Advertisement

In Vivo Hippocampal Subfield Volumes in Schizophrenia and Bipolar Disorder

  • Unn K. Haukvik
    Correspondence
    Address correspondence to Unn K. Haukvik, M.D., Ph.D., Institute of Clinical Medicine, University of Oslo, P.O. Box 1039 Blindern 0315 Oslo, Norway
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
    Search for articles by this author
  • Lars T. Westlye
    Affiliations
    Department of Psychology, University of, Oslo, Norway

    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
    Search for articles by this author
  • Lynn Mørch-Johnsen
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
    Search for articles by this author
  • Kjetil N. Jørgensen
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
    Search for articles by this author
  • Elisabeth H. Lange
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
    Search for articles by this author
  • Anders M. Dale
    Affiliations
    Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, California

    Department of Radiology, University of California, San Diego, School of Medicine, La Jolla, California
    Search for articles by this author
  • Ingrid Melle
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
    Search for articles by this author
  • Ole A. Andreassen
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
    Search for articles by this author
  • Ingrid Agartz
    Affiliations
    Norwegian Centre for Mental Disorders Research K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of, Oslo, Norway

    Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
    Search for articles by this author

      Abstract

      Background

      Hippocampal dysfunction and volume reductions have been reported in patients with schizophrenia and bipolar disorder. The hippocampus consists of anatomically distinct subfields. We investigated to determine whether in vivo volumes of hippocampal subfields differ between clinical groups and healthy control subjects.

      Methods

      Clinical examination and magnetic resonance imaging were performed in 702 subjects (patients with schizophrenia spectrum [n = 210; mean age, 32.0 ± 9.3 (SD) years; 59% male], patients with bipolar spectrum [n = 192; mean age, 35.5 ± 11.5 years; 40% male] and healthy control subjects [n = 300; mean age, 35.3 ± 9.9 years; 53% male]). Hippocampal subfield volumes were estimated with FreeSurfer. General linear models were used to explore diagnostic differences in hippocampal subfield volumes, covarying for age, intracranial volume, and medication. Post hoc analyses of associations to psychosis symptoms (Positive and Negative Syndrome Scale) and cognitive function (verbal memory [California Verbal Learning Test, second edition] and IQ [Wechsler Abbreviated Scale of Intelligence]) were performed.

      Results

      Patient groups had smaller cornu ammonis (CA) subfields CA2/3 (left, p = 7.2 × 10−6; right, p = 2.3 × 10−6), CA4/dentate gyrus (left, p = 1.4 × 10−5; right, p = 2.3 × 10−6), subiculum (left, p = 3.7 × 10−6; right, p = 2.8 × 10−8), and right CA1 (p = .006) volumes than healthy control subjects, but smaller presubiculum volumes were found only in patients with schizophrenia (left, p = 6.7 × 10−5; right, p = 1.6 × 10−7). Patients with schizophrenia had smaller subiculum (left, p = .035; right, p = .031) and right presubiculum (p = .002) volumes than patients with bipolar disorder. Smaller subiculum volumes were related to poorer verbal memory in patients with bipolar disorder and healthy control subjects and to negative symptoms in patients with schizophrenia.

