Multimodal mapping of macaque monkey somatosensory cortex.

The somatosensory cortex is a brain region responsible for receiving and processing sensory information from across the body and is structurally and functionally heterogeneous. Since the chemoarchitectonic segregation of the cerebral cortex can be revealed by transmitter receptor distribution patterns, by using a quantitative multireceptor architectonical analysis, we determined the number and extent of distinct areas of the macaque somatosensory cortex. We identified three architectonically distinct cortical entities within the primary somatosensory cortex (i.e., 3bm, 3bli, 3ble), four within the anterior parietal cortex (i.e., 3am, 3al, 1 and 2) and six subdivisions (i.e., S2l, S2m, PVl, PVm, PRl and PRm) within the lateral fissure. We provide an ultra-high resolution 3D atlas of macaque somatosensory areas in stereotaxic space, which integrates cyto- and receptor architectonic features of identified areas. Multivariate analyses of the receptor fingerprints revealed four clusters of identified areas based on the degree of (dis)similarity of their receptor architecture. Each of these clusters can be associated with distinct levels of somatosensory processing, further demonstrating that the functional segregation of cortical areas is underpinned by differences in their molecular organization.

The meso-connectomes of mouse, marmoset, and macaque: network organization and the emergence of higher cognition.

The recent publications of the inter-areal connectomes for mouse, marmoset, and macaque cortex have allowed deeper comparisons across rodent vs. primate cortical organization. In general, these show that the mouse has very widespread, "all-to-all" inter-areal connectivity (i.e. a "highly dense" connectome in a graph theoretical framework), while primates have a more modular organization. In this review, we highlight the relevance of these differences to function, including the example of primary visual cortex (V1) which, in the mouse, is interconnected with all other areas, therefore including other primary sensory and frontal areas. We argue that this dense inter-areal connectivity benefits multimodal associations, at the cost of reduced functional segregation. Conversely, primates have expanded cortices with a modular connectivity structure, where V1 is almost exclusively interconnected with other visual cortices, themselves organized in relatively segregated streams, and hierarchically higher cortical areas such as prefrontal cortex provide top-down regulation for specifying precise information for working memory storage and manipulation. Increased complexity in cytoarchitecture, connectivity, dendritic spine density, and receptor expression additionally reveal a sharper hierarchical organization in primate cortex. Together, we argue that these primate specializations permit separable deconstruction and selective reconstruction of representations, which is essential to higher cognition.

Cell type-specific connectome predicts distributed working memory activity in the mouse brain.

Recent advances in connectomics and neurophysiology make it possible to probe whole-brain mechanisms of cognition and behavior. We developed a large-scale model of the multiregional mouse brain for a cardinal cognitive function called working memory, the brain's ability to internally hold and process information without sensory input. The model is built on mesoscopic connectome data for interareal cortical connections and endowed with a macroscopic gradient of measured parvalbumin-expressing interneuron density. We found that working memory coding is distributed yet exhibits modularity; the spatial pattern of mnemonic representation is determined by long-range cell type-specific targeting and density of cell classes. Cell type-specific graph measures predict the activity patterns and a core subnetwork for memory maintenance. The model shows numerous attractor states, which are self-sustained internal states (each engaging a distinct subset of areas). This work provides a framework to interpret large-scale recordings of brain activity during cognition, while highlighting the need for cell type-specific connectomics.

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe.

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker's areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

Gradients of neurotransmitter receptor expression in the macaque cortex.

Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas.

A polygenic score indexing a DRD2-related co-expression network is associated with striatal dopamine function.

The D2 dopamine receptor (D2R) is the primary site of the therapeutic action of antipsychotics and is involved in essential brain functions relevant to schizophrenia, such as attention, memory, motivation, and emotion processing. Moreover, the gene coding for D2R (DRD2) has been associated with schizophrenia at a genome-wide level. Recent studies have shown that a polygenic co-expression index (PCI) predicting the brain-specific expression of a network of genes co-expressed with DRD2 was associated with response to antipsychotics, brain function during working memory in patients with schizophrenia, and with the modulation of prefrontal cortex activity after pharmacological stimulation of D2 receptors. We aimed to investigate the relationship between the DRD2 gene network and in vivo striatal dopaminergic function, which is a phenotype robustly associated with psychosis and schizophrenia. To this aim, a sample of 92 healthy subjects underwent 18F-DOPA PET and was genotyped for genetic variations indexing the co-expression of the DRD2-related genetic network in order to calculate the PCI for each subject. The PCI was significantly associated with whole striatal dopamine synthesis capacity (p = 0.038). Exploratory analyses on the striatal subdivisions revealed a numerically larger effect size of the PCI on dopamine function for the associative striatum, although this was not significantly different than effects in other sub-divisions. These results are in line with a possible relationship between the DRD2-related co-expression network and schizophrenia and extend it by identifying a potential mechanism involving the regulation of dopamine synthesis. Future studies are needed to clarify the molecular mechanisms implicated in this relationship.

