Dysfunction of ventral striatal reward prediction in schizophrenia
Introduction
Negative symptoms figure prominently in the prodromal and early phase of schizophrenia, adversely affecting patients' well-being and compliance with treatment (Andreasen, 1990, Harrow et al., 1994, Ruhrmann et al., 2003, Strous et al., 2004). While brain imaging research has long focused on the neurobiological correlates of cognitive dysfunction in prefrontal–striatal–thalamic neurocircuits (Andreasen et al., 1996, Callicott et al., 2000, Meyer-Lindenberg et al., 2002, Meyer-Lindenberg et al., 2005, Abi-Dargham et al., 2002, Molina et al., 2003), only a few imaging studies have examined the central correlates of negative symptoms associated with affective dysfunction in schizophrenia, such as affective flattening or anhedonia (Breiter et al., 1997, Crespo-Facorro et al., 2001, Heinz et al., 1998). Anhedonia and other predominantly affective negative symptoms may be caused by a dysfunction of dopaminergic neurons in the ventral striatum, including the nucleus accumbens—a core region of the brain reward system (Breiter et al., 1997). This condition may be the result of a primary disconnection between the prefrontal and temporolimbic cortices (Carlsson et al., 1999, Sesack and Carr, 2002, Weinberger and Lipska, 1995). The ventral striatum, including the nucleus accumbens, is activated by events essential to the survival of the species, such as those related to food, sexuality, or important social interactions (Berridge and Robinson, 1998, Robbins and Everitt, 1996, Wise, 1982). Ventral striatal activity has been associated with pleasant emotions of anticipation (Berridge and Robinson, 1998), and ventral striatal dysfunction has long been associated with reduced motivation or anhedonia (Goldstein and Volkow, 2002, Wise, 1982). Because brain imaging techniques can be used to observe activation in the ventral striatum, impairments in this area of the brain can now be visualized in humans (Breiter et al., 1997, Knutson et al., 2001).
To date, brain imaging studies investigating the central correlates of negative symptoms in schizophrenia have primarily examined patients who are on neuroleptic medication (Crespo-Facorro et al., 2001, Heinz et al., 1998). In these patients, reduced activation resulting from the presentation of affective pictures and human faces was observed in limbic and paralimbic brain areas such as the amygdala, hippocampus, prefrontal (PFC) and insular cortex, nucleus accumbens, and parahippocampal gyrus (Schneider et al., 1998, Gur et al., 2002, Taylor et al., 2002, Takahashi et al., 2004). In paradigms using event-related potentials, negative symptoms were associated with a reduction in P300 amplitude (Mathalon et al., 2000). However, in these studies, neuroleptic blockage of dopamine D2 receptors in the ventral striatum may interfere with the processing of reward-indicating cues (Berridge and Robinson, 1998, Robbins and Everitt, 1996, Wise, 1982) and may cause secondary negative symptoms that mimic primary negative symptoms associated with schizophrenia (Heinz et al., 1998, Schmidt et al., 2001). Therefore, we examined unmedicated schizophrenics and healthy controls subjects by measuring ventral striatal activation during the presentation of stimuli that predicted monetary gain or loss (Knutson et al., 2001). We hypothesized that unmedicated schizophrenics would show reduced ventral striatal activation during reward anticipation and that reductions in ventral striatal activation would, in turn, be associated with the severity of negative symptoms.
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Subjects and instruments
The local ethics committee approved the study, and written informed consent was obtained from all participants after the procedures had been fully explained. A total of 10 unmedicated schizophrenic male patients (mean age: 26.8 ± 7.8, range 19–34) who fulfilled DSM-IV and ICD-10 criteria for schizophrenia and had no other psychiatric axis I disorders (SCID interview) (First et al., 2001) and no current drug abuse or past history of drug dependence (SCID interview and random urine drug testing)
Confirmatory analysis of group differences during anticipation of reward
In accordance with previous studies (Knutson et al., 2001), healthy control subjects showed a significant increase in BOLD response during anticipation of potential monetary gain versus no outcome in the bilateral ventral striatum including the nucleus accumbens (Talairach coordinates (x, y, z) left: (−21, 6, −3), t = 5.63; right: (9, 6, −5), t = 4.26, P < 0.05 FWR-corrected for ventral striatal VOI). We also observed bilateral ventral striatal activation during anticipation of potential
Discussion
This study resulted in two major findings: (1) compared to healthy controls, unmedicated schizophrenics showed reduced ventral striatal activation during the presentation of reward-indicating cues; (2) reduced activation in the ventral striatum during exposure to reward-indicating versus neutral visual cues was inversely correlated with the severity of psychopathology in schizophrenic patients. In previous brain imaging studies, a high blockage of striatal dopamine D2 receptors has been
Acknowledgments
This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; HE 2597/4-2) and by investigator-initiated trails funded by Janssen-Cilag Germany and Lilly Germany.
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