Identifying SCS Trial Responders Immediately After Postoperative Programming with ECAP Dose-Controlled Closed-Loop Therapy.

INTRODUCTION: Drawbacks of fixed-output spinal cord stimulation (SCS) screening trials may lead to compromised trial outcomes and poor predictability of long-term success. Evoked compound action potential (ECAP) dose-controlled closed-loop (CL) SCS allows objective confirmation of therapeutic neural activation and pulse-to-pulse stimulation adjustment. We report on the immediate patient-reported and neurophysiologic treatment response post-physiologic CL-SCS and feasibility of early SCS trial responder prediction. METHODS: Patient-reported pain relief, functional improvement, and willingness to proceed to permanent implant were compared between the day of the trial procedure (Day 0) and end of trial (EOT) for 132 participants in the ECAP Study undergoing a trial stimulation period. ECAP-based neurophysiologic measurements from Day 0 and EOT were compared between responder groups. RESULTS: A high positive predictive value (PPV) was achieved with 98.4% (60/61) of patients successful on the Day 0 evaluation also responding at EOT. The false-positive rate (FPR) was 5.6% (1/18). ECAP-based neurophysiologic measures were not different between patients who passed all Day 0 success criteria ("Day 0 successes") and those who did not ("needed longer to evaluate the therapy"). However, at EOT, responders had higher therapeutic usage and dose levels compared to non-responders. CONCLUSIONS: The high PPV and low FPR of the Day 0 evaluation provide confidence in predicting trial outcomes as early as the day of the procedure. Day 0 trials may be beneficial for reducing patient burden and complication rates associated with extended trials. ECAP dose-controlled CL-SCS therapy may provide objective data and rapid-onset pain relief to improve prognostic ability of SCS trials in predicting outcomes. TRIAL REGISTRATION: The ECAP Study is registered with ClinicalTrials.gov (NCT04319887).

The role of spinal cord neuroanatomy and the variances of epidurally evoked spinal responses.

BACKGROUND: Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. METHOD: Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. RESULTS: Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an 'off-disc' stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. CONCLUSION: The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

Durability of Evoked Compound Action Potential (ECAP)-Controlled, Closed-Loop Spinal Cord Stimulation (SCS) in a Real-World European Chronic Pain Population.

INTRODUCTION: Closed-loop spinal cord stimulation (CL-SCS) is a recently introduced system that records evoked compound action potentials (ECAPs) from the spinal cord elicited by each stimulation pulse and uses this information to automatically adjust the stimulation strength in real time, known as ECAP-controlled SCS. This innovative system compensates for fluctuations in the distance between the epidural leads and the spinal cord by maintaining the neural response (ECAP) at a predetermined target level. This data collection study was designed to assess the performance of the first CL-SCS system in a real-world setting under normal conditions of use in multiple European centers. The study analyzes and presents clinical outcomes and electrophysiological and device data and compares these findings with those reported in earlier pre-market studies of the same system. METHODS: This prospective, multicenter, observational study was conducted in 13 European centers and aimed to gather electrophysiological and device data. The study focused on the real-world application of this system in treating chronic pain affecting the trunk and/or limbs, adhering to standard conditions of use. In addition to collecting and analyzing basic demographic information, the study presents data from the inaugural patient cohort permanently implanted at multiple European centers. RESULTS: A significant decrease in pain intensity was observed for overall back or leg pain scores (verbal numerical rating score [VNRS]) between baseline (mean ± standard error of the mean [SEM]; n = 135; 8.2 ± 0.1), 3 months (n = 93; 2.3 ± 0.2), 6 months (n = 82; 2.5 ± 0.3), and 12 months (n = 76; 2.5 ± 0.3). Comparison of overall pain relief (%) to the AVALON and EVOKE studies showed no significant differences at 3 and 12 months between the real-world data release (RWE; 71.3%; 69.6%) and the AVALON (71.2%; 73.6%) and EVOKE (78.1%; 76.7%) studies. Further investigation was undertaken to objectively characterize the physiological parameters of SCS therapy in this cohort using the metrics of percent time above ECAP threshold (%), dose ratio, and dose accuracy (µV), according to previously described methods. Results showed that a median of 90% (40.7-99.2) of stimuli were above the ECAP threshold, with a dose ratio of 1.3 (1.1-1.4) and dose accuracy of 4.4 µV (0.0-7.1), based on data from 236, 230, and 254 patients, respectively. Thus, across all three metrics, the majority of patients had objective therapy metrics corresponding to the highest levels of pain relief in previously reported studies (usage over threshold > 80%, dose ratio > 1.2, and error < 10 µV). CONCLUSIONS: In conclusion, this study provides valuable insights into the real-world application of the ECAP-controlled CL-SCS system, highlighting its potential for maintaining effective pain relief and objective neurophysiological therapy metrics at levels seen in randomized control trials, and potential for quantifying patient burden associated with SCS system use via patient-device interaction metrics. CLINICAL TRIAL REGISTRATION: In the Netherlands, the study is duly registered on the International Clinical Trials Registry Platform (Trial NL7889). In Germany, the study is duly registered as NCT05272137 and in the United Kingdom as ISCRTN27710516 and has been reviewed by the ethics committee in both countries.

The Origin Along the Cochlea of Otoacoustic Emissions Evoked by Mid-Frequency Tone Pips.

PURPOSE: Tone-pip-evoked otoacoustic emissions (PEOAEs) are transient-evoked otoacoustic emissions (OAEs) that are hypothesized to originate from reflection of energy near the best-frequency (BF) cochlear place of the stimulus frequency. However, individual PEOAEs have energy with a wide range of delays. We sought to determine whether some PEOAE energy is consistent with having been generated far from BF. METHODS: PEOAEs from 35 and 47 dB SPL tone pips were obtained by removing pip-stimulus energy by subtracting the ear-canal sound pressure from scaled-down 59 dB SPL tone pips (which evoke relatively small OAEs). PEOAE delays were measured at each peak in the PEOAE absolute-value waveforms. While measuring PEOAEs and auditory-nerve compound action potentials (CAPs), amplification was blocked sequentially from apex to base by cochlear salicylate perfusion. The perfusion time when a CAP was reduced identified when the perfusion reached the tone-pip BF place. The perfusion times when each PEOAE peak was reduced identified where along the cochlea it received cochlear amplification. PEOAEs and CAPs were measured simultaneously using one pip frequency in each ear (1.4 to 4 kHz across 16 ears). RESULTS: Most PEOAE peaks received amplification primarily between the BF place and 1-2 octaves basal of the BF place. PEOAE peaks with short delays received amplification basal of BF place. PEOAE peaks with longer delays sometimes received amplification apical of BF place, consistent with previous stimulus-frequency-OAE results. CONCLUSION: PEOAEs provide information about cochlear amplification primarily within ~ 1.5 octave of the tone-pip BF place, not about regions > 3 octaves basal of BF.

Astragaloside depresses compound action potential in sciatic nerve of frogs involved in L-type Ca2+-channel dependent mechanism.

The sciatic nerve is the largest sensorimotor nerve within the peripheral nervous system (PNS), possessing the ability to produce endogenous neurotrophins. Compound nerve action potentials (CNAPs) are regarded as a physiological/pathological indicator to identify nerve activity in signal transduction of the PNS. Astragaloside (AST), a small-molecule saponin purified from Astragalus membranaceus, is widely used to treat chronic disease. Nonetheless, the regulatory effects of AST on the sciatic nerve remain unknown. Therefore, the present investigation was undertaken to study the effect of AST on CNAPs of frog sciatic nerves. Here, AST depressed the conduction velocity and amplitude of CNAPs. Importantly, the AST-induced responses could be blocked by a Ca2+-free medium, or by applying all Ca2+ channel antagonists (CdCl2/LaCl3) or L-type Ca2+ channel blockers (nifedipine/diltiazem), but not the T-type and P-type Ca2+ channel antagonist (NiCl2). Altogether, these findings suggested that AST may attenuate the CNAPs of frog sciatic nerves in vitro via the L-type Ca2+-channel dependent mechanisms.

Role of tactile stimulation during the preweaning period on the development of the peripheral sensory sural (SU) nerve in adult artificially reared female rat.

