Skip to main content Accessibility help

Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder

  • U. K. Haukvik (a1) (a2), T. McNeil (a3) (a4), E. H. Lange (a1) (a2), I. Melle (a2) (a5), A. M. Dale (a6) (a7), O. A. Andreassen (a2) (a5) and I. Agartz (a1) (a2)...

Pre- and perinatal adversities may increase the risk for schizophrenia and bipolar disorder. Hypoxia-related obstetric complications (OCs) are associated with brain anatomical abnormalities in schizophrenia, but their association with brain anatomy variation in bipolar disorder is unknown.


Magnetic resonance imaging brain scans, clinical examinations and data from the Medical Birth Registry of Norway were obtained for 219 adults, including 79 patients with a DSM-IV diagnosis of bipolar disorder (age 29.4 years, s.d. = 11.8 years, 39% male) and 140 healthy controls (age 30.8 years, s.d. = 12.0 years, 53% male). Severe hypoxia-related OCs throughout pregnancy/birth and perinatal asphyxia were each studied in relation to a priori selected brain volumes (hippocampus, lateral ventricles and amygdala, obtained with FreeSurfer), using linear regression models covarying for age, sex, medication use and intracranial volume. Multiple comparison adjustment was applied.


Perinatal asphyxia was associated with smaller left amygdala volume (t = −2.59, p = 0.012) in bipolar disorder patients, but not in healthy controls. Patients with psychotic bipolar disorder showed distinct associations between perinatal asphyxia and smaller left amygdala volume (t = −2.69, p = 0.010), whereas patients with non-psychotic bipolar disorder showed smaller right hippocampal volumes related to both perinatal asphyxia (t = −2.60, p = 0.015) and severe OCs (t = −3.25, p = 0.003). No associations between asphyxia or severe OCs and the lateral ventricles were found.


Pre- and perinatal hypoxia-related OCs are related to brain morphometry in bipolar disorder in adulthood, with specific patterns in patients with psychotic versus non-psychotic illness.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder
      Available formats
The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence .
Corresponding author
* Address for correspondence: U. K. Haukvik, M.D., Ph.D., Department of Psychiatric Research, Diakonhjemmet Hospital, PO Box 85 Vinderen, 0319 Oslo, Norway. (Email:
Hide All
Abel, KM, Wicks, S, Susser, ES, Dalman, C, Pedersen, MG, Mortensen, PB, Webb, RT (2010). Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Archives of General Psychiatry 67, 923930.
Adriano, F, Caltagirone, C, Spalletta, G (2012). Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis. Neuroscientist 18, 180200.
Agartz, I, Momenan, R, Rawlings, RR, Kerich, MJ, Hommer, DW (1999). Hippocampal volume in patients with alcohol dependence. Archives of General Psychiatry 56, 356363.
Anticevic, A, Brumbaugh, MS, Winkler, AM, Lombardo, LE, Barrett, J, Corlett, PR, Kober, H, Gruber, J, Repovs, G, Cole, MW, Krystal, JH, Pearlson, GD, Glahn, DC (2013). Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biological Psychiatry 73, 565573.
Arnone, D, Cavanagh, J, Gerber, D, Lawrie, SM, Ebmeier, KP, McIntosh, AM (2009). Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis. British Journal of Psychiatry 195, 194201.
Arnone, D, McIntosh, AM, Ebmeier, KP, Munafò, MR, Anderson, IM (2012). Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. European College of Neuropsychopharmacology 22, 116.
Berretta, S, Pantazopoulos, H, Lange, N (2007). Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia. Biological Psychiatry 62, 884893.
Bezchlibnyk, YB, Sun, X, Wang, JF, MacQueen, GM, McEwen, BS, Young, LT (2007). Neuron somal size is decreased in the lateral amygdalar nucleus of subjects with bipolar disorder. Journal of Psychiatry and Neuroscience 32, 203210.
Brietzke, E, Mansur, RB, Soczynska, J, Powell, AM, McIntyre, RS (2012). A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder. Progress in Neuropsychopharmacology and Biological Psychiatry 39, 18.
