BACKGROUNDA long-held goal of vision therapy is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists.METHODSWe implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a 6-month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation.RESULTSImplantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes was associated with a significant reduction in thresholds (P < 0.001, ANOVA) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries.CONCLUSIONSOur results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02983370.FUNDINGThe Spanish Ministerio de Ciencia Innovación y Universidades, the Generalitat Valenciana (Spain), the Europan Union's Horizon 2020 programme, the Bidons Egara Research Chair of the University Miguel Hernández (Spain), and the John Moran Eye Center of the University of Utah.

Current truncating circuit designs used in some controllable pulse width transcranial magnetic stimulation systems can be adapted for use with the peripheral nervous system. Such a scaled-down stimulator produces neuromuscular activation using less stimulus energy than described in previous reports of sciatic nerve stimulation. To evaluate the energy reductions possible with current truncation, we performed six in vivo experiments in rats where the magnetic stimulating coil abutted the sciatic nerve. We used electromyographic data to quantify neuromuscular response, with a criterion level of 20%-of-maximum to indicate a useful level of neuromuscular activation. The energy required to evoke this criterion response from muscles innervated by the sciatic nerve was reduced by approximately 34% from 10.7J with a stimulus waveform lasting 300 [Formula: see text] to 7.1J with a waveform lasting 50 [Formula: see text]. In water, the 300 [Formula: see text] pulse heated the coil by 0.30°C whereas the 50 [Formula: see text] pulse heated the coil by 0.15°C. Truncated-waveform magnetic stimulation systems can be used in basic research and clinical applications not requiring rapidly pulsed stimuli. An example of such a clinical application is left vagus nerve stimulation, a treatment that is reported to reduce epileptic partial-onset seizures.

Objective. An important goal of neuroprosthetic research is to establish bidirectional communication between the user and new prosthetic limbs that are capable of controlling >20 different movements. One strategy for achieving this goal is to interface the prosthetic limb directly with efferent and afferent fibres in the peripheral nervous system using an array of intrafascicular microelectrodes. This approach would provide access to a large number of independent neural pathways for controlling high degree-of-freedom prosthetic limbs, as well as evoking multiple-complex sensory percepts. Approach. Utah Slanted Electrode Arrays (USEAs, 96 recording/stimulating electrodes) were implanted for 30 days into the median (Subject 1-M, 31 years post-amputation) or ulnar (Subject 2-U, 1.5 years post-amputation) nerves of two amputees. Neural activity was recorded during intended movements of the subject’s phantom fingers and a linear Kalman filter was used to decode the neural data. Microelectrode stimulation of varying amplitudes and frequencies was delivered via single or multiple electrodes to investigate the number, size and quality of sensory percepts that could be evoked. Device performance over time was assessed by measuring: electrode impedances, signal-to-noise ratios (SNRs), stimulation thresholds, number and stability of evoked percepts. Main results. The subjects were able to proportionally, control individual fingers of a virtual robotic hand, with 13 different movements decoded offline (r = 0.48) and two movements decoded online. Electrical stimulation across one USEA evoked >80 sensory percepts. Varying the stimulation parameters modulated percept quality. Devices remained intrafascicularly implanted for the duration of the study with no significant changes in the SNRs or percept thresholds. Significance. This study demonstrated that an array of 96 microelectrodes can be implanted into the human peripheral nervous system for up to 1 month durations. Such an array could provide intuitive control of a virtual prosthetic hand with broad sensory feedback.

This paper reviews technologies and signal processing algorithms for decoding peripheral nerve and electrocorticogram signals to interpret human intent and control prosthetic arms. The review includes a discussion of human motor system physiology and physiological signals that can be used to decode motor intent, electrode technology for acquiring neural data, and signal processing methods including decoders based on Kalman filtering and least-squares regressors. Representative results from human experiments demonstrate the progress that has been made in neural decoding and its potential for developing neuroprosthetic arms that act and feel like natural arms.

This paper briefly describes some of the recent progress in the development of penetrating microelectrode arrays and highlights the use of two of these devices, Utah electrode arrays and Utah slanted electrode arrays, in two therapeutic interventions: recording volitional skeletal motor commands from the central nervous system, and recording motor commands and evoking somatosensory percepts in the peripheral nervous system (PNS). The paper also briefly explores other potential sites for microelectrode array interventions that could be profitably pursued and that could have important consequences in enhancing the quality of life of patients that has been compromised by disorders of the central and PNSs.

