Electrode-tissue Interface Research Articles

Impedance Analysis of Ultramicroelectrodes for Neural Stimulation

Most neural stimulation techniques rely on macroelectrodes, which generate electric fields that impact neuronal groups rather than specific neurons, often resulting in unintended side effects.1,2 Ultramicroelectrodes (UMEs) offer enhanced spatial resolution, holding promise for precise targeting of specific neurons to optimize therapeutic outcomes while mitigating adverse effects. However, ultramicroelectrodes present challenges. For example, delivery of required charge may require current densities that can damage the electrode or adjacent tissue. Impedance measurements of UMEs were conducted and analyzed to understand stimulation currents and potential damage to the electrodes and tissue. The measurement-model technique was used to identify the optimal frequency range for regression analysis, to quantify the stochastic error structure, and to identify inconsistencies with the Kramers-Kronig relations. Understanding of the error structure is vital for interpretation.3 The regressions were weighted using the inverse of the variance for the stochastic error structures, and quality of fits were determined by the weighted chi-square statistic. Process modeling was used to understand and characterize the underlying physical and chemical processes that occur at the electrode-electrolyte interface and electrode-tissue interface during neural stimulation. Constant-phase element (CPE) parameters, Q and alpha, corresponding to the behavior of the electrode-tissue interface, were obtained from this model. In addition, parameters associated with a capacitive loop were identified. Work is in progress to identify the origin of this loop. References (1) Otto, K. J.; Schmidt, C. E. Neuron-Targeted Electrical Modulation. Science. March 20, 2020, pp 1303–1304. https://doi.org/10.1126/science.abb0216. (2) Orazem, M. E.; Otto, K. J., Alexander, C. L., Electrochemistry in Action-Engineering the Neuronal Response to Electrical Microstimulation. Electrochemical Society Interface 2023, 32 (1), 40–42. https://doi.org/10.1149/2.F06231IF. (3) Orazem, M. E.; Agarwal, P.; Jansen, A. N.; Wojcik, P. T.; Garcia-Rubio, L. H. Development of Physico-Chemical Models for Electrochemical Impedance Spectroscopy. Electrochim Acta 1993, 38 (14), 1903–1911.

Scalable balloon catheter assisted contact enhancement of 3D electrode array for colon electrophysiological recording

The clinical diagnosis of functional gastrointestinal disorders primarily relies on symptom assessment and physical examination, methods that are inherently limited due to undetermined specific biomarkers and susceptibility to subjective judgment. Electrophysiological techniques offer a clinically practical approach by precisely recording the electrical activities of the intestines, providing deeper biophysical insights. However, in vivo electrophysiological investigation of the intestines remains challenging, such as the stability of the electrode-tissue interface, high-frequency signal transmission, motion artifact, and signal interpretation. This study developed an endoscopic-based high spatiotemporal electrophysiological recording device, by integrating balloon catheters and flexible three-dimensional electrode arrays with a mapping function. We integrated the 3D electrode array on a scalable balloon catheter and deployed this device in rabbits, achieving a stable collection of multiphasic electrophysiological signals from the intestinal mucosa. In vivo electrophysiological recordings identified observable spike bursts associated with intestinal motility, as well as coordinated periodic pulses potentially related to intestinal pacemaker activities, revealing their activation modulation patterns. Further, longer-duration non-periodic spike bursts were also observed to link to spontaneous non-periodic peristaltic contractions. This technique realized through minimally invasive procedures, achieves a high spatiotemporal resolution in electrophysiological recording, providing a powerful tool for the diagnosis and research of functional bowel diseases.

