途径偏向矫正训练对药物成瘾相关线索反应的调节

研究目的:通过针对"相关线索-习惯性用药行为"联结的消退训练,降低渴求感,建立新联结,达到减弱或消退成瘾记忆的目的。探索以"动作消退动作"的方法对成瘾动作记忆进行消退的效果和可行性。方法:采用途径偏向矫正方法对28名男性药物成瘾者开展为期4周的训练。训练前后,分别测试渴求感、生理指标、途径偏向效应和Addiction-stroop task的干扰效应量,比较训练前后的指标变化,了解训练的效果。结果:训练组和对照组在训练前后的途径偏向效应没有显著的组间和交互效应,但训练组在训练前后途径偏向效应发生变化,趋向显著性,t=1.26,p=0.071。渴求感在训练组显著降低:t=1.38,p=0.05。Stroop的反应时间呈训练时间主效应:t=4.18,p=0.04。结论:途径偏向矫正消退训练可以改善成瘾者的途径偏向效应和渴求感状况,预示着通过身体动作建立"相关线索-拒绝用药行为"联结替代原有的"相关线索-自动化用药行为"联结,降低渴求感,减弱或消退成瘾记忆是有可能的。未来的研究需要采用更为精确的影像手段进行测试,验证基于动作认知的成瘾记忆消退训练的有效性。     

不同药物相关线索反应下感觉-运动脑区的激活及作用

药物相关线索反应不仅表现在心理渴求, 也表现在强迫性用药行为上。相关线索下, 除包括奖赏环路在内的边缘系统被激活外, 感觉-运动脑区也被激活, 引发自动化动作图式的表达, 这对相关线索反应及复吸行为具有特殊的意义。是否所有相关线索都会激活感觉-运动脑区, 目前, 还不清楚, 而这对临床治疗具有重要意义。本研究采用磁共振扫描, 生理测试等方法探索了不同类型相关线索下, 海洛因成瘾戒断者的大脑激活状况, 试图了解他们在不同线索刺激下的大脑反应。采用组内实验设计, 测量29名海洛因成瘾者相关线索反应下的血氧水平。结果发现, 相比对照线索, 所有药物相关线索, 包括药物、用药工具、用药动作线索都更多激活扣带回、海马、舌回、梭回等与奖赏机制相关的脑区; 而不同类型的药物相关线索之间的比较则显示, 用药工具和用药动作线索更多激活了双侧颞中回、双侧顶下小叶、左侧顶上小叶和右侧额下回等感觉-运动脑区。用药动作线索比单纯药物和用药工具线索, 激活了更为广泛的动作脑区。由此, 我们认为药物相关线索导致成瘾者大脑中奖赏和感觉-动作两套系统被激活, 包含用药工具、用药动作在内的相关线索会激活更多的感觉-运动脑区。     

感知觉-运动系统在药物相关线索反应中的作用及神经机制

药物相关线索反应是成瘾行为的重要标志,它直接导致心理渴求和强迫性的刺激-反应式自动化用药行为。其神经机制是包含了经典和操作条件反射的联结学习。在联结过程中,除奖赏系统外,感觉-动作系统在相关线索反应中也起到了重要作用。其机理可能是与感觉运动脑区部分重合的镜像神经的理解、分析和推测动作意图目的以及内隐模仿的功能有关。另外,动作记忆的形成及功能也可能在这种自动化动作图式的形成中起到了重要的作用。其确切的机制需要进一步研究证据。     

药物成瘾者相关线索反应的自动化用药行为特征及其消退

采用ERP技术考察海洛因成瘾者相关线索下的用药行为的性质和神经机制, 在此基础上结合虚拟现实技术(VR)和途径偏向矫正训练(AAT), 探究基于“相关线索-习惯性用药”联结的自动化用药行为的动作消退、替代训练的有效性。研究发现, (1)相比对照线索, 成瘾者在相关线索下的反应时更长, N1波幅更小, N1潜伏期更短; 相比对照组被试, 成瘾者在相关线索下的行为任务的正确率更低, 反应时更长, N1波幅更小; N1波幅的组间组内差异和潜伏期的组内差异主要集中在中央区。(2)结合VR技术的途径偏向矫正训练后, 训练组被试的生理指标和途径偏向系数显著降低, 且显著低于对照组被试; 追踪测试中, 训练组被试的分数显著低于对照组。这表明相关线索下成瘾者的用药行为具有自动化、无意识的性质, 感觉运动区N1的异常活动是其神经机制之一。VR提取用药动作记忆-AAT消退替代训练, 可以有效削弱或消退成瘾者的成瘾动作倾向, 而且训练效果持续性较好, 可达到减少或停止现实情境中的用药和复吸行为的目的。     

