Omid Talakoub1, Andrea Gomez Palacio Schjetnan2, Taufik A Valiante3, Milos R Popovic4, Kari L Hoffman5. 1. Department of Psychology, York University, Toronto, Canada; Centre for Vision Research, York University, Toronto, Canada; Krembil Neuroscience Center, Toronto, Canada. 2. Department of Psychology, York University, Toronto, Canada; Centre for Vision Research, York University, Toronto, Canada. 3. Krembil Neuroscience Center, Toronto, Canada; Division of Fundamental Neurobiology, Toronto Western Hospital Research Institute, Toronto, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada. 4. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada; Rehabilitation Engineering Laboratory, Toronto Rehabilitation Institute - University Health Network, Canada. 5. Department of Psychology, York University, Toronto, Canada; Centre for Vision Research, York University, Toronto, Canada. Electronic address: khoffman@yorku.ca.
Abstract
BACKGROUND: Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. OBJECTIVE: The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. METHOD: Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. RESULTS: The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. CONCLUSION: Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit.
BACKGROUND: Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. OBJECTIVE: The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. METHOD: Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. RESULTS: The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. CONCLUSION: Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit.