Neurocomputational and fMRI Studies of Motivational Deficits in Schizophrenia

精神分裂症动机缺陷的神经计算和功能磁共振成像研究

• 批准号: 8441471
• 负责人: JAMES A WALTZ
• 金额: $ 36.52万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441471
• 关键词: Accounting; Address; Adult; Affect; Anhedonia; Animal Model; Anterior; Area; Attenuated; Automobile Driving; Behavior; Biological Markers; Brain; Characteristics; Chronic; Clinical; Complex; Corpus striatum structure; Data Set; Decision Making; Disease; Dorsal; Exhibits; Financial cost; First Degree Relative; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Healthcare Systems; Impairment; Individual; Knowledge; Lead; Learning; Light; Link; Magnetic Resonance Imaging; Mental disorders; Modeling; Motivation; Outcome; Parietal Lobe; Patients; Physiology; Play; Population; Prefrontal Cortex; Process; Proxy; Psychological reinforcement; Psychopathology; Public Health; Relative (related person); Resistance; Rewards; Role; Schizoid Personality Disorder; Schizophrenia; Services; Signal Transduction; Stimulus; Symptoms; Testing; Therapeutic; Translating; Uncertainty; Unemployment; Update; Work; base; cingulate cortex; design; disability; experience; functional disability; hedonic; interest; neuroimaging; pleasure; reinforcer; relating to nervous system; research study; response; stem; trait; willingness

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.

描述（由申请人提供）：虽然阴性症状，如快感缺乏（迟钝的体验和/或对快乐的预期）和无意志（参与目标导向行为的倾向降低），是精神分裂症（SZ）精神病理学的衰弱和治疗抗性方面，但对其神经基础及其相互关系知之甚少。人们通常认为，逃避源于在深圳的一种迟钝的快乐体验，但是，尽管这种想法直观上很吸引人，但直接证据有限。我们小组最近的工作表明，SZ患者对药物的大脑反应与阴性症状的评级相关。此外，我们发现，SZ患者的阴性症状评分高，也显示出降低的意愿，探索响应的替代品时，不确定的。我们的主要目标是通过调查SZ患者及其一级亲属基于价值的决策（DM）和基于先前结果的价值表征更新的神经过程，促进对SZ阴性症状的机械理解。我们认为，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，基于最近的研究结果的不确定性在调节学习和DM的作用，我们将调查可能的贡献异常的不确定性处理的动机障碍在SZ。具体来说，不确定性被认为是通过调节令人惊讶的结果（称为预测错误）对关联强度变化的影响来影响学习。不确定性在推动勘探以最大限度地获取信息方面也发挥了作用。神经影像学研究表明，背侧前扣带皮层（dACC）和顶叶皮层都参与了不确定性的处理。重要的是，SZ DM研究的神经影像学结果表明这些区域功能障碍。我们提出了一组MRI实验，旨在研究：（i）相对影响和收益和损失避免学习的情况下;（ii）价值更新的不确定性的影响;（iii）基于价值的选择的神经基础;（iv）神经过程的不确定性驱动的探索。我们假设，在SZ的avolition是，在一定程度上，由衰减的神经反应，积极的结果和随之而来的预期减少奖励。我们进一步提出，即使结果是正常的，动机赤字仍然可能出现在SZ，如果神经信号相关的不确定性是异常的，导致异常值更新和不稳定的，或减少，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存在于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中快感缺乏和无意识的机制性理解。这样一种机制性的理解将对开发更好的精神分裂症阴性症状治疗方法具有重要意义。