Transcutaneous Electrical Nerve Stimulation to Improve Female Sexual Dysfunction Symptoms: A Pilot Study.

OBJECTIVES: To perform a pilot study using transcutaneous electrical nerve stimulation (TENS) on the dorsal genital nerve and the posterior tibial nerve for improving symptoms of female sexual dysfunction (FSD) in women without bladder problems. We hypothesize that this therapy will be effective at improving genital arousal deficits. MATERIALS AND METHODS: Nine women with general FSD completed the study. Subjects received 12 sessions of transcutaneous dorsal genital nerve stimulation (DGNS; n = 6) or posterior tibial nerve stimulation (PTNS; n = 3). Stimulation was delivered for 30 min at 20 Hz. Sexual functioning was evaluated with the female sexual functioning index (FSFI), and surveys were also given on general health, urological functioning, and the Patients' Global Impression of Change (PGIC) after treatment. Surveys were given before treatment (baseline), after 6 and 12 weeks of treatment, and 6 weeks after the completion of stimulation sessions. RESULTS: The average total FSFI score across all subjects significantly increased from 15.3 ± 4.8 at baseline to 20.3 ± 7.8 after six sessions, 21.7 ± 7.5 after 12 sessions, and 21.3 ± 7.1 at study completion (p < 0.05 for all time points). Increases were observed in both DGNS and PTNS subjects. Significant FSFI increases were seen in the subdomains of lubrication, arousal, and orgasm, each of which is related to genital arousal. Bladder and general health surveys did not change across the study. PGIC had a significant increase. CONCLUSIONS: This study provides evidence that transcutaneous stimulation of peripheral nerves has the potential to be a valuable therapeutic tool for women with FSD.

Regenerative Peripheral Nerve Interface for Prostheses Control: Electrode Comparison.

BACKGROUND: This study compared epimysial patch electrodes with intramuscular hook electrodes using monopolar and bipolar recording configurations. The purpose was to determine which strategy transduced muscle signals with better fidelity for control of myoelectric prostheses. METHODS: One of the two electrode styles, patch (n = 4) or hook (n = 6) was applied to the left extensor digitorum longus muscle in rats. Electrodes were evaluated at the time of placement and at monthly intervals for 4 months. Evaluations consisted of evoked electromyography signals from stimulation pulses applied to the peroneal and tibial nerves in both monopolar and bipolar recording configurations. RESULTS: Compared with hook electrodes, patch electrodes recorded larger signals of interest and minimized muscle tissue injury. A bipolar electrode configuration significantly reduced signal noise when compared with a monopolar configuration. CONCLUSION: Epimysial patch electrodes outperform intramuscular hook electrodes during chronic skeletal muscle implantation.

Surgical Model for Analysis of Signal Transfer Through Biologic and Synthetic Materials.

BACKGROUND: High-fidelity volitional control of bioengineered prosthetic limbs with multiple degrees of freedom requires the implantation of multiple recording interfaces to detect independent control signals. However, interface utilization is complicated by interfering electrophysiological signals originating from surrounding muscles and nerves, leading to equivocal signal detection. We developed and validated a surgical model to characterize signal propagation through various biomaterials to identify insulating substrates for use in implantable interfaces. The identification of these insulating materials will facilitate the acquisition of noncontaminated prosthetic control signals, thus improving manipulation of advanced prosthetic limbs. METHODS: Using a rat hindlimb model, 4 groups (n = 8/group) were tested. A medial gastrocnemius muscle flap was elevated, leaving the neurovascular pedicle intact. The flap was rotated into a chamber and secured to a silicone base. A stainless steel electrode was affixed to the surface of a muscle and encircled by 1-layer small intestinal submucosa (SIS), 4-layer SIS, silicone elastomer, or nothing (uninsulated). A superimposing electrode was attached, and an external silicone layer was wrapped around the construct and sutured in place. Electromyographic studies were then performed. RESULTS: This model was found to correspond with expected signal isolation characteristics of the nonconductive silicone group, electrically inert single and multilayer SIS group, and the uninsulated group. Signal isolation of compound muscle action potential amplitude at stimulation threshold was significantly greater using silicone (51.4%) compared with the 1-layer SIS (-6.8%), 4-layer SIS (-3.3% ), or uninsulated groups (1.2%) (P = <0.001). Isolation of the maximum compound muscle action potential peak-to-peak amplitude was also greater with silicone (56.7%) versus the 1-layer SIS (1.5%), 4-layer SIS (1.1%), or uninsulated groups (-0.7%) (P = <0.001). CONCLUSIONS: This study demonstrates and validates a novel surgical model to characterize in vivo signal propagation and subsequently identify insulating materials for use in implantable interface systems currently in development. Improved signal isolation through the utilization of these materials stands to greatly improve control fidelity of neuroprosthetic limbs.

Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces.

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

Advanced technologies for intuitive control and sensation of prosthetics.

The Department of Defense, Department of Veterans Affairs and National Institutes of Health have invested significantly in advancing prosthetic technologies over the past 25 years, with the overall intent to improve the function, participation and quality of life of Service Members, Veterans, and all United States Citizens living with limb loss. These investments have contributed to substantial advancements in the control and sensory perception of prosthetic devices over the past decade. While control of motorized prosthetic devices through the use of electromyography has been widely available since the 1980s, this technology is not intuitive. Additionally, these systems do not provide stimulation for sensory perception. Recent research has made significant advancement not only in the intuitive use of electromyography for control but also in the ability to provide relevant meaningful perceptions through various stimulation approaches. While much of this previous work has traditionally focused on those with upper extremity amputation, new developments include advanced bidirectional neuroprostheses that are applicable to both the upper and lower limb amputation. The goal of this review is to examine the state-of-the-science in the areas of intuitive control and sensation of prosthetic devices and to discuss areas of exploration for the future. Current research and development efforts in external systems, implanted systems, surgical approaches, and regenerative approaches will be explored.

In vivo performance of a microelectrode neural probe with integrated drug delivery.

OBJECT: The availability of sophisticated neural probes is a key prerequisite in the development of future brain-machine interfaces (BMIs). In this study, the authors developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery promises to extend dramatically the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. METHODS: To form the multifunctional neural probe, the authors affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted in rats to characterize the performance of the device. Experiment 1 examined cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measured the effects of saline infusions delivered through the probe on concurrent electrophysiological measurements. Experiment 3 demonstrated that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide stains were used to assess insertion trauma and the tissue distribution of the infusate. Artificial CSF (aCSF) and tetrodotoxin (TTX) were injected to determine the efficacy of drug delivery. RESULTS: The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of aCSF as a control experiment, whereas delivery of TTX produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. CONCLUSIONS: Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces using localized and feedback-controlled delivery of drugs can be realized in the near future.

Bimodal classification algorithm for atrial fibrillation detection from m-health ECG recordings.

INTRODUCTION: Atrial Fibrillation (AF) is the most common cardiac arrhythmia, presenting a significant independent risk factor for stroke and thromboembolism. With the emergence of m-Health devices, the importance of automatic detection of AF in an off-clinic setting is growing. This study demonstrates the performance of a bimodal classifier for distinguishing AF from sinus rhythm (SR) that could be used for automated detection of AF episodes. METHODS: Surface recordings from a hand-held research device and standard electrocardiograms (ECG) were collected and analyzed from 68 subjects. An additional 48 subjects from the MIT-BIH Arrythmia Database were also analyzed. All ECGs were blindly reviewed by physicians independently of the bimodal algorithm analysis. The algorithm selects an artifact-free 6-s ECG segment out of a 20-s long recording and computes a spectral Frequency Dispersion Metric (FDM) and a temporal R-R interval variability (VRR) index. RESULTS: Scatter plots of the VRR and FDM indices revealed two distinct clusters. The bimodal scattering of the indices revealed a linear classification boundary that could be employed to differentiate the SR from AF waveforms. The selected classification boundary was able to correctly differentiate all the subjects from both datasets into either SR or AF groups, except for 3 SR subjects from the MIT-BIH dataset. CONCLUSION: Our bimodal classification algorithm was demonstrated to successfully acquire, analyze and interpret ECGs for the presence of AF indicating its potential to support m-Health diagnosis, monitoring, and management of therapy in AF patients.

Regenerative Electrode Interfaces for Neural Prostheses.

