A step ahead: Exploring the gut microbiota in inpatients with bipolar disorder during a depressive episode.

OBJECTIVES: There is evidence that the gut microbiota plays a major role in the pathogenesis of diseases of the central nervous system through the gut-brain axis. The aim of the present study was to analyze gut microbiota composition in bipolar disorder (BD) and its relation to inflammation, serum lipids, oxidative stress, tryptophan (TRP)/kynurenine (KYN) levels, anthropometric measurements and parameters of metabolic syndrome. Further, microbial community differences of individuals with BD compared with healthy controls (HC) were explored. METHODS: In this cross-sectional study, we performed 16S rRNA gene sequencing of stool samples from 32 BD individuals and 10 HC. Laboratory parameters included inflammatory markers, serum lipids, KYN, oxidative stress and anthropometric measures. Microbial community analysis and correlation to clinical parameters was performed with QIIME, differential abundance analysis of taxa encompassed linear discriminant analysis effect size (LEfSe). RESULTS: We found a negative correlation between microbial alpha-diversity and illness duration in BD (R = -0.408, P = 0.021). Furthermore, we identified bacterial clades associated with inflammatory status, serum lipids, TRP, depressive symptoms, oxidative stress, anthropometrics and metabolic syndrome in individuals with BD. LEfSe identified the phylum Actinobacteria (LDA= 4.82, P = 0.007) and the class Coriobacteria (LDA= 4.75, P = 0.010) as significantly more abundant in BD when compared with HC, and Ruminococcaceae (LDA= 4.59, P = 0.018) and Faecalibacterium (LDA= 4.09, P = 0.039) as more abundant in HC when compared with BD. CONCLUSIONS: The present findings suggest that causes and/or consequences of BD may also lie outside the brain. Exploratory research of the gut microbiota in affective disorders like BD may identify previously unknown underlying causes, and offer new research and therapeutic approaches to mood disorders.

Problem solving, impulse control and planning in patients with early- and late-stage Huntington's disease.

Sub-domains of executive functions, including problems with planning, accuracy, impulsivity, and inhibition, are core features of Huntington's disease. It is known that the decline of cognitive function in Huntington's disease is related to the anatomical progression of pathology in the basal ganglia. However, it remains to be determined whether the severity of executive dysfunction depends on the stage of the disease. To examine the severity of sub-domains of executive dysfunction in early- and late-stage Huntington's disease, we studied performance in the Tower of London task of two groups of Huntington's disease patients (Group 1: early, n = 23, and Group 2: late stage, n = 29), as well as a third group of age, education, and IQ matched healthy controls (n = 34). During the task, we measured the total number of problems solved, total planning time, and total number of breaks taken. One aspect of executive function indexed by the number of solved problems seems to progress in the course of the disease. Late-stage Huntington's disease patients scored significantly worse than early-stage patients and controls, and early-stage patients scored significantly worse than controls on this measure of accuracy. In contrast, late- and early-stage HD patients did not differ in terms of planning time and number of breaks. Early- and late-stage HD pathology has a different impact on executive sub-domains. While accuracy differs between early- and late-stage HD patients, other domains like planning time and number of breaks do not. Striatal degeneration, which is a characteristic feature of the disease, might not affect all aspects of executive function in HD.

Pharmacotherapy of anxiety disorders in German-speaking countries: current status and changes between 1994 and 2011.

