Splenic arterial neurovascular bundle stimulation in esophagectomy: A feasibility and safety prospective cohort study.

Introduction: The autonomic nervous system is a key regulator of inflammation. Electrical stimulation of the vagus nerve has been shown to have some preclinical efficacy. However, only a few clinical studies have been reported to treat inflammatory diseases. The present study evaluates, for the first time, neuromodulation of the splenic arterial neurovascular bundle (SpA NVB) in patients undergoing minimally invasive esophagectomy (MIE), in which the SpA NVB is exposed as part of the procedure. Methods: This single-center, single-arm study enrolled 13 patients undergoing MIE. During the abdominal phase of the MIE, a novel cuff was placed around the SpA NVB, and stimulation was applied. The primary endpoint was the feasibility and safety of cuff application and removal. A secondary endpoint included the impact of stimulation on SpA blood flow changes during the stimulation, and an exploratory point was C-reactive protein (CRP) levels on postoperative day (POD) 2 and 3. Results: All patients successfully underwent placement, stimulation, and removal of the cuff on the SpA NVB with no adverse events related to the investigational procedure. Stimulation was associated with an overall reduction in splenic arterial blood flow but not with changes in blood pressure or heart rate. When compared to historic Propensity Score Matched (PSM) controls, CRP levels on POD2 (124 vs. 197 mg/ml, p = 0.032) and POD3 (151 vs. 221 mg/ml, p = 0.033) were lower in patients receiving stimulation. Conclusion: This first-in-human study demonstrated for the first time that applying a cuff around the SpA NVB and subsequent stimulation is safe, feasible, and may have an effect on the postoperative inflammatory response following MIE. These findings suggest that SpA NVB stimulation may offer a new method for immunomodulatory therapy in acute or chronic inflammatory conditions.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

The Effect of Electric Cross-Talk in Retinal Neurostimulation.

PURPOSE: To investigate the efficacy of electric field shaping in modulating the extent and activation threshold in retinal neurostimulation. This study aims to quantify the interference of neighboring stimulation sites by assessing the shift in the activation threshold produced by a concomitant interfering stimulus. METHODS: Electrical stimuli were applied to healthy retinae in a feline model (n = 4) using a 24-channel electrode array surgically implanted in the suprachoroidal space. A 96-channel penetrating electrode array was used for recording cortical responses to a number of stimulation paradigms. Data were analyzed offline. Concurrent monopolar and hexapolar stimuli were delivered at primary and interfering sites separated by up to 2.19 mm to evaluate electric cross-talk. The spike rate was fit to a sigmoidal curve to estimate the P50 threshold. The slope of the linear regression of the P50 value versus interfering current level was considered as a measure of cross-talk. RESULTS: Concurrent monopolar stimulation produced a proportional drop in the P50 of approximately 20% of the interfering current level in presence of a primary monopolar and hexapolar stimulus. On the other hand, hexapolar interference did not alter activation thresholds at the primary site. CONCLUSIONS: Hexapolar stimulation reduces electric cross-talk between neighboring sites and represents a technique to reduce interference between individual stimulation sites. In contrast, concurrent monopolar stimulation produces a reduction of the activation threshold of stimuli delivered nearby. Thus, a single source of subthreshold monopolar charge injection can provide benefit in the form of significant threshold reduction simultaneously at multiple stimulation sites.

Towards an assistive peripheral visual prosthesis for long-term treatment of retinitis pigmentosa: evaluating mobility performance in immersive simulations.

