PHARMACOLOGICAL BASIS OF DECISION-MAKING

描述(改编自申请者摘要)：该项目的长期目标是阐明决策的药理学基础，这一术语在心理学文献中经常被称为“执行功能”，并将所获得的知识应用于药物滥用的治疗和预防。物质滥用者和有腹内侧额前额叶损害的患者都有决策障碍。在这里，我们计划研究额叶患者，并将研究结果推广到药物滥用者。这项建议是由一个理论框架指导的，该框架旨在解释推理和决策方面的缺陷，这些缺陷在额叶患者中非常突出。该假说认为，这些决策缺陷，特别是那些涉及个人和社会行为的缺陷，是躯体标记激活缺陷的结果，这些标记通常作为隐蔽或公开的标志，帮助做出对有机体有利的选择过程。在过去的几年里，我们研究了神经网络的解剖学、生理学和认知学方面的问题，该神经网络被认为是决策和躯体标记激活的基础。我们发现，躯体状态的失败是由于神经系统的功能障碍造成的，其中腹内侧(VM)前额叶皮质是其中一个关键区域。然而，其他神经区域，包括杏仁核和躯体感觉皮质(SI、SII和脑岛)也被假设为同一神经系统的组成部分。这一系统的运行被认为是通过直接或间接的解剖学联系受到非特异性神经递质系统的影响。然而，这些神经递质系统的性质还没有被阐明。使用我们在对这些患者的研究中完善的实验策略，我们建议进行特定的神经递质操作，并调查它们对正常人和额叶病变患者决策的影响。此外，我们计划研究与决策相关的另一种额叶功能，即工作记忆，是如何受到相同操作的影响的。最近的证据表明，物质滥用者患有决策障碍，正如我们用来研究额叶患者的相同实验室测试所揭示的那样。正在进行的调查正在进一步探索决策、额叶和药物滥用之间的联系。因此，该项目的结果将有助于开发药物疗法，帮助1)药物滥用者康复；2)许多因头部损伤、中风和手术切除肿瘤而导致执行功能障碍的患者。

DESCRIPTION (adapted from applicants abstract): The long term goal of this project is elucidation of the pharmacological basis of decision making, a term which is often referred to in the psychological literature as "executive functions," and the application of the derived knowledge to the treatment and prevention of substance abuse. Both substance abusers and patients with ventromedial prefrontal frontal lobe lesions suffer from impairments in decision-making. Here we plan to study frontal patients and extend the findings to substance abusers. The proposal is guided by a theoretical framework designed to account for the defects in reasoning and decision-making that are so salient in frontal patients. The hypothesis posits that those decision-making defects, specifically those which involve personal and social behavior, are the results of defective activation of somatic markers that normally function as covert or overt signposts for helping with the process of making choices which are advantageous to the organism. In the past few years, we investigated the anatomical, physiological, and cognitive aspects of the neural network presumed to underlie decision-making and somatic marker activation. We found that the failure to enact somatic states results from dysfunction in a neural system in which the ventromedial (VM) prefrontal cortex is one critical region. However, other neural regions, including the amygdala and somatosensory cortices (SI, SII, and insula) are also hypothesized to be components of that same neural system. The operation of this system is thought to be influenced by non-specific neurotransmitter systems through direct or indirect anatomical connections. However, the nature of these neurotransmitter systems, has not been elucidated. Using experimental strategies which we perfected in the study of these patients, here we propose to carry out specific neurotransmitter manipulations and investigate their effects on decision-making in normals and in patients with frontal lobe lesions. In addition, we plan to investigate how another frontal lobe function, namely working memory, is affected by the same manipulations, relative to decision-making. Recent evidence has established that substance abusers suffer from decision-making impairments as revealed by the same laboratory tests which we used to study frontal patients. Ongoing investigations are probing further the link between decision-making, the frontal lobe, and substance abuse. Therefore, the results from this project will help the development of pharmacological therapies that assist in the rehabilitation of 1) substance abusers; and 2) many patients who suffer from disturbances of executive function caused by head injury, stroke, and surgical ablation of tumors.