Parent attention-orienting behavior is associated with neural entropy in infancy.

Parents use joint attention to direct infants to environmental stimuli. We hypothesized that infants whose parents provide more bids for joint attention will display a more complex neural response when viewing social scenes. Sixty-one 8-month-old infants underwent electroencephalography (EEG) while viewing videos of joint- and parallel-play and participated in a free play interaction. EEG data was analyzed using multiscale entropy, which quantifies neural variability. Free play interactions assessed parent alternating gaze, a behavioral mechanism for directing attention to environmental cues. We found a significant positive association between parent alternating gaze and neural entropy in frontal and central regions. These results suggest a relationship between parent behavior and infant neural mechanisms that regulate social attention, underlying the importance of parental cues in forming neural networks.

Correction to: Epigenetic tuning of brain signal entropy in emergent human social behavior.

An amendment to this paper has been published and can be accessed via the original article.

Epigenetic tuning of brain signal entropy in emergent human social behavior.

BACKGROUND: How the brain develops accurate models of the external world and generates appropriate behavioral responses is a vital question of widespread multidisciplinary interest. It is increasingly understood that brain signal variability-posited to enhance perception, facilitate flexible cognitive representations, and improve behavioral outcomes-plays an important role in neural and cognitive development. The ability to perceive, interpret, and respond to complex and dynamic social information is particularly critical for the development of adaptive learning and behavior. Social perception relies on oxytocin-regulated neural networks that emerge early in development. METHODS: We tested the hypothesis that individual differences in the endogenous oxytocinergic system early in life may influence social behavioral outcomes by regulating variability in brain signaling during social perception. In study 1, 55 infants provided a saliva sample at 5 months of age for analysis of individual differences in the oxytocinergic system and underwent electroencephalography (EEG) while listening to human vocalizations at 8 months of age for the assessment of brain signal variability. Infant behavior was assessed via parental report. In study 2, 60 infants provided a saliva sample and underwent EEG while viewing faces and objects and listening to human speech and water sounds at 4 months of age. Infant behavior was assessed via parental report and eye tracking. RESULTS: We show in two independent infant samples that increased brain signal entropy during social perception is in part explained by an epigenetic modification to the oxytocin receptor gene (OXTR) and accounts for significant individual differences in social behavior in the first year of life. These results are measure-, context-, and modality-specific: entropy, not standard deviation, links OXTR methylation and infant behavior; entropy evoked during social perception specifically explains social behavior only; and only entropy evoked during social auditory perception predicts infant vocalization behavior. CONCLUSIONS: Demonstrating these associations in infancy is critical for elucidating the neurobiological mechanisms accounting for individual differences in cognition and behavior relevant to neurodevelopmental disorders. Our results suggest that an epigenetic modification to the oxytocin receptor gene and brain signal entropy are useful indicators of social development and may hold potential diagnostic, therapeutic, and prognostic value.

Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain.

In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease.

Infant neural sensitivity to affective touch is associated with maternal postpartum depression.

Classic attachment theory emphasizes the sensitivity of the parent to perceive and appropriately respond to the infant's cues. However, parent-child attachment is a dyadic interaction that is also dependent upon the sensitivity of the child to the early caregiving environment. Individual differences in infant sensitivity to parental cues is likely shaped by both the early caregiving environment as well as the infant's neurobiology, such as perceptual sensitivity to social stimuli. Here, we investigated associations between maternal postpartum depression and infant neurological sensitivity to affective touch using brain signal entropy - a metric of the brain's moment-to-moment variability related to signal processing. We recruited two independent samples of infants aged 0-5 months. In Sample 1 (n = 79), we found increased levels of maternal postpartum depression were associated with diminished perceptual sensitivity - i.e. lower entropy - to affective tactile stimulation specifically within the primary somatosensory cortex. In Sample 2 (n = 36), we replicated this finding and showed that this effect was not related to characteristics of the touch administered during the experiment. These results suggest that decreased affective touch early in life - a common consequence of postpartum depression - likely impacts the infant's perceptual sensitivity to affective touch and ultimately the formation of experience-dependent neural networks that support the successful formation of attachment relationships.

Infant neural sensitivity to affective touch is associated with maternal postpartum depression.

