Spinal Evoked Compound Action Potentials in Rats With Clinically Relevant Stimulation Modalities.

OBJECTIVES: Rats are commonly used for translational pain and spinal cord stimulation (SCS) research. Although many SCS parameters are configured identically between rats and humans, stimulation amplitudes in rats are often programmed relative to visual motor threshold (vMT). Alternatively, amplitudes may be programmed relative to evoked compound action potential (ECAP) thresholds (ECAPTs), a sensed measure of neural activation. The objective of this study was to characterize ECAPTs, evoked compound muscle action potential thresholds (ECMAPTs), and vMTs with clinically relevant SCS modalities. MATERIALS AND METHODS: We implanted ten anesthetized rats with two quadripolar epidural SCS leads: one for stimulating in the lumbar spine, and another for sensing ECAPs in the thoracic spine. We then delivered two SCS paradigms to the rats. The first used 50-Hz SCS with 50-, 100-, 150-, and 200-µs pulse widths (PWs), whereas the second used a 50-Hz, 150-µs PW low-rate program (LRP) multiplexed to a 1200-Hz, 50-µs PW high-rate program (HRP). We increased SCS amplitudes up to the vMT in the first paradigm, and in the second, we increased HRP amplitudes up to the HRP ECAPT with a fixed amplitude (70% of the vMT) LRP. For each test case, we captured ECAPTs, ECMAPTs, and vMTs from each rat. RESULTS: vMTs were 3.0 ± 0.7 times greater than ECAPTs, with vMTs marginally (3.0 ± 3.6%) greater than ECMAPTs (mean ± SD) across all PWs with the first paradigm. With the second paradigm, we noted a negligible increase (3.6 ± 6.2%) on the LRP ECAP as HRP amplitudes were increased. CONCLUSIONS: Our results demonstrate reasonable levels of neural activation in anesthetized rats with SCS amplitudes appropriately programmed relative to vMT or ECMAPT when using clinically relevant SCS modalities. Furthermore, we demonstrate the feasibility of ECAP recording in rats with multiplexed HRP SCS.

Evaluation of Pulse-Width of Spinal Nerve Stimulation in a Rat Model of Bladder Micturition Reflex.

OBJECTIVES: The spinal nerve stimulation (SNS) evoked motor threshold (Tmot ) response across different pulse-widths (PWs) was first explored and a subset of selected stimulation PWs were further assessed with respect to bladder reflex contraction (BRC). MATERIALS AND METHODS: In anesthetized female rats, wire electrodes were placed under each of the L6 spinal nerves to produce bilateral SNS. The relationship of Tmot response with PW was analyzed using a monoexponential nonlinear regression. A cannula was placed into the bladder via the urethra to ensure an isovolumetric bladder. Saline infusion induced BRC. RESULTS: The chronaxie of the Tmot -PW curve was 0.04 ms. The stimulation charges/energies (current × PW) associated with shorter PWs of 0.02, 0.03, and 0.06 ms were significantly lower than those with longer PW (e.g., >0.15 ms). SNS (Tmot , 10 Hz) at selected PWs from 0.03 to 0.21 ms inhibited the frequency of BRCs. There were no significantly different attenuations among tested PWs. SNS of PWs of 0.03, 0.06, and 0.09 ms decreased bladder contraction frequency from 103 ± 3%, 100 ± 4%, and 103 ± 4% of controls, to 52 ± 16% (n = 8, p = 0.02, paired t-test), 56 ± 15% (n = 11, p = 0.02) and 40 ± 19% (n = 10, p = 0.01), respectively. CONCLUSIONS: Effective PWs to produce bladder inhibitory effects in the rat appear much shorter than 0.21 ms typically used with sacral neuromodulation in practice. Potential battery savings manifested by shorter PW while maintaining equivalent efficacy would provide more efficient therapy delivery and increased longevity of the stimulator.

Comparison of Active Stimulating Electrodes of Sacral Neuromodulation.