Cannon, TD, van Erp, TG, Rosso, IM, Huttunen, M, Lonnqvist, J, Pirkola, T, Salonen, O, Valanne, L, Poutanen, VP, Standertskjold-Nordenstam, CG (2002). Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Archives of General Psychiatry 59, 3541.
Carty, ML, Wixey, JA, Kesby, J, Reinebrant, HE, Colditz, PB, Gobe, G, Buller, KM (2010). Long-term losses of amygdala corticotropin-releasing factor neurons are associated with behavioural outcomes following neonatal hypoxia–ischemia. Behavioural Brain Research 208, 609618.
Cerullo, MA, Adler, CM, Delbello, MP, Strakowski, SM (2009). The functional neuroanatomy of bipolar disorder. International Review of Psychiatry 21, 314322.
Cousijn, J, Wiers, RW, Ridderinkhof, KR, van den Brink, W, Veltman, DJ, Goudriaan, AE (2012). Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. Neuroimage 59, 38453851.
Curlik, DM 2nd, Shors, TJ (2013). Training your brain: do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? Neuropharmacology 64, 506514.
Curtis, MA, Kam, M, Faull, RL (2011). Neurogenesis in humans. European Journal of Neuroscience 33, 11701174.
De Bellis, MD, Clark, DB, Beers, SR, Soloff, PH, Boring, AM, Hall, J, Kersh, A, Keshavan, MS (2000). Hippocampal volume in adolescent-onset alcohol use disorders. American Journal of Psychiatry 157, 737744.
de Kieviet, JF, Zoetebier, L, van Elburg, RM, Vermeulen, RJ, Oosterlaan, J (2012). Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis. Developmental Medicine and Child Neurology 54, 313323.
Demjaha, A, MacCabe, JH, Murray, RM (2012). How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophrenia Bulletin 38, 209214.
Ebner, F, Tepest, R, Dani, I, Pfeiffer, U, Schulze, TG, Rietschel, M, Maier, W, Traber, F, Block, W, Schild, HH, Wagner, M, Steinmetz, H, Gaebel, W, Honer, WG, Schneider-Axmann, T, Falkai, P (2008). The hippocampus in families with schizophrenia in relation to obstetric complications. Schizophrenia Research 104, 7178.
Edmiston, EE, Wang, F, Kalmar, JH, Womer, FY, Chepenik, LG, Pittman, B, Gueorguieva, R, Hur, E, Spencer, L, Staib, LH, Constable, RT, Fulbright, RK, Papademetris, X, Blumberg, HP (2011). Lateral ventricle volume and psychotic features in adolescents and adults with bipolar disorder. Psychiatry Research 194, 400402.
Ellison-Wright, I, Bullmore, E (2010). Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophrenia Research 117, 112.
Engh, JA, Friis, S, Birkenaes, AB, Jonsdottir, H, Klungsoyr, O, Ringen, PA, Simonsen, C, Vaskinn, A, Opjordsmoen, S, Andreassen, OA (2010). Delusions are associated with poor cognitive insight in schizophrenia. Schizophrenia Bulletin 36, 830835.
Fatemi, SH, Folsom, TD (2009). The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophrenia Bulletin 35, 528548.
Fischl, B (2012). FreeSurfer. Neuroimage 62, 774781.
Fischl, B, Salat, DH, Busa, E, Albert, M, Dieterich, M, Haselgrove, C, van der Kouwe, A, Killiany, R, Kennedy, D, Klaveness, S, Montillo, A, Makris, N, Rosen, B, Dale, AM (2002). Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341355.
Foland-Ross, LC, Brooks, JO 3rd, Mintz, J, Bartzokis, G, Townsend, J, Thompson, PM, Altshuler, LL (2012). Mood–state effects on amygdala volume in bipolar disorder. Journal of Affective Disorders 139, 298301.
Gilmor, ML, Skelton, KH, Nemeroff, CB, Owens, MJ (2003). The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems. Journal of Pharmacology and Experimental Therapeutics 305, 434439.
Hajek, T, Kopecek, M, Hoschl, C, Alda, M (2012). Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. Journal of Psychiatry and Neuroscience 37, 333343.
