Pro-myelinating Clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health

Abstract

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 chronic implantation. 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.

Impact of electrodes design and insertion methods to surrounding cortical tissues from high-density arrays

“…Sprague-Dawley (SD) rats (n=3) were induced with Ketamine and Xylazine and maintained with Ketamine as listed under surgical procedures. The electrophysiological recordings were taken inside a Faraday cage while single wire electrodes were implanted into the left visual cortex and a monitor was placed outside the cage in the right visual field as described in previous studies 3,28,30,32,39,44,[84][85][86][87][88] . The electrode impedance for the electrode was 0.17 Mohm at 1 kHz and recordings were made at multiple depths (0, 520 and 1000 μm) down in the brain.…”

“…Sprague-Dawley (SD) rats (n=3) were induced with Ketamine and Xylazine and maintained with Ketamine as listed under surgical procedures. The electrophysiological recordings were taken inside a Faraday cage while single wire electrodes were implanted into the left visual cortex and a monitor was placed outside the cage in the right visual field as described in previous studies 3,23,25,27,34,40,[76][77][78][79][80] . The visual stimulus was made up of 8 different directional translations of drifting gratings that moved across the monitor (1 sec) while the neural response was recorded from a single wire (20 μm in diameter) electrode 77 .…”

Neuronal functional connectivity is impaired in a layer dependent manner near the chronically implanted microelectrodes

“…3, Fig 8) could be linked to vascular injuries induced by electrode implantation, resulting in more severe tissue damage in superficial depths with large-diameter vessels than in deeper tissues with smaller capillaries [111][112][113]. Additionally, astrocytes [35,114,115 ] and oligodendrocytes [41,43] that mediate local delivery of metabolites to neurons undergo more structural changes in response to implantation injury at superficial layers [116,117], which may further compromise the metabolic supply for neural network functionality near the microelectrode. Therefore, this disruption to vascular integrity and glial reactivity potentially reduces the availability of glucose and oxygen for neuronal activity [28,31,40], which may explain the early detection loss of metabolically intensive inhibitory neurons, significant reduction in putative excitatory firing rate, and decreased network activation in L2/3 (Fig.…”

“…Additionally, oligodendrocytes and myelin, which are crucial for action potential conduction and to metabolically support axon function, are susceptible to injury during implantation, leading to progressive axonal degeneration and limited axonal regeneration capacity [41]. Thus, impaired oligodendrocyte and myelin function can also reduce the signals detected by the microelectrodes [42,43]. The brain's information processing complexity arises from its diverse anatomical structures and functional connectivity [45].…”