Reliability and predictability of phenotype information from functional connectivity in large imaging datasets.

One of the central objectives of contemporary neuroimaging research is to create predictive models that can disentangle the connection between patterns of functional connectivity across the entire brain and various behavioral traits. Previous studies have shown that models trained to predict behavioral features from the individual's functional connectivity have modest to poor performance. In this study, we trained models that predict observable individual traits (phenotypes) and their corresponding singular value decomposition (SVD) representations - herein referred to as latent phenotypes from resting state functional connectivity. For this task, we predicted phenotypes in two large neuroimaging datasets: the Human Connectome Project (HCP) and the Philadelphia Neurodevelopmental Cohort (PNC). We illustrate the importance of regressing out confounds, which could significantly influence phenotype prediction. Our findings reveal that both phenotypes and their corresponding latent phenotypes yield similar predictive performance. Interestingly, only the first five latent phenotypes were reliably identified, and using just these reliable phenotypes for predicting phenotypes yielded a similar performance to using all latent phenotypes. This suggests that the predictable information is present in the first latent phenotypes, allowing the remainder to be filtered out without any harm in performance. This study sheds light on the intricate relationship between functional connectivity and the predictability and reliability of phenotypic information, with potential implications for enhancing predictive modeling in the realm of neuroimaging research.

A sex-stratified analysis of the genetic architecture of human brain anatomy.

Large biobanks have dramatically advanced our understanding of genetic influences on human brain anatomy. However, most studies have combined rather than compared males and females - despite theoretical grounds for potential sex differences. By systematically screening for sex differences in the common genetic architecture of > 1000 neuroanatomical phenotypes in the UK Biobank, we establish a general concordance between males and females in heritability estimates, genetic correlations and variant-level effects. Notable exceptions include: higher mean h 2 in females for regional volume and surface area phenotypes; between-sex genetic correlations that are significantly below 1 in the insula and parietal cortex; and, a male-specific effect common variant mapping to RBFOX1 - a gene linked to multiple male-biased neuropsychiatric disorders. This work suggests that common variant influences on human brain anatomy are largely consistent between males and females, with a few exceptions that will guide future research as biobanks continue to grow in size.

Social reward network connectivity differs between autistic and neurotypical youth during social interaction.

A core feature of autism is difficulties with social interaction. Atypical social motivation is proposed to underlie these difficulties. However, prior work testing this hypothesis has shown mixed support and has been limited in its ability to understand real-world social-interactive processes in autism. We attempted to address these limitations by scanning neurotypical and autistic youth (n = 86) during a text-based reciprocal social interaction that mimics a "live" chat and elicits social reward processes. We focused on task-evoked functional connectivity (FC) of regions responsible for motivational-reward and mentalizing processes within the broader social reward circuitry. We found that task-evoked FC between these regions was significantly modulated by social interaction and receipt of social-interactive reward. Compared to neurotypical peers, autistic youth showed significantly greater task-evoked connectivity of core regions in the mentalizing network (e.g., posterior superior temporal sulcus) and the amygdala, a key node in the reward network. Furthermore, across groups, the connectivity strength between these mentalizing and reward regions was negatively correlated with self-reported social motivation and social reward during the scanner task. Our results highlight an important role of FC within the broader social reward circuitry for social-interactive reward. Specifically, greater context-dependent FC (i.e., differences between social engagement and non-social engagement) may indicate an increased "neural effort" during social reward and relate to differences in social motivation within autistic and neurotypical populations.

Social-interactive reward elicits similar neural response in autism and typical development and predicts future social experiences.

Challenges in initiating and responding to social-interactive exchanges are a key diagnostic feature of autism spectrum disorder, yet investigations into the underlying neural mechanisms of social interaction have been hampered by reliance on non-interactive approaches. Using an innovative social-interactive neuroscience approach, we investigated differences between youth with autism and youth with typical development in neural response to a chat-based social-interactive reward, as well as factors such as age and self-reported social enjoyment that may account for heterogeneity in that response. We found minimal group differences in neural and behavioral response to social-interactive reward, and variation within both groups was related to self-reported social enjoyment during the task. Furthermore, neural sensitivity to social-interactive reward predicted future enjoyment of a face-to-face social interaction with a novel peer. These findings have important implications for understanding the nature of social reward and peer interactions in typical development as well as for future research informing social interactions in individuals on the autism spectrum.

A bipolar taxonomy of adult human brain sulcal morphology related to timing of fetal sulcation and trans-sulcal gene expression gradients.

We developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (N=34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bipolar distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex; complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (N=228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.

The positive-negative mode link between brain connectivity, demographics and behaviour: a pre-registered replication of Smith et al. (2015).

