In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics throughMeta-AnalysisBipolar Disorder Working Group

Unn K. Haukvik*, Tiril P. Gurholt*, Stener Nerland, Torbjorn Elvsashagen, Theophilus N. Akudjedu, Martin Alda, Dag Alnaes, Silvia Alonso-Lana, Jochen Bauer, Bernhard T. Baune, Francesco Benedetti, Michael Berk, Francesco Bettella, Erlend Boen, Caterina M. Bonnin, Paolo Brambilla, Erick J. Canales-Rodriguez, Dara M. Cannon, Xavier Caseras, Orwa DandashUdo Dannlowski, Giuseppe Delvecchio, Ana M. Diaz-Zuluaga, Theo G. M. Erp, Mar Fatjo-Vilas, Sonya F. Foley, Katharina Foerster, Janice M. Fullerton, Jose M. Goikolea, Dominik Grotegerd, Oliver Gruber, Bartholomeus C. M. Haarman, Beathe Haatveit, Tomas Hajek, Brian Hallahan, Mathew Harris, Emma L. Hawkins, Fleur M. Howells, Carina Huelsmann, Neda Jahanshad, Kjetil N. Jorgensen, Tilo Kircher, Bernd Kraemer, Axel Krug, Rayus Kuplicki, Trine Lagerberg, Thomas M. Lancaster, Rhoshel K. Lenroot, Vera Lonning, Dennis Meer, ENIGMA Bipolar Disorder Working Group

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen'sd = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Original languageEnglish
Pages (from-to)385-398
Number of pages14
JournalHuman Brain Mapping
Issue number1
Early online date19 Oct 2020
Publication statusPublished - Jan 2022


  • MRI
  • bipolar disorder subtype
  • hippocampus
  • large-scale
  • lithium
  • psychosis
  • structural brain MRI

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