Childhood trauma moderates schizotypy-related brain morphology: analyses of 1182 healthy individuals from the ENIGMA schizotypy working group.

BACKGROUND: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. METHODS: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. RESULTS: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. CONCLUSIONS: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia.

BACKGROUND: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. AIMS: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. METHODS: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. RESULTS: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. CONCLUSIONS: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast's role in improving cognitive flexibility deficits in this clinical population.

Impact of the COVID-19 pandemic on the mental health and well-being of UK healthcare workers.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant psychological impact on healthcare workers (HCWs). AIMS: There is an urgent need to understand the risk and protective factors associated with poor mental well-being of UK HCWs working during the COVID-19 pandemic. METHOD: Shortly after the April 2020 UK COVID-19 peak 2773 HCWs completed a survey containing measures of anxiety, depression, post-traumatic stress disorder and stress, as well as questions around potential predictors such as roles, COVID-19 risk perception and workplace-related factors. Respondents were classified as high or low symptomatic on each scale and logistic regression revealed factors associated with severe psychiatric symptoms. Change in well-being from pre- to during COVID-19 was also quantified. RESULTS: Nearlya third of HCWs reported moderate to severe levels of anxiety and depression, and the number reporting very high symptoms was more than quadruple that pre-COVID-19. Several controllable factors were associated with the most severe level of psychiatric symptoms: insufficient personal protective equipment availability, workplace preparation, training and communication, and higher workload. Being female, 'front line', previous psychiatric diagnoses, traumatic events, and being an allied HCW or manager were also significantly associated with severe psychiatric symptoms. Sharing stress, resilience and ethical support for treatment decisions were significantly associated with low psychiatric symptoms. Front-line workers showed greater worsening of mental health compared with non-front-line HCWs. CONCLUSIONS: Poor mental well-being was prevalent during the COVID-19 response, however, controllable factors associated with severe psychiatric symptoms are available to be targeted to reduce the detrimental impact of COVID-19 and other pandemics on HCW mental health.

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients.

RATIONALE: Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. OBJECTIVES: Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia. METHODS: This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 µg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest. RESULTS: Verbal memory was significantly improved under 250 µg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03). CONCLUSIONS: Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia. TRIAL REGISTRATION: NCT02079844 .

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial.

BACKGROUND: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. AIMS: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. METHODS: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. RESULTS: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. CONCLUSIONS: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

Schizotypal traits and neuropsychological performance: The role of processing speed.

BACKGROUND: Cognitive deficits, particularly in processing speed, are widely recognized as a critical feature of schizophrenia, and are also present across schizophrenia spectrum disorders. A number of important confounders, however, such as hospitalization effects and antipsychotic medication, have been shown to affect processing speed, causing debate as to the core cognitive deficits of schizophrenia. The study of individuals who are not clinically psychotic but have schizotypal traits allows investigation of cognitive deficits associated with both positive and negative schizotypy dimensions while excluding potential confounds. METHODS: A population-based community sample of 242 healthy adult volunteers assessed using the Structured Interview of Schizotypy - Revised (SIS-R) scale, and a neuropsychological testing battery that included measures of verbal ability, visual and verbal memory, verbal fluency, working memory, executive functions and processing speed. Participants were classified in High or Low Positive Schizotypy (H-PST or L-PST), High or Low Paranoia-like traits (H-PAR or L-PAR) and High or Low Negative Schizotypy (H-NST or L-NST) groups, respectively. RESULTS: Individuals with H-PST performed significantly (p < 0.05) worse than L-PST on measures of processing speed and executive functions. Processing speed deficits were also observed in individuals with H-PAR compared to L-PAR (p < 0.05). There were no statistically significant differences in neuropsychological performance between H-NST and L-NST on any measure. CONCLUSIONS: In a population-based community sample, individuals with high positive schizotypal traits or paranoia-like traits show impairments in processing speed. Consistent with a dimensional view of psychosis, this supports the hypothesis that processing speed represents a core deficit of schizophrenia-like mental states.

Using connectivity-based real-time fMRI neurofeedback to modulate attentional and resting state networks in people with high trait anxiety.

