Publications (23) View all
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Article: From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits.
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ABSTRACT: Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.European Journal of Neuroscience 04/2013; · 3.63 Impact Factor -
Article: RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.
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ABSTRACT: 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.Proceedings of the National Academy of Sciences 12/2012; · 9.68 Impact Factor -
Dataset: Grosshans Arch Gen Psychiatry 69 2012 May
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Article: A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?
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ABSTRACT: Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.Experimental Brain Research 11/2012; 223(3):429-439. · 2.39 Impact Factor -
Article: Brain networks subserving fixed versus performance-adjusted delay stop trials in a stop signal task.
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ABSTRACT: The stop signal task is a widely used tool for assessing inhibitory motor control. Two main task variants exist: (1) a fixed delay version, where all volunteers complete the same trials, resulting in performance differences due to individual variation in inhibitory capacity, and (2) a performance-adjusted version that uses a tracking algorithm to equate performance and task difficulty across subjects, leading to ∼50% successful inhibition for every participant. Our aim was to investigate commonalities, mean differences and between-subject variability in brain activation for successful response inhibition between the performance-adjusted and fixed delay version. We conducted a functional magnetic resonance imaging (fMRI) study in 18 healthy individuals, using a within-subject, within-task design where both adjusting and fixed delay trials were analysed separately. Conjunction analyses identified a network of areas involved in successful response inhibition in both task versions. In comparing the fixed and performance-adjusted versions, we found no significant differences between delay conditions during successful inhibition. While activation measures in the inhibitory networks of both delay variants were highly comparable, the neural responses to fixed delay trials were more variable across participants. This suggests that performance-adjusted stop signal tasks may be more suitable for studies in which the performance differences need to be controlled for, such as for developmental or clinical studies. Fixed delay stop signal tasks may be more appropriate in studies assessing the neural basis of individual differences in performance, such as studies of personality traits or genetic associations.Behavioural brain research 07/2012; 235(1):89-97. · 3.22 Impact Factor
