Targeting CD14 on blood derived cells improves intracortical microelectrode performance

Abstract

Intracortical microelectrodes afford researchers an effective tool to precisely monitor neural spiking activity. Additionally, intracortical microelectrodes have the ability to return function to individuals with paralysis as part of a brain computer interface. Unfortunately, the neural signals recorded by these electrodes degrade over time. Many strategies which target the biological and/or materials mediating failure modes of this decline of function are currently under investigation. The goal of this study is to identify a precise cellular target for future intervention to sustain chronic intracortical microelectrode performance. Previous work from our lab has indicated that the Cluster of Differentiation 14/Toll-like receptor pathway (CD14/TLR) is a viable target to improve chronic laminar, silicon intracortical microelectrode recordings. Here, we use a mouse bone marrow chimera model to selectively knockout CD14, an innate immune receptor, from either brain resident microglia or blood-derived macrophages, in order to understand the most effective targets for future therapeutic options. Using single-unit recordings we demonstrate that inhibiting CD14 from the blood-derived macrophages improves recording quality over the 16 week long study. We conclude that targeting CD14 in blood-derived cells should be part of the strategy to improve the performance of intracortical microelectrodes, and that the daunting task of delivering therapeutics across the blood-brain barrier may not be needed to increase intracortical microelectrode performance.

Investigating the Association between Motor Function, Neuroinflammation, and Recording Metrics in the Performance of Intracortical Microelectrode Implanted in Motor Cortex

“…Our analysis of the histological markers used in the current study demonstrated that there were significantly fewer neurons ( Figure 2 A) within the first 50 µm of the electrode site, compared to all further distances up to 400 µm. These results are consistent with previous reports from many labs, including our own [ 29 , 31 , 42 , 53 , 54 , 55 , 56 , 57 ]. Additionally, there was significantly more activated microglia/macrophages ( Figure 2 B), reactive astrocytes ( Figure 2 C), and blood–brain barrier permeability ( Figure 2 D) within the first 50 µm of the electrode site compared to further distances.…”

“…All channels were recorded continuously at 24,414 Hz for 10 min for later offline analysis. In the offline analysis, the relative size of the recorded action potentials for each isolatable unit was assessed for each electrode contact based on established methods [ 42 , 43 ].…”

“…Signal processing of recorded units was done following previously published methods [ 12 , 41 , 42 , 43 ]. In brief, the recorded electrophysiological data was sampled at 24,414 Hz and voltage traces were bandpass filtered at 300–3000 Hz.…”

Chronically Implanted Intracranial Electrodes: Tissue Reaction and Electrical Changes

“…But for chronic implants, the body’s response at the tissue-microelectrode interface eventually leads to mechanical failure and signal degradation [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Despite extensive investigations into the inflammatory response and numerous trials investigating strategies to mitigate it, clearing this hurdle has remained elusive [ 5 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. It is consequentially one of the most important obstacles to overcome in order for neural interface technology to be fully realized.…”

The History and Horizons of Microscale Neural Interfaces

“…Despite these numerous success stories, many challenges, and as a result, great opportunities remain unexplored [ 36 , 58 , 68 ]. There remains large variability in performance even between identical devices [ 69 ] due to both biological [ 58 , 67 , 70 , 71 , 72 ] and material integrity variance [ 73 , 74 , 75 ], even within the same subject [ 71 , 72 ]. Nevertheless, the field of neural engineering has reached a tipping point due to pioneers in neuroscience, technology development, and neurosurgery.…”