Lesage Elise, Aronson Sarah E, Sutherland Matthew T, Ross Thomas J, Salmeron Betty Jo, Stein Elliot A
Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland.
Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland2School of Medicine, University of Maryland, Baltimore.
JAMA Psychiatry. 2017 Jun 1;74(6):632-640. doi: 10.1001/jamapsychiatry.2017.0400.
Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment.
To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task.
DESIGN, SETTING, AND PARTICIPANTS: Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016.
A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility.
The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline.
There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others.
clinicaltrials.gov Identifier: NCT00830739.
尼古丁戒断是导致吸烟复发的一个重要因素。了解基于奖励的决策如何受到戒烟以及尼古丁替代疗法和酒石酸伐尼克兰等药物疗法的影响，可能有助于戒烟治疗。
在概率性反转学习任务中，独立评估尼古丁依赖和烟碱型乙酰胆碱受体刺激对解读效价信息（奖励敏感性）能力的影响，以及随后随着奖励偶然性变化而改变行为（认知灵活性）的能力。
设计、设置和参与者：尼古丁依赖吸烟者和非吸烟者于2009年1月21日至2011年9月29日，在一项双药、双盲、安慰剂对照交叉设计中，于功能磁共振成像（fMRI）采集期间完成了概率性反转学习任务。所有实验环节中，吸烟者均已戒烟12小时。两组参与者均以完全拉丁方设计，在接受酒石酸伐尼克兰时进行两次MRI检查，在接受安慰剂药丸时进行两次MRI检查，同时佩戴尼古丁或安慰剂贴片。成像分析于2015年6月15日至2016年8月10日进行。
一个成熟的计算模型捕捉了吸烟状态以及尼古丁和酒石酸伐尼克兰给药对概率性反转学习选择行为的影响。在捕捉奖励敏感性和认知灵活性的MRI对比中，测试了吸烟状态、尼古丁和酒石酸伐尼克兰的神经效应。
该研究纳入了24名尼古丁依赖吸烟者（12名女性和12名男性；平均[标准差]年龄，35.8[9.9]岁）和20名非吸烟者（10名女性和10名男性；平均[标准差]年龄，30.4[7.2]岁）。计算模型表明，戒烟的吸烟者倾向于反应转换，并且他们的决策对现有证据不太敏感，这表明戒断期间冲动性增加。尼古丁和酒石酸伐尼克兰减轻了这些行为障碍。同样，在烟碱型乙酰胆碱受体刺激后，与戒烟吸烟者认知灵活性相关的中脑边缘叶活动降低恢复到了非吸烟者的水平（家族性错误校正P < .05）。相反，尼古丁或酒石酸伐尼克兰并未减轻吸烟者（与非吸烟者相比；家族性错误校正P < .05）背侧纹状体和前扣带回皮质中奖励敏感性降低的神经特征。
慢性尼古丁依赖对奖励敏感性神经表征的影响与烟碱型乙酰胆碱受体刺激对吸烟者认知灵活性的行为和神经特征的急性影响之间存在双重分离。这些慢性和急性药理作用在重叠的中脑边缘叶区域中观察到，这表明现有的药物疗法可能会减轻某些心理计算中同一神经回路的缺陷，但对其他缺陷则无效。
clinicaltrials.gov标识符：NCT00830739。
