WO2024102805A1

WO2024102805A1 - Stimulus artifact removal

Info

Publication number: WO2024102805A1
Application number: PCT/US2023/079067
Authority: WO
Inventors: Harrison Carroll WALKER
Original assignee: The Uab Research Foundation
Priority date: 2022-11-10
Filing date: 2023-11-08
Publication date: 2024-05-16

Abstract

The present disclosure provide systems and methods for removing electrical stimulus transients from electrophysiological recordings. One such method comprises delivering a single electrical stimulus pulse to electrically excitable tissue; subsequently delivering a pair of electrical stimulus pulses to the electrically excitable tissue, wherein a first of the pair of electrical stimulus pulses is not delivered during an absolute refractory period for the electrically excitable tissue and a second one of the pair of electrical pulses is delivered within the absolute refractory period; acquiring an electrical response to the single electrical stimulus pulse; acquiring an electrical response to the pair of electrical stimulus pulses; determining a template stimulus artifact based on the acquired electrical responses to the single electrical stimulus pulse and the pair of electrical stimulus pulses; and/or isolating a stimulus response from another electrical response by subtracting the template stimulus artifact from the other electrical response.

Description

STIMULUS ARTIFACT REMOVAL

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to co-pending U.S. provisional application entitled, “Stimulus Artifact Removal,” having application number 63/424,246, filed November 10, 2022, which is entirely incorporated herein by reference.

TECHNICAL FIELD

[0002] The present disclosure is generally related to the removal of electrical stimulus artifacts from electrophysiology recordings.

BACKGROUND

[0003] Implanted or external electrical stimulation devices are used widely for clinical and research purposes in basic science, clinical neuroscience, cardiology, rehabilitation, pain management, gastroenterology, and other fields. This includes but is not limited to deep brain stimulation, spinal cord stimulation, bladder stimulation, cochlear implants, cardiac pacemakers, cardiac defibrillators, functional electrical stimulation of muscles used for rehabilitation, gastrointestinal stimulation, transcranial magnetic stimulation, and other electrical and/or magnetic stimulation devices.

[0004] As treatments for a variety of disorders, electrical stimulation pulses are delivered in excitable neural and neuromuscular tissues. Measurement of direct tissue activation by the electrical stimulus pulse within an individual could represent a measurement of stimulus dose or indicate a functional interaction with a target circuit in the central, peripheral, or autonomic nervous systems. However, application of the stimulus pulse typically results in a large electrical transient in electrical recordings. This electrical transient or “stimulation artifact” obscures short latency local and distant neural activity induced by the stimulus. Existing methods for stimulus artifact removal are limited, ineffective, and not currently implemented in clinical or research domains.

SUMMARY

[0005] Embodiments of the present disclosure provide systems, apparatuses, and methods for removing electrical stimulus transients from electrophysiological recordings. One such method comprises delivering a single electrical stimulus pulse to electrically excitable tissue; subsequently delivering a pair of electrical stimulus pulses to the electrically excitable tissue, wherein a first of the pair of electrical stimulus pulses is not delivered during an absolute refractory period for the electrically excitable tissue and a second one of the pair of electrical pulses is delivered within the absolute refractory period of the electrically excitable tissue; acquiring an electrical response to the single electrical stimulus pulse; acquiring an electrical response to the pair of electrical stimulus pulses; determining a template stimulus artifact based on the acquired electrical responses to the single electrical stimulus pulse and the pair of electrical stimulus pulses; and/or isolating a stimulus response from another electrical response via delivery of another electrical stimulus pulse by subtracting the template stimulus artifact from the other electrical response.

[0006] In accordance with embodiments of the present disclosure, a system for removing electrical stimulus transients from electrophysiological recordings comprises a processor; and a tangible, non-transitory memory configured to communicate with the processor. The tangible, non-transitory memory has instructions stored thereon that, in response to execution by the processor, cause the processor to be capable of performing operations comprising: delivering a single electrical stimulus pulse to electrically excitable tissue; subsequently delivering a pair of electrical stimulus pulses to the electrically excitable tissue, wherein a first of the pair of electrical stimulus pulses is not delivered during an absolute refractory period for the electrically excitable tissue and a second one of the pair of electrical pulses is delivered within the absolute refractory period of the electrically excitable tissue; acquiring an electrical response to the single electrical stimulus pulse; acquiring an electrical response to the pair of electrical stimulus pulses; determining a template stimulus artifact based on the acquired electrical responses to the single electrical stimulus pulse and the pair of electrical stimulus pulses; and/or isolating a stimulus response from another electrical response via delivery of another electrical stimulus pulse by subtracting the template stimulus artifact from the other electrical response.

