Publications by authors named "Reza Momenan"

64 Publications

Gender-related neuroanatomical differences in alcohol dependence: findings from the ENIGMA Addiction Working Group.

Neuroimage Clin 2021 Mar 22;30:102636. Epub 2021 Mar 22.

Neuroscience of Addiction and Mental Health Program, Healthy Brain and Mind Research Centre, School of Behavioural & Health Sciences, Faculty of Health Sciences, Australian Catholic University, Melbourne, VIC, Australia. Electronic address:

Gender-related differences in the susceptibility, progression and clinical outcomes of alcohol dependence are well-known. However, the neurobiological substrates underlying such differences remain unclear. Therefore, this study aimed to investigate gender differences in the neuroanatomy (i.e. regional brain volumes) of alcohol dependence. We examined the volume of a priori regions of interest (i.e., orbitofrontal cortex, hippocampus, amygdala, nucleus accumbens, caudate, putamen, pallidum, thalamus, corpus callosum, cerebellum) and global brain measures (i.e., total grey matter (GM), total white matter (WM) and cerebrospinal fluid). Volumes were compared between 660 people with alcohol dependence (228 women) and 326 controls (99 women) recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age and education years. Compared to controls, individuals with alcohol dependence on average had (3-9%) smaller volumes of the hippocampus (bilateral), putamen (left), pallidum (left), thalamus (right), corpus callosum, total GM and WM, and cerebellar GM (bilateral), the latter more prominently in women (right). Alcohol-dependent men showed smaller amygdala volume than control men, but this effect was unclear among women. In people with alcohol dependence, more monthly standard drinks predicted smaller amygdala and larger cerebellum GM volumes. The neuroanatomical differences associated with alcohol dependence emerged as gross and widespread, while those associated with a specific gender may be confined to selected brain regions. These findings warrant future neuroscience research to account for gender differences in alcohol dependence to further understand the neurobiological effects of alcohol dependence.
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http://dx.doi.org/10.1016/j.nicl.2021.102636DOI Listing
March 2021

A neuroimaging investigation into the role of peripheral metabolic biomarkers in the anticipation of reward in alcohol use.

Drug Alcohol Depend 2021 Apr 16;221:108638. Epub 2021 Feb 16.

Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD 20814, USA; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI 02903, USA; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA; Department of Neuroscience, Georgetown University Medical Center, Washington DC 20057, USA. Electronic address:

Background: The relationship between alcohol use and metabolism has focused on the effects of alcohol use on metabolic factors. Metabolic factors, such as triglycerides, cholesterol, and glucose, have been shown to be associated with increased risk for heavy alcohol consumption and alcohol use disorder (AUD). It's been suggested that changes in metabolic factors may play a role in reward seeking behaviors and pathways. Studies on feeding behavior and obesity revealed the role of triglycerides in neural response to food cues in neurocircuitry regulating reward and feeding behaviors. This study aimed to explore the relationship of peripheral metabolism, alcohol use, and reward processing in individuals that use alcohol.

Methods: Ninety participants from a previously collected dataset were included in the analysis. Participants were treatment seeking, detoxified individuals with AUD and healthy individuals without AUD, with the following metabolic biomarkers: triglyceride, glucose, high- and low-density cholesterol, and HbA1c levels. Participants completed a neuroimaging version of the Monetary Incentive Delay task (MID).

Results: Correlations on peripheral metabolic biomarkers, alcohol use, and neural activity during reward anticipation and outcome during the MID task were not significant. Mediation models revealed triglycerides and high-density cholesterol had significant effects on left anterior insula during anticipation of potential monetary loss and this effect was not mediated by alcohol use.

Conclusion: Limbic recruitment by anticipation of monetary rewards revealed an independent relationship with peripheral metabolism and was not affected by individual differences in alcohol use, despite the effects of alcohol use on metabolic markers and reward processing neural circuitry.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108638DOI Listing
April 2021

Sex differences in the neuroanatomy of alcohol dependence: hippocampus and amygdala subregions in a sample of 966 people from the ENIGMA Addiction Working Group.

Transl Psychiatry 2021 Mar 4;11(1):156. Epub 2021 Mar 4.

Neuroscience of Addiction & Mental Health Program, Healthy Brain and Mind Research Centre, School of Behavioural & Health Sciences, Faculty of Health Sciences, Australian Catholic University, Melbourne, VIC, Australia.

Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females.
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http://dx.doi.org/10.1038/s41398-021-01204-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933136PMC
March 2021

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Addict Biol 2021 Jan 28:e13010. Epub 2021 Jan 28.

Department of Psychiatry, University of Vermont College of Medicine, Burlington, Vermont, USA.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.
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http://dx.doi.org/10.1111/adb.13010DOI Listing
January 2021

Editorial: Towards Expanded Utility of Real Time fMRI Neurofeedback in Clinical Applications.

Front Hum Neurosci 2020 12;14:606868. Epub 2020 Nov 12.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Health (NIH), Bethesda, MD, United States.

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http://dx.doi.org/10.3389/fnhum.2020.606868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689151PMC
November 2020

Predicting alcohol dependence from multi-site brain structural measures.

Hum Brain Mapp 2020 Oct 16. Epub 2020 Oct 16.

Department of Psychiatry, University of Vermont College of Medicine, Burlington, Vermont, USA.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.
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http://dx.doi.org/10.1002/hbm.25248DOI Listing
October 2020

A Distinct Neurophenotype of Fearful Face Processing in Alcohol Use Disorder With and Without Comorbid Anxiety.

Alcohol Clin Exp Res 2020 11 27;44(11):2212-2224. Epub 2020 Oct 27.

From the, Clinical NeuroImaging Research Core, (NM, SJF, EEP, RM), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.

Background: Individuals with alcohol use disorder (AUD) can present with comorbid anxiety symptoms and often have deficits in emotional processing. Previous research suggests brain response is altered during facial affect recognition tasks, especially in limbic areas, due to either AUD or anxiety symptomology; however, the impact of both AUD and clinically significant anxiety symptoms during these tasks has not yet been examined.

Methods: In this study, we investigated neural activation differences during an emotional face-matching task. Participants (N = 232) underwent fMRI scanning, as part of a larger study. Three groups were investigated: individuals with diagnosed AUD and elevated anxiety traits (AUD + ANX, n = 90), individuals with diagnosed AUD but non-clinically significant levels of anxiety (AUD-ANX, n = 39), and healthy controls (HC, n = 103).

Results: Our results illustrate distinct neurophenotypes of AUD, where individuals with comorbid anxiety symptomology have blunted emotional face processing while those with singular AUD are hyperresponsive.

Conclusions: This suggests AUD with anxiety symptomology may have a unique neurobiological underpinning, and treatment and intervention should be tailored to individual constellations of symptoms.
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http://dx.doi.org/10.1111/acer.14465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680369PMC
November 2020

How do substance use disorders compare to other psychiatric conditions on structural brain abnormalities? A cross-disorder meta-analytic comparison using the ENIGMA consortium findings.

Hum Brain Mapp 2020 Jul 9. Epub 2020 Jul 9.

Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, CHU Ste-Justine, Montreal, Canada.

Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions, and until recently there has been few large-scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case-control differences and to compare brain-correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta-analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age- and sex-matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case-control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co-variates . After correcting for multiple comparisons, AUD case-control meta-analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta-analysis of CUD case-control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross-disorder comparison of brain correlates of substance use disorders and showed alcohol-related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex.
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http://dx.doi.org/10.1002/hbm.25114DOI Listing
July 2020

Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation.

Mol Psychiatry 2020 May 12. Epub 2020 May 12.

Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, Canada.

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.
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http://dx.doi.org/10.1038/s41380-020-0734-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658001PMC
May 2020

Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder.

Neurosci Biobehav Rev 2020 06 13;113:492-506. Epub 2020 Apr 13.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, UK.

Alcohol misuse and addiction are major international public health issues. Addiction can be characterized as a disorder of aberrant neurocircuitry interacting with environmental, genetic and social factors. Neuroimaging in alcohol misuse can thus provide a critical window into underlying neural mechanisms, highlighting possible treatment targets and acting as clinical biomarkers for predicting risk and treatment outcomes. This neuroimaging review on alcohol misuse in humans follows the Addictions Neuroclinical Assessment (ANA) that proposes incorporating three functional neuroscience domains integral to the neurocircuitry of addiction: incentive salience and habits, negative emotional states, and executive function within the context of the addiction cycle. Here we review and integrate multiple imaging modalities focusing on underlying cognitive processes such as reward anticipation, negative emotionality, cue reactivity, impulsivity, compulsivity and executive function. We highlight limitations in the literature and propose a model forward in the use of neuroimaging as a tool to understanding underlying mechanisms and potential clinical applicability for phenotyping of heterogeneity and predicting risk and treatment outcomes.
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http://dx.doi.org/10.1016/j.neubiorev.2020.04.004DOI Listing
June 2020

Alcohol effects on globus pallidus connectivity: Role of impulsivity and binge drinking.

