Clinical and Computational Studies of Dopamine Function in Schizophrenia

精神分裂症多巴胺功能的临床和计算研究

• 批准号: 9441146
• 负责人: James M. Gold
• 金额: $ 13.49万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-25 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441146
• 关键词: Address; American; Anhedonia; Animal Model; Architecture; Area; Attention; Attitude; Avoidance Learning; Back; Basal Ganglia; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Belief; Clinical; Clinical Research; Clinical Treatment; Cognitive; Cognitive deficits; Computer Simulation; Computing Methodologies; Conflict (Psychology); Costs and Benefits; Coupled; Decision Making; Delusions; Dimensions; Dopamine; Electroencephalography; Electrophysiology (science); Equation; Equilibrium; Evidence based intervention; Exploratory Behavior; Failure; Feedback; Formulation; Funding; Goals; Hallucinations; Illness impact; Impairment; Influentials; Intervention; Laboratories; Lead; Learning; Link; Measurement; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Motivation; National Institute of Mental Health; Nature; Neurosciences; Outcome; Patients; Performance; Prefrontal Cortex; Process; Psychological Models; Psychological reinforcement; Psychopathology; Rehabilitation therapy; Research; Research Domain Criteria; Response to stimulus physiology; Rewards; Schizophrenia; Severities; Shapes; Short-Term Memory; Signal Transduction; Specific qualifier value; Stimulus; Symptoms; System; Testing; Time; Translating; Uncertainty; Work; base; cognitive rehabilitation; computer studies; cost; disability; dopamine system; drug development; evidence base; experience; experimental study; insight; learning outcome; memory process; motivational processes; neural circuit; neuromechanism; neurophysiology; neurotransmission; novel; predictive of treatment response; programs; psychiatric rehabilitation; public health relevance; reinforcer; relating to nervous system; research and development; response; reward circuitry; social; temporal measurement; therapy development; translational research program; treatment responders

DESCRIPTION (provided by applicant): Schizophrenia is a highly disabling illness that impacts 0.5-1% of Americans. The disability of the illness is more strongly associated with cognitive deficits and negative symptoms than it is with the positive symptoms of the illness including hallucinations and delusions. Negative symptoms are generally defined as the absence of normal function, but the actual mechanisms involved in generating this absence have remained unknown, thereby stifling rational treatment development. The overarching goal of this application is to fundamentally alter the understanding of negative symptoms by rigorously testing a highly specific hypothesis about the origins of avolition/anhedonia in people with schizophrenia. This hypothesis has been formalized in a computational model that suggests that people with schizophrenia have a deficit in the ability to represent the positive expected value of stimuli and response alternatives, coupled with an intact ability to learn from aversive outcomes. This deficit in representing value is also thought to lead to reduced exploration of behavioral alternatives when uncertain about the likely payoffs of different choices. The project uses a program of behavioral experiments to test this hypothesis in the areas of learning from outcomes and decision making. In addition, we will explore the relationship between this deficit and current cognitive psychological models of the causes of negative symptoms, as well as the importance of this deficit for the prediction of successful outcome from a behavioral treatment approach that uses reinforcement to shape behavior. This computational approach also leads to a highly specific hypothesis about the neural mechanisms that are implicated in a deficit in representing expected value. To address this hypothesis, we will take advantage of the temporal resolution of EEG to test whether abnormalities in neural activity occur at the time of decision, as predicted, or instead occur at the time of feedback delivery, as would be expected if patients were unable to use the dopamine system to signal positive prediction errors when outcomes are better than expected. The goal of both the behavioral and neurophysiological studies is to provide an explicit, mechanistic understanding of negative symptoms and evaluate the application of this approach to current treatment approaches. Because reward circuitry is highly conserved across mammalian species, it should be possible to "back translate" to the animal models needed to guide drug development research.

描述（由申请人提供）：精神分裂症是一种高度残疾的疾病，影响了0.5-1％的美国人。疾病的残疾与认知缺陷和负面症状更密切相关，与疾病的积极症状（包括幻觉和妄想）相比。负面症状通常定义为缺乏正常功能，但是涉及这种缺席的实际机制尚不清楚，从而扼杀了理性的治疗发展。本应用的总体目标是通过严格检验有关精神分裂症患者的高度特定的假设，从而从根本上改变对负面症状的理解。该假设是在计算模型中正式化的，该计算模型表明，精神分裂症患者在代表刺激和反应替代方案的正期望值的能力上存在缺陷，再加上完整的能力，可以从厌恶结果中学习。当不确定不同选择的可能收益时，代表价值的这种赤字也会导致对行为替代方案的探索。该项目使用一个行为实验计划来检验从结果和决策的学习领域中的这一假设。此外，我们将探讨这种赤字与当前负面症状原因的认知心理模型之间的关系，以及这种赤字对从采用强化来塑造行为的行为治疗方法预测成功结果的重要性。这种计算方法还导致了关于神经机制的高度特异性假设，这些假设与代表期望值的不足有关。为了解决这一假设，我们将利用脑电图的时间分辨率来测试神经活动中的异常在决策时（如预测）发生，还是在反馈递送时发生，这将是预期的，如果患者无法使用多巴胺系统在抗脉冲上比预期的更好时使用多巴胺系统来信号。行为和神经生理学研究的目的是提供对负面症状的明确的机械理解，并评估这种方法在当前治疗方法中的应用。由于奖励电路在哺乳动物物种之间是高度保守的，因此应该可以将“翻译”到指导药物开发研究所需的动物模型。

项目成果

Dopaminergic genes predict individual differences in susceptibility to confirmation bias.

• DOI: 10.1523/jneurosci.6486-10.2011
• 发表时间: 2011-04-20
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Doll BB;Hutchison KE;Frank MJ
• 通讯作者: Frank MJ

Delay discounting in schizophrenia.

• DOI: 10.1080/13546800601005900
• 发表时间: 2007-05-01
• 期刊: Cognitive neuropsychiatry
• 影响因子: 1.7
• 作者: Heerey, Erin A;Robinson, Benjamin M;Gold, James M
• 通讯作者: Gold, James M

Neurocomputational models of basal ganglia function in learning, memory and choice.

• DOI: 10.1016/j.bbr.2008.09.029
• 发表时间: 2009-04-12
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Cohen, Michael X.;Frank, Michael J.
• 通讯作者: Frank, Michael J.

Dopamine and Proximity in Motivation and Cognitive Control.

多巴胺和邻近在动机和认知控制中的作用。

• DOI: 10.1016/j.cobeha.2017.12.011
• 发表时间: 2018
• 期刊: Current opinion in behavioral sciences
• 影响因子: 5
• 作者: Westbrook,Andrew;Frank,Michael
• 通讯作者: Frank,Michael

A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency, extinction, and renewal.

• DOI: 10.1007/s00213-008-1457-4
• 发表时间: 2009-06
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Wiecki, Thomas V.;Riedinger, Katrin;von Ameln-Mayerhofer, Andreas;Schmidt, Werner J.;Frank, Michael J.
• 通讯作者: Frank, Michael J.