Publications using the IZ2

For many peripheral neuro-modulation applications, the cuff electrode has become a preferred technology for delivering electrical current into targeted volumes of tissue. While basic cuffs with low spatial selectivity, having longitudinally arranged contacts, can be produced from relatively straightforward processes, the fabrication of more complex electrode configurations typically requires iterative design and clean-room fabrication with skilled technicians. Although facile methods for fabricating cuff electrodes exist, their inconsistent products have limited their adoption for rapid manufacturing. In this article, we report a fast, low-cost fabrication process for patterning of electrode contacts in an implantable peripheral nerve cuff. Using a laser cutter as we have prescribed, the designer can render precise contact geometries that are consistent between batches. This method is enabled by the use of silicone/carbon black (CB) composite electrodes, which integrate with the patterned surface of its substrate—tubular silicone insulation. The size and features of its products can be adapted to fit a wide range of nerve diameters and applications. In this study, we specifically documented the manufacturing and evaluation of circumpolar cuffs with radial arrays of three contacts for acute implantation on the rat sciatic nerve. As part of this method, we also detail protocols for verification—electrochemical characterization—and validation—electrophysiological evaluation—of implantable cuff electrodes. Applied to our circumpolar cuff electrode, we report favorable electrical characteristics. In addition, we report that it reproduces expected electrophysiological behaviors described in prior literature. No specialized equipment or fabrication experience was required in our production, and we encountered negligible costs relative to commercially available solutions. Since, as we demonstrate, this process generates consistent and precise electrode geometries, we propose that it has strong merits for use in rapid manufacturing.

Background Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. Methods We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. Results Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001). Conclusion Electrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

Spatial hearing in cochlear implant (CI) patients remains a major challenge, with many early deaf users reported to have no measurable sensitivity to interaural time differences (ITDs). Deprivation of binaural experience during an early critical period is often hypothesized to be the cause of this shortcoming. However, we show that neonatally deafened (ND) rats provided with precisely synchronized CI stimulation in adulthood can be trained to lateralize ITDs with essentially normal behavioral thresholds near 50 μs. Furthermore, comparable ND rats show high physiological sensitivity to ITDs immediately after binaural implantation in adulthood. Our result that ND-CI rats achieved very good behavioral ITD thresholds, while prelingually deaf human CI patients often fail to develop a useful sensitivity to ITD raises urgent questions concerning the possibility that shortcomings in technology or treatment, rather than missing input during early development, may be behind the usually poor binaural outcomes for current CI patients.

Prostheses that can restore limited vision in the profoundly blind have been under investigation for several decades. Studies using epicortical macroelectrodes and intracortical microelectrodes have validated that electrical stimulation of primary visual cortical can serve as the basis for a vision prosthesis. However, neither of these approaches has resulted in a clinically viable vision prosthesis. Epicortical macroelectrodes required high levels of electrical current to evoke visual percepts, while intracortical microelectrodes faced challenges with longevity and stability. We hypothesized that epicortical microelectrodes could evoke visual percepts at lower currents than macroelectrodes and provide improved longevity and stability compared with intracortical microelectrodes. To test this hypotheses we implanted epicortical microelectrode arrays over the primary visual cortex of a nonhuman primate. Electrical stimulation via this array was used to evaluate the ability of epicortical microstimulation to evoke differentiable visual percepts. Visual percepts were evoked using the epicortical microelectrode array, and at electrical currents notably lower than those required to evoke visual percepts on macroelectrode arrays. The electrical current thresholds for evoking visual percepts on the epicortical microelectrode array were consistent across multiple array implants and over several months. Normal vision of light perception was not impaired by multiple array implants or chronic electrical stimulation, demonstrating that no gross visual deficit resulted from the experiments. We specifically demonstrate that epicortical microelectrode interfaces can serve as the basis for a vision prosthesis and more generally may provide an approach to evoking perception in multiple sensory modalities. One Sentence Summary Electrical stimulation of the brain via microelectrodes resting on the surface of primary visual cortex can evoke multiple differentiable visual percepts.

This protocol was used to collect data now published in the Journal of Neural Engineering, Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs, see Metadata for citation. Additionally, the dataset is publicly available on Pennsieve 10.26275/qcuk-a8ty.

Mammalian cortex has both local and cross-area connections, suggesting vital roles for both local and cross-area neural population dynamics in cortically-dependent tasks, like movement learning. Prior studies of movement learning have focused on how single-area population dynamics change during short-term adaptation. It is unclear how cross-area dynamics contribute to movement learning, particularly long-term learning and skill acquisition. Using simultaneous recordings of rodent motor (M1) and premotor (M2) cortex and computational methods, we show how cross-area activity patterns evolve during reach-to-grasp learning in rats. The emergence of reach-related modulation in cross-area activity correlates with skill acquisition, and single-trial modulation in cross-area activity predicts reaction time and reach duration. Local M2 neural activity precedes local M1 activity, supporting top–down hierarchy between the regions. M2 inactivation preferentially affects cross-area dynamics and behavior, with minimal disruption of local M1 dynamics. Together, these results indicate that cross-area population dynamics are necessary for learned motor skills.

Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex. We demonstrate a vast enhancement in the recording quality with a typical artifact reduction of 25-40 dB. The method is efficient and can be scaled to arbitrary number of stimulus and recording sites, making it ideal for applications in large-scale arrays, closed-loop implants, and high-resolution multi-channel brain-machine interfaces.

Retinal prostheses have been developed to restore a functional form of vision in patients affected by outer retinal layer dystrophies. Other approaches, namely optic nerve, thalamic, and cortical prostheses are under investigation to expand this toolbox both as clinical devices and as tools for fundamental research. Optic nerve stimulation is attractive since it bypasses the entire retinal network and directly activates nerve fibers. At the same time, it still takes advantage of the high-level information processing occurring downstream in the visual cortex. Here we show that a new intraneural electrode array (OpticSELINE) is effective in inducing the activation of the visual cortex upon electrical stimulation of the optic nerve. We also demonstrate that intraneural optic nerve stimulation induces selective cortical activation patterns depending on the stimulating electrode, thus suggesting that the OpticSELINE possesses spatial selectivity in fiber stimulation. In conclusion, the OpticSELINE can be used both as visual prosthesis for blind patients and as tool to further investigate the effect of the electrical stimulation in the visual system.

Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON-OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell's spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one-dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear.

Background: Despite advances in sophisticated robotic hands, intuitive control of and sensory feedback from these prostheses has been limited to only 3-degrees-of-freedom (DOF) with 2 sensory percepts in closed-loop control. A Utah Slanted Electrode Array (USEA) has been used in the past to provide up to 81 sensory percepts for human amputees. Here, we report on the advanced capabilities of multiple USEAs implanted in the residual peripheral arm nerves of human amputees for restoring control of 5 DOF and sensation of up to 131 proprioceptive and cutaneous hand sensory percepts. We also demonstrate that USEA-restored sensory percepts provide a useful source of feedback during closed-loop virtual prosthetic hand control. Methods: Two 100-channel USEAs were implanted for 4-5 weeks, one each in the median and ulnar arm nerves of two human subjects with prior long-duration upper-arm amputations. Intended finger and wrist positions were decoded from neuronal firing patterns via a modified Kalman filter, allowing subjects to control many movements of a virtual prosthetic hand. Additionally, USEA microstimulation was used to evoke numerous sensory percepts spanning the phantom hand. Closed-loop control was achieved by stimulating via an electrode of the ulnar-nerve USEA while recording and decoding movement via the median-nerve USEA. Results: Subjects controlled up to 12 degrees-of-freedom during informal, 'freeform' online movement decode sessions, and experienced up to 131 USEA-evoked proprioceptive and cutaneous sensations spanning the phantom hand. Independent control was achieved for a 5-DOF real-time decode that included flexion/extension of the thumb, index, middle, and ring fingers, and the wrist. Proportional control was achieved for a 4-DOF real-time decode. One subject used a USEA-evoked hand sensation as feedback to complete a 1-DOF closed-loop virtual-hand movement task. There were no observed long-term functional deficits due to the USEA implants. Conclusions: Implantation of high-channel-count USEAs enables multi-degree-of-freedom control of virtual prosthetic hand movement and restoration of a rich selection of both proprioceptive and cutaneous sensory percepts spanning the hand during the short 4-5 week post-implant period. Future USEA use in longer-term implants and in closed-loop may enable restoration of many of the capabilities of an intact hand while contributing to a meaningful embodiment of the prosthesis.

The ventral premotor cortex (PMv) is a key node in the neural network involved in grasping. One way PMv can carry out this function is by modulating the outputs of the primary motor cortex (M1) to intrinsic hand and forearm muscles. As many PMv neurons discharge when grasping with either arm, both PMv within the same hemisphere (ipsilateral; iPMv) and in the opposite hemisphere (contralateral; cPMv) could modulate M1 outputs. Our objective was to compare modulatory effects of iPMv and cPMv on M1 outputs to intrinsic hand and forearm muscles. We used paired-pulse protocols with intracortical microstimulations in capuchin monkeys. A conditioning stimulus was applied in either iPMv or cPMv simultaneously or prior to a test stimulus in M1 and the effects quantified in electromyographic signals. Modulatory effects from iPMv were predominantly facilitatory, and facilitation was much more common and powerful on intrinsic hand than forearm muscles. In contrast, while the conditioning of cPMv could elicit facilitatory effects, in particular to intrinsic hand muscles, it was much more likely to inhibit M1 outputs. These data show that iPMv and cPMv have very different modulatory effects on the outputs of M1 to intrinsic hand and forearm muscles.

Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants). Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time) despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs) stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron's electrical receptive field (ERF), i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

The efficacy of spinal cord stimulators is dependent on the ability of the device to functionally activate targeted structures within the spinal cord, while avoiding activation of near-by non-targeted structures. In theory, these objectives can best be achieved by delivering electrical stimuli directly to the surface of the spinal cord. The current experiments were performed to study the influence of different stimulating electrode positions on patterns of spinal cord electrophysiological activation. A custom-designed spinal cord neurostimulator was used to investigate the effects of lead position and stimulus amplitude on cortical electrophysiological responses to spinal cord stimulation. Brain recordings were obtained from subdural grids placed in four adult sheep. We systematically varied the position of the stimulating lead relative to the spinal cord and the voltage delivered by the device at each position, and then examined how these variables influenced cortical responses. A clear relationship was observed between voltage and electrode position, and the magnitude of high gamma-band oscillations. Direct stimulation of the dorsal column contralateral to the grid required the lowest voltage to evoke brain responses to spinal cord stimulation. Given the lower voltage thresholds associated with direct stimulation of the dorsal column, and its possible impact on the therapeutic window, this intradural modality may have particular clinical advantages over standard epidural techniques now in routine use.