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Toward the Bionic Face

A Novel Neuroprosthetic Device Paradigm for Facial Reanimation Consisting of Neural Blockade and Functional Electrical Stimulation

Jowett, Nate, M.D.; Kearney, Robert E., Ph.D.; Knox, Christopher J., B.S.; Hadlock, Tessa A., M.D.

Plastic and Reconstructive Surgery: January 2019 - Volume 143 - Issue 1 - p 62e–76e
doi: 10.1097/PRS.0000000000005164
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Background: Facial palsy is a devastating condition potentially amenable to rehabilitation by functional electrical stimulation. Herein, a novel paradigm for unilateral facial reanimation using an implantable neuroprosthetic device is proposed and its feasibility demonstrated in a live rodent model. The paradigm comprises use of healthy-side electromyographic activity as control inputs to a system whose outputs are neural stimuli to effect symmetric facial displacements. The vexing issue of suppressing undesirable activity resulting from aberrant neural regeneration (synkinesis) or nerve transfer procedures is addressed using proximal neural blockade.

Methods: Epimysial and nerve cuff electrode arrays were implanted in the faces of Wistar rats. Stimuli were delivered to evoke blinks and whisks of various durations and amplitudes. The dynamic relation between electromyographic signals and facial displacements was modeled, and model predictions were compared against measured displacements. Optimal parameters to achieve facial nerve blockade by means of high-frequency alternating current were determined, and the safety of continuous delivery was assessed.

Results: Electrode implantation was well tolerated. Blinks and whisks of tunable amplitudes and durations were evoked by controlled variation of neural stimuli parameters. Facial displacements predicted from electromyographic input modelling matched those observed with a variance-accounted-for exceeding 96 percent. Effective and reversible facial nerve blockade in awake behaving animals was achieved, without detrimental effect noted from long-term continual use.

Conclusions: Proof-of-principle of rehabilitation of hemifacial palsy by means of a neuroprosthetic device has been demonstrated. The use of proximal neural blockade coupled with distal functional electrical stimulation may have relevance to rehabilitation of other peripheral motor nerve deficits.

Boston, Mass.; and Montreal, Quebec, Canada

From the Massachusetts Eye and Ear Infirmary, Harvard Medical School, the Department of Otolaryngology, Surgical Photonics & Engineering Laboratory; and the Department of Biomedical Engineering, McGill University.

Received for publication December 21, 2017; accepted May 3, 2018.

Presented in part at the 2016 Annual Meeting of the American Society for Peripheral Nerve, in Scottsdale, Arizona, January 15 through 17, 2016.

Disclosure: Dr. Jowett and Dr. Hadlock hold a patent on the methods and systems described herein (WO2017124019A1).

Supplemental digital content is available for this article. Direct URL citations appear in the text; simply type the URL address into any Web browser to access this content. Clickable links to the material are provided in the HTML text of this article on the Journal’s website (www.PRSJournal.com).

A “Hot Topic Video” by Editor-in-Chief Rod J. Rohrich, M.D., accompanies this article. Go to PRSJournal.com and click on “Plastic Surgery Hot Topics” in the “Digital Media” tab to watch.

Nate Jowett, M.D., Massachusetts Eye and Ear Infirmary and, Harvard Medical School, 243 Charles Street, Boston, Mass. 02114, nate_jowett@meei.harvard.edu

Facial palsy is a devastating clinical condition with functional, aesthetic, and communication sequelae,1–18 whose ultimate clinical course yields flaccid hemifacial paralysis (Fig. 1, left), postparalytic facial palsy (Fig. 1, right), or combinations thereof. Dynamic reanimation in hemifacial palsy is principally limited to smile restoration through nerve or functional muscle transfers. Commonly, smile is reanimated using nonemotional trigeminal motor tracts requiring a conscious bite effort that provides volitional but nonspontaneous smile, together with undesired prandial activation. Reanimation outcomes are further limited in that no approach to dynamic restoration of brow elevation, blink, lip pucker, or lower lip movement has achieved consistent success.

