Validation of a functional MRI-based reward processing task as a non-invasive too

验证基于功能性 MRI 的奖励处理任务也是非侵入性的

• 批准号: 7818654
• 负责人: Mary Louise Phillips
• 金额: $ 48.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7818654
• 关键词: Acute; Address; Adult; Affect; Alcoholism; Alcohols; American; Amphetamines; Animals; Area; Arterial Lines; Attention Deficit Disorder; Attention deficit hyperactivity disorder; Binding; Biological Markers; Bipolar Disorder; Brain; Brain region; Calibration; Chemicals; Clinical; Corpus striatum structure; Development; Dextroamphetamine; Disease; Dopamine; Dorsal; Drug Addiction; Event; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Human; Imaging Techniques; Impulsive Behavior; Impulsivity; Individual; Intervention; Measures; Mental disorders; Methylphenidate; Mood Disorders; Morbidity - disease rate; Neurotransmitters; Oral; Outcome; Pharmaceutical Preparations; Physiological; Population; Positron-Emission Tomography; Prevalence; Prevention strategy; Primary Prevention; Process; Raclopride; Radiation; Regulation; Reporting; Research Support; Rewards; Risk; Role; Schizophrenia; Signal Transduction; Staging; Substance Use Disorder; Substance abuse problem; System; Techniques; Unipolar Depression; Validation; Work; Youth; addiction; base; critical developmental period; depression; design; disability-adjusted life years; disorder risk; dopamine system; emerging adult; healthy volunteer; high risk; imaging probe; in vivo; insight; male; mortality; neuroimaging; neuropsychiatry; neuroregulation; patient population; psychostimulant; public health relevance; radiotracer; receptor; relating to nervous system; reward processing; trait; transmission process

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge topic, 03-MH-101*: Biomarkers in mental disorders. Psychiatric Disorders such as alcohol and other substance abuse disorders, unipolar depression, bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) are amongst the most significant causes of morbidity and mortality in the USA. Although treatments for these disorders are available they are less than adequate. Prevention strategies for these disorders are key to any future reduction in morbidity and mortality. Abnormal function in reward systems is associated with these major psychiatric disorders. An increasingly large body of research supports the role of two central brain regions, the ventral and dorsal striatal regions, in reward processing, particularly the ventral striatal (VS) region. Increasing evidence from animal studies and human neuroimaging studies involving pharmacological challenge with amphetamine and methylphenidate support the role of dopamine (DA) release in reward-related ventral striatal (VS) functioning. Better understanding of abnormalities in neurotransmitter function associated with functional abnormalities in reward systems observed in these psychiatric disorders is a vital step forward in the development of strategies to identify those at risk who may best benefit from primary preventative interventions. Furthermore, such understanding will inform the development of new treatments that target alterations in reward systems in these different psychiatric disorders. The essential initial step in these developments is the characterization of the relationship