The potential of neuroimaging for identifying predictors of adolescent alcohol use initiation and misuse.

BACKGROUND AND AIMS: Dysfunction in brain regions underlying impulse control, reward processing and executive function have been associated previously with adolescent alcohol misuse. However, identifying pre-existing neurobiological risk factors, as distinct from changes arising from early alcohol-use, is difficult. Here, we outline how neuroimaging data can identify the neural predictors of adolescent alcohol-use initiation and misuse by using prospective longitudinal studies to follow initially alcohol-naive individuals over time and by neuroimaging adolescents with inherited risk factors for alcohol misuse. METHOD: A comprehensive narrative of the literature regarding neuroimaging studies published between 2010 and 2016 focusing on predictors of adolescent alcohol use initiation and misuse. FINDINGS: Prospective, longitudinal neuroimaging studies have identified pre-existing differences between adolescents who remained alcohol-naive and those who transitioned subsequently to alcohol use. Both functional and structural grey matter differences were observed in temporal and frontal regions, including reduced brain activity in the superior frontal gyrus and temporal lobe, and thinner temporal cortices of future alcohol users. Interactions between brain function and genetic predispositions have been identified, including significant association found between the Ras protein-specific guanine nucleotide releasing factor 2 (RASGRF2) gene and reward-related striatal functioning. CONCLUSIONS: Neuroimaging predictors of alcohol use have shown modest utility to date. Future research should use out-of-sample performance as a quantitative measure of a predictor's utility. Neuroimaging data should be combined across multiple modalities, including structural information such as volumetrics and cortical thickness, in conjunction with white-matter tractography. A number of relevant neurocognitive systems should be assayed; particularly, inhibitory control, reward processing and executive functioning. Combining a rich magnetic resonance imaging data set could permit the generation of neuroimaging risk scores, which could potentially yield targeted interventions.

Grit Is Associated with Structure of Nucleus Accumbens and Gains in Cognitive Training.

There is a long-standing interest in the determinants of successful learning in children. "Grit" is an individual trait, reflecting the ability to pursue long-term goals despite temporary setbacks. Although grit is known to be predictive of future success in real-world learning situations, an understanding of the underlying neural basis and mechanisms is still lacking. Here we show that grit in a sample of 6-year-old children (n = 55) predicts the working memory improvement during 8 weeks of training on working memory tasks (p = .009). In a separate neuroimaging analysis performed on a partially overlapping sample (n = 27), we show that interindividual differences in grit were associated with differences in the volume of nucleus accumbens (peak voxel p = .021, x = 12, y = 11, z = -11). This was also confirmed in a leave-one-out analysis of gray matter density in the nucleus accumbens (p = .018). The results can be related to previous animal research showing the role of the nucleus accumbens to search out rewards regardless of delays or obstacles. The results provide a putative neural basis for grit and could contribute a cross-disciplinary connection of animal neuroscience to child psychology.

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males.

BACKGROUND: The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.

Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis.

OBJECTIVE: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. METHOD: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. RESULTS: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. CONCLUSIONS: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance.

Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13-15 years) and BrainChild (n∼300, age 6-27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.

Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in reward sensitivity and response inhibition. The relative contribution of these frontostriatal mechanisms to ADHD symptoms and their genetic determinants is largely unexplored. METHODS: Using functional magnetic resonance imaging and genetic analysis of the monoamine oxidase A (MAOA) gene, we investigated how striatal and inferior frontal activation patterns contribute to ADHD symptoms depending on MAOA genotype in a sample of adolescent boys (n = 190). RESULTS: We demonstrate an association of ADHD symptoms with distinct blood oxygen level-dependent (BOLD) responses depending on MAOA genotype. In A hemizygotes of the expression single nucleotide polymorphism rs12843268, which express lower levels of MAOA, ADHD symptoms are associated with lower ventral striatal BOLD response during the monetary incentive delay task and lower inferior frontal gyrus BOLD response during the stop signal task. In G hemizygotes, ADHD symptoms are associated with increased inferior frontal gyrus BOLD response during the stop signal task in the presence of increased ventral striatal BOLD response during the monetary incentive delay task. CONCLUSIONS: Depending on MAOA genotype, ADHD symptoms in adolescent boys are associated with either reward deficiency or insufficient response inhibition. Apart from its mechanistic interest, our finding may aid in developing pharmacogenetic markers for ADHD.

Analytical strategies for large imaging genetic datasets: experiences from the IMAGEN study.

