Goal Representations and Motivational Drive in Schizophrenia: The Role of Prefrontal–Striatal Interactions

doi:10.1093/schbul/sbq068

Schizophr Bull. 2010 September; 36(5): 919–934.

Published online 2010 June 21. doi: 10.1093/schbul/sbq068

PMCID: PMC2930335

Copyright © The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Goal Representations and Motivational Drive in Schizophrenia: The Role of Prefrontal–Striatal Interactions

Deanna M. Barch^*¹³ and Erin C. Dowd⁴

¹Department of Psychology, Washington University, Box 1125, One Brookings Drive, St. Louis, MO

²Department of Psychiatry, Washington University, Box 1125, One Brookings Drive, St. Louis, MO

³Department of Radiology, Washington University, Box 1125, One Brookings Drive, St. Louis, MO

⁴Neuroscience Program, Washington University, St. Louis, MO

^*To whom correspondence should be addressed; tel: 314-935-8729, fax: 314-935-8790, e-mail: dbarch/at/artsci.wustl.edu.

This article has been cited by other articles in PMC.

Abstract

The past several years have seen a resurgence of interest in understanding the psychological and neural bases of what are often referred to as “negative symptoms” in schizophrenia. These aspects of schizophrenia include constructs such as asociality, avolition (a reduction in the motivation to initiate or persist in goal-directed behavior), and anhedonia (a reduction in the ability to experience pleasure). We believe that these dimensions of impairment in individuals with schizophrenia reflect difficulties using internal representations of emotional experiences, previous rewards, and motivational goals to drive current and future behavior in a way that would allow them to obtain desired outcomes, a deficit that has major clinical significance in terms of functional capacity. In this article, we review the major components of the systems that link experienced and anticipated rewards with motivated behavior that could potentially be impaired in schizophrenia. We conclude that the existing evidence suggests relatively intact hedonics in schizophrenia, but impairments in some aspects of reinforcement learning, reward prediction, and prediction error processing, consistent with an impairment in “wanting.” As of yet, there is only indirect evidence of impairment in anterior cingulate and orbital frontal function that may support value and effort computations. However, there are intriguing hints that individuals with schizophrenia may not be able to use reward information to modulate cognitive control and dorsolateral prefrontal cortex function, suggesting a potentially important role for cortical–striatal interactions in mediating impairment in motivated and goal-directed behavior in schizophrenia.

Keywords: reward, cognitive control, anhedonia

Introduction

The past several years have seen a resurgence of interest in understanding the psychological and neural bases of what are often referred to as “negative symptoms” in schizophrenia. These aspects of schizophrenia include constructs such as asociality, avolition (a reduction in the motivation to initiate or persist in goal-directed behavior), and anhedonia (a reduction in the ability to experience pleasure) as well as flat affect or the diminished expression of emotion. This resurgence of interest in negative symptoms in schizophrenia has been driven by at least 2 factors. The first factor is the realization that addressing the pervasive cognitive impairment present in schizophrenia may not be enough to fully understand and remediate the functional impairments that can make life so difficult for individuals with this disorder.¹ This is not to say that cognitive impairment is not a critical constraint on functional capacity in schizophrenia. Rather, the point is that we may also need to understand how cognitive impairments interact with reward and emotional processing systems in a way that leads to abnormalities in motivated behavior in this disorder. A second factor is that major advances have occurred in the field of affective neuroscience that provide a theoretical and empirical foundation upon which to draw in order to identify candidate psychological and neural mechanisms that drive interactions between cognitive function, reward, and motivation.²^,³

In the current discussion, we will focus on the constructs of anhedonia, avolition, asociality, and amotivation (collectively referred to as anhedonia/avolition for ease of discussion) as distinct and separable from the construct of flat affect or diminished expression of emotion. This distinction is supported by a range of exploratory and confirmatory analyses of symptom assessment scales that have consistently provided evidence for separate negative symptom factors for flat affect and anhedonia/avolition. As nicely articulated by Malaspina and colleagues,⁴ separable factors for flat affect and anhedonia/avolition have been identified in: (1) mixed groups of patients with a range of psychotic disorders⁵^–⁷, (2) schizophrenia spectrum patients⁸^–¹², (3) deficit syndrome patients⁴^,¹³, (4) patients on medications⁴^,⁹, (5) patients off medications¹², (6) first-episode patients⁸, (7) chronic patients¹¹, and (8) patients across many different cultures.⁵^,⁶^,⁸^,¹⁰^,¹³

The constructs of anhedonia/avolition play a major role in many theories of schizophrenia, including those that focus on liability to the disorder.¹⁴^–¹⁷ However, as reviewed below, studies suggest that when provided with potentially enjoyable stimuli, events or experiences, individuals with schizophrenia seem to enjoy such experiences as much as controls.¹⁸^–²³ Nonetheless, one of the fundamental challenges in the development of therapeutic interventions is that individuals with schizophrenia seem less motivated to engage in goal-directed behavior that would bring them into contact with potentially enjoyable experiences, despite an apparently intact ability to enjoy those experiences once achieved.²² This dissociation has been referred to as a distinction between “wanting” vs “liking” or between anticipatory and consummatory pleasure.²⁴^–²⁶ These problems are a major public health concern, as a failure to engage in motivated goal-directed behavior can manifest as reduced educational, occupational, and social achievement. If anhedonia/avolition does not reflect a deficit in the “enjoyment” of positive experiences in schizophrenia, then we need to understand the mechanisms that may lead to deficits in the ability to translate information about potentially rewarding events into action plans that will allow an individual to obtain such positive outcomes. The goal of this review is to outline and describe the key processes that link experienced and anticipated rewards to action plans, to review the existing literature on the integrity of these systems in schizophrenia, and to provide a summary and suggestions for future research aimed at understanding the psychological and neural bases of motivational impairments in schizophrenia.

Components of the Systems Linking Experienced or Anticipated Rewards to Action Plans

Our hypothesis is that individuals with schizophrenia seem to have difficulties using internal representations of emotional experiences, previous rewards, and motivational goals to drive current and future behavior that should allow them to obtain desired outcomes, a deficit that has major clinical significance in terms of functional capacity. However, there are many processes that contribute to linking internal representations to behavior, and it is important to understand which of these are impaired in schizophrenia so as to design appropriate intervention strategies. Fortunately, a burgeoning affective neuroscience literature in humans and animals has begun to outline the core neural systems that serve to process and integrate reward and penalty signals and then translate these signals into value and/or utility estimates that can be used to drive action selection and goal planning. Although an oversimplification, it helps to organize this large literature by thinking of 4 major components to the translation of appetitive or reward information into behavioral responses³^,²⁴^,²⁷^–²⁹ (see figure 1). The first component, referred to as “hedonics or liking,” reflects the ability of the organism to “enjoy” the stimulus or event that may provide pleasure or reward. For many years, it was suggested that the neurotransmitter dopamine (DA) was the primary substrate of liking.²⁴ However, more recent research has shown that experimental depletion of DA does not reduce liking when it can be measured by facial expression and/or subjective reports.²⁴ Instead, hedonic responses (at least to primary sensory stimuli) seem to be mediated by activation of the opioid and gamma amino butyric acidergic systems in the nucleus accumbens shell and its projections to the ventral pallidum as well as in the orbital frontal cortex (OFC).³⁰^–³³

Fig. 1.

Components of Reward to Outcome Translation.

A second component, called “reward prediction and wanting,” is thought to be mediated by the midbrain DA system, particularly the projections to ventral and dorsal striatal regions of the basal ganglia.²⁴^,²⁹ Many DA neurons in the substantia nigra and ventral tegmental area respond to stimuli that predict reward as well as to food and liquid rewards themselves. The degree to which these DA neurons respond to rewards seems to depend on reward predictability. If the reward was not predicted, then the DA neurons fire strongly (positive prediction error); if a predicted reward does not occur, then there is a transient depression in DA neuron firing (negative prediction error).²⁷^–²⁹^,³⁴^–³⁵ Furthermore, over time, DA neurons learn to fire to cues that predict reward rather than to rewards themselves. Similar effects have been found in humans in the ventral/dorsal striatum, with evidence from functional magnetic resonance imaging (fMRI) for activation of ventral and dorsal striatum to cues that predict reward³⁶^,³⁷ as well as both positive and negative prediction error responses.³⁸^,³⁹ These types of DA/striatal responses have been captured by temporal difference models that learn about stimuli in the environment that predict rewards.⁴⁰^,⁴¹ These mechanisms are also thought to underlie basic aspects of reinforcement learning that may occur without conscious awareness.⁴²^,⁴³ A prominent, though slightly different theory, emphasizes the role of the DA-learning process in transferring incentive salience from the reward itself to reward-predicting cues, thus imbuing these cues with motivational properties themselves (eg, a wanting response²⁴).

A third component is “cost-benefit analysis” or the ability to integrate information from different sources to derive and update the value of potentially rewarding outcomes (figure 1). One aspect, thought to be mediated at least in part by OFC, is the ability to “represent value information,” ie, to take into account not only the hedonic properties of a stimulus but also the internal or motivational state of the organism (eg, value of juice when thirsty vs not),⁴⁴ the delay before the reward occurs,⁴⁵^,⁴⁶ the different reward options available (eg, juice vs wine after a hard day),⁴⁷^,⁴⁸ and the changing contingencies associated with a stimulus (a previously rewarded response is now punished).⁴⁹ Some researchers have described the OFC as being involved in “working memory for value” or the ability to maintain, update, and integrate different sources of information about value over a short period of time.³^,⁵⁰ Human functional neuroimaging studies also highlight activation of OFC under conditions requiring value representations,⁵¹^,⁵² including those in which response contingencies need to be updated, such as reversal learning.⁵¹^,⁵³^,⁵⁴ In addition, humans with OFC lesions can show reversal learning impairments.⁵⁵^–⁵⁷

Another aspect of representing value information is “effort computation,” ie, determining the cost of engaging in whatever actions it will take to obtain that outcome. For example, one may really want to obtain chocolate cookies and may perceive eating these cookies as rewarding, but the effort associated with having to go to the store may prevent the person from pursuing actions to obtain the cookies. A growing body of research suggests that the dorsal anterior cingulate cortex (ACC) may be important for evaluating the effort associated with different action plans, in concert with DA input from nucleus accumbens and related forebrain circuitry.⁵⁸^–⁶¹ For example, research has shown that ACC lesions as well as depletions of accumbens DA lead animals to choose low effort but low reward options over higher reward but higher effort options.⁴⁶^,⁵⁸^,⁵⁹^,⁶²^–⁶⁵ The potential role of ACC in computing effort may fit nicely with its suggested role in responding to conflict and error-related signals,⁶⁶^–⁶⁸ as feedback about conflict and errors may be an important source of information about the amount of effort a particular course of action is likely to require. Indeed, some work in healthy populations has suggested that error/conflict effects in ACC are modulated by motivational/affective and reward variables.⁶⁹^,⁷⁰ However, it is not yet clear whether the same regions of ACC that respond to conflict/error are those involved in effort computations or whether these represent different functional subdivisions of ACC, though both types of studies have shown activation of similar regions of dorsal anterior cingulate.⁶⁰^,⁶¹^,⁶⁶^,⁷¹ Nonetheless, even if it should turn out that this reflects a common mechanism, it helps to outline the role that ACC may play in a range of decision-making domains.

