Frontal-midline (fm) theta oscillations as measured via the electroencephalogram (EEG) have been suggested as neural "working language" of executive functioning. Their power has been shown to ...increase when cognitive processing or task performance is enhanced. Thus, the question arises whether learning to increase fm-theta amplitudes would functionally impact the behavioral performance in tasks probing executive functions (EFs). Here, the effects of neurofeedback (NF), a learning method to self-up-regulate fm-theta over fm electrodes, on the four most representative EFs, memory updating, set shifting, conflict monitoring, and motor inhibition are presented. Before beginning and after completing an individualized, eight-session gap-spaced NF intervention, the three-back, letter/number task-switching, Stroop, and stop-signal tasks were tested while measuring the EEG. Self-determined up-regulation of fm-theta and its putative role for executive functioning were compared to an active control group, the so-called pseudo-neurofeedback group. Task-related fm-theta activity after training differed significantly between groups. More importantly, though, after NF significantly enhanced behavioral performance was observed. The training group showed higher accuracy scores in the three-back task and reduced mixing and shifting costs in letter/number task-switching. However, this specific protocol type did not affect performance in tasks probing conflict monitoring and motor inhibition. Thus, our results suggest a modulation of proactive but not reactive mechanisms of cognitive control. Furthermore, task-related EEG changes show a distinct pattern for fm-theta after training between the NF and the pseudo-neurofeedback group, which indicates that NF training indeed tackles EFs-networks. In sum, the modulation of fm-theta via NF may serve as potent treatment approach for executive dysfunctions.
Humans differ in their ability to learn how to control their own brain activity by neurofeedback. However, neural mechanisms underlying these inter-individual differences, which may determine ...training success and associated cognitive enhancement, are not well-understood. Here, it is asked whether neurofeedback success of frontal-midline (fm) theta, an oscillation related to higher cognitive functions, could be predicted by the morphology of brain structures known to be critically involved in fm-theta generation. Nineteen young, right-handed participants underwent magnetic resonance imaging of T1-weighted brain images, and took part in an individualized, eight-session neurofeedback training in order to learn how to enhance activity in their fm-theta frequency band. Initial training success, measured at the second training session, was correlated with the final outcome measure. We found that the inferior, superior, and middle frontal cortices were not associated with training success. However, volume of the midcingulate cortex as well as volume and concentration of the underlying white matter structures act as predictor variables for the general responsiveness to training. These findings suggest a neuroanatomical foundation for the ability to learn to control one's own brain activity.
Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced ...schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.
Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to ...patients’ quality of life. The aim of our multi-center, randomized, double-blind “Neuroleptic Strategy Study” (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment.
Mitochondria generate energy through oxidative phosphorylation (OXPHOS). The function of key OXPHOS proteins can be altered by variation in mitochondria-related genes, which may increase the risk of ...mental illness. We investigated the association of mitochondria-related genes and their genetic risk burden with cognitive performance.
We leveraged cross-sectional data from 1320 individuals with a severe psychiatric disorder and 466 neurotypical individuals from the PsyCourse Study. The cognitive tests analyzed were the Trail-Making Test, Verbal Digit Span Test, Digit-Symbol Test, and Multiple Choice Vocabulary Intelligence Test. Association analyses between the cognitive tests, and single-nucleotide polymorphisms (SNPs) mapped to mitochondria-related genes, and their polygenic risk score (PRS) for schizophrenia (SCZ) were performed with PLINK 1.9 and R program.
We found a significant association (FDR-adjusted p < 0.05) in the Cytochrome C Oxidase Assembly Factor 8 (COA8) gene locus of the OXPHOS pathway with the Verbal Digit Span (forward) test. Mitochondrial PRS was not significantly associated with any of the cognitive tests.
Moderate statistical power due to relatively small sample size.
COA8 encodes a poorly characterized mitochondrial protein involved in apoptosis. Here, this gene was associated with the Verbal Digit Span (forward) test, which evaluates short-term memory. Our results warrant replication and may lead to better understanding of cognitive impairment in mental disorders.
•Mitochondria generate energy through oxidative phosphorylation (OXPHOS) pathway.•Variation in mitochondria-related genes can affect key proteins involved in OXPHOS.•The protein COA8 is associated with cognitive performance.•Mitochondrial genetic risk burden has no clear effects on cognitive function.
Biological research and clinical management in psychiatry face two major impediments: the high degree of overlap in psychopathology between diagnoses and the inherent heterogeneity with regard to ...severity. Here, we aim to stratify cases into homogeneous transdiagnostic subgroups using psychometric information with the ultimate aim of identifying individuals with higher risk for severe illness.
397 participants of the PsyCourse study with schizophrenia- or bipolar-spectrum diagnoses were prospectively phenotyped over 18 months. Factor analysis of mixed data of different rating scales and subsequent longitudinal clustering were used to cluster disease trajectories.
Five clusters of longitudinal trajectories were identified in the psychopathologic dimensions. Clusters differed significantly with regard to Global Assessment of Functioning, disease course, and—in some cases—diagnosis while there were no significant differences regarding sex, age at baseline or onset, duration of illness, or polygenic burden for schizophrenia.
Longitudinal clustering may aid in identifying transdiagnostic homogeneous subgroups of individuals with severe psychiatric disease.
This paper analyses whether secondary buyouts have a value creation profile and offer equity returns different from those of primary buyouts. Using a sample of 2,456 buyout transactions (including ...448 secondary buyouts), we find no evidence that secondary buyouts generate lower equity returns or offer fundamentally lower operational value creation potential. However, we can show that secondary buyouts obtain 28–30% more leverage than primary buyouts, even after controlling for debt market conditions. Furthermore, we find evidence that secondary buyouts are 6–9% more expensive than other buyouts.
Religious delusions are a common symptom in patients experiencing psychosis, with varying prevalence rates of religious delusions across cultures and societies. To enhance our knowledge of this ...distinct psychotic feature, we investigated the mutually-adjusted association of genetic and environmental factors with occurrence of religious delusions.
We studied 262 adult German patients with schizophrenia or schizoaffective disorder. Association with lifetime occurrence of religious delusions was tested by multiple logistic regression for the following putative predictors: self-reported degree of religious activity, DSM-IV diagnosis, sex, age, education level, marital status, presence of acute delusion at the time of interview and an individual polygenic schizophrenia-risk score (SZ-PRS, available in 239 subjects).
Of the 262 patients, 101 (39%) had experienced religious delusions. The risk of experiencing religious delusions was significantly increased in patients with strong religious activity compared to patients without religious affiliation (OR = 3.6, p = 0.010). Low or moderate religious activity had no significant effect. The same analysis including the SZ-PRS confirmed the effect of high religious activity on occurrence of religious delusions (OR = 4.1, p = 0.008). Additionally, the risk of experiencing religious delusions increased with higher SZ-PRS (OR 1.4, p = 0.020, using pT = 0.05 for SZ-PRS calculation). None of the other variables were significantly associated with lifetime occurrence of religious delusions.
Our results suggest that strong religious activity and high SZ-PRS are independent risk factors for the occurrence of religious delusions in schizophrenia and schizoaffective disorder.
According to the World Health Organization, medication adherence is defined as the extent to which a person's behavior corresponds with an agreed recommendation from a healthcare provider. ...Approximately 50% of patients do not take their medication as prescribed, and non-adherence can contribute to the progress of a disease. For patients suffering from mental diseases non-adherence plays an important role. Various factors have been proposed as contributing to non-adherence, however the literature remains heterogeneous dependent on the analyzed patient subgroups. This study comprehensively evaluates the association of sociodemographic, clinical, personality and quality of life related factors with medication adherence by analyzing data from the PsyCourse study. The PsyCourse study is a large and cross-diagnostic cohort of psychiatric patients from the affective-to-psychotic spectrum.
The study sample comprised 1,062 patients from the PsyCourse study with various psychiatric diagnoses (mean SD age, 42.82 12.98 years; 47.4% female). Data were analyzed to identify specific factors associated with medication adherence, and adherence was measured by a self-rating questionnaire. Odds ratios (OR) were estimated by a logistic regression for binary outcomes. Missing data were imputed using multiple imputation.
The following factors showed the strongest association with medication adherence: never having used illicit drugs (OR, 0.71), number of prescribed antipsychotics (OR, 1.40), the personality trait conscientiousness (OR, 1.26), and the environmental domain of quality of life (OR, 1.09).
In a large and cross-diagnostic sample, we could show that a higher level of conscientiousness, a higher number of antipsychotic medication, a better quality of life within the environmental domain, and the absence of substance abuse contribute to a better medication adherence independent of the underlying disorder.
Abstract
Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic ...spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest
P
value = 7.2 × 10
−10
with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (
P
value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.
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