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。     

Nicotine craving and cue exposure therapy by using virtual environments.

Smokers who are exposed to cues associated with smoking show cardiovascular reactivity and an increase in smoking urges as compared to when they are presented with neutral cues. Cue exposure therapy (CET), which refers to the repeated exposure to drug-related cues in order to extinguish this learned association, has increasingly been proposed as a potential treatment of addictive behaviors, including tobacco smoking. The result of our pilot study suggests that a cue elicited using a virtual environment (VE) is more effective than other cue exposure devices. The VE was composed of craving environments (virtual bar) and objects (an alcoholic drink, a packet of cigarettes, a lighter, an ashtray, a glass of beer, and advertising posters) that are likely to trigger craving, a smoking avatar, and an audio environment that included the noisy sound and music of a restaurant. Sixteen late-adolescent males who smoked at least 10 cigarettes a day were recruited to participate in the VE-CET study. The CET virtual bar program consisted of six sessions, and the participants were exposed repeatedly to each session using different questions and procedures. Although the effects of CET did not yield significant reductions in all of the dependent variables, the craving for cigarettes was gradually decreased during the course of the sessions. This tendency was closely related to the reduction in the smoking count between the morning before the experiment and the start of the experiment. Based on these preliminary results, it appears that VE-CET maybe a useful tool to use in treatment programs to help reduce craving in those who are nicotine dependent.     

Renewal of cue-elicited urge to smoke: implications for cue exposure treatment

The effects of cue exposure therapy are limited, because renewal after extinction is an important source of relapse. In this study, 33 smokers were exposed to a cue predicting smoking availability and a cue predicting smoking unavailability in one context (acquisition context A). Following extinction in another context (extinction context B), a test for renewal took place in the original acquisition context A (i.e. ABA renewal). Urge to smoke was measured using a Visual Analogue Scale. Renewal of differential conditioned urge responding occurred when participants were tested in the acquisition context, while differential urge responding remained extinguished when tested in the extinction context. This experiment provides evidence that ABA renewal occurred in smokers. Clinical implications are discussed.     

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。     

Virtual reality cue reactivity assessment in cigarette smokers.

Drug craving has purportedly been linked to relapse and to substance use. For over two decades, cue reactivity has been a viable method to assess craving and physiological reactions to drug stimuli. However, traditional cue reactivity has faced the following limitations: austere situations or stimuli, lack of complex cues, lack of standardization, and limited generalization outside of the lab setting. In order to improve cue methodologies, a virtual reality (VR) nicotine cue reactivity assessment system (VR-NCRAS) was developed and tested in a controlled experimental trial. Ten nicotine dependent smokers were exposed to VR smoking cues and VR neutral cues in a standardized, timed, computer controlled experiment. Subjective craving and physiological responses were recorded and compared across VR-NCRAS stimuli. Subjective cigarette craving increased significantly and corresponding physiological reactivity was observed in response to VR smoking cues. VR neutral cues did not result in subjective or physiological changes consistent with craving. Implications of these findings on substance abuse research and treatment are discussed.     

Evaluation of a group cue-exposure treatment for opiate addicts

Twenty-four detoxified opiate addicts were randomized to an experimental group and a control group to evaluate efficacy of a group cue-exposure treatment to reduce or extinguish classically conditioned responses to drug-related stimuli. Assessment included psychophysiological responses (skin temperature, skin conductance level--SCL--, and heart rate) to a videotape and subjective measures (subjective craving, positive and negative affect) before and after the videotape. The experimental group received a group cue-exposure program to drug-related stimuli that comprised twelve treatment sessions administered three times weekly. The treatment program significantly reduced conditioned responses to drug-related stimuli, as measured by SCL and positive affect.     

Counterconditioning reduces cue-induced craving and actual cue-elicited consumption

Cue-induced craving is not easily reduced by an extinction or exposure procedure and may constitute an important route toward relapse in addictive behavior after treatment. In the present study, we investigated the effectiveness of counterconditioning as an alternative procedure to reduce cue-induced craving, in a nonclinical population. We found that a cue, initially paired with chocolate consumption, did not cease to elicit craving for chocolate after extinction (repeated presentation of the cue without chocolate consumption), but did so after counterconditioning (repeated pairing of the cue with consumption of a highly disliked liquid, Polysorbate 20). This effect persisted after 1 week. Counterconditioning moreover was more effective than extinction in disrupting reported expectancy to get to eat chocolate, and also appeared to be more effective in reducing actual cue-elicited chocolate consumption. These results suggest that counterconditioning may be more promising than cue exposure for the prevention of relapse in addictive behavior.     