Over the past years, international treatment guidelines have been established for the treatment of anxiety disorders. Nevertheless, little is known as to whether the actual inpatient treatment follows these guidelines. The main goal of this study was to answer the question whether patients with anxiety disorder are treated according to treatment guidelines. A total of 2,573 psychiatric inpatients with the diagnosis of anxiety disorder (920 men, 1,653 women) were identified on the basis of the data of the international drug safety programme in psychiatry AMSP. Of these patients, 25.3% presented with phobia, 26.6% with panic disorder, 18.7% with generalized anxiety disorder (GAD), and 29.4% with other diagnoses of anxiety. In all of the patients, 12.7% did not receive any psychotropic medication and 22.9% were not treated with antidepressants. Only 59.3% of patients with GAD, 73.9% of patients with panic disorder, and 52.1% of patients with phobia were treated according to diagnostic guidelines. The majority (60.3%) of all patients received one or two psychotropic drugs, and only 3.7% received five or more psychotropic drugs. In two groups of patients (one group with phobia and one with panic disorder), the annual prescription rate of antidepressants significantly increased over time. The prescription rate for anticonvulsants in patients with GAD increased from 0% in 1997 to 41.7% in 2011, and for antipsychotics, from 40.7% in 1997 to 47.2% in 2011. In particular, patients with GAD were commonly treated with antipsychotics.

Brain electrical source imaging in manic and depressive episodes of bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) electroencephalographic (EEG) studies have reported varying results. The present study compared EEG in BD during manic and depressive episodes, using brain electrical source imaging [standardized low-resolution electromagnetic tomography (sLORETA)] to assess the cortical spatial distribution of the sources of EEG oscillation frequencies. METHODS: Two independent datasets (a total of 95 patients with bipolar I disorder, of whom 59 were female) were analyzed. Dataset #1 comprised 14 patients in a manic as well as a depressive episode. Dataset #2 comprised 26 patients in a manic episode and 55 patients in a depressive episode. From the head surface-recorded EEG, sLORETA cortical activity was computed in eight EEG frequency bands, and compared between mood states in both datasets. The results from the two datasets were combined using conjunction analysis. RESULTS: Conjunction analysis yielded significant differences between mood states: In manic compared to depressive states, patients had lesser theta frequency band activity (right-hemispheric lateral lower prefrontal and anterior temporal, mainly Brodmann areas 13, 38, and 47), and greater beta-2 and beta-3 frequency band activity (extended bilateral prefrontal-to-parietal, mainly Brodmann area 6, and the cingulate). CONCLUSIONS: The spatial organization of the brain's electrical oscillations differed in patients with BD between manic and depressive mood states. The brain areas implementing the main functions that show opposing abnormalities during manic and depressive episodes were affected by unduly increased or decreased activity (beta or theta). The discussion considers that facilitating (beta) or inhibiting (theta) electrical activity can in either case result in behavioral facilitation or inhibition, depending on the function of the brain area.

Selective executive dysfunction but intact risky decision-making in early Huntington's disease.

Executive dysfunction, including problems with decision-making, inhibition of prepotent responses, and verbal fluency, are main features of Huntington's disease (HD). The decline of executive function in HD is related to the anatomical progression of HD pathology in the basal ganglia, where the earliest changes of neuronal cell death are seen in the dorsolateral caudate. To examine the specific pattern of executive dysfunction in early HD, 18 patients with early HD were assessed on: (1) the Iowa Gambling Task to measure risky decision making, (2) the Stroop test to measure inhibition of prepotent responses, and (3) the verbal fluency test to measure internally guided word search and production, necessitating suppression of retrieval/production of inappropriate words and monitoring of the output. Patients with early HD were significantly impaired on the Stroop and verbal fluency tests relative to controls. However, Iowa Gambling Task performance was comparable across the 2 groups. This pattern of selective executive dysfunction in early HD probably reflects the fact that inhibitory processing involved in both the Stroop and verbal fluency tests recruits the dorsolateral caudate and its cortical connections, which are dysfunctional in early HD, whereas risky decision-making during the Iowa Gambling Task recruits the ventromedial caudate and its connections, which remain spared early on in the disease. The current results demonstrate that the deterioration of executive functioning in HD is variable and that some types of executive processing might already be impaired in early HD, whereas others remain intact.

Responses Toward Injustice Shaped by Justice Sensitivity - Evidence From Germany.

