Colter Mitchell’s research while affiliated with Concordia University Ann Arbor and other places

Background Past experiences of maltreatment and life adversity induce DNA methylation changes in adults, but less is known about their impact on mothers’ maladaptive neglectful parenting and its negative effects. We performed an epigenome-wide association study to investigate the role of DNA methylation levels in mothers with neglectful care, who were exposed to childhood maltreatment and neglect, and their current negative effects. Saliva DNA methylation was determined with the Illumina Human Methylation EPIC BeadChip v1. The individual epigenome was the input to a machine learning algorithm for trajectory inference, which assigned a specific state to each mother in the progression from healthy controls to the extreme neglect condition. A compound epigenetic maternal neglect score (EMN) was derived from 138 mothers (n = 51 in the neglectful group; n = 87 in the control non-neglectful group) having young children. Differential methylation between groups was utilized to derive the EMNs adjusted for education level, age, experimental variables, and blood cell types in saliva samples. Results Structural equation modeling: X² (29) = 37.81; p = 0.127; RMSEA = 0.048, confirmed that EMNs link their early experience of physical neglect to current reports of psychopathological symptoms, lower cognitive status, and observed poor mother–child emotional availability. A third of the genes annotated to the CpGs that affect EMNs are related to cognitive impairment and neurodegenerative and psychopathological disorders. Conclusions EMNs are a novel index to assess the contribution of DNA methylations as a neglected girl to later neglectful caregiving behavior and other negative effects. The evidence provided expands the possibilities for earlier interventions on the neglect condition to prevent and ameliorate the direct or indirect epigenetic impact of maternal adversities on mother–child care, helping to break the cycle of maltreatment.

Poly-epigenetic scores (PEGS) are surrogate measures that help capture individual-level risk. Understanding how the associations between PEGS and cardiometabolic risk factors vary by demographics and health behaviors is crucial for lowering the burden of cardiometabolic diseases. We used results from established epigenome-wide association studies to construct trait-specific PEGS from whole blood DNA methylation for systolic and diastolic blood pressure (SBP, DBP), body mass index (BMI), C-reactive protein (CRP), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), and fasting glucose. Overall and race-stratified associations between PEGS and corresponding traits were examined in adults >50 years from the Health and Retirement Study (n = 3,996, mean age = 79.5 years). We investigated how demographics (age, sex, educational attainment) and health behaviors (smoking, alcohol consumption, physical activity) modified these associations. All PEGS were positively associated with their corresponding cardiometabolic traits (p < 0.05), and most associations persisted across all racial/ethnic groups. Associations for BMI, HDL-C, and TG were stronger in younger participants, and BMI and HDL-C associations were stronger in females. The CRP association was stronger among those with a high school degree. Finally, the HDL-C association was stronger among current smokers. These findings support PEGS as robust surrogate measures and suggest the associations may differ among subgroups.

Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in population studies. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a previously identified systemic inflammation latent variable derived from seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study. The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), strongly correlated with individual inflammation markers and performed similarly to the latent systemic inflammation when predicting multimorbidity, disability, and 4-year mortality. These results suggest that InfLaMeS provides a robust alternative to blood-chemistry measures of inflammation that can be used for further scientific insight into understanding the role of inflammation in aging and health.

Mother–child closeness, a mutually trusting and affectionate bond, is an important factor in shaping positive youth development. However, little is known about the neural pathways through which mother–child closeness is related to brain organization. Utilizing a longitudinal sample primarily from low-income families (N = 181; 76% African American youth and 54% female), this study investigated the associations between mother–child closeness at ages 9 and 15 years and structural connectivity organization (network integration, robustness, and segregation) at age 15 years. The assessment of mother–child closeness included perspectives from both mother and child. The results revealed that greater mother–child closeness is linked with increased global efficiency and transitivity, but not with modularity. Specifically, both the mother’s and child’s reports of closeness at age 15 years predicted network metrics, but report at age 9 years did not. Our findings suggest that mother–child closeness is associated with neural white matter organization, as adolescents who experienced greater mother–child closeness displayed topological properties indicative of more integrated and robust structural networks.

Enhancing the generalizability of neuroimaging studies requires actively engaging participants from under-represented communities. This paper leverages qualitative data to outline participant-driven recommendations for incorporating under-represented populations in neuroimaging protocols. Thirty-one participants, who had participated in neuroimaging research or could be eligible for one as part of an ongoing longitudinal study, engaged in semi-structured one-on-one interviews (84 % under-represented ethnic-racial identities and low-income backgrounds). Through thematic analysis, we identified nine relevant research practices from participants' reports, highlighting aspects of their experience that they appreciated and suggestions for improvement: (1) forming a diverse research team comprising members with whom participants can interact as equals; (2) increasing accessibility to research by providing transportation and flexible scheduling; (3) providing family-oriented spaces; (4) enriching the campus visits to include optional on-campus activities to connect with the University; (5) developing safe strategies to accommodate participants with tattoos during the MRI; (6) incorporating engaging and interactive tasks during neuroimaging sessions; (7) providing small gifts, such as a picture of one’s brain, in addition to financial compensation; (8) sharing research findings with the research participants; and (9) fostering long-term bidirectional relationships. The findings may be used to develop best practices for enhancing participant diversity in future neuroimaging studies.

Importance Parenting is associated with brain development and long-term health outcomes, although whether these associations depend on the developmental timing of exposure remains understudied. Identifying these sensitive periods can inform when and how parenting is associated with neurodevelopment and risk for mental illness. Objective To characterize how harsh and warm parenting during early, middle, and late childhood are associated with brain architecture during adolescence and, in turn, psychiatric symptoms in early adulthood during the COVID-19 pandemic. Design, Setting, and Participants This population-based, 21-year observational, longitudinal birth cohort study of low-income youths and families from Detroit, Michigan; Toledo, Ohio; and Chicago, Illinois, used data from the Future of Families and Child Well-being Study. Data were collected from February 1998 to June 2021. Analyses were conducted from May to October 2023. Exposures Parent-reported harsh parenting (psychological aggression or physical aggression) and observer-rated warm parenting (responsiveness) at ages 3, 5, and 9 years. Main Outcomes and Measures The primary outcomes were brainwide (segregation, integration, and small-worldness), circuit (prefrontal cortex [PFC]–amygdala connectivity), and regional (betweenness centrality of amygdala and PFC) architecture at age 15 years, determined using functional magnetic resonance imaging, and youth-reported anxiety and depression symptoms at age 21 years. The structured life-course modeling approach was used to disentangle timing-dependent from cumulative associations between parenting and brain architecture. Results A total of 173 youths (mean [SD] age, 15.88 [0.53] years; 95 female [55%]) were included. Parental psychological aggression during early childhood was positively associated with brainwide segregation (β = 0.30; 95% CI, 0.14 to 0.45) and small-worldness (β = 0.17; 95% CI, 0.03 to 0.28), whereas parental psychological aggression during late childhood was negatively associated with PFC-amygdala connectivity (β = −0.37; 95% CI, −0.55 to −0.12). Warm parenting during middle childhood was positively associated with amygdala centrality (β = 0.23; 95% CI, 0.06 to 0.38) and negatively associated with PFC centrality (β = −0.18; 95% CI, −0.31 to −0.03). Warmer parenting during middle childhood was associated with reduced anxiety (β = −0.05; 95% CI −0.10 to −0.01) and depression (β = −0.05; 95% CI −0.10 to −0.003) during early adulthood via greater adolescent amygdala centrality. Conclusions and Relevance Neural associations with harsh parenting were widespread across the brain in early childhood but localized in late childhood. Neural associations with warm parenting were localized in middle childhood and, in turn, were associated with mental health during future stress. These developmentally contingent associations can inform the type and timing of interventions.

Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in studies where the measures cannot be measured directly and often perform as well or better than direct measure. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a systemic inflammation latent variable of seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study (HRS). The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), correlated with seven individual inflammation markers (r= -0.2-0.6) and performed as well or better to the systemic inflammation latent variable measure when predicting multimorbidity, disability, and 4-year mortality in HRS. Findings were validated in an external cohort, The Irish Longitudinal Study of Ageing. These results suggest that InfLaMeS provides a robust alternative to measured blood-chemistry measures of inflammation with broad applicability in instances where values of inflammatory markers are not measured but DNAm data is available.

Associations between adversity and youth psychopathology likely vary based on the types and timing of experiences. Major theories suggest that the impact of childhood adversity may either be cumulative in type (the more types of adversity, the worse outcomes) or in timing (the longer exposure, the worse outcomes) or, alternatively, specific concerning the type (e.g., parenting, home, neighborhood) or the timing of adversity (e.g., specific developmental periods). In a longitudinal sample from the Future of Families and Wellbeing Study ( N = 4,210), we evaluated these competing hypotheses using a data-driven structured life-course modeling approach using risk factors examined at child age 1 (infancy), 3 (toddlerhood), 5 (early childhood), and 9 (middle childhood). Results showed that exposures to more types of adversity for longer durations (i.e., cumulative in both type and timing) best predicted youth psychopathology. Adversities that occurred at age 9 were better predictors of youth psychopathology as compared to those experienced earlier, except for neglect, which was predictive of internalizing symptoms when experienced at age 3. Throughout childhood (across ages 1–9), aside from the accumulation of all adversities, parental stress and low collective efficacy were the strongest predictors of internalizing symptoms, whereas psychological aggression was predictive of externalizing symptoms.

Concerns for the replicability, reliability, and generalizability of human neuroimaging research have led to intense debates over sample size and open science practices, with more recent attention on the contributions of sampling and recruitment practices. Key to understanding the state of neuroscience research is an assessment of reporting practices that influence replicability, reliability, and generalizability. In this structured review, we evaluated reporting practice across three domains: (1) demographic (e.g., reporting participant race-ethnicity, age, any measure of socioeconomic position), (2) methodological (e.g., reporting recruitment methods, inclusion and exclusion criteria, why participants were excluded from analyses), and (3) open science and generalizability (e.g., analyses were preregistered, target population was stated). Included were 919 published MRI and fMRI studies from 2019 in nine top-ranked journals (N = 3,856 records screened). Reporting across domains was infrequent, with participant racial or ethnic identity (14.8%), reasons for missing imaging data (31.2%), and identification of a target population (19.4%) being particularly low/underreported. Reporting likelihood varied by study characteristics (e.g., participant age group) and was correlated across domains. The median sample size of studies was 55 participants. Study sample size, reporting frequency, was positively associated with two-year citation counts, providing some evidence that the complete reporting of demographic characteristics, methodological decisions, and open science and generalizability practices may not be as valued as study sample size. Recommendations for structural interventions at the journal level are proposed.