大脑皮层-背侧纹状体通路在吗啡强迫性觅药和用药行为中的作用

药物成瘾是以强迫性觅药和用药行为为核心特征的慢性脑疾病。从初始用药到强迫性用药是成瘾者的觅药行为从目标导向性向习惯化发展的过程。强迫性觅药和用药行为是依赖于背外侧纹状体的习惯化行为, 同时前额叶皮层-背内侧纹状体通路对行为的控制减弱, 导致感觉运动皮层-背外侧纹状体通路对行为的控制持续占主导地位, 是成瘾行为具有强迫性特征的重要神经基础。本项目围绕这一重要问题展开研究, 在建立具有成瘾特征的动物模型的基础上, 采用行为学、行为药理学和组织形态学等方法揭示皮层-纹状体通路在强迫性觅药和用药行为中的作用。研究结果有望为进一步寻找该神经网络参与成瘾行为的分子机制提供重要线索。     

物质成瘾及其戒除:基于反转学习的视角

物质成瘾与反转学习损伤密切相关,成瘾者往往不能灵活地适应变化的刺激—结果的联结,这可能进一步加剧成瘾者的物质使用。近年来研究发现,物质成瘾者的反转学习相关的腹外侧前额和背外侧前额等脑区激活异常,这些异常与成瘾者的冲动性和强迫性有关。此外,个体的反转学习能力对其成瘾行为具有一定预测性。今后应增加对不同类型物质成瘾者的反转学习脑机制及物质相关线索对成瘾者反转学习影响的研究,并且进一步探讨成瘾者的冲动性和强迫性对其反转学习的调节及个体反转学习能力对其成瘾行为的预测。     

用药动作线索诱发海洛因戒断者的镜像神经活动:一项fMRI研究

相关线索能够诱发药物依赖者的心理渴求,而健康人不会对相关线索产生心理渴求。15名海洛因成瘾者和12名没有任何物质滥用的健康被试参与实验,收集了他们在观看相关线索与对照线索时的脑神经活动。结果发现,药物线索能够诱发戒断者更多脑区的活动,包括扣带回和楔前叶。两组被试在对照动作线索刺激诱发作用下,其颞叶、顶叶均出现了较为一致的活动。在用药动作线索诱发作用下,戒断组双侧颞中回、双侧顶下小叶、左侧顶上小叶和右侧额下回显示出显著活动,并且与对照动作线索激活脑区一致;健康组被试除枕叶-颞叶联合区外,没有出现显著的脑区活动。以上结果表明,用药动作线索诱发了海洛因戒断者颞中回、顶下小叶、额下回等镜像神经系统的活动,这些脑区对不同类型的相关线索十分敏感,它们可能通过对用药动作的心理模拟,参与了用药动作线索的快速自动化加工。     

不同相关线索下海洛因成瘾者的反应差异及反应抑制特征：来自ERP的证据

采用ERP技术, 探究海洛因成瘾者在不同相关线索下的脑电反应及其与冲动性的关系。实验采用组间实验设计和双选择Oddball范式, 要求海洛因成瘾组和健康对照组被试对标准刺激与偏差刺激分别做不同的按键反应, 记录他们的EEG数据。结果发现：相比对照组被试, 海洛因成瘾者在观看药物相关线索时诱发的N2波幅更小, P3波幅更大; 在成瘾组内, 相比用药工具线索, 用药动作线索诱发了更小的N2波幅和更大的P3波幅。这表明海洛因成瘾者对药物相关线索存在反应抑制缺陷, 且不同的药物相关线索会激发海洛因成瘾者不同程度的反应抑制缺陷, 用药动作线索比用药工具线索更大程度地影响成瘾者的反应抑制能力, 反映出更高的动作冲动性。     