Fig. 1

Fig. 1

Heretofore, the most significant barrier to more effective facial reanimation strategies in both flaccid and postparalytic facial palsy settings has been a lack of effective control mechanisms for denervated or aberrantly reinnervated facial muscles. Recent technological advances in signal-processing techniques, implantable neural and muscular electrodes, and implantable application-specific integrated circuits have led to remarkable breakthroughs in the design and control of prosthetic limbs, devices to restore hearing and other senses, devices to aid gait in the setting of central nervous system disorders, and devices to treat obstructive sleep apnea.19–26 This article presents a novel implantable neuroprosthetic device paradigm for functional electrical stimulation reanimation of the hemiparetic face (Fig. 2). This paradigm addresses not only the challenge of evoking appropriate facial movements, but also the vexing issue of suppressing undesirable facial activity resulting from aberrant neural regeneration or nerve transfer procedures. The system uses healthy-side electromyography signals as the control inputs to a neuroprosthetic device, whose outputs stimulate nerve branches on the paretic side to effect paired muscle contraction (Fig. 3); concurrently applied high-frequency alternating current stimulation provides proximal neural blockade to prevent undesired physiologic muscle activation. Proof-of-principle of this paradigm is demonstrated in a rodent facial nerve model in a series of experiments, whereby implanted nerve cuff electrodes and epimysial electrode arrays are used to deliver neural stimuli and capture facial muscle electromyographic activity.

Fig. 2

Fig. 2

Fig. 3

Fig. 3

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MATERIALS AND METHODS

Overall Approach

A three-part series of experiments was performed (Table 1) using a rodent facial nerve model.27–38 Rat blink was used as a surrogate for human blink, and rat whisking (that occurs at different frequencies and amplitudes) was used as a surrogate for continuous proportional control of human facial muscle contractions responsible for movements such as smile or brow elevation. Implanted epimysial electrode arrays were used to record healthy-side facial muscle activity, and nerve cuff electrodes were used to deliver proximal neural blockade and distal stimulatory signals. Long-term tolerance of implanted electrodes and quality of electromyographic recordings were assessed, and the capacity to evoke facial displacements of varying amplitudes and durations was evaluated. Dynamic relationships between electromyographic activity recorded from rat facial muscles and facial movements were modeled. Optimal neural blockade signal parameters to prevent synkinetic neuronal discharge while permitting distal branch functional electrical stimulation were determined. The safety of continual delivery of high-frequency alternating current to the facial nerve was assessed over the long term.

Table 1

Table 1

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Part 1: Establishment of a Rodent Model for Functional Electrical Stimulation of the Facial Nerve

Head Fixation and Conditioning

Ten female Wistar rats, 200 to 250 g, had titanium head fixation devices implanted and were conditioned to head fixation testing as described previously.28–46 Briefly, rats were trained daily for 2 weeks to acclimate to handling and restraint. Head fixation devices were then implanted under general anesthesia using ketamine hydrochloride (60 mg/kg) and dexmedetomidine hydrochloride (0.5 mg/kg) through a midline scalp incision. A subperiosteal plane was developed over the calvaria, the sterilized implant was secured to the calvaria using titanium screws, and the incision was closed in a single layer (Fig. 4, left). Daily head restraint training began 2 weeks later until animals tolerated 10-minute-long sessions. A customized resin top-hat enclosure to house the distal ends of electrode leads with their connectors was fabricated and secured to the head fixation device (Fig. 4, right). This enclosure provided protection and ease of access for subsequent recording and stimulation experiments.

Fig. 4

Fig. 4

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Electrode Implantation

Once conditioned, electrodes were implanted into the animals during a second procedure under general anesthesia. A 1-cm incision was made in the left cheek and flaps elevated immediately superior to the plane of the facial nerve. In five animals (group 1a), nerve cuff electrodes (custom bipolar design; MicroProbes for Life Science, Gaithersburg, Md.) (Fig. 5, above) were implanted around intact and meticulously dissected zygomatic and buccal branches of the facial nerve. In five other animals (group 1b), blunt dissection was carried deep to the center of the whisker pad musculature for epimysial electrode array positioning (custom bipolar design; Ripple LLC, Salt Lake City, Utah) (Fig. 5, below) concurrent with nerve cuff electrode placement around the buccal branch of the facial nerve. Electrodes were secured to the deep facial fascia overlying the masseter muscle using 5-0 polypropylene sutures, with leads tunneled in the subcutaneous plane to exit the skin over the occiput. Lead terminals were soldered to a pin connector (A11365-001; Omnetics Connector Corp, Minneapolis, Minn.) and housed in the customized top-hat enclosure (Figs. 4, right, and 6).

Fig. 5

Fig. 5

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Quantitative Whisker and Eyelid Displacement Recording

The hardware and software used for monitoring whisking movements was adapted from Bermejo et al.28–33 , 47 A single whisker (C-1) on each side of the head was entubulated using a polyacrylamide tube to increase detectability. Whisker displacements were then independently tracked using commercial laser micrometer pairs (MetraLight, Santa Mateo, Calif.). Blinks were detected using infrared sensors to measure light reflectivity from the cornea and eyelids as described by Thompson et al.48 Computer-controlled air valves were used to deliver corneal air puffs and scented air flows to elicit blink and whisking behavior, respectively.

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Evoked Stimuli

While under general anesthesia, animals in group 1a received varying neural stimuli to zygomatic and buccal branch nerve cuff electrodes, with concurrent tracking of blink and whisker displacements. Animals in group 1b received neural stimuli to the buccal branch nerve cuff electrode with concurrent capture of whisker pad electromyographic responses from implanted epimysial electrode arrays. A commercial electrophysiology system (CyberAmp 380 signal conditioner, Digidata 1322A digitizer, pCLAMP 10 software; Molecular Devices, Sunnyvale, Calif.) combined with analogue stimulus isolator units (Analog Stimulus Isolator Model 2200; ADInstruments, Colorado Springs, Colo.) were used for stimulation and electromyographic signal acquisition. Neural stimuli comprised trains of current-controlled, charge-balanced, square-wave pulses (pulse width, 0.4 msec; train durations, 0.4 to 100 msec; repetition rates, 1 to 2 Hz; peak-to-peak amplitudes, 0.1 to 2 mA). Electromyographic signals were measured with a differential amplifier with a prefilter gain of 10, high-pass filter at 10 Hz, low-pass filter at 1000 Hz, notch filter at 60 Hz, and postfilter gain of 100. Electromyographic signals were then sampled at 10 kHz with 16-bit resolution, concurrent with whisker and blink displacement signals.

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Part 2: Establishing Feasibility of Epimysial Electromyography as Functional Electrical Stimulation Control

Modeling of Electromyographic Activity to Whisker Displacement

In this study, the healthy-side electromyography activity of the whisker pad musculature, as captured using implanted epimysial electrode arrays, were used as inputs and the resulting whisker displacements as the output. Animals from group 1b above were placed under general anesthesia, and fixed stimuli were delivered to the buccal branch nerve cuff electrode (constant-current, charge-balanced, square-wave, peak-to-peak stimuli, 0.5 mA; pulse width, 0.4 msec; train width 1.2 msec; repetition rate, 1 Hz). The resulting whisker pad electromyographic responses and C-1 whisker displacements were measured. Methods for Hammerstein system identification described by Jalaleddini and Kearney49 , 50 were used to identify models relating recorded electromyographic signals to measured whisker displacements in MATLAB (v2015b; The MathWorks, Inc., Natick, Mass.). Muscle was treated as a nonlinear biological system where the relation between neural activation and force was modeled as the cascade of a static nonlinearity followed by a dynamic linear system51 , 52 (Fig. 3, above).

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Part 3: Establishing Neural Blockade Effectiveness and Safety

Determination of Optimal High-Frequency Alternating Current Parameters and Efficacy

Three animals were implanted with three nerve cuff electrodes on the left buccal branch of the facial nerve, and the animal were placed in a laser micrometer field to track evoked whisker displacements. Cathodic pulses from a pulse generator (S88; Grass Instruments, Astro-Med, Inc., West Warwick, R.I.) coupled to stimulus isolators to achieve biphasic constant-current pulses (0.5 mA, 50-µsec pulse width) were delivered to proximal (at 1 Hz) and distal (at 1.5 Hz) nerve cuff electrodes. High-frequency alternating current (constant-voltage sine wave) was delivered to the central nerve cuff electrode using a function generator (FG085 Kit; JYE Tech, Guilin, Guangxi, People’s Republic of China). The peak-to-peak amplitudes (0 to 10 V) and frequency (2 to 40 kHz) were varied to determine optimal blockade parameters. Two further animals, with head fixation devices implanted and conditioned to head fixation as described above, were implanted with nerve cuff electrodes to the buccal branch and zygomatic branches on the left side. Animals were placed in head fixation for quantitative tracking of awake behavioral whisking, with concurrent application of high-frequency alternating current and distal functional electrical stimulation neural stimuli to generate whisks and blinks.

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Establishing Safety of Continuous High-Frequency Alternating Current Delivery

Once optimal high-frequency alternating current parameters were identified, five animals underwent head fixation device implantation and restraint training, followed by single bipolar nerve cuff electrode implantation to the buccal branch of the left facial nerve. The marginal mandibular branch was resected bilaterally to eliminate its contribution to whisking. Beginning 1 week after nerve cuff electrode implantation, high-frequency alternating current was delivered continuously for 4 hours, 5 days per week, for 2 weeks (total, 40 hours) under general anesthesia. Three-minute sessions of awake behavioral whisking assessment were recorded at baseline, after nerve cuff electrode implantation, and preceding each high-frequency alternating current delivery session. The ratio of the whisking amplitudes between high-frequency alternating current–blocked and –nonblocked sides was tracked for each animal over time.

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RESULTS

Part 1: Establishment of a Rodent Model for Functional Electrical Stimulation of the Facial Nerve

Animals tolerated top-hat enclosures and electrode implantations for periods exceeding 40 days before scheduled euthanasia, without infection or marked foreign-body reaction despite the subcutaneous exit point of the electrode leads atop the head (See Video, Supplemental Digital Content 1, which demonstrates a free-roaming rat with implanted electrodes. Electrodes were positioned on facial nerve branches and musculature as demonstrated in Fig. 6, with leads tunneled subcutaneously to exit the skin atop the cranium and secured within a resin enclosure bolted to a percutaneous osseointegrated titanium cranial plate, as shown in Fig. 4, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, available at http://links.lww.com/PRS/D167.) Robust evoked epimysial electromyographic responses were recorded from the implanted epimysial electrodes, with excellent signal-to-noise ratios (Fig. 7, left) throughout this time. Electrical stimulation evoked blinks of varying durations and whisks of varying amplitudes in all nerve cuff electrode–implanted animals (Fig. 7, right). (See Video, Supplemental Digital Content 2, which demonstrates evoked blink and whisk in a live anesthetized rat by means of electrical stimulation of specific facial nerve branches by means of implanted nerve cuff electrodes. Nerve cuff electrodes were positioned around intact zygomatic and buccal branches of the facial nerve, as demonstrated in Fig. 6, left, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, available at http://links.lww.com/PRS/D168.]

Video 1

Video 1

Fig. 6

Fig. 6

Fig. 7

Fig. 7

Video 2

Video 2

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Part 2: Establishing Feasibility of Epimysial Electromyography as Functional Electrical Stimulation Control

Hammerstein modeling of the relation between epimysial electromyography signals (obtained from the undersurface of the whisker pad musculature) to evoked whisk movement demonstrated excellent predictive capacity (Fig. 8), with the model accounting for more than 96 percent of the variance in whisker displacements.

