Sex moderates family history of alcohol use disorder and childhood maltreatment effects on an fMRI stop-signal task.

Childhood maltreatment (CM) and a family history (FH) of alcohol use disorder (AUD) are each associated with increased impulsivity. However, their unique or shared brain targets remain unknown. Furthermore, both CM and FH demonstrate sex-dependent effects on brain and behavior. We hypothesized that CM and FH interact in brain regions involved in impulsivity with sex-dependent effects. 144 first-year college students (18-19 years old) with varying experiences of CM and/or FH but without current AUD performed an fMRI stop-signal task. We tested interactions between FH, CM, and sex on task performance and blood oxygen level-dependent (BOLD) signal during successful inhibitions. We examined correlations between BOLD response and psychiatric symptoms. Significant three-way interactions of FH, CM, and sex were detected for brain and behavioral data, largely driven by male subjects. In males, CM was associated with poorer response inhibition but only for those with less FH; males with higher levels of both CM and FH demonstrated better response inhibition. Three-way interaction effects on voxel-wise BOLD response during response inhibition were found in bilateral middle frontal gyrus, left inferior frontal gyrus, dorsomedial prefrontal cortex, and posterior cingulate cortex. Network-level analyses implicated the left frontoparietal network, executive control network, and default-mode network. Greater BOLD response in these networks correlated with lower depressive, impulsive, and attentional symptoms, reduced alcohol misuse, greater resilience scores, and heightened trait anxiety. The results highlight sex-divergent effects of heritable and environmental risk factors that may account for sex-dependent expression of psychopathology in response to risk factors.

Family history, childhood maltreatment, and adolescent binge drinking exert synergistic effects on delay discounting and future alcohol use.

Background: The transition to college is associated with a sharp increase in alcohol binge drinking. Family history (FH) of alcohol use disorder (AUD), childhood maltreatment (CM), and adolescent binge drinking are each associated with heightened impulsivity and greater alcohol misuse.Objectives: We hypothesized that FH, CM, and adolescent binge drinking synergistically increase impulsivity and lead to binge drinking increases over the first year of college.Methods: Overall, 329 first-semester college students (18-19 years old, 70% female) with varying degrees of FH (Family History Assessment Module), CM (Childhood Trauma Questionnaire), and adolescent binge drinking (Carolina Alcohol Use and Patterns Questionnaire) completed an online study that included a computerized delay discounting task and surveys. Binge drinking was surveyed retrospectively to measure adolescent binge drinking, in addition to baseline and one-year follow-up measures. Linear regression analyses tested the interacting effects of FH, CM, and adolescent binge drinking on delay discounting as well as changes in binge drinking severity between baseline and one-year follow-up. A moderated mediation tested whether delay discounting mediated future binge drinking.Results: Greater levels of FH, CM, and adolescent binge drinking interacted to reduce the selection of delayed rewards (ß=-0.12, SE = 0.06), indicating increased impulsivity. There was a similar interaction effect on increased binge drinking over the one-year follow-up period (ß = 0.37, SE = 0.13). Although FH, CM, and adolescent binge drinking influenced individual paths, the moderated mediation analysis was not significant.Conclusions: Heritable and environmental risk factors for AUD predicted impulsivity and prospectively predicted college binge drinking. Interventions targeting delay discounting processes may represent an effective strategy to reduce harmful drinking specifically for certain high-risk college students.

Naltrexone Acutely Enhances Connectivity Between the Ventromedial Prefrontal Cortex and a Left Frontoparietal Network.

