Frequency Shapes the Quality of Tactile Percepts Evoked through Electrical Stimulation of the Nerves.

Electrical stimulation of the peripheral nerves of human participants provides a unique opportunity to study the neural determinants of perceptual quality using a causal manipulation. A major challenge in the study of neural coding of touch has been to isolate the role of spike timing-at the scale of milliseconds or tens of milliseconds-in shaping the sensory experience. In the present study, we address this question by systematically varying the pulse frequency (PF) of electrical stimulation pulse trains delivered to the peripheral nerves of seven participants with upper and lower extremity limb loss via chronically implanted neural interfaces. We find that increases in PF lead to systematic increases in perceived frequency, up to ∼50 Hz, at which point further changes in PF have little to no impact on sensory quality. Above this transition frequency, ratings of perceived frequency level off, the ability to discriminate changes in PF is abolished, and verbal descriptors selected to characterize the sensation change abruptly. We conclude that sensation quality is shaped by temporal patterns of neural activation, even if these patterns are imposed on a fixed neural population, but this temporal patterning can only be resolved up to ∼50 Hz. These findings highlight the importance of spike timing in shaping the quality of a sensation and will contribute to the development of encoding strategies for conveying touch feedback through bionic hands and feet.SIGNIFICANCE STATEMENT A major challenge in the study of neural coding of touch has been to understand how temporal patterns in neuronal responses shape the sensory experience. We address this question by varying the pulse frequency (PF) of electrical pulse trains delivered through implanted nerve interfaces in seven amputees. We concomitantly vary pulse width to separate the effect of changing PF on sensory quality from its effect on perceived magnitude. We find that increases in PF lead to increases in perceived frequency, a qualitative dimension, up to ∼50 Hz, beyond which changes in PF have little impact on quality. We conclude that temporal patterning in the neuronal response can shape quality and discuss the implications for restoring touch via neural interfaces.

Intracortical microstimulation of somatosensory cortex enables object identification through perceived sensations.

Advances in brain-machine interfaces have helped restore function and independence for individuals with sensorimotor deficits; however, providing efficient and effective sensory feedback remains challenging. Intracortical microstimulation (ICMS) of sensorimotor brain regions is a promising technique for providing bioinspired sensory feedback. In a human participant with chronically-implanted microelectrode arrays, we provided ICMS to the primary somatosensory cortex to generate tactile percepts in his hand. In a 3-choice object identification task, the participant identified virtual objects using tactile sensory feedback and no visual information. We evaluated three different stimulation paradigms, each with a different weighting of the grip force and its derivative, to explore the potential benefits of a more bioinspired stimulation strategy. In all paradigms, the participant's ability to identify the objects was above-chance, with object identification accuracy reaching 80% correct when using only sustained grip force feedback and 76.7% when using equal weighting of both sustained grip force and its derivative. These results demonstrate that bioinspired ICMS can provide sensory feedback that is functionally beneficial in sensorimotor tasks. Designing more efficient stimulation paradigms is important because it will allow us to 1) provide safer stimulation delivery methods that reduce overall injected charge without sacrificing function and 2) more effectively transmit sensory information to promote intuitive integration and usage by the human body.

Lower-Limb Amputees Adjust Quiet Stance in Response to Manipulations of Plantar Sensation.

Interfering with or temporarily eliminating foot-sole tactile sensations causes postural adjustments. Furthermore, individuals with impaired or missing foot-sole sensation, such as lower-limb amputees, exhibit greater postural instability than those with intact sensation. Our group has developed a method of providing tactile feedback sensations projected to the missing foot of lower-limb amputees via electrical peripheral nerve stimulation (PNS) using implanted nerve cuff electrodes. As a step toward effective implementation of the system in rehabilitation and everyday use, we compared postural adjustments made in response to tactile sensations on the missing foot elicited by our system, vibration on the intact foot-sole, and a control condition in which no additional sensory input was applied. Three transtibial amputees with at least a year of experience with tactile sensations provided by our PNS system participated in the study. Participants stood quietly with their eyes closed on their everyday prosthesis while electrically elicited, vibratory, or no additional sensory input was administered for 20 s. Early and steady-state postural adjustments were quantified by center of pressure location, path length, and average angle over the course of each trial. Electrically elicited tactile sensations and vibration both caused shifts in center of pressure location compared to the control condition. Initial (first 3 s) shifts in center of pressure location with electrically elicited or vibratory sensory inputs often differed from shifts measured over the full 20 s trial. Over the full trial, participants generally shifted toward the foot receiving additional sensory input, regardless of stimulation type. Similarities between responses to electrically elicited tactile sensations projected to the missing foot and responses to vibration in analogous regions on the intact foot suggest that the motor control system treats electrically elicited tactile inputs similarly to native tactile inputs. The ability of electrically elicited tactile inputs to cause postural adjustments suggests that these inputs are incorporated into sensorimotor control, despite arising from artificial nerve stimulation. These results are encouraging for application of neural stimulation in restoring missing sensory feedback after limb loss and suggest PNS could provide an alternate method to perturb foot-sole tactile information for investigating integration of tactile feedback with other sensory modalities.

