Using fMRI to Measure Negative Symptoms in Schizophrenia

描述(由申请人提供)：本申请涉及广泛的挑战领域03：生物标记物识别和验证，以及具体的挑战主题：03-MG-101，精神障碍的生物标记物。精神分裂症是一种毁灭性的精神障碍，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(缺乏快感)、孤独感(缺乏意志力)和情感平淡。虽然抗精神病药物可以减少阳性症状，但它们对阴性症状的缓解作用很小。因此，出现严重阴性症状的患者可能会继续遭受功能衰退，并且生命非常有限。我们认为，在治疗阴性症状方面缺乏进展可能部分是由于这样一个事实，即这些症状通常是通过主观手段(例如，临床医生的评分、患者的自我报告)来衡量的，并以表面价值衡量。我们的目标是使用患者对各种奖赏和损失的神经反应作为阴性症状的标志，同时通过功能磁共振成像(FMRI)对他们的大脑进行扫描。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匹配)在相同的学习任务中。在任务的每一次试验中，受试者必须决定两个对象中哪一个更有可能导致奖励(例如，金钱)，其中每个对象导致奖励的概率保持缓慢变化。试验的准确顺序如下：(1)受试者首先在对象之间做出选择，(2)接下来得到他/她的选择是正确还是错误的反馈，以及(3)然后获得实际结果--如果选择是正确的，则获得金钱奖励，如果选择是错误的，则什么也得不到。在试验过程中，受试者逐渐学会选择更有可能带来奖励的对象。要了解这项任务和消极症状之间的联系，可以考虑反馈和结果阶段之间的时间间隔。如果反馈是积极的，那么受试者应该在这段时间内期待回报，神经反应应该反映出“预期享乐症”。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，那么受试者应该有一种享乐反应，神经反应应该反映出“反应性享乐症”。根据之前的研究，我们知道大脑的哪些区域对享乐反应有反应，其中之一是腹侧纹状体，皮质下的区域。通过确定每个受试者在上述两个时间间隔内这些区域的fMRI活动，我们可以确定精神分裂症患者是否表现出预期快感减少、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将是预期快乐症，因此我们假设，当受试者期待奖励时，正常受试者感兴趣区域的fMRI活动将比患者更多，但当他们对奖励做出反应时，不一定。期待奖励时的fMRI活动程度可能为快感缺乏的阴性症状提供一个生物学标志；为了评估这种可能性，我们将把我们的fMRI测量与快感缺乏的标准临床测量相关联。我们还将确定精神分裂症患者和匹配的对照组在学习过程中是否有所不同。当正常对照组在进行这项学习任务时对他们的大脑进行成像时，腹侧纹状体是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，而且由于患者在期待奖励时该区域的活动较少，患者在学习方面也可能受到损害。这不仅是因为这两种心理活动依赖于同一个大脑区域，而且众所周知，在这类任务中的学习依赖于对试验中是否会出现奖励的预测，而预测过程本身似乎受到了预期快乐症的推动。我们的第二个实验与第一个实验类似，不同的是，当受试者的选择错误时，他们会赔钱，而不是在一些实验中获得奖励(他们的损失将从实验开始时发给他们的钱中扣除)。同样，每一次试验都包括三个阶段：选择、反馈和结果，后者要么是失败(跟随反馈是“错误”的)，要么是什么都没有(跟随反馈“正确”)，现在受试者的目标是学会做出将导致更少损失的选择。如果反馈表明失败即将到来，反馈和结果之间的fMRI活动反映的是预期不高兴(或回避)，而结果和试验结束之间的间隔反映的是反应性不高兴。如果我们发现，与匹配的对照组相比，精神分裂症患者在预期区间但不是在反应区间再次显示较少的fMRI活动，我们将有另一种负面症状的生物标志物，情感平台化，或对情绪状态的反应性降低，无论他们是积极的还是消极的。 与公共卫生相关：虽然标准的抗精神病药物可以减少精神分裂症的阳性症状(如妄想症)，但它们对这种疾病的破坏性阴性症状(如快感缺乏、情感平缓)几乎没有好处。在治疗阴性症状方面缺乏进展可能是由于这样一个事实，即这些症状通常是通过主观手段(临床医生的评级，患者的自我报告)来衡量的。我们的目标是使用脑成像来提供各种阴性症状的客观和生物标记。

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.