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.

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.

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.

Behavioral and Neural Signatures of Working Memory in Childhood.

Working memory function changes across development and varies across individuals. The patterns of behavior and brain function that track individual differences in working memory during human development, however, are not well understood. Here, we establish associations between working memory, other cognitive abilities, and functional MRI (fMRI) activation in data from over 11,500 9- to 10-year-old children (both sexes) enrolled in the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing longitudinal study in the United States. Behavioral analyses reveal robust relationships between working memory, short-term memory, language skills, and fluid intelligence. Analyses relating out-of-scanner working memory performance to memory-related fMRI activation in an emotional n-back task demonstrate that frontoparietal activity during a working memory challenge indexes working memory performance. This relationship is domain specific, such that fMRI activation related to emotion processing during the emotional n-back task, inhibitory control during a stop-signal task (SST), and reward processing during a monetary incentive delay (MID) task does not track memory abilities. Together, these results inform our understanding of individual differences in working memory in childhood and lay the groundwork for characterizing the ways in which they change across adolescence.SIGNIFICANCE STATEMENT Working memory is a foundational cognitive ability that changes over time and varies across individuals. Here, we analyze data from over 11,500 9- to 10-year-olds to establish relationships between working memory, other cognitive abilities, and frontoparietal brain activity during a working memory challenge, but not during other cognitive challenges. Our results lay the groundwork for assessing longitudinal changes in working memory and predicting later academic and other real-world outcomes.

Altered hippocampal microstructure and function in children who experienced Hurricane Irma.

Hurricane Irma was the most powerful Atlantic hurricane in recorded history, displacing 6 million and killing over 120 people in the state of Florida alone. Unpredictable disasters like Irma are associated with poor cognitive and health outcomes that can disproportionately impact children. This study examined the effects of Hurricane Irma on the hippocampus and memory processes previously related to unpredictable stress. We used an innovative application of an advanced diffusion-weighted imaging technique, restriction spectrum imaging (RSI), to characterize hippocampal microstructure (i.e., cell density) in 9- to 10-year-old children who were exposed to Hurricane Irma relative to a non-exposed control group (i.e., assessed the year before Hurricane Irma). We tested the hypotheses that the experience of Hurricane Irma would be associated with decreases in: (a) hippocampal cellularity (e.g., neurogenesis), based on known associations between unpredictable stress and hippocampal alterations; and (b) hippocampal-related memory function as indexed by delayed recall. We show an association between decreased hippocampal cellularity and delayed recall memory in children who experienced Hurricane Irma relative to those who did not. These findings suggest an important role of RSI for assessing subtle microstructural changes related to functionally significant changes in the developing brain in response to environmental events.

Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues.

Obesity is a major public health concern that involves an interaction between genetic susceptibility and exposure to environmental cues (e.g., food marketing); however, the mechanisms that link these factors and contribute to unhealthy eating are unclear. Using a well-known obesity risk polymorphism (FTO rs9939609) in a sample of 78 children (ages 9-12 y), we observed that children at risk for obesity exhibited stronger responses to food commercials in the nucleus accumbens (NAcc) than children not at risk. Similarly, children at a higher genetic risk for obesity demonstrated larger NAcc volumes. Although a recessive model of this polymorphism best predicted body mass and adiposity, a dominant model was most predictive of NAcc size and responsivity to food cues. These findings suggest that children genetically at risk for obesity are predisposed to represent reward signals more strongly, which, in turn, may contribute to unhealthy eating behaviors later in life.

Altered ability to access a clinically relevant control network in patients remitted from major depressive disorder.

