Treatment-resistant depression (TRD) is an incapacitating condition affecting millions worldwide. Many of these patients have increased healthcare utilization but remain sick, justifying the urgent need to develop and implement improved strategies, such as deep brain stimulation (DBS). The various studies of DBS targets for TRD over the last 10+ years have shown variable response rates; the subgenual cingulate (Cg25), the most popular target, only yielded a combined response rate of near 50% at 12 months from a pooled 77 patients at eight centers. Other targets shared the same problem, where stimulation parameters have been blindly adjusted across variable anatomic locations to incur acute mood changes rather than be titrated to a defined objective measurement, leading to overall mediocre response rates. We need to 1) structurally, 2) functionally, and 3) electrophysiologically define each individual’s dysfunctional affective circuit and use these definitions to help identify biomarkers of stimulation response that can optimize the target. Structurally, we are getting closer to finding a DBS target for reproducible, significant results. Within a given target, variability in response to DBS can be due to variability of electrode position: millimeter differences within the same target in different patients means that a slightly different subset of subcortical fibers is modulated. Structural tractography – deterministic in surgical planning, probabilistic for population analysis – is a key tool to help make targeting results reproducible. This is now common across all centers, and is a large reason why a recent cohort of Cg25 patients had an 82% response rate at 1 year. The use of tractography has elucidated fiber pathways such as the medial forebrain bundle (MFB), which when stimulated has led to significantly rapid responses of over 80% before 6 months. This branch of the MFB represents the outflow fibers from the ventral tegmental area, an important node within the reward pathway, which is also part of a larger affective circuit connecting Cg25 and other DBS depression targets to certain prefrontal cortical mediators, dysfunction of which is known to underlie depression. Functionally, there are differences between targets which lead to anti-depressive effect. Each DBS white-matter target can differentially modulate this aberrantly wired network, with possibly greater acuity at specific nodes due to more concentrated fibers, which could be argued to lead to a faster anti-depressive effect. The problem is how to measure anti-depressant effect accurately: daily, weekly, monthly, by reaction to new stressors, etc., and not just by a subjective questionnaire that leads to a score that can be tracked over time. There should be some or multiple other objective measures, such as observation of improved demeanor, arousal, appetitive motivation, interpersonal relationships, or – even better – an actual biomarker, a signal that the circuit has been positively altered and success has been found. This is where functional imaging comes into the picture. We need to have some objective measure of success – a biomarker. So far, results are elusive, but we are getting closer. Metabolic changes visualized on F-fluorodeoxyglucose positron emission tomography (FDG-PET) were thought to be an answer, but these changes are not seen in all depressed patients and are not unique to DBS. Perhaps connectivity seen with resting-state functional MRI (fMRI) of the default mode network and changes therein after anti-depressive stimulation can be used as a guide, but we are just beginning to sort through this analysis. Even though these targets all lie along the same circuit, they are obviously not the same, with differential effects. More importantly, to complicate matters, is the large problem that not all depression is the same. Previous clinical trials have tried to stratify the most treatment resistant, but even so there are different phenotypes that seem more likely to have success with a given target, owing to the specific fiber tracts modulated. Potentially, we will be able to use functional imaging as a biomarker to select those specific patients (e.g., anhedonic, melancholic) that can be remedied by a specific target known to have better effect for that depressive subtype. Depression is a chronic, debilitating illness, secondary to years of aberrant wiring of an affective circuit. Stimulation to redirect fiber modulation and recruit certain areas of the cortex can have effects that are acute, but we need more proof that a change actually occurs. From an electrophysiological standpoint, proving connectivity to certain cortical mediators may help optimize outcome. There is mounting evidence that modulation of

