Using fMRI to Measure Negative Symptoms in Schizophrenia

使用功能磁共振成像测量精神分裂症的阴性症状

• 批准号: 7941959
• 负责人: Lars FREDRIK JARSKOG
• 金额: $ 49.95万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941959
• 关键词: Address; Affect; Affective; Affective Symptoms; Age; Amygdaloid structure; Anhedonia; Antipsychotic Agents; Area; Behavioral; Biological Markers; Biological Markers; Brain; Brain imaging; Brain region; Brain scan; Clinical; Corpus striatum structure; Delusions; Discrimination; Disease; Emotional; Event; Face; Feedback; Functional Magnetic Resonance Imaging; Gender; Goals; Hallucinations; Lead; Learning; Life; Measures; Mediating; Mental disorders; Outcome; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Probability; Process; Psyche structure; Reaction; Relative (related person); Research; Rewards; Schizophrenia; Symptoms; Testing; Time; Validation; Ventral Striatum; base; displeasure; experience; functional decline; hedonic; interest; pleasure; positive emotional state; public health relevance; relating to nervous system; research study; response; time interval

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area 03: Biomarker Discrimination and Validation, and the specific challenge topic: 03-MG-101, Biomarkers of mental disorders. Schizophrenia, a devastating psychiatric disorder, is chiefly characterized by positive symptoms, such as delusions and hallucinations, and negative symptoms, such as anhedonia (lack of pleasure), avolition (lack of willed-action), and a flattening of affect. While antipsychotic medications reduce positive symptoms, they provided little relief from negative symptoms. Thus patients with severe negative symptoms are likely to suffer continued functional decline, and have a very limited life. We believe that the lack of progress on treating negative symptoms may be due, in part, to the fact that they are typically measured by subjective means (e.g., a clinician's rating, a patient's self-report), and taken at face value. Our goal is to use as markers of negative symptoms the patients' neural responses to various rewards and losses while having their brains scanned by functional Magnetic Resonance Imaging (fMRI). Further, we will determine the consequences of these negative symptoms for basic learning processes. In our first experiment, we will test patients with schizophrenia as well as normal subjects (who are matched to the patients on factors like age and gender) on the same learning task. On each trial of the task, a subject has to decide which of two objects is more likely to lead to a reward (e.g., money), where the probability that each object leads to reward keeps changing slowly. The precise sequence of events on a trial is as follows: (1) the subject first makes a Choice between the objects, (2) next gets Feedback whether his/her choice is correct or wrong, and (3) then gets the actual Outcome--a monetary reward if the choice was Correct, and nothing if the choice was Wrong. Over trials, subjects gradually learn to choose the object that is more likely to lead to reward. To see the connection between this task and negative symptoms, consider the time interval between the Feedback and the Outcome phases. If the feedback is positive the subject should be anticipating reward during this interval, and the neural responses should reflect "anticipatory hedonia". Now consider the time interval between the actual Outcome and the start of the next trial. If money is the Outcome the subject should have a hedonic reaction, and the neural responses should reflect "reactive hedonia". Based on previous research, we know which regions of the brain are responsive to hedonic reactions, one of which is the ventral striatum, a subcortical area. By determining each subject's fMRI activity in these regions during the two time intervals just described, we can determine whether patients with schizophrenia show reduced anticipatory-hedonia, reduced reactive-hedonia, or both. Some behavioral experiments suggest that the main deficit for schizophrenics will be in anticipatory-hedonia, and accordingly we hypothesize that there will be more fMRI activity in the regions of interest in normal subjects than patients when subjects are anticipating a reward, but not necessarily when they are reacting to a reward. The degree of fMRI activity when anticipating a reward may provide a biological marker for the negative symptom of anhedonia; to assess this possibility, we will correlate our fMRI measure with standard clinical measures of anhedonia. We will also determine whether patients with schizophrenia and matched controls differ in their learning processes. When normal controls have their brains imaged while performing this learning task, the ventral striatum is among the main regions activated. Since the same brain region is involved in both learning and hedonia, and since patients show less activity in this region when anticipating a reward, patients may also be impaired in learning. It's not just that both mental activities depend on the same brain region; it's also that learning in this kind of task is known to depend on making predictions about whether reward will occur on that trial, and the prediction process itself seems to be fueled by anticipatory hedonia. Our second experiment is like the first one, except that instead of gaining rewards on some trials now subjects will lose money when their choice is Wrong (their losses will be taken from money given to them at the outset of the experiment). Again, each trial includes three phases: Choice, Feedback, and Outcome, with the latter being either a loss (following the feedback "Wrong"), or nothing (following the feedback "Correct"), and now the subject's goal is to learn to make the choice that will lead to less loss. If the feedback indicates a loss is coming, fMRI activity during the interval between Feedback and Outcome reflects anticipatory-displeasure (or avoidance), while the interval between the Outcome and the end of trial reflects reactive-displeasure. Should we find that, compared to matched controls, patients with schizophrenia again show less fMRI activity during the anticipatory-interval but not during the reactive-interval, we will have biological markers for another negative symptom, affective flattening, or reduced reactivity to emotional states be they positive or negative. PUBLIC HEALTH RELEVANCE: While standard antipsychotic medications reduce the positive symptoms of schizophrenia (e.g., delusions), they provide little benefit for the devastating negative symptoms of this disease (e.g., anhedonia, flattening of affect). The lack of progress in treating negative symptoms may be due to the fact that they are often measured by subjective means (a clinician' rating, a patient's self-report). Our goal is to use brain imaging to provide objective and biological markers of the various negative symptoms.