[0007] In one or more aspects for such a method or system, the electrically excitable tissue comprises nerve tissue; the electrically excitable tissue comprises muscle tissue; the electrically excitable tissue comprises brain tissue; a plurality of pairs of electrical stimulus pulses are delivered to the electrically excitable tissue, wherein the template stimulus artifact is further determined by averaging the determined stimulus artifact with determined stimulus artifacts from the plurality of pairs of electrical stimulus pulses; the template stimulus artifact is determined by subtracting the electrical response to the single electrical stimulus pulse from the electrical response to the pair of electrical stimulus pulses; the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise cathodic simulation; the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise anodic simulation; and/or the electrical responses are acquired via the one or more electrodes to the electrically excitable tissue. [0008] In one or more aspects, such method or system may involve implanting one or more electrodes in the electrically excitable tissue, wherein the electrical stimulus pulses are delivered via the one or more electrodes to the electrically excitable tissue; and/or estimating a stimulus dose for the electrically excitable tissue based on the isolated stimulus response.

[0009] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Many aspects of the present disclosure can be better understood with the accompanying schema and figures. They are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the relevant principles in this disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0011] FIG. 1 shows a flowchart for a novel method to remove the electrical stimulus artifact from electrophysiology recordings in accordance with embodiments of the present disclosure.

[0012] FIG. 2A shows a graph demonstrating event related potentials elicited by pairs of deep brain stimulation pulses in a patient with a movement disorder. [0013] FIG. 2B shows a graph demonstrating absolute refractory period, relative refractory period, and recovery, as a function of interstimulus interval in a patient with a movement disorder.

[0014] FIG. 3 shows a flow diagram of an exemplary method to remove an electrical stimulus artifact from electrophysiology recordings in accordance with embodiments of the present disclosure.

[0015] FIGS. 4A-4B are diagrams depicting the effectiveness of removal of a stimulus artifact regardless of the stimulus polarity in accordance with embodiments of the present disclosure.

[0016] FIG. 5 is a diagram of an exemplary neuromodulation system in accordance with embodiments of the present disclosure.

[0017] FIG. 6 is a schematic block diagram of a computing device that can be used to implement various embodiments of the present disclosure.

DETAILED DESCRIPTION

[0018] The present disclosure describes various embodiments of systems, apparatuses, and methods for removing electrical stimulus transients from electrophysiological recordings.

[0019] Implanted or external electrical stimulation devices are used widely for clinical and research purposes in basic science, clinical neuroscience, cardiology, rehabilitation, pain management, gastroenterology, urology, and other fields. Stimulus pulses from these devices generate large electrical transients which obscure the fast dynamics of underlying tissue response to stimulation. Crucial research and clinical/translational questions revolve around how stimulation alters the behavior of local and distant electrically excitable tissues. [0020] Large electrical transients arise from electrical stimulation pulses that are delivered in excitable neural and neuromuscular tissues. This transient or “stimulation artifact” obscures short latency local and distant neural activity induced by the stimulus. Measurement of direct tissue activation by the electrical stimulus pulse within an individual could represent a measurement of stimulus dose, or indicate a functional interaction with a target neural circuit. Existing methods for stimulus artifact removal are limited, ineffective, and not currently implemented in clinical or research domains. Thus, the large electrical stimulus transient from deep brain stimulation (DBS) and other neurostimulation devices remains an “elephant in the room” in neuromodulation research, because it often obscures the fast dynamics of the underlying neural activity. Conversely, the present disclosure presents new techniques to visualize local stimulus-evoked local field potentials that were previously obscured by the stimulation artifact, such that novel supporting data exploit the absolute refractory period of electrically excitable tissues to isolate and remove the artifact, revealing local stimulus-evoked neural potentials with unprecedented clarity and spatiotemporal resolution during both cathodic and anodic stimulation.

[0021] Therefore, in accordance with the present disclosure, a novel method is presented using pairs of stimulus pulses that exploit the absolute refractory period of the neural/neuromuscular tissue of interest. Given that the stimulus pulse within the absolute refractory period is divorced from the neural activity, it can be used as a template to subtract the stimulus artifact away from other stimuli to isolate the neural response(s) of interest. Requirements for this to work are extremely high synchronization precision (<10 psec) between stimulus timing and amplification (recording) of the resulting signals. These advances can be incorporated into novel clinical and research electrical stimulation devices to adequately remove the stimulus artifact in accordance with embodiments of the present disclosure

[0022] Referring now to FIG. 1 , a flowchart is presented of an exemplary method (100) to remove the electrical stimulus artifact from electrophysiology recordings from nerves, muscles, and other electrically excitable tissues. The method involves delivering (110) a precisely timed pair of electrical stimulus pulses, the timing of which is within the absolute refractory period of the electrically excitable tissue of interest. In particular, the second stimulus in the pair is delivered within the absolute refractory period. Therefore, the stimulus transient (artifact) resulting from the second stimulus is divorced from electrical activation of local or distant tissues. This stimulus artifact without local tissue activation can subsequently be used (120) as a template waveform to remove (130) (e.g. by subtraction) stimulus artifact from another stimuli response, thereby revealing/clarifying tissue responses to stimulation that would otherwise be invisible or unclear. This method can be applied widely to measure a dose of stimulation based on local tissue response or circuit engagement (rather than the stimulation parameters of the stimulation device). Such measures of target engagement can be integrated into the hardware of a commercial stimulator, or used as an external recording device, and then applied to research questions on mechanism of action or to guide clinical decision making regarding the choice of stimulation parameters for therapy, either with open-loop (continuous) stimulation, intermittent stimulation, or as a control signal for closed loop stimulation.

[0023] Referring now to FIG. 2A, a graph is shown demonstrating event related potentials elicited by pairs of deep brain stimulation pulses in a patient with a movement disorder. Each trace is an average of 50 stimuli, aligned in time to the test stimulus at 0 ms. In the original image that the figure is based on, the color of each trace reflects the timing of the prior conditioning stimulus. The test stimulus is aligned to 0 ms time. Absolute refractory period is identified at interstimulus intervals of <0.5 ms. In FIG. 2B, a graph is provided that shows the absolute refractory period, relative refractory period, and recovery, as a function of interstimulus interval.

[0024] In evaluating an exemplary method of the present disclosure, pairs of stimulus pulses were delivered across a range of interstimulus intervals in 4 research participants during deep brain stimulation surgery, and field potentials from unused contacts on the implanted subcortical electrode array were recorded. As such, stimuli was delivered during the absolute refractory period and transient waveforms of the underlying neural tissue were recorded and averaged into a template stimulus artifact. This template waveform was used to remove the stimulus transient from other stimuli that was not delivered during the absolute refractory period. The results show that the exemplary method for stimulus transient removal was effective in 4/4 participants. Accordingly, the exemplary method improves on prior efforts to remove stimulus transients from electrophysiological recordings and can be applied to estimate a stimulus dose and/or target or circuit engagement by neural or neuromuscular stimulation devices.

[0025] Next, a detailed discussion of the foregoing evaluation of the exemplary method to remove the electrical stimulus artifact from electrophysiological recordings from electrically excitable tissues is provided. For the evaluation study, patients were diagnosed with Parkinson's disease (PD) by a movement disorders neurologist based on consensus criteria, and deep brain stimulation (DBS) was recommended as part of routine care. This project received prior Institutional Review Board (IRB) approval, and all participants signed written consent before enrollment. As stated, the exemplary method was successfully applied on 4 PD patients. [0026] To begin, unilateral DBS contralateral was routinely placed to the most affected side of the body. The DBS surgeries were conducted under local anesthesia with the patient fully awake, and intravenous midazolam 1-2 mg was administered approximately 1.5 to 2 hours prior to initiation of electrophysiological recordings. During the electrophysiological recordings, motor symptoms were measured intraoperatively at baseline and during DBS with upper extremity subscores of the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 upper (“off” medications). Additionally, the therapeutic amplitude to be used in experimental testing was identified.

