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

严重抑郁障碍(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。电休克治疗(ECT)是治疗严重顽固性抑郁症最迅速、最有效的治疗方法之一，有效率高达70%。尽管ECT的临床疗效已有很好的文献记载，但其广泛应用受到以下因素的限制：(A)对其生物学作用机制缺乏了解；(B)潜在的(长期)认知副作用。到目前为止，现有的神经成像技术已经为人类ECT的神经机制提供了有价值的见解，主要集中在对脑结构和静息状态连通性的直接短期影响及其与即刻症状改善和临床反应的关系。然而，其生物学机制却鲜为人知。通过ECT研究脑功能和结构的长期变化及其与临床反应和神经认知副作用的关系将增加对ECT机制的有价值的认识。拟议项目的主要目标是长期研究ECT的脑结构和脑功能机制，重点是它与长期治疗成功(缓解/复发)和(神经)认知功能的关系。这项前瞻性、自然主义病例对照研究的原则设计包括三个样本和四个时间点。对接受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，在四个时间点进行结构和功能磁共振成像、神经心理学评估和临床评分：基线、ECT疗程后立即、六个月后随访和12个月后随访。这项拟议的项目旨在为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尚未解决的问题的脑结构和功能基础：(1)为什么一些患者在ECT成功后几个月表现出临床反应，包括稳定的缓解，而另一些患者在ECT后几个月没有反应或显示复发？(2)为什么一些患者表现出(短期和长期)认知障碍，而另一些患者则表现出改善？此外，后续的目标是在个性化医学的背景下，应用和评估基于神经生物学知识的多变量机器学习来预测个体患者的临床反应和认知功能。综上所述，这项拟议的项目不仅将增进我们对电疗机制的了解，还旨在扩大我们对严重抑郁症本身的神经生物学基础的理解。最后，所获得的知识将为将其转化为临床实践提供潜力。

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.