Neurobiological models to explain vulnerability of major depressive disorder (MDD) are scarce and previous functional magnetic resonance imaging studies mostly examined "static" functional connectivity (FC). Knowing that FC constantly evolves over time, it becomes important to assess how FC dynamically differs in remitted-MDD patients vulnerable for new depressive episodes. Using a recently developed method to examine dynamic FC, we characterized re-emerging FC states during rest in 51 antidepressant-free MDD patients at high risk of recurrence (≥2 previous episodes), and 35 healthy controls. We examined differences in occurrence, duration, and switching profiles of FC states after neutral and sad mood induction. Remitted MDD patients showed a decreased probability of an FC state (p < 0.005) consisting of an extensive network connecting frontal areas-important for cognitive control-with default mode network, striatum, and salience areas, involved in emotional and self-referential processing. Even when this FC state was observed in patients, it lasted shorter (p < 0.005) and was less likely to switch to a smaller prefrontal-striatum network (p < 0.005). Differences between patients and controls decreased after sad mood induction. Further, the duration of this FC state increased in remitted patients after sad mood induction but not in controls (p < 0.05). Our findings suggest reduced ability of remitted-MDD patients, in neutral mood, to access a clinically relevant control network involved in the interplay between externally and internally oriented attention. When recovering from sad mood, remitted recurrent MDD appears to employ a compensatory mechanism to access this FC state. This study provides a novel neurobiological profile of MDD vulnerability.

Individual Differences in Reward and Somatosensory-Motor Brain Regions Correlate with Adiposity in Adolescents.

The prevalence of adolescent obesity has increased dramatically over the past three decades, and research has documented that the number of television shows viewed during childhood is associated with greater risk for obesity. In particular, considerable evidence suggests that exposure to food marketing promotes eating habits that contribute to obesity. The present study examines neural responses to dynamic food commercials in overweight and healthy-weight adolescents using functional magnetic resonance imaging (fMRI). Compared with non-food commercials, food commercials more strongly engaged regions involved in attention and saliency detection (occipital lobe, precuneus, superior temporal gyri, and right insula) and in processing rewards [left and right nucleus accumbens (NAcc) and left orbitofrontal cortex (OFC)]. Activity in the left OFC and right insula further correlated with subjects' percent body fat at the time of the scan. Interestingly, this reward-related activity to food commercials was accompanied by the additional recruitment of mouth-specific somatosensory-motor cortices-a finding that suggests the intriguing possibility that higher-adiposity adolescents mentally simulate eating behaviors and offers a potential neural mechanism for the formation and reinforcement of unhealthy eating habits that may hamper an individual's ability lose weight later in life.

Humans mimicking animals: a cortical hierarchy for human vocal communication sounds.

Numerous species possess cortical regions that are most sensitive to vocalizations produced by their own kind (conspecifics). In humans, the superior temporal sulci (STSs) putatively represent homologous voice-sensitive areas of cortex. However, superior temporal sulcus (STS) regions have recently been reported to represent auditory experience or "expertise" in general rather than showing exclusive sensitivity to human vocalizations per se. Using functional magnetic resonance imaging and a unique non-stereotypical category of complex human non-verbal vocalizations-human-mimicked versions of animal vocalizations-we found a cortical hierarchy in humans optimized for processing meaningful conspecific utterances. This left-lateralized hierarchy originated near primary auditory cortices and progressed into traditional speech-sensitive areas. Our results suggest that the cortical regions supporting vocalization perception are initially organized by sensitivity to the human vocal tract in stages before the STS. Additionally, these findings have implications for the developmental time course of conspecific vocalization processing in humans as well as its evolutionary origins.

Executive Network Activation Moderates the Association between Neighborhood Threats and Externalizing Behavior in Youth.

Neighborhood threats can increase risk for externalizing problems, including aggressive, oppositional, and delinquent behavior. Yet, there is substantial variability in how youth respond to neighborhood threats. Difficulty with cognitive functioning, particularly in the face of emotional information, may increase risk for externalizing in youth who live in neighborhoods with higher threats. However, little research has examined: 1) associations between neighborhood threats and executive networks involved in cognitive functioning or 2) whether executive networks may amplify risk for externalizing in the context of neighborhood threats. Further, most research on neighborhood threats does not account for youth's experiences in other social contexts. Utilizing the large, sociodemographically diverse cohort of youth (ages 9-10) included in the Adolescent Brain Cognitive DevelopmentSM Study, we identified four latent profiles of youth based on threats in their neighborhoods, families, and schools: low threat in all contexts, elevated family threat, elevated neighborhood threat, and elevated threat in all contexts. The elevated neighborhood threat and elevated all threat profiles showed lower behavioral performance on an emotional n-back task relative to low threat and elevated family threat profiles. Lower behavioral performance in the elevated neighborhood threat profile specifically was paralleled by lower executive network activity during a cognitive challenge. Moreover, among youth with lower executive network activity, higher probability of membership in the elevated neighborhood threat profile was associated with higher externalizing. Together, these results provide evidence that interactions between threats that are concentrated in youth's neighborhoods and attenuated executive network function may contribute to risk for externalizing problems.

