Characterizing and Predicting Drug Effects on Cognition

表征和预测药物对认知的影响

基本信息

批准号：
9065623
负责人：
SUSAN E MARINO
金额：
$ 55.16万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065623
关键词：
Address Adult Adverse effects Affect Alzheimer&apos s Disease Anti-Cholinergics Antiepileptic Agents Antipsychotic Agents Area Attention Behavior Brain Brain imaging Brain region Cerebellum Characteristics Clinical Clinical Pharmacology Cognition Cognitive Cognitive deficits Communication Complex Comprehension Computational Linguistics Cross-Over Studies Data Dementia Development Disease Dose Double-Blind Method Drug Exposure Drug Kinetics Drug usage Electroencephalography Engineering Epilepsy Foundations Frequencies Future Generations Goals Grant Impaired cognition Impairment Individual Investigation Laboratories Language Life Linguistics Maintenance Malignant Neoplasms Measures Medical Memory Mental Depression Mental disorders Methodology Methods Migraine Modeling Neurosciences Obesity Pain Parietal Lobe Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacotherapy Phase Physiological Placebos Plasma Process Production Prophylactic treatment Psycholinguistics Randomized Regimen Reporting Research Retrieval Short-Term Memory Speech System Testing Therapeutic Agents Time Titrations Translating Work cognitive development cognitive performance cognitive process design drug development executive function experience frontal lobe improved outcome indexing individual patient innovation insight long term memory memory process multidisciplinary neurophysiology neuropsychological novel novel therapeutics patient subsets prototype response targeted treatment tool topiramate

项目摘要

DESCRIPTION (provided by applicant): Drug therapy for a wide range of common disorders, including epilepsy, depression, and cancer often produces adverse cognitive side effects that are disruptive to daily life. They can be particularly debilitating when an essential function, suc as verbal communication, is adversely affected. However, little is known about the mechanisms underlying a drug's impact on cognition and consequently why some individuals are more prone to experience drug-induced cognitive deficits than others. The long-term goal of this project is to enhance clinical strategies and inform drug development in order to maximize the benefits of individual medication therapy while minimizing adverse cognitive/language-related side effects. TPM, a second generation and broad spectrum antiepileptic drug, is an ideal, initial choice for our studies because, in addition to being associated with adverse effects on attention and memory, it has a unique cognitive signature affecting language use in a subset of patients. Moreover, the mechanism by which TPM affects cognition, including linguistic behavior, has not been well established. The objective of this application is to elucidate the relationship among TPM exposure as measured by plasma drug levels, its neurophysiological effects, and consequent effect on the cognitive processes observable in everyday language. In order to accomplish this objective, the tools of clinical pharmacology, computational linguistics, neuroscience, and engineering will be applied to the design and execution of randomized, double blind, crossover studies using several levels of TPM exposure in healthy adults. A novel system for automated language and speech analysis (SALSA) makes possible an objective and quantitative characterization of linguistic behavior as reflected in spontaneous speech. SALSA, EEG, and pharmacokinetic-pharmacodynamic analyses will be used to achieve the specific aims of this grant: 1. Characterize TPM-induced effects on linguistic behavior 2. Determine the neurophysiological effects of TPM on recognized ERP indices of verbal working memory load and 3. Predict individual vulnerability to TPM-induced impairments in linguistic, memory, and executive functions. Achieving these aims will offer insight into the mechanisms underlying drug-induced cognitive deficits. It will also lay the foundation for a new line of research that wil further delineate these mechanisms and provide methods to predict individual patient response. Having an understanding of the physiological mechanism(s) that underlie language use and their relationship to spontaneous speech will enable us to apply this methodology in conjunction with state-of-the- art brain imaging and pharmacokinetic-pharmacogenomic analyses to obtain a comprehensive picture of how cognitive-impairing and, later, cognitive-enhancing medications interact with individual characteristics. Future directions will extend this approach to patients across different disorders (e.g., epilepsy, Alzheimer's) and multiple drug classes (e.g., anticholinergics, antipsychotics).

描述（由申请人提供）：用于多种常见疾病的药物治疗，包括癫痫，抑郁症和癌症，通常会产生对日常生活破坏性的不良认知副作用。当基本功能（作为口头交流）受到不利影响时，他们可能会特别使人衰弱。但是，关于药物对认知影响的影响的机制知之甚少，因此为什么有些人比其他人更容易经历药物引起的认知缺陷。该项目的长期目标是增强临床策略并为药物开发提供信息，以最大程度地提高单个药物疗法的益处，同时最大程度地减少不良认知/语言相关的副作用。 TPM是第二代和广泛的抗癫痫药，是我们研究的理想选择，因为除了对注意力和记忆的不利影响相关联，它还具有影响语言使用的独特认知信号。此外，TPM影响认知（包括语言行为）的机制尚未得到充分确立。该应用的目的是通过血浆药物水平衡量TPM暴露之间的关系，其神经生理效应以及对日常语言中可观察到的认知过程的影响。为了实现这一目标，临床药理学，计算语言学，神经科学和工程的工具将应用于健康成年人中使用多个TPM暴露的随机，双盲，跨界研究的设计和执行。一种新型的自动语言和语音分析系统（SALSA）使自发语音反映的语言行为的客观和定量表征成为可能。 SALSA, EEG, and pharmacokinetic-pharmacodynamic analyses will be used to achieve the specific aims of this grant: 1. Characterize TPM-induced effects on linguistic behavior 2. Determine the neurophysiological effects of TPM on recognized ERP indices of verbal working memory load and 3. Predict individual vulnerability to TPM-induced impairments in linguistic, memory, and executive functions.实现这些目标将提供有关药物引起的认知缺陷的机制的洞察力。它还将为一项新的研究奠定基础，该研究将进一步描述这些机制，并提供预测个体患者反应的方法。了解基于语言使用及其与自发语音的关系的生理机制将使我们能够与最先进的脑成像和药代动力学 - 症状基础分析一起运用这种方法，以获得认知影响以及后来的认知能力互动的各个特征的全面图景。未来的方向将把这种方法扩展到跨不同疾病（例如癫痫，阿尔茨海默氏症）和多种药物类（例如抗胆碱能药物，抗精神病药）的患者。