Cerebral blood flow in striatal regions is associated with apathy in patients with schizophrenia.

BACKGROUND: Striatal dysfunction has been proposed as a pathomechanism for negative symptoms in schizophrenia. There is consensus that negative symptoms can be grouped into 2 dimensions: apathy and diminished expression. Recent studies suggest that different neural mechanisms underlie these dimensions, but the relationship between regional resting-state cerebral blood flow (rCBF) and negative symptom dimensions has not been investigated. METHODS: This study included 29 patients with schizophrenia and 20 healthy controls. We measured rCBF in the striatum using arterial spin labelling (ASL) MRI. We assessed negative symptoms using the Brief Negative Symptom Scale. RESULTS: In the ventral and dorsal striatum, rCBF was not different between patients with schizophrenia and controls. However, we did find a positive association between the severity of apathy and increased rCBF in the ventral and dorsal striatum in patients with schizophrenia. This effect was not present for diminished expression. LIMITATIONS: All patients were taking atypical antipsychotics, so an effect of antipsychotic medication on rCBF could not be excluded, although we did not find a significant association between rCBF and chlorpromazine equivalents. CONCLUSION: The main finding of this study was a specific association between increased striatal rCBF and the negative symptom dimension of apathy. Our results further support the separate assessment of apathy and diminished expression when investigating the neural basis of negative symptoms. The ASL technique can provide a direct and quantitative approach to investigating the role of rCBF changes in the pathophysiology of negative symptoms.

Associations Between Negative Symptoms and Effort Discounting in Patients With Schizophrenia and Major Depressive Disorder.

Deficits in goal-directed decision making and motivation are hallmark characteristics of several neuropsychiatric disorders, including schizophrenia (SZ) and major depressive disorder (MDD). Studies using effort-based decision-making tasks have shown that both patients with SZ and MDD invest less physical effort in order to obtain rewards. However, how these motivational deficits relate to clinically assessed symptom dimensions such as apathy remains controversial. Using a grip-strength-based effort discounting task we assessed effort-based decision-making behavior in healthy controls (HC) (N = 18), patients with SZ (N = 42), and MDD (N = 44). We then investigated how effort discounting relates to different symptom dimensions. There were no differences in effort discounting between HC participants and patients with SZ or MDD. In addition, we did not observe a correlation between effort discounting and negative symptoms (NS) in patients with SZ or MDD. In conclusion, the current study does not support an association between effort discounting and NS in SZ or MDD. Further studies are needed to investigate effort discounting and its relation to psychopathological dimensions across different neuropsychiatric disorders.

How far to go in deconstructing negative symptoms? Behavioural and neural level evidence for the amotivation domain.

Negative symptoms in schizophrenia are conceptualised as loading onto two factors: amotivation and diminished expression, which relate to different behavioural and neural markers. This distinction has proven useful for understanding the cognitive, motivational and neural mechanisms involved in negative symptoms, and for the development of treatments. Recently, it has been advocated that an even finer distinction into five subdomains is needed to understand the mechanisms underlying negative symptoms, and to prevent masking specific treatment and intervention effects. However, it is currently unclear whether such a fine-grained approach offers additional insights grounded in theory. In the present work, we focused on the factor amotivation, which has been shown to selectively correlate with the propensity to discount rewards in the face of effort and with the activity in the ventral striatum during reward anticipation. In a reanalysis of these studies we explored whether subdomains of amotivation - avolition, asociality, anhedonia - showed preferential correlation with these previously identified behavioural and neural markers. We show that for both behavioural and neural markers, a fine-grained model with the three subdomains did not better explain the data than a model with the amotivation factor only. Moreover, none of the three subdomains correlated significantly more or less with the behavioural or neural markers. Thus, no additional information was gained on amotivation in schizophrenia by selectively looking at its three subdomains. Consequently, the two-factor solution currently remains a valid option for the study of negative symptoms and further research is needed for behavioural and neural validation of the five-factor model.

Increased random exploration in schizophrenia is associated with inflammation.

One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known, but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration-exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high-sensitivity C-reactive protein (hsCRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. hsCRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.

