Neuroimaging hippocampal subfields in schizophrenia and bipolar disorder: A systematic review and meta-analysis.

The hippocampus is a complex structure consisting of subregions with specialized cytoarchitecture and functions. Magnetic resonance imaging (MRI) studies in psychotic disorders show hippocampal subfield abnormalities, but affected regions differ between studies. We here present an overview of hippocampal anatomy and function relevant to psychosis, and the first systematic review and meta-analysis of MRI studies of hippocampal subfield morphology in schizophrenia and bipolar disorder. Twenty-one MRI studies assessing hippocampal subfield volumes or shape in schizophrenia or bipolar disorder were included (n 15-887 subjects). Nine volumetric group comparison studies (total n = 2593) were included in random effects meta-analyses of group differences. The review showed mixed results, with volume reductions reported in most subfields in schizophrenia and bipolar disorder. Volumetric studies using ex-vivo based image analysis templates corresponded best with the shape studies, with CA1 as the most affected region. The meta-analyses showed volume reductions in all subfields in schizophrenia and bipolar disorder compared to healthy controls (all p < .005; schizophrenia: d = 0.28-0.49, bipolar disorder: d = 0.20-0.35), and smaller left CA2/3 and right subiculum in schizophrenia than bipolar disorder. In conclusion, the hippocampal subfields appear to be differently affected in psychotic disorders. However, due to the lack of control for putative confounders such as medication, alcohol and illicit substance use, and illness stage, the results from the meta-analysis should be interpreted with caution. Methodological subfield segmentation weaknesses should be addressed in future studies.

[1]  I. Melle,et al.  Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium , 2016, Molecular Psychiatry.

[2]  C. Stark,et al.  Pattern separation in the hippocampus , 2011, Trends in Neurosciences.

[3]  M. Frotscher,et al.  Distribution and morphological characteristics of oligodendrocytes in the rat hippocampusin situ andin vitro: an immunocytochemical study with the monoclonal Rip antibody , 1994, Journal of neurocytology.

[4]  N. Uranova,et al.  Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia , 2007, Synapse.

[5]  Hong-wei Dong,et al.  Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures? , 2010, Neuron.

[6]  S. Ortega-Martínez.  Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis , 2015, Behavioural Brain Research.

[7]  M. Mallar Chakravarty,et al.  Multi-atlas segmentation of the whole hippocampus and subfields using multiple automatically generated templates , 2014, NeuroImage.

[8]  Torbjørn Elvsåshagen,et al.  Evidence for reduced dentate gyrus and fimbria volume in bipolar II disorder , 2013, Bipolar disorders.

[9]  T Warbrick,et al.  Hippocampal subfields predict positive symptoms in schizophrenia: First evidence from brain morphometry , 2012, Translational Psychiatry.

[10]  C. Shannon Weickert,et al.  Cell proliferation is reduced in the hippocampus in schizophrenia , 2015, The Australian and New Zealand journal of psychiatry.

[11]  T. Schneider-Axmann,et al.  Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia , 2017, Translational Psychiatry.

[12]  B. Mwangi,et al.  Hippocampal Subfield Volumes in Mood Disorders , 2017, Molecular Psychiatry.

[13]  M. R. Covian.  [Nervous system and behavior]. , 1961, Revista de la Asociacion Medica Argentina.

[14]  Michael Weiner,et al.  Evidence for functional specialization of hippocampal subfields detected by MR subfield volumetry on high resolution images at 4T , 2011, NeuroImage.

[15]  A. Ihunwo,et al.  The dynamics of adult neurogenesis in human hippocampus , 2016, Neural regeneration research.

[16]  James J. Knierim,et al.  Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics , 2016, Neurobiology of Learning and Memory.

[17]  Brian A. Nosek,et al.  Power failure: why small sample size undermines the reliability of neuroscience , 2013, Nature Reviews Neuroscience.

[18]  S. Heckers,et al.  Hippocampal interneurons in bipolar disorder. , 2010, Archives of general psychiatry.

[19]  Anthony A Grace,et al.  Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. , 2011, Trends in pharmacological sciences.

[20]  I. Melle,et al.  Lithium treatment and hippocampal subfields and amygdala volumes in bipolar disorder , 2015, Bipolar disorders.

[21]  S. Heckers,et al.  Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region , 2011, Acta Neuropathologica.

[22]  F. Piras,et al.  Hippocampal subfield volumes in short‐ and long‐term lithium‐treated patients with bipolar I disorder , 2016, Bipolar disorders.

[23]  Polina Golland,et al.  Automated segmentation of hippocampal subfields from ultra‐high resolution in vivo MRI , 2009, Hippocampus.

[24]  D. Braus,et al.  Effects of Chronic Haloperidol and Clozapine Treatment on AMPA and Kainate Receptor Binding in Rat Brain , 2003, Pharmacopsychiatry.

