Sex and mental health are related to subcortical brain microstructure.

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

Dissociation of Reliability, Heritability, and Predictivity in Coarse- and Fine-Scale Functional Connectomes during Development.

The functional connectome supports information transmission through the brain at various spatial scales, from exchange between broad cortical regions to finer-scale, vertex-wise connections that underlie specific information processing mechanisms. In adults, while both the coarse- and fine-scale functional connectomes predict cognition, the fine scale can predict up to twice the variance as the coarse-scale functional connectome. Yet, past brain-wide association studies, particularly using large developmental samples, focus on the coarse connectome to understand the neural underpinnings of individual differences in cognition. Using a large cohort of children (age 9-10 years; n = 1,115 individuals; both sexes; 50% female, including 170 monozygotic and 219 dizygotic twin pairs and 337 unrelated individuals), we examine the reliability, heritability, and behavioral relevance of resting-state functional connectivity computed at different spatial scales. We use connectivity hyperalignment to improve access to reliable fine-scale (vertex-wise) connectivity information and compare the fine-scale connectome with the traditional parcel-wise (coarse scale) functional connectomes. Though individual differences in the fine-scale connectome are more reliable than those in the coarse-scale, they are less heritable. Further, the alignment and scale of connectomes influence their ability to predict behavior, whereby some cognitive traits are equally well predicted by both connectome scales, but other, less heritable cognitive traits are better predicted by the fine-scale connectome. Together, our findings suggest there are dissociable individual differences in information processing represented at different scales of the functional connectome which, in turn, have distinct implications for heritability and cognition.

Representational Dissimilarity of Faces and Places during a Working Memory Task is Associated with Subsequent Recognition Memory during Development.

Nearly 50 years of research has focused on faces as a special visual category, especially during development. Yet it remains unclear how spatial patterns of neural similarity of faces and places relate to how information processing supports subsequent recognition of items from these categories. The current study uses representational similarity analysis and functional imaging data from 9- and 10-year-old youth during an emotional n-back task from the Adolescent Brain and Cognitive Development Study 3.0 data release to relate spatial patterns of neural similarity during working memory to subsequent out-of-scanner performance on a recognition memory task. Specifically, we examine how similarities in representations within face categories (neutral, happy, and fearful faces) and representations between visual categories (faces and places) relate to subsequent recognition memory of these visual categories. Although working memory performance was higher for faces than places, subsequent recognition memory was greater for places than faces. Representational similarity analysis revealed category-specific patterns in face-and place-sensitive brain regions (fusiform gyrus, parahippocampal gyrus) compared with a nonsensitive visual region (pericalcarine cortex). Similarity within face categories and dissimilarity between face and place categories in the parahippocampus was related to better recognition of places from the n-back task. Conversely, in the fusiform, similarity within face categories and their relative dissimilarity from places was associated with better recognition of new faces, but not old faces. These findings highlight how the representational distinctiveness of visual categories influence what information is subsequently prioritized in recognition memory during development.

Adolescent civic engagement: Lessons from Black Lives Matter.

In 2020, individuals of all ages engaged in demonstrations condemning police brutality and supporting the Black Lives Matter (BLM) movement. Research that used parent reports and trends commented on in popular media suggested that adolescents under 18 had become increasingly involved in this movement. In the first large-scale quantitative survey of adolescents' exposure to BLM demonstrations, 4,970 youth (meanage = 12.88 y) across the United States highlighted that they were highly engaged, particularly with media, and experienced positive emotions when exposed to the BLM movement. In addition to reporting strong engagement and positive emotions related to BLM demonstrations, Black adolescents in particular reported higher negative emotions when engaging with different types of media and more exposure to violence during in-person BLM demonstrations. Appreciating youth civic engagement, while also providing support for processing complex experiences and feelings, is important for the health and welfare of young people and society.

Uncertain threat is associated with greater impulsive actions and neural dissimilarity to Black versus White faces.

Race is a social construct that contributes to group membership and heightens emotional arousal in intergroup contexts. Little is known about how emotional arousal, specifically uncertain threat, influences behavior and brain processes in response to race information. We investigated the effects of experimentally manipulated uncertain threat on impulsive actions to Black versus White faces in a community sample (n = 106) of Black and White adults. While undergoing fMRI, participants performed an emotional go/no-go task under three conditions of uncertainty: 1) anticipation of an uncertain threat (i.e., unpredictable loud aversive sound); 2) anticipation of an uncertain reward (i.e., unpredictable receipt of money); and 3) no anticipation of an uncertain event. Representational similarity analysis was used to examine the neural representations of race information across functional brain networks between conditions of uncertainty. Participants-regardless of their own race-showed greater impulsivity and neural dissimilarity in response to Black versus White faces across all functional brain networks in conditions of uncertain threat relative to other conditions. This pattern of greater neural dissimilarity under threat was enhanced in individuals with high implicit racial bias. Our results illustrate the distinct and important influence of uncertain threat on global differentiation in how race information is represented in the brain, which may contribute to racially biased behavior.

