Gianotti Lorena R R, Figner Bernd, Ebstein Richard P, Knoch Daria
Social and Affective Neuroscience, Department of Psychology, University of Basel Basel, Switzerland.
Front Neurosci. 2012 May 7;6:54. doi: 10.3389/fnins.2012.00054. eCollection 2012.
Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants' neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD.
个体在对未来奖励的折扣程度上差异很大。延迟折扣（DD）中这些稳定的个体差异的来源在很大程度上尚不清楚。一个可能的因素是儿茶酚-O-甲基转移酶（COMT）基因的Val158Met多态性，已知它可调节前额叶多巴胺水平并影响延迟折扣。为了确定这种多态性可能导致个体延迟折扣稳定差异的潜在神经机制，我们使用静息脑电图（EEG）测量了73名参与者的神经基线激活情况。这种神经基线激活测量具有高度遗传性且随时间稳定，因此是解释基因如何通过神经功能个体差异影响行为的理想内表型候选指标。在脑电图记录后，参与者做出了一系列与激励兼容的跨期选择，以确定他们延迟折扣的程度。我们发现COMT显著影响延迟折扣，并且这种影响是由左背外侧前额叶皮质（DPFC）的基线激活水平介导的：（i）COMT对延迟折扣有显著影响，使得Val等位基因的数量与更陡峭的延迟折扣呈正相关（Val等位基因数量越多意味着COMT活性越高，从而多巴胺水平越低）。（ii）全脑搜索在左DPFC中识别出一个簇，其中基线激活与延迟折扣相关；较低的激活与更陡峭的延迟折扣相关。（iii）COMT对这个左DPFC簇中的基线激活水平有显著影响，使得较高数量的Val等位基因与较低的基线激活相关。（iv）COMT对延迟折扣的影响是由左DPFC簇中神经基线激活的中介作用来解释的。因此，我们的研究确立了左DPFC中的基线激活水平作为一种显著的神经特征，以内表型的形式介导了COMT与延迟折扣之间的联系。