Neural prostheses are electrode arrays implanted in the nervous system that record or stimulate electrical activity in neurons. Rapid growth in the use of neural prostheses in research and clinical applications has occurred in recent years, but instability and poor patency in the tissue-electrode interface undermines the longevity and performance of these devices. The application of tissue engineering strategies to the device interface is a promising approach to improve connectivity and communication between implanted electrodes and local neurons, and several research groups have developed new and innovative modifications to neural prostheses with the goal of seamless device-tissue integration. These approaches can be broadly categorized based on the strategy used to maintain and regenerate neurons at the device interface: (1) redesign of the prosthesis architecture to include finer-scale geometries and/or provide topographical cues to guide regenerating neural outgrowth, (2) incorporation of material coatings and bioactive molecules on the prosthesis to improve neuronal growth, viability, and adhesion, and (3) inclusion of cellular grafts to replenish the local neuron population or provide a target site for reinnervation (biohybrid devices). In addition to stabilizing the contact between neurons and electrodes, the potential to selectively interface specific subpopulations of neurons with individual electrode sites is a key advantage of regenerative interfaces. In this study, we review the development of regenerative interfaces for applications in both the peripheral and central nervous system. Current and future development of regenerative interfaces has the potential to improve the stability and selectivity of neural prostheses, improving the patency and resolution of information transfer between neurons and implanted electrodes.

Providing a sense of touch to prosthetic hands.

Each year, approximately 185,000 Americans suffer the devastating loss of a limb. The effects of upper limb amputations are profound because a person's hands are tools for everyday functioning, expressive communication, and other uniquely human attributes. Despite the advancements in prosthetic technology, current upper limb prostheses are still limited in terms of complex motor control and sensory feedback. Sensory feedback is critical to restoring full functionality to amputated patients because it would relieve the cognitive burden of relying solely on visual input to monitor motor commands and provide tremendous psychological benefits. This article reviews the latest innovations in sensory feedback and argues in favor of peripheral nerve interfaces. First, the authors examine the structure of the peripheral nerve and its importance in the development of a sensory interface. Second, the authors discuss advancements in targeted muscle reinnervation and direct neural stimulation by means of intraneural electrodes. The authors then explore the future of prosthetic sensory feedback using innovative technologies for neural signaling, specifically, the sensory regenerative peripheral nerve interface and optogenetics. These breakthroughs pave the way for the development of a prosthetic limb with the ability to feel.

Update in facial nerve paralysis: tissue engineering and new technologies.

PURPOSE OF REVIEW: To present the recent advances in the treatment of facial paralysis, emphasizing the emerging technologies. This review will summarize the current state of the art in the management of facial paralysis and discuss the advances in nerve regeneration, facial reanimation, and use of novel biomaterials. This review includes surgical innovations in reinnervation and reanimation as well as progress with bioelectrical interfaces. RECENT FINDINGS: The last decade has witnessed major advances in the understanding of nerve injury and approaches for management. Key innovations include strategies to accelerate nerve regeneration, provide tissue-engineered constructs that may replace nonfunctional nerves, approaches to influence axonal guidance, limiting of donor-site morbidity, and optimization of functional outcomes. Approaches to muscle transfer continue to evolve, and new technologies allow for electrical nerve stimulation and use of artificial tissues. SUMMARY: The fields of biomedical engineering and facial reanimation increasingly intersect, with innovative surgical approaches complementing a growing array of tissue engineering tools. The goal of treatment remains the predictable restoration of natural facial movement, with acceptable morbidity and long-term stability. Advances in bioelectrical interfaces and nanotechnology hold promise for widening the window for successful treatment intervention and for restoring both lost neural inputs and muscle function.

Regenerative peripheral nerve interface viability and signal transduction with an implanted electrode.

BACKGROUND: The regenerative peripheral nerve interface is an internal interface for signal transduction with external electronics of prosthetic limbs; it consists of an electrode and a unit of free muscle that is neurotized by a transected residual peripheral nerve. Adding a conductive polymer coating on electrodes improves electrode conductivity. This study examines regenerative peripheral nerve interface tissue viability and signal fidelity in the presence of an implanted electrode coated or uncoated with a conductive polymer. METHODS: In a rat model, the extensor digitorum longus muscle was moved as a nonvascularized free tissue transfer and neurotized by the divided peroneal nerve. Either a stainless steel pad electrode (n = 8) or a pad electrode coated with poly(3,4-ethylenedioxythiophene) conductive polymer (PEDOT) (n = 8) was implanted on the muscle transfer and secured with an encircling acellular extracellular matrix. The contralateral muscle served as the control. RESULTS: The free muscle transfers were successfully revascularized and over time reinnervated as evidenced by serial insertional needle electromyography. Compound muscle action potentials were successfully transduced through the regenerative peripheral nerve interface. The conductive polymer coating on the implanted electrode resulted in increased recorded signal amplitude that was observed throughout the course of the study. Histologic examination confirmed axonal sprouting, elongation, and synaptogenesis within regenerative peripheral nerve interface regardless of electrode type. CONCLUSIONS: The regenerative peripheral nerve interface remains viable over seven months in the presence of an implanted electrode. Electrodes with and without conductive polymer reliably transduced signals from the regenerative peripheral nerve interface. Electrodes with a conductive polymer coating resulted in recording more of the regenerative peripheral nerve interface signal.

Electrically stimulated signals from a long-term Regenerative Peripheral Nerve Interface.

Despite modern technological advances, the most widely available prostheses provide little functional recovery beyond basic grasping. Although sophisticated upper extremity prostheses are available, optimal prosthetic interfaces which give patients high-fidelity control of these artificial limbs are limited. We have developed a novel Regenerative Peripheral Nerve Interface (RPNI), which consists of a unit of free muscle that has been neurotized by a transected peripheral nerve. In conjunction with a biocompatible electrode on the muscle surface, the RPNI facilitates signal transduction from a residual peripheral nerve to a neuroprosthetic limb. The purpose of this study was to explore signal quality and reliability in an RPNI following an extended period of implantation. Following a 14-month maturation period, electromyographic signal generation was evaluated via electrical stimulation of the innervating nerve. The long-term RPNI was viable and healthy, as demonstrated by evoked compound muscle action potentials as well as histological tissue analysis. Signals exceeding 4 mV were successfully acquired and amplitudes were consistent across multiple repetitions of applied stimuli. There were no evident signs of muscle denervation, significant scar tissue, or muscle necrosis. This study provides further evidence that after a maturation period exceeding 1 year, reliable and consistent signals can still be acquired from an RPNI.

Quantification of muscle-derived signal interference during monopolar needle electromyography of a peripheral nerve interface in the rat hind limb.

High-fidelity signal acquisition is critical for the fundamental control of a neuroprosthesis. Our group has developed a bio-artificial interface consisting of a muscle graft neurotized by a severed nerve in a rat hind limb model. This regenerative peripheral nerve interface (RPNI) permits nerve signal transmission, amplification, and detection via in situ electromyography (EMG). Our study examined the magnitude of signal interference from simultaneously contracting muscles adjacent to our muscle of interest. In eighteen F344 rats, the extensor digitorum longus (EDL) muscle was used to fabricate simulated RPNI constructs of various sizes in which the neurovascular pedicle was preserved, obviating the need for reinnervation or revascularization. After 3 weeks of recovery, in situ EMG testing was performed using electrical stimulation of the common peroneal nerve. A recording needle was placed in the EDL muscle with a reference/ground electrode in the contralateral toe webspace, comprising a monopolar recording configuration. The superficial peroneal nerve was transected to further isolate stimulation of the anterior compartment. Recordings from the EDL were performed before and after excision of the tibialis anterior (TA) and extensor hallucis longus (EHL) muscles. After TA/EHL excision, EDL compound muscle action potential (CMAP) peak-to-peak amplitudes were significantly lower by an average of 7.4±5.6(SD) mV, or 32±18%, (paired t(17)=-5.7, p<;0.0001). A significant positive linear correlation was seen between CMAP amplitude and EDL mass both before TA/EHL excision (r=0.68, n=18, p<;0.01) and after TA/EHL excision (r=0.79, n=18, p<;0.0001). EDL mass did not correlate with differences in CMAP amplitude or area caused by TA/EHL excision. Monopolar needle EMG recordings from the EDL muscle are significantly, but predictively, contaminated by concomitant muscular contractions in the anterior compartment of the rat hind limb. Further investigation of strategies to reduce this signal interference, including electrode choice or configuration, use of bioelectrical insulators, and filtering methods, is warranted to promote high-fidelity signal acquisition for prosthetic control.

Electrochemical sensing via selective surface modification of iridium microelectrodes to create a platinum black interface.

The ability to selectively deposit platinum black (PtB) on iridium microelectrodes and functionalize the surface for the purposes of choline sensing was investigated in this study. Platinum black was deposited by cycling 100-200 times between 0.5 V and -0.7 V in a solution of 1 mM K2PtCl6 in 0.1 M KCl. Deposition of PtB showed good chemical stability as well as good adhesion following insertion into agarose gel as a model for brain insertion. Electrode sites were also tested for their oxidative capabilities of hydrogen peroxide during which they showed high current change in response to small concentration changes - attributable to the high surface area of the PtB. Sites were then coated with an enzyme solution containing choline oxidase, and a permselective layer of meta-phenylenediamine was added to filter interferents. Electrode sites yielded a high sensitivity to choline compared to interferents including ascorbic acid and dopamine.

