Multimodal Imaging of the Sensory Gating Deficit in Chronic Cocaine Abusers

描述(申请人提供)：可卡因依赖是一种影响数百万美国人的衰弱疾病，目前的治疗方案对近90%的患者无效。高阶注意力和记忆过程的缺陷(即执行功能障碍、工作记忆能力下降和注意力转换困难)在这一群体中很常见，可能会导致复发。然而，更基本的缺陷，包括未能抑制重复的感觉刺激(即感觉门控)，也存在。这些门控缺陷可能在有共病精神特征的滥用者中更为严重，例如有偏执狂倾向或有更基本的注意力障碍的使用者。这两个亚组都与药物依赖增加和复发的可能性有关。能够识别这些患有相关共病问题的用户亚群的范例将增加我们对成瘾的神经生物学的知识，并可用作确定替代治疗方案有效性的生物标志，这两种方案都与NIDA的总体使命声明直接相关。因此，我们建议使用多模式神经成像，包括功能磁共振成像(FMRI)、脑电(EEG)和脑磁图(MEG)，以及新的数据融合技术来研究12名健康正常志愿者和24名慢性可卡因滥用者的基本抑制过程(即感觉门控)。神经心理学和心理学数据也将被收集，并与门控任务的表现相关联，重点是注意力障碍和可卡因引起的偏执狂的临床测量。拟议的任务将是传统门控模式的变体，因为参与者除了点击外，还将接触到成对的相同音调和不同音调。脑磁图和脑电数据将同时采集，fMRI数据将在电生理数据的24小时内采集。这个项目的具体目标是：1)通过表征慢性可卡因滥用者对重复和新刺激的潜在抑制过程的神经网络(中皮质边缘通路)，更全面地了解成瘾的神经生物学；2)确定抑制的基本失败是否表明复发率更高；以及3)确定基本的抑制缺陷是否与临床特征(即可卡因引起的偏执和注意力障碍)有关，这些特征在某些可能患有双重诊断的吸毒者亚群中更为突出。这项建议是创新和独特的，因为它是第一次尝试利用几种不同的成像方式(fMRI/MEG/EEG)来研究成瘾的神经生物学，在这一组中，抑制失败已被证明有助于复发的可能性。此外，多模式神经成像和随后的新型数据融合技术的使用将解决门控文献中的一个长期存在的问题，即门控缺陷发生在哪里和何时。我们的长期目标(计划的R01提交)是评估多模式成像数据作为治疗成功的预测因素，并使用任务表现来确定应该考虑替代治疗干预的患者子组。这项任务的最低认知要求也使其成为研究动物可卡因依赖的理想方法，以便开发新的成瘾模型并进行药理学测试。可卡因滥用仍然是美国的一个主要健康问题，目前约有180万吸毒者。慢性可卡因滥用和依赖与个人、其支持网络和整个社会的重大医疗、神经、神经精神、社会和人际并发症有关。这笔赠款将利用神经成像技术来增加我们对成瘾的神经生物学的了解，并确定这些技术是否可能是某些可卡因使用者亚群中复发的更敏感的衡量和预测指标。

DESCRIPTION (provided by applicant): Cocaine dependence is a debilitating disease affecting millions of Americans and current treatment regimens are ineffective on nearly 90% of patients. Deficits in higher-order attention and memory processes (i.e., executive dysfunction, reduced working memory capacity and difficulties with attentional switching) are common amongst this group and likely contribute to relapse. However, even more basic deficits, including the failure to inhibit repeated sensory stimuli (i.e., sensory gating), are present. These gating deficits may be more severe in abusers with co-morbid psychiatric profiles such as a proneness to experience paranoia or users with more basic attentional disorders. Both of these sub-groups are associated with increased drug dependence and likelihood of relapse. A paradigm that is capable of identifying these sub-groups of users with associated co-morbidity issues would increase our knowledge on the neurobiology of addiction and could be used as a bio-marker for determining the efficacy of alternative treatment regimens, both of which are directly relevant to NIDA's overall mission statement. Therefore, we propose to use multimodal neuroimaging, including functional magnetic resonance imaging (FMRI), electroencephalography (EEG) and magnetoencephalography (MEG), and novel data fusion techniques to investigate basic inhibitory processes (i.e., sensory gating) in 12 healthy normal volunteers and 24 chronic cocaine abusers. Neuropsychological and psychological data will also be collected and correlated with performance on the gating task, with emphasis on clinical measures of attentional dysfunction and cocaine induced paranoia. The proposed task will be a variant of the traditional gating paradigm as participants will be exposed to pairs of identical tones and non-identical tones in addition to clicks. MEG and EEG data will be collected simultaneously, and FMRI data will be collected within 24 hours of the electrophysiological data. The specific aims of this project are 1) a more comprehensive understanding of the neurobiology of addiction by characterizing the neural networks (mesocorticolimbic pathway) underlying inhibitory processes to repeated and novel stimuli in chronic cocaine abusers, 2) to determine if basic failures in inhibition are indicative of faster relapse rates, and 3) to determine if basic inhibitory deficits are related to clinical characteristics (i.e., cocaine induced paranoia and attentional deficits) that are more prominent in certain sub-populations of abusers who might carry dual-diagnoses. This proposal is innovative and unique because it is one of the first attempts to utilize several different imaging modalities (FMRI/MEG/EEG) to investigate the neurobiology of addiction in a group where failures in inhibition have been shown to contribute to likelihood of relapse. Moreover, the use of multimodal neuroimaging and subsequent novel data fusion techniques will resolve a long-standing question in the gating literature, namely "where" and "when" the gating deficit occurs. Our long-term goal (planned R01 submission) is to evaluate the multi-modal imaging data as a predictor of treatment success, and to use task performance to identify a sub-group of patients where alternative treatment interventions should be considered. The minimal cognitive demands of this task also make it ideal for studying cocaine dependence in animals so that novel models of addiction can be developed and pharmacologically tested. Cocaine abuse continues to be a major health problem in the United States with approximately 1.8 million current users. Chronic cocaine abuse and dependence are associated with major medical, neurological, neuropsychiatric, social and interpersonal complications for the individual, their support network and society at whole. This grant will utilize neuroimaging techniques to increase our understanding of the neurobiology of addiction and to determine whether these techniques may be a more sensitive measure and predictor of relapse amongst certain sub-groups of cocaine users.