James A. Waltz

A System for Relational Reasoning in Human Prefrontal Cortex

The integration of multiple relations between mental representations is critical for higher level cognition. For both deductive- and inductive-reasoning tasks, patients with prefrontal damage exhibited a selective and catastrophic deficit in the integration of relations, whereas patients with anterior temporal lobe damage, matched for overall IQ but with intact prefrontal cortex, exhibited normal relational integration. In contrast, prefrontal patients performed more accurately than temporal patients on tests of both episodic memory and semantic knowledge. These double dissociations suggest that integration of relations is a specific source of cognitive complexity for which intact prefrontal cortex is essential. The integration of relations may be the fundamental common factor linking the diverse abilities that depend on prefrontal function, such as planning, problem solving, and fluid intelligence.

Reward Processing in Schizophrenia: A Deficit in the Representation of Value

Patients with schizophrenia demonstrate deficits in motivation and learning that suggest impairment in different aspects of the reward system. In this article, we present the results of 8 converging experiments that address subjective reward experience, the impact of rewards on decision making, and the role of rewards in guiding both rapid and long-term learning. All experiments compared the performance of stably treated outpatients with schizophrenia and demographically matched healthy volunteers. Results to date suggest (1) that patients have surprisingly normal experiences of positive emotion when presented with evocative stimuli, (2) that patients show reduced correlation, compared with controls, between their own subjective valuation of stimuli and action selection, (3) that decision making in patients appears to be compromised by deficits in the ability to fully represent the value of different choices and response options, and (4) that rapid learning on the basis of trial-to-trial feedback is severely impaired whereas more gradual learning may be surprisingly preserved in many paradigms. The overall pattern of findings suggests compromises in the orbital and dorsal prefrontal structures that play a critical role in the ability to represent the value of outcomes and plans. In contrast, patients often (but not always) approach normal performance levels on the slow learning achieved by the integration of reinforcement signals over many trials, thought to be mediated by the basal ganglia.

Synchronized delta oscillations correlate with the resting-state functional MRI signal

Synchronized low-frequency spontaneous fluctuations of the functional MRI (fMRI) signal have recently been applied to investigate large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations remain largely unknown. To this end, electrophysiological recordings and resting-state fMRI measurements were conducted in α-chloralose-anesthetized rats. Using a seed-voxel analysis strategy, region-specific, anesthetic dose-dependent fMRI resting-state functional connectivity was detected in bilateral primary somatosensory cortex (S1FL) of the resting brain. Cortical electroencephalographic signals were also recorded from bilateral S1FL; a visual cortex locus served as a control site. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in the γ bands, the resting-state fMRI signal correlates with the power coherence in low-frequency bands, particularly the δ band. These data indicate that hemodynamic fMRI signal differentially registers specific electrical oscillatory frequency band activity, suggesting that fMRI may be able to distinguish the ongoing from the evoked activity of the brain.

Cortical capacity constraints for visual working memory: dissociation of fMRI load effects in a fronto-parietal network

Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached.

Selective Reinforcement Learning Deficits in Schizophrenia Support Predictions from Computational Models of Striatal-Cortical Dysfunction

BACKGROUND Rewards and punishments may make distinct contributions to learning via separate striatal-cortical pathways. We investigated whether fronto-striatal dysfunction in schizophrenia (SZ) is characterized by selective impairment in either reward- (Go) or punishment-driven (NoGo) learning. METHODS We administered two versions of a probabilistic selection task to 40 schizophrenia patients and 31 control subjects, using difficult to verbalize stimuli (experiment 1) and nameable objects (experiment 2). In an acquisition phase, participants learned to choose between three different stimulus pairs (AB, CD, EF) presented in random order, based on probabilistic feedback (80%, 70%, 60%). We used analyses of variance (ANOVAs) to assess the effects of group and reinforcement probability on two measures of contingency learning. To characterize the preference of subjects for choosing the most rewarded stimulus and avoiding the most punished stimulus, we subsequently tested participants with novel pairs of stimuli involving either A or B, providing no feedback. RESULTS Control subjects demonstrated superior performance during the first 40 acquisition trials in each of the 80% and 70% conditions versus the 60% condition; patients showed similarly impaired (<60%) performance in all three conditions. In novel test pairs, patients showed decreased preference for the most rewarded stimulus (A; t = 2.674; p = .01). Patients were unimpaired at avoiding the most negative stimulus (B; t = .737). CONCLUSIONS The results of these experiments provide additional evidence for the presence of deficits in reinforcement learning in SZ, suggesting that reward-driven learning may be more profoundly impaired than punishment-driven learning.

