Abstract
In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
Highlights
Waiting impulsivity (WI), compared with common impulsivity measures such as motor response inhibition,[1] delay discounting[2] and reflection impulsivity,[3] is defined operationally as the tendency to premature responding, that is, to respond before target onset
In a 2 × 2 × 4 repeated measure analysis of variance (ANOVA) addressing genotypeby-impulsivity by condition-specific modulation interactions, we found a significant condition by tryptophan hydroxylase-2 (TPH2) genotype-by-impulsivity interaction the way that target-specific modulation emerging from the nucleus accumbens (NAcc) and heading towards the ventromedial prefrontal cortex (vmPFC) (NAcc → vmPFC) was significantly enhanced in high impulsive T allele carriers: whereas in the low impulsive subjects, no TPH2 effect was significant, target-specific modulation of the vmPFC by the NAcc was significantly higher in the high impulsive T allele carriers compared with the high impulsive GG homozygotes
Performing effective connectivity, we focused on the interplay between the vmPFC and NAcc, and found inhibition-related and rewardspecific alterations in the vmPFC and NAcc
Summary
Waiting impulsivity (WI), compared with common impulsivity measures such as motor response inhibition,[1] delay discounting[2] and reflection impulsivity,[3] is defined operationally as the tendency to premature responding, that is, to respond before target onset. The first finding has been discussed to presumably reflect increasing top-down control demands over waiting time[14] and the second finding being associated with the processing of reward.[14,15] Highly impulsive rats (animals with high number of premature responses) showed reduced activity during the waiting period[16] predominantly in the vmPFC, hinting towards an impaired top-down control in highly impulsive animals. The relation between activity in the vmPFC and premature responding has been demonstrated in a lesion study by Christakou et al Disconnection of the vmPFC and the NAcc led to increased impulsive behavior.[17] In pharmacological studies, the transient inactivation of the vmPFC by injection of the γaminobutyric acid receptor agonist led to the dose-specific effects on behavioral performance, whereas low doses impaired impulse control indicated by heightened premature responding, high doses of muscimol induced deficits in impulse and attentional control in 5-CSRTT performance.[18,19,20] The pharmacological inactivation of the NAcc, in return, impaired general task performance in terms of impulse control deficits (accuracy) and severe general. Whereas the NAcc may have a relevant role in the prevention of premature response during anticipation of reward.[18,19,20]
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