Trait rumination and social anxiety separately influence stress-induced rumination and hemodynamic responses.

We aimed to investigate stress-reactive rumination in response to social stress and its association with social anxiety and trait rumination. From previous investigations we know that people with a certain vulnerability to rumination show increased stress-reactive rumination. However, up to date the possible influence of social anxiety on this relationship is still unclear. Therefore, we reanalyzed the data of two of our previous studies assessing healthy low and high trait ruminators and depressed patients performing the Trier Social Stress Test (TSST). We measured cortical oxygenation using functional Near-Infrared Spectroscopy (fNIRS) as well as different behavioral outcome measures (subjective stress levels, negative affect, state rumination). On a behavioral level, we found an influence of both, social anxiety and trait rumination, on state rumination, even when correcting for the other factor, respectively, implying two potentially independent factors of influence. On a neural level, we observed reduced activation in brain regions of the cognitive control network (CCN) for higher social anxiety and trait rumination, which might be a result of reduced cognitive and attentional control. Results indicate a specific role of social anxiety, at least on a behavioral level, and therefore implicate a crucial factor to be considered in the treatment of depression.

Monitoring Processes and Their Neuronal Correlates as the Basis of Auditory Verbal Hallucinations in a Non-clinical Sample.

Auditory verbal hallucinations (AVH) are a characteristic symptom of psychosis. An influential cognitive model accounting for the mechanisms in the generation of AVHs describes a defective monitoring of inner speech, leading to the misidentification of internally generated thoughts as externally generated events. In this study, we utilized an inner speech paradigm during a simultaneous measurement with functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), in order to replicate the findings of neural correlates of inner speech and auditory verbal imagery (AVI) in healthy subjects, reported in earlier studies, and to provide the first validation of the paradigm for fNIRS measurements. To this end, 20 healthy subjects were required to generate and silently recite first and second person sentences in their own voice (inner speech) and imagine the same sentences in a different, alien voice (AVI). Furthermore, questionnaires were deployed to assess the predisposition to acoustic hallucinations and schizotypal traits to investigate their connection to activation patterns associated with inner speech and monitoring processes. The results showed that both methods, fNIRS and fMRI, exhibited congruent activations in key brain areas, claimed to be associated with monitoring processes, indicating that the paradigm seems to be applicable using fNIRS alone. Furthermore, the results showed similar brain areas activated during inner speech and monitoring processes to those from earlier studies. However, our results indicate that the activations were dependent more on the sentence form and less on the imaging condition, showing more active brain areas associated with second person sentences. Integration of the sentence construction into the model of inner speech and deficient monitoring processes as the basis for the formation of AVHs should be considered in further studies. Furthermore, negative correlations between questionnaires' scores and activations in precentral gyrus and premotor cortex indicate a relationship of schizotypal characteristics and a deficient activation pattern.

Insights from a laboratory and naturalistic investigation on stress, rumination and frontal brain functioning in MDD: An fNIRS study.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures. Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination. Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination. Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

Action-Monitoring Alterations as Indicators of Predictive Deficits in Schizophrenia.

A flexible and dynamically adjustable behavior is crucial to adapt to a continuously changing environment. In order to optimally adapt, we need to learn from the consequences of our behavior. We usually learn through different kinds of prediction errors, which occur when we experience unexpected situations due to false predictions. With this literature review, we intended to contribute to current etiological models that ascribe various positive symptoms (particularly delusions and hallucinations) in patients with schizophrenia to false prediction errors and deficient predictive learning. We discuss alterations in the electrophysiological measure of the error-related negativity/error negativity (ERN/Ne) as a global deficit and a trait in schizophrenia, as they have been observed in different samples of patients with schizophrenia, in individuals at high-risk and individuals with subclinical schizotypal traits. As the ERN/Ne can itself be considered the result of predictive processes (evaluation of current action outcomes as worse than expected), we propose that the reported alterations indicate that patients suffering from schizophrenic illnesses fail to adequately classify the outcomes of their actions as better or worse than expected due to a deficit in self-monitoring. Furthermore, we discuss results in further action-monitoring components, such as the correct response negativity (CRN)-a smaller negativity elicited by correct responses; and error positivity (Pe)-a later positivity assumed to reflect conscious error processing. The reported results show normal Pe amplitudes and normal post-error adjustments (adaptations after committed error to improve performance), indicating an intact later and conscious processing. From the results of diminished differences between ERN/Ne and CRN amplitudes, we conclude a general predictive deficit in early aspects of self-monitoring associated with positive symptoms in patients with schizophrenia.

Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism.

Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.

Associative Memory Impairments Are Associated With Functional Alterations Within the Memory Network in Schizophrenia Patients and Their Unaffected First-Degree Relatives: An fMRI Study.

Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.

Visual working memory encoding in schizophrenia and first-degree relatives: neurofunctional abnormalities and impaired consolidation.

BACKGROUND: Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation - i.e. the formation of durable WM representations - is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before. METHOD: We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation. RESULTS: SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals. CONCLUSIONS: Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

Schizophrenia risk variants modulate white matter volume across the psychosis spectrum: evidence from two independent cohorts.

Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders. By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS. These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.

Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: evidences from neurobehavioral measures and functional and structural MRI.

A potential clinical and etiological overlap between schizophrenia (SZ) and bipolar disorder (BD) has long been a subject of discussion. Imaging studies imply functional and structural alterations of the hippocampus in both diseases. Thus, imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits. To examine possible shared alterations in the hippocampus, we conducted a multi-modal assessment, including functional and structural imaging as well as neurobehavioral measures of memory performance in BD and SZ patients compared with healthy controls. We assessed episodic memory performance, using tests of verbal and visual learning (HVLT, BVMT) in three groups of participants: BD patients (n = 21), SZ patients (n = 21) and matched (age, gender, education) healthy control subjects (n = 21). In addition, we examined hippocampal resting state functional connectivity, hippocampal volume using voxel-based morphometry (VBM) and fibre integrity of hippocampal connections using diffusion tensor imaging (DTI). We found memory deficits, changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls. However, SZ patients when directly compared with BD patients were more severely affected in several of the assessed parameters (verbal learning, left hippocampal volumes, mean diffusivity of bilateral cingulum and right uncinated fasciculus). The results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in BD patients and SZ patients, with SZ patients being more strongly affected. Our findings imply that these two disorders may share some common pathophysiological mechanisms. The results could thus help to further advance and integrate current pathophysiological models of SZ and BD.