OBJECTIVE: The prospective efficacy of a future peripheral retinal prosthesis complementing residual vision to raise mobility performance in non-end stage retinitis pigmentosa (RP) was evaluated using simulated prosthetic vision (SPV). APPROACH: Normally sighted volunteers were fitted with a wide-angle head-mounted display and carried out mobility tasks in photorealistic virtual pedestrian scenarios. Circumvention of low-lying obstacles, path following, and navigating around static and moving pedestrians were performed either with central simulated residual vision of 10° alone or enhanced by assistive SPV in the lower and lateral peripheral visual field (VF). Three layouts of assistive vision corresponding to hypothetical electrode array layouts were compared, emphasizing higher visual acuity, a wider visual angle, or eccentricity-dependent acuity across an intermediate angle. Movement speed, task time, distance walked and collisions with the environment were analysed as performance measures. MAIN RESULTS: Circumvention of low-lying obstacles was improved with all tested configurations of assistive SPV. Higher-acuity assistive vision allowed for greatest improvement in walking speeds-14% above that of plain residual vision, while only wide-angle and eccentricity-dependent vision significantly reduced the number of collisions-both by 21%. Navigating around pedestrians, there were significant reductions in collisions with static pedestrians by 33% and task time by 7.7% with the higher-acuity layout. Following a path, higher-acuity assistive vision increased walking speed by 9%, and decreased collisions with stationary cars by 18%. SIGNIFICANCE: The ability of assistive peripheral prosthetic vision to improve mobility performance in persons with constricted VFs has been demonstrated. In a prospective peripheral visual prosthesis, electrode array designs need to be carefully tailored to the scope of tasks in which a device aims to assist. We posit that maximum benefit might come from application alongside existing visual aids, to further raise life quality of persons living through the prolonged early stages of RP.

Towards photorealistic and immersive virtual-reality environments for simulated prosthetic vision: integrating recent breakthroughs in consumer hardware and software.

Simulated prosthetic vision (SPV) in normally sighted subjects is an established way of investigating the prospective efficacy of visual prosthesis designs in visually guided tasks such as mobility. To perform meaningful SPV mobility studies in computer-based environments, a credible representation of both the virtual scene to navigate and the experienced artificial vision has to be established. It is therefore prudent to make optimal use of existing hardware and software solutions when establishing a testing framework. The authors aimed at improving the realism and immersion of SPV by integrating state-of-the-art yet low-cost consumer technology. The feasibility of body motion tracking to control movement in photo-realistic virtual environments was evaluated in a pilot study. Five subjects were recruited and performed an obstacle avoidance and wayfinding task using either keyboard and mouse, gamepad or Kinect motion tracking. Walking speed and collisions were analyzed as basic measures for task performance. Kinect motion tracking resulted in lower performance as compared to classical input methods, yet results were more uniform across vision conditions. The chosen framework was successfully applied in a basic virtual task and is suited to realistically simulate real-world scenes under SPV in mobility research. Classical input peripherals remain a feasible and effective way of controlling the virtual movement. Motion tracking, despite its limitations and early state of implementation, is intuitive and can eliminate between-subject differences due to familiarity to established input methods.

Materials design considerations involved in the fabrication of implantable bionics by metallization of ceramic substrates.

The Pt metallization of co-fired Al2O3/SiO2 substrates containing Pt feedthroughs was shown to be a suitable means to construct implantable bionics. The use of forge welding to join an electrode to such a metallized feedthrough was demonstrated and subsequently evaluated through the use of metallography and electron microscopy. Metallurgical phenomena involved in forge welding relevant to the fabrication of all types of biomedical implants are discussed within this paper. The affect of thermal profiles used in brazing or welding to build implantable devices from metal components is analysed and the case for considered selection of alloys in implant design is put forward.

Smartphones as image processing systems for prosthetic vision.

The feasibility of implants for prosthetic vision has been demonstrated by research and commercial organizations. In most devices, an essential forerunner to the internal stimulation circuit is an external electronics solution for capturing, processing and relaying image information as well as extracting useful features from the scene surrounding the patient. The capabilities and multitude of image processing algorithms that can be performed by the device in real-time plays a major part in the final quality of the prosthetic vision. It is therefore optimal to use powerful hardware yet to avoid bulky, straining solutions. Recent publications have reported of portable single-board computers fast enough for computationally intensive image processing. Following the rapid evolution of commercial, ultra-portable ARM (Advanced RISC machine) mobile devices, the authors investigated the feasibility of modern smartphones running complex face detection as external processing devices for vision implants. The role of dedicated graphics processors in speeding up computation was evaluated while performing a demanding noise reduction algorithm (image denoising). The time required for face detection was found to decrease by 95% from 2.5 year old to recent devices. In denoising, graphics acceleration played a major role, speeding up denoising by a factor of 18. These results demonstrate that the technology has matured sufficiently to be considered as a valid external electronics platform for visual prosthetic research.

Current steering in retinal stimulation via a quasimonopolar stimulation paradigm.