Clinical, behavioural and neural validation of the PANSS amotivation factor.

Negative symptoms in schizophrenia have been suggested to map onto two distinct factors - amotivation and diminished expression. Only recently, two-factor solutions for measuring negative symptoms have been proposed for the Positive and Negative Symptom Scale (PANSS), the most commonly used scale to assess the psychopathology of patients with schizophrenia. We aimed to validate the PANSS two-factor structure on a clinical, behavioural and neural level. For this multi-level validation, we reanalysed several datasets with patients for whom both the Brief Negative Symptom Assessment Scale (BNSS) and PANSS data were collected. We used a clinical dataset (n = 120) as well as behavioural data from an effort-based decision making task (n = 31) and functional neuroimaging data from a monetary incentive delay task (n = 41). Both tasks have previously been shown to be associated with BNSS amotivation. On the clinical level, the PANSS amotivation and diminished expression were highly correlated with their BNSS counterparts. On the behavioural level, we found that the PANSS amotivation factor but not the diminished expression factor specifically associated with willingness to invest effort to obtain a reward. On the neural level, PANSS amotivation was specifically related to reduced ventral striatal activation during reward anticipation. Our data confirm that the PANSS clearly allows distinguishing amotivation from diminished expression, as it relates selectively to specific aspects of behaviour and brain function. Our results will allow a re-analysis and sharing of existing datasets that used the PANSS to further substantiate the distinction between the two factors in neuroscientific studies and clinical trials.

Cross-cultural Validation of the 5-Factor Structure of Negative Symptoms in Schizophrenia.

OBJECTIVE: Negative symptoms are currently viewed as having a 2-dimensional structure, with factors reflecting diminished expression (EXP) and motivation and pleasure (MAP). However, several factor-analytic studies suggest that the consensus around a 2-dimensional model is premature. The current study investigated and cross-culturally validated the factorial structure of BNSS-rated negative symptoms across a range of cultures and languages. METHOD: Participants included individuals diagnosed with a psychotic disorder who had been rated on the Brief Negative Symptom Scale (BNSS) from 5 cross-cultural samples, with a total N = 1691. First, exploratory factor analysis was used to extract up to 6 factors from the data. Next, confirmatory factor analysis evaluated the fit of 5 models: (1) a 1-factor model, 2) a 2-factor model with factors of MAP and EXP, 3) a 3-factor model with inner world, external, and alogia factors; 4) a 5-factor model with separate factors for blunted affect, alogia, anhedonia, avolition, and asociality, and 5) a hierarchical model with 2 second-order factors reflecting EXP and MAP, as well as 5 first-order factors reflecting the 5 aforementioned domains. RESULTS: Models with 4 factors or less were mediocre fits to the data. The 5-factor, 6-factor, and the hierarchical second-order 5-factor models provided excellent fit with an edge to the 5-factor model. The 5-factor structure demonstrated invariance across study samples. CONCLUSIONS: Findings support the validity of the 5-factor structure of BNSS-rated negative symptoms across diverse cultures and languages. These findings have important implications for the diagnosis, assessment, and treatment of negative symptoms.

Ventral Striatal Dysfunction and Symptom Expression in Individuals With Schizotypal Personality Traits and Early Psychosis.

Striatal abnormalities play a crucial role in the pathophysiology of schizophrenia. Growing evidence suggests an association between aberrant striatal activity during reward anticipation and symptom dimensions in schizophrenia. However, it is not clear whether this holds across the psychosis continuum. The aim of the present study was to investigate alterations of ventral striatal activation during reward anticipation and its relationship to symptom expression in persons with schizotypal personality traits (SPT) and first-episode psychosis. Twenty-six individuals with high SPT, 26 patients with non-affective first-episode psychosis (including 13 with brief psychotic disorder (FEP-BPD) and 13 with first-episode schizophrenia [FEP-SZ]) and 25 healthy controls underwent event-related functional magnetic resonance imaging while performing a variant of the Monetary Incentive Delay task. Ventral striatal activation was positively correlated with total symptom severity, in particular with levels of positive symptoms. This association was observed across the psychosis continuum and within each subgroup. Patients with FEP-SZ showed the strongest elevation of striatal activation during reward anticipation, although symptom levels did not differ between groups in the psychosis continuum. While our results provide evidence that variance in striatal activation is mainly explained by dimensional symptom expression, patients with schizophrenia show an additional dysregulation of striatal activation. Trans-diagnostic approaches are promising in order to disentangle dimensional and categorical neural mechanisms in the psychosis continuum.

