γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement.

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. We developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of our reagent(s). A combination of experimental mechanistic investigations and detailed computational studies (DFT) indicates a radical chain propagated reaction pathway.

MIDA- and TIDA-Boronates Stabilize α-Radicals Through B-N Hyperconjugation.

Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3 -rich small molecules. The ability of boron-containing functional groups to modify the reactivity of α-radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p-orbitals have a significant stabilizing effect on α-radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N-methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α-radicals via σB-N hyperconjugation in a manner that allows site-selective C-H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α-radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p-orbitals, but that hyperconjugation of tetrahedral boron-containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α-carbon.

Efficacy of Augmentation of Cognitive Behavioral Therapy With Transcranial Direct Current Stimulation for Depression: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) affects approximately 10% of the population globally. Approximately 20% to 30% of patients with MDD do not sufficiently respond to standard treatment. Therefore, there is a need to develop more effective treatment strategies. Objective: To investigate whether the efficacy of cognitive behavioral therapy (CBT) for the treatment of MDD can be enhanced by concurrent transcranial direct current stimulation (tDCS). Design, Setting, and Participants: The double-blind, placebo-controlled randomized clinical trial PsychotherapyPlus was conducted at 6 university hospitals across Germany. Enrollment took place between June 2, 2016, and March 10, 2020; follow-up was completed August 27, 2020. Adults aged 20 to 65 years with a single or recurrent depressive episode were eligible. They were either not receiving medication or were receiving a stable regimen of antidepressant medication (selective serotonin reuptake inhibitor and/or mirtazapine). A total of 148 women and men underwent randomization: 53 individuals were assigned to CBT alone (group 0), 48 to CBT plus tDCS (group 1), and 47 to CBT plus sham-tDCS (group 2). Interventions: Participants attended a 6-week group intervention comprising 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 mA for 30 minutes (anode over F3, cathode over F4). Main Outcomes and Measures: The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to posttreatment in the intention-to-treat sample. Scores of 0 to 6 indicate no depression; 7 to 19, mild depression; 20 to 34, moderate depression; and 34 and higher, severe depression. Results: A total of 148 patients (89 women, 59 men; mean [SD] age, 41.1 [13.7] years; MADRS score at baseline, 23.0 [6.4]) were randomized. Of these, 126 patients (mean [SD] age, 41.5 [14.0] years; MADRS score at baseline, 23.0 [6.3]) completed the study. In each of the intervention groups, intervention was able to reduce MADRS scores by a mean of 6.5 points (95% CI, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time. However, there was no significant effect of group and no significant interaction of group × time, indicating the estimated additive effects were not statistically significant. There were no severe adverse events throughout the whole trial, and there were no significant differences of self-reported adverse effects during and after stimulation between groups 1 and 2. Conclusions and Relevance: Based on MADRS score changes, this trial did not indicate superior efficacy of tDCS-enhanced CBT compared with 2 CBT control conditions. The study confirmed that concurrent group CBT and tDCS is safe and feasible. However, additional research on mechanisms of neuromodulation to complement CBT and other behavioral interventions is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02633449.

Attentional bias in German Armed Forces veterans with and without posttraumatic stress symptoms - An eye-tracking investigation and group comparison.

BACKGROUND AND OBJECTIVES: Most eye tracking based paradigms evidence patterns of sustained attention on threat coupled with low evidence for vigilance to or avoidance of threat in posttraumatic stress symptoms (PTSS). Still, eye tracking data on attention bias is particularly limited for military population. This eye tracking study investigated attentional bias in PTSS in a sample of German Armed Forces veterans. METHODS: Veterans with deployment-related PTSS (N = 24), veterans with deployment-related traumatization without PTSS (N = 28), and never-deployed healthy veterans (N = 18) were presented with pairs of combat and neutral pictures, pairs of general threat and neutral pictures, and pairs of emotional and neutral faces. Their eye gazes were tracked during a free viewing task. 3 x 3 x 2 mixed general linear model analyses were conducted. Internal consistency of attention bias indicators was calculated for the entire sample and within groups. RESULTS: Veterans with PTSS dwelled longer on general threat AOIs in contrast to non-exposed controls and shorter on general threat and combat associated neutral AOIs in contrast to both control groups. Veterans with PTSS entered faster to general threat AOIs than non-exposed controls. Veterans with PTSS showed circumscribed higher attention fluctuation in contrast to controls. Internal consistency varied across attention bias indicators. LIMITATIONS: Statistical power was reduced due to recruitment difficulties. CONCLUSIONS: Evidence is provided for the maintenance hypothesis in PTSS. No robust evidence is provided for hypervigilant behavior in PTSS. Findings on attention bias variability remain unclear, calling for more investigations in this field.

