title: Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia.
abstract: OBJECTIVE
  Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder.
  
  
  OBJECTIVE
  To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929).
  
  
  METHODS
  Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied.
  
  
  METHODS
  Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype.
  
  
  RESULTS
  Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P < .03 for multiple comparisons across the whole brain). Supplemental analyses confirmed that the identified systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P < .03 for ventral striatal response).
  
  
  CONCLUSIONS
  Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype.
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Plichta
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Pöhland
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany4Institute of Neuroscience and Medicine, Jülich Research Centre, Jülich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark6Department of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany4Institute of Neuroscience and Medicine, Jülich Research Centre, Jülich, Germany7Department of Genomics, Life and Brain Research Centre, University of Bonn, Bonn, Germany8Department of Biomedic.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany4Institute of Neuroscience and Medicine, Jülich Research Centre, Jülich, Germany7Department of Genomics, Life and Brain Research Centre, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Nöthen
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.affiliation: Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D000328:Adult; D059031:Anticipation, Psychological / Q000502:physiology*; D001479:Basal Ganglia / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D004298:Dopamine / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009042:Motivation / Q000502:physiology*; D020125:Mutation, Missense; D020890:Neuregulin-1 / Q000235:genetics; D010641:Phenotype; D012016:Reference Values; D012201:Reward; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D055815:Young Adult
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; D004298:Dopamine