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1.  White matter integrity is associated with alcohol cue reactivity in heavy drinkers 
Brain and Behavior  2013;4(2):158-170.
Neuroimaging studies have shown that white matter damage accompanies excessive alcohol use, but the functional correlates of alcohol-related white matter disruption remain unknown. This study applied tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) data from 332 heavy drinkers (mean age = 31.2 ± 9.4; 31% female) to obtain averaged fractional anisotropy (FA) values of 18 white matter tracts. Statistical analyses examined correlations of FA values with blood-oxygenation-level-dependent (BOLD) response to an alcohol taste cue, measured with functional magnetic resonance imaging (fMRI). FA values of nine white matter tracts (anterior corona radiata, body of corpus callosum, cingulate gyrus, external capsule, fornix, inferior frontooccipital fasciculus, posterior corona radiata, retrolenticular limb of internal capsule, and superior longitudinal fasciculus) were significantly, negatively correlated with BOLD activation in medial frontal gyrus, parahippocampal gyrus, fusiform gyrus, cingulum, thalamus, caudate, putamen, insula, and cerebellum. The inverse relation between white matter integrity and functional activation during the alcohol taste cue provides support for the hypothesis that lower white matter integrity in frontoparietal and corticolimbic networks is a factor in loss of control over alcohol consumption.
PMCID: PMC3967532  PMID: 24683509
Alcohol use disorders; diffusion tensor imaging; functional magnetic resonance imaging; tract-based spatial statistics; white matter
2.  Neural and Behavioral Mechanisms of Impulsive Choice in Alcohol Use Disorder 
Alcohol dependence has repeatedly been associated with impulsive choice, or the inability to choose large delayed rewards over smaller, but more immediate rewards. However, the neural basis of impulsive choice in alcohol use disorders is not well understood.
One hundred fifty one individuals with a range of alcohol use from social drinking to severe alcohol dependence completed a delay discounting task while undergoing functional magnetic resonance imaging (fMRI). Participants received customized trials designed to ensure an approximately equivalent number of immediate responses.
Delaying gratification recruited regions involved in cognitive control, conflict monitoring, and the interpretation of somatic states. Individuals with more severe alcohol use problems showed increased discounting of delayed rewards and greater activation in several regions including supplementary motor area, insula/orbitofrontal cortex, inferior frontal gyrus, and the precuneus.
These results suggest that impulsive choice in alcohol dependence is the result of functional anomolies in widely distributed, but interconnected brain regions involved in cognitive and emotional control. Further, our results suggest that the neural mechanisms of impulsive choice in alcohol use disorders both overlaps with that observed in previous studies, and shows that individuals with alcohol use disorders recruit additional mechanisms when making intertemporal choices.
PMCID: PMC3117198  PMID: 21676001
Delay discounting; intertemporal choice; impulsivity; delayed gratification
3.  Negative reinforcement learning is affected in substance dependence 
Drug and Alcohol Dependence  2011;123(1-3):84-90.
Negative reinforcement results in behavior to escape or avoid an aversive outcome. Withdrawal symptoms are purported to be negative reinforcers in perpetuating substance dependence, but little is known about negative reinforcement learning in this population. The purpose of this study was to examine reinforcement learning in substance dependent individuals (SDI), with an emphasis on assessing negative reinforcement learning. We modified the Iowa Gambling Task to separately assess positive and negative reinforcement. We hypothesized that SDI would show differences in negative reinforcement learning compared to controls and we investigated whether learning differed as a function of the relative magnitude or frequency of the reinforcer.
Thirty subjects dependent on psychostimulants were compared with 28 community controls on a decision making task that manipulated outcome frequencies and magnitudes and required an action to avoid a negative outcome.
SDI did not learn to avoid negative outcomes to the same degree as controls. This difference was driven by the magnitude, not the frequency, of negative feedback. In contrast, approach behaviors in response to positive reinforcement were similar in both groups.
Our findings are consistent with a specific deficit in negative reinforcement learning in SDI. SDI were relatively insensitive to the magnitude, not frequency, of loss. If this generalizes to drug-related stimuli, it suggests that repeated episodes of withdrawal may drive relapse more than the severity of a single episode.
PMCID: PMC3292654  PMID: 22079143
Substance dependence; decision making; negative reinforcement
4.  Effect of Homozygous Deletions at 22q13.1 on Alcohol Dependence Severity and Cue-Elicited BOLD Response in the Precuneus 
Addiction biology  2011;18(3):548-558.
