Robert Kumsta

Trauma exposure in children and young people (CYP) can lead to the development of posttraumatic stress disorder (PTSD). Identification of biomarkers prospectively associated with PTSD can provide critical insight into the mechanisms underpinning this disorder and potentially aid in identifying CYP vulnerable to persistent symptoms. A systematic search of databases was conducted up until February 2024 to identify studies testing associations of prospective biomarkers with PTSD outcomes in CYP. A narrative synthesis of study characteristics, quality, and findings was conducted. Meta-analysis using a random-effects model was performed when two or more comparable studies were identified. Searches yielded 2039 articles, with 283 identified as relevant after title/abstract screening. Twenty-one studies met eligibility criteria in the following biological domains: hormonal, immunological, cardiovascular, and multisystem. The majority of studies focussed on naturalistic recovery of CYP exposed to acute trauma. Significant heterogeneity was observed, including in trauma type, selection, and biomarker measurement. Across biomarkers, relatively consistent evidence was observed for a prospective association between elevated heart rate post-trauma and increased risk of PTSD persistence only, with limited evidence in other domains. Our review highlights a limited evidence base for prospective biomarkers of the development of PTSD in CYP, with methodological issues limiting inferences that can be drawn. A notable lack of evidence from low-and-middle income countries, despite chronic and severe trauma being endemic in these settings, was identified. Further research using standardised protocols from large, representative samples will be critical in the identification of biomarkers of PTSD risk and resilience.

Mental disorders affect not only mothers themselves but also their children and partners. Borderline personality disorder (BPD) in particular is thought to impact the mother–child relationship, but comparisons with mothers with other mental disorders are scarce. Many studies use questionnaires without examining if self‐report corresponds to observable behaviour. We assessed the perceived mother–child relationship using the Parenting Relationship Questionnaire and the Child Relationship Behaviour Inventory in three groups: (1) mothers with BPD, (2) mothers with anxiety and/or depression and (3) mothers without mental disorders with preschool children. Additionally, mother–child interactions during free‐play and structured tasks were video‐recorded and coded using the Coding Interactive Behaviour system. Compared with mothers without mental disorders, both clinical groups perceived their relationship with the child, their own parenting skills and their children's behaviour as less positive. Mothers with BPD felt less confident and more frustrated than those with anxiety and/or depression. No significant group differences emerged in observed behaviour (e.g., sensitivity, intrusiveness), and correlations between self‐report and observation were low. Overall, mothers with BPD face similar challenges as mothers with anxiety or depressive disorders, but they experience particular distress when it comes to relating to and controlling their child's affect. While mothers in both clinical groups are able to foster positive relationships with their children in a controlled laboratory setting, they find it difficult to maintain these skills permanently (e.g., during negative child affect). Trial Registration: DRKS‐ID: DRKS00020460

Polygenic scores (PGS) have become valuable tools for quantifying genetic liability to complex mental disorders. This review discusses the application of PGS in gene–environment interaction (GxE) research, focusing on depression and stress-related phenotypes. We synthesize evidence from studies testing whether genetic risk, as indexed by PGS, moderates the impact of environmental exposures, particularly stressful life events (SLEs), on psychological outcomes. Findings from large-scale population studies lend partial support to the diathesis–stress framework, with significant GxE effects observed between polygenic risk for depression and various stressors. Individuals with higher genetic liability tend to be more vulnerable to the adverse effects of stress, though effect sizes are typically modest. Some studies report robust interactions, whereas others find independent main effects of genes and environment without meaningful moderation. We further review genome-wide interaction studies (GWIS) aiming to identify variants underlying stress sensitivity and emerging research employing PGS to predict psychotherapy response. Despite methodological advances, the limited variance explained by current PGS constrains their immediate translational value. Overall, we outline both the promise and current limitations of PGS-based GxE approaches and highlight opportunities for improving their utility in elucidating how genetic predisposition and environmental adversity jointly shape risk for mental disorders.

Background: Family climate substantially influences children’s socio-emotional development. We examined mothers’ mental representations of their children and their relationships in three groups of mothers with young children (0–6 years): mothers (1) with a borderline personality disorder (BPD) (2), with a depressive or anxiety disorder but no BPD (AD/D), or (3) without a current mental disorder (CON). We expected both clinical groups to show more negative mental representations – more expressed emotion reflecting a critical attitude toward the child in general, more hostile attributions to child misbehavior in particular, and a less balanced view of the child (i.e., lower narrative coherence) – than CON mothers. We also expected mothers with BPD to have more impaired mental representations than mothers with AD/D. Methods: Data were collected as part of an intervention study (at the pre-intervention assessment). To assess parental attributions, 172 mothers with BPD, 69 mothers with AD/D, and 96 CON mothers provided responses to vignettes and participated in a five-minute speech sample coded for expressed emotion and narrative coherence. Results: BPD was associated with more criticism (OR = 3.17 and OR = 3.93) in comparison with CON mothers and mothers with AD/D, and with lower narrative coherence (OR = 5.45) compared with CON mothers but not compared with mothers with AD/D (OR = 1.41). Only narrative coherence remained significantly associated with group membership after education was controlled for. Mothers with BPD also showed more hostile attributions than CON mothers, with the AD/D group in between. Conclusion: Without controlling for maternal education, critical attitudes toward the child in general were specifically associated with BPD, hostile attributions were less clearly associated, and narrative coherence was transdiagnostically associated with mental disorders in general. Once education was controlled for, disorder-specific associations were no longer observed, while transdiagnostic associations were maintained. Early interventions may specifically aim to decrease levels of criticism, help mothers increase non-hostile attributions of child misbehavior, and support mothers in building more coherent mental representations of their children. Trial registration: This study was pre-registered at the German Registry of Clinical Studies (DRKS-ID: DRKS00020460).

Maladaptive stress responses are associated with a variety of psychological and physical disorders, often characterized by molecular indicators of dysregulated stress pathways. Small extracellular vesicles (sEVs), which play a key role in intercellular communication, may be critically involved in these processes. In this study, we quantified sEV concentrations (specifically CD9⁺, CD63⁺, and CD81⁺ markers) in the plasma of twenty young, healthy men before and after exposure to both acute psychosocial and physical stress, using imaging flow cytometry (IFCM).All participants showed significant increases in cortisol, catecholamines, and circulating cell-free DNA (cfDNA) following both stressors. In contrast, sEVs were significantly elevated only in response to physical stress. Physical stress induced a rapid increase in sEV release, particularly in CD9- and CD63-positive vesicles, followed by a return to baseline within 40 minutes. Psychosocial stress, however, triggered more variable sEV responses across individuals.Importantly, our classification approach using recursive partitioning revealed distinct sEV patterns associated with psychosocial and physical stress, with highest discriminatory value for CD44⁺ sEVs. These findings indicate that psychosocial and physical stress elicit distinct sEV signatures, which may reflect differential stress communication pathways and highlight their potential as biomarkers for stress-related processes and as possible targets for the effects of psychosocial exposures, including early adversity and trauma.

Background: Genetic variants may impact connectivity in the fear network such that genetically driven alterations of network properties (partially) explain individual differences in learning. Our aim was to identify genetic indices that predict physiological measures of fear learning mediated by MRI-based connectivity. Methods: We built prediction models using exploratory mediation analysis. Predictors were polygenic scores for several psychological disorders, neuroticism, cross-disorder risk, cognitive traits, and gene expression-based scores. Candidate mediators were structural and functional connectivity estimates between the hippocampus, amygdala, dorsal anterior cingulate, ventromedial prefrontal cortex and cerebellar nuclei. Learning measures based on skin conductance responses to conditioned fear stimuli (CS+), conditioned safety cues (CS-), and differential learning (CS+ vs. CS-), for both acquisition and extinction training served as outcomes. Results: Reliable prediction of learning indices was achieved by means of conventional polygenic score construction but also by modelling cross-trait and trait-specific effects of genetic variants. A latent factor of disorder risk as well as major depressive disorder conditioned on other traits were related to the acquisition of conditioned fear. Polygenic scores for short-term memory showed an association with safety cue learning. During extinction, genetic indices for neuroticism and verbal learning were predictive of CS+ and differential learning, respectively. While mediation effects depended on connectivity modality, prediction of fear involved all regions of interest. Expression-based scores showed no associations. Conclusions: Our findings highlight the utility of leveraging pleiotropy to improve complex trait prediction and brain connectivity as a promising endophenotype to understand the pathways between genetic variation and fear expression.

