Psychoneuroendocrinology

BackgroundPsychosocial adversity (PSA) contributes to long-term health disparities and increased risk for non-communicable diseases. The effects of PSA arise through complex interactions between genes and the environment, which involve immune, endocrine, and epigenetic dysregulation. MethodsTo examine how adversity affects mental and physical health via epigenetic alterations in a more controlled way, we examined the relationship between PSA and epigenetic aging in 28 monozygotic (MZ) twin pairs discordant for negative life experiences. Whole-blood DNA methylation (DNAm) profiling was performed using the Illumina Infinium EPIC v2 BeadChip array. Epigenetic age acceleration (EAA) was calculated using a panel of first to third-generation clocks, namely, Horvath, Hannum, PhenoAge (Levine), GrimAge (v2.0), Elastic Net and DunedinPACE. ResultsThough we did not observe any significant group-level differences in epigenetic age acceleration between PSA and control at large, sex-stratified analyses revealed that PSA exposed males exhibited significant reductions in EAA compared to their co-twins when assessed using the Hannum, PhenoAge, and DunedinPACE clocks. In females, regression analyses showed significant positive associations between EAA and both negative life events and shame perception. Application of the dimensional model of adversity further revealed that psychosocial threat was strongly associated with increased EAA in females, whereas deprivation showed a weaker but significant association with EAA in males. These findings suggest a sex-specific and context-dependent biological response to PSA, potentially reflecting either adaptive or maladaptive epigenetic remodelling. ConclusionThe observed epigenetic age deceleration in PSA-exposed males, together with the associations between EAA and threat, shame perception, and life events in females, highlight the importance of context and perception in shaping sex-specific responses to adversity. Our results underscore the utility of MZ twin study designs in isolating psychosocial stress driven epigenetic effects and support DNAm clocks as biomarkers of stress-related biological aging. Overall, this study advances our understanding of the molecular underpinnings of social health inequalities and may inform future interventions aimed at promoting resilience and stress adaptation.

BackgroundThe present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions. MethodsParticipants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples collected at age three using sodium bisulfite next-generation sequencing (NGS). Cognitive functions were assessed at age five using the SON-R 2.5-7 Intelligence Test. Results(a) DNA methylation at age three predicted lower IQ at age five through increased concentration problems; (b) participation in the three-year PAT program predicted lower methylation levels at the end of the intervention; and (c) early life stressors predicted lower IQ through increased methylation and concentration problems with descriptively stronger effects in the control group. ConclusionsThese findings demonstrate a link between early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter and later cognitive functions in children and highlight the role of early life stressors and the PAT intervention in shaping these associations.

IntroductionEarly-life adversity (ELA) encompasses a range of environmental stressors, including physical, emotional, and social challenges that can affect health during the critical early developmental period. Extensive research has linked ELA to negative long-term health outcomes, yet the underlying biological mechanisms remain poorly understood. The current study investigates how early institutional care changes the epigenetic landscape in young adults. The study also provides insights into role of DNA methylation as a potential mediator for disease susceptibility and altered health trajectories. Materials and MethodsDNA was extracted from blood samples obtained from 111 individuals (71 Controls; 40 ELA) who were part of the EpiPath cohort. DNA methylation was measured using the Infinium Methylation EPIC v2.0 BeadChip. Results3,785 differentially methylated CpG loci were identified in the ELA group in comparison with the control group (FDR <0.05). Pathway enrichment analysis highlighted biological processes involved in metabolic regulation, stress response, and neurodevelopment, with novel pathways such as GTPase-mediated signalling, efferocytosis and glucuronosyltransferase emerging as potential drivers of the ELA phenotype. A subset of 28 CpG loci was used to develop an epigenetic signature, which showed a significant association with the development of chronic diseases in ELA-exposed individuals. ConclusionThis study reinforces Barkers concept of sensitive periods and it underscores the enduring impact of ELA in shaping long-term health outcomes. The persistence of DNA methylation patterns decades after exposure to ELA, and their clear association with the resultant phenotype confirms that stable epigenetic imprints play a potential role in long-term disease risk and resilience.

