Neurocomputational and fMRI Studies of Motivational Deficits in Schizophrenia

描述（由申请人提供）：尽管阴性症状，如快感缺乏（对快乐的体验和/或预期减弱）和任性（从事目标导向行为的倾向减少）是精神分裂症（SZ）精神病理中使人衰弱和难以治疗的方面，但对其神经基础及其相互关系知之甚少。人们通常认为，“无欲”源于对快感的迟钝体验，但是，尽管这一观点具有直观的吸引力，但其直接证据有限。我们小组最近的工作表明，大脑对强化物的反应与SZ患者的阴性症状评分相关。此外，我们发现对阴性症状评分较高的SZ患者在不确定的情况下也表现出较低的探索替代反应的意愿。我们的主要目标是通过研究SZ患者及其一级亲属中基于价值的决策（DM）和基于先前结果的价值表征更新的神经过程，来促进对SZ阴性症状的机制理解。我们假设对奖励的异常神经反应导致精神分裂症大脑中期望值（EV）表征的退化。此外，基于最近发现的不确定性在调节学习和DM中的作用，我们将探讨异常不确定性加工对SZ动机损伤的可能贡献。具体来说，不确定性被认为是通过调节出人意料的结果（称为预测误差）对关联强度变化的影响来影响学习的。不确定性在推动探索以最大限度地获取所获得的信息方面也发挥了作用。神经影像学研究表明，背前扣带皮层（dACC）和顶叶皮层都参与了不确定性的处理。重要的是，在SZ的DM研究中发现的神经影像学结果指向这些区域的功能障碍。我们提出了一套MRI实验，旨在检验：(i)避免损失对学习的相对影响、收益和实例；（ii）不确定性对价值更新的影响；(3)基于价值的选择的神经基础；(4)不确定性驱动的探索背后的神经过程。我们假设，在某种程度上，SZ的进化是由对积极结果的神经反应减弱以及对奖励的预期降低所驱动的。我们进一步提出，即使结果是正常的，如果与不确定性相关的神经信号异常，SZ仍然可能出现动机缺陷，导致异常的价值更新和不稳定或减少的探索。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对SZ的快感缺乏和进化的机制理解。这种机制的理解将对开发更好的治疗精神分裂症阴性症状的方法具有重要意义。

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.