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Original Investigation |

Striatal Response to Reward Anticipation Evidence for a Systems-Level Intermediate Phenotype for Schizophrenia FREE

Oliver Grimm, MD, MSc1; Andreas Heinz, MD, PhD2; Henrik Walter, MD, PhD2; Peter Kirsch, PhD1; Susanne Erk, MD, PhD2; Leila Haddad, MSc1; Michael M. Plichta, PhD1; Nina Romanczuk-Seiferth, PhD2; Lydia Pöhland, MSc2; Sebastian Mohnke, MSc2; Thomas W. Mühleisen, PhD3,4; Manuel Mattheisen, MD, PhD5,6; Stephanie H. Witt, PhD1; Axel Schäfer, PhD1; Sven Cichon, PhD3,4,7,8; Markus Nöthen, MD, PhD3,4,7; Marcella Rietschel, MD, PhD1; Heike Tost, MD, PhD1; Andreas Meyer-Lindenberg, MD, PhD1
[+] Author Affiliations
1Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany
2Department of Psychiatry and Psychotherapy, Charité–University Medicine Berlin, Campus Mitte, Berlin, Germany
3Institute of Human Genetics, University of Bonn, Bonn, Germany
4Institute of Neuroscience and Medicine, Jülich Research Centre, Jülich, Germany
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6Department of Genomic Mathematics, University of Bonn, Bonn, Germany
7Department of Genomics, Life and Brain Research Centre, University of Bonn, Bonn, Germany
8Department of Biomedicine, University of Basel, Basel, Switzerland
JAMA Psychiatry. 2014;71(5):531-539. doi:10.1001/jamapsychiatry.2014.9.
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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.

Figures in this Article

Several lines of evidence suggest a crucial role for striatal dysfunction in the pathophysiology of schizophrenia. For humans, a widely used strategy has been the study of reward anticipation with neuroimaging.1,2 Functional magnetic resonance imaging (fMRI) experiments typically show attenuated ventral striatal activation in drug-naive and unmedicated schizophrenic patients35 and then link this anomaly to symptom severity.3,4 Treatment with atypical, but not first-generation, antipsychotics may partially normalize ventral striatal dysfunction in schizophrenia,4,6 highlighting a potential dopaminergic mechanism relevant for therapy. In agreement with this, molecular neuroimaging demonstrates increased striatal dopamine synthesis7 and dopamine release in schizophrenia,8 while the density of presynaptic dopamine terminals is unaltered.9 In support of a link between striatal hypoactivation and dopamine dysregulation, the blood oxygen level–dependent response during reward anticipation (detected by fMRI) is correlated with dopamine synthesis capacity.10

Based on these observations, it has been proposed that functional, but not structural, alterations of the striatum are a core feature of schizophrenia.11 Specifically, abnormal representation of environmental salience in a circuit (including the dopaminergic midbrain, striatum, and prefrontal cortex) has been linked to schizophrenia susceptibility.12,13 This proposal is supported by evidence suggesting striatal hypoactivation in individuals at high clinical risk for psychosis14 and associations between altered dopamine activity and the severity of prodromal symptoms.15 Further evidence comes from studies relating the sensitivity of the human reward system to genetic variation in dopamine-regulating genes.16 These data raise the possibility for a role for striatal dysfunction in the genetic risk architecture of the illness. More fundamentally, given the high heritability of schizophrenia, the question arises whether abnormal striatal activation during reward anticipation is a potential intermediate phenotype (or “endophenotype”) of the disorder (ie, a systems-level feature that mediates genetic risk).17

Among several criteria that have been proposed for candidate intermediate phenotypes, the demonstration of abnormalities in unaffected first-degree relatives is a particularly important piece of evidence.17 First-degree relatives have a strongly increased risk for the illness and share an enriched set of schizophrenia susceptibility genes.18 Studying these individuals circumvents a number of confounders that complicate the interpretation of patient data, in particular the effects of medication, substance use, and institutionalization on brain physiology. Using this research strategy, abnormal prefrontal activation and prefrontal-hippocampal connectivity have been identified as intermediate phenotypes.19,20 In the striatum, increased dopamine synthesis is evident in healthy first-degree relatives of schizophrenic patients, similar to the anomalies observed in manifest psychosis.7,21 Given the ties between dopaminergic neurotransmission, striatal function, and schizophrenia risk, blunted striatal activation during reward anticipation is a plausible candidate intermediate phenotype for the genetic risk for schizophrenia, but no data on relatives are available that would support this hypothesis.

We examined a large sample of unaffected first-degree relatives of schizophrenic patients who underwent fMRI and compared their neural response to reward anticipation to that of a sample of healthy matched controls who had no family history of psychiatric illness. Consistent with our prior work, we used a well-established reward anticipation paradigm that is known for robustly engaging the ventral striatum1,2,5 and effective in uncovering attenuated striatal response in antipsychotic-naive schizophrenic patients.22 We hypothesized a blunted neural response in our sample at high familial risk, thereby providing initial evidence that striatal dysfunction during reward processing is a potential intermediate phenotype for schizophrenia. We also investigated the relationship between activation and striatal brain volume. Here, we expected to provide evidence for a primarily functional, but not structural, abnormality because the role of structural abnormalities in the striatum remains unclear. Specifically, although some studies demonstrate reduced striatal volume in early psychosis,23,24 increased striatal volume is reported in patients with chronic illness receiving antipsychotic treatment,24,25 a finding that is not related to heritable risk,11 and thus possibly reflective of treatment effects and not genetic risk. Furthermore, because the reliability of the target measure used is an important consideration in estimating specific genetic and therapeutic effects, we performed a test-retest reliability analysis to quantify the robustness of the functional phenotype. Finally, to test the utility of the phenotype for genetic studies, we examined the effects of a well-established candidate gene of the disorder, NRG1,26,27 encoding neuregulin 1. This protein is a ligand for the tyrosine kinase receptor ErbB4, a neurodevelopmental regulator that is highly expressed in the midbrain and the striatum,28,29 and it has recently been linked to abnormal dopamine signaling and cognitive deficits in a schizophrenia rodent model.30 We studied a nonsynonymous (and thus likely functional) variant that is supported by a meta-analysis of schizophrenia association studies (rs10503929, Met/Thr).31

