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Asynchronous distributed multielectrode stimulation (ADMES) is a novel approach to deep brain stimulation for medication resistant temporal lobe epilepsy that has shown promise in rodent and in vitro seizure models. To further evaluate its effects on a pre-clinical model, we characterized the effect of unilateral ADMES in an NHP model of temporal lobe seizures induced by intra-hippocampal injection of penicillin (PCN). Four non-human primates were used for this study in two contemporaneous cohorts. One cohort (n = 3 hemispheres) was implanted with the Medtronic RC + S stimulation (GIN cohort) and recording system connected to two 4-contact ring electrodes to evaluate three unilateral stimulation patterns: 7 Hz Ring ADMES, 20 Hz Dual Ring, and 125 Hz Dual Ring (analog of clinical stimulation). In an additional cohort (EPC cohort, n = 2), two 12-contact segmented electrodes were implanted in the right hippocampus and connected to an externalized recording and stimulation system to allow more flexibility in the stimulation pattern. In this second cohort, 4 variations of stimulation were evaluated (7 Hz Full ADMES, 7 Hz Ring ADMES, 31 Hz Wide Ring, and 31 Hz Dual Ring). In the GIN cohort, we found an increase in seizure frequency and time spent in seizure during the 7 Hz Ring ADMES stimulation compared to the respective post-stimulation. A similar post-stimulation effect was found in the EPC cohort. We also found an increase in seizure frequency during the 7Hz full ADMES compared to the respective post-stimulation. However, we did not find a difference between pre-stimulation and stimulation conditions suggesting a possible post stimulation effect of the 7Hz hippocampal stimulation. In conclusion, in the NHP PCN model of temporal lobe seizures, acute asynchronous hippocampal stimulation was not therapeutic, however, our findings related to the post-stimulation effect can support future studies using hippocampal stimulation for the treatment of temporal lobe epilepsy.

Objective: A critical limitation in clinical applications using functional electrical stimulation (FES) for rehabilitation exercises is the rapid onset of muscle fatigue. Spatially distributed sequential stimulation (SDSS) has been demonstrated to reduce muscle fatigue during FES compared to conventional single electrode stimulation (SES) in single joint movements. Here we investigated the fatigue reducing ability of SDSS in a clinical application, i.e., FES-rowing, in able-bodied (AB) participants. Methods: FES was delivered to the quadriceps and hamstring of 15 AB participants (five female, ten male) for fatiguing FES-rowing trials using SES and SDSS, participants rowed with voluntary arm effort while endeavoring to keep their legs relaxed. Fatigue was characterized by the time elapsed until a percent decrease occurred in power output (TTF), as well as the trial length indicating the time elapsed until the complete stop of rowing. Result: Trial length was significantly longer in SDSS rowing than in SES (t-test, ${p} < 0.01$ , ${d}=0.71$ ), with an average SDSS:SES trial length ratio of 1.31 ± 0.47. TTF $_{SDSS}$ was significantly longer than TTF $_{SES}$ with a median TTF $_{SDSS}$ :TTF $_{SES}$ ratio of 1.34 ranging from 1.03 to 5.41 (Wilcoxon Ranked Sum, ${p} < 0.01$ , ${r}=0.62$ ). No rower experienced a decrease in TTF with SDSS. Conclusion: SDSS reduced fatigue during FES-rowing when compared to SES in AB individuals, resulting in a lengthened FES-rowing period by approximately 30%. Application of SDSS would increase the effectiveness of FES-rowing as rehabilitative exercise for individuals with paralyses.

Objective: A critical limitation in clinical applications using functional electrical stimulation (FES) for rehabilitation exercises is the rapid onset of muscle fatigue. Spatially distributed sequential stimulation (SDSS) has been demonstrated to reduce muscle fatigue during FES compared to conventional single electrode stimulation (SES) in single joint movements. Here we investigated the fatigue reducing ability of SDSS in a clinical application, i.e., FES-rowing, in able-bodied (AB) participants. Methods: FES was delivered to the quadriceps and hamstring of 15 AB participants (five female, ten male) for fatiguing FES-rowing trials using SES and SDSS, participants rowed with voluntary arm effort while endeavoring to keep their legs relaxed. Fatigue was characterized by the time elapsed until a percent decrease occurred in power output (TTF), as well as the trial length indicating the time elapsed until the complete stop of rowing. Result: Trial length was significantly longer in SDSS rowing than in SES (t-test, ${p} < 0.01$ , ${d}=0.71$), with an average SDSS:SES trial length ratio of 1.31 ± 0.47. TTF $_{SDSS}$ was significantly longer than TTF $_{SES}$ with a median TTF $_{SDSS}$ :TTF $_{SES}$ ratio of 1.34 ranging from 1.03 to 5.41 (Wilcoxon Ranked Sum, ${p} < 0.01$ , ${r}=0.62$). No rower experienced a decrease in TTF with SDSS. Conclusion: SDSS reduced fatigue during FES-rowing when compared to SES in AB individuals, resulting in a lengthened FES-rowing period by approximately 30%. Application of SDSS would increase the effectiveness of FES-rowing as rehabilitative exercise for individuals with paralyses. [ABSTRACT FROM AUTHOR]