The efficacy of cue exposure with response prevention in extinguishing drug and alcohol cue reactivity

It has been suggested that drug cue‐elicited urges and psychophysiological reactions are the results of Pavlovian conditioning processes and that it should be possible to extinguish these responses with cue exposure with response prevention. It has already been shown that subjective cue‐elicited urges can be extinguished, but it is unclear whether this is also true for cue‐elicited psychophysiological arousal. This was tested in the present study in a heterogeneous sample of drug and alcohol dependent patients. It was found that cue‐elicited urges can indeed be extinguished. However, such a clear pattern of extinguished cue reactivity was not found for the psychophysiological measures. Furthermore, the extinction of drug urges was not specific for cue exposure treatment. It is concluded that cue‐elicited psychophysiological arousal does not underlie subjective cue reactivity and may not reflect Pavlovian conditioned drug responding. Copyright © 2006 John Wiley & Sons, Ltd.     

Backward conditioning: mediation by the context

The information acquired in backward conditioning (i.e., outcome-->cue) was assessed in 3 Pavlovian lick-suppression experiments with water-deprived rats as subjects. Experiment 1 confirmed previous research that few outcome-->cue pairings made the cue into a conditioned excitor and additionally showed that massive posttraining extinction of the training context attenuated a backward-trained cue's excitatory value. Experiment 2 found that many outcome-->cue pairings made the cue into a conditioned inhibitor and that the same context manipulation attenuated this inhibitory value. Experiment 3 confirmed the observations of Experiments 1 and 2 and demonstrated that these effects of context extinction were specific to backward-trained cues conditioned in the extinguished context. These results are interpreted in terms of cue-->context and context-->outcome associations.     

Use of the ABA fear renewal paradigm to assess the effects of extinction with co-present fear inhibitors or excitors: Implications for theories of extinction and for treating human fears and phobias

In four experiments using albino rats in an ABA fear renewal paradigm, we studied conditioned fear in the A test context following extinction in Context B. Conditioned suppression of operant responding was the index of fear. In Experiments 1-3, we found that extinguishing a feared cue in compound with a putative conditioned inhibitor of fear led to more fear in the test context than did a conventional extinction procedure. In Experiments 4a and 4b, we found that extinguishing three feared cues in compound required one third the time and generally led to less fear to the cues in the test context than did the extinction of each cue separately. Thus, fear in the test context seems to vary inversely with the values of co-present cues during extinction in Context B. Results imply that cue value is actually reduced by extinction procedures rather than merely being opposed by a growing inhibitory process. Implications for theories of renewal and for clinical practice are discussed.     

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。     

Cue-exposure vs self-control in the treatment of binge eating: a pilot study.

From a recent theory on the learned nature of craving responses and binge eating, it follows that craving will extinguish when the CS-US bond is broken by prolonged exposure to the cues predicting excessive food intake with response prevention. The present authors treated six obese bulimics with cue exposure and response prevention. Six other patients learned to avoid or escape the binge-related cues with the aid of self control techniques. Although both treatments appeared to be effective in reducing the binge frequency, a most remarkable finding of the present study is that all patients treated by cue exposure were abstinent, directly after treatment and during the 1 yr follow-up. In contrast to the 100% binge-free subjects treated by cue exposure, self control techniques and relapse prevention led to abstinence in merely 33% of the subjects.     

Strategic flexibility in response preparation: Effects of cue validity on reaction time and pupil dilation

This study examined the ability of participants to strategically adapt their level of response preparation to the predictive value of preparatory cues. Participants performed the finger-precuing task under three levels of cue validity: 100, 75 and 50% valid. Response preparation was indexed by means of reaction time (RT) and pupil dilation, the latter providing a psychophysiological index of invested effort. Results showed a systematic increase in RT benefits (generated by valid cues) and RT costs (generated by invalid cues) with increments in the predictive value of cues. Converging with these behavioural effects, pupil dilation also increased systematically with greater cue validity during the cue-stimulus interval, suggesting more effortful response preparation with increases in cue validity. Together, these findings confirm the hypothesis that response preparation is flexible and that it can be strategically allocated in proportion to the relative frequency of valid/invalid preparatory cues.     