Hallahan, B, Newell, J, Soares, JC, Brambilla, P, Strakowski, SM, Fleck, DE, Kieseppa, T, Altshuler, LL, Fornito, A, Malhi, GS, McIntosh, AM, Yurgelun-Todd, DA, Labar, KS, Sharma, V, MacQueen, GM, Murray, RM, McDonald, C (2011). Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biological Psychiatry 69, 326335.
Haukvik, UK, Rimol, LM, Roddey, JC, Hartberg, CB, Lange, EH, Vaskinn, A, Melle, I, Andreassen, OA, Dale, A, Agartz, I (2013). Normal birth weight variation is related to cortical morphology across the psychosis spectrum. Schizophrenia Bulletin. Published online 18 02 2013 . doi:10.1093/schbul/sbt005.
Haukvik, UK, Saetre, P, McNeil, T, Bjerkan, PS, Andreassen, OA, Werge, T, Jonsson, EG, Agartz, I (2010). An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes. Progress in Neuropsychopharmacology and Biological Psychiatry 34, 12591265.
Haukvik, UK, Schaer, M, Nesvag, R, McNeil, T, Hartberg, CB, Jonsson, EG, Eliez, S, Agartz, I (2012). Cortical folding in Broca's area relates to obstetric complications in schizophrenia patients and healthy controls. Psychological Medicine 42, 13291337.
Howes, OD, Egerton, A, Allan, V, McGuire, P, Stokes, P, Kapur, S (2009). Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Current Pharmaceutical Design 15, 25502559.
Hultman, CM, Sparen, P, Takei, N, Murray, RM, Cnattingius, S (1999). Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case–control study. British Medical Journal 318, 421426.
Irgens, LM (2000). The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years. Acta Obstetricia et Gynecologica Scandinavica 79, 435439.
Kempton, MJ, Geddes, JR, Ettinger, U, Williams, SC, Grasby, PM (2008). Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Archives of General Psychiatry 65, 10171032.
Konradi, C, Zimmerman, EI, Yang, CK, Lohmann, KM, Gresch, P, Pantazopoulos, H, Berretta, S, Heckers, S (2011). Hippocampal interneurons in bipolar disorder. Archives of General Psychiatry 68, 340350.
Liu, L, Schulz, SC, Lee, S, Reutiman, TJ, Fatemi, SH (2007). Hippocampal CA1 pyramidal cell size is reduced in bipolar disorder. Cellular and Molecular Neurobiology 27, 351358.
Maneru, C, Serra-Grabulosa, JM, Junque, C, Salgado-Pineda, P, Bargallo, N, Olondo, M, Botet-Mussons, F, Tallada, M, Mercader, JM (2003). Residual hippocampal atrophy in asphyxiated term neonates. Journal of Neuroimaging 13, 6874.
McNeil, T, Sjöström, K (1995). The McNeil–Sjöström Scale for Obstetric Complications. University Hospital, Department of Psychiatry: Malmö.
McNeil, TF, Cantor-Graae, E, Sjöström, K (1994). Obstetric complications as antecedents of schizophrenia: empirical effects of using different obstetric complication scales. Journal of Psychiatric Research 28, 519530.
McNeil, TF, Cantor-Graae, E, Weinberger, DR (2000). Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. American Journal of Psychiatry 157, 203212.
Minassian, A, Henry, BL, Geyer, MA, Paulus, MP, Young, JW, Perry, W (2010). The quantitative assessment of motor activity in mania and schizophrenia. Journal of Affective Disorders 120, 200206.
Morales, P, Bustamante, D, Espina-Marchant, P, Neira-Pena, T, Gutierrez-Hernandez, MA, Allende-Castro, C, Rojas-Mancilla, E (2011). Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes? EPMA Journal 2, 211230.
Murray, RM, Sham, P, van, OJ, Zanelli, J, Cannon, M, McDonald, C (2004). A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophrenia Research 71, 405416.
Nosarti, C, Reichenberg, A, Murray, RM, Cnattingius, S, Lambe, MP, Yin, L, MacCabe, J, Rifkin, L, Hultman, CM (2012). Preterm birth and psychiatric disorders in young adult life. Archives of General Psychiatry 69, E1E8.