EffECTively Treating Depression: A Pilot Study Examining Manualized Group CBT as Follow-Up Treatment After ECT.

Background: There is an urgent need for effective follow-up treatments after acute electroconvulsive therapy (ECT) in depressed patients. Preliminary evidence suggests psychotherapeutic interventions to be a feasible and efficacious follow-up treatment. However, there is a need for research on the long-term usefulness of such psychotherapeutic offers in a naturalistic setting that is more representative of routine clinical practice. Therefore, the aim of the current pilot study was to investigate the effects of a half-open continuous group cognitive behavioral therapy (CBT) with cognitive behavioral analysis system of psychotherapy elements as a follow-up treatment for all ECT patients, regardless of response status after ECT, on reducing depressive symptoms and promoting psychosocial functioning. Method: Group CBT was designed to support patients during the often-difficult transition from inpatient to outpatient treatment. In a non-controlled pilot trial, patients were offered 15weekly sessions of manualized group CBT (called EffECTiv 2.0). The Montgomery-Åsberg Depression Rating Scale was assessed as primary outcome; the Beck Depression Inventory, WHO Quality of Life Questionnaire-BREF, and the Cognitive Emotion Regulation Questionnaire were assessed as secondary outcomes. Measurements took place before individual group start, after individual group end, and 6months after individual group end. Results: During group CBT, Post-ECT symptom reduction was not only maintained but there was a tendency toward a further decrease in depression severity. This reduction could be sustained 6months after end of the group, regardless of response status after ECT treatment. Aspects of quality of life and emotion regulation strategies improved during group CBT, and these improvements were maintained 6months after the end of the group. Conclusion: Even though the interpretability of the results is limited by the small sample and the non-controlled design, they indicate that manualized group CBT with cognitive behavioral analysis system of psychotherapy elements might pose a recommendable follow-up treatment option after acute ECT for depressed patients, regardless of response status after ECT. This approach might not only help to further reduce depressive symptoms and prevent relapse, but also promote long-term psychosocial functioning by improving emotion regulation strategies and psychological quality of life and thus could be considered as a valuable addition to clinical routine after future validation.

Associations Between Difficulties in Emotion Regulation and Post-Traumatic Stress Disorder in Deployed Service Members of the German Armed Forces.

BACKGROUND: Experiencing a traumatic event can lead to post-traumatic stress disorder (PTSD), but not every traumatized person develops PTSD. Several protective and risk factors have been identified in civilians and veterans to explain why some individuals develop PTSD and others do not. However, no research has confirmed the relationship between emotion regulation and PTSD in deployed German Armed Forces service members after a foreign assignment. Previous studies have identified some protective factors, such as social support, social acknowledgment, specific personal values, and posttraumatic growth, as well as risk factors, like moral injury and emotion regulation. Thus, the aim of the present study is to confirm the relationship between emotion regulation and PTSD and to test for factors that are associated with higher severity of PTSD symptoms in such a sample. METHODS: A post-hoc secondary analysis was conducted on data collected in a randomized controlled trial. Participants (N = 72) were male active and former military service members that have returned from deployment and were recruited from the German Armed Forces. These participants were separated into two groups according to PTSD diagnosis based on the results of a structured diagnostic interview. Data from evaluation questionnaires administered upon entry into the study were subjected to a cross-sectional analysis. The measures included the severity of PTSD symptoms, clusters of PTSD symptoms, clinical measures, and several measures assessing PTSD-related constructs. Analyses included the Spearman rank correlation coefficient, X2 tests for nominal data, Mann-Whitney U-tests for non-parametric data, and a mediation analysis. RESULTS: The results of the mediation analysis revealed that difficulties in emotion regulation were significantly associated with the severity of PTSD symptoms, which was mediated by social acknowledgment and experimental avoidance but not by moral injury. The analyses showed that the severity of PTSD symptoms and all clusters of PTSD symptoms were significantly associated with most of the measured constructs in expectable directions. Participants in the PTSD group showed significantly higher mean scores on questionnaires measuring constructs that have been associated with PTSD, like emotion regulation and moral injury. They also showed lower mean scores in questionnaires for social support and social acknowledgment as a victim or survivor than participants in the non-PTSD group. CONCLUSION: The present results show that difficulties in emotion regulation are directly associated with the severity of PTSD symptoms in service members of the German Armed Forces. This association is mediated by social acknowledgment and experimental avoidance, but not by moral injury. Thus, future studies should investigate these potentially crucial factors for better understanding of the development and maintenance of PTSD in service members of the German Armed Forces after deployment to create possible treatment adaptions. CLINICAL TRIAL REGISTRATION: Australian Clinical Trials Registry, identifier ACTRN 12616000956404 http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370924.