High levels of trait anxiety are associated with impaired attentional control, changes in brain activity during attentional control tasks and altered network resting state functional connectivity (RSFC). Specifically, dorsolateral prefrontal cortex to anterior cingulate cortex (DLPFC - ACC) functional connectivity, thought to be crucial for effective and efficient attentional control, is reduced in high trait anxious individuals. The current study examined the potential of connectivity-based real-time functional magnetic imaging neurofeedback (rt-fMRI-nf) for enhancing DLPFC - ACC functional connectivity in trait anxious individuals. We specifically tested if changes in DLPFC - ACC connectivity were associated with reduced anxiety levels and improved attentional control. Thirty-two high trait anxious participants were assigned to either an experimental group (EG), undergoing veridical rt-fMRI-nf, or a control group (CG) that received sham (yoked) feedback. RSFC (using resting state fMRI), anxiety levels and Stroop task performance were assessed pre- and post-rt-fMRI-nf training. Post-rt-fMRI-nf training, relative to the CG, the EG showed reduced anxiety levels and increased DLPFC-ACC functional connectivity as well as increased RSFC in the posterior default mode network. Moreover, in the EG, changes in DLPFC - ACC functional connectivity during rt-fMRI-nf training were associated with reduced anxiety levels. However, there were no group differences in Stroop task performance. We conclude that rt-fMRI-nf targeting DLPFC - ACC functional connectivity can alter network connectivity and interactions and is a feasible method for reducing trait anxiety.

Corrigendum: Dysregulated but not decreased salience network activity in schizophrenia.

[This corrects the article DOI: 10.3389/fnhum.2013.00065.].

Emerging Temporal Lobe Dysfunction in People at Clinical High Risk for Psychosis.

Clinical high-risk (CHR) individuals have been increasingly utilized to investigate the prodromal phases of psychosis and progression to illness. Research has identified medial and lateral temporal lobe abnormalities in CHR individuals. Dysfunction in the medial temporal lobe, particularly the hippocampus, is linked to dysregulation of glutamate and dopamine via a hippocampal-striatal-midbrain network that may lead to aberrant signaling of salience underpinning the formation of delusions. Similarly, lateral temporal dysfunction may be linked to the disorganized speech and language impairments observed in the CHR stage. Here, we summarize the significance of these neurobiological findings in terms of emergent psychotic symptoms and conversion to psychosis in CHR populations. We propose key questions for future work with the aim to identify the neural mechanisms that underlie the development of psychosis.

MDMA Increases Cooperation and Recruitment of Social Brain Areas When Playing Trustworthy Players in an Iterated Prisoner's Dilemma.

Social decision-making is fundamental for successful functioning and can be affected in psychiatric illness and by serotoninergic modulation. The Prisoner's Dilemma is the archetypal paradigm to model cooperation and trust. However, the effect of serotonergic enhancement is poorly characterized, and its influence on the effect of variations in opponent behavior unknown. To address this, we conducted a study investigating how the serotonergic enhancer 3,4-methylenedioxy-methamphetamine (MDMA) modulates behavior and its neural correlates during an iterated Prisoner's Dilemma with both trustworthy and untrustworthy opponents. We administered 100 mg MDMA or placebo to 20 male participants in a double-blind, placebo-controlled, crossover study. While being scanned, participants played repeated rounds with opponents who differed in levels of cooperation. On each round, participants chose to compete or cooperate and were asked to rate their trust in the other player. Cooperation with trustworthy, but not untrustworthy, opponents was enhanced following MDMA but not placebo (respectively: odds ratio = 2.01; 95% CI, 1.42-2.84, p < 0.001; odds ratio = 1.37; 95% CI, 0.78-2.30, not significant). Specifically, MDMA enhanced recovery from, but not the impact of, breaches in cooperation. During trial outcome, MDMA increased activation of four clusters incorporating precentral and supramarginal gyri, superior temporal cortex, central operculum/posterior insula, and supplementary motor area. There was a treatment × opponent interaction in right anterior insula and dorsal caudate. Trust ratings did not change across treatment sessions. MDMA increased cooperative behavior when playing trustworthy opponents. Underlying this was a change in brain activity of regions linked to social cognition. Our findings highlight the context-specific nature of MDMA's effect on social decision-making.SIGNIFICANCE STATEMENT We provide a detailed analysis of the effect of 3,4-methylenedioxy-methamphetamine (MDMA) on cooperative behavior during interpersonal interactions, as well as the neural correlates underlying these effects. We find that, following administration of MDMA, participants behave more cooperatively, but only when interacting with trustworthy partners. While breaches of trustworthy behavior have a similar impact following administration of MDMA compared with placebo, MDMA facilitates a greater recovery from these breaches of trust. Underlying this altered behavior are changes in brain activity during the viewing of opponents' behavior in regions whose involvement in social processing is well established. This work provides new insights into the impact of MDMA on social interactions, emphasizing the important role of the behavior of others toward us.