Automaintenance,contrast, and contingencies: Effects of local vs. overall and prior vs. impending reinforcement context

The pigeon's keypeck was investigated in a variety of multiple schedules of response-independent or -dependent reinforcement. Experiments 1 and 2 found that keypecking developed to a reinforcement-associated cue that signaled an increase in local rate of reinforcement, but signaled either no change or a decrease in the overall rate of reinforcement, defined as that prevailing in the cue's absence. In Experiment 3 a greater rate of responding to a target stimulus was observed when it was preceded by a second signal—associated with the same, or a lower, rate of reinforcement—and followed by extinction than when this temporal sequence was reversed. In Experiment 4 responding to a target cue increased when either a temporally prior or a subsequent reinforcement-associated cue was changed to signal extinction. Experiment 5 examined the conditioned reinforcing effectiveness of target cues in two types of situations varying the local context of reinforcement. Stimuli associated with selected target components of a response-dependent multiple schedule of reinforcement could appear as the terminal-link consequences in a two-link chain schedule. Enhanced responding during a target cue which accompanied the introduction of an extinction period following this cue was paralleled by an increase in the conditioned reinforcement effects of this cue. No such increase was found for target cues in which an enhancement of responding had been produced by the interposition of an extinction period prior to the cue.     

Extinction of conditioned flavor preferences

In a series of 4 experiments, the effects of extinction on flavor preferences conditioned by mixing flavor cues with a nutrient were examined. In each experiment it was observed that rats preferred a flavor cue that had not undergone extinction to one that had. In addition, this preference was reversed in subjects trained thirsty (Experiments 1 and 2) if the associated nutrient had been devalued prior to the test or the preference for the nonextinguished cue was attenuated by nutrient devaluation in subjects trained hungry (Experiments 3 and 4). The results suggest that extinction may weaken associations between the flavor and the specific sensory properties of the nutrient and, for subjects trained hungry, between the flavor and the motivational components of the nutrient as well.     

Trait Anxiety and Fear Responses to Safety Cues: Stimulus Generalization or Sensitization?

Abnormal fear responding to threat cues may contribute to the aetiology and maintenance of persistent fears and pathological anxiety. Chronic anxiety may also involve abnormal fear responding to ??safety?? cues, which do not signal danger. Yet investigations of fear responding to acquired safety cues are scarce and the basis of such responding remains unclear. Moreover, previous studies do not distinguish between stimulus generalization (an associative mechanism based on perceptual similarity between threat and safety cues) and sensitization (a non-associative mechanism whereby fear responses to any novel, intense, or fear-related stimulus are temporarily elevated). This study investigated responses to acquired safety cues in volunteers with varying trait anxiety, using a novel fear conditioning paradigm designed to distinguish between effects of trait anxiety on generalization and sensitization. The paradigm used three conditioned stimuli: a threat cue (CS+) and two safety cues (CS?), one perceptually similar to the CS+ and one perceptually dissimilar. Conditioned fear to these cues was indexed by fear potentiation of the startle blink reflex, skin conductance responses, and self-report. To examine how trait anxiety moderated responses to safety cues, participants were divided into high and low trait anxiety subgroups. Startle, skin conductance, and self-reported fear measures indicated that generalization of fear occurred for the safety cue which resembled the threat cue, but not for the perceptually dissimilar safety cue, consistent with the stimulus generalization hypothesis. There was some evidence that stimulus generalization was exaggerated in anxious individuals. The current study sheds light on the mechanism by which fear responses to safety cues arise in healthy individuals, and offers some insight into the influence of this mechanism in chronic anxiety.     