Anger, indignation, guilt, rumination, victim compensation, and perpetrator punishment are considered primary responses associated with justice sensitivity (JS). However, injustice and high JS may predispose to further responses. We had N = 293 adults rate their JS, 17 potential responses toward 12 unjust scenarios from the victim's, observer's, beneficiary's, and perpetrator's perspectives, and several control variables. Unjust situations generally elicited many affective, cognitive, and behavioral responses. JS generally predisposed to strong affective responses toward injustice, including sadness, pity, disappointment, and helplessness. It impaired trivialization, victim-blaming, or justification, which may otherwise help cope with injustice. It predisposed to conflict solutions and victim compensation. Particularly victim and beneficiary JS had stronger effects in unjust situations from the corresponding perspective. These findings add to a better understanding of the main and interaction effects of unjust situations from different perspectives and the JS facets, differences between the JS facets, as well as the links between JS and behavior and well-being.

Impaired ideomotor limb apraxia in cortical and subcortical dementia: a comparison of Alzheimer's and Huntington's disease.

BACKGROUND: Although ideomotor limb apraxia is often considered to occur only in dementia with cortical involvement like Alzheimer's disease (AD), it is also frequently seen in dementia with subcortical degeneration like Huntington's disease (HD). METHODS: To assess the occurrence of ideomotor limb apraxia, 46 patients with HD (27 men) and 37 patients with AD (16 men), matched for cognitive performance, were assessed with an apraxia test battery containing tests of the imitation of meaningless hand and finger gestures, the performance of meaningful gestures and of pantomimic movements. RESULTS: There was a high frequency of ideomotor limb apraxia in both AD and HD patients. For the assessment of hands' imitation 13.5% of the AD patients and 41.3% of the HD patients were apraxic, for fingers' imitation 21.6% (AD) and 41.3% (HD) were apraxic, for gestures 27.0% (AD) and 32.6% (HD), and for the assessment of pantomimic movements 24.3% (AD) and 52.2% (HD) showed apraxia. In the AD patients, disease severity was related to the occurrence of apraxia. CONCLUSIONS: Ideomotor limb apraxia is a common sign in both groups of patients, occurring in a high percentage. For particular neuropsychological deficits, including ideomotor limb apraxia, a division of dementia in a subcortical and cortical subtype seems to be clinically not meaningful.

Fundamentally altered global- and microstate EEG characteristics in Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is characterized by psychiatric, cognitive, and motor disturbances. The study aimed to determine electroencephalography (EEG) global state and microstate changes in HD and their relationship with cognitive and behavioral impairments. METHODS: EEGs from 20 unmedicated HD patients and 20 controls were compared using global state properties (connectivity and dimensionality) and microstate properties (EEG microstate analysis). For four microstate classes (A, B, C, D), three parameters were computed: duration, occurrence, coverage. Global- and microstate properties were compared between groups and correlated with cognitive test scores for patients. RESULTS: Global state analysis showed reduced connectivity in HD and an increasing dimensionality with increasing HD severity. Microstate analysis revealed parameter increases for classes A and B (coverage), decreases for C (occurrence) and D (coverage and occurrence). Disease severity and poorer test performances correlated with parameter increases for class A (coverage and occurrence), decreases for C (coverage and duration) and a dimensionality increase. CONCLUSIONS: Global state changes may reflect higher functional dissociation between brain areas and the complex microstate changes possibly the widespread neuronal death and corresponding functional deficits in brain regions associated with HD symptomatology. SIGNIFICANCE: Combining global- and microstate analyses can be useful for a better understanding of progressive brain deterioration in HD.

Comparative EEG mapping studies in Huntington's disease patients and controls.