Heightened sensitivity to high-calorie foods in children at risk for obesity: insights from behavior, neuroimaging, and genetics.

Pediatric obesity is a major public health concern. Genetic susceptibility and increased availability of energy-dense food are known risk factors for obesity. However, the extent to which these factors jointly bias behavior and neural circuitry towards increased adiposity in children remains unclear. While undergoing fMRI, 108 children (ages 5-11y) performed a food-specific go/no-go task. Participants were instructed to either respond ("go") or inhibit responding ("no-go") to images of food or toys. Half of the runs depicted high-calorie foods (e.g., pizza) whereas the other half depicted low-calorie foods (e.g., salad). Children were also genotyped for a DNA polymorphism associated with energy intake and obesity (FTO rs9939609) to examine the influence of obesity risk on behavioral and brain responses to food. Participants demonstrated differences in behavioral sensitivity to high- and low-calorie food images depending on task demands. Participants were slower but more accurate at detecting high- (relative to low-) calorie foods when responding to a neutral stimulus (i.e., toys) and worse at detecting toys when responding to high-calorie foods. Inhibition failures were accompanied by salience network activity (anterior insula, dorsal anterior cingulate cortex), which was driven by false alarms to food images. Children at a greater genetic risk for obesity (dose-dependent model of the FTO genotype) demonstrated pronounced brain and behavioral relationships such that genetic risk was associated with heightened sensitivity to high-calorie food images and increased anterior insula activity. These findings suggest that high-calorie foods may be particularly salient to children at risk for developing eating habits that promote obesity.

Longitudinal Evidence of a Vicious Cycle Between Nucleus Accumbens Microstructure and Childhood Weight Gain.

PURPOSE: Pediatric obesity is a growing public health concern. Previous work has observed diet to impact nucleus accumbens (NAcc) inflammation in rodents, measured by the reactive proliferation of glial cells. Recent work in humans has demonstrated a relationship between NAcc cell density-a proxy for neuroinflammation-and weight gain in youth; however, the directionality of this relationship in the developing brain and association with diet remains unknown. METHODS: Waist circumference (WC) and NAcc cell density were collected in a large cohort of children (n > 2,000) participating in the Adolescent Brain Cognitive Development (ABCD) Study (release 3.0) at baseline (9-10 y) and at a Year 2 follow-up (11-12 y). Latent change score modeling (LCSM) was used to disentangle contributions of baseline measures to two-year changes in WC percentile and NAcc cellularity. In addition, the role of NAcc cellularity in mediating the relationship between diet and WC percentile was assessed using dietary intake data collected at Year 2. RESULTS: LCSM indicates that baseline WC percentile influences change in NAcc cellularity and that baseline NAcc cell density influences change in WC percentile. NAcc cellularity was significantly associated with WC percentile at Year 2 and mediated the relationship between dietary fat consumption and WC percentile. CONCLUSIONS: These results implicate a vicious cycle whereby NAcc cell density biases longitudinal changes in WC percentile and vice versa. Moreover, NAcc cell density may mediate the relationship between diet and weight gain in youth. These findings suggest that diet-induced inflammation of reward circuitry may lead to behavioral changes that further contribute to weight gain.

Cortical network differences in the sighted versus early blind for recognition of human-produced action sounds.

Both sighted and blind individuals can readily interpret meaning behind everyday real-world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio-visual integration. However, it remained unclear whether, or to what degree, life-long visual experience might impact functions related to hearing perception or memory of sound-source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human-produced action sounds (excluding vocalizations) versus unrecognized, backward-played versions of those sounds. Here, we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero-lateral temporal cortices contain domain-specific hubs for biological and/or complex motion processing independent of sensory-modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, whereas the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual-related cortex. These global-level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when hearing and attempting to recognize action sounds.

