Depression is a frequent, complex, and debilitating condition with a high lifetime prevalence worldwide. Goldstandard treatments for depression include psychotherapy and pharmacotherapy. Though most patients respond to these therapies, a subset (approximately 30%) does not benefit, and may be considered as having treatmentresistant depression (TRD). For these patients, options are limited; neuromodulation approaches, such as deep brain stimulation (DBS), have been suggested to reduce suffering and improve quality of life. DBS is an invasive neuromodulation technique that consists of the implantation of electrodes in deep brain targets, followed by delivery of electrical stimulation to modulate local and neurocircuitry activity. In TRD, promising results have been reported with the use of DBS in distinct targets, which include the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), nucleus accumbens (nAcc), medial forebrain bundle (mFB), inferior thalamic peduncle (iTpn), and habenula (Hb). The SCG is a portion of the cingulum located ventral to the corpus callosum that includes Brodmann area 25 and parts of areas 24 and 32. Imaging studies have shown distinct SCG metabolic patterns in depressive patients. Specifically, healthy subjects in a sad state or patients with depression exhibit increased cerebral blood flow and glucose metabolism in the SCG, a pattern that is reversed by antidepressant interventions. To date, several studies have been conducted to assess the therapeutic effects of SCG-DBS in TRD. Open-label trials and several case reports have shown long-term clinical benefits, with an overall improvement of 50%. However, randomized clinical trials (RCTs) comparing active vs. sham stimulation failed to confirm these results. Recent work in which diffusion tensor imaging (e.g., patient specific tractography) and volume of tissue activation were used to refine DBS surgical targeting showed pronounced long-term response rates (between 73-82%), indicating that individual variability in fiber tracts may be critical for the antidepressant effects of this technique. The VC/VS (including the anterior limb of the internal capsule) has been approved by the U.S. Food and Drug Administration (FDA) as a target for DBS in patients with obsessive-compulsive disorder (OCD) that does not respond to standard therapies as a humanitarian device exemption. Interestingly, several studies using VC/ VS-DBS for OCD have reported reductions not only in obsessive-compulsive symptoms, but also in anxiety and depression. With this rationale, studies have been performed to investigate the use of VC/VS-DBS for TRD. As with SCG-DBS, the promising results of open-label studies using VC/VS-DBS (an approximate 50% reduction in depressive symptoms) were corroborated in an initial RCT comparing active vs. sham stimulation. In a more recent study, patients were initially treated in an open-label fashion and subdivided into responders and non-responders. Thereafter, they underwent a blinded crossover phase receiving active or sham stimulation. While significant improvement was noticed in responders receiving DBS, non-responders showed no difference in depression scores during active or sham treatment. These results highlight the importance of patient selection for DBS therapy. The nAcc, mFB, Hb, and iTpn are major structures involved in emotional processing and the neurocircuitry of depression. Open-label trials of nACC-DBS and mFBDBS have shown long-lasting response rates (nAcc-DBS: 40-50%; mFB-DBS: 75-85%). In particular, results following mFB-DBS have been quite impressive, as antidepressant responses were recorded soon after surgery. A recent trial compared the effects of sham vs. active mFB stimulation for 8 weeks in blinded fashion, followed by a long-term open-label phase. In the long-term, a significant antidepressant effect was observed in all patients. During the blinded phase, both sham and active stimulation groups had significant improvement, with no major differences being recorded across groups. These results are being used to guide the development of future trials. The findings described above suggest that DBS may exert a beneficial effect on depressive symptoms. Though results from open-label studies have not been corroborated by initial blinded, randomized trials of active vs. sham stimulation, findings from recently published reports are quite encouraging. The use of refined surgical

中文翻译：

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深部脑刺激治疗抑郁症

抑郁症是一种常见、复杂且使人衰弱的疾病，在全球范围内终生患病率很高。抑郁症的金标准治疗包括心理治疗和药物治疗。尽管大多数患者对这些疗法有反应，但有一部分患者（约 30%）没有获益，可能被视为患有难治性抑郁症 (TRD)。对于这些患者，选择有限；已经建议神经调节方法，例如深部脑刺激 (DBS)，以减少痛苦并提高生活质量。DBS 是一种侵入性神经调节技术，包括在大脑深部目标中植入电极，然后传递电刺激以调节局部和神经电路活动。在 TRD 中，已经报告了在不同目标中使用 DBS 的有希望的结果，其中包括胼胝体扣带回 (SCG)、腹侧囊/腹侧纹状体 (VC/VS)、伏隔核 (nAcc)、内侧前脑束 (mFB)、下丘脑脚 (iTpn) 和缰核 (Hb)。SCG 是位于胼胝体腹侧的扣带的一部分，包括 Brodmann 区域 25 和部分区域 24 和 32。影像学研究显示抑郁症患者具有不同的 SCG 代谢模式。具体而言，处于悲伤状态的健康受试者或患有抑郁症的患者在 SCG 中表现出增加的脑血流量和葡萄糖代谢，这种模式可被抗抑郁药干预逆转。迄今为止，已经进行了几项研究来评估 SCG-DBS 在 TRD 中的治疗效果。开放标签试验和多个病例报告显示出长期临床益处，总体改善了 50%。然而，比较主动刺激与假刺激的随机临床试验 (RCT) 未能证实这些结果。最近使用扩散张量成像（例如，患者特定纤维束成像）和组织激活体积来改进 DBS 手术靶向的工作显示出明显的长期反应率（73-82%），表明纤维束的个体差异可能是这种技术的抗抑郁作用至关重要。VC/VS（包括内囊前肢）已被美国食品和药物管理局 (FDA) 批准为对标准疗法无反应的强迫症 (OCD) 患者的 DBS 靶点人道主义设备豁免。有趣的是，几项使用 VC/VS-DBS 治疗强迫症的研究报告说，不仅强迫症的症状有所减轻，但也有焦虑和抑郁。有了这个基本原理，已经进行了研究来调查 VC/VS-DBS 在 TRD 中的使用。与 SCG-DBS 一样，使用 VC/VS-DBS 的开放标签研究（抑郁症状减少约 50%）的有希望的结果在比较主动刺激与假刺激的初始 RCT 中得到证实。在最近的一项研究中，患者最初以开放标签方式接受治疗，然后细分为有反应者和无反应者。此后，他们经历了接受主动或假刺激的盲交叉阶段。虽然接受 DBS 的反应者有显着改善，但无反应者在积极或假治疗期间的抑郁评分没有差异。这些结果强调了 DBS 治疗患者选择的重要性。nAcc、mFB、Hb、和 iTpn 是参与情绪处理和抑郁症神经回路的主要结构。nACC-DBS 和 mFDBBS 的开放标签试验显示出长期的反应率（nAcc-DBS：40-50%；mFB-DBS：75-85%）。特别是，mFB-DBS 后的结果非常令人印象深刻，因为手术后不久就记录了抗抑郁反应。最近的一项试验以盲法比较了 8 周假和主动 mFB 刺激的效果，然后是长期的开放标签阶段。从长远来看，在所有患者中都观察到了显着的抗抑郁作用。在盲阶段，假刺激组和主动刺激组都有显着改善，各组之间没有记录到重大差异。这些结果被用来指导未来试验的发展。上述发现表明 DBS 可能对抑郁症状产生有益影响。虽然开放标签研究的结果尚未得到主动刺激与假刺激的初始盲法随机试验的证实，但最近发表的报告的结果非常令人鼓舞。使用精细手术