Search

Objective. High-density nerve cuffs have been successfully utilized to restore somatosensation in individuals with lower-limb loss by interfacing directly with the peripheral nervous system. Elicited sensations via these devices have improved various functional outcomes, including standing balance, walking symmetry, and navigating complex terrains. Deploying neural interfaces in the lower limbs of individuals with limb loss presents unique challenges, particularly due to repetitive muscle contractions and the natural range of motion in the knee and hip joints for transtibial and transfemoral amputees, respectively. This study characterizes the long-term performance of these peripheral nerve interfaces, which is crucial for informing design modifications to optimize functionality. Approach. We evaluated the longitudinal performance of 16-contact nerve cuffs and their associated components implanted in four participants with unilateral transtibial limb loss over five years. Key outcome measures included charge density at sensory thresholds and electrical impedance. Main results. Out of 158 channels (i.e. individual contacts within the nerve cuffs and their corresponding leads), 63% were consistently responsive, 33% were partially responsive, and 4% were non-responsive. Smaller connector assemblies and increased lead length near the cuffs significantly enhanced performance, with the final two participants demonstrating notably improved responses where 77% and 96% of channels were consistently responsive, respectively, compared to 50% and 6% in the first two participants. Significance. Overall, the implanted nerve cuffs showed robust stability in the residual limbs of highly active individuals with limb loss. Furthermore, employing strategies to reduce stress on transition points in the components significantly improved overall system performance., (Creative Commons Attribution license.)

Over 50% of individuals with lower limb loss report a fear of falling and avoiding daily activities partly due to a lack of plantar sensation. Providing direct somatosensory feedback via neural stimulation holds promise for addressing this issue. In this study, three individuals with lower limb loss received a sensory neuroprosthesis (SNP) that provided plantar somatosensory feedback corresponding to prosthesis-floor interactions perceived as arising from the missing foot generated by electrically activating the peripheral nerves in the residuum. Participants walked on a treadmill while receiving perturbations involving brief increases in the belt speed. Perturbations were initiated during early stance and randomly delivered to intact and prosthetic sides with the SNP active or inactive. With the SNP active, participants exhibited decreased trunk angular sway and peak trunk flexion angular velocity during recovery from both prosthetic and intact side perturbations. For prosthetic side perturbations, peak ground reaction force magnitudes decreased when the SNP was active. For intact side perturbations, peak ground reaction force magnitudes increased on the prosthetic side's first recovery step after the perturbation, which resulted in a more symmetric recovery because the force approached the response on the intact side's first recovery step following a prosthetic side perturbation. These results suggest participants integrated the feedback from the SNP into their sensorimotor control for maintaining stability and gained confidence in relying on their prosthetic limb during recovery. Restoring plantar sensation with a SNP for individuals with lower limb loss could lead to reduced risk of falling by improving recovery from trips., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Lower limb loss is a major insult to the body's nervous and musculoskeletal systems. Despite technological advances in prosthesis design, artificial limbs are not yet integrated into the body's physiological systems. Therefore, lower limb amputees (LLAs) experience lower balance confidence, higher fear of falls, and impaired gait compared with their able-bodied peers (ABs). Previous studies have demonstrated that restored sensations perceived as originating directly from the missing limb via neural interfaces improve balance and performance in certain ambulatory tasks; however, the effects of such evoked sensations on neural circuitries involved in the locomotor activity are not well understood. In this work, we investigated the effects of plantar sensation elicited by peripheral nerve stimulation delivered by multicontact nerve cuff electrodes on gait symmetry and stability, speed perception, and motor adaptation. We found that restored plantar sensation increased stance time and propulsive force on the prosthetic side, improved gait symmetry, and yielded an enhanced perception of prosthetic limb movement. Our results show that the locomotor adaptation among LLAs with plantar sensation became similar to that of ABs. These findings suggest that our peripheral nerve-based approach to elicit plantar sensation directly affects central nervous pathways involved in locomotion and motor adaptation during walking. Our neuroprosthesis provided a unique model to investigate the role of somatosensation in the lower limb during walking and its effects on perceptual recalibration after a locomotor adaptation task. Furthermore, we demonstrated how plantar sensation in LLAs could effectively increase mobility, improve walking dynamics, and possibly reduce fall risks.

