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Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans.

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.

SUBMITTER: Neufang S

PROVIDER: S-EPMC5314122 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans.

Neufang S S Akhrif A A Herrmann C G CG Drepper C C Homola G A GA Nowak J J Waider J J Schmitt A G AG Lesch K-P KP Romanos M M

Translational psychiatry 20161108 11

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 perfo ...[more]

PMID: 27824354

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Project description:RationaleImpulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is important for understanding the neural underpinnings of dysregulated impulsive behavior.MethodsUsing a mouse model for disordered impulsivity, our goal was to identify behavioral and cognitive processes that are associated with increased impulsivity. Specifically, we were interested in the facets of impulsivity modulated by serotonin signaling. We used mice lacking the serotonin 1B receptor (5-HT1BR) and measured different types of impulsivity as well as goal-directed responding, extinction, habitual-like behavior, cue reactivity, and reward reactivity.ResultsMice lacking expression of 5-HT1BR had increased levels of impulsive action, goal-directed responding, and motivation, with no differences seen in rate of extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression also showed an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more for cues that predict reward. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action may be a result of increased reward valuation.ConclusionsTaken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Overall, this data supports a role for reward value as an important substrate in impulsive action which may drive clinically relevant increases in impulsivity.

Project description:In general, the Hurst exponent. is used as a measure of long-term memory of time series. In previous neuroimaging studies, H has been introduced as one important parameter to define resting-state networks, reflecting upon global scale-free properties emerging from a network. H has been examined in the waiting impulsivity (WI) network in an earlier study. We found that alterations of H in the anterior cingulate cortex (H A C C ) and the nucleus accumbens (H N A c c ) were lower in high impulsive (highIMP) compared to low impulsive (lowIMP) participants. Following up on those findings, we addressed the relation between altered fractality in H A C C and H N A c c and brain activation and neural network connectivity. To do so, brain activation maps were calculated, and network connectivity was determined using the Dynamic Causal Modeling (DCM) approach. Finally, 1-H scores were determined to quantify the alterations of H. This way, the focus of the analyses was placed on the potential effects of alterations of H on neural network activation and connectivity. Correlation analyses between the alterations of H A C C /H N A c c and activation maps and DCM estimates were performed. We found that the alterations of H predominantly correlated with fronto-hippocampal pathways and correlations were significant only in highIMP subjects. For example, alterations of H A C C was associated with a decrease in neural activation in the right HC in combination with increased ACC-hippocampal connectivity. Alteration inH N A c c , in return, was related to an increase in bilateral prefrontal activation in combination with increased fronto-hippocampal connectivity. The findings, that the WI network was related to H alteration in highIMP subjects indicated that impulse control was not reduced per se but lacked consistency. Additionally, H has been used to describe long-term memory processes before, e.g., in capital markets, energy future prices, and human memory. Thus, current findings supported the relation of H toward memory processing even when further prominent cognitive functions were involved.

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Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans.

Publications

Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans.

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