Biological Psychiatry Global Open Science

Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influence emotional and behavioral development. However, longitudinal evidence linking preadolescent endocrine influences to adolescent psychopathology remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (Nmax=10,562), we analyzed whether salivary DHEA during preadolescence predicted later externalizing and internalizing symptoms during adolescence. To create a more robust estimate for hormonal levels in preadolescence, hormone concentrations were averaged across baseline and 1-year follow-up (age range=8.9-12.4 years). Outcomes were measured via the Child Behavior Checklist (CBCL) at the 2-, 3-, and 4-year follow-ups (age range=10.6-15.8 years). Sex-stratified linear mixed models were employed, adjusting for age, race/ethnicity, BMI and physical activity. In males, higher DHEA levels were linked to fewer externalizing symptoms across all follow-ups (e.g., {beta}=-0.07 SD change of CBCL per SD-change of log-transformed DHEA levels (95% CI [-0.10, -0.04] at 3-year) and to fewer internalizing symptoms at 3-year and 4-year follow-ups. The effect of preadolescent DHEA in males translated into a reduced probability of externalizing symptoms crossing borderline or clinical thresholds at each follow-up (e.g., adjusted Risk Ratio=0.76 to reach clinical threshold for CBCL externalizing per SD increase in log-transformed DHEA; 95% CI [0.62, 0.98] at 3-year). In females, no hormone-symptom associations emerged. Interestingly, sex-by-DHEA interaction effects increased with age for both symptom domains. These findings suggest that preadolescent adrenal endocrine influences may play a role in thedevelopment of sex-specific vulnerability during adolescence. Future studies should consider adrenarche as a sensitive period for hormonal effects on mental health.

Insulin resistance, an often-untreated precursor of type 2 diabetes mellitus (T2DM), is implicated in cognitive decline in adults, yet its impact on the developing brain in youth with obesity remains poorly understood. We investigate whether insulin resistance moderates the relation between hippocampal volume and unhealthy food-seeking in overweight and depressed youth ages 9-17 who completed an oral glucose tolerance test and a cognitive task assessing unhealthy food-seeking motivation at baseline, 6-, and 24-months follow-up, and structural MRI at baseline and 6-months follow-up. Insulin sensitivity moderated this relation: smaller baseline hippocampal subfield volumes predicted increased unhealthy food-seeking over 24 months (ps<0.05). Categorical grouping revealed subfield CA2/3 and 4 volumes predicted this relation among insulin-resistant (ps<0.05), but not insulin-sensitive (ps>0.10), youth, suggesting that threshold criteria for insulin resistance are physiologically meaningful. These findings identify a neuro-metabolic risk phenotype that precedes T2DM and may accelerate unhealthy food-seeking severity in youth with obesity.

ImportanceMaternal diabetes (MD) and maternal obesity (MO) have been robustly established to confer health risks in offspring. Additionally, mounting evidence suggests that these fetal programming effects vary by sex, but whether these factors independently or interactively influence infant brain development remains unclear. ObjectivesTo characterize interactions between MD, MO, and sex on offspring subcortical brain volumes. Design, setting and participantsThis was a cross-sectional study of 1,966 infants from six international cohorts. ExposuresMD and MO Main outcomes and measuresMRI-based subcortical brain volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate) were segmented and mixed effects models were used to examine associations, controlling for age at scan, prematurity, birthweight, maternal education, and intracranial volume. Backward elimination regression was used to identify the best fitting model (3-way interaction, 2-way interaction, no interaction) for each region and false discovery rate (FDR) corrections were applied. ResultsOf 1,966 infants, 46% were female (N=909), 9% were exposed to MD (N=172), and 21% were exposed to MO (N=386). MRI scans were performed at (mean{+/-}SD) 25.9{+/-}18.8 days of age. There was a significant interaction between MD, MO and sex in the thalamus (standardized {beta}=-0.32, 95%CI -0.54 to -0.11, FDR corrected P=0.014). In female infants, MD (standardized {beta}=-0.10, 95%CI -0.02 to -0.003, P=0.04) and MO (standardized {beta} =-0.09, 95%CI -0.14 to -0.03, P=0.003) were independently and negatively associated with thalamic volume. In males, a significant interaction between MD and MO was observed (standardized {beta} =-0.20, 95%CI -0.34 to -0.06, P=0.005), with post hoc analysis showing that males with combined exposure to MD and MO had lower thalamic volume compared to those with one or neither exposure (all Ps<0.05). In the hippocampus, an interaction between MO and infant sex was identified (standardized {beta} =0.15, 95%CI 0.05 to 0.26, FDR corrected P=0.015), whereby MO (independent of MD) was associated with lower offspring hippocampal volume in females only (standardized {beta} =-0.12, 95%CI -0.2 to -0.05, P=0.002). Conclusion and relevanceOur results suggest independent, interactive associations of intrauterine exposure to MD and MO with infant subcortical brain volumes, varying by sex. This has implications for future metabolic disorders, among other health risks. SummaryThis study aims to investigate how sex modulates the influence of intrauterine exposure to maternal diabetes (MD) and maternal obesity (MO) on infant subcortical brain volumes. We observed sex-specific associations of gestational exposure to MD or MO with infant brain volumes in regions critical for motivation, emotion, and signal integration. In female offspring, MD and MO were negatively and independently associated with thalamic volume, while MO was negatively associated with hippocampal volume. In males, combined exposure to MD and MO was associated with lower thalamic volume. Sex modulates the influence of prenatal exposure to MD and/or MO on early brain development. This has implications for future metabolic disorders, among other health risks.

