Search

The COVID-19 pandemic has influenced people's lives in diverse ways. The authors utilized latent class analysis (LCA), a person-centered approach, to examine distinct patterns of COVID-related stressors and their associations with alcohol-related, mental health, and quality of life outcomes. Participants were 463 adults who completed the baseline assessment of the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study from June 2020 to January 2022. Using cross-sectional data, three analytic methods (continuous sum score, categorical grouping, and LCA) were applied to model 17 COVID-related stressors. Regression analyses indicated higher COVID-related stress and endorsement of four or more COVID-related stressors were generally associated with worse health-related outcomes. LCA revealed four classes: Class 1: Minimal COVID-Related Impact (51.6%); Class 2: Work Interruptions (24.8%); Class 3: Family/Friends Affected by COVID (14.5%); and Class 4: Serious Financial Stress (9.1%). Racial/ethnic minorities were more likely to be in Class 3, whereas individuals with more years of education and higher income were less likely to be in Class 4. Individuals with a history of alcohol use disorder were more likely to be in Classes 2 and 4. Compared with Class 1, Class 4 reported highest levels of perceived stress, problematic alcohol use, anxiety symptoms, depressive symptoms, alcohol craving, loneliness, drinking to cope, and lowest levels of physical, psychological, social, and environment quality of life. COVID-related stressors disproportionately affected minority and vulnerable groups. Individuals who experienced multiple financial stressors had the greatest risk for negative health-related outcomes and may benefit from holistic interventions and community outreach. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

There is substantial inter-individual variation in alcohol metabolism and response that are likely due to sex and age; however, these are not well understood. We investigated age and sex influences on alcohol elimination rate (AER) and subjective responses following intravenous (IV) administration in nondependent drinkers. Participants underwent a 2-session study where they received IV alcohol (target level: 0.05 g%) and placebo in counter-balanced order. AER was higher in males than in females across age groups. These differences were partly explained by sex differences in lean body mass and liver volume. Alcohol significantly increased peak feelings of high, intoxication, drug-effects, liking-effects, and wanting-more, with no major sex differences. There were no age-related differences in feelings of high and intoxication; however, the older group reported significantly lower peak liking-effects and stimulation responses than the younger group. These findings highlight the significant impact of sex and age as sources of variability in the clinical pharmacology of alcohol.

Low-level alcohol consumption is commonly perceived as being inconsequential or even beneficial for overall health, with some reports suggesting that it may protect against dementia or cardiovascular risks. However, these potential benefits do not preclude the concurrent possibility of negative health outcomes related to alcohol consumption. To examine whether casual, non-heavy drinking is associated with premature brain aging, we utilized the Brain-Age Regression Analysis and Computational Utility Software package to predict brain age in a community sample of adults [n = 240, mean age 35.1 (±10.7) years, 4 8% male, 4 9% African American]. Accelerated brain aging was operationalized as the difference between predicted and chronological age (“brain age gap”). Multiple regression analysis revealed a significant association between previous 90-day alcohol consumption and brain age gap (β = 0.014, p = 0.023). We replicated these results in an independent cohort [n = 231 adults, mean age 34.3 (±11.1) years, 55% male, 28% African American: β = 0.014, p = 0.002]. Our results suggest that even low-level alcohol consumption is associated with premature brain aging. The clinical significance of these findings remains to be investigated.

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., To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, we developed classifiers on data collected from multiple sites. Exploratory data analysis revealed that inclusion of case‐ and control‐only sites led to the inadvertent learning of site‐effects. Evolutionary‐based feature selection leveraging leave‐one‐site‐out cross‐validation, to combat unintentional learning, yielded a test‐set area under the receiver operating characteristic curve of 0.768.

In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.

Aims The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. Methods In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012 to 2020. Results Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Post hoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. Conclusions These findings suggest an increased concordance of networks underlying emotionality and compulsions toward drinking while also a reduction in control network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies.

