Negative reinforcement and interoceptive dysfunction in stimulant dependence.

描述(申请人提供)：安非他命是仅次于大麻的全球使用最广泛的非法药物类别。最近的一份报告估计，冰毒每年在美国造成约895人死亡，每年造成235亿美元的经济负担。当(A)选择一种行为以避免不良结果，或(B)处于厌恶状态的个体为结束这种状态而采取行动，并被认为是导致强迫性吸毒行为的重要机制时，就会发生负强化。这种令人厌恶的状态或结果是由相互感觉系统处理的，该系统包括岛叶皮质和“我们感觉如何”的信号。冒险决策是吸毒成瘾个体的主要功能障碍行为之一。然而，还没有研究考察改变内感对冒险决策的因果影响，即“感觉不好如何影响一个人的选择”。作为对RFA的回应，我们结合了两种实验方法来研究预期或经历厌恶状态如何改变甲基苯丙胺依赖(MD)个体的冒险行为决策。这些方法包括(1)使用厌恶的直接内感刺激和负效价面孔作为非内感刺激来调节个体的状态；(2)测量冒险任务中风险反应的频率，并在双选择预测任务中对错误进行调整。这些方法与功能磁共振成像(FMRI)相结合，以研究负强化机制是如何在大脑中实施的，并为神经基质特异性治疗干预奠定基础。具体目标1：确定MD个体在预期和经历厌恶和愉快的内感刺激时的行为效应，以及消极和积极面孔对风险决策的影响。具体目标2：与对照受试者相比，确定MD个体在预期和经历厌恶和愉快的内感刺激时的脑激活差异及其对大脑激活的影响。具体目标3：评估行为和神经影像表现的可塑性作为持续戒断的功能在MD个体。基于神经加工模型，我们认为MD个体表现出两种类型的异常：(1)对预期和经历厌恶事件的敏感度增加；(2)当预期或经历厌恶事件时，调整其行为的灵活性降低。提出了两个实验。首先，通过对30名最近戒毒(3-6周)的MD患者和30名健康志愿者进行的行为和神经成像研究，将检验呼吸限制的影响和消极面孔对危险决策频率的影响。其次，如果--正如我们假设的那样--MD个体未能调整他们的冒险行为，以应对消极的效价面孔，我们将在另一个实验中确定预期厌恶的内感刺激对风险选择的影响。或者，我们将测试厌恶的内感刺激对两项选择预测任务中错误的决策调整的影响。我们最近发现，岛叶皮质内的激活模式随着药物使用和/或戒毒时间的延长而变化。因此，我们将扩展这项横断面研究，以包括6个月的随访，以确定持续戒酒是否与假想的行为和神经异常的减轻有关。这些实验的结果将决定感觉间系统本身是否被“敏化”，或者来自感觉间系统的信息，例如岛叶皮质，是否没有被其他大脑区域适当地处理，这些区域对于调整冒险和决策是重要的，例如前扣带回和眼眶额叶皮质。 公共卫生相关性：导致甲基苯丙胺依赖形成和维持的基本大脑和行为过程知之甚少。在这里，我们将使用大脑成像和行为实验来解决这个问题：甲基苯丙胺依赖者之所以做出糟糕的决定，是因为他们被负面的“直觉”淹没了吗？这个问题的答案将有助于制定具体的干预措施，例如减少负面“直觉”对决策或冒险的影响，从而增加禁欲的机会。

DESCRIPTION (provided by applicant): After marijuana, amphetamines are the most widely used illicit drug class worldwide. A recent report estimates that methamphetamine causes about 895 deaths per year in the U.S. and is responsible for an annual economic burden of $23.5 billion. Negative reinforcement occurs when (a) an action is selected to avoid an aversive outcome or (b) an individual in an aversive state acts to end such a state and has been considered an important mechanism underlying compulsive drug-taking behavior. The aversive state or outcome is processed by the interoceptive system, which includes the insular cortex and signals "how we feel". Risk- taking decision-making is among the key dysfunctional behaviors in drug addicted individuals. Yet, there have been no studies to examine the causal influence of altering interoception on risk-taking decision-making, i.e. "how feeling bad affects the choices one makes". In response to the RFA, we bring together two experimental approaches to examine to how anticipating or experiencing an aversive state alters risk-taking behavior decision-making in methamphetamine dependent (MD) individuals. These approaches include (1) using aversive direct interoceptive stimulation and negatively valenced faces as non-interoceptive stimuli to modulate the state of the individual and (2) measuring the frequency of risky responses during a risk-taking task and the adjustment to errors during a two-choice prediction task. These approaches are combined with functional magnetic resonance imaging (fMRI) to examine how negative reinforcement mechanisms are implemented in the brain and to lay the groundwork for neural substrate specific treatment interventions. Specific Aim 1: To determine the behavioral effects of anticipating and experiencing an aversive and pleasant interoceptive stimulus and the impact of negatively and positively valenced faces on risky decision making in MD individuals, relative to comparison subjects. Specific Aim 2: To determine the brain activation differences associated with anticipating and experiencing an aversive and pleasant interoceptive stimulus and their impact on brain activation during risky decision making in MD individuals relative to comparison subjects. Specific Aim 3: To evaluate the plasticity of the behavioral and neuroimaging findings as a function of sustained abstinence in MD individuals. Based on a neural processing model, it is proposed that MD individuals exhibit two types of abnormalities: (1) an increased sensitivity to anticipating and experiencing aversive events and (2) a decreased flexibility to adjust their behavior when anticipating or experiencing an aversive event. Two experiments are proposed. First, the effect of breathing restriction and the effects of negatively valenced faces on the frequency of risky decision making will be examined in a behavioral and neuroimaging study of 30 recently abstinent (3-6 weeks) MD individuals and 30 healthy volunteers. Second, if - as we hypothesize - MD individuals fail to adjust their risk-taking behavior in response to negatively valenced faces, we will determine in another experiment the effect of anticipation of aversive interoceptive stimuli on risky choices. Alternatively, we will test the effect of aversive interoceptive stimuli on decision-making adjustments to errors during the two- choice prediction task. We have found recently that the activation pattern within the insular cortex change as a function of duration of drug use and/or abstinence. Thus, we will extend the cross-sectional study to include a 6 months follow-up to determine whether sustained abstinence is associated with an attenuation of the hypothesized behavioral and neural abnormalities. The results from these experiments will determine whether the interoceptive system itself is "sensitized" or whether information from the interoceptive system, e.g. insular cortex, is not appropriately processed by other brain areas that are important for adjusting risk-taking and decision making, e.g. anterior cingulate and orbitofrontal cortex. PUBLIC HEALTH RELEVANCE: The basic brain and behavioral processes that cause the development and maintenance of methamphetamine dependence are poorly understood. Here, we will use brain imaging and behavioral experiments to address the question: do methamphetamine dependent individuals make poor decisions because they are overwhelmed by negative "gut feelings"? The answer to this question will help to develop specific interventions, e.g. to dampen the influence of negative "gut feelings" on decision-making or risk-taking and thereby increase the chance of abstinence.