Maternal deprivation, as a result of the artificial rearing (AR) paradigm, disturbs electrophysiological and histological characteristics of the peripheral sensory sural (SU) nerve of infant and adult male rats. Such changes are prevented by providing tactile or social stimulation during isolation. AR also affects the female rat's brain and behavior; however, it is unknown whether this early adverse experience also alters their SU nerve development or if tactile stimulation might prevent these possible developmental effects. To assess these possibilities, the electrophysiological and histological characteristics of the SU nerve from adult diestrus AR female rats that: (i) received no tactile stimulation (AR group), (ii) received tactile stimulation in the anogenital and body area (AR-Tactile group), or (iii) were mother reared (MR group) were determined. We found that the amplitude, but not the area, of the evoked compound action potential response in SU nerves of AR rats was lower than those of SU nerves of MR female rats. Tactile stimulation prevented these effects. Additionally, we found a reduction in the outer diameter and myelin thickness of axons, as well as a large proportion of axons with low myelin thickness in nerves of AR rats compared to the nerves of the MR and AR-Tactile groups of rats; however, tactile stimulation only partially prevented these effects. Our data indicate that maternal deprivation disturbs the development of sensory SU nerves in female rats, whereas tactile stimulation partially prevents the changes generated by AR. Considering that our previous studies have shown more severe effects of AR on male SU nerve development, we suggest that sex-associated factors may be involved in these processes.

Association Between Intracochlear Electrode Design and Electrically-Evoked Compound Action Potential Measures in Cochlear Implant Users.

OBJECTIVE: Cochlear implant (CI) electrode design has changed over time. Changes in intracochlear electrode design might influence the spread of neural activation along the auditory nerve and the number of independent channels. This study aimed to investigate the impact of intracochlear electrode design on the electrode-neuron interface using electrophysiological measures. STUDY DESIGN: Prospective cohort study. SETTING: A single tertiary hospital. METHODS: Fifty-two ears who were implanted with CI divided into 3 groups based on the design of intracochlear electrode arrays. Twenty-three ears were implanted with lateral wall straight electrodes. Eighteen ears were implanted with the slim perimodiolar electrode, and 11 ears were implanted with the old perimodiolar electrode. Various electrically-evoked compound action potential (ECAP) metrics were measured to quantify spread of excitation and channel interaction. RESULTS: ECAP threshold and slope were not significantly different among groups. ECAP spread of excitation (SOE) half-width and channel interaction index (CII) were significantly larger in subjects implanted with the lateral wall straight electrodes, indicating a wider spread of excitation compared to those with perimodiolar electrodes. Electrode impedance was significantly lower in subjects implanted with perimodiolar electrodes than those with lateral wall electrodes. CONCLUSION: Perimodiolar electrode groups yielded significantly narrower SOE half-widths and smaller CII than the lateral wall straight electrode group. This may indicate that the electrode array that hugged the modiolus had less overlap in neural excitation between adjacent electrodes, resulting in reduced channel interaction and potentially better spectral resolution than the electrode array positioned more laterally.

Inhibition of compound action potentials in the frog sciatic nerve by inchinkoto, a traditional Japanese medicine used for oral mucositis.

OBJECTIVE: This study aimed to determine the effects of traditional Japanese (Kampo) medicines used to treat oral mucositis on nerve conduction. METHODS: The effects of Kampo medicines, crude drugs, and chemical compounds on compound action potentials (CAPs) were analyzed using extracellular recordings in frog sciatic nerves. RESULTS: Among the Kampo medicines, inchinkoto demonstrated the most significant reduction in CAP amplitude, with a half-maximal inhibitory concentration (IC50) of 5.4 mg/mL. Hangeshashinto, shosaikoto, hochuekkito, and juzentaihoto also showed a significant reduction. Regarding inchinkoto, Artemisiae Capillari Spica (artemisia) was the most effective crude drug, with an IC50 of 4.2 mg/mL for CAP amplitude reduction, whereas Gardeniae Fructus (gardenia) exerted no significant effect. However, the combined use of artemisia and gardenia reduced the CAP amplitude more effectively than artemisia alone, indicating a synergistic interaction. The chemical ingredient eugenol from artemisia administered at 1 and 3 mmol/L reduced CAP amplitude, whereas other chemical ingredients administered at 0.1 and 1 mmol/L had no significant effects. CONCLUSIONS: Inchinkoto exhibited the most effective reduction in CAP amplitude in the sciatic nerve of frogs, primarily through the action of artemisia, with potential synergistic interaction between artemisia and gardenia.

Estimation of Cochlear Frequency Selectivity Using a Convolution Model of Forward-Masked Compound Action Potentials.