Previous reports of magnetic stimulation of the peripheral nervous system (PNS) used various coil geometries, all with outer diameters larger than 35 mm, and stimulation energies in the 50 J range to evoke neural excitation. Recent reports of central nervous system (CNS) activation used sub-mm-scale solenoid coils with mJ energy levels. The goal of this study was to translate the lower energy levels from the CNS to the PNS via using smaller coils placed in closer proximity to the neural tissue. Such a performance improvement would advance the state of the art of magnetic stimulation and provide a path towards new neuroprosthetic devices. Primarily, we investigated the range of coil outer diameters from 25 mm down to 5 mm to better understand the dependence of coil diameter on energy required for PNS activation. Nine cm- and mm-scale copper solenoid coils, with various resistances, inductances, inner and outer diameters, and heights were compared by quantizing neuromuscular responses to magnetic stimulation via capacitive discharge excitation of rat sciatic nerves in vivo. Additionally, the effects of stimulus duration and coil position were investigated. As opposed to prior work, this study compares a subset of stimulation parameters in an intact nerve preparation, and shows that magnetic stimulation with coils that abut the nerve is a reliable, effective method of neuromuscular stimulation. Although we observed different energies required for neuromuscular activation depending on the coil and excitation parameters used, for the experimental configuration, devices, and stimulus waveform shapes presented in this manuscript, no systematic dependence of PNS activation on coil diameter was found, even for the mm-scale coils investigated herein. However, there was a clear relationship between discharge circuit capacitance and energy required to evoke a neuromuscular response. Coils approximately 12 mm in outer diameter and larger consistently evoked responses, whereas coils 5 mm in outer diameter did not. Furthermore, we observed meaningful neuromuscular excitation when stimulating with energies as low as 20 J. Although this is an improvement over prior work, it is still orders of magnitude greater than the energy required for conventional electrical stimulation, suggesting that these devices are presently not suitable for use in an application requiring continued pulsed stimulation. Nevertheless, these devices are suitable for basic research and as clinical tools that infrequently stimulate, such as in diagnostic applications.

Asynchronous intrafascicular multi-electrode stimulation (aIFMS) of small independent populations of peripheral nerve motor axons can evoke selective, fatigue-resistant muscle forces. We previously developed a real-time proportional closed-loop control method for aIFMS generation of isometric muscle force and the present work extends and adapts this closed-loop controller to the more demanding task of dynamically controlling joint position in the presence of opposing joint torque. A proportional-integral-velocity controller, with integrator anti-windup strategies, was experimentally validated as a means to evoke motion about the hind-limb ankle joint of an anesthetized feline via aIFMS stimulation of fast-twitch plantar-flexor muscles. The controller was successful in evoking steps in joint position with 2.4% overshoot, 2.3-s rise time, 4.5-s settling time, and near-zero steady-state error. Controlled step responses were consistent across changes in step size, stable against external disturbances, and reliable over time. The controller was able to evoke smooth eccentric motion at joint velocities up to 8 deg./s, as well as sinusoidal trajectories with frequencies up to 0.1 Hz, with time delays less than 1.5 s. These experiments provide important insights toward creating a robust closed-loop aIFMS controller that can evoke precise fatigue-resistant motion in paralyzed individuals, despite the complexities introduced by aIFMS.

Cortical prostheses are a subgroup of visual neuroprosthesis capable of eliciting visual percepts in profoundly blind people through direct stimulation of the occipital cortex. This approach is the only treatment available for blindness caused by glaucoma, optic atrophy or by diseases of the central visual pathways such as brain injuries or stroke. If these higher visual centers could be stimulated with visual information in a format somewhat similar to the way they were stimulated before the onset of blindness, a blind individual could be able to use this stimulation to extract information about the physical world around him/her. Here we present an update of the strategies we are using to transmit visual information in a meaningful way to the brain.

The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions.