Attractor-like Dynamics in Belief Updating in Schizophrenia.

Subjects with a diagnosis of schizophrenia (Scz) overweight unexpected evidence in probabilistic inference: such evidence becomes "aberrantly salient." A neurobiological explanation for this effect is that diminished synaptic gain (e.g., hypofunction of cortical NMDARs) in Scz destabilizes quasi-stable neuronal network states (or "attractors"). This attractor instability account predicts that (1) Scz would overweight unexpected evidence but underweight consistent evidence, (2) belief updating would be more vulnerable to stochastic fluctuations in neural activity, and (3) these effects would correlate. Hierarchical Bayesian belief updating models were tested in two independent datasets (n = 80 male and n = 167 female) comprising human subjects with Scz, and both clinical and nonclinical controls (some tested when unwell and on recovery) performing the "probability estimates" version of the beads task (a probabilistic inference task). Models with a standard learning rate, or including a parameter increasing updating to "disconfirmatory evidence," or a parameter encoding belief instability were formally compared. The "belief instability" model (based on the principles of attractor dynamics) had most evidence in all groups in both datasets. Two of four parameters differed between Scz and nonclinical controls in each dataset: belief instability and response stochasticity. These parameters correlated in both datasets. Furthermore, the clinical controls showed similar parameter distributions to Scz when unwell, but were no different from controls once recovered. These findings are consistent with the hypothesis that attractor network instability contributes to belief updating abnormalities in Scz, and suggest that similar changes may exist during acute illness in other psychiatric conditions.SIGNIFICANCE STATEMENT Subjects with a diagnosis of schizophrenia (Scz) make large adjustments to their beliefs following unexpected evidence, but also smaller adjustments than controls following consistent evidence. This has previously been construed as a bias toward "disconfirmatory" information, but a more mechanistic explanation may be that in Scz, neural firing patterns ("attractor states") are less stable and hence easily altered in response to both new evidence and stochastic neural firing. We model belief updating in Scz and controls in two independent datasets using a hierarchical Bayesian model, and show that all subjects are best fit by a model containing a belief instability parameter. Both this and a response stochasticity parameter are consistently altered in Scz, as the unstable attractor hypothesis predicts.

Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis.

A large array of studies have investigated peripheral oxytocin (OT) and vasopressin (ADH) as potential biomarkers of psychiatric disorders, with highly conflicting and heterogenous findings. We searched Web of KnowledgeSM and Scopus® for English original articles investigating OT and/or ADH levels in different biological fluids (plasma/serum, saliva, urine and cerebrospinal fluid) across several psychiatric disorders. Sixty-four studies were included. We conducted 19 preliminary meta-analyses addressing OT alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 7 psychiatric disorders and ADH alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 6 psychiatric disorders compared to controls. Hedge's g was used as effect size measure, together with heterogeneity analyses, test of publication biases and quality control. None of them (except serum OT in anorexia nervosa) revealed significant differences. There is no convincing evidence that peripheral ADH or OT might be reliable biomarkers in psychiatric disorders. However, the lack of significant results was associated with high methodological heterogeneity, low quality of the studies, small sample size, and scarce reliability of the methods used in previous studies, which need to be validated and standardized.

Self-reflection and set-shifting mediate awareness in cognitively preserved schizophrenia patients.