A fourth component is the ability to “generate and execute goal-directed action plans necessary to achieve the valued outcome.” Wallis and others have suggested that this function is carried out by the lateral prefrontal cortex (PFC) (in particular, dorsolateral PFC [DLPFC]).³^,⁷²^,⁷³ Such a role for the DLPFC in motivated behavior would be consistent with its role in top-down control of cognitive processing, planning, and response execution is consistent with models suggesting that the DLPFC provides a bias signal that helps to facilitate goal-directed behavior⁷² and is consistent with evidence for impaired action planning following lateral prefrontal lesions.⁷⁴^,⁷⁵ In other words, intact DLPFC function may be necessary to translate information about value into goal representations that can be implemented as action plans to achieve the desired outcome. Furthermore, some theories of goal maintenance in DLPFC emphasize the importance of phasic DA input as a gating signal that serves to update the contents of DLPFC and protect against interference.⁷⁶^–⁷⁸ There is also growing evidence from the human and nonhuman primate literature that the potential for reward can enhance firing in DLPFC neurons and increase fMRI responses in DLPFC during cognitive control tasks⁷⁹^–⁸² and that such changes may mediate improved performance as a function of reward.⁸³^,⁸⁴

Hedonics and Liking in Schizophrenia

Numerous studies¹⁸^,¹⁹^,²¹^,²³^,⁸⁵^–¹⁰⁵ and a recent review by Ann Kring¹⁰⁶ have demonstrated that individuals with schizophrenia and controls show similar patterns of valence and arousal (eg, liking) in their self-reported emotional responses to affect eliciting stimuli. Almost all studies show that individuals with schizophrenia discriminate between positive and negative stimuli, though some studies have found differences between individuals with schizophrenia and controls in terms of “absolute levels” of emotional experience.⁹¹^–⁹³^,⁹⁵^,⁹⁶^,¹⁰⁵^,¹⁰⁷ Findings of apparently intact hedonic responses have held true for patients with and without blunted affect⁹⁰^,¹⁰⁸ and for samples of individuals with schizophrenia who have clinical ratings of overall increased anhedonia.⁹⁰ Evidence for intact affective responses has also been found in emotion-modulated startle, such that individuals with schizophrenia show similar reductions of startle responses when presented with pleasant stimuli and given sufficient time to process the stimuli.⁹²^,⁹⁷^,¹⁰⁹ Furthermore, several studies have shown intact memory enhancement for positive stimuli in schizophrenia,²¹^,¹¹⁰^,¹¹¹ again suggesting intact “in-the-moment” response to affect eliciting stimuli (though see Herbener⁹⁹). Experience sampling studies in schizophrenia find that patients report less intense and less variable positive emotions.¹⁰⁸ It may be the case that individuals with schizophrenia encounter fewer pleasurable events in their everyday lives and that their reduced reports of pleasure are an accurate reflection of their life experiences. However, recent work suggests that such reductions may be more apparent for goal-directed (eg, work and school) than nongoal-directed activities (eg, eating and watching TV) and that individuals with schizophrenia report less anticipatory pleasure than do controls even for those goal-directed events that they do experience.²⁶

Despite the robust evidence for relatively intact self-reports of experienced pleasure or valence in group analyses of studies with individuals with schizophrenia, it is also increasingly clear that there are important individual differences in the level of anhedonia/avolition that may influence these experiences. For example, we and others have found that patients who self-report greater levels of social and physical anhedonia report experiencing less-positive responses to putatively positive stimuli such as pictures, faces, and words.¹⁰⁰^,¹⁰⁵ Interestingly, however, these relationships are not unique to positive stimuli. Individuals with schizophrenia (and controls) with higher self-reports of anhedonia also rate their experiences of negative stimuli as less negative. Such findings have 2 important implications. The first is that group comparisons of individuals with schizophrenia and controls may not be sufficiently informative and that it is critical to examine the level of clinically rated or self-reported anhedonia/avolition in relation to the processes of interest. The second is that these individual differences in anhedonia/avolition have relevance for understanding the experience of negative emotions and experiences as well as positive emotions and experiences.

Studies that have used functional imaging to examine brain responses to pleasurable or rewarding stimuli have provided a more mixed picture.⁹¹^,¹¹² A number of brain regions have been implicated in the processing of positive emotional or rewarding stimuli, including the dorsal and ventral striatum, midbrain, orbitofrontal cortex, medial PFC, amygdala, and insula, and the literature is mixed as to whether recruitment of these regions is intact in schizophrenia. For example, Plailly¹⁰⁷ found reduced activation in schizophrenia in insula and OFC during hedonicity judgments of positive and negative odors but intact activation of the amygdala. Schneider also found reduced activation of the insula during the experience of positive olfactory stimuli in schizophrenia but found reduced amygdala activation.¹⁰² Taylor reported that both medicated and unmedicated individuals with schizophrenia showed reduced phasic ventral striatal responses in the comparison of positive vs neutral pictures. In our own work, we have found that individuals with schizophrenia show the same pattern of brain activation in response to both negative and positive stimuli in a range of brain regions associated with the perception and experience of emotion, including medial frontal cortex, insula, OFC, and the amygdala.¹⁰⁵ However, we did find some evidence for reduced ventral and dorsal striatal responses to positive stimuli among individuals with schizophrenia, with the severity of these deficits correlated with the magnitude of self-reported anhedonia.

In terms of studies using explicit rewards, robust ventral striatal responses to the receipt of money have been observed in patients treated with either typical or atypical antipsychotics.¹¹³^–¹¹⁵ Interestingly, Simon found that the magnitude of the reward receipt response in the ventral striatum was inversely associated with severity of depression but not with anhedonia.¹¹⁴ Schlagenhauf did not find group differences in the response to rewards in the ventral striatum, though they did not clearly see intact responses in patients, and there were reduced striatal responses to loss avoidance among the individuals with schizophrenia.¹¹⁶ Furthermore, they did see reduced reward-related responses in medial PFC.¹¹⁶ At least one study did find some evidence for reduced striatal responses to the receipt of juice (though medication and smoking confounds were possible), with the magnitude of this reduction associated with the severity of anhedonia scores.¹¹⁷

Hedonics and Liking Summary

In sum, the self-report literature provides relatively consistent evidence for intact self-reports of liking in schizophrenia, though there is evidence that greater self-reports of anhedonia or negative symptom ratings are associated with less liking.²³^,¹⁰⁰^,¹⁰⁵^,¹¹⁸ The relatively small functional imaging literature provides a somewhat confusing picture, with some evidence for reduced insular responses, and mixed evidence for altered striatal responses. However, these studies have not always clearly established effects specific to positive stimuli (leaving open the possibility that some alterations reflect general task deficits) and relatively few have addressed clinical heterogeneity in regards to negative symptoms levels. In other words, it is increasingly clear that there are important individual differences in the level of anhedonia/avolition that may influence the magnitude of responses in regions such as the striatum. Specifically, those studies that have examined individual differences in negative symptoms do suggest an important relationship between the magnitude of striatal responses to rewarding or pleasurable stimuli and anhedonia among individuals with schizophrenia.¹⁰⁵^,¹¹⁷

Reward Prediction and Wanting in Schizophrenia

There is a clear sense in the literature that the basal ganglia play an important role in cognitive/affective impairments in schizophrenia. However, the precise nature of this impairment remains elusive.¹¹⁹^–¹²⁴ In both animal and human studies, the DA–basal ganglia neural circuit has been shown to be critically involved in reward prediction as well as reinforcement learning processes that are interdependent with reward prediction. Yet surprisingly, a large number of studies have suggested intact reinforcement learning in schizophrenia using a range of tasks in which learning is relatively easy,¹²⁵^–¹³⁴ though with a few exceptions.¹³⁵^,¹³⁶

In contrast, when the paradigms become more difficult and include varying levels of probability and discrimination, individuals with schizophrenia show more evidence of impaired reinforcement learning.¹³⁷^,¹³⁸ For example, Gold and colleagues¹³⁹ found evidence for impaired learning in schizophrenia on the Frank Probabilistic Discrimination Task. A novel feature of this task is that it enables examination of reward value learning through transfer effects. In the transfer phase, individuals with schizophrenia showed less of a tendency to choose the stimulus previously associated with higher reward value. Although this pattern could reflect impaired basal ganglia-mediated reinforcement learning mechanisms, it may also reflect impaired rapid online learning mechanisms that may be mediated in part by OFC and/or DLPFC, as hypothesized by Gold and colleagues¹⁴⁰ and discussed in more detail below.

Another task frequently used to measure reinforcement learning is a probabilistic classification task called the Weather Prediction Task. In this task, participants are presented with 4 multidimensional stimuli (tarot cards) and asked to predict whether the cards indicate that it will rain or not rain. The stimuli are complex enough to make explicit learning difficult. Whether or not one considers individuals with schizophrenia to show intact or impaired performance on this task depends on whether one focuses on asymptotic performance level or learning rate. Numerous studies have shown what appears to be a relatively intact learning rate in schizophrenia, coupled with overall impaired performance.¹⁴¹^–¹⁴⁶ In other words, individuals with schizophrenia start out the task more impaired, learn at relatively the same rate as controls (but see these for evidence of an exception¹⁴⁷^,¹⁴⁸), yet never reach the same asymptotic level of performance. There is some evidence that reinforcement learning may be more intact for patients on atypical than typical antipsychotics, though it has been found in those on typicals as well.¹⁴¹^,¹⁴³ One of the difficult aspects of interpreting performance on the Weather Prediction Task is that it can also be influenced by both implicit learning mechanisms thought to be mediated by the striatum, and explicit learning mechanisms that may be supported by OFC and DLPFC regions.¹⁴⁹ Thus, one interpretation of the Weather Prediction Task results is that the normal learning curve reflects relatively intact striatal learning mechanisms, while the impaired overall performance reflects relatively impaired cortically supported explicit learning mechanisms that may be particularly important during specific phases of learning.⁷⁸^,¹⁴⁰

Studies of reward prediction/wanting in the neuroimaging literature have tended to focus on paradigms that directly examine neural responses to reward-predicting cues following conditioning trials. Some paradigms involve passive (ie, Pavlovian) conditioning, whereas others, such as the Knutson paradigm,³⁷ require speeded responses to obtain rewards. Several studies have reported reduced ventral striatum activity in schizophrenia using the Knutson paradigm. Juckel and Schlagenhauf found such effects in unmedicated individuals with schizophrenia¹¹⁶^,¹⁵⁰ as well as in individuals taking typical antipsychotics but not in individuals treated with atypicals.¹⁵¹^,¹⁵² However, in the Schlagenhauf study, the apparent improvement in reward cue responses among the individuals switched to olanzapine (eg, lack of group difference) was strongly influenced by reduced reward cue responses in controls at follow-up. Juckel also found that the severity of negative symptoms predicted the reduction in ventral striatal responses in unmedicated and typically medicated patients, suggesting important variability in schizophrenia. Kirsch reported a reduction in ventral striatal responses to reward cues in individuals with schizophrenia taking typicals compared with atypicals, though the groups were matched on behavioral performance and did not differ in ventral striatal responses to reward receipt.¹¹³ In contrast, in more recent work, both Simon¹¹⁴ and Walter¹¹⁵ found intact striatal responses to reward anticipation in medicated patients with schizophrenia, though Simon did find that the magnitude of this response was inversely correlated with apathy ratings, and Walter et al studied a relatively low negative symptom level group of individuals with schizophrenia. Together, these findings suggest that anticipatory activation in the striatum reflecting reward prediction/wanting may be reduced in individuals with schizophrenia but that this reduction is likely influenced by individual differences in anhedonia/avolition and by dopaminergic medications.

An alternative way to examine the role of the striatum in reward prediction is to look at what is referred to as prediction error responses—an increase in striatal (presumably dopaminergic) responses to unexpected rewards and a decrease in striatal responses to a failure to receive predicted rewards. Murray et al¹⁵³ found evidence for reduced prediction error responses to rewards among schizophrenia spectrum patients in bilateral midbrain and right ventral striatum, coupled with enhanced prediction error responses to neutral stimuli. Waltz and colleagues¹¹⁷ examined positive and negative prediction error responses in a passive paradigm that required participants to learn about the timing of a potential reward. These researchers found evidence for reduced positive prediction error responses in a range of regions that included the striatum (dorsal and ventral) as well as insula but relatively intact negative prediction errors in these same regions. The reduced positive prediction error is consistent with the hypothesis that individuals with schizophrenia may not learn to predict (or “want”) the upcoming rewards, though one might expect that such deficits should also lead to reduced negative prediction errors, which in theory should also depend on a representation of expected reward. As noted above, this study did not control for the effects of smoking on taste processing in schizophrenia (which could alter responses to juice), representing a confound for assessing positive prediction errors (responses to unexpected juice rewards). Interestingly, however, Waltz et al did find that the magnitude of prediction errors in basal ganglia among patients was negatively correlated with avolition scores, suggesting a link to clinically relevant symptoms. In more recent work, Walter et al found intact prediction error responses in the striatum for both positive and negative prediction errors, though again this was a relatively low negative symptom sample.

There has also been one imaging study looking at the Weather Prediction Task. Weickert et al¹⁴⁶ found that controls showed greater activation than individuals with schizophrenia in both DLPFC and caudate. This was true even when analyses were restricted to a subset of controls and patients considered to be good learners. However, these differences were apparent throughout the course of the task and did not vary as a function of learning rate or time on task, raising questions as to the specific processes that they reflected.¹⁴⁶ In a related study, Koch et al¹³⁸ found reduced activation among individuals with schizophrenia in DLPFC and ACC in a probabilistic learning paradigm when the predictability of reward outcomes was low. Furthermore, these researchers also found reduced positive prediction error responses in frontal cortex, cingulate, and putamen.

Reward Prediction and Wanting Summary

In sum, the literature on reinforcement learning and reward prediction in schizophrenia suggests relatively intact learning on simple reinforcement learning paradigms, though this absence of impairment could reflect a lack of discriminating power of such easy tasks. In contrast, on more difficult tasks that can include multiple probabilistic learning levels, we find more consistent evidence for impaired performance, though more in terms of absolute levels of performance than in learning rates. The open question in regards to this literature is the degree to which these impairments reflect differences in striatum-influenced learning mechanisms that may be more implicit vs explicit learning mechanisms that may be more cortically mediated. Consistent with the hypothesis that some of these reinforcement learning impairments may reflect striatal mechanisms, a growing number of studies in the imaging literature suggest reduced ventral striatal reward prediction/wanting responses in unmedicated and typically medicated individuals with schizophrenia (though not in those taking atypicals) and evidence for reduced positive prediction errors. However, not all studies have found impaired striatal responses to reward prediction cues or to prediction error, and there is also evidence that the magnitude of these striatal impairments may be related to the severity of negative symptoms, again pointing to the importance of examining individual difference relationships among individuals with schizophrenia. Furthermore, at least 2 studies have also found altered activation in frontal regions during probabilistic reinforcement learning, suggesting a potentially important role for cortically mediated mechanisms.

Value Computations and OFC Function in Schizophrenia

As described above, one hypothesis is that the OFC supports the computation of value or the integration of the reinforcing properties of the stimulus with the internal state of the organism, which includes updating changes in the reinforcing properties of the stimulus. There are 2 experimental paradigms that have been frequently used as probes of lateral and medial OFC function: probabilistic reversal learning and the Iowa Gambling Task. Both require individuals to integrate information about rewards and punishments across trials and to use such information to update value representations appropriately. A number of studies suggest impaired reversal learning in schizophrenia,¹²⁵^,¹³⁰^,¹³¹^,¹³³^,¹³⁵^,¹³⁶^,¹⁵⁴ though a few studies using the Intra-Dimensional-Extra-Dimensional task did not find simple reversal learning deficits in schizophrenia.¹²⁷^–¹²⁹ These reversal learning impairments are present even when individuals with schizophrenia and controls are matched on initial acquisition performance.¹²⁶ The literature on the Iowa Gambling Task in schizophrenia also provides evidence for impairment,¹⁵⁵^–¹⁶² again with some exceptions.¹⁵⁴^,¹⁶³^–¹⁶⁵ There is also evidence for structural and functional changes in OFC in schizophrenia,¹⁰⁷^,¹⁶⁶^–¹⁶⁹ though such changes have not been directly related to reversal learning or Iowa Gambling Task performance. There is some evidence for an association between reduced OFC volume and negative symptoms.¹⁶⁶^,¹⁶⁷ There is also reasonable evidence for olfactory functioning deficits in schizophrenia, which could be related to OFC function (given that olfactory cortex is located in OFC).¹⁷⁰ However, it is not clear whether olfactory functions rely on the same OFC regions that support value computations. In sum, there is good evidence from the behavioral literature for deficits in tasks thought to reflect OFC function in schizophrenia, and at least some data suggesting that OFC changes may be related to negative symptoms. However, as of yet, there is no direct evidence of impaired OFC function in relationship to deficits in value computation, as one might find in imaging studies of probabilistic reversal learning.⁵³ Furthermore, it will be important to make a stronger link between laboratory paradigms assessing value representations and how such representations may play a role in everyday life function. It is relatively straightforward to understand how value is represented and updated for primary rewards such as juice or food in relationship to hunger and thirst levels, but more work is needed on making the translation to more abstract representations that are likely to govern daily life function.

Effort Computations and ACC Function in Schizophrenia

To our knowledge, there is no work directly addressing effort computations in schizophrenia. However, research has examined ACC function in schizophrenia using a variety of conflict and error processing paradigms. As noted above, it is not clear whether conflict monitoring and/or error processing share similar cognitive mechanisms with effort computation or rely on the same ACC regions, though there is growing evidence that both are associated with activation of the dorsal ACC.⁶⁰^,⁶¹^,⁶⁶^,⁷¹ Nevertheless, this literature does provide hints as to the functional integrity of ACC in schizophrenia. Several studies suggest that individuals with schizophrenia show reduced error-related ACC responses¹³⁷^,¹⁷¹^–¹⁷⁷ as well as reduced posterror slowing¹⁷¹^,¹⁷² on the Stroop task as well as other tasks. However, there is also evidence that patients with schizophrenia can show normal error correction performance even in the context of reduced ACC responses to errors¹⁷³^,¹⁷⁸ and that the relationship between the magnitude of the error related negativity and error-related behaviors is intact in schizophrenia.¹⁷⁵ Individuals with schizophrenia also show reduced conflict-related ACC activation on the Stroop task¹⁷²^,¹⁷³ as well as reductions in conflict adaptation effects.¹⁷² There is also evidence for ACC abnormalities in schizophrenia from structural and postmortem studies, eg.¹⁷⁹^,¹⁸⁰ Thus, there is some reason to believe that conflict monitoring, error processing, and ACC function may be altered in individuals with schizophrenia, but direct work on effort computations and ACC function in schizophrenia is needed, along with an assessment of these functions in relationship to other components of the system.

