Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [¹¹C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = −0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = −0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing.

血清素 (5-HT) 在奖励处理中发挥着重要作用，然而，研究人类在情绪刺激期间 5-HT 作用的可能性特别有限。在这里，我们展示了使用功能性 PET (fPET) 评估 5-HT 合成中奖励特异性动态的可行性，将其分子特异性与血氧水平依赖 (BOLD) fMRI 的高时间分辨率相结合。十六名健康志愿者同时接受了放射性配体 [ ¹¹ C]AMT（色氨酸羟化酶的底物）的 fPET/fMRI。在扫描过程中，参与者完成了金钱激励延迟任务，并采集了动脉血样本以量化 5-HT 合成率。 BOLD fMRI 被记录为神经元激活的代表，可以区分奖励预期和反馈。货币收益和损失导致腹侧纹状体（VStr，较基线+21%）和前岛叶（+41%）的 5-HT 合成大幅增加。在 VStr 中，任务特异性 5-HT 合成进一步与奖励反馈期间的 BOLD 信号变化相关 (ρ = -0.65)，但与预期无关。相反，前岛叶中的 5-HT 合成与 BOLD 奖励预期相关（ρ = -0.61），但与反馈无关。总之，我们提供了一个强大的工具来识别任务引起的人类 5-HT 作用的变化，以区域特定的方式将 5-HT 合成的动态与奖励处理的不同阶段联系起来。鉴于奖励处理改变与成瘾、抑郁和精神分裂症等精神疾病的相关性，我们的方法为认知和情绪处理过程中受损的 5-HT 信号提供了量身定制的评估。