Multimodal Associations of FKBP5 Methylation with Emotion-Regulatory Brain Circuits.

BACKGROUND: Understanding the biological processes underlying individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. Yet it remains unclear how FKBP5 DNA methylation (DNAm) in peripheral blood relates to individual differences in measures of neural structure and function, and their relevance to daily-life stress responsivity. METHODS: Here, we characterize multimodal correlates of FKBP5 DNAm by combining epigenetic data with neuroimaging and Ambulatory Assessment in a sample of 395 healthy individuals. RESULTS: First, we show that FKBP5 demethylation as a psychiatric risk factor relates to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex (vmPFC), a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional MRI scans during a well-established emotion processing task we find that FKBP5 DNAm in peripheral blood is associated with functional difference of prefrontal-limbic circuits modulating affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrate how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Stress-Induced Sensitization of Insula Activation Predicts Alcohol Craving and Alcohol Use in Alcohol Use Disorder.

BACKGROUND: Stress and alcohol cues trigger alcohol consumption and relapse in alcohol use disorder. However, the neurobiological processes underlying their interaction are not well understood. Thus, we conducted a randomized, controlled neuroimaging study to investigate the effects of psychosocial stress on neural cue reactivity and addictive behaviors. METHODS: Neural alcohol cue reactivity was assessed in 91 individuals with alcohol use disorder using a validated functional magnetic resonance imaging (fMRI) task. Activation patterns were measured twice, at baseline and during a second fMRI session, prior to which participants were assigned to psychosocial stress (experimental condition) or a matched control condition or physical exercise (control conditions). Together with fMRI data, alcohol craving and cortisol levels were assessed, and alcohol use data were collected during a 12-month follow-up. Analyses tested the effects of psychosocial stress on neural cue reactivity and associations with cortisol levels, craving, and alcohol use. RESULTS: Compared with both control conditions, psychosocial stress elicited higher alcohol cue-induced activation in the left anterior insula (familywise error-corrected p < .05) and a stress- and cue-specific dynamic increase in insula activation over time (F22,968 = 2.143, p = .007), which was predicted by higher cortisol levels during the experimental intervention (r = 0.310, false discovery rate-corrected p = .016). Cue-induced insula activation was positively correlated with alcohol craving during fMRI (r = 0.262, false discovery rate-corrected p = .032) and alcohol use during follow-up (r = 0.218, false discovery rate-corrected p = .046). CONCLUSIONS: Results indicate a stress-induced sensitization of cue-induced activation in the left insula as a neurobiological correlate of the effects of psychosocial stress on alcohol craving and alcohol use in alcohol use disorder, which likely reflects changes in salience attribution and goal-directed behavior.

The stress-buffering role of friendships in young people with childhood threat experiences: a preliminary report.

Background: High-quality friendships have a positive impact on the mental health of young people with childhood adversity (CA). Social stress buffering, the phenomenon of a social partner attenuating acute stress responses, is a potential yet unexplored mechanism that may underlie this relationship.Objective: This study examined whether perceived friendship quality was related to better mental health and lower neural stress response in young people with CA.Method: A total of N = 102 young people (aged 16-26) with low to moderate CA were included in the study. We first investigated associations between friendship quality, mental health, and CA. In a representative subset (n = 62), we assessed neural stress responses using the Montreal Imaging Stress Task. In our sample, CA was best described along two dimensions resembling threat or deprivation like experiences. Hence, we investigated both cumulative and dimensional effects of CA.Results: We found no support for social thinning after CA, meaning that the severity of CA (cumulative or dimensional) did not differentially impact friendship quality. High-quality friendships, on the other hand, were strongly associated with better mental health. Furthermore, acute stress increased state anxiety and enhanced neural activity in five frontolimbic brain regions, including the left hippocampus. We found weak support that threat experiences interacted with friendship quality to predict left hippocampal reactivity to stress. However, this effect did not survive multiple comparison correction.Conclusion: The absence of social thinning in our sample may suggest that the risk of developing impoverished social networks is low for rather well-functioning young people with low to moderate CA. Regardless, our findings align with prior research, consistently showing a strong association between high-quality friendships and better mental health in young people with CA. Future research is needed to examine whether friendships aid neural stress responses in young people with childhood threat experiences.

Young people with childhood adversity underwent acute stress induction, eliciting frontolimbic reactivity.High-quality friendships were strongly associated with better mental health.Weak support for friendship stress buffering did not survive multiple comparison correction.

Assessing affect in adolescents with e-diaries: multilevel confirmatory factor analyses of different factor models.