Goal-Directed Action and DLPFC Function in Schizophrenia

There is a very large body of evidence for impairments in cognitive functions thought to be mediated by DLPFC in schizophrenia,¹⁸¹^–¹⁸³ including those involving goal maintenance and planning.¹⁸¹^,¹⁸⁴^,¹⁸⁵ Furthermore, there is robust evidence for altered DLPFC function in schizophrenia during cognitive control tasks,¹⁸⁶^–¹⁸⁸ though the direction (hypoactivity vs hyperactivity) varies as a function of factors such as load and performance.¹⁸⁹ In addition, structural studies have found alterations in gray matter volume in DLPFC,¹⁹⁰^–¹⁹³ in some cases specifically associated with altered executive function.¹⁹⁴ Studies have also found a variety of cellular and molecular abnormalities in DLPFC.¹⁹¹^,¹⁹²^,¹⁹⁵^–¹⁹⁸ In addition, magnetic resonance spectroscopy studies have found reductions in N-acetylaspartate (NAA) concentrations (a measure of the metabolic integrity of neurons) in PFC in schizophrenia.¹⁹⁹^–²⁰⁴ However, there have been a few nonreplications,²⁰⁵^,²⁰⁶ and some suggestions that reduced NAA may result from antipsychotic treatment.²⁰⁷ An important question is whether the cognitive control impairments observed in schizophrenia that have been associated with altered DLPFC function reflect problems in translating reward information into goal representations. One means to examine this issue is to determine how motivational incentives impact cognitive performance, potentially via modulation of DLPFC activity. Several studies suggest that individuals with schizophrenia are not able to improve their performance on cognitive tasks when offered monetary incentives,²⁰⁸^–²¹¹ but an equal number suggest at least some evidence for improvement with reward.²¹²^–²¹⁴ There is also work on the use of token economies in schizophrenia that suggests functioning can be improved through an explicit reward system. However, token economies provide a number of “external” supports for maintaining reward-related information that could compensate for deficits in the ability to translate reward information into action plans. Thus, the schizophrenia literature provides very consistent evidence for impaired cognitive control, action planning, and DLPFC function but relatively few direct tests of the ability to use internal representations of reward information to modulate behavior and brain function.

Summary, Suggestions for Future Research, and Significance

The review of impairments in schizophrenia related to reward processing provided above suggests a number of key points. First, there is a good deal of variability across studies, and few studies have examined more than one mechanism in the same individuals. This is unfortunate, as it is difficult to determine whether variability across studies reflects sample differences (with the level of negative symptoms being key) or true differences across tasks or neural systems. Second, there is clearly heterogeneity among individuals with schizophrenia, with deficits potentially varying as a function of negative symptom severity (anhedonia/avolition in particular). These factors make it difficult to know whether variability across studies or mechanisms reflect differential impairment, different clinical profiles, differing medication states, or some combination of all. Thus, it is critical in future studies to examine the relationships between impairments at both the behavioral and neural level and the level of impairment in symptoms such as anhedonia and avolition. The importance of examining this question suggests that researchers will need to alter the design of their studies in the future, either by explicitly ascertaining a large enough sample to examine individual difference relationships with sufficient power or by including samples of individuals with schizophrenia specifically selected for varying levels of negative symptom impairment. Whichever approach one chooses to use, the large body of literature demonstrating an important effect of negative symptom severity indicates that small sample studies of unselected patients are no longer useful or informative for moving the work in this area forward. Of course, arguing that one should examine individual differences in anhedonia and avolition in schizophrenia in both behavioral and imaging studies begs the question of whether our existing measures are adequate for these purposes.²¹⁵ Recent consensus-building work has argued that the existing measures are in fact not adequate¹ and the development of new measures is underway, with a focus on incorporating constructs and findings from the basic science literature. Importantly, such measures may allow us to more validly map the phenomenology of schizophrenia to the types of deficits in specific functions described in this review rather than focusing only on global measures of severity that may conflate a number of different processes or mechanisms.

As a general summary, the current literature is consistent with the hypothesis that hedonics are relatively intact in schizophrenia, with the majority of self-report and imaging data suggesting relatively intact self-report and neural responses to pleasurable and rewarding stimuli. However, at the same time, the literature suggests that there may be a deficit in one or more of the neural mechanisms that help to translate reward information into goal-directed actions. As reviewed above, a growing body of work suggests evidence for reinforcement learning impairments on difficult tasks with varying probabilities of reinforcement and relatively consistent evidence for impaired striatal responses to cues that predict reward and to positive prediction errors. Although not all studies show these results, and the magnitude of impairment is influenced by the level of negative symptom severity, such findings suggest that impairment in striatal reward prediction mechanisms may influence wanting in schizophrenia in a way that reduces the ability of individuals with schizophrenia to use anticipated rewards to drive motivated behavior.

As of yet, there is less direct evidence for or against impairments in value or effort computation, mechanisms putatively mediated by OFC and ACC, respectively. As described above, there is certainly ample indirect evidence for impairments on OFC and ACC function, but none of these studies have directly linked OFC or ACC functions to processing involved in linking experienced or anticipated rewards with goal representations, action plans, or motivated behavior. Similarly, there is ample evidence for impaired DLPFC function and action planning in schizophrenia but relatively little work directly examining the influence of rewards on the ability to modulate these mechanisms in schizophrenia. Our prior work suggests that individuals with schizophrenia are impaired in representing goal information that enables action plans to obtain desired outcomes and that such impairments are due to altered DLPFC function.²¹⁶^–²¹⁹ However, our work has not directly tied such deficits to impairments in reward processing. Moreover, it is also difficult to disentangle DLPFC-dependent mechanisms related to reward processing from other similar processes, such as cue-based reward prediction and/or value-effort computations. Nonetheless, there are intriguing hints that individuals with schizophrenia may not be able to use reward information to modulate cognitive control and DLPFC function, suggesting a potentially important role for cortical–striatal interactions in mediating impairment in motivated and goal-directed behavior in schizophrenia. Thus, in future studies, it will be critical to examine the interaction of these mechanisms in the same individuals, taking into account clinical heterogeneity.

The above discussion reviews the potential mechanisms of impairment in schizophrenia as potentially dissociable psychological and neural systems that may make independent contributions to impairments in goal-directed behavior in schizophrenia. However, it is also possible that there are impairments in several of these functions and systems that reflect a common mechanism. One potential common denominator that could lead to impairments in each of the functions (outside of hedonics) is altered DA function in both subcortical and cortical regions.²²⁰^,²²¹ Almost all the functions described above are heavily influenced by DA function, which has widespread influences on both cognitive and motivational systems. Thus, should future research indicate that many or all the processes involved in translating reward into goal-directed action are impaired in schizophrenia, it may suggest a role for a core deficit in DA function that modulates multiple components of the system as a parsimonious explanation. However, it is also possible that ongoing research will provide evidence for more selective impairments in some components of the system, providing important clues as to pathways for intervention.

Given the widespread effects of DA on this system, antipsychotic medications that block DA receptors have the potential to impact cognitive and motivational systems at several stages and addressing potential medication confounds will therefore be critical to future work in this field. While practical constraints make rigorous examination of medication effects difficult, there are several strategies that, when combined, may yield a fuller picture of how reward-related functions are affected by medications in this population. The reward prediction literature has begun to tackle these questions by examining unmedicated patients and comparing results between different medication types. Other approaches could include: examining genetically related, medication-naïve populations such as first-degree relatives and schizotypal personality disorder patients; delaying a dose of medication in order to perform within-subjects comparisons at high and low D2R blockade and/or performing positron emission tomography studies in the same sample to gain information about individual levels of DA receptor availability.

We believe that studying the neural mechanisms of reward processing in schizophrenia is critically important for understanding the poor functional outcomes that are prominent in this population. Research has identified the persistence of cognitive deficits even with treatment as one of the key mechanisms constraining functional ability in schizophrenia.²²²^,²²³ However, symptoms such as anhedonia and avolition also represent significant constraints on functional outcome in this illness. The presence of anhedonia is associated with poor community and social function⁹⁹^,²²⁴^–²²⁸ and predicts poor long-term outcomes.⁹⁹^,²²⁹^–²³¹ It may turn out that some of the same mechanisms leading to cognitive deficits in schizophrenia also contribute to anhedonia and avolition, such as DLPFC-mediated disturbances in goal maintenance.²³²^,²³³ If so, then treatments aimed at improving cognitive function in schizophrenia may also improve anhedonia and avolition, though there is not yet clear evidence for this.²³⁴ However, if the mechanisms leading to anhedonia and avolition are different, then we need to understand the source of these impairments so as to develop more effective interventions that can enhance functional outcome and quality of life in this debilitating illness. For example, if research continues to indicate that individuals with schizophrenia show deficits in the ability to use cues to predict future rewarding outcomes, it might suggest that rehabilitation approaches should utilize environmental supports that could in a sense compensate for such deficits in the internal evaluation and/or maintenance of such cues. As another example, if research suggests that individuals with schizophrenia are impaired in the ability to use potential reinforcement to enhance goal-directed action (eg, action steps necessary for social engagement, job completion, etc.), rehabilitation approaches may again need to use environmental supports that make such outcomes more salient (eg, frequent external reminders of the payoffs associated with engagement in work, social, or occupationally related goal-directed behaviors; enhancing the immediacy or salience of small payoffs that may serve as scaffolds or bridges to more long-term positive outcomes). This suggestion is consistent with the work of Medalia and others, who have argued for a contextualized approach to rehabilitation that maximizes internal motivation.²³⁵^,²³⁶ Lastly, if the literature continues to support the crucial importance of individual differences in the degree to which schizophrenia have deficits in these different processes, this may suggest a basis for more individually tailored treatment approaches.

Funding

National Institute of Mental Health (R01 MH066031, P50 MH62130).

References

1. Kirkpatrick B, Fenton WS, Carpenter WT, Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32:214–219. [PMC free article] [PubMed]

2. Balleine BW, O'Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology. 2009;35:48–69. [PMC free article] [PubMed]

3. Wallis JD. Orbitofrontal cortex and its contribution to decision-making. Annu Rev Neurosci. 2007;30:31–56. [PubMed]

4. Kimhy D, Yale S, Goetz RR, McFarr LM, Malaspina D. The factorial structure of the schedule for the deficit syndrome in schizophrenia. Schizophr Bull. 2006;32:274–278. [PMC free article] [PubMed]

5. Minas IH, Klimidis S, Stuart GW, Copolov DL, Singh BS. Positive and negative symptoms in the psychoses: principal components analysis of items from the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Compr Psychiatry. 1994;35:135–144. [PubMed]

6. Peralta V, Cuesta MJ. Dimensional structure of psychotic symptoms: an item-level analysis of SAPS and SANS symptoms in psychotic disorders. Schizophr Res. 1999;38:13–26. [PubMed]

7. Toomey R, Kremen WS, Simpson JC, et al. Revisiting the factor structure for positive and negative symptoms: evidence from a large heterogeneous group of psychiatric patients. Am J Psychiatry. 1997;154:371–377. [PubMed]

8. Malla AK, Takhar JJ, Norman RM, et al. Negative symptoms in first episode non-affective psychosis. Acta Psychiatr Scand. 2002;105:431–439. [PubMed]

9. Mueser KT, Sayers SL, Schooler NR, Mance RM, Haas GL. A multisite investigation of the reliability of the Scale for the Assessment of Negative Symptoms. Am J Psychiatry. 1994;151:1453–1462. [PubMed]

10. Emsley RA, Niehaus DJ, Mbanga NI, et al. The factor structure for positive and negative symptoms in South African Xhosa patients with schizophrenia. Schizophr Res. 2001;47:149–157. [PubMed]

11. Keefe RS, Harvey PD, Lenzenweger MF, et al. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: negative symptoms. Psychiatry Res. 1992;44:153–165. [PubMed]

12. Kelley ME, van Kammen DP, Allen DN. Empirical validation of primary negative symptoms: independence from effects of medication and psychosis. Am J Psychiatry. 1999;156:406–411. [PubMed]

13. Nakaya M, Ohmori K. A two-factor structure for the Schedule for the Deficit Syndrome in schizophrenia. Psychiatry Res. 2008;158:256–259. [PubMed]

14. Meehl PE. Schizotaxia, schizotypy, schizophrenia. Am Psychol. 1962;17:827–838.

15. Rado S. New York, NY: Grune and Stratton; 1962. Psychoanalysis of Behavior: The Collected Papers of Sandor Rado, Vol 2.

