Striatal dysfunction in patients with schizophrenia and their unaffected first-degree relatives

Abstract

Despite empirical findings showing that patients with schizophrenia and their unaffected first-degree relatives have deficits in processing monetary incentives, it is unclear whether similar deficits could be demonstrated for affective incentives. Twenty-six patients with schizophrenia and 26 age and gender matched healthy controls; 23 unaffected first-degree relatives and 23 matched healthy controls were recruited to complete a Monetary Incentive Delay (MID) task and an Affective Incentive Delay (AID) task in a 3-Tesla MRI scanner. Hypoactivation in the dorsal striatum when anticipating monetary incentives were found in patients with schizophrenia and their unaffected first-degree relatives compared with healthy controls. Furthermore, patients with schizophrenia showed hyperactivation in the ventral striatum when receiving both monetary and affective incentives. These findings suggest that disorganized striatal function, regardless of incentive types, may be present in patients with schizophrenia and before the onset of illness in their first-degree unaffected relatives.

Introduction

The latest formulation of the dopamine hypothesis of schizophrenia suggests that disorganized mesolimbic and mesocortical dopaminergic activity underlies the pathophysiology of psychosis (Howes and Kapur, 2009). The striatal dopaminergic system, especially the ventral striatum, serves as the cornerstone of this hypothesis (Berridge and Robinson, 1998, Berridge et al., 2009, Schultz et al., 1997). Impaired dopaminergic activity in the striatum of patients with schizophrenia is associated with negative and positive symptoms (Heinz, 2002, Heinz and Schlagenhauf, 2010, Kapur, 2003, Kapur et al., 2005).

The Monetary Incentive Delay (MID) task (Knutson et al., 2001, Knutson et al., 2000) is designed to capture the anticipation and consummation of delayed incentives and is particularly useful in exploring striatal activation. Earlier studies have found hypoactivation in the ventral striatum of patients with chronic (Juckel et al., 2006a, Juckel et al., 2006b) and first-episode (Esslinger et al., 2012, Hanssen et al., 2015, Nielsen et al., 2012b, Schlagenhauf et al., 2009) schizophrenia, their unaffected first-degree relatives (de Leeuw et al., 2015, Grimm et al., 2014) and other high-risk groups for schizophrenia (Juckel et al., 2012) during the anticipation of monetary incentives. The reduced ventral striatal haemodynamic activity has been linked to temporal dopaminergic bursts which impede the retrieval of incentive-specific signals from contextual activities (Knutson and Gibbs, 2007). However, few studies have examined the neural mechanisms for the anticipation and consummation of affective incentives in patients with schizophrenia and their unaffected first-degree relatives. Heerey and Gold (2007) found that patients with schizophrenia showed impaired motivational behavioural performance during the anticipation of affective incentives, and these findings were corroborated by another study (Lui et al., 2016). These results suggest that patients with schizophrenia may have impaired processing for not only monetary incentives, but also affective incentives. Examining the mechanisms of various types of incentive processing could provide more comprehensive insights into the psychopathological mechanisms of amotivation and anhedonia, as well as negative symptoms of schizophrenia. Even though monetary incentives could, to some extent, be regarded as affective stimuli, affective incentives are more specific and are often presented using affective pictures with more social information than monetary incentives.

To the best of our knowledge, no study has explored the neural mechanisms for both affective and monetary incentives in patients with schizophrenia and their unaffected first-degree relatives simultaneously. Our preliminary findings suggest a distinct neural mechanism for affective incentives which is different from monetary incentives in healthy people using the Affective Incentive Delay (AID) and Monetary Incentive Delay (MID) tasks (Chan et al., 2015). We found that healthy volunteers showed activation in the nucleus accumbens when anticipating monetary, rather than affective incentives. However, similar striatal activation patterns were found in response to both monetary and affective stimuli (Izuma et al., 2008). These results suggest that affective and monetary incentives engage different brain regions during the anticipatory phase, but both engaged the striatal system during the consummatory phase.

The investigation of unaffected first-degree relatives of patients with schizophrenia could help to shed light on the psychopathology of dysfunctional striatal activation in schizophrenia when processing incentives. While previous studies have demonstrated impaired striatal activation in first-degree relatives of schizophrenia patients during the anticipation of monetary incentives (de Leeuw et al., 2015, Grimm et al., 2014), no study has investigated striatal dysfunction in patients with schizophrenia and their first-degree relatives simultaneously in the different phases of incentive processing. The influence of antipsychotic medications on striatal activation when anticipating monetary incentives has been reported in previous studies (Nielsen et al., 2012a, Nielsen et al., 2012b). Studying striatal dysfunction in unaffected first-degree relatives of patients with schizophrenia could avoid the confounding effect of antipsychotic medications and ascertain if this dysfunction exists along the schizophrenia spectrum, thereby providing evidence that this trait may be an endophenotype of schizophrenia (Chan et al., 2011, Gottesman and Gould, 2003).

In this study, we sought to examine the brain activations at the striatum during monetary and affective incentive processing in patients with schizophrenia and their unaffected first-degree relatives. Furthermore, in addition to the ventral striatum, reduced dorsal striatal activation has also been reported in patients with schizophrenia when anticipating monetary incentives (Mucci et al., 2015). Hence, we examined both dorsal and ventral striatal activation in both groups during the various phases of incentive processing. We hypothesized that patients with schizophrenia and their unaffected first-degree relatives would demonstrate dysfunctional striatal activation in anticipating and receiving both monetary and affective incentives.