. 2022 May 6;12(1):188.

doi: 10.1038/s41398-022-01956-4.

Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

Max M Owens¹, Matthew D Albaugh², Nicholas Allgaier², Dekang Yuan², Gabriel Robert^{3

4

5}, Renata B Cupertino², Philip A Spechler⁶, Anthony Juliano², Sage Hahn², Tobias Banaschewski⁷, Arun L W Bokde⁸, Sylvane Desrivières⁹, Herta Flor^{10

11}, Antoine Grigis¹², Penny Gowland¹³, Andreas Heinz¹⁴, Rüdiger Brühl¹⁵, Jean-Luc Martinot¹⁶, Marie-Laure Paillère Martinot^{17

18}, Eric Artiges¹⁹, Frauke Nees^{7

10

20}, Dimitri Papadopoulos Orfanos¹², Herve Lemaitre^{12

21}, Tomáš Paus^{22

23

24}, Luise Poustka²⁵, Sabina Millenet⁷, Juliane H Fröhner²⁶, Michael N Smolka²⁶, Henrik Walter¹⁴, Robert Whelan²⁷, Scott Mackey², Gunter Schumann^{28

29}, Hugh Garavan²; IMAGEN Consortium

Collaborators, Affiliations

Affiliations

¹ Department of Psychiatry, University of Vermont Larner College of Medicine, Burlington, VT, USA. owensmax03@gmail.com.
² Department of Psychiatry, University of Vermont Larner College of Medicine, Burlington, VT, USA.
³ Psychiatry Department, University of Rennes 1, Rennes, France.
⁴ Adult University Psychiatry Department, Guillaume Régnier Hospital, Rennes, France.
⁵ U1288 Empenn, UMR 6074, IRISA, Rennes, France.
⁶ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁷ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁸ Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁹ Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College London, London, UK.
¹⁰ Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany.
¹¹ Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
¹² NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France.
¹³ Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK.
¹⁴ Department of Psychiatry and Psychotherapy Campus Charité Mitte, Charité-Universitätsmedizin, corporate member of Freie Universität Berlin & Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁵ Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Braunschweig, Germany.
¹⁶ Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie"; Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.
¹⁷ Institut National de la Santé et de la Recherce Médicale, INSERM U A10 "Trajectoires développementales & psychiatrie", University Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS; Centre Borelli, Gif-sur-Yvette, France.
¹⁸ AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.
¹⁹ Institut National de la Santé et de la Recherche Médicale, INSERM U1299 "Trajectoires développementales en psychiatrie"; Ecole Normale supérieure Paris-Saclay, Université Paris-Saclay, Université de Paris, Centre Borelli; Gif-sur-Yvette, & Department of Psychiatry, EPS Barthélémy Durand, Etampes, France.
²⁰ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany.
²¹ Institut des Maladies Neurodégénératives, CNRS UMR 5293, Université de Bordeaux, Centre Broca Nouvelle-Aquitaine, Bordeaux, France.
²² Departments of Psychiatry and Neuroscience, Faculty of Medicine and Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
²³ Departments of Psychology, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.
²⁶ Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
²⁷ School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
²⁸ Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
²⁹ Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China.

PMID: 35523763
PMCID: PMC9076659
DOI: 10.1038/s41398-022-01956-4

Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

Max M Owens et al. Transl Psychiatry. 2022.

. 2022 May 6;12(1):188.

doi: 10.1038/s41398-022-01956-4.

Authors

Affiliations

¹ Department of Psychiatry, University of Vermont Larner College of Medicine, Burlington, VT, USA. owensmax03@gmail.com.
² Department of Psychiatry, University of Vermont Larner College of Medicine, Burlington, VT, USA.
³ Psychiatry Department, University of Rennes 1, Rennes, France.
⁴ Adult University Psychiatry Department, Guillaume Régnier Hospital, Rennes, France.
⁵ U1288 Empenn, UMR 6074, IRISA, Rennes, France.
⁶ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁷ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁸ Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁹ Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College London, London, UK.
¹⁰ Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany.
¹¹ Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
¹² NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France.
¹³ Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK.
¹⁴ Department of Psychiatry and Psychotherapy Campus Charité Mitte, Charité-Universitätsmedizin, corporate member of Freie Universität Berlin & Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁵ Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Braunschweig, Germany.
¹⁶ Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie"; Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.
¹⁷ Institut National de la Santé et de la Recherce Médicale, INSERM U A10 "Trajectoires développementales & psychiatrie", University Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS; Centre Borelli, Gif-sur-Yvette, France.
¹⁸ AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.
¹⁹ Institut National de la Santé et de la Recherche Médicale, INSERM U1299 "Trajectoires développementales en psychiatrie"; Ecole Normale supérieure Paris-Saclay, Université Paris-Saclay, Université de Paris, Centre Borelli; Gif-sur-Yvette, & Department of Psychiatry, EPS Barthélémy Durand, Etampes, France.
²⁰ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany.
²¹ Institut des Maladies Neurodégénératives, CNRS UMR 5293, Université de Bordeaux, Centre Broca Nouvelle-Aquitaine, Bordeaux, France.
²² Departments of Psychiatry and Neuroscience, Faculty of Medicine and Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
²³ Departments of Psychology, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.
²⁶ Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
²⁷ School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
²⁸ Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
²⁹ Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China.

PMID: 35523763
PMCID: PMC9076659
DOI: 10.1038/s41398-022-01956-4

Abstract

While there is substantial evidence that cannabis use is associated with differences in human brain development, most of this evidence is correlational in nature. Bayesian causal network (BCN) modeling attempts to identify probable causal relationships in correlational data using conditional probabilities to estimate directional associations between a set of interrelated variables. In this study, we employed BCN modeling in 637 adolescents from the IMAGEN study who were cannabis naïve at age 14 to provide evidence that the accelerated prefrontal cortical thinning found previously in adolescent cannabis users by Albaugh et al. [1] is a result of cannabis use causally affecting neurodevelopment. BCNs incorporated data on cannabis use, prefrontal cortical thickness, and other factors related to both brain development and cannabis use, including demographics, psychopathology, childhood adversity, and other substance use. All BCN algorithms strongly suggested a directional relationship from adolescent cannabis use to accelerated cortical thinning. While BCN modeling alone does not prove a causal relationship, these results are consistent with a body of animal and human research suggesting that adolescent cannabis use adversely affects brain development.

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Conflict of interest statement

This work was funded by NIH/NIDA T32DA043593 and R01DA047119. MDA is supported by K08 MH121654 and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant “STRATIFY” (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant “c-VEDA” (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01), NSFC grant 82150710554 and environMENTAL grant. Further support was provided by grants from: - the ANR (ANR-12-SAMA-0004, AAPG2019 - GeBra), the Eranet Neuron (AF12-NEUR0008-01 - WM2NA; and ANR-18-NEUR00002-01 - ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. He received conference support or speaker’s fee by Lilly, Medice, Novartis, and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. Dr. Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. LP served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fee by Shire. She received royalties from Hogrefe, Kohlhammer, and Schattauer. The present work is unrelated to the above grants and relationships. The other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Fig. 1. Primary Analysis: Bayesian network model from the hill climbing algorithm.**
Boxes represent variables used in Bayesian Causal Network models. Yellow boxes are age 14 variables, green boxes are change from age 14 to 19 variables, and blue boxes are other variables of interest. Lines indicate a dependent relationship between two variables in at least 90% of 10,000 bootstrapped models (i.e., strength ≥90%). Arrows indicate directional of relationship found between two variables. S = strength, representing the percentage of bootstrapped models in which a dependent relationship was present. D = direction, representing the percentage of bootstrapped models with a dependent relationship in which a connection was in the direction shown in the figure. (f) = connection with direction pre-specified to fit with temporal ordering. Note: all participants were cannabis-naïve at age 14. All variables were residualized for site and sex.

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Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

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Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

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