Participants

A total of 134 participants were studied: 80 healthy individuals recruited from local residents’ registration offices in Mannheim, Bonn, and Berlin, Germany, and 54 unaffected first-grade relatives of schizophrenic patients recruited from the same areas through psychiatric hospitals, support groups, and media advertisement. All participants provided written informed consent for protocols approved by the institutional review boards of the universities in Mannheim, Bonn, and Berlin. Psychological assessments included tests for visual-motor attention (part A of the Trail Making Test) and cognitive set shifting (part B of the Trail Making Test).32 See Table 1 and the eAppendix in the Supplement for further details on the sample characteristics and diagnostic procedures.

Table Graphic Jump LocationTable 1.  Demographic, Clinical, and Task Performance Characteristics
Reward Task

Brain function during reward anticipation was studied using fMRI and a well-established monetary incentive delay paradigm1,2,5 with 4 experimental conditions: a win condition, a loss avoidance condition, a verbal feedback condition, and a neutral condition. Ten trials per condition were presented in a pseudorandomized order over the course of the experiment. Further details on the methods used are given in Figure 1A and the eAppendix in the Supplement.

Place holder to copy figure label and caption
Figure 1.
Reward Anticipation Task and Group-Dependent Striatal Activation Differences

A, A scheme of the 8- to 9-minute reward anticipation task is shown. Four different conditions are shown in the leftmost column. Each condition (trial) was repeated 10 times in pseudorandom order. The conditions are sorted as belonging to the “money” or “control” class. The 6-second presentation of each cue (arrow) was followed by a target stimulus (flashing of the screen). Participants responded by pressing the button as fast as possible. A reaction time–dependent feedback followed after the response (rightmost column). Please note that the feedbacks depicted do not include all possible outcomes. B, A significant increase in striatal activation can been seen in healthy controls compared with relatives (z = 4.13, familywise error–corrected P = .013 for multiple comparisons across the whole brain) displayed on a transversal section of a structural magnetic resonance imaging template (money > control contrast). The threshold of the functional map was set at t > 3 for presentation purposes. The color bar represents t values. The map coordinates refer to the standard space as defined by the Montreal Neuroimaging Institute. L indicates the left side of brain.

Graphic Jump Location
Data Acquisition

Data acquisition was performed on 3 matching 3-T MRI systems (Siemens Trio) using identical experimental protocols. Further details are provided in the eAppendix in the Supplement.

Functional Image Processing and Analysis

The fMRI data were processed following previously published procedures1,2,5 using standard processing routines in SPM8 (http://www.fil.ion.ucl.ac.uk/spm/) (see the eAppendix in the Supplement for details on the preprocessing and first-level modeling). Consistent with our a priori hypothesis and prior work in schizophrenia,2,5 contrast images were calculated to identify brain regions with greater activation during the anticipation of monetary salient events relative to control events (contrast: [win + loss] > [verbal + neutral] that we refer to as “money > control” in the following). In addition, because prior evidence suggests a link between schizophrenia and altered striatal response to loss avoidance,14,33 contrast images were calculated for the [loss > neutral] condition. Group differences between relatives and controls in brain activation to reward anticipation were examined using random-effects group statistics at the second level. Specifically, linear regression models were defined that included a group variable (relatives vs healthy control) as a covariate of interest, and age, sex, and site as nuisance covariates. Significance was measured at familywise error (FWE)–corrected P < .05 for multiple comparisons across the whole brain. Because the subsequent reliability, morphometry, and imaging genetics analyses relate to the core intermediate phenotype region identified here, we obtained a striatal region-of-interest mask from the familiarity analysis for all subsequent studies, as detailed in the eAppendix in the Supplement.

Structural Image Processing and Analysis

Automated image processing was performed using the voxel-based morphometry (VBM) toolbox (VBM8 [http://dbm.neuro.uni-jena.de/vbm8/]) and, for cross-software validation, FreeSurfer version 5.1.0 (https://surfer.nmr.mgh.harvard.edu/fswiki/ReleaseNotes). In the VBM analysis, we examined the striatal region-of-interest mask derived from the functional analysis to test for the possibility that the observed functional differences may relate to preexisting group differences in striatal volume. Details of the VBM and FreeSurfer analyses are provided in the eAppendix in the Supplement. To maximize sensitivity, a significance threshold of P < .05, uncorrected, was adopted.

Test-Retest Reliability of Striatal Activation Measures

The robustness of activation measures was quantified by focal reanalysis of the test-retest reliability data reported in Plichta et al,1 a study that did not quantify the reliability of the functional contrasts examined here. Further details are provided in the eAppendix in the Supplement.

NRG1 Analysis

We tested the utility of the identified functional phenotype for genetic analyses in a subsample of 78 healthy volunteers from the control group with available genotypes for a missense mutation in NRG1 (ie, rs10503929). Consistent with prior evidence,31 we expected to see a protective effect (ie, a relative activation increase in the striatal core intermediate phenotype region) in carriers of the minor (C) allele. Details of the genotyping procedures and imaging analysis are given in the eAppendix in the Supplement. Details of the participants’ demographics, neuropsychology, and fMRI task performance stratified by NRG1 genotype are provided in eTable 1 in the Supplement.

Demographic and Behavioral Variables

All groups were well matched for demographics and task performance (Table 1; Figure 2). For cognitive set shifting (part B of the Trail Making Test), a significant impairment was seen in the healthy first-degree relatives (P = .003; Table 1). Moreover, for the controls included in our imaging genetics analysis, a trend-level superiority in cognitive set shifting ability was seen in the healthy carriers of the protective rs10503929 C allele (P = .06; eTable 1 in the Supplement).

