Trevathan, James K.

Abstract Selective activation of smaller diameter over large diameter nerve fibers represents a broad challenge in the electrical modulation of neural activity for clinical applications. For example, off-target activation of motor nerve fibers has been implicated in several failed vagus nerve stimulation (VNS) clinical trials by precluding achieving current amplitudes sufficient to activate the therapeutically targeted small diameter fibers. In this study, we evaluated the use of high-frequency (HF) stimulation to block unwanted activation of large diameter fibers evoked by traditional low-frequency (LF) VNS in a large animal (swine) model. We demonstrate that HF can eliminate specific unwanted LF-evoked components from neural recordings with high selectivity – along with their associated off-target physiological responses - while preserving the activation of smaller diameter fibers driving intended physiological responses. Conversely, block of the smaller diameter fibers was only observed at HF amplitudes much higher than amplitudes commonly used for HF block clinically. We found that in addition to blocking the LF-evoked compound action potential, lower HF amplitudes also drive asynchronous activity which can easily be overlooked. Only at high amplitudes did HF block LF-evoked activation without concomitant asynchronous activation. These data have numerous implications for existing and future LF and HF block neuromodulation therapies.

Carbon-based electrodes combined with fast-scan cyclic voltammetry (FSCV) enable neurochemical sensing with high spatiotemporal resolution and sensitivity. While their attractive electrochemical and conductive properties have established a long history of use in the detection of neurotransmitters both in vitro and in vivo, carbon fiber microelectrodes (CFMEs) also have limitations in their fabrication, flexibility, and chronic stability. Diamond is a form of carbon with a more rigid bonding structure (sp3-hybridized) which can become conductive when boron-doped. Boron-doped diamond (BDD) is characterized by an extremely wide potential window, low background current, and good biocompatibility. Additionally, methods for processing and patterning diamond allow for high-throughput batch fabrication and customization of electrode arrays with unique architectures. While tradeoffs in sensitivity can undermine the advantages of BDD as a neurochemical sensor, there are numerous untapped opportunities to further improve performance, including anodic pretreatment, or optimization of the FSCV waveform, instrumentation, sp2/sp3 character, doping, surface characteristics, and signal processing. Here, we review the state-of-the-art in diamond electrodes for neurochemical sensing and discuss potential opportunities for future advancements of the technology. We highlight our team’s progress with the development of an all-diamond fiber ultramicroelectrode as a novel approach to advance the performance and applications of diamond-based neurochemical sensors.

Abstract Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone‐metal‐particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSC C ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost‐effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.

Implantable devices to measure neurochemical or electrical activity from the brain are mainstays of neuroscience research and have become increasingly utilized as enabling components of clinical therapies. In order to increase the number of recording channels on these devices while minimizing the immune response, flexible electrodes under 10 µm in diameter have been proposed as ideal next-generation neural interfaces. However, the representation of motion artifact during neurochemical or electrophysiological recordings using ultra-small, flexible electrodes remains unexplored. In this short communication, we characterize motion artifact generated by the movement of 7 µm diameter carbon fiber electrodes during electrophysiological recordings and fast-scan cyclic voltammetry (FSCV) measurements of electroactive neurochemicals. Through in vitro and in vivo experiments, we demonstrate that artifact induced by motion can be problematic to distinguish from the characteristic signals associated with recorded action potentials or neurochemical measurements. These results underscore that new electrode materials and recording paradigms can alter the representation of common sources of artifact in vivo and therefore must be carefully characterized.

Study Design. Laboratory/animal-based proof of principle study. Objective. To validate the accuracy of a magnetic resonance imaging (MRI)-guided stereotactic system for intraspinal electrode targeting and demonstrate the feasibility of such a system for controlling implantation of intraspinal electrodes. Summary of Background Data. Intraspinal microstimulation (ISMS) is an emerging preclinical therapy, which has shown promise for the restoration of motor function following spinal cord injury. However, targeting inaccuracy associated with existing electrode implantation techniques remains a major barrier preventing clinical translation of ISMS. Methods. System accuracy was evaluated using a test phantom comprised of nine target locations. Targeting accuracy was determined by calculating the root mean square error between MRI-generated coordinates and actual frame coordinates required to reach the target positions. System performance was further validated in an anesthetized pig model by performing MRI-guided intraspinal electrode implantation and stimulation followed by computed tomography of electrode location. Finally, system compatibility with a commercially available microelectrode array was demonstrated by implanting the array and applying a selection of stimulation amplitudes that evoked hind limb responses. Results. The root mean square error between actual frame coordinates and software coordinates, both acquired using the test phantom, was 1.09 ± 0.20 mm. Postoperative computed tomography in the anesthetized pig confirmed spatially accurate electrode placement relative to preoperative MRI. Additionally, MRI-guided delivery of a microwire electrode followed by ISMS evoked repeatable electromyography responses in the biceps femoris muscle. Finally, delivery of a microelectrode array produced repeatable and graded hind limb evoked movements. Conclusion. We present a novel frame-based stereotactic system for targeting and delivery of intraspinal instrumentation. This system utilizes MRI guidance to account for variations in anatomy between subjects, thereby improving upon existing ISMS electrode implantation techniques. Level of Evidence: N/A