Association among childhood adversity and susceptibility to interference during varying salience: two studies in healthy males.

Childhood adversity, a prevalent experience, is related to a higher risk for externalizing and internalizing psychopathology. Alterations in the development of cognitive processes, for example in the attention-interference domain may link childhood adversity and psychopathology. Interfering stimuli can vary in their salience, i.e. ability to capture attentional focus, and valence. However, it is not known if interference by salience or valence is associated with self-reported adversity. In two independent study samples of healthy men (Study 1: n = 44; mean age [standard deviation (SD)] = 25.9 [3.4] years; Study 2: n = 37; 43.5 [9.7] years) we used the attention modulation task (AMT) that probed interference by two attention-modulating conditions, salience and valence separately across repeated target stimuli. The AMT measures the effects of visual distractors (pictures) on the performance of auditory discrimination tasks (target stimuli). We hypothesized that participants reporting higher levels of childhood adversity, measured with the childhood trauma questionnaire, would show sustained interference in trials with lower salience. Due to conflicting reports on the valence-modulation, we tested the valence condition in an exploratory manner. Linear mixed models revealed an interaction between reported childhood adversity and the salience condition across tone presentations in both study samples (Sample 1: p = .03; Sample 2: p = .04), while there were no effects for the valence condition across both studies. Our study suggests that higher self-reported childhood adversity is related to faster processing of target cues during high salience, but slower during low salience conditions. These results hint to the mechanisms linking childhood adversity and psychopathological symptoms in the attentional domain.

Trait anxiety is related to Nx4's efficacy on stress-induced changes in amygdala-centered resting state functional connectivity: a placebo-controlled cross-over trial in mildly to moderately stressed healthy volunteers.

BACKGROUND: The multicomponent drug Neurexan (Nx4) was shown to reduce the neural stress network activation. We now investigated its effects on stress-induced resting state functional connectivity (RSFC) in dependence of trait anxiety (TA), an acknowledged vulnerability factor for stress-induced psychopathologies. METHODS: Nx4 was tested in a randomized placebo-controlled crossover trial. Resting state fMRI scans were performed before and after a psychosocial stress task and exploratively analyzed for amygdala centered RSFC. Effects of Nx4 on stress-induced RSFC changes were evaluated and correlated to TA levels. A subgroup analysis based on TA scores was performed. RESULTS: Multiple linear regression analysis revealed a significant correlation between TA and Nx4 effect on stress-induced RSFC changes between right amygdala and pregenual anterior cingulate cortex (pgACC) and ventro-medial prefrontal cortex (vmPFC). For participants with above average TA, a significant amelioration of the stress-induced RSFC changes was observed. CONCLUSIONS: The data add evidence to the hypothesis that Nx4's clinical efficacy is based on a dampened activation of the neural stress network, with a greater neural response in subjects with anxious personality traits. Further studies assessing clinically relevant outcome measures in parallel to fMRI are encouraged to evaluate the real-world benefit of Nx4. Trial registration NCT02602275.

Indirect structural disconnection-symptom mapping.

In vivo tracking of white matter fibres catalysed a modern perspective on the pivotal role of brain connectome disruption in neuropsychological deficits. However, the examination of white matter integrity in neurological patients by diffusion-weighted magnetic resonance imaging bears conceptual limitations and is not widely applicable, as it requires imaging-compatible patients and resources beyond the capabilities of many researchers. The indirect estimation of structural disconnection offers an elegant and economical alternative. For this approach, a patient's structural lesion information and normative connectome data are combined to estimate different measures of lesion-induced structural disconnection. Using one of several toolboxes, this method is relatively easy to implement and is even available to scientists without expertise in fibre tracking analyses. Nevertheless, the anatomo-behavioural statistical mapping of structural brain disconnection requires analysis steps that are not covered by these toolboxes. In this paper, we first review the current state of indirect lesion disconnection estimation, the different existing measures, and the available software. Second, we aim to fill the remaining methodological gap in statistical disconnection-symptom mapping by providing an overview and guide to disconnection data and the statistical mapping of their relationship to behavioural measurements using either univariate or multivariate statistical modelling. To assist in the practical implementation of statistical analyses, we have included software tutorials and analysis scripts.

Nx4 attenuated stress-induced activity of the anterior cingulate cortex-A post-hoc analysis of a randomized placebo-controlled crossover trial.