between the neural substrates of reward processing and dopaminergic function in healthy young individuals in early adulthood, a critical developmental period, during which risk for the above psychiatric disorders increases. To do this, we aim to use functional magnetic resonance imaging (fMRI) and [11C]raclopride Positron Emission Tomography (PET) during a physiological challenge (monetary reward task) and a pharmacological challenge, (d-amphetamine) in healthy adults (N =24, 12 females/12 males). From this work we will develop a pharmacologically informed fMRI probe that can then be utilized in future studies in patient populations and youth at high risk. We have three main aims and hypotheses. 1. We want to assess the relationship between the magnitude of VS activity (measured as the regional change, in BOLD fMRI signal) and DA release (measured as the change in [11C]raclopride binding, abbreviated to BPND) during a monetary reward task. Our hypotheses is that in healthy individuals greater magnitude of VS BOLD signal change will be associated with greater VS DA release (measured as greater displacement of the radiotracer [11C]raclopride) during the same monetary reward task. 2. Our second aim is to assess the relationship between magnitude of VS activity (measured as the change in BOLD fMRI signal) during a monetary reward task and amphetamine-induced VS DA release (measured as the change in [11C]raclopride BPND following oral amphetamine 0.5 mg/kg). Our hypothesis for this second aim is that in healthy individuals greater magnitude of VS BOLD signal change during the monetary reward task will be associated with greater amphetamine-induced DA release. Our third aim is to examine the relationship of impulsivity and change in VS BOLD signal with physiological and pharmacological change in [11C]raclopride BPND as first stage toward understanding how abnormal VS DA transmission may be associated with impulsive behaviors associated with the above psychiatric disorders. Our hypothesis is that in healthy volunteers there will be a positive relationship between the magnitude of VS BOLD signal change during the monetary reward task and impulsivity. We will explore the relationship between these measures and VS physiological and amphetamine-induced DA release. In further exploratory analyses we will assess the relationship between the magnitude of task-induced VS DA release and amphetamine-induced VS DA release hypothesizing that they will be highly correlated. The findings of the proposed study have implications for understanding the pathophysiology and treatment of psychiatric disorders that involve the disruption of neural reward circuits and will have a number of potential impacts.These center around an understanding of the pathophysiology of these disorders, the development of usable biomarkers for the identification of those most at risk of the development of disorder which will allow appropriately targeted primary prevention and finally, the development of pathophysiologically based treatments. In addition, the multi-modal approach in this study will validate the use of fMRI alone in young high risk populations unable to undergo PET studies involving radiation and pharmacological challenges. The techniques developed and validated in the proposed study will therefore