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Multimodal Investigation to Understand the Role of Metabolic Dysregulations at the Electrode-Tissue Interface

Chen, Keying (2023) Multimodal Investigation to Understand the Role of Metabolic Dysregulations at the Electrode-Tissue Interface. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Intracortical microelectrodes that can be implanted in the brain have demonstrated significant potential for advancing research in the field of neuroscience and restoring functional outcomes in clinical settings. However, the stability and sensitivity of these intracortical microelectrodes tend to decrease gradually during long-term implantation, ultimately leading to the loss of neuronal signal detection and device implantation failure. Biological reactions have been considered as a critical failure mechanism of the long-term device implantation. The brain’s immune responses to microelectrode implantation that microglia activation and astrocyte reactivity for neuroinflammation are traditionally considered to contribute to loss of neuronal sources for microelectrode signal detection. However, recent evidence reveals a discrepancy between the minimal microglia activation and poor device performances, suggesting other factors may contribute to the chronic decline of signal quality, such as impaired neural network connectivity and metabolic dysregulation in brain tissue near the chronically implanted microelectrode.
In this dissertation, we employ in vivo two-photon microscopy, post-mortem immunohistology, and electrophysiology to provide novel insights into the biological reactions that contribute to chronic performance decline of implanted intracortical microelectrodes. We demonstrate that the functional network connectivity is altered within and across different laminar circuits near the chronic implanted microelectrodes. We also reveal how metabolic activity at local brain tissue near the implanted microelectrode is disrupted. The autophagy-lysosomal activity responsible for intracellular waste removal is impaired during the chronic implantation period. We also demonstrate that oligodendrocytes and myelin, which deliver metabolites to neurons, undergo progressive degeneration near the implanted microelectrode over time. Lastly, we present evidence that pharmacological treatments promoting oligodendrocyte density and myelination can rescue malfunctions in network connectivity and enhance the survival of both excitatory and inhibitory neurons. Collectively, these studies offer multiple new perspectives towards a more comprehensive understanding of the biological reactions at electrode-tissue interfaces, which will aid in designing therapeutic treatments for improving the chronic device performance of microelectrodes and developing the next generation of neural interfacing devices.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chen, Keyingchenkeying1996@gmail.comkec1980009-0007-9576-5952
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKozai, Takashi
Committee MemberCambi,
Committee MemberGonzalez-Burgos,
Committee MemberKiselyov,
Committee MemberVazquez, Alberto L.alv15@pitt.edualv15
Date: 14 September 2023
Date Type: Publication
Defense Date: 20 April 2023
Approval Date: 14 September 2023
Submission Date: 17 May 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 320
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Brain machine interfaces, neuronal survival, remyelination, glial modulation, neural network function, visual stimulation, tissue homeostasis
Date Deposited: 14 Sep 2023 13:34
Last Modified: 14 Sep 2023 13:34


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