[0027] After deactivating non-essential electrical equipment, local field potentials were recorded with an actiCHamp lab amplifier (Brain Vision LLC, Morrisville, NC), sampling at 100 kHz with an analog low pass filter of 7.6 kHz, and a ground electrode outside the sterile field on the scalp. Event-related potentials (ERPs) were elicited at therapeutically effective locations/configurations and stimulus amplitudes, as identified during intraoperative DBS macrostimulation at 160 Hz frequency and 60 psec pulse width. These clinical effective settings were determined intraoperative during DBS surgery. An external pulse generator (STG4002, MultiChannel Systems, Reutlingen, Germany) delivered monophasic square waves through the DBS lead. Stimuli were delivered through a DBS contact and field potentials nearby unused contacts were recorded as local field potentials. Anode/cathode contacts and stimulus amplitude were identical to DBS settings that elicited significant clinical efficacy during intraoperative macrostimulation. Pairs of DBS pulses of anodic or cathodic mono-polar stimulation were delivered across 16 unique inter-stimulus intervals ranging from 0.3 to 16 ms in randomized blocks, with an active charge recovery pulse at 20 ms after the test stimulus yielding an exact charge balance across all unique stimulation events per block. The charge density did not exceed the FDA (U.S. Food and Drug Administration) recommended limit of 60 pcoul/cm²/phase. Pauses between successive pairs of stimuli ranged from 50 to 60 ms in a random, uniform distribution (mean pause = 55 ms). The pulse generator delivered unique TTL signals for each stimulation event to the recording amplifier with sync precision of 10 sec. The acquired electrophysiology signals were analyzed with EEGLAB and custom routines in Matlab (Mathworks, Natick, MA). DBS contacts were re-referenced to a bipolar configuration to record local signals in close proximity to the stimulation site.

[0028] Referring to FIG. 3, an exemplary flow diagram of an exemplary method to remove an electrical stimulus artifact from electrophysiology recordings is depicted. Here, the method exploits the absolute refractory period of neurons, revealing local circuit dynamics elicited by DBS. Given that an electrical stimulus of any neural tissue produces an electrical transient and an underlining neural response, part A of FIG. 3 shows that a single pulse stimulus is applied that produces a stimulus response and a stimulus artifact. Accordingly, given enough time for the neuron to recover, a consecutive conditioning stimulus pulse will produce a similar response to the initial stimuli, as illustrated in part B of FIG. 3, that includes a subsequent stimulus response and a subsequent artifact response. However, during a very short delay period, referred to as an absolute refractory period, the consecutive pulse will never produce a neural response, but the stimulus artifact will still be present. Therefore, as illustrated in part C of FIG. 3, if a conditioning stimulus is applied during the absolute refractory period, this produces a subsequent artifact response by itself without producing another stimulus response. In other words, at very short interstimulus intervals (part C), the electrical stimulus is divorced from neural activation because of the absolute refractory period. In order to isolate the test stimulus response, all activities arising from the condition stimulus has to be removed. Thus, subtracting the condition stimulus activities (part A) from the condition in the absolute refractory period (part C) yields a template of the stimulus artifact (part D). Accordingly, the artifact template can be subtracted from test stimuli across all interstimulus intervals to reveal short latency neural activity (R1 , ERNA) that was previously obscured by the artifact. Part E of FIG. 3 shows a calculation of the response ratio, both schematically and with experimental data from 13 participants on the right (response ratios are displayed as mean ± standard error).

[0029] Although in various non-limiting examples, the exemplary method may be applied to deep brain stimulation data, it can be used in all different fields of electrical stimulations of neural tissue. Further, in addition to having significant applications in research, techniques and methods of the present disclosure can have the same or larger impact on the clinical and everyday usage of different stimulations devices. Systems and methods of the present disclosure can be implemented at either the software or hardware level (or both), which could make it a powerful addition to commercial clinical and research devices.

[0030] FIGS. 4A-4B show that an exemplary stimulus artifact removal method can be used to remove the stimulus artifact regardless of the stimulus polarity. Here, the exemplary method was used on real DBS data. As shown in part A of FIG. 4A, pairs of DBS pulses were delivered from a directional contact across a range of interstimulus intervals, and field potentials were recorded from the outer DBS rings. Afterwards, conditioning pulse responses were removed by template subtraction in accordance with embodiments of the present disclosure. The insets of part A show that stimulation elicits neural activation that is fully or partially embedded in the artifact, regardless of cathodic versus anodic stimulus polarity. For part B of FIG. 4A, at very short interstimulus intervals, the electrical stimulus is divorced from neural activation because of the absolute refractory period. In accordance with the present disclosure, this artifact template is subtracted from test stimuli across all interstimulus intervals, which reveals short latency neural activity (R1 , ERNA) that was previously obscured by artifact. It is observed that cathodic versus anodic stimulation at the same site and stimulus intensity elicit responses with distinct peak amplitudes and latencies. In part C of FIG. 4B, paired pulse ratios show absolute and relative refractory periods and recovery, in response to both cathodic and anodic stimulation. This validates the neural origin of these local tissue responses to DBS. Interestingly, ERNA alone shows paired pulse facilitation (a form of short-term plasticity) in response to both cathodic and anodic stimulation. Although our working model was that R1 and ERNA are both absent during the absolute refractory period, ERNA displayed facilitation at interstimulus intervals that correspond with clinically effective DBS frequencies (>100 Hz), as shown in part D of FIG. 4B.

