. 2021 Nov;26(11):6806-6819.

doi: 10.1038/s41380-021-01098-x. Epub 2021 Apr 16.

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals

Sean R McWhinney¹, Christoph Abé², Martin Alda¹, Francesco Benedetti^{3

4}, Erlend Bøen⁵, Caterina Del Mar Bonnin⁶, Tiana Borgers⁷, Katharina Brosch⁸, Erick J Canales-Rodríguez⁹, Dara M Cannon¹⁰, Udo Dannlowski⁷, Ana M Díaz-Zuluaga¹¹, Torbjørn Elvsåshagen^{12

13

14}, Lisa T Eyler^{15

16}, Janice M Fullerton^{17

18}, Jose M Goikolea⁶, Janik Goltermann⁷, Dominik Grotegerd⁷, Bartholomeus C M Haarman¹⁹, Tim Hahn⁷, Fleur M Howells^{20

21}, Martin Ingvar², Tilo T J Kircher⁸, Axel Krug^{8

22}, Rayus T Kuplicki²³, Mikael Landén^{24

25}, Hannah Lemke⁷, Benny Liberg², Carlos Lopez-Jaramillo¹¹, Ulrik F Malt^{5

26}, Fiona M Martyn¹⁰, Elena Mazza^{3

4}, Colm McDonald¹⁰, Genevieve McPhilemy¹⁰, Sandra Meier¹, Susanne Meinert⁷, Tina Meller^{8

27}, Elisa M T Melloni^{3

4}, Philip B Mitchell²⁸, Leila Nabulsi¹⁰, Igor Nenadic⁸, Nils Opel⁷, Roel A Ophoff^{29

30}, Bronwyn J Overs¹⁷, Julia-Katharina Pfarr⁸, Julian A Pineda-Zapata³¹, Edith Pomarol-Clotet⁹, Joaquim Raduà^{2

6

32}, Jonathan Repple⁷, Maike Richter⁷, Kai G Ringwald⁸, Gloria Roberts²⁸, Raymond Salvador⁹, Jonathan Savitz^{23

33}, Simon Schmitt⁸, Peter R Schofield^{17

18}, Kang Sim^{34

35}, Dan J Stein^{20

21

36}, Frederike Stein⁸, Henk S Temmingh²¹, Katharina Thiel⁷, Neeltje E M van Haren^{37

38}, Holly Van Gestel¹, Cristian Vargas¹¹, Eduard Vieta⁶, Annabel Vreeker³⁷, Lena Waltemate⁷, Lakshmi N Yatham³⁹, Christopher R K Ching⁴⁰, Ole Andreassen¹², Paul M Thompson⁴⁰, Tomas Hajek^{41

42}; ENIGMA Bipolar Disorders Working Group

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
² Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³ Vita-Salute San Raffaele University, Milan, Italy.
⁴ Division of Neuroscience, Psychiatry and Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁵ Unit for Psychosomatics / CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁶ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona Bipolar Disorders and Depressive Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
⁷ Department of Psychiatry, University of Münster, Münster, Germany.
⁸ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁹ FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
¹⁰ Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
¹¹ Research Group in Psychiatry GIPSI, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia.
¹² Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹³ Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁵ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Desert-Pacific MIRECC, VA San Diego Healthcare, San Diego, CA, USA.
¹⁷ Neuroscience Research Australia, Randwick, NSW, Australia.
¹⁸ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁹ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁰ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²¹ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²² Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
²³ Laureate Institute for Brain Research, Tulsa, OK, USA.
²⁴ Department of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
²⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁶ Institute of Clinical Medicine, Department of Neurology, University of Oslo, Oslo, Norway.
²⁷ Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany.
²⁸ School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
²⁹ UCLA Center for Neurobehavioral Genetics, Los Angeles, CA, USA.
³⁰ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands.
³¹ Research Group, Instituto de Alta Tecnología Médica, Ayudas diagnósticas SURA, Medellín, Colombia.
³² Institute of Psychiartry, King's College Londen, London, UK.
³³ Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA.
³⁴ West Region, Institute of Mental Health, Singapore, Singapore.
³⁵ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³⁶ South African MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁷ Department of Child and Adolescent Psychiatry and Psychology, Erasmus University, Rotterdam, The Netherlands.
³⁸ Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
³⁹ University of British Columbia, Vancouver, BC, Canada.
⁴⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁴¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. tomas.hajek@dal.ca.
⁴² National Institute of Mental Health, Klecany, Czech Republic. tomas.hajek@dal.ca.

