Replication study on the role of dopamine-dependent prefrontal reactivations in human extinction memory retrieval.

Even after successful extinction, conditioned fear can return. Strengthening the consolidation of the fear-inhibitory safety memory formed during extinction is one way to counteract return of fear. In a previous study, we found that post-extinction L-DOPA administration improved extinction memory retrieval 24 h later. Furthermore, spontaneous post-extinction reactivations of a neural activation pattern evoked in the ventromedial prefrontal cortex (vmPFC) during extinction predicted extinction memory retrieval, L-DOPA increased the number of these reactivations, and this mediated the effect of L-DOPA on extinction memory retrieval. Here, we conducted a preregistered replication study of this work in healthy male participants. We confirm that spontaneous post-extinction vmPFC reactivations predict extinction memory retrieval. This predictive effect, however, was only observed 90 min after extinction, and was not statistically significant at 45 min as in the discovery study. In contrast to our previous study, we find no evidence that L-DOPA administration significantly enhances retrieval and that this is mediated by enhancement of the number of vmPFC reactivations. However, additional non-preregistered analyses reveal a beneficial effect of L-DOPA on extinction retrieval when controlling for the trait-like stable baseline levels of salivary alpha-amylase enzymatic activity. Further, trait salivary alpha-amylase negatively predicts retrieval, and this effect is reduced by L-DOPA treatment. Importantly, the latter findings result from non-preregistered analyses and thus further investigation is needed.

Bi-Gaussian analysis reveals distinct education-related alterations in spherical equivalent and axial length-results from the Gutenberg Health Study.

PURPOSE: The aim of this study is to investigate the distribution of spherical equivalent and axial length in the general population and to analyze the influence of education on spherical equivalent with a focus on ocular biometric parameters. METHODS: The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Participants underwent comprehensive ophthalmologic examinations as part of the 5-year follow-up examination in 2012-2017 including genotyping. The spherical equivalent and axial length distributions were modeled with gaussian mixture models. Regression analysis (on person-individual level) was performed to analyze associations between biometric parameters and educational factors. Mendelian randomization analysis explored the causal effect between spherical equivalent, axial length, and education. Additionally, effect mediation analysis examined the link between spherical equivalent and education. RESULTS: A total of 8532 study participants were included (median age: 57 years, 49% female). The distribution of spherical equivalent and axial length follows a bi-Gaussian function, partially explained by the length of education (i.e., < 11 years education vs. 11-20 years). Mendelian randomization indicated an effect of education on refractive error using a genetic risk score of education as an instrument variable (- 0.35 diopters per SD increase in the instrument, 95% CI, - 0.64-0.05, p = 0.02) and an effect of education on axial length (0.63 mm per SD increase in the instrument, 95% CI, 0.22-1.04, p = 0.003). Spherical equivalent, axial length and anterior chamber depth were associated with length of education in regression analyses. Mediation analysis revealed that the association between spherical equivalent and education is mainly driven (70%) by alteration in axial length. CONCLUSIONS: The distribution of axial length and spherical equivalent is represented by subgroups of the population (bi-Gaussian). This distribution can be partially explained by length of education. The impact of education on spherical equivalent is mainly driven by alteration in axial length.

The selfish network: how the brain preserves behavioral function through shifts in neuronal network state.

Neuronal networks possess the ability to regulate their activity states in response to disruptions. How and when neuronal networks turn from physiological into pathological states, leading to the manifestation of neuropsychiatric disorders, remains largely unknown. Here, we propose that neuronal networks intrinsically maintain network stability even at the cost of neuronal loss. Despite the new stable state being potentially maladaptive, neural networks may not reverse back to states associated with better long-term outcomes. These maladaptive states are often associated with hyperactive neurons, marking the starting point for activity-dependent neurodegeneration. Transitions between network states may occur rapidly, and in discrete steps rather than continuously, particularly in neurodegenerative disorders. The self-stabilizing, metastable, and noncontinuous characteristics of these network states can be mathematically described as attractors. Maladaptive attractors may represent a distinct pathophysiological entity that could serve as a target for new therapies and for fostering resilience.

