Nerve block for small fiber stimulation

Abstract

A system may include a signal generator configured to be in electrical communication with at least one implantable electrode. A system may include a controller configured in electrical communication with the signal generator, wherein the controller is configured to cause the signal generator to generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue. The controller may be further configured to cause the signal generator to generate a second electrical signal having a shorter pulse width than the first electrical signal. The second electrical signal can be configured to activate an on-target neural component of a second target electrically excitable tissue.

Description

NERVE BLOCK FOR SMALL FIBER STIMULATIONINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 559,794, entitled “nerve block for small fiber stimulation,” filed on February 29, 2024, the entire contents of which are hereby incorporated herein by reference in their entirety.

[0002] Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated herein by reference under 37 CFR 1.57.FIELD

[0003] The present disclosure relates to inhibiting therapy and neuromodulation devices. More particularly, implementations of the present disclosure relate to systems and techniques that improve operational performance and safety of neuromodulation devices.BACKGROUND

[0004] The gate control theory of pain was developed in the 1960s and led to the advent of stimulation-based pain management therapies to reduce pain inputs from reaching the brain by selectively stimulating non-nociceptive fibers (non-pain transmitting fibers) in the spinal cord to inhibit transmission of pain stimuli to the brain. Current stimulation systems for spinal cord stimulation (SCS), which act on this gate control theory to indirectly reduce pain, typically have relied on stimulation signals in the >10 Hz frequency range and having short pulse durations, and recently in the kHz frequency range.SUMMARY

[0005] The present application relates to a comprehensive approach to providing neural system inhibition therapy (also referred to herein as “neural inhibition therapy” and / or “inhibiting therapy”) to reduce (or mitigate or prevent) activation (sometimes referred to herein as “recruitment” or “stimulation”) of off-target neural components inside and / or outside of a target nerve trunk that may otherwise result from activation of on-target neural components inside the target nerve trunk. In this context, “neural system inhibition therapy” includes applying current sufficient to inhibit initiation and / or conduction of action potentials in electrically excitable tissue, as further described herein. Neural system inhibition therapyincludes applying direct currents (DC) sufficient to cause partial and / or full neural block or attenuation, including neural suppression and / or hyper-suppression such as (but not limited to) neural block without rapid reversibility or recovery after DC application has been removed or stopped, as further described herein.

[0006] Traditional vagus nerve stimulation (VNS), which may be delivered post-acute myocardial infarction to improve cardiac function, is limited by off-target neural stimulation. Off-target neural stimulation can activate the neck muscles of a medical patient who is receiving VNS, thereby causing unwanted side effects such as choking, coughing, and / or the like, that limit the effective dosage of VNS delivered to the medical patient. Advantageously, the systems, methods, and devices, including associated functionality, of the present application (generally referred to herein as “the system”) deliver neural inhibition therapy via one or more implantable electrodes to selectively block off-target neural components within the vagus nerve and / or near electrodes that are delivering VNS. In this way, the system can enable delivery of increased dosages of VNS to a medical patient, which may increase efficacy of treatment such as for improving cardiac function, without causing unwanted side effects.

[0007] The systems described herein each have several aspects, no single one of which is solely responsible for its desirable attributes. Without limiting the scope of this disclosure, several non-limiting features will now be described briefly.

[0008] Details of one or more implementations of the subject matter described in this specification are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages will become apparent from the description, the drawings, and the claims. Note that relative dimensions of the following figures may not be drawn to scale.

[0009] The present disclosure provides a system for electrically modulating electrically excitable tissue. The system can include: a signal generator configured to be in electrical communication with at least one implantable electrode; and a controller in electrical communication with the signal generator, wherein the controller is configured to: cause the signal generator to generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and cause the signal generator to generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electricalsignal is configured to activate an on-target neural component of a second target electrically excitable tissue.

[0010] In some embodiments, the first target electrically excitable tissue can include the vagus nerve, and the second target electrically excitable tissue can include the vagus nerve.

[0011] In some embodiments, the first target electrically excitable tissue is outside of the vagus nerve, and the second target electrically excitable tissue can include the vagus nerve.

[0012] In some embodiments, the first target electrically excitable tissue can include at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

[0013] In some embodiments, the first electrical signal can be configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

[0014] In some embodiments, the first electrical signal can be configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

[0015] In some embodiments, the implantable electrode can be configured as a vagus nerve stimulation cuff electrode.

[0016] In some embodiments, the implantable electrode can be arranged on an implantable paddle lead.

[0017] In some embodiments, the first electrical signal can have a frequency of 0.01 Hz to 10 Hz.

[0018] In some embodiments, the first electrical signal can have a current magnitude of 1 mA to 6 mA.

[0019] In some embodiments, the first electrical signal can have a pulse width of 0.1 seconds to 100 seconds.

[0020] In some embodiments, the second electrical signal can have a frequency of 1 Hz to 150 Hz.

[0021] In some embodiments, the second electrical signal can have a current magnitude of 1 mA to 10 mA.

[0022] In some embodiments, the second electrical signal can have a pulse width of 90 ps to 1,000 ps.

[0023] In some embodiments, the first electrical signal can be configured to activate the on-target neural component of the second target electrically excitable tissue.

[0024] In some embodiments, the first electrical signal can have a rise time or fall time of 0.1 seconds to 0.7 seconds.

[0025] In some embodiments, the second electrical signal can have a greater slew rate than the first electrical signal.

[0026] In some embodiments, the second electrical signal can have a shorter rise time or shorter fall time than the first electrical signal.

[0027] In some embodiments, the second electrical signal can have a rise time or fall time of 0.1 ps to 15 ps.

[0028] In some embodiments, the off-target neural component can include a large- diameter myelinated fiber.

[0029] In some embodiments, the large-diameter myelinated fiber can include one or more of: an A-alpha fiber and an A-beta fiber.

[0030] In some embodiments, the on-target neural component can include a smalldiameter myelinated fiber.

[0031] In some embodiments, the small-diameter myelinated fiber can include one or more of: an A-delta fiber and a B fiber.

[0032] In some embodiments, the on-target neural component can include a nonmyelinated fiber.

[0033] In some embodiments, the controller can be further configured to cause the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

[0034] In some embodiments, the controller can be further configured to measure a level of neural inhibition of the off-target neural component using a closed-loop control system.

[0035] In some embodiments, the controller can be further configured to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.

[0036] The present disclosure provides a method for electrically modulating electrically excitable tissue. The method can include: providing a signal generator, wherein thesignal generator configured to be in electrical communication with at least one implantable electrode; and signaling the signal generator to: generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electrical signal is configured to activate an on-target neural component of a second target electrically excitable tissue.

[0037] In some embodiments, the first target electrically excitable tissue can include the vagus nerve, and the second target electrically excitable tissue can include the vagus nerve.

[0038] In some embodiments, the first target electrically excitable tissue is outside of the vagus nerve, and the second target electrically excitable tissue can include the vagus nerve.

[0039] In some embodiments, the first target electrically excitable tissue can include at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

[0040] In some embodiments, the first electrical signal can be configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

[0041] In some embodiments, the first electrical signal can be configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

[0042] In some embodiments, the implantable electrode can be configured as a vagus nerve stimulation cuff electrode.

[0043] In some embodiments, the implantable electrode can be arranged on an implantable paddle lead.

[0044] In some embodiments, the first electrical signal can have a frequency of 0.01 Hz to 10 Hz.

[0045] In some embodiments, the first electrical signal can have a current magnitude of 1 mA to 6 mA.

[0046] In some embodiments, the first electrical signal can have a pulse width of 0.1 seconds to 100 seconds.

[0047] In some embodiments, the second electrical signal can have a frequency of 1 Hz to 150 Hz.

[0048] In some embodiments, the second electrical signal can have a current magnitude of 1 mA to 10 mA.

[0049] In some embodiments, the second electrical signal can have a pulse width of 90 ps to 1,000 ps.

[0050] In some embodiments, the first electrical signal can be configured to activate the on-target neural component of the second target electrically excitable tissue.

[0051] In some embodiments, the first electrical signal can have a rise time or fall time of 0.1 seconds to 0.7 seconds.

[0052] In some embodiments, the second electrical signal can have a greater slew rate than the first electrical signal.

[0053] In some embodiments, the second electrical signal can have a shorter rise time or shorter fall time than the first electrical signal.

[0054] In some embodiments, the second electrical signal can have a rise time or fall time of 0.1 ps to 15 ps.

[0055] In some embodiments, the off-target neural component can include a large- diameter myelinated fiber.

[0056] In some embodiments, the large-diameter myelinated fiber can include one or more of an A-alpha fiber and an A-beta fiber.

[0057] In some embodiments, the on-target neural component can include a smalldiameter myelinated fiber.

[0058] In some embodiments, the small-diameter myelinated fiber can include one or more of: an A-delta fiber and a B fiber.

[0059] In some embodiments, the on-target neural component can include a nonmyelinated fiber.

[0060] In some embodiments, the controller can be further configured to cause the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

[0061] In some embodiments, the controller can be further configured to measure a level of neural inhibition of the off-target neural component using a closed-loop control system.

[0062] In some embodiments, the controller can be further configured to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Example features of the present disclosure, its nature and various advantages will be apparent from the accompanying drawings and the following detailed description of various implementations. Non-limiting and non-exhaustive implementations are described with reference to the accompanying drawings, wherein like labels or reference numbers refer to like parts throughout the various views unless otherwise specified. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements may be selected, enlarged, and positioned to improve drawing legibility. The particular shapes of the elements as drawn have been selected for ease of recognition in the drawings.

[0064] FIG. 1 A illustrates example electrode operation for delivery of neural inhibition therapy, in accordance with various aspects of the present disclosure, and FIG. IB illustrates an example waveform as between bipolar working electrodes having a constant bias current, in accordance with various aspects of the present disclosure.

[0065] FIG. 2A illustrates an example embodiment of system relating to neural inhibition therapy, in accordance with various aspects of the present disclosure.

[0066] FIG. 2B illustrates a block diagram of an example embodiment of a neuromodulation device, in accordance with various aspects of the present disclosure.

[0067] FIGS. 3A-3E illustrate example waveforms output by a neuromodulation device and suitable for neural inhibition therapy, in accordance with various aspects of the present disclosure, and FIG. 3F illustrates a table of values related to said waveforms, in accordance with various aspects of the present disclosure.

[0068] FIG. 4 illustrates an example operating range of a waveform suitable for neural inhibition therapy, in accordance with various aspects of the present disclosure.

[0069] FIG. 5 A illustrates an example embodiment of an implantable lead useable with the various implementations of the present disclosure, and FIGS. 5B-5J schematically illustrate example embodiments of said lead, in accordance with various aspects of the present disclosure.

[0070] FIG. 6 illustrates the anatomy of the cervical vagus nerve in a human subject.

[0071] FIGS. 7A-7B illustrate example waveforms output by a neuromodulation device and suitable for neural inhibition therapy, in accordance with various aspects of the present disclosure.

[0072] FIGS. 8A-8H schematically illustrate example embodiments of electrode arrangements and / or configurations useable with the various implementations of the present disclosure.

[0073] FIG. 9 illustrates an example embodiment of a process related to electrically modulating target electrically excitable tissue, in accordance with various aspects of the present disclosure.DETAILED DESCRIPTION

[0074] Although certain preferred implementations, embodiments, and examples are disclosed below, the inventive subject matter extends beyond the specifically disclosed implementations to other alternative implementations and / or uses and to modifications and equivalents thereof. Thus, the scope of the claims appended hereto is not limited by any of the particular implementations described below. For example, in any method or process disclosed herein, the acts or operations of the method or process may be performed in any suitable sequence and are not necessarily limited to any particular disclosed sequence. Various operations may be described as multiple discrete operations in turn, in a manner that may be helpful in understanding certain implementations; however, the order of description should not be construed to imply that these operations are order dependent. Additionally, the structures, systems, and / or devices described herein may be embodied as integrated components or as separate components. For purposes of comparing various implementations, certain aspects and advantages of these implementations are described. Not necessarily all such aspects or advantages are achieved by any particular implementation. Thus, for example, various implementations may be carried out in a manner that achieves or optimizes one advantage orgroup of advantages as taught herein without necessarily achieving other aspects or advantages as may also be taught or suggested herein.Overview

[0075] Heart disease is the leading cause of death in the U.S. with over 280,000 annual cases of ST-elevated myocardial infarction (STEMI) and over 460,000 annual cases of non-ST-elevated myocardial infarction (NSTEMI). Myocardial infarction (MI) initiates a sequela of often irreversible neurocardiac remodeling, which is generally driven by autonomic dysfunction. The remodeling results in high rates of deadly arrhythmias and chronic heart failure even for an MI treated in a timely fashion. New therapies that directly address autonomic dysfunction following an Ml are critical to improving the standard of care for patients afflicted with such conditions.

[0076] Invasive cervical vagus nerve stimulation (VNS) delivered post-acute MI has been shown to rebalance autonomic dysfunction and substantially improve cardiac function in a swine model. However, the translation of VNS therapy to clinical applications is critically limited by off-target neural stimulation that lowers the patient-tolerable therapeutic dosage. To minimize side effects and improve clinical dose and efficacy, the system of the present application advantageously enhances the abilities of traditional VNS by paring neural inhibition therapy with traditional VNS therapy. As further described herein, neural inhibition therapy can include delivery of long-pulse width (also referred to herein as “long-pulse duration”) waveforms, such as DC waveforms, that can hyperpolarize axons, thereby reducing and / or inhibiting neural recruitment (e.g., initiation and / or conduction of action potentials) but not spontaneous neural activity. In this context, “DC waveforms” refer to alternating current (AC) waveforms having half periods that are greater than the refractory periods of electrically excitable tissue (e g., neural tissue) such that the AC waveforms are perceived as, and functionally are, DC from the perspective of the tissue whose action potentials or neural processing is being modulated, as further described herein. In some embodiments, such DC waveforms may have periods (also referred to herein as “pulse width” or “pulse duration”) as long as about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11, seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19 seconds, about 20 seconds, or anyvalue or range within or bounded by any of these values or ranges. Longer periods are also possible. In this way, the system is configured to provide a combination of DC waveforms and stimulation waveforms (e.g., low-frequency (LF) waveforms) for delivery of VNS that may improve therapy outcomes by advantageously stimulating on-target neural components such as on-target parasympathetic fibers while causing partial or full block of action potential conduction and / or initiation in off-target neural components such as off-target motor neurons and / or nerves, as further described herein.

[0077] In this context, “on-target” neural components refer to neural components that are intended to be stimulated via delivery of VNS. On-target neural components may be located in a target nerve trunk. On-target neural components may be associated with clinically beneficial therapy (e.g., improvement of cardiac function). Non-limiting examples of such on- target neural components can include one or more of: small-diameter myelinated fibers such as A-delta fibers and / or B fibers; and non-myelinated fibers. “Off-target” neural components refer to neural components that are not intended to be stimulated via delivery of VNS. Off- target components may be located inside and / or outside of the target nerve trunk. Off-target neural components may be associated with clinically undesirable side effects (e.g., coughing, choking, and / or the like that results from activation of neck muscles of a subject). Non-limiting examples of such off-target neural components can include one or more of: large-diameter myelinated fibers such as A-alpha fibers and / or A-beta fibers. The term “neural components” can include any of neurons, fibers, nerves, and / or other electrically excitable tissue. Smalldiameter myelinated fibers and non-myelinated fibers are often the on-target fibers as they are involved in autonomic function and, in the case of muscle control, are the first to be recruited physiologically. Large-diameter myelinated fibers are often the off-target fibers as activation of said fibers can cause unwanted side effects, such as described herein. Large-diameter myelinated fibers include at least fibers that: 1) run in the same nerve trunk as the on-target neural components; or 2) are present in a nerve trunk that is nearby the stimulation electrode and that can be activated due to current escape from the stimulation electrode.

[0078] Presidio Medical’s proprietary therapeutic waveform is a long-pulse width waveform (generally referred to herein as a “DC waveform”) that has been demonstrated to be safely delivered in clinical trials. Neural block, attenuation, and suppression using DC waveforms is discussed in greater detail in at least U.S. Patent App. No. 18 / 563,859, filed onNovember 22, 2023, entitled “ACUTE BLOCKADE WITH DELAYED NEURAL SUPPRESSION,” the entire contents of which are hereby incorporated herein by reference in their entirety, and which is assigned to Presidio Medical, Inc.

[0079] The vagus nerve is the parasympathetic nervous system highway of the body. Its central role in autonomic function makes it a prime target for bioelectronic medicine therapies such as implantable cervical VNS. The vagus nerve is composed of large-diameter myelinated fibers, small-diameter myelinated fibers, and non-myelinated fibers. VNS commonly uses short-pulse width (also referred to herein as “short-pulse duration”) electrical stimulation to target and stimulate small-diameter myelinated fibers and non-myelinated fibers in the vagus nerve. However, large-diameter myelinated fibers (e.g., motor neurons) are typically, and undesirably, activated at the lowest stimulation currents, followed by smalldiameter myelinated fibers at higher stimulation currents, and lastly non-myelinated fibers at the highest stimulation currents. This is sometimes in reversal of a desired recruitment order or of the physiological recruitment order of the body. This simple principle limits the dose of bioelectronic medicine therapies (also known as electroceuticals or neuromodulation therapies). For example, traditional VNS often undesirably recruits off-target neural components such as the large-diameter myelinated fibers that are responsible for therapylimiting side effects, even though the autonomic fibers of interest (e.g., on-target fibers) are the small-diameter myelinated fibers and non-myelinated fibers. When electrical stimulation activates (sometimes referred to herein as “recruits” or “stimulates”) off-target neural components, the patient feels discomfort in the form of unintended neck muscle contractions that can cause coughing, choking, and / or the like. Consequently, due to patient discomfort and intolerance to the therapy, the VNS stimulation dosage cannot be further increased. In some cases, it is possible for off-target neural activation to so severely limit the VNS dosage (due to uncomfortable or painful effects that result from said recruitment) such that the VNS dosage is below the therapeutic range to activate the desired on-target neural components such as the smaller diameter myelinated fibers and the non-myelinated fibers, thereby rendering conventional VNS therapy ineffective.

[0080] The lack of specificity in target engagement, also conceptualized as the inability to reach the therapeutic stimulation windows in clinical patients, has led to numerous failed clinical trials. In the case of VNS, the off-target neural components may at least include:1 ) motor neurons coursing through the main cervical vagus trunk, where stimulation electrodes may be placed; and 2) motor neurons outside the main cervical vagus trunk, but close to where stimulation electrodes are placed, that are activated by current leakage from the stimulation electrodes. These neurons compose the superior laryngeal (SL) nerve and the ascending branch of the recurrent laryngeal (ARL).

[0081] Advantageously, the system as described herein can provide a long-pulse width waveform such as a DC waveform to selectively cause partial or full block of action potential conduction and / or initiation in off-target, large-diameter myelinated fibers in a target nerve and / or near stimulation electrodes and permit activation of the remaining, on-target, smalldiameter myelinated fibers and / or non-myelinated fibers. The DC waveform may have a greater pulse width than the short-pulse width waveforms used for VNS. In this way, the system can cause block of the off-target, large-diameter myelinated fibers without (significantly) reducing (or while mitigating reduction of) activation of the on-target, smalldiameter myelinated and non-myelinated fibers. Accordingly, the system can enable delivery of increased VNS dosages to medical patients, which may increase treatment efficacy, such as for improving cardiac function.

[0082] Although systems of the present application are described in the context of selectively blocking (or attenuating or suppressing) and / or activating different fiber types, this is not intended to be limiting. The system as described herein can be configured to selectively target: excitatory and / or inhibitory cell types; specific ion channels; electrically excitabletissue having various different amplitude thresholds of excitation; and / or the like that may or may not be easily excitable via application of DC waveforms. In some embodiments, short-pulse width waveforms may not be used. For example, the system may modulate the DC waveform to cause partial and / or full neural block, attenuation, and / or suppression of off-target neural components and to cause stimulation of on-target neural components. In this way, the DC waveform can include a first phase (e.g., cathodic phase) configured to stimulate on-target neural components and a second phase (e.g., anodic phase) configured to partially and / or fully block conduction and / or initiation of action potentials in off-target neural components. In some examples, the DC waveform can have a transition region (e.g., between cathodic and anodic plateaus) configured to stimulate on-target neural components while cathodic and / or anodicphases of the DC waveform are configured to partially and / or fully block conduction and / or initiation of action potentials in off-target neural components.

[0083] Moreover, while the present application describes selective targeting in the context of the vagus nerve, this is not intended to be limiting. The system as described can be configured for selective targeting of other peripheral or central nerves (and / or neurons and / or fibers thereof). This may include selective targeting of the carotid sinus nerve, for example.

[0084] Furthermore, for example, in motor unit recruitment, the physiological recruitment order involves the recruitment of small diameter motor neurons and fibers followed by large diameter motor neurons and fibers. Current functional electrical stimulation (FES) to restore motor function recruits motor units in reverse to this physiological order. Advantageously, DC selective fiber stimulation can be used to better mimic the physiological order of recruitment.Neural Inhibition Therapy

[0085] Propagation of action potentials in electrically excitable tissue (e.g., neural tissue) can lead to refractory periods on the order of milliseconds for sodium channels, typically between about 1 ms and about 20 ms, or between about 2 ms and about 5 ms, for the combined absolute and relative refractory periods. Alternating current (AC) waveforms having half periods (also referred to herein as “pulse width” or “pulse duration”) greater than this refractory period (e.g., greater than about 1 ms, about 1.5 ms, about 2 ms, about 2.5 ms, about 3 ms, about 10 ms, about 30 ms, about 50 ms, about 100 ms, about 300 ms, about 500 ms, about 1000 ms, about 2000 ms, about 5000 ms, about 6000 ms or more) and having sufficiently low differential rates (e.g., rise and fall times, also referred to herein as “slew rate”) to not invoke action potentials can also be used to reduce or prevent initiation and / or conduction of action potentials, and may be perceived by electrically excitable tissue as a DC stimulus. As such, direct current (DC) as defined herein is inclusive of AC waveforms that are perceived as, and functionally are, DC from the perspective of the tissue whose action potentials or neural processing is being modulated (generally referred to herein as “DC waveforms”). For example, DC waveforms can include (but are not limited to) waveforms with anodic and cathodic periods having half periods greater than the refractory periods listed above (e.g., greater than about 1 ms, about 1.5 ms, about 2 ms, about 2.5 ms, about 3 ms, about 10 ms, about 30 ms,about 50 ms, about 100 ms, about 300 ms, about 500 ms, about 1000 ms, about 2000 ms, about 5000 ms, about 6000 ms or more).

[0086] In some embodiments, DC waveforms (also referred to herein as “nerve block waveforms,” “DC blocking waveforms,” “activity reducing waveforms,” “ultra-low frequency waveforms,” “ULF block waveforms,” “therapeutic waveforms,” “therapeutic electrical waveforms”) can have a frequency of about 10 Hz, about 9 Hz, about 8 Hz, about 7 Hz, about 6 Hz, about 5 Hz, about 4 Hz, about 3 Hz, about 2 Hz, about 1 Hz, about 0.5 Hz, about 0.1 Hz, about 0.05 Hz, about 0.01 Hz, about 0.005 Hz, about 0.0001 Hz, or any value or range within or bounded by any of these values or ranges. In addition, in many cases, the direction of current flow is constant over at least the entire refractory period of the target electrically excitable tissue, or at least twice as long, or at least five times as long, or at least ten times as long as the refractory-causing membrane channel time constant (e.g., fast sodium channel inactivation gate time constant). Lower frequencies are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having frequencies at any of the above listed values.

