Diminishing striatal activation across adolescent development during reward anticipation in offspring of schizophrenia patients
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.
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2021, Revista de Psiquiatria y Salud MentalCitation 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.
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Both authors contributed equally.