Loneliness during the Covid-19 pandemic in Germany: Impact of social factors and polygenic risk scores on interpersonal differences in loneliness and mental health.

OBJECTIVES: The outbreak of Covid-19 negatively affected mental health and increased loneliness. The subjective feeling of loneliness is influenced by genetic and social factors and has a negative impact on mental health. METHODS: From March 2020 to June 2021 loneliness was investigated in N = 517 individuals using monthly acquired questionnaire data and Latent Growth Curve Analysis. Associations of social factors and polygenic risk scores (PRSs, n = 361) with class membership were investigated. RESULTS: Three classes ("average", 40%; "not lonely", 38%; "elevated loneliness", 22%) were identified, that differ significantly regarding loneliness, mental dysfunction, and response to the lockdown phases. Individuals with a high PRS for neuroticism are more likely to belong to the "elevated loneliness" class, living with another person is a protective factor. CONCLUSION: As the "elevated loneliness" class was at the highest risk of mental dysfunction, our findings underscore the importance of identifying those individuals to implement counteractive measures.

The impact of physical fitness on resilience to modern life stress and the mediating role of general self-efficacy.

Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness-resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.

Impact of COVID-19 lockdown on mental health in Germany: longitudinal observation of different mental health trajectories and protective factors.

The COVID-19 pandemic and resulting measures can be regarded as a global stressor. Cross-sectional studies showed rather negative impacts on people's mental health, while longitudinal studies considering pre-lockdown data are still scarce. The present study investigated the impact of COVID-19 related lockdown measures in a longitudinal German sample, assessed since 2017. During lockdown, 523 participants completed additional weekly online questionnaires on e.g., mental health, COVID-19-related and general stressor exposure. Predictors for and distinct trajectories of mental health outcomes were determined, using multilevel models and latent growth mixture models, respectively. Positive pandemic appraisal, social support, and adaptive cognitive emotion regulation were positively, whereas perceived stress, daily hassles, and feeling lonely negatively related to mental health outcomes in the entire sample. Three subgroups ("recovered," 9.0%; "resilient," 82.6%; "delayed dysfunction," 8.4%) with different mental health responses to initial lockdown measures were identified. Subgroups differed in perceived stress and COVID-19-specific positive appraisal. Although most participants remained mentally healthy, as observed in the resilient group, we also observed inter-individual differences. Participants' psychological state deteriorated over time in the delayed dysfunction group, putting them at risk for mental disorder development. Consequently, health services should especially identify and allocate resources to vulnerable individuals.

Processing of an ambiguous time phrase in posttraumatic stress disorder: Eye movements suggest a passive, oncoming perception of the future.

Metaphorically, the future can be perceived as approaching us (time-moving metaphor) or as being approached by us (ego-moving metaphor). Also, in line with findings that our eyes look more up when thinking about the future than the past, the future's location can be conceptualized in upwards terms. Eye movements were recorded in 19 participants with PTSD and 20 healthy controls. Participants with PTSD showed downward and healthy controls upward eye movements while processing an ego/time-moving ambiguous phrase, suggesting a passive (time-moving) outlook toward the future. If replicated, our findings may have implications for the conceptualization and treatment of PTSD.

Longitudinal determination of resilience in humans to identify mechanisms of resilience to modern-life stressors: the longitudinal resilience assessment (LORA) study.

Resilience is the maintenance and/or quick recovery of mental health during and after periods of adversity. It is conceptualized to result from a dynamic process of successful adaptation to stressors. Up to now, a large number of resilience factors have been proposed, but the mechanisms underlying resilience are not yet understood. To shed light on the complex and time-varying processes of resilience that lead to a positive long-term outcome in the face of adversity, the Longitudinal Resilience Assessment (LORA) study has been established. In this study, 1191 healthy participants are followed up at 3- and 18-month intervals over a course of 4.5 years at two study centers in Germany. Baseline and 18-month visits entail multimodal phenotyping, including the assessment of mental health status, sociodemographic and lifestyle variables, resilience factors, life history, neuropsychological assessments (of proposed resilience mechanisms), and biomaterials (blood for genetic and epigenetic, stool for microbiome, and hair for cortisol analysis). At 3-monthly online assessments, subjects are monitored for subsequent exposure to stressors as well as mental health measures, which allows for a quantitative assessment of stressor-dependent changes in mental health as the main outcome. Descriptive analyses of mental health, number of stressors including major life events, daily hassles, perceived stress, and the ability to recover from stress are here presented for the baseline sample. The LORA study is unique in its design and will pave the way for a better understanding of resilience mechanisms in humans and for further development of interventions to successfully prevent stress-related disorder.

