Major depressive disorder (MDD) is a global health challenge with complex etiology. The gut-brain axis, particularly neuroinflammation and synaptic dysfunction, has emerged as a critical therapeutic target. Shouhui Tongbian Capsule (SHTB), a clinically used Chinese patent medicine for constipation, has shown potential in modulating gut microbiota and alleviating comorbid mood symptoms, yet its systemic antidepressant mechanisms remain unexplored. This study aimed to evaluate the antidepressant-like effects of SHTB in mouse models and characterize accompanying gut- and brain-related biological changes. Network pharmacology was used to assess whether reported SHTB constituents were relevant to depression-related gene networks. Subsequent in vivo validation was conducted in lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS) mouse models of depression. Behavioral phenotypes, neuroinflammation, hippocampal neuronal and synaptic integrity, intestinal barrier function, and mRNA expression of selected predicted targets were evaluated. Exploratory network analysis indicated potential associations between reported SHTB constituents and depression-related gene networks, providing a preliminary rationale for animal experiments. In vivo, SHTB administration was associated with significant improvements in depressive- and anxiety-like behaviors in both LPS and CUMS-induced mouse models of depression. These behavioral effects were accompanied by attenuation of neuroinflammatory responses, preservation of hippocampal neuronal and synaptic features, maintenance of intestinal barrier integrity, and altered hippocampal expression of several neurotransmitter-related genes. SHTB showed significant antidepressant-like effects accompanied by gut-brain axis-related biological improvements. This study provides a novel, multi-evidence rationale for repurposing SHTB as a promising multi-target therapeutic agent for MDD, mediated via the gut-brain axis.
Biological systems execute discrete, often irreversible actions - from DNA replication and cell-state transitions to Venus flytrap closure, vertebrate sex change, and human symbolic behavior - not as graded responses to single variables but as threshold-governed events emerging from the convergence of multiple necessary conditions. Here we formalize this convergence logic as the ARCH × Φ framework: a multiplicative threshold function in which Archetype (A, the conserved structural substrate), Drive (D, the energetic or hormonal activation), Context (C, the releasing stimulus or social cue), and Gating Field (Φ, a sterol-modulated permissiveness variable) must jointly exceed a system-specific commitment threshold θ. The multiplicative structure enforces a zero-term veto: suppression of any single component collapses execution regardless of the state of the other three. We trace the physical origin of Φ to the incorporation of sterols into eukaryotic membranes approximately 2.4 billion years ago, at the Great Oxidation Event, when oxygen-dependent sterol biosynthesis first separated stored electrochemical drive from discharge permissiveness - two quantities physically coupled in all pre-sterol membrane systems and independently tunable only with the arrival of the cholesterol ring structure. We propose that Φ is instantiated across three cholesterol-derived tiers: rapid modulation through accessible cholesterol pools and their oxysterol derivatives, intermediate modulation through neurosteroids synthesized via mitochondrial pathways, and lifetime-scale modulation through structural cholesterol deployment in myelin and perineuronal nets - all expressions of a single biophysical mechanism. We extend this account to two additional isoprenoid-based Φ systems: non-photochemical quenching (NPQ) in plant chloroplasts, where zeaxanthin and the PsbS protein constitute a zero-term veto gate for light-energy dissipation that is characterized to picosecond resolution, and insect holometabolous metamorphosis, where juvenile hormone functions as a Φ-suppressor and the dietary sterol auxotrophy of insects produces an environmentally gated Φ architecture distinct from the endogenous sterol synthesis of vertebrates. Monogenic Φ-lock disorders - exemplified by Niemann-Pick type C disease, in which disrupted intracellular cholesterol trafficking abolishes KCNQ2/3-dependent inhibitory gating - provide pathological proof-of-concept for the Φ-lock failure mode at the molecular level. The framework is formally equivalent to the h inactivation variable derived independently by Hodgkin and Huxley from squid axon voltage-clamp data in 1952, implying that Φ is not solely a theoretical construct but a measurable property of excitable membranes with a 2.4-billion-year evolutionary history. Explicit, falsifiable predictions are derived regarding perturbation-matrix experiments, CYP46A1 polymorphism effects on behavioral thresholds, the correlation of sterol enzyme diversity with behavioral plasticity rather than execution speed across taxa, dietary sterol auxotrophy and insect developmental plasticity, and τΦ acceleration as a route to increased biological output yield.
Diet is a primary and modifiable determinant of gut microbiota composition, diversity, and metabolic activity, thereby shaping microbial-derived metabolites, immune and inflammatory signalling, neuroendocrine regulation, and neural communication with the central nervous system. Western dietary patterns, characterised by high intake of ultra-processed foods, saturated fats, and low dietary fibre, are consistently associated with gut dysbiosis, impaired intestinal barrier function, chronic low-grade inflammation, and increased risk of depression, anxiety, cognitive impairment, and neurodegenerative disorders. This narrative review synthesises evidence from human observational studies, randomised controlled trials, animal models, and mechanistic investigations examining interactions among diet, gut microbiota, and mental health or neurobiological outcomes. Literature searches were conducted in PubMed, Scopus, and Web of Science for articles published up to December 2025. The study highlights the therapeutic potential and limitations of dietary interventions, prebiotics, probiotics, and psychobiotics, and critically evaluates them. Also facilitates an improved understanding of diet-microbiome-brain interactions, which may help the development of personalised, nutrition-based strategies integrated into mental health prevention and clinical care. These findings support diet-based, microbiome-informed strategies as scalable adjuncts in mental health prevention and care.
Although depression and biological aging share dyslipidemia as a common pathological feature, the extent to which dyslipidemia is involved in their association remains unclear. This study aimed to explore the association between depressive symptoms and accelerated biological aging, with a particular focus on whether dyslipidemia, as measured by the lipid accumulation product (LAP), statistically mediates this association. A total of 4,150 American adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) database were included. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and accelerated aging was measured via phenotypic age acceleration (PhenoAgeAccel). Weighted multivariable linear regression, restricted cubic spline (RCS) analyses, subgroup analyses, and interaction tests were conducted to examine the associations between depressive symptoms and PhenoAgeAccel. Mediation analysis was subsequently conducted to assess the statistical mediating role of LAP in this association. Among the 4,150 participants, 375 (9.0%) had probable depression (PHQ-9 score ≥ 10). In the fully adjusted model, both depression status and continuous PHQ-9 score were positively associated with PhenoAgeAccel (depression: β = 0.76, 95% CI: 0.03-1.49; PHQ-9: β = 0.06, 95% CI: 0.01-0.11) and with LAP (depression: β = 4.01, 95% CI: 0.25-7.76; PHQ-9: β = 0.34, 95% CI: 0.09-0.60). Mediation analysis revealed that LAP accounted for 12.05% (95% CI: 2.52%-24.95%, P = 0.01) of the association between depression and PhenoAgeAccel in the fully adjusted model. Subgroup analyses indicated that the associations were stronger among individuals with higher income (poverty income ratio [PIR] > 3.5), those with diabetes, and those without cardiovascular disease (CVD) or chronic obstructive pulmonary disease (COPD) (all P < 0.05). Interaction analyses further indicate significant interactions of PIR and diabetes status with the association between depression and PhenoAgeAccel (both P for interaction < 0.05). Depressive symptoms were significantly associated with accelerated biological aging, and this association was partially statistically mediated by LAP. Further prospective studies with longitudinal designs are warranted to establish temporal precedence and investigate the potential biological pathways linking depression, LAP, and accelerated biological aging.
Biological heterogeneity presents a formidable challenge in understanding psychiatric illness, yet it remains underexplored at scale or in a pan-disease setting. We characterized biochemical and brain heterogeneity in 445,374 individuals, considering 9 psychiatric disorders and 30 non-psychiatric medical conditions. Psychiatric and non-psychiatric illnesses were characterized by greater biological heterogeneity than predicted by healthy variation. Notably, heterogeneity in psychiatric disorders was comparable to non-psychiatric illnesses and often diverged from diagnostic classification. Circulating glucose and glycated hemoglobin levels were the most heterogeneous traits in 65% of diagnoses, suggesting that glucose dysregulation is pervasive yet variable across diseases. Diagnosis-specific patterns also surfaced-e.g., in schizophrenia, developmental brain markers ranked among the most heterogeneous traits. These characterizations of biochemical and brain heterogeneity lay the groundwork for biological focal points to aid precision psychiatry research. To support this effort, we provide an interactive online resource for exploring and downloading illness-specific heterogeneity measures.
To assess faculty interest in veterinary biospecimens, develop a standardized multi-institutional biological fluid repository across 3 veterinary institutions, and assess quality and fitness for purpose of archived samples. We conducted a prospective multi-institutional biobanking and feasibility study from 2022 through 2025. Faculty from each institution were administered a voluntary and anonymous survey via email, and responses were recorded. Biological fluid specimens were collected and archived from the Neurology and Neurosurgery Services of each participating institution. A shared database (Freezerworks) was utilized by all 3 institutions to annotate each sample with clinical data and record the storage location. Selected serum (n = 12), CSF (n = 12), and urine (n = 9) samples were assessed for quality control and fitness for purpose by measuring concentrations of putative biomarkers via ELISAs and single-molecule array, respectively. Faculty surveys indicated widespread support for centralized institutional biobanking, with 94 of 170 respondents (55%) in favor of a combination of institutional and investigator financial support. Over 2,500 biological specimens from dogs and cats with neurological disease were collected during the 3-year study period. Sample quality across serum, urine, and CSF was consistent across institutions. Moreover, serum samples from randomly selected dogs with divergent diagnoses yielded robust and discriminatory concentrations of putative neurodegenerative disease proteins. Multi-institutional veterinary biobanking is feasible and productive, providing investigators with access to clinically annotated, high-quality biospecimens. A common repository registry, wherein investigators have reciprocal access to standardized biospecimens, will connect investigators from all domains to promote rigorous, well-powered multicenter studies.
Repetitive head impacts in former contact sport athletes are associated with cognitive impairment, accelerated cerebral atrophy and risk of neurodegenerative disease. Epigenetic clocks derived from age-associated DNA methylation (DNAm) profiles may capture accelerated biological ageing in neurodegenerative conditions; however, their application in former athletes remains unexplored. Here we aim to explore the application of epigenetic clocks as a measure of accelerated biological ageing in a cohort of former athletes. In 126 former athletes (96% male; mean age: 54.5±14.4 years; mean concussions: 6.8±6.7), we examined associations of brain volumes, plasma neurofilament light levels and cognitive/behavioural scores with DNAmAge-acceleration, AgeAccelResidual and DNAmFitAge-acceleration. We only found an association between the number of concussions and DNAmFitAge-acceleration (p=0.003, B=0.46, R²=0.063), indicating that every two additional concussions were associated with a 5-year increase in DNAmFitAge-acceleration. There was also a trend towards an association between years of play and DNAmAge-acceleration in older athletes. These preliminary findings suggest that specific epigenetic clock measures may serve as early markers of biological ageing related to repetitive head impacts.
Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer's disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this study were to characterise plasma pTau181 in a middle-aged birth cohort aged 45 years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 (n = 854, 49% female) were associated with self-reported cognitive concerns (β = 0.09, p = .008); however, no significant associations were observed with objective cognitive decline, worse structural brain integrity, or biological ageing. Higher plasma pTau181 was associated with self-reported cognitive concerns at age 45, but not objective AD-related measures. The association of plasma pTau181 and self-reported cognitive concerns in this cohort suggests that AD pathology may begin to accumulate by age 45 and may be associated with subtle changes in cognition that are not at objectively measurable levels.
Cutaneous disorders such as atopic dermatitis, psoriasis, acne vulgaris, and rosacea, together with UV-induced skin injury and photoaging, are highly prevalent conditions that involve varying contributions from dysregulated immune responses, cutaneous inflammation, oxidative stress, barrier dysfunction, microbiome alteration, and exogenous injury. However, these conditions are biologically heterogeneous and should not be regarded as a single mechanistic class. Sulforaphane, a naturally occurring isothiocyanate found primarily in broccoli and other cruciferous vegetables, has attracted interest in dermatology because of its antioxidant, cytoprotective, and context-dependent anti-inflammatory properties. Sulforaphane exerts its biological effects by modulating key signaling pathways, particularly the Keap1/Nrf2 pathway and, in some settings, NF-κB-related signaling, thereby reducing oxidative stress and inflammation, regulating immune responses, enhancing skin barrier function, and potentially influencing the cutaneous microbiome. Preclinical studies and limited human data suggest that sulforaphane may reduce erythema, edema, and other markers of cutaneous damage in selected settings. This comprehensive review explores the role of sulforaphane across heterogeneous cutaneous conditions, with emphasis on molecular mechanisms, disease-specific differences, current evidence, and discusses key translational constraints including formulation, delivery, lack of standardized dosing, and the limitations of cell culture and animal models for predicting human efficacy. Overall, sulforaphane should presently be regarded as a promising but still early-stage translational candidate in dermatology. Robust human efficacy data remain lacking for chronic inflammatory dermatoses such as psoriasis, atopic dermatitis, acne, and rosacea, whereas the strongest current human evidence relates to UV-associated skin outcomes and photoprotection.
Bipolar disorder (BD) is a chronic psychiatric illness associated with high rates of medical comorbidities, among which metabolic syndrome (MetS) is particularly prevalent and consequential. Affecting nearly half of individuals with BD, MetS compounds the risk of cardiovascular disease, type 2 diabetes, and premature mortality, while also undermining psychiatric stability and cognitive functioning. Despite these outcomes, metabolic health remains underrecognized and undertreated in psychiatric care. This narrative review aims to examine the bidirectional relationship between BD and metabolic syndrome and to highlight multidisciplinary strategies for metabolic monitoring and clinical management in this population. A targeted literature search was conducted using PubMed (2000-2025), covering studies on the epidemiology, behavioral and biological mechanisms, pharmacologic and lifestyle interventions, and clinical care integration related to BD and MetS. The review followed established quality guidance for narrative synthesis and was structured using the Population-Concept-Context framework to improve transparency in the selection and synthesis of the literature. The comorbidity between BD and MetS is shaped by multiple interacting factors, including shared behavioral risk factors, inflammatory pathways, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and the metabolic effects of psychotropic medications. While pharmacological treatment remains essential for mood stabilization, systematic metabolic monitoring is crucial to mitigate treatment-related risks. Evidence supports the central role of lifestyle interventions, including nutritional strategies and physical activity in reducing cardiometabolic risk. Emerging therapeutic approaches such as GLP-1 receptor agonists and ketogenic metabolic therapy show potential benefits but require careful clinical integration. In selected individuals with severe or refractory obesity, bariatric surgery may be considered. Therapeutic patient education (TPE) represents the cornerstone of care by supporting self-management, treatment adherence, and shared decision-making. Addressing the dual burden of BD and MetS requires a multidisciplinary and patient-centered approach integrating metabolic monitoring, lifestyle interventions, pharmacological strategies, and therapeutic patient education. Strengthening collaboration between psychiatry, primary care, and metabolic specialists is essential to reduce cardiometabolic risk and improve long-term health outcomes in this vulnerable population.