The neural basis of delayed gratification.

Balancing instant gratification versus delayed but better gratification is important for optimizing survival and reproductive success. Although delayed gratification has been studied through human psychological and brain activity monitoring and animal research, little is known about its neural basis. We successfully trained mice to perform a waiting-for-water-reward delayed gratification task and used these animals in physiological recording and optical manipulation of neuronal activity during the task to explore its neural basis. Our results showed that the activity of dopaminergic (DAergic) neurons in the ventral tegmental area increases steadily during the waiting period. Optical activation or silencing of these neurons, respectively, extends or reduces the duration of waiting. To interpret these data, we developed a reinforcement learning model that reproduces our experimental observations. Steady increases in DAergic activity signal the value of waiting and support the hypothesis that delayed gratification involves real-time deliberation.

A dopamine gradient controls access to distributed working memory in the large-scale monkey cortex.

Dopamine is required for working memory, but how it modulates the large-scale cortex is unknown. Here, we report that dopamine receptor density per neuron, measured by autoradiography, displays a macroscopic gradient along the macaque cortical hierarchy. This gradient is incorporated in a connectome-based large-scale cortex model endowed with multiple neuron types. The model captures an inverted U-shaped dependence of working memory on dopamine and spatial patterns of persistent activity observed in over 90 experimental studies. Moreover, we show that dopamine is crucial for filtering out irrelevant stimuli by enhancing inhibition from dendrite-targeting interneurons. Our model revealed that an activity-silent memory trace can be realized by facilitation of inter-areal connections and that adjusting cortical dopamine induces a switch from this internal memory state to distributed persistent activity. Our work represents a cross-level understanding from molecules and cell types to recurrent circuit dynamics underlying a core cognitive function distributed across the primate cortex.

Combining brain perturbation and neuroimaging in non-human primates.

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

Organization of the macaque monkey inferior parietal lobule based on multimodal receptor architectonics.

The macaque monkey inferior parietal lobe (IPL) is a structurally heterogeneous brain region, although the number of areas it contains and the anatomical/functional relationship of identified subdivisions remains controversial. Neurotransmitter receptor distribution patterns not only reveal the position of the cortical borders, but also segregate areas associated to different functional systems. Thus we carried out a multimodal quantitative analysis of the cyto- and receptor architecture of the macaque IPL to determine the number and extent of distinct areas it encompasses. We identified four areas on the IPL convexity arranged in a caudo-rostral sequence, as well as two areas in the parietal operculum, which we projected onto the Yerkes19 surface. We found rostral areas to have relatively smaller receptor fingerprints than the caudal ones, which is in an agreement with the functional gradient along the caudo-rostral axis described in previous studies. The hierarchical analysis segregated IPL areas into two clusters: the caudal one, contains areas involved in multisensory integration and visual-motor functions, and rostral cluster, encompasses areas active during motor planning and action-related functions. The results of the present study provide novel insights into clarifying the homologies between human and macaque IPL areas. The ensuing 3D map of the macaque IPL, and the receptor fingerprints are made publicly available to the neuroscientific community via the Human Brain Project and BALSA repositories for future cyto- and/or receptor architectonically driven analyses of functional imaging studies in non-human primates.

Multimodal 3D atlas of the macaque monkey motor and premotor cortex.