BACKGROUND: Naltrexone, an opioid receptor antagonist that is Food and Drug Administration approved for treating alcohol use disorder (AUD), reduces alcohol craving and intake. Despite known pharmacological properties, little is known regarding the effects of naltrexone on neural circuit function. Thus, a data-driven examination of the neural effects of naltrexone in human subjects may offer novel insight into its treatment mechanisms. METHODS: Twenty-one alcohol using males (22 to 39) participated in a double-blind, placebo-controlled crossover study of the effects of naltrexone on brain voxel-wise functional connectivity (FC) using intersubject FC correlation mapping. We first cross-correlated the time series from each gray matter voxel to produce a 6,356 × 6,356 FC matrix for each subject and session. We then subtracted the placebo FC matrix from the naltrexone FC matrix. To identify brain regions demonstrating significant reconfiguration of whole-brain FC patterns following naltrexone treatment, we statistically quantified the consistency of patterns of voxel FC changes across subjects. Permutation testing identified significant clusters of voxels undergoing significant reconfiguration. Using the identified clusters in a seed-based FC analysis, we then compared the FC patterns of affected brain areas on placebo versus naltrexone in a paired t-test. Ridge regression analyses identified self-report measures, including substance use, that significantly predicted individual differences in FC among naltrexone-modulated regions. RESULTS: Two clusters in the rostral anterior cingulate cortex (rACC)/ventromedial prefrontal cortex (vmPFC) demonstrated significant modulation of FC by naltrexone. Using these 2 proximal clusters as a single seed, specific FC changes were identified in regions associated with a left frontoparietal network (increasing), as well as visual and motor regions (decreasing). Stronger FC between the rACC/vmPFC and this set of regions on placebo was associated with more external locus of control, whereas weaker connectivity was associated with greater substance use problems. Naltrexone strengthened these connections most among individuals who reported greater drinking to cope. CONCLUSIONS: Enhancing connectivity between the rACC/vmPFC, implicated in alcohol craving, and components of a left frontoparietal network involved in executive control may represent an effective strategy for the treatment of AUD.

Neural Systems Underlying Individual Differences in Intertemporal Decision-making.

Excessively choosing immediate over larger future rewards, or delay discounting (DD), associates with multiple clinical conditions. Individual differences in DD likely depend on variations in the activation of and functional interactions between networks, representing possible endophenotypes for associated disorders, including alcohol use disorders (AUDs). Numerous fMRI studies have probed the neural bases of DD, but investigations of large-scale networks remain scant. We addressed this gap by testing whether activation within large-scale networks during Now/Later decision-making predicts individual differences in DD. To do so, we scanned 95 social drinkers (18-40 years old; 50 women) using fMRI during hypothetical choices between small monetary amounts available "today" or larger amounts available later. We identified neural networks engaged during Now/Later choice using independent component analysis and tested the relationship between component activation and degree of DD. The activity of two components during Now/Later choice correlated with individual DD rates: A temporal lobe network positively correlated with DD, whereas a frontoparietal-striatal network negatively correlated with DD. Activation differences between these networks predicted individual differences in DD, and their negative correlation during Now/Later choice suggests functional competition. A generalized psychophysiological interactions analysis confirmed a decrease in their functional connectivity during decision-making. The functional connectivity of these two networks negatively correlates with alcohol-related harm, potentially implicating these networks in AUDs. These findings provide novel insight into the neural underpinnings of individual differences in impulsive decision-making with potential implications for addiction and related disorders in which impulsivity is a defining feature.

Functional Network Development During the First Year: Relative Sequence and Socioeconomic Correlations.

The first postnatal year is characterized by the most dramatic functional network development of the human lifespan. Yet, the relative sequence of the maturation of different networks and the impact of socioeconomic status (SES) on their development during this critical period remains poorly characterized. Leveraging a large, normally developing infant sample with multiple longitudinal resting-state functional magnetic resonance imaging scans during the first year (N = 65, scanned every 3 months), we aimed to delineate the relative maturation sequence of 9 key brain functional networks and examine their SES correlations. Our results revealed a maturation sequence from primary sensorimotor/auditory to visual to attention/default-mode, and finally to executive control networks. Network-specific critical growth periods were also identified. Finally, marginally significant positive SES-brain correlations were observed at 6 months of age for both the sensorimotor and default-mode networks, indicating interesting SES effects on functional brain maturation. To the best of our knowledge, this is the first study delineating detailed longitudinal growth trajectories of all major functional networks during the first year of life and their SES correlations. Insights from this study not only improve our understanding of early brain development, but may also inform the critical periods for SES expression during infancy.

Intersubject variability of and genetic effects on the brain's functional connectivity during infancy.

Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy.

Task-positive Functional Connectivity of the Default Mode Network Transcends Task Domain.

The default mode network (DMN) was first recognized as a set of brain regions demonstrating consistently greater activity during rest than during a multitude of tasks. Originally, this network was believed to interfere with goal-directed behavior based on its decreased activity during many such tasks. More recently, however, the role of the DMN during goal-directed behavior was established for internally oriented tasks, in which the DMN demonstrated increased activity. However, the well-documented hub position and information-bridging potential of midline DMN regions indicate that there is more to uncover regarding its functional contributions to goal-directed tasks, which may be based on its functional interactions rather than its level of activation. An investigation of task-related changes in DMN functional connectivity during a series of both internal and external tasks would provide the requisite investigation for examining the role of the DMN during goal-directed task performance. In this study, 20 participants underwent fMRI while performing six tasks spanning diverse internal and external domains in addition to a resting-state scan. We hypothesized that the DMN would demonstrate "task-positive" (i.e., positively contributing to task performance) changes in functional connectivity relative to rest regardless of the direction of task-related changes in activity. Indeed, our results demonstrate significant increases in DMN connectivity with task-promoting regions (e.g., anterior insula, inferior frontal gyrus, middle frontal gyrus) across all six tasks. Furthermore, canonical correlation analyses indicated that the observed task-related connectivity changes were significantly associated with individual differences in task performance. Our results indicate that the DMN may not only support a "default" mode but may play a greater role in both internal and external tasks through flexible coupling with task-relevant brain regions.

Task-related modulation of functional connectivity variability and its behavioral correlations.

Two new directions of functional connectivity investigation are emerging to advance studies of the brain's functional organization. First, the identification of task-related dynamics of functional connectivity has elicited a growing interest in characterizing the brain's functional reorganization due to task demands. Second, the nonstationarity of functional connectivity [i.e., functional connectivity variability (FCV)] within a single brain state has been increasingly recognized and studied. However, a combined investigation of these two avenues of research to explore the potential task-modulation of FCV is lacking, which, nevertheless, could both improve our understanding of the potential sources of FCV and also reveal new strategies to study the neural correlates of task performance. In this study, 19 human subjects underwent four functional magnetic resonance imaging (fMRI) scans including both resting and task states to study task-related modulation of FCV. Consistent with the hypothesis that FCV is partly underpinned by unconstrained mind wandering, FCV demonstrated significant task-related decreases measured at the regional, network and system levels, which was greater for between-network interactions than within-network connections. Conversely, there remained a significant degree of residual variability during the task scans, suggesting that FCV is not specific to the resting state and likely includes an intrinsic, physiologically driven component. Finally, the degree of task-induced decreases in FCV was significantly correlated with task performance accuracy, supporting its behavior significance. Overall, task modulation of FCV may represent an important direction for future studies, not only to provide insight into normal brain functioning but also to reveal potential biomarkers of various brain disorders.

Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving.

Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n = 20) and without (n = 18) moderate to severe childhood maltreatment histories underwent functional magnetic resonance imaging during script-guided mental imagery of personalized stress, drug use and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals.

Network connectivity abnormality profile supports a categorical-dimensional hybrid model of ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity, but there is no consensus regarding whether ADHD exists on the extreme end of a continuum of normal behavior or represents a discrete disorder. In this study, we sought to characterize both the categorical and dimensional variations in network functional connectivity in order to identify neural connectivity mechanisms of ADHD. Functional connectivity analyses of resting-state fMRI data from 155 children with ADHD and 145 typically developing children (TDC) defined the dorsal attention network (DA), default mode network (DM), salience processing network (SAL) and executive control network (CON). Regional alterations in connectivity associated with categorical diagnoses and dimensional symptom measures (inattention and hyperactivity/impulsivity) as well as their interaction were systematically characterized. Dimensional relationships between symptom severity measures and functional connectivity that did not differ between TDC and children with ADHD were observed for each network, supporting a dimensional characterization of ADHD. However, categorical differences in functional connectivity magnitude between TDC and children with ADHD were detected after accounting for dimensional relationships, indicating the existence of categorical mechanisms independent of dimensional effects. Additionally, differential dimensional relationships for TDC versus ADHD children demonstrated categorical differences in brain-behavior relationships. The patterns of network functional organization associated with categorical versus dimensional measures of ADHD accentuate the complexity of this disorder and support a dual characterization of ADHD etiology featuring both dimensional and categorical mechanisms.

Childhood maltreatment is associated with a sex-dependent functional reorganization of a brain inhibitory control network.

Childhood adversity represents a major risk factor for drug addiction and other mental disorders. However, the specific mechanisms by which childhood adversity impacts human brain organization to confer greater vulnerability for negative outcomes in adulthood is largely unknown. As an impaired process in drug addiction, inhibitory control of behavior was investigated as a target of childhood maltreatment (abuse and neglect). Forty adults without Axis-I psychiatric disorders (21 females) completed a Childhood Trauma Questionnaire (CTQ) and underwent functional MRI (fMRI) while performing a stop-signal task. A group independent component analysis identified a putative brain inhibitory control network. Graph theoretical analyses and structural equation modeling investigated the impact of childhood maltreatment on the functional organization of this neural processing network. Graph theory outcomes revealed sex differences in the relationship between network functional connectivity and inhibitory control which were dependent on the severity of childhood maltreatment exposure. A network effective connectivity analysis indicated that a maltreatment dose-related negative modulation of dorsal anterior cingulate (dACC) activity by the left inferior frontal cortex (IFC) predicted better response inhibition and lesser attention deficit hyperactivity disorder (ADHD) symptoms in females, but poorer response inhibition and greater ADHD symptoms in males. Less inhibition of the right IFC by dACC in males with higher CTQ scores improved inhibitory control ability. The childhood maltreatment-related reorganization of a brain inhibitory control network provides sex-dependent mechanisms by which childhood adversity may confer greater risk for drug use and related disorders and by which adaptive brain responses protect individuals from this risk factor.

Neural network activation during a stop-signal task discriminates cocaine-dependent from non-drug-abusing men.

Cocaine dependence is defined by a loss of inhibitory control over drug-use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural-processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine-dependent men and 27 healthy control men performed a stop-signal task of motor inhibition. An independent component analysis on fMRI time courses identified task-related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop-signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine-dependent men and 18 controls. Leave-one-out cross-validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine-dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine-dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.

The independent and joint effect of socioeconomic status and Multiracial status on the prevalence and frequency of substance use and depression among U.S. adolescents.

AIM: While the United States is becoming increasingly Multiracial, much is still unknown about the behavioral health of these growing new generations of Multiracial Americans. To narrow this research gap, this study investigated the prevalence/frequency of substance use and major depressive episodes [MDE] among non-Hispanic Multiracial [NHM] adolescents compared to their non-Hispanic White [NHW] counterparts and whether racial differences vary by socioeconomic status. METHODS: We analyzed data from the 2015-2019 National Survey on Drug Use and Health (N = 3,645 NHM and 34,776 NHW adolescents aged 12-17). Average Marginal Effects derived from logistic regression and negative binomial regression were used to examine (1) differences in six outcomes (past-month use of alcohol, cannabis, or drugs other than cannabis [DOTC], past-year MDE, and the frequency of alcohol and cannabis use among past-month users) by Multiracial status; (2) the moderation effect of family income on these associations. RESULTS: Compared to high-income NHW adolescents, high-income NHM adolescents reported significantly higher prevalence of past-month cannabis and DOTC use, and past-year MDE. No racial differences were observed at other income levels. Furthermore, moderation analyses indicated that the effect of Multiracial status on MDE was larger in the highest income group compared to the lowest income group. CONCLUSION: Our findings suggested that NHM adolescents, particularly those from high income families, exhibit increased prevalence of drug use and depression than NHW adolescents. As the US becomes more diverse, there is a need to further examine the social and structural factors driving the identified racial differences.

Naltrexone engages a brain reward network in the presence of reward-predictive distractor stimuli in males.

The non-selective opioid receptor antagonist, naltrexone is one of the most prescribed medications for treating alcohol and opioid addiction. Despite decades of clinical use, the mechanism(s) by which naltrexone reduces addictive behavior remains unclear. Pharmaco-fMRI studies to date have largely focused on naltrexone's impact on brain and behavioral responses to drug or alcohol cues or on decision-making circuitry. We hypothesized that naltrexone's effects on reward-associated brain regions would associate with reduced attentional bias (AB) to non-drug, reward-conditioned cues. Twenty-three adult males, including heavy and light drinkers, completed a two-session, placebo-controlled, double-blind study testing the effects of acute naltrexone (50 mg) on AB to reward-conditioned cues and neural correlates of such bias measured via fMRI during a reward-driven AB task. While we detected significant AB to reward-conditioned cues, naltrexone did not reduce this bias in all participants. A whole-brain analysis found that naltrexone significantly altered activity in regions associated with visuomotor control regardless of whether a reward-conditioned distractor was present. A region-of-interest analysis of reward-associated areas found that acute naltrexone increased BOLD signal in the striatum and pallidum. Moreover, naltrexone effects in the pallidum and putamen predicted individual reduction in AB to reward-conditioned distractors. These findings suggest that naltrexone's effects on AB primarily reflect not reward processing per se, but rather top-down control of attention. Our results suggest that the therapeutic actions of endogenous opioid blockade may reflect changes in basal ganglia function enabling resistance to distraction by attractive environmental cues, which could explain some variance in naltrexone's therapeutic efficacy.