There has been recurring interest in using magnetic neural stimulation for implantable localized stimulation. However, the large stimulation voltages and energies necessary to evoke neuronal activity have tempered this interest. To investigate the potential of magnetic stimulation as a viable methodology and to provide the ability to investigate novel coil designs that can result in lower stimulation threshold voltages and energies, there is a need for a model that accurately predicts the magnetic field-tissue interaction that results in neuronal stimulation. In this study, we provide a computational framework to accurately estimate the stimulation threshold and have validated the model with in vivo magnetic stimulation experiments. To make such predictions, we developed a micrometer-resolution anatomically driven computational model of rat sciatic nerve and quantified the effect of tissue heterogeneity (i.e., fascicular organization, axon distribution, and density) and axonal membrane capacitance on the resulting threshold. Using the multiresolution impedance method, we computed the spatial-temporal distribution of the induced electric field in the nerve and applied this field to a Frankenhaeuser-Huxley axon model in NEURON to simulate the nonlinear mechanisms of the membrane channels. The computational model developed predicts the stimulation thresholds for four magnetic coil designs with different geometrical parameters within the 95% confidence interval (experiments count = 4) of measured in vivo stimulation thresholds for the rat sciatic nerve.

OBJECTIVES:To investigate intrafascicular pudendal nerve stimulation in felines as a means to restore urinary function in acute models of urinary incontinence, overactive bladder, and underactive bladder.MATERIALS AND METHODS:Felines were anesthetized, and high-electrode-count (48 electrodes; 25 electrodes/mm(2) ) electrode arrays were implanted intrafascicularly into the pudendal nerve trunk. Electrodes were mapped for their ability to selectively or nonselectively excite the external anal sphincter, external urethral sphincter, and the detrusor bladder muscle. Statistical analysis was carried out to quantify reflexive voiding efficiencies, mean impedances of the microelectrodes used in this study, and to determine what differences, if any, in bladder contraction amplitudes were evoked by different electrode configurations.RESULTS:Multielectrode arrays implanted into the pudendal nerve trunk were able to selectively and nonselectively excite genitourinary muscles. After inducing urinary incontinence with bilateral pudendal nerve transections (proximal to the implants), electrical stimulation delivered through certain microelectrodes was able to significantly reduce leaking (p = 0.008). Electrical stimulation delivered through detrusor selective electrodes was able to inhibit reflexive bladder contractions and excite bladder contractions, depending on the stimulation frequency. Specific electrode configurations were able to drive significantly (p < 0.001) larger bladder contractions than other electrode configurations, depending on the preparation. Successful reflexively or electrically driven bladder contractions were achieved in 46% and 38% of the preparations, respectively, an observation that has not been noted in previously published feline pudendal stimulation studies.CONCLUSIONS:Multielectrode arrays implanted intrafascicularly into the pudendal nerve trunk may provide a promising new clinical neuromodulation therapy for the restoration of urinary function.

Magnetic stimulation, as a means of evoking neuromuscular activity, has an advantage over direct electrical stimulation in that the stimulator need not directly contact the neural tissue. However, the high energy levels and large magnetic coils needed to elicit a response hinder the use of implantable magnetic stimulators for functional neural stimulation. Our group has previously reported a µm-scale computational model that quantifies the neurostimulation efficacy of a time-varying magnetic field on the myelinated axons of rat sciatic nerve, where discharging the voltage stored on a capacitor through an air-core solenoid coil creates the field. Further, we have validated the performance of this model with in vivo experiments in the rat using a small sample of solenoid coils, and we have observed that solenoid coils with ∼1cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> volumes can evoke neural excitation with discharge voltages as low as 110 V. In this work, we report on using the computational model to optimize the stimulation system and the solenoid coil design to reduce the discharge voltage necessary to evoke neural activity (i.e., threshold voltage).

Objective. Before peripheral nerve electrodes can be used for the restoration of sensory and motor functions in patients with neurological disorders, the behavioral and histological consequences of these devices must be investigated. These indices of biocompatibility can be defined in terms of desired functional outcomes; for example, a device may be considered for use as a therapeutic intervention if the implanted subject retains functional neurons post-implantation even in the presence of a foreign body response. The consequences of an indwelling device may remain localized to cellular responses at the device-tissue interface, such as fibrotic encapsulation of the device, or they may affect the animal more globally, such as impacting behavioral or sensorimotor functions. The objective of this study was to investigate the overall consequences of implantation of high-electrode count intrafascicular peripheral nerve arrays, High Density Utah Slanted Electrode Arrays (HD-USEAs; 25 electrodes mm(-2)). Approach. HD-USEAs were implanted in rat sciatic nerves for one and two month periods. We monitored wheel running, noxious sensory paw withdrawal reflexes, footprints, nerve morphology and macrophage presence at the tissue-device interface. In addition, we used a novel approach to contain the arrays in actively behaving animals that consisted of an organic nerve wrap. A total of 500 electrodes were implanted across all ten animals. Main results. The results demonstrated that chronic implantation (<= 8 weeks) of HD-USEAs into peripheral nerves can evoke behavioral deficits that recover over time. Morphology of the nerve distal to the implantation site showed variable signs of nerve fiber degeneration and regeneration. Cytology adjacent to the device-tissue interface also showed a variable response, with some electrodes having many macrophages surrounding the electrodes, while other electrodes had few or no macrophages present. This variability was also seen along the length of the electrodes. Axons remained within the proximity of the electrode tips at the distances required for theoretically effective stimulation and recording (<= 100 mu m). Significance. We conclude from these studies that HD-USEAs do not cause overall global effects on the animals, at least up to the two-month period investigated here. These results demonstrate for the first time that the consequences of high-electrode count intrafascicular arrays compare with other peripheral nerve electrodes currently available for clinical or investigational neuromodulation.

Magnetic stimulation is an evolving, non-invasive neural stimulation technology used for clinical applications, including brain mapping, treatment of mood disorders, epilepsy, and chronic pain. Based on the induction principle, magnetic stimulation induces electric fields in the conductive tissue due to the time-varying current in the magnetic coil. It requires the magnetic coil to be in close proximity to the stimulation site to produce neural activation. The stimulation threshold of magnetic stimulation depends on the magnitude and the pulse width of the induced electric field. Traditionally, the efficacy of the magnetic stimulation is studied using analytical formulations based on the coil parameters and operating conditions (Roth, B. J. et. al., IEEE TBME 1990). Several studies were performed to include the tissue boundaries in the simulation model of the induced electric field (Nagarajan, S.S. et al., IEEE TBME 1996). However, these models were over simplified and do not include the tissue heterogeneity found in the nerve bundle.

OBJECTIVE:To investigate the use of a microelectrode array with a high spatial density of penetrating intrafascicular electrodes for selective recording of pudendal nerve activity evoked by a variety of genitourinary stimuli. MATERIALS AND METHODS:Felines were anesthetized with alpha-chloralose and high-density Utah slanted electrode arrays (48 microelectrodes; 200-μm spacing) were implanted into the pudendal nerve for acute experimentation. Neural activity was recorded during bladder filling, spontaneous reflexive distention-evoked bladder contractions, and tactile somatosensory stimulation. RESULTS:The intrafascicularly implanted pudendal nerve electrodes were able to selectively record neural activity that corresponded to various genitourinary stimuli. Across all seven experimental animals, a total of 10 microelectrodes recorded neural units that were selectively driven by bladder filling or distention-evoked bladder contractions. Twenty-two electrodes were selectively driven by tactile stimulation. CONCLUSION:Microelectrode arrays implanted intrafascicularly into the pudendal nerve can be used to selectively record the neural responses that reflect bladder status and urogenital tactile stimulation. This work sets the stage for developing future implantable closed-loop neuroprosthetic devices for restoration of bladder function.

Introduction: High density Utah slanted electrode arrays (HD-USEAs) have been developed recently for intrafascicular access to submillimeter neural structures. Insertion of such high electrode density devices may cause nerve crush injury, counteracting the intended improved selective nerve fiber access. Methods: HD-USEAs were implanted into sciatic nerves of anesthetized rats. Nerve function was assessed before and after HD-USEA implantation by measuring changes in evoked muscle and nerve compound action potentials and single unit neuronal recordings. Results: Neural activity was recorded with over half of all implanted electrodes. Average decreases of 38%, 36%, and 13% in nerve, medial gastrocnemius, and tibialis anterior compound action potential amplitudes, respectively, were observed following array implantation. Only 1 of 8 implantations resulted in loss of all signals. Conclusions: These studies demonstrate that HD-USEAs provide a useful neural interface without causing a nerve crush injury that would otherwise negate their use in acute preparations (< 12 h).

Efficacy of magnetic stimulation of the central or peripheral nervous system depends on the spatial and temporal distribution of the induced electric field generated by the magnetic coil. Therefore, accurate estimation of the induced electric field is crucial to the design and optimization of magnetic coils, particularly as the coil dimensions are reduced. In this work, we developed a numerical model of a multifascicular sciatic nerve to study the effect of tissue heterogeneity on the induced electric field. Using a multi-resolution electric field solver, we can resolve feature sizes as small as 1μm, allowing inclusion of the nerve membrane and the myelination layer. Preliminary results indicate that fascicle distribution and axons' proximity to each other significantly affect the magnitude and distribution of the induced electric field as compared to traditional homogeneous tissue models for field simulation.