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Geneva VCFS longitudinal project: neurobehavioral outcomes in adolescents and adults

English title Geneva VCFS longitudinal project: neurobehavioral outcomes in adolescents and adults
Applicant Eliez Stephan
Number 121996
Funding scheme Project funding (special)
Research institution DIP - Office médico-pédagogique
Institution of higher education University of Geneva - GE
Main discipline Neurology, Psychiatry
Start/End 01.10.2009 - 31.03.2013
Approved amount 528'183.00
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Keywords (8)

VCFS; deletion 22q11; Longitudinal study; Brain; Neurobehavioral phenotype; Neuroimaging; velo-cardio-facial syndrome; Psychosis

Lay Summary (English)

Lead
Lay summary
The proposed project focuses on adolescents and adults with velo-cardio-facial syndrome (VCFS), a developmental disorder due to a deletion on chromosome 22. In addition to the physical and neuronanatomical anomalies associated with the condition, affected individuals almost always present cognitive deficits and psychological problems. Previous studies have suggested that these psychiatric symptoms may underlie the high incidence of schizophrenia in the syndrome, occurring in 30% of affected adults. Given the rare homogeneity and frequency of psychosis in VCFS, the identification of specific risk factors in affected individuals can greatly contribute to our understanding of the basis of schizophrenia in general. This requires, however, careful longitudinal study of development in VCFS to examine psychosis within the context of the disorder.We are fortunate to have developed the most thoroughly documented longitudinal cohort in Europe, whom we have closely monitored since 2001 for cerebral, cognitive and behavioral changes. This proposal requests funding for a third timepoint that will allow us to follow participating of a hundred subjects through adolescence and into adulthood, the developmental phase most associated with the onset of psychosis. We will study genetic factors involved in VCFS, observe their influence on brain structure over time, and demonstrate their subsequent contributions to the development of emotional, behavioral and cognitive problems. Moreover, we will test whether differential patterns of brain function are observed in specific sub-regions, also associated with structural brain changes, and if these patterns are correlated with cognitive and behavioral characteristics of VCFS. Finally, we seek to compare the identified changes in individuals with and without psychotic symptoms during the critical period of adolescence and young adulthood to understand developmental risk factors that signal vulnerability for psychosis.This project opens new avenues for understanding individuals with developmental disorders and monitor the onset of psychosis in some individuals, by measuring changes in both brain and behavior. The combined use of evaluation and brain imaging will greatly contribute to general knowledge of socio-emotional impairments and the underlying structure and function of the brain. In addition to these scientific contributions, the project has the potential to improve education and treatment of individuals with VCFS, thereby improving the skills they will need to go on to live autonomously.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?
Ottet Marie-Christine, Schaer Marie, Cammoun Leila, Schneider Maude, Debbané Martin, Thiran Jean-Philippe, Eliez Stephan (2013), Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?, in PloS one, 8(3), 58429-58429.
Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?
Ottet Marie-Christine, Schaer Marie, Cammoun Leila, Schneider Maude, Debbané Martin, Thiran Jean-Philippe, Eliez Stephan (2013), Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?, in PloS one, 8(3), 58429-58429.
Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.
Delio Maria, Guo Tingwei, McDonald-McGinn Donna M, Zackai Elaine, Herman Sean, Kaminetzky Mark, Higgins Anne Marie, Coleman Karlene, Chow Carolyn, Jarlbrzkowski Maria, Bearden Carrie E, Bailey Alice, Vangkilde Anders, Olsen Line, Olesen Charlotte, Skovby Flemming, Werge Thomas M, Templin Ludivine, Busa Tiffany, Philip Nicole, Swillen Ann, Vermeesch Joris R, Devriendt Koen, Schneider Maude, Dahoun Sophie (2013), Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes., in American journal of human genetics, 92(3), 439-47.
Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.
Delio Maria, Guo Tingwei, McDonald-McGinn Donna M, Zackai Elaine, Herman Sean, Kaminetzky Mark, Higgins Anne Marie, Coleman Karlene, Chow Carolyn, Jarlbrzkowski Maria, Bearden Carrie E, Bailey Alice, Vangkilde Anders, Olsen Line, Olesen Charlotte, Skovby Flemming, Werge Thomas M, Templin Ludivine, Busa Tiffany, Philip Nicole, Swillen Ann, Vermeesch Joris R, Devriendt Koen, Schneider Maude, Dahoun Sophie (2013), Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes., in American journal of human genetics, 92(3), 439-47.
How to measure cortical folding from MR images: a step-by-step tutorial to compute local gyrification index.
Schaer Marie, Cuadra Meritxell Bach, Schmansky Nick, Fischl Bruce, Thiran Jean-Philippe, Eliez Stephan (2012), How to measure cortical folding from MR images: a step-by-step tutorial to compute local gyrification index., in Journal of visualized experiments : JoVE, (59), 3417-3417.
Candidate socioemotional remediation program for individuals with intellectual disability.
Glaser Bronwyn, Lothe Amelie, Chabloz Mélanie, Dukes Daniel, Pasca Catherine, Redoute Jérôme, Eliez Stephan (2012), Candidate socioemotional remediation program for individuals with intellectual disability., in American journal on intellectual and developmental disabilities, 117(5), 368-83.
Evaluation of PRDM9 variation as a risk factor for recurrent genomic disorders and chromosomal non-disjunction.
Borel Christelle, Cheung Fanny, Stewart Helen, Koolen David A, Phillips Christopher, Thomas N Simon, Jacobs Patricia A, Eliez Stephan, Sharp Andrew J (2012), Evaluation of PRDM9 variation as a risk factor for recurrent genomic disorders and chromosomal non-disjunction., in Human genetics, 131(9), 1519-24.
Resting-state networks in adolescents with 22q11.2 deletion syndrome: associations with prodromal symptoms and executive functions.
Debbané Martin, Lazouret Marine, Lagioia Annalaura, Schneider Maude, Van De Ville Dimitri, Eliez Stephan (2012), Resting-state networks in adolescents with 22q11.2 deletion syndrome: associations with prodromal symptoms and executive functions., in Schizophrenia research, 139(1-3), 33-9.
Associations among metacognitive beliefs, anxiety and positive schizotypy during adolescence.
Debbané Martin, Van der Linden Martial, Balanzin Dario, Billieux Joël, Eliez Stephan (2012), Associations among metacognitive beliefs, anxiety and positive schizotypy during adolescence., in The Journal of nervous and mental disease, 200(7), 620-6.
Depression and anxiety disorders in children and adolescents with velo-cardio-facial syndrome (VCFS).
Fabbro Alice, Rizzi Eleonora, Schneider Maude, Debbane Martin, Eliez Stephan (2012), Depression and anxiety disorders in children and adolescents with velo-cardio-facial syndrome (VCFS)., in European child & adolescent psychiatry, 21(7), 379-85.
Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): a longitudinal study of morphometry and symptomatology.
Flahault Astrid, Schaer Marie, Ottet Marie-Christine, Debbané Martin, Eliez Stephan (2012), Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): a longitudinal study of morphometry and symptomatology., in Psychiatry research, 203(1), 1-5.
Comparing the neural bases of self-referential processing in typically developing and 22q11.2 adolescents.
Schneider Maude, Debbané Martin, Lagioia Annalaura, Salomon Roy, d'Argembeau Arnaud, Eliez Stephan (2012), Comparing the neural bases of self-referential processing in typically developing and 22q11.2 adolescents., in Developmental cognitive neuroscience, 2(2), 277-89.
Preliminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome.
Schneider Maude, Van der Linden Martial, Glaser Bronwyn, Rizzi Eleonora, Dahoun Sophie P, Hinard Christine, Bartoloni Lucia, Antonarakis Stylianos E, Debbané Martin, Eliez Stephan (2012), Preliminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome., in Psychiatry research, 196(2-3), 277-84.
Cognition and the VCFS Brain: the implications of syndrome specific deficits for school performance
Glaser Bronwyn, Eliez Stephan (2012), Cognition and the VCFS Brain: the implications of syndrome specific deficits for school performance, in Cutler-Landsman D. (ed.), 49-71.
[Validation study of the French schizotypal personality questionnaire in a sample of adolescents: A confirmatory factor analysis].
Badoud D, Chanal J, Van der Linden M, Eliez S, Debbané M (2011), [Validation study of the French schizotypal personality questionnaire in a sample of adolescents: A confirmatory factor analysis]., in L'Encéphale, 37(4), 299-307.
[Time processing in the velo-cardio-facial syndrome (22q11) and its link with the caudate nucleus].
Gabriel Mounir D, Debbané M, Schaer M, Glaser B, Eliez S (2011), [Time processing in the velo-cardio-facial syndrome (22q11) and its link with the caudate nucleus]., in L'Encéphale, 37 Suppl 1, 1-9.
Neural correlates of reality monitoring during adolescence.
Lagioia AnnaLaura, Eliez Stephan, Schneider Maude, Simons Jon S, Van der Linden Martial, Debbané Martin (2011), Neural correlates of reality monitoring during adolescence., in NeuroImage, 55(3), 1393-400.
Adolescent resting state networks and their associations with schizotypal trait expression.
Lagioia Annalaura, Van De Ville Dimitri, Debbané Martin, Lazeyras François, Eliez Stephan (2010), Adolescent resting state networks and their associations with schizotypal trait expression., in Frontiers in systems neuroscience, 4, 1-12.
Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome.
Schaer Marie, Glaser Bronwyn, Ottet Marie-Christine, Schneider Maude, Bach Cuadra Meritxell, Debbané Martin, Thiran Jean-Philippe, Eliez Stephan (2010), Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome., in Journal of neurodevelopmental disorders, 2(4), 224-234.
Visual processing and social cognition in children and adolescents with autistic traits
Debbané M., Murray R., Damsa C., Cocchi L., Glaser B., Eliez S. (2010), Visual processing and social cognition in children and adolescents with autistic traits, in Neuropsychiatrie de l'enfance et de l'adolescence, 58(8), 368-463.
Monitoring of self-generated speech in adolescents with 22q11.2 deletion syndrome.
Debbané Martin, Van der Linden Martial, Glaser Bronwyn, Eliez Stephan (2010), Monitoring of self-generated speech in adolescents with 22q11.2 deletion syndrome., in The British journal of clinical psychology / the British Psychological Society, 49(Pt 3), 373-86.
Eye gaze during face processing in children and adolescents with 22q11.2 deletion syndrome.
Glaser Bronwyn, Debbané Martin, Ottet Marie-Christine, Vuilleumier Patrik, Zesiger Pascal, Antonarakis Stylianos E, Eliez Stephan (2010), Eye gaze during face processing in children and adolescents with 22q11.2 deletion syndrome., in Journal of the American Academy of Child and Adolescent Psychiatry, 49(7), 665-74.
[22q11.2 microdeletion].
Schneider M, Eliez S (2010), [22q11.2 microdeletion]., in Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie, 17(4), 431-4.
Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study.
Schaer Marie, Debbané Martin, Bach Cuadra Meritxell, Ottet Marie-Christine, Glaser Bronwyn, Thiran Jean-Philippe, Eliez Stephan (2009), Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study., in Schizophrenia research, 115(2-3), 182-90.
Prefrontal plasticity and stress inoculation-induced resilience.
Katz Maor, Liu Chunlei, Schaer Marie, Parker Karen J, Ottet Marie-Christine, Epps Averi, Buckmaster Christine L, Bammer Roland, Moseley Michael E, Schatzberg Alan F, Eliez Stephan, Lyons David M (2009), Prefrontal plasticity and stress inoculation-induced resilience., in Developmental neuroscience, 31(4), 293-9.
Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome.
Schaer Marie, Glaser Bronwyn, Cuadra Meritxell Bach, Debbane Martin, Thiran Jean-Philippe, Eliez Stephan (2009), Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome., in Developmental medicine and child neurology, 51(9), 746-53.