中文翻译：

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深部脑刺激治疗抑郁症的挑战

难治性抑郁症 (TRD) 是一种影响全世界数百万人的丧失能力的疾病。其中许多患者的医疗保健利用率有所提高，但仍然生病，因此迫切需要制定和实施改进的策略，例如深部脑刺激 (DBS)。在过去 10 多年里，针对 TRD 的 DBS 目标的各种研究显示出不同的响应率；亚膝扣带回 (Cg25) 是最受欢迎的目标，在 12 个月时，来自 8 个中心的 77 名患者的综合反应率仅接近 50%。其他目标也存在同样的问题，即在不同的解剖位置盲目调整刺激参数以引起急性情绪变化，而不是调整到定义的客观测量值，导致总体反应率平庸。我们需要 1) 结构上，2) 功能上，3) 电生理学定义每个人功能失调的情感回路，并使用这些定义来帮助识别可以优化目标的刺激反应的生物标志物。从结构上讲，我们越来越接近于为可重复的、显着的结果找到 DBS 目标。在给定的目标内，对 DBS 响应的可变性可能是由于电极位置的可变性：不同患者的同一目标内的毫米差异意味着调节了略微不同的皮质下纤维子集。结构纤维束成像——在手术计划中是确定性的，在人口分析中是概率性的——是帮助使靶向结果可重复的关键工具。这现在在所有中心都很常见，这也是为什么最近的一组 Cg25 患者在 1 年时有 82% 的反应率的一个重要原因。纤维束成像的使用阐明了诸如内侧前脑束 (MFB) 之类的纤维通路，当受到刺激时，它在 6 个月前可产生超过 80% 的显着快速反应。MFB 的这个分支代表来自腹侧被盖区的流出纤维，这是奖赏通路中的一个重要节点，它也是将 Cg25 和其他 DBS 抑郁症目标连接到某些前额叶皮质介质的更大情感回路的一部分，已知其功能障碍抑郁症的基础。在功能上，导致抗抑郁作用的目标之间存在差异。每个 DBS 白质目标都可以对这种异常有线网络进行不同的调节，由于纤维更集中，特定节点的敏锐度可能更高，这可能会导致更快的抗抑郁效果。问题是如何准确衡量抗抑郁效果：每天、每周、每月、通过对新压力源的反应等，而不仅仅是通过主观问卷得出可以随时间跟踪的分数。应该有一些或多个其他客观衡量标准，例如观察改善的风度、唤醒、食欲动机、人际关系，或者——甚至更好——一个实际的生物标志物，一个信号，表明回路已被积极改变并已发现成功。这就是功能成像的用武之地。我们需要有一些客观的成功衡量标准——一个生物标志物。到目前为止，结果难以捉摸，但我们越来越接近了。在 F-氟脱氧葡萄糖正电子发射断层扫描 (FDG-PET) 上可视化的代谢变化被认为是一个答案，但这些变化并非在所有抑郁症患者中都能看到，也不是 DBS 独有的。也许可以将默认模式网络的静息状态功能 MRI (fMRI) 的连接性以及抗抑郁刺激后的变化用作指导，但我们才刚刚开始对这一分析进行分类。尽管这些目标都位于同一条线路上，但它们显然并不相同，具有不同的效果。更重要的是，使事情复杂化的是一个大问题，即并非所有的抑郁症都是一样的。以前的临床试验曾试图对治疗抵抗力最强的进行分层，但即便如此，由于特定的纤维束受到调节，不同的表型似乎更有可能在给定的目标上取得成功。潜在地，我们将能够使用功能成像作为生物标志物来选择那些可以通过已知对抑郁亚型具有更好效果的特定目标进行治疗的特定患者（例如，快感缺失、忧郁症）。抑郁症是一种慢性、使人衰弱的疾病，继发于情感回路多年的异常连接。刺激以重定向纤维调制和招募皮层的某些区域可能会产生严重的影响，但我们需要更多的证据来证明确实发生了变化。从电生理学的角度来看，证明与某些皮质介质的连接可能有助于优化结果。越来越多的证据表明 继发于情感电路多年的异常布线。刺激以重定向纤维调制和招募皮层的某些区域可能会产生严重的影响，但我们需要更多的证据来证明确实发生了变化。从电生理学的角度来看，证明与某些皮质介质的连接可能有助于优化结果。越来越多的证据表明 继发于情感电路多年的异常布线。刺激以重定向纤维调制和招募皮层的某些区域可能会产生严重的影响，但我们需要更多的证据来证明确实发生了变化。从电生理学的角度来看，证明与某些皮质介质的连接可能有助于优化结果。越来越多的证据表明