Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults.

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

Functional brain connectivity during social attention predicts individual differences in social skill.

Social attention involves selectively attending to and encoding socially relevant information. We investigated the neural systems underlying the wide range of variability in both social attention ability and social experience in a neurotypical sample. Participants performed a selective social attention task, while undergoing fMRI and completed self-report measures of social functioning. Using connectome-based predictive modeling, we demonstrated that individual differences in whole-brain functional connectivity patterns during selective attention to faces predicted task performance. Individuals with more cerebellar-occipital connectivity performed better on the social attention task, suggesting more efficient social information processing. Then, we estimated latent communities of autistic and socially anxious traits using exploratory graph analysis to decompose heterogeneity in social functioning between individuals. Connectivity strength within the identified social attention network was associated with social skills, such that more temporal-parietal connectivity predicted fewer challenges with social communication and interaction. These findings demonstrate that individual differences in functional connectivity strength during a selective social attention task are related to varying levels of self-reported social skill.

An epigenetic mechanism for differential maturation of amygdala-prefrontal connectivity in childhood socio-emotional development.

Functional connectivity between the amygdala and the medial prefrontal cortex (mPFC) has been identified as a neural substrate of emotion regulation that undergoes changes throughout development, with a mature profile typically emerging at 10 years of age. Maternal bonding in childhood has been shown to buffer amygdala reactivity and to influence the trajectory of amygdala-mPFC coupling. The oxytocinergic system is critical in the development of social behavior and maternal bonding. Early-life parental care influences the methylation status of the oxytocin receptor (OXTRm) in animal models and humans, and higher OXTRm is associated with lower amygdala-PFC functional connectivity in adults. Using a neuroimaging-epigenetic approach, we investigated saliva-derived OXTRm as a biological marker of structural and functional connectivity maturation in 57 typically developing children (P < 0.05). We utilized seed-based connectivity analysis during a novel abstract movie paradigm and find that higher levels of OXTRm are associated with a more adult-like functional connectivity profile. Concurrently, more adult-like functional connectivity was associated with higher reported self-control and more diffusion streamlines between the amygdala and mPFC. OXTRm mediates the association between structural and functional connectivity with higher levels of OXTRm being associated with more streamlines. Lastly, we also find that lower OXTRm blunts the association between amygdala-mPFC connectivity and future internalizing behaviors in early adolescence. These findings implicate OXTRm as a biological marker at the interface of the social environment and amygdala-mPFC connectivity in emotional and behavioral regulation. Ultimately, identification of neurobiological markers may lead to earlier detection of children at risk for socio-emotional dysfunction.

Neuroepigenetic impact on mentalizing in childhood.

Mentalizing, or the ability to understand the mental states and intentions of others, is an essential social cognitive function that children learn and continue to cultivate into adolescence. While most typically developing children acquire sufficient mentalizing skills, individual differences in mentalizing persist throughout childhood and are likely influenced by a combination of cognitive functioning, the social environment, and biological factors. DNA methylation of the oxytocin receptor gene (OXTRm) impacts gene expression and is associated with increased brain activity in mentalizing regions during displays of animacy in healthy young adults. The establishment, fine-tuning, and implications of such associations in the context of broader social functioning remain unclear. Using a developmental neuroimaging epigenetic approach, we investigated the contributions of OXTRm to individual variability in brain function during animate motion perception in middle childhood. We find that higher levels of OXTRm are associated with increased neural responses in the left temporo-parietal junction and inferior frontal gyrus. We also find a positive association between neural activity in LTPJ and social skills. These findings provide evidence of epigenetic influence on the developing child brain and demonstrate that variability in neural social perception in childhood is multifaceted with contributions from individual social experience and the endogenous oxytocin system.