Subcortical volumetric abnormalities in bipolar disorder

D P Hibar¹, L T Westlye^{2

3}, T G M van Erp⁴, J Rasmussen⁴, C D Leonardo¹, J Faskowitz¹, U K Haukvik^{2

5}, C B Hartberg², N T Doan², I Agartz^{2

5}, A M Dale^{6

7}, O Gruber^{8

9}, B Krämer⁸, S Trost⁸, B Liberg¹⁰, C Abé¹¹, C J Ekman¹⁰, M Ingvar^{11

12

13}, M Landén^{14

15}, S C Fears^{16

17}, N B Freimer¹⁷, C E Bearden^{17

18

19}; Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes; E Sprooten^{20

21}, D C Glahn^{20

21}, G D Pearlson^{20

21

22}, L Emsell²³, J Kenney²³, C Scanlon²³, C McDonald²³, D M Cannon²³, J Almeida²⁴, A Versace²⁵, X Caseras²⁶, N S Lawrence²⁷, M L Phillips²⁶, D Dima^{28

29}, G Delvecchio²⁸, S Frangou²⁹, T D Satterthwaite³⁰, D Wolf³⁰, J Houenou^{31

32}, C Henry^{32

33}, U F Malt^{34

35

36}, E Bøen^{5

34

35

37}, T Elvsåshagen^{2

34

35

38}, A H Young³⁹, A J Lloyd⁴⁰, G M Goodwin⁴¹, C E Mackay⁴¹, C Bourne^{41

42}, A Bilderbeck^{41

43}, L Abramovic⁴⁴, M P Boks⁴⁴, N E M van Haren⁴⁴, R A Ophoff^{17

44}, R S Kahn⁴⁴, M Bauer⁴⁵, A Pfennig⁴⁵, M Alda⁴⁶, T Hajek^{46

47}, B Mwangi⁴⁸, J C Soares⁴⁸, T Nickson⁴⁹, R Dimitrova⁴⁹, J E Sussmann⁴⁹, S Hagenaars⁴⁹, H C Whalley⁴⁹, A M McIntosh⁴⁹, P M Thompson^{1

18}, O A Andreassen²

Affiliations

¹ Imaging Genetics Center, University of Southern California, Los Angeles, CA, USA.
² Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
³ Department of Psychology, University of Oslo, Oslo, Norway.
⁴ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
⁵ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁶ MMIL, Department of Radiology, University of California, San Diego, CA, USA.
⁷ Department of Cognitive Science, Neurosciences and Psychiatry, University of California, San Diego, CA, USA.
⁸ Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, Georg August University Goettingen, Goettingen, Germany.
⁹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Department of Clinical Neuroscience, Section of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
¹¹ Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
¹² Karolinska MR Research Center, Karolinska Institutet, Stockholm, Sweden.
¹³ Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
¹⁷ Center for Neurobehavioral Genetics, University of California, Los Angeles, CA, USA.
¹⁸ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
¹⁹ Department of Psychology, University of California, Los Angeles, CA, USA.
²⁰ Department of Psychiatry, Yale University, New Haven, CT, USA.
²¹ Olin Neuropsychiatric Research Center, Institute of Living, Hartford, CT, USA.
²² Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
²³ Clinical Neuroimaging Laboratory, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
²⁴ Department of Psychiatry, Brown University, Providence, RI, USA.
²⁵ Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA.
²⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
²⁷ School of Psychology, University of Exeter, Exeter, UK.
²⁸ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁰ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³¹ Neurospin, Uniact, I2BM, CEA Saclay, Saclay, France.
³² Inserm, U955, Equipe 15 Psychiatrie génétique, Créteil, France.
³³ Université Paris-Est, UMR-S955, UPEC, Créteil, France.
³⁴ Department of Psychosomatic Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
³⁵ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³⁶ Department of Research and Education, Oslo University Hospital, Oslo, Norway.
³⁷ Norwegian Research Network On Mood Disorders, Oslo, Norway.
³⁸ Department of Neurology, Oslo University Hospital, Oslo, Norway.
³⁹ Centre for Affective Disorders, King's College London, London, UK.
⁴⁰ Academic Psychiatry and Regional Affective Disorders Service, Newcastle University, Newcastle, UK.
⁴¹ Department of Psychiatry, University of Oxford, Oxford, UK.
⁴² Department of Psychology and Counselling, Newman University, Birmingham, UK.
⁴³ University of Oxford Centre for Clinical Magnetic Resonance Research, Oxford, UK.
⁴⁴ Department of Psychiatry, University Medical Centre Utrecht - Brain Centre Rudolf Magnus, Utrecht, The Netherlands.
⁴⁵ Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Medizinische Fakultät, Technische Universität Dresden, Dresden, Germany.
⁴⁶ Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁴⁷ National Institute of Mental Health, Klecany, Czech Republic.
⁴⁸ UT Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, UT Houston Medical School, Houston, TX, USA.
⁴⁹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

PMID: 26857596
PMCID: PMC5116479
DOI: 10.1038/mp.2015.227

Subcortical volumetric abnormalities in bipolar disorder

D P Hibar et al. Mol Psychiatry. 2016 Dec.

