Sexual dimorphism of the cerebellar vermis in schizophrenia

Converging lines of evidence implicate structural and functional abnormalities in the cerebellum in schizophrenia (SCZ). The cerebellar vermis is of particular interest given its association with clinical symptoms and cognitive deficits in SCZ and its known connections with cortical regions such as the prefrontal cortex. Prior neuroimaging studies have shown structural and functional abnormalities in the vermis in SCZ. In this study, we examined the cerebellar vermis in 50 individuals with SCZ and 54 healthy controls (HC) using a quantitative volumetric approach. All participants underwent high-resolution structural magnetic resonance imaging (MRI). The vermis was manually traced for each participant, and vermis volumes were computed using semiautomated methods. Volumes for total vermis and vermis subregions (anterior and posterior vermis) were analyzed in the SCZ and HC groups. Significant diagnosis-by-sex interaction effects were found in total vermis and vermis subregion analyses. These effects appeared to be driven by significantly decreased posterior vermis volumes in males with SCZ. Exploratory analyses did not reveal significant effects of clinical variables (FEP status, illness duration, and BPRS total score and subscores) on vermis volumes. The findings herein highlight the presence of neural sex differences in SCZ and the need for considering sex-related factors in studying the disorder.

[1]  D. Rai,et al.  Risks for nonaffective psychotic disorder and bipolar disorder in young people with autism spectrum disorder: a population-based study. , 2015, JAMA psychiatry.

[2]  Daniel R. Weinberger,et al.  The global cognitive impairment in schizophrenia: Consistent over decades and around the world , 2013, Schizophrenia Research.

[3]  I. Agartz,et al.  Smaller cerebellar vermis but not hemisphere volumes in patients with chronic schizophrenia. , 2003, The American journal of psychiatry.

[4]  N. Ramnani The primate cortico-cerebellar system: anatomy and function , 2006, Nature Reviews Neuroscience.

[5]  Deanna M Barch,et al.  Cerebellar-thalamic connectivity in schizophrenia. , 2014, Schizophrenia bulletin.

[6]  Jill M Goldstein,et al.  Sex differences in language dysfunction in schizophrenia. , 2006, The American journal of psychiatry.

[7]  V. Calhoun,et al.  Regional cerebellar volume and cognitive function from adolescence to late middle age , 2015, Human brain mapping.

[8]  René S. Kahn,et al.  Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings , 2011, Front. Psychiatry.

[9]  Nancy C Andreasen,et al.  An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept , 1999, Biological Psychiatry.

[10]  L. Selemon,et al.  Schizophrenia: a tale of two critical periods for prefrontal cortical development , 2015, Translational Psychiatry.

[11]  M. Essig,et al.  Gray Matter Alterations in First‐Admission Adolescents with Schizophrenia , 2011, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[12]  I. Melle,et al.  Sex differences in neuropsychological performance and social functioning in schizophrenia and bipolar disorder. , 2011, Neuropsychology.

[13]  Elsdon Storey,et al.  The cerebellum and neuropsychological functioning: A critical review , 2012, Journal of clinical and experimental neuropsychology.

[14]  S. Baron-Cohen,et al.  Neuroscience and Biobehavioral Reviews a Meta-analysis of Sex Differences in Human Brain Structure , 2022 .

[15]  I. Weiner,et al.  Tracing the development of psychosis and its prevention: What can be learned from animal models , 2012, Neuropharmacology.

[16]  S. Risch,et al.  Sexual dimorphism, brain morphology, and schizophrenia. , 1990, Schizophrenia bulletin.

[17]  T. Ruigrok,et al.  Organization of Cerebral Projections to Identified Cerebellar Zones in the Posterior Cerebellum of the Rat , 2012, The Journal of Neuroscience.

[18]  X. Papademetris,et al.  Sexually dimorphic features of vermis morphology in bipolar disorder. , 2009, Bipolar disorders.

[19]  L. Srivastava,et al.  Can the neurodevelopmental theory account for sex differences in schizophrenia across the life span? , 2015, Journal of psychiatry & neuroscience : JPN.

[20]  C. Fahim,et al.  Sex Differences in the Cerebral Function Associated with Processing Of Aversive Stimuli by Schizophrenia Patients , 2007, The Australian and New Zealand journal of psychiatry.

[21]  S. Paradiso,et al.  "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? , 1998, Schizophrenia bulletin.

[22]  N. Makris,et al.  Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. , 2002, Archives of general psychiatry.

[23]  Neonatal neuronal necrosis: its relationship to the distribution and maturation of oxidative enzymes of newborn cerebral and cerebellar cortex. , 1980, Early human development.

[24]  Greg Allen,et al.  Magnetic resonance imaging of cerebellar–prefrontal and cerebellar–parietal functional connectivity , 2005, NeuroImage.

[25]  Exacerbation of auditory verbal hallucinations with adjunctive high-frequency cerebellar vermal repetitive transcranial magnetic stimulation in schizophrenia: a case report. , 2013, The journal of ECT.

[26]  D. Barch,et al.  Brain Network Connectivity in Individuals with Schizophrenia and Their Siblings , 2011, Biological Psychiatry.

[27]  Nicolas Guizard,et al.  Regional Cerebellar Volumes Predict Functional Outcome in Children with Cerebellar Malformations , 2011, The Cerebellum.

[28]  M. Steinlin The cerebellum in cognitive processes: Supporting studies in children , 2008, The Cerebellum.

[29]  J. Desmond,et al.  Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia. , 2000, Archives of general psychiatry.

[30]  Martin H. Teicher,et al.  The neurobiological consequences of early stress and childhood maltreatment , 2003, Neuroscience & Biobehavioral Reviews.

[31]  V. Calhoun,et al.  In Search of Multimodal Neuroimaging Biomarkers of Cognitive Deficits in Schizophrenia , 2015, Biological Psychiatry.

[32]  Tyrone D. Cannon,et al.  Brain Imaging During the Transition from Psychosis Prodrome to Schizophrenia , 2015, The Journal of nervous and mental disease.

[33]  Peter B. Jones,et al.  Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. , 2015, The lancet. Psychiatry.

[34]  E Courchesne,et al.  The cerebellum in sagittal plane--anatomic-MR correlation: 1. The vermis. , 1989, AJR. American journal of roentgenology.

[35]  J. Hámori,et al.  Developmental dynamics of Purkinje cells and dendritic spines in rat cerebellar cortex , 1994, Journal of neuroscience research.

[36]  M Deanna,et al.  Cerebellar-Thalamic Connectivity in Schizophrenia , 2014 .

[37]  Adham Mancini-Marı̈e,et al.  Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia , 2010, Schizophrenia Research.

[38]  A. Wheeler,et al.  A review of structural neuroimaging in schizophrenia: from connectivity to connectomics , 2014, Front. Hum. Neurosci..

[39]  Martin Lepage,et al.  Neurocognition: Clinical and Functional Outcomes in Schizophrenia , 2014, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[40]  A M McIntosh,et al.  Structural magnetic resonance imaging markers of susceptibility and transition to schizophrenia: A review of familial and clinical high risk population studies , 2015, Journal of psychopharmacology.

[41]  R. Kikinis,et al.  Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia: clinical and cognitive correlates. , 1999, The American journal of psychiatry.

[42]  N. Andreasen,et al.  The Role of the Cerebellum in Schizophrenia , 2008, Biological Psychiatry.

[43]  Stephan J Sanders,et al.  The female protective effect in autism spectrum disorder is not mediated by a single genetic locus , 2015, Molecular Autism.

[44]  Stefan Arnborg,et al.  Morphological correlates to cognitive dysfunction in schizophrenia as studied with Bayesian regression , 2006, BMC psychiatry.

[45]  N. Bargalló,et al.  Cerebellar deficits in schizophrenia are associated with executive dysfuntion , 2008, Neuroreport.

[46]  Susanne M. Jaeggi,et al.  Resting state cortico-cerebellar functional connectivity networks: a comparison of anatomical and self-organizing map approaches , 2012, Front. Neuroanat..