Classic attachment theory emphasizes the sensitivity of the parent to perceive and appropriately respond to the infant's cues. However, parent-child attachment is a dyadic interaction that is also dependent upon the sensitivity of the child to the early caregiving environment. Individual differences in infant sensitivity to parental cues is likely shaped by both the early caregiving environment as well as the infant's neurobiology, such as perceptual sensitivity to social stimuli. Here, we investigated associations between maternal postpartum depression and infant neurological sensitivity to affective touch using brain signal entropy - a metric of the brain's moment-to-moment variability related to signal processing. We recruited two independent samples of infants aged 0-5 months. In Sample 1 (n=79), we found increased levels of maternal postpartum depression were associated with diminished perceptual sensitivity - i.e. lower entropy - to affective tactile stimulation specifically within the primary somatosensory cortex. In Sample 2 (n=36), we replicated this finding and showed that this effect was not related to characteristics of the touch administered during the experiment. These results suggest that decreased affective touch early in life - a common consequence of postpartum depression - likely impacts the infant's perceptual sensitivity to affective touch and ultimately the formation of experience-dependent neural networks that support the successful formation of attachment relationships.

Parent attention-orienting behavior is associated with neural entropy in infancy.

Parents play a significant role in directing infant's attention to environmental stimuli via joint attention. We hypothesized that infants whose parents provide more bids for joint attention will display a more complex neural response when viewing social scenes. Sixty-one 8-month-old infants underwent electroencephalography (EEG) while viewing videos of joint- and parallel-play and participated in a parent-infant free play interaction. EEG data was analyzed using multiscale entropy, which quantifies moment-to-moment neural variability. Free play interactions were coded for parent alternating gaze, a behavioral mechanism for directing attention to environmental cues. We found a significant positive association between parent alternating gaze and neural entropy in frontal and central brain regions. These results suggest a relationship between parent behavior and infant neural mechanisms that regulate social attention, underlying the importance of parent cues in the formation of neural networks in infancy.

Epigenetic and neural correlates of selective social attention across adulthood.

Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene ( OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Here we explore age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young and older adults. We find that older adults activate diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We find a significant age-by- OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults display a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association does not hold for older adults. Instead, perceived social support interacts with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

DNA methylation of the oxytocin receptor interacts with age to impact neural response to social stimuli.

Introduction: Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene (OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Methods: Here we explored age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young (age 18-31) and older (age 58-81) adults. Participants underwent fMRI during a selective social attention task and provided a DNA sample for the assessment of OXTR methylation. Results and Discussion: We found that older adults activated diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We found a significant age-by-OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults displayed a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association did not hold for older adults. Instead, perceived social support interacted with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

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.

Preterm birth accelerates the maturation of spontaneous and resting activity in the visual cortex.

Prematurity is among the leading risks for poor neurocognitive outcomes. The brains of preterm infants show alterations in structure and electrical activity, but the underlying circuit mechanisms are unclear. To address this, we performed a cross-species study of the electrophysiological activity in the visual cortices of prematurely born infants and mice. Using electroencephalography (EEG) in a sample of healthy preterm (N = 29) and term (N = 28) infants, we found that the maturation of the aperiodic EEG component was accelerated in the preterm cohort, with a significantly flatter 1/f slope when compared to the term infants. The flatter slope was a result of decreased spectral power in the theta and alpha bands and was correlated with the degree of prematurity. To determine the circuit and cellular changes that potentially mediate the changes in 1/f slope after preterm birth, we used in vivo electrophysiology in preterm mice and found that, similar to infants, preterm birth results in a flattened 1/f slope. We analyzed neuronal activity in the visual cortex of preterm (N = 6) and term (N = 9) mice and found suppressed spontaneous firing of neurons. Using immunohistochemistry, we further found an accelerated maturation of inhibitory circuits. In both preterm mice and infants, the functional maturation of the cortex was accelerated, underscoring birth as a critical checkpoint in cortical maturation. Our study points to a potential mechanism of preterm birth-related changes in resting neural activity, highlighting the utility of a cross-species approach in studying the neural circuit mechanisms of preterm birth-related neurodevelopmental conditions.

Preterm birth accelerates the maturation of spontaneous and resting activity in the visual cortex.

Prematurity is among the leading risks for poor neurocognitive outcomes. The brains of preterm infants show alterations in structure and electrical activity, but the underlying circuit mechanisms are unclear. To address this, we performed a cross-species study of the electrophysiological activity in the visual cortices of prematurely born infants and mice. Using electroencephalography (EEG) in a sample of healthy preterm (N=29) and term (N=28) infants, we found that the maturation of the aperiodic EEG component was accelerated in the preterm cohort, with a significantly flatter 1/f slope when compared to the term infants. The flatter slope was a result of decreased spectral power in the theta and alpha bands and was correlated with the degree of prematurity. To determine the circuit and cellular changes that potentially mediate the changes in 1/f slope after preterm birth, we used in vivo electrophysiology in preterm mice and found that, similar to infants, preterm birth results in a flattened 1/f slope. We analyzed neuronal activity in the visual cortex of preterm mice (N=6 preterm and 9 term mice) and found suppressed spontaneous firing of neurons. Using immunohistochemistry, we further found an accelerated maturation of inhibitory circuits. In both preterm mice and infants, the functional maturation of the cortex was accelerated, underscoring birth as a critical checkpoint in cortical maturation. Our study points to a potential mechanism of preterm birth-related changes in resting neural activity, highlighting the utility of a cross-species approach in studying the neural circuit mechanisms of preterm birth-related neurodevelopmental conditions.

The automated preprocessing pipe-line for the estimation of scale-wise entropy from EEG data (APPLESEED): Development and validation for use in pediatric populations.

It is increasingly understood that moment-to-moment brain signal variability - traditionally modeled out of analyses as mere "noise" - serves a valuable functional role related to development, cognitive processing, and psychopathology. Multiscale entropy (MSE) - a measure of signal irregularity across temporal scales - is an increasingly popular analytic technique in human neuroscience calculated from time series such as electroencephalography (EEG) signals. MSE provides insight into the time-structure and (non)linearity of fluctuations in neural activity and network dynamics, capturing the brain's moment-to-moment complexity as it operates on multiple time scales. MSE is emerging as a powerful predictor of developmental processes and outcomes. However, differences in data preprocessing and MSE computation make it challenging to compare results across studies. Here, we (1) provide an introduction to MSE for developmental researchers, (2) demonstrate the effect of preprocessing procedures on scale-wise entropy estimates, and (3) establish a standardized EEG preprocessing and entropy estimation pipeline that adapts a critical modification to the original MSE algorithm, and generates reliable scale-wise entropy estimates capable of differentiating developmental stages and cognitive states. This novel pipeline - the Automated Preprocessing Pipe-Line for the Estimation of Scale-wise Entropy from EEG Data (APPLESEED) is fully automated, customizable, and freely available for download from https://github.com/mhpuglia/APPLESEED.

Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism.

Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p < 0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p < 0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study.

Epigenetic modification of the oxytocin receptor gene is associated with emotion processing in the infant brain.

The neural capacity to discriminate between emotions emerges early in development, though little is known about specific factors that contribute to variability in this vital skill during infancy. In adults, DNA methylation of the oxytocin receptor gene (OXTRm) is an epigenetic modification that is variable, predictive of gene expression, and has been linked to autism spectrum disorder and the neural response to social cues. It is unknown whether OXTRm is variable in infants, and whether it is predictive of early social function. Implementing a developmental neuroimaging epigenetics approach in a large sample of infants (N = 98), we examined whether OXTRm is associated with neural responses to emotional expressions. OXTRm was assessed at 5 months of age. At 7 months of age, infants viewed happy, angry, and fearful faces while functional near-infrared spectroscopy was recorded. We observed that OXTRm shows considerable variability among infants. Critically, infants with higher OXTRm show enhanced responses to anger and fear and attenuated responses to happiness in right inferior frontal cortex, a region implicated in emotion processing through action-perception coupling. Findings support models emphasizing oxytocin's role in modulating neural response to emotion and identify OXTRm as an epigenetic mark contributing to early brain function.

Oxytocin receptor genotype and low economic privilege reverses ventral striatum-social anxiety association.

Oxytocin receptor gene (OXTR) polymorphisms, lower ventral striatum (VS) response to social stimuli, and lower economic privilege have been independently associated with depression and anxiety. However, the interactions between these risk factors are unknown. One hundred and fifty-seven healthy adult participants genotyped for OXTR rs237915 completed a common emotion-matching task during functional magnetic resonance imaging. Past economic privilege and depression and anxiety symptoms were concurrently assessed through validated self-report measures. The data revealed an interaction between rs237915 genotype and economic privilege on the neural response to negative faces. C-carriers showed decreased VS activation and increased connectivity between the VS and ventromedial prefrontal cortex with increased economic privilege. TT homozygotes showed the reverse pattern. Low VS response to negative faces predicted increased social anxiety, but only for those with either lower economic privilege or the C allele. For those with both, low VS response was associated with paradoxically lower social anxiety. Findings suggest that economic privilege and OXTR rs237915 genotype may calibrate social motivational neural systems for better or worse. While lower VS response to negative faces may generally constitute a risk factor for social anxiety, lower response to social cues may be a benefit for those with dual risk.

