Cross-tissue comparison of telomere length and quality metrics of DNA among individuals aged 8 to 70 years.

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N = 197). DNA was extracted from all tissue cells using the Gentra Puregene DNA Extraction Kit. Absolute TL (aTL) in kilobase pairs was measured in buccal epithelial cells, saliva, dried blood spots (DBS), buffy coat, and peripheral blood mononuclear cells (PBMCs) using qPCR. aTL significantly shortened with age for all tissues except saliva and buffy coat, although buffy coat was available for a restricted age range (8 to 15 years). aTL did not significantly differ across blood-based tissues (DBS, buffy coat, PBMC), which had significantly longer aTL than buccal cells and saliva. Additionally, aTL was significantly correlated for the majority of tissue pairs, with partial Spearman's correlations controlling for age and sex ranging from ⍴ = 0.18 to 0.51. We also measured quality metrics of DNA including integrity, purity, and quantity of extracted DNA from all tissues and explored whether controlling for DNA metrics improved predictions of aTL. We found significant tissue variation: DNA from blood-based tissues had high DNA integrity, more acceptable A260/280 and A260/230 values, and greater extracted DNA concentrations compared to buccal cells and saliva. Longer aTL was associated with lower DNA integrity, higher extracted DNA concentrations, and higher A260/230, particularly for saliva. Model comparisons suggested that incorporation of quality DNA metrics improves models of TL, although relevant metrics vary by tissue. These findings highlight the merits of using blood-based tissues and suggest that incorporation of quality DNA metrics as control variables in population-based studies can improve TL predictions, especially for more variable tissues like buccal and saliva.

[Emotional Abuse in Childhood and Adolescence: Biological Embedding and Clinical Implications]. / Emotionaler Missbrauch in Kindheit und Jugend ­ Biologische Einbettung und klinische Implikationen.

Emotional abuse, defined as degrading, manipulative, or neglectful behaviors by caregivers, represents a common adverse experience for children and adolescents, often co-occurring with other maltreatment types. Exposure to emotional abuse significantly affects mental health across the lifespan and is particularly associated with elevated depression risk.This review examinesmechanisms, by which emotional abuse influences brain development and the neuroendocrine stress response system and discusses the roles of genetic vulnerability and epigenetic processes in contributing to an elevated mental health risk. Emotional abuse has similar effects on brain networks responsible for emotion processing and regulation as other maltreatment types.Moreover, it uniquely affects networks related to self-relevant information and socio-cognitive processes. Furthermore, emotional abuse is associated with an impaired recovery of the neuroendocrine response to acute stress. Similar to other maltreatment types, emotional abuse is associated with epigenetic changes in genes regulating the neuroendocrine stress response system that are implicated in increased mental health risk.These findings suggest that emotional abuse has equally detrimental effects on children'smental health as physical or sexual abuse, warranting broader societal awareness and enhanced early detection efforts. Early interventions should prioritize emotion regulation, social cognition, self-esteemenhancement, and relationship- oriented approaches for victims of emotional abuse.

Children with maltreatment exposure exhibit rumination-like spontaneous thought patterns: association with symptoms of depression, subcallosal cingulate cortex thickness, and cortisol levels.

BACKGROUND: Childhood maltreatment is associated with pervasive risk for depression. However, the immediate cognitive and neural mechanisms that mediate this risk during development are unknown. We here studied the impact of maltreatment on self-generated thought (SGT) patterns and their association with depressive symptoms, subcallosal cingulate cortex (SCC) thickness, and cortisol levels in children. METHODS: We recruited 183 children aged 6-12 years, 96 of which were exposed to maltreatment. Children performed a mind wandering task to elicit SGTs. A subgroup of children underwent structural magnetic resonance imaging (N = 155) for SCC thickness analyses and saliva collection for quantification of free cortisol concentrations (N = 126) was collected. Using network analysis, we assessed thought networks and compared these networks between children with and without maltreatment exposure. Using multilevel analyses, we then tested the association between thought networks of children with maltreatment exposure with depressive symptoms, SCC thickness, and cortisol levels. RESULTS: Children exposed to maltreatment generated fewer positively valenced thoughts. Network analysis revealed rumination-like thought patterns in children with maltreatment exposure, which were associated with depressive symptoms, SCC thickness, and cortisol levels. Children with maltreatment exposure further exhibited decreased future-self thought coupling, which was associated with depressive symptoms, while other-related and past-oriented thoughts had the greatest importance within the network. CONCLUSIONS: Using a novel network analytic approach, we provide evidence that children exposed to maltreatment exhibit ruminative clustering of thoughts, which is associated with depressive symptoms and neurobiological correlates of depression. Our results provide a specific target for clinical translation to design early interventions for middle childhood. Targeting thought patterns in children with maltreatment exposure may be an effective strategy to effectively mitigate depression risk early in life.

Greater maltreatment severity is associated with smaller brain volume with implication for intellectual ability in young children.

Background: Childhood maltreatment profoundly alters trajectories of brain development, promoting markedly increased long-term health risks and impaired intellectual development. However, the immediate impact of maltreatment on brain development in children and the extent to which altered global brain volume contributes to intellectual development in children with maltreatment experience is currently unknown. We here utilized MRI data obtained from children within 6 months after the exposure to maltreatment to assess the association of maltreatment severity with global brain volume changes. We further assessed the association between maltreatment severity and intellectual development and tested for the mediating effect of brain volume on this association. Method: We used structural MRI (3T) in a sample of 49 children aged 3-5 years with maltreatment exposure, i.e. emotional and physical abuse and/or neglect within 6 months, to characterize intracranial and tissue-specific volumes. Maltreatment severity was coded using the Maternal Interview for the Classification of Maltreatment. IQ was tested at study entry and after one year using the Snijders Oomen Nonverbal Test. Results: Higher maltreatment severity was significantly correlated with smaller intracranial volume (r = -.393, p = .008), which was mainly driven by lower total brain volume (r = -.393, p = .008), which in turn was primarily due to smaller gray matter volume (r = -.454, p = .002). Furthermore, smaller gray matter volume was associated with lower IQ at study entry (r = -.548, p < .001) and predicted IQ one year later (r = -.493, p = .004.). The observed associations were independent of potential confounding variables, including height, socioeconomic status, age and sex. Importance: We provide evidence that greater maltreatment severity in early childhood is related to smaller brain size at a very young age with significant consequences for intellectual ability, likely setting a path for far-reaching long-term disadvantages. Insights into the molecular and neural processes that underlie the impact of maltreatment on brain structure and function are urgently needed to derive mechanism-driven targets for early intervention.

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.

Maximal telomerase activity capacity (mTAC) underlies the link between the cortisol response to stress and telomere length.

Exposure to various forms of stress has been associated with shorter telomere length (TL). However, the molecular underpinnings of this effect are poorly understood. Based on an understanding of the key role of the reverse transcriptase enzyme telomerase in regulating TL, and building upon our previous work in developing and validating a biomarker of the capacity of cells to express telomerase (maximal telomerase activity capacity (mTAC)), we examine here the hypotheses that mTAC is positively associated with TL and that the effect of stress on TL is mediated by individual differences in mTAC. In a proof-of-principle study of 28 healthy women and men we quantified the cortisol response to a standardized stress challenge, the Trier Social Stress Test (TSST), and we concurrently assessed peripheral blood mononuclear cell (PBMC) mTAC and TL. Our results indicated that higher mTAC levels were associated with longer TL (r = 0.50, p = .01). Moreover, mediational analysis suggested that the effect of the cortisol stress response on TL was mediated by mTAC (completely standardized ß = -0.17, bootstrap CI95 %: -0.44 to -0.01). Thus, our findings support the premise that individual differences in the capacity of cells to up-regulate telomerase may represent a key mediator in the link between stress and TL.

Investigating the effects of maltreatment and acute stress on the concordance of blood and DNA methylation methods of estimating immune cell proportions.