BackgroundThe Michigan Freshman Study on Stress and Resilience aims to identify factors that predict the emergence of depression and/or anxiety symptoms in college freshmen. We previously showed that a combination of psychiatric instruments (Affect Score) strongly predicts who will develop such symptoms during the freshman year. Here, we ask: a) Can we replicate the predictive power of the Affect Score in an independent cohort? and b) Can the neuroendocrine profile during the Trier Social Stress Test (TSST) serve as an additional predictor? MethodsA new cohort of subjects (N= 357) was used for Affect Score replication. The TSST study involved 337 subjects (Females 184, Males 153). Self-report questionnaires at the start of the year were used to derive the Affect Score. GAD-7 and PHQ-9 were used to monitor anxiety and depression, respectively. TSST measures involved plasma ACTH and Cortisol and heart rate monitoring. ResultsThe Affect Score proved to be a highly replicable predictor of future depression and anxiety. In the TSST, subjects not currently depressed but who developed depression at another timepoint during the year showed a higher and delayed peak of the CORT response. Female subjects not currently anxious but who developed anxiety at another timepoint had an elevated CORT response throughout the TSST. This hyperresponsiveness was not correlated with Affect Score and was an independent predictor of anxiety. ConclusionsThe Affect Score is a powerful predictor of depression and anxiety in college freshmen. The combination of Affect Score and TSST is strongly predictive of anxiety in females.

Epigenetic clocks and scores have been investigated as potential biomarkers of later-life health outcomes following early-life exposures. In pediatric settings, DNA methylation (DNAm) is often measured in saliva; however, most clocks and scores have been trained in adult blood. Therefore, we assessed the performance, correlation, longitudinal stability, and association with early-life adversity (ELA) for established epigenetic measures in matched pediatric blood and saliva samples. Leveraging the Kids2Health cohort of 291 children (3-12 years, 56% exposed to ELA), we assessed DNAm (Illumina EPICv2) from matched blood and saliva. We calculated 22 commonly used epigenetic measures (chronological and biological clocks, scores for body mass index [BMI], C-reactive protein [CRP], cognition, maternal smoking, telomere length) and compared them with corresponding measured phenotypes (chronological age, BMI, CRP, IQ, telomere length). Overall, performance of epigenetic clocks and scores in children varied widely. Nine epigenetic measures were significantly and equally correlated with their corresponding phenotype across tissues. Six measures were highly correlated between blood and saliva (r[&ge;]0.7). All age acceleration estimates showed low to moderate cross-tissue correlations (r=0.20-0.68). Epigenetic scores indicating lower cognitive ability and elevated inflammation were associated with ELA and low SES in both tissues. We additionally provide epigenome-wide blood-saliva correlations across 815,069 CpGs. The results indicate limited generalizability of adult-trained epigenetic clocks and scores to pediatric blood and saliva, even when accounting for cell type composition. We advise caution for cross-tissue and cross-age-range applications of epigenetic measures in research and clinical settings and provide a resource to optimize epigenetic biomarkers in children.

IntroductionResearch has shown that social and physical stressors of early-life adversity (ELA) can negatively affect long-term health trajectories. Despite differences in types of ELA exposure, previous studies have identified common health-related outcomes in adults who had experienced less favourable conditions during developmentally sensitive periods. This meta-analysis investigates the potential role of DNA methylation in mediating these adverse health trajectories by identifying common biological signatures across cohorts with distinct adversity exposures and environmental backgrounds. Materials and MethodsDNA methylation data from previously published studies was used to perform a meta-analysis on 227 individuals across three cohorts. These include the EpiPath cohort consisting of adults who were exposed early institutional care, ImmunoTwin cohort consisting of adversity discordant monozygotic twin pairs and lastly a cohort of young children exposed to early institutional care. ResultsDNA methylation analysis across the three cohorts revealed differential methylation at CpG loci associated with 15 genes common to all cohorts. These genes are involved in neuronal development, chromatin remodeling and metabolism. Pathway enrichment analysis of the combined dataset showed potential associations with oxytocin signalling, regulation of nervous system development, and calcium signalling in relation to the later-life phenotype of the adversity exposed individuals. In addition, a poly-epigenetic score was developed by identifying a subset of 200 differentially methylated CpG sites through PLS-DA analysis with the combined beta matrix of these cohorts. ConclusionThis study highlights the long-term impact of adversity by identifying common DNA methylation signatures of negative life experiences across three cohorts. The development of a poly-epigenetic score represents the first steps towards identifying group differences by combining weighted methylation values for CpG sites of interest. This method illustrates the potential to track changes in individuals across long-term studies that may benefit research in lifelong healthoutcomes.

Menopause is a major psychoneuroendocrine transition which can impact emotional functioning and mental health. Although emotion regulation (ER) is fundamental for mental health, intrinsic neural connectivity supporting ER during the menopausal transition remains unexplored. Addressing this gap, this study provides the first examination of intrinsic effective connectivity within an ER-related network across menopausal stages. Resting-state fMRI data were acquired from 76 healthy premenopausal (n = 32), perimenopausal (n = 19), and postmenopausal (n = 25) women. Effective connectivity within a predefined ER network was examined using spectral dynamic causal modeling. Further, we assessed how intrinsic connectivity predicts self-reported ER ability within each group. While self-reported ER ability did not differ across groups, resting-state effective connectivity within the ER network varied in a stage-dependent manner, with most heterogeneous effects observed between pre- and perimenopause, suggesting a non-monotonic trajectory. Perimenopause was characterized by distinct changes in frontal interactions, reflecting a redistribution rather than a gradual shift toward postmenopausal connectivity. Differences regarding postmenopause were restricted to greater weighting of temporo-parietal network components. Connectivity-ER ability associations revealed stage-specific predictive profiles, with distributed fronto-temporal connectivity predicting ER ability in premenopause, frontal-restricted connectivity in perimenopause, and a single frontal connection with reversed predictive direction in postmenopause. Our findings demonstrate that comparable levels of trait-based ER ability are associated with divergent intrinsic network configurations rather than a uniform architecture. Identifying perimenopause as distinct transition window of intrinsic network organization advances hormone-sensitive models of intrinsic connectivity and provides a framework for understanding how baseline network organization may adapt during psychoneuroendocrine transitions in women.

Aging is the strongest known risk factor for Alzheimers disease (AD), and elevated plasma amyloid-{beta} (A{beta}) levels in healthy adults are associated with increased AD risk. Aging is also associated with autonomic imbalance, characterized by increased sympathetic and decreased parasympathetic activity. In our previous randomized clinical trial, we found that four weeks of daily slow-paced breathing designed to enhance parasympathetic activity reduced plasma A{beta}42 and A{beta}40 levels in younger and older adults and showed a trend toward increasing A{beta}42/A{beta}40 ratio only in older adults. The primary goal of the current study was to extend these findings in 62 adults aged 50 to 70 years using randomized assignment to 10 weeks of slow-paced breathing or a random-paced breathing control with three assessment time points. Secondary objectives included examining the effects of slow-paced breathing on brain structure (i.e., perivascular space and hippocampal volumes) and cognitive performance. Consistent with prior findings, the slow-paced breathing group showed greater decreases in plasma A{beta}42 than the control group. However, group differences were not significant for A{beta}40 or A{beta}42/A{beta}40 ratios, and no significant effects were observed for the secondary outcomes. The non-significant findings may be due to changes we made to both intervention and control condition methods relative to our previous trial. Further research is needed to explore the underlying mechanisms and potential effects of slow-paced breathing on A{beta} accumulation in the brain. HighlightsO_LIParticipants were randomly assigned to slow-placed breathing or a breathing control C_LIO_LIIndividualized protocols determined breathing paces C_LIO_LITen weeks of daily slow-paced breathing practice reduced plasma A{beta}42 levels C_LI

Very preterm infants (<30 weeks gestation) are at elevated risk for neurodevelopmental and social-behavioral challenges. DNA methylation (DNAm) may provide a biological link between preterm birth and later behavioral outcomes. We examined associations between DNAm profiles at neonatal intensive care unit (NICU) discharge and at age 5 with Social Responsiveness Scale (SRS) scores which measure social communication, social interaction, and repetitive behaviors at age 5, including sex-specific effects, in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study. Epigenome-wide buccal DNAm was profiled at NICU discharge (n=218) and at 5 years (n=188). We identified 38 neonatal and 6 age-5 CpG sites associated with SRS scores (all q<0.05) using epigenome-wide association studies (EWAS) at each time point. Several CpGs mapped to genes involved in neurodevelopment including TCF4, KLC4, CAP2, PTDSS1, ADAM12, SENP1, CHN2, SH3D19, and ITGA1, with sex-specific effects observed for CpGs in CAMTA1 and GABBR1. Enriched pathways included neurodevelopment, cytoskeletal regulation, stress-response, and metabolic processes. DNAm patterns during early life, particularly the neonatal period, were associated with social-behavioral development in very preterm children. Findings in key genes such as TCF4 and CAMTA1 highlight potential epigenetic mechanisms linking early-life biology to later behavioral challenges.

ImportanceTraumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. ObjectiveSince TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI. Design, Settings and ParticipantsData were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences. ResultsTBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohens d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications. Conclusions and RelevanceNatural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.

ObjectiveAlthough mental health and healthy lifestyle interventions are associated with functional outcomes in adolescence, the extent to which particular lifestyle factors explain relationships between mental health and outcome are unclear. Here we examined mediating effects of lifestyle factors on relationships between mental health and two functional outcomes measured 2-3 years later as well as the moderating effect of environmental risk factors on mediation strength in early adolescence. MethodsThis study analyzed data from 3 waves of the Adolescent Brain Cognitive Development Study (ages 10-11, 11-12, and 12-13). Mediating effects of sleep quality, screen time, physical activity and Mediterranean diet on the relationships between depression, anxiety, psychotic-like experience (PLE) distress, and total problems with two subsequent functional outcomes (academic functioning and social problems) were examined. Secondary analyses included environmental factors as moderators. ResultsSleep quality mediated 18.5%, 36.3%, 8.3%, and 3.4% of the relationships between depression, anxiety, PLE distress and total problems with academic functioning, respectively. Screen time was the second strongest mediating factor. For social problems, only sleep quality showed > 3% mediation (19.6% - 23.3%). Mediating effects of sleep and screen time on academic functioning decreased as financial adversity increased. Conversely, mediating effects of sleep quality on social problems increased with worsening family conflict, financial adversity, and school environment. ConclusionsThese results suggest that healthy lifestyle factors (in particular sleep quality) may partially explain the associations between mental health and functioning in adolescents and suggest that these effects are modulated by environmental factors. These results may have important implications for future intervention studies.

The brain age gap (BAG) -- the difference between chronological and neuroimaging-based predicted brain age -- has emerged as a sensitive biomarker of brain health. A higher BAG, reflecting an older-appearing brain, has been linked to cognitive decline, neurodegenerative disease, and mental disorders. Whether such apparent aging can be mitigated by targeted interventions remains unclear. Oestradiol (E2), a sex hormone fluctuating across the menstrual cycle and known for its neuromodulatory and cognitive effects, may represent one such target intervention. To test this, we conducted a double-blind, randomized, placebo-controlled crossover study in 28 premenopausal females. Each participant was assessed twice during the follicular phase, with at least two cycles between sessions, and received either 12 mg E2-valerate or a placebo before undergoing a T1-weighted MRI scan. BAG was estimated using a pre-trained Simple Fully Convolutional Network model. Predicted brain age was significantly younger following E2 administration compared to placebo. Exploratory analyses indicated that this effect may be moderated by resilience factors for mental health: Higher self-esteem and use of greater social support seeking was nominally associated with lower BAG, whereas females applying more expressive suppression showed more apparent brain aging. These findings suggest that even short-term increases in E2, together with resilience factors, can influence brain age estimates. Thus, E2 interventions may provide a targeted approach to support both brain and mental health. These findings underscore the urgent need for further research into the impact of E2 on mental health across the female lifespan.

ObjectiveTo examine whether screen time predicts interindividual variability regarding pubertal development across adolescence. Study designThis longitudinal cohort study included 10786 participants (47.9% female) from the Adolescent Brain Cognitive Development (ABCD) study. First, associations were examined between average daily screen time (hours/day, parent-reported Screen Time Survey) at baseline (mean age = 9.91 {+/-} 0.63 years) and pubertal timing, derived from Pubertal Development Scale (PDS) scores through 4-year follow-up (mean age = 14.08 {+/-} 0.68 years) and standardized by age and sex. Second, associations were examined between screen time groups (very low: 0-1.29 h/day; low: 1.29-2.07 h/day; moderate: 2.07-2.86 h/day; high: 2.86-4.0 h/day; very high: 4.00-12.43 h/day) and age at mid-puberty, defined as the age at first parent report of Pubertal Development Scale (PDS) category at least 3. ResultsIn linear mixed models adjusting for age, sex, race/ethnicity, socioeconomic status, BMI, and physical activity, higher log-transformed screen time at baseline was associated with more advanced pubertal timing at 1-, 2- and 3- year follow-ups, with the strongest effect observed at year 2 (standardized {beta}=0.07 [95%-CI, 0.05 to 0.10]). The associations were more pronounced in girls. The group of participants with very high screen time reached mid-puberty 2.47 months earlier [adjusted effect size, 95%-CI, -3.38 to -1.56) than participants with very low screen time. ConclusionThese findings suggest that screen time in late childhood is linked with earlier pubertal development and highlight its relevance for parental guidance on preadolescents screen media use.

BackgroundPsycho-affective symptoms and repetitive negative thinking (RNT) may increase Alzheimers disease (AD) risk. As sleep plays a key role in emotional regulation, we investigated both cross-sectional and longitudinal associations between sleep disturbances and psycho-affective health, according to amyloid-beta (A{beta}) status. MethodsOne hundred and thirty-four cognitively unimpaired older adults from the Age-Well interventional study (mean age = 68.8 {+/-} 3.8 years; 82 women; 37 A{beta}+ individuals) completed psycho-affective (Geriatric Depression Scale, State-Trait Anxiety Inventory), RNT (Rumination Response Scale-brooding, Penn State Worry Questionnaire) and sleep questionnaires (Pittsburgh Sleep Quality Index, Insomnia Severity Index). Wrist actigraphy (n=131; mean recording duration = 7.7 {+/-} 0.5 nights) provided objective measures of sleep fragmentation (sleep fragmentation index, wake time after sleep onset) and their night-to-night variability. Cross-sectional multiple linear regressions and longitudinal linear mixed-effects models (mean follow-up = 3.98 {+/-} 1.15 years) examined associations between sleep and psycho-affective symptoms, adjusting for age, sex, continuous positive airway pressure use, and the non-pharmacological intervention group (for longitudinal analyses). ResultsIn the whole cohort and in A{beta}- individuals, higher self-reported sleep difficulties and insomnia symptoms were cross-sectionally associated with greater anxiety, depression and RNT (all pFDR-corr<0.05). In A{beta}+ individuals, objective sleep fragmentation and instability were cross-sectionally associated with higher anxiety, depression and RNT. Longitudinally, higher baseline insomnia severity, mean sleep fragmentation, and night-to-night sleep instability predicted brooding worsening in A{beta}+ individuals only, while poorer perceived sleep quality predicted depressive symptoms worsening (all pFDR-corr<0.05). ConclusionsIn cognitively unimpaired older adults, associations between sleep disturbances and psycho-affective symptoms differ according to A{beta} status. In A{beta}+ individuals specifically, objective sleep fragmentation and instability are linked to psycho-affective vulnerability and brooding worsening over time. Sleep disturbances could thus represent early modifiable targets to mitigate psycho-affective symptomatology in older adults.

