Quantifying brain-functional dynamics using deep dynamical systems: Technical considerations.

Both mental health and mental illness unfold in complex and unpredictable ways. Novel artificial intelligence approaches from the area of dynamical systems reconstruction can characterize such dynamics and help understand the underlying brain mechanisms, which can also be used as potential biomarkers. However, applying deep learning to model dynamical systems at the individual level must overcome numerous computational challenges to be reproducible and clinically useful. In this study, we performed an extensive analysis of these challenges using generative modeling of brain dynamics from fMRI data as an example and demonstrated their impact on classifying patients with schizophrenia and major depression. This study highlights the tendency of deep learning models to identify functionally unique solutions during parameter optimization, which severely impacts the reproducibility of downstream predictions. We hope this study guides the future development of individual-level generative models and similar machine learning approaches aimed at identifying reproducible biomarkers of mental illness.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Parkinsonism, Psychomotor Slowing, Negative and Depressive Symptoms in Schizophrenia Spectrum and Mood Disorders: Exploring Their Intricate Nexus Using a Network Analytic Approach.

BACKGROUND AND HYPOTHESIS: Parkinsonism, psychomotor slowing, negative and depressive symptoms show evident phenomenological similarities across different mental disorders. However, the extent to which they interact with each other is currently unclear. Here, we hypothesized that parkinsonism is an independent motor abnormality showing limited associations with psychomotor slowing, negative and depressive symptoms in schizophrenia spectrum (SSD), and mood disorders (MOD). STUDY DESIGN: We applied network analysis and community detection methods to examine the interplay and centrality (expected influence [EI] and strength) between parkinsonism, psychomotor slowing, negative and depressive symptoms in 245 SSD and 99 MOD patients. Parkinsonism was assessed with the Simpson-Angus Scale (SAS). We used the Positive and Negative Syndrome Scale (PANSS) to examine psychomotor slowing (item #G7), negative symptoms (PANSS-N), and depressive symptoms (item #G6). STUDY RESULTS: In SSD and MOD, PANSS item #G7 and PANSS-N showed the largest EI and strength as measures of centrality. Parkinsonism had small or no influence on psychomotor slowing, negative and depressive symptoms in SSD and MOD. In SSD and MOD, exploratory graph analysis identified one community, but parkinsonism showed a small influence on its occurrence. Network Comparison Test yielded no significant differences between the SSD and MOD networks (global strength p value: .396 and omnibus tests p value: .574). CONCLUSIONS: The relationships between the individual domains followed a similar pattern in both SSD and MOD highlighting their transdiagnostic relevance. Despite evident phenomenological similarities, our results suggested that parkinsonism is more independent of negative and depressive symptoms than psychomotor slowing in both SSD and MOD.

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

BACKGROUND: Understanding the biological processes that underlie 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. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. METHODS: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. RESULTS: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, 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 magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Measuring interpersonal trauma: Development and validation of the German version of the victimization experience schedule (VES).

OBJECTIVE: Interpersonal victimization experiences (VEs) significantly affect mental and physical health, particularly in disorders associated with life-time adversities, like fibromyalgia syndrome (FMS) and major depressive disorder (MDD). However, assessing VEs comprehensively remains challenging due to limited tools that encompass sub-traumatic events, such as bullying or discrimination, and contextual dimensions. We aimed to address this gap by validating the Victimization Experience Schedule (VES) in German, examining its reliability, and assessing VEs in clinical populations with FMS and MDD. METHODS: We investigated the relationship between VEs and clinical symptoms in individuals with FMS, MDD and healthy controls (N = 105) in a case-control study. We also analyzed correlations between different types of VEs and categories of early childhood abuse and posttraumatic-stress-disorder instruments. Additionally, we validated our findings in an independent sample of individuals with FMS (N = 97) from a clinical study. RESULTS: We observed excellent inter-rater reliability (Kw = 0.90-0.99), and VEs assessed using the VES were in alignment with subcategories of early childhood abuse. The prevalence of VEs extended beyond the categories covered by traditional survey instruments and was higher in individuals with MDD (4.0 ± 2.6) and FMS (5.9 ± 3.1) compared to controls (1.5 ± 1.7). We consistently identified a significant association between the number of VEs, the associated subjective distress, and clinical scores. Furthermore, distinct correlation patterns between VEs and clinical outcomes emerged across different cohorts. CONCLUSION: Our study emphasizes the VES's value in understanding VEs within MDD and FMS. These experiences span from traumatic to sub-traumatic and correlate with posttraumatic-stress and clinical symptoms, underscoring the VES's importance as an assessment tool.

[Diagnosis and admission center : Establishment and evaluation of an integrated translational infrastructure for clinical psychiatric research]. / Diagnose- und Aufnahmezentrum : Etablierung und Evaluation einer integrierten translationalen Infrastruktur für die klinisch-psychiatrische Forschung.

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as a starting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables a better coordinated and demand-oriented allocation. In addition, DAZ enables a faster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during a pilot phase. The patient sample corresponded to a representative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data.

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.

Female sex and burden of depressive symptoms predict insufficient response to telemedical treatment in adult attention-deficit/hyperactivity disorder: results from a naturalistic patient cohort during the COVID-19 pandemic.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder, that typically manifests itself during childhood and persists in a majority of the affected individuals into adulthood, negatively affecting physical and mental health. Previous studies have shown detrimental effects of the COVID-19 pandemic on mental health in individuals with ADHD. Thus, telemedicine could be a useful tool for optimizing treatment-outcomes in adult ADHD by improving treatment adherence and persistence. However, data on telemedical treatment outcomes in adult patients with ADHD is scarce. Methods: We report here the sub-cohort analysis of a naturalistic cohort of adult patients (N = 254) recruited between April 2020-April 2021, comparing the effects of telemedical treatment on participants either clinically diagnosed with depression (N = 54) or ADHD (N = 67). Participants were asked to fill out the WHO-5 repetitively during >12 weeks of telemedical treatment. Furthermore scores of WHO-5, SCL-90R and BDI-II, psychopathology, psychosocial functioning, sociodemographic data, medical records and a feedback survey were analyzed for both groups and compared. Participants with ADHD were further stratified according to the development of well-being during the study period in order to identify factors associated with a satisfactory treatment outcome. Results: Participants with depression reported a significant improvement of well-being during the course of the study, while no such effect could be seen in participants with ADHD on a group level. Despite the good outcome, participants with depression were more severely affected at baseline, with significantly worse psychopathology and a more precarious labor and financial situation. A detailed analysis of ADHD participants without clinical improvement revealed significantly higher BDI-II scores than for ADHD participants with a satisfactory outcome (p = 0.03, Mann-Whitney-U-Test), suggesting successful treatment was hampered by the combination of ADHD and depressive symptoms. Furthermore, female sex among ADHD patients was correlated with an unfavorable treatment outcome during the course of the study (p = 0.001, Spearman correlation) as well as living with children (p = 0.02, Spearman correlation). Conclusion: Besides screening for depressive symptoms before telemedical treatment, future research should address the specific needs of female ADHD patients as these patients may be at a particularly high risk of being overburdened with family work.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study.

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ.

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.

Clinical Phenomenology of Fibromyalgia Syndrome in Male Patients: Same But Different.

The majority of knowledge about fibromyalgia syndrome (FMS) derives from studies of female patients. Little is known about the clinical characteristics and treatment outcomes of male patients with FMS. In this retrospective cohort study with a prospective posttreatment follow-up, we investigated whether male patients with FMS differ from female patients in terms of 1) symptom burden, 2) psychological characteristics, and 3) clinical treatment response. We identified 263 male (4%) out of 5,541 patients with FMS completing a 3-week multimodal pain-treatment program. Male patients (51.3 ± 9.1 years) were age- and time-matched (1:4) with female patients (N = 1,052, 51.3 ± 9.0 years). Data on clinical characteristics, psychological comorbidities, and treatment responses were obtained from medical records and validated questionnaires. Levels of perceived pain, psychological comorbidity, and functional capacity were similar between genders, although male patients with FMS showed a higher prevalence of alcohol abuse. Compared to female patients, male patients experienced themselves less often as overly accommodating (Cohen's d = -.42) but more often as self-sacrificing (d = .26) or intrusive (d = .23). Regarding pain coping, male patients were less likely to utilize mental distraction, rest- and relaxation techniques, or counteractive activities (d = .18-.27). Male patients showed a slightly worse overall response rate than women (69% vs 77%), although differences between individual outcome measures were small (d < .2). Although male and female patients in our cohort were similar in clinical presentation and treatment response, the gender-specific differences in interpersonal problems and pain coping suggest consideration of these aspects in the treatment of male patients with FMS. PERSPECTIVE: Knowledge about fibromyalgia mostly derives from studies of female patients. Identifying and understanding gender-specific differences in fibromyalgia is an important roadmap in the treatment of this syndrome by focusing on specific gender aspects such as differences in interpersonal problems and pain coping mechanisms.

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.

Investigating the neural correlates of affective mentalizing and their association with general intelligence in patients with schizophrenia.

BACKGROUND AND HYPOTHESIS: Mentalizing impairment in schizophrenia has been linked to altered neural responses. This study aimed to replicate previous findings of altered activation of the mentalizing network in schizophrenia and investigate its possible association with impaired domain-general cognition. STUDY DESIGN: We analyzed imaging data from two large multi-centric German studies including 64 patients, 64 matched controls and a separate cohort of 300 healthy subjects, as well as an independent Australian study including 46 patients and 61 controls. All subjects underwent functional magnetic resonance imaging while performing the same affective mentalizing task and completed a cognitive assessment battery. Group differences in activation of the mentalizing network were assessed by classical as well as Bayesian two-sample t-tests. Multiple regression analysis was performed to investigate effects of neurocognitive measures on activation of the mentalizing network. STUDY RESULTS: We found no significant group differences in activation of the mentalizing network. Bayes factors indicate that these results provide genuine evidence for the null hypothesis. We found a positive association between verbal intelligence and activation of the medial prefrontal cortex, a key region of the mentalizing network, in three independent samples. Finally, individuals with low verbal intelligence showed altered activation in areas previously implicated in mentalizing dysfunction in schizophrenia. CONCLUSIONS: Mentalizing activation in patients with schizophrenia might not differ compared to large well-matched groups of healthy controls. Verbal intelligence is an important confounding variable in group comparisons, which should be considered in future studies of the neural correlates of mentalizing dysfunction in schizophrenia.

Structure/function interrelationships and illness insight in patients with schizophrenia: a multimodal MRI data fusion study.

Illness insight in schizophrenia (SZ) has an important impact on treatment outcome, integration into society and can vary over the course of the disorder. To deal with and treat reduced or absent illness insight, we need to better understand its functional and structural correlates. Previous studies showed regionally abnormal brain volume in brain areas related to cognitive control and self-reference. However, little is known about associations between illness insight and structural and functional network strength in patients with SZ. This study employed a cross-sectional design to examine structural and functional differences between patients with SZ (n = 74) and healthy controls (n = 47) using structural and resting-state functional magnetic resonance imaging (MRI). Voxel-based morphometry was performed on structural data, and the amplitude of low frequency fluctuations (ALFF) was calculated for functional data. To investigate abnormal structure/function interrelationships and their association with illness insight, we used parallel independent component analysis (pICA). Significant group (SZ vs. HC) differences were detected in distinct structural and functional networks, predominantly comprising frontoparietal, temporal and cerebellar regions. Significant associations were found between illness insight and two distinct structural networks comprising frontoparietal (pre- and postcentral gyrus, inferior parietal lobule, thalamus, and precuneus) and posterior cortical regions (cuneus, precuneus, lingual, posterior cingulate, and middle occipital gyrus). Finally, we found a significant relationship between illness insight and functional network comprising temporal regions (superior temporal gyrus). This study suggests that aberrant structural and functional integrity of neural systems subserving cognitive control, memory and self-reference are tightly coupled to illness insight in SZ.

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.

Processing of social and monetary rewards in autism spectrum disorders.

BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.

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.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks.

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.