In mental health research, it has proven difficult to find measures of brain function that provide reliable indicators of mental health and well-being, including susceptibility to mental health disorders. Recently, a family of data-driven analyses have provided such reliable measures when applied to large, population-level datasets. In the current pre-registered replication study, we show that the canonical correlation analysis (CCA) methods previously developed using resting-state magnetic resonance imaging functional connectivity and subject measures (SMs) of cognition and behaviour from healthy adults are also effective in measuring well-being (a 'positive-negative axis') in an independent developmental dataset. Our replication was successful in two out of three of our pre-registered criteria, such that a primary CCA mode's weights displayed a significant positive relationship and explained a significant amount of variance in both functional connectivity and SMs. The only criterion that was not successful was that compared to other modes the magnitude of variance explained by the primary CCA mode was smaller than predicted, a result that could indicate a developmental trajectory of a primary mode. This replication establishes a signature neurotypical relationship between connectivity and phenotype, opening new avenues of research in neuroscience with clear clinical applications.

Developmental differences in brain functional connectivity during social interaction in middle childhood.

The transition from childhood to adolescence is marked by significant changes in peer interactions. However, limited research has examined the brain systems (e.g., mentalizing and reward networks) involved in direct peer interaction, particularly during childhood and early adolescence. Here, we analyzed fMRI data from 50 children aged 8-12 years while they participated in a task in which they chatted with a peer (Peer) or answered questions about a story character (Character). Using a beta-series correlation analysis, we investigated how social interaction modulates functional connectivity within and between mentalizing and reward networks and whether this modulation changes with age. We observed effects of social interaction on functional connectivity were modulated by age within the mentalizing and reward networks. Further, greater connectivity within and between these networks during social interaction was related to faster reaction time to the Peer versus Character condition. Similar effects were found in the salience and mirror neuron networks. These findings provide insights into age-related differences in how the brain supports social interaction, and thus have the potential to advance our understanding of core social difficulties in social-communicative disorders, such as autism spectrum disorder.

Effects of social and emotional context on neural activation and synchrony during movie viewing.

Sharing emotional experiences impacts how we perceive and interact with the world, but the neural mechanisms that support this sharing are not well characterized. In this study, participants (N = 52) watched videos in an MRI scanner in the presence of an unfamiliar peer. Videos varied in valence and social context (i.e., participants believed their partner was viewing the same (joint condition) or a different (solo condition) video). Reported togetherness increased during positive videos regardless of social condition, indicating that positive contexts may lessen the experience of being alone. Two analysis approaches were used to examine both sustained neural activity averaged over time and dynamic synchrony throughout the videos. Both approaches revealed clusters in the medial prefrontal cortex that were more responsive to the joint condition. We observed a time-averaged social-emotion interaction in the ventromedial prefrontal cortex, although this region did not demonstrate synchrony effects. Alternatively, social-emotion interactions in the amygdala and superior temporal sulcus showed greater neural synchrony in the joint compared to solo conditions during positive videos, but the opposite pattern for negative videos. These findings suggest that positive stimuli may be more salient when experienced together, suggesting a mechanism for forming social bonds.

X-chromosome influences on neuroanatomical variation in humans.

The X-chromosome has long been hypothesized to have a disproportionate influence on the brain based on its enrichment for genes that are expressed in the brain and associated with intellectual disability. Here, we verify this hypothesis through partitioned heritability analysis of X-chromosome influences (XIs) on human brain anatomy in 32,256 individuals from the UK Biobank. We first establish evidence for dosage compensation in XIs on brain anatomy-reflecting larger XIs in males compared to females, which correlate with regional sex-biases in neuroanatomical variance. XIs are significantly larger than would be predicted from X-chromosome size for the relative surface area of cortical systems supporting attention, decision-making and motor control. Follow-up association analyses implicate X-linked genes with pleiotropic effects on cognition. Our study reveals a privileged role for the X-chromosome in human neurodevelopment and urges greater inclusion of this chromosome in future genome-wide association studies.

Explaining Variance in Social Symptoms of Children with Autism Spectrum Disorder.

The social symptoms of autism spectrum disorder are likely influenced by multiple psychological processes, yet most previous studies have focused on a single social domain. In school-aged autistic children (n = 49), we compared the amount of variance in social symptoms uniquely explained by theory of mind (ToM), biological motion perception, empathy, social reward, and social anxiety. Parent-reported emotional contagion-the aspect of empathy in which one shares another's emotion-emerged as the most important predictor, explaining 11-14% of the variance in social symptoms, with higher levels of emotional contagion predicting lower social symptom severity. Our findings highlight the role of mutual emotional experiences in social-interactive success, as well as the limitations of standard measures of ToM and social processing in general.

Cortical temporal hierarchy is immature in middle childhood.

The development of successful social-cognitive abilities requires one to track, accumulate, and integrate knowledge of other people's mental states across time. Regions of the brain differ in their temporal scale (i.e., a cortical temporal hierarchy) and those receptive to long temporal windows may facilitate social-cognitive abilities; however, the cortical development of long timescale processing remains to be investigated. The current study utilized naturalistic viewing to examine cortical development of long timescale processing and its relation to social-cognitive abilities in middle childhood - a time of expanding social spheres and increasing social-cognitive abilities. We found that, compared to adults, children exhibited reduced low-frequency power in the temporo-parietal junction (TPJ) and reduced specialization for long timescale processing within the TPJ and other regions broadly implicated in the default mode network and higher-order visual processing. Further, specialization for long timescales within the right dorsal medial prefrontal cortex became more 'adult-like' as a function of children's comprehension of character mental states. These results suggest that cortical temporal hierarchy in middle childhood is immature and may be important for an accurate representation of complex naturalistic social stimuli during this age.