Deficits in reinforcement learning but no link to apathy in patients with schizophrenia.

Negative symptoms in schizophrenia have been linked to selective reinforcement learning deficits in the context of gains combined with intact loss-avoidance learning. Fundamental mechanisms of reinforcement learning and choice are prediction error signaling and the precise representation of reward value for future decisions. It is unclear which of these mechanisms contribute to the impairments in learning from positive outcomes observed in schizophrenia. A recent study suggested that patients with severe apathy symptoms show deficits in the representation of expected value. Considering the fundamental relevance for the understanding of these symptoms, we aimed to assess the stability of these findings across studies. Sixty-four patients with schizophrenia and 19 healthy control participants performed a probabilistic reward learning task. They had to associate stimuli with gain or loss-avoidance. In a transfer phase participants indicated valuation of the previously learned stimuli by choosing among them. Patients demonstrated an overall impairment in learning compared to healthy controls. No effects of apathy symptoms on task indices were observed. However, patients with schizophrenia learned better in the context of loss-avoidance than in the context of gain. Earlier findings were thus partially replicated. Further studies are needed to clarify the mechanistic link between negative symptoms and reinforcement learning.

Deficits in context-dependent adaptive coding of reward in schizophrenia.

Theoretical principles of information processing and empirical findings suggest that to efficiently represent all possible rewards in the natural environment, reward-sensitive neurons have to adapt their coding range dynamically to the current reward context. Adaptation ensures that the reward system is most sensitive for the most likely rewards, enabling the system to efficiently represent a potentially infinite range of reward information. A deficit in neural adaptation would prevent precise representation of rewards and could have detrimental effects for an organism's ability to optimally engage with its environment. In schizophrenia, reward processing is known to be impaired and has been linked to different symptom dimensions. However, despite the fundamental significance of coding reward adaptively, no study has elucidated whether adaptive reward processing is impaired in schizophrenia. We therefore studied patients with schizophrenia (n=27) and healthy controls (n=25), using functional magnetic resonance imaging in combination with a variant of the monetary incentive delay task. Compared with healthy controls, patients with schizophrenia showed less efficient neural adaptation to the current reward context, which leads to imprecise neural representation of reward. Importantly, the deficit correlated with total symptom severity. Our results suggest that some of the deficits in reward processing in schizophrenia might be due to inefficient neural adaptation to the current reward context. Furthermore, because adaptive coding is a ubiquitous feature of the brain, we believe that our findings provide an avenue in defining a general impairment in neural information processing underlying this debilitating disorder.

The association of neurocognitive impairment with diminished expression and apathy in schizophrenia.

Negative symptoms can be grouped into the two dimensions of diminished expression and apathy, which have been shown to be dissociable regarding external validators, such as functional outcome. Here, we investigated whether these two dimensions differentially relate to neurocognitive impairment in schizophrenia. 47 patients with schizophrenia or schizoaffective disorder and 33 healthy control participants were subjected to a neurocognitive test battery assessing multiple cognitive domains (processing speed, working memory, verbal fluency, verbal learning and memory, mental planning), which are integrated into a composite cognition score. Negative symptoms in patients were assessed using the Brief Negative Symptom Scale. We found that diminished expression significantly related to neurocognitive impairment, while severity of apathy symptoms was not directly associated with neurocognition. Other assessed clinical variables include chlorpromazine equivalents, positive symptoms, and depressive symptoms and did not influence the results. Our results are in line with a cognitive resource limitation model of diminished expression in schizophrenia and indicate that cognitive remediation therapy might be helpful to ameliorate expressive deficits.

Reward-dependent modulation of working memory is associated with negative symptoms in schizophrenia.

The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward-cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior.