Souza Rimenez R, Robertson Nicole M, Mathew Ezek, Tabet Michel N, Bucksot Jesse E, Pruitt David T, Rennaker Robert L, Hays Seth A, McIntyre Christa K, Kilgard Michael P
Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States of America; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States of America.
Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States of America.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109848. doi: 10.1016/j.pnpbp.2019.109848. Epub 2019 Dec 19.
Vagus nerve stimulation (VNS) has shown promise as an adjuvant treatment for posttraumatic stress disorder (PTSD), as it enhances fear extinction and reduces anxiety symptoms in multiple rat models of this condition. Yet, identification of the optimal stimulation paradigm is needed to facilitate clinical translation of this potential therapy. Using an extinction-resistant rat model of PTSD, we tested whether varying VNS intensity and duration could maximize extinction learning while minimizing the total amount of stimulation. We confirmed that sham rats failed to extinguish after a week of extinction training. Delivery of the standard LONG VNS trains (30 s) at 0.4 mA enhanced extinction and reduced anxiety but did not prevent fear return. Increasing the intensity of LONG VNS trains to 0.8 mA prevented fear return and attenuated anxiety symptoms. Interestingly, delivering 1, 4 or 16 SHORT VNS bursts (0.5 s) at 0.8 mA during each cue presentation in extinction training also enhanced extinction. LONG VNS trains or multiple SHORT VNS bursts at 0.8 mA attenuated fear renewal and reinstatement, promoted extinction generalization and reduced generalized anxiety. Delivering 16 SHORT VNS bursts also facilitated extinction in fewer trials. This study provides the first evidence that brief bursts of VNS can enhance extinction training, reduce relapse and support symptom remission using much less VNS than previous protocols. These findings suggest that VNS parameters can be adjusted in order to minimize total charge delivery and maximize therapeutic effectiveness.
迷走神经刺激(VNS)已显示出作为创伤后应激障碍(PTSD)辅助治疗方法的潜力,因为在该病症的多个大鼠模型中,它能增强恐惧消退并减轻焦虑症状。然而,需要确定最佳刺激模式以促进这种潜在疗法的临床转化。我们使用一种对消退有抗性的PTSD大鼠模型,测试了改变VNS强度和持续时间是否能在使刺激总量最小化的同时,最大程度地促进消退学习。我们证实,假手术大鼠在经过一周的消退训练后未能实现消退。以0.4毫安的强度进行标准的长时VNS刺激(30秒)可增强消退并减轻焦虑,但不能防止恐惧复发。将长时VNS刺激的强度增加到0.8毫安可防止恐惧复发并减轻焦虑症状。有趣的是,在消退训练的每次线索呈现期间,以0.8毫安的强度给予1次、4次或16次短时VNS脉冲(0.5秒)也能增强消退。0.8毫安的长时VNS刺激或多次短时VNS脉冲可减轻恐惧恢复和重现,促进消退泛化并减轻广泛性焦虑。给予16次短时VNS脉冲还能在更少的试验次数中促进消退。本研究提供了首个证据,即与先前方案相比,短时的VNS脉冲能使用更少的VNS增强消退训练、减少复发并支持症状缓解。这些发现表明,可以调整VNS参数,以最小化总电荷传递并最大化治疗效果。
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