Place holder to copy figure label and caption
Figure 2.
Structure-Function Relationship and Reaction Times Between Groups

A, Striatal estimates derived from the money > control contrast are shown; the error bars indicate the standard error for each condition. B, Reaction times between healthy controls (HC) and relatives of schizophrenia patients (REL) are not different for the 3 tasks of the reward anticipation task; the error bars indicate the standard error for each condition. C, A scatterplot of the function-structure relation demonstrates no significant interaction between groups and no association between structure and function. D, The functional map shows the consistency of the intraclass correlation coefficients (ICCs) within the core intermediate phenotype region (see text for details). The whole-brain map of the group difference (relatives < controls, with a threshold set at t > 3 for presentation purposes) is coded red, voxels within the striatal region of interest with an absolute ICC of greater than 0.4 are coded green, and the overlap between both areas is coded yellow. GM indicates gray matter; L, left side of the brain.

Graphic Jump Location
Functional Neuroimaging Data

In line with our expectations, we detected a significant activation decrease during reward anticipation in first-degree relatives compared with controls in the money > control contrast in the left (Montreal Neurological Institute coordinates: x = −18, y = 23, z = −6; z = 4.48, FWE-corrected P< .03 for multiple comparisons across the whole brain) and right ventral striatum (x = 12, y = 20, z = −9; z = 4.74, FWE-corrected P< .13 for multiple comparisons across the whole brain [Figure 1B; Figure 2A]). Moreover, the relatives showed a significant decrease in activation in the loss > neutral contrast in the left (x = −12, y = 23, z = 3; z = 4.61, FWE-corrected P< .03 for multiple comparisons across the whole brain) and right ventral striatum (x = 9, y = 20, z = −6; z = 4.86, FWE-corrected P< .006 for multiple comparisons across the whole brain). No significant effects were seen outside the striatum. See eTable 2 in the Supplement for the outcome of other functional contrasts. Supplementary analyses did not provide any evidence for significant effects of head motion or type of first-degree kinship (see eAppendix in the Supplement for details). Across all participants, correlation analysis of striatal β estimates from the money > control contrast and part B of the Trail Making Test performance demonstrated a significant association, with higher striatal activation predicting better (ie, less time needed for) cognitive set shifting (r = −0.23, P = .006).

Effects of NRG1 rs10503929 Genotype

In the healthy control group, we detected a significant striatal activation decrease in homozygotes of the risk-associated T-allele relative to C-allele carriers in the money > control contrast (FWE-corrected P< .03; see Figure 3 and eAppendix in the Supplement for details).

Place holder to copy figure label and caption
Figure 3.
Effects of NRG1 Genotype on Ventral Striatal Physiology During Reward Anticipation

A, Significantly greater activation in healthy controls carrying 1 or 2 rs10503929 C alleles compared with T/T homozygotes can be seen during the performance of the money trials relative to the control trials (z = 3.34, familywise error–corrected P = .03 for the striatal core intermediate phenotype region identified in the relatives analysis; see the eAppendix in the Supplement for details). The z coordinate refers to the standard space as defined by the Montreal Neuroimaging Institute. The color bar represents t values. B, Bar plot of the genotype-dependent activation differences in the money > control contrast in the ventral striatum. Plotted are the mean contrast estimates extracted from the striatal core intermediate phenotype region identified in the analysis of the relatives (P = .004). The bars represent the mean values across participants, and the error bars represent standard errors of the mean.

Graphic Jump Location
Test-Retest Reliability of Reward Anticipation Contrasts

Our test-retest analysis of an independent sample of healthy controls provided evidence for good robustness of the striatal activation estimates derived from the money > control (with intraclass correlation coefficients of 0.68-0.73) and loss > neutral (with intraclass correlation coefficients of 0.59-0.60) contrasts. In light of the test-retest reliability of fMRI studies (with a mean intraclass correlation coefficient of 0.50) reported in a prior meta-analysis,34 this indicates fairly good reliability of the reward anticipation task in the specific region and functional contrasts where anomalies were detected in the unaffected relatives. Further details of the calculated intraclass correlation coefficients and the spatial distribution of reliable voxels are given in Table 2 and Figure 2D.

Table Graphic Jump LocationTable 2.  Test-Retest Reliability of Striatal Activation Estimates
Voxel-Based Morphometry

In our VBM group comparisons of first-degree relatives and controls regarding the striatum, we did not observe any differences in striatal volume either voxelwise (uncorrected P > .05) or in our analyses with extracted mean gray matter volumes from the core intermediate phenotype region (F = 0.17, P = .68). Also, no associations of striatal volume with local activation estimates of the money > control contrast were found (F < 0.63, P > .43), and no group-by-volume interaction effect on striatal activations was seen (F < 0.80, P > .37; Figure 2C). See the eAppendix in the Supplement for details on the likewise negative FreeSurfer analysis.