Psychometric properties of the German version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) in clinical routine settings: study design and protocol of a multitrait-multimethod study.

INTRODUCTION: The aim of this study is to investigate the diagnostic accuracy, psychometric properties and clinical utility of the German version of the Clinician-Administered Post-Traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) in routine clinical settings. METHODS AND ANALYSIS: This study is a non-interventional, multitrait-multimethod design, multicentre study that will be carried out at German civil and military inpatient and outpatient clinics. A total sample size of n=219 participants who have experienced at least one traumatic event according to criteria as defined in the DSM-5 will be recruited. For the investigation of the diagnostic accuracy and clinical utility of the CAPS-5, participants will be categorised into one of three groups, depending on their traumatic experiences and post-traumatic symptomatology: (1) monotraumatisation with PTSD; (2) multiple traumatisation with PTSD and (3) traumatisation without PTSD. Interviews will be conducted face to face by interviewers in routine clinical settings. All participants will also be asked to complete a comprehensive set of questionnaires in order to investigate different facets of construct validity and clinical utility. First, differences between all three groups in CAPS-5 sum and subscale scores will be investigated. Test-retest reliability and inter-rater reliability will be determined. Internal consistency will be calculated using structural equation modeling (SEM) based internal consistency coefficients. Construct validity will be measured with Spearman's rank correlation analyses and multivariate analyses of variance with Holm-Bonferroni corrected post hoc analysis of variances. In order to test diagnostic accuracy, receiver operating characteristics and sensitivity and specificity analyses will be conducted. The model structure of the German CAPS-5 will be analysed using confirmatory factor analyses. ETHICS AND DISSEMINATION: The study received ethical approval by the Ethics Committees of the Faculty of Psychology at the Ruhr-Universität Bochum (reference numbers: 331 and 358). The results of the study will be presented nationally and internationally at scientific conferences and will be published in scientific journals. TRIAL REGISTRATION NUMBER: DRKS00015325.

Evaluation of an internet-based intervention for service members of the German armed forces with deployment-related posttraumatic stress symptoms.

BACKGROUND: The present study was designed to evaluate the efficacy of a therapist-guided internet-based cognitive-behavioral therapy (iCBT) intervention for service members of the German Armed Forces with posttraumatic stress disorder (PTSD). The iCBT was adapted from Interapy, a trauma-focused evidence-based treatment based on prolonged exposure and cognitive restructuring. It lasted for 5 weeks and included 10 writing assignments (twice a week). The program included a reminder function if assignments were overdue, but no multimedia elements. Therapeutic written feedback was provided asynchronously within one working day. METHODS: Male active and former military service members were recruited from the German Armed Forces. Diagnoses were assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Mini-International Neuropsychiatric Interview. Psychopathology was assessed at pre-treatment, post-treatment, and 3-month follow-up. Severity of PTSD was the primary outcome and anxiety was the secondary outcome. Participants were randomly allocated to a treatment group that received iCBT immediately or to a waitlist group that received iCBT after 6 weeks. Due to the overall small sample size (n = 37), the two groups were collapsed for the statistical analyses. Change during the intervention period was investigated using latent-change score models. RESULTS: Improvements in the CAPS-5 were small and not statistically significant. For anxiety, small significant improvements were observed from pre- to follow-up assessment. The dropout rate was 32.3%. CONCLUSIONS: The low treatment utilization and the high dropout rate are in line with previous findings on treatment of service members. The interpretation of the current null results for the efficacy of iCBT is limited due to the small sample size, however for military samples effect estimates were also smaller in other recent studies. Our results demonstrate the need to identify factors influencing treatment engagement and efficacy in veterans. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12616000956404.