[0087] In some embodiments, the DC waveform can have a pulse width (e.g., pulse duration) of about 0.1 seconds, about 0.125 seconds, about 0.15 seconds, about 0.2 seconds, about 0.3 seconds, about 0.4 seconds, about 0.5 seconds, about 1 seconds, about 2 seconds, about 5 seconds, about 10 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 100 seconds, about 200 seconds, about 500 seconds, about 1,000 seconds, about 5,000 seconds, about 10,000 seconds, or any value or range within or bounded by any of these values or ranges. In some embodiments, the DC waveform may have a pulse width of about 12 seconds. Longer pulse widths are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having pulse widths at any of the above listed values.

[0088] “Neuromodulation” generally includes modulation of activity, excitability, or cellular state of electrically excitable tissue, including but not limited to neural tissue (e.g., neurons, glial cells, and / or the like), non-neural excitable tissue, and tissue that can be impacted by electrical fields or currents. Neuromodulation can be inclusive of neural system inhibition therapy (also referred to herein as “neural inhibition therapy”). In this way, “neural inhibition therapy” includes modulation of activity, excitability, or cellular state of electrically excitabletissue, including but not limited to neural tissue (e.g., neurons, glial cells, and / or the like), non- neural excitable tissue, and tissue that can be impacted by electrical fields or currents, such that initiation and / or conduction of action potentials is reduced or prevented. Neural inhibition therapy can be inclusive of inhibiting excitatory neurons and / or activating inhibitory neurons.

[0089] Neural inhibition therapy can include generating DC waveforms suitable to cause partial or full neural block and / or attenuation. In this context, “block,” “neural block,” and / or “nerve block” is inclusive of partially and / or fully preventing initiation and / or conduction of action potentials in electrically excitable tissue. In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of stimulation-evoked action potentials in electrically excitable tissue. In this context, “stimulation-evoked action potentials” may refer to action potentials resulting from application of external stimuli (e g., electrical signals generated via signal generator 210). In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of spontaneous action potentials in electrically excitable tissue. In this context, “spontaneous action potentials” may refer to naturally occurring action potentials that result without any external stimuli. In some embodiments, delivered DC waveforms may be configured to cause partial or full block of conduction and / or initiation of only stimulation- evoked action potentials in electrically excitable tissue and not of spontaneous action potentials in electrically excitable tissue.

[0090] In some embodiments, DC waveforms described herein may be suitable to generate subthreshold effects that are associated with preventing (or reducing) initiation of action potentials in electrically excitable tissue. In this context, “subthreshold effects” generally refer to neuromodulation resulting from delivery of electrical charge (e.g., by anodic and / or cathodic phases of the DC waveform) where the amount of electrical charge is inadequate to overcome the threshold of excitation of electrically excitable tissue, such as neural tissue. In this way, subthreshold effects may be inclusive of any electrical change in electrically excitable tissue that does not reach the threshold required to trigger an action potential. Generation of subthreshold effects may directly or indirectly cause synaptic modulation in which synaptic coupling and / or neural excitability is disrupted. In this context, “synaptic coupling” is inclusive of the process by which neurons and synapses interact with one another. “Neural excitability” is inclusive of the magnitude of the response of electricallyexcitable tissue to stimulation (e.g., electrical stimulation, chemical stimulation, optical stimulation, and the like). In some embodiments, generating subthreshold effects can modify neural properties of electrically excitable tissue, such as adjusting a threshold potential of electrically excitable tissue (e.g., an excitatory neuron).

[0091] Neural inhibition therapy can include generating DC waveforms suitable to generate suprathreshold effects that are associated with preventing (or reducing) conduction of action potentials in electrically excitable tissue. In this context, “suprathreshold effects” generally refer to neuromodulation resulting from delivery of electrical charge (e g., by anodic and / or cathodic phases of the DC waveform) where the amount of electrical charge is adequate to overcome the threshold of excitation of electrically excitable tissue, such as neural tissue. In this way, suprathreshold effects may be inclusive of any electrical change in electrically excitable tissue that reaches the threshold required to trigger an action potential. Suprathreshold effects may result from delivery of electrical charge that is significantly above the threshold required to trigger an action potential. Generation of suprathreshold effects may directly or indirectly alter ion channel (e.g., voltage-gated ion channel) expression and / or electrical gradients of electrically excitable tissue such that ions are unable to move (or are prevented from moving) across cell membranes. The movement of ions across cell membranes may be necessary for an action potential to propagate as such ion movement generates electrical signals that can travel along electrically excitable tissue as an action potential.

[0092] Neural inhibition therapy can include generating DC waveforms suitable to cause suppression, including hyper-suppression. “Suppression” refers to a phenomenon when neural activity remains blocked or reduced for a period of time even after removal or discontinuation of DC application. Suppression can occur as a result of wash-in effects. Suppression can be inclusive of “hyper-suppression,” which includes but is not limited to when neural activity remains blocked or reduced without rapid reversibility after removal or cessation of DC application.

[0093] The system of the present disclosure can facilitate management of chronic and acute pain states via application of DC waveforms sufficient to deliver neural inhibition therapy. In some embodiments, the system disclosed herein facilitates delivery of neural inhibition therapy to electrically excitable tissue by delivering cycled cathodic and anodic current. In this way, DC waveforms can include cathodic and anodic phases. In someembodiments, either the anodic or cathodic phases of a DC waveform delivered to a patient (or both the anodic and cathodic phases) can have a clinically beneficial therapeutic effect on electrically excitable tissue. Charge delivered during an anodic phase of a DC waveform may be least balanced by charge delivered during a cathodic phase of the DC waveform. In some embodiments, charge delivered during an anodic phase may be greater or less than charge delivered during a cathodic phase.

[0094] Depending on the specific DC application of neural block, neural suppression may occur, and hyper suppression may result for continued block in excess of one minute after removal of the DC source to delay nerve conduction recovery. The neural block and / or suppression may be generated in an intermittent or continuous manner depending on the desired application. In this context, “intermittent” block and / or suppression can include a treatment period punctuated with long rest periods. For example, the treatment period can include one or more delivery periods (e.g., periods of time during which DC waveforms are delivered by one or more implantable electrodes) separated by one or more long rest periods (e.g., periods of time during which there is no delivery of DC waveforms). The long rest period may be of long enough time duration such that nerve conduction is recovered prior to resuming delivery of DC waveforms. In this way, neural block may not be sustained during intermittent block. “Continuous” block can include a treatment period characterized by an absence of any rest periods and / or a treatment period punctuated with short rest periods. For example, one or more implantable leads may deliver DC waveforms (e.g., duty cycled DC waveforms) to a target tissue for the entire treatment period without any intervening rest periods. In some examples, delivery periods may be separated by short rest periods having short enough time durations such that nerve conduction is not recovered prior to resuming delivery of DC waveforms. Neural block may be sustained during continuous block, such as once wash-in has occurred. Both intermittent and continuous block can include generation and delivery of pulsed or continuous waveforms, or combinations thereof.

[0095] Safe delivery of DC waveforms is highly desirable. Advantageously, tissue safety can be maintained by operating electrodes below reaction potentials for undesired reactions, as well as by limiting the amount of irreversible reactions (e.g., electrolysis of water, oxidation and reduction of water (H2O), and / or the like), which can create harmful reactive species such as OH-, H+, or oxygen free radicals. In some cases, this may be achieved bymaintaining a bias current, as described further herein. For example, systems configured to allow for an intentional net bias current (e.g., DC bias), such as via a control system described herein (see FIGS. 2A-2B, for example), can, in some cases, advantageously maintain the health of the high charge capacity electrodes (by preventing or inhibiting corrosion, e.g., oxidation, or other damage to the electrodes) as well as reduce, minimize, or prevent undesired electrochemical reactions and generation of species such as OH-, H+, oxygen free radicals, peroxide formation, and other undesired reactions (such as depending on material and / or location) that can lead to tissue damage.

[0096] The system of the present disclosure can be configured to treat nociceptive pain. In some embodiments, the system as described herein can involve selective block and / or attenuation of antero-lateral column tissue in the spinal cord.

[0097] In some embodiments, the system as described herein can safely block or attenuate pain signals (which includes modulation of pain processing) in the spinal column by delivering DC waveforms in the epidural space for up to two or more weeks to achieve clinically measurable pain reduction in patients with chronic low back pain who are candidates for spinal cord stimulation (SCS), such as further described herein. With targeted neural block, pain from specific dermatomes and pain in regional body sites can be managed. A number of localized targets implicated in moderating pain signal transduction can be addressed. For example, both more centrally located nerve tissues such as the spinothalamic tract and dorsal root ganglion can be targeted to manage lower back pain, sciatica, and complex regional pain syndrome (CPRS) among other pain considerations. Neural block, activity reduction, and suppression using DC waveforms is discussed in greater detail in at least incorporated U.S. Patent App. No. 18 / 563,859.

[0098] Direct current (DC) delivery to a patient can be targeted to any number of anatomical locations, including but not limited to: the dorsal root ganglion; dorsal roots; dorsal columns; dorsal horn; Lissauer’s tract; and / or the antero-lateral pain tracts. In the spine, the DC delivery can be targeted to any number of vertebral levels including but not limited to: the sacral region, the lumbar spine, the thoracic spine, the cervical spine, as well as over specific spinal disk locations such as, for example, any number of disks between any two of Cl, C2, C3, C4, C5, C6, C7, Tl, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, LI, L2, L3, L4, L5, SI, S2, S3, or S4, including but not limited to the disk bridging the T9 and T10 vertebra. Insome embodiments, DC delivery can be directed to a peripheral nerve, or other target locations as described elsewhere herein. In some embodiments, DC delivery can modulate small diameter fibers in the spinal cord and depolarize spinal cord neurons. However, DC delivery may not necessarily be sensitive to fiber size and may have a wide therapeutic window. DC delivery can be utilized for a wide variety of indications, including but not limited to, cardiac mapping for arrhythmias, epilepsy, and movement disorders, as well as a variety of other conditions disclosed elsewhere herein.

[0099] To deliver DC to electrically excitable tissue to facilitate a block, an electrode may be positioned at or near said tissue and connected via a conductive lead to one or more current sources (e.g., signal generator 210 shown and / or described in FIG. 2B). A single electrode-tissue interface can provide neural block when DC is applied in one polarity (blocking phase). When the current polarity is reversed to return the electrode to its original state (which may be a non-blocking phase or also a blocking phase), the electrically excitable tissue may or may not continue to block pain stimulus from passing along the nerve (e.g., passing along the axon). If the electrically excitable tissue has been placed into a state of hyper suppression, the electrically excitable tissue will continue to prevent action potential propagation and block pain signals regardless of the phase state of the electrode. However, if the electrically excitable tissue is not placed into a state of hyper suppression, the nerve may pass undesirable signals when the blocking phase signal is absent.

[0100] Some techniques enable continuous block when current polarity is reversed such that the electrically excitable tissue sees a constant current while each driving electrode experiences an alternating current (AC) by using a series of valves to control current flow direction. However, it is desirable to have a simpler system that does not require the use of valves, which present additional failure points and add bulk to a neuromodulation system, such as an implantable or external system. A simpler, more robust system may be configured without valves and such moving parts by using multiple electrodes to provide constant stimulation of the electrically excitable tissue itself, such as described herein. In some embodiments, two electrode-tissue interfaces are present and connected to one or more current sources to provide continuous block. The first electrode-tissue interface can be run with the current in one polarity to drive a block while the second electrode-tissue interface can run with the opposite polarity. After a period of time, the current polarities of the first and secondelectrodes are reversed, and the second electrode-tissue interface provides a block while the first electrode-tissue interface is reversed to its prior state. By cycling the electrode currents, a continuous block can be maintained at the target electrically excitable tissue. In some embodiments, two or more electrodes, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more electrodes, may be used to facilitate continuous block. Electrodes may be run in monopolar and / or bipolar configurations. In some embodiments, the system described herein are configured to not have any actuating or mechanically moving parts, such as valves or hinges.

[0101] Additionally or alternatively, neural activity may be suppressed, in which neural activity remains blocked or reduced even after removal or discontinuation of the therapeutic electrical current. The electrically excitable tissue may be further put into a state of hyper suppression, in which neural activity can remain blocked or reduced without rapid reversibility after cessation of DC delivery. Modulation of the initial current delivered to the electrically excitable tissue including ramp rate, current amplitude (and / or magnitude), total charge delivery, waveform shape, and / or the like, can be used to place the electrically excitable tissue in a state of suppression. During the state of suppression, electrodes may be returned to their initial state by reversing the current polarity used to generate the initial block and suppression state. During the period of reverse current flow, the electrically excitable tissue may remain in a state of hyper suppression. In some embodiments, the system described herein may deliver subsequent blocking activity reducing current inputs that extend the suppression duration, with periods of no current delivery (or of reversal current) in between current doses. The electrically excitable tissue may remain in a state of hyper suppression during the periods of non-blocking or non-activity reducing current input. Placing target electrically excitable tissue in a state of hyper suppression can include delivering a DC waveform (e.g., waveform 500 shown and / or described in FIG. 3E) having any of the waveform parameters described herein (e.g., current amplitude and / or magnitude, level of charge, pulse width, rise / plateau / fall times, frequency, and / or the like). The DC waveform (e.g., current amplitude and duration) may be tuned to enable hyper suppression in the range of, for example, about 0 to about 0.5 times the duration of initial blocking or activity reducing waveform delivery, about 0.5 to about 1 times the duration of initial waveform delivery, about 1 to about 1.5 times the duration of initial waveform delivery, about 1.5 to about 2 times the duration of initial waveform delivery, or about, at least about, or no more than about O.lx, 0.2x,0.3x, 0.4x, 0.5x, 0.6x, 0.7x, 0.8x,0.9x, lx, l . lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 2.5x, 3x, 4x, 5x, or more relative to the duration of initial waveform delivery, or any value or range within or bounded by any of these values or ranges.

[0102] Sensing the local state of and proximal to target electrically excitable tissue can provide a useful measure for determining when to provide current inputs to extend neural suppression, as well as to provide a feedback loop for initial current delivery to generate the initial neural block by modulating the nerve potential such that it cannot transmit action potentials. In some embodiments, the target electrically excitable tissue’s ability to conduct action potentials is monitored such that as DC is delivered to the nerve tissue, the DC delivery can be maintained to ensure that the neural block is maintained. Nerve conduction ability may be monitored by any suitable measure, such as delivering a stimulus pulse and measuring compound action potential signals.

[0103] In some embodiments, sensing is in the form of a reference electrode to measure potential differences relative to two electrodes that are passing the therapeutic electrical current. Measurement of electrode potentials can include voltages across any two electrodes (e g., working electrode, counter electrode, indifferent electrode, or reference electrode) when stimulated with a known current. These measurements can be used to measure and statically or dynamically track characteristics of the electrode, including the impedance and capacitance of the electrode, during delivery of blocking electrical signals to assess the condition of each electrode and the system in general. For example, the voltage on an electrode may indicate what electrochemical reactions are going to occur. In some examples, if the voltage is outside of the water window for the electrode (the window varying based upon the material of the electrode), then water may break down into H2 and 02, which can be damaging to neural tissue or the electrode. In some examples, if the voltage causes a reaction associated with corrosion, then electrode corrosion and deterioration may occur. If the voltage is in either of these ranges where such faradaic electrochemical reaction (or other undesirable reactions) occurs, it may be desirable to permanently or tentatively cease therapy, such as, for example, by stopping operation of the signal generator 210 (see FIG. 2B, for example).

[0104] In some embodiments, the therapeutic electrical current can be modulated in response to one or more measured electrode potentials relative to the reference electrode. In some embodiments, the therapeutic electrical current can be modulated when measuredelectrode potential indicates that undesired electrochemical reactions may occur at one or more active electrodes. For example, therapeutic electrical current may be reduced or ceased upon measurement of an active electrode potential that indicates water electrolysis is occurring or possible. The system may be operated with a direct current input or by applying a potential difference between the working electrode and an auxiliary or indifferent electrode. In some embodiments, a reference electrode may be located within the system or at the distal end of the system proximal to the nerve tissue.

[0105] In some embodiments, neuromodulation systems can include monitoring systems and / or devices such as a controller (e.g., controller 202 shown and / or described in FIG. 2B), implemented in hardware and / or via software, configured to measure electrode potentials (or other parameters) to generate therapeutic electrical current for neural block, activity reduction, and / or suppression. If the measured electrode voltage satisfies a threshold (e g., a predetermined threshold), the controller can adjust (e.g., increase or decrease) the current output (e.g., from a signal generator) to bring the electrode voltage level into an acceptable range relative to the threshold voltage level. For example, if the measured voltage is too high, the output current level may be reduced, set to zero, and / or reversed to the point that the voltage falls below the threshold.

[0106] In some embodiments, a therapeutic electrical signal may take the form of a waveform (such as a square wave or any other suitable shape) in which current is passed between two electrodes having opposite polarity. The voltage waveform required to drive the current between the electrodes may fall within an upper and lower voltage threshold limit. Over time, if the underlying electrode charge capacity is found to change because of various conditions, the driving voltage waveform required to maintain the target current waveform may also change. If the excursions / deviations from the target thresholds are significant enough, this may be indicative of undesired electrochemical reactions occurring. In some embodiments, the system described herein may be configured to limit the amount of time an electrode is exposed to voltages above the driving voltage upper threshold, which can lead to generation of deleterious byproducts that can damage tissue.

[0107] The voltage threshold limits and associated voltages may alternatively or additionally be measured between the working electrode and reference electrode to directly assess the voltage drop across the working electrode-electrolyte interface to assess thepropensity for undesirable electrochemical reactions and voltage potentials across that interface. In some embodiments, the voltages between two or more working electrodes may be used to assess electrode status. In some embodiments, the voltages between a working electrode and indifferent electrode may be used to assess electrode status. To prevent excursions into undesirable zones, the current delivered may be adjusted to reduce the driving voltages as described above.

[0108] In some cases, voltage excursions may be due to changes in electrochemistry. For example, in a system in which a reaction occurs where the same target amount of charge is transferred from one electrode to a second electrode and back to the first electrode, the net charge over time may drift from zero (e.g., become unbalanced) due to imperfect charge accounting. This in turn may lead to changes in voltage required to generate the desired current and be indicative of undesired electrochemical reactions occurring. The drift in net charge transfer from a target level may be countered in some embodiments by monitoring the drive voltage and implementing a control loop that generates additional charge on an electrode that has been detected via its drive voltage characteristics to be deficient in reactants. In some embodiments, a bias current may be used to explicitly unbalance the charge transfer and drive the electrode operating voltage into a more cathodic or more anodic state.

[0109] In some embodiments, block modalities can include but are not limited to monopolar operation, bipolar operation, multipolar operation. Therapeutic electrical current (e g., block current) can be delivered to one or more lead electrode contacts, and a DC bias (e.g., offset) can be added such that working electrodes (WEs) are biased into a safe voltage range, such as further described herein. Monopolar operation can include delivering block current through a lead electrode contact (WE) with positive and negative pulses of current, where the current is sinked by one or more indifferent electrodes (IES). In the monopolar arrangement, block current is conducted between a working electrode (WE) and a counter electrode (CE) or IE. The CE or IE can be a surface or implanted electrode or transcutaneous electrode that can accommodate the opposite voltage of the WE. DC or similar current injection (bias) can be affected by shifting each waveform positively or negatively, and any imbalance can be absorbed by one or more IEs.

[0110] Bipolar operation can include delivering therapeutic electrical current having opposite polarities through a pair of lead electrode contacts operating alternatively in the WEand CE roles, where any imbalance is absorbed by one or more TEs. FIG. 1A illustrates an example bipolar operation with bias (e.g., offset) current. In a bipolar configuration, a therapeutic electrical current is conducted between two working electrodes (WEI, WE2). An offset current is added to each WE and is absorbed by the indifferent electrode (IE), which can be either a surface or implanted electrode that can accommodate the opposite voltage of the WEs. DC or similar current injection (bias) can be affected by shifting each waveform positively or negatively, and any imbalance is absorbed by one or more IES.

[0111] Multipolar operation can include driving therapeutic electrical current with opposite polarities onto a set of lead electrode contacts operating alternatively in the WE and CE roles, where any imbalance is absorbed by one or more IEs. DC or similar current injection (bias) can be affected by shifting each waveform positively or negatively, and any imbalance is absorbed by one or more IEs.

[0112] In some embodiments, therapeutic electrical current outputs can be realized via: bipolar power supplies where current sources are driven by the positive supply and current sinks are driven by the negative supply providing unconstrained simultaneous positive and negative currents and the IE is tied to the Ground (0 V); and / or a monopolar power supply where a current source and sink are put in series and a virtual ground develops between the two supplies.

[0113] Conventional therapeutic waveforms are intentionally AC and have short pulse duration, and may have an unintentional DC component. The unintentional DC component is typically kept as low as possible to balance the charge, leaving the voltage equilibrium point not directly controlled. Advantageously, the system as described herein can be configured to intentionally inject or absorb DC bias. This can permit deliberate control of the voltage equilibrium point (quasi-steady state) and range. Such deliberate control can be achieved, for example, via one or more of the following non-limiting examples:• In the case of monopolar operation, DC bias or similar current injection or absorption can occur by creating an imbalance on one or more working electrodes (WE) and one or more counter electrodes operating as an indifferent electrode (CE / IE) without current control that will absorb all of the current.• In the case of bipolar operation, DC bias or similar current injection or absorption can occur by creating an imbalance on one or more workingelectrodes (WE) and one or more counter electrodes (CE) where the excess current will be absorbed on the indifferent electrode (IE). During bipolar operation between two electrode contacts, the WE and CE change between the two contacts depending on the system polarity, and the IE absorbs the imbalance between the WE and CE regardless of polarity. In some embodiments, a system or method can include only a single WE and a plurality of CEs to advantageously reduce the stress and driving voltages on electrodes. In some embodiments, two WEs can be operated together for a given collective current output to reduce the driving voltages of the two WEs as compared to having the same current output on a single WE.• In the case of multipolar operation (e.g., some hybrid of (a) and (b)), DC bias or similar current injection or absorption can occur by creating an imbalance between M number of WEs and N number of CEs and absorbing the difference with at least one IE, which may or may not be the same as the CE (e.g., source and sink are imbalanced on multiple current outputs).

[0114] In some embodiments, the bias current is the current resulting from the summation of currents being simultaneously delivered to the electrode contacts or working electrodes in proximity to the target electrically excitable or voltage-sensitive tissue. In some embodiments, the bias current is equal in magnitude and opposite in polarity to the summation of the currents being simultaneously delivered to the electrode contacts or working electrodes. In some embodiments, the currents being simultaneously delivered to the electrode contacts or working electrodes can be adjusted to modulate the bias current.

[0115] A signal that averages a non-zero current over the duration of block can include, for example, a charge imbalance, including but not limited to an intraphase bias, phase-to- phase bias, a cycle-to-cycle bias, an intermittent bias or offset, or any combination thereof. The bias may also be configured to be time-varying independent of the DC waveform.

[0116] FIG. IB illustrates an example DC waveform between working electrodes and having a constant bias current. As illustrated in FIG. IB, the example waveform is biphasic, and each waveform is biased down by one unit of current leading to a total bias current of 2 units. As further illustrated in FIG. IB, all currents sum to zero.