BACKGROUND: Poor insight in schizophrenia has been linked to poor cognitive functioning, psychological processes such as denial, or more recently with impaired metacognitive capacity. Few studies, however, have investigated the potential co-dependency of multiple factors in determining level of insight, but such a model is necessary in order to account for patients with good cognitive functioning who have very poor awareness. As evidence suggests that set-shifting and cognitive insight (self-reflection (SR) and self-certainty) are strong predictors of awareness we proposed that these factors are key mediators in the relationship between cognition and awareness. We hypothesised that deficits specifically in SR and set-shifting determine level of awareness in the context of good cognition. METHODS: Thirty schizophrenia patients were stratified by high and low awareness of illness and executive functioning scores. Cognitive insight, cognition, mood and symptom measures were compared between sub-groups. RESULTS: A low insight/high executive functioning (LI-HE) group, a high insight/high executive functioning (HI-HE) group and a low insight/low executive functioning (LI-LE) group were revealed. As anticipated, the LI-HE patients showed significantly lower capacity for SR and set-shifting than the HI-HE patients. CONCLUSIONS: This study indicates that good cognitive functioning is necessary but not sufficient for good awareness; good awareness specifically demands preserved capacity to self-reflect and shift-set. Results support Nelson and Narens' [1990. Metamemory: A theoretical framework and new findings. The Psychology of Learning and Motivation, 26, 125-173] model of metacognition by which awareness is founded on control (set-shifting) and monitoring (SR) processes. These specific factors could be targeted to improve insight in patients with otherwise unimpaired cognitive function.

The relationship between cognitive insight and depression in psychosis and schizophrenia: a review and meta-analysis.

Lack of insight is a commonly observed problem in patients with psychosis and schizophrenia. Clinical insight in patients has been associated with low mood. Cognitive insight is a recently defined concept, relating to the ability to self-reflect and the degree to which patients are over-confident regarding their interpretations of illness-related experiences, and is related to clinical insight. We therefore sought to investigate whether there is a positive relationship between cognitive insight and mood. A literature search identified 17 relevant papers published between 2004 and 2014. Our analysis indicated that there was a small but significant positive correlation between the composite index (CI) of the Beck Cognitive Insight Scale (BCIS) and depression scores, but this was driven by a significant positive relationship between depression and the BCIS self-reflection (SR) sub-scale, where low mood was related to higher SR scores. There was no significant relationship between the self-certainty sub-scale and depression. Post-hoc analysis indicated that different depression scales did not significantly affect the relationship with SR. Our results support the idea that cognitive insight is significantly related to mood in schizophrenia, and the effect size is similar to that between clinical insight and mood. Potential applications of this knowledge into treatment and rehabilitation are discussed and a model of cognitive insight is proposed.

Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

The role of memory in awareness of memory deficits in Alzheimer's disease, schizophrenia, and brain injury.

Patients with neuropsychiatric disorders such as Alzheimer's disease (AD), schizophrenia (Sz), and brain injury (BI) often show memory deficits and lack of awareness of those deficits. This study aimed to investigate the role of memory in awareness of memory deficits and illness in multiple patient groups. Comparison of awareness profiles between groups can reveal common or distinct patterns of awareness and predictors, which may inform theories about the structure of awareness. Using the same standardized measures, AD (N = 27) Sz (N = 31), and BI (N = 26) patients were compared on memory functioning, awareness of illness, and awareness of memory deficits-measured by discrepancy of pretest estimate and actual test scores. All groups were poor at pretest estimation of memory functioning, particularly the AD and BI groups. In AD, patients with the lowest memory functioning rated their performance highest. The BI group and to a lesser extent the AD group showed improved estimations of performance following the memory test. Those with the poorest memory showed the greatest improvement in ratings accuracy post test. The relationship between memory and awareness of memory was stronger than the association between memory and awareness of illness. There was a double dissociation between awareness of memory and awareness of illness across patient groups. The study shows that awareness of memory is linked to memory functioning, while memory is only modestly related to awareness of illness. Dissociations in the role of memory in different domains of awareness and "online" awareness of performance provide information to refine cognitive models of awareness. However, the results should be interpreted with caution given the heterogeneous nature of the sample.