Chronic stress disrupts glutamatergic and GABAergic plasticity in the medial prefrontal cortex (mPFC), impairing circuit integration and contributing to the pathophysiology of stress-related disorders, such as Major Depressive Disorder (MDD). Rapid-acting antidepressants like ketamine can rapidly reverse these deficits, but its clinical use is limited by psychotomimetic side effects. Notably, the 5-GABAAR negative allosteric modulator (5-NAM) Basmisanil (BSM), reproduces ketamine-like behavioral outcomes in preclinical models, although the cellular mechanisms underlying its actions remain unclear. Here, we investigated whether BSM promotes ketamine-like enhancement of cortical plasticity and engages cell type-specific mechanisms to support adaptive behaviors over time. We show that BSM produced rapid and sustained facilitation of motivational, hedonic, and active coping behaviors via mPFC circuits. BSM induced c-Fos expression in mPFC D1R- and somatostatin-expressing cells, suggesting activation of specific subsets of pyramidal and GABA interneurons. In both mPFC and hippocampus, BSM rapidly activated Erk- or Akt-mTOR signaling pathways as well as increased synaptic proteins critical for glutamatergic and GABAergic function. BSM also reversed maladaptive behaviors induced by chronic unpredictable stress, including impairment in object recognition memory and social interaction. Finally, chemogenetic silencing of mPFC CaMKII-expressing neurons blocked both rapid and sustained actions of BSM, whereas inhibition of mPFC GABA interneurons reversed only long-term behavioral outcomes. These results indicate that 5-GABAAR modulation requires early activation of pyramidal neurons to drive rapid plasticity, while GABAergic adaptations support sustained improvements. This dynamic mechanism restores excitation-inhibition (E/I) balance and highlights GABAergic pathways as therapeutic targets for prefrontal dysfunction in stress disorders.

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interests neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes. Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early mid-gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of prenatal insults in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.

Elevated manganese (Mn) exposure is associated with attentional deficits in children, and is an environmental risk factor for attention deficit hyperactivity disorder (ADHD). We have shown that developmental Mn exposure causes lasting attention and sensorimotor deficits in a rat model of early childhood Mn exposure, and that these deficits are associated with a hypofunctioning catecholaminergic system in the prefrontal cortex (PFC), though the mechanistic basis for these deficits is not well understood. To address this, male Long-Evans rats were exposed orally to Mn (50 mg/kg/d) over PND 1-21 and attentional function was assessed in adulthood using the 5-Choice Serial Reaction Time Task. Targeted catecholaminergic system and epigenetic gene expression, followed by unbiased differential DNA methylation and gene regulation expression transcriptomics in the PFC, were performed in young adult littermates. Results show that developmental Mn exposure causes lasting focused attention deficits that are associated with reduced gene expression of tyrosine hydroxylase, dopamine transporter, and DNA methyltransferase 3a. Further, developmental Mn exposure causes broader lasting methylation and gene expression dysregulation associated with epigenetic regulation, inflammation, cell development, and hypofunctioning catecholaminergic neuronal systems. Pathway enrichment analyses uncovered mTOR and Wnt signaling pathway genes as significant transcriptomic regulators of the Mn altered transcriptome, and Western blot of total, C1 and C2 phospho-mTOR confirmed mTOR pathway dysregulation. Our findings deepen our understanding of the mechanistic basis of how developmental Mn exposure leads to lasting catecholaminergic dysfunction and attention deficits, which may aid future therapeutic interventions of environmental exposure associated disorders. Significance StatementAttention deficit hyperactivity disorder (ADHD) is associated with environmental risk factors, including exposure to neurotoxic agents. Here we used a rodent model of developmental manganese (Mn) exposure producing lasting attention deficits to show broad epigenetic and gene expression changes in the prefrontal cortex, and to identify disrupted mTOR and Wnt signaling pathways as a novel mechanism for how developmental Mn exposure may induce lasting attention and catecholaminergic system impairments. Importantly, our findings establish early development as a critical period of susceptibility to lasting deficits in attentional function caused by elevated environmental toxicant exposure. Given that environmental health threats disproportionately impact communities of color and low socioeconomic status, our findings can aid future studies to assess therapeutic interventions for vulnerable populations.