[0031] Accordingly, the results of FIGS. 4A-4B show that an exemplary stimulus artifact removal method can be used to remove a stimulus artifact regardless of stimulus polarity. The subject shown in these figures represent the ideal case where the earliest response (R1 ) to electrical stimulation is not completely obstructed by the stimulus transient. Using the exemplary method did not alter this R1 response which indicates that this method extracts the true transient signal produced by the stimulus pulse. The paired pulse ratio plot is very similar to previous published manuscripts in this field, which adds more support for systems and methods of the present disclosure and provides further evidence of the successful stimulus artifact removal.

[0032] Next, FIG. 5 illustrates an example of a neuromodulation system in accordance with embodiments of the present disclosure. The neuromodulation system 500 may include electrodes 510, a pulse generator stimulation device 520, a programming controller device 530, and/or a monitoring unit 540. One or more portions of the neuromodulation system may be implanted in a patient's body. For example, the electrodes 510 may be configured to be placed on or near one or more neural targets in a patient. The pulse generator stimulation device 520 may be configured to be electrically connected to the electrodes 510 and deliver neuromodulation energy, such as in the form of an electrical waveform, to the one or more neural targets though the electrodes 510. A power source is contained within the housing of the pulse generator stimulation device 520 and is generally a battery. At least some parameters of a plurality of stimulation parameters may be programmable by a user, such as a physician or other caregiver who treats the patient using the neuromodulation system 500. The programming controller device 530 may be configured to be communicatively coupled to pulse generator stimulation device 520 via a wired or wireless link.

[0033] In certain embodiments, one or more electrodes may additionally or alternatively be positioned and/or configured to sense, detect, or monitor neuroelectric activity corresponding to a set of monitoring sites. A monitoring site may be identical to or different from a stimulation site. In one embodiment, a single electrode assembly 510 may be configured both for applying stimulation signals and monitoring neuroelectric activity. Accordingly, the programming controller device 530 may be configured to receive electrical signals representing evoked compound action potentials generated by the patient in response to external stimulation of a location on the patient's body and record the received electrical signals in a memory and/or transmit the received electrical signals to the monitoring unit 540. At the programming controller device 530 and/or the monitoring unit 540, the recordings may be processed to remove stimulus artifact(s) in accordance with techniques of the present disclosure before being analyzed, such as being used to determine a stimulation parameter set for the electrodes 510.

[0034] Correspondingly, FIG. 6 depicts a schematic block diagram of a computing device 600 that can be used to implement various embodiments of the present disclosure, such as, but not limited to, the monitoring unit 540. An exemplary computing device 600 includes at least one processor circuit, for example, having a processor (CPU) 602 and a memory 604, both of which are coupled to a local interface 606, and one or more input and output (I/O) devices 608. The local interface 606 may comprise, for example, a data bus with an accompanying address/control bus or other bus structure as can be appreciated. The CPU can perform various operations including any of the various operations described herein.

[0035] Stored in the memory 604 are both data and several components that are executable by the processor 602. In particular, stored in the memory 604 and executable by the processor 602 is a stimulus artifact removal routine 610 in accordance with embodiments of the present disclosure. Also stored in the memory 604 may be a data store 612 and other data. The data store 612 can include electrophysiological recordings, and potentially other data. In addition, an operating system may be stored in the memory 604 and executable by the processor 602. The I/O devices 608 may include input devices, for example but not limited to, a touchscreen, communication devices, sensors, neuromodulation devices, etc. Furthermore, the I/O devices 608 may also include output devices, for example but not limited to, a display, speaker, earbuds, audio output port, a printer, etc.

[0036] Certain embodiments of the present disclosure can be implemented in hardware, software, firmware, or a combination thereof. If implemented in software, stimulus artifact removal logic or functionality, in accordance with embodiments of the present disclosure, are implemented in software orfirmware that is stored in a memory and that is executed by a suitable instruction execution system. If implemented in hardware, the logic or functionality can be implemented with any or a combination of the following technologies, which are all well known in the art: a discrete logic circuit(s) having logic gates for implementing logic functions upon data signals, an application specific integrated circuit (ASIC) having appropriate combinational logic gates, a programmable gate array(s) (PGA), a field programmable gate array (FPGA), etc.