      Conclusions

      Hippocampal subfield volume reductions are found in patients with schizophrenia and bipolar disorder. The magnitude of reduction is greater in patients with schizophrenia, particularly in the hippocampal outflow regions presubiculum and subiculum.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Simonsen C.
        • Sundet K.
        • Vaskinn A.
        • Birkenaes A.B.
        • Engh J.A.
        • Faerden A.
        • et al.
        Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group.
        Schizophr Bull. 2011; 37: 73-83
        • Rimol L.M.
        • Hartberg C.B.
        • Nesvag R.
        • Fennema-Notestine C.
        • Hagler Jr, D.J.
        • Pung C.J.
        • et al.
        Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder.
        Biol Psychiatry. 2010; 68: 41-50
        • Andreassen O.A.
        • Thompson W.K.
        • Schork A.J.
        • Ripke S.
        • Mattingsdal M.
        • Kelsoe J.R.
        • et al.
        Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate.
        PLoS Genet. 2013; 9: e1003455
        • Lichtenstein P.
        • Yip B.H.
        • Bjork C.
        • Pawitan Y.
        • Cannon T.D.
        • Sullivan P.F.
        • et al.
        Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study.
        Lancet. 2009; 373: 234-239
        • Craddock N.
        • O’Donovan M.C.
        • Owen M.J.
        Psychosis genetics: Modeling the relationship between schizophrenia, bipolar disorder, and mixed (or “schizoaffective”) psychoses.
        Schizophr Bull. 2009; 35: 482-490
        • Frey B.N.
        • Andreazza A.C.
        • Nery F.G.
        • Martins M.R.
        • Quevedo J.
        • Soares J.C.
        • et al.
        The role of hippocampus in the pathophysiology of bipolar disorder.
        Behav Pharmacol. 2007; 18: 419-430
        • Tamminga C.A.
        • Stan A.D.
        • Wagner A.D.
        The hippocampal formation in schizophrenia.
        Am J Psychiatry. 2010; 167: 1178-1193
        • Small S.A.
        • Schobel S.A.
        • Buxton R.B.
        • Witter M.P.
        • Barnes C.A.
        A pathophysiological framework of hippocampal dysfunction in ageing and disease.
        Nat Rev Neurosci. 2011; 12: 585-601
        • Adriano F.
        • Caltagirone C.
        • Spalletta G.
        Hippocampal volume reduction in first-episode and chronic schizophrenia: A review and meta-analysis.
        Neuroscientist. 2012; 18: 180-200
        • Hallahan B.
        • Newell J.
        • Soares J.C.
        • Brambilla P.
        • Strakowski S.M.
        • Fleck D.E.
        • et al.
        Structural magnetic resonance imaging in bipolar disorder: An international collaborative mega-analysis of individual adult patient data.
        Biol Psychiatry. 2011; 69: 326-335
        • Shepherd A.M.
        • Laurens K.R.
        • Matheson S.L.
        • Carr V.J.
        • Green M.J.
        Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia.
        Neurosci Biobehav Rev. 2012; 36: 1342-1356
        • Gilbert P.E.
        • Brushfield A.M.
        The role of the CA3 hippocampal subregion in spatial memory: A process oriented behavioral assessment.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 774-781
        • Harrison P.J.
        The hippocampus in schizophrenia: A review of the neuropathological evidence and its pathophysiological implications.
        Psychopharmacology (Berl). 2004; 174: 151-162
        • Liu L.
        • Schulz S.C.
        • Lee S.
        • Reutiman T.J.
        • Fatemi S.H.
        Hippocampal CA1 pyramidal cell size is reduced in bipolar disorder.
        Cell Mol Neurobiol. 2007; 27: 351-358
        • Kolomeets N.S.
        • Orlovskaya D.D.
        • Uranova N.A.
        Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia.
        Synapse. 2007; 61: 615-621
        • Konradi C.
        • Yang C.K.
        • Zimmerman E.I.
        • Lohmann K.M.
        • Gresch P.
        • Pantazopoulos H.
        • et al.
        Hippocampal interneurons are abnormal in schizophrenia.
        Schizophr Res. 2011; 131: 165-173
        • Konradi C.
        • Zimmerman E.I.
        • Yang C.K.
        • Lohmann K.M.
        • Gresch P.
        • Pantazopoulos H.
        • et al.
        Hippocampal interneurons in bipolar disorder.
        Arch Gen Psychiatry. 2011; 68: 340-350
        • Wang A.Y.
        • Lohmann K.M.
        • Yang C.K.
        • Zimmerman E.I.
        • Pantazopoulos H.
        • Herring N.
        • et al.
        Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region.
