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

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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.