BackgroundEarly life adversity (ELA) is associated with altered insulin signaling and altered EF behaviors, in a potentially sex-specific manner. Considering the high co-morbidity between altered metabolism and executive function (EF) problems, we hypothesized that the genetic background associated with altered fasting insulin (FI) and EF could be shared MethodsOur study used conjunctional false discovery rate (ConjFDR) to identify the shared genetic architecture between FI and two EFs: impulsivity and attention deficit-hyperactivity disorder (ADHD). We identified the polygenic risk score (PRS) threshold from a FI genome-wide association study (GWAS) that best predicted insulin levels in male and female ALSPAC children [Nmales=1,901, Nfemales=1,834; pt-intial-males= 0.05 (11,121 SNPs), pt-intial-females= 0.15 (27,202 SNPs)], further refining it to only include SNPs significantly associated with insulin levels in children [NSNP-males= 635 SNPs, NSNP-females = 1,449 SNPs]. A phenome-wide association study (PheWAS) was also run to identify EFs associated with the interaction between the refined PRS (rPRS) and early adversity. To investigate the presence of a direct causal relationship between FI and impulsivity in the presence of adversity, we applied mendelian randomization (MR) ResultsConjFDR suggested that environmental factors could be involved in the association between insulin and EFs, as there was no shared genetic background. PheWAS highlighted impulsivity and attention-related outcomes in interaction models between FI rPRS and early adversity. Finally, two-sample MR suggested a causal association between higher fasting insulin levels and impulsive behavior, specifically in females exposed to adversity (p < 0.001). Overall, a sex-specific impulsivity GWAS demonstrated that MYT1L and TSSC1, genes that are associated with motor impulsivity, were enriched only in females. ConclusionsOur study solidifies the evidence that the relationship between high FI and EF is not direct, but rather interacting with ELA exposure, especially in females. Key pointsO_LIEarly life adversity is associated with alterations in insulin signaling and executive functioning behaviors. C_LIO_LIWe report a causal association between high fasting insulin and increased impulsivity in females exposed to adversity. C_LIO_LIOur findings also support the idea that fasting insulin moderates the long-term effects of early life adversity on executive functions in females. C_LIO_LIThis research provides insights into the mechanisms by which insulin moderates the effects of early life adversity on executive function disorders and informs the development of potential interventions. C_LI

BackgroundPrenatal exposure to maternal stress is linked to behavioural and neurodevelopmental disorders in childhood. Maternal hair cortisol concentration in pregnancy associates with neonatal amygdala microstructure and structural connectivity ascertained from MRI, suggesting that amygdala development is sensitive to the impact of antenatal stress via hypothalamic-pituitary-adrenal axis. Here, we investigate whether amygdala microstructure and/or connectivity associate with neurodevelopment at 2 years of age. Methods174 participants (105 very preterm) underwent brain MRI at term-equivalent age and assessment of neurodevelopment, autistic traits, temperament, and executive function at 2 years corrected age. We calculated diffusion tensor imaging and neurite orientation dispersion and density imaging metrics for left and right amygdalae. Structural connectivity was measured by mean fractional anisotropy from the amygdalae to 6 ipsilateral regions of interest (insula, putamen, thalamus, inferior temporal gyrus, medial orbitofrontal cortex, rostral anterior cingulate cortex). We used linear regression to model amygdala-outcome associations, adjusting for gestational age at birth and at scan, sex, maternal education, and maternal postnatal depression score. Network-based statistics (NBS) was used for a whole-brain analysis. ResultsAfter adjusting for multiple comparisons, lower amygdala mean diffusivity bilaterally (left: {beta}=-0.32, p=0.026, right: {beta}=-0.38, p=0.012), higher left amygdala neurite density index ({beta}=0.35, p=0.026), and increased left amygdala-putamen connectivity ({beta}=0.31, p=0.026) associated with higher autistic traits. NBS revealed amygdala-involving networks associated with cognition and surgency temperament trait among preterm infants. Other neurodevelopmental outcomes did not significantly associate with amygdala imaging features. ConclusionsMicrostructural variation in the neonatal amygdala may be important in the development of autistic traits.