Noise annoyance and cardiovascular disease risk: results from a 10-year follow-up study.

The relationship between noise annoyance and risk of cardiovascular disease (CVD) still needs to be fully elucidated. Thus, we examined the relationship between noise annoyance and CVD risk in a large population-based cohort study. Cross-sectional (N = 15,010, aged 35-74 years, baseline investigation period 2007-2012) and prospective data (5- and 10-year follow-up from 2012 to 2022) from the Gutenberg Health Study were used to examine the relationship between noise annoyance due to different sources and risk of prevalent and incident CVD comprising atrial fibrillation, coronary artery disease, myocardial infarction, stroke, chronic heart failure, peripheral artery disease, and venous thromboembolism. In cross-sectional analyses, noise annoyance was an independent risk factor for prevalent CVD, with the strongest associations seen for noise annoyance during sleep (e.g., neighborhood noise annoyance: odds ratio 1.20, 95% confidence interval 1.13-1.27, p < 0.0001). While in the 10-year follow-up, mostly positive associations (although not significant) between noise annoyance and incident CVD were observed, no indication of increased CVD risk was observed after 5 years of follow-up. Noise annoyance due to different sources was associated with prevalent CVD, whereas only weak associations with incident CVD were found. Further large-scale studies are needed to establish the relationship between noise annoyance and risk of CVD.

Validation of a German version of the Boredom Proneness Scale and the Multidimensional State Boredom Scale.

The scientific interest in boredom is growing over the past decades. Boredom has not only been linked to symptoms of psychopathology, but also shows a remarkable effect on individual behavior under healthy conditions. Current characterizations of boredom in humans mostly rely on self-report assessments which proved to faithfully reflect boredom in a vast range of experimental environments. Two of the most commonly used and prominent self-report scales in order to assess boredom are the Multidimensional State Boredom Scale (MSBS) and the Boredom Proneness Scale (BPS). Here, we present the German translations of both questionnaires and their validation. We obtained and analyzed psychometric data from more than 800 healthy individuals. We find that the German MSBS and BPS show vast congruence with their originals in respect to item statistics, internal reliability and validity. In particular, we find remarkable associations of state boredom and trait boredom with indicators of mental burden. Testing the factor structure of both questionnaires, we find supporting evidence for a 5-factor model of the MSBS, whereas the BPS in line with its original shows an irregular, inconsistent factor structure. Thus, we validate the German versions of MSBS and BPS and set a starting point for further studies of boredom in German-speaking collectives.

Digital interventions to promote psychological resilience: a systematic review and meta-analysis.

Societies are exposed to major challenges at an increasing pace. This underscores the need for preventive measures such as resilience promotion that should be available in time and without access barriers. Our systematic review summarizes evidence on digital resilience interventions, which have the potential to meet these demands. We searched five databases for randomized-controlled trials in non-clinical adult populations. Primary outcomes were mental distress, positive mental health, and resilience factors. Multilevel meta-analyses were performed to compare intervention and control groups at post-intervention and follow-up assessments. We identified 101 studies comprising 20,010 participants. Meta-analyses showed small favorable effects on mental distress, SMD = -0.24, 95% CI [-0.31, -0.18], positive mental health, SMD = 0.27, 95% CI [0.13, 0.40], and resilience factors, SMD = 0.31, 95% CI [0.21, 0.41]. Among middle-aged samples, older age was associated with more beneficial effects at follow-up, and effects were smaller for active control groups. Effects were comparable to those of face-to-face interventions and underline the potential of digital resilience interventions to prepare for future challenges.

Change of Intraocular Pressure Over 5 Years and its Relationship to Cardiovascular Parameters: Results From the Gutenberg Health Study.