Introduction: Individuals with lower limb loss experience an increased risk of falls partly due to the lack of sensory feedback from their missing foot. It is possible to restore plantar sensation perceived as originating from the missing foot by directly interfacing with the peripheral nerves remaining in the residual limb, which in turn has shown promise in improving gait and balance. However, it is yet unclear how these electrically elicited plantar sensation are integrated into the body's natural sensorimotor control reflexes. Historically, the H-reflex has been used as a model for investigating sensorimotor control. Within the spinal cord, an array of inputs, including plantar cutaneous sensation, are integrated to produce inhibitory and excitatory effects on the H-reflex., Methods: In this study, we characterized the interplay between electrically elicited plantar sensations and this intrinsic reflex mechanism. Participants adopted postures mimicking specific phases of the gait cycle. During each posture, we electrically elicited plantar sensation, and subsequently the H-reflex was evoked both in the presence and absence of these sensations., Results: Our findings indicated that electrically elicited plantar sensations did not significantly alter the H-reflex excitability across any of the adopted postures., Conclusion: This suggests that individuals with lower limb loss can directly benefit from electrically elicited plantar sensation during walking without disrupting the existing sensory signaling pathways that modulate reflex responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential competing interest., (Copyright © 2023 Li, Triolo and Charkhkar.)

Introduction: Lower limb prosthesis users often struggle to navigate uneven terrain or ambulate in low light conditions where it can be challenging to rely on visual cues for balance and walking. Sensory feedback about foot-floor interactions may allow users to reduce reliance on secondary sensory cues and improve confidence and speed when navigating difficult terrain. Our group has developed a Sensory Neuroprosthesis (SNP) to restore sensation to people with lower limb amputation by pairing electrical stimulation of nerves in the residual limb applied via implanted neurotechnology with pressure sensors in the insole of a standard prosthesis. Stimulation applied to the nerves evoked sensations perceived as originating on the missing leg and foot., Methods: This qualitative case study reports on the experiences of a 68-year-old with a unilateral trans-tibial amputation who autonomously used the SNP at home for 31 weeks. Interview data collected throughout the study period was analyzed using a grounded theory approach with constant comparative methods to understand his experience with this novel technology and its impacts on his daily life., Results: A conceptual model was developed that explained the experience of integrating SNP-provided sensory feedback into his body and motor plans. The model described the requirements of integration, which were a combination of a low level of mental focus and low stimulation levels. While higher levels of stimulation and focus could result in distinct sensory percepts and various phantom limb experiences, optimal integration was associated with SNP-evoked sensation that was not readily perceivable. Successful sensorimotor integration of the SNP resulted in improvements to locomotion, a return to a more normal state, an enhancement of perceived prosthesis utility, and a positive outlook on the experience., Discussion: These outcomes emerged over the course of the nearly 8 month study, suggesting that findings from long-term home studies of SNPs may differ from those of short-term in-laboratory tests. Our findings on the experience of sensorimotor integration of the SNP have implications for the optimal training of SNP users and the future deployment of clinical SNP systems for long-term home use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schmitt, Wright, Triolo, Charkhkar and Graczyk.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shell, Christie, Marasco, Charkhkar and Triolo.)

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.

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.

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., (Published by Elsevier B.V.)

Objective: Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits., Approach: This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate., Main Results: Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products., Significance: This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

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.

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.

Objective: Sensory input in lower-limb amputees is critically important to maintaining balance, preventing falls, negotiating uneven terrain, responding to unexpected perturbations, and developing the confidence required for societal participation and public interactions in unfamiliar environments. Despite noteworthy advances in robotic prostheses for lower-limb amputees, such as microprocessor knees and powered ankles, natural somatosensory feedback from the lost limb has not yet been incorporated in current prosthetic technologies., Approach: In this work, we report eliciting somatic sensation with neural stimulation delivered by chronically-implanted, non-penetrating nerve cuff electrodes in two transtibial amputees. High-density, flexible, 16-contact nerve cuff electrodes were surgically implanted for the selective activation of sensory fascicles in the nerves of the posterior thigh above the knee. Electrical pulses at safe levels were delivered to the nerves by an external stimulator via percutaneous leads attached to the cuff electrodes., Main Results: The neural stimulation was perceived by participants as sensation originating from the missing limb. We quantitatively and qualitatively ascertained the intensity, modality as well as the location and stability of the perceived sensations. Stimulation through individual contacts within the nerve cuffs evoked repeatable sensations of various modalities and at discrete locations projected to the missing toes, foot and ankle, as well as in the residual limb. In addition, we observed a high overlap in reported locations between distal versus proximal cuffs suggesting that the same sensory responses could be elicited from more proximal points on the nerve., Significance: Based on these findings, the high-density cuff technology is suitable for restoring natural sensation to lower-limb amputees and could be utilized in developing a neuroprosthesis with natural sensory feedback. The overlap in reported locations between proximal and distal cuffs indicates that our approach might be applicable to transfemoral amputees where distal muscles and branches of sciatic nerve are not available.