. 2016 Dec;21(12):1710-1716.

doi: 10.1038/mp.2015.227. Epub 2016 Feb 9.

Authors

Affiliations

¹ Imaging Genetics Center, University of Southern California, Los Angeles, CA, USA.
² Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
³ Department of Psychology, University of Oslo, Oslo, Norway.
⁴ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
⁵ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁶ MMIL, Department of Radiology, University of California, San Diego, CA, USA.
⁷ Department of Cognitive Science, Neurosciences and Psychiatry, University of California, San Diego, CA, USA.
⁸ Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, Georg August University Goettingen, Goettingen, Germany.
⁹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Department of Clinical Neuroscience, Section of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
¹¹ Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
¹² Karolinska MR Research Center, Karolinska Institutet, Stockholm, Sweden.
¹³ Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
¹⁷ Center for Neurobehavioral Genetics, University of California, Los Angeles, CA, USA.
¹⁸ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
¹⁹ Department of Psychology, University of California, Los Angeles, CA, USA.
²⁰ Department of Psychiatry, Yale University, New Haven, CT, USA.
²¹ Olin Neuropsychiatric Research Center, Institute of Living, Hartford, CT, USA.
²² Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
²³ Clinical Neuroimaging Laboratory, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
²⁴ Department of Psychiatry, Brown University, Providence, RI, USA.
²⁵ Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA.
²⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
²⁷ School of Psychology, University of Exeter, Exeter, UK.
²⁸ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁰ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³¹ Neurospin, Uniact, I2BM, CEA Saclay, Saclay, France.
³² Inserm, U955, Equipe 15 Psychiatrie génétique, Créteil, France.
³³ Université Paris-Est, UMR-S955, UPEC, Créteil, France.
³⁴ Department of Psychosomatic Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
³⁵ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³⁶ Department of Research and Education, Oslo University Hospital, Oslo, Norway.
³⁷ Norwegian Research Network On Mood Disorders, Oslo, Norway.
³⁸ Department of Neurology, Oslo University Hospital, Oslo, Norway.
³⁹ Centre for Affective Disorders, King's College London, London, UK.
⁴⁰ Academic Psychiatry and Regional Affective Disorders Service, Newcastle University, Newcastle, UK.
⁴¹ Department of Psychiatry, University of Oxford, Oxford, UK.
⁴² Department of Psychology and Counselling, Newman University, Birmingham, UK.
⁴³ University of Oxford Centre for Clinical Magnetic Resonance Research, Oxford, UK.
⁴⁴ Department of Psychiatry, University Medical Centre Utrecht - Brain Centre Rudolf Magnus, Utrecht, The Netherlands.
⁴⁵ Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Medizinische Fakultät, Technische Universität Dresden, Dresden, Germany.
⁴⁶ Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁴⁷ National Institute of Mental Health, Klecany, Czech Republic.
⁴⁸ UT Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, UT Houston Medical School, Houston, TX, USA.
⁴⁹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

PMID: 26857596
PMCID: PMC5116479
DOI: 10.1038/mp.2015.227

Abstract

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10^-7) and thalamus (d=-0.148; P=4.27 × 10^-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10^-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

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Figures

**Figure 1**
Adjusted Cohen's d estimates for all BD patients versus controls. Effect sizes for the volumetric differences between bipolar disorder (BD) cases and controls (CTL), after accounting for age, sex and intracranial volume over all brain regions of interest. Error bars show mean effect size ± s.e.m. Effect sizes were considered significant (marked with *) if they exceeded the study-wide significance threshold (P<4.91 × 10⁻³).

**Figure 2**
Adjusted Cohen's d estimates for BD patients split by diagnosis subtype (type I or type II) versus controls. Effect sizes for the volumetric differences between bipolar disorder (BD) type I and controls (CTL) are shown in red and BD II and controls are shown in green. All effect sizes are reported after accounting for age, sex and intracranial volume. Error bars show mean effect size ± s.e.m. Effect sizes were considered significant (marked with *) if they exceeded the study-wide significance threshold (P<4.91 × 10⁻³).

See this image and copyright information in PMC

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Subcortical volumetric abnormalities in bipolar disorder

Affiliations

Subcortical volumetric abnormalities in bipolar disorder

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

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LinkOut - more resources

Full Text Sources

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Medical