Dynamic changes in the structure and function of brain mural cells around chronically implanted microelectrodes

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring at the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

Biocompatible dipeptide coated on Pt/PEDOT:PSS modified silicon probes for tissues rejection alleviation

The implantable neural probe is an indispensable tool to record the high-quality spike signals. However, the high interface impedance of electrode-tissue and severe tissue rejection degrade the signal quality and shorten the service life of neural probes in-vivo. Here, a Pt/PEDOT:PSS modified silicon probes with biocompatible dipeptide layer is proposed to avoid these issues. First, a bilayer Pt/PEDOT:PSS was electrochemically deposited on gold microelectrodes to reduce the impedance. Then, a layer of dipeptide was deposited on the modified probe by physical vapor deposition (PVD) to mitigate tissue rejection. The electrochemical results show that the electrode-tissue interface impedance can be reduced by two orders of magnitude by the Pt/PEDOT:PSS modification, with negligible impedance variation by the following dipeptide layer. From the in-vitro accelerated aging, it can be inferred that the Pt/PEDOT:PSS/dipeptide modified microelectrodes can survive for more than 10 weeks. In-vitro cytotoxicity experiments show that the dipeptide can help improve the biocompatibility. Lastly, in-vivo implantation further proves that dipeptide may contribute to the realization of lower tissues rejection and higher signal-to-noise ratio within 8 weeks of implantation. The widely used silicon neural probes with the Pt/PEDOT:PSS modification and overall dipeptide coating provide as a new solution for long-term biocompatibility and high-quality neural signals.

Addressing Model Uncertainties in Finite Element Simulation of Electrically Stimulated Implants for Critical-Size Mandibular Defects.

Electrical stimulation is known to enhance bone healing. Novel electrostimulating devices are currently being developed for the treatment of critical-size bone defects in the mandible. Previous numerical models of these devices did not account for possible uncertainties in the input data. We present the numerical model of an electrically stimulated minipig mandible, including optimization and uncertainty quantification (UQ) methods that allow us to determine the most influential parameters. Uncertainties in the optimized finite element model are quantified using the polynomial chaos method that is implemented in the open-source Python toolbox Uncertainpy. The volumes of understimulated, beneficially stimulated, and overstimulated tissue are considered quantities of interest because they may significantly impact the expected healing success. Further, the current is a substantial quantity, limiting the lifetime of a battery-driven stimulation unit. With sensitivity analyses, the most critical parameters in the numerical model can be identified. Thus, we can learn which parameters are particularly relevant, for example, when conceptualizing the stimulation unit or planning the manufacturing process. The results of this study show that the parameters of the electrode-tissue interface (ETI), as well as the conductivity within the defect volume, have the most significant impact on the model results. The UQ results suggest that careful characterization of the ETI and the dielectric tissue properties is crucial to reduce these uncertainties. The numerical model regarding uncertainties yields important implications for reliable implant design and clinical translation.

A 3-mV Precision Dual-Mode-Controlled Fast Charge Balancing for Implantable Biphasic Neural Stimulators.

This paper presents a novel charge balancing (CB) with a current-control (CC) mode and a voltage-control (VC) mode for implantable biphasic stimulators, which can achieve one-step accurate anodic pulse generating. Compared with the conventional short-pulse-injection-based CB, the proposed method could reduce the balancing time and avoid inducing undesired artifact. The CC operation compensates the majority stimulation charge at high speed, while the VC operation guarantees a high CB precision. In order to eliminate the oscillation during the mode transition, a smooth CC-VC transition method is adopted. In addition, a digital auxiliary monitoring loop is introduced against the variations of the tissue-electrode interface impedance during the stimulation process to meet long-term CB requirement. The proposed stimulator has been fabricated in a 0.18 μm BCD process with 10 V voltage compliance, and the measured CB precision is less than 3 mV. The functionalities of the proposed CB have been verified successfully through in vitro experiments.

Dynamic changes in structure and function of brain mural cells around chronically implanted microelectrodes.