[CBASP as an Inpatient Concept for Treatment-Resistant Chronic Depression: A Pilot Study of the Relationship between Adverse Effects and Treatment Outcome]. / CBASP als stationäres Behandlungskonzept der therapieresistenten chronischen Depression: Eine Pilotstudie zum Zusammenhang von Nebenwirkungen und Therapieerfolg.

BACKGROUND: Inpatient psychotherapy might trigger adverse effects among others due to short but intensive treatment. Thus, in this pilot study, certain adverse effects of the multidisciplinary inpatient Cognitive Behavioral Analysis System of Psychotherapy (CBASP) for treatment-resistant chronically depressed patients as well as their relationship to treatment outcome (response-, remission-, and relapse-rates) are examined. MATERIAL AND METHODS: 50 patients with treatment-resistant and chronic depression completed the structured 12-weeks inpatient treatment program. Adverse effects were assessed by 1) deterioration of depressive symptoms (measured by the Hamilton Depression Rating Scale, HDRS) at discharge and 2) a self-report questionnaire measuring Adverse Effects of Inpatient Psychotherapy (ADEFIP), which were filled out 6 to 12 months after discharge by the patients. RESULTS: After 12 weeks of treatment, 84% could be classified as responder, of whom 44% fulfilled the remission criterion. 16% were Non-Responder. According to HDRS, none of the patients showed objective deterioration of the depressive symptoms. Six months after discharge, 40% of the responders suffered from relapse. Concerning the ADEFIP, 66% of the patients reported transient deterioration of symptoms. These patients were less likely to achieve remission. Over 50% reported interpersonal conflicts with treatment team members or other patients without any relation to outcome. Finally, more than half of the patients reported significant changes in social relationships after discharge. These patients were less likely to relapse. Overall, 94% of the patients reported at least one of the in this study assessed adverse effects. CONCLUSIONS: Despite some limitations, this pilot study suggests that the CBASP inpatient program could indeed cause adverse effects. However, only subjective transient deterioration appeared to have a negative impact on the individual treatment outcome in the short-term. Results encourage further research concerning adverse treatment effects in the context of short- and long-term treatment outcome investigating how relevant adverse effects are.

Automated detection and manipulation of sleep in C. elegans reveals depolarization of a sleep-active neuron during mechanical stimulation-induced sleep deprivation.

Across species, sleep is characterized by a complex architecture. Sleep deprivation is a classic method to study the consequences of sleep loss, which include alterations in the activity of sleep circuits and detrimental consequences on well being. Automating the observation and manipulation of sleep is advantageous to study its regulation and functions. Caenorhabditis elegans shows sleep behavior similar to other animals that have a nervous system. However, a method for real-time automatic sleep detection that allows sleep-specific manipulations has not been established for this model animal. Also, our understanding of how sleep deprivation affects sleep neurons in this system is incomplete. Here we describe a system for real-time automatic sleep detection of C. elegans grown in microfluidic devices based on a frame-subtraction algorithm using a dynamic threshold. As proof of principle for this setup, we used automated mechanical stimulation to perturb sleep behavior and followed the activity of the sleep-active RIS neuron. We show that our system can automatically detect sleep bouts and deprive worms of sleep. We found that mechanical stimulation generally leads to the activation of the sleep-active RIS neuron, and this stimulation-induced RIS depolarization is most prominent during sleep deprivation.

PsychotherapyPlus: augmentation of cognitive behavioral therapy (CBT) with prefrontal transcranial direct current stimulation (tDCS) in major depressive disorder-study design and methodology of a multicenter double-blind randomized placebo-controlled trial.