IntroductionTotal and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses (aff-P) cases could be a roadblock if these differ in cellular pathology. MethodsWe examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis, including 20 schizophrenia and 13 aff-P cases. ResultsNP-aff and HC had similar total cognition (46.64{+/-}12.01 vs 41.10{+/-}17.88), both superior psychosis (28.34{+/-}12.34; ps<0.01). Metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, ps<.05), although no biomarker predicted total cognition in the clinical groups. For NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). In all psychotic cases only reduced myelin/membrane concentrations predicted deficits (-.514, p<.05); but separating schizophrenia from aff-P, respectively showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) but higher myelin/membrane and neuronal integrity concentrations (.575, .581, ps<.05) in aff-P. ConclusionsSchizophrenia and aff-P significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

The cerebellum rapidly integrates with cerebral networks during infancy and shows consistent structural and functional alterations in Autism Spectrum Disorder (ASD), suggesting that early cerebellar development may be consequential for later behavioral and psychiatric outcomes. Yet, little is known about the effect of ASD genetic liability on cerebello-cerebral functional connectivity in infancy or whether effects may differ by biological sex. Here, we leveraged neonatal functional magnetic resonance imaging, genetic, and behavioral follow-up data from the Developing Human Connectome Project (dHCP) to examine the relationship between ASD polygenic scores (PGS) and functional connectivity of cerebellar regions associated with sensorimotor and social-cognitive functions in 198 term-born neonates (mean age: 9.7 days). We report widespread sex differences in neonatal cerebello-cerebral connectivity that are regionally specific across cerebellar subdivisions. Across the full sample, elevated ASD PGS predicted alterations in cerebello-cerebral connectivity, with hemisphere-dependent differences in sensorimotor cerebellar connectivity with temporal cortex, and hyperconnectivity between the right social-cognitive seed and posterior cingulate. Notably, elevated ASD PGS predicted opposing patterns of cerebello-cerebral connectivity in males and females, including male hyperconnectivity between the right sensorimotor cerebellum and default mode areas, and female hyperconnectivity between the right social-cognitive seed and sensorimotor cortex. Connectivity associated with elevated ASD PGS showed nominal, sex-specific associations with 18-month language ability, attention problems, and emotional reactivity. Our findings show that ASD PGS influences the functional configuration of the cerebellum at birth and suggest that underlying cerebellar connectivity profiles associated with ASD may partially underlie distinct behavioral presentations in males and females.

BackgroundOutdoor air pollution is associated with an increased risk for psychopathology. Although the neural mechanisms remain unclear, air pollutants may impact mental health by altering limbic brain regions, such as the amygdala. Here, we examine the association between ambient air pollution exposure and amygdala subregion volumes in 9-10-year-olds. MethodsCross-sectional Adolescent Brain Cognitive DevelopmentSM (ABCD) Study(R) data from 4,473 participants (55.4% male) were leveraged. Air pollution was estimated for each participants primary residential address. Using the probabilistic CIT168 atlas, we quantified total amygdala and 9 distinct subregion volumes from T1- and T2-weighted images. First, we examined how criteria pollutants (i.e., fine particulate matter [PM2.5], nitrogen dioxide, ground-level ozone) and 15 PM2.5 components related with total amygdala volumes using linear mixed-effect (LME) regression. Next, partial least squares correlation (PLSC) analyses were implemented to identify relationships between co-exposure to criteria pollutants as well as PM2.5 components and amygdala subregion volumes. We also conducted complementary analyses to assess subregion apportionment using amygdala relative volume fractions (RVFs). ResultsNo significant associations were detected between pollutants and total amygdala volumes. Using PLSC, one latent dimension (LD) (52% variance explained) captured a positive association between calcium and several basolateral subregions. LDs were also identified for amygdala RVFs (ranging from 30% to 82% variance explained), with PM2.5 and component co-exposure associated with increases in lateral, but decreases in medial and central, RVFs. ConclusionsFine particulate and its components are linked with distinct amygdala differences, potentially playing a role in risk for adolescent mental health problems. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/617429v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@e9f2ecorg.highwire.dtl.DTLVardef@14b677forg.highwire.dtl.DTLVardef@177f8daorg.highwire.dtl.DTLVardef@172dc0c_HPS_FORMAT_FIGEXP M_FIG C_FIG

Air pollution is currently the greatest environmental threat to public health, but we know little about its effects on adolescent brain development. In this context, exposure to air pollution co-occurs, and could interact, with social factors that also affect brain development, such as early life stress (ELS). Here, we show that severity of ELS moderates the association between fine particle air pollution (particulate matter 2.5; PM2.5) and structural brain development. We interviewed adolescents about ELS, used census-tract data to characterize PM2.5 concentrations, and conducted longitudinal tensor-based morphometry to assess regional changes in brain volume over a two-year period. Across various cortical, thalamic, and white matter tract regions, there was a remarkably consistent effect of PM2.5 on volumetric change for adolescents who had experienced less, rather than more, severe ELS. Furthermore, exposure to higher levels of PM2.5 and experiencing moderate to severe ELS were associated with comparable volumetric changes in the brain in adolescence.

Background: Attention problems are common transdiagnostic symptoms of psychiatric illness. Although environmental exposures and experiences influence attention during adolescent development, the underlying neural pathways by which they do so is unclear. Methods: We measured attention problems, attention-related brain networks, and multidimensional environmental experiences (the exposome) using data from the ABCD Study (N = 11,878). We tested whether the exposome is associated with 9-10-year-olds attention-related brain network strength and current and future attention problems. We further examined cross-sectional indirect pathways linking the exposome, brain network strength, and attention problems. Results: The exposome predicted youths current and future self-, caregiver-, and teacher-reported attention problems as well as their current attention-related brain network strength. This brain network signature of sustained attention also predicted attention problems from all three reporters. Indirect effects models revealed that the exposome was associated with current reported attention problems both directly and indirectly though this brain signature. Conversely, predictive brain network strength was related to attention problems both directly and indirectly through the exposome. Conclusion: Interactions between environmental exposures, experiences, and brain network organization are associated with attention problems in early adolescence. These findings support a bidirectional framework linking the environment and functional brain networks in the development of attention problems.

Clinical studies have revealed a high comorbidity between autoimmune and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes linking adaptive immune abnormalities and depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. Activation of social stress-induced antibody responses were confirmed by detecting expansion of specific T and B cell populations particularly in the cervical lymph nodes, where brain-derived antigens are preferentially delivered. IgG antibody concentrations in the brain were significantly higher in stress-susceptible mice than in unstressed mice, and positively correlated with social avoidance. IgG antibodies accumulated around the blood vessels in brain sections from stress-susceptible mice. Moreover, sera from stress-susceptible mice exhibited high reactivity against brain tissue, and brain-reactive IgG antibody levels positively correlated with depression-like behavior. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. Furthermore, high stress-resilience was observed in B cell-depleted mice, confirming a causal link between antibody-producing cells and depression-like behavior. This study provides novel mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses can therefore be devised to treat patients with MDD featuring immune abnormalities.

BackgroundThe etiology and nosological status of seasonal affective disorder (SAD) as a specifier of depressive episodes versus a transdiagnostic disorder are the subject of debate. In this study, we investigated the underlying etiology of SAD and dimensional seasonality by examining their association with latitude and genetic risk for a range of traits, and investigated gene-environment interactions. MethodsThis study included 12,460 adults aged 18-90 with a history of depression from the Australian Genetics of Depression Study. Regression models included predictors for latitude (distance from equator) and polygenic scores for eight traits; major depressive disorder, bipolar disorder, anxiety disorders, chronotype, sleep duration, body mass index, vitamin D levels, and educational attainment. Outcomes were SAD status and general seasonality score. ResultsSAD was positively associated with latitude (OR[95%CI] = 1.05[1.03-1.06], padjusted<0.001), and there was nominal evidence of additive and multiplicative interactions between chronotype genetic risk and latitude (OR = 0.99[0.99-0.99], padjusted=0.381; OR=0.98[0.97-0.99], padjusted=0.489). General seasonality score was associated with latitude (IRR=1.01[1.01-1.01], padjusted 0.001) and genetic risk for major depressive disorder (IRR =1.02[1.01-1.03], padjusted<0.001), bipolar disorder (IRR=1.02[1.01-1.03], padjusted=0.001), anxiety disorders (IRR=1.03[1.01-1.04], padjusted<0.001), vitamin D levels (OR=0.89[0.80-0.95], padjusted=0.048), and educational attainment (IRR=0.97[0.96-0.99], padjusted<0.001). ConclusionsThese findings enhance understanding of SAD etiology, highlighting contributions of psychiatric genetic risk and geographic measures on seasonal behavior, and support examining seasonality as a continuous dimension.

Prenatal and early postnatal life is a period of rapid brain growth, making the developing brain particularly susceptible to external influences. Adapting the biopsychosocial model of mental health and illness, this review provides a systematic overview of how biological, psychological, and social exposures from conception to age three critically converge to shape brain development and neurodevelopmental outcomes. Following a pre-registered protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 55 studies were included, primarily published in the past 15 years. Earlier studies focused predominantly on biological exposures, while more recent work has increasingly examined psychological exposures and, more rarely, social exposures. While each exposure exhibited its own pattern of brain alterations and neurodevelopmental changes, an overarching pattern emerged across the different components of the biopsychosocial model. Adverse biological exposures were consistently associated with delayed brain maturation as reflected by brain imaging measures. Adverse psychosocial exposures showed a more complex pattern of associations with both delayed and accelerated brain maturation. Crucially, adverse exposures, whether associated with delayed or accelerated brain maturation, were consistently associated with poorer neurodevelopmental outcomes, underscoring the necessity of considering both brain and behavior when estimating the impact of early exposures. We conclude that research into early-life exposures on brain maturation and neurodevelopmental outcomes is on the rise, but there is a great need for further investigation, in particular of psychological and social exposures. The interactions between exposures, the brain, and outcomes are highly complex, requiring assessment of both brain development and behavior together, ideally in within-subject longitudinal designs in future studies.

BackgroundStress is a significant risk factor for depression and anxiety, two highly comorbid disorders with sex differences in symptom presentation and prevalence. The Chronic Variable Stress (CVS) mouse model is a useful method for examining sex-specific susceptibility, as stress can be titrated in a sex-specific manner to produce depressive- and anxiety-like behaviours across both sexes. However, the sex-specific mechanisms regarding how CVS reorganizes brain anatomy remain unclear. MethodsUsing structural magnetic resonance imaging (MRI), we provide the first whole-brain characterization of neuroanatomical changes induced by 6 or 28 days of exposure to CVS in female and male mice, respectively, and their association to behavior. We then examined the structural connectome underlying sex-specific latent dimensions of stress-susceptibility and potential molecular mechanisms using spatial gene expression analyses. ResultsCVS induced significant neuroanatomical changes in regions already implicated in depression in both sexes (e.g. nucleus accumbens and hippocampus) as well as female- and male-specific neuroanatomical changes. In females, these changes were associated with both depressive- and anxiety-like behavior. While in males, we identified two orthogonal dimensions of neuroanatomical changes associated with anxiety-like behavior or social preference. These latent dimensions are associated with sex-specific hub regions and, in females, were associated with genes enriched for protein localization to the cell surface. ConclusionOur findings indicate that different durations of CVS result in similar neuroanatomical changes in both sexes, however the direction of change and association to behavior is sex-specific. In females, these changes may be attributed to alterations in synaptic connectivity.

