The University of Texas at Dallas, School of Behavior and Brain Sciences, 800 West Campbell Road, Richardson, TX, 75080-3021, United States; The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road, Richardson, TX, 75080-3021, United States.
The University of Texas at Dallas, School of Behavior and Brain Sciences, 800 West Campbell Road, Richardson, TX, 75080-3021, United States.
Brain Stimul. 2019 Jan-Feb;12(1):9-18. doi: 10.1016/j.brs.2018.09.013. Epub 2018 Sep 21.
BACKGROUND: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. OBJECTIVE: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. METHODS: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. RESULTS: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. CONCLUSION: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.
背景：暴露疗法通过在治疗过程中在提示暴露后产生成功的消退，用于治疗各种创伤和焦虑相关障碍。开发辅助策略，加速消退学习，提高耐受性，并提高治疗效率，可以提高暴露疗法的疗效。迷走神经刺激（VNS）与暴露相结合可以增强精神疾病模型大鼠的恐惧消退，慢性 VNS 给药可降低大鼠和人类的焦虑。 目的：我们测试了 VNS 是否像其他认知增强剂一样，可以对在消退过程中未呈现但与恐惧事件相关的刺激产生消退的泛化。 方法：雄性 Sprague Dawley 大鼠进行听觉恐惧条件反射，使用两种易于区分的听觉刺激。恐惧条件反射后，消退训练包括仅暴露于条件刺激之一。一半的大鼠在声音呈现时接受 VNS 治疗，另一半接受假刺激。在高架十字迷宫上进行测试之前，在单独的研究中检查了 VNS 对焦虑的影响。 结果：在消退过程中接受 20 次条件刺激（CS）呈现的假刺激大鼠表现出与仅接受 4 次 CS 呈现的 VNS 治疗大鼠相匹配的表现。尽管对呈现的 CS 有类似的冻结水平，但只有 VNS 治疗的大鼠对未呈现的 CS 表现出显著的冻结减少。仅当两个声音在同一恐惧条件反射会话中与足底电击配对时，才观察到 VNS 诱导的消退泛化；当两个声音在不同的日子或不同的环境中条件反射时，VNS 不会促进消退的泛化。在焦虑测试中，VNS 给药显著增加了高架十字迷宫的开放臂中花费的时间。 结论：这些结果提供了证据表明 VNS 可以促进与特定恐惧体验相关的其他刺激的消退泛化。此外，非条件 VNS 似乎可以降低焦虑。泛化消退和降低焦虑的能力使 VNS 成为作为辅助策略的潜在候选药物，以提高暴露疗法的疗效和耐受性。
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