In our study, we investigated the potential of striatal response during reward anticipation as an intermediate phenotype for schizophrenia. Our key finding is a regionally specific and highly significant attenuation of striatal activation during reward anticipation in unaffected first-degree relatives of schizophrenic patients. Both the directionality and the localization of this result conform well to previous results of drug-naive, unmedicated,4,5 and chronic schizophrenic patients6,35 and to our own study using the same paradigm,5 thereby providing initial evidence for a systems-level intermediate phenotype. Supporting the utility of this phenotype, we found that striatal function could be measured reliably and was not confounded with potential preexisting structural abnormalities in the striatum, differences in task performance, or head motion. We further demonstrate that in the healthy controls, the identified phenotype is affected by a genetic variant in NRG1 that has been linked by meta-analysis to the genetic risk for schizophrenia.31 Here, the carriers of the protective C allele (Thr) showed a significant increase in striatal activation relative to the carriers of the risk allele (T, Met), a finding that conforms to the directionality seen in both our relatives here and our prior work in manifest schizophrenia.5

Two key cognitive processes have been associated with ventral striatal function: salience36 and reward37 processing. Current schizophrenia models propose that a dysregulated hyperdopaminergic state linked to altered midbrain-striatal-prefrontal function promotes the development of delusions through an aberrant assignment of salience to unimportant elements of perception.12,13 Antipsychotics are expected to “dampen the salience” of these abnormal experiences, thereby advancing the resolution of positive symptoms.12 In addition, reward-related signaling in the striatum has been linked to negative schizophrenia symptoms such as anhedonia or reduced volition.3,38 Consistent with prior data, we observed attenuation of striatal responses in unaffected relatives in contrasts reflecting the anticipation of desirable and unpleasant monetary consequences5 and loss avoidance.3 Owing to the purely monetary nature of our paradigm, the present data do not allow for a final conclusion on the kind of cognitive process that drives the observed dysfunction. However, given that in prior work5 we observed an association between striatal hypoactivation during reward anticipation in the current paradigm and the increased attribution of salience to stimuli in a task devoid of monetary incentives, we propose that the detected striatal hypoactivations may reflect a genetic mechanism involving salience processing, a proposal that is in good agreement with fMRI evidence linking striatal signaling to the salience, and not the valence, of stimuli.36

Because our data support a familial component to striatal signaling in schizophrenia, we further investigated the test-retest reliability of this phenotype because our previous reliability work on this paradigm1 did not examine the contrasts that provided the basis of the striatal signaling deficits detected here. Our analysis proved the robustness of the derived activation estimates, relative to both previously established criteria39 and the reliability of fMRI studies reported in prior meta-analytic work.34 These data support future work on this risk phenotype with this paradigm, particularly in the context of pharmacogenetic studies.

Our study also addressed several important potential confounders. Consistent with established standards of imaging genetics, our samples did not exhibit significant differences in any of the assessed demographic variables or clinical ratings. We also carefully controlled for potential between-group differences in task performance, thereby ensuring that the detected neural abnormalities are not reflective of differences in overt behavior. The observed effects were still very strong, which supports the idea that methods capable of surveying the intermediate neural level (eg, fMRI) are sensitive to alterations that may be missed in neurocognitive behavioral tests.20,40 Finally, given the inconsistent literature on striatal structure in schizophrenia, we further studied the relationship between striatal volume and activation in our sample. Here, no evidence emerged suggesting that the striatal hypoactivations are rooted in preexisting volumetric differences. Our data therefore support the hypothesis that striatal abnormalities related to schizophrenia risk are primarily functional, consistent with our prior findings indicating that striatal volume abnormalities are not heritable and likely related to the exposure to antipsychotics.11

Our study does not support any conclusions on the specific molecular processes that promote the observed blood oxygen level–dependent activation deficits. Even so, it is tempting to speculate that striatal presynaptic disinhibition of dopamine signaling may contribute to the observed functional anomalies. This molecular phenotype is well established in schizophrenia and already present prior to the onset of frank psychosis,41 and a familial risk component to striatal dopamine synthesis has previously been reported.21 In our study, striatal activation related to cognitive set shifting, a function that is impaired in manifest schizophrenia,42 has been linked to striatal presynaptic dopamine synthesis capacity43 and was observed in our healthy first-degree relatives. Consistent with this, reduced striatal function and cognitive set shifting were seen in the carriers of a likely functional NRG1 risk variant, a gene whose product has been linked to the (mal)development of the dopaminergic system and related hyperdopaminergic states and cognitive deficits in a rodent model of schizophrenia.30 Although not a direct proof, these data thus support the idea that the identified striatal phenotype reflects facets of schizophrenia susceptibility that are influenced by genetic risk, possibly through alterations in presynaptic dopaminergic function.

On the systems level, our findings are certainly compatible with a primary striatal risk mechanism, as proposed by Kellendonk et al,44 but may as well be reflective of downstream effects of disturbances in higher-order nodes of the salience system. The striatum and prefrontal cortex are anatomically highly connected, and abnormalities in these structures and their interconnecting pathways have been linked to the development of cognitive symptoms in schizophrenia,45 which may be mediated by dopamine.46 Because the prefrontal cortex projects directly to the striatum and ventral tegmentum,47 a primary dysfunction of the prefrontal cortex or of its glutamatergic efferents could lead to abnormal striatal function43,48 and could increase schizophrenia risk.49,50 Previous work supports a relationship between striatal dopamine synthesis capacity and prefrontal cortex function in healthy volunteers,43 prodromal patients,51 and patients with manifest schizophrenia.48 Future work with relatives is necessary to study the molecular and connectivity alterations that could contribute to the altered striatal signaling during the reward anticipation that we report here.

Our study has several limitations. Although our samples were relatively large (the detected effects were strong and were not affected by the type of kinship), we included first-degree relatives of several generations, whereas previous experiments11,20 in other domains studied siblings only. Also, although all samples were carefully matched, we cannot exclude the potential effect of factors that we might have missed. Specifically, although our data on unaffected relatives and NRG1 risk allele carriers suggest that the phenotype is indeed modulated by genetic rather than just familial influences, we cannot rule out the influences of a shared environment. Furthermore, we did not study index patients with neuroimaging, which would have allowed for more formal measurements of heritability.11 However, we demonstrate the presence of the same blunted activation phenotype in relatives with the same paradigm that we previously used for antipsychotic-naive first-episode patients.5

In summary, we provide the first evidence that striatal hypoactivation during reward anticipation is a robust functional intermediate phenotype for schizophrenia that is useful for imaging genetics analyses. Our data provide the basis for further studies on the genetic architecture of more proximal mechanisms that contribute to the observed systems-level abnormalities, such as alterations in dopamine and glutamate neurotransmission and their relationship to higher-order prefrontal functional deficits. In addition, because risk mechanisms are attractive systems-level targets for early treatment and prevention, the effect of established and novel treatments on this circuitry should be further investigated and explored for genetic contributions. Finally, our data strongly support the study of the effect of genome-wide–significant genetic variants for schizophrenia on the striatal risk phenotype that we describe.

