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.

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

Major Depressive Disorder (MDD) is a prevalent, chronic, and multidimensional mental disorder characterized by widespread functional dysconnectivity in the whole brain. However, the potential molecular, cellular, and neural mechanisms, contributing to the diverse symptomatology and heterogeneity of MDD remain poorly understood. This study aims to elucidate the multi-scale pathophysiological mechanisms underlying MDD subtypes by integrating functional connectivity, transcriptomic, neurotransmitter, and cell-type analyses across two Asian cohorts: the Chinese REST-meta-MDD Consortium (Discovery) and the Japanese Decoded Neurofeedback Project (Validation). The discovery cohort identified distinct patterns of distance-dependent functional connectivity strength (FCS) alterations in MDD, revealing short- to medium-range hyperconnectivity in both total MDD and recurrent MDD (RMDD) patients, with long-range hyperconnectivity specifically observed in RMDD. In contrast, first-episode drug-naive (FEDN) patients did not exhibit significant distance-dependent alterations in FCS. Genes associated with the FCS differences between FEDN and RMDD were enriched in pathways related to chemical synaptic transmission, neuron projection, and synaptic signaling. Moreover, FCS alterations in MDD subtypes were correlated with neurotransmitter receptor densities, particularly in the monoaminergic (e.g., 5HT1a, 5HT2a, and KappaOp) and GABAergic (GABAa) systems. Distinctive cell-type associations were observed, with astrocytes, endothelial cells, and oligodendrocyte precursor cells (OPCs) linked to FCS changes in RMDD, while only OPCs were associated with alterations in FEDN. The validation cohort partially replicated the key findings regarding distance-dependent FCS alterations, transcriptomic signatures, neurotransmitter associations, and cell-type specific relationships. These findings provide novel insights into the neurobiological underpinnings of functional dysconnections in MDD subtypes.

Complex clinical presentations are common in youth seeking mental health treatment, complicating attempts to identify specific biological underpinnings to guide precision psychiatry. We defined four classes of such youth based on their symptom profiles and identified unique patterns of amygdala functional connectivity in each class. Subjects were 215 youth who varied along major symptom dimensions commonly associated with pediatric affective psychopathology: depression, irritability, anxiety, and attention-deficit/hyperactivity (ADHD). We used latent profile analysis to identify classes of symptom patterns. Functional MRI data were obtained while subjects completed a gender identification task of face-emotions that varied in emotion type and intensity. We used generalized psychophysiological interaction analysis to examine associations between the probability of being in each symptom class and amygdala functional connectivity. The likelihood of being in the class with high parent-reported irritability and ADHD symptoms was associated with amygdala connectivity to the insula and superior temporal gyrus while processing high-intensity angry and fearful faces; to the precuneus while processing intensity across emotions; and to the ventrolateral prefrontal cortex across all task conditions. The likelihood of being in the class with high anxious and depressive symptoms was negatively associated with amygdala-thalamic connectivity across task conditions. This is the first study to identify distinct associations between symptom profile classes and amygdala connectivity in a transdiagnostic sample of youth. These neural correlates provide external validity to latent classes derived from symptom clusters. This is an essential first step toward identifying the biological basis of common transdiagnostic symptom presentations in youth.

IntroductionThe externalizing disorders of ADHD, Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) exhibit a strong uptick in incidence in late childhood to become some of the most common mental health conditions in adolescence and strong predictors of adult psychopathology. While treatable, substantial diagnostic overlap exists among the externalizing disorders, complicating intervention planning. Thus, early adolescence is a period of considerable interest in understanding which factors predict the onset of externalizing disorders and disambiguating those that may differentially predict the development of ADD versus (vs) ODD and CD. Materials and MethodsHere, we analyzed 5,777 multimodal candidate predictors collected from children age 9-10 yrs and their parents in the ABCD cohort spanning demographics; developmental and medical history; physiologic function; academic performance; social, physical and cultural environment; activities of everyday life, substance use and cortical and subcortical brain structure, volumetrics, connectivity and function to predict the future onset of ADHD, ODD and CD at 2-year follow-up. We used deep learning optimized with an innovative AI algorithm that jointly optimizes model training and performs automated feature selection to construct prospective, individual-level predictions of illness onset in this high-dimension data. Additional experiments furnished predictive models of all prevailing cases at 11-12 yrs and examined relative predictive performance when candidate predictors were restricted to only neural metrics derived from MRI. ResultsMultimodal models achieved strong, consistent performance with [~]86-97% accuracy, 0.919-0.996 AUROC and [~]82-97% precision and recall in testing in held-out, unseen data. In neural-only models, predictive performance dropped substantially but nonetheless accuracy and AUROC of [~]80% were achieved. Parent aggressive and externalizing traits uniquely differentiated the onset of ODD while structural MRI metrics in the limbic system specifically predicted the onset of CD. Psychosocial measures of sleep disorders, parent mental health and behavioral traits and school performance proved valuable across all disorders but cognitive and non-neural physiologic metrics were never selected. In neural-only models, structural and functional MRI metrics in subcortical regions and cortical-subcortical connectivity were emphasized over task fMRI or diffusion measures. Overall, we identified a strong correlation between accuracy and final predictor importance. ConclusionsDeep learning optimized with AI can generate highly accurate individual-level predictions of the onset of early adolescent externalizing disorders using multimodal features. Analysis of 5,777 multimodal candidate predictors highlighted psychosocial predictors related to sleep disorders, school performance and parent mental health and behavioral traits over other feature types. While externalizing disorders are frequently co-morbid in adolescents, certain predictors appeared specific to the onset of ODD or CD vs ADHD with structural MRI metrics in the limbic system offering particular promise in identifying children at risk for the onset of CD, a highly disabling disorder. The strong observed correlation between predictive accuracy and final predictor importance suggests that principled, data-driven searches for impactful predictors may facilitate the construction of robust, individual-level models in high-dimension data. To our knowledge, this is the first machine learning study to predict the onset of all three major adolescent externalizing disorders with the same design and participant cohort to enable direct comparisons, analyze >200 multimodal features and include as many types of neuroimaging metrics. Future work to test our observations in external validation data will help further test the generalizability of these findings.

Exposure is considered the most active element of cognitive behavioral therapy (CBT) for pediatric anxiety, and its efficacy is theorized to depend on cognitive control and its supporting neural substrates (e.g., central executive [CEN], salience [SN], and default mode networks [DMN]). However, little work has identified how CBT, or exposure specifically, modulates intrinsic connectivity of these networks. Progress may be limited by heterogeneity in network connectivity in anxiety, which may obscure treatment-related effects in group-averaged analyses. This randomized clinical trial (RCT) leverages person-specific network modeling to test how exposure-focused CBT (EF-CBT) influences resting-state connectivity of cognitive control networks in pediatric anxiety, relative to an active control (relaxation mentorship training; RMT). Youth aged 7-18 years with an anxiety disorder (N = 104) or low/no anxiety (L/NA; N = 37) completed resting-state fMRI scans before being randomized to EF-CBT or RMT. Resting-state connectivity was reassessed following treatment (or commensurate time L/NA youth) in 113 participants. Changes in within-CEN, CEN-SN, and CEN-DMN density were examined using Group Iterative Multiple Model Estimation, which yields sparse, person-specific networks capturing both shared and individual connectivity structure. At baseline, anxious youth exhibited lower density within-CEN, between CEN-SN, and between CEN-DMN than L/NA youth. Treatment effects differed by intervention: EF-CBT selectively increased (i.e., normalized) CEN-SN density, whereas RMT increased within-CEN density. These findings demonstrate dissociable effects of exposure and relaxation on cognitive control network organization in pediatric anxiety. Exposure-focused CBT uniquely strengthens coordination between control and salience systems, consistent with a mechanism supporting top-down control of threat-related signals during exposure. Network-based measures of cognitive control may help identify mechanistic targets for optimizing and personalizing treatment. Clinical Trial NumberNCT02810171.

Children with ADHD often exhibit fluctuations in attention and heightened reward sensitivity. Psychostimulants, such as methylphenidate (MPH), improve these behaviors in many, but not all, children with ADHD. Given the extent to which psychostimulants are prescribed for children, coupled with variable efficacy on an individual level, a better understanding of the mechanisms through which MPH changes brain function and behavior is necessary. MPHs primary action is on catecholamines, including dopamine and norepinephrine. Catecholaminergic signaling can influence the tradeoff between flexibility and stability of brain function, which is one candidate mechanism through which MPH may alter brain function and behavior. Time-varying functional connectivity, which models how functional brain networks reconfigure on short timescales, can be used to examine brain flexibility versus stability, and is thus well-suited to test how MPH impacts brain function. Here, we scanned stimulant-naive children with ADHD (8-12 years) on and off a single dose of MPH. In the MRI machine, participants completed two attention-demanding tasks: 1) a standard go/no-go task and 2) a rewarded go/no-go task. For both tasks, using a within-subjects design, we compared the degree to which brain organization changed throughout the course of the MRI scan, termed whole brain flexibility, on and off MPH. We found that whole brain flexibility decreased on MPH. Further, individuals with greater decreases in whole brain flexibility on MPH exhibited greater improvements in task performance. Together, these results provide novel insights into the neurobiological mechanisms underlying the effectiveness of MPH administration for children with ADHD.

Adverse childhood experiences (ACEs) are common, altering behaviour and stress reactivity, with persistent structural and functional brain changes. ACEs are associated with a greater risk of physical and mental health morbidities, including depression and chronic pain (CP), which often co-exist. While changes in the reward system have been implicated in each condition, it remains unclear whether there are common neural mechanisms. Using brain scans from a large community sample, we examined how ACEs, depression, and CP affected the reward system. Individuals reporting both ACEs and CP exhibited reduced volume in the nucleus accumbens, a brain region associated with motivation and pleasure, particularly among women. Blunted reward-related activity in the basal ganglia was linked to higher depression scores, CP severity, and experiences of childhood sexual abuse. Importantly, these functional changes remained significant even after accounting for structural brain differences. Interestingly, brain structural-functional associations were weak, suggesting distinct underlying mechanisms. Structural brain alterations likely represent cumulative, enduring consequences of ACEs and CP, whereas altered reward activity appears more closely tied to current symptom severity. These findings reveal separable but converging neurobiological signatures of early adversity, pain, and depression within the brains reward system.

Mice offer a wealth of opportunities for investigating brain circuits regulating multiple behaviors, largely due to their genetic tractability. Social behaviors are translationally relevant, considering both mice and humans are highly social mammals, and human social behavior disruptions are key symptoms of myriad neuropsychiatric disorders. Stresses related to social experiences are particularly influential in the severity and maintenance of neuropsychiatric disorders like anxiety disorders, and trauma and stressor-related disorders. Yet, induction and study of social stress in mice has disproportionately focused on males, influenced heavily by their inherent territorial nature. Social target-instigated stress (i.e., defeat), while ethologically relevant, is quite variable and predominantly specific to males, making rigorous and sex-inclusive studies challenging. In pursuit of a controllable, consistent, high throughput, and sex-inclusive method for social stress elicitation, we modified a paradigm to train male and female F1 129S1/SvlmJ x C57BL/6J mice to associate (via classical conditioning) same or different sex C57BL/6J targets with a mild, aversive stimulus. While further paradigm optimization is required, social interaction testing 24 h after conditioning indicates males socially conditioned better to male targets by exhibiting reduced social interaction, whereas females appeared not to form social stimulus associations. Serum corticosterone levels inversely corresponded to social avoidance after different sex, but not same sex, conditioning, suggesting corticosterone-mediated arousal influences cross-sex interactions. These rigorously controlled null outcomes align with past pursuits limited success in creating a sex-inclusive social stress paradigm. Significance StatementValidated paradigms to study social stress in female mice, and across sexes, are needed. We modified a published male mouse protocol by using classical conditioning to pair an aversive stressor with a target. Our goal was to create a uniform, cross-sex, high-throughput social stress technique to advance future research. Though our modified paradigm requires future improvements, we did acquire evidence that males can be socially conditioned in this way, and female same sex social engagement can be attenuated by a preceding non-social aversive experience. These null findings, while not achieving our goal, provide useful information to advance future sex-inclusive social stress investigations.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder with significant implications for educational attainment. Previous research has established a bidirectional relationship between ADHD symptoms and academic outcomes, but the underlying mechanisms remain poorly understood. This study employs a novel Random Intercept Cross-Lagged Panel Model (RI-CLPM) incorporating instrumental variables to improve precision of bidirectional effects estimation between ADHD and educational performance. Utilizing a large, longitudinal dataset from the Adolescent Brain and Cognitive Development Study (ABCD Study(R)), we examine the reciprocal influences between ADHD symptoms and academic achievement across multiple time points. Our findings reveal significant within-wave bidirectional effects, with ADHD symptoms negatively impacting subsequent academic attainment, and poor academic outcomes exacerbating ADHD symptoms over time. These results underscore the need for integrated interventions targeting both ADHD symptoms and academic support.

Adverse early experiences significantly alter behavioral and neural trajectories via aberrant brain maturation. Children with a history of early life stress (ELS) exhibit maladaptive behaviors and increased risk of mental illness later in life. Evidence in ELS-exposed humans identifies a role of atypical corticolimbic development; specifically, within amygdala-prefrontal cortex (PFC) circuits, and show precocially mature task-based corticolimbic functional connectivity (FC). However, the neurobiological substrates of such ELS-driven developmental changes remain unknown. Here, we identify putative neurobiological changes to determine the timeline of developmental perturbations following ELS in rats. Anterograde axonal tracing from basolateral amygdala (BLA) to pre- and infralimbic (PL, IL) PFC was quantified at postnatal days (PD)28, 38, and 48, along with anxiety-like behavior, in maternally separated (ELS) or control reared (CON) male and female rats. Resting state (rs)FC was assessed at PD28 and PD48 in a separate cohort. We report that ELS-exposed female rats show early maturation of BLA-PFC innervation at PD28, with ELS-related changes in males not appearing until PD38. ELS disrupted the maturation of rsFC from PD28 to PD48 in females, with enduring relationships between early rsFC and later anxiety-like behavior. Only transient ELS-related changes in rsFC were seen in male PL. Together, these data provide evidence that female rats may be more vulnerable to the effects of ELS via precocial BLA-PFC innervation, which may drive altered corticolimbic rsFC. These data also provide evidence that increased BLA-IL rsFC is associated with behavioral resiliency following ELS in female rats, providing mechanistic insight into the underlying etiology of adversity-induced vulnerability and resiliency.

ImportanceThe pathophysiology of ADHD is complicated by high rates of psychiatric comorbidities, thus delineating unique versus shared functional brain perturbations is critical in elucidating illness pathophysiology. ObjectiveTo investigate resting-state fMRI (rsfMRI)-complexity alterations among children with ADHD, oppositional defiant disorder (ODD), and obsessive-compulsive disorder (OCD), respectively, and comorbid ADHD, ODD, and OCD, within the cool and hot executive function (EF) networks. DesignWe leveraged baseline data (wave 0) from the Adolescent Brain and Cognitive Development (ABCD) Study. SettingThe data was collected between September 2016 and September 2019 from 21 sites in the USA. ParticipantsChildren who singularly met all DSM-5 behavioral criteria for ADHD (N = 61), ODD (N = 38), and OCD (N = 48), respectively, were extracted, alongside children with comorbid ADHD, ODD, OCD, and/or other psychiatric diagnoses (N = 833). A control sample of age-, sex-, and developmentally-matched children was also extracted (N = 269). Main Outcomes and MeasuresVoxel-wise sample entropy (SampEn) was computed using the LOFT Complexity Toolbox. Mean SampEn within all regions of the EF networks was calculated for each participant and hierarchical models with Generalized Estimating Equations compared SampEn of comorbid-free and comorbid ADHD, ODD, and OCD within the EF networks. ResultsSampEn was reduced in comorbid-free ADHD and ODD in overlapping regions of both EF networks, including the bilateral superior frontal gyrus, anterior/posterior cingulate gyrus, and bilateral caudate (Wald statistic = 5.682 to 10.798, p < 0.05 & BH corrected), with ADHD additionally affected in the right inferior/middle frontal gyrus and bilateral frontal orbital cortex (Wald statistic = 7.231 to 9.420, p < 0.05 & BH corrected). Among comorbid presentations, the additional presence of ADHD symptomatology was associated with significantly lower SampEn in every region of interest (z = -3.973 to -2.235, p < 0.05 & BH corrected). Conclusions and RelevanceADHD and ODD shared common impairments underlying the EF networks in the comorbid-free presentations, with ADHD showing more widespread complexity reduction. When ADHD co-occurred with other psychiatric disorders, the reduction in SampEn extended beyond the regions affected in comorbid-free ADHD, indicating that comorbidities amplify neural complexity deficits.

Neurodevelopmental conditions are highly heritable, heterogeneous, and frequently co-occur with one another. Transdiagnostic dimensional approaches have advanced our understanding of psychiatric disorders and informed their classification, but have largely omitted neurodevelopmental conditions. We investigated the structure of a transdiagnostic "neurodevelopmental spectrum", its etiology, and its ability to predict functional outcomes across development, using longitudinal data for >10,000 twins from the Twins Early Development Study (TEDS). Hierarchical exploratory factor modeling of traits/symptoms from a broad questionnaire battery delineated a phenotypic neurodevelopmental spectrum alongside internalizing and externalizing dimensions at ages 7, 12, and 16. Twin, polygenic score, and longitudinal analyses showed that this neurodevelopmental spectrum was highly heritable across development (h2=0.60-0.82) and predicted by polygenic scores (PGS) for neurodevelopmental, cognitive and educational phenotypes (R2 up to 2.30% in single-PGS analyses, 3.36% in multi-PGS analyses) as well as by perinatal environmental and early developmental factors (e.g., low birth weight, language delays) (R2 up to 8.65%). Differences between children in this neurodevelopmental spectrum predicted cognitive and educational outcomes both concurrently and longitudinally (R2 up to 21%), largely due to overlapping genetic effects. Most results were unchanged when controlling for other transdiagnostic dimensions, indicating specificity of associations with the neurodevelopmental spectrum. Our new data on the phenotypic architecture, etiology, and predictive utility of the neurodevelopmental spectrum across development supports the integration of this spectrum into transdiagnostic frameworks, with important implications for advancing future research, psychiatric classification, and clinical care.

The link between poverty and mental illness has sparked discussions concerning the poverty role as a risk factor for poor mental health. If poverty has as a causal role in mental illness, it would have profound implications for our comprehension of mental well-being and guide efforts to address the increasing incidence of mental health disorders. Building on the recent breakthrough discovery of heritability of poverty traits and utilizing large-scale genome-wide association studies of mental illness, we used Genomic Structural Equation Modeling (GSEM) and Mendelian randomization (MR) to examine the evidence of a causal relationship between poverty and mental illness. A common factor of poverty was derived from household income (HI), occupational income (OI), and social deprivation (SD). The causal effect of poverty was examined on 9 mental illnesses: attention deficit and hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety disorders (ANX), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia (SZ), while accounting for the influence of cognitive ability (CA). Our analysis highlights HI as the measure of poverty with the strongest correlation with the common factor, when compared to OI and SD. Using the common factor of poverty, bidirectional MR provided evidence that mental illness leads to poverty, consistent with the existing paradigm. What is new is evidence that higher levels of poverty likely pose a causal factor in developing ADHD (Inverse Variance Weighted Odds Ratio per Standard Deviation change [IVW OR]=3.43[95%CI:2.95-3.99]), MDD (IVW OR=1.49[95%CI:1.29-1.72]), and SZ (IVW OR=1.53[95%CI:1.35-1.73]), but exerts a protective effect against AN (IVW OR=0.50[95%CI:0.40-0.62]). The direct effect of poverty on mental illness remained following adjustment for CA, albeit with reduced effect sizes. Our research indicates that higher poverty levels are likely causal risk factors for MDD and SZ, but protective against AN. Notably, CA explains a significant portion of the impact of poverty, aligning with prior reports that highlight the contribution of impaired cognitive function to severe mental illnesses. Although individuals skills and abilities tied to earning capacity may be the variables with the actual causal effect of poverty on mental illness, our findings warrant further investigations into interventions targeting poverty and cognitive abilities to advance mental health.

Using a longitudinal approach, we sought to define the interplay between genetic and non-genetic factors in shaping vulnerability or resilience to COVID-19 pandemic stress, as indexed by the emergence of symptoms of depression and/or anxiety. University of Michigan freshmen were characterized at baseline using multiple psychological instruments. Subjects were genotyped and a polygenic risk score for depression (MDD-PRS) was calculated. Daily physical activity and sleep were captured. Subjects were sampled at multiple time points throughout the freshman year on clinical rating scales, including GAD-7 and PHQ-9 for anxiety and depression, respectively. Two cohorts (2019-2021) were compared to a pre-COVID-19 cohort to assess the impact of the pandemic. Across cohorts, 26%-40% of freshmen developed symptoms of anxiety or depression (N=331). Depression symptoms significantly increased in the pandemic years, especially in females. Physical activity was reduced and sleep was increased by the pandemic, and this correlated with the emergence of mood symptoms. While Low MDD-PRS predicted lower risk for depression during a typical freshman year, this apparent genetic advantage was no longer evident during the pandemic. Indeed, females with lower genetic risk accounted for the majority of the pandemic-induced rise in depression. We developed a model that explained approximately half of the variance in follow-up depression scores based on psychological trait and state characteristics at baseline and contributed to resilience in genetically vulnerable subjects. We discuss the concept of multiple types of resilience, and the interplay between genetic, sex and psychological factors in shaping the affective response to different types of stressors. Significance StatementBiological and psychological factors that propelled the great rise in mood disorders during the COVID-19 pandemic remain unknown. We used a longitudinal design in three cohorts of college freshmen to parse the variables that contributed to susceptibility vs. resilience to pandemic stress. Low genetic risk (based on a depression polygenic risk score) was protective prior to the pandemic but this "genetic resilience" lost its effectiveness during the pandemic. Paradoxically, female students with low genetic risk showed enhanced vulnerability to depression during the pandemic across two cohorts. By contrast, we defined a baseline Affect Score (AS) comprising psychological variables that were predictive of future stress susceptibility or "psychological resilience" to stress even in the genetically vulnerable subjects.

Understanding how genetic variability shapes responses to environmental and developmental factors is critical for advancing translational neuroscience. However, most preclinical studies rely on inbred mouse strains that do not capture the genetic complexity of human populations. One key area of translational research focuses on identifying the neural and behavioral consequences of early life trauma. Rodent models of childhood neglect, such as maternal separation with early weaning (MSEW), have been used in isogenic mouse strains like C57BL/6J (B6) to identify behavioral domains and neural loci of deficits stemming from exposure to MSEW. To understand how genetic diversity may contribute to the outcomes produced by MSEW, and thus inform future studies on the topic, we utilized the Jackson Laboratory Diversity Outbred (DO) line, a population derived from eight founder strains that exhibit broad genetic and phenotypic heterogeneity. We first compared MSEW effects on social behavior in DO mice versus B6 mice, because we have previously found social behavior deficits in B6 mice with a history of MSEW. Indeed, we established that MSEW incited social motivation deficits in DO mice, in a sex-specific manner. We then expanded our investigation of DO mice to test MSEW-related changes in anxiety-like behavior, fear learning and expression, and reward-seeking. Results revealed that MSEW produces distinct, sex-specific phenotypes: female DO mice displayed reduced social motivation and elevated anxiety-like behavior, while male DO mice showed attenuated CS-evoked fear expression and diminished reward-seeking behavior. Additionally, immunohistochemical analysis revealed increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in MSEW-exposed DO mice, both at baseline and following acute stress. These findings highlight the importance of incorporating genetically diverse models to better capture the nuances of early life adversity-related outcomes relevant to human populations.

BackgroundTemperament traits, which reflect early emerging individual differences in reactivity and regulation, are well-established correlates of psychopathology. However, studies have historically examined static temperament-psychopathology associations within limited age ranges. Research is required to understand the developmental dynamics of these associations. MethodsWe leveraged data from a longitudinal cohort (N = 767) with repeated measures in infancy and at ages 2 years, 3 years, 5 years, 7 years, and 11 years to examine predictive and concurrent associations between temperament traits (negative affectivity, surgency, effortful control, behavioral inhibition) and psychopathology (internalizing, externalizing) symptoms. We estimated time-varying associations using generalized additive mixed models to quantify variation in the significance and magnitude of associations from infancy through early adolescence. ResultsGreater negative affectivity consistently predicted higher internalizing and externalizing symptoms from infancy through 11 years. Surgency showed differential patterns, with higher surgency associated with lower internalizing symptoms but greater externalizing symptoms. Surgency from 2 years was associated with both internalizing and externalizing symptoms over proximal developmental intervals, whereas at 3 years, associations with externalizing extended distally through 11 years, while associations with internalizing remained proximal. Higher effortful control was associated with fewer internalizing and externalizing symptoms, with stronger effects for externalizing symptoms. Behavioral inhibition at 3 years was associated with internalizing symptoms ages 3 and 5 years. The significance and magnitude of associations between temperament domains and psychopathology symptoms varied based on developmental timing. ConclusionsTemperament traits show differential associations with psychopathology symptoms, depending on the specific temperament trait and psychopathology domain. Further, the significance and magnitude of associations vary based on developmental timing. These findings highlight the importance of considering differential traits, domains, and developmental timing when considering the potential role of temperament in psychopathology.

Many psychiatric disorders are associated with specific risk factors, including biological sex, chronic stress, and adversity in childhood, but mechanisms underlying these relationships are unknown. The locus coeruleus (LC) is a brain area that contains adrenergic norepinephrine (NE)-releasing neurons with established sex differences in excitability and stress sensitivity. To understand how adversity in early life affects cognitive/affective behavior and LC physiology, we exposed C57BL/6J mice to a dual-phase (early development and adolescence) early life variable stress (ELVS) paradigm and assessed behavior and LC physiology in early adulthood. ELVS caused females, but not males, to display increased novel environment exploration and reduced preference for sucrose. In addition, ELVS caused elevated activity in a familiar environment, modest deficits in Y-maze performance, and altered attention in an operant task, regardless of sex. A reduction in LC neuron excitability, partly due to an increase in action potential delay time, was also found only in female mice exposed to ELVS, paralleling robust behavioral changes. Pharmacological compensation of these changes in LC activity with reboxetine corrected some ELVS-induced behavioral changes. CRF-induced changes in LC neuron activity were also mediated by different preferential signaling pathways in male and female mice, a potential mechanism for lasting sex-specific changes in LC physiology in response to ELVS. Through this animal model of early life stress, we identified sex differences in behavior and parallel changes in LC neuron excitability and CRF sensitivity, identifying mechanisms involved in determining how stress and sex interact to cause LC activity dysregulation and related behavioral changes.

Neither the neurological underpinnings of autism spectrum disorder (ASD) nor their contribution to sex differences are well understood. In previous cross-sectional studies of axonal conduction velocity, the speed of action potential transmission, was observed to be decreased in autistic individuals, and this deficiency was associated with cognitive and behavioral differences. This longitudinal study aims to better understand how changes in neuronal microstructure contribute to the developmental trajectory of individuals with ASD and specifically to sex-differences in behavior during the adolescent period. Eighty-two participants (34 ASD, 41 female) completed multi-year longitudinal behavioral and neuroimaging testing. Pubertal development significantly mediated and accelerated age-related increases in conduction velocity, with girls with autism exhibiting greater increases in cortex over time and boys exhibiting greater increases in white matter (WM). Girls with autism exhibited more rapid increases in frontal and parietal cortices while boys showed relatively higher increases in insular cortex compared to girls. Across all boys, conduction velocity increased in WM at a higher rate than girls, but increased more slowly in autistic relative to non-autistic boys. Parent-reported anxious and depressive symptomatology also increased over time in girls with autism, whereas behavioral metrics associated with ASD declined, especially in boys. Notably, conduction velocity showed significant associations with parent-reported anxious and depressive symptomatology in many of the same brain regions that showed sex-specific developmental changes. These results indicate that neurodevelopmental changes in conduction velocity may underlie sex-linked biological mechanisms and contribute to differences in behavioral expression in autistic and non-autistic development.

Adolescence is a sensitive period for the emergence of psychopathology. During this time, physiological changes and environmental exposures jointly shape brain development and influence cognitive and personality maturation, collectively heightening vulnerability to mental disorders. However, the complexity of interactions between these factors has hindered a systems-level understanding of mental health and the causal roles of cognition and personality in psychopathology. In this study, we proposed a multifactorial causal framework integrating brain, pubertal, environmental, and behavioral factors to characterize heterogeneity in adolescent mental health trajectories at the individual level. We then investigated latent causal pathways linking cognition and personality to mental health outcomes and identified potential personalized intervention targets. Leveraging the Adolescent Brain Cognitive Development (ABCD) dataset (N = 4,501), we analyzed 165 behavioral pairs connecting cognition and personality traits to mental health symptoms. Using cross-sectional multivariate mediation and longitudinal interaction-inclusive analyses, we identified 68 behavioral pairs showing significant causal relationships, with brain and environmental exposures contributing to most pathways, while pubertal factors exhibited limited involvement. Individualized interpretive analyses further revealed 23 pairs suggesting potential interventions with response rates exceeding 50%. Among these, behavioral inhibition, negative urgency, and processing speed emerged as the most common intervention targets, whereas psychosis symptoms and attention problems were the most likely issues to improve. Overall, our study advances a comprehensive framework capturing the multifactorial and heterogeneous nature of adolescent mental health, delineates specific causal pathways from cognitive and personality traits to psychopathology, and provides a principled basis for potential individualized intervention strategies.