Reward-dependent modulation of working memory is associated with negative symptoms in schizophrenia

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Abstract

The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward–cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior.

Introduction

Negative symptoms – comprising the domains of blunted affect, alogia, asociality, anhedonia, and avolition – are an integral component of schizophrenia. They are a strong predictor of poor prognosis and contribute to functional impairment (Azorin et al., 2014, Kirkpatrick et al., 2006, Milev et al., 2005, Rabinowitz et al., 2012). A recent consensus suggests that negative symptoms can be grouped into two factors. One factor is referred to as diminished expression, comprising blunted affect and alogia. The other factor is referred to as diminished motivation and pleasure, or apathy, and comprises asociality, anhedonia and avolition (Kring and Barch, 2014, Strauss et al., 2012). This distinction might allow a more differentiated approach in the search of underlying pathophysiological mechanisms (Blanchard and Cohen, 2006, Foussias and Remington, 2010, Liemburg et al., 2013, Messinger et al., 2011).

Negative symptoms have been consistently associated with dysfunctional reward processing, in particular with diminished reward anticipation. On a neural level, this has been linked to a reduction in ventral striatal activity (Juckel et al., 2006, Nielsen et al., 2012, Schlagenhauf et al., 2008, Simon et al., 2010, Waltz et al., 2008). Negative symptoms have also been linked to neurocognitive deficits, although this association is rather modest (Lin et al., 2013, Milev et al., 2005, Ventura et al., 2013, Ventura et al., 2009). The cognitive deficits, and to a lesser extent negative symptoms, have been associated with abnormal activity in the prefrontal cortex, particularly the dorsolateral prefrontal cortex (dlPFC; Barch and Ceaser, 2012, Manoach, 2003).

Recent work suggests that there is a strong interaction of reward anticipation with cognitive performance. Knowing that a certain cognitive effort might result in the receipt of a reward leads to the prioritization of the respective process and influences the assignment of limited cognitive resources (Beck et al., 2010, Braver et al., 2014, Kennerley and Wallis, 2009, Krawczyk et al., 2007, Locke and Braver, 2008, Rowe et al., 2008). On the neural level, the anterior cingulate cortex (ACC) has been suggested to play an essential role in this interaction and to act as a hub linking reward and cognition (Krebs et al., 2012, Pessoa, 2009, Pessoa, 2008, Vassena et al., 2014). It is presumed that the ACC receives reward information from the ventral striatum (VS), thereby enhancing cognitive performance (Holroyd and Yeung, 2012, Pessoa, 2009, van Steenbergen et al., 2014). It remains unknown how negative symptoms in schizophrenia relate to the reward–cognition interaction at the neural level.

In the current study, we measured cognitive performance with a letter variant of the n-back working memory (WM) task and varied the financial incentives for the performance. We hypothesized that patients with schizophrenia would show impairments in the modulation of cognitive performance by reward and that these impairments are correlated with the severity of negative symptoms. On a neural level, we expected that the prospect of a future reward leads to the activation of the ACC as well as to a stronger activation in WM related regions in the lateral PFC. We expected that these effects are diminished in the patient group and show an inverse correlation with the severity of negative symptoms.

Section snippets

Participants

We studied 29 individuals meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 2000) criteria for schizophrenia (n = 23) or schizoaffective disorder (n = 6) and 27 healthy control subjects with no personal history of a DSM-IV axis 1 disorder. All participants provided written informed consent to participate in the study, which was approved by the local Ethics committee. Patients were recruited either as inpatients (n = 16) or outpatients (n = 13)

Sample characteristics

Demographic and clinical data are summarized in Table 1. There were no significant group differences with regard to age, gender, handedness, and education. As expected, we found a significant group difference in the composite score of all cognitive tests. The healthy control group performed significantly better than the patient group. However, we found no significant difference in the test scores measuring working memory performance (see below).

Behavioral data

In the n-back task, the main effect of group on

Discussion

To our knowledge, this is the first study to investigate the neural effects of reward modulation on working memory in patients with schizophrenia and healthy controls. On the neural level, we found evidence that reward modulation influences working memory in both groups. In the patient group, we found a negative correlation of activity in the ACC with the negative symptom factor diminished expression, but not with the factor apathy.

Across all subjects, our behavioral data suggest that

Role of funding source

The study was supported by the Swiss National Science Foundation (Grant No. 105314_140351 to Stefan Kaiser). Philippe N Tobler was supported by the Swiss National Science Foundation (PP00P1_128574, PP00P1_150739, and CRSII3_141965).

Contributors

S. Kaiser, O. Hager, and P. Tobler designed the study. O. Hager, M. Kirschner, M. Bischof, A. Kluge, and M.N. Hartmann conducted the study. O. Hager conducted the analyses and wrote the first draft of the manuscript. O. Hager, S. Kaiser, P. Tobler, and E. Seifritz revised the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

Stefan Kaiser has received speaker honoraria from Roche, Takeda, Janssen and Lundbeck. He receives royalties for cognitive test and training software from Schuhfried. Erich Seifritz has received grant support from H. Lundbeck and has served as a consultant and/or speaker for AstraZeneca, Otsuka, Eli Lilly, Janssen, Lundbeck, Novartis, Pfizer, Roche, and Servier. None of these activities is related to the present study. All other authors declare no biomedical financial interests or potential

Acknowledgment

We are grateful to Dr. Philipp Staempfli for his excellent technical support. Furthermore, we want to thank Giulia Elsaesser for her support during data collection.

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