Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.

SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

啮齿动物的神经生物学证据表明，威胁消除涉及奖励神经回路。因此，将奖励关联与灭绝记忆结合起来可能是持续减弱威胁反应的有效策略。此外，虽然有大量关于灭绝策略对人类的短期影响的研究，但很少考虑灭绝的长期影响。在一项针对女性和男性参与者的受试者内 fMRI 研究中，我们在最近（24 小时）和远程（大约一个月）检索测试中将反条件反射（CC；一种奖励消退形式）与标准消退进行了比较。相对于标准消退，奖励消退减少了 24 小时唤醒和威胁预期的复发，并减少了与威胁评估和表达相关的大脑区域（例如丘脑、岛叶、导水管周围灰质）的活动。奖赏相关的消退记忆的检索伴随着杏仁核和腹侧纹状体之间的功能连接，而标准消退记忆的检索则与杏仁核和腹内侧前额叶皮层（vmPFC）之间的连接相关。一个月后，标准消退和奖励消退的恢复都与杏仁核-vmPFC 连接相关。然而，只有奖励性消退才能在 vmPFC 中创建稳定的记忆痕迹，这是通过从消退到 24 小时和一个月检索的功能磁共振成像活动的重叠多元模式来识别的。这些发现提供了新的证据，表明奖励可能会在人类中产生更稳定、更持久的减弱威胁的记忆痕迹。

意义声明病理性恐惧和焦虑的流行治疗方法基于巴甫洛夫灭绝原理。不幸的是，灭绝会形成微弱的记忆，只能暂时抑制威胁关联的检索。因此，为了增加灭绝研究的转化相关性，至关重要的是研究是否可以增强灭绝以形成更持久的记忆，尤其是在长时间间隔之后。在这里，我们使用人类的多日功能磁共振成像范例来比较厌恶-食欲反调节（CC）（一种增强灭绝的形式）的短期和长期神经行为效应。我们的研究结果提供了新的证据，表明在学习后至少一个月内，在消退过程中加入食欲刺激可以减少短期威胁复发，并稳定腹内侧前额叶皮层（vmPFC）中消退的记忆痕迹。