Elucidating the Role of the Hippocampus in Motor Memory using Temporal Interference Stimulation

/Abstract The hippocampus was long described by seminal memory models to not be necessary for procedural (motor) learning. In contrast, neuroimaging studies from the last two decades consistently show hippocampal recruitment during motor sequence learning. These conflicting results show that the extent to which the hippocampus contributes to motor learning is unknown. We argue that this knowledge gap is attributed to a lack of causal neuroimaging evidence elucidating the role of the hippocampus in motor memory. Failing to address this critical gap will be a missed opportunity to update the field’s conceptualization of memory system organization and will prevent the development of interventions targeting hippocampal-mediated motor learning and memory processes. The overarching goal of this project is therefore to causally test for the role of the hippocampus in motor memory in young healthy adults using a novel non-invasive experimental intervention (i.e., temporal interference stimulation - TIS). TIS is a potentially groundbreaking intervention that was developed in rodents and recently translated to human research. It enables focused - yet safe and noninvasive - neural stimulation at depth and therefore holds immense promise for the modulation of activity in deep brain regions. In this project, we will evaluate the effect of TIS on human hippocampal responses related to motor learning using functional magnetic resonance imaging (MRI). We will causally test a framework of hippocampal involvement in motor learning that will potentially reconcile previous contradictory findings. This framework proposes that the hippocampus supports abstract representations of motor sequences encompassing their spatio-temporal coordinates that are reactivated offline and can be generalizable across learning episodes. To causally test this framework, we will administer HC or sham TIS during motor learning and examine the effect of stimulation on both the behavioral (Aim 1) and neural (Aim 2) correlates of online and offline learning. Our central hypothesis is HC-TIS will specifically enhance offline motor learning via the modulation of HC responses. This innovative research project will lead to a breakthrough, as it will provide direct causal evidence for a role of the hippocampus in motor learning. It will also significantly impact the biomedical, behavioral and clinical fields because it will validate the use of TIS as a novel and groundbreaking technique to modulate motor learning-related (re)activation patterns in deep brain regions of the human brain. Ultimately, such an approach can be translated to the clinical domain in order to mitigate motor learning-related deficits in specific populations. Project Number: 1R21MH140335-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Genevieve Albouy (+1 co-PI) | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $402,802 | Activity Code: R21 | Study Section: Human Complex Mental Function Study Section[HCMF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304311