Subcortical volumetric abnormalities in bipolar disorder

D P Hibar, L T Westlye, T G M van Erp, J Rasmussen, C D Leonardo, J Faskowitz, U K Haukvik, C B Hartberg, N T Doan, I Agartz, A M Dale, O Gruber, B Krämer, S Trost, B Liberg, C Abé, C J Ekman, M Ingvar, M Landén, S C Fears, N B Freimer, C E Bearden, Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes, E Sprooten, D C Glahn, G D Pearlson, L Emsell, J Kenney, C Scanlon, C McDonald, D M Cannon, J Almeida, A Versace, X Caseras, N S Lawrence, M L Phillips, D Dima, G Delvecchio, S Frangou, T D Satterthwaite, D Wolf, J Houenou, C Henry, U F Malt, E Bøen, T Elvsåshagen, A H Young, A J Lloyd, G M Goodwin, C E Mackay, C Bourne, A Bilderbeck, L Abramovic, M P Boks, N E M van Haren, R A Ophoff, R S Kahn, M Bauer, A Pfennig, M Alda, T Hajek, B Mwangi, J C Soares, T Nickson, R Dimitrova, J E Sussmann, S Hagenaars, H C Whalley, A M McIntosh, P M Thompson, O A Andreassen, D P Hibar, L T Westlye, T G M van Erp, J Rasmussen, C D Leonardo, J Faskowitz, U K Haukvik, C B Hartberg, N T Doan, I Agartz, A M Dale, O Gruber, B Krämer, S Trost, B Liberg, C Abé, C J Ekman, M Ingvar, M Landén, S C Fears, N B Freimer, C E Bearden, Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes, E Sprooten, D C Glahn, G D Pearlson, L Emsell, J Kenney, C Scanlon, C McDonald, D M Cannon, J Almeida, A Versace, X Caseras, N S Lawrence, M L Phillips, D Dima, G Delvecchio, S Frangou, T D Satterthwaite, D Wolf, J Houenou, C Henry, U F Malt, E Bøen, T Elvsåshagen, A H Young, A J Lloyd, G M Goodwin, C E Mackay, C Bourne, A Bilderbeck, L Abramovic, M P Boks, N E M van Haren, R A Ophoff, R S Kahn, M Bauer, A Pfennig, M Alda, T Hajek, B Mwangi, J C Soares, T Nickson, R Dimitrova, J E Sussmann, S Hagenaars, H C Whalley, A M McIntosh, P M Thompson, O A Andreassen

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.

Figures

Figure 1
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
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).

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