冲动还是习惯?成瘾不同阶段中冲动性的性质与机制

冲动性是一种缺乏充分思考、不顾后果的冒险行为或行为倾向, 它既表现在人格特质中, 也会表现为各类环境中的行为。成瘾者具有典型的冲动性特征, 但成瘾者的冲动性是如何影响和促进成瘾行为的发生、发展, 目前还并不明朗。从成瘾形成的不同阶段, 也许可以对此有更进一步的了解。在药物使用的开始阶段, 冲动性人格特质作为动机原因, 促进成瘾物质的首次使用; 接着操作性条件学习导致用药者进入“目标-导向”阶段, 呈现出选择冲动性。第三阶段, 经典条件学习又使相关线索和药物效应不断匹配, 形成条件反射性药物使用行为。成瘾者进入习惯性用药阶段, 表现出显著的停止冲动性。     

网络游戏成瘾与海洛因成瘾存在相同的神经机制吗?——基于MRI的证据

网游成瘾与海洛因成瘾具有许多相似的临床表现,但其神经机制是否相同还不得而知。综合近5年来的MRI研究发现,两类成瘾存在部分相同区域的脑结构和功能损害,且在成瘾线索诱发下二者的4个成瘾相关环路(认知控制环路、奖赏环路、动机环路和记忆-学习环路)均出现了广泛而增强的脑区激活反应。但海洛因成瘾的脑损害区域偏向更高级的认知控制环路和奖赏环路,损害范围也更广(4个环路的功能连通性均降低),而网游成瘾的脑损害主要发生在相对低级的记忆-学习环路和动机环路,损害范围也较窄(功能连通性降低只发生在认知控制和记忆-学习环路之间)。这些结果说明,两类成瘾行为的神经机制既有相同点,又有差异性。     

Parallel goal-directed and habitual control of human drug-seeking: implications for dependence vulnerability

Dual-process theories of learning and addiction propose that whereas freely elected drug/reward-seeking is goal-directed in being mediated by the expected value of the outcome, cue-elicited drug/reward-seeking is habitual in being elicited directly by antecedent stimuli, without retrieving a representation of outcome value. To substantiate this claim, the current study conducted a human devaluation-transfer procedure in which young adult smokers were first trained on a concurrent choice task to earn tobacco and chocolate points before one outcome was devalued by specific satiety or health warnings against consumption of that outcome. When choice was again tested in extinction, the selective reduction in performance of the action associated with the devalued outcome indicated that choice was controlled by an expectation of outcome value, that is, was goal-directed. Moreover, the presentation of tobacco and chocolate cues enhanced selection of the response associated with that outcome, indicating that transfer was also mediated by the retrieval of the outcome representation. Paradoxically, however, the magnitude of this transfer effect was unaffected by devaluation, indicating that the stimulus retrieved a representation of outcome identity but not current incentive value. Individual differences in tobacco dependence in the young adult sample were associated with tobacco preference in the concurrent choice task but not with the devaluation or transfer effects. These data accord with dual-process theories in suggesting that drug/reward-seeking are mediated by goal-directed and habitual controllers under freely elected and cued conditions, respectively, and that initial uptake of drug use is associated with hyper-valuation of the drug as an outcome of goal-directed drug-seeking rather than with accelerated habit formation.     

Drug Tolerance, Drug Addiction, and Drug Anticipation

ABSTRACT— Environmental cues associated with drugs often elicit withdrawal symptoms and relapse to drug use. Such cues also modulate drug tolerance. The contribution of drug-associated stimuli to withdrawal and tolerance is emphasized in a Pavlovian-conditioning analysis of drug administration. Conditional responses occur in the presence of cues that have been associated with the drug in the past, such as the setting in which the drug was taken. These conditional responses mediate the expression of tolerance and withdrawal symptoms. Recently, it has become apparent that internal predrug cues, as well as environmental cues, elicit pharmacological conditional responses that contribute to tolerance and withdrawal. Such internal cues include cognitive or proprioceptive cues incidental to self-administration, drug-onset cues that are experienced shortly after administration, and emotional cues. According to the conditioning analysis, addiction treatment should incorporate learning principles to extinguish the association between stimuli (environmental and internal) present at the time of drug administration and the effects of the addictive drug.     

