Human Brain Function And Drug Abuse

该项目的总体目标是确定导致或导致药物依赖的大脑功能模式，并为开发新的治疗方法提供线索。我们的研究策略包括使用正电子发射断层扫描（PET）来评估各种药物滥用和认知激活对大脑活动的影响，使用[F-18]氟脱氧葡萄糖的大脑葡萄糖代谢率，使用[O-15]-水的局部脑血流量和使用BOLD方法的功能性磁共振成像（fMRI）。所有这些方法都提供了神经元活动的间接指标。在PET血流研究中，使用20名对照受试者，我们观察到激活的前扣带回，眶额，背外侧前额叶和下顶叶皮质，丘脑和丘脑主要是在右侧在决策（爱荷华州赌博任务）。这项任务也激活了小脑，主要是在左侧。对有可卡因滥用史的人进行的研究表明，当参与者执行抑制性处理（Stroop色词干扰任务）和决策（爱荷华州赌博任务）时，与匹配的对照组相比，对血流的影响不同。在执行Stroop任务时，滥用者的左前扣带皮层和右背外侧前额叶皮层的激活比对照组被置换。然而，与对照组相比，执行赌博任务，可卡因滥用者有更大的激活在右眶额叶皮层和较少的激活在背外侧前额叶皮层双边。在25天禁欲期之前每周使用的可卡因克数与两项任务的预测感兴趣区域的正常化血流呈负相关。在另一项PET血流研究中，初步结果表明，在执行和情感功能任务期间，与对照组受试者相比，戒断药物滥用者的眶额皮质、海马和杏仁核中的正常化血流减少。此外，在执行功能测试期间，通过皮肤电导和心率测量的生理反应在物质滥用者中发生了改变。这些结果表明，认知障碍和血流减少都是药物滥用者的特征，并且这些差异在至少三个月的戒断后仍然存在。在有阿片类药物滥用史的个体中，在连续执行任务期间葡萄糖利用的PET研究表明，与没有药物滥用史的个体相比，先前接受美沙酮维持治疗的脱毒阿片类药物滥用者在左侧中扣带回、左侧上级额叶皮质和双侧额叶皮质中的正常化葡萄糖代谢较低。美沙酮维持阿片类药物滥用者的左前额叶代谢也较低，但左顶叶下皮层代谢较高。这些结果表明，阿片类药物成瘾导致异常的神经回路subserving负的情感状态和美沙酮的维护，这些异常。 基于体素的形态测量（VBM）用于检测所采集的结构MR图像上灰质和白色物质中的组织密度差异。到目前为止，我们已经使用VBM来评估一组14名可卡因滥用者和一组11名非使用者的组织密度差异。基于来自这些参与者的O-15 PET成像的先验假设，我们研究了仅限于额叶皮质的组织密度差异。在13个额叶区域中的10个区域，可卡因滥用组的灰质密度低于非使用者组。这些区域包括扣带回和眶额皮质的内侧和外侧。这些结果扩展了我们对脑血流改变的发现，包括在同一额叶区域的灰质组织异常。 Matochik JA，伦敦艾德，Eldreth DA，学员J-L，Bolla KI.可卡因戒断者额叶皮质组织成分的磁共振成像研究。神经影像学2003; 19：1095-1102. 在安装Siemens 3 testa MRI后，雇用了新的MRI工作人员，包括3名临床医生、1名高级MRI物理学家和3名MRI研究助理、1名信号处理物理学家、1名MRI操作员、2名IRTA博士后研究员和2名研究技术人员。在磁体的典型启动/验收期之后，涉及几种新的IRB批准的人体方案的研究已经开始。这些协议涉及使用功能性MRI（fMRI）和BOLD（血氧水平依赖）技术对各种滥用药物的调查。这种技术使用血氧的变化，主要是由于血流的变化，作为神经元活动的间接标记。新方案包括研究大麻和尼古丁戒断对大脑认知和情感过程的影响，研究急性尼古丁给药如何影响注意力和认知过程，并研究尼古丁在各种给药条件下的药代动力学和药效学作用部位。除了这些协议之外，MRI物理单元已经开始开发和优化MRI脉冲序列，以提高我们的扫描仪获取数据的能力。特别相关的是脉冲序列，专门用于改善大脑眶额和内侧颞区的信号丢失，这些区域与药物滥用有关。我们还在研究改进的动脉自旋标记脉冲序列，用于血流的绝对量化，以及扩散张量成像，以研究与滥用药物相关的纤维跟踪变化。

The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategies involve the use of positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on brain activity using cerebral metabolic rates for glucose using [F-18]fluorodeoxyglucose, regional cerebral blood flow using [O-15]-water and functional magnetic resonance imaging (fMRI) using the BOLD method. All of these methodologies provide indirect indices of neuronal activity. In a PET blood flow study using 20 control subjects, we observed activation of the anterior cingulate, orbital frontal, dorsolateral prefrontal and inferior parietal cortices, insula and thalamus predominantly on the right side during decision-making (Iowa gambling task). This task also activated the cerebellum predominantly on the left side. Studies of individuals with histories of cocaine abuse, who were abstinent for 25 days, compared to a matched control group demonstrated differential effects on blood flow while the participants performed tasks of inhibitory processing (Stroop Color Word Interference task) and decision-making (Iowa gambling task). While performing the Stroop task, abusers displacyed activation in the left anterior cingulate cortex and right dorsolateral prefrontal cortex than control subjects. Whereas, compared to control subjects performing the Gambling task, cocaine abusers had greater activation in the right orbital frontal cortex and less activation in the dorsolateral prefrontal cortex bilaterally. Grams per week of cocaine used prior to the 25-days abstinence period correlated negatively with normalized blood flow in the predicted regions of interest for both tasks. In another PET blood flow study, preliminary results indicate reduced normalized blood flow in the orbitofrontal cortex, hippocampus, and amygdala in abstinent drug abusers relative to control subjects during performance of executive and emotional function tasks. In