Neural Markers of Emotion Reactivity and Regulation Before and After a Targeted Social Rejection: Differences Among Girls With and Without Suicidal Ideation and Behavior Histories.

BACKGROUND: Suicidal thoughts and behaviors (STBs) are common among adolescent girls and increase risk for suicide death. Emotion regulation difficulties are linked with STBs, particularly in response to targeted social rejection. However, neural correlates of this link have not been investigated and may identify novel targets for interventions. Here, we examined neural correlates of emotion regulation before and after an experimentally delivered targeted social rejection in adolescent girls with STBs and girls without STBs (i.e., control participants). METHODS: Girls (N = 138; age range, 9-15 years; mean [SD] age = 11.6 [1.79] years) completed a functional neuroimaging emotion regulation task. In the middle of the task, participants were socially rejected by an unfamiliar confederate whom the participants had elected to meet. Participants also completed a multimethod STB assessment. RESULTS: Before rejection, girls with a history of STBs, compared with control participants, showed greater activation in the right superior frontal gyrus when passively viewing negative stimuli, and girls with suicidal behavior (SB) versus those without SB showed less activation in the right frontal pole during emotion regulation attempts. Following the rejection, girls with STBs, compared with control participants, showed greater activation in the right inferior frontal gyrus during emotion regulation. CONCLUSIONS: Before social rejection, girls with SB versus without SB may not activate brain regions implicated in emotion regulation, suggesting a vulnerability to poor regulation at their baseline emotional state. After social rejection, girls with any history of STBs showed altered activation in a brain region strongly associated with inhibition and emotion regulation success, possibly reflecting increased effort at inhibiting emotional responses during regulation following stress exposure.

Risk and resilience for alcohol use disorder revealed in brain functional connectivity.

A family history of alcoholism (FH) increases risk for alcohol use disorder (AUD), yet many at-risk individuals never develop alcohol use problems. FH is associated with intermediate levels of risk phenotypes, whereas distinct, compensatory brain changes likely promote resilience. Although several cognitive, behavioral, and personality factors have been associated with AUD, the relative contributions of these processes and their neural underpinnings to risk or resilience processes remains less clear. We examined whole-brain resting-state functional connectivity (FC) and behavioral metrics from 841 young adults from the Human Connectome Project, including healthy controls, individuals with AUD, and their unaffected siblings. First, we identified functional connections in which unaffected siblings were intermediate between controls and AUD, indicating AUD risk, and those in which siblings diverged, indicating resilience. Canonical correlations relating brain risk and resilience FC to behavioral patterns revealed AUD risk and resilience phenotypes. Risk phenotypes primarily implicated frontal-parietal networks corresponding with executive function, impulsivity, externalizing behaviors, and social-emotional intelligence. Conversely, resilience-related phenotypes were underpinned by networks of medial prefrontal, striatal, temporal, brainstem and cerebellar connectivity, which associated with high trait attention and low antisocial behavior. Additionally, we calculated "polyphenotypic" risk and resilience scores, to investigate how the relative load of risk and resilience phenotypes influenced the probability of an AUD diagnosis. Polyphenotypic scores predicted AUD in a dose-dependent manner. Moreover, resilience phenotypes interacted with risk phenotypes, reducing their effects. The hypothesis-generating results revealed interpretable AUD-related phenotypes and offer brain-informed targets for developing more effective interventions.

Acute depletion of dopamine precursors in the human brain: effects on functional connectivity and alcohol attentional bias.

