Prenatal Social Determinants of Health: Narrative review of maternal environments and neonatal brain development.

The Social Determinants of Health, a set of social factors including socioeconomic status, community context, and neighborhood safety among others, are well-known predictors of mental and physical health across the lifespan. Recent research has begun to establish the importance of these social factors at the earliest points of brain development, including during the prenatal period. Prenatal socioeconomic status, perceived stress, and neighborhood safety have all been reported to impact neonatal brain structure and function, with exploratory work suggesting subsequent effects on infant and child behavior. Secondary effects of the Social Determinants of Health, such as maternal sleep and psychopathology during pregnancy, have also been established as important predictors of infant brain development. This research not only establishes prenatal Social Determinants of Health as important predictors of future outcomes but may be effectively applied even before birth. Future research replicating and extending the effects in this nascent literature has great potential to produce more specific and mechanistic understanding of the social factors that shape early neurobehavioral development. IMPACT: This review synthesizes the research to date examining the effects of the Social Determinants of Health during the prenatal period and neonatal brain outcomes. Structural, functional, and diffusion-based imaging methodologies are included along with the limited literature assessing subsequent infant behavior. The degree to which results converge between studies is discussed, in combination with the methodological and sampling considerations that may contribute to divergence in study results. Several future directions are identified, including new theoretical approaches to assessing the impact of the Social Determinants of Health during the perinatal period.

Threat experiences moderate the link between hippocampus volume and depression symptoms prospectively in adolescence.

Identifying neuroimaging risk markers for depression has been an elusive goal in psychopathology research. Despite this, smaller hippocampal volume has emerged as a potential risk marker for depression, with recent research suggesting this association is moderated by family income. The current pre-registered study aimed to replicate and extend these findings by examining the moderating role of family income and three dimensions of environmental experience on the link between hippocampus volume and later depression. Data were drawn from the Adolescent Brain Cognitive Development (ABCD) study and were comprised of 6693 youth aged 9-10 years at baseline. Results indicated that psychosocial threat moderated the association between right hippocampus volume and depression symptoms two years later, such that a negative association was evident in low-threat environments (std. beta=0.15, 95% CI [0.05, 0.24]). This interaction remained significant when baseline depression symptoms were included as a covariate, though only in youth endorsing 1 or more depression symptoms at baseline (ß = 0.13, 95% CI = [0.03, 0.22]). These results suggest that hippocampus volume may not be a consistent correlate of depression symptoms in high risk environments and emphasize the importance of including measures of environmental heterogeneity when seeking risk markers for depression.

Basic Environmental Supports for Positive Brain and Cognitive Development in the First Year of Life.

Importance: Defining basic psychosocial resources to facilitate thriving in the first year of life could tangibly inform policy and enhance child development worldwide. Objective: To determine if key environmental supports measured as a thrive factor (T-factor) in the first year of life positively impact brain, cognitive, and socioemotional outcomes through age 3. Design, Setting, and Participants: This prospective longitudinal cohort study took place at a Midwestern academic medical center from 2017 through 2022. Participants included singleton offspring oversampled for those facing poverty, without birth complications, congenital anomalies, or in utero substance exposures (except cigarettes and marijuana) ascertained prenatally and followed up prospectively for the first 3 years of life. Data were analyzed from March 9, 2023, through January 3, 2024. Exposures: Varying levels of prenatal social disadvantage advantage and a T-factor composed of environmental stimulation, nutrition, neighborhood safety, positive caregiving, and child sleep. Main outcomes & measures: Gray and white matter brain volumes and cortical folding at ages 2 and 3 years, cognitive and language abilities at age 3 years measured by the Bayley-III, and internalizing and externalizing symptoms at age 2 years measured by the Infant-Toddler Social and Emotional Assessment. Results: The T-factor was positively associated with child cognitive abilities (ß = 0.33; 95% CI, 0.14-0.52), controlling key variables including prenatal social disadvantage (PSD) and maternal cognitive abilities. The T-factor was associated with child language (ß = 0.36; 95% CI, 0.24-0.49), but not after covarying for PSD. The association of the T-factor with child cognitive and language abilities was moderated by PSD (ß = -0.32; 95% CI, -0.48 to -0.15 and ß = -0.36; 95% CI, -0.52 to -0.20, respectively). Increases in the T-factor were positively associated with these outcomes, but only for children at the mean and 1 SD below the mean of PSD. The T-factor was negatively associated with child externalizing and internalizing symptoms over and above PSD and other covariates (ß = -0.30; 95% CI, -0.52 to -0.08 and ß = -0.32; 95% CI, -0.55 to -0.09, respectively). Increasing T-factor scores were associated with decreases in internalizing symptoms, but only for children with PSD 1 SD above the mean. The T-factor was positively associated with child cortical gray matter above PSD and other covariates (ß = 0.29; 95% CI, 0.04-0.54), with no interaction between PSD and T-factor. Conclusions and Relevance: Findings from this study suggest that key aspects of the psychosocial environment in the first year impact critical developmental outcomes including cognitive, brain, and socioemotional development at age 3 years. This suggests that environmental resources and enhancement in the first year of life may facilitate every infant's ability to thrive, setting the stage for a more positive developmental trajectory.