PURPOSE: Frequency selectivity is a fundamental property of the peripheral auditory system; however, the invasiveness of auditory nerve (AN) experiments limits its study in the human ear. Compound action potentials (CAPs) associated with forward masking have been suggested as an alternative to assess cochlear frequency selectivity. Previous methods relied on an empirical comparison of AN and CAP tuning curves in animal models, arguably not taking full advantage of the information contained in forward-masked CAP waveforms. METHODS: To improve the estimation of cochlear frequency selectivity based on the CAP, we introduce a convolution model to fit forward-masked CAP waveforms. The model generates masking patterns that, when convolved with a unitary response, can predict the masking of the CAP waveform induced by Gaussian noise maskers. Model parameters, including those characterizing frequency selectivity, are fine-tuned by minimizing waveform prediction errors across numerous masking conditions, yielding robust estimates. RESULTS: The method was applied to click-evoked CAPs at the round window of anesthetized chinchillas using notched-noise maskers with various notch widths and attenuations. The estimated quality factor Q10 as a function of center frequency is shown to closely match the average quality factor obtained from AN fiber tuning curves, without the need for an empirical correction factor. CONCLUSION: This study establishes a moderately invasive method for estimating cochlear frequency selectivity with potential applicability to other animal species or humans. Beyond the estimation of frequency selectivity, the proposed model proved to be remarkably accurate in fitting forward-masked CAP responses and could be extended to study more complex aspects of cochlear signal processing (e.g., compressive nonlinearities).

Evoked compound action potential (ECAP)-controlled closed-loop spinal cord stimulation in an experimental model of neuropathic pain in rats.

BACKGROUND: Preclinical models of spinal cord stimulation (SCS) are lacking objective measurements to inform translationally applicable SCS parameters. The evoked compound action potential (ECAP) represents a measure of dorsal column fiber activation. This measure approximates the onset of SCS-induced sensations in humans and provides effective analgesia when used with ECAP-controlled closed-loop (CL)-SCS systems. Therefore, ECAPs may provide an objective surrogate for SCS dose in preclinical models that may support better understanding of SCS mechanisms and further translations to the clinics. This study assessed, for the first time, the feasibility of recording ECAPs and applying ECAP-controlled CL-SCS in freely behaving rats subjected to an experimental model of neuropathic pain. METHODS: Adult male Sprague-Dawley rats (200-300 g) were subjected to spared nerve injury (SNI). A custom-made six-contact lead was implanted epidurally covering T11-L3, as confirmed by computed tomography or X-ray. A specially designed multi-channel system was used to record ECAPs and to apply ECAP-controlled CL-SCS for 30 min at 50 Hz 200 µs. The responses of dorsal column fibers to SCS were characterized and sensitivity towards mechanical and cold stimuli were assessed to determine analgesic effects from ECAP-controlled CL-SCS. Comparisons between SNI rats and their controls as well as between stimulation parameters were made using omnibus analysis of variance (ANOVA) tests and t-tests. RESULTS: The recorded ECAPs showed the characteristic triphasic morphology and the ECAP amplitude (mV) increased as higher currents (mA) were applied in both SNI animals and controls (SNI SCS-ON and sham SCS-ON). Importantly, the use of ECAP-based SCS dose, implemented in ECAP-controlled CL-SCS, significantly reduced mechanical and cold hypersensitivity in SNI SCS-ON animals through the constant and controlled activation of dorsal column fibers. An analysis of conduction velocities of the evoked signals confirmed the involvement of large, myelinated fibers. CONCLUSIONS: The use of ECAP-based SCS dose implemented in ECAP-controlled CL-SCS produced analgesia in animals subjected to an experimental model of neuropathic pain. This approach may offer a better method for translating SCS parameters between species that will improve understanding of the mechanisms of SCS action to further advance future clinical applications.

A new method for removing artifacts from recordings of the electrically evoked compound action potential: Single-pulse stimulation.

This report presents a new method for removing electrical artifact contamination from the electrically evoked compound action potential (eCAP) evoked by single cathodic-leading, biphasic-pulse stimulation. The development of the new method is motivated by results recorded in human cochlear implant (CI) users showing that the fundamental assumption of the classic forward masking artifact rejection technique is violated in up to 45% of cases tested at high stimulation levels when using default stimulation parameters. Subsequently, the new method developed based on the discovery that a hyperbola best characterizes the artifacts created during stimulation and recording is described. The eCAP waveforms obtained using the new method are compared to those recorded using the classic forward masking technique. The results show that eCAP waveforms obtained using both methods are comparable when the fundamental assumption of the classic forward masking technique is met. In contrast, eCAP amplitudes obtained using the two methods are significantly different when the fundamental assumption of the classic forward masking technique is violated, with greater differences in the eCAP amplitude for greater assumption violations. The new method also has excellent test-retest reliability (Intraclass correlation > 0.98). Overall, the new method is a viable alternative to the classic forward masking technique for obtaining artifact-free eCAPs evoked by single-pulse stimulation in CI users.