Ambulatory searching task reveals importance of somatosensation for lower-limb amputees.

The contribution of somatosensation to locomotor deficits in below-knee amputees (BKAs) has not been fully explored. Unilateral disruption of plantar sensation causes able-bodied individuals to adopt locomotor characteristics that resemble those of unilateral BKAs, suggesting that restoring somatosensation may improve locomotion for amputees. In prior studies, we demonstrated that electrically stimulating the residual nerves of amputees elicited somatosensory percepts that were felt as occurring in the missing foot. Subsequently, we developed a sensory neuroprosthesis that modulated stimulation-evoked sensation in response to interactions between the prosthesis and the environment. To characterize the impact of the sensory neuroprosthesis on locomotion, we created a novel ambulatory searching task. The task involved walking on a horizontal ladder while blindfolded, which engaged plantar sensation while minimizing visual compensation. We first compared the performance of six BKAs to 14 able-bodied controls. Able-bodied individuals demonstrated higher foot placement accuracy than BKAs, indicating that the ladder test was sensitive enough to detect locomotor deficits. When three of the original six BKAs used the sensory neuroprosthesis, the tradeoff between speed and accuracy significantly improved for two of them. This study advanced our understanding of how cutaneous plantar sensation can be used to acquire action-related information during challenging locomotor tasks.

Sensory neuroprosthesis improves postural stability during Sensory Organization Test in lower-limb amputees.

To maintain postural stability, unilateral lower-limb amputees (LLAs) heavily rely on visual and vestibular inputs, and somatosensory cues from their intact leg to compensate for missing somatosensory information from the amputated limb. When any of these resources are compromised, LLAs exhibit poor balance control compared to able-bodied individuals. We hypothesized that restoring somatosensation related to the missing limb via direct activation of the sensory nerves in the residuum would improve the standing stability of LLAs. We developed a closed-loop sensory neuroprosthesis utilizing non-penetrating multi-contact cuff electrodes implanted around the residual nerves to elicit perceptions of the location and intensity of plantar pressures under the prosthetic feet of two transtibial amputees. Effects of the sensory neuroprosthesis on balance were quantified with the Sensory Organization Test and other posturographic measures of sway. In both participants, the sensory neuroprosthesis improved equilibrium and sway when somatosensation from the intact leg and visual inputs were perturbed simultaneously. One participant also showed improvement with the sensory neuroprosthesis whenever somatosensation in the intact leg was compromised via perturbations of the platform. These observations suggest the sensory feedback elicited by neural stimulation can significantly improve the standing stability of LLAs, particularly when other sensory inputs are depleted or otherwise compromised.

A translational framework for peripheral nerve stimulating electrodes: Reviewing the journey from concept to clinic.

The purpose of this review article is to describe the underlying methodology for successfully translating novel interfaces for electrical modulation of the peripheral nervous system (PNS) from basic design concepts to clinical applications and chronic human use. Despite advances in technologies to communicate directly with the nervous system, the pathway to clinical translation for most neural interfaces is not clear. FDA guidelines provide information on necessary evidence which should be generated and submitted to allow the agency evaluate safety and efficacy of a new medical device. However, a knowledge gap exists on translating neural interfaces from pre-clinical studies into the clinical domain. Our article is intended to inform the field on some of the key considerations for such a transition process specific to neural interfaces that may not be already covered by FDA guidances. This framework focuses on non-penetrating peripheral nerve stimulating electrodes that have been proven effective for motor and sensory neural prostheses and successfully transitioned from pre-clinical through first-in-human and chronic clinical deployment. We discuss the challenges of moving these neural interfaces along the translational continuum and ultimately through FDA approval for human feasibility studies. Specifically, we describe a translational process involving: quantitative human anatomy, neural modeling and simulation, acute intraoperative testing and verification, clinical demonstration with temporary percutaneous access, and finally chronic clinical deployment and functional performance. To clarify and demonstrate the importance of each step of this translational framework, we present case studies from electrodes developed at Case Western Reserve University (CWRU), specifically the spiral cuff, the Flat Interface Nerve Electrode (FINE), and the Composite FINE (C-FINE). In addition, we demonstrate that success along this translational pathway can be further expedited by: appropriate selection of well-characterized materials, validation of fabrication and sterilization protocols, well-implemented quality control measures, and quantification of impact on neural structure, health, and function. The issues and approaches identified in this review for the peripheral nervous system may also serve to accelerate the dissemination of any new neural interface into clinical practice, and consequently advance the performance, utility, and clinical value of new neural prostheses or neuromodulation systems.