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

Electrical rejuvenation of chronically implanted macroelectrodes in nonhuman primates

Objective. Electrodes chronically implanted in the brain undergo complex changes over time that can lower the signal to noise ratio (SNR) of recorded signals and reduce the amount of energy delivered to the tissue during therapeutic stimulation, both of which are relevant for the development of robust, closed-loop control systems. Several factors have been identified that link changes in the electrode-tissue interface (ETI) to increased impedance and degraded performance in micro- and macro-electrodes. Previous studies have demonstrated that brief pulses applied every few days can restore SNR to near baseline levels during microelectrode recordings in rodents, a process referred to as electrical rejuvenation. However, electrical rejuvenation has not been tested in clinically relevant macroelectrode designs in large animal models, which could serve as preliminary data for translation of this technique. Here, several variations of this approach were tested to characterize parameters for optimization. Approach. Alternating-current (AC) and direct-current (DC) electrical rejuvenation methods were explored in three electrode types, chronically implanted in two adult male nonhuman primates (NHP) (Macaca mulatta), which included epidural electrocorticography (ECoG) electrodes and penetrating deep-brain stimulation (DBS) electrodes. Electrochemical impedance spectroscopy (EIS) was performed before and after each rejuvenation paradigm as a gold standard measure of impedance, as well as at subsequent intervals to longitudinally track the evolution of the ETI. Stochastic error modeling was performed to assess the standard deviation of the impedance data, and consistency with the Kramers–Kronig relations was assessed to evaluate the stationarity of EIS measurement. Main results. AC and DC rejuvenation were found to quickly reduce impedance and minimize the tissue component of the ETI on all three electrode types, with DC and low-frequency AC producing the largest impedance drops and reduction of the tissue component in Nyquist plots. The effects of a single rejuvenation session were found to last from several days to over 1 week, and all rejuvenation pulses induced no observable changes to the animals’ behavior. Significance. These results demonstrate the effectiveness of electrical rejuvenation for diminishing the impact of chronic ETI changes in NHP with clinically relevant macroelectrode designs.

Spatially Precise Genetic Engineering at the Electrode-Tissue Interface.

The interface between electrodes and neural tissues plays a pivotal role in determining the efficacy and fidelity of neural activity recording and modulation. While considerable efforts have been made to improve the electrode-tissue interface, the majority of studies have primarily concentrated on the development of biocompatible neural electrodes through abiotic materials and structural engineering. In this study, an approach is presented that seamlessly integrates abiotic and biotic engineering principles into the electrode-tissue interface. Specifically, ultraflexible neural electrodes with short hairpin RNAs (shRNAs) designed to silence the expression of endogenous genes within neural tissues are combined. The system facilitates shRNA-mediated knockdown of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and polypyrimidine tract-binding protein 1 (PTBP1), two essential genes associated in neural survival/growth and neurogenesis, within specific cell populations located at the electrode-tissue interface. Additionally, it is demonstrated that the downregulation of PTEN in neurons can result in an enlargement of neuronal cell bodies at the electrode-tissue interface. Furthermore, the system enables long-term monitoring of neuronal activities following PTEN knockdown in a mouse model of Parkinson's disease and traumatic brain injury. The system provides a versatile approach for genetically engineering the electrode-tissue interface with unparalleled precision, paving the way for the development of regenerative electronics and next-generation brain-machine interfaces.

Active recharge biphasic stimulation for the intraoperative monopolar review in deep brain stimulation.