16. Meehl PE. Primary and secondary hypohedonia. J Abnorm Psychol. 2001;110:188–193. [PubMed]

17. Collins LM, Blanchard JJ, Biondo KM. Behavioral signs of schizoidia and schizotypy in social anhedonics. Schizophr Res. 2005;78:309–322. [PubMed]

18. Kring AM, Kerr SL, Smith DA, Neale JM. Flat affect in schizophrenia does not reflect diminished subjective experience of emotion. J Abnorm Psychol. 1993;102:507–517. [PubMed]

19. Kring AM, Neale JM. Do schizophrenic patients show a disjunctive relationship among expression, experiential, and psychophysiological components of emotion? J Abnorm Psychol. 1996;105:249–257. [PubMed]

20. Kring AM. Emotion in schizophrenia: old mystery, new understanding. Curr Dir Psychol Sci. 1999;8:160–163.

21. Mathews JR, Barch DM. Episodic memory for emotional and nonemotional words in schizophrenia. Cogn Emot. 2004;18:721–740.

22. Heerey EA, Gold JM. Patients with schizophrenia demonstrate dissociation between affective experience and motivated behavior. J Abnorm Psychol. 2007;116:268–278. [PubMed]

23. Burbridge JA, Barch DM. Anhedonia and the experience of emotion in individuals with schizophrenia. J Abnorm Psychol. 2007;116:30–42. [PubMed]

24. Berridge KC. Motivation concepts in behavioral neuroscience. Physiol Behav. 2004;81:179–209. [PubMed]

25. Barch DM. The relationships among cognition, motivation, and emotion in schizophrenia: how much and how little we know. Schizophr Bull. 2005;31:875–881. [PubMed]

26. Gard DE, Kring AM, Gard MG, Horan WP, Green MF. Anhedonia in schizophrenia: distinctions between anticipatory and consummatory pleasure. Schizophr Res. 2007;93:253–260. [PMC free article] [PubMed]

27. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science. 1997;275:1593–1599. [PubMed]

28. Schultz W. Neural coding of basic reward terms of animal learning theory, game theory, microeconomics, and behavioral ecology. Curr Opin Neurobiol. 2004;14:139–147. [PubMed]

29. Schultz W. Multiple dopamine functions at different time courses. Annu Rev Neurosci. 2007;30:259–288. [PubMed]

30. Richardson DK, Reynolds SM, Cooper SJ, Berridge KC. Endogenous opioids are necessary for benzodiazepine palatability enhancement: naltrexone blocks diazepam-induced increase of sucrose-'liking'. Pharmacol Biochem Behav. 2005;81:657–663. [PubMed]

31. Smith KS, Berridge KC. Opioid limbic circuit for reward: interaction between hedonic hotspots of nucleus accumbens and ventral pallidum. J Neurosci. 2007;27:1594–1605. [PubMed]

32. Pecina S, Smith KS, Berridge KC. Hedonic hot spots in the brain. Neuroscientist. 2006;12:500–511. [PubMed]

33. Burgdorf J, Panksepp J. The neurobiology of positive emotions. Neurosci Biobehav Rev. 2006;30:173–187. [PubMed]

34. Schultz W. Activity of dopamine neurons in the behaving primate. Semin Neurosci. 1992;4:129–138.

35. Schultz W, Apicella P, Ljungberg T. Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J Neurosci. 1993;13:900–913. [PubMed]

36. Knutson B, Westdorp A, Kaiser E, Hommer D. FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage. 2000;12:20–27. [PubMed]

37. Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport. 2001;12:3683–3687. [PubMed]

38. Abler B, Walter H, Erk S, Kammerer H, Spitzer M. Prediction error as a linear function of reward probability is coded in human nucleus accumbens. Neuroimage. 2006;31:790–795. [PubMed]

39. McClure SM, Berns GS, Montague PR. Temporal prediction errors in a passive learning task activate human striatum. Neuron. 2003;38:339–346. [PubMed]

40. Montague PR, Sejnowski TJ. The predictive brain: temporal coincidence and temporal order in synaptic learning mechanisms. Learn Mem. 1994;1:1–33. [PubMed]

41. Montague PR, Dayan P, Sejnowski TJ. A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J Neurosci. 1996;16:1936–1947. [PubMed]

42. Frank MJ, Seeberger LC, O'Reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science. 2004;306:1940–1943. [PubMed]

43. Dayan P, Balleine BW. Reward, motivation, and reinforcement learning. Neuron. 2002;36:285–298. [PubMed]

44. Rolls ET, Sienkiewicz ZJ, Yaxley S. Hunger modulates the responses to gustatory stimuli of single neurons in the caudolateral orbitofrontal cortex of the macaque monkey. Eur J Neurosci. 1989;1:53–60. [PubMed]

45. Roesch MR, Olson CR. Neuronal activity in primate orbitofrontal cortex reflects the value of time. J Neurophysiol. 2005;94:2457–2471. [PubMed]

46. Rudebeck PH, Walton ME, Smyth AN, Bannerman DM, Rushworth MF. Separate neural pathways process different decision costs. Nat Neurosci. 2006;9:1161–1168. [PubMed]

47. Padoa-Schioppa C, Assad JA. Neurons in the orbitofrontal cortex encode economic value. Nature. 2006;441:223–226. [PMC free article] [PubMed]

48. Padoa-Schioppa C. Orbitofrontal cortex and the computation of economic value. Ann N Y Acad Sci. 2007;441:223–226. [PubMed]

49. Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69–72. [PubMed]

50. Frank MJ, Claus ED. Anatomy of a decision: striato-orbitofrontal interactions in reinforcement learning, decision making, and reversal. Psychol Rev. 2006;113:300–326. [PubMed]

51. O'Doherty J, Critchley H, Deichmann R, Dolan RJ. Dissociating valence of outcome from behavioral control in human orbital and ventral prefrontal cortices. J Neurosci. 2003;23:7931–7939. [PubMed]

52. O'Doherty JP. Lights, camembert, action! The role of human orbitofrontal cortex in encoding stimuli, rewards and choices. Ann N Y Acad Sci. 2007;1121:254–272. [PubMed]

53. Cools R, Clark L, Owen AM, Robbins TW. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J Neurosci. 2002;22:4563–4567. [PubMed]

54. Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW. L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson's disease. Neuropsychopharmacology. 2007;32:180–189. [PubMed]

55. Hornak J, O'Doherty J, Bramham J, et al. Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans. J Cogn Neurosci. 2004;16:463–478. [PubMed]

56. Fellows LK, Farah MJ. Different underlying impairments in decision-making following ventromedial and dorsolateral frontal lobe damage in humans. Cereb Cortex. 2005;15:58–63. [PubMed]

57. Fellows LK, Farah MJ. Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain. 2003;126:1830–1837. [PubMed]

58. Salamone JD, Correa M, Farrar A, Mingote SM. Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl) 2007;191:461–482. [PubMed]

59. Salamone JD. Functions of mesolimbic dopamine: changing concepts and shifting paradigms. Psychopharmacology (Berl) 2007;191:389. [PubMed]

60. Croxson PL, Walton ME, O'Reilly JX, Behrens TE, Rushworth MF. Effort-based cost-benefit valuation and the human brain. J Neurosci. 2009;29:4531–4541. [PMC free article] [PubMed]

61. Botvinick MM, Huffstetler S, McGuire JT. Effort discounting in human nucleus accumbens. Cogn Affect Behav Neurosci. 2009;9:16–27. [PMC free article] [PubMed]

62. Rudebeck PH, Buckley MJ, Walton ME, Rushworth MF. A role for the macaque anterior cingulate gyrus in social valuation. Science. 2006;313:1310–1312. [PubMed]

63. Rudebeck PH, Walton ME, Millette BH, Shirley E, Rushworth MF, Bannerman DM. Distinct contributions of frontal areas to emotion and social behaviour in the rat. Eur J Neurosci. 2007;26:2315–2326. [PMC free article] [PubMed]

64. Rushworth MF, Behrens TE, Rudebeck PH, Walton ME. Contrasting roles for cingulate and orbitofrontal cortex in decisions and social behaviour. Trends Cogn Sci. 2007;11:168–176. [PubMed]

65. Walton ME, Rudebeck PH, Bannerman DM, Rushworth MF. Calculating the cost of acting in frontal cortex. Ann N Y Acad Sci. 2007;1104:340–356. [PMC free article] [PubMed]

66. Botvinick MM, Braver TS, Barch DM, Carter CS, Cohen JC. Conflict monitoring and cognitive control. Psychol Rev. 2001;108:624–652. [PubMed]

67. Holroyd CB, Coles MG. The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity. Psychol Rev. 2002;109:679–709. [PubMed]

68. Brown JW, Braver TS. Learned predictions of error likelihood in the anterior cingulate cortex. Science. 2005;307:1118–1121. [PubMed]

69. Taylor SF, Martis B, Fitzgerald KD, et al. Medial frontal cortex activity and loss-related responses to errors. J Neurosci. 2006;26:4063–4070. [PubMed]

70. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4:215–222. [PubMed]

71. Botvinick MM, Nystrom L, Fissel K, Carter CS, Cohen JD. Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature. 1999;402:179–181. [PubMed]

72. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;21:167–202. [PubMed]

73. Braver TS, Cohen JD. Dopamine, cognitive control, and schizophrenia: the gating model. Prog Brain Res. 1999;121:327–349. [PubMed]

74. Manes F, Sahakian B, Clark L, et al. Decision-making processes following damage to the prefrontal cortex. Brain. 2002;125:624–639. [PubMed]

75. Zalla T, Plassiart C, Pillon B, Grafman J, Sirigu A. Action planning in a virtual context after prefrontal cortex damage. Neuropsychologia. 2001;39:759–770. [PubMed]

76. Braver TS, Cohen JD. On the control of control: the role of dopamine in regulating prefrontal function and working memory. In: Monsell S, Driver J, editors. Attention and Performance XVIII. Cambridge, MA: MIT Press; 2000. pp. 713–738.