Visual inputs and postural manipulations affect the location of somatosensory percepts elicited by electrical stimulation.

The perception of somatosensation requires the integration of multimodal information, yet the effects of vision and posture on somatosensory percepts elicited by neural stimulation are not well established. In this study, we applied electrical stimulation directly to the residual nerves of trans-tibial amputees to elicit sensations referred to their missing feet. We evaluated the influence of congruent and incongruent visual inputs and postural manipulations on the perceived size and location of stimulation-evoked somatosensory percepts. We found that although standing upright may cause percept size to change, congruent visual inputs and/or body posture resulted in better localization. We also observed visual capture: the location of a somatosensory percept shifted toward a visual input when vision was incongruent with stimulation-induced sensation. Visual capture did not occur when an adopted posture was incongruent with somatosensation. Our results suggest that internal model predictions based on postural manipulations reinforce perceived sensations, but do not alter them. These characterizations of multisensory integration are important for the development of somatosensory-enabled prostheses because current neural stimulation paradigms cannot replicate the afferent signals of natural tactile stimuli. Nevertheless, multisensory inputs can improve perceptual precision and highlight regions of the foot important for balance and locomotion.

Visuotactile synchrony of stimulation-induced sensation and natural somatosensation.

OBJECTIVE: Previous studies suggest that somatosensory feedback has the potential to improve the functional performance of prostheses, reduce phantom pain, and enhance embodiment of sensory-enabled prosthetic devices. To maximize such benefits for amputees, the temporal properties of the sensory feedback must resemble those of natural somatosensation in an intact limb. APPROACH: To better understand temporal perception of artificial sensation, we characterized the perception of visuotactile synchrony for tactile perception restored via peripheral nerve stimulation. We electrically activated nerves in the residual limbs of two trans-tibial amputees and two trans-radial amputees via non-penetrating nerve cuff electrodes, which elicited sensations referred to the missing limbs. MAIN RESULTS: Our findings suggest that with respect to vision, stimulation-induced sensation has a point of subjective simultaneity (PSS; processing time) and just noticeable difference (JND; temporal sensitivity) that are similar to natural touch. The JND was not significantly different between the participants with upper- and lower-limb amputations. However, the PSS indicated that sensations evoked in the missing leg must occur significantly earlier than those in the hand to be perceived as maximally synchronous with vision. Furthermore, we examined visuotactile synchrony in the context of a functional task during which stimulation was triggered by pressure applied to the prosthesis. Stimulation-induced sensation could be delayed up to 111 ± 62 ms without the delay being reliably detected. SIGNIFICANCE: The quantitative temporal properties of stimulation-induced perception were previously unknown and will contribute to design specifications for future sensory neuroprostheses.

"Long-term stability of stimulating spiral nerve cuff electrodes on human peripheral nerves".

BACKGROUND: Electrical stimulation of the peripheral nerves has been shown to be effective in restoring sensory and motor functions in the lower and upper extremities. This neural stimulation can be applied via non-penetrating spiral nerve cuff electrodes, though minimal information has been published regarding their long-term performance for multiple years after implantation. METHODS: Since 2005, 14 human volunteers with cervical or thoracic spinal cord injuries, or upper limb amputation, were chronically implanted with a total of 50 spiral nerve cuff electrodes on 10 different nerves (mean time post-implant 6.7 ± 3.1 years). The primary outcome measures utilized in this study were muscle recruitment curves, charge thresholds, and percent overlap of recruited motor unit populations. RESULTS: In the eight recipients still actively involved in research studies, 44/45 of the spiral contacts were still functional. In four participants regularly studied over the course of 1 month to 10.4 years, the charge thresholds of the majority of individual contacts remained stable over time. The four participants with spiral cuffs on their femoral nerves were all able to generate sufficient moment to keep the knees locked during standing after 2-4.5 years. The dorsiflexion moment produced by all four fibular nerve cuffs in the active participants exceeded the value required to prevent foot drop, but no tibial nerve cuffs were able to meet the plantarflexion moment that occurs during push-off at a normal walking speed. The selectivity of two multi-contact spiral cuffs was examined and both were still highly selective for different motor unit populations for up to 6.3 years after implantation. CONCLUSIONS: The spiral nerve cuffs examined remain functional in motor and sensory neuroprostheses for 2-11 years after implantation. They exhibit stable charge thresholds, clinically relevant recruitment properties, and functional muscle selectivity. Non-penetrating spiral nerve cuff electrodes appear to be a suitable option for long-term clinical use on human peripheral nerves in implanted neuroprostheses.

