Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.Significance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

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.

In this review, we detail the clinical evidence supporting the role of psychological and physiological stress in instrumental motivation for alcohol consumption during the development of mild to moderate alcohol use disorders (AUDs) and in the compulsive, habitual alcohol consumption seen in severe, chronic, relapsing AUDs. Traditionally, the study of AUDs has focused on the direct and indirect effects of alcohol on striatal dopaminergic pathways and their role in the reinforcing effects of alcohol. However, growing evidence also suggests that alcohol directly stimulates the hypothalamic pituitary adrenal (HPA) axis and has effects on glucocorticoid receptors in extrahypothalamic, limbic forebrain, and medial Prefrontal Cortex (PFC) circuits, which contribute to the development of AUDs and their progression in severity, chronicity, and relapse risk. Evidence indicates HPA axis, glucocorticoid, and PFC dysfunction during protracted withdrawal and under high arousal conditions in those with severe AUDs, and novel evidence is also emerging to suggest HPA axis dysfunction with binge/heavy drinking, which is associated with motivation for alcohol in non-dependent individuals. Specifically, alcohol-associated alterations in HPA axis responses to stress and alcohol cues may serve as interoceptive physiological signals and facilitate conditioning mechanisms to influence alcohol motivation. Thus, this dysfunction may serve as a potential biomarker of both risk and of relapse. Based on this emerging data, we conceptualize and present early evidence for treatment targets that may improve PFC function and/or normalize HPA axis functioning and may be beneficial in the treatment and relapse prevention of AUDs. Finally, we suggest that individual differences in alcohol-related pathophysiology in these circuits may modulate treatment and recovery response, thereby supporting the need for building personalized medicine algorithms to understand and treat AUDs.

Enhanced motivational salience towards smoking cues is a consequence of chronic nicotine use, but the degree to which this value increases beyond that of other appetitive cues is unknown. In addition, it is unclear how connectivity between brain regions influences cue reactivity and how cue reactivity and functional connectivity are related to nicotine dependence severity. This study examined neural responses during the presentation of smoking cues and appetitive control cues, as well as functional connectivity in 116 smokers with a range of nicotine dependence severity. Smoking cues elicited greater response above baseline than food cues in orbitofrontal cortex (OFC) and supplementary motor area (SMA) and less deactivation below baseline in middle frontal gyrus, inferior parietal lobe, and middle temporal gyrus. Psychophysiological interaction (PPI) analysis using right OFC as a seed revealed increased connectivity with somatosensory cortex and lateral inferior parietal lobe during smoking cues compared with food cues. Similarly, a PPI analysis using left insula as a seed showed stronger connectivity with somatosensory cortex, right insula, OFC, and striatum. Finally, relationships with nicotine dependence scores showed enhanced response in insula and dorsal anterior cingulate cortex in the smoking vs food comparison, and increased connectivity between insula and circuits involved in motivated behavior. Combined, these results suggest that smokers engage attentional networks and default mode networks involved in self-referential processing to a greater degree during smoking cues. In addition, individuals with greater nicotine dependence severity show increased engagement of sensorimotor and motor preparation circuits, suggesting increased reliance on habitual behavior.

Alcohol use disorders are associated with high craving and disruption of stress biology, but their role in behavioral alcohol motivation is less clear. We examined the effects of craving and cortisol responses on behavioral alcohol motivation to stress, alcohol cue and neutral-relaxing context cues, in addition to discrete alcohol cues, in demographically matched binge/heavy (BH) and moderate (MD) social drinkers. Subjects participated in a 3-day laboratory experiment of provocation by three personalized guided imagery contexts and discrete alcohol cues followed by the 'alcohol taste test' (ATT) to assess behavioral motivation, as measured by ATT intake. Post-ATT alcohol effects on craving and cortisol responses were also examined. Results indicate BH consumed significantly more alcohol than MD in the ATT. Stress and alcohol cue contexts, relative to neutral, led to significantly greater ATT intake across both groups, which also correlated positively with self-reported alcohol use in past 30 days. Stress and alcohol context and discrete alcohol cues each significantly increased alcohol craving, more so in the BH than MD, and significantly predicted greater ATT intake in BH only. The BH showed significantly lower cortisol responses than MD overall and blunted cortisol responses to cues predicted significantly greater ATT intake in the stress condition for BH and in the alcohol cue condition for MD. Higher ATT intake predicted greater cortisol response and higher craving post-ATT, and these effects were moderated by group status. In sum, findings suggest a role for sensitized context-induced craving and blunted cortisol responses in increased behavioral motivation for alcohol.

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 multina

Previous research has shown that hyperactivation in ventral medial prefrontal cortex (VmPFC) and rostral anterior cingulate cortex (rACC) and high cortisol to corticotrophin ratio (cort:ACTH ratio) during neutral-relaxed states predict relapse in alcohol dependent (AD) patients. Other studies have shown that VmPFC/rACC deactivation and blunted cortisol release to stress and alcohol cues are predictive of time to relapse and relapse severity. However, no previous study has assessed the relationship between these markers of central and peripheral nervous system dysfunction in AD participants and their potential joint effects on relapse risk. Forty early abstinent, treatment engaged AD patients underwent a laboratory experiment with exposure to neutral, alcohol, and stress cues and a separate functional magnetic resonance imaging (fMRI) scan with similar cue exposure. Neutral-relaxed state cort:ACTH ratio was significantly associated with VmPFC hyperreactivity to neutral-relaxing cues, and also with hypoactivation in response to alcohol and stress cues in AD patients. Basal heart rate, neutral cort:ACTH ratio, and neutral VmPFC hyperreactivty were each associated with risk of relapse. However, abnormal VmPFC activation and elevated cort:ACTH ratio overlap in predicting risk for relapse, and dysfunctional VmPFC response was the sole significant predictor of odds of relapse in a joint model of relapse risk. These findings suggest that the Cort:ACTH ratio may serve as a peripheral marker of VmPFC brain dysfunction while aberrant VmPFC responses needs further evaluation as a potential biomarker of alcohol relapse risk in clinical outcome studies.

The corticotropin-releasing hormone type I receptor (CRHR1) gene has been implicated in the liability for neuropsychiatric disorders, particularly under conditions of stress. Based on the hypothesized effects of CRHR1 variation on stress reactivity, measures of adulthood traumatic stress exposure were analyzed for their interaction with CRHR1 haplotypes and SNPs in predicting the risk for alcoholism. Phenotypic data on 2,533 non-related Caucasian individuals (1167 alcoholics and 1366 controls) were culled from the publically available Study of Addiction: Genetics and Environment (SAGE) genome-wide association study (GWAS). Genotypes were available for 19 tag SNPs. Logistic regression models examined the interaction between CRHR1 haplotypes / SNPs and adulthood traumatic stress exposure in predicting alcoholism risk. Two haplotype blocks spanned CRHR1. Haplotype analyses identified one haplotype in the proximal block 1 (p = 0.029) and two haplotypes in the distal block 2 (p = 0.026, 0.042) that showed nominally significant (corrected p < .025) genotype × traumatic stress interactive effects on the likelihood of developing alcoholism. The block 1 haplotype effect was driven by SNPs rs110402 (p = 0.019) and rs242924 (p = 0.019). In block 2, rs17689966 (p = 0.018) showed significant, and rs173365 (p = 0.026) showed nominally significant, gene × environment (G × E) effects on alcoholism status. This study extends the literature on the interplay between CRHR1 variation and alcoholism, in the context of exposure to traumatic stress. These findings are consistent with the hypothesized role of the extra hypothalamic CRF system dysregulation in the initiation and maintenance of alcoholism. Molecular and experimental studies are needed to more fully understand the mechanisms of risk and protection conferred by genetic variation at the identified loci.