Brain functional and structural long-term effects of electroconvulsive therapy and its association with clinical response and cognitive side effects

重度抑郁症（MDD）是全球残疾的主要原因，也是全球疾病负担的主要贡献者。电休克疗法（ECT）是治疗难治性抑郁症最有效的方法之一，有效率高达70%。尽管ECT的临床疗效已得到充分证明，但其广泛使用受到以下因素的限制：（a）缺乏对其生物学作用机制的了解和（B）潜在的（长期）认知副作用。迄今为止，可用的神经影像学技术提供了宝贵的见解ECT在人类的神经元机制，主要集中在大脑结构和静息状态连接的直接短期影响，其关系到即时症状改善和临床反应。然而，其生物学机制知之甚少。通过ECT研究长期脑功能和结构变化及其与临床反应和神经认知副作用的关系，将为ECT的机制提供有价值的知识。该项目的主要目的是对ECT的脑结构和脑功能机制进行长期研究，重点关注其与长期治疗成功（缓解/复发）和（神经）认知功能的关系。本前瞻性自然病例对照研究的主要设计包括三个样本和四个时间点。应在四个时间点使用结构和功能磁共振成像、神经心理学评估和临床评级评估接受ECT治疗的重度MDD患者样本、仅接受药物治疗的重度MDD患者对照样本和健康对照样本：基线时、约6周ECT疗程后即刻、6个月后随访时和12个月后随访时。拟议的项目旨在为ECT的（长期）神经生物学效应提供新的见解，这可能有助于理解两个临床相关和未解决的问题的大脑结构和功能基础：（1）为什么有些患者在成功的ECT后几个月表现出临床反应，包括稳定缓解，而其他人对ECT没有反应或在随访时复发？(2)为什么有些患者表现出（短期和长期）认知障碍，而另一些患者则表现出改善？此外，后续目标是应用和评估多变量机器学习，以在个性化医疗背景下基于神经生物学知识预测个体患者的临床反应和认知功能。 总而言之，本研究计划不仅能增进我们对电休克治疗机制的认识，也能加深我们对重性抑郁症的神经生物学基础的理解。最后，所获得的知识将提供转化为临床实践的潜力。

Major depressive disorder (MDD) is the leading cause of disability worldwide and a major contributor to the global burden of disease. Electroconvulsive therapy (ECT) is one of the most rapid-acting and effective treatments for patients suffering from severe treatment-refractory depression with response rates of up to 70%. Although the clinical efficacy of ECT is well-documented, its widespread use has been limited by (a) the lack of knowledge about its biological mechanism of action and (b) potential (long-term) cognitive side-effects. To date, available neuroimaging techniques have provided valuable insights into the neuronal mechanisms of ECT in humans, mainly focusing on direct short-term effects on brain structure and resting state connectivity and its relation to immediate symptom improvement and clinical response. However, its biological mechanism is poorly understood. The investigation of long-term brain functional and structural changes through ECT and their relation to clinical response and neurocognitive side-effects would add valuable knowledge about the mechanisms of ECT. The main objective of the proposed project is the long-term investigation of the brain structural and brain functional mechanisms of ECT, with a focus on its association with long-term treatment success (remission/relapse) and (neuro-) cognitive functioning. The principle design of this prospective, naturalistic case-control study comprises three samples and four time-points. A sample of patients with severe MDD treated with ECT, a control sample of patients with severe MDD treated only with medication, and a healthy control sample shall be assessed using structural and functional magnetic resonance imaging, neuropsychological assessments and clinical ratings at four time-points: At baseline, directly after an ECT course of about six weeks, at follow-up after six months, and at follow-up after 12 months. The proposed project aims to provide new insights into (long-term) neurobiological effects of ECT, which might help to understand the brain-structural and functional underpinnings of two clinically relevant and unresolved questions: (1) Why do some patients show clinical response, including a stable remission, months after a successful ECT while others do not respond to ECT or show a relapse at follow-up? (2) Why do some patients show (short-term and long-term) cognitive impairments while others show improvements? In addition, a subsequent objective is the application and evaluation of multivariate machine-learning to predict individual patients’ clinical response and cognitive functioning based on the neurobiological knowledge in the context of personalized medicine. In summary, the proposed project would not only enhance our knowledge of mechanisms of ECT, but also aims to expand our understanding of the neurobiological underpinnings of major depression itself. Finally, the knowledge gained would provide the potential for a translation into clinical practice.