Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.     

Attentional window in schizophrenia and schizotypal personality: Insight from negative priming studies

One of the core deficits that characterizes schizophrenia is an increase in distractibility and disinhibition at all levels of information processing. Patients with schizophrenia seem unable to focus attention on the relevant events while ignoring the irrelevant stimuli. This pattern of behavior is also observed in unmedicated schizotypal individuals who may carry liability for schizophrenia. In this review, we focus on studies of attentional inhibition, as assessed by the negative priming paradigm, to elucidate the relationships among deficits in inhibition, clinical symptoms and medication effects. We then consider models of the etiology of deficits in negative priming in schizophrenia and schizotypal personality. Finally, we discuss the potential power of utilizing hypothesis-driven cognitive paradigms in psychiatric research.     

Suicide schema in schizophrenia: the effect of emotional reactivity, negative symptoms and schema elaboration

Suicide risk is thought to increase with a greater potential for activation of suicide-related schemas. Suicide schemas are less likely to be activated with reductions of emotional range associated with certain negative symptoms of schizophrenia. The study tested whether suicide risk would increase in patients with recent onset schizophrenia with increased potential for suicide schema activation as indicated by lower levels of specific negative symptoms that reflected emotional reactivity, namely emotional withdrawal and blunted affect. A logistic regression analysis of baseline data of 278 recent onset schizophrenic patients with a measure of suicide behaviour as the dependent variable and negative symptoms, delusions, hallucinations, depression, gender, episode, ethnicity, education, age, duration of untreated psychosis and substance use as independent variables was carried out. Emotional withdrawal, but not blunted affect was significant and negatively associated, and depression positively associated with suicide behaviour. There was evidence to indicate that restricted emotions are associated with reduced suicide risk as predicted.     

Rumination, reflection, intrusive thoughts, and hallucination-proneness: Towards a new model

Although rumination has been proposed to play an important role in the creation of hallucinations, direct empirical tests of this proposal have not yet been performed. Employing a distinction between ruminative and reflective self-consciousness, we set out to test a new model of the relations among rumination, reflection, intrusive thoughts, thought suppression, social anxiety, and hallucination-proneness. This model proposed that rumination would be related to hallucination-proneness through the mediating variable of intrusive thoughts, but that reflection would not be related to hallucination-proneness. The model was tested in a student population (N = 296) using path analyses. A modified version of the model was found to be a good fit to the data, once a direct path from reflection to hallucination-proneness had been added. As hypothesized, rumination was related to hallucination-proneness only indirectly, through the mediating variable of intrusive thoughts. Implications for interventions and future directions for research are considered.     

Neural functional organization of hallucinations in schizophrenia: Multisensory dissolution of pathological emergence in consciousness

Although complex hallucinations are extremely vivid, painful symptoms in schizophrenia, little is known about the underlying mechanisms of multisensory integration in such a phenomenon. We investigated the neural basis of these altered states of consciousness in a patient with schizophrenia, by combining state of the art neuroscientific exploratory methods like functional MRI, diffusion tensor imaging, cortical thickness analysis, electrical source reconstruction and trans-cranial magnetic stimulation. The results shed light on the functional architecture of the hallucinatory processes, in which unimodal information from different modalities is strongly functionally connected to higher-order integrative areas.     

Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 47 healthy comparison participants were enrolled. Participants performed a 20-min handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r = .91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients.     

Rephrasing the madness and creativity debate: What is the nature of the creativity construct?

This paper aims to reframe the debates about the association between creativity and mental illness. For centuries the link between the two has been debated, yet research has largely ignored the underlying nature of creativity in this context. The full understanding of the creativity construct, however, is essential to completely grasp its relationship with psychopathology. Three possible models for the creativity construct are proposed: the existence of different kinds of creativity each associated with specific types of psychopathology, creativity operating as a continuum, and creativity as a single entity. Support for each model is examined among the current literature. It is concluded that all three models are viable possibilities for the conceptualization of the creativity construct, each offering ample predictions and hypotheses for future research.     

Executive function tests in early‐onset psychosis: which one to choose?

People with schizophrenia exhibit executive functioning deficits, an area well investigated in the adult onset schizophrenia (AOS) group, but far less so in early-onset schizophrenia (EOS). Since EOS in general seems to exhibit poorer cognitive functions and is clinically more compromised than AOS, choice of efficient and sensitive assessment measures is not necessarily the same within the two groups. The MATRICS Consensus Cognitive Battery was developed for adults when studying treatment effects and uses Mazes (Neuropsychological Assessment Battery [NAB]) to assess executive functioning. We tested 31 adolescents with schizophrenia spectrum disorders and 66 healthy controls in order to examine how Mazes compares to two other commonly used tests to measure executive functioning, D-KEFS Color Word Interference Test (Stroop) and the Wisconsin Card Sorting Test (WCST). Significant discriminating power was found for all three measures. Patients performed 0.8-1.5 SD below controls with Stroop as the most sensitive measure, followed by Mazes and WCST. Mazes was selected by the MATRICS to assess treatment effects in AOS and is shown to be able. We find the instrument also able to separate adolescent patients from controls and thus, it appears a sensible choice in clinical settings. If a more elaborated neuropsychological evaluation of the executive functioning domain is needed, Stroop should be considered a complementary test.     

Facial affect recognition deficits: A potential contributor to aggression in psychotic illness

The current literature suggests a relationship between psychosis and the likelihood of engaging in aggressive behavior, though the factors involved are unclear. In this paper we use a social information processing framework to consider mediators of aggressive behavior in psychosis, especially facial affect recognition (FAR) deficits. The theoretical underpinnings of aggressive behavior are explored using the General Aggression Model (GAM) and FAR deficits are posited as a possible contributor to increased aggression in psychosis. Current research investigating the relationship between FAR, psychosis, and aggression is critically examined, and the role of potential confounding variables including positive symptoms, psychopathic personality traits, childhood trauma, and substance use briefly explored. In conclusion, we argue that socioemotional processing deficits, such as impaired FAR, are a fruitful area for research aimed at understanding, and hence reducing the risk of violence in psychosis.     

Psychiatric rehabilitation of schizophrenia: Unresolved issues, current trends, and future directions

Psychiatric rehabilitation refers to a treatment philosophy and to a set of assessment and treatment techniques designed to reduce disability and maximize environmental adaptation. The field of psychiatric rehabilitation of schizophrenia is now well developed, and successful interventions exist for teaching many essential community-living skills and for promoting maintenance and generalization of these gains. Recent developments include the creation of new skills-training interventions and cognitive rehabilitation techniques and improvements in the delivery of vocational and substance abuse treatments. As a field, psychiatric rehabilitation is continuing to develop in a manner that is responsive to perceived treatment needs, shortcomings of existing interventions, and developments in related fields (e.g., social psychology, neuroscience of schizophrenia). Some of these developments in theory and research point to areas of conceptual/theoretical weaknesses in existing treatments and assessment measures and suggest directions for further development. This article reviews the current status of a number of areas within the psychiatric rehabilitation of schizophrenia, highlighting future needs.