BACKGROUND: Immune cell proportions can be used to detect pathophysiological states and are also critical covariates in genomic analyses. The complete blood count (CBC) is the most common method of immune cell proportion estimation, but immune cell proportions can also be estimated using whole-genome DNA methylation (DNAm). Although the concordance of CBC and DNAm estimations has been validated in various adult and clinical populations, less is known about the concordance of existing estimators among stress-exposed individuals. As early life adversity and acute psychosocial stress have both been associated with unique DNAm alterations, the concordance of CBC and DNAm immune cell proportion needs to be validated in various states of stress. RESULTS: We report the correlation and concordance between CBC and DNAm estimates of immune cell proportions using the Illumina EPIC DNAm array within two unique studies: Study 1, a high-risk pediatric cohort of children oversampled for exposure to maltreatment (N = 365, age 8 to 14 years), and Study 2, a sample of young adults who have participated in an acute laboratory stressor with four pre- and post-stress measurements (N = 28, number of observations = 100). Comparing CBC and DNAm proportions across both studies, estimates of neutrophils (r = 0.948, p < 0.001), lymphocytes (r = 0.916, p < 0.001), and eosinophils (r = 0.933, p < 0.001) were highly correlated, while monocyte estimates were moderately correlated (r = 0.766, p < 0.001) and basophil estimates were weakly correlated (r = 0.189, p < 0.001). In Study 1, we observed significant deviations in raw values between the two approaches for some immune cell subtypes; however, the observed differences were not significantly predicted by exposure to child maltreatment. In Study 2, while significant changes in immune cell proportions were observed in response to acute psychosocial stress for both CBC and DNAm estimates, the observed changes were similar for both approaches. CONCLUSIONS: Although significant differences in immune cell proportion estimates between CBC and DNAm exist, as well as stress-induced changes in immune cell proportions, neither child maltreatment nor acute psychosocial stress alters the concordance of CBC and DNAm estimation methods. These results suggest that the agreement between CBC and DNAm estimators of immune cell proportions is robust to exposure to child maltreatment and acute psychosocial stress.

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 association between history of prenatal loss and maternal psychological state in a subsequent pregnancy: an ecological momentary assessment (EMA) study.

BACKGROUND: Prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using ecological momentary assessment (EMA)-based measures of pregnancy-specific distress and mood in everyday life. METHOD: This study was conducted in a cohort of N = 155 healthy pregnant women, of which N = 40 had a history of prenatal loss. An EMA protocol was used in early and late pregnancy to collect repeated measures of maternal stress and mood, on average eight times per day over a consecutive 4-day period. The association between a history of prenatal loss and psychological state was estimated using linear mixed models. RESULTS: Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group. CONCLUSION: Our findings suggest that prenatal loss in a prior pregnancy is associated with a subsequent pregnancy with significantly higher stress and impaired mood levels in everyday life across gestation. These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.

Relationship between Borderline Personality Disorder, Emotional Availability, and Cortisol Output in Mother-Child Dyads.

BACKGROUND: Mothers with borderline personality disorder (BPD) often show altered emotional availability toward their own child and heightened stress vulnerability. The aims of the present study were (1) to examine total cortisol output in saliva during mother-child interaction in mothers with BPD and their children and (2) to test whether maternal nonhostility as a subscale of emotional availability mediates the relationship between maternal BPD and child total cortisol output. METHODS: We investigated 16 mothers with BPD and 30 healthy control mothers (HC) and 29 children of mothers with BPD and 33 children of HC mothers. Children were between 5 and 12 years old. Salivary cortisol was collected prior to and twice after an episode of a 21-min standardized play situation between mother and child. Nonhostility was rated using the emotional availability scales. Analyses of covariance were computed to test for group differences in total cortisol output (measured with area under the curve with respect to ground). Pearson's correlation was calculated to test the association between maternal and child total cortisol output. To test the second question, a mediation analysis according to Preacher and Hayes was conducted. RESULTS: Mothers with BPD and their children had lower total cortisol output. Maternal and child total cortisol output was significantly correlated. Contrary to our hypothesis, maternal nonhostility did not mediate the relationship between BPD and child total cortisol output. CONCLUSION: Results imply that the hormonal stress activity of mothers with BPD and their children is altered, which may reflect modified stress regulation and stress vulnerability in mother and child and may impact on mother-child interaction. The finding of a positive association between mother's and child total cortisol output could indicate an intergenerational transmission of these alterations.

The Flexible Regulation of Emotional Expression Scale for Youth (FREE-Y): Adaptation and Validation Across a Varied Sample of Children and Adolescents.

Flexible self-regulation has been shown to be an adaptive ability. This study adapted and validated the adult Flexible Regulation of Emotional Expression (FREE) Scale for use with youth (FREE-Y) in community and maltreatment samples. The FREE-Y measures the ability to flexibly enhance and suppress emotion expression across an array of hypothetical social scenarios. Participants (N = 654, 8-19 years) were included from three studies. Confirmatory factor analysis (CFA) confirmed a theoretically appropriate higher order factor structure. Using multiple-group CFAs, measurement invariance was achieved across maltreatment status, age, and gender. Reliabilities were adequate and construct validity was demonstrated through associations with measures of emotion regulation, psychopathology, IQ, and executive functioning. Group comparisons indicated lower Suppression and Flexibility scores for maltreated versus comparison participants. Findings suggest that the FREE-Y is a valid measure of expressive regulation ability in youth that can be applied across a range of populations.

The effects of social isolation stress and discrimination on mental health.

Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and mortality and reduced quality of life. Despite their detrimental effects on health, there is a lack of knowledge regarding translation across the domains of experimental research, clinical studies, and real-life applications. Here, we review and synthesize evidence from basic research in animals and humans to clinical translation and interventions. Animal models indicate that social separation stress, particularly in early life, activates the hypothalamic-pituitary-adrenal axis and interacts with monoaminergic, glutamatergic, and GABAergic neurotransmitter systems, inducing long-lasting reductions in serotonin turnover and alterations in dopamine receptor sensitivity. These findings are of particular importance for human social isolation stress, as effects of social isolation stress on the same neurotransmitter systems have been implicated in addictive, psychotic, and affective disorders. Children may be particularly vulnerable due to lasting effects of social isolation and discrimination stress on the developing brain. The effects of social isolation and loneliness are pronounced in the context of social exclusion due to discrimination and racism, during widespread infectious disease related containment strategies such as quarantine, and in older persons due to sociodemographic changes. This highlights the importance of new strategies for social inclusion and outreach, including gender, culture, and socially sensitive telemedicine and digital interventions for mental health care.

Impaired empathic functioning in chronic depression: Behavioral evidence for the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) model.

The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) model proposes preoperational functioning as a core feature of persistent depressive disorders (PDD). Empathy deficits comprise one aspect. Resulting from childhood maltreatment, empathy deficits may aggravate social isolation, a key factor in the maintenance of depression. CBASP targets empathy by teaching patients to disengage from past experiences and to engage successfully in present social interactions. However, behavioral evidence for empathy deficits in PDD has remained elusive. We reasoned that deficits become apparent only under stress and that these deficits improve after CBASP-treatment. Twenty-two patients and 21 controls performed two parallel versions of the Multifaceted Empathy Test. For stress induction, a negative autobiographical event was presented before performing the task. A neutral event served as control. Fifteen patients performed the experiment twice, before and after a 12-week inpatient CBASP-treatment. Supporting our hypotheses, patients showed reduced empathy under stress, while no group difference was found in the absence of stress. Reduced empathy correlated with the level of re-experiencing negative memories. Pre-post-treatment comparison revealed that the stress-induced empathy deficit improved in patients over time. Post-treatment empathic capacity correlated positively with clinical improvement. Our findings provide empirical support for the CBASP model, but highlight an important new aspect: Empathy is not generally deficient in PDD but becomes impaired under stress. In real-life situations, stress-induced empathy impairments may exacerbate interpersonal conflicts. CBASP's interpersonal focus improved empathy, accompanied by clinical improvement as the model predicts.

Obesity and accelerated epigenetic aging in a high-risk cohort of children.

New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N = 273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models. Higher age-and sex- adjusted z-scored BMI was significantly correlated with household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r = 0.31, P < .0001), PhenoAge (r = 0.24, P < .0001), and DunedinPoAm (r = 0.38, P < .0001). In fully adjusted models, GrimAge (ß = 0.07; P = .0009) and DunedinPoAm (ß = 0.0017; P < .0001) remained significantly associated with higher age- and sex-adjusted z-scored BMI. Maltreatment-status was not associated with accelerated epigenetic aging. In a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.

Immediate impact of child maltreatment on mental, developmental, and physical health trajectories.