Nucleus accumbens cytoarchitecture predicts weight gain in children.

The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

Adolescent-specific memory effects: evidence from working memory, immediate and long-term recognition memory performance in 8-30 yr olds.

Working memory and recognition memory develop across adolescence, but the relationship between them is not fully understood. We investigated associations between n-back task performance and subsequent recognition memory in a community sample (8-30 yr, n = 150) using tasks from the Adolescent Brain Cognitive Development Study (ABCD Study) to cross-sectionally assess memory in an age range that will be sampled longitudinally. We added a 24-h delay condition to assess long-term recognition. Overall working memory, immediate and long-term recognition performance peaked in adolescence. Age effects in recognition memory varied by items (old targets, old distractors, and new items) and delay (0 and 24 h). For immediate recognition, accuracy was higher for targets and new items than for distractors, with accuracy for targets peaking in adulthood and accuracy for new items peaking during adolescence. For long-term recognition, adolescents' accuracy was higher for targets than distractors, while adults showed similarly high accuracy for targets and distractors and children showed low accuracy for both. This pattern appeared to be specific to recognition of items from the high working memory load condition. The results suggest that working memory may facilitate long-term recognition of task-relevant over irrelevant items and may benefit the detection of new information during adolescence.

Associations among Household and Neighborhood Socioeconomic Disadvantages, Resting-state Frontoamygdala Connectivity, and Internalizing Symptoms in Youth.

Exposure to socioeconomic disadvantages (SED) can have negative impacts on mental health, yet SED are a multifaceted construct and the precise processes by which SED confer deleterious effects are less clear. Using a large and diverse sample of preadolescents (ages 9-10 years at baseline, n = 4038, 49% female) from the Adolescent Brain Cognitive Development Study, we examined associations among SED at both household (i.e., income-needs and material hardship) and neighborhood (i.e., area deprivation and neighborhood unsafety) levels, frontoamygdala resting-state functional connectivity, and internalizing symptoms at baseline and 1-year follow-up. SED were positively associated with internalizing symptoms at baseline and indirectly predicted symptoms 1 year later through elevated symptoms at baseline. At the household level, youth in households characterized by higher disadvantage (i.e., lower income-to-needs ratio) exhibited more strongly negative frontoamygdala coupling, particularly between the bilateral amygdala and medial OFC (mOFC) regions within the frontoparietal network. Although more strongly positive amygdala-mOFC coupling was associated with higher levels of internalizing symptoms at baseline and 1-year follow-up, it did not mediate the association between income-to-needs ratio and internalizing symptoms. However, at the neighborhood level, amygdala-mOFC functional coupling moderated the effect of neighborhood deprivation on internalizing symptoms. Specifically, higher neighborhood deprivation was associated with higher internalizing symptoms for youth with more strongly positive connectivity, but not for youth with more strongly negative connectivity, suggesting a potential buffering effect. Findings highlight the importance of capturing multilevel socioecological contexts in which youth develop to identify youth who are most likely to benefit from early interventions.

An open-access accelerated adult equivalent of the ABCD Study neuroimaging dataset (a-ABCD).

As public access to longitudinal developmental datasets like the Adolescent Brain Cognitive Development StudySM (ABCD Study®) increases, so too does the need for resources to benchmark time-dependent effects. Scan-to-scan changes observed with repeated imaging may reflect development but may also reflect practice effects, day-to-day variability in psychological states, and/or measurement noise. Resources that allow disentangling these time-dependent effects will be useful in quantifying actual developmental change. We present an accelerated adult equivalent of the ABCD Study dataset (a-ABCD) using an identical imaging protocol to acquire magnetic resonance imaging (MRI) structural, diffusion-weighted, resting-state and task-based data from eight adults scanned five times over five weeks. We report on the task-based imaging data (n = 7). In-scanner stop-signal (SST), monetary incentive delay (MID), and emotional n-back (EN-back) task behavioral performance did not change across sessions. Post-scan recognition memory for emotional n-back stimuli, however, did improve as participants became more familiar with the stimuli. Functional MRI analyses revealed that patterns of task-based activation reflecting inhibitory control in the SST, reward success in the MID task, and working memory in the EN-back task were more similar within individuals across repeated scan sessions than between individuals. Within-subject, activity was more consistent across sessions during the EN-back task than in the SST and MID task, demonstrating differences in fMRI data reliability as a function of task. The a-ABCD dataset provides a unique testbed for characterizing the reliability of brain function, structure, and behavior across imaging modalities in adulthood and benchmarking neurodevelopmental change observed in the open-access ABCD Study.

Genetic variation in endocannabinoid signaling is associated with differential network-level functional connectivity in youth.

The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [<0.001, <0.001]) and lesser (95% CI for p values = [0.006, <0.001]) in A-allele carriers relative to non-carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A-allele carriers, such that non-carriers with connectivity more similar to A-allele carriers (i.e., greater connectivity) had lower anxiety symptoms (ß = -0.041, p = 0.030). These findings provide novel evidence of network-level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype-associated neural differences may emerge at a younger age than genotype-associated differences in anxiety.