PMID: 33863996
PMCID: PMC8760047
DOI: 10.1038/s41380-021-01098-x

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals

Sean R McWhinney et al. Mol Psychiatry. 2021 Nov.

. 2021 Nov;26(11):6806-6819.

doi: 10.1038/s41380-021-01098-x. Epub 2021 Apr 16.

Authors

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
² Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³ Vita-Salute San Raffaele University, Milan, Italy.
⁴ Division of Neuroscience, Psychiatry and Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁵ Unit for Psychosomatics / CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁶ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona Bipolar Disorders and Depressive Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
⁷ Department of Psychiatry, University of Münster, Münster, Germany.
⁸ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁹ FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
¹⁰ Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
¹¹ Research Group in Psychiatry GIPSI, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia.
¹² Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹³ Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁵ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Desert-Pacific MIRECC, VA San Diego Healthcare, San Diego, CA, USA.
¹⁷ Neuroscience Research Australia, Randwick, NSW, Australia.
¹⁸ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁹ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁰ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²¹ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²² Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
²³ Laureate Institute for Brain Research, Tulsa, OK, USA.
²⁴ Department of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
²⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁶ Institute of Clinical Medicine, Department of Neurology, University of Oslo, Oslo, Norway.
²⁷ Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany.
²⁸ School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
²⁹ UCLA Center for Neurobehavioral Genetics, Los Angeles, CA, USA.
³⁰ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands.
³¹ Research Group, Instituto de Alta Tecnología Médica, Ayudas diagnósticas SURA, Medellín, Colombia.
³² Institute of Psychiartry, King's College Londen, London, UK.
³³ Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA.
³⁴ West Region, Institute of Mental Health, Singapore, Singapore.
³⁵ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³⁶ South African MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
³⁷ Department of Child and Adolescent Psychiatry and Psychology, Erasmus University, Rotterdam, The Netherlands.
³⁸ Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
³⁹ University of British Columbia, Vancouver, BC, Canada.
⁴⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁴¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. tomas.hajek@dal.ca.
⁴² National Institute of Mental Health, Klecany, Czech Republic. tomas.hajek@dal.ca.

PMID: 33863996
PMCID: PMC8760047
DOI: 10.1038/s41380-021-01098-x

Abstract

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

PubMed Disclaimer

Conflict of interest statement

PMT & CRKC received a grant from Biogen, Inc., for research unrelated to this manuscript. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. LNY has received speaking/consulting fees and/or research grants from Abbvie, Alkermes, Allergan, AstraZeneca, CANMAT, CIHR, Dainippon Sumitomo Pharma, Janssen, Lundbeck, Otsuka, Sunovion, and Teva. TE received speaker’s honoraria from Lundbeck and Janssen Cilag. EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda.

Figures

**Fig. 1. Effect size of between-group volume differences in each region without adjusting for BMI (left), and after adjusting for BMI (right).**
Statistically significant group differences are denoted by asterisks. BMI slopes shown where significant (FDR-adjusted p < 0.05).

**Fig. 2. Changes in differences between BD and control individuals with versus without controlling for BMI.**
Change in group effect size after controlling for BMI, shown in regions where both BD and BMI were significantly associated with regional volume.

**Fig. 3. The effect of diagnosis and BMI on ventricular volume.**
Path (c) represents the direct effect of diagnosis, while (a) through (b) represents the indirect path of diagnosis through BMI. The adjusted effect of diagnosis on volume is shown after accounting for BMI (c′). We show unstandardized coefficients along with their 95% CI derived from bootstrap. Significant effects (p < 0.05) are marked by asterisks. In all effects, we controlled for the covariates age, sex, and data collection site, while those impacting volume additionally adjusted for hemisphere, ICV.

See this image and copyright information in PMC

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Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals

Affiliations

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals

Authors

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Abstract

Conflict of interest statement

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