Randomized controlled trial of individualized arousal-biofeedback for children and adolescents with disruptive behavior disorders (DBD).

Disruptive behavior disorders [including conduct disorder (CD) and oppositional defiant disorder (ODD)] are common childhood and adolescent psychiatric conditions often linked to altered arousal. The recommended first-line treatment is multi-modal therapy and includes psychosocial and behavioral interventions. Their modest effect sizes along with clinically and biologically heterogeneous phenotypes emphasize the need for innovative personalized treatment targeting impaired functions such as arousal dysregulation. A total of 37 children aged 8-14 years diagnosed with ODD/CD were randomized to 20 sessions of individualized arousal biofeedback using skin conductance levels (SCL-BF) or active treatment as usual (TAU) including psychoeducation and cognitive-behavioral elements. The primary outcome was the change in parents´ ratings of aggressive behavior measured by the Modified Overt Aggression Scale. Secondary outcome measures were subscales from the Child Behavior Checklist, the Inventory of Callous-Unemotional traits, and the Reactive-Proactive Aggression Questionnaire. The SCL-BF treatment was neither superior nor inferior to the active TAU. Both groups showed reduced aggression after treatment with small effects for the primary outcome and large effects for some secondary outcomes. Importantly, successful learning of SCL self-regulation was related to reduced aggression at post-assessment. Individualized SCL-BF was not inferior to active TAU for any treatment outcome with improvements in aggression. Further, participants were on average able to self-regulate their SCL, and those who best learned self-regulation showed the highest clinical improvement, pointing to specificity of SCL-BF regulation for improving aggression. Further studies with larger samples and improved methods, for example by developing BF for mobile use in ecologically more valid settings are warranted.

Age-related brain deviations and aggression.

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression.

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression.

The effects of callous-unemotional traits and aggression subtypes on amygdala activity in response to negative faces.

BACKGROUND: Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing. METHODS: We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8-18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task. RESULTS: Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression. CONCLUSIONS: Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.

Resilience and the brain: a key role for regulatory circuits linked to social stress and support.

Given the high prevalence and burden of mental disorders, fostering the understanding of protective factors is an urgent issue for translational medicine in psychiatry. The concept of resilience describes individual and environmental protective factors against the backdrop of established adversities linked to mental illness. There is convergent evidence for a crucial role of direct as well as indirect adversity impacting the developing brain, with persisting effects until adulthood. Direct adversity may include childhood maltreatment and family adversity, while indirect social adversity can include factors such as urban living or ethnic minority status. Recently, research has begun to examine protective factors which may be able to buffer against or even reverse these influences. First evidence indicates that supportive social environments as well as trait-like individual protective characteristics might impact on similar neural substrates, thus strengthening the capacity to actively cope with stress exposure in order to counteract the detrimental effects evoked by social adversity. Here, we provide an overview of the current literature investigating the neural mechanisms of resilience with a putative social background, including studies on individual traits and genetic variation linked to resilience. We argue that the regulatory perigenual anterior cingulate cortex and limbic regions, including the amygdala and the ventral striatum, play a key role as crucial convergence sites of protective factors. Further, we discuss possible prevention and early intervention approaches targeting both the individual and the social environment to reduce the risk of psychiatric disorders and foster resilience.

The Long-Term Impact of Early Life Stress on Orbitofrontal Cortical Thickness.

Early adversity has been related to brain structure alterations and to an increased risk of psychiatric disorders. The orbitofrontal cortex (OFC) is a key region for emotional processing, with structural alterations being described in several mental disorders. However, little is known about how its cortical thickness (CT) is affected by the long-term impact of life stress (LS) at different developmental stages. The present study aimed to investigate the effect of LS during infancy, childhood, and adolescence on CT alterations in the OFC and on psychopathology in 190 adults of an ongoing prospective cohort study. Chronic stressful life events were assessed in regular intervals. Participants rated depressive symptoms at the ages of 22 and 23 years. Morphometric data were collected at the participants' age of 25 years. Chronic LS during infancy was associated with reduced CT in the right OFC and increased depressive symptoms. Moreover, the impact of chronic LS during infancy on OFC thickness was partially mediated by depressive symptoms in adulthood, suggesting an interplay of early LS, psychopathology, and CT alterations. Our findings highlight the long-term impact of early LS on an affective core brain structure and psychopathology later in life.