Asynchronous distributed multielectrode stimulation (ADMES) is a novel approach to deep brain stimulation for medication resistant temporal lobe epilepsy that has shown promise in rodent and in vitro seizure models. To further evaluate its effects on a pre-clinical model, we characterized the effect of unilateral ADMES in an NHP model of temporal lobe seizures induced by intra-hippocampal injection of penicillin (PCN). Four non-human primates were used for this study in two contemporaneous cohorts. One cohort (n = 3 hemispheres) was implanted with the Medtronic RC + S stimulation (GIN cohort) and recording system connected to two 4-contact ring electrodes to evaluate three unilateral stimulation patterns: 7 Hz Ring ADMES, 20 Hz Dual Ring, and 125 Hz Dual Ring (analog of clinical stimulation). In an additional cohort (EPC cohort, n = 2), two 12-contact segmented electrodes were implanted in the right hippocampus and connected to an externalized recording and stimulation system to allow more flexibility in the stimulation pattern. In this second cohort, 4 variations of stimulation were evaluated (7 Hz Full ADMES, 7 Hz Ring ADMES, 31 Hz Wide Ring, and 31 Hz Dual Ring). In the GIN cohort, we found an increase in seizure frequency and time spent in seizure during the 7 Hz Ring ADMES stimulation compared to the respective post-stimulation. A similar post-stimulation effect was found in the EPC cohort. We also found an increase in seizure frequency during the 7Hz full ADMES compared to the respective post-stimulation. However, we did not find a difference between pre-stimulation and stimulation conditions suggesting a possible post stimulation effect of the 7Hz hippocampal stimulation. In conclusion, in the NHP PCN model of temporal lobe seizures, acute asynchronous hippocampal stimulation was not therapeutic, however, our findings related to the post-stimulation effect can support future studies using hippocampal stimulation for the treatment of temporal lobe epilepsy., Competing Interests: Mohammad Sendi provides consulting services for Niji Corp. Robert E. Gross serves as a consultant to Medtronic, which manufactures products related to the research described in this manuscript and receives compensation for these services. He also receives support for unrelated research. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Robert E. Gross leads a clinical trial NCT04710004 “Electrophysiological Biomarkers in MTLE Patients.” This clinical trial aims to apply asynchronous distributed multi-electrode stimulation in the hippocampus of subject with medial temporal lobe epilepsy to identify biomarker related to the pre-ictal state., (© 2024 The Authors. Published by Elsevier Ltd.)

Neuromuscular electrical stimulation (NMES) induces muscle contractions via electrical stimuli. NMES can be used for rehabilitation and to enable functional movements; however, a fundamental limitation is the early onset of fatigue. Asynchronous stimulation is a method that can reduce fatigue by utilizing multiple stimulation channels to segregate and switch between different sets of recruited motor units. However, switching between stimulation channels is challenging due to each channel’s differing response to stimulation. To address this challenge, a switched systems analysis is used in the present work to design a controller that allows for instantaneous switching between stimulation channels. The developed controller yields semi-global exponential tracking of a desired angular trajectory for a person’s knee-joint. Experiments were conducted in six able-bodied individuals. Compared to conventional stimulation, the results indicate that asynchronous stimulation with the developed controller yields longer durations of successful tracking despite different responses between the stimulation channels. [ABSTRACT FROM PUBLISHER]

Asynchronous intrafascicular multi-electrode stimulation (aIFMS) of small independent populations of peripheral nerve motor axons can evoke selective, fatigue-resistant muscle forces. We previously developed a real-time proportional closed-loop control method for aIFMS generation of isometric muscle force and the present work extends and adapts this closed-loop controller to the more demanding task of dynamically controlling joint position in the presence of opposing joint torque. A proportional-integral-velocity controller, with integrator anti-windup strategies, was experimentally validated as a means to evoke motion about the hind-limb ankle joint of an anesthetized feline via aIFMS stimulation of fast-twitch plantar-flexor muscles. The controller was successful in evoking steps in joint position with 2.4% overshoot, 2.3-s rise time, 4.5-s settling time, and near-zero steady-state error. Controlled step responses were consistent across changes in step size, stable against external disturbances, and reliable over time. The controller was able to evoke smooth eccentric motion at joint velocities up to 8 deg./s, as well as sinusoidal trajectories with frequencies up to 0.1 Hz, with time delays less than 1.5 s. These experiments provide important insights toward creating a robust closed-loop aIFMS controller that can evoke precise fatigue-resistant motion in paralyzed individuals, despite the complexities introduced by aIFMS.