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala, prefrontal and anterior cingulate cortex reactivity and habituation in a large, healthy fMRI cohort.

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.

5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus.

The s/s-genotype of the 5-HTTLPR polymorphism and the personality trait of neuroticism have both been associated with experiences of negative affect, anxiety and mood disorders, as well as an emotional processing bias towards negative facial emotions. On a neural level, this bias can be characterized by altered amygdala and fusiform gyrus (FFG) activity during perception of negative facial expressions. Using resting-state functional magnetic resonance imaging in a multi-center-sample of 178 healthy subjects of European descent, this study investigated the association of 5-HTTLPR (short s- and long l-allele) including the genotype of the single nucleotide polymorphism (SNP) rs25531 (A/G) within this region polymorphism, and trait neuroticism on resting-state functional connectivity (rs-FC) between amygdala and the FFG. Moreover, we aimed to identify additional brain regions with associations of 5-HTTLPR/rs25531 (combined according to its expression; low: s/s; high: l(A)/l(A); intermediate: s/l(A), s/l(G), l(G)/l(G), l(A)/l(G)) and trait neuroticism to amygdala rs-FC. Separate analyses for 5-HTTLPR/rs25531 and neuroticism (controlling for age, gender, handedness, and research site) revealed that s/s-homozygotes and individuals high in neuroticism obtained altered amygdala rs-FC in the right occipital face area, which is considered to be a "core component" of the face processing system. Importantly, effects of neuroticism were replicated across three independent research sites. Additionally, associations of 5-HTTLPR/rs25531 genotype and amygdala rs-FC were observed in the anterior and posterior cingulate cortex, whereas neuroticism was not related to rs-FC in these areas. The presented data implies that 5-HTTLPR/rs25531 variants and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus and suggests that variants of 5-HTTLPR/rs25531 genotype and different levels of neuroticism may partly account for altered processing of negative facial emotions.

Auditory cortex activation is modulated by emotion: a functional near-infrared spectroscopy (fNIRS) study.

Visual emotional stimuli evoke enhanced activation in early visual cortex areas which may help organisms to quickly detect biologically salient cues and initiate appropriate approach or avoidance behavior. Functional neuroimaging evidence for the modulation of other sensory modalities by emotion is scarce. Therefore, the aim of the present study was to test whether sensory facilitation by emotional cues can also be found in the auditory domain. We recorded auditory brain activation with functional near-infrared-spectroscopy (fNIRS), a non-invasive and silent neuroimaging technique, while participants were listening to standardized pleasant, unpleasant, and neutral sounds selected from the International Affective Digitized Sound System (IADS). Pleasant and unpleasant sounds led to increased auditory cortex activation as compared to neutral sounds. This is the first study to suggest that the enhanced activation of sensory areas in response to complex emotional stimuli is apparently not restricted to the visual domain but is also evident in the auditory domain.

ADHD related behaviors are associated with brain activation in the reward system.

Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) suggest dysfunctional reward processing, with hypo-responsiveness during reward anticipation in the reward system including the nucleus accumbens (NAcc). In this study, we investigated the association between ADHD related behaviors and the reward system using functional magnetic resonance imaging in a non-clinical sample. Participants were 31 healthy, female undergraduate students with varying levels of self-reported ADHD related behaviors measured by the adult ADHD self-report scale. The anticipation of different types of reward was investigated: monetary reward, punishment avoidance, and verbal feedback. All three reward anticipation conditions were found to be associated with increased brain activation in the reward system, with the highest activation in the monetary reward anticipation condition, followed by the punishment avoidance anticipation condition, and the lowest activation in the verbal feedback anticipation condition. Most interestingly, in all three conditions, NAcc activation was negatively correlated with ADHD related behaviors. In conclusion, our results from a non-clinical sample are in accordance with reported deficits in the reward system in ADHD patients: the higher the number and severity of ADHD related behaviors, the lower the neural responses in the dopaminergic driven reward anticipation task. Thus, our data support current aetiological models of ADHD which assume that deficits in the reward system might be responsible for many of the ADHD related behaviors.

Influence of muscle activity on brain oxygenation during verbal fluency assessed with functional near-infrared spectroscopy.

A large part of the literature of functional near-infrared spectroscopy (fNIRS) deals with overt verbal fluency. It has been claimed that fNIRS has a low susceptibility to movement related artefacts as, for example, associated with overt speech. However, so far, no study has investigated this assumption in an experimental design. Therefore, we examined a group of 16 healthy subjects during performance of two verbal fluency tasks (experiment 1: phonological fluency; experiment 2: semantical fluency, paced answers, pronouncing vs. writing). We measured changes of oxygenated (O(2)Hb) and deoxygenated haemoglobin (HHb) over fronto-temporal (brain) areas via fNIRS, while temporalis muscle activity was simultaneously assessed by means of electromyography (EMG). Statistical analyses indicated comparable word production, higher increases of O(2)Hb and higher decreases of HHb over fronto-temporal areas during word fluency in contrast to the control task weekday reciting. This fNIRS pattern indicates fluency related activation and was found for pronouncing and for writing in both experiments. Regarding the EMG data, fluency related activity was only found for pronouncing, not for writing. Thus, muscle activity cannot account for fluency related fNIRS activity during writing. Additionally, correlation analyses showed no systematic associations of fNIRS and EMG signals. In conclusion, we found arguments that fNIRS actually allows for the measurement of brain activity over fronto-temporal areas during verbal fluency. Nonetheless, further studies should evaluate more direct associations between fNIRS and EMG signals by specific experimental manipulations and data analysing approaches that allow dealing fNIRS and EMG raw data simultaneously.

Cortical correlates of auditory sensory gating: a simultaneous near-infrared spectroscopy event-related potential study.

Sensory gating refers to the ability of cerebral networks to inhibit responding to irrelevant environmental stimuli, a mechanism that protects the brain from information overflow. The reduction of the P50 amplitude (an early component of the event-related potential/ERP in electrophysiological recordings) after repeated occurrence of a particular acoustic stimulus is one means to quantitatively assess gating mechanisms. Even though P50 suppression has been extensively investigated, neuroimaging studies on the cortical correlates of auditory sensory gating are so far very sparse. Near-infrared spectroscopy (NIRS) is an optical imaging technique perfectly suitable for the investigation of auditory paradigms, since it involves virtually no noise. We conducted a simultaneous NIRS-ERP measurement to assess cortical correlates of auditory sensory gating in humans. The multi-channel NIRS recording indicated a specific activation of prefrontal and temporo-parietal cortices during conditions of increased sensory gating (dual-click trials). Combining the hemodynamic data with an electrophysiological index of the "gating quality" (gating quotient Q) revealed a positive correlation between the amount of sensory gating and the strength of the hemodynamic response during dual-clicks in the left prefrontal and temporal cortices. The results are in line with previous findings and confirm a possible inhibitory influence of the prefrontal cortex on primary auditory cortices.

Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals.

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n=124) and healthy controls (n=84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go- and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

Non-invasive measurement of vagus activity in the brainstem - a methodological progress towards earlier diagnosis of dementias?

In Alzheimer's disease (AD), mild functional disturbances should precede gross structural damage and even more clinical symptoms, possibly by decades. Moreover, alterations in the brainstem are supposed to occur earlier as cortical affections. Based on these considerations, we developed a new method aiming at the measurement of vagal brainstem functioning by means of evoked potentials after electrical stimulation of the cutaneous representation of the vagus nerve in the external auditory channel. In the current study, a first sample of patients with Alzheimer's disease (n = 7) and mild cognitive impairment (n = 3) were investigated (6m, 4f, range from 57 to 78 y, mean age 68.6 years). Vagus somatosensory evoked potentials (VSEP) were characterized by significantly longer latencies as compared to healthy age- and gender-matched controls (p < 0.05). Future large scale studies - also including preclinical stages of AD - have to assess the value of this non-invasive, fast and cheap method in the early diagnosis of neurodegenerative disorders.

Model-based analysis of rapid event-related functional near-infrared spectroscopy (NIRS) data: a parametric validation study.

To validate the usefulness of a model-based analysis approach according to the general linear model (GLM) for functional near-infrared spectroscopy (fNIRS) data, a rapid event-related paradigm with an unpredictable stimulus sequence was applied to 15 healthy subjects. A parametric design was chosen wherein four differently graded contrasts of a flickering checkerboard were presented, allowing directed hypotheses about the rank order of the evoked hemodynamic response amplitudes. The results indicate the validity of amplitude estimation by three main findings (a) the GLM approach for fNIRS data is capable to identify human brain activation in the visual cortex with inter-stimulus intervals of 4-9 s (6.5 s average) whereas in non-visual areas no systematic activation was detectable; (b) the different contrast level intensities lead to the hypothesized rank order of the GLM amplitude parameters: visual cortex activation evoked by highest contrast>moderate contrast>lowest contrast>no stimulation; (c) analysis of null-events (no stimulation) did not produce any significant activation in the visual cortex or in other brain areas. We conclude that a model-based GLM approach delivers valid fNIRS amplitude estimations and enables the analysis of rapid event-related fNIRS data series, which is highly relevant in particular for cognitive fNIRS studies.

Event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations: reproducibility of activation?

The purpose of the present study was to assess the retest reliability of cortical activation detected by event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations. Isolated functional activation was evoked in the motor cortex by a periodically performed finger-tapping task. During 44-channel fNIRS recording, 12 subjects performed 30 trials of right and left index finger tapping in two sessions. The retest interval was set to 3 weeks. Simple correlations of the contrast t-values supplemented by scatterplots, channel-wise intraclass correlation coefficients (ICC), as well as reproducibility indices for the size and the location of the detected activation were calculated. The results at the group level showed sufficient single measure ICCs (up to 0.80) and excellent reproducibility of the size and the location (up to 89% were reproducible). Comparisons of the intersession group amplitudes demonstrate that the fNIRS signals were stable across time in a retest study design: the number of significant differences was less than randomly occurring false-positive activated channels if an alpha level of 5% is chosen. Effect size analyses indicated that the intersession amplitude differences are small (mean < 0.25). For deoxyhemoglobin and oxyhemoglobin distinct statistical power profiles were revealed regarding the activation vs. baseline contrast as well as the intersession amplitude differences, indicating a higher sensitivity of deoxyhemoglobin for local hemodynamic changes. The results suggest that sensorimotor activation assessed by event-related fNIRS based on craniocerebral correlations is sufficiently reproducible at the group level.

Event-related visual versus blocked motor task: detection of specific cortical activation patterns with functional near-infrared spectroscopy.

The purpose of this study was to investigate the regional specificity of multi-channel functional near-infrared spectroscopy (fNIRS) in the detection of cortical activation in humans. Therefore, brain activation evoked by a visual as well as a motor task was examined using 52-channel fNIRS. Analyses demonstrated an isolated activation in the occipital area during visual stimulation, whereas other regions exhibited little or no activation. Analyses of the motor task data clearly identified a differential activation pattern. The observation of an extensive cortical area by multi-channel measurement during two different tasks made it possible to examine the extent to which fNIRS measurements detect regional specific activations. We conclude that fNIRS measurements can detect regionally isolated cortical activation.

Event-related functional near-infrared spectroscopy (fNIRS): are the measurements reliable?

The purpose of the present study was to investigate the retest reliability of event-related functional near-infrared spectroscopy (fNIRS). Therefore, isolated functional activation was evoked in the occipital cortex by a periodic checkerboard stimulation. During a 52-channel fNIRS recording, 12 subjects underwent 60 trials of visual stimulation in two sessions. The retest interval was set to 3 weeks. Linear correlations of the contrast t values supplemented by scatter plots, channel-wise intraclass correlation coefficients (ICC) as well as reproducibility indices for the quantity of activated channels (RQUANTITY) and the location (ROVERLAP) of the detected activation were calculated. The results at the group level showed good reliability in terms of the single measure ICCs (up to 0.84) and excellent reproducibility quantified by RQUANTITY and ROVERLAP (up to 96% of the quantity and the location were reproducible), whereas the results at the single subjects' level were mediocre. Furthermore, the reliability assessed by single measurement ICCs improved if regarded at a cluster level.