Kent E. Hutchison

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

A Polymorphism of the μ-Opioid Receptor Gene (OPRM1) and Sensitivity to the Effects of Alcohol in Humans

BACKGROUND Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol. METHODS Participants who were either homozygous for the A allele (n = 23) or heterozygous (n = 15) received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration: 0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three target breath alcohol concentrations. RESULTS The results suggested that individuals with the G allele reported higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A allele. Furthermore, participants with the G allele were almost three times more likely to report a positive family history of alcohol use disorders than participants with the A allele. CONCLUSIONS These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.

Prefrontal Cortex Activity is Reduced in Gambling and Nongambling Substance Users During Decision-Making

Objective: Poor decision‐making is a hallmark of addiction, whether to substances or activities. Performance on a widely used test of decision‐making, the Iowa Gambling Task (IGT), can discriminate controls from persons with ventral medial frontal lesions, substance‐dependence, and pathological gambling. Positron emission tomography (PET) studies indicate that substance‐dependent individuals show altered prefrontal activity on the task. Here we adapted the IGT to an fMRI setting to test the hypothesis that defects in ventral medial and prefrontal processing are associated with impaired decisions that involve risk but may differ depending on whether substance dependence is comorbid with gambling problems. Method: 18 controls, 14 substance‐dependent individuals (SD), and 16 SD with gambling problems (SDPG) underwent fMRI while performing a modified version of the IGT. Result: Group differences were observed in ventral medial frontal, right frontopolar, and superior frontal cortex during decision‐making. Controls showed the greatest activity, followed by SDPG, followed by SD. Conclusion: Our results support a hypothesis that defects in ventral medial frontal processing lead to impaired decisions that involve risk. Reductions in right prefrontal activity during decision‐making appear to be modulated by the presence of gambling problems and may reflect impaired working memory, stimulus reward valuation, or cue reactivity in substance‐dependent individuals. Hum Brain Mapp, 2007.

Exposure to the Taste of Alcohol Elicits Activation of the Mesocorticolimbic Neurocircuitry

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems.

Marijuana craving in the brain

Craving is one of the primary behavioral components of drug addiction, and cue-elicited craving is an especially powerful form of this construct. While cue-elicited craving and its underlying neurobiological mechanisms have been extensively studied with respect to alcohol and other drugs of abuse, the same cannot be said for marijuana. Cue-elicited craving for other drugs of abuse is associated with increased activity in a number of brain areas, particularly the reward pathway. This study used functional magnetic resonance imaging (fMRI) to examine cue-elicited craving for marijuana. Thirty-eight regular marijuana users abstained from use for 72 h and were presented with tactile marijuana-related and neutral cues while undergoing a fMRI scan. Several structures in the reward pathway, including the ventral tegmental area, thalamus, anterior cingulate, insula, and amygdala, demonstrated greater blood oxygen level dependent (BOLD) activation in response to the marijuana cue as compared with the neutral cue. These regions underlie motivated behavior and the attribution of incentive salience. Activation of the orbitofrontal cortex and nucleus accumbens was also positively correlated with problems related to marijuana use, such that greater BOLD activation was associated with greater number of items on a marijuana problem scale. Thus, cue-elicited craving for marijuana activates the reward neurocircuitry associated with the neuropathology of addiction, and the magnitude of activation of these structures is associated with severity of cannabis-related problems. These findings may inform the development of treatment strategies for cannabis dependence.

A Study of the Influence of Sex on Genome Wide Methylation

Sex differences in methylation status have been observed in specific gene-disease studies and healthy methylation variation studies, but little work has been done to study the impact of sex on methylation at the genome wide locus-to-locus level or to determine methods for accounting for sex in genomic association studies. In this study we investigate the genomic sex effect on saliva DNA methylation of 197 subjects (54 females) using 20,493 CpG sites. Three methods, two-sample T-test, principle component analysis and independent component analysis, all successfully identify sex influences. The results show that sex not only influences the methylation of genes in the X chromosome but also in autosomes. 580 autosomal sites show strong differences between males and females. They are found to be highly involved in eight functional groups, including DNA transcription, RNA splicing, membrane, etc. Equally important is that we identify some methylation sites associated with not only sex, but also other phenotypes (age, smoking and drinking level, and cancer). Verification was done through an independent blood cell DNA methylation data (1298 CpG sites from a cancer panel array). The same genomic site-specific influence pattern and potential confounding effects with cancer were observed. The overlapping rate of identified sex affected genes between saliva and blood cell is 81% for X chromosome, and 8% for autosomes. Therefore, correction for sex is necessary. We propose a simple correction method based on independent component analysis, which is a data driven method and accommodates sample differences. Comparison before and after the correction suggests that the method is able to effectively remove the potentially confounding effects of sex, and leave other phenotypes untouched. As such, our method is able to disentangle the sex influence on a genome wide level, and paves the way to achieve more accurate association analyses in genome wide methylation studies.

The DRD4 VNTR Polymorphism Moderates Craving After Alcohol Consumption

Recent research has suggested that alterations in mesolimbic dopamine neurotransmission are central to the development and expression of craving for alcohol. Because the D4 dopamine receptor gene, variable numbers of tandem repeats (DRD4 VNTR) polymorphism putatively expresses functional differences in dopamine receptors, the present study tested whether this polymorphism influences the effects of a priming dose of alcohol on craving. Participants consumed 3 alcoholic drinks or 3 control drinks and completed measures of craving after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele were classified as DRD4 L, whereas the other participants were classified as DRD4 S. Results suggested that DRD4 L participants demonstrated significantly higher craving after consumption of alcohol as compared with the control beverage.

Population Stratification in the Candidate Gene Study: Fatal Threat or Red Herring?

Advances in molecular genetics have provided behavioral scientists with a means of investigating the influence of genetic factors on human behavior. Unfortunately, recent candidate gene studies have produced inconsistent results, and a frequent scapegoat for the lack of replication across studies is the threat of population stratification. This review of the literature on population stratification suggests that the threat may be a red herring. Reliable findings will require improved specification and measurement of the behavioral phenotypes in question, a renewed focus on internal validity, and the specification and testing of genetic factors in the context of longitudinal multivariate models. In this respect, behavioral scientists are well suited to investigating genetic factors that influence psychological mechanisms.

Differential neural response to alcohol priming and alcohol taste cues is associated with DRD4 VNTR and OPRM1 genotypes.

BACKGROUND Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, mu 1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown. METHODS Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined. RESULTS The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol (p < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use. CONCLUSIONS The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.

The DRD4 VNTR polymorphism influences reactivity to smoking cues

Recent research has indicated that craving for tobacco can be reliably elicited by exposure to smoking cues, suggesting that cue-elicited craving for tobacco may be a useful phenotype for research on genetic factors related to nicotine dependence. Given the potential role of dopamine in cue-elicited craving, the authors examined whether the DRD4 VNTR polymorphism is associated with cue-elicited craving for tobacco. Participants who were homozygous or heterozygous for the 7 repeat (or longer) allele were classified as DRD4 L, and all other participants were classified as DRD4 S. Participants were exposed to smoking cues before smoking either high-nicotine cigarettes or control cigarettes. Analyses suggested that participants in the L group demonstrated significantly greater craving, more arousal, less positive affect, and more attention to the smoking cues than did the participants in the S group.