Purpose: To investigate the longitudinal change in intraocular pressure (IOP) over 5 years and its relationship with cardiovascular parameters in a population-based sample in Germany. Methods: The Gutenberg Health Study is a prospective, observational, single-center cohort study. The sample was equally stratified for sex, residence, and age decade. IOP was measured with noncontact tonometry at baseline and at 5-year follow-up. Cardiovascular parameters, including body mass index (BMI), systolic blood pressure, and diabetes status, were assessed. Participants without IOP measurement at one time point, who were taking IOP-lowering medications, or who had ophthalmic surgery during the 5-year follow-up interval were excluded, as well as those with glaucoma diagnosis. Univariable and multivariable linear regression analyses were conducted. Results: This analysis included 9633 participants (48.9% female). The mean IOP increased from 14.04 ± 2.78 mmHg at baseline to 14.77 ± 2.92 mmHg at 5-year follow-up (P < 0.001). In multivariable linear regression analyses, an increase in BMI was associated with an increase in IOP over time (P < 0.001), whereas a higher baseline BMI was associated with a lower IOP change (P < 0.001). Higher age and male sex were associated with higher IOP change (P < 0.001). A change in systolic blood pressure was associated with IOP change, whereas baseline systolic blood pressure and diabetes status were not associated. Conclusions: This population-based study found a relationship between IOP change over 5 years and BMI and systolic blood pressure change, respectively. These findings suggest the importance of monitoring cardiovascular risk factors in IOP management.

[Retinal OCT biomarkers and neurodegenerative diseases of the central nervous system beyond Alzheimer's disease]. / Retinale OCT-Biomarker und neurodegenerative Erkrankungen des zentralen Nervensystems jenseits der Alzheimer-Krankheit.

BACKGROUND: Optical coherence tomography (OCT) biomarkers are increasingly used by neurologists, psychiatrists, and ophthalmologists for the diagnosis, prognosis, and follow-up of neurodegenerative diseases. Long-term data on OCT biomarkers of selected primary and secondary neurodegenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS) or Parkinson's disease, are already available in part. In addition, there are rare neurodegenerative diseases with early disease onset that may show OCT abnormalities. METHODS: A literature review on the association of OCT biomarkers with neurodegenerative diseases of the CNS beyond Alzheimer's disease is presented. Parkinson's disease, MS, Friedreich's ataxia, Huntington's disease, spinocerebellar ataxia, and lysosomal storage diseases are addressed. RESULTS: Relevant OCT biomarkers of neurodegenerative diseases are the macular ganglion cell inner plexiform layer (GCIPL) and the peripapillary retinal nerve fiber layer (pRNFL) thickness. Different sectors may be affected depending on the disease entity in addition to global pRFNL reduction. OCT­angiography (OCT-A) is also increasingly used as a biomarker in neurodegenerative diseases. CONCLUSION: Optical coherence tomography biomarkers are used in an interdisciplinary context. Retinal pathologies should be excluded by an ophthalmologist. While OCT biomarkers are increasingly used clinically in MS, the benefit in other neurodegenerative diseases, especially the rare ones, is less well documented. Further longitudinal studies are required.

Chronic Administration of Δ9-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat.

Introduction: Δ9-Tetrahydrocannabinol (THC) acts as an agonist at cannabinoid receptors. Its chronic intake affects many behaviors, including cognitive processes. The aims of this study in rats are to assess the chronic effects of THC on impulsivity and on regional brain glucose uptake. Materials and Methods: For the determination of "waiting impulsivity," a total of 20 male Lister Hooded rats were trained to perform a reaction time task, followed by a baseline test of impulsivity and baseline glucose uptake measurements with [18F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Then, 10 rats each received 3 mg/kg THC or vehicle injected intraperitoneally daily for 21 days. Subsequently, a second behavioral test and PET measurements were performed, and blood THC concentrations were determined. Analyses of variance of brain regions of the impulsivity network with the parameter "standardized uptake value" regarding glucose uptake and correlation analyses of the collected parameters were carried out. Discussion: After chronic THC treatment, decreased glucose uptake (p-values <0.05) was found in cingulate cortex, hippocampus, amygdala, thalamus, and cerebellar cortex, as compared with vehicle-treated rats. The number of correct no-go responses (increased waiting time) significantly increased (p<0.05) in THC-treated rats. Furthermore, correct no-go responses correlated positively and strongly with the THC blood concentrations (Spearman's ρ=0.79, p<0.01). Conclusion: These findings reflect a specific reduction in impulsive behavior after chronic THC treatment, showing a functionally relevant influence of THC on "waiting impulsivity" with reduced selective glucose uptake at the same time.