Based on our current understanding of insular regions, effects of chronic alcohol use on the insula may affect the integration of sensory-motor, socio-emotional, and cognitive function. There is no comprehensive understanding about these differences in individuals with alcohol use disorder that accounts for both structural and functional differences related to chronic alcohol use. The purpose of this study was to investigate these variations in both the anterior and posterior insula in persons with alcohol use disorder. We investigated insula gray matter volume, morphometry, white matter structural connectivity, and resting state functional connectivity in 75 participants with alcohol use disorder (females = 27) and 75 age-matched healthy control participants (females = 39). Results indicated structural differences mostly in the anterior regions, while functional connectivity differences were observed in both the anterior and posterior insula in those with alcohol use disorder. Differing connectivity was observed with frontal, parietal, occipital, cingulate, cerebellar, and temporal brain regions. While these results align with prior studies showing differences primarily in anterior insular regions, they also contribute to the existing literature suggesting differences in anterior insular connectivity with brain regions shown to be engaged during higher cognitive and emotional tasks.

Growing evidence suggests greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. However, the underlying neurobiological mechanisms are still poorly understood. Here, we examined sex difference in resting state functional connectivity in alcohol use disorder using a whole-brain data driven approach and tested for relationships with mood and self-reported sleep. To examine whether sex effects vary by severity of alcohol use disorder, we studied two cohorts: non-treatment seeking n = 141 participants with alcohol use disorder (low severity; 58 females) from the Human Connectome project and recently detoxified n = 102 treatment seeking participants with alcohol use disorder (high severity; 34 females) at the National Institute on Alcohol Abuse and Alcoholism. For both cohorts, participants with alcohol use disorder had greater sleep and mood problems than healthy control, whereas sex by alcohol use effect varied by severity. Non-treatment seeking females with alcohol use disorder showed significant greater impairments in sleep but not mood compared to non-treatment seeking males with alcohol use disorder, whereas treatment-seeking females with alcohol use disorder reported greater negative mood but not sleep than treatment-seeking males with alcohol use disorder. Greater sleep problems in non-treatment seeking females with alcohol use disorder were associated with lower cerebello-parahippocampal functional connectivity, while greater mood problems in treatment-seeking females with alcohol use disorder were associated with lower fronto-occipital functional connectivity during rest. The current study suggests that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder. The effect of severity on sex differences might reflect neuroadaptive processes with progression of alcohol use disorder and needs to be tested with longitudinal data in the future.

Background Heavy alcohol consumption-associated chemosensory dysfunction is understudied, and early detection can help predict disease-associated comorbidities, especially those related to four quality of life (QOL) domains (physical, psychological, social and environment). We examined self-reports of chemosensory ability of individuals with different alcohol drinking behaviors and their association with changes in QOL domains. Methods Participants (n = 466) were recruited between June 2020 and September 2021 into the NIAAA COVID-19 Pandemic Impact on Alcohol study. Group-based trajectory modeling was used to categorize participants without any known COVID-19 infection into three groups (non-drinkers, moderate drinkers and heavy drinkers) based on their Alcohol Use Disorders Identification Test consumption scores at four different time points (at enrollment, week 4, week 8 and week 12). Linear mixed models were used to examine chemosensory differences between these groups. The associations between chemosensory abilities and QOL were determined in each group. Results We observed significant impairment in self-reported smell ability of heavy drinking individuals compared to non-drinkers. In contrast, taste ability showed marginal impairment between these groups. There were no significant differences in smell and taste abilities between the moderate and non-drinking groups. Heavy drinkers’ impairment in smell and taste abilities was significantly associated with deterioration in their physical, psychological, social and environmental QOL. Conclusion Persistent heavy drinking was associated with lower chemosensory ability. Heavy drinkers’ reduced smell and taste function and association with poorer QOL indicate that early assessment of chemosensory changes may be crucial in identifying poorer well-being outcomes in heavy drinkers at risk for alcohol use disorder.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Contains fulltext : 219494.pdf (Publisher’s version ) (Closed access) 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. 15 p.