Cortical Oscillatory Activity Is Critical for Working Memory as Revealed by Deficits in Early-Onset Schizophrenia

Impairments in working memory (WM) are a core cognitive deficit in schizophrenia. Neurophysiological models suggest that deficits during WM maintenance in schizophrenia may be explained by abnormalities in the GABAergic system, which will lead to deficits in high-frequency oscillations. However, it is not yet clear which of the three WM phases (encoding, maintenance, retrieval) are affected by dysfunctional oscillatory activity. We investigated the relationship between impairments in oscillatory activity in a broad frequency range (3–100 Hz) and WM load in the different phases of WM in 14 patients with early-onset schizophrenia and 14 matched control participants using a delayed matching to sample paradigm. During encoding, successful memorization was predicted by evoked theta, alpha, and beta oscillatory activity in controls. Patients showed severe reductions in the evoked activity in these frequency bands. During early WM maintenance, patients showed a comparable WM load-dependent increase in induced alpha and gamma activity to controls. In contrast, during the later maintenance phase, patients showed a shift in the peak of induced gamma activity to the lower WM load conditions. Finally, induced theta and gamma activity were reduced in patients during retrieval. Our findings suggest that the WM deficit in schizophrenia is associated with impaired oscillatory activity during all phases of the task and that the cortical storage system reaches its capacity limit at lower loads. Inability to maintain oscillatory activity in specific frequency bands could thus result in the information overload that may underlie both cognitive deficits and psychopathological symptoms of schizophrenia.

Probabilistic reversal learning impairments in schizophrenia: Further evidence of orbitofrontal dysfunction

Impairments in feedback processing and reinforcement learning appear to be prominent aspects of schizophrenia (SZ), which may relate to symptoms of the disorder. Evidence from cognitive neuroscience investigations indicates that disparate brain systems may underlie different kinds of feedback-driven learning. The ability to rapidly shift response tendencies in the face of negative feedback, when reinforcement contingencies are reversed, is an important type of learning thought to depend on ventral prefrontal cortex (PFC). Schizophrenia has long been associated with dysfunction in dorsolateral areas of PFC, but evidence for ventral PFC impairment in more mixed. In order to assess whether SZ patients experience particular difficulty in carrying out a cognitive function commonly linked to ventral PFC function, we administered to 34 patients and 26 controls a modified version of an established probabilistic reversal learning task from the experimental literature [Cools, R., Clark, L., Owen, A.M., Robbins, T.W., 2002. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J. Neurosci. 22, 4563-4567]. Although SZ patients and controls performed similarly on the initial acquisition of probabilistic contingencies, patients showed substantial learning impairments when reinforcement contingencies were reversed, achieving significantly fewer reversals [chi(2)(6)=15.717, p=0.008]. Even when analyses were limited to subjects who acquired all probabilistic contingencies initially (22 patients and 20 controls), patients achieved significantly fewer reversals [chi(2)(3)=9.408, p=0.024]. These results support the idea that ventral PFC dysfunction is a prevalent aspect of schizophrenic pathophysiology, which may contribute to deficits in reinforcement learning exhibited by patients. Further studies are required to investigate the roles of dopaminergic systems in these impairments.

