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.

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.

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.

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.

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.

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.

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.

Pharmacodynamic effects of intravenous alcohol on hepatic and gonadal hormones: influence of age and sex.

BACKGROUND: Growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis and gonadal hormones demonstrate extensively associated regulation; however, little is known about the effects of acute alcohol exposure on these hormones. This study examined the effects of intravenous alcohol on the GH-IGF-1 axis and gonadal hormone concentrations, and the influence of age and sex on their regulation. METHODS: Forty-eight healthy volunteers (24 men and 24 women each in the 21 to 25 and 55 to 65 year age groups) underwent a 2-session single-blinded study. Subjects received in randomized counter-balanced order, alcohol infusions, individually computed based on a physiologically based pharmacokinetic model, to maintain a steady-state ("clamped") exposure of 50 mg% or saline for 3 hours in separate sessions. Blood samples collected at baseline and postinfusion in each session were assayed for levels of GH, IGF-1, free testosterone, and estradiol. RESULTS: Acute alcohol administration resulted in changes in gonadal hormones that differed by sex. Change in free testosterone showed a significant treatment × baseline interaction (p < 0.001), indicating that alcohol-induced suppression of testosterone occurred predominantly in men. On the other hand, change in estradiol showed a significant treatment × sex interaction (p = 0.028), indicating that alcohol-induced increases in estradiol occurred predominantly in women. There was a trend for alcohol-induced decreases in IGF-1 levels. Change in GH showed a significant main effect of baseline (p < 0.001) and a trend for treatment by baseline interaction, suggesting an alcohol-induced decrease in individuals with high baseline GH values. There was also a significant main effect of sex (p = 0.046) indicating that men had greater changes in GH across treatment compared with women. CONCLUSIONS: Alcohol induced a complex pattern of hormonal responses that varied between younger and older men and women. Some of the observed sex-based differences may help improve our understanding of the greater susceptibility to alcohol-related hepatic damage seen in women.

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.

Incentive-elicited mesolimbic activation and externalizing symptomatology in adolescents.

BACKGROUND: Opponent-process theories of externalizing disorders (ExD) attribute them to some combination of overactive reward processing systems and/or underactive behavior inhibition systems. Reward processing has been indexed by recruitment of incentive-motivational neurocircuitry of the ventral striatum (VS), including nucleus accumbens (NAcc). METHODS: We used functional magnetic resonance imaging (fMRI) with an incentive task to determine whether externalizing symptomatology in adolescence is correlated with an enhanced VS recruitment by cues for rewards, or by deliveries of rewards. Twelve community-recruited adolescents with externalizing disorders (AED) and 12 age/gender-matched controls responded to targets to win or avoid losing $0, $0.20, $1, $5, or an unknown amount (ranging from $0.20 to $5). RESULTS: Cues to respond for rewards activated the NAcc (relative to cues for no incentive), in both subject groups similarly, with greatest NAcc recruitment by cues for the largest reward. Loss-anticipatory NAcc signal increase was detected in a volume-of-interest analysis - but this increase occurred only in trials when subjects hit the target. Relative to controls, AED showed significantly elevated NAcc activation by a linear contrast between reward notification versus notification of failure to win reward. In a post hoc reanalysis, VS and pregenual anterior cingulate activation by the reward versus non-reward outcome contrast also directly correlated with Child Behavior Checklist (CBCL) Externalizing total scores (across all subjects) in lieu of a binary diagnosis. Finally, both groups showed right insula activation by loss notifications (contrasted with avoided losses). CONCLUSIONS: Externalizing behavior, whether assessed dimensionally with a questionnaire, or in the form of a diagnostic categorization, is associated with an exaggerated limbic response to outcomes of reward-directed behavior. This could be a neurobiological signature of the behavioral sensitivity to laboratory reward delivery that is characteristic of children with externalizing symptomatology. Of interest is future research on incentive-motivational processing in more severe, clinically referred AED.

Greater activation in left hemisphere language-related regions during simple judgment tasks among substance-dependent patients in treatment for alcoholism.

BACKGROUND: Alcoholism is often associated with impaired emotional control. Alcoholics have also been found to have deficits in frontal lobe executive functions. Recent functional imaging studies have suggested that alcoholics show greater activation than nonalcoholics in circuits involving frontal lobes, as well as more posterior brain regions, when engaged in executive-type tasks. In this study, we compared brain activations of alcohol-dependent patients and healthy nonalcoholics while they performed 2 simple judgment tasks designed to activate frontal circuits involved in a basic form of decision making. Participants completed 1 judgment task that required an emotional judgment and 1 task that did not, which enabled us to study whether alcoholics had greater brain activation while performing executive tasks, and to determine if emotional tasks elicited even greater activation than nonemotional tasks. METHODS: We performed functional magnetic resonance imaging scans while alcoholic patients and nonalcoholic controls viewed pictures from the International Affective Picture System. In 3 separate runs, participants viewed the images without making a judgment, determined whether the images were indoor or outdoor scenes, or decided if they liked or disliked the images. RESULTS: There was little difference in brain activation between alcoholics and controls when no judgment was required. When participants made judgments about either the location or whether they liked or disliked an image, however, we observed significantly increased activation in frontal, limbic, and temporal regions in the patients relative to the controls. Increases were particularly robust in the frontal lobe and in areas of the brain associated with language. When we compared the emotional to the nonemotional judgment, the alcoholics, but not the controls, showed greater activation in the ventral mesial frontal cortex. CONCLUSIONS: Alcoholic patients appear to use brain language areas more than nonalcoholics while making judgments about the setting or liking of emotionally arousing visual images. This increased activation may reflect a compensatory recruitment of brain regions to perform simple decision-making tasks.

Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol.

People typically drink alcohol to induce euphoria or reduce anxiety, and they frequently drink in social settings, yet the effect of alcohol on human brain circuits involved in reward and emotion has been explored only sparingly. We administered alcohol intravenously to social drinkers while brain response to visual threatening and nonthreatening facial stimuli was measured using functional magnetic resonance imaging (fMRI). Alcohol robustly activated striatal reward circuits while attenuating response to fearful stimuli in visual and limbic regions. Self-ratings of intoxication correlated with striatal activation, suggesting that activation in this area may contribute to subjective experience of pleasure and reward during intoxication. These results show that the acute pharmacological rewarding and anxiolytic effects of alcohol can be measured with fMRI.

Developmental differences in posterior mesofrontal cortex recruitment by risky rewards.

Might increased risk taking in adolescence result in part from underdeveloped conflict-monitoring circuitry in the posterior mesofrontal cortex (PMC)? Adults and adolescents underwent functional magnetic resonance imaging during a monetary game of "chicken." As subjects watched ostensible winnings increase over time, they decided when to press a button to bank their winnings, knowing that if they did not stop pursuing money reward before a secret varying time limit, they would "bust" and either lose the money accrued on the current trial (low-penalty trials) or forfeit trial winnings plus a portion of previous winnings (high-penalty trials). Reward accrual at risk of low penalty (contrasted with guaranteed reward) activated the PMC in adults but not in adolescents. Across all subjects, this activation (1) correlated positively with age but negatively with risk exposure and (2) was greater when subjects busted on the previous low-penalty trial. Reward accrual at risk of high penalty was terminated sooner and recruited the PMC in both adults and adolescents when contrasted with guaranteed reward. Predecision PMC activation in the high-penalty trials was significantly reduced in trials when subjects busted. These data suggest that (1) under threat of an explicit severe penalty, recruitment of the PMC is similar in adolescents and adults and correlates with error avoidance, and (2) when potential penalties for a rewarding behavior are mild enough to encourage some risk taking, predecision PMC activation by a reward/risk conflict is sensitive to previous error outcomes, predictive of risk-aversive behavior in that trial, and underactive in adolescents.

Striatal sensitivity to reward deliveries and omissions in substance dependent patients.

Some motivational theories of substance dependence (SD) posit either pathologically increased or decreased ventral striatum (VS) recruitment by cues for nondrug rewards. The incentive-sensitization hypothesis, alternatively, attributes SD to enhanced incentive salience of drug-predictive cues specifically, with no requirement for altered nondrug incentive processing. We assessed whether individuals undergoing inpatient therapy for SD are characterized by altered recruitment of mesolimbic incentive neurocircuitry by cues and deliveries of nondrug rewards. During functional magnetic resonance imaging, substance-dependent patients (SDP) and controls performed a modified monetary incentive delay task featuring: a) anticipatory cues that signaled opportunities to respond to a target to either win money or avoid losing money, b) notifications of wins and losses, and c) unexpected replacement of reward trial outcomes with a demand to repeat the trial. Both anticipatory reward cues and loss cues elicited similar mood responses and VS activation between SDP and controls. However, in SDP (but not controls), reward notifications also activated VS and mesial frontal cortex, and loss notifications activated anterior insula. Finally, substitution of expected outcomes in reward trials with notifications to repeat the trial deactivated the VS in SDP but not in controls. These data do not suggest that SD is characterized by altered recruitment of VS circuitry by cues for nondrug incentives. Rather, SDP may instead have increased limbic system sensitivity to reward and loss delivery, consistent with the role of impulsivity in SD.

Incentive-elicited striatal activation in adolescent children of alcoholics.