Cumulative social disadvantage and cardiovascular disease burden and mortality.

AIMS: To investigate the association between cumulative social disadvantage and cardiovascular burden and mortality in a large cohort of the general population. METHODS AND RESULTS: Cross-sectional (n = 15 010, aged 35 to 74 years, baseline investigation period 2007 to 2012) and longitudinal data (5- and 10-year follow-ups from 2012 to 2022) from the Gutenberg Health Study were used to investigate the association between individual socioeconomic status (SES, measured via a validated questionnaire) and cardiovascular disease (CVD, composite of atrial fibrillation, coronary artery disease, myocardial infarction, stroke, chronic heart failure, peripheral artery disease, and/or venous thromboembolism) risk and mortality. Subjects with prevalent CVD had a lower SES sum score, as well as lower education, occupation, and household net-income scores (all P < 0.0001). Logistic regression analysis showed that a low SES (vs. high, defined by validated cut-offs) was associated with 19% higher odds of prevalent CVD [odds ratio (OR) 1.19, 95% CI 1.01; 1.40] in the fully adjusted model. At 5-year follow-up, low SES was associated with both increased cardiovascular [hazard ratio (HR) 5.36, 2.24; 12.82] and all-cause mortality (HR 2.23, 1.51; 3.31). At 10-year follow-up, low SES was associated with a 68% higher risk of incident CVD (OR 1.68, 1.12; 2.47) as well as 86% higher all-cause mortality (HR 1.86, 1.55; 2.24). In general, the education and occupation scores were stronger related to risk of CVD and death than the household net-income score. Low SES was estimated to account for 451.45 disability-adjusted life years per 1000 people (years lived with disability 373.41/1000 and years of life lost 78.03/1000) and an incidence rate of 11 CVD cases and 3.47 CVD deaths per 1000 people per year. The population attributable fraction for CVD incidence after 5 years was 4% due to low SES. CONCLUSION: Despite universal healthcare access, cumulative social disadvantage remains associated with higher risk of CVD and mortality. Dimensions of education and occupation, but not household net income, are associated with outcomes of interest.

Low socioeconomic status is associated with higher risk of incident cardiovascular disease (CVD) and mortality in a large cohort of the general population even after comprehensive adjustment for associated variables. Education and occupation may be more important regarding CVD and mortality risk as compared to the household net income. From a public health perspective, policies should strengthen efforts to reduce socioeconomic inequalities by ensuring equal access to education and employment.

Interhemispheric transfer time correlates with white matter integrity of the corpus callosum in healthy older adults.

The corpus callosum (CC) has been identified as an important structure in the context of cognitive aging (Fling et al., 2011). Interhemispheric transfer time (IHTT) is regularly used in order to estimate interhemispheric integration enabled by the CC (Marzi, 2010; Nowicka and Tacikowski, 2011). However, only little is known with regards to the relationship between IHTT and the structural properties of the CC with only few studies with specific samples and methods available (Whitford et al., 2011). Thus, the present study aimed at investigating this relationship applying an event-related potentials (ERP) based approach of estimating IHTT as well as diffusion weighted imaging (DWI) with fractional anisotropy (FA) as an indicator of white matter integrity (WMI) of the genu, corpus and splenium of the CC. 56 healthy older adults performed a Dimond Task while ERPs were recorded and underwent DWI scanning. IHTT derived from posterior electrode sites correlated significantly with FA of the splenium (r = -0.286*, p = .03) but not the corpus (r = -0.187, p = .08) or genu (r = -0.189, p = .18). The present results support the notion that IHTT is related to WMI of the posterior CC. It may be concluded that ERP based IHTT is a suitable indicator of CC structure and function, however, likely specific to the interhemispheric transfer of visual information. Future studies may wish to confirm these findings in a more divers sample further exploring the precise interrelation between IHTT and structural or functional properties of the CC.

