The role of lifestyle factors in the association between early-life stress and adolescent psycho-physical health: Moderation analysis in two European birth cohorts.

OBJECTIVE: Early-life stress (ELS) is an established risk factor for a host of adult mental and physical health problems, including both depression and obesity. Recent studies additionally showed that ELS was associated with an increased risk of comorbidity between mental and physical health problems, already in adolescence. Healthy lifestyle factors, including physical activity, sleep and diet have also been robustly linked to both emotional and physical wellbeing. However, it is yet unclear whether these lifestyle factors may moderate the association between ELS and psycho-physical comorbidity. METHODS: We investigated whether (a) participation in physical activity, (b) sleep duration, and (c) adherence to a Mediterranean diet, moderated the relationship between cumulative ELS exposure over the first 10 years of life and psycho-physical comorbidity at the age of 13.5 years. Analyses were conducted in 2022-2023, using data from two large adolescent samples based in the UK (ALSPAC; n = 8428) and The Netherlands (Generation R; n = 4268). RESULTS: Exposure to ELS was significantly associated with a higher risk of developing comorbidity, however this association was not modified by any of the three lifestyle factors investigated. Only physical activity was significantly associated with a reduced risk of comorbidity in one cohort (ORALSPAC [95%CI] = 0.73 [0.59;0.89]). CONCLUSIONS: In conclusion, while we found some evidence that more frequent physical activity may be associated with a reduction in psycho-physical comorbidity, we did not find evidence in support of the hypothesised moderation effects. However, more research is warranted to examine how these associations may evolve over time.

Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants.

BACKGROUND: Childhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence ("comorbidity") of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood. METHODS: We carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types. RESULTS: Childhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types. CONCLUSIONS: This meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288).

Associations of prenatal maternal depressive symptoms with cord blood glucocorticoids and child hair cortisol levels in the project viva and the generation R cohorts: a prospective cohort study.

BACKGROUND: Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers. METHODS: In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts. RESULTS: 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort. CONCLUSIONS: The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels.

Attentional modulation of neural dynamics in tactile perception of complex regional pain syndrome patients.

Body perceptual disturbances are an increasingly acknowledged set of symptoms and possible clinical markers of complex regional pain syndrome (CRPS), but the neurophysiological and neurocognitive changes that underlie them are still far from being clear. We adopted a multivariate and neurodynamical approach to the analysis of EEG modulations evoked by touch to highlight differences between patients and healthy controls, between affected and unaffected side of the body, and between "passive" (i.e., no task demands and equiprobable digit stimulation) and "active" tactile processing (i.e., where a digit discrimination task was administered and spatial probability manipulated). When correct identifications are considered, an early reduction in cortical decodability (28-56 ms) distinguishes CRPS patients from healthy volunteers. However, when error trials are included in the classifier's training, there is an unexpected increased decodability in the CRPS group compared with healthy volunteers (280-320 ms). These group differences in neural processing seemed to be driven by the affected rather than the unaffected side. We corroborated these findings with several exploratory analyses of neural representation dynamics and behavioural modelling, highlighting the need for single participant analyses. Although several limitations impacted the robustness and generalizability of these comparisons, the proposed analytical approach yielded promising insights (as well as possible biomarkers based on neural dynamics) into the relatively unexplored alterations of tactile decision-making and attentional control mechanisms in chronic CRPS.

Arterial Health Markers in Relation to Behavior and Cognitive Outcomes at School Age.

BACKGROUND: Impaired arterial health is associated with a decline in cognitive function and psychopathology in adults. We hypothesized that these associations originate in early life. We examined the associations of blood pressure, common carotid artery intima media thickness, and carotid distensibility with behavior and cognitive outcomes during adolescence. METHODS AND RESULTS: This study was embedded in the Dutch Generation R Study, a population-based prospective cohort study from early fetal life onwards. Blood pressure, carotid intima media thickness, and carotid distensibility were measured at the age of 10 years. At the age of 13 years, total, internalizing and externalizing problems and attention-deficit hyperactivity disorder symptoms were measured using the parent-reported Child Behavior Checklist (CBCL/6-18), autistic traits were assessed by the Social Responsiveness Scale, and IQ was assessed using the Wechsler Intelligence Scale for Children-Fifth Edition. A 1-SD score higher mean arterial pressure was associated with lower odds of internalizing problems (odds ratio [OR], 0.92 [95% CI, 0.85-0.99]). However, this association was nonsignificant after correction for multiple testing. Carotid intima media thickness and carotid distensibility were not associated with behavior and cognitive outcomes at 13 years old. CONCLUSIONS: From our results, we cannot conclude that the associations of blood pressure, carotid intima media thickness, and carotid distensibility at age 10 years with behavior and cognitive outcomes are present in early adolescence. Further follow-up studies are needed to identify the critical ages for arterial health in relation to behavior and cognitive outcomes at older ages.

