The role of inflammation on the functionality of intracortical microelectrodes.

OBJECTIVE: Neuroinflammation has long been associated with the performance decline of intracortical microelectrodes (IMEs). Consequently, several strategies, including the use of anti-inflammatories, have been employed to mitigate the inflammation surrounding IMEs. However, these strategies have had limited success towards achieving a chronically viable cortical neural interface, questioning the efficacy of anti-inflammatory approach. APPROACH: Herein, we conducted a systematic study in rats implanted with functional devices by modulating inflammation via systemic injection of lipopolysaccharide (LPS), dexamethasone (DEX), a combination of both, or none to assess the degree of inflammation on device functionality. We hypothesized that implanted rats treated with LPS will have a negative impact, and rats treated with DEX will have a positive impact on functionality IMEs and histological outcome. MAIN RESULTS: Contrary to our hypothesis, we did not observe adverse effects in recording metrics among different groups with LPS and/or DEX treatment despite alterations in initial pro-inflammatory markers. We also did not observe any functional benefit of anti-inflammatory treatment. Regardless of the treatment conditions, the recording quality degraded at chronic time points. In end-point histology, implanted rats that received LPS had significantly lower NeuN density and higher levels of CD68 surrounding the implant site, indicative of the pro-inflammatory effect of LPS, which, however, contradicted with the recorded results. SIGNIFICANCE: Collectively, our results suggest that acute inflammatory events may not be the key driver for functional degradation of IMEs. Future intervention strategies geared towards improving the functional longevity of intracortical devices may benefit using multi-modal approaches rather than a single approach, such as controlling the initial inflammatory response.

PrismPlus: a mouse line expressing distinct fluorophores in four different brain cell types.

To screen the complex central nervous system (CNS) injury responses, we created a quadruple-labelled 'PrismPlus' mouse line with a genetically encoded distinct fluorescent tag in oligodendrocytes, microglia, neurons, and astrocytes. Cx3cr1-gfp and Prism mice originally developed by Jung et al., 2000 and Dougherty et al., 2012, respectively, were cross-bred. First, we confirmed the presence of fluorophores in appropriate cell types in PrismPlus mice. PrismPlus mice were then used to examine the cellular responses to brain implanted micro-devices. We observed an increase in microglial response at earlier time points as compared to 4 weeks, a progressive astrocytic response, and fewer neurons at the vicinity of an implanted device. These results are similar to what has been described in literature using other rodent strains, previously attainable only through time-consuming and variable immunohistochemistry methods. Finally, we demonstrate the compatibility of PrismPlus brain tissue with CLARITY, an advanced tissue clearing technique, opening the door to future thick tissue imaging studies. This report confirms PrismPlus transgenic fluorescence and highlights the utility of these mice to study CNS injuries. The work herein seeks to establish a novel transgenic mouse line to improve experimental scope, consistency, and efficiency for CNS researchers.

Placing Sites on the Edge of Planar Silicon Microelectrodes Enhances Chronic Recording Functionality.

OBJECTIVE: This study aims to identify the impact of using edge sites over center sites on a planar silicon microelectrode array. METHODS: We used custom-designed, silicon-substrate multisite microelectrode arrays with sites on the center, edge, and tip. We compared their single unit recording capability, noise level, impedance, and histology to identify the differences between each site location. Wide and narrow devices were used to evaluate if the differences are consistent and meet theoretical expectations. RESULTS: On the wide device, significantly more number of edge sites were functional than center sites over the course of 8 weeks with generally higher signal-to-noise amplitude ratio. On the narrow device, edge sites also performed generally better than center sites, but the differences were not significant and smaller than wide devices. The data from the tip sites were inconclusive. CONCLUSION: Edge sites outperformed center sites in terms of single unit recording capability. This benefit decreased as the device gets narrower and the distance to center sites decreases. SIGNIFICANCE: We showed that a simple alteration to the site placement can greatly enhance the functionality of silicon microelectrodes. This study promotes the idea that not only the substrate but also the site architecture needs attention to lengthen the lifetime of neural implants.

Histological evaluation of flexible neural implants; flexibility limit for reducing the tissue response?

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.

Variable step size methods for solving simultaneous algebraic reconstruction technique (SART)-type cbct reconstructions.