[0117] In some embodiments, the bias current can be a cathodic bias current (e.g., for TiN or tantalum electrodes). In some embodiments, the bias current can be an anodic bias current, with (+) positive values substituted for any (-) values disclosed herein (e.g., for IrOx electrodes). In some embodiments, the total bias current can be, for example, between about - 10 pA and about -1 mA, between about -10 pA and about -100 pA, between about -0.01 pA and about -1000 pA, between about -0.01 pA and about -0.1 pA, between about -0.1 pA and about -1 pA, between about -1 pA and about -1000 pA, between about -20 pA and about -100 pA, or about -0.01 pA , about -0.05 pA, about -0.10 pA, about -0.50 pA, about -1 pA, about - 5 pA, about -10 pA, about -15 pA, about -20 pA, about -25 pA, about -30 pA, about -35 pA, about -40 pA, about -45 pA, about -50 pA, about -55 pA, about -60 pA, about -65 pA, about - 70 pA, about -75 pA, about -80 pA, about -85 pA, about -90 pA, about -95 pA, about -100 pA, or any value or range within or bounded by any of these values or ranges. Smaller or greater currents are also possible. The bias current can be any of these values, and in some embodiments, between about -40 pA and about -50 pA, such as about -40 pA, about -41 pA, about -42 pA, about -43 pA, about -44 pA, about -45 pA, about -46 pA, about -47 pA, about - 48 pA, about -49 pA, about -50 pA, or any value or range within or bounded by any of these values or ranges. As noted, the bias current can be either negative or positive (e.g., the absolute value of any of the values or ranges of values disclosed herein).

[0118] In some embodiments, the total bias current can be split (e.g., evenly) among a number N of working electrodes. For example, in a bipolar system with 2 working electrodes, the bias current of each working electrode can be the total bias current / 2, such as -50 pA / 2 = - 25 pA or +50 pA / 2 = +25 pA. In some embodiments, the total bias current is the offset experienced by the indifferent electrode and the bias current / N is experienced by the working electrode.

[0119] In some embodiments, the bias current resulting from the working electrode currents can be delivered to one, two, or more indifferent electrodes (e.g., only a single indifferent electrode in some embodiments). The indifferent electrode(s) may be configured to be a passive current sink or source. In some embodiments, the indifferent electrode(s) may be a therapeutic electrical current sink or source. In some embodiments, the indifferent electrode(s) can have a relatively high working surface area to minimize the current density on the electrode surface and minimize or prevent discomfort or other sensations of the deliveredcurrent to the patient. The indifferent electrode(s) may be implanted, transcutaneous, or be a body surface electrode (e.g., completely external, such as further described herein).

[0120] In some embodiments, high frequency stimulation (e.g., high frequency alternating current or HF AC stimulation) can be biased with a low frequency signal to reduce onset effects. For example, a low frequency signal (e.g., DC waveform,) may be provided before an HF AC signal, concurrent with an HF AC signal, constantly with an HF AC signal, or only during onset and / or offset with HF AC.

[0121] In some embodiments, the system, methods, and devices of the present disclosure may be configured to deliver subsequent current inputs on a schedule. In some embodiments, DC waveforms can be used, in addition to blocking and / or suppressing action potentials, to allow for superposition of an electric field across neurons for the purposes of inducing a transmembrane potential that can allow modulation of one or more of the following neuronal properties: Spiking properties; Excitability (increase or decrease sensitivity); conduction velocity; control of electroporation; synchronization of neural populations; induction of secondary effects in cells that affect neighboring cells including vascular changes and blood brain barrier permeability; shift strength duration curve; DNA or RNA transcription or translation modification; and / or protein or drug transport (electrophoresis), among others.

[0122] Multidimensional field shaping can be implemented to target various different nerve targets and / or other electrically excitable tissue for block, activity reduction, and / or suppression. In some embodiments, multiple electrodes can be spatially employed to focus energy at various different targeted localities including the dorsal root entry zone, spinal column, spinothalamic tract, and / or any specific spatial region in and around the stimulating electrodes. In some embodiments, electrical signals delivered to and / or by electrodes may be frequency and / or phase shifted to vary the field such that the focal point moves with time, and / or recruits different classes and diameters of neurons, axons, or ion channels. For example, positioning electrodes along the spinal column and tuning the electric field (e.g., the electrical current, signal, and / or the like) to generate neural block, activity reduction, and / or suppression, specific targets for pain attenuation can be facilitated. Trunk pain, which is moderated by the thoracic vertebral levels, can be modulated by placing leads along the thoracic spine, while neck pain may be moderated by providing block or activity reduction and / or suppression in the cervical spine. Upper limb pain may be moderated by providing a combination of cervical andthoracic level block or activity reduction and / or suppression, while lower limb pain may be moderated by a combination of lumbar and sacral level block or activity reduction and / or suppression in the spine.

[0123] Generation of neural block, activity reduction, and / or suppression can be used to facilitate periprocedural pain block where motor control and non-pain sensations are desired. For example, in labor and delivery of a child, one of the challenges with pain management (particularly with epidural anesthesia) is the reduction in ability to be sensate in the lower body. Due to the nonspecific nature of the delivered anesthesia in the epidural space, sensory, pain, and motor neurons are impacted. The epidural anesthesia can lead to difficulty with generating pushing force during the birthing process and can lead to numbness a few hours after birth, thereby impairing motor abilities such as the ability to walk. In some instances, epidurals are further implicated in fetal and newborn health including breastfeeding difficulty. Using blocking electrodes described herein to target the spinothalamic tract and / or dorsal root ganglia, the undesired pain can be targeted without generating side effects (or reducing or mitigating side effects) associated with current epidural anesthesia techniques because only the pain tracts are targeted and not any other motor or sensory tracts. Furthermore, in the case in which therapeutic electrical current is delivered to the nerve tissue in a reversible blocking fashion, the stopping of block can enable the patient to immediately be restored to normal pain sensation if desired, and any off-target block can be reversed to enable immediate body function restoration.

[0124] Beyond central nervous system interventions, a safe neural block or activity reduction can be facilitated in the peripheral nervous system in which electrodes described herein are placed in contact or in proximity to peripheral nerves. Pain targets can include, for example, focal pain, phantom limb pain, neuroma pain, and neuralgias, post-operative pain, among others. Targeting the peripheral nerves proximally (e.g., closer to the spinal cord) from the site of pain for block or activity reduction can suppress pain from the distal site. Specific to neuralgias, postherpetic neuralgia (after shingles) can be targeted based on the presentation of the outbreak which will trace specific dermatomes. For trigeminal neuralgia, the trigeminal nerve (and / or trigeminal ganglion and / or trigeminal nucleus in the brainstem) can be targeted for block to reduce pain that commonly manifests as facial pain. For glossopharyngeal neuralgia, the glossopharyngeal nerve (and / or glossopharyngeal ganglion and / orglossopharyngeal nucleus in the brainstem) can be targeted to block to reduce pain that commonly manifests as neck and throat pain. Neuralgia in extremities such as the hands, arms, feet, and legs as frequently caused due to diabetes-related neuropathies are also potential targets.

[0125] In some embodiments, neuromodulation of tissue including delivery of high charge densities via a DC waveform and use of at least one indifferent electrode to absorb a bias current can unexpectedly, advantageously, and safely enable continued suppression of neural activity after cessation of current delivery (wash-out period), which can provide multiple benefits. For example, power can be saved or power consumption can be slowed. In some examples, the sudden return of neural activity can be prevented in case of device failure (e.g., connection failure, battery failure, and / or the like), which can improve safety and / or enable patient / physician intervention during prolonged suppression periods. Similarly, the rapid return of pain in the event of device failure and / or the rapid return of sympathetic signaling that may lead to acute sympathetic events (such as acute decompensation or cardiac arrhythmias) can be prevented. In some examples, when implemented as an electronic medicine dosing system / method, a long-lasting therapeutic benefit can be created from acute application. Furthermore, the system as described herein can be very safe, reducing (or mitigating or preventing) the creation of toxic species at the electrode-nerve interface, as further described herein.

[0126] In some embodiments, the system of the present disclosure can be configured for generation of neural block or activity reduction for disorders and diseases that can be addressed by reducing neural activity in specific regions of the brain responsible for the specific disorder. Neural activity reduction can be facilitated by directly blocking and / or reducing activity of specific neurons as well as by blocking pathways along which excessive neural signaling is occurring. In some embodiments, systems for deep brain block (DBB) comprise all or some of the steps of identification of the anatomic target site for block, creating an access site to the exterior of the brain tissue, creating a path through the brain tissue to the target site, evaluating the suitability of the target site for block, adjusting or refining the location of the target site, providing neural block at the target site, and adjusting the nerve tissue block strength or location. Practically, this process may be implemented using techniques known in the field of deep brain stimulation (DBS) in which a target anatomic siteis identified using a combination of imaging techniques such as but not limited to magnetic resonance imaging (MRI) including functional MRI (fMRI), computed tomography (CT), PET scanning, and / or X-rays. This site can then be accessed using stereotactic techniques to register an identified region from imaging to the physical anatomy on the patient. A frame may be fixed to the patient’s head and skull to allow for spatial registration during the procedure. An access site to the brain tissue in the form of a burr hole or craniotomy can be formed with or without additional access tools fixed to the skull such as insertion cannula and advancement / retraction equipment to access the target site. Advancement of a nerve tissue activity measurement probe through the brain tissue to the target site may be used to enable evaluation of the suitability of the brain region. This probe may record neural activity to determine that the measured signals are consistent with that of tissue requiring block or activity reduction. If the signal characteristics indicate that the location is not optimal or appropriate for block or activity reduction, the probe may be adjusted until the correct location is identified. The measurement probe may be exchanged with the therapeutic electrode, which can then be inserted with the active portion of the electrode positioned within the target site. Activation of the blocking or activity reducing signal can then be used to assess efficacy of the block as well as to tune the strength of the signal. The therapeutic electrode can then be fixed to the skull to maintain the active portion’s (e.g., region delivering current) position at the target site. An extension lead can be connected to the affixed therapeutic electrode and connected to an implantable current source, similar to an implantable pulse generator (IPG), whose output signal can be adjusted to facilitate optimal symptom reduction. Blocking or activity reducing electrodes may be implanted unilaterally or bilaterally as the contralateral side of the body is affected by specific anatomic target sites.Example System Relating to Neural Inhibition Therapy

[0127] FIG. 2A schematically illustrates an example implementation of a neuromodulation system 100. The neuromodulation system 100 can include, but is not limited to, a neuromodulation device 104, one or more user devices 106, a network 108, one or more sensors 110, and one or more servers 112.

[0128] The neuromodulation device 104 can be used in a standalone manner and / or in combination with other devices and / or sensors. As shown in FIG. 2A, the neuromodulation device 104 can be implanted within the body of a subject (e g., a patient) 102 and communicate(for example, wirelessly) with a plurality of devices, including but not limited to one or more user devices 106, one or more sensors 110, and / or one or more servers 112. Additionally, the neuromodulation device 104 can connect to a computing network 108 (for example, via any of the connected devices disclosed herein, or directly). The network 108 can include any one or more communications networks. The network 108 can include a plurality of computing devices configured to communicate with one another. The network 108 can include routers. The network 108 can include the Internet. The network 108 can include any combination of networks, such as a personal area network (PAN), a local area network (LAN), a metropolitan area network (MAN), a wide area network (WAN), or the like, and may allow geographically dispersed devices, systems, databases, servers (e.g., cloud-based), and the like to connect (e.g., wirelessly) and to communicate (e.g., transfer data) with each other. Accordingly, various components of the neuromodulation system 100 can communicate with one another directly or indirectly via any appropriate communications links and / or networks, such as network 108 (e.g., one or more communications links, one or more computer networks, one or more wired or wireless connections, the Internet, any combination of the foregoing, and / or the like).

[0129] The neuromodulation device 104 can communicate with the one or more user devices 106 either directly or via network 108. The user device(s) 106 may be a mobile communication device (e.g., smartphone), a patient monitor (e.g., a bedside monitor, a patient monitoring and connectivity hub, any handheld patient monitoring devices, and any other wearable patient monitoring devices), a computer (which can be a laptop or a desktop), a tablet, a wearable device (e.g., smart watch, glasses such as smart glasses configured to display images on a surface of the glasses), and / or the like

[0130] In some embodiments, the neuromodulation device 104 may be in wired (or wire-like) communication with one or more user devices 106 via a wire or cable connection or any other suitable electronic connection that can permit transfer of data between the neuromodulation device 104 and the one or more user devices 106. In some embodiments, the neuromodulation device 104 may be in wireless connection with the one or more user devices 106 via any variety of communication protocols, including near-field communication protocols and far-field communication protocols. Near-field communication (NFC) protocols, which may also be referred to as non-radiative communication, can implement inductive coupling between coils of wire to transfer energy via magnetic fields (e.g., NFMI). Near-fieldcommunication protocols can implement capacitive coupling between conductive electrodes to transfer energy via electric fields. Far-field communication protocols, which may also be referred to as radiative communication, can transfer energy via electromagnetic radiation (e.g., radio waves). In some embodiments, the neuromodulation device 104 may communicate with the one or more user devices 106 via any variety of communication protocols such as Wi-Fi (e.g., 2.4 GHz channel, 5 GHz channel), Bluetooth® (e.g., Bluetooth Low Energy 5.0 / Mesh), ZigBee®, Z-wave®, cellular telephony, 1G, 2G, 3G, 4G, 5G, infrared, near-field communication (NFC), radio frequency identification (RFID), satellite transmission, inductive coupling, capacitive coupling, proprietary protocols, any combination of the foregoing, and / or any other suitable wireless connection. The neuromodulation device 104 may communicate data to the one or more user devices 106 and / or receive data from the one or more user devices 106. For example, user devices 106 may receive physiological data and / or neuromodulation data (e.g., data associated with one or more therapy parameters) from the neuromodulation device 104.

[0131] The neuromodulation device 104 can communicate with the one or more sensors 110 either directly or via network 108. In some embodiments, the neuromodulation device 104 may be in wired (or wire-like) communication with one or more sensors 110 via a wire or cable connection or any other suitable electronic connection that can permit transfer of data between the neuromodulation device 104 and the one or more sensors 110. In some embodiments, the neuromodulation device 104 may be in wireless connection with the one or more sensors 110 via any variety of communication protocols, including near-field communication protocols and far-field communication protocols. The neuromodulation device 104 may communicate with the sensor(s) 110 via any variety of communication protocols such as Wi-Fi (e.g., 2.4 GHz channel, 5 GHz channel), Bluetooth® (e.g., Bluetooth Low Energy 5.0 / Mesh), ZigBee®, Z-wave®, cellular telephony, 1G, 2G, 3G, 4G, 5G, infrared, near-field communication (NFC), radio frequency identification (RFID), satellite transmission, inductive coupling, capacitive coupling, proprietary protocols, any combination of the foregoing, and / or any other suitable wireless connection. The neuromodulation device 104 may communicate data to the one or more sensors 110 and / or receive data from the one or more sensors 110. For example, the neuromodulation device 104 may receive physiological data and / or neuromodulation data from the one or more sensors 110.

[0132] The neuromodulation device 104 can be integrated with one more sensors 1 10 and / or configured to connect to a plurality of external sensors 110, wirelessly or with a connecting cable. The connecting cable can be a universal connector configured to connect to any of the medical devices and / or sensors disclosed herein to provide communication between the neuromodulation device 104 and the connected medical devices and / or sensors. The cable can optionally include a board-in-cable device that includes its own processor.

[0133] The neuromodulation device 104 can include open architecture to allow connection of third-party wireless sensors, and / or allow third party access to a plurality of sensors on the neuromodulation device 104 or connected to the neuromodulation device 104. The plurality of sensors can include, for example, a temperature sensor, an altimeter, a gyroscope, an accelerometer, emitters, LEDs, and the like. Third party applications can be installed on one or more devices shown in FIG. 2A, such as a user device 106 (e.g., a mobile communication device), and can use data from one or more of the sensors on the neuromodulation device 104 and / or in electrical communication with the neuromodulation device 104.

[0134] The neuromodulation device 104 can communicate with any other suitable noninvasive sensor, such as an acoustic sensor, a PPG sensor, a physiological sensor, a blood pressure sensor, temperature sensor, movement sensor, ECG sensor, and the like. The neuromodulation device 104 can communicate with chemical sensors, which can detect, for example, chemicals on the subject’s skin, and / or sweat, and / or the odor of certain chemicals in the air. The chemical sensors can include electrochemical sensors or any other suitable types of chemical sensors.

[0135] The neuromodulation device 104 can communicate with the server(s) 112 via network 108. The neuromodulation device 104 may, via the network 108, communicate data to the server(s) 112 and / or receive data from the server(s) 112 including communication data (e.g., device addresses and / or link keys corresponding to one or more devices of neuromodulation system 100), physiological data, neuromodulation data, identification data (e.g., user ID), or the like. The neuromodulation device 104 may communicate with the server(s) 112 via any variety of communication protocols such as Wi-Fi (e.g., 2.4 GHz channel, 5 GHz channel), Bluetooth® (e.g., Bluetooth Low Energy 5.0 / Mesh), ZigBee®, Z-wave®, cellular telephony, 1G, 2G, 3G, 4G, 5G, infrared, near-field communication (NFC), radiofrequency identification (RFID), satellite transmission, inductive coupling, capacitive coupling, proprietary protocols, any combination of the foregoing, and / or any other suitable wireless connection. In some embodiments, a neuromodulation device 104 may communicate with the server(s) 112 via a different wireless communication protocol than which it communicates with the one or more other devices. For example, the neuromodulation device 104 may communicate with the server(s) 112 via a first wireless communication protocol, such as Wi-Fi, and may communicate with the one or more user devices and / or sensors via a second wireless communication protocol, such as Bluetooth. In some embodiments, the neuromodulation device 104 may not communicate directly with the server(s) 112. For example, data may be transmitted from the neuromodulation device 104 to the server(s) 112 via one or more user devices 106 and / or via one or more sensors 110, or vice versa.

[0136] In some embodiments, the network 108 can be configured to handle increased data traffic as sensors, monitoring hubs, servers, and / or other computing and / or physiological monitoring devices are added to the neuromodulation system 100. For example, the network 108 can include hardware such as switches, routers, WAN optimization devices, other connection points and the like for handling increased data throughput and more connections simultaneously. In some examples, the network 108 may implement virtual local area networks (“VLANs”) to segment traffic within specific areas of the network. In some examples, the network 108 can include quality-of-service rules to set priorities for certain data traffic. In some embodiments, the network 108 may implement advanced routing techniques to adapt network conditions to find efficient paths for data traffic. For example, the network 108 can implement dynamic routing, load balancing, and the like.

[0137] In some embodiments, the user device(s) 106 may optionally communicate with the server(s) 112 via the network 108. For example, the user device(s) 106 may transmit and / or receive data (e.g., communication data, physiological data, neuromodulation data, identification data, and / or the like) to and / or from the server(s) 112. In some embodiments, the user devices(s) 106 may not communicate directly with the server(s) 112. For example, data may be transmitted from the user device(s) 106 to the server(s) 112 via the neuromodulation device 104 and / or via one or more sensors 110, or vice versa.

[0138] In some embodiments, the sensor(s) 110 may optionally communicate with the server(s) 112 via the network 108. For example, the sensor(s) 110 may transmit and / or receivedata (e.g., communication data, physiological data, neuromodulation data, identification data, and / or the like) to and / or from the server(s) 112. In some embodiments, the sensor(s) 110 may not communicate directly with the server(s) 112. In some implementations, data may be transmitted from the sensor(s) 110 to the server(s) 112 via the neuromodulation device 104 and / or one or more user device 106, or vice versa.

[0139] The server(s) 112 may comprise one or more computing devices including one or more hardware processors. The one or more hardware processors may be configured to analyze, cleanse, edit, reduce, wrangle, or otherwise process data. The server(s) 112 may comprise program instructions configured to cause the server(s) 112 to perform one or more operations when executed by the hardware processors. The server(s) 112 may include, and / or have access to (e.g., be in communication with) a database or storage component or storage system which can include any computer readable storage medium and / or device (or collection of data storage mediums and / or devices), including, but not limited to, one or more memory devices that store data, including without limitation, dynamic and / or static random access memory (RAM), programmable read-only memory (PROM), erasable programmable readonly memory (EPROM), electrically erasable programmable read-only memory (EEPROM), optical disks (e.g., CD-ROM, DVD-ROM, and / or the like), magnetic disks (e.g., hard disks, floppy disks, and / or the like), memory circuits (e.g., solid state drives, random-access memory (RAM), and / or the like), and / or the like. In some embodiments, the server(s) 112 may host a database which can be any data structure (and / or combinations of multiple data structures) for storing and / or organizing data, including, but not limited to, relational databases (e.g., Oracle databases, PostgreSQL databases, MySQL databases and the like), non-relational databases (e.g., NoSQL databases, and the like), in-memory databases, spreadsheets, as comma separated values (“CSV”) files, extensible markup language (“XML”) files, TeXT (“TXT”) files, flat files, spreadsheet files, and / or any other widely used or proprietary format for data storage. Databases can be stored in one or more data stores. In some implementations, the server(s) 112 may include and / or be in communication with a hosted storage environment that includes a collection of physical data storage devices that may be remotely accessible and may be rapidly provisioned as needed (commonly referred to as “cloud” storage).

[0140] Data stored in and / or accessible by the server(s) 112 can include processed and / or unprocessed physiological data including historical physiological data previouslyobtained by the neuromodulation device 104 (and / or by one or more sensors in communication with the neuromodulation device 104). Data stored in and / or accessible by the server(s) 112 can include processed and / or unprocessed neuromodulation data associated with one or more therapy parameters including, for example, voltage levels, current levels, frequencies, pulse widths, neuromodulation waveforms, body impedance, and other parameters associated with nerve response data.

[0141] In some embodiments, the network 108 may comprise and / or be in communication with an electronic medical records (EMR). In some embodiments, the server(s) 112 may comprise and / or be in communication with an EMR. In some embodiments, the one or more user devices 106 may be in communication with an EMR. An EMR can comprise a propriety EMR. An EMR can comprise an EMR associated with a hospital. An EMR can store data including medical records.

[0142] In some implementations, the server(s) 112 can manage and / or process data received from the neuromodulation device 104, user device(s) 106, and / or sensor(s) 110. For example, the server(s) 112 can process physiological data originating at sensor(s) 110 to generate processed physiological data, which can include physiological parameter values, alarms, alerts, notifications, trends, comparisons, or the like. In some examples, the server(s) 112 can process neuromodulation data originating at sensor(s) 110 to generate processed neuromodulation data, which can include therapy parameter values, alarms, alerts, notifications, trends, comparisons, or the like. In some embodiments, the server(s) 112 can be configured to perform one or more operations, functions, or algorithms, such as data filtering, data averaging, identifying maximums or minimums, identifying trends, extrapolating data, interpolating data, and the like. The server(s) 112 can continuously measure physiological and / or neuromodulation data of a subject and / or monitor such data in real-time. In this way, the server(s) 112 can include hardware capabilities for continuous and / or real-time processing.

[0143] In some implementations, the server(s) 112 can generate user interface data corresponding to physiological data for rendering user interfaces comprising indicia of the physiological data. Advantageously, the server(s) 112 may act as a central processing computing system that processes data from distributed computing devices (e.g., neuromodulation device 104, user devices 106, sensors, and / or the like) which may reduce local processing requirements on the distributed computing devices. In some implementations,the server(s) 112 may store data received from the neuromodulation device 104, user device(s) 106, sensor(s) 110, and / or the like, such as physiological data. Advantageously, the server(s) 112 may act as a central storage (e.g., database) such that distributed computing devices (e.g., neuromodulation device 104, user device(s) 106, sensor(s) 110, and / or the like) can access the same data stored at the server(s) 112, which may reduce local storage requirements at the distributed computing devices.

[0144] FIG. 2B depicts a block diagram illustrating a non-limiting example implementation of neuromodulation device 104. neuromodulation device 104 may be implemented as, integrated into, and / or include any of the features and / or functions (or similar features and / or functions) of any of the devices described herein. The neuromodulation device 104 may be a separate device operably connected to and in communication with (e.g., transfer data) with any of the devices described herein. The neuromodulation device 104 can include a controller 202, a memory 204, a communication interface 206, a power source 208, one or more sensors 110, a signal generator 210, one or more implantable leads 212, and a display 214.

[0145] Controller 202 can be configured to receive and send signals to and from various components of the neuromodulation device 104 and / or neuromodulation system 100 shown and / or described in FIG. 2A. The controller 202 may control the operations of various components within the neuromodulation system 100. Controller 202 can be implemented as a processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A processor can also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0146] The controller 202 can be configured to execute program instructions to cause the neuromodulation device 104 to perform one or more operations. The controller 202 can be configured, among other things, to process data (e.g., analyze, cleanse, edit, reduce, wrangle, or otherwise process data), execute instructions to perform one or more functions, and / orcontrol the operation of the neuromodulation device 104 or components thereof. For example, the controller 202 can process sensor data obtained from sensor(s) 110 and can execute instructions to perform functions related to storing and / or transmitting such sensor data. In some examples, the controller 202 can process data received from one or more devices described herein, such as shown and / or described in FIG. 2A. In some embodiments, the controller 202 can be configured to perform one or more operations based on user input received via, for example, a user interface or other device (e.g., a device in communication with neuromodulation device 104). For example, the controller 202 may cause (via, for example, one or more control signals) a signal generator, such as signal generator 210, to generate and deliver a therapeutic electrical signal to one or more implantable leads (e.g., implantable lead(s) 212) to deliver therapeutic energy at a treatment site at a certain frequency, for a certain period of time, at a certain current level, at a certain duty cycle, and the like, based on received user input (such as any frequency, treatment time, current level, and / or duty cycle described herein).

[0147] In some embodiments, the controller 202 may be remote to the neuromodulation device 104. For example, the controller 202 may be implemented as a clinician programming device (CPD) in communication with the neuromodulation device 104 (or one or more components thereof). In some examples, one or more functions of the controller 202 may be embodied in a clinician programming application (CPA) executing separately on a user device (e.g., user device(s) 106) or in the cloud. For example, a computing device (e.g., controller 202, neuromodulation device 104, user device(s) 106) comprising a CPA can communicate wirelessly with a signal generator (e.g., signal generator 210) via a CPD, which may be in wired, wirelike, or wireless communication with the signal generator 210. The CPD can upload a waveform to the signal generator 210 based on parameters set by a user (e.g., programmer, clinician, and / or the like). The CPD may also download logs and performance data from previous therapy sessions.

[0148] In some embodiments, the controller 202 can include one or more features and / or functions such as described in greater detail in at least U.S. Patent App. No. 18 / 563,861, filed on November 22, 2023, entitled “PULSE GENERATION AND STIMULATION ENGINE SYSTEMS,” the entire contents of which are hereby incorporated herein by reference in their entirety.

[0149] The memory 204 can include any computer readable storage medium and / or device (or collection of data storage mediums and / or devices), including, but not limited to, one or more memory devices that store data, including without limitation, dynamic and / or static random-access memory (RAM), programmable read-only memory (PROM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), optical disks (e.g., CD-ROM, DVD-ROM, and / or the like), magnetic disks (e.g., hard disks, floppy disks, and / or the like), memory circuits (e.g., solid state drives, random-access memory (RAM), and / or the like), and / or the like. The memory 204 can store data including processed and / or unprocessed physiological data originating from one or more sensors (e.g., sensor(s) 110). The memory 204 can store data including processed or unprocessed neuromodulation data originating from one or more sensors (e.g., sensor(s) 110). Stored data can be processed and / or unprocessed data obtained from one or more devices described herein, such as shown and / or described in FIG. 2A. Stored data may include time- stamped data, including but not limited to time instants and time durations of nerve inhibiting therapeutic treatment, such as to permit a clinician to monitor compliance. This may be done through connection with a neuromodulation device (e.g., neuromodulation device 104) or other connected device for download of usage data, wireless synchronization to handheld devices or clinical remote monitoring devices, and / or the like, via the communication interface 206, for example. Stored data can include user input such as therapy parameters selected by a user via, for example, a user interface. Synchronization with a device, such as a handheld device or other computing device, may allow a user to enter therapy parameters to be transmitted to the neuromodulation device 104. The memory 204 can store program instructions that when executed by the controller 202 cause the neuromodulation device 104 to perform one or more operations.

[0150] The memory 204 can store persistent data and / or non-persistent data. Persistent data may be data that is preserved (e.g., not deleted from storage) when the computing system is powered down and / or when an application is terminated. Persistent data may be stored for longer than 30 seconds, longer than 60 seconds, longer than 5 minutes, longer than 10 minutes, longer than 30 minutes, longer than 1 hour, longer than 6 hours, longer than 12 hours, longer than 24 hours, or the like. Non-persistent data may be data that is deleted or otherwise lost when the computing system is powered down and / or when an application is terminated. Non-persistent data may be stored for less than 24 hours, less than 12 hours, less than 6 hours, less than 1 hour, less than 30 minutes, less than 10 minutes, less than 5 minutes, less than 60 seconds, less than 30 seconds, less than 20 seconds, less than 10 seconds, less than 5 seconds, less than 1 seconds, or the like. Non-persistent data may be stored for a shorter period of time than persistent data. In some implementations, persistent data may be stored in non-volatile memory. In some implementations, non-persistent data may be stored in volatile memory such as RAM. The memory 204 can store data in a buffer. A buffer may store data for a period of time before deleting the data. The period of time can be fixed. The buffer may automatically delete data stored therein upon expiration of a period of time. The period of time may be between about 0.01 seconds and 0.15 seconds, between 0.1 seconds and 1.5 seconds, between 1 second and 5 seconds, between 1 second and 10 seconds, between 10 seconds and 60 seconds, between 30 seconds and 60 seconds, between 1 minute and 3 minutes, between 1 minute and 5 minutes, between 1 minute and 10 minutes, between 5 minutes and 30 minutes, between 20 minutes and 60 minutes, or greater than 60 minutes.

[0151] The communication interface 206, which may also be referred to as a communication system, can facilitate communication (via wired and / or wireless connection) between the neuromodulation device 104 (and / or components thereof) and separate computing devices, such as separate monitoring hubs, monitoring devices, sensors, systems, servers, or the like. For example, the communication interface 206 can be configured to allow the neuromodulation device 104 to wirelessly communicate with other devices and / or systems using any combination of a variety of communication protocols and / or over one or more networks. The communication interface 206 can be configured to implement any combination of a variety of wireless communication protocols, such as Wi-Fi (e.g., 802.1 lx, 2.4 GHz channel, 5 GHz channel), Bluetooth® (e.g., Bluetooth Low Energy 5.0 / Mesh), ZigBee®, Z- wave®, cellular telephony, 1G, 2G, 3G, 4G, 5G, infrared, near-field communications (NFC), radio frequency identification (RFID), satellite transmission, inductive coupling, capacitive coupling, proprietary protocols, combinations of the foregoing, and the like. The communication interface 206 can allow data and / or instructions to be transmitted and / or received to and / or from the neuromodulation device 104 and separate computing devices. The communication interface 206 can be configured to transmit and / or receive (for example, wirelessly) processed and / or unprocessed data such as physiological data, neuromodulationdata, and the like, with separate computing devices including sensors (e.g., sensor(s) 110), monitoring hubs, remote servers, or the like.

[0152] In some embodiments, communication interface 206 can transfer power required for operation of a computing device. The communication interface 206 can be embodied in one or more components that are in communication with each other. The communication interface 206 can include one or more of transceivers, antennas, transponders, radios, emitters, detectors, coils of wire (e.g., for inductive coupling), and / or electrodes (e.g., for capacitive coupling). The communication interface 206 can wirelessly communicate or connect to one or more remote computing devices over a network such as by implementing one or more wireless communication protocols.

[0153] The power source 208 can provide power for the neuromodulation device 104 or components thereof. Power source 208 can include one or more batteries and can be rechargeable. Battery capacitance / voltage design can be sufficient in some cases to power the neuromodulation device 104 for 8 hours of use, 12 hours of use, 16 hours of use, 24 hours of use, 2 days of use, 3 days of use, 4 days of use, 5 days of use, 6 days of use, 7 days of use, 8 days of use, 9 days of use, 10 days of use, or more, such as any suitable time period according to various therapy parameters described herein. In some embodiments, the power source 208 may be external to the neuromodulation device 104. For example, the neuromodulation device 104 can include or can be configured to connect to a cable which can itself connect to an external power source to provide power to the neuromodulation device 104. The power source 208 may be a portable battery. In some embodiments, power source 208 can be embodied in one or more components that are in communication with each other. For example, power source 208 may be operably connected to, or integrated into, a signal generator (e.g., signal generator 210) to allow programming for pulsed or continuous wave therapeutic electrical signals. For example, the power source 208 may be operably connected to, or integrated into, a generator / interface console that includes one or more features and / or functions of neuromodulation device 104. Some embodiments can include wired AC power connections.

[0154] The one or more sensors 110 can include various types of sensors configured to collect data of a subject, such as relating to neural inhibition therapy. Such data can include physiological data associated with effects of therapy delivery, neuromodulation data relating to therapy parameters, and the like. For example, the one or more sensors 110 can collectpatient physiological data including, but not limited to, data relating to heart rate, pulse rate, respiration rate, blood pressure, blood oxygen saturation, hemoglobin content, ECG data, EEG data, temperature, subject orientation, subject position, subject movement, as non-limiting examples, and the like. In some examples, the one or more sensors 110 can collect patient neuromodulation data including, but not limited to, voltage levels, current levels, frequencies, pulse widths, therapy waveforms, body impedance, as non-limiting examples, and the like.

[0155] The one or more sensors 110 may be located at a target site, such as at a target tissue (e.g., a target nerve), including but not limited to any of the nerve targets described herein. Additionally, or alternatively, the sensor(s) 110 can attach or couple to different parts of a subject such as, but not limited to, arms, legs, torso, chest, head, neck, fingers, forehead, and the like. In some embodiments, the sensor(s) 110 may be high-charge density stimulation electrodes (e.g., TiN).

[0156] The one or more sensors 110 can transmit data to the neuromodulation device 104, user device(s) 106, and / or to the server(s) 112 in real-time as the one or more sensors 110 collect the data. In some embodiments, one or more sensors 110 can include processors that can fully or partially process the data obtained by the sensors 110. For example, the one or more sensors 110 can process data obtained by the sensors 110 to generate processed data which can include parameter values (e.g., physiological parameters, therapy parameters), alarms, alerts, notifications, trends, comparisons, or the like. In some examples, the one or more sensors 110 can be configured to perform one or more operations, functions, or algorithms, such as data filtering, data averaging, identifying maximums or minimums, identifying trends, extrapolating data, interpolating data, and the like. In some embodiments, one or more sensors 110 can continuously measure physiological and / or neuromodulation data of a subject and / or monitor such data in real-time. In this way, the one or more sensors 110 can include hardware capabilities for continuous and / or real-time processing.

[0157] The signal generator 210 may be in electrical communication with one or more implantable leads (e.g., implantable lead(s) 212) and can be configured to generate therapeutic electrical signals (e.g., pulses) to the one or more implantable leads. In some embodiments, the neuromodulation device 104 can utilize the signal generator 210 in the delivery of neural inhibition therapy, such as spinal neural inhibition therapy. Signal generator 210 may be located internal of the subject (e.g., in a surgical pocket, placed near a target nerve structure),or contained within the therapy leads. In some embodiments, the signal generator 210 may be placed externally. For example, in some embodiments, the signal generator 210 may be affixed to the skin (e.g., via an adhesive, suture, wrapping), worn on the patient (e.g., in a belt, backpack, pouch, pocket, and / or the like), or handheld and connected wirelessly to the implantable leads. In some embodiments, the signal generator 210 may be provided as an external device. For example, in some embodiments, the signal generator 210 may be external and separate from the patient (e.g., a trial signal generator) and connect to the implantable lead(s) 212. Further, the signal generator 210 may be located in the ICU, in a Catheter Lab, in an inpatient setting, and / or in in a remote telemetry unit.

[0158] Signal generator 210 may be connected to a power source (e.g., power source 208). In some embodiments, the signal generator 210 may be powered via a battery. For example, the signal generator 210 may be powered via: primary cell battery (e g., does not require recharging), replaceable primary cell battery, rechargeable battery, and the like. In some embodiments, the signal generator 210 may be powered via wireless charging (e.g., inductive, ultrasound, optical, magnetic, removable rechargeable battery). In some embodiments, the signal generator 210 may be battery -free and may be powered via transcutaneous energy delivery (e.g., inductive, ultrasound, optical, magnetic, and / or the like). In some embodiments, the signal generator 210 may be powered via energy harvesting from the body, or AC power such as from a building.

[0159] In some embodiments, the signal generator 210 can include or be operably connected to a switch. The switch can be configured to direct therapeutic electrical signals from the signal generator 210 to the one or more implantable leads. The signal generator 210 may generate a signal to be delivered through channels to electrodes (e.g., anode and cathode pair). Because the implantable lead(s) 212 may, in some cases, include more than two electrodes, the switch may direct the signal from the signal generator 210 to be delivered between different pairs of electrodes on the implantable lead(s) 212. In some embodiments, depending on the selected anode and cathode pair on the implantable lead 212, the switch may direct signals from the signal generator 210 to be delivered between the selected pair.

[0160] In some embodiments, the signal generator 210 can include a channel for each electrode. For example, the signal generator 210 can include one or more discrete channels, such as 1, 2, 3, 4, 5, 6, 7, 8, or more discrete channels, for each electrode of an implantablelead. Therefore, the signal generator 210 may bypass, or not require the use of, a switch for directing the signals between different electrodes. In some embodiments, the signal generator 210 can include one or more features and / or functions such as described in greater detail in at least incorporated U.S. Patent App. No. 18 / 563,861.

[0161] The signal generator 210, in some embodiments, can generate an electrode drive current between about 0 mA and about 1 mA, between about 1 mA and about 2 mA, between about 2 mA and about 4 mA, between about 4 mA and about 8 mA, higher than about 8 mA, about 0.5 mA, about 1 mA, about 2 mA, about 3 mA, about 4 mA, about 5 mA, about 6 mA, about 7 mA, about 8 mA, about 9 mA, about 10 mA, or any value or range within or bounded by any of these values or ranges. Smaller or larger drive currents are also possible. The signal generator 210 can be configured to generate a therapeutic electrical signal (e.g., corresponding to waveform 500 shown and / or described in Fig. 3E) at any of the above listed values. In some embodiments, the therapeutic electrical signal may be used to generate a corresponding ionic current in electrically excitable tissue.

[0162] Neural inhibition therapy may be delivered via electrical leads, such as implantable lead(s) 212. The implantable lead(s) 212 may be a percutaneous system cylindrical lead, a paddle lead, a cuff lead, and the like. Implantable lead(s) 212 may include electrical electrodes. In this context, an “electrical electrode” is an electrode configured to deliver electrical stimuli (e.g., electrical current, electrical signals, and / or the like) and / or detect electrical responses (e.g., neural activity), such as at a target tissue. For example, electrical electrodes may include a cuff electrode, a pellet electrode, a pin electrode, a skin-mounted electrode (e.g., 3M® Red Dot®), a catheter style electrode, a separated-interface nerve electrode (e.g., “SINE” electrode) such as described in greater detail in at least U.S. Patent No. 11,752,329, fded on July 1, 2019, entitled “SYSTEMS AND METHODS FOR NERVE CONDUCTION BLOCK,” the entire contents of which are hereby incorporated herein by reference in their entirety, and the like. Implantable lead(s) 212 may include non-electrical electrodes. In this context, a “non-electrical electrode” is an electrode configured to deliver non-electrical stimuli and / or detect non-electrical responses (e.g., physiological responses). For example, non-electrical electrodes may include sensors (e.g., sensor(s) 110) such as ultrasound sensors (e.g., piezoelectric transducers), optical sensors, electrochemical sensors, pressure or strain sensors, thermocouples, thermal transducers, and the like.

[0163] In some embodiments, the implantable lead(s) 212 can include a plurality of electrodes. The plurality of electrodes can deliver therapy to a target tissue. The plurality of electrodes may be placed in various configurations on the one or more implantable leads 212. In some embodiments, the implantable lead(s) 212 can include one or more electrodes, such as 1, 2, 3, 4, 5, 6, 7, 8 or more electrodes. The plurality of electrodes can deliver therapy (e.g., electrical signals) to the target tissue. To deliver therapy, the plurality of electrodes may include delivering a current between an anode and a cathode. In some embodiments, the neuromodulation device 104 may designate one or more of the electrodes on the implantable lead(s) 212 as a cathode, and one or more of the electrodes on the implantable lead(s) 212 as an anode. The neuromodulation device 104 can then deliver current between the anode and the cathode, such as described herein. In some embodiments, the neuromodulation device 104 designates any one of the electrodes as either the anode or the cathode. There may be a plurality of configurations of anode / cathode pairs depending on how many electrodes are included on the implantable lead(s) 212.

[0164] In some embodiments, a multi-electrode lead (see FIGS. 5A-5J, for example) may be positioned to target a desired nerve or other electrically excitable tissue. The electrodes may be configured to have a multitude of tissue contacting regions whose outputs can be individually adjusted to optimize nerve block. Adjusting the current input and corresponding output at the distal end of the electrode can enable electric field shaping to facilitate desired nerve block while minimizing block of undesired structures. Similarly, individual electrodes may also be individually addressable and can be tuned to enable desired nerve block. In this way, the neuromodulation device 104 may target (e.g., via positioning of one or more implantable leads 212) one or more nerves for delivery of neural inhibition therapy, such as spinal neural inhibition therapy. Nerve targets can include, but are not limited to, any ganglia associated with the spinal cord or portions of the spinal cord, such as any of the cervical sympathetic chain (e.g., vertebral levels C1-C8), the thoracic sympathetic chain (e.g., vertebral levels T1-T12), the lumbar sympathetic chain (e.g., vertebral levels L1-L5), the sacral sympathetic chain (e.g., vertebral levels S1-S5), and / or the Coccygeal spinal segment and root.. For example, trunk pain, which is moderated by the thoracic vertebral levels, can be modulated by placing leads along the thoracic spine for delivery of therapeutic electrical currents. Additionally, or alternatively, nerve targets can include, among others: the intercostal nerves(Tl -Tl 1), the subcostal nerve (T12), the splanchnic nerves (T5-T12), the brachial plexus (T1 contribution), the cutaneous branches (T2-T12), the iliohypogastric / ilioinguinal nerves (T12), and the dorsal and ventral rami of thoracic spine nerves.

[0165] The display 214 can display user interfaces such as any of the example user interfaces, or aspects thereof, that are shown and / or described herein. The display 214 can include an LED screen, an LCD screen, an OLED screen, a QLED screen, a plasma display screen, a quantum dot display, or the like. The display 214 can be a colored display or a monochrome display. The display 214 may be responsive to touch. For example, the display 214 may comprise a touch screen such as a resistive touch screen, a capacitive touchscreen, an infrared touchscreen, a surface acoustic wave touchscreen, or the like. In some aspects, the display 214 can display various information such as information based on data gathered from sensor(s) 110. In some aspects, the displayed information may be based on data gathered from a server of system 100 such as server 112. In some aspects, the displayed information may be based on data gathered from a cloud-based or internet-based service. In some aspects, the displayed information may be based on data gathered from one or more components of system 100 such as neuromodulation device 104 and / or user device(s) 106.

[0166] In some embodiments, the display 214 may be operably connected to the neuromodulation device 104. For example, a separate device (e.g., user device(s) 106) in communication with the neuromodulation device 104 (e.g., via network 108) may comprise the display 214. In some embodiments, the neuromodulation device 104 may comprise the display 214.Example Waveform Parameters Relating to Neural Inhibition Therapy

[0167] The system of the present disclosure may facilitate neural block, attenuation, and / or suppression by providing a variety of DC waveforms. In some embodiments, either anodic or cathodic phases of a delivered waveform to a subject (or both the anodic and cathodic phases) can have a therapeutic effect on electrically excitable tissue, such as neural tissue. For example, systems and devices (e.g., electrodes) can be configured to deliver DC waveforms to nerves and / or other electrically excitable tissue by delivering cycled cathodic and anodic current.

[0168] Neural inhibition therapy, including spinal neural inhibition therapy, may utilize a variety of different electrical waveforms generated by the signal generator 210 (seeFIG. 2B, for example). For example, in some embodiments, the neuromodulation device 104 and / or neuromodulation system 100 may utilize any of DC waveforms, high-frequency AC waveforms, high-frequency AC having a DC component configured to mitigate onset response, monophasic DC, charge-balanced DC carousel (CBDCC), charge-balanced DC, biphasic DC, complex / hybrid DC waveforms, low- / moderate-frequency waveforms for generating excitation-induced information lesion in the target tissue, combinations thereof, and the like. In some embodiments, AC signals can be used, for example, to induce action potential, paresthesia, and / or disable neurons to block neural signals.

[0169] In some embodiments, the system of the present disclosure (e.g., controller 202, signal generator 210) can generate waveform shapes, such as defined by B -splines, infinitely differentiable functions, and / or other mathematical functions (e.g., sine waves) to control / limit the rate of voltage and current change to: limit / control the onset of neural recruitment; and / or limit or control electrochemical reactions.

[0170] Asymmetric waveforms can be generated where the duration and amplitude of a cathodic phase of the waveform is different from the duration and amplitude of an anodic phase of the waveform. The shape of the waveform may comprise changes in amplitudes over time including a linear and non-linear, monotonic, or non-monotonic, increases and decreases in amplitude, as well as periods of constant amplitude or zero amplitude. In some embodiments, a waveform may comprise a sequence with an increasing current amplitude (or magnitude), a substantially constant current amplitude (or magnitude), a decreasing current amplitude (or magnitude) followed by the same sequence of the opposite polarity. The magnitude of the slope of the increasing current amplitude may be greater than, equal to, or less than the magnitude of the slope of the decreasing current amplitude.

[0171] To reduce (or mitigate or prevent) undesired neural activity, the magnitude of the slope of the increasing current amplitude of the DC waveform may be configured to be lower than the magnitude of the slope of the decreasing current amplitude of the DC waveform. Furthermore, the transition regions between increasing, substantially constant, and decreasing current amplitudes may be smoothed and rounded to control / limit the rate of voltage and current change to limit / control the onset of neural recruitment. In some embodiments, the first derivative of the waveform current with respect to time comprises a continuous function overtime. In some embodiments, the second derivative of the waveform current with respect to time comprises a continuous function over time.

[0172] FIGS. 3A-3D illustrate example waveforms generable and deliverable by the neuromodulation device 104 and / or neuromodulation system 100 (see FIGS. 2A-2B, for example), or components thereof. Such waveforms can include conventional, burst, high- frequency (e.g., greater than about 1 kHz), low-frequency (e.g., from about 10 Hz to about 1 kHz), and DC (e.g., less than about 10 Hz) waveforms. FIG. 3A illustrates a waveform having curved waveform features, whereas FIGS. 3B-3D illustrate waveforms having sharp waveform features. The waveform illustrated in FIG. 3A may be referred to as having a spline waveform shape or smooth waveform shape. The waveforms illustrated in FIGS. 3B-3D may be referred to as having square waveform shapes or sharp waveform shapes.

[0173] In some embodiments, a DC waveform (see FIG. 3 A, for example) used for delivery of neural inhibition therapy can have a frequency of about 10 Hz, about 9 Hz, about 8 Hz, about 7 Hz, about 6 Hz, about 5 Hz, about 4 Hz, about 3 Hz, about 2 Hz, about 1 Hz, about 0.5 Hz, about 0.1 Hz, about 0.05 Hz, about 0.01 Hz, about 0.005 Hz, about 0.0001 Hz, or any value or range within or bounded by any of these values. Lower frequencies are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having frequencies at any of the above listed values.

[0174] In some embodiments, the DC waveform can have a pulse width (e.g., pulse duration) of about 0.1 seconds, about 0.125 seconds, about 0.15 seconds, about 0.2 seconds, about 0.3 seconds, about 0.4 seconds, about 0.5 seconds, about 1 seconds, about 2 seconds, about 5 seconds, about 10 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 100 seconds, about 200 seconds, about 500 seconds, about 1,000 seconds, about 5,000 seconds, about 10,000 seconds, or any value or range within or bounded by any of these values or ranges. In some embodiments, the DC waveform may have a pulse width of about 12 seconds. Longer pulse widths are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having pulse widths at any of the above listed values. In this context, “pulse width” refers to the time duration between crossing points of the waveform (e.g., where current changes sign / direction), such as between the zero-crossing points of the waveform. The crossing point typically represents a voltage orcurrent level of zero. However, this is not intended to be limiting. The crossing point may represent another voltage or current level, such as based on a DC offset.

[0175] DC waveforms can have various rise times / durations, plateau times / durations, and / or fall times / duration depending on the desired clinical result. For example, in some embodiments, the DC waveform can include a rise time of about, or at least about, or no more than about 0.25 s, about 0.5 s, about 1 s, about 1.5 s, about 2 s, about 2.5 s, about 3 s, about 3.5 s, about 4 s, about 4.5 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about 15 s, about 20 s, or any value or range within or bounded by any of these values or ranges. Longer rise times are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having rise times at any of the above listed values. The rise can be a single continuous rise, or multiple rises interspersed with one or more plateaus and / or falls.

[0176] In some embodiments, the DC waveform can include a plateau time of about, or at least about, or no more than about 0.25 s, about 0.5 s, about 1 s, about 1.5 s, about 2 s, about 2.5 s, about 3 s, about 3.5 s, about 4 s, about 4.5 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about 15 s, about 20 s, or any value or range within or bounded by any of these values or ranges. Longer plateau times are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having plateau times at any of the above listed values. The plateau can be a single continuous plateau, or multiple plateaus interspersed with one or more rises and / or falls.

[0177] In some embodiments, the DC waveform can include a fall time of about, or at least about, or no more than about 0.25 s, about 0.5 s, about 1 s, about 1.5 s, about 2 s, about 2.5 s, about 3 s, about 3.5 s, about 4 s, about 4.5 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about 15 s, about 20 s, or any value or range within or bounded by any of these values or ranges. Longer fall times are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having fall times at any of the above listed values. The fall can be a single continuous fall, or multiple falls interspersed with one or more rises and / or plateaus.

[0178] In some embodiments, the DC waveform starts cathodic and rises, plateaus, falls, plateaus again, then rises again at which point the waveform becomes anodic and then plateaus, and then falls. Such waveform propagation (rise, plateau, fall, and / or the like) mayoccur for a set time period (e.g., a duration of delivery of therapy). In some embodiments, the DC waveform starts anodic. The set time period can be, for example, about, at least about, or no more than about 1 s, about 2 s, about 3 s, about 4 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about I l s, about 12 s, about 13 s, about 14 s, about 15 s, about 16 s, about 17 s, about 18 s, about 19 s, about 20 s, about 25 s, about 30 s, about 35 s, about 40 s, about 45 s, about 50 s, about 55 s, about 60 s, or any value or range within or bounded by any of these values or ranges. Greater time periods are also possible. In some embodiments, the cathodic and anodic phases are separated by a plateau. In some embodiments, the cathodic and anodic phases are symmetrical or asymmetrical. In this way, charge delivered during an anodic phase and / or cathodic phase of the DC waveform can be balanced by, greater than, or less than charge delivered during a cathodic phase and / or anodic phase, respectively, of the DC waveform.

[0179] In some embodiments, a current amplitude (e.g., generated by signal generator 210 shown and / or described in FIG. 2B ), such as for any DC waveform described herein, can be between about 0 mA and about 1 mA, between about 0.5 mA and about 1.5 mA, between about 1 mA and about 2 mA, between about 2 mA and about 4 mA, between about 2.5 mA and about 5 mA, between about 4 mA and about 8 mA, between about 5 mA and about 15 mA, or at about 0.05 mA, about 0.1 mA, about 0.15 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA, about 1 mA, about 2 mA, about 3 mA, about 4 mA, about 5 mA, about 6 mA, about 7 mA, about 8 mA, about 9 mA, about 10 mA, or any value or range within or bounded by any of these values or ranges. Response has been seen, for example, in animal studies at between about 0 mA and 1.5 mA. Paresthesia onset in peripheral human nerves has been seen at about 1.5 mA (cathodic and anodic) with complete block at about 2.5 mA. Therapeutic values for pain relief have seen in application to the spinal cord in, for example, the 0.5 mA - 1.5 mA range. In some embodiments, the current amplitude can be about 0.3 mA, about 0.4 mA, about 0.5 mA, about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, about 1 mA, about 1.1 mA, about 1.2 mA, about 1.3 mA, about 1.4 mA, about 1.5 mA, about 1.6 mA, about 1.7 mA, about 1.8 mA, about 1.9 mA, about 2 mA, about 2.1 mA, about 2.2 mA, about 2.3 mA, about 2.4 mA, about 2.5 mA, about 3 mA, about 3.5 mA, about 4 mA, about 4.5 mA, about 5 mA, or any value or range within or bounded by any of these values or ranges. Smaller or larger current amplitudes are also possible. Any of the systems and devicesdisclosed herein can generate and / or deliver DC waveforms having a current amplitude at any of the above listed values. In some embodiments, the therapeutic electrical current generated by the signal generator may be used to generate a corresponding ionic current in a nerve and / or other electrically excitable tissue.

[0180] In some embodiments, the DC waveform can have a current magnitude at any of the current amplitude values described herein. Current magnitude can be the absolute value of a particular current amplitude (e.g., + or - of the stated value).

[0181] In some embodiments, charge per anodic and / or cathodic phase of a DC waveform can be, for example, about 100 pC, about 150 pC, about 200 pC, about 250 pC , about 500 pC, about 1,000 pC, about 1,500 pC, about 2,000 pC, about 2,500 pC, about 3,000 pC, about 3,500 pC, about 4,000 pC, about 4,500 pC, about 5,000 pC, about 5,500 pC, about 6,000 pC, about 7,00 pC, about 8,000 pC, about 9,000 pC, about 10,000 pC, about 11,000 pC, about 12,000 pC, about 13,000 pC, about 14,000 pC, about 15,000 pC, about 16,000 pC, about 17,000 pC, about 18,000 pC, about 19,000 pC, about 20,000 pC, or any value or range within or bounded by any of these values or ranges. Smaller or greater charge per phase is also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having a charge per phase at any of the above listed values. Charge per phase may be calculated as follows: C = A * T, where C is the charge in coulombs, A is the current in amperes, and T is the period (e.g., pulse width) of a phase in seconds. In some embodiments, waveform charge per phase can be controlled (e g., via amplitude, waveform shape, pulse width, and / or the like) to selectively modulate and recruit neurons of differing diameter, conduction speed, and / or type (e.g., myelinated and unmyelinated).

[0182] FIG. 3E illustrates an example waveform 500 suitable for neural inhibition therapy. Waveform 500 may be referred to as a DC waveform. The signal generator 210 (see FIG. 2B, for example) can generate and deliver pulses that are ramped up and ramped down, such as gradually ramped up and gradually ramped down. Gradually ramping up and / or down the waveform can include slowly and progressively increasing and / or decreasing the current amplitude over a period of time. For example, the waveform amplitude may be increased and / or decreased linearly, exponentially, sigmoidally, and / or the like, over a period of time, such as over any of the rise times and / or fall times described herein, until the waveform reaches a desired amplitude or intensity. Advantageously, gradually ramping up / down the waveformcan reduce (or mitigate or prevent) sudden sensations and unwanted side effects (e.g., muscle twitching) experienced by a subject undergoing therapy, which may otherwise be uncomfortable or painful. Moreover, gradually ramping up / down the waveform can facilitate better control over activation or block of electrically excitable tissue, allowing the subject’s body to adapt to the therapy more comfortably. Ramp up / down times may be adjusted (e.g., increased or decreased) based on treatment goals of the therapy.

[0183] The pulse width, frequency, amplitude, phase, slew rate, and / or the like, of waveform 500 can be programmed and / or modified, such as via the neuromodulation device 104 and / or neuromodulation system 100, or components thereof. In some embodiments the signal generator 210 can output a current of about 0 mA to about 10 mA, or other values / ranges as disclosed herein (and is configurable to not exceed the electrode charge injection capacity). In some embodiments, the signal generator 210 can output a waveform 500 having a frequency from about 0.05 Hz to about 2 Hz, or other values / ranges as disclosed herein. In some embodiments, the signal generator 210 can output a waveform 500 having a pulse width from about 250 ms to about 30 s, or other values / ranges as disclosed herein.

[0184] In some embodiments, the waveform 500 includes an anodic (e.g., positive) phase 502 and a cathodic (e.g., negative) phase 504. The waveform 500 also includes an anodic plateau phase 506 and a cathodic plateau phase 508. Transition regions (sometimes referred to as regions where breakthrough conduction occurs) 510, 512 separate the waveform’s anodic and cathodic plateau phases 502, 504.

[0185] Each transition region 510, 512 can include one or more transition waveform portions. In the illustrated example of FIG. 3E, the waveform 500 transitions from its cathodic plateau phase 508 to its anodic plateau phase 506 at a first transition region 510. The first transition region 510 includes four transition waveform portions: a progressively increasing curved slope portion 518, a substantially linear slope first portion 520, a substantially linear slope second portion 522, and a progressively decreasing slope curved portion 524. During the progressively increasing curved portion 518, current amplitude gradually decreased at a slowly increasing rate from the cathodic plateau phase 508 to the first substantially linear portion 520. During the first substantially linear portion 520, current amplitude is decreased at a first substantially constant rate until a transition point 514 is reached. At the transition point 514, current amplitude is increased at a second substantially constant rate until the progressivelydecreasing curved portion 524 is reached. During the progressively decreasing curved portion 524, current delivery amplitude continues to increase, but at a gradually decreasing rate until the anodic plateau phase 506 is reached.

[0186] At the end of the anodic plateau phase 506, the waveform 500 transitions to its cathodic plateau phase 508 at a second transition region 512. The second transition region 512 includes four transition waveform portions: a progressively decreasing slope curved portion 526, a substantially linear first portion 528, a substantially linear second portion 530, and a progressively increasing slope curved portion 532. During the progressively decreasing curved portion 526, current amplitude is gradually decreased at a slowly increasing rate from the anodic plateau phase 506 to the first substantially linear portion 528. During the first substantially linear portion 528, current amplitude is decreased at a first substantially constant rate until a transition point 516 is reached. At the transition point 516, current amplitude is increased at a second substantially constant rate until the progressively increasing slope curved portion 532 is reached. During the progressively increasing slope curved portion 532, current delivery amplitude continues to increase, but at a gradually decreasing rate until the cathodic plateau phase 508 is reached. The cycle is repeated for subsequent waveforms 500.

[0187] Advantageously, waveform 500 provides significant clinical advantages when providing a therapy to electrically excitable tissue to induce a neural block such that neural activation (e.g., pain sensations, paresthesia, and / or the like) do not occur. The waveform plateau phases 506, 508 have much longer durations than the typical millisecond time constant of a neuron. In this way, the length or duration of the waveform’s anodic and cathodic plateau phases 506, 508 “appears” as direct current to neurons and / or other electrically excitable tissue, as described elsewhere herein. Accordingly, the waveform plateau regions 506, 508 can cause an immediate or almost immediate clinical effect of neural block or attenuation.

[0188] During the transition from anodic to cathodic plateaus, or from cathodic to anodic plateaus, there is a possibility of activating electrically excitable tissue. To avoid such activation, relatively linear transition portions 520, 522, 528, 530 of increasing or decreasing current can be provided to control the rate of current amplitude change experienced by the electrically excitable tissue, and to hold the current amplitude change rate at a constant or substantially constant amount. By providing the current in a linear ramp (either increasing ordecreasing), neural activation may be reduced or prevented as waveform 500 transitions between anodic and cathodic phases 504, 502 and / or between cathodic and anodic phases 502, 504.

[0189] In some embodiments, the slope of the first linear transition portion 520 (the first substantially constant rate) is about 4x, about 3x, about 2x, about lx, about 0.75x, about 0.5x, about 0.25x, about 0.125x, about 0.062x, or any value or range within or bounded by any of these values or ranges, the slope of the second linear transition portion 522 (the second substantially constant rate). In some embodiments, the slope of the first linear transition portion 528 (the first substantially constant rate) is about 4x, about 3x, about 2x, about lx, about 0.75x, about 0.5x, about 0.25x, about 0.125x, about 0.062x, or any value or range within or bounded by any of these values or ranges, the slope of the second linear transition portion 530 (the second substantially constant rate).

[0190] The slope of the rising and falling waveforms (e.g., during the increasing transitional phase 510 and during the decreasing transitional phase 512), as well as the maximum amplitude (both anodic and cathodic), individually or together, can affect whether neural activation can be avoided. Therefore, in some embodiments, the slopes of the waveform portions 520, 522, 528, 530, the plateau phase 506, 508 current levels, or both, are selected (e.g., via controller 202) to cause neural block or reduce (or mitigate or prevent) inadvertent neural activation.

[0191] Rounded comers 518, 524, 526, 532 of waveform 500 provide progressively decreasing rates of current amplitude increases as the waveform 500 transitions into its plateau phases 506, 508 (at regions 524, 532) as well as a progressively increasing rates of current amplitude decreases as the waveform 500 transitions out of its plateau phases 506, 508 (at regions 518, 526). Such rounded corners 518, 524, 526, 532 can further prevent inadvertent neural activation as the waveform 500 transitions between anodic and cathodic periodic phases 502, 504.

[0192] FIG. 3F illustrates a table of example neuromodulation parameters including pulse widths, frequencies, current amplitudes, and charge per pulse. Waveforms described herein may have any of the parameters shown and / or described in the table of FIG. 3F, including any of the parameters described elsewhere herein.Example System / Device Parameters Relating to Neural Inhibition Therapy

[0193] As further described herein, safe and effective delivery of neural inhibition therapy utilizing multiple electrodes and / or sequenced electrode contact can be achieved without a need for complex mechanical systems. As described herein, systems and devices of the present disclosure may be fully or partially implantable, or completely non-implantable (e.g., transcutaneous), with all tissue-contacting materials biocompatible for tissue contact and / or implantation.

[0194] Electrodes can comprise biocompatible materials that do not easily dissolve. In some embodiments, the electrode (working electrode, indifferent electrode, or any other electrode described herein) can comprise material(s) configured to optimize the charge capacity, durability, and biocompatibility of the electrode. Such material can include, but are not limited to, any of: Iridium Oxide; Tantalum, MP35N, Titanium Nitride; Diamond; Boron- doped diamond; Nanotubes (e.g., TiN, MnO2 / TiN); Metal Oxides (e g., RuO2, IrO2, Mn02, CoO2, NiO2, FeO2, SnO2 and CuO2); Mixed Metal Oxides (e g., RuO2 / SnO, RuO2 / NiO, RuO2 / Ta2O5, RuO2 / Pt, RuO2 / TiO2, RuO2 / MoO3, RuO2 / CaO and RuO2 / V2O4 or IrRu); Carbon / Graphene; metal carbides, carbonitrides and nitrides aka MXenes (or transition metal carbides, carbonitrides and nitrides); and / or combinations of any of the foregoing, including two or more metal oxides, two or more mixed metal oxides, a first material with a coating including the first material, and / or a second material, and the like.

[0195] In some embodiments, electrodes can comprise high-charge capacity materials. An electrode (e.g., a working electrode, reference electrode, indifferent electrode, or any other electrode described herein), in some embodiments, can include a contact comprising a high charge-capacity material and / or any other material described herein. The electrode contact can have, in some cases, a geometric surface area of between about 1 mm2and about 10 mm2, or about 1 mm2, about 2 mm2, about 3 mm2, about 4 mm2, about 5 mm2, about 6 mm2, about 7 mm2, about 8 mm2, about 9 mm2, about 10 mm2, about 11 mm2, about 12 mm2, about 13 mm2, about 14 mm2, about 15 mm2, about 16 mm2, about 17 mm2, about 18 mm2, about 19 mm2, about 20 mm2, about 21 mm2, about 22 mm2, about 23 mm2, about 24 mm2, about 25 mm2, about 30 mm2, about 35 mm2, about 40 mm2, about 45 mm2, about 50 mm2, about 55 mm2, about 60 mm2, about 65 mm2, about 70 mm2, about 75 mm2, about 80 mm2, about 85 mm2, about 90 mm2, about 95 mm2, about 100 mm2, or any value or range within or bounded by anyof these values or ranges. Any of the electrode contacts disclosed herein can have a surface area of any of these values.

[0196] In some embodiments, the indifferent electrode can have a working surface area of about or at least about 1 cm2, about 5 cm2, about 10 cm2, about 25 cm2, about 50 cm2, about 75 cm2, about 100 cm2, about 125 cm2, about 150 cm2, about 175 cm2, about 200 cm2, about 500 cm2, about 1000 cm2, or any value or range within or bounded by any of these values or ranges. Smaller or larger surface areas are also possible.

[0197] In some embodiments, an electrode (e.g., an indifferent electrode) can have a relatively low DC resistance (without skin resistance), such as, for example, less than about 1,000 Q, about 900 Q, about 800 Q, about 700 Q, about 600 Q, about 500 Q, about 400 Q, about 300 Q, about 200 Q, about 100 Q, about 90 Q, about 80 Q, about 70 Q, about 60 Q, about 50 Q, about 40 Q, about 30 Q, about 20 Q, about 10 Q, or any value or range within or bounded by any of these values or ranges. Smaller or larger DC resistances are also possible.

[0198] In some embodiments, to increase the available electrochemical surface area (ESA), the substrate of an electrode may comprise microstructural features that increase the available surface area. In some embodiments, the substrate may comprise an open porosity sintered component. In some embodiments, the substrate may comprise an open porosity foam component such as a reticulate foam structure. In some embodiments, the substrate may comprise surface texturing from micromachining to generate features such as grooves or roughness to increase the overall ESA. These micromachining tools may comprise laser ablation to generate channels or grooves or general surface roughness. Additional micromachining techniques, which can accomplish these goals are electric discharge machining (EDM), material etching techniques, pattern masking and etching techniques, bead or grit blasting, and surface sanding. The ESA can also be increased by, for example, electrophoretic deposition (EPD), electrolytic deposition (ELD), and / or electroplating. The substrate material can, for example, be coated with a high charge capacity material such as sputtered iridium oxide (SIROF), Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT), titanium nitride (TiN), fractal titanium nitride, porous titanium nitride, or combinations thereof. Methods for depositing such coatings on compatible substrates may include chemical vapor deposition (CVD) and physical vapor deposition (PVD). Substratesmay comprise electrically conductive materials to allow for ease of charge transfer to the coating.

[0199] In some embodiments, electrodes may comprise materials on which reversible electrochemical reactions can occur such as platinum, which forms a hydride complex on its surface in aqueous solutions. To generate more surface area for reversible electrochemical reactions to occur, traditional electrodes and electrode materials may be made from high surface area to volume structures such as electroplated surfaces, (e.g., platinum black / electrodeposited iridium oxide for example), roughened surfaces, woven surfaces, patterned surfaces, reticulated foam structures, porous sintered bead structures, nano- or micropatterned structures to expose additional material surface area. High-charge chemistry electrodes can be biocompatible, or suitably sequestered from body tissue if not.

[0200] In some embodiments, electrodes can include a material such as tantalum or titanium nitride to generate a capacitive traditional electrode interface instead of an interface at which an electrochemical reaction occurs. Transparent conducting oxides (TCOs) such as fluorine-doped tin oxide (FTO), nickel titanium dioxide (Ni / TiO2), and other titanium dioxide (TiO2) constructs are also candidate materials that have high charge carrying capacities, as well as others disclosed herein. In some embodiments, the electrodes can include tantalum coated with titanium nitride. In some embodiments, the electrodes can include MP35N coated with titanium nitride. In some embodiments, charge generation at the traditional electrode surface would attract ionic species from the ionically conductive material until the charge at the traditional electrode interface is passivated. Charging of the capacitive material with an electric current of one polarity can generate current flow in the form of ions. Reversing the polarity of the current flow to the capacitive material can effectively reset the system for a subsequent charging to generate further ionic current flow. To generate more surface area for increased ion current flow capacity to occur, traditional electrodes may be made from high surface area to volume structures such as roughened surfaces, reticulated foam structures, porous sintered bead structures, nano- or micro-patterned structures, to expose additional material surface area.

[0201] In some embodiments, the electrode contact can be fabricated of a high charge capacity material, such as those described, for example, in at least U.S. Patent No. 10,071,241, filed on November 16, 2017, entitled “THERAPY DELIVERY DEVICES AND METHODSFOR NON-DAMAGING NEURAL TISSUE CONDUCTION BLOCK,” the entire contents of which are hereby incorporated herein by reference in their entirety. Alternatively, or additionally, the electrode contact can comprise a base at least partially, or entirely, coated with a high charge capacity material.

[0202] High charge capacity materials can have high Q values. The Q value of a material is a dimensionless parameter and may refer to a material’s ability to store electrical energy with minimal loss. In this context, the Q value of an electrode contact can refer to the total amount of charge that can be delivered through the electrode contact before the electrode contact begins generating irreversible chemical reactions at a rate that cannot be cleared through the body ’ s nominal transport mechanism. These chemical reactions include but are not limited to oxygen or hydrogen evolution, or dissolution of the electrode materials. Nonlimiting examples of high charge capacity materials are titanium grade 2, platinum black, iridium oxide, titanium nitride, tantalum, silver chloride, poly(ethylenedioxythiophene), and suitable combinations thereof. In some embodiments, one or more electrodes can include fluorine-free tantalum carbide MXene (two-dimensional transition metal carbide) hybrid structures. The electrodes can comprise fractal coatings or high surface area formats, in some embodiments. In some embodiments, a high charge capacity material can have a Q value of at least about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 1,000, about 2,500, about 5,000, about 10,000, about 50,000, about 100,000, about 500,000, or any value or range within or bounded by any of these values or ranges. Greater Q values are also possible. Any of the electrode contacts disclosed herein can have a base coated with a material having a Q value at any of the above listed values.

[0203] High charge capacity materials may be configured to be monolithic or as coatings on base substrates. Non-limiting examples of substrates for coating include stainless steel such as 304 and 316LVM, nickel cobalt chrome alloys such as MP35N®, platinum and platinum-iridium, platinum-iridium (90 / 10), platinum-iridium (80 / 20), titanium, nickeltitanium alloys such as Nitinol. In some embodiments, the electrodes can include tantalum coated with titanium nitride. Tantalum as one non-limiting example can be a particularly advantageous material for its superior radiopacity, thus allowing for improved implantation, verification, and / or removal of implantable neuromodulation devices. To generate more surface area for the electrochemical reactions to occur, the traditional electrodes may be madefrom high surface-area-to-volume structures such as electroplated surfaces, (e.g., platinum black / electrodeposited iridium oxide for example), roughened surfaces, woven surfaces, patterned surfaces, reticulated foam structures, porous sintered bead structures, nano- or micropatterned structures to expose additional material surface area. In some embodiments, the electrode can be a SINE (separated interface nerve electrode) or EICCC (electron to ion current conversion cell) electrode in which an electrode is immersed in an electrolyte solution that is in contact with an ion-conductive material-electrolyte solution interface with an ion- conductive material that electrically contacts the cardiac tissue or area proximal to cardiac tissue, as described, for example, in at least U.S. Patent No. 9,008,800, filed on November 16, 210, entitled “SEPARATED-INTERFACE NERVE ELECTRODE” and U.S. Patent No. 10,272,240, filed on April 2, 2018, entitled “SYSTEMS AND METHODS FOR DIRECT CURRENT NERVE CONDUCTION BLOCK,” the entire contents of which are hereby incorporated herein by reference in their entirety.

[0204] In some embodiments, the system as disclosed herein include high-surface area electrode coatings implemented in conjunction with a bias current (e.g., DC bias). Advantageously, this can help to maintain electrode voltages in the optimal range for a particular electrode material for long-term operational durability. This approach can boost the charge density per phase from about 50 pC / cm2used in conventional systems to about or at least about 5,000 pC / cm2, about or at least about 25,000 pC / cm2, about or at least about 50,000 pC / cm2, or any value or range within or bounded by any of these values or ranges without causing (or reducing or mitigating cause of) damage to either the electrode or the electrically excitable tissue. Greater charge density per phase is also possible. Any of the systems and devices disclosed herein can operate electrodes having a charge density per phase at any of the above listed values.

[0205] In some embodiments, the maximum electrode voltage limit can be about -0.3 V, about -0.2 V, about -0.1 V, about 0 V, about 0.1 V, about 0.2 V, about 0.3 V, about 0.4 V, about 0.5 V, about 0.6 V, about 0.7 V, about 0.8 V, about 0.9 V, about 1.0 V, about 1.1 V, about 1.2 V, about 1.3 V, about 1.4 V, about 1.5 V, about 1.6 V, about 1.7 V, about 1.8 V, about 1.9 V, about 2 V, about 2.5 V, about 3 V, about 3.5 V, about 4 V, about 4.5 V, about 5 V, or any value or range within or bounded by any of these values or ranges.

[0206] In some embodiments, the peak-to-peak voltage limit can be about 500 mV, about 600 mV, about 700 mV, about 800 mV, about 900 mV, about 1000 mV, about 1100 mV, about 1200 mV, about 1300 mV, about 1400 mV, about 1500 mV, about 2000 mV, about 2500 mV, about 3000 mV, about 4000 mV, about 5000 mV, about 10000 mV, or any value or range within or bounded by any of these values or ranges.

[0207] In some embodiments, the voltage variation limit can be about 0.1 mV, about 0.5 mV, about 1 mV, about 5 mV, about 10 mV, about 15 mV, about 20 mV, about 25 mV, about 50 mV, about 75 mV, about 100 mV, about 125 mV, about 150 mV, about 175 mV, about 200 mV, about 225 mV, about 250 mV, or any. value or range within or bounded by any of these values or ranges.

[0208] In some embodiments, the increase in driving voltage of the system from the initial driving voltage can be less than about 100 mV, about 200 mV, about 300 mV, about 400 mV, about 500 mV, about 600 mV, about 700 mV, about 800 mV, about 900 mV, about 1,000 mV, about 1,100 mV, about 1,200 mV, about 1,300 mV, about 1,400 mV, about 1,500 mV, or any value or range within or bounded by any of these values or ranges, over the wear duration. Greater increases are also possible.

[0209] Charge can be categorized as recoverable and unrecoverable, and electrochemical reactions exponentially increase with voltage (voltage is directly proportional to charge). Recoverable charge can cause reversible electrochemical reactions. Unrecoverable charge can cause irreversible electrochemical reactions; however, due to their exponential nature as a function of voltage, irreversible electrochemical reactions cannot be completely avoided. Thus, it is desirable to reduce (or mitigate) such reactions so that the byproducts can be removed by the transport properties of surrounding tissues, including diffusion and fluid flow. Thus, it is further desirable to reduce (or mitigate) the unrecoverable charge to a level such that the body can safely transport away generated byproducts resulting from said electrochemical reactions to reduce (or mitigate) tissue damage. Recoverable charge can cause reversible electrochemical reactions. Therefore, it is desirable to reverse reversable electrochemical reactions and recover byproducts to the extent possible such that byproduct accumulation remains below tissue toxicity levels. The rate of removal can be dependent upon the location in the body and the mechanical and electromechanical characteristics of the electrode.

[0210] Controlling voltages on electrode surfaces can be an effective way to minimize undesired electrochemical reactions. Advantageously, tissue safety can be maintained by operating electrodes below reaction potentials for undesired reactions, as well as by limiting the amount of irreversible reactions, such as electrolysis of water, or oxidation and reduction of water (H2O), which can create harmful reactive species such as OH-, H+, or oxygen free radicals, by maintaining a bias current. Moreover, tissue safety and electrode integrity can be maintained by reducing (or mitigating or preventing) corrosion of electrode material (e.g., oxidation) by maintaining a bias current. For example, the system of the present disclosure (e.g., control systems shown and / or described in FIGS. 2A-2B, for example) can be configured to control voltages on electrode surfaces by biasing electrodes with a DC bias or similar current.

[0211] In some embodiments, cathodically biasing titanium nitride and / or tantalum electrodes can mitigate formation of oxides that occur with anodic voltages. In some embodiments, anodically biasing titanium electrodes can cause development of a protective oxide on the titanium surface that can reduce material corrosion. Cathodically biasing an electrode can protect against corrosion in a similar manner. Any conductive materials (e.g., metals, conductive coatings, and / or the like) exposed to surrounding fluid or electrolyte can be subject to corrosion, and biasing these materials can provide protection against deleterious corrosion to enhance the longevity of service of the active conductive elements of the system. These active conductive elements may comprise any exposed metal on an implantable device or component thereof (e.g., electrodes) that passes current or is subject to voltages that cause undesirable reactions.

[0212] Each type of electrode material has specific operating ranges (e.g., appropriate voltage ranges) for predominantly reversible and limited irreversible reactions, and it can be highly advantageous to operate within those ranges. For example, if the electrode potential is outside of the water window of the material, then water (e.g., water at the electrode-tissue interface) may break down into H2 and O2, which can damage electrically excitable tissue and / or the electrode. In some examples, if the electrode potential corresponds to a voltage at which reactions associated with corrosion occur, then the electrode material may corrode and electrode performance may deteriorate. By biasing electrodes (e.g., via DC offset), electrodes may be operated withing a voltage range so as to avoid (or reduce or minimize) waterelectrolysis and / or material corrosion. Electrodes designed to produce uniform (or substantially uniform) current densities can allow the use of average voltage to be representative of the electrochemical reactions.

[0213] FIG. 4 illustrates an example graph 1000 representative of non-limiting electrode operating ranges (e.g., voltage ranges). Graph 1000 illustrates voltage of a DC waveform (e.g., waveform 500 shown and / or described in FIG. 3E) over time, a water window (indicated as between designating lines 1002 and 1006), and an anti-corrosion range (indicated as between designating lines 1004 and 1008). In some embodiments, electrodes may be biased to operate in voltage range 1010 (e.g., between designating lines 1004 and 1006) to limit potentially irreversible byproduct formation (e.g., due to irreversible electrochemical reactions), thereby promoting electrode longevity. Bias may be adjusted (e.g., increased or decreased) to bring electrodes within operating range 1010. In some embodiments, the bias current may be adjusted such as to accommodate larger or smaller electrode surface areas. In some embodiments, the bias current may be adjusted depending on voltage and / or other considerations, such as when a waveform exhibits nonlinearity or linearity. In some embodiments, the bias current can be fixed or programmable.

[0214] Deliberate control of the voltage equilibrium can be utilized for the purpose of adjusting electrode potentials (quasi-steady state voltage), and can be achieved using, for example, a generalized proportional integral derivative (PID) control algorithm where the process variable (PV) can be some environmental measure including but not limited to: a maximum peak voltage; a minimum peak voltage; a combination of a specified voltage rail and peak-to-peak voltage; average voltage levels; root-mean-square; running average; absolute voltage change; rate of voltage change; access resistance; electrical property of the electrode (e.g., capacitance); charge (e.g., accumulation of current over time); and / or chemical measurement, such as pH.

[0215] In some embodiments, directly controlling electrode surface voltages during stimulation and / or block can require additional techniques since the interaction between all elements is related. This can be addressed, for example, in the following ways:• Periodically turning off current to all but one electrode pair and making measurements at that time.• Shifting phase between electrode pairs and making measurements when other pair(s) crosses zero current.• Utilizing reference electrodes located in proximity to the working electrodes that are to be measured.• Limiting using worst-case voltages from the electronic current sources at the expense of not deriving all the performance of each electrode.• Control using voltages rather than current sources (e.g., voltage clamping), and / or control by using injected currents (e.g., bias currents) rather than voltages.

[0216] In some embodiments, the system described herein can include electrode restoration techniques, including but not limited to: Periodic Restoration — drive voltage / current to reset electrochemical surfaces, for example, by periodically delivering a cathodic charge to drive down electrode voltage; Adaptive Restoration — cycle by cycle drive voltage / current to preserve electrochemical surfaces, for example., by dynamically adjusting the charge driven through the electrode to control electrode voltage.

[0217] In some embodiments, compliance voltage limiting can be utilized as an automatic way to limit chemical reactions (e.g., by setting compliance voltage such that there is enough voltage to drive the current sources and safe chemical reactions, but not enough voltage to provide electrode voltages sufficient to drive undesired reactions). In some embodiments, compliance voltage tracking can be utilized to reduce power dissipation. Current sources and sinks can be used to control current, and a switching variable power supply can generate just enough voltage to keep current sources and sinks in compliance (e.g., to supply the requested current). An alternate topology can be a variable voltage source to drive a specified current. One advantage of compliance tracking is that the current sources using MOSFET gate ratios (e.g., Wilson current sources) are inherently stable.

[0218] In some embodiments, drive voltage levels can be limited between pairs of electrodes as a means to limit chemical reactions or stop an electrode that is degrading and requires a higher driving voltage to deliver the target stimulation current.

[0219] In some embodiments, the system described herein can be configured for voltage and / or pulse clamping. Pulse clamping can facilitate forcing a voltage on an electrode surface to avoid irreversible chemical reactions. Pulse clamping can include control of thevoltage, such as, for example, during an interpulse interval, to control the electrochemistry of the electrode so as to “reset” the electrode or control the electrochemistry to allow for more charge to be injected in the next stimulation cycle.

[0220] Clamping can also be utilized to increase charge injection capabilities. Clamping and / or utilizing current limits can limit the recruitment of neural tissue and voltage slew rate on an electrode surface. Current passing through the electrode can be used to assess the current state of the electrode, allowing adaptive control of the DC waveform to affect parameters such those described herein.

[0221] In some embodiments, electrodes can be conditioned in a manner that allows for delivery of therapeutic current amplitude for a desired duration with a driving voltage below a set threshold (such as the electrolysis potential). For example, in some embodiments, systems and methods herein can include pre- or post-conditioning before or after quasi steadystate blocking. This can be important to, for example: limiting or ramping the voltage change rate so as not to invoke undesired electrode chemical reactions; slowly transitioning voltages or currents between on and off states to limit neural recruitment changes that can result in patient discomfort or off-target effects; and / or managing charge on, or voltage across, the electrode surface by effectively time shifting (especially in the case of bipolar / multipolar) where it can be desirable that waveforms on each electrode start and stop on cathodic cycles. Pre- / post-conditioning can allow an effective time shift and ramp.

[0222] In some embodiments, the system as described herein can include in vitro or in vivo preconditioning of electrodes using cyclic voltammetry or electroplating techniques. These can be used, for example, to remove electrode material defects in a controlled fashion to not overstress defect areas with high current densities and cause expansion rather than removal of defects. For example, a sharp point or edge on the surface of an electrode can generally have a higher current density relative to the rest of the electrode surface. This may lead to metal dissolution and formation of undesirable chemical species that may, in that particular area, accelerate electrode degradation. By etching away sharp edges in a controlled fashion (e.g., in vitro), the process can be directly controlled. Preconditioning can also be utilized for material deposition or controlled electrochemical conversion (e.g., formation of a protective oxide layer). Oxide growth can also be used to increase the charge capacity of the material, such activated iridium oxide (AIROF), for example.Example Implantable Leads

[0223] FIG. 5 A illustrates a non-limiting embodiment of an implantable lead 212 connectable to the neuromodulation device 104 and having one or more electrodes 402. In some embodiments, the controller 202 may be in electrical communication with a single implantable lead. In some embodiments, the controller 202 may be in electrical communication with two or more implantable leads, such as according to available epidural space. The implantable lead 212 can be an epidural lead.

[0224] In some embodiments, lead 212 can have, for example, a diameter of between about 1 mm and about 2 mm, and can embody any shape (e.g., cylindrical) suitable for positioning / placement of working electrodes at or near a target nerve. In some embodiments, the implantable lead 212 may be, for example, about 40 cm to about 100 cm in length, such as in increments of about 5 cm (or more or less) in length. The lead 212 can be of sufficient length to accommodate movement of the subject (e.g., during a trial period) such that tugging of the leads is prevented. For example, the lead 212 can have some slack (e g., loops) such that, as the subject moves, that leads are not pulled from the neuromodulation device 104 or dislodge from the implant site.

[0225] In the example illustrated in FIG. 5 A, the implantable lead 212 includes 8 working electrodes 402 having contacts configured to deliver block current, where the electrodes are arranged at a distal end of the lead. However, this is not intended to be limiting. The implantable lead 212 can include fewer or more working electrodes 402. For example, the lead 212 can include a number N of electrodes.

[0226] A working electrode (WE) can be configured to deliver block current via an electrode contact. A counter electrode (CE) can be configured allow current to flow from the WE by applying potential to the WE (e.g., completing the circuit). A reference electrode (RE) can be configured to provide a known and stable voltage reference so as to monitor WE potentials, and no current passes through the RE. An indifferent electrode (IE), as described herein, can be configured as a current sink for current delivered by the WE. In some embodiments, the IE can deliver a DC bias. In some embodiments, the CE may be configured as a WE or an IE, depending on the neuromodulation modality. For example, the CE may be configured as an IE for a monopolar electrode configuration. In some examples, the CE may be configured as a WE for a bipolar electrode configuration.

[0227] In some embodiments, any electrode (e.g., on the lead 212) that is not delivering block current may be assigned to operate as an RE and measure voltages / impedances based at least in part on physical location to image and characterize physiological tissue. Any of the electrodes 402 can be switched between states, such as from a WE to an RE, or from an RE to a WE. Electrodes 402 may be switched to different states based at least in part on the phase of the block signal, whether current is being transmitted through the electrode, or some other parameter. In some embodiments, the WE or RE can be interchangeable depending at least in part on therapeutic needs (e g., nerve block delivered by a first group of electrodes arranged at a first portion of the lead followed by nerve block delivered by a second group of electrodes arranged at a second portion of the lead so as to target different regions of electrically excitable tissue).

[0228] The voltage on a WE can be monitored to determine whether the system / device (e g., neuromodulation system 100, neuromodulation device 104, or components thereof) is operating in a desired voltage range. Relative or absolute voltage may be monitored. For example, controller 202 may be configured to monitor a value, a change, a rate of change, or a change in the rate of change of the relative voltage or absolute voltage (or combination thereof). In some embodiments, when using a WE-IE pair, with DC bias flowing through IE at steady state, the controller 202 can monitor changes in WE potential for adaptive control of delivery of block current.

[0229] Relative voltage can correspond to the peak-to peak voltage of the waveform and / or its subcomponents. If the relative voltage is out of range (e.g., above a threshold), the electrode may decay, which can increase capacitance, which can cause the magnitude of the peak-to-peak voltage to further increase. The peak-to-peak voltage may be determined as a difference between the maximum voltage and the minimum voltage, an average of peak-to- peak voltages, or a ratio of peak-to-peak voltages, for example, during anodic and cathodic phases of an output waveform (e.g., waveform 500 shown and / or described in FIG. 3E.). The relative voltage may be measured between a WE and an RE, or between a WE and an IE. Peak- to-peak voltages can be measured once the system has reached a steady state (e.g., a steady state voltage on the IE).

[0230] Absolute voltage can correspond to the voltage as measured relative to a common ground. If absolute voltage is below a threshold, water may break down (e.g., absolutevoltage is outside of the water window) into species such as OH- and H+ and damage tissue, and / or other deleterious electrochemical reactions may occur. If the absolute voltage is above a threshold, water may break down and damage tissue and / or the electrode may corrode or dissolve.

[0231] The working electrodes 402 can be made of a substrate coated with a high charge capacity material (such as described herein). For example, the electrode contacts can comprise titanium coated with titanium nitride, tantalum coated with titanium nitride, platinum-iridium coated with titanium nitride, or other materials as disclosed herein for high charge capacity current delivery. Each contact may be welded to a conductor, which may comprise, for example, platinum-iridium, MP35N, 35N LT, stainless steel (e.g., 304SS, 316LVM), or titanium wire that terminates in a connector. The conductors may also terminate in ring-style connector contacts such as Bal Seal style connectors.

[0232] The body of the implantable lead 212 itself can be made of medical-grade polyurethane. The lead 212 can include one or more lumens, such as at least one for each wire, and at least one central lumen for a stylet, which may be used for steering and increasing the column strength of the lead 212 during insertion.

[0233] The implantable lead 212 can include one or more one or more spacers 404 arranged between electrodes 402. The spacers 404 can comprise electrically insulative material, such as polyurethane and the like. The implantable lead 212 can terminate in a tip 406, which can be a fused end.

[0234] FIG. 5B illustrates a non-limiting embodiment of a lead (e.g., lead 212) subassembly 400 and a lead 212 having one or more electrodes 402. The example configuration illustrated in FIG. 5B may be incorporated onto implantable lead 212. The electrodes 402 can deliver therapeutic electric signals (e.g., block current) as described herein. FIG. 5C illustrates schematic views of electrode 402 coupled to a plurality of ends of insulated wires 408. One or more conduits 410 can be housed at least partially within each electrode 402.

[0235] FIGS. 5D-5G illustrate schematic views of implantable lead 212. The electrodes 402 can be coupled to lead 212 via a binding material 420 and / or have a coating 422 such as described herein. FIG. 5E illustrates a binding material 420, which can be a silicone overmold having a shape suitable to connect and / or cover the electrodes 402, and FIG. 5D illustrates the binding material 420 applied to the electrodes 402. FIG. 5G illustrates the coating 422, whichcan be an ion exchange coating, prepared to coat the electrodes 402, and FIG. 5F illustrates the coating 422 coating the electrodes 402.

[0236] FIGS. 5H-5J illustrate schematic views of implantable lead 212. FIG. 5H illustrates electrodes 402 without binding material or a coating layer, while FIG. 51 illustrates electrodes 402 secured to lead 212 via binding material 420 that may, for example, comprise silicone that has been overmolded onto one or more components of lead 212 (except where excluded, such as along outer electrode contact surfaces). FIG. 5J illustrates coating 422 applied as a surface layer over the lead 212. In some embodiments, coating layer 422 may comprise an ionically conductive polymer such as an anion exchange membrane.Neural Inhibition Therapy Relating to the Vagus Nerve

[0237] FIG. 6 illustrates a portion of the anatomy of the vagus nerve of a human subject. An example treatment location 600 is illustrated via a bounding box to indicate various portions along the cervical vagus nerve at which electrodes of the neuromodulation device 104 may be arranged. However, this is not intended to be limiting. Electrodes for delivery of DC may be arranged on either of the left or right vagus nerve (as further described herein), and / or along other portions of the right and / or left vagus nerve such as may be suitable for treating myocardial infarction (MI) (e g., where there is sufficient epidural space for lead and / or electrode placement).

[0238] The vagus nerve is the longest cranial nerve in the human body and is responsible for both motor and sensory functions in afferent and efferent regards. The nerve travels widely throughout the body, affecting several organ systems and regions of the body, such as the tongue, pharynx, heart, and gastrointestinal system. The vagus nerve originates in the medulla oblongata and exits the skull via the jugular foramen. There are two ganglia on the vagus nerve (superior and inferior) as it exits the jugular foramen. The spinal accessory nerve joins the vagus nerve just distal to the inferior ganglion.

[0239] Cell bodies for the vagus nerve originate from the nucleus ambiguus, the dorsal motor nucleus of the vagus nerve, the superior ganglion of the vagus nerve, and the inferior ganglion of the vagus nerve. Nerve fibers originating from the nucleus ambiguus are efferent, special visceral (ESV) fibers that help to mediate swallowing and phonation. Fibers originating from the dorsal motor nucleus are efferent, general visceral (EGV) fibers that provide the involuntary muscle control of organs that the vagus nerve innervates (e.g., cardiac, pulmonary,esophageal). These fibers further provide innervation to glands throughout the gastrointestinal tract. The superior ganglion of the vagus nerve provides afferent general somatic (EGS) innervation to the external ear and tympanic membrane. The inferior ganglion of the vagus nerve provides EGV fibers to the carotid and aortic bodies. These EGV fibers travel to the nucleus tractus solitarius. The inferior ganglion also provides taste sensation to the pharynx and relays this information to the nucleus tractus solitarius.

[0240] The vagus nerve continues by traveling inferiorly within the carotid sheath, located posterior and lateral to the internal and common carotid arteries and medial to the internal jugular vein. The right vagus nerve travels anteriorly to the subclavian artery and then posterior to the innominate artery. It makes its descent into the thoracic cavity by traveling to the right of the trachea and posterior to the hilum on the right, moving medially to form the esophageal plexus with the left vagus nerve. The left vagus nerve (see FIG. 6, for example) travels anteriorly to the subclavian artery and enters the thoracic cavity wedged between the left common carotid and subclavian arteries. It then descends posteriorly to the phrenic nerve and posterior to the left lung, then travels medially towards the esophagus forming the esophageal plexus with the right vagus nerve.

[0241] There are four branches of the vagus nerve within the neck: the pharyngeal branches, the superior laryngeal nerve, the recurrent laryngeal nerve, and the superior cardiac nerve. The pharyngeal nerve branches arise from the inferior ganglion of the vagus nerve, which contains both sensory and motor fibers. These fibers form the pharyngeal plexus. Branches of this plexus innervate the pharyngeal and palate muscles (except the tensor palatine muscle). The pharyngeal plexus also supplies the innervation to the intercarotid plexus, which mediates information from the carotid body.

[0242] The superior laryngeal nerve travels between the external and internal carotid arteries. The nerve divides into internal and external branches near the level of the hyoid. The internal laryngeal nerve goes through the thyrohyoid membrane, entering the larynx. The external portion travels distally with the superior thyroid vessels. The external portion supplies the cricothyroid muscle, whereas the internal branch supplies the mucosa superior to the glottis.

[0243] The right recurrent laryngeal nerve fibers branch from the vagus nerve near the right subclavian artery, traveling superiorly to enter the larynx between the cricopharyngeus muscle and the esophagus. The left recurrent laryngeal nerve then loops around the aortic archdistal to the ligamentum arteriosus and enters the larynx. All of the laryngeal musculatures receive supply via the recurrent laryngeal nerve except for the cricothyroid muscle, which is supplied by the laryngeal nerve.

[0244] FIGS. 7A-7B illustrate example therapeutic waveforms 500(a), 500(b) that are useable with the neuromodulation device 104 for delivering neural inhibition therapy with VNS. Each of the waveforms 500(a), 500(b) include one or more features and / or functions similar or identical to any of those of waveform 500 such as shown and / or described with reference to FIG. 3E. For example, waveforms 500(a) and 500(b) include anodic phases 502(a) and 502(b), cathodic phases 504(a) and 504(b), and transition regions 510(a) and 510(b), respectively. The system may utilize high-charge density electrodes, such as described elsewhere herein (e.g., electrode(s) 402), to deliver DC waveforms (e.g., any of waveforms 500, 500(a), or 500(b)) to cause partial or full block of certain off-target neural components, such as off-target neurons, fibers, and / or nerves to reduce (or mitigate or prevent) off-target stimulation that may otherwise result from application of VNS.Off-Target Neural Components Inside the Target Nerve Trunk

[0245] In some cases, off-target neural components may be located within a target nerve trunk, such as within the vagus nerve. In such cases, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of action potentials in off-target neural components such as large-diameter myelinated fibers (e.g., A-alpha and / or A- beta fibers) of the vagus nerve and / or the vagus trunk. In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of stimulation-evoked action potentials in the off-target neural components such as the large- diameter myelinated fibers. In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of spontaneous action potentials in the off-target neural components such as the large-diameter myelinated fibers. In some embodiments, delivered DC waveforms may be configured to not cause partial or full block of conduction and / or initiation of spontaneous action potentials in the off-target neural components such as the large-diameter myelinated fibers. For example, delivered DC waveforms may be configured to cause partial or full block of conduction and / or initiation of only stimulation-evoked action potentials in the off-target neural components and not of spontaneous action potentials in said off-target neural components.

[0246] However, DC waveforms may not be delivered at so high of current amplitudes so as to cause partial or full block of conduction and / or initiation of action potentials (e.g., spontaneous and / or stimulation-evoked action potentials) in on-target neural components such as small-diameter myelinated and / or non-myelinated fibers (e.g., A-delta fibers and / or B fibers) of the vagus nerve and / or vagus trunk. In this way, traditional VNS (e.g., via shortpulse width stimulation) can be provided to activate (sometimes referred to herein as “recruit” or “stimulate”) on-target neural components such as the small-diameter myelinated and / or nonmyelinated fibers without activating (or while mitigating activation of) off-target neural components such as the large-diameter myelinated fibers. In some embodiments, DC waveforms may cause partial block of conduction and / or initiation of action potentials (e.g., spontaneous and / or stimulation-evoked action potentials) in some of the on-target neural components; however, the block may be below a threshold amount such that the VNS dosage is still sufficient to activate the on-target neural components to achieve clinically beneficial effects, such as improved cardiac function.

[0247] The DC waveform may have a current amplitude of about 0.1 mA, about 0.5 mA, about 1 mA, about 2 mA, about 3 mA, about 4 mA, about 5 mA, about 6 mA, or any value or range within or bounded by any of these values or ranges. Greater or smaller current amplitudes are also impossible. In some embodiments, the DC waveform may have a current amplitude of any other value described herein. The DC waveform, in some embodiments, can have a current magnitude at any of the current amplitude values described herein. Current magnitude can be the absolute value of a particular current amplitude (e.g., + or - of the stated value). Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having current amplitudes and / or magnitudes at any of the above listed values.

[0248] The waveform delivered for application of traditional VNS (generally referred to herein as a “VNS waveform”) may have a current amplitude of about 0.1 mA, about 0.5 mA, about 1 mA, about 2 mA, about 3 mA, about 4 mA, about 5 mA, about 6mA, or any value or range within or bounded by any of these values or ranges. Greater or smaller current amplitudes are also impossible. In some embodiments, for example, the VNS waveform may have a current amplitude of about 1 mA to about 3 mA. In some embodiments, the VNS waveform may have a current amplitude of any other value described herein. The VNS waveform, in some embodiments, can have a current magnitude at any of the current amplitudevalues described herein. Any of the systems and devices disclosed herein can generate and / or deliver VNS waveforms having current amplitudes and / or magnitudes at any of the above listed values.

[0249] In some embodiments, the VNS waveform may have a frequency of about 1 Hz, about 5 Hz, about 10 Hz, about 20 Hz, about 30 Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 70 Hz, about 80 Hz, about 90 Hz, about 100 Hz, about 110 Hz, about 120 Hz, about 130 Hz, about 140 Hz, about 150 Hz, or any value or range within or bounded by any of these values or ranges. Greater frequencies are also possible. In some embodiments, the VNS waveform may have a frequency of 25 Hz. Any of the systems and devices disclosed herein can generate and / or deliver VNS waveforms having frequencies at any of the above listed values. The VNS waveform may have a greater frequency than the DC waveform.

[0250] In some embodiments, the VNS waveform may have a pulse width of about 90 ps, about 100 ps, about 150 ps, about 200 ps, about 250 ps, about 300 ps, about 350 ps, about 400 ps, about 450 ps, about 500 ps, about 600 ps, about 700 ps, about 800 ps, about 900 ps, about 1,000 ps, or any value or range within or bounded by any of these values or ranges. Longer or shorter pulse widths are also possible. Any of the systems and devices disclosed herein can generate and / or deliver VNS waveforms having pulse widths at any of the above listed values. The VNS waveform may have a shorter pulse width than the DC waveform.

[0251] In some embodiments, the neuromodulation device 104 (e.g., via controller 202) may be configured to deliver a VNS waveform concurrently with delivery of a DC waveform. For example, the controller 202 may be configured to send one or more control signals to one or more signal generators 210 to generate and deliver the VNS waveform during delivery of at least a portion of the DC waveform. In some embodiments, the controller 202 may be configured to deliver the VNS waveform during the cathodic phase and / or the anodic phase of the DC waveform. For example, the controller 202 may be configured to deliver the VNS waveform when nerve block of off-target neural components is maximal, such as during a cathodic and / or anodic plateau of the DC waveform. The controller 202, in some embodiments, may be configured to deliver the VNS waveform during a transition region of the DC waveform, such as when the DC waveform transitions from its cathodic phase to its anodic phase (e.g., during a rise stage of the DC waveform), and / or when the DC waveformtransitions from its anodic phase to its cathodic phase (e.g., during a fall stage of the DC waveform).

[0252] In some embodiments, the VNS waveform can have a greater slew rate than the DC waveform. For example, the VNS waveform can have a transition region duration (e.g., rise time and / or fall time) of about 0.1 ps, about 0.5 ps, about 1 ps, about 2 ps, about 3 ps, about 4 ps, about 5 ps, about 6 ps, about 7 ps, about 8 ps, about 9 ps, about 10 ps, about 11 ps, about 12 ps, about 13 ps, about 14 ps, about 15 ps, or any value or range within or bounded by any of these values or ranges. Longer or shorter transition region durations are also possible. Any of the systems and devices disclosed herein can generate and / or deliver VNS waveforms having transition region durations at any of the above listed values.

[0253] Delivery of DC and LF waveforms may be duty cycled so as to reduce fatigue of the target nerve and / or other nearby or surrounding, electrically excitable tissue. For example, the controller 202 may send one or more control signals to one or more signal generators 210 to duty cycle delivery of DC and / or VNS waveforms. Typically, traditional VNS is applied to a medical patient for about 30 seconds, followed by a 5-minute off-period. However, as described hereinabove, the system may be configured to deliver VNS during an anodic phase and / or cathodic phase of a delivered DC waveform. The system may be configured to turn off or prevent delivery of VNS as delivered DC waveforms transition from an anodic phase to a cathodic phase and / or from a cathodic phase to an anodic phase. In some embodiments, the system may be configured to turn off or prevent delivery of VNS during an anodic phase and / or a cathodic phase of a delivered DC waveform. In some embodiments, the neuromodulation device 104 (e.g., via controller 202) may duty cycle delivery of DC to the extent necessary for VNS indication. In some cases, only a few minutes of VNS may be required daily for inflammatory regulating indications of VNS.

[0254] In cases where afferent and / or efferent block is desired, electrodes configured to deliver DC waveforms (generally referred to herein as “DC electrodes”) may be positioned in relation to electrodes configured to deliver VNS waveforms (generally referred to herein as “VNS electrodes”) such that action potentials, as may result from stimulation of on-target neural components, do not propagate in undesired directions. For example, DC electrodes may be located proximal and / or distal to VNS electrodes such that delivery of DC waveforms by the DC electrodes prevents action potentials (resulting from VNS) from propagating to saidundesired locations, such as in proximal or distal directions. Advantageously, such DC electrode arrangements can enable VNS to be applied to an increased number of locations of the vagus nerve. For example, the right vagus nerve is typically not targeted during VNS due to concerns regarding cardiac innervation and effects of the right vagus nerve over the left vagus nerve. However, distal and / or proximal placement of DC electrodes relative to the VNS electrodes can prevent efferent signal propagation to the heart while traditional VNS is delivered to the right vagus nerve. In this way, the system as described herein (e.g., neuromodulation device 104) can make safe the application of right VNS. Various example electrode configurations are further described with reference to FIGS. 8A-8H.

[0255] In some embodiments, the neuromodulation device 104 may not deliver any neural inhibition therapy during application of VNS. For example, for maintenance therapy, LF waveforms may have current amplitudes that are insufficient to stimulate off-target neural components such as the large-diameter myelinated fibers. In such instances, application of DC may be unnecessary for the delivered dosage of VNS. If the dosage of VNS is increased such that off-target neural components may be stimulated, the neuromodulation device 104 may begin or resume generation and delivery of DC waveforms to cause partial or full block of the off-target neural components. For example, the controller 202 may monitor the level of current and / or intensity of generated and delivered VNS waveforms and (e.g., in response to a determination that the level of current and / or intensity associated with a VNS waveform satisfies or exceeds one or more threshold conditions) may send one or more control signals to the signal generator 210 to begin or resume generation and delivery of DC waveforms.

[0256] In some embodiments, the DC waveform may be configured to exhibit both inhibitory and stimulatory properties such that the DC waveform facilities partial or full block of off-target neural components (e.g., the large-diameter myelinated fibers of the vagus nerve) and stimulates on-target neural components (e.g., the small-diameter myelinated and / or nonmyelinated fibers of the vagus nerve). Such DC waveforms may be referred to herein as “dual modulation” DC waveforms. For example, in some embodiments, the dual modulation DC waveform can include an anodic and / or cathodic phase that is configured to cause partial or full block of the large-diameter myelinated fibers of the vagus nerve, and can include a transition region configured to stimulate the small-diameter myelinated and / or non-myelinated fibers of the vagus nerve. Small-diameter myelinated and / or non-myelinated fibers can havedifferent voltage-gated ion channels than large-diameter myelinated fibers, and consequently may be activated by faster (e.g., shorter in duration, greater in slope, and / or the like) transition regions than the large-diameter myelinated fibers. In this way, the dual-modulation DC waveform may have a greater slew rate than that of a standard DC waveform. In this context, a “standard” DC waveform refers to a DC waveform having only inhibitory properties so as not to stimulate on-target neural components.

[0257] As described elsewhere herein, DC waveforms may suppress conduction and / or initiation of action potentials in certain neural components. For example, when therapeutic energy sufficient for neural inhibition is delivered, such as during a cathodic and / or anodic phase of the DC waveform, partial or full block of conduction and / or initiation of action potentials in off-target neural components (e.g., large-diameter myelinated fibers within the vagus nerve) may continue for a duration of time thereafter, such as once wash-in effects have occurred. In some embodiments, the DC waveform may suppress conduction and / or initiation of action potentials in off-target neural components for a duration of time that is longer than the time taken for the DC waveform to transition from its cathodic phase to it anodic phases or from its anodic phase to its cathodic phase. In this way, the DC waveform may continue to inhibit neural activity in off-target neural components for sufficient duration such that stimulation of on-target neural components by the same DC waveform does not thereby stimulate the off-target neural components (or such that stimulation of off-target neural components is reduced or mitigated). In some embodiments, the DC waveform may suppress conduction and / or initiation of action potentials in off-target neural components for a duration of time that is longer than at least a portion of the cathodic and / or anodic phases of the DC waveform. Accordingly, the neuromodulation device 104 can generate and deliver DC waveforms for delivery of neural inhibition therapy and VNS without requiring generation and delivery of VNS waveforms.

[0258] Returning to the discussion of FIGS. 7A-7B, waveforms 500(a) and 500(b) can include transition regions 510(a) and 510(b), respectively. Transition regions 510(a) and 510(b) may be located between cathodic and anodic plateaus of waveforms 500(a) and 500(b), respectively. As illustrated in the example of FIG. 7B, the waveform 500(b) may be a dual modulation DC waveform having a greater slew rate than that of waveform 500(a) illustrated in FIG. 7A, as indicated by the greater slope (e.g., in units of mA / s) of transition region 510(b)compared to that of transition region 510(a). In some embodiments, waveform 500(a) may be a standard DC waveform. A greater slew rate may correspond to a shorter transition region duration (also referred to herein as a “rise time” or a “fall time”). For example, transition region 510(b) may have a duration of about 0.05 seconds, about 0.06 seconds, about 0.07 seconds, about 0.08 seconds, about 0.09 seconds, about 0.1 seconds, about 0.11 seconds, about 0.12 seconds, about 0.13 seconds, about 0.14 seconds, about 0.15 seconds, about 0.16 seconds, about 0.17 seconds, about 0.18 seconds, about 0.19 seconds, about 0.2 seconds, about 0.21 seconds, about 0.22 seconds, about 0.23 seconds, about 0.24 seconds, about 0.25 seconds, about 0.26 seconds, about 0.27 seconds, about 0.28 seconds, about 0.29 seconds, about 0.3 seconds, about 0.4 seconds, about 0.5 seconds, about 1 second, or any value or range within or bounded by any of these values or ranges. Longer or shorter durations are also possible. In some embodiments, the transition region 510(b) may have a duration of 0.125 seconds. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having transition region durations (e.g., rise times and / or fall times) at any of the above listed values. In some embodiments, transition region 510(b) may have a duration of any other rise time / fall time described herein

[0259] A smaller slew rate may correspond to a longer transition region duration. For example, transition region 510(a) may have a duration of about 0.5 s, about 1 s, about 1.5 s, about 2 s, about 2.5 s, about 3 s, about 3.5 s, about 4 s, about 4.5 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about 15 s, about 20 s, or any value or range within or bounded by any of these values or ranges. Longer or shorter durations are also possible. Any of the systems and devices disclosed herein can generate and / or deliver DC waveforms having transition region durations at any of the above listed values. In some embodiments, transition region 510(a) may have a duration of any other rise time / fall time described herein.

[0260] Although the example embodiments of FIGS. 7A-7B illustrate transition regions having rise times (e.g., transitioning from cathodic to anodic), this is not intended to be limiting. The transition regions 510(a) 510(b) can have fall times (e.g., transitioning from anodic to cathodic) at any of the above listed values. In some embodiments, rise times and fall times of the transition region 510(a) may be different from one another. In some embodiments, the rise times and fall times of the transition region 510(b) may be different from one another. In some embodiments, the rise time can include the time duration from the cathodic maximum(e.g., cathodic plateau) to the crossing point and from the crossing point to the anodic maximum (e.g., anodic plateau). In some embodiments, the fall time can include the time duration from the anodic maximum to the crossing point and from the crossing point to the cathodic maximum. In some embodiments, the time duration from the crossing point to a cathodic maximum may be different than the time duration from the cathodic maximum to the crossing point. In some embodiments, the time duration from the crossing point to an anodic maximum may be different than the time duration from the anodic maximum to the crossing point.

[0261] The transition regions 510(a), 510(b), in some embodiments, may have a slope equal to the current amplitude or magnitude of the DC waveform (such as any of the current amplitude or magnitude values described herein) divided by the transition region duration, such as the rise time and / or fall time (e g., any of the transition region duration, rise time, and / or fall time values described herein).

[0262] In this way, waveform 500(b) may be configured to cause partial or full block of conduction and / or initiation of action potentials in off-target neural components within the vagus nerve (e.g., large-diameter myelinated fibers) during delivery of the cathodic and / or anodic phase, and may be configured to stimulate on-target neural components within the vagus nerve (e.g., small-diameter myelinated and / or non-myelinated fibers) as the waveform 500(b) transitions from its cathodic phase to its anodic phase. In some embodiments, the waveform 500(b) may be configured to stimulate on-target neural components as the waveform 500(b) transitions from its anodic phase to its cathodic phase. In some embodiments, the waveform 500(b) can be configured to cause partial or full block of off-target neural components during delivery of the cathodic or anodic phase and may be configured to stimulate on-target neural components during delivery of the anodic or cathodic phase, respectively.Off-Target Neural Components Outside the Target Nerve Trunk

[0263] In some cases, off-target neural components may be located outside of a target nerve trunk, such as outside of the vagus nerve. In such cases, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of action potentials in off-target neural components such as large-diameter myelinated fibers (e.g., A-alpha and / or A- beta fibers) of the non-target electrically excitable tissue, such as (but not limited to) the superior laryngeal nerve (including the external laryngeal nerve and the internal laryngealnerve), the left recurrent laryngeal nerve (in the case of left VNS), and / or the right recurrent laryngeal nerve (in the case of right VNS). In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of stimulation- evoked action potentials in the off-target neural components such as the large-diameter myelinated fibers. In some embodiments, delivered DC waveforms may be sufficient to cause partial or full block of conduction and / or initiation of spontaneous action potentials in the off- target neural components such as the large-diameter myelinated fibers. In some embodiments, delivered DC waveforms may be configured to not cause partial or full block of conduction and / or initiation of spontaneous action potentials in the off-target neural components such as the large-diameter myelinated fibers. For example, delivered DC waveforms may be configured to cause partial or full block of conduction and / or initiation of only stimulation- evoked action potentials in the off-target neural components and not of spontaneous action potentials in said off-target neural components.

[0264] However, DC waveforms may not be delivered at so high of current amplitudes so as to cause partial or full block of conduction and / or initiation of action potentials (e.g., spontaneous and / or stimulation-evoked action potentials) in on-target neural components such as small-diameter myelinated and / or non-myelinated fibers (e.g., A-delta fibers and / or B fibers) of the vagus nerve and / or vagus trunk. In this way, traditional VNS (e.g., via shortpulse width stimulation) can be provided to activate on-target neural components such as the small-diameter myelinated and / or non-myelinated fibers without activating (or while mitigating activation of) off-target neural components such as the large-diameter myelinated fibers. In some embodiments, DC waveforms may cause partial block of conduction and / or initiation of action potentials (e.g., spontaneous and / or stimulation-evoked action potentials) in some of the on-target neural components; however, the block may be below a threshold amount such that the VNS dosage is still sufficient to activate the on-target neural components to achieve clinically beneficial effects, such as improved cardiac function.

[0265] When applying VNS to the vagus nerve, there is the possibility to activate off- target neural components in other electrically excitable tissue, such as may be located near the vagus nerve and / or vagus trunk, including but not limited to the superior laryngeal nerve (including the external laryngeal nerve and the internal laryngeal nerve), the left recurrent laryngeal nerve (in the case of left VNS), and the right recurrent laryngeal nerve (in the caseof right VNS). For example, during application of VNS to the vagus nerve, current can escape from stimulation electrodes (e.g., VNS electrodes) and stimulate off-target neural components in other nearby nerves, such as large-diameter myelinated fibers in other nearby nerves. This can cause activation of the neck muscles and lead to unwanted side effects such as throat tightness and / or coughing. In this context, “current escape” refers to a phenomenon where therapeutic electrical signals delivered for VNS does not stay localized to the target nerve or the target stimulation area. Instead, current may escape to surrounding tissue or unintended areas. This can occur due to changes in the resistance around the electrode and / or in tissue near the stimulation site, improper electrode placement, device degradation that can lead to current leakage, and / or high-intensity stimulation or waveform settings that contribute to current dispersing beyond the vagus nerve. In such cases, application of neural inhibition therapy via delivery of DC waveforms to an off-target nerve may cause partial or full block of initiation and / or conduction of action potentials in off-target neural components in off-target nerves that may otherwise result from current escaping from VNS electrodes.

[0266] In some embodiments, electrical insulation may be applied around and / or to VNS electrodes to reduce (or mitigate or prevent) current escape from said VNS electrodes. For example, any available type of biocompatible electrical insulation may be applied around and / or to the VNS electrodes, such as a polymer coating (e.g., silicone, polyamide, and / or the like). The electrical insulation may be applied around and / or to at least a portion of at least one VNS electrode. In some embodiments, all VNS electrodes may include electrical insulation.

[0267] Electrode position, in some embodiments, may be selected such that therapeutic electrical signals for VNS are directed away from off-target neural components in off-target nerves. For example, in cases of monopolar operation, an indifferent electrode (IE) configured to sink the therapeutic electrical signal that is delivered by a working electrode (WE) may be positioned so as to reduce (or mitigate or prevent) stimulation of off-target neural components in an off-target nerve as therapeutic electrical signals travel from the WE to the IE. In cases of bipolar operation, WE pairs may be selected and / or positioned so as to reduce (or mitigate or prevent) stimulation of off-target neural components in an off-target nerve as a therapeutic electrical signal is delivered between a first and second WEs.Off-Target Neural Components Inside and / or Outside the Target Nerve Trunk

[0268] The system (e.g., neuromodulation device 104 and / or components thereof), in some embodiments, may be configured to monitor the efficacy of neural inhibition therapy that is applied in combination with (or in some embodiments, in lieu of) VNS. For example, a controller (e.g., controller 202) may be configured to implement one or more closed-loop feedback algorithms to monitor neural parameters (e g., biomarkers) and / or physiological parameters that can be indicative of a level of neural inhibition in off-target neural components. In this way, the system can include hardware capable of detecting neural and / or physiological inputs (e.g., sensor(s) 110), pre-processing said inputs (e.g., front-end circuitry), extracting features from pre-processed inputs and generating processed outputs, and determining a level of neural inhibition based on said processed outputs. Based on the determined level of neural inhibition of off-target neural components, the controller may be configured to send one or more control signals to a signal generator (e.g., signal generator 210) to adjust (e.g., increase or decrease) or keep same the amount of neural inhibition therapy delivered to a medical patient. For example, the controller may be configured to adjust one or more of a frequency of the DC waveform; a current amplitude of the DC waveform; a current magnitude of the DC waveform; a pulse width of the DC waveform; a duty cycle of the DC waveform; a phase of the DC waveform; a slew rate of the DC waveform; and / or any other waveform parameter described herein. Neural parameters, in some embodiments, may include any of: electrically evoked compound action potentials (ECAP); EMG recordings of off-target muscles; and / or the like.