Brain connectivity networks underlying resting heart rate variability in acute ischemic stroke.

Acute strokes can affect heart rate variability (HRV), the mechanisms how are not well understood. We included 42 acute stroke patients (2-7 days after ischemic stroke, mean age 66 years, 16 women). For analysis of HRV, 20 matched controls (mean age 60.7, 10 women) were recruited. HRV was assessed at rest, in a supine position and individual breathing rhythmus for 5 min. The coefficient of variation (VC), the root mean square of successive differences (RMSSD), the powers of low (LF, 0.04-0.14 Hz) and high (HF, 0.15-0.50 Hz) frequency bands were extracted. HRV parameters were z-transformed related to age- and sex-matched normal subjects. Z-values < -1 indicate reduced HRV. Acute stroke lesions were marked on diffusion-weighted images employing MRIcroN and co-registered to a T1-weighted structural volume-dataset. Using independent component analysis (ICA), stroke lesions were related to HRV. Subsequently, we used the ICA-derived lesion pattern as a seed and estimated the connectivity between these brain regions and seven common functional networks, which were obtained from 50 age-matched healthy subjects (mean age 68.9, 27 women). Especially, LF and VC were frequently reduced in patients. ICA revealed one covarying lesion pattern for LF and one similar for VC, predominantly affecting the right hemisphere. Activity in brain areas corresponding to these lesions mainly impact on limbic (r = 0.55 ± 0.08) and salience ventral attention networks (0.61 ± 0.10) in the group with reduced LF power (z-score < -1), but on control and default mode networks in the group with physiological LF power (z-score > -1). No different connectivity could be found for the respective VC groups. Our results suggest that HRV alteration after acute stroke might be due to affecting resting-state brain networks.

Comparison of Frailty and Chronological Age as Determinants of the Murine Gut Microbiota in an Alzheimer's Disease Mouse Model.

The ageing of an organism is associated with certain features of functional decline that can be assessed at the cellular level (e.g., reduced telomere length, loss of proteostasis, etc.), but also at the organismic level. Frailty is an independent syndrome that involves increased multidimensional age-related deficits, heightens vulnerability to stressors, and involves physical deficits in mainly the locomotor/muscular capacity, but also in physical appearance and cognition. For sporadic Alzheimer's disease, age per se is one of the most relevant risk factors, but frailty has also been associated with this disease. Therefore, we aimed to answer the two following questions within a cross-sectional study: (1) do Alzheimer's model mice show increased frailty, and (2) what changes of the microbiota occur concerning chronological age or frailty? Indeed, aged 5xFAD mice showed increased frailty compared to wild type littermates. In addition, 5xFAD mice had significantly lower quantities of Bacteroides spp. when only considering frailty, and lower levels of Bacteroidetes in terms of both frailty and chronological age compared to their wild type littermates. Thus, the quality of ageing-as assessed by frailty measures-should be taken into account to unravel potential changes in the gut microbial community in Alzheimer's disease.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

High state boredom vastly affects psychiatric inpatients and predicts their treatment duration.