Dysregulated but not decreased salience network activity in schizophrenia.

Effective estimation of the salience of environmental stimuli underlies adaptive behavior, while related aberrance is believed to undermine rational thought processes in schizophrenia. A network including bilateral frontoinsular cortex (FIC) and dorsal anterior cingulate cortex (dACC) has been observed to respond to salient stimuli using functional magnetic resonance imaging (fMRI). To test the hypothesis that activity in this salience network (SN) is less discriminately modulated by contextually-relevant stimuli in schizophrenia than in healthy individuals, fMRI data were collected in 20 individuals with schizophrenia and 13 matched controls during performance of a modified monetary incentive delay (MID) task. After quantitatively identifying spatial components representative of the FIC and dACC features of the SN, two principal analyses were conducted. In the first, modulation of SN activity by salience was assessed by measuring response to trial outcome. First-level general linear models were applied to individual-specific time-courses of SN activity identified using spatial independent component analysis (ICA). This analysis revealed a significant salience-by-performance-by-group interaction on the best-fit FIC component's activity at trial outcome, whereby healthy individuals but not individuals with schizophrenia exhibited greater distinction between the response to hits and misses in high salience trials than in low salience trials. The second analysis aimed to ascertain whether SN component amplitude differed between the study groups over the duration of the experiment. Independent-samples T-tests on back-projected, percent-signal-change scaled SN component images importantly showed that the groups did not differ in the overall amplitude of SN expression over the entire dataset. These findings of dysregulated but not decreased SN activity in schizophrenia provide physiological support for mechanistic conceptual frameworks of delusional thought formation.

Exploring psychotic symptoms: a comparison of motor related neuronal activation during and after acute psychosis.

BACKGROUND: Delusions and hallucinations are classic positive symptoms of schizophrenia. A contemporary cognitive theory called the 'forward output model' suggests that the misattribution of self-generated actions may underlie some of these types of symptoms, such as delusions of control - the experience of self-generated action being controlled by an external agency. In order to examine the validity of this suggestion, we performed a longitudinal functional magnetic resonance imaging (fMRI) study examining neuronal activation associated with motor movement during acute psychosis. METHODS: We studied brain activation using fMRI during a motor task in 11 patients with schizophrenia and 9 healthy controls. The patient group was tested at two time points separated by 6-8 weeks. RESULTS: At initial testing, the patient group had a mean Positive and Negative Syndrome Scale score of 56.3, and showed significantly increased activation within the left inferior parietal lobe (IPL) compared to controls. Patients reported significantly decreased positive symptoms at 6-8 week followup and IPL activation had returned to normal. Our results demonstrate that first-rank positive symptoms are associated with hyperactivation in the secondary somatosensory cortex (IPL). CONCLUSIONS: These findings lend further credence to the theory that a dysfunction in the sensory feedback system located in the IPL, and which is thought to underlie our sense of agency, may contribute to the aetiology of delusions of control.

Failures of metacognition and lack of insight in neuropsychiatric disorders.

Lack of insight or unawareness of illness are the hallmarks of many psychiatric disorders, especially schizophrenia (SCZ) and other psychoses and could be conceived of as a failure in metacognition. Research in this area in the mental health field h as burgeoned with the development and widespread use of standard assessment instruments and the mapping out of the clinical and neuropsychological correlates of insight and its loss. There has been a growing appreciation of the multi-faceted nature of the concept and of the different 'objects' of insight, such as the general awareness that one is ill, to more specific metacognitive awareness of individual symptoms, impairments and performance. This in turn has led to the notion that insight may show modularity and may fractionate across different domains and disorders, supported by work that directly compares metacognition of memory deficits and illness awareness in patients with SCZ, Alzheimer's disease and brain injury. The focus of this paper will be on the varieties of metacognitive failure in psychiatry, particularly the psychoses. We explore cognitive models based on self-reflectiveness and their possible social and neurological bases, including data from structural and functional MRI. The medial frontal cortex appears to play an important role in self-appraisal in health and disease.