Understanding the Role of Innate Immunity in the Response to Intracortical Microelectrodes.
ABSTRACT: Intracortical microelectrodes exhibit enormous potential for researching the nervous system, steering assistive devices and functional electrode stimulation systems for severely paralyzed individuals, and augmenting the brain with computing power. Unfortunately, intracortical microelectrodes often fail to consistently record signals over clinically useful periods. Biological mechanisms, such as the foreign body response to intracortical microelectrodes and self-perpetuating neuroinflammatory cascades, contribute to the inconsistencies and decline in recording performance. Unfortunately, few studies have directly correlated microelectrode performance with the neuroinflammatory response to the implanted devices. However, of those select studies that have, the role of the innate immune system remains among the most likely links capable of corroborating the results of different studies, across laboratories. Therefore, the overall goal of this review is to highlight the role of innate immunity signaling in the foreign body response to intracortical microelectrodes and hypothesize as to appropriate strategies that may become the most relevant in enabling brain-dwelling electrodes of any geometry, or location, for a range of clinical applications.
Project description:Intracortical microelectrodes record neuronal activity of individual neurons within the brain, which can be used to bridge communication between the biological system and computer hardware for both research and rehabilitation purposes. However, long-term consistent neural recordings are difficult to achieve, in large part due to the neuroinflammatory tissue response to the microelectrodes. Prior studies have identified many factors that may contribute to the neuroinflammatory response to intracortical microelectrodes. Unfortunately, each proposed mechanism for the prolonged neuroinflammatory response has been investigated independently, while it is clear that mechanisms can overlap and be difficult to isolate. Therefore, we aimed to determine whether the dual targeting of the innate immune response by inhibiting innate immunity pathways associated with cluster of differentiation 14 (CD14), and the mechanical mismatch could improve the neuroinflammatory response to intracortical microelectrodes. A thiol-ene probe that softens on contact with the physiological environment was used to reduce mechanical mismatch. The thiol-ene probe was both softer and larger in size than the uncoated silicon control probe. Cd14-/- mice were used to completely inhibit contribution of CD14 to the neuroinflammatory response. Contrary to the initial hypothesis, dual targeting worsened the neuroinflammatory response to intracortical probes. Therefore, probe material and CD14 deficiency were independently assessed for their effect on inflammation and neuronal density by implanting each microelectrode type in both wild-type control and Cd14-/- mice. Histology results show that 2 weeks after implantation, targeting CD14 results in higher neuronal density and decreased glial scar around the probe, whereas the thiol-ene probe results in more microglia/macrophage activation and greater blood-brain barrier (BBB) disruption around the probe. Chronic histology demonstrate no differences in the inflammatory response at 16 weeks. Over acute time points, results also suggest immunomodulatory approaches such as targeting CD14 can be utilized to decrease inflammation to intracortical microelectrodes. The results obtained in the current study highlight the importance of not only probe material, but probe size, in regard to neuroinflammation.
Project description:Intracortical neural microelectrodes, which can directly interface with local neural microcircuits with high spatial and temporal resolution, are critical for neuroscience research, emerging clinical applications, and brain computer interfaces (BCI). However, clinical applications of these devices remain limited mostly by their inability to mitigate inflammatory reactions and support dense neuronal survival at their interfaces. Herein we report the development of microelectrodes primarily composed of extracellular matrix (ECM) proteins, which act as a bio-compatible and an electrochemical interface between the microelectrodes and physiological solution. These ECM-microelectrodes are batch fabricated using a novel combination of micro-transfer-molding and excimer laser micromachining to exhibit final dimensions comparable to those of commercial silicon-based microelectrodes. These are further integrated with a removable insertion stent which aids in intracortical implantation. Results from electrochemical models and in vivo recordings from the rat's cortex indicate that ECM encapsulations have no significant effect on the electrochemical impedance characteristics of ECM-microelectrodes at neurologically relevant frequencies. ECM-microelectrodes are found to support a dense layer of neuronal somata and neurites on the electrode surface with high neuronal viability and exhibited markedly diminished neuroinflammation and glial scarring in early chronic experiments in rats.
Project description:Thiol-ene based shape memory polymers (SMPs) have been developed for use as intracortical microelectrode substrates. The unique chemistry provides precise control over the mechanical and thermal glass-transition properties. As a result, SMP substrates are stiff at room temperature, allowing for insertion into the brain without buckling and subsequently soften in response to body temperatures, reducing the mechanical mismatch between device and tissue. Since the surface chemistry of the materials can contribute significantly to the ultimate biocompatibility, as a first step in the characterization of our SMPs, we sought to isolate the biological response to the implanted material surface without regards to the softening mechanics. To accomplish this, we tightly controlled for bulk stiffness by comparing bare silicon 'dummy' devices to thickness-matched silicon devices dip-coated with SMP. The neuroinflammatory response was evaluated after devices were implanted in the rat cortex for 2 or 16 weeks. We observed no differences in the markers tested at either time point, except that astrocytic scarring was significantly reduced for the dip-coated implants at 16 weeks. The surface properties of non-softening thiol-ene SMP substrates appeared to be equally-tolerated and just as suitable as silicon for neural implant substrates for applications such as intracortical microelectrodes, laying the groundwork for future softer devices to improve upon the prototype device performance presented here.
