Neurocomputational and fMRI Studies of Motivational Deficits in Schizophrenia

描述(由申请人提供)：虽然阴性症状，如快感缺乏(钝化的体验和/或对快乐的预期)和孤独感(从事目标导向行为的倾向减少)，是精神分裂症(SZ)精神病理学中虚弱和治疗抵抗的方面，但人们对它们的神经基础和相互关系知之甚少。人们经常认为，爱情源于在深圳的一次迟钝的快乐体验，但尽管这一想法具有直觉上的吸引力，但直接证据有限。我们小组最近的研究表明，对强化剂的大脑反应与SZ患者的阴性症状分级相关。此外，我们还发现，阴性症状评分高的SZ患者在不确定时也表现出探索替代反应的意愿降低。我们的主要目标是通过研究SZ患者及其一级亲属基于价值的决策(DM)的神经过程和基于先前结果的价值表征的更新，来促进对SZ阴性症状的机械性理解。我们假设，对奖励的异常神经反应导致精神分裂症患者大脑中期望值(EV)的表征退化。此外，根据最近发现的不确定性在调节学习和DM中的作用，我们将调查异常不确定性处理对SZ动机障碍的可能贡献。具体地说，不确定性被认为是通过调节令人惊讶的结果(称为预测误差)对联想强度变化的影响来影响学习的。在推动探索以最大限度地利用所获得的信息方面，也确立了不确定性的作用。神经影像研究表明，背侧前扣带回皮质(DACC)和顶叶皮质都参与了不确定性的加工。重要的是，深圳糖尿病研究的神经成像结果表明，这些区域存在功能障碍。我们提出了一组MRI实验，旨在检验：(I)损失避免对学习的相对影响、收益和实例；(Ii)不确定性对价值更新的影响；(Iii)基于价值的选择的神经基础；以及(Iv)潜在的不确定性驱动的探索的神经过程。我们假设，SZ的悲痛情绪在一定程度上是由对积极结果的神经反应减弱以及随之而来的对回报的预期降低所驱动的。我们进一步提出，即使体验正常的结果，如果与不确定性相关的神经信号异常，导致异常的价值更新和不稳定的或减少的探索，SZ仍然可能出现动机缺陷。最后，我们预计，在SZ患者中观察到的许多异常神经信号将出现在SZ患者的一级亲属中。我们建议，我们提出的实验结果将有助于从机制上理解SZ患者的快感缺失和失眠。这种机械性的理解将对开发更好地治疗精神分裂症的阴性症状具有重要意义。 与公共卫生相关：精神分裂症是一种复杂的精神障碍，影响大约1%的人口，导致超过三分之一的受影响个人在成年后长期残疾，并造成巨大的公共卫生负担，因为精神分裂症患者的失业率极高，公共卫生保健系统的财政成本巨大。由于精神分裂症的功能性残疾与精神障碍的负面症状之间存在密切关系，如快感缺失(体验快乐的能力降低)和精神分裂(动力降低)，因此在理解和开发治疗这类症状的治疗机制方面取得进展至关重要。这项拟议项目的目标是调查精神分裂症患者及其一级亲属基于奖励的学习和动机背后的神经过程，以增加我们对阴性症状起源的了解，并确定潜在的治疗目标。

DESCRIPTION (provided by applicant): Although negative symptoms, such as anhedonia (the blunted experience and/or anticipation of pleasure) and avolition (a reduced tendency to engage in goal-directed behavior), are among the debilitating and treatment-resistant aspects of the psychopathology of schizophrenia (SZ), little is known about their neural basis and their inter-relationships. It has often been thought that avolition stems from a blunted experience of pleasure in SZ, but, despite the intuitive appeal of this idea, direct evidence for it is limited. Recent work from our group indicates that brain responses to reinforcers correlate with ratings of negative symptoms in SZ patients. Furthermore, we have found that SZ patients with high ratings for negative symptoms also show a reduced willingness to explore response alternatives when uncertain. Our primary goal is to contribute to a mechanistic understanding of negative symptoms in SZ by investigating neural processes underlying value-based decision making (DM) and the updating of value representations based on prior outcomes, in SZ patients and their first-degree relatives. We posit that abnormal neural responses to rewards lead to degraded representations of expected value (EV) in the schizophrenic brain. Furthermore, based on recent findings of a role for uncertainty in modulating learning and DM, we will investigate a possible contribution of aberrant uncertainty processing to motivational impairments in SZ. Specifically, uncertainty is thought to influence learning by modulating the impact of surprising outcomes, called prediction errors, on changes in the strength of associations. A role for uncertainty has also been established in driving exploration in the service of maximizing the information obtained. Neuroimaging studies have implicated both dorsal anterior cingulate cortex (dACC) and parietal cortex in the processing of uncertainty. Importantly, neuroimaging findings from studies of DM in SZ point to dysfunction in these areas. We propose a set of MRI experiments designed to examine: (i) the relative impact and gains and instances of loss-avoidance on learning; (ii) the impact of uncertainty on value updating; (iii the neural basis of value- based choice; and (iv) neural processes underlying uncertainty-driven exploration. We hypothesize that avolition in SZ is, in part, driven by an attenuated neural response to positive outcomes and a consequent reduced anticipation of rewards. We further propose that, even if outcomes were experienced normally, motivational deficits could still arise in SZ if neural signals related to uncertainty were aberrant, leading to abnormal value updating and erratic, or reduced, exploration. Finally, we anticipate that many of the aberrant neural signals observed in SZ patients will be present in first-degree relatives of SZ patients We propose that the results of our proposed experiments will contribute to a mechanistic understanding of anhedonia and avolition in SZ. Such a mechanistic understanding would have important implications for developing better treatments for the negative symptoms of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex mental disorder affecting approximately 1% of the population, that results in chronic disability for more than 3 of affected individuals through their adult lives, as well as a tremendous public health burden, in terms of the extremely high rate of unemployment in individuals with schizophrenia and the enormous financial costs to public health care system. Because of the close relationship between functional disability in schizophrenia and negative symptoms of the disorder, such as anhedonia (a reduced ability to experience pleasure) and avolition (reduced motivation), it is critical that progress be made in understanding and developing therapeutic mechanisms for treating this class of symptoms. The goal of the proposed project is to investigate the neural processes underlying reward-based learning and motivation in patients with schizophrenia, and their first-degree relatives, in order to increase our knowledge of the origins of negative symptoms and to identify potential treatment targets.