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Mol Psychiatry. 2018 Apr;23(4):932-942. doi: 10.1038/mp.2017.73. Epub 2017 May 2.

Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.

Hibar DP1,2, Westlye LT3,4,5, Doan NT3,4, Jahanshad N1, Cheung JW1, Ching CRK1,6, Versace A7, Bilderbeck AC8, Uhlmann A9,10, Mwangi B11, Krämer B12, Overs B13, Hartberg CB3, Abé C14, Dima D15,16, Grotegerd D17, Sprooten E18, Bøen E19, Jimenez E20, Howells FM9, Delvecchio G21, Temmingh H9, Starke J9, Almeida JRC22, Goikolea JM20, Houenou J23,24, Beard LM25, Rauer L12, Abramovic L26, Bonnin M20, Ponteduro MF16, Keil M27, Rive MM28, Yao N29,30, Yalin N31, Najt P32, Rosa PG33,34, Redlich R17, Trost S27, Hagenaars S35, Fears SC36,37, Alonso-Lana S38,39, van Erp TGM40, Nickson T35, Chaim-Avancini TM33,34, Meier TB41,42, Elvsåshagen T3,43, Haukvik UK3,44, Lee WH18, Schene AH45,46, Lloyd AJ47, Young AH31, Nugent A48, Dale AM49,50, Pfennig A51, McIntosh AM35, Lafer B33, Baune BT52, Ekman CJ14, Zarate CA48, Bearden CE53,54, Henry C23,55, Simhandl C56, McDonald C32, Bourne C8,57, Stein DJ9,10, Wolf DH25, Cannon DM32, Glahn DC29,30, Veltman DJ58, Pomarol-Clotet E38,39, Vieta E20, Canales-Rodriguez EJ38,39, Nery FG33,59, Duran FLS33,34, Busatto GF33,34, Roberts G60, Pearlson GD29,30, Goodwin GM8, Kugel H61, Whalley HC35, Ruhe HG8,28,62, Soares JC11, Fullerton JM13,63, Rybakowski JK64, Savitz J42,65, Chaim KT66,67, Fatjó-Vilas M38,39, Soeiro-de-Souza MG33, Boks MP26, Zanetti MV33,34, Otaduy MCG66,67, Schaufelberger MS33,34, Alda M68, Ingvar M14,69, Phillips ML7, Kempton MJ16, Bauer M51, Landén M14,70, Lawrence NS71, van Haren NEM26, Horn NR9, Freimer NB72, Gruber O12, Schofield PR13,63, Mitchell PB60, Kahn RS26, Lenroot R13,73, Machado-Vieira R33,74, Ophoff RA26,72, Sarró S38,39, Frangou S18, Satterthwaite TD25, Hajek T68,75, Dannlowski U17, Malt UF76,77, Arolt V17, Gattaz WF33, Drevets WC78, Caseras X79, Agartz I3,19, Thompson PM1, Andreassen OA3,4.

Author information

1
Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, University of Southern California, Marina del Rey, CA, USA.
2
Janssen Research & Development, San Diego, CA, USA.
3
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
4
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
5
Department of Psychology, University of Oslo, Oslo, Norway.
6
Neuroscience Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA, USA.
7
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
8
University Department of Psychiatry and Oxford Health NHS Foundation Trust, University of Oxford, Oxford, UK.
9
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
10
MRC Unit on Anxiety and Stress Disorders, Groote Schuur Hospital (J-2), University of Cape Town, Cape Town, South Africa.
11
UT Center of Excellence on Mood Disorders, Department of Psychiatry & Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
12
Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
13
Neuroscience Research Australia, Sydney, NSW, Australia.
14
Department of Clinical Neuroscience, Osher Centre, Karolinska Institutet, Stockholm, Sweden.
15
Department of Psychology, City University London, London, UK.
16
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
17
Department of Psychiatry, University of Münster, Münster, Germany.
18
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
19
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
20
Hospital Clinic, IDIBAPS, University of Barcelona, CIBERSAM, Barcelona, Spain.
21
IRCCS "E. Medea" Scientific Institute, San Vito al Tagliamento, Italy.
22
Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
23
INSERM U955 Team 15 'Translational Psychiatry', University Paris East, APHP, CHU Mondor, Fondation FondaMental, Créteil, France.
24
NeuroSpin, UNIACT Lab, Psychiatry Team, CEA Saclay, Gif Sur Yvette, France.
25
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
26
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
27
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
28
Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
29
Department of Psychiatry, Yale University, New Haven, CT, USA.
30
Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
31
Centre for Affective Disorders, King's College London, London, UK.
32
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.
33
Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
34
Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil.
35
Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
36
Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA, USA.
37
West Los Angeles Veterans Administration, Los Angeles, CA, USA.
38
FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
39
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
40
Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
41
Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA.
42
Laureate Institute for Brain Research, Tulsa, OK, USA.
43
Department of Neurology, Oslo University Hospital, Oslo, Norway.
44
Department of Adult Psychiatry, University of Oslo, Oslo, Norway.
45
Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
46
Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands.
47
Academic Psychiatry and Northern Centre for Mood Disorders, Newcastle University/Northumberland Tyne & Wear NHS Foundation Trust, Newcastle, UK.
48
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA.
49
MMIL, Department of Radiology, University of California San Diego, San Diego, CA, USA.
50
Department of Cognitive Science, Neurosciences and Psychiatry, University of California, San Diego, San Diego, CA, USA.
51
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
52
Department of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
53
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
54
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
55
Institut Pasteur, Unité Perception et Mémoire, Paris, France.
56
Bipolar Center Wiener Neustadt, Wiener Neustadt, Austria.
57
Department of Psychology & Counselling, Newman University, Birmingham, UK.
58
Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
59
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
60
School of Psychiatry and Black Dog Institute, University of New South Wales, Sydney, NSW, Australia.
61
Department of Clinical Radiology, University of Münster, Münster, Germany.
62
Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
63
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
64
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
65
Faculty of Community Medicine, The University of Tulsa, Tulsa, OK, USA.
66
Department of Radiology, University of São Paulo, São Paulo, Brazil.
67
LIM44-Laboratory of Magnetic Resonance in Neuroradiology, University of São Paulo, São Paulo, Brazil.
68
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
69
Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
70
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Goteborg, Sweden.
71
Department of Psychology, University of Exeter, Exeter, UK.
72
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
73
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
74
National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
75
National Institute of Mental Health, Klecany, Czech Republic.
76
Division of Clinical Neuroscience, Department of Research and Education, Oslo University Hospital, Oslo, Norway.
77
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
78
Janssen Research & Development, Titusville, NJ, USA.
79
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

Abstract

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

PMID:
28461699
PMCID:
PMC5668195
DOI:
10.1038/mp.2017.73
[Indexed for MEDLINE]
Free PMC Article

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