In the last two decades, e-diary studies have gained increasing interest, with a dominant focus on mood and affect. Although requested in current guidelines, psychometric properties are rarely reported, and methodological investigations of factor structure, model fit, and the reliability of mood and affect assessment are limited. We used a seven-day e-diary dataset of 189 adolescent participants (12-17 years). The e-diary affect assessments revealed a considerable portion of within-person variance. The six-factor model showed the best model fit compared to the less complex models. Factor loadings also improved with the complexity of the models. Accordingly, we recommend that future e-diary studies of adolescents use the six-factor model of affect as well as reporting psychometric properties and model fit. For future e-diary scale development, we recommend using a minimum of three items per scale to enable the use of confirmatory multilevel factor analyses.

Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure.

BACKGROUND: Childhood trauma exposures (CTEs) are frequent, well-established risk factor for the development of psychopathology. However, knowledge of the effects of CTEs in healthy individuals in a real life context, which is crucial for early detection and prevention of mental disorders, is incomplete. Here, we use ecological momentary assessment (EMA) to investigate CTE load-dependent changes in daily-life affective well-being and psychosocial risk profile in n = 351 healthy, clinically asymptomatic, adults from the community with mild to moderate CTE. FINDINGS: EMA revealed significant CTE dose-dependent decreases in real-life affective valence (p = 0.007), energetic arousal (p = 0.032) and calmness (p = 0.044). Psychosocial questionnaires revealed a broad CTE-related psychosocial risk profile with dose-dependent increases in mental health risk-associated features (e.g., trait anxiety, maladaptive coping, loneliness, daily hassles; p values < 0.003) and a corresponding decrease in factors protective for mental health (e.g., life satisfaction, adaptive coping, optimism, social support; p values < 0.021). These results were not influenced by age, sex, socioeconomic status or education. CONCLUSIONS: Healthy community-based adults with mild to moderate CTE exhibit dose-dependent changes in well-being manifesting in decreases in affective valence, calmness and energy in real life settings, as well as a range of established psychosocial risk features associated with mental health risk. This indicates an approach to early detection, early intervention, and prevention of CTE-associated psychiatric disorders in this at-risk population, using ecological momentary interventions (EMI) in real life, which enhance established protective factors for mental health, such as green space exposure, or social support.

Initial response to the COVID-19 pandemic on real-life well-being, social contact and roaming behavior in patients with schizophrenia, major depression and healthy controls: A longitudinal ecological momentary assessment study.

The COVID-19 pandemic strongly impacted people's daily lives. However, it remains unknown how the pandemic situation affects daily-life experiences of individuals with preexisting severe mental illnesses (SMI). In this real-life longitudinal study, the acute onset of the COVID-19 pandemic in Germany did not cause the already low everyday well-being of patients with schizophrenia (SZ) or major depression (MDD) to decrease further. On the contrary, healthy participants' well-being, anxiety, social isolation, and mobility worsened, especially in healthy individuals at risk for mental disorder, but remained above the levels seen in patients. Despite being stressful for healthy individuals at risk for mental disorder, the COVID-19 pandemic had little additional influence on daily-life well-being in psychiatric patients with SMI. This highlights the need for preventive action and targeted support of this vulnerable population.

Early Social Adversity, Altered Brain Functional Connectivity, and Mental Health.

Early adverse environmental exposures during brain development are widespread risk factors for the onset of severe mental disorders and strong and consistent predictors of stress-related mental and physical illness and reduced life expectancy. Current evidence suggests that early negative experiences alter plasticity processes during developmentally sensitive time windows and affect the regular functional interaction of cortical and subcortical neural networks. This, in turn, may promote a maladapted development with negative consequences on the mental and physical health of exposed individuals. In this review, we discuss the role of functional magnetic resonance imaging-based functional connectivity phenotypes as potential biomarker candidates for the consequences of early environmental exposures-including but not limited to-childhood maltreatment. We take an expanded concept of developmentally relevant adverse experiences from infancy over childhood to adolescence as our starting point and focus our review of functional connectivity studies on a selected subset of functional magnetic resonance imaging-based phenotypes, including connectivity in the limbic and within the frontoparietal as well as default mode networks, for which we believe there is sufficient converging evidence for a more detailed discussion in a developmental context. Furthermore, we address specific methodological challenges and current knowledge gaps that complicate the interpretation of early stress effects on functional connectivity and deserve particular attention in future studies. Finally, we highlight the forthcoming prospects and challenges of this research area with regard to establishing functional connectivity measures as validated biomarkers for brain developmental processes and individual risk stratification and as target phenotypes for mechanism-based interventions.

Lack of amygdala habituation to negative emotional faces in alcohol use disorder and the relation to adverse childhood experiences.

