Electrical stimulation of nerve tissue and recording of neural electrical activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurological disorders. An understanding of the electrochemical mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large numbers of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and maximum electrochemical potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochemical properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes.

Objective Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. Approach In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. Main results For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. Significance It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device safety.

Iridium oxide films formed by electrodeposition onto noniridium metal substrates are compared with activated iridium oxide films (AIROFs) as a low impedance, high charge capacity coating for neural stimulation and recording electrodes. The electrodeposited iridium oxide films (EIROFs) were deposited on Au, Pt, PtIr, and 316 LVM stainless steel substrates from a solution of IrCl4, oxalic acid, and K2CO3. A deposition protocol involving 50 potential sweeps at 50 mV/s between limits of 0.0 V and 0.55 V (versus Ag AgCl) followed by potential pulsing between the same limits produced adherent films with a charge storage capacity of >25 mC/cm2. Characterization by cyclic voltammetry and impedance spectroscopy revealed no differences in the electrochemical behavior of EIROF on non-Ir substrates and AIROF. The mechanical stability of the oxides was evaluated by ultrasonication in distilled water followed by dehydration and rehydration. Stability under charge injection was evaluated using 200 micros, 5.9 A/cm2 (1.2 mC/cm2) cathodal pulses. Loss of iridium oxide charge capacity was comparable for AIROFs and the EIROFs, ranging from 1% to 8% of the capacity immediately after activation or deposition. The EIROFs were deposited and evaluated on silicon microprobe electrodes and on metallized polyimide electrodes being developed for neural recording and stimulation applications.

No abstract

Sputtered iridium oxide films (SIROFs) deposited by DC reactive sputtering from an iridium metal target have been characterized in vitro for their potential as neural recording and stimulation electrodes. SIROFs were deposited over gold metallization on flexible multielectrode arrays fabricated on thin (15 microm) polyimide substrates. SIROF thickness and electrode areas of 200-1300 nm and 1960-125,600 microm(2), respectively, were investigated. The charge-injection capacities of the SIROFs were evaluated in an inorganic interstitial fluid model in response to charge-balanced, cathodal-first current pulses. Charge injection capacities were measured as a function of cathodal pulse width (0.2-1 ms) and potential bias in the interpulse period (0.0 to 0.7 V vs. Ag|AgCl). Depending on the pulse parameters and electrode area, charge-injection capacities ranged from 1-9 mC/cm(2), comparable with activated iridium oxide films (AIROFs) pulsed under similar conditions. Other parameters relevant to the use of SIROF on nerve electrodes, including the thickness dependence of impedance (0.05-10(5) Hz) and the current necessary to maintain a bias in the interpulse region were also determined.

The charge-injection limits of activated iridium oxide electrodes (AIROF) and PtIr microelectrodes with similar geometric area and shape have been compared in vitro using a stimulation waveform that delivers cathodal current pulses with current-limited control of the electrode bias potential in the interpulse period. Charge-injection limits were compared over a bias range of 0.1-0.7 V (versus Ag/AgCl) and pulse frequencies of 20, 50, and 100 Hz. The AIROF was capable of injecting between 4 and 10 times the charge of the PtIr electrode, with a maximum value of 3.9 mC/cm2 obtained at a 0.7 V bias and 20 Hz frequency.

Amorphous silicon carbide (a-SiC) films, deposited by plasma-enhanced chemical vapor deposition (PECVD), have been evaluated as insulating coatings for implantable microelectrodes. The a-SiC was deposited on platinum or iridium wire for measurement of electrical leakage through the coating in phosphate-buffered saline (PBS, pH 7.4). Low leakage currents of <10(-11) A were observed over a +/-5-V bias. The electronic resistivity of a-SiC was 3 x 10(13) Omega-cm. Dissolution rates of a-SiC in PBS at 37 and 90 degrees C were determined from changes in infrared absorption band intensities and compared with those of silicon nitride formed by low-pressure chemical vapor deposition (LPCVD). Dissolution rates of LPCVD silicon nitride were 2 nm/h and 0.4 nm/day at 90 and 37 degrees C, respectively, while a-SiC had a dissolution rate of 0.1 nm/h at 90 degrees C and no measurable dissolution at 37 degrees C. Biocompatibility was assessed by implanting a-SiC-coated quartz discs in the subcutaneous space of the New Zealand White rabbit. Histological evaluation showed no chronic inflammatory response and capsule thickness was comparable to silicone or uncoated quartz controls. Amorphous SiC-coated microelectrodes were implanted in the parietal cortex for periods up to 150 days and the cortical response evaluated by histological evaluation of neuronal viability at the implant site. The a-SiC was more stable in physiological saline than LPCVD Si(3)N(4) and well tolerated in the cortex.

We report on our efforts to establish an animal model for the development and testing of a cortical visual prostheses. One-hundred-fifty-two electrodes were implanted in the primary visual cortex of a rhesus monkey. The electrodes were made from iridium with an activated iridium oxide film, which has a large charge capacity for a given surface area, and insulated with parylene-C. One-hundred-fourteen electrodes were functional after implantation. The activity of small (2-3) neuronal clusters was first recorded to map the visually responsive region corresponding to each electrode. The animal was then trained in a memory (delayed) saccade task, first with a visual target, then to a target defined by direct cortical stimulation with coordinates specified by the stimulating electrode's mapped receptive field. The SD of saccade endpoints was approximately 2.5 larger for electrically stimulated versus visual saccades; nevertheless, when trial-to-trial scatter was averaged out, the correlation between saccade end points and receptive field locations was highly significant and approached unity after several months of training. Five electrodes were left unused until the monkey was fully trained; when these were introduced, the receptive field-saccade correlations were high on the first day of use (R = 0.85, P = 0.03 for angle, R = 0.98, P < 0.001 for eccentricity), indicating that the monkey had not learned to perform the task empirically by memorizing reward zones. The results of this experiment suggest the potential for rigorous behavioral testing of cortical visual prostheses in the macaque.