Exploring Electrode Placements to Optimize the Identification and Measurement of Early Auditory Evoked Potentials.

Cochlear synaptic loss (termed cochlear synaptopathy) has been suggested to contribute to suprathreshold hearing difficulties. However, its existence and putative effects in humans remain inconclusive, largely due to the heterogeneous methods used across studies to indirectly evaluate the health of cochlear synapses. There is a need to standardize proxies of cochlear synaptopathy to appropriately compare and interpret findings across studies. Early auditory evoked potentials (AEPs), including the compound action potential (AP)/Wave I of the auditory brainstem response are a popular proxy, yet remain variable based on technical considerations. This study evaluated one such consideration-electrode array (i.e., montage)-to optimize the use of early AEP waveforms. In 35 young adults, electrocochleography (ECochG) responses were collected using vertical and horizontal montages. Standard ECochG measures and AP/Wave I and Wave II peak-to-trough amplitudes and latencies were compared between montages. Vertical montage recordings consistently produced significantly larger AP/Wave I peak-to-trough amplitudes compared to horizontal recordings. These findings support the use of a vertical electrode montage for optimal recordings of peripheral cochlear nerve activity. As cochlear synaptopathy continues to be explored in humans, the methods highlighted here should be considered in the development of a standardized assessment.

Vestibular Testing-New Physiological Results for the Optimization of Clinical VEMP Stimuli.

Both auditory and vestibular primary afferent neurons can be activated by sound and vibration. This review relates the differences between them to the different receptor/synaptic mechanisms of the two systems, as shown by indicators of peripheral function-cochlear and vestibular compound action potentials (cCAPs and vCAPs)-to click stimulation as recorded in animal studies. Sound- and vibration-sensitive type 1 receptors at the striola of the utricular macula are enveloped by the unique calyx afferent ending, which has three modes of synaptic transmission. Glutamate is the transmitter for both cochlear and vestibular primary afferents; however, blocking glutamate transmission has very little effect on vCAPs but greatly reduces cCAPs. We suggest that the ultrafast non-quantal synaptic mechanism called resistive coupling is the cause of the short latency vestibular afferent responses and related results-failure of transmitter blockade, masking, and temporal precision. This "ultrafast" non-quantal transmission is effectively electrical coupling that is dependent on the membrane potentials of the calyx and the type 1 receptor. The major clinical implication is that decreasing stimulus rise time increases vCAP response, corresponding to the increased VEMP response in human subjects. Short rise times are optimal in human clinical VEMP testing, whereas long rise times are mandatory for audiometric threshold testing.

Histological Correlates of Auditory Nerve Injury from Kainic Acid in the Budgerigar (Melopsittacus undulatus).

PURPOSE: Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure. The perceptual consequences of synaptopathy in isolation from other cochlear pathologies are still unclear. Animal models provide an effective approach to resolve uncertainty regarding the physiological and perceptual consequences of auditory nerve loss, because neural lesions can be induced and readily quantified. The budgerigar, a parakeet species, has recently emerged as an animal model for synaptopathy studies based on its capacity for vocal learning and ability to behaviorally discriminate simple and complex sounds with acuity similar to humans. Kainic acid infusions in the budgerigar produce a profound reduction of compound auditory nerve responses, including wave I of the auditory brainstem response, without impacting physiological hair cell measures. These results suggest selective auditory nerve damage. However, histological correlates of neural injury from kainic acid are still lacking. METHODS: We quantified the histological effects caused by intracochlear infusion of kainic acid (1 mM; 2.5 µL), and evaluated correlations between the histological and physiological assessments of auditory nerve status. RESULTS: Kainic acid infusion in budgerigars produced pronounced loss of neural auditory nerve soma (60% on average) in the cochlear ganglion, and of peripheral axons, at time points 2 or more months following injury. The hair cell epithelium was unaffected by kainic acid. Neural loss was significantly correlated with reduction of compound auditory nerve responses and auditory brainstem response wave I. CONCLUSION: Compound auditory nerve responses and wave I provide a useful index of cochlear synaptopathy in this animal model.

Electrically evoked compound action potentials in cochlear implant users with preoperative residual hearing.

Introduction: Residual hearing in cochlear implant (CI) candidates requires the functional integrity of the nerve in particular regions of the cochlea. Nerve activity can be elicited as electrically evoked compound action potentials (ECAP) after cochlear implantation. We hypothesize that ECAP thresholds depend on preoperative residual hearing ability. Materials and methods: In a retrospective study, we analyzed 84 adult cochlear implant users who had received a Nucleus® CI632 Slim Modiolar Electrode and who preoperatively had had residual hearing. Inclusion criteria were severe to profound hearing loss with preoperative measurable hearing in the ear to receive the implant, postlingual hearing loss, German as native language and correct placement of the electrode, inserted completely into the scala tympani. Electrically evoked compound action potential (ECAP) was recorded intraoperatively. The angular insertion was measured for each electrode contact from postoperative computed tomography to estimate the corresponding spiral ganglion frequency. Pure-tone audiometry and allocated ECAP thresholds were tested to investigate possible correlation. Results: The average of hearing thresholds, tested at 0.5, 1, 2, and 4 kHz (4FPTA) was 82 ± 18 (range 47-129) dB HL. The success rate for recording ECAP thresholds was 96.9%. For all comparable pure-tone frequencies (1, 2, 4, and 8 kHz), there was significant correlation between preoperative hearing levels and intraoperative ECAP thresholds (p < 0.001). Higher hearing thresholds are associated with increased ECAP thresholds. Conclusion: In CI candidates with adequate residual hearing, intraoperative electrophysiological measurement records lower thresholds. This outcome may be explained by the neural survival density of the peripheral system, with less neural degeneration.

First Report on Real-World Outcomes with Evoked Compound Action Potential (ECAP)-Controlled Closed-Loop Spinal Cord Stimulation for Treatment of Chronic Pain.

INTRODUCTION: A novel closed-loop spinal cord stimulation (SCS) system has recently been approved for use which records evoked compound action potentials (ECAPs) from the spinal cord and utilizes these recordings to automatically adjust the stimulation strength in real time. It automatically compensates for fluctuations in distance between the epidural leads and the spinal cord by maintaining the neural response (ECAP) at a determined target level. This data collection was principally designed to evaluate the performance of this first closed-loop SCS system in a 'real-world' setting under normal conditions of use in a single European center. METHODS: In this prospective, single-center observational data collection, 22 patients were recruited at the outpatient pain clinic of the St. Antonius Hospital. All candidates were suffering from chronic pain in the trunk and/or limbs due to PSPS type 2 (persistent spinal pain syndrome). As standard of care, follow-up visits were completed at 3 months, 6 months, and 12 months post-device activation. Patient-reported outcome data (pain intensity, patient satisfaction) and electrophysiological and device data (ECAP amplitude, conduction velocity, current output, pulse width, frequency, usage), and patient interaction with their controller were collected at baseline and during standard of care follow-up visits. RESULTS: Significant decreases in pain intensity for overall back or leg pain scores (verbal numerical rating score = VNRS) were observed between baseline [mean ± SEM (standard error of the mean); n = 22; 8.4 ± 0.2)], 3 months (n = 12; 1.9 ± 0.5), 6 months (n = 16; 2.6 ± 0.5), and 12 months (n = 20; 2.0 ± 0.5), with 85.0% of the patients being satisfied at 12 months. Additionally, no significant differences in average pain relief at 3 months and 12 months between the real-world data (77.2%; 76.8%) and the AVALON (71.2%; 73.6%) and EVOKE (78.1%; 76.7%) studies were observed. CONCLUSIONS: These initial 'real-world' data on ECAP-controlled, closed-loop SCS in a real-world clinical setting appear to be promising, as they provide novel insights of the beneficial effect of ECAP-controlled, closed-loop SCS in a real-world setting. The presented results demonstrate a noteworthy maintenance of pain relief over 12 months and corroborate the outcomes observed in the AVALON prospective, multicenter, single-arm study and the EVOKE double-blind, multicenter, randomized controlled trial. TRIAL REGISTRATION: The data collection is registered on the International Clinical Trials Registry Platform (Trial NL7889).

Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers.