77. O'Reilly RC, Braver TS, Cohen JD. A biologically-based computational model of working memory. In: Miyake A, Shah P, editors. Models of Working Memory: Mechanisms of Active Maintenance and Executive Control. New York, NY: Cambridge University Press; 1999. pp. 375–411.

78. Frank MJ, Loughry B, O'Reilly RC. Interactions between frontal cortex and basal ganglia in working memory: a computational model. Cogn Affect Behav Neurosci. 2001;1:137–160. [PubMed]

79. Watanabe M. Reward expectancy in primate prefrontal neurons. Nature. 1996;382:629–632. [PubMed]

80. Sakagami M, Watanabe M. Integration of cognitive and motivational information in the primate lateral prefrontal cortex. Ann N Y Acad Sci. 2007;1104:89–107. [PubMed]

81. Krawczyk DC, Gazzaley A, D'Esposito M. Reward modulation of prefrontal and visual association cortex during an incentive working memory task. Brain Res. 2007;1141:168–177. [PubMed]

82. Kobayashi S, Nomoto K, Watanabe M, Hikosaka O, Schultz W, Sakagami M. Influences of rewarding and aversive outcomes on activity in macaque lateral prefrontal cortex. Neuron. 2006;51:861–870. [PubMed]

83. Locke H, Braver TS. Motivational influences on cognitive control: behavior, brain activation, and individual differences. Cogn Affect Behav Neurosci. 2008;8:99–112. [PubMed]

84. Tsujimoto S, Sawaguchi T. Context-dependent representation of response-outcome in monkey prefrontal neurons. Cereb Cortex. 2005;15:888–898. [PubMed]

85. Taylor SF, Liberzon I, Decker LR, Koeppe RA. A functional anatomic study of emotion in schizophrenia. Schizophr Res. 2002;58:159–172. [PubMed]

86. Kring AM, Kerr SL, Earnst KS. Schizophrenic patients show facial reactions to emotional facial expressions. Psychophysiology. 1999;36:186–192. [PubMed]

87. Earnst KS, Kring AM, Kadar MA, Salem JE, Shepard DA, Loosen PT. Facial expression in schizophrenia. Biol Psychiatry. 1996;40:556–558. [PubMed]

88. Earnst KS, Kring AM. Emotional responding in deficit and non-deficit schizophrenia. Psychiatry Res. 1999;88:191–207. [PubMed]

89. Flack WF, Laird JD, Cavallaro LA. Emotional expression and feeling in schizophrenia: effects of specific expressive behaviors on emotional experiences. J Clin Psychol. 1999;55:1–20. [PubMed]

90. Berenbaum H, Oltmanns TF. Emotional experience and expression in schizophrenia and depression. J Abnorm Psychol. 1992;101:37–44. [PubMed]

91. Crespo-Facorro B, Paradiso S, Andreasen NC, et al. Neural mechanisms of anhedonia in schizophrenia. J Am Med Assoc. 2001;286:427–435. [PubMed]

92. Curtis CE, Lebow B, Lake DS, Katsanis J, Iacono WG. Acoustic startle reflex in schizophrenic patients and their first-degree relatives: evidence of normal emotional modulation. Psychophysiology. 1999;36:469–475. [PubMed]

93. Quirk SW, Strauss ME, Sloan DM. Emotional response as a function of symptoms in schizophrenia. Schizophr Res. 1998;32:31–39. [PubMed]

94. Quirk SW, Strauss ME. Visual exploration of emotion eliciting images by patients with schizophrenia. J Nerv Ment Dis. 2001;189:757–765. [PubMed]

95. Taylor SF, Phan KL, Britton JC, Liberzon I. Neural response to emotional salience in schizophrenia. Neuropsychopharmacology. 2005;30:984–995. [PubMed]

96. Moberg PJ, Arnold SE, Doty RL, et al. Impairment of odor hedonics in men with schizophrenia. Am J Psychiatry. 2003;160:1784–1789. [PubMed]

97. Schlenker R, Cohen R, Hopmann G. Affective modulation of the startle reflex in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci. 1995;245:309–318. [PubMed]

98. Rupp CI, Fleischhacker WW, Kemmler G, et al. Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia. Schizophr Res. 2005;74:149–161. [PubMed]

99. Herbener ES, Rosen C, Khine T, Sweeney JA. Failure of positive but not negative emotional valence to enhance memory in schizophrenia. J Abnorm Psychol. 2007;116:43–55. [PubMed]

100. Herbener ES, Song W, Khine TT, Sweeney JA. What aspects of emotional functioning are impaired in schizophrenia? Schizophr Res. 2007;98:239–246. [PMC free article] [PubMed]

101. Doop ML, Park S. On knowing and judging smells: identification and hedonic judgment of odors in schizophrenia. Schizophr Res. 2006;81:317–319. [PubMed]

102. Schneider F, Habel U, Reske M, Toni I, Falkai P, Shah NJ. Neural substrates of olfactory processing in schizophrenia patients and their healthy relatives. Psychiatry Res. 2007;155:103–112. [PubMed]

103. Aghevli MA, Blanchard JJ, Horan WP. The expression and experience of emotion in schizophrenia: a study of social interactions. Psychiatry Res. 2003;119:261–270. [PubMed]

104. Tremeau F, Antonius D, Cacioppo JT, et al. Anticipated, on-line and remembered positive experience in schizophrenia. Schizophr Res. 2009 In press.

105. Dowd E, Barch DM. Subjective emotional experience in schizophrenia: neural and behavioral markers. Biol Psychiatry. 2010;67:902–911. [PMC free article] [PubMed]

106. Kring AM, Moran EK. Emotional response deficits in schizophrenia: insights from affective science. Schizophr Bull. 2008;34:819–834. [PMC free article] [PubMed]

107. Plailly J, d'Amato T, Saoud M, Royet JP. Left temporo-limbic and orbital dysfunction in schizophrenia during odor familiarity and hedonicity judgments. Neuroimage. 2006;29:302–313. [PubMed]

108. Myin-Germeys I, Delespaul PA, Marten W. Schizophrenia patients are more emotionally active than is assumed based on their behavior. Schizophr Bull. 2000;26:847–853. [PubMed]

109. Volz M, Hamm AO, Kirsch P, Rey ER. Temporal course of emotional startle modulation in schizophrenia patients. Int J Psychophysiol. 2003;49:123–137. [PubMed]

110. Hall J, Harris JM, McKirdy JW, Johnstone EC, Lawrie SM. Emotional memory in schizophrenia. Neuropsychologia. 2007;45:1152–1159. [PubMed]

111. Horan WP, Green MF, Kring AM, Nuechterlein KH. Does anhedonia in schizophrenia reflect faulty memory for subjectively experienced emotions? J Abnorm Psychol. 2006;115:496–508. [PubMed]

112. Paradiso S, Andreasen NC, Crespo-Facorro B, et al. Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography. Am J Psychiatry. 2003;160:1775–1783. [PubMed]

113. Kirsch P, Ronshausen S, Mier D, Gallhofer B. The influence of antipsychotic treatment on brain reward system reactivity in schizophrenia patients. Pharmacopsychiatry. 2007;40:196–198. [PubMed]

114. Simon JJ, Biller A, Walther S, et al. Neural correlates of reward processing in schizophrenia—relationship to apathy and depression. Schizophr Res. 2009;118:154–161. [PubMed]

115. Walter H, Kammerer H, Frasch K, Spitzer M, Abler B. Altered reward functions in patients on atypical antipsychotic medication in line with the revised dopamine hypothesis of schizophrenia. Psychopharmacology (Berl) 2009;206:121–132. [PubMed]

116. Schlagenhauf F, Sterzer P, Schmack K, et al. Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions. Biol Psychiatry. 2009;65:1032–1039. [PubMed]

117. Waltz JA, Schweitzer JB, Gold JM, et al. Patients with schizophrenia have a reduced neural response to both unpredictable and predictable primary reinforcers. Neuropsychopharmacology. 2009;34:1567–1577. [PubMed]

118. Blanchard JJ, Bellack AS, Mueser KT. Affective and social-behavioral correlates of physical and social anhedonia in schizophrenia. J Abnorm Psychol. 1994;103:719–728. [PubMed]

119. Laruelle M, VanDyck C, Abi-Dargham A. SPECT imaging of dopamine release following amphetamine challenge in healthy subjects and in patients with schizophrenia. J Nucl Med. 1995;36:10P.