[25]  D. Moher,et al.  Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement , 2009, BMJ : British Medical Journal.

[26]  Lauren E. Ethridge,et al.  Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers. , 2016, The American journal of psychiatry.

[27]  Murat Yücel,et al.  Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment , 2016, Front. Hum. Neurosci..

[28]  Erick Jorge Canales-Rodríguez,et al.  Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group , 2017, Molecular Psychiatry.

[29]  Koenraad Van Leemput,et al.  A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI , 2015, NeuroImage.

[30]  M. Schira,et al.  Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users , 2018, Cannabis and cannabinoid research.

[31]  H. Uylings,et al.  Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study , 2016, Bipolar disorders.

[32]  M. Ota,et al.  Structural differences in hippocampal subfields among schizophrenia patients, major depressive disorder patients, and healthy subjects , 2017, Psychiatry Research: Neuroimaging.

[33]  Bernd Weber,et al.  In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology , 2014, Human brain mapping.

[34]  J. Turner,et al.  Abnormal asymmetries in subcortical brain volume in schizophrenia , 2016, Molecular Psychiatry.

[35]  Stephan Heckers,et al.  Hippocampal interneurons are abnormal in schizophrenia , 2011, Schizophrenia Research.

[36]  Tania B. Huedo-Medina,et al.  Assessing heterogeneity in meta-analysis: Q statistic or I2 index? , 2006, Psychological methods.

[37]  T. Kašpárek,et al.  Hippocampal volume in first-episode schizophrenia and longitudinal course of the illness , 2016, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[38]  I. Lucki,et al.  Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology , 2009, Neuroscience & Biobehavioral Reviews.

[39]  T. Insel,et al.  Toward the future of psychiatric diagnosis: the seven pillars of RDoC , 2013, BMC Medicine.

[40]  Michael Weiner,et al.  Nearly automatic segmentation of hippocampal subfields in in vivo focal T2-weighted MRI , 2010, NeuroImage.

[41]  W. Honer,et al.  Hippocampal Subfield Volumes in First Episode and Chronic Schizophrenia , 2015, PloS one.

[42]  T. Schneider-Axmann,et al.  Stereologic investigation of the posterior part of the hippocampus in schizophrenia , 2009, Acta Neuropathologica.

[43]  Hagen B. Huttner,et al.  Dynamics of Hippocampal Neurogenesis in Adult Humans , 2013, Cell.

[44]  Beatriz Paniagua,et al.  Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver , 2013, Neuron.

[45]  A. Wagner,et al.  The hippocampal formation in schizophrenia. , 2010, The American journal of psychiatry.

[46]  Wagner F. Gattaz,et al.  Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness☆ , 2016, NeuroImage: Clinical.

[47]  M. Webster,et al.  Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients , 2012, Translational Psychiatry.

[48]  O. Andreassen,et al.  Subcortical volumetric abnormalities in bipolar disorder , 2016, Molecular Psychiatry.

[49]  Anthony D Wagner,et al.  Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. , 2012, Schizophrenia bulletin.

[50]  J. E. Iglesias,et al.  Progression from selective to general involvement of hippocampal subfields in schizophrenia , 2016, Molecular Psychiatry.

[51]  Graham C. Wiggins,et al.  In vivo 7Tesla imaging of the dentate granule cell layer in schizophrenia , 2013, Schizophrenia Research.

[52]  K. Lesch,et al.  Neural stem cell proliferation is decreased in schizophrenia, but not in depression , 2006, Molecular Psychiatry.

[53]  S. Bray,et al.  Cognitive insight is associated with cortical thickness in first-episode psychosis , 2016, Schizophrenia Research.

[54]  T. Schneider-Axmann,et al.  Decreased Oligodendrocyte and Neuron Number in Anterior Hippocampal Areas and the Entire Hippocampus in Schizophrenia: A Stereological Postmortem Study. , 2016, Schizophrenia bulletin.

[55]  J. Gonçalves,et al.  Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior , 2016, Cell.

[56]  D. Braus,et al.  Hippocampal volume and cell proliferation after acute and chronic clozapine or haloperidol treatment , 2004, Journal of Neural Transmission.

[57]  Paul M. Thompson,et al.  Regional specificity of hippocampal volume reductions in first-episode schizophrenia , 2004, NeuroImage.

[58]  T. Schneider-Axmann,et al.  Oligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits , 2016, Front. Cell. Neurosci..

[59]  D. Javitt.  Biotypes in Psychosis: Has the RDoC Era Arrived? , 2016, The American journal of psychiatry.

[60]  Anders M. Dale,et al.  CORTICAL THICKNESS AND SUBCORTICAL VOLUMES IN SCHIZOPHRENIA AND BIPOLAR DISORDER , 2010, Schizophrenia Research.

[61]  M. Mallar Chakravarty,et al.  Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol , 2015, NeuroImage.