Social cognition in context: A naturalistic imaging approach.

Social processing occurs within dynamic, complex, and multimodal contexts, but the study of social cognition typically involves static, artificial stimuli. Naturalistic approaches (e.g., movie viewing) can recapture the richness and complexity of real-world interactions. Novel analytic approaches allow for the investigation of functional brain organization in response to contextually embedded and extended events with a complex temporal structure during movie viewing or narrative processing. In addition to these within-brain measures, movies afford between-brain analyses such as inter-subject correlation, which allows for identification of stimulus-specific brain response through the correlation of brain activity between participants' brains. Research using these approaches offers both practical and theoretical advantages in understanding how we navigate our social world. Practically, movies are engaging stimuli that allow for more rapid presentation of multiple event types and improve compliance even in very young populations. Theoretically, studies have validated the use of these measures by demonstrating functional selectivity to contextually embedded stimuli. Naturalistic approaches also allow for novel insights. For example, regions associated with social cognition have longer temporal receptive windows, making them well suited to social-cognitive processes that require integration of information over longer timescales. Furthermore, the similarity in the temporal and spatial brain response between individuals during naturalistic viewing is related to age, predictive of friendships, and reduced in autism spectrum disorder. These findings offer first glimpses into the power of using these naturalistic, dynamic approaches to understand how we perceive, reason about, and interact with others.

Separable neural representations of sound sources: Speaker identity and musical timbre.

Human listeners can quickly and easily recognize different sound sources (objects and events) in their environment. Understanding how this impressive ability is accomplished can improve signal processing and machine intelligence applications along with assistive listening technologies. However, it is not clear how the brain represents the many sounds that humans can recognize (such as speech and music) at the level of individual sources, categories and acoustic features. To examine the cortical organization of these representations, we used patterns of fMRI responses to decode 1) four individual speakers and instruments from one another (separately, within each category), 2) the superordinate category labels associated with each stimulus (speech or instrument), and 3) a set of simple synthesized sounds that could be differentiated entirely on their acoustic features. Data were collected using an interleaved silent steady state sequence to increase the temporal signal-to-noise ratio, and mitigate issues with auditory stimulus presentation in fMRI. Largely separable clusters of voxels in the temporal lobes supported the decoding of individual speakers and instruments from other stimuli in the same category. Decoding the superordinate category of each sound was more accurate and involved a larger portion of the temporal lobes. However, these clusters all overlapped with areas that could decode simple, acoustically separable stimuli. Thus, individual sound sources from different sound categories are represented in separate regions of the temporal lobes that are situated within regions implicated in more general acoustic processes. These results bridge an important gap in our understanding of cortical representations of sounds and their acoustics.

Inter-subject synchrony as an index of functional specialization in early childhood.

Early childhood is a time of significant change within multiple cognitive domains including social cognition, memory, executive function, and language; however, the corresponding neural changes remain poorly understood. This is likely due to the difficulty in acquiring artifact-free functional MRI data during complex task-based or unconstrained resting-state experiments in young children. In addition, task-based and resting state experiments may not capture dynamic real-world processing. Here we overcome both of these challenges through use of naturalistic viewing (i.e., passively watching a movie in the scanner) combined with inter-subject neural synchrony to examine functional specialization within 4- and 6-year old children. Using a novel and stringent crossed random effect statistical analysis, we find that children show more variable patterns of activation compared to adults, particularly within regions of the default mode network (DMN). In addition, we found partial evidence that child-to-adult synchrony increased as a function of age within a DMN region: the temporoparietal junction. Our results suggest age-related differences in functional brain organization within a cross-sectional sample during an ecologically valid context and demonstrate that neural synchrony during naturalistic viewing fMRI can be used to examine functional specialization during early childhood - a time when neural and cognitive systems are in flux.

Perceived live interaction modulates the developing social brain.

Although children's social development is embedded in social interaction, most developmental neuroscience studies have examined responses to non-interactive social stimuli (e.g. photographs of faces). The neural mechanisms of real-world social behavior are of special interest during middle childhood (roughly ages 7-13), a time of increased social complexity and competence coinciding with structural and functional social brain development. Evidence from adult neuroscience studies suggests that social interaction may alter neural processing, but no neuroimaging studies in children have directly examined the effects of live social-interactive context on social cognition. In the current study of middle childhood, we compare the processing of two types of speech: speech that children believed was presented over a real-time audio-feed by a social partner and speech that they believed was recorded. Although in reality all speech was prerecorded, perceived live speech resulted in significantly greater neural activation in regions associated with social cognitive processing. These findings underscore the importance of using ecologically-valid and interactive methods to understand the developing social brain.