A Review of Reward Processing and Motivational Impairment in Schizophrenia

This article reviews and synthesizes research on reward processing in schizophrenia, which has begun to provide important insights into the cognitive and neural mechanisms associated with motivational impairments. Aberrant cortical-striatal interactions may be involved with multiple reward processing abnormalities, including: (1) dopamine-mediated basal ganglia systems that support reinforcement learning and the ability to predict cues that lead to rewarding outcomes; (2) orbitofrontal cortex-driven deficits in generating, updating, and maintaining value representations; (3) aberrant effort-value computations, which may be mediated by disrupted anterior cingulate cortex and midbrain dopamine functioning; and (4) altered activation of the prefrontal cortex, which is important for generating exploratory behaviors in environments where reward outcomes are uncertain. It will be important for psychosocial interventions targeting negative symptoms to account for abnormalities in each of these reward processes, which may also have important interactions; suggestions for novel behavioral intervention strategies that make use of external cues, reinforcers, and mobile technology are discussed.

Patients with schizophrenia have a reduced neural response to both unpredictable and predictable primary reinforcers.

One prevalent theory of learning states that dopamine neurons signal mismatches between expected and actual outcomes, called temporal difference errors (TDEs). Evidence indicates that dopamine system dysfunction is involved in negative symptoms of schizophrenia (SZ), including avolition and anhedonia. As such, we predicted that brain responses to TDEs in dopamine midbrain nuclei and target areas would be abnormal in SZ. A total of 18 clinically stable patients with chronic SZ and 18 controls participated in an fMRI study, which used a passive conditioning task. In the task, the delivery of a small amount of juice followed a light stimulus by exactly 6 s on approximately 75% of 78 total trials, and was further delayed by 4–7 s on the remaining trials. The delayed juice delivery was designed to elicit the two types of TDE signals, associated with the recognition that a reward was omitted at the expected time, and delivered at an unexpected time. Main effects of TDE valence and group differences in the positive–negative TDE contrast (unexpected juice deliveries–juice omissions) were assessed through whole-brain and regions of interest (ROI) analyses. Main effects of TDE valence were observed for the entire sample in the midbrain, left putamen, left cerebellum, and primary gustatory cortex, bilaterally. Whole-brain analyses revealed group differences in the positive–negative TDE contrast in the right putamen and left precentral gyrus, whereas ROI analyses revealed additional group differences in the midbrain, insula, and parietal operculum, on the right, the putamen and cerebellum, on the left, and the frontal operculum, bilaterally. Further, these group differences were generally driven by attenuated responses in patients to positive TDEs (unexpected juice deliveries), whereas responses to negative TDEs (unexpected juice omissions) were largely intact. Patients also showed reductions in responses to juice deliveries on standard trials, and more blunted reinforcer responses in the left putamen corresponded to higher ratings of avolition. These results provide evidence that SZ patients show abnormal brain responses associated with the processing of a primary reinforcer, which may be a source of motivational deficits.

Deficits in Positive Reinforcement Learning and Uncertainty-Driven Exploration Are Associated with Distinct Aspects of Negative Symptoms in Schizophrenia

BACKGROUND Negative symptoms are core features of schizophrenia (SZ); however, the cognitive and neural basis for individual negative symptom domains remains unclear. Converging evidence suggests a role for striatal and prefrontal dopamine in reward learning and the exploration of actions that might produce outcomes that are better than the status quo. The current study examines whether deficits in reinforcement learning and uncertainty-driven exploration predict specific negative symptom domains. METHODS We administered a temporal decision-making task, which required trial-by-trial adjustment of reaction time to maximize reward receipt, to 51 patients with SZ and 39 age-matched healthy control subjects. Task conditions were designed such that expected value (probability × magnitude) increased, decreased, or remained constant with increasing response times. Computational analyses were applied to estimate the degree to which trial-by-trial responses are influenced by reinforcement history. RESULTS Individuals with SZ showed impaired Go learning but intact NoGo learning relative to control subjects. These effects were most pronounced in patients with higher levels of negative symptoms. Uncertainty-based exploration was substantially reduced in individuals with SZ and selectively correlated with clinical ratings of anhedonia. CONCLUSIONS Schizophrenia patients, particularly those with high negative symptoms, failed to speed reaction times to increase positive outcomes and showed reduced tendency to explore when alternative actions could lead to better outcomes than the status quo. Results are interpreted in the context of current computational, genetic, and pharmacological data supporting the roles of striatal and prefrontal dopamine in these processes.