Large imaging genetic studies are becoming increasingly common in psychiatric research. In order to fully explore the collected information, analytical strategies that allow comprehensive investigations of the genetic and neural underpinnings of psychiatric disorders are needed. On the basis of our experience with the IMAGEN study, this review evaluates univariate and multivariate analytical strategies for exploring large imaging genetic datasets, with particular focus on reinforcement mechanisms in adolescents. Heritability estimates of functional and structural MRI endophenotypes are presented along with analytical strategies, ranging from those used in univariate candidate gene studies to genome-wide association studies. Finally, data reduction strategies are discussed at both the genotype level, in the form of expression SNPs and pathway analyses, and the phenotype level, as network analyses of neuroimaging data. Overall, imaging genetic studies have the potential to significantly contribute to our understanding of neurophysiological processes underlying human behavior. The analytical strategies presented here may aid in the comprehensive investigation of reinforcement and other neurobehavioral phenotypes.

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

The responsiveness of biological motion processing areas to selective attention towards goals.

A growing literature indicates that visual cortex areas viewed as primarily responsive to exogenous stimuli are susceptible to top-down modulation by selective attention. The present study examines whether brain areas involved in biological motion perception are among these areas-particularly with respect to selective attention towards human movement goals. Fifteen participants completed a point-light biological motion study following a two-by-two factorial design, with one factor representing an exogenous manipulation of human movement goals (goal-directed versus random movement), and the other an endogenous manipulation (a goal identification task versus an ancillary color-change task). Both manipulations yielded increased activation in the human homologue of motion-sensitive area MT+ (hMT+) as well as the extrastriate body area (EBA). The endogenous manipulation was associated with increased right posterior superior temporal sulcus (STS) activation, whereas the exogenous manipulation was associated with increased activation in left posterior STS. Selective attention towards goals activated a portion of left hMT+/EBA only during the perception of purposeful movement-consistent with emerging theories associating this area with the matching of visual motion input to known goal-directed actions. The overall pattern of results indicates that attention towards the goals of human movement activates biological motion areas. Ultimately, selective attention may explain why some studies examining biological motion show activation in hMT+ and EBA, even when using control stimuli with comparable motion properties.

Genetic and environmental determinants of stress responding.

The risk for alcohol dependence throughout development is determined by both genetic and environmental factors. Genetic factors that are thought to modulate this risk act on neurobiological pathways regulating reward, impulsivity, and stress responses. For example, genetic variations in pathways using the brain signaling molecule (i.e., neurotransmitter) dopamine, which likely mediate alcohol's rewarding effects, and in two hormonal systems involved in the stress response (i.e., the hypothalamic-pituitary-adrenal axis and the corticotropin-releasing factor system) affect alcoholism risk. This liability is modified further by exposure to environmental risk factors, such as environmental stress and alcohol use itself, and the effects of these factors may be enhanced in genetically vulnerable individuals. The transition from alcohol use to dependence is the result of complex interactions of genes, environment, and neurobiology, which fluctuate throughout development. Therefore, the relevant genetic and environmental risk factors may differ during the different stages of alcohol initiation, abuse, and dependence. The complex interaction of these factors is yet to be fully elucidated, and translational studies, ranging from animal studies to research in humans, and well-characterized longitudinal studies are necessary to further understand the development of alcohol dependence.

Biological motion task performance predicts superior temporal sulcus activity.

Numerous studies implicate superior temporal sulcus (STS) in the perception of human movement. More recent theories hold that STS is also involved in the understanding of human movement. However, almost no studies to date have associated STS function with observable variability in action understanding. The present study directly associated STS activity with performance on a challenging task requiring the interpretation of human movement. During functional MRI scanning, fourteen adults were asked to identify the direction (left or right) in which either a point-light walking figure or spinning wheel were moving. The task was made challenging by perturbing the dot trajectories to a level (determined via pretesting) where each participant achieved 72% accuracy. The walking figure condition was associated with increased activity in a constellation of social information processing and biological motion areas, including STS, MT+/V5, right pars opercularis (inferior frontal gyrus), fusiform gyrus, and amygdala. Correctly answered walking figure trials were uniquely associated with increased activity in two right hemisphere STS clusters and right amygdala. Present findings provide some of the strongest evidence to date that STS plays a critical role in the successful interpretation of human movement.

Summaries from the XVIII World Congress of Psychiatric Genetics, Athens, Greece, 3-7 October 2010.

The XVIIIth World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics took place in Athens, Greece on October 3-7, 2010. Approximately 950 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by junior travel awardees, as well as others who were volunteers from student meeting attendees. Each was assigned sessions as rapporteurs. This report represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2010 World Congress of Psychiatric Genetics.