Fig. 8

Fig. 8

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Part 3: Establishing Neural Blockade Effectiveness and Safety

A 30-kHz sine wave with a peak-to-peak amplitude of 5 V was found to be optimal for inducing blockade of evoked and spontaneous whisking activity in the rat using the customized nerve cuff electrode. In anesthetized animals, this achieved an approximately 90 percent reduction in evoked whisking amplitude, without restriction of distal neuromuscular excitability (Fig. 9, left and center). In awake animals, a similar reduction in behavioral whisking power was observed between blocked and normal sides with high-frequency alternating current application (Fig. 9, right). (See Video, Supplemental Digital Content 3, which demonstrates neural blockade of physiologic whisking activity in the live awake rat, with concurrent electrical stimulation to evoke blink and whisk by means of implanted nerve cuff electrodes. Nerve cuff electrodes were positioned around intact zygomatic and buccal branches of the facial nerve, as demonstrated in Fig. 6, left. Neural blockade was achieved by delivery of high-frequency alternating current, as demonstrated in Fig. 9, center, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, available at http://links.lww.com/PRS/D169.) No differences were observed in whisking amplitudes between sides with prolonged unilateral daily delivery of high-frequency alternating current (Fig. 10). Full results of this series of experiments will be reported in more detail in subsequent publications.

Fig. 9

Fig. 9

Video 3

Video 3

Fig. 10

Fig. 10

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DISCUSSION

Although the basic concept of using signals from the contralateral face to drive functional electrical stimulation of paralyzed facial muscles has been demonstrated,53–63 prior work has not addressed critical issues relevant to the long-term implementation of this approach. Optimal functional electrical stimulation of dysfunctional muscle requires three conditions: muscle must be neurotized, capable of being stimulated in purposeful and timely fashion, and devoid of undesirable activity. Neurotization of muscle prevents denervation atrophy and permits functional electrical stimulation through neural stimulation without the need for direct muscle stimulation. Although direct muscle stimulation of denervated muscle may prevent atrophy, it requires delivery of high and potentially injurious stimulus amplitudes to evoke contractions.64–66 Such an approach is not feasible in the setting of facial palsy because of excessive power demands on an implanted neuroprosthetic device, coupled with regional nociceptive fiber activation that would result from the delivery of high stimulus amplitudes. In the setting of facial palsy, neurotization of facial muscles may occur spontaneously following neural insult, through interposition graft repair or through nerve transfer. In cases of longstanding or congenital facial palsy, dynamic facial reanimation may be achieved by functional muscle transfer. Here, we propose that muscle contraction be evoked through stimulation of distal native facial nerve branches (or transferred nerves) using electrically shielded nerve cuff electrodes. Such distal facial nerve branches to individual paired muscles or functional muscle groups of the face are straightforward to access surgically. Likewise, in cases where nerve or muscle transfers are required for dynamic reanimation, nerve branches to the target muscle are readily accessible for cuff implantation at the time of reanimation surgery or during future reexploration.

Dynamic reanimation of muscle requires an adequate control signal to effect desired movements at appropriate times. Use of myoelectric activity to reliably drive neuroprostheses has already been demonstrated.67 , 68 In this article, we have demonstrated that electromyography signals from contralateral, healthy facial muscles may be used as control signals to drive functional electrical stimulation of the paretic hemiface. In this study, electromyographic activity was captured through the use of implanted epimysial electrode arrays, obviating the need for external sensors, and a clear mathematical relationship capable of predicting facial displacements from electromyographic inputs was demonstrated. Use of the contralateral healthy hemiface for dynamic reanimation of unilateral facial paralysis is a natural choice, as the majority of—especially positive expressions—are symmetric.69 The neuroprosthetic device proposed in this study could evoke paired-muscle contraction without a conspicuous phase delay in movement onset between sides. Modern implantable application-specific integrated circuits achieve delays of 5 msec or better on signal receiving and stimulus transmitting arms, with submillisecond processing times for most functional electrical stimulation applications. When coupled with typical delays on the order of 10 msec for physiologic transduction of the neural stimulus to effect myocyte depolarization, the maximum expected delay between healthy-side detected electromyographic activity (and subsequent muscular contraction) and paretic-side neural stimulation is on the order of 20 msec, below the approximately 33-msec threshold above which humans are able to detect asymmetric movement.70 , 71

Although stimulation of desirable muscle activity is necessary for functional reanimation, concurrent inhibition of undesirable neural activity is often just as important. No prior work has addressed the vexing issue of how to prevent undesirable muscle activation from aberrantly regenerated axons (i.e., in the case of aberrantly regenerated native facial nerve) or from the normal functioning of transferred cranial nerves (e.g., prandial activation of muscle innervated by transfer of the masseteric branch of the trigeminal nerve). In this article, we describe for the first time the use of concurrent proximal application of high-frequency alternating current over prolonged periods to prevent such undesired facial contractions. Delivery of high-frequency alternating current to peripheral nerve trunks results in reversible induction of localized blockade of propagating action potentials, without impeding distal neuromuscular excitability72–83; proximal application of high-frequency alternating current to a motor nerve squelches physiologic activity and maintains the capacity for distal functional electrical stimulation. Although there exists brief tetanic onset and offset responses with high-frequency alternating current application,72 , 75 , 84 such repeated responses would be avoided through continual proximal delivery of high-frequency alternating current during waking hours concurrent with distal functional electrical stimulation to drive expression. The device could also be implemented in “functional electrical stimulation–only” mode to allow physiologic action potentials to pass concurrent with evoked potentials, or “neural blockade–only” mode to induce targeted flaccidity.

In contrast to a recent publication,58 the novelty of the work described in this article lies in (1) use of clinically relevant biocompatible epimysial electrodes to capture electromyography signals as opposed to transdermal wires, (2) use of clinically relevant implantable neural cuffs to evoke facial displacements through neural as opposed to direct muscle stimulation by means of transdermal wires, (3) characterization of a mathematical model capable of predicting whisker displacements from electromyography signals as opposed to correlation of signal envelopes, (4) recognition of the clinically vexing issue of undesirable physiologic neural activity that occurs with aberrantly innervated muscle, and (5) proposing and demonstrating the long-term efficacy of proximal high-frequency alternating current application concurrent with distal functional electrical stimulation as a solution. Although the ultimate goal of reanimation is to restore dynamic function of the entire facial musculature, restoration of three symmetric facial movements alone—brow elevation, blink, and smile—would dramatically improve clinical outcomes. Such an approach would require implantation of only three miniature epimysial electrode arrays and nerve cuff electrodes coupled to an implanted application-specific integrated circuit, and would represent a paradigm shift in management. The proposed neuroprosthetic device could also be readily used in patients undergoing, or who have previously undergone, successful trigeminal nerve–driven smile reanimation to reestablish spontaneity. In this realization, smile activation—resulting from the contraction of transferred free functional muscle or native facial musculature driven by the nerve to the masseter—could be controlled through electromyography signals from healthy side zygomaticus major activity through the functional electrical stimulation paradigm proposed in this article, with elimination of highly undesirable prandial activation through proximal high-frequency alternating current neural blockade (Fig. 11). Similar to cochlear implant programming, stimulation parameters could be tuned wirelessly as innervation and tissue response to implanted electrodes reach a steady state.

Fig. 11

Fig. 11

This work has demonstrated the feasibility of using epimysial electromyography signals from healthy-side facial musculature captured using biocompatible and fully implantable miniature electrodes as a means for control of a functional electrical stimulation paradigm to drive reanimation of symmetric expression in hemifacial palsy. The capacity to effect independent facial movements of varied duration and amplitudes by means of functional electrical stimulation of distal facial nerve branches was established. Importantly, the efficacy and safety of proximal neural blockade by means of continuous high-frequency alternating current delivery as a means of extinguishing undesirable facial muscle activity arising from the intrinsic activity of damaged or transferred nerves have been proposed and demonstrated.

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CONCLUSIONS

The combination of proximal high-frequency alternating current with distal functional electrical stimulation to achieve total extrinsic control over a motor nerve has clinical implications elsewhere where undesirable activity of a peripheral nerve resulting from disease, injury, or nerve transfer exists. Future work will seek to study this paradigm over the long term using a fully implantable, miniaturized, application-specific integrated circuit currently under development. Beyond functional electrical stimulation applications, application of high-frequency alternating current to peripheral nerves might ultimately prove efficacious for management of spastic disorders and painful neuropathies, as focal blockade of action potential propagation occurs for efferent and afferent pathways.85

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ACKNOWLEDGMENT

This study was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (5R01NS071067-07).

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PATIENT CONSENT

Patients provided written consent for the use of patients’ images.

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