OBJECTIVE: The goal of this study was to compare the motor response to sacral neuromodulation (SNM) with different pairs of stimulating electrodes in anesthetized and awake sheep. MATERIALS AND METHODS: Similar to SNM clinical use in humans, the InterStim® quadripolar tined lead was implanted adjacent to the S3 nerve root in sheep and bipolar stimulation was configured with one electrode negative and one electrode positive on the four contacts (0 most distal to device, 1, 2, and 3 most proximal). RESULTS: Electrode 3-cathode and electrode 0-anode (3-/0+) stimulation had the lowest visual response threshold (0.46 ± 0.14V, anesthetized, 0.56 ± 0.21V, conscious), representing the most sensitive stimulation. Stimulation on electrode 0 (0-/1+) had the highest response threshold among tested electrodes (2.70 ± 0.23V, anesthetized, 3.38 ± 0.96V, conscious). The order according to response threshold from low to high was 3 < 2 < 1 < 0. The triggered response by 3-/0+ stimulation solely occurred in the perineum, tail, or bellows. In contrast, the 0-/1+ stimulation frequently evoked response in gluteal and thigh regions. The electromyographic activities from the anus were sensitive to low intensities of stimulation on electrode 3 (e.g., 3-/0+, 3-/2+). CONCLUSIONS: Objective motor responses to SNM as a functional indicator for optimal lead placement may be used to demonstrate that the contact which is most proximal to the foramen (electrode 3) is an optimal electrode to trigger an "on-target" response to lower intensity stimulation. Data from this preclinical work suggest that there are several principles that may be referenced to simplify and expedite the programming process in clinical practice.

Cardiac sensing at a spinal cord stimulation lead: a promising on-device potential biomarker for pain and wellbeing.

Introduction: In the search for objective measures of therapeutic outcomes for patients with spinal cord stimulation (SCS) devices, various metrics of cardiac performance have been linked to pain as well as overall health. To track such measures at home, recent studies have incorporated wearables to monitor cardiac activity over months or years. The drawbacks to wearables, such as patient compliance, would be obviated by on-device sensing that incorporates the SCS lead. This study sought to evaluate the feasibility of using SCS leads to record cardiac electrograms. Methods: The quality of signals sensed by externalized, percutaneous leads in the thoracic spine of 10 subjects at the end of their SCS trial were characterized across various electrode configurations and postures by detecting R-peaks and calculating signal-to-noise ratio (SNR). In a subset of 5 subjects, cardiac metrics were then compared to those measured simultaneously with a wearable. Results: The average signal quality was acceptable for R-peak detection (i.e., SNR > 5) for all configurations and positions across all 10 subjects, with higher signal quality achieved when recording in resting positions. Notably, the spinal lead recordings enabled more reliable beat detection compared to the wearable (n = 29 recording pairs; p < 0.001). When excluding wearable recordings with over 35% missed beats, the inter-beat intervals across devices were highly correlated (n = 22 recording pairs; Pearson correlation: R = 0.99, p < 0.001). Further comparisons in these aligned wearable and corresponding spinal-lead recordings revealed significant differences in the frequency domain metrics (i.e., absolute and normalized high and low frequency HRV power, p < 0.05), but not in time domain HRV parameters. Discussion: The ability of an implanted SCS system to record electrocardiograms, as demonstrated here, could provide the basis of automated SCS therapy by tracking potential biomarkers of the patient's overall health state without the need for additional external devices.

A distributed, high-channel-count, implanted bidirectional system for restoration of somatosensation and myoelectric control.

Objective. We intend to chronically restore somatosensation and provide high-fidelity myoelectric control for those with limb loss via a novel, distributed, high-channel-count, implanted system.Approach.We have developed the implanted Somatosensory Electrical Neurostimulation and Sensing (iSens®) system to support peripheral nerve stimulation through up to 64, 96, or 128 electrode contacts with myoelectric recording from 16, 8, or 0 bipolar sites, respectively. The rechargeable central device has Bluetooth® wireless telemetry to communicate to external devices and wired connections for up to four implanted satellite stimulation or recording devices. We characterized the stimulation, recording, battery runtime, and wireless performance and completed safety testing to support its use in human trials.Results.The stimulator operates as expected across a range of parameters and can schedule multiple asynchronous, interleaved pulse trains subject to total charge delivery limits. Recorded signals in saline show negligible stimulus artifact when 10 cm from a 1 mA stimulating source. The wireless telemetry range exceeds 1 m (direction and orientation dependent) in a saline torso phantom. The bandwidth supports 100 Hz bidirectional update rates of stimulation commands and data features or streaming select full bandwidth myoelectric signals. Preliminary first-in-human data validates the bench testing result.Significance.We developed, tested, and clinically implemented an advanced, modular, fully implanted peripheral stimulation and sensing system for somatosensory restoration and myoelectric control. The modularity in electrode type and number, including distributed sensing and stimulation, supports a wide variety of applications; iSens® is a flexible platform to bring peripheral neuromodulation applications to clinical reality. ClinicalTrials.gov ID NCT04430218.

Evoked compound action potentials during spinal cord stimulation: effects of posture and pulse width on signal features and neural activation within the spinal cord.

Objective.Evoked compound action potential (ECAP) recordings have emerged as a quantitative measure of the neural response during spinal cord stimulation (SCS) to treat pain. However, utilization of ECAP recordings to optimize stimulation efficacy requires an understanding of the factors influencing these recordings and their relationship to the underlying neural activation.Approach.We acquired a library of ECAP recordings from 56 patients over a wide assortment of postures and stimulation parameters, and then processed these signals to quantify several aspects of these recordings (e.g., ECAP threshold (ET), amplitude, latency, growth rate). We compared our experimental findings against a computational model that examined the effect of variable distances between the spinal cord and the SCS electrodes.Main results.Postural shifts strongly influenced the experimental ECAP recordings, with a 65.7% lower ET and 178.5% higher growth rate when supine versus seated. The computational model exhibited similar trends, with a 71.9% lower ET and 231.5% higher growth rate for a 2.0 mm cerebrospinal fluid (CSF) layer (representing a supine posture) versus a 4.4 mm CSF layer (representing a prone posture). Furthermore, the computational model demonstrated that constant ECAP amplitudes may not equate to a constant degree of neural activation.Significance.These results demonstrate large variability across all ECAP metrics and the inability of a constant ECAP amplitude to provide constant neural activation. These results are critical to improve the delivery, efficacy, and robustness of clinical SCS technologies utilizing these ECAP recordings to provide closed-loop stimulation.

Using evoked compound action potentials to quantify differential neural activation with burst and conventional, 40 Hz spinal cord stimulation in ovines.

Unlike conventional dorsal spinal cord stimulation (SCS)-which uses single pulses at a fixed rate-burst SCS uses a fixed-rate, five-pulse stimuli cluster as a treatment for chronic pain; mechanistic explanations suggest burst SCS differentially modulate the medial and lateral pain pathways vs conventional SCS. Neural activation differences between burst and conventional SCS are quantifiable with the spinal-evoked compound action potential (ECAP), an electrical measure of synchronous neural activation. Methods: We implanted 7 sheep with a dorsal stimulation lead at T9/T10, a dorsal ECAP sensing lead at T6/T7, and a lead also at T9/T10 but adjacent to the anterolateral system (ALS). Both burst and conventional SCS with stimulation amplitudes up to the visual motor threshold (vMT) were delivered to 3 different dorsal spinal locations, and ECAP thresholds (ECAPTs) were calculated for all combinations. Then, changes in ALS activation were assessed with both types of SCS. Results: Evoked compound action potential thresholds and vMTs were significantly higher (P < 0.05) with conventional vs burst SCS, with no statistical difference (P > 0.05) among stimulation sites. However, the vMT-ECAPT window (a proxy for the useable therapeutic dosing range) was significantly wider (P < 0.05) with conventional vs burst SCS. No significant difference (P > 0.05) in ALS activation was noted between conventional and burst SCS. Conclusion: When dosed equivalently, no differentially unique change in ALS activation results with burst SCS vs conventional SCS; in addition, sub-ECAPT burst SCS results in no discernable excitability changes in the neural pathways feeding pain relevant supraspinal sites.

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control.

OBJECTIVES: Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms - both sub- and supra-threshold - are programmed relative to the patient's perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems. METHODS: ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed. RESULTS: ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT (r = 0.93; p < 0.0001) and DT (r = 0.93; p < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture. CONCLUSION: We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.