OBJECTIVE: Stress-related symptoms are associated with significant health and economic burden. Several studies suggest Nx4 for the pharmacological management of the stress response and investigated the underlying neural processes. Here we hypothesized that Nx4 can directly affect the stress response in a predefined stress network, including the anterior cingulate cortex (ACC), which is linked to various stress-related symptoms in patients. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 39 healthy males took a single dose of placebo or Nx4. Psychosocial stress was induced by the ScanSTRESS paradigm inside an MRI scanner, and stress network activation was analyzed in brain regions defined a priori. RESULTS: Using the placebo data only, we could validate the activation of a distinct neural stress pattern by the ScanSTRESS paradigm. For Nx4, we provide evidence of an attenuating effect on this stress response. A statistically significant reduction in differential stress-induced activation in the right supracallosal ACC was observed for the rotation stress task of the ScanSTRESS paradigm. The results add to previously published results of Nx4 effects on emotion regulation. CONCLUSIONS: Our results strengthen the hypothesis that Nx4 modulates the stress response by reducing the activation in parts of the neural stress network, particularly in the ACC. TRIAL REGISTRATION: NCT02602275; ClinicalTrials.gov.

Strategies for feature extraction from structural brain imaging in lesion-deficit modelling.

High-dimensional modelling of post-stroke deficits from structural brain imaging is highly relevant to basic cognitive neuroscience and bears the potential to be translationally used to guide individual rehabilitation measures. One strategy to optimise model performance is well-informed feature selection and representation. However, different feature representation strategies were so far used, and it is not known what strategy is best for modelling purposes. The present study compared the three common main strategies: voxel-wise representation, lesion-anatomical componential feature reduction and region-wise atlas-based feature representation. We used multivariate, machine-learning-based lesion-deficit models to predict post-stroke deficits based on structural lesion data. Support vector regression was tuned by nested cross-validation techniques and tested on held-out validation data to estimate model performance. While we consistently found the numerically best models for lower-dimensional, featurised data and almost always for principal components extracted from lesion maps, our results indicate only minor, non-significant differences between different feature representation styles. Hence, our findings demonstrate the general suitability of all three commonly applied feature representations in lesion-deficit modelling. Likewise, model performance between qualitatively different popular brain atlases was not significantly different. Our findings also highlight potential minor benefits in individual fine-tuning of feature representations and the challenge posed by the high, multifaceted complexity of lesion data, where lesion-anatomical and functional criteria might suggest opposing solutions to feature reduction.

fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial.

Social stress contributes to major societal health burdens, such as anxiety disorders and nervousness. Nx4 has been found to modulate stress responses. We investigated whether dampening of such responses is associated with neuronal correlates in brain regions involved in stress and anxiety. In a randomized, placebo-controlled, double-blind, cross-over trial, 39 healthy males took a single dose (three tablets) of either placebo or Nx4, 40 to 60 minutes before an fMRI scan session. We here report on drug effects on amygdala responses during a face-matching task, which was performed during a complex test battery further including resting-state brain connectivity and a social stress experiment. The first of the Primary Outcomes, defined in a hierarchical order, concerned reduced amygdala effects after intake of verum compared to placebo. We found a statistically significant reduction in differential activations in the left amygdala for the contrast negative faces versus forms during verum versus placebo condition. Our results indicate that effects of Nx4 can be monitored in the brain. Previously noted effects on stress responses may thus be modulated by affective brain regions including the amygdala.

Concepts and Dysfunctions of Emotion in Neuropsychiatric Research.

This chapter aims to provide a perspective of the complex formation of emotion and its operational usage in neuroscience. In the first section, the essence and function of emotion will be introduced from different perspectives. After an overview of historical and ongoing debates in the second section, the neuroscientific findings regarding emotional instances in healthy subjects and psychiatric patients will be outlined throughout the third and fourth sections. In the last section, a comprehensive approach of the newly developing field of computational psychiatry to emotion will be introduced.

The Role of Depressive Subtypes within the Neuroinflammation Hypothesis of Major Depressive Disorder.

Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points toward an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset. Next, we examine the regional specificity of neuroinflammation, which shows striking overlaps with neural patterns activated in atypical MDD. Furthermore, we outline how inflammation may translate to subtype-specific clinical features and we suggest how this could be used for diagnostic and treatment purposes. By providing a link back to a dysregulated immune system as a contributing factor to MDD subtypes, we explain how brain regions particularly affected by certain subtypes may regulate the cortisol circuitry.