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

Abstract

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 et al. 2002). 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 [Χ^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 [Χ^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. Keywordsschizophrenia; dopamine; reinforcement; basal ganglia; prefrontal; orbitofrontal One of the most common neuropsychological findings in the schizophrenia (SZ) literature is that of impaired attentional set-shifting, as evidenced by studies using tasks like the Wisconsin Card Sort Test (WCST) and the intradimensional/extradimensional (ID/ED) attentional setshifting task. This deficit has often been linked to dysfunction of dorsolateral prefrontal cortex (DLPFC), one of the most frequently-observed neural correlates of schizophrenia (Weinberger et al. 1986;Berman et al. 1988). One possible source of set-shifting deficits in patients may be set-learning impairments related to limitations in DLPFC-dependent attentional and working memory resources. Another possible source of set-shifting difficulties, however, may be a specific impairment in reversing learned associations. The reversal of learned associations is known to depend on ventral and medial areas of prefrontal cortex (PFC) from a variety of studies involving both human and nonhuman animal subjects, including both lesion studies (Dias et al. 1996;Fellows and Farah 2003;Hornak et al. 2004) and those using physiological Corresponding Author: Dr. James Andrew Waltz, PhD, Maryland Psychiatric Research Center Pu...

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

“…Conversely, schizophrenia has long been associated with excessive activation of D 2 receptors. Impairments in set-shifting and reversal learning observed in these patients have been attributed to disruptions in frontal lobe functioning (Goldberg and Weinberger, 1988;Waltz and Gold, 2007;Murray et al, 2008). However, the finding that excessive stimulation of D 2 receptors in the NAc severely impedes these forms of behavioral flexibility suggests that pathophysiological increases in mesolimbic DA activity may also be a contributing factor to inflexible patterns of behavior observed in this disorder.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…These findings support the premise that these mice exhibit impaired anticipation of reward. Such impaired probabilistic (rewardassociative) learning has also been linked to anhedonia and negative symptoms in schizophrenia (Dowd and Barch, 2010;Waltz and Gold, 2007), via impaired reward anticipation Gold et al, 2008). However, these deficits could still be linked to impaired cognition, given that probabilistic learning was suggested by the CNTRICS initiative to measure long-term relational memory (Armstrong et al, 2012;Ragland et al, 2012b).…”

Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs

“…These latter findings, together with another study that reported OFC volume deficits in drug-naive patients (37), strongly suggest that OFC anomalies are components of the disease process and not a consequence of chronic antipsychotic drug treatment. Accordingly, individuals with schizophrenia show significant performance deficits in cognitive paradigms, such as a probabilistic reversal learning task and the Iowa Gambling Task, which involve feedback processing and which are classically used to assess OFC function (12,38,39). In related functional imaging studies, hyperactivation of OFC is reported in patients during performance of cognitive tasks that generally occur concomitantly with hypoactivation of dorsal PFC regions (26,27).…”