The perinatal period represents a vulnerable period in which women may experience high psychic distress due to psychological, biological and social changes. The prevalence of perinatal depression (PND) is estimated around 15%-20% during pregnancy and 16%-18% after childbirth. Although several risk factors have been investigated in the PND development, few studies explored the role of affective temperaments, well known to exert a role in any mood disorders. The aim of our study was to explore which is the most represented affective temperamental profile in PND as well as which is its role in the development and severity of depressive symptoms during perinatal period. All pregnant women admitted at the Perinatal Mental Health Outpatient Service, Unit of Clinical Psychiatry, University Hospital of Marche, Polytechnic University of Marche, Ancona, Italy, between April 2021 and July 2025, were screened for PND through Edinburgh Postnatal Depression Scale (EPDS) and a semi-structured clinical interview (SCID-5-CV). Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-M) was administered to all pregnant women. The PND prevalence was 33.1%. PND was significantly associated with higher cyclothymic (B = 0.356, p = 0.001) and anxious TEMPS-M scores (B = 0.247, p = 0.026) and a positive psychiatric history (B = 5.245, p < 0.001) (R = 0.6, R2 = 0.36, F(3,129) = 24.189, p < 0.001). Logistic regression indicated that cyclothymic (Exp(B)=1.118, p=0.008), hyperthymic (Exp(B)=0.911, p=0.049), anxious temperaments (Exp(B)=1.109, p=0.029), presence of medical comorbidities (Exp(B)=0.224, p=0.003) and psychiatric history (Exp(B)=5.144, p=0.001) were independent predictors of PND. Affective temperaments, particularly cyclothymic and anxious profiles, and prior psychiatric history are predictors of perinatal depression. Incorporating temperament assessment alongside standard screening tools such as the EPDS may improve early identification of women at risk, supporting tailored preventive and therapeutic strategies.
Environmental adversity is linked to major depressive disorder (MDD), potentially via sustained low-grade inflammation. However, serum markers such as C-reactive protein (CRP) are transient and sensitive to acute states. In contrast, epigenetic signatures of inflammation may provide a more stable trace of how stress becomes biologically embedded and contributes to depression risk over time. In a subsample of the Marburg-Münster Affective Disorders Cohort Study (MACS; N = 579; 320 healthy controls, 259 with MDD), we examined whether early life adversity (ELA; CTQ) and recent life stress (RLS; LEQ) are associated with CRP-related DNA methylation (CRPm) at baseline. We further tested whether CRPm predicts depressive symptom severity (HAMD) at baseline and at two-year follow-up (n = 407). DNA was extracted from whole blood, and CRPm scores were computed using publicly available genome-wide summary statistics. CRPm explained 21.3% of the variance in serum high-sensitivity CRP (hsCRP). Higher CRPm was significantly associated with both ELA (b = 0.01, SE = 0.003, p = 0.017) and RLS (b = 0.01, SE = 0.004, p = 0.032), after adjusting for age and sex. CRPm also predicted depressive symptom severity at baseline (b = 0.68, SE = 0.27, p = 0.013) and at follow-up (b = 0.79, SE = 0.25, p = 0.002). These associations remained after controlling for white blood cell-type composition but were attenuated after adjusting for BMI and smoking. In contrast, hsCRP was not associated with adversity or depressive symptoms. Our study indicates that a methylation-based index of chronic inflammation is associated with stress exposure and depressive symptoms over time, in contrast to fluctuating serum hsCRP. The findings are more consistent with an indirect pathway in which environmental adversity is linked to inflammatory biology via stress-related health behaviors, rather than with a model of direct biological embedding.
Depression is a major psychiatric illness with a global burden, poor treatment response, and limited biological markers, leaving diagnosis reliant on behavioral rather than biological methods. While there is an increasing number of individual metabolomic studies investigating depression, comprehensive meta-analyses remain lacking. In this study, we conducted three meta-analyses integrating 11 publicly available blood mass spectrometry (MS) datasets with 1050 samples (386 depression patients, 664 controls) and 1111 unique metabolites. Robust Rank Aggregation (RRA), Uniform Manifold Approximation and Projection (UMAP)-based clustering, and Partial Least Squares Discriminant Analysis (PLS-DA) were used as complementary integrative approaches. We identified 42 altered metabolites, with consistent elevations in glutamate, aspartate, 2-hydroxybutyrate, and ketone bodies, and reductions in glycine, glutamine, taurine, branched-chain amino acids, citrate, and urea-cycle intermediates. RRA replicated strong disruptions in glutamatergic, tryptophan, aromatic amino acid, and branched-chain amino acid metabolism. Pathway enrichment indicated coordinated alterations in amino acid, nitrogen, and nucleotide metabolism, and neurotransmitter signaling. Together, these results suggest that dysregulation in neurotransmitter synthesis and signal transduction, impaired excitatory-inhibitory cycles in the brain, altered energy metabolism, and nitrogen and nucleotide metabolism contribute to the development of depression. This metabolomic signature offers a potential access point to the development of novel therapeutic and diagnostic approaches.
Consciousness can persist, transform, and dissolve across wakefulness, sleep, and advanced meditation. Despite empirical and theoretical advances within each domain, these states are rarely examined within an integrated scientific framework. An interdisciplinary perspective reveals converging phenomena that challenge binary accounts of consciousness and highlight its graded, dynamic, and trainable nature. Here, we argue that the interface of advanced meditation, sleep, and consciousness science constitutes a promising yet underexplored frontier for understanding the structure, dynamics, and limits of conscious experience. Advanced meditation offers cultivable, reproducible, and controlled means for modulating these dimensions. Sleep provides recurring biological states in which awareness, experiential content, embodiment, and sensory input coupling systematically dissociate and recombine. Consciousness science contributes conceptual and theoretical frameworks for relating phenomenology to neural dynamics across waking, sleeping, and meditative states. We synthesize evidence from these domains to highlight a set of informative states -including deep absorption meditation, cessations, lucid dreaming, sleep-wake transitions, clear light sleep- that challenge binary distinctions between consciousness and unconsciousness, and reveal a modulation, reorganization, and interruption of conscious experience that may not be fully captured within any single domain. By bridging advanced meditation, sleep, and consciousness science we outline how an integrated, interdisciplinary, and mixed-methods perspective enables a more nuanced examination of graded and minimal forms of conscious experience. This integrative approach offers a biologically and empirically grounded pathway for advancing theories of consciousness and examining how conscious awareness may be accessed, modulated, and trained across waking and sleeping states, including in relation to health and well-being.
Late-onset mood disorders frequently emerge in the context of aging-related brain changes, medical comorbidity, and cognitive vulnerability, complicating diagnosis and treatment. Symptom-based criteria alone lack biological specificity in older adults, contributing to diagnostic heterogeneity and variable outcomes. Converging neuropathological, neuroimaging, and circulating biomarker evidence suggests that vascular injury, chronic neuroinflammation, and early neurodegeneration may contribute to a meaningful subset of late-onset depressive and bipolar syndromes. This perspective synthesizes current evidence and proposes a neuropathology-informed framework integrating accessible biomarkers (including white matter hyperintensities, C-reactive protein, and neurofilament light chain) into staged clinical and research pathways. We emphasize that current evidence is largely observational and that randomized trials testing biomarker-guided care are needed before routine implementation. A phased research and infrastructure-building agenda is outlined, alongside ethical considerations including equity, diagnostic uncertainty, and the potential harms of premature adoption. This framework offers a hypothesis-generating path toward precision geriatric psychiatry while underscoring the need for rigorous validation.
Diverse refugee, immigrant, and migrant (RIM) populations in the United States face complex mental health needs that are shaped by migration experiences, cultural transitions, and structural barriers to accessing care. Although RIM populations have different legal statuses, cultural backgrounds, and lengths of U.S. residence, many encounter common stressors related to uncertain immigration policies, economic instability, and limited access to culturally responsive services. Recent federal actions-including suspension of the U.S. Refugee Admissions Program and revocation of "protected areas" policies-have intensified fears and mental health vulnerabilities among these populations. Using a multilevel, biopsychosocial approach, the authors aimed to provide clinical guidance on the biological, structural, sociocultural, and health care system factors that affect mental health care delivery for RIM populations. This article provides evidence-based clinical guidance and actionable recommendations that allow clinicians to selectively apply interventions (e.g., trauma-informed practices, low-barrier care models, medical-legal partnerships, and culturally responsive approaches that respect alternative healing frameworks) on the basis of individual patient circumstances. Key recommendations pertain to working with professional interpreters, navigating diagnostic ambiguity, and interfacing with immigration enforcement.
Childhood maltreatment is a major public health concern in the U.S. and globally with long-term consequences for physical and mental health. Whether childhood maltreatment predicts problematic reproductive health outcomes is unknown as the existing literature reveals mixed results with a heavy reliance on retrospective studies, and of the very few prospective studies, follow-up does not extend beyond 21 years of age. This study leveraged a unique prospective cohort with court documented cases of childhood abuse and neglect and 30-years follow-up in middle adulthood on pregnancy-related reproductive health outcomes. Conduct a rigorous, prospective study of associations between childhood maltreatment and reproductive health in middle adulthood, leveraging a unique prospective cohort, to overcome methodological weaknesses in previous studies that rely primarily on retrospective reports of childhood maltreatment. A prospective longitudinal follow-up of children aged 0-11 years with court documented cases of physical abuse, sexual abuse, and neglect, from a U.S. Midwestern County (1967-1971) and a demographically matched comparison group (original study of 1,575 children). At 30-years follow-up (2003-2005), 807 adult participants completed medical status examinations and comprehensive health interviews; the final sample includes N = 426 (52.7%) females, based on biological sex at birth, who responded to a module on reproductive health. In regression analyses, we investigated whether childhood maltreatment (any exposure) and subtypes of childhood maltreatment (physical abuse, sexual abuse, and neglect) affected giving birth preterm or to low birth weight infants, infertility, teen pregnancy, and breastfeeding, and explored gravidity (number of pregnancies) and parity (number of live births). Covariates considered were demographic factors and physical health indicators previously associated with childhood maltreatment and reproductive health, including poor glycemic control (indicator of risk for diabetes), high body mass index (BMI), sexually transmitted infections and diseases (STIs and STDs), hepatitis C, human immunodeficiency virus (HIV), and smoking. At 30-years follow-up, participants were mean age = 41.39 years (SD = 3.58, range 32-49). Adjusting for age, race, employment, marital status, and high school education (selected based on group differences p < .05), the childhood maltreatment group had increased odds of giving birth to low birth weight infants (< 5.5lbs; p < .05) and significantly higher gravidity (p < .05). By maltreatment subtype, the sexual abuse subgroup had increased odds for infertility (p < .05) and engagement with breastfeeding (p < .05), and the neglect subgroup had increased odds of giving birth to low birth weight infants (p < .01) and significantly higher gravidity (p < .05). Sensitivity analyses adjusting for poor glycemic control attenuated the associations. Childhood maltreatment influences reproductive health, in some instances leading to increased risk, such as infants born low birth weight, and in others leading to a positive health behavior, greater breastfeeding engagement. Maltreatment also led to higher gravidity (pregnancies) but not parity (live births), possibly indicating increased pregnancy loss. Poor glycemic control played an important role in understanding these associations, interpreted as possible chronic alterations in stress hormones affecting reproductive health. Findings suggest opportunity for trauma-responsive preventive interventions for individuals exposed to childhood maltreatment. Future research directions are the systematic examination of biological and behavioral mechanisms in these associations.
Chronic post-surgical pain (CPSP), pain lasting at least three months past the expected recovery time of a surgery, affects up to 30% of post-surgical populations. It is multifaceted and influenced by biological and psychological factors. One such factor is exposure to adverse childhood experiences (ACEs), with previous research indicating that exposure to a greater number of ACEs increases the risk of chronic pain development. One of the most frequently experienced types of ACEs is parental upheaval, including divorce and separation, yet its impact on pain-related cognitions and experiences remains understudied. 65 individuals with CPSP were included in this cross-sectional analysis. Individuals provided self-reported data on their childhood trauma history, as well as measures related to pain perception. Individuals were sorted into two groups based on parental upheaval status: upheaval (n = 18) and non-upheaval (n = 47). Participants in the upheaval group demonstrated a more globally connected pattern with pain-related cognitions, anxiety, and somatic arousal contributing to pain interference, while in the non-upheaval group, pain catastrophizing was the central factor influencing interference. Across the sample, pain catastrophizing not parental upheaval status was the most significant variable related to CPSP development. Finally, age and perceived trauma intensity (of the parental upheaval) were positively correlated. CPSP is a complex condition and warrants biopsychosocial research to elucidate the mechanisms contributing to its onset and maintenance. This study indicates that parental upheaval, one of the more common traumatic events that can happen in childhood, may play an indirect role in pain experiences, potentially increasing vulnerability to maladaptive pain-related cognitions. These findings highlight the importance of considering the influence of ACEs and how they can impact development and subsequently lead to pain-related outcomes across the lifespan.
Although morphological abnormalities of the corpus callosum (CC) have been reported in schizophrenia, findings across studies have been inconsistent. We systematically examined whether these morphological alterations are influenced by age. A total of 151 individuals with treatment-naïve first-episode schizophrenia (FES) and 278 healthy controls were included. T1-weighted structural MRI scans were used to segment the CC on the midsagittal plane into 100 equidistant points, and CC thickness was estimated at each point. To determine whether CC thickness abnormalities associated with schizophrenia were moderated by age, we applied the Johnson-Neyman technique. Additionally, we investigated the relationship between age-dependent CC thickness abnormalities and clinical symptoms using partial least-squares correlation analysis. Abnormal CC thickness was observed in individuals with treatment-naïve FES, specifically within the rostral body, anterior midbody, isthmus, and splenium. These regions were thinner in younger patients compared with healthy controls but appeared thicker in older patients. Furthermore, increased CC thickness in older patients was associated with greater clinical symptom severity, whereas this association was not observed in younger patients. Our findings demonstrate that CC thickness abnormalities in treatment-naïve FES are age-dependent. The relationship between CC thickness and symptom severity also varies as a function of age. These results suggest that the CC may represent a critical biological target for age-sensitive, individualized therapeutic interventions in schizophrenia.
This study examined whether the association between early post-trauma cortisol levels and posttraumatic stress disorder (PTSD) onset is moderated by the burden of preexisting physical disorders (PDs), with attention to earlier- versus delayed-onset PTSD. Given evidence that earlier-onset and delayed-onset PTSD may involve distinct temporal and pathophysiological mechanisms, we hypothesized that cortisol and number of PDs would more strongly predict earlier-onset PTSD. Data were drawn from a prospective cohort of 895 adults hospitalized for traumatic injuries. Morning serum cortisol was measured within one month post-trauma. The number of PDs was assessed as a count of affected organ system categories, based on a 15-category system that integrated medical history, treatment records, and self/caregiver reports, without accounting for severity or functional impact. PTSD was evaluated at 3, 6, 12, and 24 months using the CAPS-5, and classified as earlier-onset (≤6 months) or delayed-onset (>6 months). Logistic regression models tested main and interaction effects of cortisol and number of PDs on PTSD onset, controlling for relevant covariates. Neither cortisol nor number of PDs independently predicted PTSD onset. However, lower cortisol predicted earlier-onset PTSD only among individuals with higher number of PDs (adjusted interaction p = 0.021). No association was found in those with lower number of PDs or for delayed-onset PTSD. Cortisol and number of PDs were modestly negatively correlated. number of PDs moderates the association between early post-trauma cortisol and earlier-onset PTSD. These findings highlight a context-dependent biological vulnerability and may help explain prior inconsistencies in cortisol-PTSD research. Integrating somatic health status into early PTSD risk models may improve prediction and prevention strategies.