Huntington's disease (HD) is a devastating neurodegenerative disorder with prominent motor and cognitive decline. Previous studies with small sample sizes and methodological limitations have described abnormal electroencephalograms (EEG) in this cohort. The aim of the present study was to investigate objectively and quantitatively the neurophysiological basis of the disease in HD patients as compared to normal controls, utilizing EEG mapping. In 55 HD patients and 55 healthy controls, a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Evaluation of 36 EEG variables was carried out by spectral analysis and visualized by EEG mapping techniques. To elucidate drug interference, the analysis was performed for the total group, unmedicated patients only and between treated and untreated patients. Statistical overall analysis by the omnibus significance test demonstrated significant (p < 0.01 and p < 0.05) EEG differences between HD patients and controls. Subsequent univariate analysis revealed a general decrease in total power and absolute alpha and beta power, an increase in delta/theta power, and a slowing of the centroids of delta/theta, beta and total power. The slowing of the EEG in HD reflects a disturbed brain function in the sense of a vigilance decrement, electrophysiologically characterized by inhibited cortical areas (increased delta/theta power) and a lack of normal routine and excitatory activity (decreased alpha and beta power). The results are similar to those found in other dementing disorders. Medication did not affect the overall interpretation of the quantitative EEG analysis, but certain differences might be due to drug interaction, predominantly with antipsychotics. Spearman rank correlations revealed significant correlations between EEG mapping and cognitive and motor impairment in HD patients.

Reduced Brain Electric Activity and Functional Connectivity in Bipolar Euthymia: An sLORETA Source Localization Study.

Bipolar disorder (BD) is a chronic illness with a relapsing and remitting time course. Relapses are manic or depressive in nature and intermitted by euthymic states. During euthymic states, patients lack the criteria for a manic or depressive diagnosis, but still suffer from impaired cognitive functioning as indicated by difficulties in executive and language-related processing. The present study investigated whether these deficits are reflected by altered intracortical activity in or functional connectivity between brain regions involved in these processes such as the prefrontal and the temporal cortices. Vigilance-controlled resting state EEG of 13 euthymic BD patients and 13 healthy age- and sex-matched controls was analyzed. Head-surface EEG was recomputed into intracortical current density values in 8 frequency bands using standardized low-resolution electromagnetic tomography. Intracortical current densities were averaged in 19 evenly distributed regions of interest (ROIs). Lagged coherences were computed between each pair of ROIs. Source activity and coherence measures between patients and controls were compared (paired t tests). Reductions in temporal cortex activity and in large-scale functional connectivity in patients compared to controls were observed. Activity reductions affected all 8 EEG frequency bands. Functional connectivity reductions affected the delta, theta, alpha-2, beta-2, and gamma band and involved but were not limited to prefrontal and temporal ROIs. The findings show reduced activation of the temporal cortex and reduced coordination between many brain regions in BD euthymia. These activation and connectivity changes may disturb the continuous frontotemporal information flow required for executive and language-related processing, which is impaired in euthymic BD patients.

Longitudinal Links between Executive Function, Anger, and Aggression in Middle Childhood.

Previous research has indicated that executive function (EF) is negatively associated with aggressive behavior in childhood. However, there is a lack of longitudinal studies that have examined the effect of deficits in EF on aggression over time and taken into account different forms and functions of aggression at the same time. Furthermore, only few studies have analyzed the role of underlying variables that may explain the association between EF and aggression. The present study examined the prospective paths between EF and different forms (physical and relational) and functions (reactive and proactive) of aggression. The habitual experience of anger was examined as a potential underlying mechanism of the link between EF and aggression, because the tendency to get angry easily has been found to be both a consequence of deficits in EF and a predictor of aggression. The study included 1,652 children (between 6 and 11 years old at the first time point), who were followed over three time points (T1, T2, and T3) covering 3 years. At T1, a latent factor of EF comprised measures of planning, rated via teacher reports, as well as inhibition, set shifting, and working-memory updating, assessed experimentally. Habitual anger experience was assessed via parent reports at T1 and T2. The forms and functions of aggression were measured via teacher reports at all three time points. Structural equation modeling revealed that EF at T1 predicted physical, relational, and reactive aggression at T3, but was unrelated to proactive aggression at T3. Furthermore, EF at T1 was indirectly linked to physical aggression at T3, mediated through habitual anger experience at T2. The results indicate that deficits in EF influence the later occurrence of aggression in middle childhood, and the tendency to get angry easily mediates this relation.

Prioritizing information topics for relatives of critically ill patients : Cross-sectional survey among intensive care unit relatives and professionals.

A patient's admission to an intensive care unit (ICU) has a significant impact on family members and other relatives. In order for them to be able to cope with such a stressful situation, the availability of appropriate understandable and accessible information is crucial. The information asymmetry between relatives and medical professionals may adversely affect satisfaction of relatives and their risk of subsequent anxiety, depression and stress symptoms. The aim of this study was therefore to understand which topics are most important to the relatives of ICU patients and to quantify the perceptions of medical professionals regarding the information needs of relatives. A cross-sectional survey was conducted in 2015. The survey had 42 questions, such as 'diagnosis', 'treatment', 'comfort', 'family' and 'end of life'. In total, the survey was handed out to four different groups. A total of 336 persons answered the survey (26 relatives, 28 ICU physicians, 202 ICU nurses and 80 ICU medical professionals in a closed Facebook© group [Facebook, Menlo Park, California, USA]). Relatives ranked the five most important topics as follows: 'recent events (crisis)', 'my participation', 'contamination in hospital', 'physical pain', and 'probability'. Several significant differences (p<0.001) were detected, for example for the topics fever, medication, recent events (crisis), appointments, relapse, and investigations. Even the topic with the lowest ranking (religion) had a score of 3.15 (min. 1.00, max. 5.00) among relatives. The ICU professionals appear to have divergent opinions regarding the most important topics for ICU relatives as compared to relatives themselves.

The role of dopamine in positive and negative prediction error utilization during incidental learning - Insights from Positron Emission Tomography, Parkinson's disease and Huntington's disease.

Incidental learning of appropriate stimulus-response associations is crucial for optimal functioning within our complex environment. Positive and negative prediction errors (PEs) serve as neural teaching signals within distinct ('direct'/'indirect') dopaminergic pathways to update associations and optimize subsequent behavior. Using a computational reinforcement learning model, we assessed learning from positive and negative PEs on a probabilistic task (Weather Prediction Task - WPT) in three populations that allow different inferences on the role of dopamine (DA) signals: (1) Healthy volunteers that repeatedly underwent [11C]raclopride Positron Emission Tomography (PET), allowing for assessment of striatal DA release during learning, (2) Parkinson's disease (PD) patients tested both on and off L-DOPA medication, (3) early Huntington's disease (HD) patients, a disease that is associated with hyper-activation of the 'direct' pathway. Our results show that learning from positive and negative feedback on the WPT is intimately linked to different aspects of dopaminergic transmission. In healthy individuals, the difference in [11C]raclopride binding potential (BP) as a measure for striatal DA release was linearly associated with the positive learning rate. Further, asymmetry between baseline DA tone in the left and right ventral striatum was negatively associated with learning from positive PEs. Female patients with early HD exhibited exaggerated learning rates from positive feedback. In contrast, dopaminergic tone predicted learning from negative feedback, as indicated by an inverted u-shaped association observed with baseline [11C]raclopride BP in healthy controls and the difference between PD patients' learning rate on and off dopaminergic medication. Thus, the ability to learn from positive and negative feedback is a sensitive marker for the integrity of dopaminergic signal transmission in the 'direct' and 'indirect' dopaminergic pathways. The present data are interesting beyond clinical context in that imbalances of dopaminergic signaling have not only been observed for neurological and psychiatric conditions but also been proposed for obesity and adolescence.

Probabilistic classification learning with corrective feedback is selectively impaired in early Huntington's disease--evidence for the role of the striatum in learning with feedback.

