Using treatment with electroconvulsive therapy as a human model to study the involvement of the dentate gyrus in pattern separation

使用电休克疗法作为人体模型来研究齿状回在模式分离中的参与

• 批准号: RGPIN-2021-03517
• 负责人: Rabin, Jennifer
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742598
• 关键词: Using; treatment; electroconvulsive; therapy; human

It is well established that the hippocampus, a region deep within the brain, is critical for recalling past experiences. The hippocampus is comprised of several subregions, including the dentate gyrus. To avoid confusing similar memories (e.g., where you parked your car today versus yesterday), the hippocampus must ``separate'' similar experiences, a process known as pattern separation. Animal studies have shown that pattern separation is supported by the dentate gyrus. Consistent with this, neuroimaging studies in humans report activity within the dentate gyrus during tasks that assess pattern separation. While neuroimaging studies in healthy adults can show the involvement of different brain regions, they cannot pinpoint the regions that are necessary for a task. To date, only one human study has provided evidence that the dentate gyrus is necessary for pattern separation in humans. In that study, a rare patient with damage to the dentate gyrus was found to perform poorly on pattern separation tasks. Additional human models that can evaluate the role of the dentate gyrus in pattern separation are needed. In the present study, we will use electroconvulsive therapy (ECT) as a novel human model to examine whether the dentate gyrus is involved in pattern separation. ECT is an effective treatment for severe depression and has been shown to increase the volume of the dentate gyrus. We will test patients with severe depression on behavioural and neuroimaging tasks of pattern separation before and after ECT. We will also measure the volume of the dentate gyrus and other hippocampal subregions before and after ECT. Control participants who will not undergo ECT will be tested twice on the same measures to ensure that the effects are specific to ECT. To assess changes in pattern separation, we will use the Mnemonic Similarity Test (MST), a memory task that is known to rely on the dentate gyrus. Participants will complete a version of this task on a computer and while undergoing  functional neuroimaging, a technique that allows visualization of on-line brain activity (blood flow) as participants perform tasks. We expect that the volume of the dentate gyrus will increase following ECT and this will be accompanied by improved performance and greater activity in the dentate gyrus on tasks assessing pattern separation. These changes will not be observed in control who do not undergo ECT. Given the importance of pattern separation in daily life, it is important to study its neural substrates. This work will lead to a greater understanding of the role the dentate gyrus plays in pattern separation in the healthy human brain and will help establish ECT as a novel human model for studying dentate gyrus function. Finally, this research will provide unique opportunities for trainees in my lab to gain cutting edge experience with neuroimaging techniques and longitudinal data analysis.

众所周知，海马体是大脑深处的一个区域，对回忆过去的经历至关重要。海马体由几个亚区组成，包括齿状回。为了避免混淆相似的记忆（例如，你今天把车停在哪里和昨天停在哪里），海马体必须“分离”相似的经历，这个过程被称为模式分离。动物研究表明，模式分离是由齿状回支持的。与此一致的是，人类的神经成像研究报告了在评估模式分离的任务中齿状回内的活动。虽然对健康成年人的神经成像研究可以显示不同的大脑区域参与其中，但它们无法精确定位出完成任务所必需的区域。迄今为止，只有一项人类研究提供了证据，证明齿状回是人类模式分离所必需的。在那项研究中，发现一名罕见的齿状回损伤患者在模式分离任务中表现不佳。需要更多的人类模型来评估齿状回在模式分离中的作用。在本研究中，我们将使用电休克疗法（ECT）作为一种新的人体模型来检查齿状回是否参与模式分离。电痉挛疗法是一种治疗严重抑郁症的有效方法，并已被证明可以增加齿状回的体积。我们将测试严重抑郁症患者在ECT之前和之后的行为和模式分离的神经成像任务。我们还将测量电痉挛前后齿状回和其他海马亚区的体积。不接受电休克治疗的对照组参与者将接受两次同样的测试，以确保电休克的效果是特异性的。为了评估模式分离的变化，我们将使用助记相似性测试（MST），这是一种已知依赖于齿状回的记忆任务。参与者将在电脑上完成该任务的一个版本，同时进行功能性神经成像，这是一种允许参与者在执行任务时在线可视化大脑活动（血流）的技术。我们预计，在ECT后，齿状回的体积会增加，这将伴随着在评估模式分离的任务中，齿状回的表现和活动的改善。这些变化在不接受电痉挛治疗的对照组中是观察不到的。鉴于模式分离在日常生活中的重要性，研究其神经基质具有重要意义。这项工作将有助于更好地了解齿状回在健康人脑模式分离中的作用，并将有助于建立ECT作为研究齿状回功能的新型人体模型。最后，这项研究将为我实验室的实习生提供独特的机会，以获得神经成像技术和纵向数据分析的前沿经验。