OBJECTIVE: The immediate impact of child maltreatment on health and developmental trajectories over time is unknown. Longitudinal studies starting in the direct aftermath of exposure with repeated follow-up are needed. METHOD: We assessed health and developmental outcomes in 6-month intervals over 2 years in 173 children, aged 3-5 years at study entry, including 86 children with exposure to emotional and physical abuse or neglect within 6 months and 87 nonmaltreated children. Assessments included clinician-administered, self- and parent-report measures of psychiatric and behavioral symptoms, development, and physical health. Linear mixed models and latent growth curve analyses were used to contrast trajectories between groups and to investigate the impact of maltreatment features on trajectories. RESULTS: Maltreated children exhibited greater numbers of psychiatric diagnoses (b = 1.998, p < .001), externalizing (b = 13.29, p < .001) and internalizing (b = 11.70, p < .001) symptoms, impairments in cognitive (b = -11.586, p < .001), verbal (b = -10.687, p < .001), and motor development (b = -7.904, p = .006), and greater numbers of medical symptoms (b = 1.021, p < .001) compared to nonmaltreated children across all time-points. Lifetime maltreatment severity and/or age at earliest maltreatment exposure predicted adverse outcomes over time. CONCLUSION: The profound, immediate, and stable impact of maltreatment on health and developmental trajectories supports a biological embedding model and provides foundation to scrutinize the precise underlying mechanisms. Such knowledge will enable the development of early risk markers and mechanism-driven interventions that mitigate adverse trajectories in maltreated children.

Longitudinal developmental trajectories do not follow cross-sectional age associations in hippocampal subfield and memory development.

Cross-sectional findings suggest that volumes of specific hippocampal subfields increase in middle childhood and early adolescence. In contrast, a small number of available longitudinal studies reported decreased volumes in most subfields over this age range. Further, it remains unknown whether structural changes in development are associated with corresponding gains in children's memory. Here we report cross-sectional age differences in children's hippocampal subfield volumes together with longitudinal developmental trajectories and their relationships with memory performance. In two waves, 109 participants aged 6-10 years (wave 1: MAge=7.25, wave 2: MAge=9.27) underwent high-resolution magnetic resonance imaging to assess hippocampal subfield volumes (imaging data available at both waves for 65 participants) and completed tasks assessing hippocampus dependent memory processes. We found that cross-sectional age-associations and longitudinal developmental trends in hippocampal subfield volumes were discrepant, both by subfields and in direction. Further, volumetric changes were largely unrelated to changes in memory, with the exception that increase in subiculum volume was associated with gains in spatial memory. Longitudinal and cross-sectional patterns of brain-cognition couplings were also discrepant. We discuss potential sources of these discrepancies. This study underscores that children's structural brain development and its relationship to cognition cannot be inferred from cross-sectional age comparisons.

Transmission of the adverse consequences of childhood maltreatment across generations: Focus on gestational biology.

Childhood maltreatment (CM) has well-established consequences for the mental and physical health of the exposed individual. Accumulating evidence now suggests that the detrimental sequelae of CM may be transmitted from one generation to the next, thereby extending the long-term ramifications of early adverse experiences and constituting intergenerational continuity in poor health outcomes. In this review, the current state of knowledge on the intergenerational effects of maternal exposure to CM is summarized and transmission pathways are discussed, specifically direct as well as indirect pathways involving variation in gestational biology. The review begins with a definition of CM and an overview of the clinical and neurobiological consequences of CM in the exposed and the offspring generation. The intrauterine period and variation in gestational biology are identified as a potential time window and a mechanism of transmission, respectively. Furthermore, a summary of the available evidence supporting both direct and indirect effects of gestational biological variation on offspring development is included. Finally, knowledge gaps and challenges in the investigation of the role of gestational biological mechanisms in the intergenerational transmission of CM sequelae are addressed and considerations for future study designs along with experiences from our current studies are provided.

Exposure to childhood maltreatment and systemic inflammation across pregnancy: The moderating role of depressive symptomatology.