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior.

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.

[The domain "social processes" in the system of research domain criteria: current state and perspectives]. / Die Domäne "soziale Prozesse" im System der Research Domain Criteria: aktueller Stand und Perspektive.

Social processes and their dysfunction, e.g. in autism spectrum disorders and psychotic disorders, have always been at the core of psychiatry. The last decades have led to impressive advances in our understanding of the underlying neurobiological mechanisms and also in the way we study and analyze social processes. Since their establishment, the research domain criteria have provided a powerful framework of how to operationalize and subdivide complex social processes in a way that it closely aligns to underlying neurobiological substrates while still enabling clinical approaches. In this article we summarize and discuss the most important findings for each of the four fundamental constructs of the social processes domain (a) binding and attachment, (b) social communication, (c) perception and understanding of self and (d) perception and understanding of others. We highlight the clinical relevance of the insights generated by the field of social neurosciences and discuss the resulting increasing importance of transdiagnostic concepts in applied research. Finally, we showcase three innovative research methods that build on the accelerating technological advances of the last decade and which will increasingly enable the study of complex social interactions in more realistic and ecologically valid settings.

[The importance of social neurosciences for psychiatry]. / Soziale Neurowissenschaften und deren Bedeutung für die Psychiatrie.

BACKGROUND: The social brain is dysfunctional in numerous stress-related psychiatric disorders. OBJECTIVE: The definition of social brain networks and their susceptibility for social environmental stress. It is also reviewed how social brain networks are disrupted in schizophrenia, autism and conduct disorder. MATERIAL AND METHODS: Literature search in PubMed. RESULTS: The social brain consists of several subnetworks that act in concert to foster empathy. Interestingly, except for the mirror neuron system, the neural networks of the social brain have been reported to be vulnerable to social environmental stress and have also been highlighted as being compromised in psychiatric disorders. As an example, schizophrenia is related to dysfunction in social perception, mentalizing, and affiliation, whereas the most pronounced deficits in autism are seen during social perception and mentalizing. Patients with conduct disorder are more prone to dysfunction in perception, affiliation and aversion. CONCLUSION: Social stress affects subnetworks also compromised in psychiatric disorders. Therefore, it is plausible that the social brain might mediate the association between social stress and psychiatric disorders. To advance ecological validity in social neuroscience, recent research has highlighted the role of hyperscanning and virtual reality as means by which a more naturalistic assessment of social interactions might be feasible.

Association between pubertal stage at first drink and neural reward processing in early adulthood.

Puberty is a critical time period during human development. It is characterized by high levels of risk-taking behavior, such as increased alcohol consumption, and is accompanied by various neurobiological changes. Recent studies in animals and humans have revealed that the pubertal stage at first drink (PSFD) significantly impacts drinking behavior in adulthood. Moreover, neuronal alterations of the dopaminergic reward system have been associated with alcohol abuse or addiction. This study aimed to clarify the impact of PSFD on neuronal characteristics of reward processing linked to alcohol-related problems. One hundred sixty-eight healthy young adults from a prospective study covering 25 years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. PSFD was determined according to the age at menarche or Tanner stage of pubertal development, respectively. Alcohol-related problems in early adulthood were assessed with the Alcohol Use Disorder Identification Test (AUDIT). During reward anticipation, decreased fMRI activation of the frontal cortex and increased preparatory EEG activity (contingent negative variation) occurred with pubertal compared to postpubertal first alcohol intake. Moreover, alcohol-related problems during early adulthood were increased in pubertal compared to postpubertal beginners, which was mediated by neuronal activation of the right medial frontal gyrus. At reward delivery, increased fMRI activation of the left caudate and higher feedback-related EEG negativity were detected in pubertal compared to postpubertal beginners. Together with animal findings, these results implicate PSFD as a potential modulator of psychopathology, involving altered reward anticipation. Both PSFD timing and reward processing might thus be potential targets for early prevention and intervention.

Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

BACKGROUND: Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. METHODS: 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. RESULTS: At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. CONCLUSIONS: These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention.

Long-term impact of maternal prenatal smoking on EEG brain activity and internalizing/externalizing problem symptoms in young adults.

OBJECTIVE: The objective of this study was to investigate the impact of smoking during pregnancy on the development of the child. While previous research has established its detrimental effects during early childhood, understanding potential long-term consequences into adulthood remains limited. This study specifically aimed to explore the influence of prenatal smoking exposure on brain activity and whether internalizing and externalizing symptoms are influenced by prenatal smoking exposure in a cohort of young adults. METHODS: Utilizing data from 176 participants (mean age M = 24.68, SD = 0.49) and their mothers enrolled in a longitudinal risk study (MARS), we employed Generalized Additive Mixed Models (GAMMs) to analyze electroencephalography (EEG) power at rest and behavioral outcomes derived from the Young Adult-Self-Report (YASR) scales. Both covariate-unadjusted and -adjusted models were used, taking into account participant variables such as sex and age, as well as maternal factors like psychopathology and alcohol consumption, in addition to smoking and alcohol intake by the participants themselves. RESULTS: The study revealed a significant impact of prenatal smoking on delta and theta band power, indicating decreased slower brain activity in prenatally exposed individuals compared to unexposed counterparts. Additionally, individuals exposed to prenatal smoking exhibited significantly higher levels of externalizing behavior. While this association was strongly influenced by maternal psychopathology, the child's gender, and the child's own substance use, the effect on delta power band remained after adjusting for covariates. CONCLUSION: The findings suggest that prenatal smoking exposure may have enduring effects on brain activity patterns in young adulthood. Conversely, the influence on externalizing behaviors depended on familial factors (maternal psychopathology) and the lifestyle of the individual (substance use).

Lifespan adversities affect neural correlates of behavioral inhibition in adults.

Introduction: Growing evidence suggests that adverse experiences have long-term effects on executive functioning and underlying neural circuits. Previous work has identified functional abnormalities during inhibitory control in frontal brain regions in individuals exposed to adversities. However, these findings were mostly limited to specific adversity types such as maltreatment and prenatal substance abuse. Methods: We used data from a longitudinal birth cohort study (n = 121, 70 females) to investigate the association between adversities and brain responses during inhibitory control. At the age of 33 years, all participants completed a stop-signal task during fMRI and an Adult Self-Report scale. We collected seven prenatal and postnatal adversity measures across development and performed a principal component analysis to capture common variations across those adversities, which resulted in a three-factor solution. Multiple regression analysis was performed to identify links between adversities and brain responses during inhibitory control using the identified adversity factors to show the common effect and single adversity measures to show the specific contribution of each adversity. To find neural correlates of current psychopathology during inhibitory control, we performed additional regression analyses using Adult Self-Report subscales. Results: The first adversity factor reflecting prenatal maternal smoking and postnatal psychosocial adversities was related to higher activation during inhibitory control in bilateral inferior frontal gyri, insula, anterior cingulate cortex, and middle temporal gyri. Similar results were found for the specific contribution of the adversities linked to the first adversity factor. In contrast, we did not identify any significant association between brain responses during inhibitory control and the second adversity factor reflecting prenatal maternal stress and obstetric risk or the third adversity factor reflecting lower maternal sensitivity. Higher current depressive symptoms were associated with higher activation in the bilateral insula and anterior cingulate cortex during inhibitory control. Conclusion: Our findings extended previous work and showed that early adverse experiences have a long-term effect on the neural circuitry of inhibitory control in adulthood. Furthermore, the overlap between neural correlates of adversity and depressive symptomatology suggests that adverse experiences might increase vulnerability via neural alterations, which needs to be investigated by future longitudinal research.

Early-Life Adversities Are Associated With Lower Expected Value Signaling in the Adult Brain.

BACKGROUND: Early adverse experiences are assumed to affect fundamental processes of reward learning and decision making. However, computational neuroimaging studies investigating these circuits in the context of adversity are sparse and limited to studies conducted in adolescent samples, leaving the long-term effects unexplored. METHODS: Using data from a longitudinal birth cohort study (n = 156; 87 female), we investigated associations between adversities and computational markers of reward learning (i.e., expected value, prediction errors). At age 33 years, all participants completed a functional magnetic resonance imaging-based passive avoidance task. Psychopathology measures were collected at the time of functional magnetic resonance imaging investigation and during the COVID-19 pandemic. We applied a principal component analysis to capture common variations across 7 adversity measures. The resulting adversity factors (factor 1: postnatal psychosocial adversities and prenatal maternal smoking; factor 2: prenatal maternal stress and obstetric adversity; factor 3: lower maternal stimulation) were linked with psychopathology and neural responses in the core reward network using multiple regression analysis. RESULTS: We found that the adversity dimension primarily informed by lower maternal stimulation was linked to lower expected value representation in the right putamen, right nucleus accumbens, and anterior cingulate cortex. Expected value encoding in the right nucleus accumbens further mediated the relationship between this adversity dimension and psychopathology and predicted higher withdrawn symptoms during the COVID-19 pandemic. CONCLUSIONS: Our results suggested that early adverse experiences in caregiver context might have a long-term disruptive effect on reward learning in reward-related brain regions, which can be associated with suboptimal decision making and thereby may increase the vulnerability of developing psychopathology.

A coordinate-based meta-analysis of human amygdala connectivity alterations related to early life adversities.

By affecting core neurobiological systems early in development, early life adversities (ELAs) might confer latent vulnerability to future psychopathologies. This coordinate-based meta-analysis aims to identify significant convergent alterations in functional connectivity of the amygdala related to ELAs across resting-state and task-based fMRI-studies. Five electronic databases were systematically searched until 22 October 2020, retrieving 49 eligible studies (n = 3162 participants). Convergent alterations in functional connectivity related to ELAs between the amygdala and the anterior cingulate cortex (ACC) and left hippocampus were found. Sub-analyses based on hemisphere and direction showed that connectivity seeded in the right amygdala was affected and, moreover, revealed that connectivity with ACC was decreased. Analyses based on paradigm and age showed that amygdala-ACC coupling was altered during resting state and that amygdala-left hippocampus connectivity was mostly affected during task-based paradigms and in adult participants. While both regions showed altered connectivity during emotion processing and following adverse social postnatal experiences such as maltreatment, amygdala-ACC coupling was mainly affected when ELAs were retrospectively assessed through self-report. We show that ELAs are associated with altered functional connectivity of the amygdala with the ACC and hippocampus. As such, ELAs may embed latent vulnerability to future psychopathologies by systematically affecting important neurocognitive systems.

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.

The importance of high quality real-life social interactions during the COVID-19 pandemic.

The coronavirus pandemic has brought about dramatic restrictions to real-life social interactions and a shift towards more online social encounters. Positive social interactions have been highlighted as an important protective factor, with previous studies suggesting an involvement of the amygdala in the relationship between social embeddedness and well-being. The present study investigated the effect of the quality of real-life and online social interactions on mood, and explored whether this association is affected by an individual's amygdala activity. Sixty-two participants of a longitudinal study took part in a one-week ecological momentary assessment (EMA) during the first lockdown, reporting their momentary well-being and their engagement in real-life and online social interactions eight times per day (N ~ 3000 observations). Amygdala activity was assessed before the pandemic during an emotion-processing task. Mixed models were calculated to estimate the association between social interactions and well-being, including two-way interactions to test for the moderating effect of amygdala activity. We found a positive relationship between real-life interactions and momentary well-being. In contrast, online interactions had no effect on well-being. Moreover, positive real-life social interactions augmented this social affective benefit, especially in individuals with higher amygdala being more sensitive to the interaction quality. Our findings demonstrate a mood-lifting effect of positive real-life social interactions during the pandemic, which was dependent on amygdala activity before the pandemic. As no corresponding effect was found between online social interactions and well-being, it can be concluded that increased online social interactions may not compensate for the absence of real-life social interactions.

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

A stable and replicable neural signature of lifespan adversity in the adult brain.

Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years (n = 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years (n = 114) and in an independent sample at 22 years (n = 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology.