Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

A flexible platform for biofeedback-driven control and personalization of electrical nerve stimulation therapy.

Electrical vagus nerve stimulation is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. However, the fixed stimulus, open loop dosing mechanism limits its efficacy and precludes major advances in the quality of therapy. A real-time, responsive form of vagus nerve stimulation is needed to control nerve activation according to therapeutic need. This personalized approach to therapy will improve efficacy and reduce the number and severity of side effects. We present autonomous neural control, a responsive, biofeedback-driven approach that uses the degree of measured nerve activation to control stimulus delivery. We demonstrate autonomous neural control in rats, showing that it rapidly learns how to most efficiently activate any desired proportion of vagal A, B, and/or C fibers over time. This system will maximize efficacy by minimizing patient response variability and by minimizing therapeutic failures resulting from longitudinal decreases in nerve activation with increasing durations of treatment. The value of autonomous neural control equally applies to other applications of electrical nerve stimulation.

The effect of site placement within silicon microelectrodes on the long-term electrophysiological recordings.

Intracortical microelectrodes can be used to treat various neurological disorders given their capabilities to interface with single or multiple populations of neurons. However, most of these penetrating devices have been reported to fail over time, within weeks to months, putatively due to the foreign body response (FBR) which persistently aggravates the surrounding brain tissues. A number of studies have confirmed that various electrode properties, such as size, shape, and surface area, may play a role in the biological responses to the microelectrode. Further experimental data is needed to determine the effect of these properties on the FBR and the recording performance. In this paper, we evaluate the effect of site placement using Michigan arrays with sites on the center, edge, and tip of the shank. The results show that there is significant performance variance between the center, edge, and tip sites.

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining.

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously.

Evaluation of micro-electrocorticographic electrodes for electrostimulation.

Chronic neural recording and stimulation on the surface of the cortex with macroelectrodes has been shown to be promising for treating a wide range of neurological deficits. To enhance the specificity of these devices, dense arrangements of small area electrodes have been microfabricated for precise recording and control of neural populations. In this study micro-electrocorticographic (microECoG) electrodes were evaluated for electrostimulation. Surface modification with electrodeposited iridium oxide (EIrOx) resulted in lower impedance, higher charge carrying capacity, and lower, more linear voltage excursions during current controlled stimulation.

Titanium-based multi-channel, micro-electrode array for recording neural signals.

Micro-scale brain-machine interface (BMI) devices have provided an opportunity for direct probing of neural function and have also shown significant promise for restoring neurological functions lost to stroke, injury, or disease. However, the eventual clinical translation of such devices may be hampered by limitations associated with the materials commonly used for their fabrication, e.g. brittleness of silicon, insufficient rigidity of polymeric devices, and unproven chronic biocompatibility of both. Herein, we report, for the first time, the development of titanium-based "Michigan" type multi-channel, microelectrode arrays that seek to address these limitations. Titanium provides unique properties of immediate relevance to microelectrode arrays, such as high toughness, moderate modulus, and excellent biocompatibility, which may enhance structural reliability, safety, and chronic recording reliability. Realization of these devices is enabled by recently developed techniques which provide the opportunity for fabrication of high aspect ratio micromechanical structures in bulk titanium substrates. Details regarding the design, fabrication, and characterization of these devices for eventual use in rat auditory cortex and thalamus recordings are presented, as are preliminary results.

Poly(3,4-ethylenedioxythiophene) as a Micro-Neural Interface Material for Electrostimulation.

Chronic microstimulation-based devices are being investigated to treat conditions such as blindness, deafness, pain, paralysis, and epilepsy. Small-area electrodes are desired to achieve high selectivity. However, a major trade-off with electrode miniaturization is an increase in impedance and charge density requirements. Thus, the development of novel materials with lower interfacial impedance and enhanced charge storage capacity is essential for the development of micro-neural interface-based neuroprostheses. In this report, we study the use of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) as a neural interface material for microstimulation of small-area iridium electrodes on silicon-substrate arrays. Characterized by electrochemical impedance spectroscopy, electrodeposition of PEDOT results in lower interfacial impedance at physiologically relevant frequencies, with the 1 kHz impedance magnitude being 23.3 +/- 0.7 kOmega, compared to 113.6 +/- 3.5 kOmega for iridium oxide (IrOx) on 177 mum(2) sites. Further, PEDOT exhibits enhanced charge storage capacity at 75.6 +/- 5.4 mC/cm(2) compared to 28.8 +/- 0.3 mC/cm(2) for IrOx, characterized by cyclic voltammetry (50 mV/s). These improvements at the electrode interface were corroborated by observation of the voltage excursions that result from constant current pulsing. The PEDOT coatings provide both a lower amplitude voltage and a more ohmic representation of the applied current compared to IrOx. During repetitive pulsing, PEDOT-coated electrodes show stable performance and little change in electrical properties, even at relatively high current densities which cause IrOx instability. These findings support the potential of PEDOT coatings as a micro-neural interface material for electrostimulation.