Disrupted Ultradian activity rhythms and Differential expression of several clock genes in interleukin-6-Deficient Mice

The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer's disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders

Generic critical points of normal matrix ensembles

The evolution of the degenerate complex curve associated with the ensemble at a generic critical point is related to the finite time singularities of Laplacian Growth. It is shown that the scaling behavior at a critical point of singular geometry $x^3 \sim y^2$ is described by the first Painlev\'e transcendent. The regularization of the curve resulting from discretization is discussed.Comment: Based on a talk given at the conference on Random Matrices, Random Processes and Integrable Systems, CRM Montreal, June 200

Genetics of Resilience: Gene-by-Environment Interaction Studies as a Tool to Dissect Mechanisms of Resilience

The identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies

Symptoms are not the solution but the problem: Why psychiatric research should focus on processes rather than symptoms

Progress in psychiatric research has been hindered by the use of artificial disease categories to map distinct biological substrates. Efforts to overcome this obstacle have led to the misconception that relevant psychiatric dimensions are not biologically reducible. Consequently, the return to phenomenology is once again advocated. We propose a process-centered paradigm of biological reduction compatible with non-reductive materialism

Neural stress reactivity depends on individual characteristics

Acute and chronic stress are important factors in the etiology of affective disorders. While research has focused on alterations of the hypothalamus-pituitary-adrenal axis, only few studies have investigated alterations of the neural stress response and its recovery. Here, we characterized the neural and psychological stress response in a heterogenous patient sample (N =56) and healthy controls (HC, N =57), as variance in the stress response could be critical in phenotypic heterogeneity within patients. We used an adapted psychosocial stress paradigm (Elbau et al. 2019) to investigate the acute stress response as well as stress recovery. In addition to stress-induced activations and deactivations, we compared the similarity of brain activity Pre- and PostStress between patients and HC. Patients reported stronger changes in negative (p =.010) and positive emotions (p =.017). In contrast, stress-induced neural activation was not different in patients compared to HC. However, similarity of activation patterns Pre- and PostStress was lower in patients (p =.040). Crucially, highly similar or dissimilar activation patterns PostStress and PreStress were associated with greater subjectively experienced stress (multivariate p =.024). Furthermore, better-than-chance quantitative predictions of experienced emotions based on region-of-interest activation maps were associated with stress-induced changes in similarity (multivariate p =.0004). Patients with affective disorders were characterized by lower similarity of the brain response before and after stress. However, the absence of significant group differences suggests considerable heterogeneity in the neural stress response within patients. Thus, considering individual characteristics of patients will be critical to find underlying neural changes in affective disorders

Neural stress reactivity depends on individual characteristics

Introduction: Acute and chronic stress are important factors in the etiology of affective disorders. Most research has focused on alterations of the HPA-axis response in affective disorders. However, increasing evidence has shown that psychological and physiological stress responses are not necessarily correlated as distinct networks may drive the different stress dimensions. Nonetheless, only few studies have investigated alterations of the neural stress response, its dynamics, and its recovery in patients with stress-related disorders. In this study, we characterized the neural and psychological stress response in a heterogenous patient sample and healthy individuals (HC), as variance in the stress response could be critical in determining phenotypic heterogeneity within patients. Methods: We assessed the neural stress response of 56 HC and 57 patients diagnosed with heterogeneous affective disorders including depression and anxiety. Participants were scanned on a 3T scanner while psychosocial stress was induced with an adapted [1] version of the Montreal imaging stress task [2]. Psychological and physiological stress reactivity was measured, including pulse-rate, skin conductance and cortisol. First, we tested differences in the neural stress response (Stress-PreStress) and stress recovery (Post-Stress-PreStress) between patients and HC using univariate, voxel-wise t-tests. To capture individual changes in brain activity independent of their directionality, we assessed the similarity (correlation between β-estimates from 268 regions[3]) of the brain response between the three conditions for each participant. Subsequently, we tested differences of similarity between patients and HC. Lastly, we applied leave-one-out cross-validated linear regression models to determine if region-of-interest based stress-induced brain activity profiles were sufficient to predict the individual psychological stress response. Results: Stress-induction was successful with increased negative and decreased positive (ps < .001) emotions after stress across all participants. On the neural level, stress led to stronger deactivations in the posterior cingulate cortex, insulae, and bilateral superior frontal and temporal gyri and activation in the occipital lobe (pFWE <.05, figure 1). Patients differed from HC in their subjective stress experience, reporting stronger increases in negative (p =.010) and decreases in positive emotions (p =.017). In contrast, stress-induced neural activation was not different in patients compared to HC on the group level. However, similarity of activation patterns Pre- and PostStress was lower in patients (p =.04, figure 2). Crucially, both extremes, namely highly similar or dissimilar activation patterns PostStress compared to PreStress were associated with greater subjectively experienced stress (multivariate p =.024). Furthermore, both positive (p =.029) as well as negative (p =.030) subjective stress experience was predicted better than chance with cross-validated regression models based on activation maps and these quantitative predictions were also associated with stress-induced changes in similarity (multivariate p =.0004). Conclusions: Patients with affective disorders were characterized by lower similarity of the brain response before and after stress, indicating a slowed stress recovery. Since there were no group differences in stress response in specific regions or directions, this suggests considerable heterogeneity in the individual characteristics of the neural stress response within patients. Moreover, absent or strong changes in brain responses after stress were associated with stronger subjective effects of stress. Thus, taking individual characteristics of patients, such as their subjective, autonomous, and endocrine stress response or genetic background, personality traits, and environmental factors into account will be critical to find underlying neural changes in affective disorders and define more homogeneous subgroups of patients