Negative reinforcement and interoceptive dysfunction in stimulant dependence.

描述（由申请人提供）：在大麻之后，安非他明是世界上使用最广泛的非法药物类别。最近的一份报告估计，甲基苯丙胺在美国每年造成约895人死亡，每年造成235亿美元的经济负担。负强化发生在（a）选择一个行为来避免一个令人厌恶的结果或（B）一个人在一个厌恶的状态下采取行动来结束这种状态，并已被认为是强迫性吸毒行为的一个重要机制。厌恶的状态或结果是由内感受系统处理的，内感受系统包括岛叶皮层和信号“我们的感受”。风险决策是药物成瘾者的主要功能失调行为之一。然而，目前还没有研究来研究改变内感受对冒险决策的因果影响，即“感觉不好如何影响一个人所做的选择”。在响应RFA，我们汇集了两个实验方法来研究如何预期或经历一个厌恶的状态改变冒险行为的决策甲基苯丙胺依赖（MD）的个人。这些方法包括（1）使用厌恶的直接内感受性刺激和负效价面孔作为非内感受性刺激来调节个体的状态，以及（2）测量冒险任务期间风险反应的频率和对两个选择预测任务期间错误的调整。这些方法与功能性磁共振成像（fMRI）相结合，以检查负强化机制是如何在大脑中实现的，并为神经基质特异性治疗干预奠定基础。具体目标1：为了确定预期和经历一个令人厌恶和愉快的内感受性刺激的行为效果和负面和正面的面孔对MD个体的风险决策的影响，相对于比较对象。具体目标二：为了确定与预期和经历一个令人厌恶和愉快的内感受性刺激的大脑激活的差异，以及它们对大脑激活的影响，在危险的决策过程中，在MD个人相对于比较科目。具体目标3：评估行为和神经影像学结果的可塑性作为MD个体持续禁欲的函数。基于神经加工模型，提出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性增加，以及（2）在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，呼吸限制的影响和负效价的面孔对风险决策的频率的影响将在30个最近禁欲（3-6周）MD个体和30个健康志愿者的行为和神经影像学研究中进行检查。第二，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，以应对负效价的面孔，我们将在另一个实验中确定预期的厌恶性内感受性刺激对风险选择的影响。或者，我们将测试厌恶性内感受性刺激对二选一预测任务中错误决策调整的影响。我们最近发现，岛叶皮层内的激活模式的变化作为一个功能的持续时间的药物使用和/或禁欲。因此，我们将扩大横断面研究，包括6个月的随访，以确定是否持续禁欲与假设的行为和神经异常的衰减。这些实验的结果将确定内感受系统本身是否是“敏感的”，或者来自内感受系统的信息（例如岛叶皮层）是否没有被其他对调整冒险和决策很重要的大脑区域（例如前扣带回和眶额皮层）适当地处理。 公共卫生相关性：导致甲基苯丙胺依赖的发展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：甲基苯丙胺依赖者做出错误的决定是因为他们被负面的“直觉”所压倒吗？对这一问题的回答将有助于制定具体的干预措施，例如减少消极的“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.