Bari Bilal A, Krystal Andrew D, Pizzagalli Diego A, Gershman Samuel J
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; McLean Hospital, Harvard Medical School, Belmont, Massachusetts.
Department of Psychiatry, University of California San Francisco, San Francisco, California; Departments of Psychiatry and Behavioral Sciences and Radiology, Duke University School of Medicine, Durham, North Carolina.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 May 28. doi: 10.1016/j.bpsc.2025.05.011.
Anhedonia, the loss of pleasure, is prevalent and impairing. Parsing its computational basis promises to explain its transdiagnostic character. One manifestation of anhedonia, reward insensitivity, may be linked to limited memory. Furthermore, the need to economize on limited memory engenders a perseverative bias toward frequently chosen actions. Anhedonia may also be linked with deviations from optimal perseveration for a given memory capacity, a pattern that causes inefficiency because it results in less reward for the same memory cost.
To test these hypotheses, we applied a theory of optimal decision making under memory constraints that decomposes behavior into a memory component and an efficiency component. We applied this theory to behavior on the Probabilistic Reward Task, a reward learning paradigm that has been validated in anhedonia, and performed secondary analysis of a randomized controlled trial testing kappa opioid receptor (KOR) antagonism for anhedonia (n = 24 KOR; n = 31 placebo), as well as analyses of 3 other datasets (n = 100, 66, 24, respectively). We fit a resource-bounded reinforcement learning model to behavior.
Across clinical and nonclinical populations, anhedonia was associated with deficits in efficiency but not memory. The reinforcement learning models demonstrated that deficits in efficiency arise from the inability to perseverate optimally. KOR antagonism, which likely elevates tonic dopamine, increases both memory and efficiency, and the model demonstrated that this arises from increased reward sensitivity and perseveration.
Therefore, KOR antagonism has distinct cognitive effects, only one related to anhedonia. These findings have potential implications for the applications of KOR antagonists.
快感缺失，即愉悦感丧失，普遍存在且会造成损害。剖析其计算基础有望解释其跨诊断特征。快感缺失的一种表现形式，即奖励不敏感，可能与有限的记忆有关。此外，由于需要节省有限的记忆，会对频繁选择的行为产生持续偏差。快感缺失也可能与在给定记忆容量下偏离最佳持续性有关，这种模式会导致效率低下，因为在相同的记忆成本下获得的奖励更少。
为了验证这些假设，我们应用了一种在记忆限制下的最优决策理论，该理论将行为分解为记忆成分和效率成分。我们将此理论应用于概率奖励任务中的行为，这是一种在快感缺失研究中已得到验证的奖励学习范式，并对一项测试κ阿片受体（KOR）拮抗剂治疗快感缺失的随机对照试验（n = 24 名 KOR 组；n = 31 名安慰剂组）进行了二次分析，以及对其他 3 个数据集（分别为 n = 100、66、24）进行了分析。我们将一个资源受限的强化学习模型拟合到行为数据上。
在临床和非临床人群中，快感缺失与效率缺陷而非记忆缺陷有关。强化学习模型表明，效率缺陷源于无法进行最佳持续行为。KOR 拮抗剂可能会提高多巴胺张力，它既能提高记忆又能提高效率，并且模型表明这是由于奖励敏感性和持续性增加所致。
因此，KOR 拮抗剂具有独特的认知效应，其中只有一种与快感缺失有关。这些发现对 KOR 拮抗剂的应用具有潜在意义。
