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Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa.

ABSTRACT: Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.

SUBMITTER: Pearson-Fuhrhop KM

PROVIDER: S-EPMC3629211 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa.

Pearson-Fuhrhop Kristin M KM Minton Brian B Acevedo Daniel D Shahbaba Babak B Cramer Steven C SC

PloS one 20130417 4

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, doub ...[more]

PMID: 23613810

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Project description:The addition of rewarding feedback to motor learning tasks has been shown to increase the retention of learning, spurring interest in its possible utility for rehabilitation. However, motor tasks using rewarding feedback have repeatedly been shown to lead to great interindividual variability in performance. Understanding the causes of such variability is vital for maximizing the potential benefits of reward-based motor learning. Thus, using a large human cohort of both sexes (n = 241), we examined whether spatial (SWM), verbal, and mental rotation (RWM) working memory capacity and dopamine-related genetic profiles were associated with performance in two reward-based motor tasks. The first task assessed the participant's ability to follow a slowly shifting reward region based on hit/miss (binary) feedback. The second task investigated the participant's capacity to preserve performance with binary feedback after adapting to the rotation with full visual feedback. Our results demonstrate that higher SWM is associated with greater success and an enhanced capacity to reproduce a successful motor action, measured as change in reach angle following reward. In contrast, higher RWM was predictive of an increased propensity to express an explicit strategy when required to make large reach angle adjustments. Therefore, SWM and RWM were reliable, but dissociable, predictors of success during reward-based motor learning. Change in reach direction following failure was also a strong predictor of success rate, although we observed no consistent relationship with working memory. Surprisingly, no dopamine-related genotypes predicted performance. Therefore, working memory capacity plays a pivotal role in determining individual ability in reward-based motor learning.SIGNIFICANCE STATEMENT Reward-based motor learning tasks have repeatedly been shown to lead to idiosyncratic behaviors that cause varying degrees of task success. Yet, the factors determining an individual's capacity to use reward-based feedback are unclear. Here, we assessed a wide range of possible candidate predictors, and demonstrate that domain-specific working memory plays an essential role in determining individual capacity to use reward-based feedback. Surprisingly, genetic variations in dopamine availability were not found to play a role. This is in stark contrast with seminal work in the reinforcement and decision-making literature, which show strong and replicated effects of the same dopaminergic genes in decision-making. Therefore, our results provide novel insights into reward-based motor learning, highlighting a key role for domain-specific working memory capacity.

Dataset Information

Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa.

Publications

Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa.

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