Aberrant limbic circuit reactivity to negative stimuli might be related to alterations in emotion processing and regulation in alcohol use disorder (AUD). The current study tested for the first time in AUD the hypothesis of aberrant amygdala habituation to repeated aversive stimuli-a robust and reliable neuroimaging marker for emotion processing. We explored the link between deficits in habituation to adverse childhood experience (ACE), a common risk factor for impaired emotion regulation and AUD. AUD individuals (N = 36) and healthy controls (HC; N = 26) participated in an observational case-control functional magnetic resonance imaging (fMRI) study. An established habituation index was used to investigate processing of aversive emotional faces of the amygdala. AUD individuals showed an overall deficit in amygdala habituation (right: t = 4.26, pFWE = 0.004; left: t = 4.79, pFWE ≤ 0.001). Amygdala habituation was significantly related to increased exposure to ACE in HC (t = 3.88, pFWE = 0.012), whereas this association was not observed in AUD individuals (T = 1.80, pFWE = 0.662). Further, a significant association between higher alcohol consumption and reduced amygdala habituation (right: R2  = -0.356, F = 8.736, p = 0.004; left: R2  = -0.309, F = 6.332, p = 0.015) was observed. We found novel evidence for neural alterations in emotion processing in AUD individuals, indexed by deficient amygdala habituation to negative emotional content. We replicated a prior report on a link between ACE and amygdala habituation, a well-established environmental risk factor for mental disorders and emotion dysregulation, in our control sample. Additionally, deficient amygdala habituation related to the amount of alcohol consumption in the overall sample might indicate a short-term substance effect.

Reduced Real-life Affective Well-being and Amygdala Habituation in Unmedicated Community Individuals at Risk for Depression and Anxiety.

BACKGROUND: Early identification of risk for depression and anxiety disorders is important for prevention, but real-life affective well-being and its biological underpinnings in the population remain understudied. Here, we combined methods from epidemiology, psychology, ecological momentary assessment, and functional magnetic resonance imaging to study real-life and neural affective functions in individuals with subclinical anxiety and depression from a population-based cohort of young adults. METHODS: We examined psychological measures, real-life affective valence, functional magnetic resonance imaging amygdala habituation to negative affective stimuli, and the relevance of neural readouts for daily-life affective function in 132 non-help-seeking community individuals. We compared psychological and ecological momentary assessment measures of 61 unmedicated individuals at clinical risk for depression and anxiety (operationalized as subthreshold depression and anxiety symptoms or a former mood or anxiety disorder) with those of 48 nonrisk individuals and 23 persons with a mood or anxiety disorder. We studied risk-associated functional magnetic resonance imaging signals in subsamples with balanced sociodemographic and image quality parameters (26 nonrisk, 26 at-risk persons). RESULTS: Compared with nonrisk persons, at-risk individuals showed significantly decreased real-life affective valence (p = .038), reduced amygdala habituation (familywise error-corrected p = .024, region of interest corrected), and an intermediate psychological risk profile. Amygdala habituation predicted real-life affective valence in control subjects but not in participants at risk (familywise error-corrected p = .005, region of interest corrected). CONCLUSIONS: Our data suggest real-life and neural markers for affective alterations in unmedicated community individuals at risk for depression and anxiety and highlight the significance of amygdala habituation measures for the momentary affective experience in real-world environments.

Clinical Outcomes of Severe Forms of Early Social Stress.

Early social stress, particularly severe but nevertheless frequent forms such as abuse and neglect, are among the major risk factors for the development of mental disorders. However, we only have very limited knowledge of the psychobiological disease mechanisms underlying the influence of early life stress and stress-related disorders during this vulnerable phase of life. Early stress can have long-lasting adverse effects on the brain and other somatic systems, e.g. through influences on brain development. In adulthood, the prior experience of abuse or neglect can result in complex clinical profiles. Besides conditions such as mood and anxiety disorders as well as posttraumatic stress disorder, substance use disorders (SUD) are among the most prevalent sequelae of early social stress. Current social stress further influences the development and maintenance of these disorders, e.g., by increasing the risk of relapses. In this chapter, we will first give an overview of currently used methods to assess the phenomenology and pathophysiology of stress-related disorders and then focus on the phenomenological and neurobiological background of the interaction between early social stress and SUD. We will give an overview of important insights from neuroimaging studies and will also highlight recent findings from studies using digital tools such as ecological momentary assessment or virtual reality to capture the influence of early social stress as well as current social stress in everyday life of persons with SUD.

Brain structural correlates of upward social mobility in ethnic minority individuals.

PURPOSE: Perigenual anterior cingulate cortex (pACC) is a neural convergence site for social stress-related risk factors for mental health, including ethnic minority status. Current social status, a strong predictor of mental and somatic health, has been related to gray matter volume in this region, but the effects of social mobility over the lifespan are unknown and may differ in minorities. Recent studies suggest a diminished health return of upward social mobility for ethnic minority individuals, potentially due to sustained stress-associated experiences and subsequent activation of the neural stress response system. METHODS: To address this issue, we studied an ethnic minority sample with strong upward social mobility. In a cross-sectional design, we examined 64 young adult native German and 76 ethnic minority individuals with comparable sociodemographic attributes using whole-brain structural magnetic resonance imaging. RESULTS: Results showed a significant group-dependent interaction between perceived upward social mobility and pACC gray matter volume, with a significant negative association in the ethnic minority individuals. Post-hoc analysis showed a significant mediation of the relationship between perceived upward social mobility and pACC volume by perceived chronic stress, a variable that was significantly correlated with perceived discrimination in our ethnic minority group. CONCLUSION: Our findings extend prior work by pointing to a biological signature of the "allostatic costs" of socioeconomic attainment in socially disadvantaged upwardly mobile individuals in a key neural node implicated in the regulation of stress and negative affect.

Ambulatory assessment for precision psychiatry: Foundations, current developments and future avenues.

Precision psychiatry stands to benefit from the latest digital technologies for assessment and analyses to tailor treatment towards individuals. Insights into dynamic psychological processes as they unfold in humans' everyday life can critically add value in understanding symptomatology and environmental stressors to provide individualized treatment where and when needed. Towards this goal, ambulatory assessment encompasses methodological approaches to investigate behavioral, physiological, and biological processes in humans' everyday life. It combines repeated assessments of symptomatology over time, e.g., via Ecological Momentary Assessment (e.g., smartphone-diaries), with monitoring of physical behavior, environmental characteristics (such as geolocations, social interactions) and physiological function via sensors, e.g., mobile accelerometers, global-positioning-systems, and electrocardiography. In this review, we expand on promises of ambulatory assessment in the investigation of mental states (e.g., real-life, dynamical and contextual perspective), on chances for precision psychiatry such as the prediction of courses of psychiatric disorders, detection of tipping points and critical windows of relapse, and treatment effects as exemplified by ongoing projects, and on future avenues of how ambulatory interventions can benefit personalized care for psychiatric patients (e.g., through real-time feedback in everyday life). Ambulatory assessment is a key contributor to precision psychiatry, opening up promising avenues in research, diagnoses, prevention and treatment.

Rapid Neural Representations of Personally Relevant Faces.

The faces of those most personally relevant to us are our primary source of social information, making their timely perception a priority. Recent research indicates that gender, age and identity of faces can be decoded from EEG/MEG data within 100 ms. Yet, the time course and neural circuitry involved in representing the personal relevance of faces remain unknown. We applied simultaneous EEG-fMRI to examine neural responses to emotional faces of female participants' romantic partners, friends, and a stranger. Combining EEG and fMRI in cross-modal representational similarity analyses, we provide evidence that representations of personal relevance start prior to structural encoding at 100 ms, with correlated representations in visual cortex, but also in prefrontal and midline regions involved in value representation, and monitoring and recall of self-relevant information. Our results add to an emerging body of research that suggests that models of face perception need to be updated to account for rapid detection of personal relevance in cortical circuitry beyond the core face processing network.

Deficient Amygdala Habituation to Threatening Stimuli in Borderline Personality Disorder Relates to Adverse Childhood Experiences.

BACKGROUND: Heightened amygdala response to threatening cues has been repeatedly observed in borderline personality disorder (BPD). A previous report linked hyperactivation to deficient amygdala habituation to repeated stimuli, but the biological underpinnings are incompletely understood. METHODS: We examined a sample of 120 patients with BPD and 115 healthy control subjects with a well-established functional magnetic resonance imaging emotional face processing task to replicate the previously reported amygdala habituation deficit in BPD and probed this neural phenotype for associations with symptom severity and early social risk exposure. RESULTS: Our results confirm a significant reduction in amygdala habituation to repeated negative stimuli in BPD (pFWE = .015, peak-level familywise error [FWE] corrected for region of interest). Post hoc comparison and regression analysis did not suggest a role for BPD clinical state (pFWE > .56) or symptom severity (pFWE > .45) for this phenotype. Furthermore, deficient amygdala habituation was significantly related to increased exposure to adverse childhood experiences (pFWE = .013, region of interest corrected). CONCLUSIONS: Our data replicate a prior report on deficient amygdala habituation in BPD and link this neural phenotype to early adversity, a well-established social environmental risk factor for emotion dysregulation and psychiatric illness.