In the present study we reevaluated the parcellation scheme of the macaque frontal agranular cortex by implementing quantitative cytoarchitectonic and multireceptor analyses, with the purpose to integrate and reconcile the discrepancies between previously published maps of this region. We applied an observer-independent and statistically testable approach to determine the position of cytoarchitectonic borders. Analysis of the regional and laminar distribution patterns of 13 different transmitter receptors confirmed the position of cytoarchitectonically identified borders. Receptor densities were extracted from each area and visualized as its "receptor fingerprint". Hierarchical and principal components analyses were conducted to detect clusters of areas according to the degree of (dis)similarity of their fingerprints. Finally, functional connectivity pattern of each identified area was analyzed with areas of prefrontal, cingulate, somatosensory and lateral parietal cortex and the results were depicted as "connectivity fingerprints" and seed-to-vertex connectivity maps. We identified 16 cyto- and receptor architectonically distinct areas, including novel subdivisions of the primary motor area 4 (i.e. 4a, 4p, 4m) and of premotor areas F4 (i.e. F4s, F4d, F4v), F5 (i.e. F5s, F5d, F5v) and F7 (i.e. F7d, F7i, F7s). Multivariate analyses of receptor fingerprints revealed three clusters, which first segregated the subdivisions of area 4 with F4d and F4s from the remaining premotor areas, then separated ventrolateral from dorsolateral and medial premotor areas. The functional connectivity analysis revealed that medial and dorsolateral premotor and motor areas show stronger functional connectivity with areas involved in visual processing, whereas 4p and ventrolateral premotor areas presented a stronger functional connectivity with areas involved in somatomotor responses. For the first time, we provide a 3D atlas integrating cyto- and multi-receptor architectonic features of the macaque motor and premotor cortex. This atlas constitutes a valuable resource for the analysis of functional experiments carried out with non-human primates, for modeling approaches with realistic synaptic dynamics, as well as to provide insights into how brain functions have developed by changes in the underlying microstructure and encoding strategies during evolution.

Altered Cortical Gyrification in Adults Who Were Born Very Preterm and Its Associations With Cognition and Mental Health.

BACKGROUND: The last trimester of pregnancy is a critical period for the establishment of cortical gyrification, and altered folding patterns have been reported following very preterm birth (< 33 weeks of gestation) in childhood and adolescence. However, research is scant on the persistence of such alterations in adulthood and their associations with cognitive and psychiatric outcomes. METHODS: We studied 79 very preterm and 81 age-matched full-term control adults. T1-weighted magnetic resonance images were used to measure a local gyrification index (LGI), indicating the degree of folding across multiple vertices of the reconstructed cortical surface. Group and group-by-sex LGI differences were assessed by means of per-vertex adjustment for cortical thickness and overall intracranial volume. Within-group correlations were also computed between LGI and functional outcomes, including general intelligence (IQ) and psychopathology. RESULTS: Very preterm adults had significantly reduced LGI in extensive cortical regions encompassing the frontal, anterior temporal, and occipitoparietal lobes. Alterations in lateral fronto-temporal-parietal and medial occipitoparietal regions were present in both men and women, although men showed more extensive alterations. In both very preterm and control adults, higher LGI was associated with higher IQ and lower psychopathology scores, with the spatial distribution of these associations substantially differing between the two groups. CONCLUSIONS: Very preterm adults' brains are characterized by significant and widespread local hypogyria, and these alterations might be implicated in cognitive and psychiatric outcomes. Gyrification reflects an early developmental process and provides a fingerprint for very preterm birth.

The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study.

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [18F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [18F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as Kicer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal Kicer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.

Interindividual Variability of Functional Connectivity in Awake and Anesthetized Rhesus Macaque Monkeys.

BACKGROUND: Nonhuman primate (NHP) models are commonly used to advance our understanding of brain function and organization. However, to date, they have offered few insights into individual differences among NHPs. In large part, this is due to the logistical challenges of NHP research, which limit most studies to 5 subjects or fewer. METHODS: We leveraged the availability of a large-scale open NHP imaging resource to provide an initial examination of individual differences in the functional organization of the NHP brain. Specifically, we selected one awake functional magnetic resonance imaging dataset (Newcastle University: n = 10) and two anesthetized functional magnetic resonance imaging datasets (Oxford University: n = 19; University of California, Davis: n = 19) to examine individual differences in functional connectivity characteristics across the cortex as well as potential state dependencies. RESULTS: We noted significant individual variations of functional connectivity across the macaque cortex. Similar to the findings in humans, during the awake state, the primary sensory and motor cortices showed lower variability than the high-order association regions. This variability pattern was significantly correlated with T1-weighted and T2-weighted mapping and degree of long-distance connectivity, but not short-distance connectivity. The interindividual variability under anesthesia exhibited a very distinct pattern, with lower variability in medial frontal cortex, precuneus, and somatomotor regions and higher variability in the lateral ventral frontal and insular cortices. CONCLUSIONS: This work has implications for our understanding of the evolutionary origins of individual variation in the human brain and methodological implications that must be considered in any pursuit to study individual variation in NHP models.

Verbal Fluency Is Affected by Altered Brain Lateralization in Adults Who Were Born Very Preterm.