Differential development of selectivity for faces and bodies in the fusiform gyrus.
Peelen Marius V, Glaser Bronwyn, Vuilleumier Patrik, Eliez Stephan (2009), Differential development of selectivity for faces and bodies in the fusiform gyrus., in Developmental science, 12(6), 16-25.
Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome.
Green Tamar, Gothelf Doron, Glaser Bronwyn, Debbane Martin, Frisch Amos, Kotler Moshe, Weizman Abraham, Eliez Stephan (2009), Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome., in Journal of the American Academy of Child and Adolescent Psychiatry, 48(11), 1060-8.
Contribution of structural brain imaging to our understanding of cortical development process
Schaer M., Eliez S. (2009), Contribution of structural brain imaging to our understanding of cortical development process, in European Psychiatry Review, 2(1), 13-16.
Adaptive strategy for the statistical analysis of connectomes.
Meskaldji Djalel Eddine, Ottet Marie-Christine, Cammoun Leila, Hagmann Patric, Meuli Reto, Eliez Stephan, Thiran Jean Philippe, Morgenthaler Stephan, Adaptive strategy for the statistical analysis of connectomes., in PloS one, 6(8), e23009-e23009.
Hippocampal volume reduction in 22q11.2DS: a morphometric and symptomatic longitudinal study
Flahaut A, Schaer M, Ottet M.-C., Debbané M., Eliez S., Hippocampal volume reduction in 22q11.2DS: a morphometric and symptomatic longitudinal study, in Psychiatry Research: Neuroimaging, 6.
Practical guidelines for managing patients with 22q11.2 deletion syndrome.
Bassett Anne S, McDonald-McGinn Donna M, Devriendt Koen, Digilio Maria Cristina, Goldenberg Paula, Habel Alex, Marino Bruno, Oskarsdottir Solveig, Philip Nicole, Sullivan Kathleen, Swillen Ann, Vorstman Jacob, International 22q11.2 Deletion Syndrome Consortium, Practical guidelines for managing patients with 22q11.2 deletion syndrome., in The Journal of pediatrics, 159(2), 332.
Prelminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome
Van der Linden M., Glaser B., Rizzi E., Dahoun S.P., Antonarakis S.E., Debbané M., Eliez S., Prelminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome, in Psychiatry Research, 7.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Relais 22 General Assembly (association de familles) 17.11.2012 Bruxelles
Lemanic Neuroscience Annual Meeting (LNAM) 28.09.2012 Les Diablerets
22q11 congress (association de familles danoises) 22.09.2012 Copenhague, Danemark
8th Biennial International 22q11.2 DS Conference 07.07.2012 Orlando, USA
Society of Biological Psychiatry's 67th Annual Meeting 03.05.2012 Philadelphie, USA
BBL/CIBM reserach day 18.04.2012 Genève
Symbiosium 2012 organisé par association de familles Génération 22 02.03.2012 Paris
Connect 22 general assembly (association de familles) 05.11.2011 Genève
17th Annual IPA research training program 11.08.2011 London
7th Biennal International 22q11.2 Deletion Syndrome Conference 29.07.2011 Coventry, UK
18th Annual International Scientific Meeting. The Velo-Cardio-Facial Syndrome Educational Foundation, Inc. 14.07.2011 New Brunswick, USA
European Society for Child and Adolescent Psychiatry 11.06.2011 Helsinki, Finland
European Association of Child and Adolescent Psychopathology (AEPEA) 05.05.2011 Bologna, Italy
Brain & Mind Seminar 16.03.2011 Geneva, Switzerland
Brain Week 14.03.2011 Geneva, Switzerland
38th Conference of the SENP 11.03.2011 Geneva, Switzerland
Brain Meeting Seminar 01.02.2011 Lausanne, Switzerland
16th Biennal Winter Workshop in Psychoses 30.01.2011 Innsbruck, Austria
Lemanic Neuroscience Annual Meeting 29.10.2010 Geneva, Switzerland
17th Annual Internatinal Scientific Meeting of the Velo-Cardio-Facial Syndrome Educational Foundation 17.07.2010 Salt Lake City, Utah, USA
2nd Meeting organized of the V.A.L.D. Network 18.06.2010 Montpellier, France
Generation 22 General Assembly 13.03.2010 Paris, France
Gen 22 05.12.2009 Lyon, France
Relais 22 General Assembly 21.11.2009 Brussels, Belgium
22q11 29.10.2009 Dublin, Ireland
16th Annual International Scientific Meeting of the Velo-Cardio-Facial Syndrome Educational Foundation 03.07.2009 Rome, Italy
Generation 22 General Assembly 19.03.2009 Paris, France


Self-organised

Title Date Place
Connect 22 General Assembly 06.10.2011 Geneva, Switzerland
1st 22q11.2. Deletion Syndrome Workshop in cognitive neuroscience and neuroimaging 05.02.2011 Geneva, Switzerland
Connect 22 General Assembly 10.10.2009 Geneva, Switezerland

Knowledge transfer events



Self-organised

Title Date Place
Connect 22 General Assembly 06.11.2010 Geneva, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Brain Week Western Switzerland 14.03.2011

Associated projects

Number Title Start Funding scheme
144260 Swiss VCFS Cohort: a 10-year longitudinal investigation from genes to brain to cognition for understanding psychosis proneness in 22q11.2 deletion 01.04.2013 Project funding (special)
63135 Neurobehavioral Phenotype and Brain Development in velo-cardio- facial syndrome (de122q11.2). (zu SCORE B) 01.10.2001 Project funding
102864 Neurobehavioral Phenotype and Brain Development in velo-cardio-facial syndrome (del22q11.2) - a longitudinal study 01.10.2004 SNSF Professorships
144260 Swiss VCFS Cohort: a 10-year longitudinal investigation from genes to brain to cognition for understanding psychosis proneness in 22q11.2 deletion 01.04.2013 Project funding (special)
179404 The Swiss 22q11DS longitudinal cohort: understanding psychosis proneness through negative symptoms 01.10.2018 Project funding

Abstract

Velo-cardio-facial syndrome (VCFS) is the result of the most frequent interstitial deletion, affecting at least 1 per 4000 live births. In addition to the physical and neuronanatomical anomalies associated with the condition, affected individuals almost always present cognitive deficits and psychological problems, among which high rates of social withdrawal, mood problems and psychotic manifestations figure most conspicuously. Previous studies have suggested that these psychiatric symptoms may underlie the high incidence of schizophrenia in the syndrome, occurring in 30% of affected adults. Given the rare homogeneity and frequency of psychosis in VCFS, the identification of specific risk factors in affected individuals can greatly contribute to our understanding of the basis of schizophrenia in general. This requires, however, careful longitudinal study of development in VCFS to examine psychosis within the context of the disorder. For this reason, longitudinal research is essential for determining how changes in brain structure influence brain function, and produce subsequent cognitive, behavioral, and psychiatric outcomes. Given that VCFS and its associated symptoms result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations between genes, brain development, and behavior throughout development. However, detection of the deletion and the means necessary to follow affected individuals longitudinally is rare; we are fortunate to have developed the most thoroughly documented longitudinal cohort in Europe, whom we have closely monitored since 2001 for cerebral, cognitive and behavioral changes. This proposal requests funding for a third timepoint that will allow us to follow participating subjects through adolescence and into adulthood, the developmental phase most associated with the onset of psychosis. The goals of this proposal and for the continuation of our longitudinal work are twofold: First, to continue data collection into adolescence and early adulthood to be able to continue to identify genetic factors involved in VCFS, observe their influence on brain structure over time, and demonstrate their subsequent contributions to the development of emotional, behavioral and cognitive problems. Moreover, we will test whether differential functional patterns are observed in sub-regions with detectable structural changes, and if these patterns are correlated with cognitive and behavioral characteristics of the VCFS phenotype. Second, we seek to compare the identified changes in individuals with and without psychotic symptoms during the critical period of adolescence and young adulthood to understand developmental risk factors that signal vulnerability for psychosis.These goals concretely translate into a project that has stayed consistent in its longitudinal structure and approach, while making room for new methodology and the testing of specific hypotheses. Indeed, changes in cortical morphology between persons with VCFS and comparison subjects and between individuals with VCFS with and without psychosis have been observed, thanks to new techniques for three-dimensional quantification of gyral folding, cortical thickness and volume. These new techniques are cutting edge, but our consistent neuroimaging protocol has allowed us to apply them to all previously collected data at the first two timepoints, increasing our sensitivity to cerebral change. Moreover, the structure of the ongoing longitudinal study also allows for innovation at each timepoint, enabling us to test candidate risk factors for psychosis as we go. In the enclosed proposal, we propose a series of functional neuroimaging experiments targeting visual perception, social cognition and functional specificity in cortical networks in VCFS. These experiments will provide important information about cortical development, helping to bridge longitudinal results in structural imaging with both cognitive and behavioral observations. Benefits from the Geneva Longitudinal Project are numerous. In addition to adding to knowledge about the intersection between genes, brain development, and psychiatric risk, this project concurrently provides participating families with developmental evaluations and up-to-date information about their child’s academic and psychiatric needs, contributes to individuals with similar syndromes by furnishing a model for documenting developmental trajectories within the framework of a specific neurodevelopmental disorder, and directly contributes to knowledge of some of the most frequent psychiatric disorders (anxiety disorder, ADHD, psychosis). Finally, strong interest in the study by colleagues in local Radiology, Neuroscience, Signal Processing, and Psychiatry departments has triggered innovative and fruitful collaborations that merge research expertise in Switzerland and push scientific knowledge forward.
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