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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760852
• 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，对于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”类似的经历，这一过程被称为模式分离。动物研究表明，齿状回支持模式分离。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的活动。虽然对健康成年人的神经成像研究可以显示不同大脑区域的参与，但他们无法准确定位任务所需的区域。到目前为止，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，一名罕见的齿状回受损患者被发现在模式分离任务中表现不佳。还需要更多的人体模型来评估齿状回在模式分离中的作用。在这项研究中，我们将使用电休克治疗(ECT)作为一种新的人类模型来检查齿状回是否参与模式分离。ECT是一种治疗重度抑郁症的有效方法，已被证明可以增加齿状回的体积。我们将在ECT前后对重度抑郁症患者进行行为和神经成像任务的模式分离测试。我们还将测量ECT前后齿状回和其他海马区的体积。不接受电疗的对照组参与者将接受两次相同措施的测试，以确保影响是特定于电疗的。为了评估模式分离的变化，我们将使用记忆相似性测试(MST)，这是一项已知依赖于齿状回的记忆任务。参与者将在计算机上完成这项任务的一个版本，同时接受功能神经成像，这是一项技术，可以在参与者执行任务时在线显示大脑活动(血液流动)。我们预计ECT后齿状回的体积将增加，这将伴随着齿状回在评估模式分离的任务中的性能改善和更大的活动。在未接受电疗的对照组中，不会观察到这些变化。鉴于模式分离在日常生活中的重要性，对其神经基础的研究具有重要意义。这项工作将有助于更好地理解齿状回在健康人脑模式分离中所起的作用，并将有助于建立ECT作为研究齿状回功能的新的人类模型。最后，这项研究将为我实验室的学员提供独特的机会，获得神经成像技术和纵向数据分析的前沿经验。