Compared to analytical reconstruction by Feldkamp-Davis-Kress (FDK), simultaneous algebraic reconstruction technique (SART) offers a higher degree of flexibility in input measurements and often produces superior quality images. Due to the iterative nature of the algorithm, however, SART requires intense computations which have prevented its use in clinical practice. In this paper, we developed a fast-converging SART-type algorithm and showed its clinical feasibility in CBCT reconstructions. Inspired by the quasi-orthogonal nature of the x-ray projections in CBCT, we implement a simple yet much faster algorithm by computing Barzilai and Borwein step size at each iteration. We applied this variable step-size (VS)-SART algorithm to numerical and physical phantoms as well as cancer patients for reconstruction. By connecting the SART algebraic problem to the statistical weighted least squares problem, we enhanced the reconstruction speed significantly (i.e., less number of iterations). We further accelerated the reconstruction speed of algorithms by using the parallel computing power of GPU.

Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a monte carlo study.

The aim of this study is to compare between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT) and to analyze dose escalation using a Monte Carlo simulation. We simulated a proton beam passing through the water with a boron uptake region (BUR) in MCNPX. To estimate the interaction between neutrons/protons and borons by the alpha particle, the simulation yielded with a variation of the center of the BUR location and proton energies. The variation and influence about the alpha particle were observed from the percent depth dose (PDD) and cross-plane dose profile of both the neutron and proton beams. The peak value of the maximum dose level when the boron particle was accurately labeled at the region was 192.4% among the energies. In all, we confirmed that prompt gamma rays of 478 keV and 719 keV were generated by the nuclear reactions in PBFT and BNCT, respectively. We validated the dramatic effectiveness of the alpha particle, especially in PBFT. The utility of PBFT was verified using the simulation and it has a potential for application in radiotherapy.

An efficient iterative CBCT reconstruction approach using gradient projection sparse reconstruction algorithm.

The purpose of this study is to develop a fast and convergence proofed CBCT reconstruction framework based on the compressed sensing theory which not only lowers the imaging dose but also is computationally practicable in the busy clinic. We simplified the original mathematical formulation of gradient projection for sparse reconstruction (GPSR) to minimize the number of forward and backward projections for line search processes at each iteration. GPSR based algorithms generally showed improved image quality over the FDK algorithm especially when only a small number of projection data were available. When there were only 40 projections from 360 degree fan beam geometry, the quality of GPSR based algorithms surpassed FDK algorithm within 10 iterations in terms of the mean squared relative error. Our proposed GPSR algorithm converged as fast as the conventional GPSR with a reasonably low computational complexity. The outcomes demonstrate that the proposed GPSR algorithm is attractive for use in real time applications such as on-line IGRT.

The effect of site placement within silicon microelectrodes on the long-term electrophysiological recordings.

Intracortical microelectrodes can be used to treat various neurological disorders given their capabilities to interface with single or multiple populations of neurons. However, most of these penetrating devices have been reported to fail over time, within weeks to months, putatively due to the foreign body response (FBR) which persistently aggravates the surrounding brain tissues. A number of studies have confirmed that various electrode properties, such as size, shape, and surface area, may play a role in the biological responses to the microelectrode. Further experimental data is needed to determine the effect of these properties on the FBR and the recording performance. In this paper, we evaluate the effect of site placement using Michigan arrays with sites on the center, edge, and tip of the shank. The results show that there is significant performance variance between the center, edge, and tip sites.

Spontaneous synchronized burst firing of subthalamic nucleus neurons in rat brain slices measured on multi-electrode arrays.

The current study presents an organotypic rat midbrain slice culture that served as a consistent and informative framework, where the STN neurons and their interconnectivity were closely examined with respect to electrophysiological and pharmacological properties. From multi-electrode array recordings, it was found that the majority of STN neurons spontaneously fired in bursts rather than tonically under control conditions, and the neural activity between pairs of burst-firing STN neurons was tightly correlated. This spontaneous synchronized burst firing was also affected by a glutamate receptor antagonist, yet unaffected by a GABA receptor antagonist. Moreover, even when the STN was isolated from all its known external inputs, spontaneous synchronized burst firing was still observed under control conditions and consistently switched to tonic firing following the application of a glutamate receptor antagonist. Therefore, the results indicated the existence of glutamatergic projections to the STN in the slice preparation, and these excitatory synaptic connections appeared to originate from axon collaterals within the STN rather than other basal ganglia nuclei. It could be concluded that the STN neurons and their interconnectivity are essential requirements in the rat brain slice preparation to produce spontaneous synchronized burst firing.