Effects of Varenicline on Neural Correlates of Alcohol Salience in Heavy Drinkers.

BACKGROUND: Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. METHODS: In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. RESULTS: During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. CONCLUSIONS: Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.

Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons.

The insula, a structure involved in higher order representation of interoceptive states, has recently been implicated in drug craving and social stress. Here, we performed brain magnetic resonance imaging to measure volumes of the insula and amygdala, a structure with reciprocal insular connections, in 26 alcohol-dependent patients and 24 healthy volunteers (aged 22-56 years, nine females in each group). We used an established morphometry method to quantify total and regional insular volumes. Volumetric measurements of the amygdala were obtained using a model-based segmentation/registration tool. In alcohol-dependent patients, anterior insula volumes were bilaterally reduced compared to healthy volunteers (left by 10%, right by 11%, normalized to total brain volumes). Furthermore, alcohol-dependent patients, compared with healthy volunteers, had bilaterally increased amygdala volumes. The left amygdala was increased by 28% and the right by 29%, normalized to total brain volumes. Post-mortem studies of the anterior insula showed that the reduced anterior insular volume may be associated with a population of von Economo neurons, which were 60% diminished in subjects with a history of alcoholism (n = 6) as compared to subjects without a history of alcoholism (n = 6) (aged 32-56 years, all males). The pattern of neuroanatomical change observed in our alcohol-dependent patients might result in a loss of top-down control of amygdala function, potentially contributing to impaired social cognition as well as an inability to control negatively reinforced alcohol seeking and use.

Cumulative gains enhance striatal response to reward opportunities in alcohol-dependent patients.

Substance use disorder is characterized by a transition from volitional to compulsive responding for drug reward. A possible explanation for this transition may be that alcohol-dependent patients (ADP) show a general propensity for a history of rewarded instrumental responses, and these rewarded responses may boost the activation of motivational neurocircuitry for additional reward. Brain imaging studies of decision-making have demonstrated that ADP relative to controls (CON) often show altered neural activation in response to anticipating and receiving rewards, but the majority of studies have not investigated how past performance affects activation. A potential exists for ADP to show increased sensitivity to reward as a function of reward delivery history. In the current study, we used functional magnetic resonance imaging to investigate the neural correlates of risky decision-making in ADP (n = 18) and CON (n = 18) while they played a two-choice monetary risk-taking game. In addition to investigating general neural recruitment by risky decision-making, we also modeled each participant's running total of monetary earnings in order to determine areas of activation that correlated with cumulative reward. We found that ADP and CON showed few differences in behavior or in mesolimbic activation by choice for, and receipt of, risky gains. However, when including a cumulative-earnings covariate, ADP exhibited heightened striatal activation that correlated with total earnings during the choice event in the task. The heightened contextual sensitivity of striatal responses to cumulative earnings in ADP may represent a general neurobiological affective substrate for development of automatized instrumental behavior.

Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes.

Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving.

The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study.

RATIONALE: Posttraumatic stress disorder (PTSD) and alcoholism are frequently comorbid, suggesting the possibility of overlapping neural substrates. The neurokinin 1 (NK1) receptor for substance P (SP) has been implicated in both stress- and alcohol-related behaviors. The NK1 antagonist aprepitant, clinically available as a treatment for chemotherapy-induced nausea, offers a tool to probe a potential role of the SP/NK1 system in comorbid PTSD and alcoholism. OBJECTIVES: The aim of this study is to evaluate the efficacy of aprepitant for treatment of comorbid PTSD and alcoholism. METHODS: Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to an inpatient unit at the NIH Clinical Center and randomized to double-blind aprepitant (125 mg/day; based on PET studies reporting >90 % central receptor occupancy at this dose) or placebo. After reaching steady state, subjects were assessed for PTSD symptom severity, behavioral and neuroendocrine responses to stress and alcohol cues, and functional magnetic resonance imaging (fMRI) responses to stimuli with positive or negative emotional valence. RESULTS: Aprepitant treatment had no effect on PTSD symptoms or subjective or physiological responses to stress or alcohol cues. However, aprepitant robustly potentiated ventromedial prefrontal cortex (mPFC) fMRI responses to aversive visual stimuli. CONCLUSIONS: Despite the lack of effect on PTSD symptoms and responses to stress/alcohol cues, NK1 antagonism activated the ventral mPFC, an area considered hypoactive in PTSD, during exposure to aversive stimuli. Because this brain area is critically important for extinction of fear memories and in alcohol craving and relapse, our finding suggests that NK1 antagonism might be a useful pharmacological treatment to enhance extinction-based cue-exposure therapies.

Cardiac reactivity during the ascending phase of acute intravenous alcohol exposure and association with subjective perceptions of intoxication in social drinkers.

BACKGROUND: The aim of this study was to characterize cardiac reactivity measures, heart rate (HR), and heart rate variability (HRV), following acute intravenous (IV) alcohol administration and their association with subjective responses in social drinkers. METHODS: Twenty-four subjects (11 females) received IV alcohol infusions to attain and clamp the breath alcohol concentration (BrAC) at 50 mg% or placebo in separate sessions. Serial 5-minute cardiac recordings at baseline and during the infusion were analyzed to obtain frequency and time domain cardiac measures. Self-reported subjective perceptions were also obtained at the same time points. RESULTS: HR showed significant decreases from baseline, while the HRV measure pNN50 showed steady increases during the ascending phase of alcohol infusion. HR was inversely correlated with pNN50 across time and treatment. There was a significant association of HR with subjective feelings of high, intoxication, feeling drug effects, and liking drug effects across time during the ascending phase. CONCLUSIONS: Acute IV alcohol resulted in decreases in HR and increases in HRV consistent with autonomic parasympathetic activation. The association of these changes with subjective responses suggests that cardiac reactivity may serve as a physiological marker of subjective alcohol effects. This study broadens the understanding of acute cardiovascular effects of alcohol and clinically significant cardiac conditions such as arrhythmia and cardiomyopathy associated with chronic alcohol drinking.

Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing.

Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

Gender differences in neural-behavioral response to self-observation during a novel fMRI social stress task.

UNLABELLED: The neural correlates of response to psychosocial stress and gender differences therein are difficult to model experimentally as this type of stressor is difficult to induce in a brain imaging environment. The Trier Social Stress Test (TSST), a behavioral paradigm that reliably induces moderate levels of stress was thus modified for the MRI environment. To determine the neurobehavioral basis of gender differences in response to observing oneself under social evaluative stress, 26 subjects (14 females) performed the TSST while being videotaped. During fMRI scanning, subjects were shown alternating video clips of two CONDITIONS: SELF or a same-sex OTHER performing the TSST. Subjects rated their stress level immediately after the video clips. GENDER differences in the [SELF-OTHER] contrast were analyzed. There was a GENDER×CONDITION interaction such that only women reported increased subjective stress during video feedback of their TSST session. A whole brain analysis (SELF vs. OTHER) showed activation in the bilateral insula, inferior, middle and superior frontal gyri. Greater recruitment was seen among males in some of these same areas in the context of significantly lower stress ratings. Activation of areas involved in inhibitory control and sensory awareness might contribute to the significantly lower stress ratings in males. Understanding these gender differences is relevant to disorders of stress and self-concept.

White matter microstructure alterations: a study of alcoholics with and without post-traumatic stress disorder.

Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.

Deficits in cortical, diencephalic and midbrain gray matter in alcoholism measured by VBM: Effects of co-morbid substance abuse.

OBJECTIVE: Alcoholism has been associated with a widespread pattern of gray matter atrophy. This study sought to investigate the spectrum of volume alterations in a population of alcoholics with only alcohol dependence, polysubstance abusing alcoholics, and a comparison population of healthy controls. METHOD: Thirty-seven 'pure' alcoholics, 93 polysubstance abusing alcoholics, and 69 healthy controls underwent structural T1 MRI scans. Voxel-based morphometry was performed to investigate gray matter alterations. RESULTS: Alcoholic dependent inpatients (both with and without a history of DSM-IV substance abuse/dependence diagnosis) displayed significant gray matter differences in the mesial region of the frontal lobe and right temporal lobe. 'Pure' alcoholics exhibited a pattern of subcortical changes similar to that seen in Wernicke-Korsakoff Syndrome when compared to polysubstance abusing alcoholics. 'Pure' alcoholics and polysubstance abusing alcoholics did not differ significantly in measures of cortical gray matter, liver function, or nutrition. CONCLUSIONS: These findings reinforce the accepted literature in regards to frontal lobe gray matter atrophy in alcohol dependence. This study calls for additional research in order to investigate the spectrum from uncomplicated alcoholism to Wernicke-Korsakoff Syndrome. Further research is needed to elucidate the exact cause of this pattern of differences and to determine what factors are responsible for the patterns of gray matter reduction or difference in 'pure' and polysubstance abusing alcoholics.

Development of the complex general linear model in the Fourier domain: application to fMRI multiple input-output evoked responses for single subjects.

