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Robinson OJ, Overstreet C, Charney DR, Vytal K, Grillon C. Stress increases aversive prediction error signal in the ventral striatum. Proc Natl Acad Sci U S A. 2013 Feb 11 ; Pubmed Abstract

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Primary Papers: Stress increases aversive prediction error signal in the ventral striatum.

Comment by:  James Gold, SRF AdvisorGregory StraussJames A. Waltz
Submitted 26 February 2013
Posted 26 February 2013

A recent report from Robinson and colleagues provides evidence that induced stress enhances aversive, but not appetitive, prediction error (PE) signaling in the ventral striatum (VS). This paper helps to potentially integrate findings from the human and nonhuman animal literatures, where non-rewarding salient events seem to "paradoxically" evoke reward system activation (Zink et al., 2003), including dopamine release (Horvitz, 2000). Robinson et al. show that a threatening environment may enhance the negative PE signal in the VS, at the expense of the positive PE signal, by biasing attention toward negative outcomes.

The finding by Robinson et al. has clear relevance for anxiety disorders, where enhanced processing of threat is thought to be a fundamental pathophysiological mechanism. Might these findings have relevance for schizophrenia? At first glance, one might think that this process could be involved as people begin to become psychotic. It is thought that stress is a critical contributor to the development of psychosis, and enhanced processing of threatening information might serve to amplify suspicion to the point of becoming a delusion. Thus, there is a case to be made that this same mechanism might contribute to the evolution of psychosis.

Interestingly, the same case can be made for negative symptoms. In three different studies, we have found that patients with high levels of negative symptoms appear to have preserved loss avoidance/"no-go" learning coupled with impaired positive reward-driven learning (Gold et al., 2012; Strauss et al., 2011; Waltz et al., 2007). This is supported by fMRI evidence of fully normal (if not enhanced) signaling of negative prediction errors with diminished processing of positive prediction errors in an experiment using a primary reinforcer (Waltz et al., 2009). These findings suggest that normal or enhanced punishment-driven learning, in the presence of compromised reward-driven learning, might be a path to motivational deficits and/or depression. Could a case be made that many patients with schizophrenia are basically chronically stressed, thereby enhancing the processing of aversive outcomes relative to positive outcomes, leading to behavioral deactivation and symptoms like avolition, anhedonia, and asociality? In fact, schizophrenia patients do consistently report reduced positive and increased negative trait affectivity relative to healthy populations (Horan et al., 2008).

While it may seem a bit far-fetched to think that increased trait negative affect can be equated with acute threat, the ongoing experience of negative emotion is likely a form of chronic stress. Multiple studies have linked elevated stress and high trait negative affect to an emotion regulation abnormality, i.e., difficulty applying strategies to reduce negative affect (Gross, 1998). We recently found evidence that high trait negative affect was associated with ineffective use of reappraisal strategies intended to decrease negative emotion at the neural level in patients with schizophrenia (Strauss et al., 2013). Perhaps high trait negative affect sets the stage for being more sensitive to negative PE signaling and forming aversive associations with outcomes, and emotion regulation abnormalities cause patients to be less able to recover from those aversive experiences quickly.

Several issues remain to be resolved, regarding the finding of Robinson et al. For example, does the threat environment actually flip the sign of the prediction error signal in the VS, or is the VS response to fearful faces in the threatening environment a sign-less salience signal? Should an enhancement of the negative PE signal in the threat condition involve extreme deactivation of the VS, or activation of the VS?

Nonetheless, the work of Robinson and colleagues provides us with several new questions to consider in people with schizophrenia.

References:

Gold JM, Waltz JA, Matveeva TM, Kasanova Z, Strauss GP, Herbener ES, Collins AG, Frank MJ. Negative symptoms and the failure to represent the expected reward value of actions: behavioral and computational modeling evidence. Arch Gen Psychiatry . 2012 Feb ; 69(2):129-38. Abstract

Gross JJ. The emerging field of emotion regulation: an integrative review. Review of General Psychology. 1998;2:271-99.

Horan WP, Blanchard JJ, Clark LA, Green MF. Affective traits in schizophrenia and schizotypy. Schizophr Bull. 2008;34:856-874. Abstract

Horvitz JC. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience. 2000;96(4):651-6. Review. Abstract

Strauss GP, Frank MJ, Waltz JA, Kasanova Z, Herbener ES, Gold JM. Deficits in positive reinforcement learning and uncertainty-driven exploration are associated with distinct aspects of negative symptoms in schizophrenia. Biol Psychiatry . 2011 Mar 1 ; 69(5):424-31. Abstract

Strauss GP, Kappenman ES, Culbreth AJ, Catalano LT, Lee BG, Gold JM. Emotion Regulation Abnormalities in Schizophrenia: Cognitive Change Strategies Fail to Decrease the Neural Response to Unpleasant Stimuli. Schizophr Bull . 2013 Jan 11. Abstract

Waltz JA, Frank MJ, Robinson BM, Gold JM. Selective reinforcement learning deficits in schizophrenia support predictions from computational models of striatal-cortical dysfunction. Biol Psychiatry . 2007 Oct 1 ; 62(7):756-64. Abstract

Waltz JA, Schweitzer JB, Gold JM, Kurup PK, Ross TJ, Salmeron BJ, Rose EJ, McClure SM, Stein EA. Patients with schizophrenia have a reduced neural response to both unpredictable and predictable primary reinforcers. Neuropsychopharmacology . 2009 May ; 34(6):1567-77. Abstract

Zink CF, Pagnoni G, Martin ME, Dhamala M, Berns GS. Human striatal response to salient nonrewarding stimuli. J Neurosci. 2003 Sep 3;23(22):8092-7. Abstract

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