Anxiety is marked by exaggerated vigilance which may be linked to impaired sensory habituation, yet the physiological mechanisms linking anxiety to dysregulated habituation in the brain remain unclear. The brains ability to filter sensory input is characteristic of healthy functioning and disruption of this can lead to over-responsiveness and hypervigilance that may underlie pathological anxiety. Here, we examined how state and trait anxiety relate to acoustic startle reflex habituation across somatic (EMG), cortical (EEG), and autonomic (electrodermal; EDR) responses, and whether casual modulation of the right anterior insula (AI) or anterior mid-cingulate cortex (aMCC) using low-intensity focused ultrasound (LIFU) modulates these dynamics. As part of a larger study, forty participants (median STAI-T = 39.5; range 25 - 68) completed three LIFU sessions (AI, aMCC, Sham) while EMG, EEG, and EDR were recorded during 12 acoustic startle stimuli both before and after LIFU. Habituation slopes were computed separately for early (Trials 2-6) and late (Trials 7-12) windows using Theil-Sen estimators and analyzed with linear mixed-effects models controlling for baseline magnitude (Trial 1) and anxiety covariates. Before LIFU, higher trait anxiety predicted weaker EMG habituation ({rho} {approx} 0.3), whereas state anxiety showed no reliable association with any modality. Across sessions, early slopes were steeper than late slopes for all measures, indicating reduced adaptation with repetition. LIFU to AI or aMCC did not alter EMG or EEG habituation but significantly enhanced early-phase EDR habituation relative to sham, suggesting transient facilitation of autonomic adaptation. Cross-modal analyses revealed robust coupling between EMG and EEG habituation ({rho} {approx} 0.4-0.5, p < 0.01), independent of anxiety, whereas EDR habituation varied independently. Mean response magnitudes of EMG, EEG or EDR across trials were unrelated to anxiety and were not affected by LIFU. These findings identify coordinated cortical-somatic habituation as an anxiety-relevant biomarker and demonstrate that the AI and aMCC are involved in autonomic adaptation to sensory stimuli. Neuromodulation of these regions may provide potential therapeutic benefit to reduce autonomic reactivity to anxiety provoking stimuli.

ObjectiveSome evidence suggests that higher serum TSH may be a part of normal aging, but current studies are limited to 13-year follow-up. We examined TSH changes during 22 years of follow-up across the adult lifespan. DesignLongitudinal analyses of the population-based HUNT Study in Norway, with TSH measurements from 1995-97, 2006-08 and 2017-19. MethodsIn the overall population and in individuals without thyroid medication or disease, we estimated i) geometric mean serum TSH by age, integrating cross-sectional and longitudinal measurements using linear mixed models, ii) percentiles of the TSH distribution by age, and iii) within-individual TSH change during follow-up, expressed by geometric mean ratios (GMR) reflecting the fold change in geometric mean TSH. ResultsWe included 136,925 TSH measurements among 84,342 participants, of whom 40,615 had [&ge;]2 measurements and 13,613 had [~]22-year follow-up. Mean TSH was higher at older age in men, but weaker and less consistent in women. The TSH distribution widened at older age in men and women. Among individuals without thyroid medication or disease, mean TSH increased modestly by 0.13 mIU/L (GMR 1.09; 95%CI 1.08,1.11) during 22-year follow-up in men, but not in women (GMR 0.99; 95%CI 0.98,1.00). This increase was stronger at 0.5 mIU/L in men aged [&ge;]70 years at baseline (GMR 1.32; 95%CI 1.18,1.48). ConclusionsMean serum TSH increased with age in older men, but showed only modest or no age-related change in younger men and in women. The wider TSH distribution at older age supports the need for age-specific TSH reference ranges. Significance statementPrevious evidence of higher TSH concentrations at older age comes from cross-sectional studies and longitudinal studies with up to 13-year follow-up. We utilized a large population-based study to extend the evidence on within-individual TSH changes to [~]22-year follow-up across the adult lifespan. Mean TSH increased with age in men, modestly at 0.13 mIU/L overall, but stronger at 0.5 mIU/L in men followed from their 70s to their 90s. In women, mean serum TSH appeared stable during follow-up, but more frequent thyroid hormone supplementation may have skewed the TSH distribution away from higher, but still physiological levels. The TSH distribution widened at older age in both men and women, supporting the need for age-specific TSH reference ranges.

PTSD is defined by a core of inter-connected symptom clusters. It is currently unclear whether this pattern of interconnections remains stable across the lifespan or differs across key developmental periods. Synthesising seven international trauma-exposed samples (N=5,470), we compared network interrelationships among core self-reported and/or caregiver-reported PTSD symptom clusters (re-experiencing, avoidance and arousal) in preschoolers, school-aged children, adolescents, and adults. For self-report from school-age to adulthood, within-cluster connectivity (associations among symptoms within the same cluster) was consistently stronger than between-cluster connectivity (associations among symptoms from different clusters) across all age groups. This was especially true for the re-experiencing symptom cluster. These inter-relationships appeared stable across with lifecourse with no significant age-related differences. In contrast, caregiver reports from preschool to adolescence, showed stronger within-cluster connectivity among arousal symptoms but these only emerged in school-aged children and adolescents. Longitudinal analyses across approximately the first year post-trauma of self-report symptoms indicated that adults overall symptom connectivity increased over time, whereas school-aged childrens and adolescents networks became sparser. These findings suggest that while PTSD network architecture is broadly stable across different age groups, reporter discrepancies and temporal dynamics warrant close attention, especially with regards to less visible, internalised symptoms such as re-experiencing.

Background and AimIndividuals with non-binary gender commonly face minority stress such as invisibility, identity invalidation or even hostility within various social contexts. The COVID-19 pandemic represented an exceptional form of societal stress that presented mental health challenges in the population and probably even more so for vulnerable groups including non-binary gender individuals. We investigated whether there are gender differences in the impact of the COVID-19 pandemic on functional ability. MethodUniversity students and personnel (n=1998) responded to an online survey in May 2021, when the measures for preventing COVID-19 infections had sustained about a year and a half. Based on the gender option responses, groups of non-binary and binary (male or female) gender identity were formed. Current functioning (FUNCT), and subjective assessment of the effect of COVID-19 on functioning (COFUNCT) were recorded. Psychosocial and mental health characteristics were included in the statistical models. ResultsThe non-binary group represented 3,6 % of all study participants. The gender option "Male" was selected by 23.8% and the gender option "Female" by 72.7% of respondents. Compared to the binary group, those in the non-binary group exhibited poorer socioeconomic living situation and less favourable previous psychosocial development. Non-binary participants reported lower FUNCT and more negative COFUNCT than binary participants. In non-binary participants, a poor work situation was directly associated with poor FUNCT, while multiple adverse childhood experiences and loneliness were indirectly associated with lower FUNCT via depressive symptoms. Conversely, high family support and previous mental health care were directly associated with more negative COFUNCT, and loneliness was indirectly associated with low COFUNCT via depression. In binary participants, family support, good economy, resilience and active physical exercise associated with good FUNCT, while age, family support, good economy, resilience, active physical exercise and adverse childhood experiences associated with good COFUNCT. ConclusionsIndividuals with non-binary gender are more vulnerable for functional deficits in a period of serious societal stress such as COVID-19 pandemic. The related psychosocial and mental health factors should be taken into account when planning tailored interventions for vulnerable groups during periods of exceptional societal circumstances. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/25343131v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1bd9d76org.highwire.dtl.DTLVardef@1acee78org.highwire.dtl.DTLVardef@5c1eaeorg.highwire.dtl.DTLVardef@1e26602_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundWorldwide, common mental disorders such as anxiety and depression are major contributors to disability. However, the role of diet as a risk factor for anxiety and depression remains underexplored. Therefore, we investigated the associations between food groups and major depressive disorder (MDD) and anxiety disorders, following a harmonized protocol to enable integration of studies. MethodsWe analysed data from 1,634 participants in the Netherlands Study of Depression and Anxiety to examine cross-sectional associations between 14 dietary exposures--derived from a 238-item Food Frequency Questionnaire (fruit, vegetables, legumes, whole grains, nuts and seeds, milk, red meat, processed meat, sweet drinks, fibre, calcium, omega-3 fatty acids, polyunsaturated fatty acids, and trans fats)--and anxiety and depressive disorders in the past month (assessed with the Composite International Diagnostic Interview). Secondary outcomes were depressive symptoms (Quick Inventory of Depressive Symptomatology score [&ge;]13 vs. <13) and anxiety symptoms (Beck Anxiety Index score [&ge;]16 vs. <16). Logistic regression analyses were conducted for each dietary exposure, with depression and anxiety measures as outcomes. Results8.7% had MDD and 14.4% had an anxiety disorder in the past month. Higher vegetable intake was associated with lower odds of depression and anxiety disorders. Additionally, higher intakes of omega-3 fatty acids, red meat, whole grains, and fibre were associated with lower odds of depression and anxiety, whereas higher intake of trans fats was associated with increased odds of these disorders. Other dietary exposures were not significantly related to depression or anxiety. DiscussionCertain dietary exposures, particularly vegetables, as well as omega-3 fatty acids, red meat, whole grains, and fibre, were associated with depression and anxiety outcomes. These findings may contribute to integration of results in Global Burden of Diseases initiatives on exploring dietary risk factors of depression and anxiety.

ImportancePain is inherently aversive but provides emotional relief for individuals engaging in non-suicidal self-injury (NSSI). Despite the high prevalence and severity of NSSI, the neural mechanisms underlying pain processing in individuals with NSSI remain poorly understood. ObjectiveTo compare brain structure and functional connectivity between individuals with NSSI and controls and to relate brain function to pain inhibition. DesignCross-sectional, experimental. SettingMR Center at the Karolinska University Hospital in Stockholm, Sweden. ParticipantsWomen aged 18-35 years with NSSI (n=41) or matched healthy controls (n=40). ExposuresEngagment in self-injury [&ge;] 5 days during the last year. Main outcomes and measuresMagnetic Resonance Imaging (MRI) was used to examine brain structure and function related to pain regulation in individuals with NSSI (n=41) and healthy controls (n=40). The experimental pain test Conditioned Pain Modulation (CPM) was used to determine descending pain inhibition. ResultsWe found higher connectivity between the brains somatomotor networks and subcortical areas during resting-state functional MRI in NSSI compared to controls (P=.009; Bonferroni corrected), particularly involving the thalamus and caudate nucleus. The connectivity was linked to the level of descending pain inhibition during CPM. There was no difference between NSSI and controls regarding brain morphometry. Conclusions and relevanceOur findings suggest that individuals with NSSI may rely more on sensory-motor activations to regulate emotions. This study provides the first evidence linking specific brain circuits to pain regulation and self-injury behavior, highlighting potential pathways for more effective treatments for NSSI and related mental health conditions.