Approaches to a cortical vision prosthesis: implications of electrode size and placement.

OBJECTIVE: In order to move forward with the development of a cortical vision prosthesis, the critical issues in the field must be identified. APPROACH: To begin this process, we performed a brief review of several different cortical and retinal stimulation techniques that can be used to restore vision. MAIN RESULTS: Intracortical microelectrodes and epicortical macroelectrodes have been evaluated as the basis of a vision prosthesis. We concluded that an important knowledge gap necessitates an experimental in vivo performance evaluation of microelectrodes placed on the surface of the visual cortex. A comparison of the level of vision restored by intracortical versus epicortical microstimulation is necessary. Because foveal representation in the primary visual cortex involves more cortical columns per degree of visual field than does peripheral vision, restoration of foveal vision may require a large number of closely spaced microelectrodes. Based on previous studies of epicortical macrostimulation, it is possible that stimulation via surface microelectrodes could produce a lower spatial resolution, making them better suited for restoring peripheral vision. SIGNIFICANCE: The validation of epicortical microstimulation in addition to the comparison of epicortical and intracortical approaches for vision restoration will fill an important knowledge gap and may have important implications for surgical strategies and device longevity. It is possible that the best approach to vision restoration will utilize both epicortical and intracortical microstimulation approaches, applying them appropriately to different visual representations in the primary visual cortex.

Surveying the interest of individuals with upper limb loss in novel prosthetic control techniques.

BACKGROUND: Novel techniques for the control of upper limb prostheses may allow users to operate more complex prostheses than those that are currently available. Because many of these techniques are surgically invasive, it is important to understand whether individuals with upper limb loss would accept the associated risks in order to use a prosthesis. METHODS: An online survey of individuals with upper limb loss was conducted. Participants read descriptions of four prosthetic control techniques. One technique was noninvasive (myoelectric) and three were invasive (targeted muscle reinnervation, peripheral nerve interfaces, cortical interfaces). Participants rated how likely they were to try each technique if it offered each of six different functional features. They also rated their general interest in each of the six features. A two-way repeated measures analysis of variance with Greenhouse-Geisser corrections was used to examine the effect of the technique type and feature on participants' interest in each technique. RESULTS: Responses from 104 individuals were analyzed. Many participants were interested in trying the techniques - 83 % responded positively toward myoelectric control, 63 % toward targeted muscle reinnervation, 68 % toward peripheral nerve interfaces, and 39 % toward cortical interfaces. Common concerns about myoelectric control were weight, cost, durability, and difficulty of use, while the most common concern about the invasive techniques was surgical risk. Participants expressed greatest interest in basic prosthesis features (e.g., opening and closing the hand slowly), as opposed to advanced features like fine motor control and touch sensation. CONCLUSIONS: The results of these investigations may be used to inform the development of future prosthetic technologies that are appealing to individuals with upper limb loss.

Comparison of spike sorting and thresholding of voltage waveforms for intracortical brain-machine interface performance.

OBJECTIVE: For intracortical brain-machine interfaces (BMIs), action potential voltage waveforms are often sorted to separate out individual neurons. If these neurons contain independent tuning information, this process could increase BMI performance. However, the sorting of action potentials ('spikes') requires high sampling rates and is computationally expensive. To explicitly define the difference between spike sorting and alternative methods, we quantified BMI decoder performance when using threshold-crossing events versus sorted action potentials. APPROACH: We used data sets from 58 experimental sessions from two rhesus macaques implanted with Utah arrays. Data were recorded while the animals performed a center-out reaching task with seven different angles. For spike sorting, neural signals were sorted into individual units by using a mixture of Gaussians to cluster the first four principal components of the waveforms. For thresholding events, spikes that simply crossed a set threshold were retained. We decoded the data offline using both a Naïve Bayes classifier for reaching direction and a linear regression to evaluate hand position. MAIN RESULTS: We found the highest performance for thresholding when placing a threshold between -3 and -4.5 × Vrms. Spike sorted data outperformed thresholded data for one animal but not the other. The mean Naïve Bayes classification accuracy for sorted data was 88.5% and changed by 5% on average when data were thresholded. The mean correlation coefficient for sorted data was 0.92, and changed by 0.015 on average when thresholded. SIGNIFICANCE: For prosthetics applications, these results imply that when thresholding is used instead of spike sorting, only a small amount of performance may be lost. The utilization of threshold-crossing events may significantly extend the lifetime of a device because these events are often still detectable once single neurons are no longer isolated.