Cell-free DNA (cfDNA) is continuously shed by all cells in the body, but the regulation of this process and its physiological functions are still largely unknown. Previous research has demonstrated that both nuclear (cf-nDNA) and mitochondrial (cf-mtDNA) cfDNA levels increase in plasma in response to acute psychosocial and physical stress in males. This study further investigated these findings by testing 31 female participants (16 using oral hormonal contraception and 15 not using oral hormonal contraception), and the results were subsequently compared with those of 16 male participants. In addition, cf-nDNA and cf-mtDNA were comparatively quantified in both plasma and saliva at four time points, 2 min before and 2, 15, and 45 min after stress induction. A novel method was implemented to facilitate the straightforward collection of capillary blood by non-medical personnel for plasma analysis. While cf-mtDNA is readily detectable in body fluids due to its high copy number, the quantification of cf-nDNA is challenging due to its low abundance. To overcome this, a multiplex quantitative polymerase chain reaction (qPCR) protocol targeting L1PA2 elements, which are prevalent in the human genome, was utilized. The analysis indicated significantly elevated levels of cf-nDNA in both plasma and saliva in all participants, irrespective of gender, following psychosocial and physical stress. Conversely, neither plasma nor saliva exhibited a consistent or stress-induced release pattern for cf-mtDNA. CfDNA is a promising biomarker that is consistently released after stress in both men and women and can be detected in both plasma and saliva. However, further research is necessary to elucidate the mechanisms of cfDNA release from specific cells and to understand its biological function in the body.

Intelligence is associated with important life outcomes. Behavioral, genetic, structural, and functional brain correlates of intelligence have been studied for decades, but questions remain as to how genetics are related to trait expression and what intermediary role brain properties play. This study investigated these mediations in a representative sample of 434 individuals, comprising young and older adults. Polygenic scores (PGS) for intelligence were calculated. Resting-state EEG recordings were analyzed using graph theory quantifying functional connectivity across different frequencies. We tested whether global and local graph metrics like efficiency and clustering mediated the association between PGS and intelligence. PGS significantly predicted variance in intelligence and were related to frequency-specific graph metrics in areas predominantly located in parieto-frontal regions, which in turn were associated with intelligence. These findings, which are based on the first study linking PGS to intelligence using EEG-derived graph metrics, advance our understanding of the neurogenetics of intelligence.

White matter is fundamental for efficient and accurate information transfer throughout the human brain and thus crucial for intelligence. Previous studies often demonstrated associations between fractional anisotropy (FA) as a metric of white matter “microstructural integrity” and intelligence, but it is still unclear, whether this relation is due to greater axon density, parallel, homogenous fiber orientation distributions, or greater myelination since all of these measures influence FA. Using neurite orientation dispersion and density imaging (NODDI) and myelin water fraction (MWF) imaging data, we analyzed the microstructural architecture of intelligence in more detail in a sample of 500 healthy young adults. Furthermore, we were interested whether specific white matter microstructural indices play intermediary roles in the pathway that links genetic disposition for intelligence to phenotype. Thus, we conducted for the first time mediation analyses investigating whether neurite density (NDI), orientation dispersion (ODI), and MWF of 64 white matter fiber tracts mediate the effects of polygenic scores for intelligence (PGS _GI ) on general intelligence. By doing so, we showed that NDI, but not ODI or MWF of white matter fiber tracts was significantly associated with general intelligence and that the NDI of six fiber tracts mediated the relation between genetic variability and g . These findings are a crucial step forward in decoding the neurogenetic underpinnings of general intelligence, as they identify that neurite density of specific fiber tracts relates polygenic variation to g , whereas orientation dispersion and myelination did not.