Several lines of evidence suggest that vagus nerve stimulation (VNS) triggers transient release of plasticity promoting neuromodulators throughout the cortex, such as acetylcholine and norepinephrine [1]. Cervical VNS can effectively treat medication resistant epilepsy [2,3] and treatment resistant depression over the course of many years [4,5]. In some cases, cervically implanted VNS depression patients continue to have depressive episodes requiring treatment with medications, electroconvulsive therapy (ECT), or prefrontal transcranial magnetic stimulation (TMS). The FDA initially ruled that TMS was contraindicated in patients with VNS, but this was later shown to be safe [6]. At first, TMS providers turned off the VNS device during TMS as they do in ECT. However, as TMS does not need to produce a seizure, a common clinical practice is to simply have the VNS device remain on and deliver the TMS ignoring the VNS firing pattern. A new development with TMS for depression is the use of intermittent theta burst (iTBS) patterns, and combining multiple treatments in one day in accelerated, high dose protocols [7e10]. While preliminary, these accelerated iTBS treatments have shown clinical promise in even highly treatment resistant patients. We wondered if it would be feasible and safe to pair and synchronously deliver accelerated iTBS with cervically implanted VNS, reasoning that the additional VNS phase dependent plasticity might theoretically improve the antidepressant effects of TMS. Here we describe one patient where we used a simple, clinically feasible approach with good outcome and no adverse events. The patient was a 55-year-old woman with a long history of treatment resistant depression. Her initial onset was at age 15 with the first medication and counseling treatments at age 24. At age 36, she was hospitalized and required a course of bilateral electroconvulsive therapy (ECT), with good response. She required three more rounds of ECT over the next six years. At age 43 she had cervical VNS implanted, with no further need for hospitalizations or ECT. Her VNS battery died and was replaced at age 50. She stayed on multiple medications for most of this time but was able to continue to work. A year prior to this TMS course, her depression worsened, and she was unable to continue working. Her VNS settings and medications were adjusted with no improvement. Her pre-treatment PHQ-9 was 22 (Fig. 1A). During this treatment course, the patient’s medications were quetiapine 150mg, levetiracetam 1000mg twice daily, lorazepam 3mg nightly, lamotrigine 400mg nightly, and cytomel 37.5 mg each morning. Her VNS device was initially set at 0.75mA intensity, 10Hz, 250 ms pulse width, 7s on, and 108s off. We increased the VNS

中文翻译：

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同步宫颈 VNS 与加速 Theta Burst TMS 用于治疗抵抗性抑郁症

多项证据表明，迷走神经刺激 (VNS) 会触发可塑性促进神经调节剂（例如乙酰胆碱和去甲肾上腺素）在整个皮层的瞬时释放 [1]。多年来，宫颈 VNS 可以有效治疗药物耐药性癫痫 [2,3] 和治疗抵抗性抑郁症 [4,5]。在某些情况下，颈椎植入的 VNS 抑郁症患者会继续出现抑郁发作，需要药物治疗、电休克疗法 (ECT) 或前额经颅磁刺激 (TMS)。FDA 最初裁定 VNS 患者禁用 TMS，但后来证明这是安全的 [6]。起初，TMS 提供商在 TMS 期间关闭了 VNS 设备，就像他们在 ECT 中所做的那样。然而，由于 TMS 不需要产生癫痫发作，一个常见的临床实践是简单地让 VNS 设备保持开启并提供 TMS，而忽略 VNS 发射模式。TMS 治疗抑郁症的一项新进展是使用间歇性 theta 爆发 (iTBS) 模式，并在一天内以加速、高剂量方案组合多种治疗 [7e10]。虽然是初步的，但这些加速的 iTBS 治疗已在甚至高度抗药性患者中显示出临床前景。我们想知道将加速 iTBS 与宫颈植入的 VNS 配对并同步传递是否可行和安全，推理额外的 VNS 相位依赖性可塑性理论上可能会提高 TMS 的抗抑郁作用。在这里，我们描述了一位患者，我们使用了一种简单的、临床上可行的方法，结果良好且没有不良事件。患者是一名 55 岁的女性，患有长期的难治性抑郁症。她的首次发病年龄为 15 岁，24 岁时首次接受药物治疗和咨询治疗。 36 岁时，她入院接受了双侧电休克疗法 (ECT) 的疗程，反应良好。在接下来的六年里，她需要再进行三轮 ECT。43 岁时，她植入了颈椎 VNS，不再需要住院或接受 ECT。她的 VNS 电池没电了，并在 50 岁时更换了。她大部分时间都在服用多种药物，但能够继续工作。在参加 TMS 课程前一年，她的抑郁症恶化，她无法继续工作。她的 VNS 设置和药物进行了调整，但没有任何改善。她的治疗前 PHQ-9 为 22（图 1A）。在这个疗程中，患者的药物是喹硫平150mg，左乙拉西坦1000mg，每天两次，劳拉西泮3mg每晚，拉莫三嗪400mg每晚，细胞溶胶37.5mg每天早上。她的 VNS 设备最初设置为 0.75mA 强度、10Hz、250 ms 脉冲宽度、7s 开启和 108s 关闭。我们增加了 VNS