Sarah Eisenacher

Investigation of metamemory functioning in the at-risk mental state for psychosis

BACKGROUND Metamemory describes the monitoring and knowledge about ones memory capabilities. Patients with schizophrenia have been found to be less able in differentiating between correct and false answers (smaller confidence gap) when asked to provide retrospective confidence ratings in previous studies. Furthermore, higher proportions of very-high-confident but false responses have been found in this patient group (high knowledge corruption). Whether and how these biases contribute to the early pathogenesis of psychosis is yet unclear. This study thus aimed at investigating metamemory function in the early course of psychosis. METHOD Patients in an at-risk mental state for psychosis (ARMS, n = 34), patients with a first episode of psychosis (FEP, n = 21) and healthy controls (HCs, n = 38) were compared on a verbal recognition task combined with retrospective confidence-level ratings. RESULTS FEP patients showed the smallest confidence gap, followed by ARMS patients, followed by HCs. All groups differed significantly from each other. Regarding knowledge corruption, FEP patients differed significantly from HCs, whereas a statistical trend was revealed in comparison of ARMS and FEP groups. Correlations were revealed between metamemory, measures of positive symptoms and working memory performance. CONCLUSIONS These data underline the presence of a metamemory bias in ARMS patients which is even more pronounced in FEP patients. The bias might represent an early cognitive marker of the beginning psychotic state. Longitudinal studies are needed to unravel whether metacognitive deficits predict the transition to psychosis and to evaluate therapeutic interventions.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens’s d=−0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=−0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16–66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Bias against disconfirmatory evidence in the 'at-risk mental state' and during psychosis.

Prior studies have confirmed a bias against disconfirmatory evidence (BADE) in schizophrenia which has been associated with delusions. However, its role in the pathogenesis of psychosis is yet unclear. The objective was to investigate BADE for the first time in subjects with an at-risk-mental-state for psychosis (ARMS), patients with a first episode of psychosis without antipsychotic treatment (FEP) and healthy controls (HC). A standard BADE test presenting written scenarios was employed. In addition, psychometric rating scales and a neuropsychological test battery were applied. A three-staged image was revealed. FEP-patients showed a significant BADE compared to the other groups. The performance of ARMS-patients lay in between HC and FEP-patients. A trend towards significance became evident for a bias against confirmatory evidence (BACE) in FEP-patients. Results were not attributable to antipsychotic or other medication or depressive symptoms. Correlations with delusions reached medium effect sizes but failed significance after Bonferroni-corrections. These results provide evidence for aberrations in evidence integration in the pathogenesis of psychosis and contribute to our knowledge of metacognitive functioning which can be used for (meta-)cognitive intervention in psychosis.

Early cognitive basic symptoms are accompanied by neurocognitive impairment in patients with an 'at-risk mental state' for psychosis.

Patients with an increased risk for psychosis (‘at‐risk mental state’ (ARMS)) present various neurocognitive deficits. Not least because of differences in identifying the ARMS, results of previous studies are inconsistent. In most studies ARMS‐patients are classified by the experience of attenuated psychotic symptoms (APS) and/or brief limited intermittent psychotic symptoms (BLIPS). Few studies additionally assessed cognitive basic symptoms (BS). A comprehensive assessment in the very early stage of the ARMS is missing.

Aberrant activity and connectivity of the posterior superior temporal sulcus during social cognition in schizophrenia

Abstract Schizophrenia is associated with significant impairments in social cognition. These impairments have been shown to go along with altered activation of the posterior superior temporal sulcus (pSTS). However, studies that investigate connectivity of pSTS during social cognition in schizophrenia are sparse. Twenty-two patients with schizophrenia and 22 matched healthy controls completed a social-cognitive task for functional magnetic resonance imaging that allows the investigation of affective Theory of Mind (ToM), emotion recognition and the processing of neutral facial expressions. Moreover, a resting-state measurement was taken. Patients with schizophrenia performed worse in the social-cognitive task (main effect of group). In addition, a group by social-cognitive processing interaction was revealed for activity, as well as for connectivity during the social-cognitive task, i.e., patients with schizophrenia showed hyperactivity of right pSTS during neutral face processing, but hypoactivity during emotion recognition and affective ToM. In addition, hypoconnectivity between right and left pSTS was revealed for affective ToM, but not for neutral face processing or emotion recognition. No group differences in connectivity from right to left pSTS occurred during resting state. This pattern of aberrant activity and connectivity of the right pSTS during social cognition might form the basis of false-positive perceptions of emotions and intentions and could contribute to the emergence and sustainment of delusions.

Holding on to false beliefs: The bias against disconfirmatory evidence over the course of psychosis.

