Das Ansprechen auf therapeutischen Schlafentzug: Klinische und genetische Charakterisierung

Therapeutischer Schlafentzug stellt eine vielversprechende Therapieoption bei depressiven Patienten dar, deren Mechanismen noch größtenteils unverstanden sind. Die klinische Studienlage ist durch heterogene Ergebnisse gekennzeichnet, während sich aktuellere Studien vermehrt der Gentechnik bedienen. Der Polygenetische Risikoscore stellt eine in der Depressionsforschung zunehmend eingesetzte Untersuchungsmethode dar, die jedoch in der Schlafentzugsforschung bisher keine Anwendung fand. Diese Arbeit fokussiert sich auf die Charakterisierung von Respondern und Non-Respondern auf Schlafentzug und deren Unterscheidung, wobei klinisch-demographische Eigenschaften sowie, erstmalig in der Schlafentzugsforschung, das polygenetische Risiko für die Depression heran gezogen wurden. Achtundsiebzig Patienten und 15 Kontrollpersonen führten therapeutischen Schlafentzug, teilweise mit Schlafphasenverschiebung, durch. Vor der Teilnahme wurden klinisch-demographische Daten erhoben und depressive Symptome über den Verlauf von 31 Tagen ermittelt. Anhand von Fremdbeurteilungsbögen wurde die Verbesserung einzelner Symptome durch die Therapie erhoben. Während des Schlafentzuges wurden wiederholt Müdigkeit und Stimmung der Teilnehmer angegeben. Darüber hinaus wurde für jeden Teilnehmer der Polygenetische Risikoscore für die Depression ermittelt. Niedrigeres Alter und ein höheres Alter bei Ersterkrankung an der Depression waren mit einer erhöhten Responsewahrscheinlichkeit assoziiert. Während der Therapie besserte sich die Stimmung bei Respondern und Non-Respondern, Responder zeigten jedoch (bei vergleichbarer initialer Depressionsschwere) eine initial bessere Stimmung auf. Die stärkste Symptomverbesserung lag bei beiden Untergruppen bei der Traurigkeit. Im Langzeitverlauf zeigten Responder kurz- und mittelfristig niedrigere Werte als Non-Responder und eine stärker ausgeprägte Symptombesserung über 31 Tage. Der Polygenetische Risikoscore war bei Patienten höher als bei Kontrollpersonen und, wenngleich nicht statistisch signifikant, bei Non-Respondern höher als bei Respondern. Das niedrigere Alter und höhere Alter bei Ersterkrankung der Responder solle in zukünftigen Studien auf eine prädiktive Aussagekraft untersucht werden. Die initial bessere Stimmung bei Respondern könnte auf eine höhere Therapieerwartung zurückzuführen sein. Die vorliegenden Daten sprechen gegen einen Gruppenunterschied in der Besserung einzelner Symptome, während der longitudinale Verlauf aufzeigt, dass therapeutischer Schlafentzug als Indikator für ein besseres Ansprechen auf andere Therapien dienen könnte. Der höhere Polygenetische Risikoscore bei Non-Respondern deutet ein besseres Ansprechen bei Personen mit einer niedrigeren genetischen Last für die Depression an

Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways

Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic 'clocks' and that SD functions through 'resetting' dysregulated genes;additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD;in non-responders, little response was observed. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level

Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways

Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic 'clocks' and that SD functions through 'resetting' dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level

Response to Therapeutic Sleep Deprivation: A Naturalistic Study of Clinical and Genetic Factors and Post-treatment Depressive Symptom Trajectory

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD. Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression

A coordinate-based meta-analysis of white matter alterations in patients with alcohol use disorder

Introduction: Besides the commonly described grey matter (GM) deficits, there is growing evidence of significant white matter (WM) alterations in patients with alcohol use disorder (AUD). WM changes can be assessed using volumetric and diffusive magnetic resonance imaging methods, such as voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). The aim of the present meta-analysis is to investigate the spatial convergence of the reported findings on WM alterations in AUD. Methods: Systematic literature search on PubMed and further databases revealed 18 studies eligible for inclusion, entailing a total of 462 AUD patients and 416 healthy controls (up to January 18, 2021). All studies that had used either VBM or DTI whole-brain analyzing methods and reported results as peak-coordinates in standard reference space were considered for inclusion. We excluded studies using approaches nonconcordant with recent guidelines for neuroimaging meta-analyses and studies investigating patient groups with Korsakoff syndrome or other comorbid substance use disorders (except tobacco). Results: Anatomical Likelihood Estimation (ALE) revealed four significant clusters of convergent macro- and microstructural WM alterations in AUD patients that were assigned to the genu and body of the corpus callosum, anterior and posterior cingulum, fornix, and the right posterior limb of the internal capsule. Discussion: The changes in WM could to some extent explain the deteriorations in motor, cognitive, affective, and perceptual functions seen in AUD. Future studies are needed to clarify how WM alterations vary over the course of the disorder and to what extent they are reversible with prolonged abstinence

Investigation of the atomic structure of curium and determination of its first ionization potential

We report on the investigation of the atomic structure of curium ($$Z=96$$) by resonance ionization spectroscopy. Three different excited energy levels were populated from the 5f^{7}6d7s^{2}\,^{9}D^{o}_{2} ground state as first excitation steps. Wide-range scans were performed for the search of second excitation steps around the literature value of the ionization potential. These spectra were analyzed to identify Rydberg levels and auto-ionizing resonances. The ionization potential was consistently determined as 48330.68(16)$$\hbox {cm} ^{-1}$$ through the evaluation of Rydberg convergences and the complementary approach of DC electric field ionization by evaluating the ionization threshold according to the saddle point model. The new result deviates by 6.7$$\hbox {cm} ^{-1}$$ from the literature value of 48324(2)$$\hbox {cm} ^{-1}$$ by Köhler et al. [15] and is about one order of magnitude more precise