Individuals who abuse alcohol often show exaggerated attentional bias (AB) towards alcohol-related cues, which is thought to reflect reward conditioning processes. Rodent studies indicate that dopaminergic pathways play a key role in conditioned responses to reward- and alcohol-associated cues. However, investigation of the dopaminergic circuitry mediating this process in humans remains limited. We hypothesized that depletion of central dopamine levels in adult alcohol drinkers would attenuate AB and that these effects would be mediated by altered function in frontolimbic circuitry. Thirty-four male participants (22-38 years, including both social and heavy drinkers) underwent a two-session, placebo-controlled, double-blind dopamine precursor depletion procedure. At each visit, participants consumed either a balanced amino acid (control) beverage or an amino acid beverage lacking dopamine precursors (order counterbalanced), underwent resting-state fMRI, and completed behavioral testing on three AB tasks: an alcohol dot-probe task, an alcohol attentional blink task, and a task measuring AB to a reward-conditioned cue. Dopamine depletion significantly diminished AB in each behavioral task, with larger effects among subjects reporting higher levels of binge drinking. The depletion procedure significantly decreased resting-state functional connectivity among ventral tegmental area, striatum, amygdala, and prefrontal regions. Beverage-related AB decreases were mediated by decreases in functional connectivity between the fronto-insular cortex and striatum and, for alcohol AB only, between anterior cingulate cortex and amygdala. The results support a substantial role for dopamine in AB, and suggest specific dopamine-modulated functional connections between frontal, limbic, striatal, and brainstem regions mediate general reward AB versus alcohol AB.

High Trait Attention Promotes Resilience and Reduces Binge Drinking Among College Students With a Family History of Alcohol Use Disorder.

Binge patterns of alcohol use among post-high school emerging adults are associated with both immediate negative consequences and increased risk of long-term drinking problems, particularly among individuals with a family history (FH) of alcohol use disorder (AUD). Therefore, the developmental time period of emerging adulthood, paired with the high-risk environment of college campuses, represents an important target for interventions. Attentional ability has recently emerged as a mediator of resilience to stress-related psychopathology and offers a potential neurocognitive target for interventions. We tested the hypothesis that attentional ability promotes resilience to binge drinking in a sample of 464 college students with (n = 221) or without (n = 243) familial risk for AUD. Two-way analyses of covariance (ANCOVA) tested effects of FH and self-reported binge drinking on attention scores from the Barratt Impulsiveness Scale (BIS). In addition, mediation analyses tested whether BIS attention scores mediated the relationship between Conner-Davidson Resilience Scale scores and binge drinking. ANCOVA results indicated a significant FH-by-binge drinking interaction (p = 0.008) in which FH positive subjects who did not binge drink had the fewest attention problems, consistent with a marker of resilience. Furthermore, BIS attention scores significantly mediated the effect of Conner-Davidson Resilience Scale scores on binge drinking, with stronger effects in FH positive subjects (p < 0.001) than FH negative subjects (p = 0.49). The findings suggest that attention promotes resilience to binge drinking in individuals with familial risk for AUD. Interventions targeting attentional ability in this high-risk population, particularly FH positive individuals with attention deficits, may serve to reduce binge drinking and its consequences.

Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making.

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.

Multivariate pattern analysis of the neural correlates of smoking cue attentional bias.

The automatic capture of attention by drug cues, or attentional bias, is associated with craving and predicts future drug use. Despite its clinical significance, the neural bases of attentional bias to drug cues is not well understood. To address this gap, we undertook a neuroimaging investigation of the neural correlates of attentional bias towards smoking cues. Twenty-nine adults, including 14 active smokers and 15 non-smokers, completed a spatial cuing task during fMRI. A multivariate pattern analysis (MVPA) decoded the neural responses to the brief presentation of smoking versus neutral images. These data were correlated with behavioral measures of attentional bias, which included analyses targeting the neural correlates of response facilitation and cue-related task interference. We detected a set of brain-behavioral correlates that were similar across both smokers and non-smokers, indicating a role for stimuli salience in the absence of nicotine conditioning in smoking cue attentional bias. However, multiple smoking-related modifications to the neural correlates of attentional bias and its components were also identified. For example, regions demonstrating smoking-related differences in the neural correlates of attentional bias included the rostral anterior cingulate cortex and inferior frontal gyrus. Response facilitation effects of smoking were observed in the right orbitofrontal gyrus and bilateral middle temporal gyrus. Smoking-cue related task interference was related to smoking-related effects in the frontal eye fields. Our findings suggest that multiple cognitive, affective, and visual object recognition processes contribute to attentional bias towards smoking cues, and suggest multiple circuit modifications that may contribute to perpetuation of addiction.