Pajonk, FG, Wobrock, T, Gruber, O, Scherk, H, Berner, D, Kaizl, I, Kierer, A, Muller, S, Oest, M, Meyer, T, Backens, M, Schneider-Axmann, T, Thornton, AE, Honer, WG, Falkai, P (2010). Hippocampal plasticity in response to exercise in schizophrenia. Archives of General Psychiatry 67, 133143.
Perry, W, Minassian, A, Henry, B, Kincaid, M, Young, JW, Geyer, MA (2010). Quantifying over-activity in bipolar and schizophrenia patients in a human open field paradigm. Psychiatry Research 178, 8491.
Peterson, BS, Vohr, B, Staib, LH, Cannistraci, CJ, Dolberg, A, Schneider, KC, Katz, KH, Westerveld, M, Sparrow, S, Anderson, AW, Duncan, CC, Makuch, RW, Gore, JC, Ment, LR (2000). Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. Journal of the American Medical Association 284, 19391947.
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752.
Rapoport, JL, Giedd, JN, Gogtay, N (2012). Neurodevelopmental model of schizophrenia: update 2012. Molecular Psychiatry 17, 12281238.
Rees, S, Harding, R, Walker, D (2008). An adverse intrauterine environment: implications for injury and altered development of the brain. International Journal of Developmental Neuroscience 26, 311.
Rimol, LM, Hartberg, CB, Nesvåg, R, Fennema-Notestine, C, Hagler, DJ Jr, Pung, CJ, Jennings, RG, Haukvik, UK, Lange, E, Nakstad, PH, Melle, I, Andreassen, OA, Dale, AM, Agartz, I (2010). Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biological Psychiatry 68, 4150.
Schulze, K, McDonald, C, Frangou, S, Sham, P, Grech, A, Toulopoulou, T, Walshe, M, Sharma, T, Sigmundsson, T, Taylor, M, Murray, RM (2003). Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives. Biological Psychiatry 53, 562570.
Shepherd, AM, Laurens, KR, Matheson, SL, Carr, VJ, Green, MJ (2012). Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neuroscience and Biobehavioral Reviews 36, 13421356.
Simonsen, C, Sundet, K, Vaskinn, A, Birkenaes, AB, Engh, JA, Faerden, A, Jonsdottir, H, Ringen, PA, Opjordsmoen, S, Melle, I, Friis, S, Andreassen, OA (2011). Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophrenia Bulletin 37, 7383.
Spijker, AT, van Rossum, EF, Hoencamp, E, DeRijk, RH, Haffmans, J, Blom, M, Manenschijn, L, Koper, JW, Lamberts, SW, Zitman, FG (2009). Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder. Bipolar Disorder 11, 95101.
Spitzer, RL, Williams, JB, Kroenke, K, Linzer, M, deGruy, FV, Hahn, SR, Brody, D, Johnson, JG (1994). Utility of a new procedure for diagnosing mental disorders in primary care: The PRIME-MD 1000 study. Journal of the American Medical Association 272, 17491756.
Spitzer, RL, Williams, JBW, Gibbon, M, First, MB (1988). Structured Clinical Interview for DSM-III-R – Patient Version. Biometrics Research Department, New York State Psychiatric Institute: New York.
Strasser, HC, Lilyestrom, J, Ashby, ER, Honeycutt, NA, Schretlen, DJ, Pulver, AE, Hopkins, RO, Depaulo, JR, Potash, JB, Schweizer, B, Yates, KO, Kurian, E, Barta, PE, Pearlson, GD (2005). Hippocampal and ventricular volumes in psychotic and non-psychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biological Psychiatry 57, 633639.
Townsend, J, Altshuler, LL (2012). Emotion processing and regulation in bipolar disorder: a review. Bipolar Disorder 14, 326339.
van Erp, TG, Saleh, PA, Rosso, IM, Huttunen, M, Lonnqvist, J, Pirkola, T, Salonen, O, Valanne, L, Poutanen, VP, Standertskjold-Nordenstam, CG, Cannon, TD (2002). Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. American Journal of Psychiatry 159, 15141520.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed