Causal role of delta-beta coupling for goal-directed behavior in anhedonia

快感缺失--无法寻找和体验快乐--是抑郁症的一种常见症状 预测治疗耐药性，有时会因一线抗抑郁药而加重。快感缺乏症瀑布 在研究领域标准框架的“正价系统”内，该框架包括两个 主要成分：“喜欢”和“想要”。“喜好”或消耗性的成分反映了 奖赏依赖于内侧前额叶皮质和腹侧纹状体的评估。“想要”，或者 预见性，组件调节在目标导向的行为依赖上花费的努力的程度 在外侧前额叶皮质和背侧纹状体上。先前的研究发现，老年人的神经活动减少 这两种神经回路在患有快感缺乏症的抑郁症患者中都存在，但尚未对 这些神经回路或它们的时间动力学在基于奖励的不同组成部分中的作用 决策。初步数据发现，患有抑郁症的患者目标导向行为减少 快感缺失和减少的交频耦合之间的相增量振荡(2-4赫兹)在 外侧前额叶皮质和任务调制的β振荡(15-30赫兹)(增量-β耦合)。这个 这项研究计划的目的是剖析额叶-纹状体环路在不同组成部分中的因果作用。 快感缺乏症的奖赏决策及其损害。中心假设是 快感缺乏症是由于目标导向行为减少和外侧脑区β-β偶联中断所致。 前额叶皮质和背侧纹状体。其基本原理是空间和时间上有针对性的非侵入性 在基于奖励的决策任务执行过程中的大脑刺激将提供因果证据 快感缺乏症患者的网络动力受损。在K99阶段，本研究(1)因果 分离了实现目标导向行为和奖励评估的神经回路 决策和(2)抑郁症快感缺乏患者目标导向行为的增加 网络定向非侵入性脑刺激。现在，R00阶段将(3)调查目标 β-β偶联在潜在治疗范例中与网络靶向刺激的结合 抑郁症伴快感缺乏症状的随机临床试验。这项建议意义重大 因为它对网络和认知过程的机械模型进行了因果评估， 快感缺乏症中断了。这项工作具有创新性，因为它使用了同时进行的神经生理学和神经刺激，集成了高分辨率的空间和时间调查工具，并利用了个性化的刺激参数，如具有功能连接性的皮质下靶向和特定于任务的频率靶向。这项提议的积极影响是，根据生物学机制对快感缺失进行了改进，这可能与精神分裂症和物质使用障碍等其他精神疾病具有跨诊断相关性。这项提议的含义是，所获得的知识可以直接用于利用精确医学开发新的干预措施。

Anhedonia - the inability to seek-out and experience pleasure - is a common symptom in depression that predicts treatment resistance and is sometimes exacerbated by first-line antidepressants. Anhedonia falls within the "Positive Valence System" of the Research Domain Criteria framework that comprises two primary components: "liking" and "wanting." The "liking," or consummatory, component reflects the evaluation of rewards reliant on the medial prefrontal cortex and ventral striatum. The "wanting," or anticipatory, component modulates the degree to which effort is expended in goal-directed behavior reliant on the lateral prefrontal cortex and dorsal striatum. Previous research found decreased neural activity in both of these neural circuits in depressed patients with anhedonia but has not causally investigated the role of these neural circuits, or their temporal dynamics, in different components of reward-based decision-making. The preliminary data found decreased goal-directed behavior in depressed patients with anhedonia and reduced cross-frequency coupling between the phase of delta oscillations (2-4 Hz) in lateral prefrontal cortex and task-modulated beta oscillations (15-30 Hz) ( delta-beta coupling). The objective of this research plan is to dissect the causal role of frontal-striatal circuity in different components of reward-based decision-making and their impairment in anhedonia. The central hypothesis is that anhedonia arises from decreased goal-directed behavior and disruption of delta-beta coupling in lateral prefrontal cortex and dorsal striatum. The rationale is that spatially and temporally-targeted non-invasive brain stimulation during performance of a reward-based decision-making task will provide causal evidence for which network dynamics are impaired in anhedonia. In the K99 phase, this research (1) Causally dissociated the neural circuits that implement goal-directed behavior and reward-evaluation in decision-making and (2) Increased goal-directed behavior in depressed patients with anhedonia using network-targeted non-invasive brain stimulation. Now, the R00 phase will (3) Investigate target engagement of delta-beta coupling in a potential treatment paradigm with network-targeted stimulation in a randomized clinical trial for depressed patients with symptoms of anhedonia. This proposal is significant because it causally evaluates mechanistic models of the networks and cognitive processes that are disrupted in anhedonia. The work is innovative because it uses concurrent neurophysiology and neurostimulation, integrates high-resolution spatial and temporal investigation tools, and utilizes individualized stimulation parameters such as subcortical-targeting with functional-connectivity and task-specific frequency targeting. The positive impact of this proposal is a refined definition of anhedonia based in biological mechanism that may have transdiagnostic relevance for other psychiatric illnesses such as schizophrenia and substance use disorder. The implication of this proposal is that the knowledge gained can be directly used for the development of novel interventions using precision medicine.