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1. Pro-myelinating clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health

   https://doi.org/10.1016/j.biomaterials.2023.122210  

   Chen, Keying; Cambi, Franca; Kozai, Takashi D.Y. (October 2023, Biomaterials)

   Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over the chronic implantation period. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period. 

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2. Cell-specific alterations in autophagy-lysosomal activity near the chronically implanted microelectrodes

   https://doi.org/10.1016/j.biomaterials.2023.122316  

   Chen, Keying; Garcia Padilla, Camila; Kiselyov, Kirill; Kozai, Takashi D.Y. (November 2023, Biomaterials)

   Intracortical microelectrodes that can record and stimulate brain activity have become a valuable technique for basic science research and clinical applications. However, long-term implantation of these microelectrodes can lead to progressive neurodegeneration in the surrounding microenvironment, characterized by elevation in disease-associated markers. Dysregulation of autophagy-lysosomal degradation, a major intracellular waste removal process, is considered a key factor in the onset and progression of neurodegenerative diseases. It is plausible that similar dysfunctions in autophagy-lysosomal degradation contribute to tissue degeneration following implantation-induced focal brain injury, ultimately impacting recording performance. To understand how the focal, persistent brain injury caused by long-term microelectrode implantation impairs autophagylysosomal pathway, we employed two-photon microscopy and immunohistology. This investigation focused on the spatiotemporal characterization of autophagy-lysosomal activity near the chronically implanted microelectrode. We observed an aberrant accumulation of immature autophagy vesicles near the microelectrode over the chronic implantation period. Additionally, we found deficits in autophagy-lysosomal clearance proximal to the chronic implant, which was associated with an accumulation of autophagy cargo and a reduction in lysosomal protease level during the chronic period. Furthermore, our evidence demonstrates reactive astrocytes have myelin-containing lysosomes near the microelectrode, suggesting its role of myelin engulfment during acute implantation period. Together, this study sheds light on the process of brain tissue degeneration caused by longterm microelectrode implantation, with a specific focus on impaired intracellular waste degradation. 

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3. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex

   https://doi.org/10.1038/s41467-022-35536-3  

   Wilson, Madison N.; Thunemann, Martin; Liu, Xin; Lu, Yichen; Puppo, Francesca; Adams, Jason W.; Kim, Jeong-Hoon; Ramezani, Mehrdad; Pizzo, Donald P.; Djurovic, Srdjan; et al (December 2022, Nature Communications)

   Abstract Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain. 

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4. Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation

   https://doi.org/10.1038/s41467-024-49709-9  

   Li, Fan; Gallego, Jazlyn; Tirko, Natasha_N; Greaser, Jenna; Bashe, Derek; Patel, Rudra; Shaker, Eric; Van_Valkenburg, Grace_E; Alsubhi, Alanoud_S; Wellman, Steven; et al (June 2024, Nature Communications)

   Abstract Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes. 

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5. Microscale Physiological Events on the Human Cortical Surface

   https://doi.org/10.1093/cercor/bhab040  

   Paulk, Angelique C; Yang, Jimmy C; Cleary, Daniel R; Soper, Daniel J; Halgren, Mila; O’Donnell, Alexandra R; Lee, Sang Heon; Ganji, Mehran; Ro, Yun Goo; Oh, Hongseok; et al (March 2021, Cerebral Cortex)

   Abstract Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their “intermediate” microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit. 

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