A pinboard by
Nicholas Nolta

Postdoc, University of Connecticut


Understanding the biological response to electrodes in the brain, using 3D image reconstruction

Neural interfaces allow prosthetic legs, arms, and hands to be directly controlled by a patient's nervous system, as if it were their own natural limb. These devices will greatly improve the independence and quality of life of people with paralysis and limb loss. Although proof-of-concept has been achieved in animal and small-scale human clinical trials, the consistency, longevity, and level of performance are not yet high enough to warrant widespread clinical adoption. A critical component of the system are the microelectrode arrays in brain tissue that pick up signals from neurons in the brain and pass those signals to the prosthetic device. One leading hypothesis is that the foreign body response, mounted by the body's immune system, over time sickens or pushes away the neurons immediately adjacent to the microelectrode array, so that eventually there are no healthy neurons close enough to detect signals from. Numerous studies have investigated this hypothesis by implanting animals with microelectrode arrays and looking at 2D slices of post-mortem brain tissue near the arrays, staining for various specific "biomarkers." However, the foreign body response is difficult to visualize as a series of 2D images, and biases the analysis in certain ways. Our study's unique contribution is to assemble series of 2D images into 3D images using image reconstruction techniques. Additionally, the "hybrid" arrays we implanted contain devices from three different manufacturers, allowing us to compare the effects of different device designs. Finally, our study is rare in that we used functional devices for many months in cat cortex, which is a better model for humans than rodents and allows us to compare our observations of the foreign body response with data on device performance. This combination of advantages in our approach has allowed us to gain new insights into how these devices may be improved in the future.


Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates.

Abstract: Brain-computer interfaces (BCIs) using chronically implanted intracortical microelectrode arrays (MEAs) have the potential to restore lost function to people with disabilities if they work reliably for years. Current sensors fail to provide reliably useful signals over extended periods of time for reasons that are not clear. This study reports a comprehensive retrospective analysis from a large set of implants of a single type of intracortical MEA in a single species, with a common set of measures in order to evaluate failure modes.Since 1996, 78 silicon MEAs were implanted in 27 monkeys (Macaca mulatta). We used two approaches to find reasons for sensor failure. First, we classified the time course leading up to complete recording failure as acute (abrupt) or chronic (progressive). Second, we evaluated the quality of electrode recordings over time based on signal features and electrode impedance. Failure modes were divided into four categories: biological, material, mechanical, and unknown.Recording duration ranged from 0 to 2104 days (5.75 years), with a mean of 387 days and a median of 182 days (n = 78). Sixty-two arrays failed completely with a mean time to failure of 332 days (median = 133 days) while nine array experiments were electively terminated for experimental reasons (mean = 486 days). Seven remained active at the close of this study (mean = 753 days). Most failures (56%) occurred within a year of implantation, with acute mechanical failures the most common class (48%), largely because of connector issues (83%). Among grossly observable biological failures (24%), a progressive meningeal reaction that separated the array from the parenchyma was most prevalent (14.5%). In the absence of acute interruptions, electrode recordings showed a slow progressive decline in spike amplitude, noise amplitude, and number of viable channels that predicts complete signal loss by about eight years. Impedance measurements showed systematic early increases, which did not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicates that insulating material failure is the most significant factor.This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade.

Pub.: 13 Nov '13, Pinned: 28 Jun '17

Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays.

Abstract: Implantable silicon microelectrode array technology is a useful technique for obtaining high-density, high-spatial resolution sampling of neuronal activity within the brain and holds promise for a wide range of neuroprosthetic applications. One of the limitations of the current technology is inconsistent performance in long-term applications. Although the brain tissue response is believed to be a major cause of performance degradation, the precise mechanisms that lead to failure of recordings are unknown. We observed persistent ED1 immunoreactivity around implanted silicon microelectrode arrays implanted in adult rat cortex that was accompanied by a significant reduction in nerve fiber density and nerve cell bodies in the tissue immediately surrounding the implanted silicon microelectrode arrays. Persistent ED1 up-regulation and neuronal loss was not observed in microelectrode stab controls indicating that the phenotype did not result from the initial mechanical trauma of electrode implantation, but was associated with the foreign body response. In addition, we found that explanted electrodes were covered with ED1/MAC-1 immunoreactive cells and that the cells released MCP-1 and TNF-alpha under serum-free conditions in vitro. Our findings suggest a potential new mechanism for chronic recording failure that involves neuronal cell loss, which we speculate is caused by chronic inflammation at the microelectrode brain tissue interface.

Pub.: 28 Jul '05, Pinned: 28 Jun '17

BBB leakage, astrogliosis, and tissue loss correlate with silicon microelectrode array recording performance.

Abstract: The clinical usefulness of brain machine interfaces that employ penetrating silicon microelectrode arrays is limited by inconsistent performance at chronic time points. While it is widely believed that elements of the foreign body response (FBR) contribute to inconsistent single unit recording performance, the relationships between the FBR and recording performance have not been well established. To address this shortfall, we implanted 4X4 Utah Electrode Arrays into the cortex of 28 young adult rats, acquired electrophysiological recordings weekly for up to 12 weeks, used quantitative immunohistochemical methods to examine the intensity and spatial distribution of neural and FBR biomarkers, and examined whether relationships existed between biomarker distribution and recording performance. We observed that the FBR was characterized by persistent inflammation and consisted of typical biomarkers, including presumptive activated macrophages and activated microglia, astrogliosis, and plasma proteins indicative of blood-brain-barrier disruption, as well as general decreases in neuronal process distribution. However, unlike what has been described for recording electrodes that create only a single penetrating injury, substantial brain tissue loss generally in the shape of a pyramidal lesion cavity was observed at the implantation site. Such lesions were also observed in stab wounded animals indicating that the damage was caused by vascular disruption at the time of implantation. Using statistical approaches, we found that blood-brain barrier leakiness and astrogliosis were both associated with reduced recording performance, and that tissue loss was negatively correlated with recording performance. Taken together, our data suggest that a reduction of vascular damage at the time of implantation either by design changes or use of hemostatic coatings coupled to a reduction of chronic inflammatory sequela will likely improve the recording performance of high density intracortical silicon microelectrode arrays over long indwelling periods and lead to enhanced clinical use of this promising technology.

Pub.: 22 Apr '15, Pinned: 28 Jun '17