pave the way for future studies of dopamine system functioning in clinical and high-risk populations utilizing fMRI alone. By identifying pathophysiologically based fMRI biomarkers and allowing primary prevention, these future studies will potentially have a major impact on the prevalence and outcome of alcohol and substance use disorders, unipolar depression, bipolar disorder, and impulsivity-related disorders such as ADHD, which currently together affect at least 17% of the US population in any 12-month period and comprise some of the leading causes of lost disability-adjusted life years. PUBLIC HEALTH RELEVANCE: Psychiatric disorders such as alcoholism, drug dependence, depression, bipolar disorder and attention deficit disorder affect almost a fifth of Americans every year and are also some of the top causes of lost working years. We will combine functional Magnetic resonance imaging, (fMRI), which shows how the brain activates, and positron emission tomography, which shows how much the brain chemical dopamine is released during the activations. Understanding more about how the brain works like this will allow us to do studies using just fMRI that will identify people most at risk for these disorders before they get sick, hopefully allow us to stop them from getting sick and develop better treatments for those already sick.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (03) 生物标志物发现和验证以及特定挑战主题 03-MH-101*：精神障碍中的生物标志物。酒精和其他药物滥用障碍、单相抑郁症、双相情感障碍和注意力缺陷/多动障碍 (ADHD) 等精神疾病是美国发病率和死亡率的最重要原因之一。虽然这些疾病的治疗方法是可用的，但还不够。这些疾病的预防策略是未来降低发病率和死亡率的关键。奖励系统的异常功能与这些主要的精神疾病有关。越来越多的研究支持两个中央大脑区域（腹侧纹状体区域和背侧纹状体区域）在奖励处理中的作用，特别是腹侧纹状体（VS）区域。越来越多的动物研究和人类神经影像学研究涉及苯丙胺和哌醋甲酯的药理学挑战，支持多巴胺 (DA) 释放在奖赏相关的腹侧纹状体 (VS) 功能中的作用。更好地了解与这些精神疾病中观察到的奖励系统功能异常相关的神经递质功能异常，是制定策略以确定哪些高危人群最能从初级预防干预措施中受益的策略的重要一步。此外，这种理解将为针对这些不同精神疾病的奖励系统改变的新疗法的开发提供信息。这些发展的重要第一步是表征健康年轻个体在成年早期的奖励处理的神经基质与多巴胺能功能之间的关系，这是一个关键的发育时期，在此期间上述精神疾病的风险增加。为此，我们的目标是在健康成年人（N = 24，12 名女性/12 名男性）的生理挑战（金钱奖励任务）和药理学挑战（d-苯丙胺）期间使用功能磁共振成像（fMRI）和[11C]雷氯必利正电子发射断层扫描（PET）。通过这项工作，我们将开发一种药理学信息丰富的功能磁共振成像探针，可用于未来对高危患者群体和青少年的研究。我们有三个主要目标和假设。 1. 我们想要评估货币奖励任务期间 VS 活动强度（以 BOLD fMRI 信号的区域变化来衡量）和 DA 释放（以 [11C]雷氯必利结合的变化来衡量，缩写为 BPND）之间的关系。我们的假设是，在健康个体中，在相同的金钱奖励任务中，更大程度的 VS BOLD 信号变化将与更大的 VS DA 释放（以放射性示踪剂 [11C]雷氯必利的更大位移来测量）相关。 2. 我们的第二个目标是评估金钱奖励任务期间 VS 活动强度（以 BOLD fMRI 信号的变化来衡量）与安非他明诱导的 VS DA 释放（以口服安非他明 0.5 mg/kg 后 [11C]雷氯必利 BPND 的变化来衡量）之间的关系。我们对第二个目标的假设是，在健康个体中，在金钱奖励任务期间，更大程度的 VS BOLD 信号变化将与更大的安非他明诱导的 DA 释放相关。我们的第三个目标是检查冲动性和 VS BOLD 信号变化与 [11C]雷氯必利 BPND 的生理和药理学变化之间的关系，作为了解异常 VS DA 传输如何与上述精神疾病相关的冲动行为相关的第一步。我们的假设是，在健康志愿者中，金钱奖励任务期间 VS BOLD 信号变化的幅度与冲动之间存在正相关关系。我们将探讨这些措施与 VS 生理和安非他明诱导的 DA 释放之间的关系。在进一步的探索性分析中，我们将评估任务诱导的 VS DA 释放量与安非他明诱导的 VS DA 释放量之间的关系，假设它们高度相关。 拟议研究的结果对于了解涉及神经奖赏回路破坏的精神疾病的病理生理学和治疗具有重要意义，并将产生许多潜在影响。这些中心围绕了解这些疾病的病理生理学，开发可用的生物标志物来识别那些最有可能发生疾病的人，这将允许适当有针对性的一级预防，最后，开发基于病理生理学的治疗方法 治疗。此外，本研究中的多模式方法将验证功能磁共振成像在无法接受涉及放射和药理学挑战的 PET 研究的年轻高危人群中的单独使用。因此，拟议研究中开发和验证的技术将为未来仅利用功能磁共振成像研究多巴胺系统在临床和高危人群中的功能铺平道路。通过识别基于病理生理学的 fMRI 生物标志物并进行一级预防，这些未来的研究可能会对酒精和物质使用障碍、单相抑郁症、双相情感障碍和冲动相关疾病（如多动症）的患病率和结果产生重大影响，这些疾病目前在任何 12 个月内总共影响至少 17% 的美国人口，是丧失伤残调整寿命的一些主要原因 年。 公共卫生相关性：酗酒、药物依赖、抑郁症、双相情感障碍和注意力缺陷障碍等精神疾病每年影响近五分之一的美国人，也是导致工作年限缩短的主要原因之一。我们将结合功能性磁共振成像（fMRI）和正电子发射断层扫描（显示大脑如何激活）和正电子发射断层扫描（显示激活过程中大脑化学多巴胺的释放量）。更多地了解大脑如何这样工作，将使我们能够仅使用功能磁共振成像进行研究，从而在人们生病之前识别出最有可能患这些疾病的人，希望能够让我们阻止他们生病，并为那些已经生病的人开发更好的治疗方法。