120. Laruelle M, D'Souza GD, Zoghbi S, Baldwin R, Charney D, Innis R. SPECT measurement of dopamine synaptic concentration in the resting state. J Nucl Med. 1996;37:32. [PubMed]

121. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56–72. [PubMed]

122. Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep. 2007;9:329–336. [PubMed]

123. Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 2007;30:220–227. [PubMed]

124. Guillin O, Abi-Dargham A, Laruelle M. Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol. 2007;78:1–39. [PubMed]

125. Waltz JA, Gold JM. Probabilistic reversal learning impairments in schizophrenia: further evidence of orbitofrontal dysfunction. Schizophr Res. 2007;93:296–303. [PMC free article] [PubMed]

126. Weiler JA, Bellebaum C, Brune M, Juckel G, Daum I. Impairment of probabilistic reward-based learning in schizophrenia. Neuropsychology. 2009;23:571–580. [PubMed]

127. Joyce E, Hutton S, Mutsatsa S, et al. Executive dysfunction in first-episode schizophrenia and relationship to duration of untreated psychosis: the West London Study. Br J Psychiatry Suppl. 2002;43:s38–s44. [PubMed]

128. Jazbec S, Pantelis C, Robbins T, Weickert T, Weinberger DR, Goldberg TE. Intra-dimensional/extra-dimensional set-shifting performance in schizophrenia: impact of distractors. Schizophr Res. 2007;89:339–349. [PubMed]

129. Hutton SB, Puri BK, Duncan LJ, Robbins TW, Barnes TR, Joyce EM. Executive function in first-episode schizophrenia. Psychol Med. 1998;28:463–473. [PubMed]

130. Elliott R, McKenna PJ, Robbins TW, Sahakian BJ. Neuropsychological evidence for frontostriatal dysfunction in schizophrenia. Psychol Med. 1995;25:619–630. [PubMed]

131. Tyson PJ, Laws KR, Roberts KH, Mortimer AM. Stability of set-shifting and planning abilities in patients with schizophrenia. Psychiatry Res. 2004;129:229–239. [PubMed]

132. Turner DC, Clark L, Pomarol-Clotet E, McKenna PJ, Robbins S, Sahakian B. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. 2004;29:1363–1373. [PubMed]

133. Ceaser AE, Goldberg TE, Egan MF, McMahon RP, Weinberger DR, Gold JM. Set-shifting ability and schizophrenia: a marker of clinical illness or an intermediate phenotype? Biol Psychiatry. 2008;64:782–788. [PMC free article] [PubMed]

134. Pizzagalli DA, Jahn AL, O'Shea JP. Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry. 2005;57:319–327. [PMC free article] [PubMed]

135. Oades RD. Stimulus dimension shifts in patients with schizophrenia, with and without paranoid hallucinatory symptoms, or obsessive compulsive disorder: strategies, blocking and monoamine status. Behav Brain Res. 1997;88:115–131. [PubMed]

136. Pantelis C, Barber FZ, Barnes TR, Nelson HE, Owen AM, Robbins TW. Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res. 1999;37:251–270. [PubMed]

137. Morris SE, Heerey EA, Gold JM, Holroyd CB. Learning-related changes in brain activity following errors and performance feedback in schizophrenia. Schizophr Res. 2008;99:274–285. [PMC free article] [PubMed]

138. Koch K, Schachtzabel C, Wagner G, et al. Altered activation in association with reward-related trial-and-error learning in patients with schizophrenia. Neuroimage. 2009;50:223–232. [PubMed]

139. 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;62:756–764. [PMC free article] [PubMed]

140. Gold JM, Waltz JA, Prentice KJ, Morris SE, Heerey EA. Reward processing in schizophrenia: a deficit in the representation of value. Schizophr Bull. 2008;34:835–847. [PubMed]

141. Beninger RJ, Wasserman J, Zanibbi K, Charbonneau D, Mangels J, Beninger BV. Typical and atypical antipsychotic medications differentially affect two nondeclarative memory tasks in schizophrenic patients: a double dissociation. Schizophr Res. 2003;61:281–292. [PubMed]

142. Keri S, Kelemen O, Szekeres G, et al. Schizophrenics know more than they can tell: probabilistic classification learning in schizophrenia. Psychol Med. 2000;30:149–155. [PubMed]

143. Keri S, Nagy O, Kelemen O, Myers CE, Gluck MA. Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia. Schizophr Res. 2005;77:321–328. [PubMed]

144. Keri S, Juhasz A, Rimanoczy A, et al. Habit learning and the genetics of the dopamine D3 receptor: evidence from patients with schizophrenia and healthy controls. Behav Neurosci. 2005;119:687–693. [PubMed]

145. Weickert TW, Terrazas A, Bigelow LB, et al. Habit and skill learning in schizophrenia: evidence of normal striatal processing with abnormal cortical input. Learn Mem. 2002;9:430–442. [PubMed]

146. Weickert TW, Goldberg TE, Callicott JH, et al. Neural correlates of probabilistic category learning in patients with schizophrenia. J Neurosci. 2009;29:1244–1254. [PMC free article] [PubMed]

147. Horan WP, Green MF, Knowlton BJ, Wynn JK, Mintz J, Nuechterlein KH. Impaired implicit learning in schizophrenia. Neuropsychology. 2008;22:606–617. [PMC free article] [PubMed]

148. Foerde K, Poldrack RA, Khan BJ, et al. Selective corticostriatal dysfunction in schizophrenia: examination of motor and cognitive skill learning. Neuropsychology. 2008;22:100–109. [PubMed]

149. Gluck MA, Shohamy D, Myers C. How do people solve the “weather prediction” task?: individual variability in strategies for probabilistic category learning. Learn Mem. 2002;9:408–418. [PubMed]

150. Juckel G, Schlagenhauf F, Koslowski M, et al. Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage. 2006;29:409–416. [PubMed]

151. Juckel G, Schlagenhauf F, Koslowski M, et al. Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology (Berl) 2006;187:222–228. [PubMed]

152. Schlagenhauf F, Juckel G, Koslowski M, et al. Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine. Psychopharmacology (Berl) 2008;196:673–684. [PubMed]

153. Murray GK, Corlett PR, Clark L, et al. Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry. 2008;13:267–276. [PMC free article] [PubMed]

154. Turnbull OH, Evans CE, Kemish K, Park S, Bowman CH. A novel set-shifting modification of the Iowa gambling task: flexible emotion-based learning in schizophrenia. Neuropsychology. 2006;20:290–298. [PubMed]

155. Shurman B, Horan WP, Nuechterlein KH. Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task. Schizophr Res. 2005;72:215–224. [PubMed]

156. Sevy S, Burdick KE, Visweswaraiah H, et al. Iowa gambling task in schizophrenia: a review and new data in patients with schizophrenia and co-occurring cannabis use disorders. Schizophr Res. 2007;92:74–84. [PMC free article] [PubMed]

157. Lee Y, Kim YT, Seo E, et al. Dissociation of emotional decision-making from cognitive decision-making in chronic schizophrenia. Psychiatry Res. 2007;152:113–120. [PubMed]

158. Martino DJ, Bucay D, Butman JT, Allegri RF. Neuropsychological frontal impairments and negative symptoms in schizophrenia. Psychiatry Res. 2007;152:121–128. [PubMed]

159. Kester HM, Sevy S, Yechiam E, Burdick KE, Cervellione KL, Kumra S. Decision-making impairments in adolescents with early-onset schizophrenia. Schizophr Res. 2006;85:113–123. [PubMed]

160. Premkumar P, Fannon D, Kuipers E, Simmons A, Frangou S, Kumari V. Emotional decision-making and its dissociable components in schizophrenia and schizoaffective disorder: a behavioural and MRI investigation. Neuropsychologia. 2008;46:2002–2012. [PMC free article] [PubMed]

161. Yip SW, Sacco KA, George TP, Potenza MN. Risk/reward decision-making in schizophrenia: a preliminary examination of the influence of tobacco smoking and relationship to Wisconsin Card Sorting Task performance. Schizophr Res. 2009;110:156–164. [PMC free article] [PubMed]

162. Kim YT, Lee KU, Lee SJ. Deficit in decision-making in chronic, stable schizophrenia: from a reward and punishment perspective. Psychiatry Investig. 2009;6:26–33. [PMC free article] [PubMed]

163. Evans CE, Bowman CH, Turnbull OH. Subjective awareness on the Iowa Gambling Task: the key role of emotional experience in schizophrenia. J Clin Exp Neuropsychol. 2005;27:656–664. [PubMed]

164. Rodriguez-Sanchez JM, Crespo-Facorro B, Perez-Iglesias R, et al. Prefrontal cognitive functions in stabilized first-episode patients with schizophrenia spectrum disorders: a dissociation between dorsolateral and orbitofrontal functioning. Schizophr Res. 2005;77:279–288. [PubMed]

165. Wilder KE, Weinberger DR, Goldberg TE. Operant conditioning and the orbitofrontal cortex in schizophrenic patients: unexpected evidence for intact functioning. Schizophr Res. 1998;30:169–174. [PubMed]

166. Gur RE, Cowell PE, Latshaw A, et al. Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Arch Gen Psychiatry. 2000;57:761–768. [PubMed]

167. Baare WF, Pol HE, Hijman R, Mali WP, Viergever MA, Kahn RS. Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology. Biol Psychiatry. 1999;45:1597–1605. [PubMed]

168. Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361:281–288. [PubMed]

169. Bertollo DN, Cowen MA, Levy AV. Hypometabolism in olfactory cortical projection areas of male patients with schizophrenia: an initial positron emission tomography study. Psychiatry Res. 1996;60:113–116. [PubMed]

170. Moberg PJ, Turetsky BI. Scent of a disorder: olfactory functioning in schizophrenia. Curr Psychiatry Rep. 2003;5:311–319. [PubMed]

171. Alain C, McNeely HE, Yu H, Christensen BK, West R. Neurophysiological evidence of error monitoring deficits in patients with schizophrenia. Cereb Cortex. 2002;12:840–846. [PubMed]

172. Kerns JG, Cohen JD, MacDonald AW, 3rd, et al. Decreased conflict- and error-related activity in the anterior cingulate cortex in subjects with schizophrenia. Am J Psychiatry. 2005;162:1833–1839. [PubMed]

173. Kopp B, Rist F. An event-related brain potential substrate of disturbed response monitoring in paranoid schizophrenic patients. J Abnorm Psychol. 1999;108:337–346. [PubMed]

174. Mathalon DH, Dedor M, Faustman WO, Gray M, Askari N, Ford JM. Response-monitoring dysfunction in schizophrenia: an event-related brain potential study. J Abnorm Psychol. 2002;111:22–41. [PubMed]

175. Morris SE, Yee CM, Nuechterlein KH. Electrophysiological analysis of error monitoring in schizophrenia. J Abnorm Psychol. 2006;115:239–250. [PubMed]

176. Laurens KR, Ngan ET, Bates AT, Kiehl KA, Liddle PF. Rostral anterior cingulate cortex dysfunction during error processing in schizophrenia. Brain. 2003;126:610–622. [PubMed]

177. Polli FE, Barton JJ, Thakkar KN, et al. Reduced error-related activation in two anterior cingulate circuits is related to impaired performance in schizophrenia. Brain. 2008;131:971–986. [PubMed]

178. Polli FE, Barton JJ, Vangel M, Goff DC, Iguchi L, Manoach DS. Schizophrenia patients show intact immediate error-related performance adjustments on an antisaccade task. Schizophr Res. 2006;82:191–201. [PubMed]

179. Benes FM. Emerging principles of altered neural circuitry in schizophrenia. Brain Res Rev. 2000;31:251–269. [PubMed]

180. Barch DM, Braver TS, Sabb FW, Noll DC. The anterior cingulate cortex and response competition: evidence from an fMRI study of overt verb generation. J Cogn Neurosci. 2000;12:298–305. [PubMed]

181. Barch DM. The cognitive neuroscience of schizophrenia. In: Cannon T, Mineka S, editors. Annual Review of Clinical Psychology. Vol 1. Washington, DC: American Psychological Association; 2005. pp. 321–353.

182. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12:426–445. [PubMed]

183. Lee J, Park S. Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol. 2005;114:599–611. [PubMed]

184. Semkovska M, Stip E, Godbout L, Paquet F, Bedard MA. Behavioral disorganization in schizophrenia during a daily activity: the kitchen behavioral scoring scale. Brain Cogn. 2002;48:546–553. [PubMed]

185. Semkovska M, Bedard MA, Godbout L, Limoge F, Stip E. Assessment of executive dysfunction during activities of daily living in schizophrenia. Schizophr Res. 2004;69:289–300. [PubMed]

186. Glahn DC, Ragland JD, Abramoff A, et al. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005;25:60–69. [PubMed]

187. Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res. 2003;122:69–87. [PubMed]

188. Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry. 2009;66:811–822. [PMC free article] [PubMed]

189. Van Snellenberg JX, Torres IJ, Thornton AE. Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable. Neuropsychology. 2006;20:497–510. [PubMed]

190. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49:1–52. [PMC free article] [PubMed]

191. Selemon LD, Mrzljak J, Kleinman JE, Herman MM, Goldman-Rakic PS. Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. Arch Gen Psychiatry. 2003;60:69–77. [PubMed]

192. Selemon LD, Rajkowska G. Cellular pathology in the dorsolateral prefrontal cortex distinguishes schizophrenia from bipolar disorder. Curr Mol Med. 2003;3:427–436. [PubMed]

193. Kasparek T, Prikryl R, Mikl M, Schwarz D, Ceskova E, Krupa P. Prefrontal but not temporal grey matter changes in males with first-episode schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:151–157. [PubMed]

194. Rusch N, Spoletini I, Wilke M, et al. Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007;93:79–89. [PubMed]

195. Selemon LD, Rajkowska G, Goldman-Rakic PS. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry. 1995;52:805–818. [PubMed]

196. Rajkowska G, Selemon LD, Goldman-Rakic PS. Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington's disease. Arch Gen Psychiatry. 1998;55:215–224. [PubMed]

197. Pierri JN, Volk CL, Auh S, Sampson A, Lewis DA. Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry. 2001;58:466–473. [PubMed]

198. Cullen TJ, Walker MA, Eastwood SL, Esiri MM, Harrison PJ, Crow TJ. Anomalies of asymmetry of pyramidal cell density and structure in dorsolateral prefrontal cortex in schizophrenia. Br J Psychiatry. 2006;188:26–31. [PubMed]

199. Bertolino A, Nawroz S, Mattay VS, et al. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry. 1996;153:1554–1563. [PubMed]

200. Bertolino A, Callicott JH, Elman I, et al. Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry. 1998;43:641–648. [PubMed]

201. Bertolino A, Callicott JH, Nawroz S, et al. Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia. Neuropsychopharmacology. 1998;18:1–9. [PubMed]

202. Sigmundsson T, Maier M, Toone BK, et al. Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res. 2003;64:63–71. [PubMed]

203. Thomas MA, Ke Y, Levitt J, et al. Preliminary study of frontal lobe 1H MR spectroscopy in childhood-onset schizophrenia. J Magn Reson Imaging. 1998;8:841–846. [PubMed]

204. Cecil KM, Lenkinski RE, Gur RE, Gur RC. Proton magnetic resonance spectroscopy in the frontal and temporal lobes of neuroleptic naive patients with schizophrenia. Neuropsychopharmacology. 1999;20:131–140. [PubMed]

205. Delamillieure P, Constans JM, Fernandez J, et al. Proton magnetic resonance spectroscopy (1H MRS) in schizophrenia: investigation of the right and left hippocampus, thalamus, and prefrontal cortex. Schizophr Bull. 2002;28:329–339. [PubMed]

206. Wood SJ, Berger G, Velakoulis D, et al. Proton magnetic resonance spectroscopy in first episode psychosis and ultra high-risk individuals. Schizophr Bull. 2003;29:831–843. [PubMed]

207. Bustillo JR, Lauriello J, Rowland LM, et al. Longitudinal follow-up of neurochemical changes during the first year of antipsychotic treatment in schizophrenia patients with minimal previous medication exposure. Schizophr Res. 2002;58:313–321. [PubMed]

208. Green MF, Satz P, Ganzell S, Vaclav JF. Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit. Am J Psychiatry. 1992;149:62–67. [PubMed]

209. Hellman SG, Kern RS, Neilson LM, Green MF. Monetary reinforcement and Wisconsin Card Sorting performance in schizophrenia: why show me the money? Schizophr Res. 1998;34:67–75. [PubMed]

210. Vollema MG, Geurtsen GJ, van Voorst AJ. Durable improvements in Wisconsin Card Sorting Test performance in schizophrenic patients. Schizophr Res. 1995;16:209–215. [PubMed]

211. Roiser JP, Stephan KE, den Ouden HE, Barnes TR, Friston KJ, Joyce EM. Do patients with schizophrenia exhibit aberrant salience? Psychol Med. 2009;39:199–209. [PMC free article] [PubMed]

212. Penn DL, Combs D. Modification of affect perception deficits in schizophrenia. Schizophr Res. 2000;46:217–229. [PubMed]

213. Kern RS, Green MF, Goldstein MJ. Modification of performance on the span of apprehension, a putative marker of vulnerability to schizophrenia. J Abnorm Psychol. 1995;104:385–389. [PubMed]

214. Rassovsky Y, Green MF, Nuechterlein KH, Breitmeyer B, Mintz J. Modulation of attention during visual masking in schizophrenia. Am J Psychiatry. 2005;162:1533–1535. [PubMed]

215. Horan WP, Kring AM, Blanchard JJ. Anhedonia in schizophrenia: a review of assessment strategies. Schizophr Bull. 2006;32:259–273. [PMC free article] [PubMed]

216. Edwards B, Barch DM, Braver TS. Improving prefrontal cortex function in schizophrenia through focused training of cognitive control. Front Neurosci. 2010;4:32; doi:10.3389/fnhum.2010.00032.

217. Barch DM, Braver TS, Cohen JD, Servan-Screiber D. Context processing deficits in schizophrenia. Arch Gen Psychiatry. 1998;55:187–188.

218. Barch DM, Braver TS, Snyder A, Conturo T. Dorsolateral prefrontal cortex dysfunction in schizophrenia: relationship to both working memory and long term memory. Neuroimage. 2000;11:S193.

219. Barch DM, Carter CS, Braver TS, et al. Selective deficits in prefrontal cortex regions in medication naive schizophrenia patients. Arch Gen Psychiatry. 2001;50:280–288. [PubMed]

220. Laviolette SR. Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizophr Bull. 2007;33:971–981. [PMC free article] [PubMed]

221. West AR, Floresco SB, Charara A, Rosenkranz JA, Grace AA. Electrophysiological interactions between striatal glutamatergic and dopaminergic systems. Ann N Y Acad Sci. 2003;1003:53–74. [PubMed]

222. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull. 2000;26:119–136. [PubMed]

223. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72:41–51. [PubMed]

224. Rey ER, Bailer J, Brauer W, Handel M, Laubenstein D, Stein A. Stability trends and longitudinal correlations of negative and positive syndromes within a three-year follow-up of initially hospitalized schizophrenics. Acta Psychiatr Scand. 1994;90:405–412. [PubMed]

225. Ho BC, Nopoulos P, Flaum M, Arndt S, Andreasen NC. Two-year outcome in first-episode schizophrenia: predictive value of symptoms for quality of life. Am J Psychiatry. 1998;155:1196–1201. [PubMed]

226. Blanchard JJ, Mueser KT, Bellack AS. Anhedonia, positive and negative affect, and social functioning in schizophrenia. Schizophr Bull. 1998;24:413–424. [PubMed]

227. Mueser KT, Bellack AS, Morrison RL, Wixted JT. Social competence in schizophrenia: premorbid adjustment, social skill, and domains of functioning. J Psychiatr Res. 1990;24:51–63. [PubMed]

228. Bellack AS, Morrison RL, Wixted JT, Mueser KT. An analysis of social competence in schizophrenia. Br J Psychiatry. 1990;156:809–818. [PubMed]

229. Mueser KT, Douglas MS, Bellack AS, Morrison RL. Assessment of enduring deficit and negative symptom subtypes in schizophrenia. Schizophr Bull. 1991;17:565–582. [PubMed]

230. Fenton WS, McGlashan TH. Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course. Arch Gen Psychiatry. 1991;48:978–986. [PubMed]

231. Herbener ES, Harrow M, Hill SK. Change in the relationship between anhedonia and functional deficits over a 20-year period in individuals with schizophrenia. Schizophr Res. 2005;75:97–105. [PubMed]

232. Barch DM, Carter CS, Cohen JD. Context processing deficit in schizophrenia: diagnostic specificity, 4-week course, and relationships to clinical symptoms. J Abnorm Psychol. 2003;112:132–143. [PubMed]

233. Delawalla Z, Barch DM, Fisher Eastep JL, et al. Factors mediating cognitive deficits and psychopathology among siblings of individuals with schizophrenia. Schizophr Bull. 2006;32:525–537. [PMC free article] [PubMed]

234. Hogarty GE, Flesher S, Ulrich R, et al. Cognitive enhancement therapy for schizophrenia: effects of a 2-year randomized trial on cognition and behavior. Arch Gen Psychiatry. 2004;61:866–876. [PubMed]

235. Choi J, Medalia A. Intrinsic motivation and learning in a schizophrenia spectrum sample. Schizophr Res. 2009;118:12–19. [PMC free article] [PubMed]

236. Medalia A, Choi J. Cognitive remediation in schizophrenia. Neuropsychol Rev. 2009;19:353–364. [PubMed]

Articles from Schizophrenia Bulletin are provided here courtesy of
Oxford University Press