Charge balancing is used in deep brain stimulation (DBS) to avoid net charge accumulation at the tissue-electrode interface that can result in neural damage. Charge balancing paradigms include passive recharge and active recharge. In passive recharge, each cathodic pulse is accompanied by a waiting period before the next stimulation, whereas active recharge uses energy to deliver symmetric anodic and cathodic stimulation pulses sequentially, producing a net zero charge. We sought to determine differences in stimulation induced side effect thresholds between active vs. passive recharge during the intraoperative monopolar review. Sixty-five consecutive patients undergoing DBS from 2021 to 2022 were retrospectively reviewed. Intraoperative monopolar review was performed with both active recharge and passive recharge for all included patients to determine side effect stimulation thresholds. Sixteen patients with 64 total DBS contacts met inclusion criteria for further analysis. Intraoperative monopolar review results were compared with the monopolar review from the first DBS programming visit. The mean intraoperative active recharge stimulation threshold was 4.1 mA, while the mean intraoperative passive recharge stimulation threshold was 3.9 mA, though this difference was not statistically significant on t-test (p = 0.442). Mean stimulation threshold at clinic follow-up was 3.2 mA. In Pearson correlation, intraoperative passive recharge thresholds had stronger correlation with follow-up stimulation thresholds (Pearson r = 0.5281, p < 0.001) than intraoperative active recharge (Pearson r = 0.340, p = 0.018), however the difference between these correlations was not statistically significant on Fisher Z correlation test (p = 0.294). The mean difference between intraoperative passive recharge stimulation threshold and follow-up stimulation threshold was 0.8 mA, while the mean difference between intraoperative active recharge threshold and follow-up threshold was 1.2 mA. This difference was not statistically significant on a t-test (p = 0.134). Both intraoperative active recharge and passive recharge stimulation were well-correlated with the monopolar review at the first programming visit. No statistically significant differences were observed suggesting that either passive or active recharge may be utilized intraoperatively.

Nonlinear effects at the electrode-tissue interface of deep brain stimulation electrodes.

Objective.The electrode-tissue interface provides the critical path for charge transfer in neurostimulation therapies and exhibits well-established nonlinear properties at high applied currents or voltages. These nonlinear properties may influence the efficacy and safety of applied stimulation but are typically neglected in computational models. In this study, nonlinear behavior of the electrode-tissue interface impedance was incorporated in a computational model of deep brain stimulation (DBS) to simulate the impact on neural activation and safety considerations.Approach.Nonlinear electrode-tissue interface properties were incorporated in a finite element model of DBS electrodesin vitroandin vivo,in the rat subthalamic nucleus, using an iterative approach. The transition point from linear to nonlinear behavior was determined for voltage and current-controlled stimulation. Predicted levels of neural activation during DBS were examined and the region of linear operation of the electrode was compared with the Shannon safety limit.Main results.A clear transition of the electrode-tissue interface impedance to nonlinear behavior was observed for both current and voltage-controlled stimulation. The transition occurred at lower values of activation overpotential for simulatedin vivothanin vitroconditions (91 mV and 165 mV respectively for current-controlled stimulation; 110 mV and 275 mV for voltage-controlled stimulation), corresponding to an applied current of 30μA and 45μA, or voltage of 330 mV at 1 kHz. The onset of nonlinearity occurred at lower values of the overpotential as frequency was increased. Incorporation of nonlinear properties resulted in activation of a higher proportion of neurons under voltage-controlled stimulation. Under current-controlled stimulation, the predicted transition to nonlinear behavior and Faradaic charge transfer at stimulation amplitudes of 30μA, corresponds to a charge density of 2.29μC cm-2and charge of 1.8 nC, well-below the Shannon safety limit.Significance.The results indicate that DBS electrodes may operate within the nonlinear region at clinically relevant stimulation amplitudes. This affects the extent of neural activation under voltage-controlled stimulation and the transition to Faradaic charge transfer for both voltage- and current-controlled stimulation with important implications for targeting of neural populations and the design of safe stimulation protocols.

An electrode-impedance-aware neurostimulator IC that achieves low-power consumption and fast charge balance

Implantable neural stimulation is becoming increasingly popular for treating neurologically impaired patients, restoring neural functions which would otherwise be lost due to diseases or injuries. The charge balance of the stimulus pulses is of paramount importance for the long-term safety of the electrode-tissue interface. This paper presents a novel neurostimulator integrated circuit in which two novel charge balancing schemes are proposed. One is based on acquiring the access resistance part (RS) of the inter-electrode impedance. Thanks to its adaptive anodic phase, the RS-based charge balance circuit does not require an additional discharge phase, achieving faster charge balance than most existing stimulator ICs. The other scheme is based on acquiring the double-layer capacitance part (CDL) of the inter-electrode impedance and the entire charge balancing process (inc. monitoring, computation and compensation) is performed in the analog domain. This is in sharp contrast to the existing electrode-impedance-aware charge balancing schemes which require ADCs and compute the net charge in the digital domain. Hence the new impedance-aware charge-balancing scheme is faster and more power friendly. The impedance-aware stimulator ASIC has been implemented using X-FAB’s 180-nm CMOS process. The post-layout simulation results suggest a good charge balance is achieved as the voltage deviation from the electrode offset voltage on the electrode after the charge compensation reduces to 2.64 mV and –1.39 mV under the RS-based and CDL-based charge balancing schemes, respectively. The additional power overhead due to the proposed CDL-based charge balancer circuit is 2.46 μW at a stimulation rate of 400 Hz.

Dopamine-integrated all-hydrogel multi-electrode arrays for neural activity recording.

Investigation of brain neural circuits is essential for deciphering the diagnostics and therapeutics of neurodegenerative diseases. The main concerns with traditional rigid metal electrodes include intrinsic mechanical mismatch between sensing electrodes and tissues, unavoidable foreign body responses, and inadequate spatiotemporal resolution, resulting in a deficiency of sensing performance. All-hydrogel neural electrodes with multi-electrode arrays (MEAs) suggest a viable way to modulate the trade-off between tissue-mechanical compliance and excellent spatiotemporal recording capacity, but still face the issues of insufficient conductivity and unstable interlayer bonding. Herein, we constructed a four-layer all-hydrogel neural electrode, by sandwiching a conductive hydrogel layer within two encapsulation hydrogel layers, with a shielding hydrogel layer located on top. We introduce a dual-strategy treatment to induce controllable phase separation in poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) hydrogel, which achieved ultra-high conductivity (up to 4176 S cm-1) comparable to that of metals and precise spatial resolution (∼15 μm) suitable for single neuron recording. In addition, the utilization of polyphenol chemistry mediated adaptive adhesion endowed this neural electrode with flexible and stable interlayer bonding among conductive-encapsulation-shielding layers and the tissue-electrode interface. Consequently, the all-hydrogel neural electrode exhibited a tenfold higher signal-to-noise ratio than a commercial silver electrode, realized the recording of weak neural activity signals within single and multiple neurons in epileptic rats, and applied man-made stimulation to the cerebral cortex of rats during seizures. This work provides a useful tool to understand the development, function and treatment of neurodegenerative diseases.

Short-Term Effects of Gamma Stimulation on Neuroinflammation at the Tissue-Electrode Interface in Motor Cortex

ObjectivesThe reliability of long-term neural recordings as therapeutic interventions for motor and sensory disorders is hampered by the brain tissue response. Previous work showed that flickering light at gamma frequencies (ie, 20–50 Hz) causes enhanced microglial recruitment in the visual cortex. The effects of gamma stimulation on glial cells surrounding implanted neural electrodes are not well understood. We hypothesized that invasive stimulation in the gamma frequency band increases microglial recruitment in the short term and reduces astrogliosis at the tissue-electrode interface. Materials and MethodsMale Long Evans rats were implanted with dual-shank silicon microelectrode arrays into the motor cortex. After implantation, rats received one hour of 40-Hz stimulation at a constant current of 10 μA using charge-balanced, biphasic pulses on one shank, and the other shank served as the nonstimulated control. Postmortem, tissue sections were stained with ectodermal dysplasia 1 (ED1) for activated microglia, glial fibrillary acidic protein (GFAP) for astrocytes, and 4′,6-diamidino-2-phenylindole (DAPI) for nonspecific nuclei. Fluorescent intensity and cell number as a function of distance from the tissue-electrode interface were used to quantify all stained sections. ResultsFluorescent intensity for ED1 was nearly 40% lower for control than for stimulated sites (0–500 μm away from the implant), indicating increased microglial recruitment to the stimulated site (p < 0.05). Fluorescent intensity for GFAP was >67% higher for control than for stimulated sites (0–500 μm away from the implant), indicating reduced astrogliosis at the stimulated site (p < 0.05). No differences were observed in DAPI-stained sections between conditions. ConclusionsThese results suggest that short-term gamma stimulation modulates glial recruitment in the immediate vicinity of the microelectrode. Future studies will investigate the long-term effects of gamma stimulation on glial recruitment at the tissue-electrode interface as a strategy to improve long-term recording reliability.