Associations of Arterial Thickness, Stiffness, and Blood Pressure With Brain Morphology in Early Adolescence: A Prospective Population-Based Study.

BACKGROUND: Arterial wall thickness and stiffness, and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health-related brain changes may be observable already in adolescence. METHODS: We examined whether (1) carotid intima-media thickness, (2) carotid distensibility, and (3) systolic blood pressure and diastolic blood pressure, measured at the age of 10 years, were associated with brain volumes and white matter microstructure (ie, fractional anisotropy and mean diffusivity) at the age of 14 years. In addition to cross-sectional analyses, we explored associations with longitudinal change in each brain outcome from 10 to 14 years. Analyses were based on 5341 children from the Generation R Study. RESULTS: Higher diastolic blood pressure was associated with lower total brain volume (ß, -0.04 [95% CI, -0.07 to -0.01]) and gray matter volume (ß, -0.04 [95% CI, -0.07 to -0.01]) at the age of 14 years, with stronger associations in higher diastolic blood pressure ranges. Similar associations emerged between systolic blood pressure and brain volumes, but these were no longer significant after adjusting for birth weight. No associations were observed between blood pressure and white matter microstructure or between carotid intima-media thickness or distensibility and brain morphology. CONCLUSIONS: Arterial blood pressure, but not intima-media thickness and distensibility, is associated with structural neuroimaging markers in early adolescence. Volumetric measures may be more sensitive to these early arterial health differences compared with microstructural properties of the white matter, but further studies are needed to confirm these results and assess potential causal mechanisms.

Effects of Pre- and Postnatal Early-Life Stress on Internalizing, Adiposity, and Their Comorbidity.

OBJECTIVE: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. METHOD: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. RESULTS: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (ß [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. CONCLUSION: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.

Mapping gene by early life stress interactions on child subcortical brain structures: A genome-wide prospective study.

Background: Although it is well-established that both genetics and the environment influence brain development, they are typically examined separately. Here, we aimed to prospectively investigate the interactive effects of genetic variants-from a genome-wide approach-and early life stress (ELS) on child subcortical brain structures, and their association with subsequent mental health problems. Method: Primary analyses were conducted using data from the Generation R Study (N = 2257), including genotype and cumulative prenatal and postnatal ELS scores (encompassing life events, contextual risk, parental risk, interpersonal risk, direct victimisation). Neuroimaging data were collected at age 10 years, including intracranial and subcortical brain volumes (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus). Genome-wide association and genome-wide-by-environment interaction analyses (GWEIS, run separately for prenatal/postnatal ELS) were conducted for eight brain outcomes (i.e., 24 genome-wide analyses) in the Generation R Study (discovery). Polygenic scores (PGS) using the resulting weights were calculated in an independent (target) cohort (adolescent brain cognitive development Study; N = 10,751), to validate associations with corresponding subcortical volumes and examine links to later mother-reported internalising and externalising problems. Results: One GWEIS-prenatal stress locus was associated with caudate volume (rs139505895, mapping onto PRSS12 and NDST3) and two GWEIS-postnatal stress loci with the accumbens (rs2397823 and rs3130008, mapping onto CUTA, SYNGAP1, and TABP). Functional annotation revealed that these genes play a role in neuronal plasticity and synaptic function, and have been implicated in neuro-developmental phenotypes, for example, intellectual disability, autism, and schizophrenia. None of these associations survived a more stringent correction for multiple testing across all analysis sets. In the validation sample, all PGSgenotype were associated with their respective brain volumes, but no PGSGxE associated with any subcortical volume. None of the PGS associated with internalising or externalising problems. Conclusions: This study lends novel suggestive insights into gene-environment interplay on the developing brain as well as pointing to promising candidate loci for future replication and mechanistic studies.