Boredom is a ubiquitous, aversive human experience typically elicited by low information and monotony. Boredom can occur either as a transient mental state that prompts individuals to adapt their behavior to avoid monotony or as a temporally stable trait, describing a chronic susceptibility to feeling bored. Increased trait boredom was found to correlate with various psychopathologies and indicators of mental burden. However, the role of state boredom in psychopathological conditions and its implications for psychiatric treatment remain elusive. Here, we address this issue by investigating state boredom and trait boredom in a cohort of psychiatric inpatients and a healthy control cohort. We find that in both groups, state boredom, even more than trait boredom, shows remarkable associations with psychopathology. In the inpatient group, state boredom is implicated broadly in multiple mental disorders and shows an association with treatment in closed psychiatric wards. Furthermore, through statistical modeling, we find that high-state boredom during inpatient therapy is predictive of a longer therapy duration. Thus, we show that state boredom constitutes an indicator of mild and severe psychopathology in different mental disorders, affecting the outcome of psychiatric patients. Potential therapeutic interventions are discussed, aiming to enhance information flow in the brain in order to alleviate boredom in clinical settings.

Discriminative machine learning for maximal representative subsampling.

Biased population samples pose a prevalent problem in the social sciences. Therefore, we present two novel methods that are based on positive-unlabeled learning to mitigate bias. Both methods leverage auxiliary information from a representative data set and train machine learning classifiers to determine the sample weights. The first method, named maximum representative subsampling (MRS), uses a classifier to iteratively remove instances, by assigning a sample weight of 0, from the biased data set until it aligns with the representative one. The second method is a variant of MRS - Soft-MRS - that iteratively adapts sample weights instead of removing samples completely. To assess the effectiveness of our approach, we induced artificial bias in a public census data set and examined the corrected estimates. We compare the performance of our methods against existing techniques, evaluating the ability of sample weights created with Soft-MRS or MRS to minimize differences and improve downstream classification tasks. Lastly, we demonstrate the applicability of the proposed methods in a real-world study of resilience research, exploring the influence of resilience on voting behavior. Through our work, we address the issue of bias in social science, amongst others, and provide a versatile methodology for bias reduction based on machine learning. Based on our experiments, we recommend to use MRS for downstream classification tasks and Soft-MRS for downstream tasks where the relative bias of the dependent variable is relevant.

Cognitive reappraisal in mHealth interventions to foster mental health in adults: a systematic review and meta-analysis.

Background: An increasing number of mHealth interventions aim to contribute to mental healthcare of which interventions that foster cognitive reappraisal may be particularly effective. Objectives: To evaluate the efficacy of mHealth interventions enhancing cognitive reappraisal to improve mental health in adult populations. Methods: The literature search (four databases) yielded 30 eligible randomized controlled trials (comprising 3,904 participants). We performed a multi-level meta-analysis to examine differences between intervention and comparator conditions at post-intervention assessment. Moderator analyses were conducted for potential moderator variables (e.g., type of comparators). Results: Most interventions were CBT-based with other training components in addition to cognitive reappraisal. We found preliminary evidence for a small to medium effect favouring mHealth interventions to enhance cognitive reappraisal over comparators, M(SMD) = 0.34, p = .002. When analysing single symptoms, there was evidence for a small to medium effect of mHealth interventions on anxiety and depressive symptoms, but not for psychological distress and well-being. All analyses showed substantial heterogeneity. Moderator analyses revealed evidence for more favourable effects in studies with passive comparators. There was an overall high risk of bias in most of the studies. Conclusions: We found preliminary evidence for a small to medium effect of mHealth interventions including a cognitive reappraisal component to improve mental health. However, most of the interventions were complex (i.e., reappraisal was provided alongside other components), which prevents us from examining reappraisal-specific effects beyond general mental health promotion in mHealth. Dismantling studies examining the effects of single intervention components are warranted to corroborate these promising results. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=142149, identifier [CRD42019142149].

Psychological Resilience Factors and Their Association With Weekly Stressor Reactivity During the COVID-19 Outbreak in Europe: Prospective Longitudinal Study.