PLoS One 2020 26;15(3):e0224906. Epub 2020 Mar 26.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe-frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224906PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098584PMC
May 2020

A Guide to Literature Informed Decisions in the Design of Real Time fMRI Neurofeedback Studies: A Systematic Review.

Front Hum Neurosci 2020 25;14:60. Epub 2020 Feb 25.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.

Although biofeedback using electrophysiology has been explored extensively, the approach of using neurofeedback corresponding to hemodynamic response is a relatively young field. Real time functional magnetic resonance imaging-based neurofeedback (rt-fMRI-NF) uses sensory feedback to operantly reinforce patterns of neural response. It can be used, for example, to alter visual perception, increase brain connectivity, and reduce depression symptoms. Within recent years, interest in rt-fMRI-NF in both research and clinical contexts has expanded considerably. As such, building a consensus regarding best practices is of great value. This systematic review is designed to describe and evaluate the variations in methodology used in previous rt-fMRI-NF studies to provide recommendations for rt-fMRI-NF study designs that are mostly likely to elicit reproducible and consistent effects of neurofeedback. We conducted a database search for fMRI neurofeedback papers published prior to September 26th, 2019. Of 558 studies identified, 146 met criteria for inclusion. The following information was collected from each study: sample size and type, task used, neurofeedback calculation, regulation procedure, feedback, whether feedback was explicitly related to changing brain activity, feedback timing, control group for active neurofeedback, how many runs and sessions of neurofeedback, if a follow-up was conducted, and the results of neurofeedback training. rt-fMRI-NF is typically upregulation practice based on hemodynamic response from a specific region of the brain presented using a continually updating thermometer display. Most rt-fMRI-NF studies are conducted in healthy samples and half evaluate its effect on immediate changes in behavior or affect. The most popular control group method is to provide sham signal from another region; however, many studies do not compare use a comparison group. We make several suggestions for designs of future rt-fMRI-NF studies. Researchers should use feedback calculation methods that consider neural response across regions (i.e., SVM or connectivity), which should be conveyed as intermittent, auditory feedback. Participants should be given explicit instructions and should be assessed on individual differences. Future rt-fMRI-NF studies should use clinical samples; effectiveness of rt-fMRI-NF should be evaluated on clinical/behavioral outcomes at follow-up time points in comparison to both a sham and no feedback control group.
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http://dx.doi.org/10.3389/fnhum.2020.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052377PMC
February 2020

Addiction neurocircuitry and negative affect: A role for neuroticism in understanding amygdala connectivity and alcohol use disorder.

Neurosci Lett 2020 03 8;722:134773. Epub 2020 Feb 8.

National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Bethesda, MD, 20892, USA. Electronic address:

The purpose of this study was to investigate the effect neuroticism has on the relationship between alcohol use severity and amygdala connectivity. Previous studies have indicated that amygdala connectivity and negative affect play a role in the cycle of addiction, and that neuroticism, which shares similar qualities with negative affect, is also related to amygdala connectivity, but the role neuroticism plays in mediating the relationship between AUD and amygdala connectivity has not been examined. To complete this study, 158 participants (58 female) enrolled in studies through NIAAA (National Institutes of Alcohol Abuse and Alcoholism) underwent resting state functional MRI (rs-fMRI) scans. The Alcohol Use Disorders Identification Test (AUDIT) was used to quantify alcohol use severity and the Revised NEO Personality Assessment (NEO PI-R) was used to quantify levels of neuroticism. A whole brain analysis was conducted to investigate the relationship of rs-fMRI amygdala connectivity with AUDIT and NEO neuroticism scores. A latent variable model (LVM) was used to measure the mediation effect of neuroticism on alcohol use severity and rs-fMRI amygdala connectivity. The whole brain analysis showed a positive relationship between right amygdala-right temporal fusiform gyrus connectivity and AUDIT scores and a negative relationship between left amygdala-left temporal parietal junction (TPJ) connectivity and NEO neuroticism scores. The indirect effect of neuroticism was significant for the LVMs of left amygdala connectivity with the nucleus accumbens (NAcc), posterior insula, and dorsal anterior cingulate cortex (dACC). These results suggest that personality plays an important role in the cycle of addiction.
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http://dx.doi.org/10.1016/j.neulet.2020.134773DOI Listing
March 2020

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

Addict Biol 2020 11 20;25(6):e12830. Epub 2019 Nov 20.