An individuals risk of substance use disorder (SUD) is shaped by a complex interplay of potent biosocial factors. Current neurodevelopmental models posit vulnerability to SUD in youth is due to an overreactive reward system and reduced inhibitory control. Having a family history of SUD is a particularly strong risk factor, yet few studies have explored its impact on brain function and structure prior to substance exposure. Herein, we utilized a network control theory approach to quantify sex-specific differences in brain activity dynamics in youth with and without a family history of SUD, drawn from a large cohort of substance-naive youth from the Adolescent Brain Cognitive Development Study. We summarize brain dynamics by calculating transition energy, which probes the ease with which a whole brain, region or network drives the brain towards a specific spatial pattern of activation (i.e., brain state). Our findings reveal that a family history of SUD is associated with alterations in the brains dynamics wherein: i) independent of sex, certain regions transition energies are higher in those with a family history of SUD and ii) there exist sex-specific differences in SUD family history groups at multiple levels of transition energy (global, network, and regional). Family history-by-sex effects reveal that energetic demand is increased in females with a family history of SUD and decreased in males with a family history of SUD, compared to their same-sex counterparts with no SUD family history. Specifically, we localize these effects to higher energetic demands of the default mode network in females with a family history of SUD and lower energetic demands of attention networks in males with a family history of SUD. These results suggest a family history of SUD may increase reward saliency in males and decrease efficiency of top-down inhibitory control in females. This work could be used to inform personalized intervention strategies that may target differing cognitive mechanisms that predispose individuals to the development of SUD.

BackgroundThe longitudinal trajectory of body mass index (BMI) and brain structure development during peri-adolescence is not clearly defined in offspring prenatally exposed to gestational diabetes mellitus (GDM) vs. un-exposed offspring. MethodsParticipants between age 9 and 10 years (N=9,583) were included from the Adolescent Brain and Cognitive Development (ABCD) Study and followed yearly though 4-year follow-up. GDM and puberty status were self-reported. BMI was calculated yearly, and MRI assessed brain structure biennially. Mixed-effects models analyzed trajectories of BMI and brain structural measures between groups controlling for sociodemographic covariates, and linear spline was defined with a knot at onset of puberty. ResultsThere was an interaction of exposure by age in change in BMI [{beta} (95% CI) = 0.032 (0.008, 0.056), P=0.009] and mean cortical thickness [{beta} (95% CI) = -0.038 (-0.071, -0.004), P=0.027]. The former was driven by greater pre-pubertal increases in BMI [{beta} (95% CI) = 0.051 (0.002, 0.100), P=0.043], whereas the latter was driven by faster post-pubertal declines in cortical thickness among GDM-exposed offspring [{beta} (95% CI) = -0.051 (-0.095, -0.007), P=0.046]. ConclusionPrenatal GDM exposure is associated with greater pre-pubertal increases in BMI and faster post-pubertal cortical thinning in youth age between 9 and 15. Practitioner Points- Prenatal GDM exposure is associated with greater pre-pubertal increases in BMI and faster post-pubertal cortical thinning in youth age between 9 and 15. - It is important to recognize puberty as a window of vulnerability for altered brain development among youth prenatally exposed to GDM.

BackgroundUnderstanding how variation in brain structure and function contributes to psychiatric and behavioral phenotypes remains a key challenge. The absence of neuroimaging data in many study samples limits this effort. MethodsWe used genome-wide association study (GWAS) summary statistics from the UK Biobank to impute 301 brain imaging-derived phenotype (IDP) genetic scores (IGS) in the Yale-Penn cohort, which is enriched for substance use disorders (n = 10,275; 52.8% European-like [EUR] and 47.2% African-like [AFR] genetic ancestry). The brain IDPs include white matter microstructure, regional volume, and resting-state functional connectivity measures, for which we generated IGS in the Yale-Penn participants. We then conducted a brain-wide phenome-wide association study (pheWAS) of the 301 IGS across 692 behavioral, psychiatric, and environmental traits. ResultsAmong EUR individuals, we identified 19 IGS with significant associations that survived within-trait corrections for multiple testing. These included links between genetically predicted white matter integrity and sedative abuse, tobacco withdrawal, attention deficit hyperactivity disorder (ADHD); structural brain volumes and cocaine dependence, ADHD, and conduct disorder; and functional connectivity with substance-related symptoms and social phobia. Among AFR individuals, we identified 15 IDPs with significant associations, including associations between genetically predicted white matter integrity and stimulant use disorder, regional brain volumes and opioid withdrawal/dependence, and functional connectivity and cocaine craving. ConclusionsGenetically imputed brain features capture biological variation associated with psychiatric traits. This work provides a framework for leveraging genetic data to link neuroimaging measures to substance use and mental health outcomes in samples that lack imaging data.