Submitted for Publication: July 2, 2013; final revision received December 10, 2013; accepted December 15, 2013.

Corresponding Author: Andreas Meyer-Lindenberg, MD, PhD, Central Institute of Mental Health Mannheim, J5, D-68159 Mannheim, Germany (a.meyer-lindenberg@zi-mannheim.de).

Published Online: March 12, 2014. doi:10.1001/jamapsychiatry.2014.9.

Author Contributions: Drs Grimm and Tost had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Grimm, Heinz, Walter, Tost, and Meyer-Lindenberg contributed equally to the study.

Study concept and design: Grimm, Heinz, Walter, Kirsch, Erk, Romanczuk-Seiferth, Rietschel, Tost, Meyer-Lindenberg.

Acquisition of data: Grimm, Walter, Erk, Haddad, Romanczuk-Seiferth, Pöhland, Mohnke, Mühleisen, Mattheisen, Witt, Cichon, Nöthen.

Analysis and interpretation of data: Grimm, Walter, Kirsch, Erk, Plichta, Schäfer, Tost.

Drafting of the manuscript: Grimm, Tost, Meyer-Lindenberg.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Grimm, Kirsch, Plichta, Mattheisen, Schäfer, Tost.

Obtained funding: Walter, Nöthen, Rietschel, Meyer-Lindenberg.

Administrative, technical, and material support: Walter, Kirsch, Erk, Haddad, Romanczuk-Seiferth, Pöhland, Mohnke, Schäfer, Cichon, Nöthen, Tost.

Study supervision: Heinz, Walter, Kirsch, Witt, Nöthen, Tost, Meyer-Lindenberg.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the German Federal Ministry of Education and Research through the Integrated Genome Research Network Molecular Causes of Major Mood Disorders and Schizophrenia (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to Drs Nöthen, Cichon, and Walter, grant 01GS08147 to Drs Rietschel and Meyer-Lindenberg, and grant 01GS08148 to Dr Heinz), under the auspices of the National Genome Research Network plus. Further funding was received through the German Research Foundation (Deutsche Forschungsgemeinschaft; Sonderforschungsbereich 636-B7). Dr Tost also acknowledges support from the German Federal Ministry of Education and Research (grant 01GQ1102).

Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Information: Dr Nöthen is a member of the Excellence Cluster “ImmunoSensation,” which is funded by Deutsche Forschungsgemeinschaft.

Plichta  MM, Schwarz  AJ, Grimm  O,  et al.  Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery. Neuroimage. 2012;60(3):1746-1758.
PubMed   |  Link to Article
Kirsch  P, Schienle  A, Stark  R,  et al.  Anticipation of reward in a nonaversive differential conditioning paradigm and the brain reward system: an event-related fMRI study. Neuroimage. 2003;20(2):1086-1095.
PubMed   |  Link to Article
Juckel  G, Schlagenhauf  F, Koslowski  M,  et al.  Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage. 2006;29(2):409-416.
PubMed   |  Link to Article
Nielsen  MO, Rostrup  E, Wulff  S,  et al.  Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry. 2012;69(12):1195-1204.
PubMed   |  Link to Article
Esslinger  C, Englisch  S, Inta  D,  et al.  Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients. Schizophr Res. 2012;140(1-3):114-121.
PubMed   |  Link to Article
Juckel  G, Schlagenhauf  F, Koslowski  M,  et al.  Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology (Berl). 2006;187(2):222-228.
PubMed   |  Link to Article
Fusar-Poli  P, Meyer-Lindenberg  A.  Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies. Schizophr Bull. 2013;39(1):33-42.
PubMed   |  Link to Article
Miyake  N, Thompson  J, Skinbjerg  M, Abi-Dargham  A.  Presynaptic dopamine in schizophrenia. CNS Neurosci Ther. 2011;17(2):104-109.
PubMed   |  Link to Article
Fusar-Poli  P, Meyer-Lindenberg  A.  Striatal presynaptic dopamine in schizophrenia, part I: meta-analysis of dopamine active transporter (DAT) density. Schizophr Bull. 2013;39(1):22-32.
PubMed   |  Link to Article
Schott  BH, Minuzzi  L, Krebs  RM,  et al.  Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311-14319.
PubMed   |  Link to Article
Goldman  AL, Pezawas  L, Mattay  VS,  et al.  Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol Psychiatry. 2008;63(5):475-483.
PubMed   |  Link to Article
Kapur  S.  Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160(1):13-23.
PubMed   |  Link to Article
Heinz  A.  Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates. Eur Psychiatry. 2002;17(1):9-16.
PubMed   |  Link to Article
Juckel  G, Friedel  E, Koslowski  M,  et al.  Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia. Neuropsychobiology. 2012;66(1):50-56.
PubMed   |  Link to Article
Howes  OD, Kapur  S.  The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35(3):549-562.
PubMed   |  Link to Article
Dreher  JC, Kohn  P, Kolachana  B, Weinberger  DR, Berman  KF.  Variation in dopamine genes influences responsivity of the human reward system. Proc Natl Acad Sci U S A. 2009;106(2):617-622.
PubMed   |  Link to Article
Gottesman  II, Gould  TD.  The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636-645.
PubMed   |  Link to Article
Kendler  KS, Gruenberg  AM, Tsuang  MT.  Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients: a family study using DSM-III criteria. Arch Gen Psychiatry. 1985;42(8):770-779.
PubMed   |  Link to Article
Rasetti  R, Sambataro  F, Chen  Q, Callicott  JH, Mattay  VS, Weinberger  DR.  Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A. Arch Gen Psychiatry. 2011;68(12):1207-1217.
PubMed   |  Link to Article
Callicott  JH, Egan  MF, Mattay  VS,  et al.  Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am J Psychiatry. 2003;160(4):709-719.
PubMed   |  Link to Article
Huttunen  J, Heinimaa  M, Svirskis  T,  et al.  Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. Biol Psychiatry. 2008;63(1):114-117.
PubMed   |  Link to Article
Esslinger  C, Kirsch  P, Haddad  L,  et al.  Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. Neuroimage. 2011;54(3):2514-2523.
PubMed   |  Link to Article
Ballmaier  M, Schlagenhauf  F, Toga  AW,  et al.  Regional patterns and clinical correlates of basal ganglia morphology in non-medicated schizophrenia. Schizophr Res. 2008;106(2-3):140-147.
PubMed   |  Link to Article
Glenthoj  A, Glenthoj  BY, Mackeprang  T,  et al.  Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res. 2007;154(3):199-208.
PubMed   |  Link to Article
Li  M, Chen  Z, Deng  W,  et al.  Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment. Psychol Med. 2012;42(7):1475-1483.
PubMed   |  Link to Article
Stefansson  H, Sigurdsson  E, Steinthorsdottir  V,  et al.  Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71(4):877-892.
PubMed   |  Link to Article
Law  AJ, Lipska  BK, Weickert  CS,  et al.  Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006;103(17):6747-6752.
PubMed   |  Link to Article
Zheng  Y, Watakabe  A, Takada  M,  et al.  Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(4):701-706.
PubMed   |  Link to Article
Fox  IJ, Kornblum  HI.  Developmental profile of ErbB receptors in murine central nervous system: implications for functional interactions. J Neurosci Res. 2005;79(5):584-597.
PubMed   |  Link to Article
Kato  T, Abe  Y, Sotoyama  H,  et al.  Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. Mol Psychiatry. 2011;16(3):307-320.
PubMed   |  Link to Article
Allen  NC, Bagade  S, McQueen  MB,  et al.  Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40(7):827-834.
PubMed   |  Link to Article
Corrigan  JD, Hinkeldey  NS.  Relationships between parts A and B of the 3611374. J Clin Psychol. 1987;43(4):402-409.
PubMed   |  Link to Article
Schlagenhauf  F, Sterzer  P, Schmack  K,  et al.  Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions. Biol Psychiatry. 2009;65(12):1032-1039.
PubMed   |  Link to Article
Bennett  CM, Miller  MB.  How reliable are the results from functional magnetic resonance imaging? Ann N Y Acad Sci. 2010;1191:133-155.
PubMed   |  Link to Article
Grimm  O, Vollstädt-Klein  S, Krebs  L, Zink  M, Smolka  MN.  Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study. Schizophr Res. 2012;134(2-3):151-157.
PubMed   |  Link to Article
Zink  CF, Pagnoni  G, Martin-Skurski  ME, Chappelow  JC, Berns  GS.  Human striatal responses to monetary reward depend on saliency. Neuron. 2004;42(3):509-517.
PubMed   |  Link to Article
Knutson  B, Adams  CM, Fong  GW, Hommer  D.  Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci. 2001;21(16):RC159.
PubMed
Simon  JJ, Biller  A, Walther  S,  et al.  Neural correlates of reward processing in schizophrenia—relationship to apathy and depression. Schizophr Res. 2010;118(1-3):154-161.
PubMed   |  Link to Article
Shrout  PE, Fleiss  JL.  Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86(2):420-428.
PubMed   |  Link to Article
Meyer-Lindenberg  A.  Intermediate or brainless phenotypes for psychiatric research? Psychol Med. 2010;40(7):1057-1062.
PubMed   |  Link to Article
Howes  OD, Montgomery  AJ, Asselin  MC,  et al.  Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66(1):13-20.
PubMed   |  Link to Article
Sánchez-Torres  AM, Basterra  V, Moreno-Izco  L,  et al.  Executive functioning in schizophrenia spectrum disorder patients and their unaffected siblings: a ten-year follow-up study. Schizophr Res. 2013;143(2-3):291-296.
PubMed   |  Link to Article
Vernaleken  I, Buchholz  HG, Kumakura  Y,  et al.  ‘Prefrontal’ cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. Hum Brain Mapp. 2007;28(10):931-939.
PubMed   |  Link to Article
Kellendonk  C, Simpson  EH, Polan  HJ,  et al.  Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006;49(4):603-615.
PubMed   |  Link to Article
Tan  HY, Chen  AG, Kolachana  B,  et al.  Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment. Brain. 2012;135(pt 5):1436-1445.
PubMed   |  Link to Article
Yoon  JH, Minzenberg  MJ, Raouf  S, D’Esposito  M, Carter  CS.  Impaired prefrontal-basal ganglia functional connectivity and substantia nigra hyperactivity in schizophrenia. Biol Psychiatry. 2013;74(2):122-129.
PubMed   |  Link to Article
Guillin  O, Abi-Dargham  A, Laruelle  M.  Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol. 2007;78:1-39.
PubMed
Meyer-Lindenberg  A, Miletich  RS, Kohn  PD,  et al.  Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002;5(3):267-271.
PubMed   |  Link to Article
Weinberger  DR, Berman  KF, Illowsky  BP.  Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: III, a new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988;45(7):609-615.
PubMed   |  Link to Article
Grace  AA.  Cortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia. J Neural Transm Gen Sect. 1993;91(2-3):111-134.
PubMed   |  Link to Article
Fusar-Poli  P, Howes  OD, Allen  P,  et al.  Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry. 2010;67(7):683-691.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Reward Anticipation Task and Group-Dependent Striatal Activation Differences

A, A scheme of the 8- to 9-minute reward anticipation task is shown. Four different conditions are shown in the leftmost column. Each condition (trial) was repeated 10 times in pseudorandom order. The conditions are sorted as belonging to the “money” or “control” class. The 6-second presentation of each cue (arrow) was followed by a target stimulus (flashing of the screen). Participants responded by pressing the button as fast as possible. A reaction time–dependent feedback followed after the response (rightmost column). Please note that the feedbacks depicted do not include all possible outcomes. B, A significant increase in striatal activation can been seen in healthy controls compared with relatives (z = 4.13, familywise error–corrected P = .013 for multiple comparisons across the whole brain) displayed on a transversal section of a structural magnetic resonance imaging template (money > control contrast). The threshold of the functional map was set at t > 3 for presentation purposes. The color bar represents t values. The map coordinates refer to the standard space as defined by the Montreal Neuroimaging Institute. L indicates the left side of brain.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Structure-Function Relationship and Reaction Times Between Groups

A, Striatal estimates derived from the money > control contrast are shown; the error bars indicate the standard error for each condition. B, Reaction times between healthy controls (HC) and relatives of schizophrenia patients (REL) are not different for the 3 tasks of the reward anticipation task; the error bars indicate the standard error for each condition. C, A scatterplot of the function-structure relation demonstrates no significant interaction between groups and no association between structure and function. D, The functional map shows the consistency of the intraclass correlation coefficients (ICCs) within the core intermediate phenotype region (see text for details). The whole-brain map of the group difference (relatives < controls, with a threshold set at t > 3 for presentation purposes) is coded red, voxels within the striatal region of interest with an absolute ICC of greater than 0.4 are coded green, and the overlap between both areas is coded yellow. GM indicates gray matter; L, left side of the brain.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Effects of NRG1 Genotype on Ventral Striatal Physiology During Reward Anticipation

A, Significantly greater activation in healthy controls carrying 1 or 2 rs10503929 C alleles compared with T/T homozygotes can be seen during the performance of the money trials relative to the control trials (z = 3.34, familywise error–corrected P = .03 for the striatal core intermediate phenotype region identified in the relatives analysis; see the eAppendix in the Supplement for details). The z coordinate refers to the standard space as defined by the Montreal Neuroimaging Institute. The color bar represents t values. B, Bar plot of the genotype-dependent activation differences in the money > control contrast in the ventral striatum. Plotted are the mean contrast estimates extracted from the striatal core intermediate phenotype region identified in the analysis of the relatives (P = .004). The bars represent the mean values across participants, and the error bars represent standard errors of the mean.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Demographic, Clinical, and Task Performance Characteristics
Table Graphic Jump LocationTable 2.  Test-Retest Reliability of Striatal Activation Estimates