Asynchronous intrafascicular multi-electrode stimulation (aIFMS) of small independent populations of peripheral nerve motor axons can evoke selective, fatigue-resistant muscle forces. We previously developed a real-time proportional closed-loop control method for aIFMS generation of isometric muscle force and the present work extends and adapts this closed-loop controller to the more demanding task of dynamically controlling joint position in the presence of opposing joint torque. A proportional-integral-velocity controller, with integrator anti-windup strategies, was experimentally validated as a means to evoke motion about the hind-limb ankle joint of an anesthetized feline via aIFMS stimulation of fast-twitch plantar-flexor muscles. The controller was successful in evoking steps in joint position with 2.4% overshoot, 2.3-s rise time, 4.5-s settling time, and near-zero steady-state error. Controlled step responses were consistent across changes in step size, stable against external disturbances, and reliable over time. The controller was able to evoke smooth eccentric motion at joint velocities up to 8 deg./s, as well as sinusoidal trajectories with frequencies up to 0.1Hz, with time delays less than 1.5 s. These experiments provide important insights toward creating a robust closed-loop aIFMS controller that can evoke precise fatigue-resistant motion in paralyzed individuals, despite the complexities introduced by aIFMS. [ABSTRACT FROM AUTHOR]

Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitative settings and is also used for assistive purposes to create functional movements, where it is termed functional electrical stimulation (FES). One limitation of NMES/FES is early onset of muscle fatigue. NMES-induced fatigue can be reduced by switching between multiple stimulation channels that target different motor units or synergistic muscles (i.e., asynchronous stimulation). However, switching stimulation channels introduces additional complexity due to the need to consider the switching dynamics and differing muscle response to stimulation. The objective of this study was to develop and test a closed-loop controller for asynchronous stimulation. The developed closed-loop controller yields asymptotic tracking of a desired trajectory for a person’s knee-shank complex despite switching between stimulation channels. The developed controller was implemented on four able-bodied individuals with four-channel asynchronous stimulation as well as single-channel conventional stimulation. The results indicate that asynchronous stimulation extends the duration that functional movements can be performed during feedback control. This result is promising for the implementation of asynchronous stimulation in closed-loop rehabilitative procedures and in assistive devices as a method to reduce muscle fatigue while maintaining a person's ability to track a desired limb trajectory. [ABSTRACT FROM AUTHOR]

Neuromuscular electrical stimulation (NMES) has been shown to impart a number of health benefits and can be used to produce functional outcomes. However, one limitation of NMES is the onset of NMES-induced fatigue. Multi-channel asynchronous stimulation has been shown to reduce NMES-induced fatigue compared to conventional single-channel stimulation. However, in previous studies in man, the effect of stimulation frequency on the NMES-induced fatigue has not been examined for asynchronous stimulation. Low stimulation frequencies are known to reduce fatigue during conventional stimulation. Therefore, the aim of this study was to examine the fatigue characteristics of high- and low-frequency asynchronous stimulation as well as high- and low-frequency conventional stimulation. Experiments were performed in both able-bodied and spinal cord injured populations. Low frequency asynchronous stimulation is found to have significant fatigue benefits over high frequency asynchronous stimulation as well as high- and low-frequency conventional stimulation, motivating its use for rehabilitation and functional electrical stimulation (FES). [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Asynchronous stimulation has been shown to reduce fatigue during electrical stimulation; however, it may also exhibit a force ripple. We quantified the ripple during asynchronous and conventional single-channel transcutaneous stimulation across a range of stimulation frequencies. Methods: The ripple was measured during 5 asynchronous stimulation protocols, 2 conventional stimulation protocols, and 3 volitional contractions in 12 healthy individuals. Results: Conventional 40 H z and asynchronous 16 H z stimulation were found to induce contractions that were as smooth as volitional contractions. Asynchronous 8, 10, and 12 H z stimulation induced contractions with significant ripple. Conclusions: Lower stimulation frequencies can reduce fatigue; however, they may also lead to increased ripple. Future efforts should study the relationship between force ripple and the smoothness of the evoked movements in addition to the relationship between stimulation frequency and NMES-induced fatigue to elucidate an optimal stimulation frequency for asynchronous stimulation. Muscle Nerve 50: 549-555, 2014 [ABSTRACT FROM AUTHOR]

Objective. The spatial resolution of an implantable neural stimulator can be improved by creation of virtual channels (VCs). VCs are commonly achieved through synchronized stimulation of multiple electrodes. It remains unknown whether asynchronous stimulation is able to generate comparable VC performance in retinal stimulation, and how VC can be optimized by re-designing stimulation settings. This study begins with exploring the feasibility of creating VCs using synchronous and asynchronous epiretinal stimulation, and ending with predicting the possible VC performance with a thorough exploration of stimulation parameter space. Approach. A computational model of epiretinal dual-electrode stimulation is developed to simulate the neural activity of a population of retinal ganglion cells (RGCs) under both synchronous and asynchronous stimulation conditions. The interaction between the electrode and RGCs under a range of stimulation parameters are simulated. Main results. Our simulation based on direct RGC activation suggests that VCs can be created using asynchronous stimulation. Two VC performance measures: 1) linearity in the change in centroid location of activated RGC populations, and 2) consistency in the size of activated RGC populations, have comparable performance under asynchronous and synchronous stimulation with appropriately selected stimulation parameters. Significance. Our findings support the possibility of creating VCs by directly activating RGCs under synchronous and asynchronous stimulation conditions. This study establishes the fundamental capability of VC creation based on temporal interactions within the RGC population alone and does not include the effects of potential indirect activation of any surviving inner retinal network neurons. Our results provide theoretical evidence for designing next-generation retinal prosthesis with higher spatial resolution., (© 2020 IOP Publishing Ltd.)

Introduction: Functional electrical stimulation is a common technique used in the rehabilitation of individuals with a spinal cord injury to produce functional movement of paralysed muscles. However, it is often associated with rapid muscle fatigue which limits its applications. Methods: The objective of this study is to investigate the effects on the onset of fatigue of different multi-electrode patterns of stimulation via multiple pairs of electrodes using doublet pulses: Synchronous stimulation is compared to asynchronous stimulation patterns which are activated sequentially (AsynS) or randomly (AsynR), mimicking voluntary muscle activation by targeting different motor units. We investigated these three different approaches by applying stimulation to the gastrocnemius muscle repeatedly for 10 min (300 ms stimulation followed by 700 ms of no-stimulation) with 40 Hz effective frequency for all protocols and doublet pulses with an inter-pulse-interval of 6 ms. Eleven able-bodied volunteers (28 ± 3 years old) participated in this study. Ultrasound videos were recorded during stimulation to allow evaluation of changes in muscle morphology. The main fatigue indicators we focused on were the normalised fatigue index, fatigue time interval and pre-post twitch-tetanus ratio. Results: The results demonstrate that asynchronous stimulation with doublet pulses gives a higher normalised fatigue index (0.80 ± 0.08 and 0.87 ± 0.08) for AsynS and AsynR, respectively, than synchronous stimulation (0.62 ± 0.06). Furthermore, a longer fatigue time interval for AsynS (302.2 ± 230.9 s) and AsynR (384.4 ± 279.0 s) compared to synchronous stimulation (68.0 ± 30.5 s) indicates that fatigue occurs later during asynchronous stimulation; however, this was only found to be statistically significant for one of two methods used to calculate the group mean. Although no significant difference was found in pre-post twitch-tetanus ratio, there was a trend towards these effects. Conclusion: In this study, we proposed an asynchronous stimulation pattern for the application of functional electrical stimulation and investigated its suitability for reducing muscle fatigue compared to previous methods. The results show that asynchronous multi-electrode stimulation patterns with doublet pulses may improve fatigue resistance in functional electrical stimulation applications in some conditions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cochlear implants currently fail to convey phase information, which is important for perceiving music, tonal languages, and for hearing in noisy environments. We propose a bio-inspired asynchronous interleaved sampling (AIS) algorithm that encodes both envelope and phase information, in a manner that may be suitable for delivery to cochlear implant users. Like standard continuous interleaved sampling (CIS) strategies, AIS naturally meets the interleaved-firing requirement, which is to stimulate only one electrode at a time, minimizing electrode interactions. The majority of interspike intervals are distributed over 1-4 ms, thus staying within the absolute refractory limit of neurons, and form a more natural, pseudostochastic pattern of firing due to complex channel interactions. Stronger channels are selected to fire more often but the strategy ensures that weaker channels are selected to fire in proportion to their signal strength as well. The resulting stimulation rates are considerably lower than those of most modern implants, saving power yet delivering higher potential performance. Correlations with original sounds were found to be significantly higher in AIS reconstructions than in signal reconstructions using only envelope information. Two perceptual tests on normal-hearing listeners verified that the reconstructed signals enabled better melody and speech recognition in noise than those processed using tone-excited envelope-vocoder simulations of cochlear implant processing. Thus, our strategy could potentially save power and improve hearing performance in cochlear implant users. [ABSTRACT FROM AUTHOR]