Introduction: Electrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges. In this study we employed a combined protocol of optical and electrical stimulation to the sciatic nerve in an optogenetic mouse model to allow for better selectivity, efficiency, and safety to overcome fundamental limitations of electrical-only and optical-only stimulation. Methods: The sciatic nerve was surgically exposed in anesthetized mice (n = 12) expressing the ChR2-H134R opsin via the parvalbumin promoter. A custom-made peripheral nerve cuff electrode and a 452 nm laser-coupled optical fiber were used to elicit neural activity utilizing optical-only, electrical-only, or combined stimulation. Activation thresholds for the individual and combined responses were measured. Results: Optically evoked responses had a conduction velocity of 34.3 m/s, consistent with ChR2-H134R expression in proprioceptive and low-threshold mechanoreceptor (Aα/Aß) fibers which was also confirmed via immunohistochemical methods. Combined stimulation, utilizing a 1 ms near-threshold light pulse followed by an electrical pulse 0.5 ms later, approximately halved the electrical threshold for activation (p = 0.006, n = 5) and resulted in a 5.5 dB increase in the Aα/Aß hybrid response amplitude compared to the electrical-only response at equivalent electrical levels (p = 0.003, n = 6). As a result, there was a 3.25 dB increase in the therapeutic stimulation window between the Aα/Aß fiber and myogenic thresholds (p = 0.008, n = 4). Discussion: The results demonstrate that light can be used to prime the optogenetically modified neural population to reside near threshold, thereby selectively reducing the electrical threshold for neural activation in these fibers. This reduces the amount of light needed for activation for increased safety and reduces potential off-target effects by only stimulating the fibers of interest. Since Aα/Aß fibers are potential targets for neuromodulation in chronic pain conditions, these findings could be used to develop effective strategies to selectively manipulate pain transmission pathways in the periphery.

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation.

Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave ("S1") starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trunk EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared with ECAPs. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; a selective competitive antagonist of AMPA receptors (AMPARs)] significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50-Hz SCS resulted in dampening of S1-wave but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: evoked synaptic activity potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.

Comparison Between the Effect of Intra-Scalar Methylprednisolone and Sodium Hyaluronate in Impedance and Electrically Evoked Compound Action Potentials in Cochlear Implant Patients.

To evaluate and compare the effect of intra-scalar methylprednisolone and sodium hyaluronate on cochlear implants' impedance and electrically evoked compound action potentials thresholds. In a prospective randomized clinical trial, 103 children with pre-lingual hearing loss candidates for cochlear implantation at a tertiary hospital were divided into three groups based on intervention. Intraoperatively, one group received intra-scalar methylprednisolone, the second sodium hyaluronate, and the third group was the control group. Impedance and electrically evoked compound action potentials (e-ECAP) thresholds on long-term follow-up were evaluated and compared in these three groups. Significant decrease in impedance and e-ECAP thresholds were observed in all groups in a 4-year follow-up. No statistically significant difference was observed among all mentioned groups. Impedance and e-ECAP thresholds decrease in the long term, and using topical intra-scalar Healon or methylprednisolone may not significantly affect these parameters.

Characterization and applications of evoked responses during epidural electrical stimulation.

BACKGROUND: Epidural electrical stimulation (EES) of the spinal cord has been FDA approved and used therapeutically for decades. However, there is still not a clear understanding of the local neural substrates and consequently the mechanism of action responsible for the therapeutic effects. METHOD: Epidural spinal recordings (ESR) are collected from the electrodes placed in the epidural space. ESR contains multi-modality signal components such as the evoked neural response (due to tonic or BurstDR™ waveforms), evoked muscle response, stimulation artifact, and cardiac response. The tonic stimulation evoked compound action potential (ECAP) is one of the components in ESR and has been proposed recently to measure the accumulative local potentials from large populations of neuronal fibers during EES. RESULT: Here, we first review and investigate the referencing strategies, as they apply to ECAP component in ESR in the domestic swine animal model. We then examine how ECAP component can be used to sense lead migration, an adverse outcome following lead placement that can reduce therapeutic efficacy. Lastly, we show and isolate concurrent activation of local back and leg muscles during EES, demonstrating that the ESR obtained from the recording contacts contain both ECAP and EMG components. CONCLUSION: These findings may further guide the implementation of recording and reference contacts in an implantable EES system and provide preliminary evidence for the utility of ECAP component in ESR to detect lead migration. We expect these results to facilitate future development of EES methodology and implementation of use of different components in ESR to improve EES therapy.