Intracortical probe technology, consisting of arrays of microelectrodes, offers a means of recording the bioelectrical activity from neural tissue. A major limitation of existing intracortical probe technology pertains to limited lifetime of 6 months to a year of recording after implantation. A major contributor to device failure is widely believed to be the interfacial mechanical mismatch of conventional stiff intracortical devices and the surrounding brain tissue. We describe the design, development, and demonstration of a novel functional intracortical probe technology that has a tunable Young's modulus from ∼2 GPa to ∼50 MPa. This technology leverages advances in dynamically softening materials, specifically thiol-ene/acrylate thermoset polymers, which exhibit minimal swelling of < 3% weight upon softening in vitro. We demonstrate that a shape memory polymer-based multichannel intracortical probe can be fabricated, that the mechanical properties are stable for at least 2 months and that the device is capable of single unit recordings for durations up to 77 days in vivo. This novel technology, which is amenable to processes suitable for manufacturing via standard semiconductor fabrication techniques, offers the capability of softening in vivo to reduce the tissue-device modulus mismatch to ultimately improve long term viability of neural recordings. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 159-168, 2017., (© 2016 Wiley Periodicals, Inc.)

Microelectrode arrays have been extensively utilized to record extracellular neuronal activity for brain-machine interface applications. Modifying the microelectrodes with conductive polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT) has been reported to be advantageous because it increases the effective surface area of the microelectrodes, thereby decreasing impedance and enhancing charge transfer capacity. However, the long term stability and integrity of such coatings for chronic recordings remains unclear. Previously, our group has demonstrated that use of the smaller counter ion tetrafluoroborate (TFB) during electrodeposition increased the stability of the PEDOT coatings in vitro compared to the commonly used counter ion poly(styrenesulfonate) (PSS). In the current work, we examined the long-term in vivo performance of PEDOT-TFB coated microelectrodes. To do so, we selectively modified half of the microelectrodes on NeuroNexus single shank probes with PEDOT-TFB while the other half of the microelectrodes were modified with gold as a control. The modified probes were then implanted into the primary motor cortex of rats. Single unit recordings were observed on both PEDOT-TFB and gold control microelectrodes for more than 12 weeks. Compared to the gold-coated microelectrodes, the PEDOT-TFB coated microelectrodes exhibited an overall significantly lower impedance and higher number of units per microelectrode specifically for the first four weeks. The majority of PEDOT-TFB microelectrodes with activity had an impedance magnitude lower than 400 kΩ at 1 kHz. Our equivalent circuit modeling of the impedance data suggests stability in the polymer-related parameters for the duration of the study. In addition, when comparing PEDOT-TFB microelectrodes with and without long-term activity, we observed a distinction in certain circuit parameters for these microelectrodes derived from equivalent circuit modeling prior to implantation. This observation may prove useful in qualifying PEDOT-TFB microelectrodes with a greater likelihood of registering long-term activity. Overall, our findings confirm that PEDOT-TFB is a chronically stable coating for microelectrodes to enable neural recording., Statement of Significance: Microelectrode arrays have been extensively utilized to record extracellular neuronal activity for brain-machine interface applications. Poly(3,4-ethylenedioxythiophene) (PEDOT) has gained interest because of its unique electrochemical characteristics and its excellent intrinsic electrical conductivity. However, the long-term stability of the PEDOT film, especially for chronic neural applications, is unclear. In this manuscript, we report for the first time the use of highly stable PEDOT doped with tetrafluoroborate (TFB) for long-term neural recordings. We show that PEDOT-TFB coated microelectrodes on average register more units compared to control gold microelectrodes for at least first four weeks post implantation. We collected the in vivo impedance data over a wide frequency spectrum and developed an equivalent circuit model which helped us determine certain parameters to distinguish between PEDOT-TFB microelectrodes with and without long-term activity. Our findings suggest that PEDOT-TFB is a chronically stable coating for neural recording microelectrodes. As such, PEDOT-TFB could facilitate chronic recordings with ultra-small and high-density neural arrays., (Copyright © 2015 Acta Materialia Inc. All rights reserved.)

In vitro assays offer a means of screening potential therapeutics and accelerating the drug development process. Here, we utilized neuronal cultures on planar microelectrode arrays (MEA) as a functional assay to assess the neurotoxicity of amyloid-β 1-42 (Aβ42), a biomolecule implicated in the Alzheimer׳s disease (AD). In this approach, neurons harvested from embryonic mice were seeded on the substrate-integrated microelectrode arrays. The cultured neurons form a spontaneously active network, and the spiking activity as a functional endpoint could be detected via the MEA. Aβ42 oligomer, but not monomer, significantly reduced network spike rate. In addition, we demonstrated that the ionotropic glutamate receptors, NMDA and AMPA/kainate, play a role in the effects of Aβ42 on neuronal activity in vitro. To examine the utility of the MEA-based assay for AD drug discovery, we tested two model therapeutics for AD, methylene blue (MB) and memantine. Our results show an almost full recovery in the activity within 24h after administration of Aβ42 in the cultures pre-treated with either MB or memantine. Our findings suggest that cultured neuronal networks may be a useful platform in screening potential therapeutics for Aβ induced changes in neurological function., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Conducting polymers, especially poly(3,4-ethylenedioxythiophene) (PEDOT) based materials, are important for developing highly sensitive and microscale neural probes. In the present work, we show that the conductivity and stability of PEDOT can be significantly increased by switching the widely used counter anion poly(styrenesulfonate) (PSS) to the smaller tetrafluoroborate (TFB) anion during the electrodeposition of the polymer. Time-dependent impedance measurements of polymer modified implantable microwires were conducted in physiological buffer solutions under accelerated aging conditions and the relative stability of PEDOT:PSS and PEDOT:TFB modified microwires was compared over time. This study was also extended to carbon nanotube (CNT) incorporated PEDOT:PSS which, according to some reports, is claimed to enhance the stability and electrical performance of the polymer. However, no noticeable difference was observed between PEDOT:PSS and CNT:PEDOT:PSS in our measurements. At the biologically relevant frequency of 1kHz, PEDOT:TFB modified microwires exhibit approximately one order of magnitude higher conductivity and demonstrate enhanced stability over both PEDOT:PSS and CNT:PEDOT:PSS modified microwires. In addition, PEDOT:TFB is not neurotoxic and we show the proof-of-concept for both in vitro and in vivo neuronal recordings using PEDOT:TFB modified microelectrode arrays and chronic electrodes, respectively. Our findings suggest that PEDOT:TFB is a promising conductive polymer coating for the recording of neural activities., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Neural interfaces aim to restore neurological function lost during disease or injury. Novel implantable neural interfaces increasingly capitalize on novel materials to achieve microscale coupling with the nervous system. Like any biomedical device, neural interfaces should consist of materials that exhibit biocompatibility in accordance with the international standard ISO10993-5, which describes in vitro testing involving fibroblasts where cytotoxicity serves as the main endpoint. In the present study, we examine the utility of living neuronal networks as functional assays for in vitro material biocompatibility, particularly for materials that comprise implantable neural interfaces. Embryonic mouse cortical tissue was cultured to form functional networks where spontaneous action potentials, or spikes, can be monitored non-invasively using a substrate-integrated microelectrode array. Taking advantage of such a platform, we exposed established positive and negative control materials to the neuronal networks in a consistent method with ISO 10993-5 guidance. Exposure to the negative controls, gold and polyethylene, did not significantly change the neuronal activity whereas the positive controls, copper and polyvinyl chloride (PVC), resulted in reduction of network spike rate. We also compared the functional assay with an established cytotoxicity measure using L929 fibroblast cells. Our findings indicate that neuronal networks exhibit enhanced sensitivity to positive control materials. In addition, we assessed functional neurotoxicity of tungsten, a common microelectrode material, and two conducting polymer formulations that have been used to modify microelectrode properties for in vivo recording and stimulation. These data suggest that cultured neuronal networks are a useful platform for evaluating the functional toxicity of materials intended for implantation in the nervous system., (© 2013 Elsevier B.V. All rights reserved.)

Neuronal networks cultured on microelectrode arrays (MEAs) have been utilized as biosensors that can detect all or nothing extracellular action potentials, or spikes. Coating the microelectrodes with carbon nanotubes (CNTs), either pristine or conjugated with a conductive polymer, has been previously reported to improve extracellular recordings presumably via reduction in microelectrode impedance. The goal of this work was to examine the basis of such improvement in vitro. Every other microelectrode of in vitro MEAs was electrochemically modified with either conducting polymer, poly-3,4-ethylenedioxythiophene (PEDOT) or a blend of CNT and PEDOT. Mouse cortical tissue was dissociated and cultured on the MEAs to form functional neuronal networks. The performance of the modified and unmodified microelectrodes was evaluated by activity measures such as spike rate, spike amplitude, burst duration and burst rate. We observed that the yield, defined as percentage of microelectrodes with neuronal activity, was significantly higher by 55% for modified microelectrodes compared to the unmodified sites. However, the spike rate and burst parameters were similar for modified and unmodified microelectrodes suggesting that neuronal networks were not physiologically altered by presence of PEDOT or PEDOT-CNT. Our observations from immunocytochemistry indicated that neuronal cells were more abundant in proximity to modified microelectrodes.