Endogenous variation in ventromedial prefrontal cortex state dynamics during naturalistic viewing reflects affective experience.

How we process ongoing experiences is shaped by our personal history, current needs, and future goals. Consequently, ventromedial prefrontal cortex (vmPFC) activity involved in processing these subjective appraisals appears to be highly idiosyncratic across individuals. To elucidate the role of the vmPFC in processing our ongoing experiences, we developed a computational framework and analysis pipeline to characterize the spatiotemporal dynamics of individual vmPFC responses as participants viewed a 45-minute television drama. Through a combination of functional magnetic resonance imaging, facial expression tracking, and self-reported emotional experiences across four studies, our data suggest that the vmPFC slowly transitions through a series of discretized states that broadly map onto affective experiences. Although these transitions typically occur at idiosyncratic times across people, participants exhibited a marked increase in state alignment during high affectively valenced events in the show. Our work suggests that the vmPFC ascribes affective meaning to our ongoing experiences.

A Neurobiological Model of Alcohol Marketing Effects on Underage Drinking.

OBJECTIVE: Although an association between exposure to alcohol advertising and underage drinking is well documented, the underlying neurobiological contributions to this association remain largely unexplored. From an epidemiological perspective, identifying the neurobiological plausibility of this exposure-outcome association is a crucial step toward establishing marketing as a contributor to youth drinking and informing public policy interventions to decrease this influence. METHOD: We conducted a critical review of the literature on neurobiological risk factors and adolescent brain development, social influences on drinking, and neural contributions to reward sensitization and risk taking. By drawing from these separate areas of research, we propose a unified, neurobiological model of alcohol marketing effects on underage drinking. RESULTS: We discuss and extend the literature to suggest that responses in prefrontal-reward circuitry help establish alcohol advertisements as reward-predictive cues that may reinforce consumption upon exposure. We focus on adolescence as a sensitive window of development during which youth are particularly susceptible to social and reward cues, which are defining characteristics of many alcohol advertisements. As a result, alcohol marketing may promote positive associations early in life that motivate social drinking, and corresponding neurobiological changes may contribute to later patterns of alcohol abuse. CONCLUSIONS: The neurobiological model proposed here, which considers neurodevelopmental risk factors, social influences, and reward sensitization to alcohol cues, suggests that exposure to alcohol marketing could plausibly influence underage drinking by sensitizing prefrontal-reward circuitry.

Behavioral and brain signatures of substance use vulnerability in childhood.

The prevalence of risky behavior such as substance use increases during adolescence; however, the neurobiological precursors to adolescent substance use remain unclear. Predictive modeling may complement previous work observing associations with known risk factors or substance use outcomes by developing generalizable models that predict early susceptibility. The aims of the current study were to identify and characterize behavioral and brain models of vulnerability to future substance use. Principal components analysis (PCA) of behavioral risk factors were used together with connectome-based predictive modeling (CPM) during rest and task-based functional imaging to generate predictive models in a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain & Cognitive Development (ABCD) study (NDA release 2.0.1). Dimensionality reduction (n = 9,437) of behavioral measures associated with substance use identified two latent dimensions that explained the largest amount of variance: risk-seeking (PC1; e.g., curiosity to try substances) and familial factors (PC2; e.g., family history of substance use disorder). Using cross-validated regularized regression in a subset of data (Year 1 Fast Track data; n>1,500), functional connectivity during rest and task conditions (resting-state; monetary incentive delay task; stop signal task; emotional n-back task) significantly predicted individual differences in risk-seeking (PC1) in held-out participants (partial correlations between predicted and observed scores controlling for motion and number of frames [rp]: 0.07-0.21). By contrast, functional connectivity was a weak predictor of familial risk factors associated with substance use (PC2) (rp: 0.03-0.06). These results demonstrate a novel approach to understanding substance use vulnerability, which-together with mechanistic perspectives-may inform strategies aimed at early identification of risk for addiction.