Project description:BACKGROUND:Brain-implanted devices, including intracortical microelectrodes, are used in neuroscience applications ranging from research to rehabilitation and beyond. Significant efforts are focused on developing new device designs and insertion strategies that mitigate initial trauma and subsequent neuroinflammation that occurs as a result of implantation. A frequently published metric is the neuroinflammatory response quantified as a function of distance from the interface edge, using fluorescent immunohistochemical markers. NEW METHOD:Here, we sought to develop a graphical user interface software in Matlab to provide an objective, repeatable, and easy-to-use method for analyzing fluorescence immunohistochemistry images of neuroinflammation. The user interface allows for efficient batch-processing and review of images, and incorporates zoom and contrast features to improve the accuracy of identifying the 'region of interest' (ROI). RESULTS:The software was validated against previously published results and demonstrated equivalent scientific conclusions. Furthermore, a comparison between novice and expert users demonstrated consistency across levels of training and a rapid learning-curve. COMPARISON WITH EXISTING METHOD(S):Existing methods published in the intracortical microelectrode literature include a wide variety of procedures within ImageJ and Matlab. However, specific procedural details are often lacking. CONCLUSIONS:The distribution of the methodology may promote efficiency and reproducibility across the field seeking to characterize the tissue response to implanted neural interfaces. It may also serve as a template for researchers seeking to perform other types of histological quantification as a function of distance from an ROI.
Project description: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.
Project description:OBJECTIVE:Our objective was to determine how readily disruption of the blood-brain barrier (BBB) occurred as a result of bone drilling during a craniotomy to implant microelectrodes in rat cortex. While the phenomenon of heat production during bone drilling is well known, practices to evade damage to the underlying brain tissue are inconsistently practiced and reported in the literature. APPROACH:We conducted a review of the intracortical microelectrode literature to summarize typical approaches to mitigate drill heating during rodent craniotomies. Post mortem skull-surface and transient brain-surface temperatures were experimentally recorded using an infrared camera and thermocouple, respectively. A number of drilling conditions were tested, including varying drill speed and continuous versus intermittent contact. In vivo BBB permeability was assayed 1?h after the craniotomy procedure using Evans blue dye. MAIN RESULTS:Of the reviewed papers that mentioned methods to mitigate thermal damage during craniotomy, saline irrigation was the most frequently cited (in six of seven papers). In post mortem tissues, we observed increases in skull-surface temperature ranging from??+3 °C to??+21 °C, dependent on drill speed. In vivo, pulsed-drilling (2 s-on/2 s-off) and slow-drilling speeds (1000 r.p.m.) were the most effective methods we studied to mitigate heating effects from drilling, while inconclusive results were obtained with saline irrigation. SIGNIFICANCE:Neuroinflammation, initiated by damage to the BBB and perpetuated by the foreign body response, is thought to play a key role in premature failure of intracortical recording microelectrodes. This study demonstrates the extreme sensitivity of the BBB to overheating caused by bone drilling. To avoid damage to the BBB, the authors recommend that craniotomies be drilled with slow speeds and/or with intermittent drilling with complete removal of the drill from the skull during 'off' periods. While saline alone was ineffective at preventing overheating, its use is still recommended to remove bone dust from the surgical site and to augment other cooling methods.
Project description:OBJECTIVE:Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH:Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS:The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE:Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.
Project description:Long-term reliability of intracortical microelectrodes remains a challenge for increased acceptance and deployment. There are conflicting reports comparing measurements associated with recording quality with postmortem histology, in attempts to better understand failure of intracortical microelectrodes (IMEs). Our group has recently introduced the assessment of motor behavior tasks as another metric to evaluate the effects of IME implantation. We hypothesized that adding the third dimension to our analysis, functional behavior testing, could provide substantial insight on the health of the tissue, success of surgery/implantation, and the long-term performance of the implanted device. Here we present our novel analysis scheme including: (1) the use of numerical formal concept analysis (nFCA) and (2) a regression analysis utilizing modern model/variable selection. The analyses found complimentary relationships between the variables. The histological variables for glial cell activation had associations between each other, as well as the neuronal density around the electrode interface. The neuronal density had associations to the electrophysiological recordings and some of the motor behavior metrics analyzed. The novel analyses presented herein describe a valuable tool that can be utilized to assess and understand relationships between diverse variables being investigated. These models can be applied to a wide range of ongoing investigations utilizing various devices and therapeutics.
Project description:The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point-and-click control of a computer interface to an individual with tetraplegia 1000 days after implantation of this sensor.
Project description:Improving the long-term performance of neural electrode interfaces requires overcoming severe biological reactions such as neuronal cell death, glial cell activation, and vascular damage in the presence of implanted intracortical devices. Past studies traditionally observe neurons, microglia, astrocytes, and blood-brain barrier (BBB) disruption around inserted microelectrode arrays. However, analysis of these factors alone yields poor correlation between tissue inflammation and device performance. Additionally, these studies often overlook significant biological responses that can occur during acute implantation injury. The current study employs additional histological markers that provide novel information about neglected tissue components-oligodendrocytes and their myelin structures, oligodendrocyte precursor cells, and BBB -associated pericytes-during the foreign body response to inserted devices at 1, 3, 7, and 28 days post-insertion. Our results reveal unique temporal and spatial patterns of neuronal and oligodendrocyte cell loss, axonal and myelin reorganization, glial cell reactivity, and pericyte deficiency both acutely and chronically around implanted devices. Furthermore, probing for immunohistochemical markers that highlight mechanisms of cell death or patterns of proliferation and differentiation have provided new insight into inflammatory tissue dynamics around implanted intracortical electrode arrays.