PURPOSE: Research to restore some degree of vision to patients suffering from retinal degeneration is becoming increasingly more promising. Several groups have chosen electrical stimulation of the remaining network of a degenerate retina as a means to generate discrete light percepts (phosphenes). Approaches vary significantly, with the greatest difference being the location of the stimulating electrode itself. METHODS: Suprachoroidal positioning offers excellent mechanical stability and surgical simplicity; however, at the cost of activation thresholds and focused stimulation due to the distance from the electrodes to the target neurons. Past studies proposed a hexapolar electrode configuration to focus the cortical activation and minimize cross-talk between electrodes during concurrent stimulation. The high impedance nature of the choroid and pigment epithelium, however, cause current to shunt between the stimulating and return electrodes, resulting in even higher activation thresholds. In our study, we analyzed the effect of stimulating the feline retina using a quasimonopolar stimulation by simultaneously stimulating a hexapolar and distant monopolar return configurations. RESULTS: Results of in vivo studies showed that quasimonopolar stimulation can be used to maintain the activation containment properties of hexapolar stimulation, while lowering the activation threshold to values almost equivalent to those of monopolar stimulation. CONCLUSIONS: The optimal stimulus was found to be composed of a subthreshold monopolar stimulus combined with a suprathreshold hexapolar stimulation. This resulted in a decrease of activation threshold of 60% with respect to hexapolar alone, but with no discernible deleterious effect on the charge containment of a pure hexapolar stimulation.

Threshold analysis of a quasimonopolar stimulation paradigm in visual prosthesis.

The complexity of surgical implantation has always been a significant obstacle in the development of visual prosthetics. Implanting in the epi and sub-retinal spaces allows the prosthesis direct access to the retina, resulting in lower stimulation thresholds, potentially at the expense of robust mechanical stability and interface longevity. Implanting the stimulating electrode in the supra-choroidal space greatly simplifies surgery and improves mechanical stability. This is achieved at the cost of a higher activation threshold and reduced focus of the electric field at the target site of stimulation, given the increased distance between the stimulating electrodes and the target tissue. In order to contain the spread of the stimulating field, the authors proposed a hexagonal arrangement of return electrodes, at a further cost to the stimulation threshold over that of a monopolar stimulation paradigm. This study analyses the effect on activation thresholds of activating simultaneously the hexpolar guard electrodes and the distant monopolar return in what we have termed a quasimonopolar configuration. Results show that introducing a small element of monopolar stimulation significantly lowers the activation threshold otherwise required by a pure hexpolar return.

Analysis of the voltage response to identify macromolecule quantities in an electrolyte.

Current techniques of detecting proteins in solution can prove to be time consuming and expensive. Although low cost techniques are available, these are often slow and inaccurate. The authors propose an innovative technique for detecting the presence of proteins and other organic macromolecules in an electrolyte by analyzing the voltage waveform resulting from a biphasic, constant-current, charge-balanced electrical stimulation. Initial experiments have proven the viability of the technique. However due to the limitation of technique accuracy, further refinement of the measurement approach is required.

ARM-based visual processing system for prosthetic vision.

A growing number of prosthetic devices have been shown to provide visual perception to the profoundly blind through electrical neural stimulation. These first-generation devices offer promising outcomes to those affected by degenerative disorders such as retinitis pigmentosa. Although prosthetic approaches vary in their placement of the stimulating array (visual cortex, optic-nerve, epi-retinal surface, sub-retinal surface, supra-choroidal space, etc.), most of the solutions incorporate an externally-worn device to acquire and process video to provide the implant with instructions on how to deliver electrical stimulation to the patient, in order to elicit phosphenized vision. With the significant increase in availability and performance of low power-consumption smart phone and personal device processors, the authors investigated the use of a commercially available ARM (Advanced RISC Machine) device as an externally-worn processing unit for a prosthetic neural stimulator for the retina. A 400 MHz Samsung S3C2440A ARM920T single-board computer was programmed to extract 98 values from a 1.3 Megapixel OV9650 CMOS camera using impulse, regional averaging and Gaussian sampling algorithms. Power consumption and speed of video processing were compared to results obtained to similar reported devices. The results show that by using code optimization, the system is capable of driving a 98 channel implantable device for the restoration of visual percepts to the blind.