Clinical factors associated with replantation after traumatic major upper extremity amputation.

BACKGROUND: Little knowledge exists concerning replantation following traumatic major upper extremity amputation. This study characterizes the injury patterns and outcomes of patients suffering major upper extremity amputation and ascertains clinical factors associated with the decision to attempt replantation. METHODS: A retrospective cohort study was conducted on patients treated at a Level I trauma center between June of 2000 and August of 2011. Patients who experienced traumatic upper extremity amputation at or proximal to the radiocarpal joint were included in the study. The subset of patients subsequently undergoing replantation was identified. Medical records were reviewed and bivariate analysis was performed to identify factors associated with attempted replantation and replant survival. RESULTS: Sixty-two patients were treated for traumatic upper extremity amputation and 20 patients underwent replantation. Injury factors associated with attempted replantation included a sharp/penetrating injury (p = 0.004), distal level of amputation (p = 0.017), Injury Severity Score less than 16 (p = 0.020), absence of avulsion (p = 0.002), absence of significant contamination (p ≤ 0.001), and lack of multilevel involvement (p = 0.007). Replantation exhibited a complete replant survival rate of 70 percent. An Injury Severity Score of 16 or more was associated with replant failure (p = 0.004). Patients who underwent replantation demonstrated increased rates of secondary surgical revisions (p ≤ 0.001) and complications (p = 0.023) and had a greater length of hospital stay (p = 0.024). CONCLUSIONS: Several injury characteristics are associated with the decision to attempt replantation of the major upper extremity. A high global injury severity (Injury Severity Score ≥ 16) is associated with replantation failure when attempted. Patients who undergo replantation demonstrate higher resource use, warranting further cost-analysis and outcomes investigation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Innovations in prosthetic interfaces for the upper extremity.

Advancements in modern robotic technology have led to the development of highly sophisticated upper extremity prosthetic limbs. High-fidelity volitional control of these devices is dependent on the critical interface between the patient and the mechanical prosthesis. Recent innovations in prosthetic interfaces have focused on several control strategies. Targeted muscle reinnervation is currently the most immediately applicable prosthetic control strategy and is particularly indicated in proximal upper extremity amputations. Investigation into various brain interfaces has allowed acquisition of neuroelectric signals directly or indirectly from the central nervous system for prosthetic control. Peripheral nerve interfaces permit signal transduction from both motor and sensory nerves with a higher degree of selectivity. This article reviews the current developments in each of these interface systems and discusses the potential of these approaches to facilitate motor control and sensory feedback in upper extremity neuroprosthetic devices.

Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes.

We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well-isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high-quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 µm in diameter.

Use of a Bayesian maximum-likelihood classifier to generate training data for brain-machine interfaces.

Brain-machine interface decoding algorithms need to be predicated on assumptions that are easily met outside of an experimental setting to enable a practical clinical device. Given present technological limitations, there is a need for decoding algorithms which (a) are not dependent upon a large number of neurons for control, (b) are adaptable to alternative sources of neuronal input such as local field potentials (LFPs), and (c) require only marginal training data for daily calibrations. Moreover, practical algorithms must recognize when the user is not intending to generate a control output and eliminate poor training data. In this paper, we introduce and evaluate a Bayesian maximum-likelihood estimation strategy to address the issues of isolating quality training data and self-paced control. Six animal subjects demonstrate that a multiple state classification task, loosely based on the standard center-out task, can be accomplished with fewer than five engaged neurons while requiring less than ten trials for algorithm training. In addition, untrained animals quickly obtained accurate device control, utilizing LFPs as well as neurons in cingulate cortex, two non-traditional neural inputs.

Validation of a novel three-dimensional electrode array within auditory cortex.

Three-dimensional electrode arrays have a variety of potential applications in the fields of both intracortical mapping as well as basic research studies designed to characterize and understand the physiology of the brain. While higher channels counts are desired in brain-machine interface applications, the ability to analyze synchronous data from multiple cortical locations, including various depths is pivotal to fully mapping the underlying neurophysiology of sensory cortices. Within this study, we present a proof of concept validation of a 3D probe technology consisting of 16 silicon shanks in a 4x4 grid arrangement with four electrode sites per shank. This 3D array has been implanted in a rat primary auditory cortex and electrophysiological data are presented showing the utility of electrode sites spanning multilateral cortical space as well as cortical depth.