A linear time-invariant model based on statistical time series analysis in the Fourier domain for single subjects is further developed and applied to functional MRI (fMRI) blood-oxygen level-dependent (BOLD) multivariate data. This methodology was originally developed to analyze multiple stimulus input evoked response BOLD data. However, to analyze clinical data generated using a repeated measures experimental design, the model has been extended to handle multivariate time series data and demonstrated on control and alcoholic subjects taken from data previously analyzed in the temporal domain. Analysis of BOLD data is typically carried out in the time domain where the data has a high temporal correlation. These analyses generally employ parametric models of the hemodynamic response function (HRF) where prewhitening of the data is attempted using autoregressive (AR) models for the noise. However, this data can be analyzed in the Fourier domain. Here, assumptions made on the noise structure are less restrictive, and hypothesis tests can be constructed based on voxel-specific nonparametric estimates of the hemodynamic transfer function (HRF in the Fourier domain). This is especially important for experimental designs involving multiple states (either stimulus or drug induced) that may alter the form of the response function.

Conditioned preference to a methamphetamine-associated contextual cue in humans.

Classical conditioning is widely used to study motivational properties of addictive drugs in animals, but has rarely been used in humans. We established a procedure suitable for studying the neurobiology and individual determinants of classical conditioning in humans. Healthy volunteers were randomly assigned to four groups that received methamphetamine or placebo in the presence of distinctive environmental cues under paired or unpaired conditions. During each session, subjects performed tasks known to activate the ventral striatum. Tasks were performed in the presence of a distinctive context, consisting of a screen background image of a beach or mountains, accompanied by corresponding sounds. Separate groups of subjects carried out the tasks under high ($35-50) or low ($5-20) reward conditions. Within each of the two reward conditions, one group (paired) received methamphetamine (20 mg, oral) or placebo consistently associated with one of the contexts, while the other (unpaired) received drug or placebo unrelated to context. A fifth group (paired) performed the tasks with contextual cues but in the absence of monetary incentives. Before and after conditioning, participants carried out a series of forced choice tasks for the contextual cues, and change of preference over time was analyzed. All paired groups showed a significant increase in preference for the drug-associated context, with a linear trend for increase across the levels of reward. Preference was unrelated to subjective drug effects, and did not change in the unpaired group. These data support the translational utility of our conditioning procedure for studies of reward mechanisms in humans.

Childhood trauma exposure and alcohol dependence severity in adulthood: mediation by emotional abuse severity and neuroticism.

BACKGROUND: Childhood trauma has been linked with a number of negative outcomes later in life, including alcohol dependence (AD). Previous studies have suggested a mediating role for neuroticism in the relationship between childhood trauma and psychopathology. In this study, we investigate the prevalence of multiple types of childhood trauma in treatment-seeking alcohol-dependent patients, and the associations between childhood trauma and AD severity using multiple mediation analysis. METHODS: The prevalence of 5 types of childhood trauma-emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect-was assessed in treatment-seeking alcohol-dependent patients (n = 280) and healthy controls (n = 137) using the Childhood Trauma Questionnaire. Multiple mediation analyses were used to model associations between childhood trauma measures and alcohol-related outcomes, primarily the severity of AD in the alcohol-dependent sample. RESULTS: Childhood trauma was significantly more prevalent and more severe in the alcohol-dependent subjects. In addition, childhood trauma was found to influence AD severity, an effect that was mediated by neuroticism. When individual trauma types were examined, emotional abuse was found to be the primary predictor of AD severity, both directly and through the mediating effects of the impulsivity subfacet of neuroticism. Physical abuse also had a moderate direct effect on AD severity. Mediation analysis did not reveal any association between childhood trauma and Alcohol Use Disorders Identification Test score in the nondependent control sample. CONCLUSIONS: Childhood trauma is highly prevalent in treatment-seeking alcoholics and may play a significant role in the development and severity of AD through an internalizing pathway involving negative affect. Our findings suggest that alcoholics with a history of childhood emotional abuse may be particularly vulnerable to severe dependence.

Stimulant and sedative effects of alcohol.

Alcohol produces both stimulant and sedating effects in humans. These two seemingly opposite effects are central to the understanding of much of the literature on alcohol use and misuse. In this chapter we review studies that describe and attempt to measure various aspects of alcohol's subjective, autonomic, motor, cognitive and behavioral effects from the perspective of stimulation and sedation. Although subjective sedative and stimulatory effects can be measured, it is not entirely clear if all motor, cognitive and behavioral effects can be unambiguously assigned to either one or the other category. Increased heart rate and aggression seem strongly associated with stimulation, but motor slowing and cognitive impairment can also show a similar time course to stimulation, making their relation to sedation problematic. There is good agreement that alcohol's ability to induce striatal dopamine release is the mechanism underlying alcohol's stimulatory effects; however, the change in brain function underlying sedation is less well understood. In general, stimulatory effects are thought to be more rewarding than sedative effects, but this may not be true for anxiolytic effects which seem more closely related to sedation than stimulation. The two major theories of how response to alcohol predicts risk for alcoholism both postulate that individuals at high risk for alcohol use disorders have a reduced sedative response to alcohol compared to individuals not at high risk. In addition one theory proposes that alcoholism risk is also associated with a larger stimulatory response to alcohol.

