Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions.

Advanced fabrication techniques have now made it possible to produce microelectrode arrays for recording the electrical activity of a large number of neurons in the intact brain for both clinical and basic science applications. However, the long-term recording performance desired for these applications is hindered by a number of factors that lead to device failure or a poor signal-to-noise ratio (SNR). The goal of this study was to identify factors that can affect recording quality using theoretical analysis of intracortical microelectrode recordings of single-unit activity. Extracellular microelectrode recordings were simulated with a detailed multi-compartment cable model of a pyramidal neuron coupled to a finite-element volume conductor head model containing an implanted recording microelectrode. Recording noise sources were also incorporated into the overall modeling infrastructure. The analyses of this study would be very difficult to perform experimentally; however, our model-based approach enabled a systematic investigation of the effects of a large number of variables on recording quality. Our results demonstrate that recording amplitude and noise are relatively independent of microelectrode size, but instead are primarily affected by the selected recording bandwidth, impedance of the electrode-tissue interface and the density and firing rates of neurons surrounding the recording electrode. This study provides the theoretical groundwork that allows for the design of the microelectrode and recording electronics such that the SNR is maximized. Such advances could help enable the long-term functionality required for chronic neural recording applications.

Current neuroprosthetic systems based on electrophysiological recording have an extended, yet finite working lifetime. Some posited lifetime-extension solutions involve improving device biocompatibility or suppressing host immune responses. Our objective was to test an alternative solution comprised of applying a voltage pulse to a microelectrode site, herein termed "rejuvenation." Previously, investigators have reported preliminary electrophysiological results by utilizing a similar voltage pulse. In this study we sought to further explore this phenomenon via two methods: 1) electrophysiology; 2) an equivalent circuit model applied to impedance spectroscopy data. The experiments were conducted via chronically implanted silicon-substrate iridium microelectrode arrays in the rat cortex. Rejuvenation voltages resulted in increased unit recording signal-to-noise ratios (10%/spl plusmn/2%), with a maximal increase of 195% from 3.74 to 11.02. Rejuvenation also reduced the electrode site impedances at 1 kHz (67%/spl plusmn/2%). Neither the impedance nor recording properties of the electrodes changed on neighboring microelectrode sites that were not rejuvenated. In the equivalent circuit model, we found a transient increase in conductivity, the majority of which corresponded to a decrease in the tissue resistance component (44%/spl plusmn/7%). These findings suggest that rejuvenation may be an intervention strategy to prolong the functional lifetime of chronically implanted microelectrodes.

Reactive tissue encapsulation of chronically implanted microelectrode probes can preclude long-term recording of extracellular action potentials. We investigated an intervention strategy for functionally encapsulated microelectrode sites. This method, known as "rejuvenation," involved applying a +1.5 V dc bias to an iridium site for 4 s. Previous studies have demonstrated that rejuvenation resulted in higher signal-to-noise ratios (SNRs) by decreasing noise levels, and reduced 1-kHz site impedances by decreasing the tissue interface resistances. In this study, we have investigated: 1) the duration of a single-voltage bias session and 2) the efficacy of multiple sessions. These questions were addressed through electrophysiological recordings, cyclic voltammetry, and modeling the electrode-tissue interface via an equivalent circuit model fit to impedance spectroscopy data. In the six implants studied, we found SNRs improved for 1-7 days with a peak typically occurring within 24 h of the voltage bias. Root-mean square (RMS) noise of the extracellular recordings decreased for 1-2 days, which paralleled a similar decrease in the adsorbed tissue resistance (R/sub en/) from the model. Implants whose SNR effects lasted more than a day showed stabilized reductions in the extracellular tissue resistance (R/sub ex/) and cellular membrane area (A/sub m/). Subsequent stimulus sessions were found to drop neural tissue parameters consistently to levels observed immediately after surgery. In most cases, these changes did parallel an improvement in SNR. These findings suggest that rejuvenation may be a useful intervention strategy to prolong the lifetime of chronically implanted microelectrodes.

Objective . Flexible neural probes are hypothesized to reduce the chronic foreign body response (FBR) mainly by reducing the strain–stress caused by an interplay between the tethered probe and the brain’s micromotion. However, a large discrepancy of Young’s modulus still exists (3–6 orders of magnitude) between the flexible probes and the brain tissue. This raises the question of whether we need to bridge this gap; would increasing the probe flexibility proportionally reduce the FBR? Approach . Using novel off-stoichiometry thiol-enes-epoxy (OSTE+) polymer probes developed in our previous work, we quantitatively evaluated the FBR to four types of probes with different softness: silicon (~150 GPa), polyimide (1.5 GPa), OSTE+ _Hard (300 MPa), and OSTE+ _Soft (6 MPa). Main results . We observed a significant reduction in the fluorescence intensity of biomarkers for activated microglia/macrophages and blood-brain barrier (BBB) leakiness around the three soft polymer probes compared to the silicon probe, both at 4 weeks and 8 weeks post-implantation. However, we did not observe any consistent differences in the biomarkers among the polymer probes. Significance . The results suggest that the mechanical compliance of neural probes can mediate the degree of FBR, but its impact diminishes after a hypothetical threshold level. This infers that resolving the mechanical mismatch alone has a limited effect on improving the lifetime of neural implants.