Benjamin M. Neale, Giovanni Coppola, Carol A. Mathews, Jeremiah M. Scharf, Thomas V. Fernandez, Joseph D. Buxbaum, Silvia De Rubeis, Dorothy E. Grice, Jinchuan Xing, Gary A. Heiman, Jay A. Tischfield, Peristera Paschou, A. Jeremy Willsey, Matthew W. State, Mohamed Abdulkadir, Benjamin Bodmer, Yana Bromberg, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Li Deng, Lonneke Elzerman, Carolin Fremer, Blanca Garcia-Delgar, Donald L. Gilbert, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Pieter J. Hoekstra, Hyun Ju Hong, Chaim Huyser, Eun-Joo Kim, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L Leventhal, Andrea G. Ludolph, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Astrid Morer, Montana T Morris, Kirsten Müller-Vahl, Alexander Münchau, Tara L. Murphy, Kerstin J. Plessen, Hannah Poisner, Veit Roessner, Stephan J. Sanders, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Joshua K. Thackray, Jennifer Tübing, Frank Visscher, Sina Wanderer, A Jeremy Willsey, Martin Woods, Yeting Zhang, Samuel H. Zinner, Christos Androutsos, Csaba Barta, Luca Farkas, Jakub Fichna, Marianthi Georgitsi, Piotr Janik, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Joanna Puchala, Renata Rizzo, Natalia Szejko, Urszula Szymanska, Zsanett Tarnok, Vaia Tsironi, Tomasz Wolanczyk, Cezary Zekanowski, Cathy L. Barr, James R. Batterson, Cheston Berlin, Ruth D. Bruun, Cathy L. Budman, Danielle C. Cath, Sylvain Chouinard, Nancy J. Cox, Sabrina Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Matthew E. Hirschtritt, Cornelia Illmann, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. MacMahon, Michael S. Okun, Lisa Osiecki, David L. Pauls, Danielle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Tourette International Collaborative Genetics Study (TIC Genetics), Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE), Tourette Association of America International Consortium for Genetics (TAAICG), Abdulkadir, M., Arbelaez, J., Bodmer, B., Bromberg, Y., Brown, L.W., Cheon, K.A., Coffey, B.J., Deng, L., Dietrich, A., Dong, S., Duhn, C., Elzerman, L., Fernandez, T.V., Fremer, C., Garcia-Delgar, B., Gilbert, D.L., Grice, D.E., Hagstrøm, J., Hedderly, T., Heiman, G.A., Heyman, I., Hoekstra, P.J., Hong, H.J., Huyser, C., Kim, E.J., Kim, Y.K., Kim, Y.S., King, R.A., Koh, Y.J., Kook, S., Kuperman, S., Leventhal, B.L., Ludolph, A.G., Madruga-Garrido, M., Mandell, J.D., Maras, A., Mir, P., Morer, A., Morris, M.T., Müller-Vahl, K., Münchau, A., Murphy, T.L., Nasello, C., Plessen, K.J., Poisner, H., Roessner, V., Sanders, S.J., Shin, E.Y., Song, D.H., Song, J., State, M.W., Sun, N., Thackray, J.K., Tischfield, J.A., Tübing, J., Visscher, F., Wanderer, S., Wang, S., Willsey, A.J., Woods, M., Xing, J., Zhang, Y., Zhao, X., Zinner, S.H., Androutsos, C., Barta, C., Farkas, L., Fichna, J., Georgitsi, M., Janik, P., Karagiannidis, I., Koumoula, A., Nagy, P., Paschou, P., Puchala, J., Rizzo, R., Szejko, N., Szymanska, U., Tarnok, Z., Tsironi, V., Wolanczyk, T., Zekanowski, C., Barr, C.L., Batterson, J.R., Berlin, C., Bruun, R.D., Budman, C.L., Cath, D.C., Chouinard, S., Coppola, G., Cox, N.J., Darrow, S., Davis, L.K., Dion, Y., Freimer, N.B., Grados, M.A., Hirschtritt, M.E., Huang, A.Y., Illmann, C., Kurlan, R., Leckman, J.F., Lyon, G.J., Malaty, I.A., Mathews, C.A., MacMahon, W.M., Neale, B.M., Okun, M.S., Osiecki, L., Pauls, D.L., Posthuma, D., Ramensky, V., Robertson, M.M., Rouleau, G.A., Sandor, P., Scharf, J.M., Singer, H.S., Smit, J., Sul, J.H., and Yu, D.

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, DNA Copy Number Variations, Receptors, Cell Surface, Biology, Genome, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, RARE, SCHIZOPHRENIA, medicine, Humans, Copy-number variation, Child, NEURODEVELOPMENTAL DISORDERS, Gene, lcsh:QH301-705.5, Exome sequencing, 030304 developmental biology, Medicinsk genetik, Sequence (medicine), Genetics, 0303 health sciences, SEVERE INTELLECTUAL DISABILITY, Cadherin, MUTATIONS, AUTISM SPECTRUM DISORDER, Cell Polarity, OBSESSIVE-COMPULSIVE DISORDER, Cadherins, medicine.disease, Pedigree, PREVALENCE, CONGENITAL HEART-DISEASE, GENOME, 030104 developmental biology, lcsh:Biology (General), Schizophrenia, Medical genetics, Female, Cadherins/genetics, Receptors, Cell Surface/genetics, Tourette Syndrome/genetics, Tourette Syndrome/pathology, TIC Genetics, Tourette disorder, cell polarity, copy number variants, de novo variants, gene discovery, microarray genotyping, multiplex, simplex, whole exome sequencing, Medical Genetics, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

SUMMARY We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk., In Brief Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis., Graphical Abstract

Published
2018

31. The Puzzle of Emotion Regulation: Development and Evaluation of the Tangram Emotion Coding Manual for Children

Author

Katrine Søborg Spang, Kerstin J. Plessen, Barbara Hoff Esbjørn, Katrine Maigaard, Signe Vangkilde, Julie Hagstrøm, Jens Richardt Møllegaard Jepsen, and Bianca Munkebo Christiansen

Subjects
convergent validity, construct validity, content validity, development, discriminant validity, emotion regulation, interrater reliability, intrarater reliability, lcsh:RC435-571, 03 medical and health sciences, 0302 clinical medicine, lcsh:Psychiatry, Content validity, Methods, Reliability (statistics), Psychiatry, Discriminant validity, Construct validity, Intra-rater reliability, 030227 psychiatry, Test (assessment), Psychiatry and Mental health, Inter-rater reliability, Convergent validity, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

The ability to regulate one’s emotions is crucial to engaging successfully in social contexts. Difficulties in emotion regulation are seen in multiple psychiatric disorders, prompting an increased interest in the concept. Suitable methods for assessing emotion regulation, however, are lacking. In this study, we investigated the interrater and intrarater reliability, construct validity, and content validity of a new observational method for evaluating children’s emotion regulation abilities (a complex puzzle task) in a sample of 62 children without psychiatric disorders and 23 children with attention-deficit/hyperactivity disorder (ADHD) aged 7–12, using intra-class correlation coefficients for the reliability analyses and Spearman’s rank-order correlations for analyses of convergent and discriminant validity. A panel of experts examined the content validity of the test, and Mann–Whitney U-tests were used to investigate the ability of the test to differentiate the non-clinical group from the ADHD group. Results showed a high level of interrater and intrarater reliability of the test. There was mixed evidence for convergent and discriminant validity as expected due to the novelty and experimental nature of the test, making it difficult to compare with questionnaire-based measures. Content validity analysis was satisfactory, and the group comparison showed that the test differentiated the groups on the primary outcome measure. Overall, the measure demonstrated high feasibility and satisfactory psychometric properties. The generic nature of the test makes it suitable for use across psychiatric disorders and age groups with potential relevance in both research and clinical settings.

Published
2019

32. Antibodies to neuronal surface proteins in Tourette Syndrome: Lack of evidence in a European paediatric cohort

Author

V. Baglioni, E. Coutinho, D.A. Menassa, M.P. Giannoccaro, L. Jacobson, M. Buttiglione, O. Petruzzelli, F. Cardona, A. Vincent, Zacharias Anastasiou, Alan Apter, Erika Bartolini, Noa Benaroya-Milshtein, Benjamin Bodmer, Emese Bognar, Bianka Burger, Marta Correa Vela, Roberta Creti, Andrea Dietrich, Nanette M. Debes, Androulla Efstratiou, Maria Cristina Ferro, Carolin Fremer, Blanca Garcia-Delgar, Maria Gariup, Marianthi Georgitsi, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Tammy J. Hedderly, Isobel Heyman, Pieter J. Hoekstra, Chaim Huyser, Monica Imperi, Iordanis Karagiannidis, Giovanni Laviola, Simone Macri, Marcos Madruga-Garrido, Immaculada Margarit, Anna Marotta, Davide Martino, Ute C. Meier, Pablo Mir, Natalie Moll, Astrid Morer, Kirsten Müller-Vahl, Alexander Münchau, Peter Nagy, Valeria Neri, Thaïra J.C. Openneer, Graziella Orefici, Peristera Paschou, Alessandra Pellico, Cesare Porcelli, Marina Redondo, Renata Rizzo, Paolo Roazzi, Veit Roessner, Daphna Ruhrman, Jaana M.L. Schnell, Anette Schrag, Gregor A. Schütze, Markus J. Schwarz, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Sara Stöber, Marco Tallon, Zsanett Tarnok, Baglioni V., Coutinho E., Menassa D.A., Giannoccaro M.P., Jacobson L., Buttiglione M., Petruzzelli O., Cardona F., Vincent A., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
0301 basic medicine, Male, Tics, Adolescent, DISORDERS, CNTNAP2, Immunology, Primary Cell Culture, CHILDREN, Hippocampal formation, Tourette syndrome, Hippocampus, Receptors, N-Methyl-D-Aspartate, Epitope, White People, Cohort Studies, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Antigen, medicine, Animals, Humans, Child, Autoantibodies, Neurons, antibodies to neuronal antigens, movement disorders, biology, RECEPTOR, Endocrine and Autonomic Systems, business.industry, Dentate gyrus, Autoantibody, Brain, Membrane Proteins, medicine.disease, Rats, Tourette Syndrome, Tic Disorders, Neurodevelopmental Disorders, Neuronal- Surface Antibodies, Antineuronal Antibodies, Voltage-Gated Potassium Channels Antibodies, CASPR2, NMDAR, 030104 developmental biology, nervous system, Child, Preschool, Dentate Gyrus, biology.protein, Female, Antibody, business, 030217 neurology & neurosurgery
Abstract

The EMTICS collaborative group: Anastasiou, Zacharias; Apter, Alan; Baglioni, Valentina; Bartolini, Erika; Benaroya-Milshtein, Noa; Bodmer, Benjamin; Bognar, Emese; Burger', Bianka; Buttiglione, Maura; Cardona, Francesco; Vela, Marta Correa; Creti, Roberta; Dietrich, Andrea; Debes, Nanette M.; Efstratiou, Androulla; Ferro, Maria Cristina; Fremer, Carolin; Garcia-Delgar, Blanca; Gariup, Maria; Georgitsi, Marianthi; Gulisano, Mariangela; Hagen, Annelieke; Hagstrom, Julie; Hedderly, Tammy J.; Heyman, Isobel; Hoekstra, Pieter J.; Huyser, Chaim; Imperi, Monica; Karagiannidis, Iordanis; Laviola, Giovanni; Macri, Simone; Madruga-Garrido, Marcos; Margarit, Immaculada; Marotta, Anna; Martino, Davide; Meier, Ute C.; Mir, Pablo; Mo, Natalie; More, Astrid; Mueller-Vahl, Kirsten; Muenchau, Alexander; Nagy, Peter; Neri, Valeria; Openneer, Thafra J. C.; Orefici, Graziella; Paschou, Peristera; Pellico, Alessandra; Petruzzelli, Onofrio; Porcelli, Cesare; Redondo, Marina; Rizzo, Renata; Roazzi, Paolo; Roessner, Veit; Ruhrman, Daphna; Schnell, Jaana M. L.; Schrag, Anette; Schutze, Gregor A.; Schwarz, Markus J.; Silvestri, Paola Rosaria; Skov, Liselotte; Steinberg, Tamar; Stober, Sara; Tallon, Marco; Tarnok, Zsanett, In Tourette Syndrome (TS) a role for autoantibodies directed against neuronal proteins has long been suspected, but so far results are still inconsistent. The aim of this study was to look for antibodies to specific or undefined neuronal proteins that could be involved in the aetiology of the disease. Sera from children with Tourette Syndrome or another chronic tic disorder (TS/TD), collected as part of the longitudinal European Multicenter Tics in Children Study, were investigated. Participants included 30 siblings of patients with TS/TD prior to developing tics (preclinical stage) and the same children after the first tic onset (onset), and 158 patients in the chronic phase undergoing an acute relapse (exacerbation). Presence of antibodies binding to rodent brain tissue was assessed by immunohistology on rat brain sections and by immunofluorescent staining of live hippocampal neurons. Live cell-based assays were used to screen for antibodies to NMDAR, CASPR2, LGI1, AMPAR and GABAAR. Immunohistology indicated evidence of antibodies reactive with brain tissue, binding mainly to the hippocampus, the basal ganglia or the cerebellum in 26/218 (12%), with 8% of the preclinical or onset sera binding to the dentate gyrus/CA3 region or cerebellum. Only two individuals (one pre-clinical, one chronic) had antibodies binding the NMDAR and the binding was only weakly positive. No other specific antibodies were detected. Despite some immunoreactivity towards neuronal antigens on brain tissue, this was not mirrored by antibodies binding to live neurons, suggesting the presence of non-specific antibodies or those that bind non-pathogenic intracellular epitopes. NMDAR or the other neuronal surface antibodies tested were very infrequent in these patients. The evidence for pathogenic antibodies that could be causative of TS is weak.