BACKGROUND AND OBJECTIVES The ability to integrate evidence into a reasoning process is crucial in order to react to changing information, e.g. to adapt ones beliefs according to new evidence or to generate new beliefs when facing better alternatives. Evidence integration ability is thus associated with belief flexibility. A specific bias of evidence integration, a bias against disconfirmatory evidence (BADE), can be found in patients with schizophrenia and has been linked to delusion development and maintenance. Knowledge about whether the BADE occurs already in risk constellations of psychosis can clarify its role in the pathogenesis of psychosis. METHODS This article reviews the current literature on BADE. Many studies demonstrate BADE over the course of illness, ranging from healthy controls with subclinical properties of schizotypy, over patients with at-risk mental states (ARMS) and patients with a first episode of psychosis to patients with chronic schizophrenia. These data allow a comparison of competences and deficits over the course of illness. Underlying mechanisms of BADE are discussed, including interrelations with neurocognitive performance and dopaminergic processes. RESULTS The BADE could be found in different phases of psychosis development and can be regarded as a cognitive marker of the beginning psychotic state. LIMITATIONS The presented findings are derived from independent cross-sectional studies. So far, no comprehensive longitudinal assessment has been published. CONCLUSIONS Treatments of metacognitive deficits in general and as early as in the ARMS might interfere with the cognitive pathogenesis of psychosis, and thereby ameliorate, postpone or even prevent the transition to psychosis.

Agomelatine for the Treatment of Major Depressive Episodes in Schizophrenia-Spectrum Disorders: An Open-Prospective Proof-of-Concept Study.

Background Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia. Methods Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis. Results Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms. Conclusions Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.

The Importance of Metamemory Functioning to the Pathogenesis of Psychosis

Many studies up to date have implied that biases in the metacognition of memory, so called metamemory, contribute to the development and maintenance of positive symptoms in schizophrenia. However, no study exists which has longitudinally followed patients experiencing positive symptoms. The present article therefore reviews cross-sectional studies on retrospective metamemory abilities in participants within different stages of a schizophrenia spectrum disorder, with heterogeneous symptom severities, creating a pseudo-longitudinal overview. Summarized, a deterioration of these abilities correlating with psychosis development can be inferred. The reviewed publications indicate that metamemory biases can already be found in patients with an at-risk mental state for psychosis (ARMS). Patients in their first episode of psychosis (FEP) seem to be more severely impaired than ARMS-patients but similarly affected compared to chronic patients. The contribution of these biases to the pathogenesis of psychosis is discussed, giving consideration to relations with other cognitive- and metacognitive functions, neurochemical processes and neural correlates. It is hypothesized that the biases represent early cognitive markers of the beginning and persisting psychotic state. An early treatment program could help patients to ameliorate the general course of illness or even to prevent the risk of a transition to psychosis.

Genetics of brain age suggest an overlap with common brain disorders

Numerous genetic and environmental factors contribute to psychiatric disorders and other brain disorders. Common risk factors likely converge on biological pathways regulating the optimization of brain structure and function across the lifespan. Here, using structural magnetic resonance imaging and machine learning, we estimated the gap between brain age and chronological age in 36,891 individuals aged 3 to 96 years, including individuals with different brain disorders. We show that several disorders are associated with accentuated brain aging, with strongest effects in schizophrenia, multiple sclerosis and dementia, and document differential regional patterns of brain age gaps between disorders. In 16,269 healthy adult individuals, we show that brain age gap is heritable with a polygenic architecture overlapping those observed in common brain disorders. Our results identify brain age gap as a genetically modulated trait that offers a window into shared and distinct mechanisms in different brain disorders.

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk.

Importance Between-subject variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients. However, such group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature Objective To compare brain structural variability between individuals with SZ and healthy controls (HC) and to test if respective variability reflects the polygenic risk for SZ (PRS) in HC. Design, Setting, and Participants We compared MRI derived cortical thickness and subcortical volumes between 2,010 healthy controls and 1,151 patients with SZ across 16 cohorts. Secondly, we tested for associations between PRS and MRI features in 12,490 participants from UK Biobank. Main Outcomes and Measures We modeled mean and dispersion effects of SZ and PRS using double generalized linear models. We performed vertex-wise analyses for thickness, and region-of-interest analysis for cortical, subcortical and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, controlling for intracranial volume and population covariates, test of robustness of PRS threshold, and outlier removal. Results Compared to controls, patients with SZ showed higher heterogeneity in cortical thickness, cortical and ventricle volumes, and hippocampal subfields. Higher PRS was associated with thinner frontal and temporal cortices, as well as smaller left CA2/3, but was not significantly associated with dispersion. Conclusion and relevance SZ is associated with substantial brain structural heterogeneity beyond the mean differences. These findings possibly reflect higher differential sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of SZ. Higher PRS for SZ was associated with thinner fronto-temporal cortices and smaller subcortical volumes, but there were no significant associations with the heterogeneity in these measures, i.e. the variability among individuals with high PRS were comparable to the variability among individuals with low PRS. This suggests that brain variability in SZ results from interactions between environmental and genetic factors that are not captured by the PGR. Factors contributing to heterogeneity in fronto-temporal cortices and hippocampus are thus key to further our understanding of how genetic and environmental factors shape brain biology in SZ. Key Points Question: Is schizophrenia and its polygenic risk associated with brain structural heterogeneity in addition to mean changes? Findings: In a sample of 1151 patients and 2010 controls, schizophrenia was associated with increased heterogeneity in fronto-temporal thickness, cortical, ventricle, and hippocampal volumes, besides robust reductions in mean estimates. In an independent sample of 12,490 controls, polygenic risk for schizophrenia was associated with thinner fronto-temporal cortices and smaller CA2/3 of the left hippocampus, but not with heterogeneity. Meaning: Schizophrenia is associated with increased inter-individual differences in brainstructure, possibly reflecting clinical heterogeneity, gene-environment interactions, or secondary disease factors.