Maternal prenatal social disadvantage and neonatal functional connectivity: Associations with psychopathology symptoms at age 12 months.

Recent research has reported effects of socioeconomic status on neurobehavioral development as early as infancy, including positive associations between income and brain structure, functional connectivity, and behavior later in childhood (Ramphal, Whalen, et al., 2020; Triplett et al., 2022). This study extends this literature by investigating the relation of maternal prenatal social disadvantage (PSD) to neonatal amygdala and hippocampus functional connectivity and whether socioeconomic-related alterations in functional connectivity subsequently predict behavior at age 12 months in a large, socioeconomically diverse sample (N = 261 mother-infant dyads). PSD was assessed across gestation; neonatal magnetic resonance imaging was completed within the first weeks of life; and infant internalizing and externalizing symptoms were evaluated using the Infant-Toddler Social and Emotional Assessment at age 12 months. The results showed that PSD was significantly related to neonatal right amygdala and left hippocampus functional connectivity with prefrontal and motor-related regions. Social disadvantage-related right amygdala and left hippocampus functional connectivity with these regions was subsequently related to infant externalizing and internalizing symptoms at age 12 months. Building off an emerging literature exploring prenatal impacts on neonatal functional connectivity, this study further emphasizes the important role of the maternal environment during gestation on infant brain function and its relationship with externalizing and internalizing behavior in the first years of life. The results suggest that the prenatal socioeconomic environment may be a promising target for interventions aimed at improving infant neurobehavioral outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Association Between Maternal Cortisol and Infant Amygdala Volume Is Moderated by Socioeconomic Status.

Background: It has been well established that socioeconomic status is associated with mental and physical health as well as brain development, with emerging data suggesting that these relationships begin in utero. However, less is known about how prenatal socioeconomic environments interact with the gestational environment to affect neonatal brain volume. Methods: Maternal cortisol output measured at each trimester of pregnancy and neonatal brain structure were assessed in 241 mother-infant dyads. We examined associations between the trajectory of maternal cortisol output across pregnancy and volumes of cortisol receptor-rich regions of the brain, including the amygdala, hippocampus, medial prefrontal cortex, and caudate. Given the known effects of poverty on infant brain structure, socioeconomic disadvantage was included as a moderating variable. Results: Neonatal amygdala volume was predicted by an interaction between maternal cortisol output across pregnancy and socioeconomic disadvantage (standardized ß = -0.31, p < .001), controlling for postmenstrual age at scan, infant sex, and total gray matter volume. Notably, amygdala volumes were positively associated with maternal cortisol for infants with maternal disadvantage scores 1 standard deviation below the mean (i.e., less disadvantage) (simple slope = 123.36, p < .01), while the association was negative in infants with maternal disadvantage 1 standard deviation above the mean (i.e., more disadvantage) (simple slope = -82.70, p = .02). Individuals with disadvantage scores at the mean showed no association, and there were no significant interactions in the other brain regions examined. Conclusions: These data suggest that fetal development of the amygdala is differentially affected by maternal cortisol production at varying levels of socioeconomic advantage.

Family income buffers the relationship between childhood adverse experiences and putamen volume.

Adverse experiences and family income in childhood have been associated with altered brain development. While there is a large body of research examining these associations, it has primarily used cross-sectional data sources and studied adverse experiences and family income in isolation. However, it is possible that low family income and adverse experiences represent dissociable and potentially interacting profiles of risk. To address this gap in the literature, we examined brain structure as a function of adverse experiences in childhood and family income in 158 youths with up to five waves of MRI data. Specifically, we assessed the interactive effect of these two risk factors on six regions of interest: hippocampus, putamen, amygdala, nucleus accumbens, caudate, and thalamus. Adverse experiences and family income interacted to predict putamen volume (B = 0.086, p = 0.011) but only in participants with family income one standard deviation below the mean (slope estimate = -0.11, p = 0.03). These results suggest that adverse experiences in childhood result in distinct patterns of brain development across the socioeconomic gradient. Given previous findings implicating the role of the putamen in psychopathology-related behaviors, these results emphasize the importance of considering life events and socioeconomic context when evaluating markers of risk. Future research should include interactive effects of environmental exposures and family income to better characterize risk for psychopathology in diverse samples.

Preschool Depression and Hippocampal Volume: The Moderating Role of Family Income.

OBJECTIVE: Depression and low socioeconomic status have both been associated with hippocampal volume alterations. Whether these factors interact to predict neurobehavioral outcomes has not been adequately studied. The authors investigated family income as a moderator of the relationship between depression and hippocampal volume in a longitudinal sample. METHOD: Longitudinal behavioral data, beginning at preschool age, and behavioral and neuroimaging data from school age to adolescence were used to assess the impact of preschool only and total preschool to adolescent depression symptoms on hippocampal volumes using family income as a moderator (N = 176). RESULTS: Depression severity during the preschool period interacted with family income to predict hippocampal volumes at the intercept (ie, age 13 years; B = -0.078, p = .003). Interaction decomposition revealed that only individuals with relatively high family income exhibited smaller hippocampal volume with increasing depression severity (B = -0.146, p = .005). Family income was associated with hippocampus volumes only in individuals with low to moderate preschool depression severity (B = 0.289, p = .007 and B = 0.169, p = .030, respectively). CONCLUSION: Preschool depression severity interacts with family income to predict hippocampal volume across development, such that the effects of early depression are evident only in those with higher income. These findings suggest that hippocampal volume may not be an effective marker of risk for depression at different levels of socioeconomic status, and emphasizes the importance of the environmental context when assessing risk markers for depression. Future research should explore how socioeconomic stress may eclipse the effects of depression on hippocampal development, setting alternative neurodevelopmental risk trajectories.

Early Childhood Socioeconomic Status and Cognitive and Adaptive Outcomes at the Transition to Adulthood: The Mediating Role of Gray Matter Development Across Five Scan Waves.

BACKGROUND: Early low socioeconomic status (SES) is associated with poor outcomes in childhood, many of which endure into adulthood. It is critical to determine how early low SES relates to trajectories of brain development and whether these mediate relationships to poor outcomes. We use data from a unique 17-year longitudinal study with five waves of structural brain imaging to prospectively examine relationships between preschool SES and cognitive, social, academic, and psychiatric outcomes in early adulthood. METHODS: Children (n = 216, 50% female, 47.2% non-White) were recruited from a study of early onset depression and followed approximately annually. Family income-to-needs ratios (SES) were assessed when children were ages 3 to 5 years. Volumes of cortical gray and white matter and subcortical gray matter collected across five scan waves were processed using the FreeSurfer Longitudinal pipeline. When youth were ages 16+ years, cognitive function was assessed using the NIH Toolbox, and psychiatric diagnoses, high-risk behaviors, educational function, and social function were assessed using clinician administered and parent/youth report measures. RESULTS: Lower preschool SES related to worse cognitive, high-risk, educational, and social outcomes (|standardized B| = 0.20-0.31, p values < .003). Lower SES was associated with overall lower cortical (standardized B = 0.12, p < .0001) and subcortical gray matter (standardized B = 0.17, p < .0001) volumes, as well as a shallower slope of subcortical gray matter growth over time (standardized B = 0.04, p = .012). Subcortical gray matter mediated the relationship of preschool SES to cognition and high-risk behaviors. CONCLUSIONS: These novel longitudinal data underscore the key role of brain development in understanding the long-lasting relations of early low SES to outcomes in children.

Measurement matters: An individual differences examination of family socioeconomic factors, latent dimensions of children's experiences, and resting state functional brain connectivity in the ABCD sample.

The variation in experiences between high and low-socioeconomic status contexts are posited to play a crucial role in shaping the developing brain and may explain differences in child outcomes. Yet, examinations of SES and brain development have largely been limited to distal proxies of these experiences (e.g., income comparisons). The current study sought to disentangle the effects of multiple socioeconomic indices and dimensions of more proximal experiences on resting-state functional connectivity (rsFC) in a sample of 7834 youth (aged 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) study. We applied moderated nonlinear factor analysis (MNLFA) to establish measurement invariance among three latent environmental dimensions of experience (material/economic deprivation, caregiver social support, and psychosocial threat). Results revealed measurement biases as a function of child age, sex, racial group, family income, and parental education, which were statistically adjusted in the final MNLFA scores. Mixed-effects models demonstrated that socioeconomic indices and psychosocial threat differentially predicted variation in frontolimbic networks, and threat statistically moderated the association between income and connectivity between the dorsal and ventral attention networks. Findings illuminate the importance of reducing measurement biases to gain a more socioculturally-valid understanding of the complex and nuanced links between socioeconomic context, children's experiences, and neurodevelopment.

The Pubertal Stress Recalibration Hypothesis: Potential Neural and Behavioral Consequences.

Recent research has suggested that the pubertal period provides an opportunity for recalibrating the stress-responsive systems in youth whose responses to stress have been altered by early adversity. Such recalibration may have cascading effects that affect brain and behavioral development. In this article, we consider a large, cross-species literature to demonstrate the potential importance of pubertal stress recalibration for understanding the development of psychopathology following early deprivation by caregivers. We review the evidence for recalibration of the hypothalamic-pituitary-adrenal axis in humans, examine research on rodents that has established mechanisms through which stress hormones affect brain structure and function, and summarize the literature on human neuroimaging to assess how these mechanisms may translate into changes in human behavior. Finally, we suggest ideas for elucidating the consequences of pubertal stress recalibration that will improve our understanding of adaptive and maladaptive adolescent behavior following early adversity.

Accelerated maturation in functional connectivity following early life stress: Circuit specific or broadly distributed?

Psychosocial acceleration theory and other frameworks adapted from life history predict a link between early life stress and accelerated maturation in several physiological systems. Those findings led researchers to suggest that the emotion-regulatory brain circuits of previously-institutionalized (PI) youth are more mature than youth raised in their biological families (non-adopted, or NA, youth) during emotion tasks. Whether this accelerated maturation is evident during resting-state fMRI has not yet been established. Resting-state fMRI data from 83 early adolescents (Mage = 12.9 years, SD = 0.57 years) including 41 PI and 42 NA youth, were used to examine seed-based functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). Additional whole-brain analyses assessed group differences in functional connectivity and associations with cognitive performance and behavior. We found group differences in amygdala - vmPFC connectivity that may be consistent with accelerated maturation following early life stress. Further, whole-brain connectivity analyses revealed group differences associated with internalizing and externalizing symptoms. However, the majority of whole-brain results were not consistent with an accelerated maturation framework. Our results suggest early life stress in the form of institutional care is associated with circuit-specific alterations to a frontolimbic emotion-regulatory system, while revealing limited differences in more broadly distributed networks.

Differential brain activity as a function of social evaluative stress in early adolescence: Brain function and salivary cortisol.

Understanding individual differences in neural responses to stressful environments is an important avenue of research throughout development. These differences may be especially critical during adolescence, which is characterized by opportunities for healthy development and increased susceptibility to the development of psychopathology. While the neural correlates of the psychosocial stress response have been investigated in adults, these links have not been explored during development. Using a new task, the Minnesota Imaging Stress Test in Children (MISTiC), differences in activation are found in fusiform gyrus, superior frontal gyrus, insula, and anterior cingulate cortex when comparing a stressful math task to a nonstressful math task. The MISTiC task successfully elicits cortisol responses in a similar proportion of adolescents as in behavioral studies while collecting brain imaging data. Cortisol responders and nonresponders did not differ in their perceived stress level or behavioral performance during the task despite differences in neuroendocrine function. Future research will be able to leverage the MISTiC task for many purposes, including probing associations between individual differences in stress responses with environmental conditions, personality differences, and the development of psychopathology.

Early life stress and brain function: Activity and connectivity associated with processing emotion and reward.

Investigating the developmental sequelae of early life stress has provided researchers the opportunity to examine adaptive responses to extreme environments. A large body of work has established mechanisms by which the stressful experiences of childhood poverty, maltreatment, and institutional care can impact the brain and the distributed stress systems of the body. These mechanisms are reviewed briefly to lay the foundation upon which the current neuroimaging literature has been built. More recently, developmental cognitive neuroscientists have identified a number of the effects of early adversity, including differential behavior and brain function. Among the most consistent of these findings are differences in the processing of emotion and reward-related information. The neural correlates of emotion processing, particularly frontolimbic functional connectivity, have been well studied in early life stress samples with results indicating accelerated maturation following early adversity. Reward processing has received less attention, but here the evidence suggests a deficit in reward sensitivity. It is as yet unknown whether the accelerated maturation of emotion-regulation circuits comes at the cost of delayed development in other systems, most notably the reward system. This review addresses the early life stress neuroimaging literature that has investigated emotion and reward processing, identifying important next steps in the study of brain function following adversity.

Risk taking, decision-making, and brain volume in youth adopted internationally from institutional care.

Early life stress in the form of early institutional care has been shown to have wide-ranging impacts on the biological and behavioral development of young children. Studies of brain structure using magnetic resonance imaging have reported decreased prefrontal volumes, and a large literature has detailed decreased executive function (EF) in post-institutionalized (PI) youth. Little is known about how these findings relate to decision-making, particularly in PI youth entering adolescence-a period often characterized by social transition and increased reliance upon EF skills and the still-maturing prefrontal regions that support them. As decision-making in risky situations can be an especially important milestone in early adolescence, a clearer knowledge of the relationship between risky decision making and prefrontal structures in post-institutionalized youth is needed. The youth version of the Balloon Analogue Risk Task and a two-deck variant of the Iowa Gambling Task were used to assess risky decision-making in post-institutionalized youth and a community control group (N = 74, PI = 44, Non-adopted = 30; mean age = 12.93). Participants also completed a structural MRI scan for the assessment of group differences in brain structure. We hypothesized that participants adopted from institutions would display poorer performance on risky-decision making tasks and smaller brain volumes compared to non-adopted youth. Results indicated that later-adopted participants made fewer risky decisions than those experiencing shorter periods of deprivation or no institutional rearing. Further, decreased prefrontal volumes were observed in later-adopted youth and were significantly associated with task performance. Our results suggest that changes in risky-decision making behavior and brain structure are associated with the duration of early institutional care.

A Hexokinase 2 Modulator for Field-Directed Treatment of Experimental Actinic Keratoses.

Overexpression of hexokinase 2, and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches hexokinase 2 from the mitochondria. Detachment of hexokinase 2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting hexokinase 1-expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice. Topical treatment with Comp-1 led to 70% reduction in lesion number and area. This in vivo efficacy was obtained without local skin reactions or other safety findings. Mechanism-related pharmacodynamic markers, including hexokinase 2 and cleaved caspase 3 levels, are affected by Comp-1 treatment in vivo. Good Laboratory Practice toxicology studies in minipigs for 28 days and 13 weeks established no systemic toxicities and minimal dermal reaction for once-daily application of up to 20% and 15% ointment strengths, respectively. Thus, Comp-1 may address a significant unmet medical need for a non-irritating efficacious topical actinic keratosis treatment.