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]氟脱氧葡萄糖和局部脑血流量的葡萄糖代谢率使用[O-15]-水和磁共振成像（MRI）来评估药物滥用的结构后遗症。 前额叶皮层及其与边缘系统结构的连接调节可能在药物滥用者中受损的执行认知和情绪调节功能的特定方面，例如，冲动控制、决策、持续注意力、冒险和唤醒能力。戒毒药物滥用者（N=21）和非用户控制参与者（N=20）在情绪Stroop，冲动性连续性能任务（CPT）和警惕CPT的性能表现相似，在简单的任务，测量警惕，冲动性和情绪干扰，但药物滥用者表现出更强的皮肤电导反应。药物滥用者在赌博和罗杰斯决策任务上表现更差，表明对后果的敏感性相对不足，风险承担增加;药物滥用者在这些任务中的皮肤电导增加也明显低于对照组。药物滥用者在所有任务中表现出较低的心率。我们得出的结论是，复杂的任务，涉及决策，对后果的敏感性和情绪调节的药物滥用者和控制之间的区别。由于风险决策是药物滥用的一个标志性行为表型，对其生物学基础的理解可能会为开发成瘾性疾病的治疗方法提供信息。因此，我们将测量这种功能的认知任务（罗杰斯决策任务）与局部脑灌注测量（PET-[O-15]-水）配对，以确定可能导致戒断药物滥用者（> 3个月）和健康对照受试者这种类型决策缺陷的大脑结构或回路。与对照组相比，药物滥用者表现出更大的风险承担和对奖励的敏感性。他们还表现出任务相关的左膝前扣带皮层失活，而对照组显示激活。在药物滥用组中，任务表现与右侧杏仁核、左侧前扣带回、左侧眶额皮质和左侧顶小叶的激活呈负相关，但与右侧杏仁核的激活呈正相关。药物滥用严重程度与右内侧眶额活动呈正相关。控制组被试的激活与任务绩效之间无显著相关。任务相关的区域灌注和风险决策之间的不同关联，比较两组，表明在一个分布式网络的药物滥用者响应这种类型的认知挑战的皮质边缘区的异常反应。 美沙酮维持治疗是阿片类药物成瘾的主要治疗方法，但围绕其在长期治疗中使用的优点存在争议。15名无美沙酮（6-24个月）阿片类药物滥用者，12名接受美沙酮维持（稳定剂量超过6个月）的阿片类药物滥用者和13名对照受试者参加了本研究。美沙酮戒断受试者在双侧膝周和左侧扣带回中部的相对代谢活性较低，通过[F-18]氟脱氧葡萄糖和PET测量。与此相反，美沙酮维持组受试者在左侧丘脑、丘脑和左侧顶下小叶表现出较低的相对活性（与对照组相比）;然而，他们在膝周前扣带回和右侧顶下小叶中的活性高于对照组。在美沙酮戒断受试者中，抑郁的测量与左膝周回和中扣带回的相对活动呈正相关;在对照受试者中，类似的关联呈负相关。美沙酮维持的受试者表现出负协方差之间的状态措施的抑郁症和相对活动的右下顶叶小叶和右膝周前扣带回，抑郁症和相对活动的左下顶叶小叶之间的特质措施。美沙酮维持治疗可改善负性情感状态下神经回路的功能异常，但可抑制阿片受体密度高的某些区域的脑功能。 我们证明了重度大麻使用者在爱荷华州决策任务中表现出缺陷，但与非使用者相比，在Stroop冲突任务中没有表现出缺陷。使用基于体素的形态测量法，发现重度大麻使用者的样本在结构MR图像上的前叶区域和中央前回的脑组织组成（灰质和白色物质）与非使用者相比发生了改变。

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 and regional cerebral blood flow using [O-15]-water and and magnetic resonance imaging (MRI) to evaluate structural sequelae of drug abuse. The prefrontal cortex and its connections to limbic structures modulate particular aspects of executive cognitive and emotional regulatory functions that may be impaired in drug abusers, e.g., impulse control, decision-making, sustained attention, risk taking, and arousability. Performance of abstinent drug abusers (N=21) and nonuser control participants (N=20) in the Emotional Stroop, an impulsivity continuous performance task (CPT) and a vigilance CPT revealed similar performance during simple tasks that measured vigilance, impulsivity and emotional interference, but drug abusers showed stronger skin conductance responses. Drug abusers performed more poorly on the Gambling and Rogers Decision Making Tasks, suggesting relative deficits in sensitivity to consequences and increased risk taking; drug abusers also showed significantly less increase in skin conductance than controls during these tasks. Drug abusers exhibited lower heart rates throughout performance on all tasks. We concluded that complex tasks involving decision-making, sensitivity to consequences and emotional regulation discriminated between drug abusers and controls. As risky decision-making is a hallmark behavioral phenotype of drug abuse, an understanding of its biological bases might inform efforts to develop therapies for addictive disorders. We therefore paired a cognitive task that measures this function (Rogers Decision-making Task) with measures of regional cerebral perfusion (PET-[O-15]-water) to identify brain structures or circuits that may underlie deficits in this type of decision-making in abstinent drug abusers (> 3 months) and healthy control subjects. The drug abusers showed greater risk-taking and heightened sensitivity to rewards than the control subjects. They also exhibited task-related deactivation of the left pregenual anterior cingulate cortex, whereas the control subjects showed activation. In the drug abuser group, performance on the task negatively correlated with activation in the right amygdala, left anterior cingulate gyrus, left lateral orbitofrontal cortex, and left parietal lobule, but positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. No significant correlations were found between activation and task performance of control subjects. The different associations between task-related regional perfusion and risky decision-making, comparing the two groups, suggest an abnormal response in a distributed network of corticolimbic regions in drug abusers responding to this type of cognitive challenge. Methadone maintenance is the primary treatment for opiate addiction, but controversy surrounds the merits of its use in long-term treatment. Fifteen methadone-free (6-24 months) opiate abusers, twelve opiate abusers receiving methadone maintenance (stable dose over 6 months), and thirteen control subjects participated in this study. Methadone-withdrawn subjects had lower relative metabolic activity measured by [F-18]fluorodeoxyglucose and PET than control subjects in bilateral perigenual and the left middle cingulate gyrus. In contrast, methadone-maintained subjects exhibited lower relative activity (vs. control) in the left insula, the thalamus, and the left inferior parietal lobule; however, they exceeedded control aactivity in the perigenual anterior cingulate gyrus and the right inferior parrietal lobule. Measures of depression covaried positively with relative activity in the left perigenual and mid-cingulate gyrus in methadone-withdrawn subjects; analogous associations in control subjects covaried negatively. Methadone-maintained subjects exhibited negative covariance between state measures of depression and relative activity in the right inferior parietal lobule and the right perigenual anterior cingulate, and between trait measures of depression and relative activity in the left inferior parietal lobule. Methadone maintenance ameliorates functional abnormalities in the neural circuitry sub-serving negative affective states, but depresses brain function in some regions of high opiate receptor density. We demonstrated that heavy marijuana users have performance deficits on the Iowa decision-making task, but not on the Stroop conflict task when compared to non-users. A sample of heavy marijuana users was found to have altered brain tissue composition (gray matter and white matter) in the hippocampa region and precentral gyrus on structural MR images compared to non-users using voxel-based morphometry.