A Nanozyme-Based Electrode for High-Performance Neural Recording.

Implanted neural electrodes have been widely used to treat brain diseases that require high sensitivity and biocompatibility at the tissue-electrode interface. However, currently used clinical electrodes cannot meet both these requirements simultaneously, which hinders the effective recording of electronic signals. Herein, nanozyme-based neural electrodes incorporating bioinspired atomically precise clusters are developed as a general strategy with a heterogeneous design for multiscale and ultrasensitive neural recording via quantum transport and biocatalytic processes. Owing to the dual high-speed electronic and ionic currents at the electrode-tissue interface, the impedance of nanozyme electrodes is 26 times lower than that of state-of-the-art metal electrodes, and the acquisition sensitivity for the local field potential is ≈10 times higher than that of clinical PtIr electrodes, enabling a signal-to-noise ratio (SNR) of up to 14.7dB for single-neuron recordings in rats. The electrodes provide more than 100-fold higher antioxidant and multi-enzyme-like activities, which effectively decrease 67% of the neuronal injury area by inhibiting glial proliferation and allowing sensitive and stable neural recording. Moreover, nanozyme electrodes can considerably improve the SNR of seizures in acute epileptic rats and are expected to achieve precise localization of seizure foci in clinical settings.

Electrically Controlled Vasodilator Delivery from PEDOT/Silica Nanoparticle Modulates Vessel Diameter in Mouse Brain.

Vascular damage and reduced tissue perfusion are expected to majorly contribute to the loss of neurons or neural signals around implanted electrodes. However, there are limited methods of controlling the vascular dynamics in tissues surrounding these implants. This work utilizes conducting polymer poly(ethylenedioxythiophene) and sulfonated silica nanoparticle composite (PEDOT/SNP) to load and release a vasodilator, sodium nitroprusside, to controllably dilate the vasculature around carbon fiber electrodes (CFEs) implanted in the mouse cortex. The vasodilator release is triggered via electrical stimulation and the amount of release increases with increasing electrical pulses. The vascular dynamics are monitored in real-time using two-photon microscopy, with changes in vessel diameters quantified before, during, and after the release of the vasodilator into the tissues. This work observes significant increases in vessel diameters when the vasodilator is electrically triggered to release, and differential effects of the drug release on vessels of different sizes. In conclusion, the use of nanoparticle reservoirs in conducting polymer-based drug delivery platforms enables the controlled delivery of vasodilator into the implant environment, effectively altering the local vascular dynamics on demand. With further optimization, this technology could be a powerful tool to improve the neural electrode-tissue interface and study neurovascular coupling.

Calculation of the Faradaic Impedance of the Electrode-Tissue Interface Improves Prediction of Behavioral T/C Levels in Cochlear Implant Patients.

Fitting of cochlear implants is a labor-intensive process, and therefore automated fitting procedures are being sought. The objective of this study was to evaluate if decomposition of the complex impedance of the electrode-tissue interface could provide additional parameters that show improved correlation with the behavioral T/C levels. A new method for decomposing the complex impedance of the electrode-tissue interface was developed and tested in 18 patients in a prospective study in a tertiary otologic referral center. The averaged near-field Faradaic resistance (RF) calculated in study subjects shows a very strong correlation (R2=0.80) with the behavioral C levels and can be used for automated fitting in most patients. The standard deviation for the T levels and the C levels calculated for each of the electrode contacts in all study subjects is in the range of 10-15 CL and 15-20 CL, respectively. These higher values of the standard deviations are caused by a few outliers who require that additional parameters have to be added to the metric equation, allowing for the automated prediction of the T/C levels. A new method for deriving information from the electrode impedance measurements shows excellent correlation of the Faradaic resistance with the behavioral T/C levels in most patients and can be very useful for fitting cochlear implants based on objective measures. Since some patients still show discrepancies between the predicted T/C levels based on the RF calculation, additional parameters have to be added to the metric equation, allowing for automated prediction of the T/C levels.

Dense, 11 V-Tolerant, Balanced Stimulator IC with Digital Time-Domain Calibration for 100 nA Error.

This article presents a multichannel neurostimulator implementing a novel charge balancing technique to achieve maximal integration. Safe neurostimulation demands accurate charge balancing of the stimulation waveforms to prevent charge build-up on the electrode-tissue interface. We propose digital time-domain calibration (DTDC), which adjusts the second phase of the biphasic stimulation pulses digitally, based on a one-time characterization of all stimulator channels with an on-chip ADC. Accurate control of the stimulation current amplitude is loosened in exchange for time-domain corrections, relieving circuit matching constraints and consequentially saving channel area. A theoretical analysis of DTDC is presented, establishing expressions for the required time resolution and the new, relaxed circuit matching constraints. To validate the DTDC principle, a 16-channel stimulator was implemented in 65 nm CMOS, requiring only 0.0141 mm 2 area/channel. Despite being implemented in a standard CMOS technology, 10.4 V compliance is achieved for compatibility with high-impedance microelectrode arrays typical for high-resolution neural prostheses. To the authors' knowledge, this is the first stimulator in a 65 nm low-voltage process achieving over 10 V output swing. Measurements after calibration show the DC error is successfully reduced below 96 nA on all channels. Static power consumption is 20.3 µW/channel.

Generation of direct current electrical fields as regenerative therapy for spinal cord injury: A review.

Electrical stimulation (ES) shows promise as a therapy to promote recovery and regeneration after spinal cord injury. ES therapy establishes beneficial electric fields (EFs) and has been investigated in numerous studies, which date back nearly a century. In this review, we discuss the various engineering approaches available to generate regenerative EFs through direct current electrical stimulation and very low frequency electrical stimulation. We highlight the electrode-tissue interface, which is important for the appropriate choice of electrode material and stimulator circuitry. We discuss how to best estimate and control the generated field, which is an important measure for comparability of studies. Finally, we assess the methods used in these studies to measure functional recovery after the injury and treatment. This work reviews studies in the field of ES therapy with the goal of supporting decisions regarding best stimulation strategy and recovery assessment for future work.

Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimer’s disease

Objective. Electrical stimulation has had a profound impact on our current understanding of nervous system physiology and provided viable clinical options for addressing neurological dysfunction within the brain. Unfortunately, the brain’s immune suppression of indwelling microelectrodes currently presents a major roadblock in the long-term application of neural recording and stimulating devices. In some ways, brain trauma induced by penetrating microelectrodes produces similar neuropathology as debilitating brain diseases, such as Alzheimer’s disease (AD), while also suffering from end-stage neuron loss and tissue degeneration. The goal of the present study was to understand whether there may be any parallel mechanisms at play between brain injury from chronic microelectrode implantation and those of neurodegenerative disorder. Approach. We used two-photon microscopy to visualize the accumulation, if any, of age- and disease-associated factors around chronically implanted electrodes in both young and aged mouse models of AD. Main results. We determined that electrode injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in wild-type and AD mice alike. Furthermore, we reveal that chronic microelectrode implantation reduces the growth of pre-existing Alzheimer’s plaques while simultaneously elevating amyloid burden at the electrode-tissue interface. Lastly, we uncover novel spatial and temporal patterns of glial reactivity, axonal and myelin pathology, and neurodegeneration related to neurodegenerative disease around chronically implanted microelectrodes. Significance. This study offers multiple novel perspectives on the possible neurodegenerative mechanisms afflicting chronic brain implants, spurring new potential avenues of neuroscience investigation and design of more targeted therapies for improving neural device biocompatibility and treatment of degenerative brain disease.