Language difficulties have been reported in children and adolescents who were born very preterm (<32 weeks' gestation) and associated with an atypical lateralization of language processing, i.e., increased right-hemispheric engagement. This study used functional magnetic resonance imaging (fMRI) and spherical deconvolution tractography to study the hemodynamic responses associated with verbal fluency processing (easy and hard letter trials) and verbal fluency-related white matter fiber tracts in 64 very preterm born adults and 36 adult controls (mean age: 30 years). Tractography of the arcuate fasciculus (AF) and frontal aslant tract (FAT) was performed. Tracts were quantified in terms of mean volume, hindrance modulated orientational anisotropy, and lateralization, assessed using a laterality index (LI) to indicate hemispheric dominance. During verbal fluency fMRI, very preterm participants displayed decreased hemodynamic response suppression in both the Easy > Rest and Hard > Rest conditions, compared to controls, in superior temporal gyrus (STG), insula, thalamus, and sensorimotor cortex, particularly in the right hemisphere. At the whole-group level, decreased hemodynamic response suppression in the right sensorimotor cortex was associated with worse on-line performance on the hard letter trials. Increased left-laterality in the AF was present alongside increased right hemispheric hemodynamic response suppression in controls. When only right-handed participants were considered, decreased hemodynamic response suppression in the right STG during hard letter trials was related to weaker left and right FAT white matter integrity in the preterm group only. These results show that verbal fluency is affected by altered functional lateralization in adults who were born very preterm.

Macro-connectomics and microstructure predict dynamic plasticity patterns in the non-human primate brain.

The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not.

An Open Resource for Non-human Primate Imaging.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis.

While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

The Rhesus Monkey Hippocampus Critically Contributes to Scene Memory Retrieval, But Not New Learning.

Humans can recall a large number of memories years after the initial events. Patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. Rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to temporally graded or ungraded amnesia, which could be a consequence of differences between rodent and human studies. In the current study, rhesus monkeys of both sexes received either bilateral neurotoxic hippocampal lesions or remained unoperated controls and were tested on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but the role of the damaged hippocampus can be taken over by spared hippocampal tissue or extra-hippocampal regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.SIGNIFICANCE STATEMENT Recalling old memories, creating new memories, and the process by which memories transition from temporary to permanent storage all may rely on the hippocampus. Whether the hippocampus is necessary for encoding and retrieval of multiple related visual memories in primates is not known. Monkeys that learned many visual memory problems before precise lesions of the hippocampus were impaired at recalling those memories after hippocampal damage regardless of when the memories were formed, but could learn new memory problems at a normal rate. This suggests the hippocampus is normally vital for retrieval of complex visual memories regardless of their age, and also points to the importance of investigating mechanisms by which memories may be acquired in the presence of hippocampal damage.

Reward-Based Learning as a Function of Severity of Substance Abuse Risk in Drug-Naïve Youth with ADHD.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is associated with elevated risk for later development of substance use disorders (SUD), specifically because youth with ADHD, similar to individuals with SUD, exhibit deficits in learning abilities and reward processing. Another known risk factor for SUD is familial history of substance dependence. Youth with familial SUD history show reward processing deficits, higher prevalence of externalizing disorders, and higher impulsivity scores. Thus, the main objective of this proof-of-concept study is to investigate whether risk loading (ADHD and parental substance use) for developing SUD in drug-naïve youth impacts reward-related learning. METHODS: Forty-one drug-naïve youth, stratified into three groups: Healthy Controls (HC, n = 13; neither ADHD nor parental SUD), Low Risk (LR, n = 13; ADHD only), and High Risk (HR, n = 15; ADHD and parental SUD), performed a novel Anticipation, Conflict, and Reward (ACR) task. In addition to conventional reaction time (RT) and accuracy analyses, we analyzed computational variables including learning rates and assessed the influence of learned predictions of reward probability and stimulus congruency on RT. RESULTS: The multivariate ANOVA on learning rate, congruence, and prediction revealed a significant main Group effect across these variables [F(3, 37) = 3.79, p = 0.018]. There were significant linear effects for learning rate (Contrast Estimate = 0.181, p = 0.038) and the influence of stimulus congruency on RTs (Contrast Estimate = 1.16, p = 0.017). Post hoc comparisons revealed that HR youth showed the most significant deficits in accuracy and learning rates, while stimulus congruency had a lower impact on RTs in this group. LR youth showed scores between those of the HC and HR youth. CONCLUSION: These preliminary results suggest that deficits in learning and in adjusting to task difficulty are a function of increasing risk loading for SUD in drug-naïve youth. These results also highlight the importance of developing and applying computational models to study intricate details in behavior that typical analytic methodology may not be sensitive to.