Smaller right amygdala in Caucasian alcohol-dependent male patients with a history of intimate partner violence: a volumetric imaging study.

Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men (n = 54), ages 24-55, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs (n = 27), non-violent ADs (n = 14) and HCs (n = 13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV.

Effects of alcohol dependence on cortical thickness as determined by magnetic resonance imaging.

Alterations of brain structures have been seen in patients suffering from drug abuse or mental disorders like schizophrenia. Similar changes in volume of brain structures have been observed in both alcoholic men and women. We examined the thickness of gray matter in the cerebral cortex in control men and women (n=69, 47 men) and alcohol-dependent subjects (n=130, 83 men) to test the hypothesis that alcoholic inpatients would have more cortical damage than controls. We also hypothesized that alcoholic women would be more affected than alcoholic men. Alcoholic participants with a history of schizophrenia, psychotic, or bipolar disorder were excluded from the study. Volumetric structural magnetic resonance images were collected, 3D surfaces were created using Freesurfer, and statistical testing for cortical thickness differences was carried out using AFNI/SUMA. Covarying for age and years of education, we confirmed significant differences between alcoholics and healthy controls in cortical thickness in both the left and right hemispheres. Significant differences in cortical thickness between control men and women were also observed. These differences may reflect sexual dimorphisms in the human brain, a genetic predisposition to alcoholism and comorbid drug use, and the extent of gray matter damage in alcoholism and substance use.

Mesolimbic recruitment by nondrug rewards in detoxified alcoholics: effort anticipation, reward anticipation, and reward delivery.

Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two-stage presentation of reward-predictive information, subjects saw cues signaling opportunities to win $0, $1, or $10 for responding to a target. Following this response, subjects were notified whether their success would be indicated by a lexical notification ("Hit?") or by delivery of a monetary reward ("Win?"). After a variable interval, subjects then viewed the trial outcome. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. Across all subjects, a questionnaire measure of "hot" impulsivity correlated with VS recruitment by post-response anticipation of low rewards and with VS recruitment by delivery of low rewards. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction.

Relationship between liver function and brain shrinkage in patients with alcohol dependence.

BACKGROUND: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence. METHODS: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. RESULTS: Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. CONCLUSIONS: Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.

The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers.

Alcohol is thought to contribute to an increase in risk-taking behavior, but the neural correlates underlying this effect are not well understood. In this study, participants were given intravenous alcohol or placebo while undergoing functional magnetic resonance imaging (fMRI) and playing a risk-taking game. The game allowed us to examine the neural response to choosing a safe or risky option, anticipating outcome and receiving feedback. We found that alcohol increased risk-taking behavior, particularly among participants who experienced more stimulating effects of alcohol. fMRI scans demonstrated that alcohol increased activation in the striatum to risky compared with safe choices and dampened the neural response to notification of both winning and losing throughout the caudate, thalamus and insula. This study suggests that alcohol may increase risk-taking behavior by both activating brain regions involved in reward when a decision is made, and dampening the response to negative and positive feedback.

Psychopathic tendencies and mesolimbic recruitment by cues for instrumental and passively obtained rewards.

Psychopathy is a constellation of self-serving attitudes and antisocial behaviors with little regard to cost to self and others. Might this symptomatology arise in part from an exaggerated response of brain motivational circuitry to prospective rewards? We examined whether psychopathic tendencies are associated with increased recruitment of incentive neurocircuitry during anticipation of instrumental and conditioned rewards. Healthy controls completed the Psychopathic Personality Inventory (PPI), then were presented with response-contingent and passively delivered rewards during functional MRI. PPI scores correlated negatively with reaction time to incentivized targets, but not with reaction time to non-incentivized targets. PPI scores also correlated positively with recruitment of ventral striatum and anterior cingulate cortex during instrumental reward anticipation. PPI scores also correlated with middle frontal cortex recruitment during anticipation of passively received rewards. These data indicate that in psychiatrically healthy controls, individuals with greater endorsement of psychopathic tendencies show more robust neurophysiological and behavioral signatures of incentive motivation.