BACKGROUND: Childhood maltreatment (CM) has long-term consequences for dysregulation of the immune system which is particularly pronounced when mental and physical health sequelae have manifested. Higher proinflammatory state has been shown in non-pregnant state in association with CM as well as with depression, one of the most frequent and pernicious psychiatric sequelae of CM. During pregnancy, however, this association is less clear. Given the important role of maternal inflammatory state during pregnancy for fetal, pregnancy, and birth outcomes, we sought to examine the association between CM and proinflammatory state during pregnancy considering the moderating role of maternal depressive symptoms characterized serially across pregnancy. METHODS: A prospective, longitudinal study of 180 healthy pregnant women was conducted with serial assessments in early (12.98 ± 1.71 weeks gestation), mid (20.53 ± 1.38 weeks gestation) and late (30.42 ± 1.4 weeks gestation) pregnancy. Maternal history of CM was assessed with the Childhood Trauma Questionnaire (CTQ) and the total score was used as an indicator of CM experience. Maternal depressive symptoms were assessed at each pregnancy visit with the Center for Epidemiologic Studies Depression Scale (CES-D). Serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were obtained at each pregnancy visit and combined to a composite maternal proinflammatory score. Linear mixed effects models were employed to assess the association between CTQ score, CES-D score, and proinflammatory score during pregnancy, adjusting for potential confounders. RESULTS: Gestational age was associated with the proinflammatory score (B = 0.02; SE = 0.00; p < .001), indicating an increase in inflammation across gestation. Neither CTQ score nor depressive symptoms were independently associated with the proinflammatory score (ps > 0.28). However, the interaction between CTQ score and depressive symptoms was associated with the proinflammatory score (B = 0.03, SE = 0.01, p < .05), indicating higher inflammation across pregnancy with increasing levels of depressive symptoms during pregnancy in women with higher CTQ scores. Exploratory analyses suggested that this interaction was mainly driven by CTQ subscale scores assessing experiences of abuse rather than neglect. CONCLUSIONS: These findings suggest a moderating role of maternal depressive symptoms during pregnancy on the association of early life stress with inflammation and thus highlight the importance of the timely assessment of both CM exposure and depressive symptoms which might allow for the development of targeted and individualized interventions to impact inflammation during pregnancy and to ameliorate the detrimental long-term effects of CM. The current findings add to a better understanding of the prenatal biological pathways that may underlie intergenerational transmission of maternal CM.

Comparing qPCR and DNA methylation-based measurements of telomere length in a high-risk pediatric cohort.

Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (N = 269; age: 8-13 years, 83% investigated for maltreatment). aTL and DNAmTL measurements were correlated with one another (r = 0.20, p = 0.001), but exhibited poor measurement agreement and were significantly different in paired-sample t-tests (Cohen's d = 0.77, p < 0.001). Shorter DNAmTL was associated with older age (r = -0.25, p < 0.001), male sex (ß = -0.27, p = 0.029), and White race (ß = -0.74, p = 0.008). By contrast, aTL was less strongly associated with age (r = -0.13, p = 0.040), was longer in males (ß = 0.31, p = 0.012), and was not associated with race (p = 0.820). These findings highlight strengths and limitations of high-throughput measures of TL; although DNAmTL replicated hypothesized associations, aTL measurements were positively skewed and did not replicate associations with external validity measures. These results also extend previous research in adults and suggest that DNAmTL is a sensitive TL measure for use in pediatric populations.

Sensory-Tactile Functional Mapping and Use-Associated Structural Variation of the Human Female Genital Representation Field.

The precise location of the human female genital representation field in the primary somatosensory cortex (S1) is controversial and its capacity for use-associated structural variation as a function of sexual behavior remains unknown. We used a functional magnetic resonance imaging (fMRI)-compatible sensory-tactile stimulation paradigm to functionally map the location of the female genital representation field in 20 adult women. Neural response to tactile stimulation of the clitoral region (vs right hand) identified individually-diverse focal bilateral activations in dorsolateral areas of S1 (BA1-BA3) in alignment with anatomic location. We next used cortical surface analyses to assess structural thickness across the 10 individually most activated vertices per hemisphere for each woman. We show that frequency of sexual intercourse within 12 months is correlated with structural thickness of the individually-mapped left genital field. Our results provide a precise functional localization of the female genital field and provide support for use-associated structural variation of the human genital cortex.SIGNIFICANCE STATEMENT We provide a precise location of the human female genital field in the somatosensory cortex and, for the first time, provide evidence in support of structural variation of the human genital field in association with frequency of genital contact. Our study represents a significant methodological advance by individually mapping genital fields for structural analyses. On a secondary level, our results suggest that any study investigating changes in the human genital field must map the field individually to achieve sufficient precision. Our results pave the way for future research into the plasticity of the human genital cortex as a function of normal or adverse experience as well as changes in pathologic conditions, i.e., sexual dysfunction, sexual deviation, or sexual risk-taking behavior.