Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia

JAMA Psychiatry. 2014 May;71(5):531-9. doi: 10.1001/jamapsychiatry.2014.9.


Importance: 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).

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anticipation, Psychological / physiology*
  • Basal Ganglia / physiopathology*
  • Brain / physiopathology*
  • Brain Mapping
  • Dopamine / metabolism
  • Female
  • Genetic Association Studies
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Motivation / physiology*
  • Mutation, Missense
  • Neuregulin-1 / genetics
  • Phenotype*
  • Reference Values
  • Reward*
  • Schizophrenia / diagnosis
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology*
  • Schizophrenic Psychology*
  • Young Adult


  • NRG1 protein, human
  • Neuregulin-1
  • Dopamine