Diminishing striatal activation across adolescent development during reward anticipation in offspring of schizophrenia patients

https://doi.org/10.1016/j.schres.2015.11.018Get rights and content

Abstract

Schizophrenia is a severe psychiatric disorder associated with impaired fronto-striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto-striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10–19 years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia.

Introduction

Schizophrenia is a highly heritable psychiatric disorder that is characterized by positive symptoms such as delusions and hallucinations, negative symptoms including affective flattening, as well as cognitive impairments (van Os and Kapur, 2009). Underlying these symptoms may be dysfunctions in the frontal lobe and the striatum (Emsley et al., 2015, Hahn et al., 2012, McGuire et al., 2008, van Veelen et al., 2010, van Veelen et al., 2011, Waltz and Gold, 2007, Weinberger and Gallhofer, 1997, Zandbelt et al., 2011). Indeed, the striatum is the primary target of effective antipsychotics. Functional MRI studies in adult schizophrenia patients have consistently demonstrated abnormal fronto-striatal activity in the context of various cognitive tasks (Ehrlich et al., 2012, Koch et al., 2008, Murty et al., 2011, Quidé et al., 2013, Tu et al., 2006, van Veelen et al., 2010, van Veelen et al., 2011, Vink et al., 2006, Wolf et al., 2011, Zandbelt et al., 2011), in particular those that require the processing of rewards (Esslinger et al., 2012, Juckel et al., 2006, Morris et al., 2011, Murray et al., 2008, Nielsen et al., 2012, Schlagenhauf et al., 2009). These studies report blunted ventral striatum activation during reward anticipation (Esslinger et al., 2012, Juckel et al., 2006, Morris et al., 2011, Murray et al., 2008, Nielsen et al., 2012, Schlagenhauf et al., 2009) and decreased orbitofrontal activation (Schlagenhauf et al., 2009) during reward receipt. Fronto-striatal deficits are also present in first-degree relatives (de Leeuw et al., 2013, de Leeuw et al., 2014, de Leeuw et al., 2015, Raemaekers et al., 2006, Vink et al., 2006, Zandbelt et al., 2011). Specifically, as in patients, we recently observed hypoactivation in the ventral striatum during reward anticipation in unaffected siblings of schizophrenia patients compared to matched healthy controls (de Leeuw et al., 2014), but found orbitofrontal cortex activation to be increased during receipt of reward. These findings are consistent with those of Grimm et al. (2014), who also identified reduced ventral striatum activation in relatives of patients. Taken together, these findings underscore the fact that impaired fronto-striatal function is associated with the familial vulnerability of the disorder.

This familial vulnerability, probably in interaction with environmental factors, may be at the basis of an abnormal fronto-striatal brain development (Paus et al., 2008) preceding the overt manifestation of schizophrenia. Evidence in support of such a developmental hypothesis of schizophrenia comes primarily from neuropsychological studies showing deficits in cognition and behavior (Keshavan et al., 2008, Rapoport et al., 2012) in at-risk adolescents prior to the clinical diagnosis. However, to date almost no functional neuroimaging studies have been performed to investigate the development of fronto-striatal functioning in young subjects at risk for schizophrenia. For the current study, we included adolescent offspring of schizophrenia patients, as they are clearly at increased familial risk: they have a tenfold increased incidence of schizophrenia-related or not otherwise specified psychosis in adulthood (Erlenmeyer-Kimling and Cornblatt, 1987). Importantly, and in contrast to clinical at-risk adolescents (i.e. at-risk mental state), these adolescents are selected based on familial risk alone and are usually not symptomatic or treatment seeking; therefore, they typically have not been exposed to psychotropic medication, including antipsychotic medication.

In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across adolescence. We obtained functional MRI data from 25 adolescent offspring of schizophrenia patients and 36 age-matched healthy controls across the age range of 10–19 years. Subjects performed a modified version of the Monetary Incentive Delay task (Knutson et al., 2001a, Knutson et al., 2001b) which was optimized to analyze changes in brain activation related to the anticipation and receipt of reward separately (Figee et al., 2011, van Hell et al., 2010, Vink et al., 2015). Two bilateral anatomical ROIs were a priori selected, based on their known involvement in the anticipation and outcome of reward (Haber and Knutson, 2010, Knutson et al., 2001a, Knutson et al., 2001b): the ventral striatum and orbitofrontal cortex. Based on findings of reduced ventral striatum activation levels in both adult schizophrenia patients and their siblings, combined with what is already known from normal adolescent development (Hoogendam et al., 2013), we hypothesized that ventral striatum activation will either (a) be reduced or (b) diminish across adolescence in offspring of schizophrenia patients compared to that in healthy control adolescents. Formulating a hypothesis for the cross-sectional development of orbitofrontal cortex activation is less clear cut, as activation levels during adulthood differ between patients (reduced levels; Schlagenhauf et al., 2009) and their siblings (increased levels; de Leeuw et al., 2014) and this region has never been investigated in the context of reward processing in adolescent offspring of patients. Furthermore, the frontal cortex is one of the last regions to reach its mature state, so that the impact of the increased familial risk may be expressed only at the very end of adolescence (Casey et al., 2010).

Section snippets

Participants

Twenty-five adolescent offspring of patients with schizophrenia (14.2 ± 2.7 years, 9 males) and 36 unrelated healthy control subjects (13.1 ± 1.9 years, 21 males) participated in this study. All subjects were right-handed. None of the participants received psychotropic medication, had any contraindications for MRI, suffered from alcohol or drug dependence, had a history of a neurological diagnosis or psychotic disorder. Psychopathology in SZ-offspring and controls was operationalized as current and

Effect of reward on reaction times

Behavioral results are presented in Fig. 2. An ANCOVA analyses revealed that the group by age interaction was not significant (F(1,57) = 1.01, p = 0.31). A subsequent analysis showed that the main effect of age was not significant (F(1,57) = 0.04, p = 0.85). Finally, the main effect of group was significant (F(1,57) = 5.58, p = 0.02), with SZ offspring showing a larger effect of reward on reaction times (RT) (17 ms ± 18.3 ms) than controls (5.1 ± 21.1 ms).

Amount of money won

An ANCOVA analyses revealed that the group by age

Discussion

In this cross-sectional study, we show for the first time that activation in the ventral striatum during reward anticipation declines across age in adolescent offspring of schizophrenia patients (SZ offspring, range 10–19 years), indicating impaired development of the striatum during adolescence in subjects at familial risk for schizophrenia. This pattern of decline across adolescence matches ventral striatum hypoactivation observed in both adult schizophrenia patients and their siblings (de

Conclusion

In conclusion, we show here for the first time a decline in ventral striatum activation across adolescent development in offspring of schizophrenia patients. Such a pattern, although established in a cross-sectional study, appears to be consistent with reduced ventral striatum activation in adult schizophrenia patients and their siblings. This finding provides additional evidence for the notion that impaired ventral striatum activation signifies a familial vulnerability for schizophrenia. In

Conflict of interest

We declare that there is no conflict of interest.

Role of funding source

We did not receive funding for this research.

References (62)

  • K. Koch et al.

    Fronto-striatal hypoactivation during correct information retrieval in patients with schizophrenia: an fMRI study

    Neuroscience

    (2008)
  • M. de Leeuw et al.

    Working memory and default mode network abnormalities in unaffected siblings of schizophrenia patients

    Schizophr. Res.

    (2013)
  • P. McGuire et al.

    Functional neuroimaging in schizophrenia: diagnosis and drug discovery

    Trends Pharmacol. Sci.

    (2008)
  • V.P. Murty et al.

    Selective updating of working memory content modulates meso–cortico–striatal activity

    NeuroImage

    (2011)
  • M.Ø. Nielsen et al.

    Alterations of the brain reward system in antipsychotic naïve schizophrenia patients

    Biol. Psychiatry

    (2012)
  • J. van Os et al.

    Schizophrenia

    Lancet

    (2009)
  • K.M. Prasad et al.

    Cortical surface characteristics among offspring of schizophrenia subjects

    Schizophr. Res.

    (2010)
  • Y. Quidé et al.

    Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia

    Schizophr. Res.

    (2013)
  • M. Raemaekers et al.

    Brain activation during antisaccades in unaffected relatives of schizophrenic patients

    Biol. Psychiatry

    (2006)
  • F. Schlagenhauf et al.

    Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions

    Biol. Psychiatry

    (2009)
  • P.C. Tu et al.

    Neural correlates of antisaccade deficits in schizophrenia, an fMRI study

    J. Psychiatr. Res.

    (2006)
  • N. Tzourio-Mazoyer et al.

    Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain

    Neuroimage

    (2002)
  • K.R.A. Van Dijk et al.

    The influence of head motion on intrinsic functional connectivity MRI

    NeuroImage

    (2012)
  • N.M.J. van Veelen et al.

    Left dorsolateral prefrontal cortex dysfunction in medication-naive schizophrenia

    Schizophr. Res.

    (2010)
  • N.M.J. van Veelen et al.

    Prefrontal lobe dysfunction predicts treatment response in medication-naive first-episode schizophrenia

    Schizophr. Res.

    (2011)
  • M. Vink et al.

    Functional differences in emotion processing during adolescence and early adulthood

    NeuroImage

    (2014)
  • M. Vink et al.

    Ventral striatum is related to within-subject learning performance

    Neuroscience

    (2013)
  • M. Vink et al.

    Striatal dysfunction in schizophrenia and unaffected relatives

    Biol. Psychiatry

    (2006)
  • J.A. Waltz et al.

    Probabilistic reversal learning impairments in schizophrenia: further evidence of orbitofrontal dysfunction

    Schizophr. Res.

    (2007)
  • D.H. Zald et al.

    Neuropsychological assessment of the orbital and ventromedial prefrontal cortex

    Neuropsychologia

    (2010)
  • E. Bijleveld et al.

    Distinct neural responses to conscious versus unconscious monetary reward cues

    Hum. Brain Mapp.

    (2014)
  • Cited by (20)

    • Activation of Internal Correctness Monitoring Circuitry in Youths With Psychosis Spectrum Symptoms

      2023, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
    • Neural Circuitry of Salience and Reward Processing in Psychosis

      2023, Biological Psychiatry Global Open Science
    • The Role of Dysfunctional Reward Processing in Psychotic Disorders

      2023, Biological Psychiatry Global Open Science
    • Effectiveness of enhancing cognitive reserve in children, adolescents and young adults at genetic risk for psychosis: Study protocol for a randomized controlled trial

      2021, Revista de Psiquiatria y Salud Mental
      Citation Excerpt :

      Gray matter reduction appears to be more pronounced in Off-SZ than in Off-BP27,28 and has been associated with lifetime psychiatric disorders and general cognitive capacity,30 as well as affective31 and psychotic spectrum32 symptoms. Changes in brain functional connectivity have also been described in Off-BPSZ, both at the level of the connectome33 and more specifically in emotion regulation and reward processing circuits.34–38 Despite evidence that Off-BDSZ already show impairments in various domains during youth, no study so far has assessed the effect of psychological interventions in child and adolescent offspring of parents affected by these severe mental health conditions.

    View all citing articles on Scopus
    1

    Both authors contributed equally.

    View full text