        Acta Neuropathol. 2011; 122: 615-626
        • O’Mara S.M.
        • Sanchez-Vives M.V.
        • Brotons-Mas J.R.
        • O’Hare E.
        Roles for the subiculum in spatial information processing, memory, motivation and the temporal control of behaviour.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 782-790
        • Fanselow M.S.
        • Dong H.W.
        Are the dorsal and ventral hippocampus functionally distinct structures?.
        Neuron. 2010; 65: 7-19
        • Lodge D.J.
        • Grace A.A.
        Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
        Trends Pharmacol Sci. 2011; 32: 507-513
        • Tamminga C.A.
        • Southcott S.
        • Sacco C.
        • Wagner A.D.
        • Ghose S.
        Glutamate dysfunction in hippocampus: Relevance of dentate gyrus and CA3 signaling.
        Schizophr Bull. 2012; 38: 927-935
        • Van Leemput K.
        • Bakkour A.
        • Benner T.
        • Wiggins G.
        • Wald L.L.
        • Augustinack J.
        • et al.
        Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI.
        Hippocampus. 2009; 19: 549-557
        • Kuhn S.
        • Musso F.
        • Mobascher A.
        • Warbrick T.
        • Winterer G.
        • Gallinat J.
        Hippocampal subfields predict positive symptoms in schizophrenia: First evidence from brain morphometry.
        Transl Psychiatry. 2012; 2: e127
        • Elvsashagen T.
        • Westlye L.T.
        • Boen E.
        • Hol P.K.
        • Andersson S.
        • Andreassen O.A.
        • et al.
        Evidence for reduced dentate gyrus and fimbria volume in bipolar II disorder.
        Bipolar Disord. 2013; 15: 167-176
        • Francis A.N.
        • Seidman L.J.
        • Tandon N.
        • Shenton M.E.
        • Thermenos H.W.
        • Mesholam-Gately R.I.
        • et al.
        Reduced subicular subdivisions of the hippocampal formation and verbal declarative memory impairments in young relatives at risk for schizophrenia.
        Schizophr Res. 2013; 151: 154-157
        • Spitzer R.L.
        • Williams J.B.
        • Gibbon M.
        • First M.B.
        Structured Clinical Interview for DSM-III-R—Patient version. Biometrics Research Department, New York State Psychiatric Institute, New York1988
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The positive and negative syndrome scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
        • Engh J.A.
        • Friis S.
        • Birkenaes A.B.
        • Jonsdottir H.
        • Klungsoyr O.
        • Ringen P.A.
        • et al.
        Delusions are associated with poor cognitive insight in schizophrenia.
        Schizophr Bull. 2010; 36: 830-835
        • Spitzer R.L.
        • Williams J.B.
        • Kroenke K.
        • Linzer M.
        • deGruy 3rd, F.V.
        • Hahn S.R.
        • et al.
        Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME-MD 1000 study.
        JAMA. 1994; 272: 1749-1756
        • Eldridge L.L.
        • Engel S.A.
        • Zeineh M.M.
        • Bookheimer S.Y.
        • Knowlton B.J.
        A dissociation of encoding and retrieval processes in the human hippocampus.
        J Neurosci. 2005; 25: 3280-3286
        • Lim H.K.
        • Hong S.C.
        • Jung W.S.
        • Ahn K.J.
        • Won W.Y.
        • Hahn C.
        • et al.
        Automated segmentation of hippocampal subfields in drug-naive patients with Alzheimer disease.
        AJNR Am J Neuroradiol. 2013; 34: 747-751
        • Zeineh M.M.
        • Engel S.A.
        • Thompson P.M.
        • Bookheimer S.Y.
        Dynamics of the hippocampus during encoding and retrieval of face-name pairs.
        Science. 2003; 299: 577-580
        • Delis D.
        • Kramer J.
        • Kaplan E.
        • Ober B.A.
        California Verbal Learning Test–Second Edition (CVLT-II). Norwegian Manual Supplement. Pearson Assessment, Stockholm, Sweden2004
        • Wechsler D.
        Wechsler Abbreviated Scale Of Intelligence (WASI). Norwegian Manual Supplement. Harcourt Assessement, Stockholm, Sweden2007
        • Fischl B.
        FreeSurfer.
        Neuroimage. 2012; 62: 774-781
        • Reuter M.
        • Rosas H.D.
        • Fischl B.
        Highly accurate inverse consistent registration: A robust approach.
        Neuroimage. 2010; 53: 1181-1196
        • Segonne F.
        • Dale A.M.
        • Busa E.
        • Glessner M.
        • Salat D.
        • Hahn H.K.
        • et al.
        A hybrid approach to the skull stripping problem in MRI.
        Neuroimage. 2004; 22: 1060-1075
        • Fischl B.
        • Salat D.H.
        • Busa E.
        • Albert M.
        • Dieterich M.
        • Haselgrove C.
        • et al.
        Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain.
        Neuron. 2002; 33: 341-355
        • Fischl B.
        • Salat D.H.
        • van der Kouwe A.J.
        • Makris N.
        • Segonne F.
        • Quinn B.T.
        • et al.
        Sequence-independent segmentation of magnetic resonance images.
        Neuroimage. 2004; 23: S69-S84
        • Haukvik U.K.
        • McNeil T.
        • Lange E.H.
        • Melle I.
        • Dale A.M.
        • Andreassen O.A.
        • Agartz I.
        Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder.
        Psychol Med. 2014; 44: 975-985
        • Benes F.M.
        Evidence for altered trisynaptic circuitry in schizophrenic hippocampus.
        Biol Psychiatry. 1999; 46: 589-599
        • Zierhut K.C.
        • Grassmann R.
        • Kaufmann J.
        • Steiner J.
        • Bogerts B.
        • Schiltz K.
        Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia.
        Brain. 2013; 136: 804-814
        • Schobel S.A.
        • Lewandowski N.M.
        • Corcoran C.M.
        • Moore H.
        • Brown T.
        • Malaspina D.
        • et al.
        Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders.
        Arch Gen Psychiatry. 2009; 66: 938-946
        • Schobel S.A.
        • Chaudhury N.H.
        • Khan U.A.
        • Paniagua B.
        • Styner M.A.
        • Asllani I.
        • et al.
        Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.
        Neuron. 2013; 78: 81-93
        • Narr K.L.
        • Thompson P.M.
        • Szeszko P.
        • Robinson D.
        • Jang S.
        • Woods R.P.
        • et al.
        Regional specificity of hippocampal volume reductions in first-episode schizophrenia.
        Neuroimage. 2004; 21: 1563-1575
        • Cole J.
        • Toga A.W.
        • Hojatkashani C.
        • Thompson P.
        • Costafreda S.G.
        • Cleare A.J.
        • et al.
        Subregional hippocampal deformations in major depressive disorder.
        J Affect Disord. 2010; 126: 272-277
        • Guest P.C.
        • Martins-de-Souza D.
        • Vanattou-Saifoudine N.
        • Harris L.W.
        • Bahn S.
        Abnormalities in metabolism and hypothalamic-pituitary-adrenal axis function in schizophrenia.
        Int Rev Neurobiol. 2011; 101: 145-168
        • Watson S.
        • Gallagher P.
        • Ritchie J.C.
        • Ferrier I.N.
        • Young A.H.
        Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder.
        Br J Psychiatry. 2004; 184: 496-502
        • Zanelli J.
        • Reichenberg A.
        • Morgan K.
        • Fearon P.
        • Kravariti E.
        • Dazzan P.
        • et al.
        Specific and generalized neuropsychological deficits: A comparison of patients with various first-episode psychosis presentations.
        Am J Psychiatry. 2010; 167: 78-85
        • Tregellas J.R.
        • Smucny J.
        • Harris J.G.
        • Olincy A.
        • Maharajh K.
        • Kronberg E.
        • et al.
        Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia.
        Am J Psychiatry. 2014; 171: 549-556
        • Kirov I.I.
        • Hardy C.J.
        • Matsuda K.
        • Messinger J.
        • Cankurtaran C.Z.
        • Warren M.
        • et al.
        In vivo 7 Tesla imaging of the dentate granule cell layer in schizophrenia.
        Schizophr Res. 2013; 147: 362-367
        • Reif A.
        • Fritzen S.
        • Finger M.
        • Strobel A.
        • Lauer M.
        • Schmitt A.
        • et al.
        Neural stem cell proliferation is decreased in schizophrenia, but not in depression.
        Mol Psychiatry. 2006; 11: 514-522
        • Schmitt A.
        • Steyskal C.
        • Bernstein H.G.
        • Schneider-Axmann T.
        • Parlapani E.
        • Schaeffer E.L.
        • et al.
        Stereologic investigation of the posterior part of the hippocampus in schizophrenia.
        Acta Neuropathol. 2009; 117: 395-407
      1. Schoene-Bake JC, Keller SS, Niehusmann P, Volmering E, Elger C, Deppe M, et al. (2014): In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology [published online ahead of print Mar 17]. Hum Brain Mapp.

        • Duvernoy H.M.
        • Cattin F.
        • Fatterpekar G.
        • Th Naidich
        • Ch Raybaud
        • Risold P.Y.
        • Salvolini U.
        • Scarabino T.
        The Human Hippocampus, Functional Anatomy, Vascularization and Serial Section with MRI. Springer-Verlag, New York2005