James D. Ross

Stimulus-Artifact Elimination in a Multi-Electrode System

To fully exploit the recording capabilities provided by current and future generations of multi-electrode arrays, some means to eliminate the residual charge and subsequent artifacts generated by stimulation protocols is required. Custom electronics can be used to achieve such goals, and by making them scalable, a large number of electrodes can be accessed in an experiment. In this work, we present a system built around a custom 16-channel IC that can stimulate and record, within 3 ms of the stimulus, on the stimulating channel, and within 500 mus on adjacent channels. This effectiveness is achieved by directly discharging the electrode through a novel feedback scheme, and by shaping such feedback to optimize electrode behavior. We characterize the different features of the system that makes such performance possible and present biological data that show the system in operation. To enable this characterization, we present a framework for measuring, classifying, and understanding the multiple sources of stimulus artifacts. This framework facilitates comparisons between artifact elimination methodologies and enables future artifact studies.

Use of resuscitative endovascular balloon occlusion of the aorta in a highly lethal model of noncompressible torso hemorrhage

ABSTRACT Noncompressible torso hemorrhage is a leading cause of death in trauma, with many patients dying before definitive hemorrhage control. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an adjunct than can be used to expand the window of salvage in patients with end-stage hemorrhagic shock. The aim of this study was to evaluate the effect of continuous and intermittent REBOA (iREBOA) on mortality using a highly lethal porcine model of noncompressible torso hemorrhage. Male splenectomized pigs (70–90 kg) underwent a laparoscopic liver injury (80% resection of left lobe) followed by a 10-min free-bleed period. Animals were then divided into three groups (n = 8) for a 60-min intervention phase (n = 8): continuous occlusion (cREBOA), iREBOA, or no occlusion (nREBOA). Groups then underwent whole blood resuscitation, damage control surgery, and further critical care. Endpoints were mortality and hemodynamic and circulating measures of shock and resuscitation. Systolic blood pressure (in mmHg) at the end of the free-bleed period for cREBOA, iREBOA, and nREBOA was 31 ± 14, 48 ± 28, and 28 ± 17, respectively (P = 0.125). Following the start of the intervention phase, systolic blood pressure was higher in the iREBOA and cREBOA groups compared with the nREBOA (85 ± 37 and 96 ± 20 vs. 42 ± 4; P < 0.001). Overall mortality for the cREBOA, iREBOA, and nREBOA groups was 25.0%, 37.5%, and 100.0% (P = 0.001). Resuscitative endovascular balloon occlusion of the aorta can temporize exsanguinating hemorrhage and restore life-sustaining perfusion, bridging critical physiology to definitive hemorrhage control. Prospective observational studies of REBOA as a hemorrhage control adjunct should be undertaken in appropriate groups of human trauma patients.

An Integrated System for Simultaneous, Multichannel Neuronal Stimulation and Recording

Precision electronics that provide multi-electrode stimulation and recording capabilities are an important tool for the experimental study of neuronal development and plasticity. Towards this end, we present a custom analog integrated circuit (IC), fabricated in a 0.35-mum process, incorporating stimulation buffers and recording preamplifiers for multiple electrodes onto a single die. The architecture of the IC allows for arbitrary, independent configuration of electrodes for stimulation or recording, and the IC includes artifact-elimination circuitry that returns the stimulation electrode to its previous voltage following stimulation, minimizing the interference with recording. We analyze the thermal noise levels in the recording preamplifiers and experimentally measure input-referred noise as low as 4.77 muVrms in the frequency range of 30 Hz-3 kHz at a power consumption of 100 muW from a total power supply of 3.8 V. We also consider the temporal response and stability of the artifact elimination circuitry. We demonstrate that the use of the artifact-elimination circuitry with a 30-mum diameter stimulation electrode permits a return to recording mode in les 2 ms after stimulation, facilitating near-simultaneous stimulation and recording of neuronal signals. (Patent applied for, U.S. No. 2007/0178579.)

The epidemiology of noncompressible torso hemorrhage in the wars in Iraq and Afghanistan.

BACKGROUND Noncompressible torso hemorrhage (NCTH) is the leading cause of potentially survivable trauma in the battlefield and has recently been defined using anatomic and physiologic criteria. The objective of this study was to characterize the frequency and mortality in combat of NCTH using a contemporary definition. METHODS Four categories of torso injury, each based on vascular disruption, were identified in US military casualties from the Department of Defense Trauma Registry (2002–2010): (1) thoracic, including lung; (2) solid organ (high-grade spleen, liver, and kidney); (3) named axial vessel; and (4) pelvic fracture with ring disruption. Injuries within these categories were evaluated in the context of physiologic indicator of shock and/or the need for operative hemorrhage control. RESULTS Of 15,209 battle injuries sustained during the study period, 12.7% (n = 1,936) had sustained one or more categories of torso injury. Of these, 331 (17.1%) had evidence of shock or the need for urgent hemorrhage control, with a mean (SD) Injury Severity Score (ISS) and mortality rate of 30 (13) and 18.7%, respectively. Pulmonary injuries were most numerous (41.7%), followed by solid-organ (29.3%), vascular (25.7%), and pelvic (15.1%) injuries. Following multivariate analysis, the most mortal injury complexes were identified as major arterial injury (odds ratio, 3.38; 95% confidence interval, 1.17–9.74) and pulmonary injury (odds ratio, 2.23; 95% confidence interval, 1.23–4.98). CONCLUSION NCTH can be defined using anatomic parameters combined with physiologic and operative interventions suggestive of hemorrhage. Major arterial and pulmonary injuries contribute most significantly to the mortality burden. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level III.

The inflammatory sequelae of aortic balloon occlusion in hemorrhagic shock

BACKGROUND Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a hemorrhage control and resuscitative adjunct that has been demonstrated to improve central perfusion during hemorrhagic shock. The aim of this study was to characterize the systemic inflammatory response associated and cardiopulmonary sequelae with 30, 60, and 90 min of balloon occlusion and shock on the release of interleukin 6 (IL-6) and tumor necrosis factor alpha. MATERIALS AND METHODS Anesthetized female Yorkshire swine (Sus scrofa, weight 70-90 kg) underwent a 35% blood volume-controlled hemorrhage followed by thoracic aortic balloon occlusion of 30 (30-REBOA, n = 6), 60 (60-REBOA, n = 8), and 90 min (90-REBOA, n = 6). This was followed by resuscitation with whole blood and crystalloid over 6 h. Animals then underwent 48 h of critical care with sedation, fluid, and vasopressor support. RESULTS All animals were successfully induced into hemorrhagic shock without mortality. All groups responded to aortic occlusion with a rise in blood pressure above baseline values. IL-6, as measured (picogram per milliliter) at 8 h, was significantly elevated from baseline values in the 60-REBOA and 90-REBOA groups: 289 ± 258 versus 10 ± 5; P = 0.018 and 630 ± 348; P = 0.007, respectively. There was a trend toward greater vasopressor use (P = 0.183) and increased incidence of acute respiratory distress syndrome (P = 0.052) across the groups. CONCLUSIONS REBOA is a useful adjunct in supporting central perfusion during hemorrhagic shock; however, increasing occlusion time and shock results in a greater IL-6 release. Clinicians must anticipate inflammation-mediated organ failure in post-REBOA use patients.

Mechanical trauma induces immediate changes in neuronal network activity.

During a traumatic insult to the brain, tissue is subjected to large stresses at high rates which often surpass cellular thresholds leading to cell dysfunction or death. The acute response of neurons to a mechanical trauma, however, is poorly understood. Plasma membrane disruption may be the earliest cellular outcome from a mechanical trauma. The increase in membrane permeability due to such disruptions may therefore play an important role in the initiation of deleterious cascades following brain injury. The immediate consequences of an increase in plasma membrane permeability on the electrophysiological behavior of a neuronal network exposed to the trauma have not been elucidated. We have developed an in vitro model of traumatic brain injury (TBI) that utilizes a novel device capable of applying stress at high rates to neuronal cells cultured on a microelectrode array. The mechanical insult produced by the device caused a transient increase in neuronal plasma membrane permeability, which subsided after 10 min. We were able to monitor acute spontaneous electrophysiological activity of injured cultures for at least 10 min following the insult. Firing frequency, average burst interval and spikes within burst were assessed before and after injury. The electrophysiological responses to the insult were heterogeneous, although an increase in burst intervals and in the variability of the assessed parameters were common. This study provides a multi-faceted approach to elucidate the role of neuronal plasma membrane disruptions in TBI and its functional consequences.