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. About 20-30% of patients do not respond to the standard psychopharmacological and/or psychotherapeutic interventions. Mounting evidence from neuroimaging studies in MDD patients reveal altered activation patterns in lateral prefrontal brain areas. Successful cognitive behavioral therapy (CBT) is associated with a recovery of these neural alterations. Moreover, it has been demonstrated that transcranial direct current stimulation (tDCS) is capable of influencing prefrontal cortex activity and cognitive functions such as working memory and emotion regulation. Thus, a clinical trial investigating the effects of an antidepressant intervention combining CBT with tDCS seems promising. The present study investigates the antidepressant efficacy of a combined CBT-tDCS intervention as compared to CBT with sham-tDCS or CBT alone. A total of 192 patients (age range 20-65 years) with MDD (Hamilton Depression Rating Scale Score ≥ 15, 21-item version) will be recruited at four study sites across Germany (Berlin, Munich, Tuebingen, and Freiburg) and randomly assigned to one of the following three treatment arms: (1) CBT + active tDCS; (2) CBT + sham-tDCS; and (3) CBT alone. All participants will attend a 6-week psychotherapeutic intervention comprising 12 sessions of CBT each lasting 100 min in a closed group setting. tDCS will be applied simultaneously with CBT. Active tDCS includes stimulation with an intensity of 2 mA for 30 min with the anode placed over F3 and the cathode over F4 according to the EEG 10-20 system, if assigned. The primary outcome measure is the change in Montgomery-Åsberg Depression Rating Scale scores from baseline to 6, 18, and 30 weeks after the first session. Participants also undergo pre- and post-treatment neuropsychological testing and functional magnetic resonance imaging (fMRI) to assess changes in prefrontal functioning and connectivity. The study investigates whether CBT can be augmented by non-invasive brain stimulation techniques such as tDCS in the treatment of MDD. It is designed as a proof-of-principle trial for the combined tDCS-CBT treatment, but also allows the investigation of the neurobiological underpinnings of the interaction between both interventions in MDD. Trial registration ClinicalTrials.gov Identifier NCT02633449.

Sleep-active neuron specification and sleep induction require FLP-11 neuropeptides to systemically induce sleep.

Sleep is an essential behavioral state. It is induced by conserved sleep-active neurons that express GABA. However, little is known about how sleep neuron function is determined and how sleep neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-active neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state.

Automated analysis of sleep control via a single neuron active at sleep onset in C. elegans.

Longitudinal analyses are crucial for understanding long-term processes such as development and behavioral rhythms. For a complete understanding of such processes, both organism-level observations as well as single-cell observations are necessary. Sleep is an example for a long-term process that is under developmental control. This behavioral state is induced by conserved sleep-active neurons, but little is known about how sleep neurons control the physiology of an animal systemically. In the nematode C. elegans, sleep induction crucially requires the single RIS interneuron to actively induce a developmentally regulated sleep behavior. Here, we used RIS-induced sleep as an example of how longitudinal analyses can be automated. We developed methods to analyze both behavior and neural activity in larva across the sleep-wake cycle. To image behavior, we used an improved DIC contrast to extract the head and detect the nose. To image neural activity, we used GCaMP3 expression in a small number of neurons including RIS combined with a neuron discrimination algorithm. Thus, we present a comprehensive platform for automatically analyzing behavior and neural activity in C. elegans exemplified by using RIS-induced sleep during C. elegans development.

Reduced muscle contraction and a relaxed posture during sleep-like Lethargus.

Sleep is characterized by reduced muscle activity resulting in reduced movement and a typical posture compatible with relaxed muscles. Prior to each molt, C. elegans larvae go through a phase of behavioral quiescence called Lethargus. Lethargus has sleep-like properties, but a specific posture has not yet been described. Do C. elegans larvae relax their muscles during sleep and do they assume a typical posture? We measured worm posture and body wall muscle activity using calcium imaging across the sleep-wake-like cycle. We found that worms were less curved and had less muscle activity during the sleep-like state. We conclude that during Lethargus, muscle activity is reduced, resulting in a relaxed body posture typical for a sleep-like state.