Brain morphology in Anorexia Nervosa and its subtypes: A multi-cohort study of individual participant data.
Authors
Affiliations (29)
Affiliations (29)
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
- Maurice Wohl Clinical Neuroscience Institute, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
- Centre de recherche CHU Sainte Justine, Department of Psychiatry and Addictology, University of Montreal, Montreal, Québec, Canada.
- Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway.
- Department of Neurosciences 'Rita Levi Montalcini', University of Turin, Turin, Italy.
- Eating Disorders Center for Treatment and Research, University of Turin, Turin, Italy.
- PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
- Division of Mental Health and Substance Abuse, Diakonhjemmet Hospital, Oslo, Norway.
- Centre for Research in Eating and Weight Disorders, Institute of Psychitry, Psychology and Neuroscience, King's College London, London, United Kingdom.
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
- Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
- Eating Disorders Center for Treatment and Research, University of California San Diego, La Jolla, California, United States of America.
- Department of Child and Adolescent Psychiatry, Bielefeld University, Medical School and University Medical Center OWL, Protestant Hospital of the Bethel Foundation, Bielefeld, Germany.
- Department of Child and Adolescent Psychiatry, University Clinic Erlangen, Erlangen, Germany.
- Institute of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, University of Erlangen-Nuremberg, Erlangen, Germany.
- Department of Neuroradiology, University of Erlangen-Nuremberg, Erlangen, Germany.
- FAU NeW - Research Center for New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
- Centre for Psychosocial Medicine, Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany.
- Padova Neuroscience Center, Department of Neurosciences, University of Padova, Padova, Italy.
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, United States of America.
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
- UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.
- Altrecht Eating Disorders Rintveld, Altrecht Mental Health Institute, Zeist, the Netherlands.
- Faculty of Social Sciences, Utrecht University, Utrecht, the Netherlands.
- Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
- Imaging Genetics Center, Stevens Institute for Neuroimaging and Informatics, Keck USC School of Medicine, Marina del Rey, California, United States of America.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
- Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Dresden University of Technology, Dresden, Germany.
Abstract
In a recent coordinated meta-analysis of neuroimaging data, we reported gray matter (GM) alterations in acutely underweight patients with anorexia nervosa (AN). Here, we extend these findings by examining individual variation in brain structure within AN, individual-level differentiation between AN and healthy controls (HC), and differences between AN subtypes, with potential relevance for understanding clinical heterogeneity. We analyzed individual-level data from 11 international sites in the ENIGMA Eating Disorders Working Group, including 570 female participants with AN and 739 HC. We examined cortical thickness, cortical surface area and subcortical volumes in AN versus HC using three complementary approaches: (i) group-level differences in a mega-analysis correcting for age effects, (ii) frequencies of extreme deviations (infra-/supranormal; z < -1.96/z > 1.96) based on normative reference models by the CentileBrain Initiative, and (iii) individual-level classification performance using machine learning. The same analytic framework was applied to compare AN restricting versus binge-eating/purging subtype, additionally correcting for BMI effects. Mega-analyses reinforced previous meta-analytic findings of pronounced and widespread GM deficits in AN compared to HC. Normative modelling revealed that the frequency of infranormal z-scores (23/68 cortical thickness, 13/14 subcortical volume metrics) and supranormal z-scores (35/68 cortical thickness, 17/68 cortical surface area metrics) was significantly higher in AN than expected based on reference data. Individuals with AN could be reliably differentiated from HC using machine-learning classifiers (ROC-AUC = 0.75-0.81). In contrast, neither group-level differences nor frequency of extreme z-scores differed between AN subtypes, and individuals with different subtypes could not be reliably differentiated from each other. Importantly, the observational design cannot distinguish neurobiological differences related to AN from the effects of starvation or low BMI in the AN versus HC analyses. The lack of differences between subtypes does not exclude brain structural differences between AN subtypes that might be detectable with other modalities or analytic approaches. Using a mega-analytic approach, we confirm widespread GM deficits in AN, show that these alterations are (in some patients) extreme, and demonstrate that they enable robust classification with superior performance compared to most MRI-based psychiatric classification studies. The absence of differences between AN subtypes may reflect shared neurobiology, though other imaging modalities may reveal distinctions beyond brain structure.