Published
2019

33. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. Davis, Lenka Slachtova, Olav B. Smeland, Erin C. Dunn, Nicholas G. Martin, Allan L. Naarden, Jo Knight, Cristina Sánchez-Mora, Masashi Ikeda, Lorraine Southam, Sandro Sorbi, Barbara Franke, Martin Schalling, Russell Schachar, Yen-Chen Anne Feng, Kirsten R. Müller-Vahl, André Scherag, Zhaozhong Zhu, Eric A. Storch, Páll Magnússon, David Cohen, Olafur O Gudmundsson, Harvey S. Singer, Brian Kelly, Jonas Bybjerg-Grauholm, Blanca Garcia-Delgar, Thomas Hansen, Carmel M. Loughland, Christine Lochner, Stacy Steinberg, Martin Woods, Jorge A. Quiroz, Raquel Rabionet, Alden Y. Huang, Janice M. Fullerton, María Soler Artigas, Hans J. Grabe, Philip Asherson, Margit Burmeister, Alicia R. Martin, Martin A. Kennedy, Janet Treasure, Anders D. Børglum, Eva C. Schulte, Andreas Hartmann, Frans Henskens, Youl-Ri Kim, Jens Treutlein, Joanna Hauser, Manfred M. Fichter, Damiaan Denys, Ann E. Pulver, Kelly L. Klump, Paul Sandor, Michael Wagner, Philippe Courtet, Sandra Van der Auwera, Susanne Lucae, Eystein Stordal, Michel G. Nivard, Maurizio Clementi, Astrid Morer, Philip B. Mitchell, Huda Akil, Edwin H. Cook, Jennifer L. Moran, Donald W. Black, Jeremiah M. Scharf, Jana Strohmaier, Colm McDonald, Meg M.-J. Wang, Richard M. Myers, Stephanie Godard, Pablo V. Gejman, Athanasios Maras, Marcella Rietschel, Nancy G. Buccola, Konstantinos Hatzikotoulas, Dalila Pinto, Jouke-Jan Hottenga, Kari Stefansson, James S. Sutcliffe, Andres Metspalu, Amaia Hervás, Joel Gelernter, Wolfgang Herzog, Paula Rovira, Gunnar Morken, Tara Murphy, Mark Weiser, Vincent Millischer, Frank Dudbridge, Dan Rujescu, Vladimir Bencko, Valdo Ricca, Kimberly Chambert, Guy A. Rouleau, James J. Crowley, Thomas G. Schulze, Toni-Kim Clarke, Triinu Peters, Gudrun Wagner, Daniel A. Geller, Henry R. Kranzler, G. Bragi Walters, Vera Golimbet, Clement C. Zai, Nigel Williams, Andreas Birgegård, Joseph D. Buxbaum, Elliot M. Tucker-Drob, Jerome C. Foo, Tracey L. Petryshen, Daniel P. Howrigan, Hunna J. Watson, Franziska Degenhardt, Peter R. Schofield, Jesper Buchhave Poulsen, Stefan Herms, Johannes Hebebrand, Mario Maj, George Kirov, Fabrizio Piras, Sara McDevitt, James T. McCracken, Carol A. Mathews, Michael John Owen, Peter Falkai, Donald L. Gilbert, Enda M. Byrne, Fernando Fernández-Aranda, Csaba Barta, Stéphane Jamain, Jubao Duan, Dongmei Yu, Danielle C. Cath, Ole Mors, Sigrun Hope, Laramie E. Duncan, Alan R. Sanders, Sang-Yun Oh, Carsten Bøcker Pedersen, Henning Tiemeier, Roseann E. Peterson, Raymond K. Walters, Margarita C T Slof-Op 't Landt, Madeline Alexander, Stephanie Le Hellard, Ina Giegling, Annemarie A. van Elburg, Steven P. Hamilton, Vesna Boraska Perica, Thomas V. Fernandez, Danielle M. Dick, Francesco Bettella, Roel A. Ophoff, Grant W. Montgomery, Gerald Nestadt, Nakao Iwata, Jessica H. Baker, Walter H. Kaye, Jeremy M. Silverman, Mark J. Daly, Robert A. King, Sarah E. Medland, Anastasios Konstantinidis, Robert D. Oades, Samuel H. Zinner, Steven Crawford, Daniel H. Geschwind, Patrick W. L. Leung, Martin Alda, Marie Navratilova, Pak C. Sham, Paul A. Tooney, Tian Ge, Veit Roessner, Martin Preisig, Thomas Werge, Eli A. Stahl, David A. Collier, Stephanie H. Witt, Dermot Walsh, Miquel Casas, Anna Keski-Rahkonen, Jane H. Christensen, Silvia De Rubeis, Giorgio Pistis, Sven Cichon, Bruno Etain, Dominique Campion, O. Joseph Bienvenu, Christian Dina, Manolis Kogevinas, Thomas Espeseth, Benjamin M. Neale, Ditte Demontis, Klaus-Peter Lesch, Marina Mitjans, Tiffany A. Greenwood, Marcos Madruga-Garrido, Sibylle G. Schwab, Oedegaard Ketil Joachim, Hreinn Stefansson, Sara A. Paciga, Monica Forzan, Dieter B. Wildenauer, Lena Backlund, A. Jeremy Willsey, Carlos N. Pato, Nicholas John Craddock, Inge A. Meijer, Sandra K. Loo, Filip Rybakowski, Tracey D. Wade, Scott J. Crow, Bernard Lerer, Valsamma Eapen, Esben Agerbo, Andrew M. McIntosh, Luis Augusto Rohde, Susan L. McElroy, Stephan Zipfel, Peter P. Zandi, Cathryn M. Lewis, Lars Klareskog, Martin Begemann, Phil Lee, Richard Anney, Mark A. Bellgrove, Lisa Jones, Andreas J. Forstner, Agnieszka Słopień, Hilary Coon, Dong Li, Alessandro Serretti, Carsten Horn, Christos Pantelis, Ryan L. Collins, David M. Howard, Lucía Colodro-Conde, Pippa A. Thomson, Martin Hautzinger, Alysa E. Doyle, Julie Hagstrøm, Oliver S. P. Davis, Karen S. Mitchell, Jordan W. Smoller, Michael Strober, John I. Nurnberger, Andrea G. Ludolph, Monika Budde, Anna Maaser, Lambertus Klei, Aribert Rothenberger, Yulia Worbe, Fabian Streit, James L. Kennedy, Barbara E. Stranger, Ashley Dumont, Jianxin Shi, Dale R. Nyholt, Craig Johnson, Jonna Kuntsi, Yun-Joo Koh, Loes M. Olde Loohuis, Robert B. Freedman, Anke Hinney, Susanne Walitza, Enrico Domenici, Margarita Rivera, Sodahm Kook, Erica Greenberg, Tetyana Zayats, Josef Frank, Gary A. Heiman, Andrew McQuillin, Abraham Reichenberg, Piotr M. 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H., Anttila, V., Won, H., Feng, Y. -C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., Wang, M. M. -J., Yu, D., Stahl, E. A., Walters, R. K., Anney, R. J. L., Duncan, L. E., Ge, T., Adolfsson, R., Banaschewski, T., Belangero, S., Cook, E. H., Coppola, G., Derks, E. M., Hoekstra, P. J., Kaprio, J., Keski-Rahkonen, A., Kirov, G., Kranzler, H. R., Luykx, J. J., Rohde, L. A., Zai, C. C., Agerbo, E., Arranz, M. J., Asherson, P., Baekvad-Hansen, M., Baldursson, G., Bellgrove, M., Belliveau, R. A., Buitelaar, J., Burton, C. L., Bybjerg-Grauholm, J., Casas, M., Cerrato, F., Chambert, K., Churchhouse, C., Cormand, B., Crosbie, J., Dalsgaard, S., Demontis, D., Doyle, A. E., Dumont, A., Elia, J., Grove, J., Gudmundsson, O. O., Haavik, J., Hakonarson, H., Hansen, C. S., Hartman, C. A., Hawi, Z., Hervas, A., Hougaard, D. M., Howrigan, D. P., Huang, H., Kuntsi, J., Langley, K., Lesch, K. -P., Leung, P. W. L., Loo, S. K., Martin, J., Martin, A. R., Mcgough, J. J., Medland, S. E., Moran, J. L., Mors, O., Mortensen, P. B., Oades, R. D., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Peters, T., Poterba, T., Poulsen, J. B., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Rothenberger, A., Rovira, P., Sanchez-Mora, C., Satterstrom, F. K., Schachar, R., Artigas, M. S., Steinberg, S., Stefansson, H., Turley, P., Walters, G. B., Werge, T., Zayats, T., Arking, D. E., Bettella, F., Buxbaum, J. D., Christensen, J. H., Collins, R. L., Coon, H., De Rubeis, S., Delorme, R., Grice, D. E., Hansen, T. F., Holmans, P. A., Hope, S., Hultman, C. M., Klei, L., Ladd-Acosta, C., Magnusson, P., Naerland, T., Nyegaard, M., Pinto, D., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Roeder, K., Rouleau, G. A., Saemundsen, E., Sanders, S. J., Sandin, S., St Pourcain, B., Stefansson, K., Sutcliffe, J. S., Talkowski, M. E., Weiss, L. A., Willsey, A. J., Agartz, I., Akil, H., Albani, D., Alda, M., Als, T. 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B., Brandt, H., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Courtet, P., Crawford, S., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Docampo, E., Egberts, K., Ehrlich, S., Espeseth, T., Fernandez-Aranda, F., Fichter, M. M., Foretova, L., Forzan, M., Gambaro, G., Giegling, I., Gonidakis, F., Gorwood, P., Mayora, M. G., Guo, Y., Halmi, K. A., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Imgart, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Julia, A., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kaye, W. H., Kennedy, M. A., Kim, Y. -R., Klareskog, L., Klump, K. L., Knudsen, G. P. S., Landen, M., Le Hellard, S., Levitan, R. D., Li, D., Lichtenstein, P., Maj, M., Marsal, S., Mcdevitt, S., Mitchell, J., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., O'Toole, J. 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S., Paschou, P., Piras, F., Pittenger, C., Plessen, K. J., Richter, M. A., Rizzo, R., Robertson, M., Roessner, V., Ruhrmann, S., Samuels, J. F., Sandor, P., Schlogelhofer, M., Shin, E. -Y., Singer, H., Song, D. -H., Song, J., Spalletta, G., Stein, D. J., Stewart, S. E., Storch, E. A., Stranger, B., Stuhrmann, M., Tarnok, Z., Tischfield, J. A., Tubing, J., Visscher, F., Vulink, N., Wagner, M., Walitza, S., Wanderer, S., Woods, M., Worbe, Y., Zai, G., Zinner, S. H., Sullivan, P. F., Franke, B., Daly, M. J., Bulik, C. M., Mcintosh, A. M., O'Donovan, M. C., Zheutlin, A., Andreassen, O. A., Borglum, A. D., Breen, G., Edenberg, H. J., Fanous, A. H., Faraone, S. V., Gelernter, J., Mathews, C. A., Mattheisen, M., Mitchell, K. S., Neale, M. C., Nurnberger, J. I., Ripke, S., Santangelo, S. L., Scharf, J. M., Stein, M. B., Thornton, L. M., Walters, J. T. R., Wray, N. R., Geschwind, D. H., Neale, B. M., Kendler, K. S., and Smoller, J. W.

Subjects
Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019

34. Reappraisal is an effective emotion regulation strategy in children with Tourette syndrome and ADHD

Author

Katrine Maigaard, Liselotte Skov, Signe Vangkilde, Kerstin J. Plessen, Anne Katrine Pagsberg, and Julie Hagstrøm

Subjects
Male, 050103 clinical psychology, Blinding, Child psychopathology, Emotions, Coding (therapy), Experimental and Cognitive Psychology, Tourette syndrome, Cognitive reappraisal, 03 medical and health sciences, 0302 clinical medicine, Attention Problems, Arts and Humanities (miscellaneous), medicine, Humans, ADHD, 0501 psychology and cognitive sciences, Child, Reactivity (psychology), Reappraisal, Emotion regulation, Reactivity, 05 social sciences, Adhd group, medicine.disease, Emotional Regulation, 030227 psychiatry, Psychiatry and Mental health, Clinical Psychology, Attention Deficit Disorder with Hyperactivity, Female, Psychology, Tourette Syndrome, Clinical psychology
Abstract

Background and objectives Difficulties in emotion regulation (ER) have been associated with several psychiatric disorders, emphasizing a need for a greater understanding of the concept and its associations with disruptive behavior. We aimed to study the ER strategy of cognitive reappraisal with an experimental test to increase our knowledge of emotional processes in child psychopathology. Methods In the present study, we examined emotional reactivity and cognitive reappraisal with a computer task in 160 medication-naive children aged 8–12 comprising four groups: Fifty-eight children with Tourette syndrome (TS), 26 children with attention-deficit/hyperactivity disorder (ADHD), 19 children with TS and ADHD, and 57 typically developing controls. Results The use of cognitive reappraisal reduced negative affect across all participants and the ability to reappraise was positively correlated with age, whereas reactivity was not. Overall, groups did not differ in reactivity or regulation success. Looking at specific differences within groups, however, only the ADHD group did not significantly decrease negative affect when reappraising. Finally, the use of strategies considered to be efficacious was correlated with regulation success, whereas the use of a less adaptive strategy related to suppression was associated with reactivity, but not regulation of emotions. Limitations The study was limited by small, clinical contrast groups and a lack of blinding to diagnostic status in the coding of verbal strategies employed during the task. Conclusions Cognitive reappraisal appears to be a beneficial ER strategy for children regardless of diagnostic status. Our findings indicate that children can learn and employ an adaptive ER strategy when instructed in the technique, even in the presence of attention problems, which is highly relevant to therapeutic approaches to dysregulated behavior.

Published
2020

35. A superior ability to suppress fast inappropriate responses in children with Tourette syndrome is further improved by prospect of reward

Author

Kasper Winther Andersen, Ayna Baladi Nejad, Liselotte Skov, Anne Katrine Pagsberg, Damian M. Herz, Kerstin J. Plessen, Katrine Maigaard, Julie Hagstrøm, and Hartwig R. Siebner

Subjects
Male, medicine.medical_specialty, Tics, Adolescent, Cognitive Neuroscience, Psychological intervention, Experimental and Cognitive Psychology, Audiology, Neuropsychological Tests, Tourette syndrome, 050105 experimental psychology, Task (project management), 03 medical and health sciences, Behavioral Neuroscience, Typically developing, Executive Function, 0302 clinical medicine, Reward, medicine, Reaction Time, Humans, 0501 psychology and cognitive sciences, Attention, Child, Response inhibition, 05 social sciences, Repeated measures design, medicine.disease, Inhibition, Psychological, Female, Psychology, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

In children with Tourette syndrome (TS), tics are often attributed to deficient self-control by health-care professionals, parents, and peers. In this behavioural study, we examined response inhibition in TS using a modified Simon task which probes the ability to solve the response conflict between a new non-spatial rule and a highly-overlearned spatial stimulus-response mapping rule. We applied a distributional analysis to the behavioural data, which grouped the trials according to the individual distribution of reaction times in four time bins. Distributional analyses enabled us to probe the children's ability to control fast, impulsive, responses, which corresponded to the trials in the fastest time bin. Additionally, we tested whether the ability to suppress inappropriate action tendencies can be improved further by the prospect of a reward. Forty-one clinically well-characterized medication-naive children with TS, 20 children with attention-deficit/hyperactivity disorder (ADHD), and 43 typically developing children performed a Simon task during alternating epochs with and without a prospect of reward. We applied repeated measures ANCOVAs to estimate how the prospect of reward modulated reaction times and response accuracy, while taking into account the distribution of the reaction times across trials. We found between-group differences in accuracy when subjects responded relatively fast. The TS group responded more accurately than typically developing control children when resolving the response conflict introduced by the Simon task. The opposite pattern was found in children with ADHD. Prospect of reward improved accuracy rates in all groups. Although the Tourette group performed with superior accuracy in the fast trials, it was still possible for them to benefit from prospect of reward in fast trials. The findings corroborate the notion that children with TS have an enhanced capacity to inhibit fast inappropriate response tendencies. This ability can be improved further by offering a prospect of reward which might be useful during non-pharmacological therapeutic interventions.

Published
2018

36. Prefrontal cortex and hippocampus in behavioural flexibility and posttraumatic functional recovery: Reversal learning and set-shifting in rats

Author

David Meder, Julie Hagstrøm, Rie Friis Christensen, Jesper Mogensen, Hadley Pearce, Lykke Grønbech Andersen, Hana Malá, and Anita Felbinger

Subjects
Male, Flexibility (anatomy), Spatial discrimination, Prefrontal Cortex, Spatial Behavior, Hippocampus, Reversal Learning, Neuropsychological Tests, Neurosurgical Procedures, Lesion, Sham group, Executive Function, Random Allocation, Discrimination, Psychological, medicine, Animals, Rats, Wistar, Maze Learning, Prefrontal cortex, General Neuroscience, Cognitive flexibility, Recovery of Function, Functional recovery, Disease Models, Animal, medicine.anatomical_structure, medicine.symptom, Psychology, Neuroscience
Abstract

Within one experiment and one T-maze, we examined the consequences of (i) bilateral lesions of the anteromedial prefrontal cortex (PFC), (ii) bilateral transections of the fimbria-fornix (FF), or (iii) combined lesions of both PFC and FF (COMB) on rats’ ability to perform reversal or set-shifting. Postoperatively, the animals were trained to perform a spatial discrimination go-right task. This was followed by (1) a spatial reversal go-left task (reversal learning), or (2) a visual pattern discrimination task (set-shift). Neither single (PFC or FF) lesion nor combined (COMB) lesions affected the animals’ ability to acquire the original spatial discrimination task. Regarding the reversal learning, the performance of the PFC and the FF groups was not significantly different from that of the sham operated control animals (Sham). In contrast, animals with combined lesion of both structures were impaired on both error rate and acquisition speed relative to all other groups. Regarding the set-shifting, all lesioned groups were impaired relative to the Sham group both regarding the error rate and the acquisition speed. There was, however, no difference in the degree of impairment between the lesioned groups. We conclude that both the PFC and the hippocampus contributed to the mediation of the reversal learning and set-shifting. During functional recovery of reversal learning, these two structures exhibited a mutual dependency, whilst the functional recovery of set-shifting was mediated by a substrate outside these two structures.

Published
2015

37. The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

Author

Dong Ho Song, Andrea Dietrich, Jay Tischfield, Julie Hagstrøm, Gary Heiman, Marta Correa Vela, Chaim Huyser, Keun-Ah Cheon, Astrid Morer, Samuel Kuperman, Blanca Garcia-Delgar, Isobel Heyman, Veit Roessner, Dorothy E Grice, Child Psychiatry, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
medicine.medical_specialty, Tics, Genetic Linkage, Trios, CHILDREN, Genomics, VARIANTS, Tourette syndrome, Genetic linkage, Methods, Developmental and Educational Psychology, Child and adolescent psychiatry, medicine, Humans, Genetic Predisposition to Disease, Pediatrics, Perinatology, and Child Health, Cooperative Behavior, AUTISM, Child, Genetics, MAJOR GENE, PSYCHIATRIC-DISORDERS, Repository, Inheritance (genetic algorithm), Rare variants, Original Contribution, OBSESSIVE-COMPULSIVE DISORDER, General Medicine, SEVERITY-SCALE, medicine.disease, Mental health, Pedigree, 3. Good health, Psychiatry and Mental health, Genes, EUROPEAN CLINICAL GUIDELINES, BEHAVIOR-THERAPY, Attention Deficit Disorder with Hyperactivity, Tic Disorders, RELIABILITY, Pediatrics, Perinatology and Child Health, Multiplex families, Autism, Female, Gene-Environment Interaction, Psychology
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS.