Neurological disorders are often characterized by abnormal neuronal activity. In the case of epilepsy, this can manifest itself in the form of uncontrolled synchronous activity often in the form of bursting. Pattern steering is the ability to apply stimulation to a network that effectively changes its dynamical firing pattern. In an epileptic network, the stimulation would be used to move the seizing network from its abnormal state to a normal state. This idea is explored here in cultured networks of cortical neurons plated on microelectrode arrays. Stimulation was applied to the bath resulting in an electric field generated throughout the network. This field was verified as sub-threshold in strength using a finite element model simulation. Stimulated networks showed a significant suppression in the number of bursts and increase in the interburst interval as compared to control networks. This observed burst suppression suggests that the sub-threshold stimulating field moved networks from a state of high frequency bursting to a state of low frequency bursting.

People without disabilities seamlessly control devices with their hands. Interestingly, their hands can perform coarse and fine control. Implementing smooth control for computerized systems is not straightforward and most of the time it is not intuitive either. Here we offer a solution to that problem: smooth control through humming. Voice commands have become ubiquitous in modern technology. Speech-to-text applications abound. Smooth control, on the other hand, has not been tackled yet. Here we design and implement a humming control technique, and demonstrate a hardware implementation with a powered wheelchair. Once actuated, the speed with which the chair moves will depend on the subtle variation on the fundamental frequency of the user's humming, acquired through an accelerometer measuring vocal cord vibration. We also discuss two signal processing techniques that handle commonly encountered issues when trying to resolve frequencies in real time data. The hardware implementation shows performance of 80% and higher in speech recognition for signal-to-noise ratio (SNR) higher than 8dB and 100% in smooth control and frequency detection for all tested SNRs. We also discuss potential applications of smooth humming control to other assistive technology., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

ω-Agatoxin-IVA is a well known P/Q-type Ca(2+) channel blocker and has been shown to affect presynaptic Ca(2+) currents as well postsynaptic potentials. P/Q-type voltage gated Ca(2+) channels play a vital role in presynaptic neurotransmitter release and thus play a role in action potential generation. Monitoring spontaneous activity of neuronal networks on microelectrode arrays (MEAs) provides an important tool for examining this neurotoxin. Changes in extracellular action potentials are readily observed and are dependent on synaptic function. Given the efficacy of murine frontal cortex and spinal cord networks to detect neuroactive substances, we investigated the effects of ω-agatoxin on spontaneous action potential firing within these networks. We found that networks derived from spinal cord are more sensitive to the toxin than those from frontal cortex; a concentration of only 10nM produced statistically significant effects on activity from spinal cord networks whereas 50 nM was required to alter activity in frontal cortex networks. Furthermore, the effects of the toxin on frontal cortex are more complex as unit specific responses were observed. These manifested as either a decrease or increase in action potential firing rate which could be statistically separated as unique clusters. Administration of bicuculline, a GABAA inhibitor, isolated a single response to ω-agatoxin, which was characterized by a reduction in network activity. These data support the notion that the two clusters detected with ω-agatoxin exposure represent differential responses from excitatory and inhibitory neuronal populations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have developed a novel method to study the effects of electrical stimulation of the local retina directly under an epiretinal stimulus electrode in real time. Using optical coherence tomography (OCT) and a superfused retinal eyecup preparation, we obtained high-resolution images of the rabbit retina directly under an optically transparent saline-filled fluoropolymer stimulation tube electrode. During OCT imaging, 50 Hz trains of biphasic current pulses 1 ms/phase (23-749 µC cm(-2) ph(-1)) were applied to the retinal surface for 5 min. After imaging, the stimulated regions were stained with the dye propidium iodide (PI) to reveal cytotoxic damage. Pulse train stimulation at 44-133 µC cm(-2) ph(-1) had little effect on the retina; however, trains ≥442 µC cm(-2) ph(-1) caused increases in the reflectance of the inner plexiform layer (IPL) and edema. The damage seen in retinal OCT images matched the pattern observed in histological sections, and in the PI staining. With pulse trains ≥442 µC cm(-2) ph(-1), rapid increases in the reflectivity of the IPL could be observed under the stimulus electrode. Below the electrode, we observed a ring-like pattern of retinal detachment in the subretinal space. The OCT imaging method may be useful for analyzing overstimulation of neuronal tissue by electrodes in many brain regions.