Although negative symptoms, such as anhedonia (the blunted experience and/or anticipation of pleasure) and avolition (a reduced tendency to engage in goal-directed behavior), are among the debilitating and treatment-resistant aspects of the psychopathology of schizophrenia (SZ), little is known about their neural basis and their inter-relationships. It has often been thought that avolition stems from a blunted experience of pleasure in SZ, but, despite the intuitive appeal of this idea, direct evidence for it is limited. Recent work from our group indicates that brain responses to reinforcers correlate with ratings of negative symptoms in SZ patients. Furthermore, we have found that SZ patients with high ratings for negative symptoms also show a reduced willingness to explore response alternatives when uncertain. Our primary goal is to contribute to a mechanistic understanding of negative symptoms in SZ by investigating neural processes underlying value-based decision making (DM) and the updating of value representations based on prior outcomes, in SZ patients and their first-degree relatives. We posit that abnormal neural responses to rewards lead to degraded representations of expected value (EV) in the schizophrenic brain. Furthermore, based on recent findings of a role for uncertainty in modulating learning and DM, we will investigate a possible contribution of aberrant uncertainty processing to motivational impairments in SZ. Specifically, uncertainty is thought to influence learning by modulating the impact of surprising outcomes, called prediction errors, on changes in the strength of associations. A role for uncertainty has also been established in driving exploration in the service of maximizing the information obtained. Neuroimaging studies have implicated both dorsal anterior cingulate cortex (dACC) and parietal cortex in the processing of uncertainty. Importantly, neuroimaging findings from studies of DM in SZ point to dysfunction in these areas. We propose a set of MRI experiments designed to examine: (i) the relative impact and gains and instances of loss-avoidance on learning; (ii) the impact of uncertainty on value updating; (iii the neural basis of value- based choice; and (iv) neural processes underlying uncertainty-driven exploration. We hypothesize that avolition in SZ is, in part, driven by an attenuated neural response to positive outcomes and a consequent reduced anticipation of rewards. We further propose that, even if outcomes were experienced normally, motivational deficits could still arise in SZ if neural signals related to uncertainty were aberrant, leading to abnormal value updating and erratic, or reduced, exploration. Finally, we anticipate that many of the aberrant neural signals observed in SZ patients will be present in first-degree relatives of SZ patients We propose that the results of our proposed experiments will contribute to a mechanistic understanding of anhedonia and avolition in SZ. Such a mechanistic understanding would have important implications for developing better treatments for the negative symptoms of schizophrenia.

Public Health Relevance

Schizophrenia is a complex mental disorder affecting approximately 1% of the population, that results in chronic disability for more than 3 of affected individuals through their adult lives, as well as a tremendous public health burden, in terms of the extremely high rate of unemployment in individuals with schizophrenia and the enormous financial costs to public health care system. Because of the close relationship between functional disability in schizophrenia and negative symptoms of the disorder, such as anhedonia (a reduced ability to experience pleasure) and avolition (reduced motivation), it is critical that progress be made in understanding and developing therapeutic mechanisms for treating this class of symptoms. The goal of the proposed project is to investigate the neural processes underlying reward-based learning and motivation in patients with schizophrenia, and their first-degree relatives, in order to increase our knowledge of the origins of negative symptoms and to identify potential treatment targets.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Rumsey, Judith M
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University of Maryland Baltimore
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United States
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Waltz, James A; Xu, Ziye; Brown, Elliot C et al. (2018) Motivational Deficits in Schizophrenia Are Associated With Reduced Differentiation Between Gain and Loss-Avoidance Feedback in the Striatum. Biol Psychiatry Cogn Neurosci Neuroimaging 3:239-247
Waltz, James A (2017) The neural underpinnings of cognitive flexibility and their disruption in psychotic illness. Neuroscience 345:203-217
Reddy, Lena Felice; Waltz, James A; Green, Michael F et al. (2016) Probabilistic Reversal Learning in Schizophrenia: Stability of Deficits and Potential Causal Mechanisms. Schizophr Bull 42:942-51
Waltz, James A; Gold, James M (2016) Motivational Deficits in Schizophrenia and the Representation of Expected Value. Curr Top Behav Neurosci 27:375-410
Culbreth, Adam J; Westbrook, Andrew; Xu, Ziye et al. (2016) Intact Ventral Striatal Prediction Error Signaling in Medicated Schizophrenia Patients. Biol Psychiatry Cogn Neurosci Neuroimaging 1:474-483
Gold, James M; Waltz, James A; Frank, Michael J (2015) Effort cost computation in schizophrenia: a commentary on the recent literature. Biol Psychiatry 78:747-53
Brown, Elliot C; Hack, Samantha M; Gold, James M et al. (2015) Integrating frequency and magnitude information in decision-making in schizophrenia: An account of patient performance on the Iowa Gambling Task. J Psychiatr Res 66-67:16-23
Strauss, Gregory P; Waltz, James A; Gold, James M (2014) A review of reward processing and motivational impairment in schizophrenia. Schizophr Bull 40 Suppl 2:S107-16