[62]  Paul J. Harrison.  The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[63]  A. Egerton,et al.  Altered Relationship Between Hippocampal Glutamate Levels and Striatal Dopamine Function in Subjects at Ultra High Risk of Psychosis , 2010, Biological Psychiatry.

[64]  F. Piras,et al.  Unrealistic self-overconfidence in schizophrenia is associated with left presubiculum atrophy and impaired episodic memory , 2017, Cortex.

[65]  L. Lanfumey,et al.  Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice , 2015, Translational Psychiatry.

[66]  A. Dobra,et al.  Transcriptome profiling of human hippocampus dentate gyrus granule cells in mental illness , 2014, Translational Psychiatry.

[67]  C. Schultz,et al.  Anatomy of the hippocampal formation. , 2014, Frontiers of neurology and neuroscience.

[68]  Elizabeth Allen,et al.  How to do a Meta Analysis , 2013 .

[69]  Anders M. Dale,et al.  In Vivo Hippocampal Subfield Volumes in Schizophrenia and Bipolar Disorder , 2015, Biological Psychiatry.

[70]  Andy P Field,et al.  How to do a meta-analysis. , 2010, The British journal of mathematical and statistical psychology.

[71]  L. Squire,et al.  The cognitive neuroscience of human memory since H.M. , 2011, Annual review of neuroscience.

[72]  Sabine Peters,et al.  Longitudinal development of hippocampal subregions from childhood to adulthood , 2017, Developmental Cognitive Neuroscience.

[73]  I. Melle,et al.  Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. , 2011, Schizophrenia bulletin.

[74]  B. Bogerts,et al.  Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia. , 2013, Brain : a journal of neurology.

[75]  Kiralee M. Hayashi,et al.  Three-Dimensional Mapping of Hippocampal Anatomy in Unmedicated and Lithium-Treated Patients with Bipolar Disorder , 2008, Neuropsychopharmacology.

[76]  J. E. Iglesias,et al.  Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study , 2017, Neuropsychopharmacology.

[77]  S. Djurovic,et al.  Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. , 2014, Journal of psychiatric research.

[78]  Nicholas B. Turk-Browne,et al.  Hippocampal Structure Predicts Statistical Learning and Associative Inference Abilities during Development , 2017, Journal of Cognitive Neuroscience.

[79]  H. Lim,et al.  Automated Segmentation of Hippocampal Subfields in Drug-Naïve Patients with Alzheimer Disease , 2013, American Journal of Neuroradiology.

[80]  Jeonghwa Lee,et al.  Volume of hippocampal subfields in patients with alcohol dependence , 2016, Psychiatry Research: Neuroimaging.

[81]  J. Chau.  Quantitative comparison , 2019 .

[82]  A. Vita,et al.  Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies , 2012, Translational Psychiatry.

[83]  T. Schneider-Axmann,et al.  Stereological investigation of the posterior hippocampus in affective disorders , 2015, Journal of Neural Transmission.

[84]  Godfrey D Pearlson,et al.  Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. , 2014, JAMA psychiatry.

[85]  T. Kircher,et al.  Structural brain changes in schizophrenia at different stages of the illness: A selective review of longitudinal magnetic resonance imaging studies , 2017, The Australian and New Zealand journal of psychiatry.

[86]  S. Schulz,et al.  Hippocampal CA1 Pyramidal Cell Size is Reduced in Bipolar Disorder , 2007, Cellular and Molecular Neurobiology.

[87]  In-Sue Oh,et al.  Fixed- versus random-effects models in meta-analysis: model properties and an empirical comparison of differences in results. , 2009, The British journal of mathematical and statistical psychology.

[88]  Godfrey D Pearlson,et al.  Hippocampal volume is reduced in schizophrenia and schizoaffective disorder but not in psychotic bipolar I disorder demonstrated by both manual tracing and automated parcellation (FreeSurfer). , 2015, Schizophrenia bulletin.

[89]  G. V. Van Hoesen,et al.  Organization and detailed parcellation of human hippocampal head and body regions based on a combined analysis of Cyto‐ and chemoarchitecture , 2015, The Journal of comparative neurology.

[90]  M. Boldrini,et al.  Hippocampal Angiogenesis and Progenitor Cell Proliferation Are Increased with Antidepressant Use in Major Depression , 2012, Biological Psychiatry.

[91]  Valerie A. Carr,et al.  A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals? , 2017, Hippocampus.

[92]  J. Rybakowski,et al.  The effect of lithium on hematopoietic, mesenchymal and neural stem cells , 2016, Pharmacological reports : PR.

[93]  L. DeLisi,et al.  Reduced subicular subdivisions of the hippocampal formation and verbal declarative memory impairments in young relatives at risk for schizophrenia , 2013, Schizophrenia Research.

[94]  Lei Wang,et al.  Subcortical neuromorphometry in schizophrenia spectrum and bipolar disorders , 2016, NeuroImage: Clinical.