Published
2015

38. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Author

A. Jeremy Willsey, Thomas V. Fernandez, Dongmei Yu, Robert A. King, Andrea Dietrich, Jinchuan Xing, Stephan J. Sanders, Jeffrey D. Mandell, Alden Y. Huang, Petra Richer, Louw Smith, Shan Dong, Kaitlin E. Samocha, Benjamin M. Neale, Giovanni Coppola, Carol A. Mathews, Jay A. Tischfield, Jeremiah M. Scharf, Matthew W. State, Gary A. Heiman, Mohamed Abdulkadir, Julia Bohnenpoll, Yana Bromberg, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Li Deng, Lonneke Elzerman, Odette Fründt, Blanca Garcia-Delgar, Erika Gedvilaite, Donald L. Gilbert, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Pieter J. Hoekstra, Hyun Ju Hong, Chaim Huyser, Laura Ibanez-Gomez, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Andreas Lamerz, Bennett Leventhal, Andrea G. Ludolph, Claudia Lühr da Silva, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Astrid Morer, Alexander Münchau, Tara L. Murphy, Cara Nasello, Thaïra J.C. Openneer, Kerstin J. Plessen, Veit Roessner, Stephan Sanders, Eun-Young Shin, Deborah A. Sival, Dong-Ho Song, Jungeun Song, Anne Marie Stolte, Nawei Sun, Jennifer Tübing, Frank Visscher, Michael F. Walker, Sina Wanderer, Shuoguo Wang, Martin Woods, Yeting Zhang, Anbo Zhou, Samuel H. Zinner, Cathy L. Barr, James R. Batterson, Cheston Berlin, Ruth D. Bruun, Cathy L. Budman, Danielle C. Cath, Sylvain Chouinard, Nancy J. Cox, Sabrina Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Matthew E. Hirschtritt, Cornelia Illmann, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. MaMahon, Michael S. Okun, Lisa Osiecki, David L. Pauls, Danielle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Psychiatry, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Reproduction & Development (AR&D), Human genetics, Other departments, and Child Psychiatry

Subjects
0301 basic medicine, Proband, Adult, Male, Parents, INTELLECTUAL DISABILITY, FUNCTIONAL GENOMICS EXPERIMENTS, DNA-SEQUENCING DATA, AUTISM SPECTRUM DISORDERS, Cell Cycle Proteins, Receptors, Cell Surface, Biology, medicine.disease_cause, Bioinformatics, Tourette syndrome, Article, TIC DISORDERS, Cohort Studies, 03 medical and health sciences, medicine, Odds Ratio, Missense mutation, Humans, Genetic Predisposition to Disease, Copy-number variation, Child, Gene, Exome sequencing, Genetics, COPY NUMBER VARIANTS, Mutation, MUTATIONS, General Neuroscience, PSYCHIATRIC-DISORDERS, Intracellular Signaling Peptides and Proteins, Genetic Variation, Proteins, NIPBL, OBSESSIVE-COMPULSIVE DISORDER, LANGE-SYNDROME, Sequence Analysis, DNA, medicine.disease, Cadherins, Phosphoproteins, Fibronectins, 030104 developmental biology, Female, Tourette Syndrome
Abstract

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. Video Abstract [Figure presented]

Published
2017

39. Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder

Author

Gary A. Heiman, Pablo Mir, Jennifer Tübing, Yun Joo Koh, Julie Hagstrøm, Donald L. Gilbert, Andreas Lamerz, Thaïra J.C. Openneer, Els van den Ban, Jungeun Song, Jay A. Tischfield, Barbara J. Coffey, Mohamed Abdulkadir, Young Key Kim, Blanca Garcia-Delgar, Matthew W. State, Chaim Huyser, Alexander Münchau, Laura Ibanez-Gomez, Kerstin J. Plessen, Tamasine Hedderly, Keun-Ah Cheon, Thomas V. Fernandez, Odette Fründt, Andrea G. Ludolph, Marcos Madruga-Garrido, Isobel Heyman, Andrea Dietrich, Anne Marie Stolte, Athanasios Maras, Lawrence W. Brown, Robert A. King, Deborah A Sival, Sodahm Kook, Samuel Kuperman, Astrid Morer, Marieke D. Messchendorp, Samuel H. Zinner, Lonneke Elzerman, Dorothy E. Grice, Veit Roessner, Sebastian F T M de Bruijn, Sina Wanderer, Dong-Ho Song, Judith J G Rath, Pieter J. Hoekstra, Martin Woods, Young Shin Kim, Tara Murphy, Bennett L. Leventhal, Hyun Ju Hong, Eun Young Shin, Frank Visscher, Child and Adolescent Psychiatry / Psychology, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Child Psychiatry, and ANS - Compulsivity, Impulsivity & Attention

Subjects
Male, Pediatrics, Tic disorder, Obsessive-Compulsive Disorder, SYMPTOMS, CHILDREN, Neurodegenerative, Low Birth Weight and Health of the Newborn, Medical and Health Sciences, Tourette syndrome, Severity of Illness Index, 0302 clinical medicine, Pregnancy, Infant Mortality, Morning sickness, ADOLESCENTS, 80 and over, Obsessive-compulsive disorder, 2.1 Biological and endogenous factors, Prenatal, LOW-BIRTH-WEIGHT, MATERNAL SMOKING, Aetiology, Young adult, Parent-Child Relations, Child, Pediatric, Psychiatry, Aged, 80 and over, TIC-SEVERITY-SCALE, Age Factors, Middle Aged, Serious Mental Illness, PRENATAL RISK-FACTORS, Europe, Psychiatry and Mental health, Mental Health, PREGNANCY, Child, Preschool, Female, medicine.symptom, Attention-deficit hyperactivity disorder, Psychology, Delivery, Adult, medicine.medical_specialty, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Article, 03 medical and health sciences, Young Adult, Sex Factors, Clinical Research, Preterm, Severity of illness, mental disorders, Republic of Korea, medicine, Attention deficit hyperactivity disorder, ADHD, Humans, Preschool, Biological Psychiatry, Aged, Retrospective Studies, Psychiatric Status Rating Scales, Psychology and Cognitive Sciences, Neurosciences, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), United States, Brain Disorders, 030227 psychiatry, Pregnancy Complications, Low birth weight, Good Health and Well Being, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Tic Disorders, Chronic Tic Disorder, 030217 neurology & neurosurgery
Abstract

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR=1.72) and morning sickness requiring medical attention (OR=2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR=1.07). Furthermore, neonatal complications were related to the presence (OR=1.46) and severity (b=2.27) of co-occurring OCD and also to ADHD severity (b=1.09). Delivery complications were only related to co-occurring OCD (OR=1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

Published
2016

42. Transforming Motivation for Exercise in a Safe and Kind Environment-A Qualitative Study of Experiences among Individuals with Type 2 Diabetes.

Author

Nielsen SG, Danielsen JH, Grønbæk HN, Molsted S, Jacobsen SS, Vilsbøll T, and Varming AR

Subjects
Exercise, Exercise Therapy, Humans, Qualitative Research, Diabetes Mellitus, Type 2 therapy, Motivation
Abstract

Exercise is a cornerstone in diabetes care; however, adherence is low and sustaining physical activity remains a challenge. Patient-centered diabetes self-management education and support are recommended; however, sparse literature exists on how to design exercise interventions that improve self-management in individuals with complications of type 2 diabetes mellitus (T2D). We aimed to gain insights into needs, barriers, and motivation based on experiences with exercise participation among individuals with T2D and complications to adjust and develop new types of tailored, supervised exercise classes in specialized care at three hospitals in Denmark. In keeping with a constructivist research paradigm, a qualitative hermeneutic approach using focus group interviews was applied to explore perspectives among different participants in terms of disease severity. Seven interviews with 30 participants (aged 49-88) representing seven different exercise classes, were conducted over three years. Reflective thematic analysis was used. Four themes were generated: People like us, Getting started with exercise, Game changers, and Moving forward. An overarching theme 'The transformation of motivation when exercising in a safe and kind environment' links the themes together, resembling the participants' development of physical literacy encompassing motivation, confidence, physical competence as well as an ability to value physical activity. Supportive patient-centered exercise classes promoted a transformation of motivation grounded in the development of physical literacy among participants in specialized diabetes care. However, participants were concerned with continuing to exercise on their own after the intervention, as they experienced a lack of continuous, supervised exercise opportunities in local communities.

Published
2022
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43. Effectiveness and acceptability of a pragmatic exercise intervention for patients with type 2 diabetes in specialized care.

Author

Nielsen SG, Danielsen JH, Jacobsen SS, Kristensen PL, Storgaard H, Molsted S, and Vilsbøll T

Subjects
Exercise, Exercise Therapy, Humans, Psychometrics, Surveys and Questionnaires, Diabetes Mellitus, Type 2 therapy, Quality of Life
Abstract

Aims: Physical activity improves glycaemic control in type 2 diabetes (T2D), but adherence is low, and diabetes complications are barriers towards adopting physical activity. We investigated adherence and effects of individualized supervised exercise., Methods: Patients with intermediate (level 2) to high (level 3) risk of complications to T2D (stratified by Danish risk stratification model) were offered 12 weeks of exercise. Primary outcomes were working capacity assessed with the Åstrand-Rhyming cycling test (Åstrand), functional capacity assessed with the 30-second chair-stand test(30 s-CST) and health-related quality of life assessed with EuroQoL-5D-5L (EQ-5D-5L). Associations between stratification levels (2vs3) and drop-out, changes in 30 s-CST and EQ-5D-5L were analysed using multiple regression., Results: In total 350 patients accepted participation and 254 (73%) completed with 26 patients experiencing an adverse event. Odds ratio (OR) for non-completion were 1.82 [1.02-3.23] (p = 0.043) for patients stratified level 3 vs 2.Improvements were seen in Åstrand 2.71 [1.59; 3.83] ml O 2 /kg/min (p < 0.001), in 30 s-CST2.34 [2.01; 2.67] repetitions (p < 0.001) andin EQ-5D-5L 0.01 (-0.05 to 0.11) (p = 0.002). There were no associations between changes and risk-stratification levels., Conclusions: Clinically relevant changes were seen after exercising regardless of the stratification levels in patients with intermediate to high risk of complications to T2D., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.G.N., J.H.D., S.S.J. and S.M. had no interests to declare. H.S. has served on scientific advisory panels for Boehringer Ingelheim and Novo Nordisk. P.L.K. has received speaker fee from Novo Nordisk A/S, Boehringer Ingelheim A/S and Astra Zeneca A/S. T.V. has served on scientific advisory panels and/or speakers’ bureaus or has served as a consultant to and/or received research support from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Gilead, MSD/Merck, Mundipharma, Novo Nordisk, Sanofi, and SunPharmaceuticals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Published
2022
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