[47]  David R. Hampson,et al.  Autism spectrum disorders and neuropathology of the cerebellum , 2015, Front. Neurosci..

[48]  Mikail Rubinov,et al.  Schizophrenia and abnormal brain network hubs , 2013, Dialogues in clinical neuroscience.

[49]  D. Barch,et al.  The Cognitive Neuroscience of Schizophrenia , 2005 .

[50]  E. Susser,et al.  Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: Differential influences of fetal sex , 2016, Psychiatry Research.

[51]  Jari Tiihonen,et al.  MRI volumetry of the vermis and the cerebellar hemispheres in men with schizophrenia , 2004, Psychiatry Research: Neuroimaging.

[52]  M. Tsuang,et al.  Sex differences in the genetic risk for schizophrenia: History of the evidence for sex‐specific and sex‐dependent effects , 2013, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[53]  B. Turetsky,et al.  A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia , 2004, Biological Psychiatry.

[54]  Kwang-Hyuk Lee,et al.  Increased cerebellar vermis white-matter volume in men with schizophrenia. , 2007, Journal of psychiatric research.

[55]  R. Hill Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology , 2016, Neuroscience & Biobehavioral Reviews.

[56]  J. Schmahmann The role of the cerebellum in affect and psychosis , 2000, Journal of Neurolinguistics.

[57]  Jaime S. Ide,et al.  A cerebellar thalamic cortical circuit for error-related cognitive control , 2011, NeuroImage.

[58]  M. Rietschel,et al.  From nature versus nurture, via nature and nurture, to gene × environment interaction in mental disorders , 2010, European Child & Adolescent Psychiatry.

[59]  Cerebellar volumes in men with schizophrenia and alcohol dependence , 2007, Psychiatry and clinical neurosciences.

[60]  Peter B. Jones,et al.  Brain structure in different psychosis risk groups in the Northern Finland 1986 Birth Cohort , 2014, Schizophrenia Research.

[61]  Tyrone D. Cannon,et al.  Genetic and perinatal determinants of structural brain deficits in schizophrenia , 1989, Schizophrenia Research.

[62]  P. Strick,et al.  Cerebellar Projections to the Prefrontal Cortex of the Primate , 2001, The Journal of Neuroscience.

[63]  Jon E. Grant,et al.  Impulse Control Disorders: Updated Review of Clinical Characteristics and Pharmacological Management , 2011, Front. Psychiatry.

[64]  Julia M Longenecker,et al.  Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses , 2015, Psychiatry Research: Neuroimaging.

[65]  Jeremy D. Schmahmann,et al.  Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies , 2009, NeuroImage.

[66]  R. Araneda,et al.  Maternal stress induces long-lasting Purkinje cell developmental impairments in mouse offspring , 2010, European Journal of Pediatrics.

[67]  J. Remes,et al.  Brain structural changes in women and men during midlife , 2016, Neuroscience Letters.

[68]  C. Epperson,et al.  Sex differences and stress across the lifespan , 2015, Nature Neuroscience.

[69]  T. Schneider-Axmann,et al.  Reduction of gyrification index in the cerebellar vermis in schizophrenia: A post-mortem study , 2011, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[70]  Joseph M. Orr,et al.  Cerebellar networks in individuals at ultra high‐risk of psychosis: Impact on postural sway and symptom severity , 2014, Human brain mapping.

[71]  G. Strauss,et al.  Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery. , 2008, Comprehensive psychiatry.

[72]  Joseph M. Orr,et al.  Cerebellar Morphology and Procedural Learning Impairment in Neuroleptic-Naive Youth at Ultrahigh Risk of Psychosis , 2014, Clinical psychological science : a journal of the Association for Psychological Science.

[73]  Fei Wang,et al.  Changes in cerebellar functional connectivity and anatomical connectivity in schizophrenia: A combined resting‐state functional MRI and diffusion tensor imaging study , 2011, Journal of magnetic resonance imaging : JMRI.

[74]  S. Fatemi,et al.  The neurodevelopmental hypothesis of schizophrenia, revisited. , 2009, Schizophrenia bulletin.

[75]  Kelvin O. Lim,et al.  Brain structure and function correlates of cognitive subtypes in schizophrenia , 2015, Psychiatry Research: Neuroimaging.

[76]  V. Mittal,et al.  Dysfunctional Activation of the Cerebellum in Schizophrenia , 2015, Clinical psychological science : a journal of the Association for Psychological Science.

[77]  N. Andreasen,et al.  Selective reduction of the posterior superior vermis in men with chronic schizophrenia , 2002, Schizophrenia Research.

[78]  N C Andreasen,et al.  Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[79]  A. Jackowski,et al.  Reduced cerebellar left hemisphere and vermal volume in adults with PTSD from a community sample. , 2011, Journal of psychiatric research.

[80]  J. Rapoport,et al.  Cerebellar development in childhood onset schizophrenia and non-psychotic siblings , 2011, Psychiatry Research: Neuroimaging.

[81]  Peter L Strick,et al.  Cerebellar vermis is a target of projections from the motor areas in the cerebral cortex , 2011, Proceedings of the National Academy of Sciences.

[82]  S. Chance,et al.  The neuropathology of schizophrenia: A selective review of past studies and emerging themes in brain structure and cytoarchitecture , 2015, Neuroscience.

[83]  P. Stratta,et al.  Cerebellar vermal size in schizophrenia: A male effect , 1993, Biological Psychiatry.

[84]  Sidney H Kennedy,et al.  Is the cerebellum relevant in the circuitry of neuropsychiatric disorders? , 2005, Journal of psychiatry & neuroscience : JPN.

[85]  E. Walker,et al.  Developmental mechanisms in the prodrome to psychosis , 2013, Development and Psychopathology.

[86]  N. Makris,et al.  A review of neuroimaging studies of young relatives of individuals with schizophrenia: A developmental perspective from schizotaxia to schizophrenia , 2013, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[87]  Activity-dependent structural plasticity of Purkinje cell spines in cerebellar vermis and hemisphere , 2015, Brain Structure and Function.

[88]  John Suckling,et al.  Voxel-based structural magnetic resonance imaging (MRI) study of patients with early onset schizophrenia , 2008, Annals of general psychiatry.

[89]  J. Houenou,et al.  Gene X Environment Interactions in Schizophrenia and Bipolar Disorder: Evidence from Neuroimaging , 2013, Front. Psychiatry.

[90]  C. Wellman,et al.  Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex , 2016, Brain, Behavior, and Immunity.

[91]  H. Nasrallah,et al.  Perinatal brain injury and cerebellar vermal lobules I–X in schizophrenia , 1991, Biological Psychiatry.

[92]  S. Wood,et al.  The association between autism and schizophrenia spectrum disorders: A review of eight alternate models of co-occurrence , 2015, Neuroscience & Biobehavioral Reviews.

[93]  Jean-Philippe Ranjeva,et al.  Corrigendum: Neural substrate of quality of life in patients with schizophrenia: a magnetisation transfer imaging study , 2016, Scientific Reports.

[94]  Yoshiro Okubo,et al.  Reduced volume of the cerebellar vermis in neuroleptic-naive schizophrenia , 2001, Biological Psychiatry.

[95]  Ann K. Shinn,et al.  Aberrant cerebellar connectivity in motor and association networks in schizophrenia , 2015, Front. Hum. Neurosci..

[96]  S. Bilbo,et al.  Sex, glia, and development: Interactions in health and disease , 2012, Hormones and Behavior.

[97]  C. Rosenfeld Sex-Specific Placental Responses in Fetal Development. , 2015, Endocrinology.

[98]  T. Kinoshita,et al.  Cerebellar Posterior Superior Vermis and Cognitive Cluster Scores in Drug-Naive Patients with First-Episode Schizophrenia , 2008, Neuropsychobiology.

[99]  Faith M. Gunning-Dixon,et al.  Age and sex differences in the cerebellum and the ventral pons: a prospective MR study of healthy adults. , 2001, AJNR. American journal of neuroradiology.

[100]  D. Barch The cognitive neuroscience of schizophrenia. , 2005, Annual review of clinical psychology.