A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional reactivity, and determining their predictive value for the development of frequent psychiatric disorders. Comprehensive behavioural and neuropsychological characterization, functional and structural neuroimaging and genome-wide association analyses of 2000 14-year-old adolescents are combined with functional genetics in animal and human models. Results will be validated in 1000 adolescents from the Canadian Saguenay Youth Study. The sample will be followed up longitudinally at the age of 16 years to investigate the predictive value of genetics and intermediate phenotypes for the development of frequent psychiatric disorders. This review describes the strategies the IMAGEN consortium used to meet the challenges posed by largescale multicentre imaging-genomics investigations. We provide detailed methods and Standard Operating Procedures that we hope will be helpful for the design of future studies. These include standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large-scale genetic neuroimaging analyses.

The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior.

Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.

Binge drinking is an increasingly recognized problem within the UK. We have studied the relationship of binge drinking to cognitive and emotional functioning in young adults, and have found evidence for increased impulsivity, impairments in spatial working memory and impaired emotional learning. Since in human studies it is difficult to understand whether such behavioural changes predate or are a consequence of binge drinking, we have also studied parallel behaviours in a rodent model, in which rats are exposed to intermittent episodes of alcohol consumption and withdrawal. In this model, and in parallel with our findings in human binge drinkers, and alcoholic patients who have undergone multiple episodes of detoxification, we have found evidence for impairments in aversive conditioning as well as increased impulsivity. These behavioural changes are accompanied by facilitated excitatory neurotransmission and reduced plasticity (long-term potentiation (LTP)) in amygdala and hippocampus. The impaired LTP is accompanied by both impaired associative learning and inappropriate generalization of previously learned associations to irrelevant stimuli. We propose that repeated episodes of withdrawal from alcohol induce aberrant neuronal plasticity that results in altered cognitive and emotional competences.

Because GABA A receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltageclamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABA A receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABA A receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABA A receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.GABRA2 | behavioral sensitization | nucleus accumbens | mutant mouse | human genetics

Alcoholic patients who have undergone multiple detoxifications/relapses show altered processing of emotional signals. We performed functional magnetic resonance imaging during performance of implicit and explicit versions of a task in which subjects were presented with morphs of fearful facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n=12) or singly detoxified patients (SDTx; n=17), and social drinker controls (n=31). Alcoholic patients were less able than controls to recognize fearful expressions, and showed lower activation in prefrontal areas, including orbitofrontal cortex and insula, which mediate emotional processing. The decrease in activation was greater in MDTx patients who also showed decreased connectivity between insula and prefrontal areas, and between amygdala and globus pallidus. In the explicit condition, the strength of connectivity between insula and areas involved in regulation of emotion (inferior frontal cortex and frontal pole) was negatively correlated with both the number of detoxifications and dependency (measured by the severity of alcohol dependency (SADQ) and control over drinking score (Impaired Control questionnaire, ICQ)). In contrast, increased connectivity was found between insula and the colliculus neuronal cluster, and between amygdala and stria terminalis bed nucleus. In the implicit condition, number of detoxifications and ICQ score correlated positively with connectivity between amygdala and prefrontal cortical areas involved in attentional and executive processes. Repeated episodes of detoxification from alcohol are associated with altered function both in fear perception pathways and in cortical modulation of emotions. Such changes may confer increased sensitivity to emotional stress and impaired social competence, contributing to relapse.

Repeated experience of withdrawal from alcohol is thus associated with impaired cognitive function although it appears that for some of these effects, other factors associated with the history of alcoholism might also be involved.

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