Visual percepts evoked with an intracortical 96-channel microelectrode array inserted in human occipital cortex.

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.

Reduced Heat Generation During Magnetic Stimulation of Rat Sciatic Nerve Using Current Waveform Truncation.

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.

Clinical applications of penetrating neural interfaces and Utah Electrode Array technologies.

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.

Control of Dynamic Limb Motion Using Fatigue-Resistant Asynchronous Intrafascicular Multi-Electrode Stimulation.

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.

In Vivo Magnetic Stimulation of Rat Sciatic Nerve With Centimeter- and Millimeter-Scale Solenoid Coils.

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.

A µm-Scale Computational Model of Magnetic Neural Stimulation in Multifascicular Peripheral Nerves.

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.

The BRAIN Initiative: developing technology to catalyse neuroscience discovery.

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.

Acute human brain responses to intracortical microelectrode arrays: challenges and future prospects.

The emerging field of neuroprosthetics is focused on the development of new therapeutic interventions that will be able to restore some lost neural function by selective electrical stimulation or by harnessing activity recorded from populations of neurons. As more and more patients benefit from these approaches, the interest in neural interfaces has grown significantly and a new generation of penetrating microelectrode arrays are providing unprecedented access to the neurons of the central nervous system (CNS). These microelectrodes have active tip dimensions that are similar in size to neurons and because they penetrate the nervous system, they provide selective access to these cells (within a few microns). However, the very long-term viability of chronically implanted microelectrodes and the capability of recording the same spiking activity over long time periods still remain to be established and confirmed in human studies. Here we review the main responses to acute implantation of microelectrode arrays, and emphasize that it will become essential to control the neural tissue damage induced by these intracortical microelectrodes in order to achieve the high clinical potentials accompanying this technology.

Acute monitoring of genitourinary function using intrafascicular electrodes: selective pudendal nerve activity corresponding to bladder filling, bladder fullness, and genital stimulation.

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.

Assessment of rat sciatic nerve function following acute implantation of high density Utah slanted electrode array (25 electrodes/mm(2) ) based on neural recordings and evoked muscle activity.

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).

Using multiple high-count electrode arrays in human median and ulnar nerves to restore sensorimotor function after previous transradial amputation of the hand.

Peripheral nerve interfaces that can record from and stimulate large numbers of different nerve fibers selectively and independently may help restore intuitive and effective motor and sensory function after hand amputation. To this end, and extending previous work in two subjects, two 100-electrode Utah Slanted Electrode Arrays (USEAs) were implanted for four weeks in the residual ulnar and median nerves of a 50-year-old male whose left, dominant hand had been amputated 21 years previously. Subsequent experiments involved 1) recording from USEAs for real-time control of a virtual prosthetic hand; 2) stimulation to evoke somatosensory percepts; and 3) closed-loop sensorimotor control. Overall, partial motor control and sensation were achieved using USEAs. 1) Isolated action potentials recorded from nerve motor fibers, although sparse at these distal implant sites, were activated during fictive movements of the phantom hand. Unlike in our previous two subjects, electromyographic (EMG) activity contributed to most online recordings and decodes, but was reduced in offline analyses using common average referencing. Online and offline Kalman-filter decodes of thresholded neural or EMG spikes independently controlled different digits of the virtual hand with one or two degrees of freedom. 2) Microstimulation through individual electrodes of the two USEAs evoked up to 106 different percepts, covering much of the phantom hand. The subject discriminated among five perceived stimulus locations, and between two somatosensory submodalities at a single location. 3) USEA-evoked percepts, mimicking contact with either a near or distal virtual target, were used to terminate movements of the virtual hand controlled with USEA recordings comprised wholly or mostly of EMG. These results further indicate that USEAs can help restore sensory and motor function after hand loss.

Magnetic stimulation of mammalian peripheral nerves in vivo: an alternative to functional electrical stimulation.

Functional electrical stimulation is the current gold standard for stimulating neuronal interfaces for functional neuromuscular and cortical applications, but it is not without its drawbacks. One such fault is the need to have direct electrical contact with the nerve tissue, and any side effects this causes. Functional magnetic stimulation, which works though electromagnetic induction, does not require electrical contact and may be a viable alternative to functional electrical stimulation. We are investigating the capabilities of magnetic stimulation with centimeter scale (< 2.5 cm) coils in feline and rodent sciatic nerves in vivo. We have shown that magnetic stimulation can consistently produce the same levels of neuromuscular activation as electrical stimulation. Additionally, the position of the coil relative to the nerve influences neuromuscular activation, suggesting the possibility of selective muscle activation.

A µm-resolution heterogeneous tissue model for the magnetic stimulation of multifascicular sciatic nerve.

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.

The functional consequences of chronic, physiologically effective intracortical microstimulation.

Many studies have demonstrated the ability of chronically implanted multielectrode arrays (MEAs) to extract information from the motor cortex of both humans and nonhuman primates. Similarly, many studies have shown the ability of intracortical microstimulation to impart information to the brain via a single or a few electrodes acutely implanted in sensory cortex of nonhuman primates, but relatively few microstimulation studies characterizing chronically implanted MEAs have been performed. Additionally, device and tissue damage have been reported at the levels of microstimulation used in these studies. Whether the damage resulting from microstimulation impairs the ability of MEAs to chronically produce physiological effects, however, has not been directly tested. In this study, we examined the functional consequences of multiple months of periodic microstimulation via chronically implanted MEAs at levels capable of evoking physiological responses, that is, electromyogram (EMG) activity. The functionality of the MEA and neural tissue was determined by measuring impedances, the ability of microstimulation to evoke EMG responses, and the recording of action potentials. We found that impedances and the number of recorded action potentials followed the previously reported trend of decreasing over time in both animals that received microstimulation and those which did not receive microstimulation. Despite these trends, the ability to evoke EMG responses and record action potentials was retained throughout the study. The results of this study suggest that intracortical microstimulation via MEAs did not cause functional failure, suggesting that MEA-based microstimulation is ready to transition into subchronic (< 30 days) human trials to determine whether complex spatiotemporal sensory percepts can be evoked by patterned microstimulation.

Selective neural activation in a histologically derived model of peripheral nerve.

Functional electrical stimulation (FES) is a general term for therapeutic methods that use electrical stimulation to aid or replace lost ability. For FES systems that communicate with the nervous system, one critical component is the electrode interface through which the machine-body information transfer must occur. In this paper, we examine the influence of inhomogeneous tissue conductivities and positions of nodes of Ranvier on activation of myelinated axons for neuromuscular control as a function of electrode configuration. To evaluate these effects, we developed a high-resolution bioelectric model of a fascicle from a stained cross-section of cat sciatic nerve. The model was constructed by digitizing a fixed specimen of peripheral nerve, extruding the image along the axis of the nerve, and assigning each anatomical component to one of several different tissue types. Electrodes were represented by current sources in monopolar, transverse bipolar, and longitudinal bipolar configurations; neural activation was determined using coupled field-neuron simulations with myelinated axon cable models. We found that the use of an isotropic tissue medium overestimated neural activation thresholds compared with the use of physiologically based, inhomogeneous tissue medium, even after controlling for mean impedance levels. Additionally, the positions of the cathodic sources relative to the nodes of Ranvier had substantial effects on activation, and these effects were modulated by the electrode configuration. Our results indicate that physiologically based tissue properties cause considerable variability in the neural response, and the inclusion of these properties is an important component in accurately predicting activation. The results are used to suggest new electrode designs to enable selective stimulation of small diameter fibers.

Multiple-input single-output closed-loop isometric force control using asynchronous intrafascicular multi-electrode stimulation.

Although asynchronous intrafascicular multi-electrode stimulation (IFMS) can evoke fatigue-resistant muscle force, a priori determination of the necessary stimulation parameters for precise force production is not possible. This paper presents a proportionally-modulated, multiple-input single-output (MISO) controller that was designed and experimentally validated for real-time, closed-loop force-feedback control of asynchronous IFMS. Experiments were conducted on anesthetized felines with a Utah Slanted Electrode Array implanted in the sciatic nerve, either acutely or chronically ( n = 1 for each). Isometric forces were evoked in plantar-flexor muscles, and target forces consisted of up to 7 min of step, sinusoidal, and more complex time-varying trajectories. The controller was successful in evoking steps in force with time-to-peak of less than 0.45 s, steady-state ripple of less than 7% of the mean steady-state force, and near-zero steady-state error even in the presence of muscle fatigue, but with transient overshoot of near 20%. The controller was also successful in evoking target sinusoidal and complex time-varying force trajectories with amplitude error of less than 0.5 N and time delay of approximately 300 ms. This MISO control strategy can potentially be used to develop closed-loop asynchronous IFMS controllers for a wide variety of multi-electrode stimulation applications to restore lost motor function.

Muscle-selective block using intrafascicular high-frequency alternating current.

High-frequency alternating current (HFAC) applied to a peripheral nerve can reversibly block skeletal muscle contractions. We evaluated the ability of HFAC delivered via intrafascicular electrodes to selectively block activation of targeted muscles without affecting activation of other muscles. Utah slanted electrode arrays (USEAs) were implanted into the sciatic nerves of five cats, and HFAC was delivered to individual USEA electrodes. The effects of HFAC block were monitored by recording evoked electromyograms (EMGs) and three-dimensional endpoint forces. In each animal, activity evoked in targeted muscles by nerve cuff stimulation could be selectively abolished by HFAC delivered via individual USEA electrodes. Two mechanisms of blockade were evoked: selective neuromuscular blocks were achieved with 500-8000-HZ HFAC, and selective nerve conduction block was achieved in one animal using 16-kHZ HFAC. These results show that intrafascicular HFAC can be used to block selected muscles independent of activation of other muscles.

Selective and graded recruitment of cat hamstring muscles with intrafascicular stimulation.

The muscles of the hamstring group can produce different combinations of hip and knee torque. Thus, the ability to activate the different hamstring muscles selectively is of particular importance in eliciting functional movements such as stance and gait in a person with spinal cord injury. We investigated the ability of intrafascicular stimulation of the muscular branch of the sciatic nerve to recruit the feline hamstring muscles in a selective and graded fashion. A Utah Slanted Electrode Array, consisting of 100 penetrating microelectrodes, was implanted into the muscular branch of the sciatic nerve in six cats. Muscle twitches were evoked in the three compartments of biceps femoris (anterior, middle, and posterior), as well as semitendinosus and semimembranosus, using pulse-width modulated constant-voltage pulses. The resultant compound muscle action potentials were recorded using intramuscular fine-wire electrodes. 74% of the electrodes per implant were able to evoke a threshold response in these muscles, and these electrodes were evenly distributed among the instrumented muscles. Of the five muscles instrumented, on average 2.5 could be selectively activated to 90% of maximum EMG, and 3.5 could be selectively activated to 50% of maximum EMG. The muscles were recruited selectively with a mean stimulus dynamic range of 4.14 +/- 5.05 dB between threshold and either spillover to another muscle or a plateau in the response. This selective and graded activation afforded by intrafascicular stimulation of the muscular branch of the sciatic nerve suggests that it is a potentially useful stimulation paradigm for eliciting distinct forces in the hamstring muscle group in motor neuroprosthetic applications.

Automated stimulus-response mapping of high-electrode-count neural implants.

Over the past decade, research in the field of functional electrical stimulation (FES) has led to a new generation of high-electrode-count (HEC) devices that offer increasingly selective access to neural populations. Incorporation of these devices into research and clinical applications, however, has been hampered by the lack of hardware and software platforms capable of taking full advantage of them. In this paper, we present the first generation of a closed-loop FES platform built specifically for HEC neural interface devices. The platform was designed to support a wide range of stimulus-response mapping and feedback-based control routines. It includes a central control module, a 1100-channel stimulator, an array of biometric devices, and a 160-channel data recording module. To demonstrate the unique capabilities of this platform, two automated software routines for mapping stimulus-response properties of implanted HEC devices were implemented and tested. The first routine determines stimulation levels that produce perithreshold muscle activity, and the second generates recruitment curves (as measured by peak impulse response). Both routines were tested on 100-electrode Utah Slanted Electrode Arrays (USEAs) implanted in cat hindlimb nerves using joint torque or emg as muscle output metric. Mean time to map perithreshold stimulus level was 16.4 s for electrodes that evoked responses (n = 3200), and 3.6 s for electrodes that did not evoke responses (n = 1800). Mean time to locate recruitment curve asymptote for an electrode (n = 155) was 9.6 s , and each point in the recruitment curve required 0.87 s. These results demonstrate the utility of our FES platform by showing that it can be used to completely automate a typically time- and effort-intensive procedure associated with using HEC devices.