A Novel Dexamethasone-releasing, Anti-inflammatory Coating for Neural Implants

The long-term stability of implanted micromachined neural probes is compromised due to the glial scar formation at the insertion site. In this study, we developed a novel nitrocellulose-based coating for the sustained local delivery of the anti-inflammatory drug dexamethasone, a synthetic glucocorticoid that effectively reduces inflammation in the CNS. In vitro dexamethasone release was observed over 16 days, with a relatively high release in the first three days and a slow, stable release thereafter. When Michigan neural recording probes coated with and without dexamethasone-loaded nitrocellulose coatings were implanted into the adult rat brains, immunohistochemical evidence shows a marked reduction of reactive astrocytes (GFAP), reactive microglia (EDl), and chondroitin sulfate proteoglycans (CS56) expression around the insertion site compared to uncoated probes. Impedance spectroscopy showed that the dexamethasone-loaded nitrocellulose coatings slightly reduce the magnitude of electrode impedance at the biologically relevant frequency of 1 kHz through an increase of capacitance. In vivo acute recordings demonstrate that extracellular recordings with coated probes are akin to non-coated probes and it is anticipated that with time, the coated probes will exhibit superior performance. In conclusion, we developed a novel nitrocellulose-based, drug releasing coating for neural electrodes that can effectively reduce scar tissue formation without adversely affecting the electrical performance of the electrodes

Micromachined three-dimensional electrode arrays for transcutaneous nerve tracking

We report the development of metal transfer micromolded (MTM) three-dimensional microelectrode arrays (3D MEAs) for a transcutaneous nerve tracking application. The measurements of electrode?skin?electrode impedance (ESEI), electromyography (EMG) and nerve conduction utilizing these minimally invasive 3D MEAs are demonstrated in this paper. The 3D MEAs used in these measurements consist of a metalized micro-tower array that can penetrate the outer layers of the skin in a painless fashion and are fabricated using MTM technology. Two techniques, an inclined UV lithography approach and a double-side exposure of thick negative tone resist, have been developed to fabricate the 3D MEA master structure. The MEAs themselves are fabricated from the master structure utilizing micromolding techniques. Metal patterns are transferred during the micromolding process, thereby ensuring reduced process steps compared to traditional silicon-based approaches. These 3D MEAs have been packaged utilizing biocompatible Kapton? substrates. ESEI measurements have been carried out on test human subjects with standard commercial wet electrodes as a reference. The 3D MEAs demonstrate an order of magnitude lower ESEI (normalized to area) compared to wet electrodes for an area that is 12.56 times smaller. This compares well with other demonstrated approaches in literature. For a nerve tracking demonstration, we have chosen EMG and nerve conduction measurements on test human subjects. The 3D MEAs show 100% improvement in signal power and SNR/?area as compared to standard electrodes. They also demonstrate larger amplitude signals and faster rise times during nerve conduction measurements. We believe that this microfabrication and packaging approach scales well to large-area, high-density arrays required for applications like nerve tracking. This development will increase the stimulation and recording fidelity of skin surface electrodes, while increasing their spatial resolution by an order of magnitude or more. Although biopotential electrode systems are not without their challenges, the non-invasive access to neural information, along with the potential for automation with associated electronic and software development, is precisely what makes this technology an excellent candidate for the next generation in diagnostic, therapeutic, and prosthetic devices.

Models of stimulation artifacts applied to integrated circuit design

The goal of this research is to develop a monolithic stimulation and recording system capable of simultaneous, multichannel stimulation and recording. Monolithic systems are advantageous for large numbers of recording sites because they scale better than systems composed of discrete amplifiers. A major problem in recording systems is the stimulation artifact, a transient distortion present after stimulation. In order to improve recording systems, we analyze models of the stimulation artifact. Comparisons between model predictions and physical measurements verify the models. We show that the linear model, suitable for inclusion in circuit simulators, can assist in the design of an integrated recording system capable of artifact removal. The proposed design occupies 18,000 /spl mu//sup 2/ and is suitable for monolithic integration.

Three-Dimensional Metal Transfer Micromolded Microelectrode Arrays (MEAS) for In-Vitro Brain Slice Recordings

We report successful electrical characterization and electrophysiological recordings from hippocampal brain slices using metal transfer micromolded three-dimensional microelectrode arrays (3-D MEAs). These MEAs have been fabricated on polymer substrates using metal transfer micromolding. They have further been packaged on glass substrates and insulated using parylene deposition. Recording sites have been defined using laser micromachining and RIE etching. Initial electrical and electrophysiological characterization of the MEAs has been successfully demonstrated in this paper. We believe this fabrication approach enables manufacturing-friendly batch fabrication of truly disposable, biocompatible and cost-effective MEAs, which will be indispensable to the neurophysiology and pharmacology communities.