Investigating the causal nature of the relationship of subcortical brain volume with smoking and alcohol use.

BACKGROUND: Structural variation in subcortical brain regions has been linked to substance use, including the most commonly used substances nicotine and alcohol. Pre-existing differences in subcortical brain volume may affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. AIMS: We assess the causal nature of the complex relationship of subcortical brain volume with smoking and alcohol use, using bi-directional Mendelian randomisation. METHOD: Mendelian randomisation uses genetic variants predictive of a certain 'exposure' as instrumental variables to test causal effects on an 'outcome'. Because of random assortment at meiosis, genetic variants should not be associated with confounders, allowing less biased causal inference. We used summary-level data of genome-wide association studies of subcortical brain volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus; n = 50 290) and smoking and alcohol use (smoking initiation, n = 848 460; cigarettes per day, n = 216 590; smoking cessation, n = 378 249; alcoholic drinks per week, n = 630 154; alcohol dependence, n = 46 568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. RESULTS: There was strong evidence that liability to alcohol dependence decreased amygdala and hippocampal volume, and smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. CONCLUSIONS: Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and likely mental health, warranting more recognition in public health efforts.

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

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.

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

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.

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics.

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

OBJECTIVE: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. METHOD: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. RESULTS: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. CONCLUSIONS: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Fronto-striatal dysregulation in drug addiction and pathological gambling: Consistent inconsistencies?

Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a 'toxicity free' addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.

Physiological and endocrine reactions to psychosocial stress in alcohol use disorders: duration of abstinence matters.

BACKGROUND: Recent research findings suggest that heavy alcohol use is associated with alterations of the hypothalamic-pituitary-adrenal axis and autonomic nervous system function and that early abstinence is associated with blunted stress responsiveness. METHODS: This study investigated abstinent alcohol-dependent participants (AADs; n = 31), who had a drinking history of levels about 97 drinks per week (abstinence range: 2 weeks to 24 months), actively drinking problem drinkers (PRDs; n = 23), who reported drinking levels about 47 drinks per week and who were abstinent for at least 24 hours, and healthy control (HC) participants (n = 20). It was investigated how participants responded to a psychosocial stress task. All of them were exposed to a modified Trier Social Stress Test. Salivary cortisol, heart rate, skin conductance levels, and negative affect were assessed as stress indicators. RESULTS: AADs showed stress reactions comparable to HC participants, whereas active PRDs showed increased heart rate and cortisol stress responses. In the AAD group, duration of abstinence was positively related to cortisol stress responses. CONCLUSIONS: Active PRDs showed increased responses to psychosocial stress. Results indicate that duration of abstinence is a key factor when analyzing and interpreting stress responses in alcohol abuse and dependence.

A voxel-based morphometry study comparing problem gamblers, alcohol abusers, and healthy controls.

BACKGROUND: Alcohol use disorders (AUDs) are associated with smaller grey matter volumes in cortical and subcortical brain regions which are related to cognitive impairments often found in these disorders. Similar cognitive impairments have been found in patients suffering from problem gambling behaviour. However, in contrast to AUDs, gambling behaviour does not entail brain exposure to toxic agents. Although there are many clinical, neuropsychological, and neurobiological similarities between PG and substance use disorders it has not yet been established whether pathological gambling, similar to alcohol use disorders, is associated with abnormal regional grey matter volumes. METHODS: With whole-brain voxel-based morphometry we compared a group of 40 treatment seeking problem gamblers, 36 subjects with an alcohol use disorder, and 54 healthy controls to evaluate potential group differences in regional grey matter volumes, corrected for age, IQ, smoking status, and total intracranial volume (TIV). RESULTS: Significantly smaller grey matter volumes in left superior frontal cortex, left precentral cortex, right insula, right putamen, left thalamus, bilateral superior parietal cortex and right supramarginal cortex were present in subjects with an alcohol use disorder compared to healthy controls and problem gamblers. No significant grey matter volume differences were present between problem gamblers and healthy controls. CONCLUSION: In conclusion, we replicated previous findings of smaller grey matter volumes in subjects with an alcohol use disorder and found no significant morphological brain abnormalities in problem gamblers.

Drug-related decrease in neuropsychological functions of abstinent drug users.

This article reviews neuropsychological performance in frequent users of cocaine, (meth)amphetamines, ecstasy, opiates, alcohol, and cannabis. We searched the scientific literature published in the last five years, focusing on studies that required at least 2 weeks of abstinence from drug use, and included a control group. All substances of abuse, except cannabis, were associated with sustained deficits in executive functioning, especially inhibition. In addition, verbal memory decrements were consistently found in cocaine, (meth)amphetamines and ecstasy users, but not in heroin or cannabis users. More specific executive functioning deficits were reported depending on the substance of abuse. Cocaine was associated with diminished cognitive flexibility, whereas (meth)amphetamines were associated with worse cognitive planning functions compared to controls. Opiate studies showed lower scores on verbal fluency in opiate dependent subjects compared to controls. Working memory and visuospatial abilities were compromised in alcohol abusers. In ecstasy users, inconsistent findings have been reported across neuropsychological domains, with the exception of inhibition and verbal memory. There was little evidence for sustained cognitive impairments in adult abstinent cannabis users. Recognition of neuropsychological problems related to different substances can help to select subjects that will benefit most from treatment. Furthermore, a better understanding of the neuropsychological impairments in drug abusing individuals could help to explain the remitting course of substance abuse disorders and to improve psychological interventions.