描述（由申请人提供）：本申请涉及广泛的挑战领域03：生物标志物的识别和验证，以及具体的挑战主题：03- mg -101，精神障碍的生物标志物。精神分裂症是一种毁灭性的精神疾病，其主要特征是阳性症状，如妄想和幻觉，以及阴性症状，如快感缺失（缺乏快乐）、不自主（缺乏自愿行动）和情感低落。虽然抗精神病药物可以减轻阳性症状，但它们对阴性症状的缓解作用很小。因此，有严重阴性症状的患者很可能遭受持续的功能衰退，寿命非常有限。我们认为，在治疗阴性症状方面缺乏进展，部分原因可能是它们通常是通过主观手段来衡量的（例如，临床医生的评级，患者的自我报告），并且只看表面价值。我们的目标是利用功能性磁共振成像（fMRI）扫描患者大脑时，患者对各种奖励和损失的神经反应作为阴性症状的标记。此外，我们将确定这些负面症状对基本学习过程的影响。在我们的第一个实验中，我们将测试精神分裂症患者以及正常受试者（他们在年龄和性别等因素上与患者相匹配）在相同的学习任务上的表现。在每次试验中，受试者必须决定两个物体中哪一个更有可能带来奖励（例如，钱），其中每个物体导致奖励的概率一直在缓慢变化。实验中事件的确切顺序如下：(1)受试者首先在物体之间做出选择，(2)接下来得到他/她的选择是对还是错的反馈，(3)然后得到实际的结果——如果选择是正确的，就会得到金钱奖励，如果选择是错误的，就什么也得不到。经过试验，受试者逐渐学会选择更有可能带来奖励的物体。要查看此任务与阴性症状之间的联系，请考虑“反馈”阶段和“结果”阶段之间的时间间隔。如果反馈是积极的，受试者应该在这段时间内期待奖励，神经反应应该反映出“预期性享乐”。现在考虑实际结果和下一次试验开始之间的时间间隔。如果金钱是结果，受试者应该有享乐反应，神经反应应该反映“反应性享乐”。根据之前的研究，我们知道大脑的哪个区域对享乐反应有反应，其中一个是腹侧纹状体，一个皮层下区域。通过确定每个受试者在上述两个时间间隔内这些区域的功能磁共振成像活动，我们可以确定精神分裂症患者是否表现出预期性快感减少，反应性快感减少，或两者兼而有之。一些行为实验表明，精神分裂症患者的主要缺陷是预期性享乐症，因此我们假设，当受试者预期奖励时，正常人感兴趣的区域会比患者有更多的fMRI活动，但当他们对奖励做出反应时，就不一定了。期待奖励时的fMRI活动程度可能为快感缺乏的负面症状提供生物学标记；为了评估这种可能性，我们将把fMRI测量与标准的快感缺乏临床测量相关联。我们还将确定精神分裂症患者和对照组在学习过程中是否存在差异。当正常人在完成学习任务时对他们的大脑进行成像时，腹侧纹状体是被激活的主要区域之一。由于同一个大脑区域同时参与学习和享乐，并且由于患者在预期奖励时该区域的活动较少，因此患者的学习能力也可能受损。这不仅是因为两种心理活动都依赖于同一个大脑区域；而且，在这类任务中学习，已知依赖于对该试验中是否会出现奖励的预测，而预测过程本身似乎是由预期享乐症推动的。我们的第二个实验与第一个实验相似，除了现在在某些试验中，当受试者选择错误时，他们将失去奖励（他们的损失将从实验开始时给他们的钱中扣除）。同样，每次试验都包括三个阶段：选择、反馈和结果，后者要么是失败（反馈“错误”），要么什么都没有（反馈“正确”），现在受试者的目标是学会做出能减少损失的选择。如果反馈表明损失即将到来，反馈和结果之间的fMRI活动反映了预期的不快（或回避），而结果和试验结束之间的间隔反映了反应性不快。如果我们发现，与对照组相比，精神分裂症患者在预期间歇期表现出更少的fMRI活动，而不是在反应间歇期，我们将有另一种阴性症状的生物学标记，情感平坦，或对情绪状态的反应减少，无论是积极的还是消极的。