基于驱动与控制相互作用的成瘾冲动性结构与机制

物质成瘾者具有明显的冲动性特征, 表现为难以戒断的成瘾物质使用。这种行为的产生除了抑制控制的问题外, 源于多个维度的驱动力也是重要的原因。低弱的抑制力无法抵挡驱力的作用, 出现不平衡状态, 形成难以控制的渴求下的强迫性用药或习惯性用药行为倾向。驱动力来源于多方面, 奖赏效应, 通过条件作用形成的S-R式相关线索反应以及感觉寻求等人格特质; 控制成分则包括了反应抑制与无法延迟满足的执行控制功能。     

Occasion setting and drug tolerance

There is considerable evidence that drug-paired cues become associated with drug effects. It has been hypothesized that these cues act as Pavlovian conditional stimuli (CSs), and elicit conditional compensatory responses that contribute to tolerance. On the basis of a conditioning analysis of tolerance, we would expect that is should be possible to establish drug-paired cues as occasion setters, as well as conditional stimuli. Using feature-positive discrimination training, we evaluated the contribution of occasion-setting stimuli (as well as CSs) to tolerance to the hypothermic effect of ethanol in rats. The results indicated that a complete associative analysis of drug tolerance should incorporate not only the CS properties of predrug cues, but also the occasion-setting properties of such cues. The findings have implications for interpreting conflicting findings concerning extinction of tolerance and for cue-exposure treatments of addiction.     

Occasion Setting and Drug Tolerance

There is considerable evidence that drug-paired cues become associated with drug effects. It has been hypothesized that these cues act as Pavlovian conditional stimuli (CSs), and elicit conditional compensatory responses that contribute to tolerance. On the basis of a conditioning analysis of tolerance, we would expect that it should be possible to establish drug-paired cues as occasion setters, as well as conditional stimuli. Using feature-positive discrimination training, we evaluated the contribution of occasion-setting stimuli (as well as CSs) to tolerance to the hypothermic effect of ethanol in rats. The results indicated that a complete associative analysis of drug tolerance should incorporate not only the CS properties of predrug cues, but also the occasion-setting properties of such cues. The findings have implications for interpreting conflicting findings concerning extinction of tolerance and for cue-exposure treatments of addiction.     

Negative prospective memory: Remembering not to perform an action

Sometimes it is important to remember not to perform an action, such as remembering to stop taking seasonal allergy medicine when it is no longer needed. Mistakes in accomplishing this goal can involve prospective memory commission errors when individuals mistakenly perform a prospective response. In two experiments, we investigated the role of attentional resources in preventing prospective memory errors to cues that had been associated with a habitual prospective response. In Phase 1 of our experiments, participants performed a prospective memory task during which they either routinely responded to prospective memory cues or responded to these cues one time only. On a subsequent prospective memory task, the participants who had routinely responded to prospective memory cues were vulnerable to commission errors when their attentional resources were taxed. By contrast, dividing attention did not increase commission errors to cues that had not been routinely performed on an earlier task. These data indicate that attentional resources are needed to withhold making habitual prospective memory responses, and they suggest that inhibitory failures are a cause of these prospective memory errors. Finally, we suggest a broader definition of prospective memory that includes remembering to withhold performing actions.     

Extinction of drug cue reactivity in methamphetamine-dependent individuals

Conditioned responses to drug-related environmental cues (such as craving) play a critical role in relapse to drug use. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses, but the few existing clinical trials focused on extinction of conditioned responses to drug-related cues in drug-dependent individuals show equivocal results. The current study examined drug-related cue reactivity and response extinction in a laboratory setting in methamphetamine-dependent individuals. Methamphetamine cue-elicited craving was extinguished during two sessions of repeated (3) within-session exposures to multi-modal (picture, video, and in-vivo) cues, with no evidence of spontaneous recovery between sessions. A trend was noted for a greater attenuation of response in participants with longer (4-7 day) inter-session intervals. These results indicate that extinction of drug cue conditioned responding occurs in methamphetamine-dependent individuals, offering promise for the development of extinction- based treatment strategies.