[0037] It should be emphasized that the above-described embodiments are merely possible examples of implementations, merely set forth for a clear understanding of the principles of the present disclosure. Many variations and modifications may be made to the above-described embodiment(s) without departing substantially from the principles of the present disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure.

Claims

CLAIMS Therefore, at least the following is claimed:

1. A method comprising: delivering a single electrical stimulus pulse to electrically excitable tissue; subsequently delivering a pair of electrical stimulus pulses to the electrically excitable tissue, wherein a first of the pair of electrical stimulus pulses is not delivered during an absolute refractory period for the electrically excitable tissue and a second one of the pair of electrical pulses is delivered within the absolute refractory period of the electrically excitable tissue; acquiring an electrical response to the single electrical stimulus pulse; acquiring an electrical response to the pair of electrical stimulus pulses; determining a template stimulus artifact based on the acquired electrical responses to the single electrical stimulus pulse and the pair of electrical stimulus pulses; and isolating a stimulus response from another electrical response via delivery of another electrical stimulus pulse by subtracting the template stimulus artifact from the other electrical response.

2. The method of claim 1 , wherein the electrically excitable tissue comprises nerve tissue.

3. The method of claim 1 , wherein the electrically excitable tissue comprises muscle tissue.

4. The method of claim 1 , wherein the electrically excitable tissue comprises brain tissue.

5. The method of claim 1 , further comprising implanting one or more electrodes in the electrically excitable tissue, wherein the electrical stimulus pulses are delivered via the one or more electrodes to the electrically excitable tissue.

6. The method of claim 1 , wherein the electrical responses are acquired via the one or more electrodes to the electrically excitable tissue.

7. The method of claim 1 , wherein a plurality of pairs of electrical stimulus pulses are delivered to the electrically excitable tissue, wherein the template stimulus artifact is further determined by averaging the determined stimulus artifact with determined stimulus artifacts from the plurality of pairs of electrical stimulus pulses.

8. The method of claim 1 , further comprising estimating a stimulus dose for the electrically excitable tissue based on the isolated stimulus response.

9. The method of claim 1 , wherein the template stimulus artifact is determined by subtracting the electrical response to the single electrical stimulus pulse from the electrical response to the pair of electrical stimulus pulses.

10. The method of claim 1 , wherein the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise cathodic simulation.

11 . The method of claim 1 , wherein the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise anodic simulation.

12. A system comprising: a processor; and a tangible, non-transitory memory configured to communicate with the processor, the tangible, non-transitory memory having instructions stored thereon that, in response to execution by the processor, cause the processor to be capable of performing operations comprising: delivering a single electrical stimulus pulse to electrically excitable tissue; subsequently delivering a pair of electrical stimulus pulses to the electrically excitable tissue, wherein a first of the pair of electrical stimulus pulses is not delivered during an absolute refractory period for the electrically excitable tissue and a second one of the pair of electrical pulses is delivered within the absolute refractory period of the electrically excitable tissue; acquiring an electrical response to the single electrical stimulus pulse; acquiring an electrical response to the pair of electrical stimulus pulses; determining a template stimulus artifact based on the acquired electrical responses to the single electrical stimulus pulse and the pair of electrical stimulus pulses; and isolating a stimulus response from another electrical response via delivery of another electrical stimulus pulse by subtracting the template stimulus artifact from the other electrical response.

13. The system of claim 12, wherein the electrically excitable tissue comprises nerve tissue.

14. The system of claim 12, wherein the electrically excitable tissue comprises muscle tissue.

15. The system of claim 12, wherein the electrically excitable tissue comprises brain tissue.

16. The system of claim 12, wherein a plurality of pairs of electrical stimulus pulses are delivered to the electrically excitable tissue, wherein the template stimulus artifact is further determined by averaging the determined stimulus artifact with determined stimulus artifacts from the plurality of pairs of electrical stimulus pulses.

17. The system of claim 12, wherein the operations further comprise estimating a stimulus dose for the electrically excitable tissue based on the isolated stimulus response.

18. The system of claim 12, wherein the template stimulus artifact is determined by subtracting the electrical response to the single electrical stimulus pulse from the electrical response to the pair of electrical stimulus pulses.

19. The system of claim 1 , wherein the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise cathodic simulation.

20. The system of claim 1 , wherein the single electrical stimulus pulse and the pair of electrical stimulus pulses comprise anodic simulation.