AIMS: Deficient recruitment of motivational circuitry by non-drug rewards has been postulated as a pre-morbid risk factor for substance dependence (SD). We tested whether parental alcoholism, which confers risk of SD, is correlated with altered recruitment of ventral striatum (VS) by non-drug rewards in adolescence. DESIGN: During functional magnetic resonance imaging, adolescent children of alcoholics (COA; age 12-16 years) with no psychiatric disorders (including substance abuse) and similarly aged children with no risk factors responded to targets to win or avoid losing $0, $0.20, $1, $5 or a variable amount (ranging from $0.20 to $5). RESULTS: In general, brain activation by either reward anticipation or outcome notification did not differ between COA and age/gender-matched controls. Cue-elicited reward anticipation activated portions of VS in both COA and controls. In nucleus accumbens (NAcc), signal change increased with anticipated reward magnitude (with intermediate recruitment by variable incentives) but not with loss magnitudes. Reward deliveries activated the NAcc and mesofrontal cortex in both COA and controls. Losses activated anterior insula bilaterally in both groups, with more extensive right anterior insula activation by losses in controls. NAcc signal change during anticipation of maximum rewards (relative to non-reward) correlated positively with both Brief Sensation-Seeking Scale scores and with self-reported excitement in response to maximum reward cues (relative to cues for non-reward). CONCLUSIONS: Among adolescents with no psychiatric disorders, incentive-elicited VS activation may relate more to individual differences in sensation-seeking personality than to presence of parental alcoholism alone. Future research could focus on adolescents with behavior disorders or additional risk factors.

Reduced posterior mesofrontal cortex activation by risky rewards in substance-dependent patients.

Substance-dependent individuals show disadvantageous decision-making, as well as alterated frontocortical recruitment when performing experimental tasks. We investigated whether substance-dependent patients (SDP) would show blunted recruitment of posterior mesofrontal cortex (PMC) by a conflict between concurrently increasing reward and risk of penalty in a monetary game of "chicken." SDP and controls performed: motor control (no reward) trials, guaranteed reward trials in which reward was not at risk, and risky trials where subjects were required to terminate their reward accrual before a secret varying time limit or else "bust" and forfeit that trial's winnings (low penalty) or the current trial's winnings plus an equal amount of previous winnings (high penalty). Reward accrual duration at risk of "busting" correlated negatively with trait neuroticism. The contrast between winning guaranteed reward versus non-reward activated the caudate head bilaterally in SDP but not controls. Accumulation of money at risk of low- or high-penalty (contrasted with accumulating guaranteed money) activated the PMC in both groups, but with a greater magnitude and more anterior extent in controls. Pre-decision signal increase in a PMC volume of interest negatively correlated with risk-taking in low-penalty trials, and was blunted in SDP relative to controls under both penalty conditions after controlling for individual differences in actual risk-taking and the higher neuroticism of SDP. These data suggest that SDP are characterized by a combination of: (a) striatal hypersensitivity to reward, and (b) under-recruitment of the specialized conflict-monitoring circuitry of the PMC when reward entails potential penalties.

Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients.

Alcohol is often used to modulate mood states. Alcohol drinkers report that they use alcohol both to enhance positive affect and to reduce dysphoria, and alcohol-dependent patients specifically state reduction of negative affect as a primary reason for drinking. The current study proposes that alcohol cues may reduce negative affect in alcoholics. We used functional magnetic resonance imaging to examine brain activation in response to combination images that juxtaposed negative or positive International Affective Picture System (IAPS) images with an alcohol or non-alcohol-containing beverage. We found that in the absence of the alcohol cue, alcoholics showed more activation to negative than to positive images and greater activation than controls to negative images. When the IAPS images were presented with the alcohol cue, there was a decreased difference in activation between the positive and negative images among the alcoholics, and a decreased difference in response to the negative images between controls and alcoholics. Additionally, in the neutral-beverage conditions, anxiety ratings significantly predicted activation in the right parahippocampal gyrus but did not predict activation when the alcohol cues were presented. In conclusion, the alcohol cues may have modulated cortical networks involved in the processing of emotional stimuli by eliciting a conditioned response in the alcoholics, but not in the controls, which may have decreased responsiveness to the negative images.

Parental alcohol use and brain volumes in early- and late-onset alcoholics.

BACKGROUND: Studies have shown that alcoholics have smaller brain volumes than non-alcoholic cohorts, but an effect of family history (FH) of heavy drinking on brain volume has not been demonstrated. We examined the relationship between an FH of heavy drinking and both brain shrinkage as measured by the ratio of brain volumes to intracranial volume (ICV) as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. METHODS: With T1-weighted resonance imaging, we measured ICV, brain volume, and white and gray matter volume in adult treatment-seeking late-onset and early-onset alcoholics with either a positive or a negative FH of heavy alcohol use, and in healthy control subjects. We also calculated brain shrinkage using a ratio of soft tissue volumes to ICV. RESULTS: The FH positive alcoholic patients had significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth. Brain shrinkage did not correlate with FH. Late-onset alcoholics showed a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. Late-onset FH positive patients also had significantly lower IQ scores than late-onset FH negative patients, and IQ scores were correlated with ICV. CONCLUSIONS: These data provide evidence that parental alcohol use might increase risk for alcoholism in offspring in part by a genetic and/or environmental effect that might be related to reduced brain growth.