Outcome-specific transfer between predictive and instrumental learning is unaffected by extinction but reversed by counterconditioning in human participants

Three experiments were conducted to explore the effects of different interference treatments upon outcome-specific transfer from predictive learning to instrumental responding. A computer game was designed in which participants had to defend Andalusia from navy and air-force attacks. Participants learned the relationship between two instrumental responses (two keys in a standard keyboard) and two different outcomes (destruction of the ships or destruction of the planes). Then, they learned to predict which of two different cues predicted either outcome. Finally, participants were allowed to give either of the two instrumental responses in the presence of each cue. Outcome-specific transfer was shown as a preference for the response that shared the outcome with the current cue. Extinction of the cue before the transfer test had no effect upon transfer, regardless of the level of extinction (Experiments 1-3). However, pairing the cue with the alternative outcome (counterconditioning) reversed the outcome-based transfer effect (Experiment 3). The implications of these results for the contents of extinction in human predictive learning are discussed.     

Facilitation of Extinction of Conditioned Fear by D-Cycloserine

Abstract— Excessive fear and anxiety are characteristic of disorders such as post-traumatic stress disorder (PTSD) and phobias and are believed to reflect abnormalities in neural systems governing the development and reduction of conditioned fear. Conditioned fear can be suppressed through a process known as extinction, in which repeated exposure to a feared stimulus in the absence of an aversive event leads to a gradual reduction in the fear response to that stimulus. Like conditioned fear learning, extinction is dependent on a particular protein (the N-methyl-D-aspartate or NMDA receptor) in a part of the brain called the amygdala. Blockade of this receptor blocks extinction and improving the activity of this receptor with a drug called D-cycloserine speeds up extinction in rats. Because exposure-based psychotherapy for fear disorders in humans resembles extinction in several respects, we investigated whether D-cycloserine might facilitate the loss of fear in human patients. Consistent with findings from the animal laboratory, patients receiving D-cycloserine benefited more from exposure-based psychotherapy than did placebo-treated controls. Although very preliminary, these data provide initial support for the use of cognitive enhancers in psychotherapy and demonstrate that preclinical studies in rodents can have direct benefits to humans.     

基于“相关线索-自动化用药行为”联结的成瘾记忆消退

成瘾记忆消退致力于消除成瘾者相关线索与药物奖赏效应的联结,以达到消除心理渴求、戒断成瘾行为的目的,但其效果还十分有限。最近,大量的动物和人类实验研究发现:在相关线索下,成瘾者的激活脑区不仅包括中脑边缘皮层-背内侧纹状体,还延伸到感觉运动脑区-背外侧纹状体。这意味着成瘾记忆中存在相关线索与自动化(习惯性)用药行为的联结。所以,与成瘾相关的记忆可能包含两种不同的成分:一是与药物奖赏效应相关的情绪记忆,另一种是与用药动作、技能有关的动作记忆(程序记忆)。由于在成瘾阶段,药物奖赏效应对药物使用和复发的作用已经相对减少,因此,针对成瘾记忆的消退训练,以相关线索与自动化用药行为的联结为标靶,可能可以取得更好的效果,值得做进一步的深入探索。     

A placebo-controlled randomized trial of D-cycloserine augmentation of cue exposure therapy for smoking cessation

Recent studies underscore the importance of studying d-cycloserine (DCS) augmentation under conditions of adequate cue exposure treatment (CET) and protection from reconditioning experiences. In this randomized trial, we evaluated the efficacy of DCS for augmenting CET for smoking cessation under these conditions.

Sixty-two smokers attained at least 18 hours abstinence following 4 weeks of smoking cessation treatment and were randomly assigned to receive a single dose of DCS (n=30) or placebo (n=32) prior to each of two sessions of CET. Mechanistic outcomes were self-reported cravings and physiologic reactivity to smoking cues. The primary clinical outcome was 6-week, biochemically-verified, continuous tobacco abstinence.

DCS, relative to placebo, augmentation of CET resulted in lower self-reported craving to smoking pictorial and in vivo cues (d = 0.8 to 1.21) in a relevant subsample of participants who were reactive to cues and free from smoking-related reconditioning experiences. Select craving outcomes were correlated with smoking abstinence, and DCS augmentation was associated with a trend toward a higher continuous abstinence rate (33% vs. 13% for placebo augmentation).

DCS augmentation of CET can significantly reduce cue-induced craving, supporting the therapeutic potential of DCS augmentation when applied under appropriate conditions for adequate extinction learning.