Departments of Psychiatry, University of Vermont, Burlington, VT, USA.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.
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http://dx.doi.org/10.1111/adb.12830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237314PMC
November 2020

Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity.

Addict Biol 2021 01 8;26(1):e12835. Epub 2019 Nov 8.

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P = .009), depressive symptoms (r = .37, P = .015), trait anxiety (r = .41, P = .006), and perceived stress (r = .45, P = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.
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http://dx.doi.org/10.1111/adb.12835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205585PMC
January 2021

A role for the rs3796863 polymorphism in alcohol and monetary reward: evidence from CD38 knockout mice and alcohol self-administration, [11C]-raclopride binding, and functional MRI in humans.

Am J Drug Alcohol Abuse 2020 31;46(2):167-179. Epub 2019 Jul 31.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA and NIDA, NIH, Bethesda, MD, USA.

: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a common single nucleotide polymorphism (SNP) within , rs3796863, is associated with increased social reward.: Examine whether rs3796863 and knockout (KO) are associated with reward-related neural and behavioral phenotypes.: Data from four independent human studies were used to test whether rs3796863 genotype is associated with: (1) intravenous alcohol self-administration (n = 64, 30 females), (2) alcohol-stimulated dopamine (DA) release measured using C-raclopride positron emission tomography (n = 22 men), (3) ventral striatum (VS) response to positive feedback measured using a card guessing functional magnetic resonance imaging (fMRI) paradigm (n = 531, 276 females), and (4) resting state functional connectivity (rsfc) of the VS (n = 51, 26 females). In a fifth study, we used a mouse model to examine whether knockout influences stimulated DA release in the NAc core and dorsal striatum using fast-scanning cyclic voltammetry.: Relative to T allele carriers, G homozygotes at rs3796863 within were characterized by greater alcohol self-administration, alcohol-stimulated dopamine release, VS response to positive feedback, and rsfc between the VS and anterior cingulate cortex. High-frequency stimulation reduced DA release among KO mice had reduced dopamine release in the NAc.: Converging evidence suggests that rs3796863 genotype may increase DA-related reward response and alcohol consumption.
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http://dx.doi.org/10.1080/00952990.2019.1638928DOI Listing
December 2020

Lack of Association Between Serotonin Transporter Gene (SLC6A4) Promoter Methylation and Amygdala Response During Negative Emotion Processing in Individuals With Alcohol Dependence.

Alcohol Alcohol 2019 May;54(3):209-215

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive (10CRC), Bethesda, MD, USA.

Aims: Differences in DNA methylation of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression and predict brain functions in healthy individuals. This study investigated the association between SLC6A4 promoter methylation and threat-related amygdala activation in individuals with alcohol dependence (AD).

Methods: Methylation of the SLC6A4 promoter region was assessed using peripheral blood DNA from 45 individuals with AD and 45 healthy controls (HCs). All participants completed an emotional face matching task in a 3-T magnetic resonance imaging (MRI) scanner.

Results: Results did not reveal any association between SLC6A4 promoter methylation variation and threat-related amygdala activation in HCs or individuals with AD. Furthermore, methylation in the promoter region of SLC6A4 did not significantly differ between the groups.

Conclusions: Our results do not replicate a previous finding that increased methylation in the promoter region of SLC6A4 is associated with threat-related amygdala activation in healthy individuals and further show that there is no such association in individuals with AD. Given that the number of imaging epigenetics studies on SLC6A4 is very limited to date, these inconsistent results indicate that future research is needed to clarify its association with amygdala reactivity in both healthy and clinical populations.
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http://dx.doi.org/10.1093/alcalc/agz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516430PMC
May 2019

Resting state connectivity best predicts alcohol use severity in moderate to heavy alcohol users.

Neuroimage Clin 2019 19;22:101782. Epub 2019 Mar 19.

Clinical NeuroImaging Research Core, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive, Bethesda, MD 20814, MSC 1108, United States. Electronic address:

Background: In the United States, 13% of adults are estimated to have alcohol use disorder (AUD). Most studies examining the neurobiology of AUD treat individuals with this disorder as a homogeneous group; however, the theories of the neurocircuitry of AUD call for a quantitative and dimensional approach. Previous imaging studies find differences in brain structure, function, and resting-state connectivity in AUD, but few use a multimodal approach to understand the association between severity of alcohol use and the brain differences.

Methods: Adults (ages 22-60) with problem drinking patterns (n = 59) completed a behavioral and neuroimaging protocol at the National Institutes of Health. Alcohol severity was quantified with the Alcohol Use Disorders Identification Test (AUDIT). In a 3 T MRI scanner, participants underwent a structural MRI as well as resting-state, monetary incentive delay, and face matching fMRI scans. Machine learning was applied and trained using the neural data from MRI scanning. The model was tested for generalizability in a validation sample (n = 24).

Results: The resting state-connectivity features model best predicted AUD severity in the naïve sample, compared to task fMRI, structural MRI, combined MRI features, or demographic features. Network connectivity features between salience network, default mode network, executive control network, and sensory networks explained 33% of the variance associated with AUDIT in this model.

Conclusions: These findings indicate that the neural effects of AUD vary according to severity. Our results emphasize the utility of resting state fMRI as a neuroimaging biomarker for quantitative clinical evaluation of AUD.
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http://dx.doi.org/10.1016/j.nicl.2019.101782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438989PMC
January 2020

The relationship between delay discounting and alcohol dependence in individuals with and without comorbid psychopathology.

Psychopharmacology (Berl) 2019 Feb 19;236(2):775-785. Epub 2018 Nov 19.

Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, Building 10, Room 2-2352, Bethesda, MD, 20892-1540, USA.

Rationale: Alcohol use disorder (AUD) has been associated with greater discounting of delayed monetary rewards, but it is unclear whether this association is primarily related to alcohol consumption or is secondary to the presence of psychiatric comorbidities. It is also unclear if steeper rates of discounting are associated with greater AUD severity.

Objective: We sought to determine whether the presence of comorbid psychiatric disorders affected the relationship between AUD and delay discounting. We also examined whether more severe AUD was associated with greater delay discounting.

Methods: In this cross-sectional study, 793 adults completed a delay discounting task. Subjects were divided into four groups based on diagnosis: current AUD with psychiatric comorbidities (N = 226), current AUD without psychiatric comorbidities (N = 203), past AUD (N = 69), and healthy controls (N = 295). In those with AUD, we investigated the relationship between delay discounting and alcohol dependence symptom count and recent drinking history. We also compared individuals seeking treatment to non-treatment seeking individuals. Psychiatric comorbidities examined included mood disorders, anxiety disorders, and substance use disorders.

Results: After adjusting for age, sex, income, and education, individuals with current AUD showed significantly higher rates of delay discounting than healthy controls and individuals with a past diagnosis of AUD. The presence of comorbid psychiatric diagnoses was not associated with steeper discounting. Among those with AUD, there was no evidence for a continuous relationship between delay discounting and AUD severity or alcohol consumption. Finally, non-treatment seekers with AUD had steeper delay discounting than treatment seekers.

Conclusions: Individuals with AUD show steeper delay discounting than healthy adults, but the effect is small and there is no added effect from comorbid psychopathology or increased AUD severity. This suggests that steeper delay discounting may have a more limited effect on human alcohol use than previously supposed.
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http://dx.doi.org/10.1007/s00213-018-5113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401281PMC
February 2019

Mega-Analysis of Gray Matter Volume in Substance Dependence: General and Substance-Specific Regional Effects.

Am J Psychiatry 2019 02 19;176(2):119-128. Epub 2018 Oct 19.

From the Department of Psychiatry and the Department of Mathematics and Statistics, University of Vermont, Burlington; Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Australia; the Department of Psychology, University of Oregon, Eugene; the Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York; the Department of Psychiatry and Psychology, University of Barcelona, Barcelona, Spain; the Department of Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn; the Department of Psychiatry and the MRC Unit on Anxiety and Stress Disorders, University of Cape Town, Cape Town, South Africa; the Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore; the Monash Institute of Cognitive and Clinical Neurosciences and the School of Psychological Sciences, Monash University, Melbourne, Australia; the Departments of Developmental and Experimental Psychology, Utrecht University, Utrecht, the Netherlands; the Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal; the Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London; the Department of Psychiatry, Oregon Health and Science University, Portland; the Department of Neuroscience and the Ernest J. Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, N.Y.; the Department of Psychiatry, University of Amsterdam, Amsterdam; the Amsterdam Institute for Addiction Research and Arkin Mental Health Care, Amsterdam; the Department of Psychiatry, University of Michigan, Ann Arbor; the Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia; the Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder; the Department of Psychiatry, Washington University School of Medicine, St. Louis; the David Geffen School of Medicine, University of California at Los Angeles, Los Angeles; the School of Psychology, Faculty of Health Sciences, Australian Catholic University, Melbourne, Australia; the Department of Psychological Sciences, University of Liverpool, Liverpool, U.K.; the Behavioral Science Institute, Radboud University, Nijmegen, the Netherlands; the Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego; the Clinical Neuroimaging Research Core, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md.; the VA San Diego Healthcare System and the Department of Psychiatry, University of California San Diego, La Jolla; the Laureate Institute for Brain Research, Tulsa, Okla.; the Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia; the Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; the Institute of Psychology, Cognitive Psychology Unit, and the Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands; the School of Psychology and the Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia; the Department of Psychiatry, University of California San Diego, La Jolla; the Department of Psychiatry, VU University Medical Center, Amsterdam; the Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia; the QIMR Berghofer Medical Research Institute, Brisbane, Australia; the Department of Psychiatry, University of Utah School of Medicine, Salt Lake City; the Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey; and the Department of Psychiatry, University of Montreal, CHU Sainte-Justine Hospital, Montreal.

Objective: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes.

Method: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings.

Results: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects.

Conclusions: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.
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http://dx.doi.org/10.1176/appi.ajp.2018.17040415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427822PMC
February 2019

Neural Correlates of Compulsive Alcohol Seeking in Heavy Drinkers.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 12 9;3(12):1022-1031. Epub 2018 Jul 9.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.

Background: Compulsive alcohol use, the tendency to continue alcohol seeking and taking despite negative consequences, is a hallmark of alcohol use disorder. Preclinical rodent studies have suggested a role for the medial prefrontal cortex, anterior insula, and nucleus accumbens in compulsive alcohol seeking. It is presently unknown whether these findings translate to humans. We used a novel functional magnetic resonance imaging paradigm and tested the hypothesis that heavy drinkers would compulsively seek alcohol despite the risk of an aversive consequence, and that this behavior would be associated with the activity of frontostriatal circuitry.

Methods: Non-treatment-seeking heavy and light drinkers (n = 21 per group) completed a functional magnetic resonance imaging paradigm in which they could earn alcohol or food points at various threat levels (i.e., various probabilities of incurring an aversive consequence). Brain function was evaluated when individuals had the opportunity to earn reward points at the risk of an aversive consequence, an electric shock on the wrist.

Results: Compared with light drinkers, heavy drinkers attempted to earn more aversion-paired alcohol points. Frontostriatal circuitry, including the medial prefrontal cortex, anterior insula, and striatum, was more active in this group when viewing threat-predictive alcohol cues. Heavy drinkers had increased connectivity between the anterior insula and the nucleus accumbens. Greater connectivity was associated with more attempts to earn aversion-paired alcohol points and self-reported compulsive alcohol use scores.

Conclusions: Higher activation of frontostriatal circuitry in heavy drinkers may contribute to compulsive alcohol seeking. Treatments that disrupt this circuitry may result in a decrease in compulsive alcohol use.
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http://dx.doi.org/10.1016/j.bpsc.2018.06.009DOI Listing
December 2018

The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence.

Transl Psychiatry 2018 07 13;8(1):131. Epub 2018 Jul 13.

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (β = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (β = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.
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http://dx.doi.org/10.1038/s41398-018-0184-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045574PMC
July 2018

Random forest based classification of alcohol dependence patients and healthy controls using resting state MRI.

Neurosci Lett 2018 05 4;676:27-33. Epub 2018 Apr 4.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States. Electronic address:

Currently, classification of alcohol use disorder (AUD) is made on clinical grounds; however, robust evidence shows that chronic alcohol use leads to neurochemical and neurocircuitry adaptations. Identifications of the neuronal networks that are affected by alcohol would provide a more systematic way of diagnosis and provide novel insights into the pathophysiology of AUD. In this study, we identified network-level brain features of AUD, and further quantified resting-state within-network, and between-network connectivity features in a multivariate fashion that are classifying AUD, thus providing additional information about how each network contributes to alcoholism. Resting-state fMRI were collected from 92 individuals (46 controls and 46 AUDs). Probabilistic Independent Component Analysis (PICA) was used to extract brain functional networks and their corresponding time-course for AUD and controls. Both within-network connectivity for each network and between-network connectivity for each pair of networks were used as features. Random forest was applied for pattern classification. The results showed that within-networks features were able to identify AUD and control with 87.0% accuracy and 90.5% precision, respectively. Networks that were most informative included Executive Control Networks (ECN), and Reward Network (RN). The between-network features achieved 67.4% accuracy and 70.0% precision. The between-network connectivity between RN-Default Mode Network (DMN) and RN-ECN contribute the most to the prediction. In conclusion, within-network functional connectivity offered maximal information for AUD classification, when compared with between-network connectivity. Further, our results suggest that connectivity within the ECN and RN are informative in classifying AUD. Our findings suggest that machine-learning algorithms provide an alternative technique to quantify large-scale network differences and offer new insights into the identification of potential biomarkers for the clinical diagnosis of AUD.
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http://dx.doi.org/10.1016/j.neulet.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960433PMC
May 2018

Insula Sensitivity to Unfairness in Alcohol Use Disorder.

Alcohol Alcohol 2018 May;53(3):201-208

Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden.

Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown.

Methods: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded.

Results: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD.

Conclusion: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups.

Short Summary: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.
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http://dx.doi.org/10.1093/alcalc/agx115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075077PMC
May 2018

Dopamine Transporter Gene Methylation is Associated with Nucleus Accumbens Activation During Reward Processing in Healthy but not Alcohol-Dependent Individuals.

Alcohol Clin Exp Res 2018 Jan 27;42(1):21-31. Epub 2017 Nov 27.

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.

Background: Alcohol's reinforcement is mediated by dopamine signaling in the ventral striatum, which is modulated by the dopamine transporter (DAT). We hypothesized that methylomic variation in the DAT gene (DAT1/SLC6A3) affects DAT expression, thus contributing to differences in brain reward circuitry in individuals with alcohol dependence (ALC).

Methods: Blood from 45 recently detoxified ALC and 45 healthy control (HC) individuals was used to assess DNA methylation across 5 functional regions of SLC6A3. Participants completed the monetary incentive delay task in a 3-Tesla magnetic resonance imaging (MRI) scanner. Employing regression models, we examined effects of SLC6A3 methylation on nucleus accumbens (NAc) blood-oxygen-level dependent (BOLD) responses during anticipation of high/low reward/loss.

Results: Results showed that decreased methylation of the promoter region of SLC6A3 predicted NAc activation during high loss anticipation (p = 0.028) and low loss anticipation (at trend-level; p = 0.057) in HC but not in individuals with ALC. Specifically, percentage of methylation at 2 CpG sites, located -1,001 and -993 base pairs from the transcription start site, accounted for significant variability in NAc activation in the HC group during high (ps ≤ 0.010) and low (ps ≤ 0.006) loss anticipation. There was no effect on reward anticipation. Furthermore, promoter methylation was positively associated with age, which replicates previous findings.

Conclusions: Our data suggest that methylation in the promoter region of SLC6A3 predicts NAc activation during the anticipation of monetary loss in HCs. However, this effect was not present in the ALC group, suggesting that epigenetic regulation of striatal DAT expression might be disrupted in ALC, which may contribute to previously reported differences in sensitivity to reward and punishment in this population. Alternatively, it is possible that a similar relationship in the ALC group remained undetected possibly due to methodological limitations inherent in functional MRI (e.g., poor spatial resolution, low signal-to-noise ratio) that generally restrict interpretations regarding mechanisms of epigenetic factors involved in group differences in BOLD responses. Future neuroimaging studies are needed to further elucidate the relationship between SLC6A3 methylation and NAc activation in ALC.
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http://dx.doi.org/10.1111/acer.13526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010188PMC
January 2018

Commentary on Schmitz et al. (2017): Advancing medication development for addiction-behavioral and neuroimaging outcomes as indirect biomarkers of target engagement.

Addiction 2017 10;112(10):1869-1870

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacolgy, NIAAA and NIDA, NIH, Bethesda, MD, USA.

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http://dx.doi.org/10.1111/add.13959DOI Listing
October 2017

Structural deficits in salience network regions are associated with increased impulsivity and compulsivity in alcohol dependence.

Drug Alcohol Depend 2017 10 22;179:100-108. Epub 2017 Jul 22.