In general, declarative learning is associated with the activation of the medial temporal lobes (MTL), while the basal ganglia (BG) are considered the substrate for procedural learning. More recently it has been demonstrated the distinction of these systems may not be as absolute as previously thought and that not only the explicit or implicit nature of the memory task alone is important for the distinction of MTL or BG systems. Nevertheless, patients with BG dysfunction - such as patients with Parkinson's disease (PD) or Huntington's disease (HD) - are considered to be impaired at implicit learning. However, a more recent study demonstrated that one implicit learning task, probabilistic classification learning (examples include the weather prediction (WPT) and Mr. Potato Head tasks) is only impaired in PD when it involves learning with corrective feedback (FB) but not when it involves learning in a paired associate (PA) manner, without feedback. Therefore, it has been argued that the presence of feedback rather than the implicit nature of these tasks determines whether or not the BG are recruited. As patients with HD as well as those with PD, have also been shown to be impaired on the standard FB based version of probabilistic classification learning, the question remains as to whether or not there is a similar selective deficit in FB but not PA based probabilistic classification learning in HD. 18 patients with early HD and 18 healthy controls completed FB and PA versions of the WPT task. Relative to controls, HD patients were selectively impaired at WPT learning with feedback. These findings are consistent with previous evidence from studies of probabilistic classification learning in PD. Unlike PD, selective deficits in WPT learning in HD cannot be attributed to the effects of dopaminergic medication and must be directly related to BG dysfunction; for instance even in early HD, only 50% of the neurons in the medial head of caudate remain. We conclude that the striatum is important for WPT learning with feedback. Our findings are consistent with imaging evidence showing recruitment of the caudate during FB based WPT learning, while the MTL is associated with PA based learning.

EEG low-resolution brain electromagnetic tomography (LORETA) in Huntington's disease.

Previous studies have shown abnormal electroencephalography (EEG) in Huntington's disease (HD). The aim of the present investigation was to compare quantitatively analyzed EEGs of HD patients and controls by means of low-resolution brain electromagnetic tomography (LORETA). Further aims were to delineate the sensitivity and utility of EEG LORETA in the progression of HD, and to correlate parameters of cognitive and motor impairment with neurophysiological variables. In 55 HD patients and 55 controls a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Power spectra and intracortical tomography were computed by LORETA in seven frequency bands and compared between groups. Spearman rank correlations were based on V-EEG and psychometric data. Statistical overall analysis by means of the omnibus significance test demonstrated significant (p < 0.01) differences between HD patients and controls. LORETA theta, alpha and beta power were decreased from early to late stages of the disease. Only advanced disease stages showed a significant increase in delta power, mainly in the right orbitofrontal cortex. Correlation analyses revealed that a decrease of alpha and theta power correlated significantly with increasing cognitive and motor decline. LORETA proved to be a sensitive instrument for detecting progressive electrophysiological changes in HD. Reduced alpha power seems to be a trait marker of HD, whereas increased prefrontal delta power seems to reflect worsening of the disease. Motor function and cognitive function deteriorate together with a decrease in alpha and theta power. This data set, so far the largest in HD research, helps to elucidate remaining uncertainties about electrophysiological abnormalities in HD.

Combating depression in Huntington's disease: effective antidepressive treatment with venlafaxine XR.

Patients with Huntington's disease (HD) often suffer from psychiatric symptoms including affective disorder, psychosis, irritability, and apathy, which may be present in all stages of the disease. However--despite the obvious likelihood that these symptoms may be reduced by antidepressive treatments--to date, the effectiveness of such treatments in HD has only ever been examined in case studies. Twenty-six HD patients (17 men), with a diagnosis of major depression, were studied. The symptoms of HD and depression were systematically measured using the Beck Depression Inventory and the Hamilton Rating Scale for Depression both at baseline and after 4 weeks of treatment with venlafaxine XR. After 4 weeks of venlafaxine XR treatment, the symptoms of depression in HD patients decreased significantly relative to baseline. However, approximately one in five patients developed significant venlafaxine-related side effects (nausea and irritability). Venlafaxine XR is highly effective in the treatment of depression in HD, although it may produce unpleasant side effects. Further studies are required to establish the most suitable treatment for depression in HD.