Discrimination Learning, Reversal, and Set-Shifting in First-Episode Schizophrenia: Stability Over Six Years and Specific Associations with Medication Type and Disorganization Syndrome

Abstract

BackgroundThe intradimensional/extradimensional (IDED) task assesses different forms of learning from feedback. Limited evidence suggests that attentional set-shifting deteriorates over time in schizophrenia. We tested this hypothesis and examined the specificity of learning impairments identified by this task.MethodTwo hundred sixty-two first-episode patients and 76 healthy control subjects, matched for age and premorbid IQ, were tested; 104 patients and 25 control subjects were reassessed 1 and 3 years later, and 31 patients were reassessed additionally 6 years later.ResultsPatients showed impaired set-shifting that correlated with current IQ and working memory, but there were no impairments when subgroups were matched on current IQ. In contrast, patients showed marked impairments in rule reversal learning that survived correction for IQ, were present in the context of intact rule abstraction, and correlated with disorganization symptoms. Patients prescribed second-generation antipsychotics were worse on set-shifting compared with first-generation, a finding not explained by demographic data, illness characteristics, or IQ. Patients and control subjects showed stable IDED performance over the first 6 years of illness, although set-shifting was inconsistent over the first year. Those with residual negative symptoms were more likely to fail the set-shifting stage at follow-up.ConclusionsFirst-episode schizophrenia patients can learn and generalize rules but are inflexible when rules change, reflecting reduced responsiveness to negative feedback and difficulty in switching attention. Rule-reversal is a promising target for translational studies, because it is specific, clinically relevant, and might reflect orbitofrontal dysfunction. Set-shifting is related to poor function more generally but might be sensitive to medication effects and valuable for clinical trials.

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

“…Impaired reversal learning has recently been highlighted to occur reliably in schizophrenia. Indeed, Leeson et al (2009) found in a large group of first episode schizophrenic patients that although they were impaired on set-shifting, they also exhibited small but consistent and highly significant deficits in reversal learning. These deficits in reversal learning, unlike those of set-shifting, were unrelated to general intelligence and correlated significantly with the disorganization syndrome, especially of positive formal thought disorder, which presumably interferes with cognitive function and has been shown to be related to reductions in OFC volume (Nakamura et al, 2008).…”

“…Cognitive flexibility in both models was assessed using the rodent attentional set-shifting 'digging' paradigm (Birrell and Brown, 2000). The use of the digging task was justified (i) as it is a test of 'reasoning and problem-solving' that conforms to one of the seven cognitive domains of impairment as described in the MATRICS battery (Nuechterlein et al, 2008); (ii) by its recent adoption as a valid cognitive test paradigm by the CNTRICS initiative, assaying the construct of 'rule-generation and selection' (Barch et al, 2009);and (iii) by considerable evidence showing impairments in cognitive flexibility in schizophrenia, using homologous human neuropsychological tests with established translational validity (Leeson et al, 2009). The rodent digging task is particularly informative because as well as measuring the ability to shift attentional set, it also incorporates three tests of reversal learning and a test of compound discrimination learning.…”

Methamphetamine Exposure Combined with HIV-1 Disease or gp120 Expression: Comparison of Learning and Executive Functions in Humans and Mice

“…The percentage of subjects that failed to successfully reach criterion during any stage of the task is a commonly used metric of cognitive impairment (Leeson et al, 2009). Thus, Figure 1 Levels of cognitive impairment in humans (n = 25-36 per group).…”

“…A growing number of translational tests have been developed in both rodents and humans including the ASST (Leeson et al, 2009;Young et al, 2010), the Behavioral Pattern Monitor (Young et al, 2007), the Response Bias Probabilistic Reward Task (Der-Avakian et al, 2013), and the 5-choice Continuous Performance Test among others. Clinical data sets face confounds such as variations in age and the use of other substances that can be controlled in animal studies.…”

Transient Inactivation of the Neonatal Ventral Hippocampus Impairs Attentional Set-Shifting Behavior: Reversal with an α7 Nicotinic Agonist

“…As such, cognitive flexibility represents an important property underlying many higher order executive functions (Miller and Cohen, 2001;Robbins, 2007). Clinical evaluations of cognitive flexibility in SZ indicate impairments in their ability to shift attention between perceptual attributes of complex stimuli in response to changing contingencies while concurrently inhibiting previously reinforced responses (Pantelis et al, 1999;Leeson et al, 2009).…”