Clinical Neuroimaging Research Core, NIAAA, NIH, Bethesda, MD 20892, United States. Electronic address:

Background: Convergent preclinical and clinical evidence has linked the anterior insula to impulsivity and alcohol-associated compulsivity. The anterior insula is functionally connected to the anterior cingulate cortex, together comprising the major nodes of the salience network, which serves to signal salient events, including negative consequences. Clinical studies have found structural and functional alterations in the anterior insula and anterior cingulate cortices of alcohol dependent individuals. No studies have yet investigated the association between morphometric abnormalities in salience network regions and the phenotype of high levels of impulsivity and compulsivity seen in alcohol dependent individuals.

Methods: In the current study, we compared self-report impulsivity, decisional impulsivity, self-report compulsivity, and structural neuroimaging measures in a sample of alcohol dependent individuals (n=60) and a comparison group of healthy controls (n=49). From the structural magnetic resonance images, we calculated volume and cortical thickness for 6 regions of interest: left and right anterior insula, posterior insula, and anterior cingulate.

Results: We found that alcohol dependent individuals had smaller anterior insula and anterior cingulate volumes, as well as thinner anterior insula cortices. There were no group differences in posterior insula morphometry. Anterior insula and anterior cingulate structural measures were negatively associated with self-report impulsivity, decisional impulsivity, and compulsivity measures.

Conclusions: Our results suggest that addiction endophenotypes are associated with salience network morphometry in alcohol addiction. These relationships indicate that salience network hubs represent potential treatment targets for impulse control disorders, including alcohol addiction.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.06.014DOI Listing
October 2017

Addictions Neuroclinical Assessment: A reverse translational approach.

Neuropharmacology 2017 Aug 7;122:254-264. Epub 2017 Mar 7.

Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA; Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.

Incentive salience, negative emotionality, and executive function are functional domains that are etiologic in the initiation and progression of addictive disorders, having been implicated in humans with addictive disorders and in animal models of addictions. Measures of these three neuroscience-based functional domains can capture much of the effects of inheritance and early exposures that lead to trait vulnerability shared across different addictive disorders. For specific addictive disorders, these measures can be supplemented by agent specific measures such as those that access pharmacodynamic and pharmacokinetic variation attributable to agent-specific gatekeeper molecules including receptors and drug-metabolizing enzymes. Herein, we focus on the translation and reverse translation of knowledge derived from animal models of addiction to the human condition via measures of neurobiological processes that are orthologous in animals and humans, and that are shared in addictions to different agents. Based on preclinical data and human studies, measures of these domains in a general framework of an Addictions Neuroclinical Assessment (ANA) can transform the assessment and nosology of addictive disorders, and can be informative for staging disease progression. We consider next steps and challenges for implementation of ANA in clinical care and research. This article is part of the Special Issue entitled "Alcoholism".
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http://dx.doi.org/10.1016/j.neuropharm.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569299PMC
August 2017

Altered Striatal Response During Effort-Based Valuation and Motivation in Alcohol-Dependent Individuals.

Alcohol Alcohol 2016 Nov 17;51(6):638-646. Epub 2016 Feb 17.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

Aims: To use functional magnetic resonance imaging (fMRI) to investigate the neural circuitry behind effort-related valuation and motivation in a population of alcohol-dependent participants and healthy controls.

Methods: Seventeen alcohol-dependent participants and a comparison group of 17 healthy control participants completed an effort-based motivation paradigm during an fMRI scan, in which they were required to exert effort at varying levels in order to earn a monetary reward.

Results: We found that alcohol-dependent participants were less motivated during trials requiring high levels of effort. The whole-brain fMRI analysis revealed that alcohol-dependent participants displayed an increased blood-oxygen-level dependent (BOLD) signal during low and unknown effort cues in the dorsal and ventral striatum compared with healthy controls.

Conclusion: These findings provide the first evidence that alcohol-dependent participants and healthy controls differ in their effort-based valuation and motivation processing. Alcohol-dependent participants displayed a hyperactive mesolimbic reward circuitry recruited by non-drug rewards, potentially reflecting a sensitization to reward in this patient population.
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http://dx.doi.org/10.1093/alcalc/agw003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091291PMC
November 2016

Reply to: Neuroclinical Assessment of Addiction Needs to Incorporate Decision-Making Measures and Ecological Validity.

Biol Psychiatry 2017 04 30;81(7):e55. Epub 2016 Aug 30.

Office of the Clinical Director, Bethesda, Maryland; Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.biopsych.2016.08.029DOI Listing
April 2017