Contains fulltext : 240530.pdf (Publisher’s version ) (Closed access) Background: Nicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention. Methods: Eleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence. Results: The cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p < 0.001) and methamphetamine (AUC = 0.71, p < 0.001) relative to non-dependent controls. Classifications related to nicotine dependence proved modest (AUC = 0.62, p = 0.014). Conclusions: Stimulant dependence was related to FA disturbances within tracts consistent with a role in addiction. The multivariate pattern of white matter differences proved sufficient to identify individuals with stimulant dependence, particularly for cocaine and methamphetamine. 10 p.

Contains fulltext : 229772.pdf (Publisher’s version ) (Closed access) 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. 9 p.

BACKGROUND Alterations in white matter microstructure associated with chronic alcohol use have been demonstrated in previous diffusion tensor imaging (DTI) research. However, there is conflicting evidence as to whether such differences are influenced by an individual's biological sex. The purpose of the present study was to investigate the prevalence of sex differences in the white matter microstructure of the brains of individuals with alcohol use disorder (AUD) and healthy controls. METHODS One hundred participants with AUD (38 female, aged 21 to 68) participating in the National Institute on Alcohol Abuse and Alcoholism's inpatient treatment program and 98 healthy control participants (52 female) underwent a diffusion-weighted scan. Images collected were processed for each subject individually, and voxelwise, tract-based spatial statistics analysis was conducted to test for differences in the DTI measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). RESULTS A 2-way, between-subjects ANCOVA that tested for differences by group and sex revealed widespread differences between AUD and control subjects, but no interaction between group and sex. Additional analyses exploring demographic and alcohol use variables showed significant impacts of age on white matter microstructure that were more pronounced in individuals with AUD. Plots of FA by age, sex, and group in major white matter tracts suggest a need to explore higher order interactions in larger samples. CONCLUSIONS These results bolster recent findings of similar microstructural properties in men and women with AUD but provide a rationale for the consideration of age when investigating the impacts of chronic alcohol use on the brain's white matter.

Background: 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 commo...

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.

Highlights • We tested gender differences in brain volumes of alcohol dependent vs control groups. • Group differences in brain volumes emerged as gross and widespread. • Group-by-gender effects emerged in selected brain regions (cerebellum, amygdala) • In dependent users, greater alcohol use predicted smaller amygdala and larger cerebellum GM volume. • Our results highlight the need to account for gender differences in MRI studies of alcohol dependence., 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.

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.

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.

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

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.

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 two; 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.

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.

Charitable giving depends on individuals' abilities to make altruistic decisions. Previous studies suggest that altruism involves recruitment of neural resources in regions including social processing, reward/reinforcement learning, emotional response, and cognition. Despite evolutionary and social benefits to altruism, we know that humans do not always engage in altruistic behavior, like charitable giving. Understanding the underlying processes leading to decisions to donate is vital to improve prosocial community engagement. The present study examined how characteristics of the charitable giving opportunity influence an individual's decision to give and the neural engagement underlying these features. Twenty-nine participants subjectively rated ten charities on their value, effectiveness, and the subject's personal chance of donating. Participants then completed an fMRI task requiring them to decide to donate to certain charities given the probability of the donation helping, their personal preference for the charity, and whether the donation came at cost to themselves. There was a significant reduction in donating when the probability of helping was low versus high, and subjects were significantly less likely to donate to their lowest-rated charities. Further, probability of a donation being helpful and how much the subject favored a charity moderated PCC and left IFG engagement. Interestingly, reward neurocircuitry did not demonstrate similar sensitivity to these variations. These results may suggest individuals engage motivated reasoning to justify failure to donate, while donations are driven by emotion mentalizing that focuses on the welfare of others. This may provide valuable insight into how to engage individuals in altruistic giving.

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.

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg-1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.