Gagan Fervaha

Incentive motivation deficits in schizophrenia reflect effort computation impairments during cost-benefit decision-making

BACKGROUND Motivational impairments are a core feature of schizophrenia and although there are numerous reports studying this feature using clinical rating scales, objective behavioural assessments are lacking. Here, we use a translational paradigm to measure incentive motivation in individuals with schizophrenia. METHODS Sixteen stable outpatients with schizophrenia and sixteen matched healthy controls completed a modified version of the Effort Expenditure for Rewards Task that accounts for differences in motoric ability. Briefly, subjects were presented with a series of trials where they may choose to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Additionally, the probability of receiving money for a given trial was varied at 12%, 50% and 88%. Clinical and other reward-related variables were also evaluated. RESULTS Patients opted to expend greater effort significantly less than controls for trials of high, but uncertain (i.e. 50% and 88% probability) incentive value, which was related to amotivation and neurocognitive deficits. Other abnormalities were also noted but were related to different clinical variables such as impulsivity (low reward and 12% probability). These motivational deficits were not due to group differences in reward learning, reward valuation or hedonic capacity. CONCLUSIONS Our findings offer novel support for incentive motivation deficits in schizophrenia. Clinical amotivation is associated with impairments in the computation of effort during cost-benefit decision-making. This objective translational paradigm may guide future investigations of the neural circuitry underlying these motivational impairments.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia

Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one‐year longitudinal functional outcomes in patients with schizophrenia.

Negative symptoms of schizophrenia: Clinical features, relevance to real world functioning and specificity versus other CNS disorders

Negative symptoms have long been recognized as a central feature of the phenomenology of schizophrenia, dating back to the early descriptions by Kraepelin and Bleuler. Over the ensuing century, there have been important clarifications and reconceptualizations regarding the phenomenology of negative symptoms in schizophrenia. This review explores these developments, including the delineation of two underlying subdomains of negative symptoms - amotivation (i.e., avolition/apathy and asociality) and diminished expression (i.e., poverty of speech and affective flattening). Further, advances in our understanding of specific motivational and hedonic deficits seen in schizophrenia are explored. The findings that negative symptoms stand apart from depressive and cognitive symptoms in schizophrenia are also discussed. In terms of the predictors of functional outcomes in schizophrenia, we explore both the direct role of negative symptoms in this regard, as well as their indirect role through cognition. We then broaden our examination of negative symptoms to related disorders across the schizophrenia spectrum, as well as to other neuropsychiatric illnesses, where negative symptoms have been increasingly recognized. We explore the differential characteristics of negative symptoms across these illnesses, and their relevance to functional outcomes. This transdiagnostic presence and relevance of negative symptoms highlights the need for continued exploration of their phenomenology and neurobiology as we move to develop effective interventions to address these debilitating symptoms and improve functional outcomes.

Motivational Deficits and Cognitive Test Performance in Schizophrenia

IMPORTANCE Motivational and cognitive deficits are core features of schizophrenia, both closely linked with functional outcomes. Although poor effort and decreased motivation are known to affect performance on cognitive tests, the extent of this relationship is unclear in patients with schizophrenia. OBJECTIVE To evaluate the association between intrinsic motivation and cognitive test performance in patients with schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional and 6-month prospective follow-up study performed at 57 sites in the United States, including academic and community medical treatment centers, participating in the Clinical Antipsychotic Trials of Intervention Effectiveness study. The primary sample included 431 stable patients with a DSM-IV diagnosis of schizophrenia currently receiving a stable medication regimen. INTERVENTIONS Cognitive performance and intrinsic motivation were evaluated using a comprehensive neuropsychological test battery and a derived measure from the Heinrichs-Carpenter Quality of Life Scale, respectively. Symptom severity and functional status were also assessed. MAIN OUTCOMES AND MEASURES The primary outcome variable was global neurocognition. Individual domains of cognition were also evaluated for their association with motivation. RESULTS Level of intrinsic motivation was significantly and positively correlated with global cognitive test performance, a relationship that held for each domain of cognition evaluated (correlation range, 0.20-0.34; P < .001). This association was found to be reliable after statistically accounting for positive, negative, depressive, and overall symptom severity (P < .05) and after accounting for community functioning (P < .001). The relationship between motivation and cognitive performance also remained significant after controlling for antipsychotic dose (P < .05). Prospective increase in motivation during the 6-month follow-up was also found to be significantly related to improvement in global cognitive performance (P < .05). CONCLUSIONS AND RELEVANCE The present findings provide strong support for a robust and reliable relationship between motivation and cognitive performance and suggest that test performance is not purely a measure of ability. Future studies assessing cognition in patients with schizophrenia should consider potential moderating variables such as effort and motivation. Implications for the assessment and interpretation of cognitive impairment based on neuropsychological test measures in schizophrenia are discussed, especially in the case of clinical trials for cognition-enhancing treatments. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00014001.

Impact of primary negative symptoms on functional outcomes in schizophrenia.

OBJECTIVE Negative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia. METHOD The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale. RESULTS Negative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients. CONCLUSIONS Primary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery.

Neural substrates underlying effort computation in schizophrenia

The lack of initiative, drive or effort in patients with schizophrenia is linked to marked functional impairments. However, our assessment of effort and motivation is crude, relying on clinical rating scales based largely on patient recall. In order to better understand the neurobiology of effort in schizophrenia, we need more rigorous measurements of this construct. In the behavioural neuroscience literature, decades of work has been carried out developing various paradigms to examine the neural underpinnings of an animals willingness to expend effort for a reward. Here, we shall review this literature on the nature of paradigms used in rodents to assess effort, as well as those used in humans. Next, the neurobiology of these effort-based decisions will be discussed. We shall then review what is known about effort in schizophrenia, and what might be inferred from experiments done in other human populations. Lastly, we shall discuss future directions of research that may assist in shedding light on the neurobiology of effort cost computations in schizophrenia.

Motivational deficits in early schizophrenia: Prevalent, persistent, and key determinants of functional outcome

Negative symptoms, in particular motivational deficits, are reported as impediments to functional recovery in patients with schizophrenia. This study examined the prevalence of motivational deficits in patients early in the illness, and the impact these deficits have on community functioning. Patients with schizophrenia between the ages of 18 and 35years, and within 5years of initiating antipsychotic treatment were included in the present investigation (N=166). The impact of motivation and cognition on concurrent and longitudinal functioning was evaluated. Motivational impairments were found in more than 75% of participants, and were not associated with receipt of social support. These deficits served as the most robust and reliable predictor of functional outcome, while neurocognition demonstrated significantly weaker associations with outcome. When considered together, motivational deficits demonstrated a reliable link with concurrent and longitudinal functioning, with cognition not offering any independent predictive value. Moreover, motivation was found to mediate the relationship between cognition and outcome. Changes in motivation were linked to changes in functioning; however, this was not the case for changes in cognitive performance. Motivation emerged as a significant predictor of functioning even after selected demographic and clinical characteristics (e.g., positive symptoms) were accounted for. These data indicate that motivational deficits are prevalent in patients with schizophrenia, even in the early stages of the illness, and these deficits stand as one of the most robust barriers to people with schizophrenia achieving functional recovery. Greater understanding of the mechanisms underlying these deficits is critical to effective treatment innovation.

Amotivation and functional outcomes in early schizophrenia.

Negative symptoms, particularly amotivation/apathy, are intimately tied to functional outcomes. In the present study, apathy strongly predicted psychosocial functioning in a sample of early course schizophrenia patients. This relationship remained robust even after controlling for other clinical variables. These data suggest amotivation is core to functioning across the disease course.

Impaired insight into illness and cognitive insight in schizophrenia spectrum disorders: Resting state functional connectivity

BACKGROUND Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions. METHODS Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses. RESULTS As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC). CONCLUSION Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample.

Motivated to do well: An examination of the relationships between motivation, effort, and cognitive performance in schizophrenia

The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients.