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

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物的发现和验证以及特定的挑战主题，03- mh -101*：精神障碍中的生物标志物。精神疾病，如酒精和其他物质滥用障碍、单极抑郁症、双相情感障碍和注意力缺陷/多动障碍（ADHD）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，但还不够充分。这些疾病的预防战略是今后降低发病率和死亡率的关键。奖励系统功能异常与这些主要精神疾病有关。越来越多的研究支持两个中央脑区，腹侧纹状体区和背侧纹状体区，在奖励处理中的作用，特别是腹侧纹状体（VS）区域。来自动物研究和人类神经影像学研究的越来越多的证据，包括安非他明和哌甲酯的药理学挑战，支持多巴胺（DA）释放在奖励相关的腹侧纹状体（VS）功能中的作用。更好地了解在这些精神疾病中观察到的与奖励系统功能异常相关的神经递质功能异常，是制定策略的重要一步，有助于识别那些可能从初级预防干预中获益最多的高危人群。此外，这种理解将有助于开发针对这些不同精神疾病中奖励系统改变的新疗法。在这些发展中至关重要的第一步是表征在成年早期的健康年轻人中奖励加工和多巴胺能功能的神经基质之间的关系，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，我们在健康成人（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-安非他明）期间使用功能性磁共振成像（fMRI）和[11C]raclopride正电子发射断层扫描（PET）。从这项工作中，我们将开发一种药理学上知情的功能磁共振成像探针，然后可以在未来的研究中用于患者群体和高风险青年。我们有三个主要目标和假设。1. 我们想要评估在货币奖励任务中VS活动的大小（在BOLD fMRI信号中以区域变化来测量）和DA释放（以[11C]raclopride结合的变化来测量，缩写为BPND）之间的关系。我们的假设是，在相同的金钱奖励任务中，健康个体的VS BOLD信号变化幅度越大，VS DA释放越大（以放射性示踪剂[11C]raclopride的位移越大来测量）。2. 我们的第二个目标是评估货币奖励任务期间VS活动的强度（通过BOLD fMRI信号的变化来测量）与安非他明诱导的VS DA释放之间的关系（通过口服安非他明0.5 mg/kg后[11C]raclopride BPND的变化来测量）。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，VS BOLD信号变化的幅度越大，安非他明诱导的DA释放就越大。我们的第三个目的是研究冲动和VS BOLD信号变化与[11C]雷氯pride BPND的生理和药理学变化之间的关系，作为了解异常VS DA传递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，在健康的志愿者中，在金钱奖励任务中VS BOLD信号的变化幅度与冲动之间存在正相关关系。我们将探讨这些指标与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释放量和安非他明诱导的VS DA释放量之间的关系，假设它们将高度相关。

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.