BACKGROUND: Cross-sectional relationships between psychosocial resilience factors (RFs) and resilience, operationalized as the outcome of low mental health reactivity to stressor exposure (low "stressor reactivity" [SR]), were reported during the first wave of the COVID-19 pandemic in 2020. OBJECTIVE: Extending these findings, we here examined prospective relationships and weekly dynamics between the same RFs and SR in a longitudinal sample during the aftermath of the first wave in several European countries. METHODS: Over 5 weeks of app-based assessments, participants reported weekly stressor exposure, mental health problems, RFs, and demographic data in 1 of 6 different languages. As (partly) preregistered, hypotheses were tested cross-sectionally at baseline (N=558), and longitudinally (n=200), using mixed effects models and mediation analyses. RESULTS: RFs at baseline, including positive appraisal style (PAS), optimism (OPT), general self-efficacy (GSE), perceived good stress recovery (REC), and perceived social support (PSS), were negatively associated with SR scores, not only cross-sectionally (baseline SR scores; all P<.001) but also prospectively (average SR scores across subsequent weeks; positive appraisal (PA), P=.008; OPT, P<.001; GSE, P=.01; REC, P<.001; and PSS, P=.002). In both associations, PAS mediated the effects of PSS on SR (cross-sectionally: 95% CI -0.064 to -0.013; prospectively: 95% CI -0.074 to -0.0008). In the analyses of weekly RF-SR dynamics, the RFs PA of stressors generally and specifically related to the COVID-19 pandemic, and GSE were negatively associated with SR in a contemporaneous fashion (PA, P<.001; PAC,P=.03; and GSE, P<.001), but not in a lagged fashion (PA, P=.36; PAC, P=.52; and GSE, P=.06). CONCLUSIONS: We identified psychological RFs that prospectively predict resilience and cofluctuate with weekly SR within individuals. These prospective results endorse that the previously reported RF-SR associations do not exclusively reflect mood congruency or other temporal bias effects. We further confirm the important role of PA in resilience.

Effect of the addition of a mental health specialist for evaluation of undiagnosed patients in centres for rare diseases (ZSE-DUO): a prospective, controlled trial with a two-phase cohort design.

Background: People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome. Methods: Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N = 684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N = 695). The cohorts consisted mainly of adult participants with only a minority of children included (N = 67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677. Findings: The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N = 131 of 672) in the SC and 42% (N = 286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99-5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1-2), and significantly more patients could be referred to local regular care in the IC (27.5%; N = 181 of 659) compared to the SC (12.3%; N = 81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02-3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts. Interpretation: Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease. Funding: The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031.

Interrelations of resilience factors and their incremental impact for mental health: insights from network modeling using a prospective study across seven timepoints.

Resilience can be viewed as trajectory of stable good mental health or the quick recovery of mental health during or after stressor exposure. Resilience factors (RFs) are psychological resources that buffer the potentially negative effects of stress on mental health. A problem of resilience research is the large number of conceptually overlapping RFs complicating their understanding. The current study sheds light on the interrelations of RFs in the face of the COVID-19 pandemic as a use case for major disruptions. The non-preregistered prospective study assessed a sample of 1275 German-speaking people from February 2020 to March 2021 at seven timepoints. We measured coping, hardiness, control beliefs, optimism, self-efficacy, sense of coherence (SOC), sense of mastery, social support and dispositional resilience as RFs in February 2020, and mental health (i.e., psychopathological symptoms, COVID-19-related rumination, stress-related growth) at all timepoints. Analyses used partial correlation network models and latent growth mixture modeling (LGMM). Pre-pandemic RFs were strongly interrelated, with SOC being the most central node. The strongest associations emerged between coping using emotional support and social support, SOC and sense of mastery, and dispositional resilience and self-efficacy. SOC and active coping were negatively linked. When we examined RFs as predictors of mental health trajectories, SOC was the strongest predictor of psychopathological symptoms and rumination, while trajectories of stress-related growth were predicted by optimism. Subsequent network analyses, including individual intercepts and slopes from LGMM, showed that RFs had small to moderate associations with intercepts but were unrelated to slopes. Our findings provide evidence for SOC playing an important role in mental distress and suggest further examining SOC's incremental validity. However, our results also propose that RFs might be more important for stable levels of mental health than for adaptation processes over time. The differential associations for negative and positive outcomes support the use of multidimensional outcomes in resilience research.