References

Plichta  MM, Schwarz  AJ, Grimm  O,  et al.  Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery. Neuroimage. 2012;60(3):1746-1758.
PubMed   |  Link to Article
Kirsch  P, Schienle  A, Stark  R,  et al.  Anticipation of reward in a nonaversive differential conditioning paradigm and the brain reward system: an event-related fMRI study. Neuroimage. 2003;20(2):1086-1095.
PubMed   |  Link to Article
Juckel  G, Schlagenhauf  F, Koslowski  M,  et al.  Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage. 2006;29(2):409-416.
PubMed   |  Link to Article
Nielsen  MO, Rostrup  E, Wulff  S,  et al.  Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry. 2012;69(12):1195-1204.
PubMed   |  Link to Article
Esslinger  C, Englisch  S, Inta  D,  et al.  Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients. Schizophr Res. 2012;140(1-3):114-121.
PubMed   |  Link to Article
Juckel  G, Schlagenhauf  F, Koslowski  M,  et al.  Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology (Berl). 2006;187(2):222-228.
PubMed   |  Link to Article
Fusar-Poli  P, Meyer-Lindenberg  A.  Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies. Schizophr Bull. 2013;39(1):33-42.
PubMed   |  Link to Article
Miyake  N, Thompson  J, Skinbjerg  M, Abi-Dargham  A.  Presynaptic dopamine in schizophrenia. CNS Neurosci Ther. 2011;17(2):104-109.
PubMed   |  Link to Article
Fusar-Poli  P, Meyer-Lindenberg  A.  Striatal presynaptic dopamine in schizophrenia, part I: meta-analysis of dopamine active transporter (DAT) density. Schizophr Bull. 2013;39(1):22-32.
PubMed   |  Link to Article
Schott  BH, Minuzzi  L, Krebs  RM,  et al.  Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311-14319.
PubMed   |  Link to Article
Goldman  AL, Pezawas  L, Mattay  VS,  et al.  Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol Psychiatry. 2008;63(5):475-483.
PubMed   |  Link to Article
Kapur  S.  Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160(1):13-23.
PubMed   |  Link to Article
Heinz  A.  Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates. Eur Psychiatry. 2002;17(1):9-16.
PubMed   |  Link to Article
Juckel  G, Friedel  E, Koslowski  M,  et al.  Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia. Neuropsychobiology. 2012;66(1):50-56.
PubMed   |  Link to Article
Howes  OD, Kapur  S.  The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35(3):549-562.
PubMed   |  Link to Article
Dreher  JC, Kohn  P, Kolachana  B, Weinberger  DR, Berman  KF.  Variation in dopamine genes influences responsivity of the human reward system. Proc Natl Acad Sci U S A. 2009;106(2):617-622.
PubMed   |  Link to Article
Gottesman  II, Gould  TD.  The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636-645.
PubMed   |  Link to Article
Kendler  KS, Gruenberg  AM, Tsuang  MT.  Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients: a family study using DSM-III criteria. Arch Gen Psychiatry. 1985;42(8):770-779.
PubMed   |  Link to Article
Rasetti  R, Sambataro  F, Chen  Q, Callicott  JH, Mattay  VS, Weinberger  DR.  Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A. Arch Gen Psychiatry. 2011;68(12):1207-1217.
PubMed   |  Link to Article
Callicott  JH, Egan  MF, Mattay  VS,  et al.  Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am J Psychiatry. 2003;160(4):709-719.
PubMed   |  Link to Article
Huttunen  J, Heinimaa  M, Svirskis  T,  et al.  Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. Biol Psychiatry. 2008;63(1):114-117.
PubMed   |  Link to Article
Esslinger  C, Kirsch  P, Haddad  L,  et al.  Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. Neuroimage. 2011;54(3):2514-2523.
PubMed   |  Link to Article
Ballmaier  M, Schlagenhauf  F, Toga  AW,  et al.  Regional patterns and clinical correlates of basal ganglia morphology in non-medicated schizophrenia. Schizophr Res. 2008;106(2-3):140-147.
PubMed   |  Link to Article
Glenthoj  A, Glenthoj  BY, Mackeprang  T,  et al.  Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res. 2007;154(3):199-208.
PubMed   |  Link to Article
Li  M, Chen  Z, Deng  W,  et al.  Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment. Psychol Med. 2012;42(7):1475-1483.
PubMed   |  Link to Article
Stefansson  H, Sigurdsson  E, Steinthorsdottir  V,  et al.  Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71(4):877-892.
PubMed   |  Link to Article
Law  AJ, Lipska  BK, Weickert  CS,  et al.  Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006;103(17):6747-6752.
PubMed   |  Link to Article
Zheng  Y, Watakabe  A, Takada  M,  et al.  Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(4):701-706.
PubMed   |  Link to Article
Fox  IJ, Kornblum  HI.  Developmental profile of ErbB receptors in murine central nervous system: implications for functional interactions. J Neurosci Res. 2005;79(5):584-597.
PubMed   |  Link to Article
Kato  T, Abe  Y, Sotoyama  H,  et al.  Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. Mol Psychiatry. 2011;16(3):307-320.
PubMed   |  Link to Article
Allen  NC, Bagade  S, McQueen  MB,  et al.  Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40(7):827-834.
PubMed   |  Link to Article
Corrigan  JD, Hinkeldey  NS.  Relationships between parts A and B of the 3611374. J Clin Psychol. 1987;43(4):402-409.
PubMed   |  Link to Article
Schlagenhauf  F, Sterzer  P, Schmack  K,  et al.  Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions. Biol Psychiatry. 2009;65(12):1032-1039.
PubMed   |  Link to Article
Bennett  CM, Miller  MB.  How reliable are the results from functional magnetic resonance imaging? Ann N Y Acad Sci. 2010;1191:133-155.
PubMed   |  Link to Article
Grimm  O, Vollstädt-Klein  S, Krebs  L, Zink  M, Smolka  MN.  Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study. Schizophr Res. 2012;134(2-3):151-157.
PubMed   |  Link to Article
Zink  CF, Pagnoni  G, Martin-Skurski  ME, Chappelow  JC, Berns  GS.  Human striatal responses to monetary reward depend on saliency. Neuron. 2004;42(3):509-517.
PubMed   |  Link to Article
Knutson  B, Adams  CM, Fong  GW, Hommer  D.  Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci. 2001;21(16):RC159.
PubMed
Simon  JJ, Biller  A, Walther  S,  et al.  Neural correlates of reward processing in schizophrenia—relationship to apathy and depression. Schizophr Res. 2010;118(1-3):154-161.
PubMed   |  Link to Article
Shrout  PE, Fleiss  JL.  Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86(2):420-428.
PubMed   |  Link to Article
Meyer-Lindenberg  A.  Intermediate or brainless phenotypes for psychiatric research? Psychol Med. 2010;40(7):1057-1062.
PubMed   |  Link to Article
Howes  OD, Montgomery  AJ, Asselin  MC,  et al.  Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66(1):13-20.
PubMed   |  Link to Article
Sánchez-Torres  AM, Basterra  V, Moreno-Izco  L,  et al.  Executive functioning in schizophrenia spectrum disorder patients and their unaffected siblings: a ten-year follow-up study. Schizophr Res. 2013;143(2-3):291-296.
PubMed   |  Link to Article
Vernaleken  I, Buchholz  HG, Kumakura  Y,  et al.  ‘Prefrontal’ cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. Hum Brain Mapp. 2007;28(10):931-939.
PubMed   |  Link to Article
Kellendonk  C, Simpson  EH, Polan  HJ,  et al.  Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006;49(4):603-615.
PubMed   |  Link to Article
Tan  HY, Chen  AG, Kolachana  B,  et al.  Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment. Brain. 2012;135(pt 5):1436-1445.
PubMed   |  Link to Article
Yoon  JH, Minzenberg  MJ, Raouf  S, D’Esposito  M, Carter  CS.  Impaired prefrontal-basal ganglia functional connectivity and substantia nigra hyperactivity in schizophrenia. Biol Psychiatry. 2013;74(2):122-129.
PubMed   |  Link to Article
Guillin  O, Abi-Dargham  A, Laruelle  M.  Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol. 2007;78:1-39.
PubMed
Meyer-Lindenberg  A, Miletich  RS, Kohn  PD,  et al.  Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002;5(3):267-271.
PubMed   |  Link to Article
Weinberger  DR, Berman  KF, Illowsky  BP.  Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: III, a new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988;45(7):609-615.
PubMed   |  Link to Article
Grace  AA.  Cortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia. J Neural Transm Gen Sect. 1993;91(2-3):111-134.
PubMed   |  Link to Article
Fusar-Poli  P, Howes  OD, Allen  P,  et al.  Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry. 2010;67(7):683-691.
PubMed   |  Link to Article

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Multimedia

Supplement.

eAppendix. Methods

eFigure 1. Course of cue-dependent striatal responses

eFigure 2. One sample t-test results for controls and relatives

eTable 1. Demographics and psychological parameter for NRG1 genotypes

eTable 2. Additional contrast of between group (HC>REL) analysis

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