addition, physiological responses measured by skin conductance and heart rate were altered in substance abusers during tests of executive function. These results suggest that both cognitive impairment and reduced blood flow characterize drug abusers, and that these differences persist after a minimum of three months of abstinence. PET studies of glucose utilization during a continuous performance task in individuals with a history of opiate abuse showed that detoxified opiate abusers previously on methadone maintenance therapy had lower normalized glucose metabolism in the left midcingulate gyrus, the left superior frontal cortex and the insula, bilaterally compared to individuals who had no history of drug abuse. Methadone maintained opiate abusers also had lower metabolism in the left insula, but higher metabolism in the left inferior parietal cortex. These results suggest that opiate addiction leads to abnormalities in neural circuitry subserving negative affective states and the methadone maintenance alleviates these abnormalities. Voxel-based morphometry (VBM) is being used to detect tissue density differences in gray matter and white matter on the acquired structural MR images. To date, we have used VBM to evaluate tissue density differences in a group of 14 cocaine abusers and a group of 11 non-users. Based on a priori hypotheses derived from O-15 PET imaging of these participants, we looked at tissue density differences restricted to the frontal cortex. In 10 of 13 frontal regions, the cocaine abuse group had lower gray matter density than the non-users group. These regions included the cingulate gyrus and medial and lateral aspects of the orbitofrontal cortex. These results extend our findings of altered cerebral blood flow to include abnormalities in gray matter tissue in the same frontal regions. Matochik JA, London ED, Eldreth DA, Cadet J-L, Bolla KI. Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study. NeuroImage 2003; 19:1095-1102. After installation of a Siemens 3 testa MRI, new MRI staff were hired including 3 Staff Clinicians, a senior MRI physicist and 3 MRI research associates, a signal processing physicist, an MRI operator, 2 IRTA postdoctoral fellows and 2 research technologists. Following the typical startup/acceptance period for the magnet, research involving several new, IRB-approved human protocols have begun. These protocols involve the investigation of various drugs of abuse using functional MRI (fMRI) and the BOLD (Blood Oxygen Level Dependant) technique. This technique uses changes in blood oxygenation, mostly due to changes in blood flow, as an indirect marker of neuronal activity. The new protocols include looking at the effects of marijuana and nicotine withdrawal on cognitive and affective processes in the brain, examining how acute nicotine administration affects attentional and cognitive process, and investigating the pharmacokinetic and pharacodynamic sites of action of nicotine under a variety of administration conditions. In addition to these protocols, the MRI Physics Unit has started work on the development and optimization of MRI pulse sequences to enhance our scanners abilities to acquire data. Especially relevant are pulse sequences tailored to improve signal loss from orbitofrontal and medial temporal regions of the brain, areas implicated in drug abuse. We are also working on improved Arterial Spin Labeling pulse sequences, for absolute quantification of blood flow, and Diffusion Tensor Imaging, to investigate changes in fiber tracking associated with drugs of abuse.