Early nurture epigenetically tunes the oxytocin receptor.

Mammalian sociality is regulated in part by the neuropeptide oxytocin. In prairie voles, subtle variation in early life experience changes oxytocin receptor-mediated social behaviors. We report that low levels of early care in voles leads to de novo DNA methylation at specific regulatory sites in the oxytocin receptor gene (Oxtr), impacting gene expression and protein distribution in the nucleus accumbens. DNA methylation state of the blood predicts expression in the brain indicating the utility of the blood as a biomarker for the transcription state of the brain. These experience-sensitive CpG sites are conserved in humans, are related to gene expression in the brain, and have been associated with psychiatric disorders and individual differences in neural response to social stimuli. These results identify a mechanism by which early care regulates later displays of typical prairie vole social behavior and suggest the potential for nurture driven epigenetic tuning of OXTR in humans.

Epigenetic regulation of the oxytocin receptor is associated with neural response during selective social attention.

Aberrant attentional biases to social stimuli have been implicated in a number of disorders including autism and social anxiety disorder. Oxytocin, a naturally-occurring mammalian hormone and neuromodulator involved in regulating social behavior, has been proposed to impact basic biological systems that facilitate the detection of and orientation to social information. Here, we investigate a role for naturally-occurring variability in the endogenous oxytocinergic system in regulating neural response during attention to social information. Participants performed a selective social attention task while undergoing fMRI, provided a blood sample for epigenetic analysis, and completed self-report measures of social functioning. We find that a functional epigenetic modification to the oxytocin receptor, OXTR methylation, is associated with increased neural response within and decreased functional coupling between regions of the salience and attentional control networks during selective social attention. We also show that subclinical variability in autistic and social anxiety traits moderates this epigenetic regulation of neural response. These data offer a mechanistic explanation to a growing literature associating social behavior and disorder with epigenetic modification to OXTR by suggesting that OXTR methylation reflects a decrease in the extent to which social information automatically captures attention. We highlight the importance that treatment efficacy be considered in relation to individual differences in molecular makeup, and that future studies aimed at uncovering biomarkers of disorder carefully consider measurement at both the biological and phenotypic level.

DNA methylation of OXTR is associated with parasympathetic nervous system activity and amygdala morphology.

Oxytocin has anxiolytic properties whose mechanisms of action are still being identified. DNA methylation in the promoter region of the oxytocin receptor gene (OXTR), an epigenetic modification that putatively reflects a downtuning of the oxytocin system, has previously been implicated in the regulation of fear-related responses through the amygdala. In this study, we attempted to characterize the relationship between methylation of OXTR and anxiogenesis using two distinct endophenotypes: autonomic nervous system activity and subcortical brain structure. In 79 participants, we found that increased OXTR methylation is associated with attenuated resting parasympathetic tone, measured using high-frequency heart rate variability. Further, we found that this relationship is mediated by brain morphology, such that OXTR methylation is associated with increased gray matter of the central amygdala which is, in turn, associated with decreased parasympathetic tone. These results further our understanding of epigenetic regulation of the human oxytocin system and its role in anxiogenesis.

Neural Response to Biological Motion in Healthy Adults Varies as a Function of Autistic-Like Traits.

Perception of biological motion is an important social cognitive ability that has been mapped to specialized brain regions. Perceptual deficits and neural differences during biological motion perception have previously been associated with autism, a disorder classified by social and communication difficulties and repetitive and restricted interests and behaviors. However, the traits associated with autism are not limited to diagnostic categories, but are normally distributed within the general population and show the same patterns of heritability across the continuum. In the current study, we investigate whether self-reported autistic-like traits in healthy adults are associated with variable neural response during passive viewing of biological motion displays. Results show that more autistic-like traits, particularly those associated with the communication domain, are associated with increased neural response in key regions involved in social cognitive processes, including prefrontal and left temporal cortices. This distinct pattern of activation might reflect differential neurodevelopmental processes for individuals with varying autistic-like traits, and highlights the importance of considering the full trait continuum in future work.