Copy number variations (CNV) can alter the DNA sequence in blocks ranging from kilobases to megabases, involving more total nucleotides than single nucleotide polymorphisms. Yet, its impact in humans is far from fully understood. In this study, we investigate the relationship of genome wide CNVs with brain function elicited by an alcohol cue in 300 participants with alcohol use disorders. First, we extracted refined neurobiological phenotypes, the brain responses to an alcohol cue versus a juice cue in the precuneus, thalamus, and anterior cingulate cortex (ACC). Then, we correlated the CNVs with incidence frequency >1% to the neurobiological phenotypes. One CNV region at 22q13.1 was identified to be associated with alcohol dependence severity and the brain response to alcohol cues. Specifically, the 22k base-pair homozygous deletion at 22q13.1 affects genes APOBEC3a and APOBEC3b. Carriers of this homozygous deletion show a significantly higher score in the alcohol dependence severity (p < 0.05) and increased response to alcohol cues in the precuneus (p < 10-12) than other participants. Tests of a mediation model indicate that the precuneus mediates the association between the homozygous deletions and alcohol dependence severity. Interestingly, the precuneus is not only anatomically and functionally connected to the ACC and thalamus (the main active regions to the alcohol cue), but also has the most predictive power to the alcohol dependence severity. These findings suggest that the homozygous deletion at 22q13.1 may have an important impact on the function of the precuneus with downstream implications for alcohol dependence.
PMCID: PMC3262113  PMID: 21995620
Alcohol use disorders; copy number variation; homozygous deletion; neurobiological phenotype; 22q13.1; precuneus; alcohol dependence
5.  Identifying Neurobiological Phenotypes Associated with Alcohol Use Disorder Severity 
Neuropsychopharmacology  2011;36(10):2086-2096.
Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies.
PMCID: PMC3158325  PMID: 21677649
craving; alcohol use disorder; phenotype; striatum; anterior cingulate cortex; alcohol & alcoholism; addiction & substance abuse; imaging; clinical or preclinical; biological psychiatry; craving; alcohol use disorder; phenotype; insula; anterior cingulate cortex
6.  Cognitive Control Reflects Context Monitoring, Not Motoric Stopping, in Response Inhibition 
PLoS ONE  2012;7(2):e31546.
The inhibition of unwanted behaviors is considered an effortful and controlled ability. However, inhibition also requires the detection of contexts indicating that old behaviors may be inappropriate – in other words, inhibition requires the ability to monitor context in the service of goals, which we refer to as context-monitoring. Using behavioral, neuroimaging, electrophysiological and computational approaches, we tested whether motoric stopping per se is the cognitively-controlled process supporting response inhibition, or whether context-monitoring may fill this role. Our results demonstrate that inhibition does not require control mechanisms beyond those involved in context-monitoring, and that such control mechanisms are the same regardless of stopping demands. These results challenge dominant accounts of inhibitory control, which posit that motoric stopping is the cognitively-controlled process of response inhibition, and clarify emerging debates on the frontal substrates of response inhibition by replacing the centrality of controlled mechanisms for motoric stopping with context-monitoring.
PMCID: PMC3288048  PMID: 22384038
7.  Cognitive Control in Adolescence: Neural Underpinnings and Relation to Self-Report Behaviors 
PLoS ONE  2011;6(6):e21598.
Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established.
Methodology/Principal Findings
To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution.
Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors.
PMCID: PMC3125248  PMID: 21738725
8.  Differential Neural Response to Alcohol Priming and Alcohol Taste Cues Is Associated With DRD4 VNTR and OPRM1 Genotypes 
Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, μ1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown.
Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined.
The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol (p < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use.
The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.
PMCID: PMC2856650  PMID: 18540916
DRD4; OPRM1; Alcohol; Craving; fMRI; Mesocorticolimbic
9.  Brain activation during the Stroop task in adolescents with severe substance and conduct problems: A pilot study 
Drug and alcohol dependence  2007;90(2-3):175-182.
Although many neuroimaging studies have examined changes in brain function in adults with substance use disorders, far fewer have examined adolescents. This study investigated patterns of brain activation in adolescents with severe substance and conduct problems (SCP) compared to controls.
Functional magnetic resonance imaging (fMRI) at 1.5 Tesla assessed brain activation in 12 adolescent males with SCP, ranging in age from 14 to 18, and 12 controls similar in age, gender, and neighborhood while performing the attentionally-demanding Stroop task.
Even though the adolescents with SCP performed as well as the controls, they activated a more extensive set of brain structures for incongruent (e.g., “red” in blue ink) versus congruent (e.g. “red” in red ink) trials. These regions included parahippocampal regions bilaterally, posterior regions involved in language-related processing, right-sided medial prefrontal areas, and subcortical regions including the the thalamus and caudate.
These preliminary results suggest that the neural mechanisms of attentional control in youth with SCP differ from youth without such problems. This difficulty may prevent SCP youth from ignoring salient but distracting information in the environment, such as drug-related information.
PMCID: PMC2828145  PMID: 17499456

Results 1-9 (9)