[0269] In some embodiments, the system may use a test pulse to cause detectable changes in the off-target neural components. For example, the controller may generate and deliver, at various time periods, a waveform configured to invoke an action potential in off- target neural components. Delivered DC waveforms may be configured to interfere with said evoked action potentials. This interference may be monitored by the controller and used to determine a level of neural inhibition of the off-target neural components. For example, the controller may determine measures of interference and compare these determined values to one or more threshold conditions. Based on whether a threshold condition is satisfied (e.g., a measured value is greater than a threshold value, greater than or equal to a threshold value, less than a threshold value, less than or equal to a threshold value, exceeds a threshold value, equalsa threshold value, and / or the like), the controller can adjust or keep same the amount of neural inhibition therapy delivered to the medical patient. In some embodiments, the controller may monitor neural and / or physiological inputs associated with the interference of the evoked action potentials by the DC waveforms using a closed-loop control system. The closed-loop control system can include any one or more of: a fuzzy logic control system; a proportional- integral-derivative (PID) control system; a linear control system; and / or any other available type of closed-loop system.

[0270] In some embodiments, an electrode-tissue interface may be designed to bring on- and / or off-target neural components closer to VNS and / or or DC electrodes, respectively. For example, neural bundles may be teased out of the nerve. In some examples, a tissue graft or growth factor may be used to ‘grow’ particular neurons toward the edge of, or out of, a nerve. Alternatively or additionally, an electrode-tissue interface may be designed to alter the relative excitability of on-target and / or off-target neural components. For example, the nerve may be squeezed (e.g., using a tight cuff electrode design) to alter the relative excitability of large-diameter myelinated fibers and small-diameter myelinated and non-myelinated fibers of the nerve. In some embodiments, other techniques may be used to alter ion channel expression in on- and off-target neural components so that they are preferentially activated and / or blocked by VNS and DC, respectively.Example Implantable Leads and Electrodes Relating to Neural Inhibition Therapy Applied to the Vagus Nerve

[0271] FIGS. 8A-8H illustrate various example embodiments of implantable leads and / or electrodes useable with the system for delivering neural inhibition therapy to the vagus nerve. Although the following drawings are described in the context of the vagus nerve, this is not intended to be limiting. The following lead and / or electrode configurations may be applied to any other nerve.

[0272] FIG. 8A schematically illustrates an example embodiment of an arrangement of electrodes located at a treatment site of the vagus nerve. As depicted in the example of FIG. 8 A, the arrangement includes two DC electrodes 402(a), two VNS electrodes 402(b), and two signal generators. The set of DC electrodes 402(a) may be configured to electrically communicate with a signal generator (labeled as “Signal generator 1” for purposes of illustration). The set of VNS electrodes 402(b) may be configured to electrically communicatewith another signal generator (labeled as “Signal generator 2” for purposes of illustration). Although pairs of electrodes and signal generators are illustrated in the example of FIG. 8A, this is not intended to be limiting. Any number of DC electrodes 402(a) may be used, such as 1, 2, 3, 4, 5, 6, 7, 8, or more DC electrodes 402(a). In some embodiments, any number of VNS electrodes 402(a) may be used, such as 1, 2, 3, 4, 5, 6, 7, 8, or more VNS electrodes 402(a). In some embodiments, a single signal generator may be used. In some embodiments, three or more signal generators may be used, such as a separate signal generator for each electrode.

[0273] The DC electrodes 402(a) may be arranged caudal to the VNS electrodes 402(b) such that the VNS electrodes 402(b) are located between the DC electrodes 402(a). The electrodes 402(a), 402(b) may be equally spaced apart from each other. In some embodiments, the VNS electrodes 402(b) may be spaced closer to each other than to either of the DC electrodes 402(a). Although the example of FIG. 8A illustrates the VNS electrodes 402(b) arranged between the DC electrodes 402(a), this is not intended to be limiting. In some embodiments, the VNS electrodes 402(b) may be arranged caudal to the UFL electrodes 402(a) such that the DC electrodes 402(a) are located between the VNS electrodes 402(b). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be arranged in an alternating sequence.

[0274] The DC electrodes 402(a) can include one or more features and / or functions similar or identical to any of those of any other electrode shown and / or described elsewhere herein (e g., electrode 402). The DC electrodes 402(a) can be configured to deliver neural inhibition therapy to a medical patient. For example, the DC electrodes 402(a) may be configured to deliver any of the DC waveforms shown and / or described elsewhere herein, such as any of waveforms 500, 500(a), and / or waveform 500(b). In this way, the DC electrodes 402(a) may be configured to partially or fully block initiation and / or conduction of action potentials in off-target neural components of the vagus nerve, such as large-diameter myelinated fibers of the vagus nerve. In some embodiments, the DC electrodes 402(a) may be configured to activate on-target neural components of the vagus nerve, such as small-diameter myelinated and non-myelinated fibers of the vagus nerve. For example, the DC electrodes 402(a) may be configured to deliver a dual-modulation DC waveform (e.g., waveform 500(b)) configured to partially or fully block initiation and / or conduction of action potentials in off-target neural components and cause initiation and / or conduction of action potential in on-target neural components.

[0275] In some embodiments, the DC electrodes 402(a) may be configured to cause partial or full block of conduction of action potentials in a certain direction and / or initiation of action potentials in off-target neural components located in a certain portion of the vagus nerve. For example, if it is desirable to block efferent signal propagation to the left in the vagus nerve and / or if off-target neurons and / or fibers are located only in a left portion of the vagus nerve, then one or more DC electrodes 402(a) may be arranged at a left portion of the vagus nerve to partially and / or fully block these neural components. Similarly, if it is desirable to block efferent signal propagation to the right in the vagus nerve and / or if off-target neurons and / or fibers are located only in a right portion of the vagus nerve, then one or more DC electrodes 402(a) may be arranged at a right portion of the vagus nerve to partially and / or fully block these neural components. In this context, “left” and “right” may be defined in relation to the location of the VNS electrodes 402(b). For example, a left portion of the vagus nerve may be any portion to the left of the VNS electrodes 402(b), whereas a right portion of the vagus nerve may be any portion to the right of the VNS electrodes 402(b).

[0276] The VNS electrodes 402(b) can include one or more features and / or functions similar or identical to any of those of any other electrode shown and / or described elsewhere herein (e.g., electrode 402). The VNS electrodes 402(b) can be configured to deliver VNS to the medical patient. For example, the VNS electrodes 402(b) may be configured to deliver VNS waveforms. In this way, the VNS electrode may be configured to cause initiation and / or conduction of action potentials in on-target neural components of the vagus nerve, such as small-diameter myelinated and non-myelinated fibers of the vagus nerve.

[0277] Signal generator 1 can include one or more features and / or functions similar or identical to any of those of signal generator 210 such as shown and / or described with reference to FIG. 2B. Signal generator 1 can be configured to electrically communicate with DC electrodes 402(a). Signal generator 1 can be configured to generate and deliver any of the DC waveforms described elsewhere herein (e.g., waveform 500, waveform 500(a), waveform 500(b)) through one or more DC electrodes 402(a).

[0278] Signal generator 2 can include one or more features and / or functions similar or identical to any of those of signal generator 210 such as shown and / or described with referenceto FIG. 2B. Signal generator 2 can be configured to electrically communicate with VNS electrodes 402(b). Signal generator 2 can be configured to generate and deliver VNS waveforms through one or more VNS electrodes 402(b).

[0279] In some embodiments, a singe signal generator may generate and deliver DC waveforms through the DC electrodes 402(a) and may generate and deliver VNS waveforms through the VNS electrodes 402(b). Each electrode 402(a), 402(b), in some embodiments, may be in electrical communication with a separate signal generator.

[0280] FIG. 8B schematically illustrates an example embodiment of an arrangement of electrodes located at a treatment site of the vagus nerve. FIG. 8B depicts a DC electrode 402(a) and a plurality of VNS electrodes 402(b).

[0281] The DC electrode 402(a) may be arranged at the surface of the vagus nerve. In some embodiments, the DC electrode 402(a) may be positioned within signaling contact of the vagus nerve. The DC electrode 402(a) may be configured as a cuff electrode having one or more electrode contacts that are configured to deliver neural inhibition therapy to the vagus nerve. For example, the active electrode contacts may be arranged on an inner surface that is facing the vagus nerve such that the electrode contacts are in signaling contact with the vagus nerve. In some embodiments, the DC cuff electrode 402(a) may be disposed around at least a portion of the vagus nerve. For example, the DC cuff electrode 402(a) may be configured to encircle at least a portion of the vagus nerve, such as 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any value or range within or bounded by any of these values or ranges, of the circumference of the vagus nerve. In some examples, the DC cuff electrode 402(a) may encircle at least a portion of the vagus nerve based on the location of off-target neural components. For example, if off-target neural components are located at or near a particular sidewall of the vagus nerve, then the DC cuff electrode 402(a) may be configured to encircle the corresponding outer surface of the vagus nerve. In this way, the DC cuff electrode 402(a) may be configured to partially or fully block initiation and / or conduction of action potentials of off-target neural components located in a particular portion of the vagus nerve.

[0282] The DC cuff electrode 402(a) can include one or more features and / or functions similar or identical to any of those of any other electrode shown and / or described elsewhere herein (e.g., electrode 402). The DC cuff electrode 402(a) can be configured to deliver neural inhibition therapy to a medical patient. For example, the DC cuff electrode 402(a) may beconfigured to deliver any of the DC waveforms shown and / or described elsewhere herein, such as any of waveforms 500, 500(a), and / or waveform 500(b). In this way, the DC cuff electrode 402(a) may be configured to partially or fully block initiation and / or conduction of action potentials in off-target neural components of the vagus nerve, such as large-diameter myelinated fibers of the vagus nerve.

[0283] The plurality of VNS electrodes 402(b) may be disposed on the inner surface of the DC cuff electrode 402(a). The VNS electrodes 402(b) may be spaced from each other on the inner surface of the DC cuff electrode 402(a). In some embodiments, the VNS electrodes 402(b) may be spaced equidistant from each other, or have another spacing arrangement. The VNS electrodes 402(b) may extend from the inner surface of the cuff electrode 402(a). For example, the VNS electrodes 402(b) may extend inward of the inner surface of the cuff electrode 402(a) toward the vagus nerve. In some examples, the VNS electrode 402(b) may extend toward the cross-sectional center of the vagus nerve. In some examples, the VNS electrodes 402(b) may extend in the direction of on-target neural components of the vagus nerve. The VNS electrodes 402(b), in some embodiments, may be configured to penetrate the vagus nerve to deliver VNS to on-target neural components.

[0284] The VNS electrodes 402(b) can include one or more features and / or functions similar or identical to any of those of any other electrode shown and / or described elsewhere herein (e.g., electrode 402). The VNS electrodes 402(b) can be configured to deliver VNS to the medical patient. For example, the VNS electrodes 402(b) may be configured to deliver LF waveforms. In this way, the VNS electrode may be configured to cause initiation and / or conduction of action potentials in on-target neural components of the vagus nerve, such as small-diameter myelinated and non-myelinated fibers of the vagus nerve.

[0285] In the example embodiment of FIG. 8B, the DC cuff electrode 402(a) may be in electrical communication with a first signal generator configured to generate and deliver DC waveforms through the DC cuff electrode 402(a). The VNS electrodes 402(b) may be in electrical communication with a second signal generator that is configured to generate and deliver VNS waveforms through the VNS electrodes 402(b). In some embodiments, the DC cuff electrode 402(a) and the VNS electrodes 402(b) may be in electrical communication with the same signal generator. In some embodiments, the DC cuff electrode 402(a) and each of the VNS electrodes 402(b) may be in electrical communication with separate signal generators.

[0286] FIG. 8C schematically illustrates an example embodiment of an arrangement of electrodes located at a treatment site of the vagus nerve. As depicted in FIG. 8C, a percutaneous approach may be utilized to deliver neural inhibition therapy to a medical patient, such as a medical patient already receiving VNS (e.g., a patient with a VNS implant). For example, a shielded needle may penetrate the vagus nerve to position one or more DC electrodes 402(a) within at least a portion of the vagus nerve. In this way, the DC electrodes 402(a) may deliver DC waveforms to cause partial or full block of conduction and / or initiation of action potentials in off-target neural components of the vagus nerve, such as large-diameter myelinated fibers. In some embodiments, the percutaneous approach may be used to cause partial or full block of off-target components in a certain portion of the vagus nerve. For example, if off-target neural components group toward a particular sidewall of the vagus nerve, DC electrodes 402(a) may be inserted into that region of the vagus nerve to cause partial or full block of said off-target neural components.

[0287] FIG. 8D schematically illustrates an example embodiment of an arrangement of electrodes located at a treatment site of the vagus nerve. FIG. 8D depicts a plurality of DC electrodes 402(a) arranged on the surface of the vagus nerve. The DC electrodes 402(a) may be in signaling contact with the vagus nerve. The DC electrodes 402(a) may be spaced from each other on the surface of the vagus nerve. In some embodiments, the DC electrodes 402(a) may be spaced equidistant from each other, or have another spacing arrangement.

[0288] The DC electrodes 402(a) may be arranged as a cuff electrode that is configured to encircle at least a portion of the vagus nerve (see FIG. 8B, for example). In some embodiments, high-charge density electrodes used for delivery of neural inhibition therapy may necessitate a flat contact design. In such cases, the cuff may be segmented into various portions to accommodate the plurality of flat electrode contacts. For example, the segmented cuff may cause conformance of the DC electrodes 402(a) to the curved surface of the vagus nerve. In this way, the segmented cuff can help ensure that each electrode contact is in signaling contact with the vagus nerve. In the example embodiment of FIG. 8D, each of the plurality of DC electrodes 402(a) may be in electrical communication with a signal generator that is configured to generate and deliver DC waveforms through the DC electrodes 402(a). In some embodiments, each DC electrode 402(a) may be in electrical communication with a separate signal generator.

[0289] FIGS. 8E-8F schematically illustrate example embodiments of an arrangement of electrodes located at a treatment site of the vagus nerve. FIGS. 8E-8G depict paddle leads 800 having a plurality of electrodes 402(a), 402(b) arranged on said lead. The paddle leads 800 can include one or more features and / or functions similar or identical to any of those of implantable lead(s) 212 such as shown and / or described with reference to FIGS. 2B, 5A-5J. The paddle leads 800 can include a plurality of DC electrodes 402(a) and a plurality of VNS electrodes 402(b). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be arranged on the same surface of the paddle leads 800. For example, the DC and VNS electrodes 402(a) and 402(b) may be arranged on a surface of the paddle leads 800 that faces toward the vagus nerve such that the DC and VNS electrodes 402(a), 402(b) are in signaling contact with the vagus nerve. The DC electrodes 402(a) may be spaced from each other on the surface of the paddle lead 800. In some embodiments, the DC electrodes 402(a) may be spaced equidistant from each other, or have another spacing arrangement. The VNS electrodes 402(b) may be spaced from each other on the surface of the paddle lead 800. In some embodiments, the VNS electrodes 402(b) may be spaced equidistant from each other, or have another spacing arrangement.

[0290] As illustrated in the example of FIG. 8E, the DC electrodes 402(a) may be arranged at the distal end 802 and / or proximal end 804 of the paddle lead 800. The VNS electrodes 402(b) may be arranged between the sets of DC electrodes 402(a), such as at or near the center of the paddle lead 800. As further illustrated in the example of FIG. 8F, the DC electrodes 402(a) may be arranged along the peripheral edge 806 of the paddle lead 800, and the VNS electrodes 402(b) may arranged at or near the center of the paddle lead 800. Although pairs of electrodes are illustrated in FIGS. 8E-8F, this is not intended to be limiting. Any number of DC and / or VNS electrodes 402(a), 402(b) may be arranged on the paddle lead 800 as can be permitted by available space for positioning of said electrodes.

[0291] The VNS electrodes 402(b) may be smaller in size than the DC electrodes 402(a). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be arranged in an alternating sequence, such as along a length and / or width of the paddle lead 800.

[0292] In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be arranged on different surfaces of the paddle leads 800. For example, the VNS electrodes 402(b) may be arranged on a first surface of the paddle leads 800 that faces toward the vagus nervesuch that the VNS electrodes 402(b) are in signaling contact with the vagus nerve, and the DC electrodes 402(a) may be arranged on a second surface of the paddle leads 800 that faces toward another nerve such as an off-target nerve so that the DC electrodes 402(a) are in signaling contact with the off-target nerve. In this way, the paddle lead 800 can be configured to apply VNS to the vagus nerve and neural inhibition therapy to another nerve.

[0293] In FIGS. 8E-8F, the DC electrodes 402(a) may be in electrical communication with a first signal generator that is configured to generate and deliver DC waveforms through the DC electrodes 402(a). The VNS electrodes 402(b) may be in electrical communication with a second signal generator that is configured to generate and deliver VNS waveforms through the VNS electrodes 402(b). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with a single signal generator. In some embodiments, each of the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with separate signal generators.

[0294] FIGS. 8G-8H schematically illustrate example embodiments of an arrangement of electrodes located at a treatment site of the vagus nerve. FIG. 8G illustrates an implantable lead 212, such as shown and / or described with reference to FIGS. 2B, 5A-5J. The implantable lead 212 can include a plurality of DC electrodes 402(a) and a plurality of VNS electrodes 402(b). One or more DC electrodes 402(a) may be arranged at the proximal end and / or distal end 406 of the implantable lead 212. The DC electrodes 402(a) may be spaced apart from one another. In some embodiments, the DC electrodes 402(a) may be spaced equidistant from each other, or have another spacing arrangement.

[0295] The VNS electrodes 402(b) may be arranged between sets of DC electrodes 402(a). The VNS electrodes 402(b) may be spaced from each other. In some embodiments, the VNS electrodes 402(b) may be spaced equidistant from each other, or have another spacing arrangement. The VNS electrodes 402(b) may be smaller in size than the DC electrodes 402(a). In some embodiments, the DC electrodes 402(a) and the VNS electrodes 402(b) may be arranged in an alternating sequence.

[0296] In the example embodiment of FIG. 8G, the DC electrodes 402(a) may be in electrical communication with a first signal generator that is configured to generate and deliver DC waveforms through the DC electrodes 402(a). The VNS electrodes 402(b) may be in electrical communication with a second signal generator that is configured to generate anddeliver VNS waveforms through the VNS electrodes 402(b). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with a single signal generator. In some embodiments, each of the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with separate signal generators.

[0297] FIG. 8H depicts a helical cuff 808 having one or more DC electrodes 402(a) and one or more VNS electrodes 402(b). The helical cuff 808 can include one or more features and / or functions similar or identical to any of those of implantable lead(s) 212 such as shown and / or described with reference to FIGS. 2B, 5A-5J. The helical cuff 808, in some embodiments, can include one or more features and / or functions similar or identical to any of those of the DC cuff electrode 402(a) such as shown and / or described with reference to FIG. 8B. The helical cuff 808 may be configured to encircle at least a portion of the vagus nerve. In some embodiments, a portion 812 of the helical cuff 808 may be configured to encircle the vagus nerve. The DC electrodes 402(a) may be arranged at a proximal end and / or distal end 810 of the helical cuff 808. The DC electrodes 402(a) may be spaced apart from one another. In some embodiments, the DC electrodes 402(a) may be spaced equidistant from each other, or have another spacing arrangement.

[0298] The VNS electrodes 402(b) may be arranged between sets of DC electrodes 402(a). For example, the VNS electrodes 402(b) may be arranged on the helical portion 812 of the helical cuff 808. The VNS electrodes 402(b) may be spaced from each other. In some embodiments, the VNS electrodes 402(b) may be spaced equidistant from each other, or have another spacing arrangement. The VNS electrodes 402(b) may be smaller in size than the DC electrodes 402(a). In some embodiments, the DC electrodes 402(a) and the VNS electrodes 402(b) may be arranged in an alternating sequence.

[0299] In the example embodiment of FIG. 8H, the DC electrodes 402(a) may be in electrical communication with a first signal generator that is configured to generate and deliver DC waveforms through the DC electrodes 402(a). The VNS electrodes 402(b) may be in electrical communication with a second signal generator that is configured to generate and deliver VNS waveforms through the VNS electrodes 402(b). In some embodiments, the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with a single signal generator. In some embodiments, each of the DC and VNS electrodes 402(a), 402(b) may be in electrical communication with separate signal generators.Example Routines Relating to Electrically Modulating Target Electrically Excitable Tissue

[0300] FIG. 9 is a diagram illustrating an example process 900 for electrically modulating target electrically excitable tissue. The process 900, or portions thereof, can be implemented by a computing device such as a hardware processor. In some embodiments, the process 900, or portions thereof, can be performed by a computing device associated with the neuromodulation device 104 (e.g., physically integrated with the neuromodulation device and / or remote to the neuromodulation device and in communication with the neuromodulation device) such as any user device described herein (e.g., user device(s) 106). In some embodiments, the process 900, or portions thereof, can be performed by the controller 202 described herein.

[0301] Although multiple blocks are illustrated in FIG. 9, not all blocks may necessarily be performed in the ordinary course when performing routines associated with electrically modulating target electrically excitable tissue. Moreover, although blocks depicted in FIG. 9 are illustrated in a particular order, this is not intended to be limiting. One or more blocks illustrated in FIG. 9 may be performed in one or more different orders, may be performed simultaneously, may be combined into fewer blocks, may be separated into additional blocks, or may not be performed at all.

[0302] At block 902, a signal generator (e.g., signal generator 210) may be provided. The signal generator can be configured to generate one or more electrical signals. The signal generator may be configured to be in electrical communication with at least one implantable electrode. The implantable electrode can include one or more features and / or functions similar or identification to any of those described with reference to electrode(s) 402, as discussed elsewhere herein. The implantable electrode may be configured to receive electrical signals generated by the signal generator. In some embodiments, the implantable electrode may be configured as a cuff electrode, such as a vagus nerve cuff stimulation electrode. In some embodiments, the implantable electrode may be arranged on an implantable lead (e g., lead(s) 212). The implantable lead may be a paddle lead (e.g., paddle lead 800).

[0303] At block 904, a controller (e.g., controller 202) can cause generation of a first electrical signal. For example, the controller may send one or more control signals to the signal generator to cause the signal generator to generate the first electrical signal. The first electrical signal can be configured to cause partial or full block of action potential initiation and / orconduction in an off-target neural component of a first target electrically excitable tissue. Off- target neural components can include large-diameter myelinated fibers, such as A-alpha fibers and / or A-beta fibers. In some embodiments, the first electrical signal may be configured to cause partial or full block of stimulation-evoked and / or spontaneous action potential initiation and / or conduction in the off-target neural component of a first target electrically excitable tissue. In some embodiments, the first electrical signal may be configured to cause partial or full block of only stimulation-evoked action potential conduction and / or initiation in the off- target neural component of a first target electrically excitable tissue, and configured to not cause partial or full block of spontaneous action potential initiation and / or conduction in said off-target neural component.

[0304] The first electrical signal, in some embodiments, may be configured to not cause partial or full block of action potential (e.g., stimulation-evoked and / or spontaneous action potentials) initiation and / or conduction in on-target neural components. However, in some embodiments, the first electrical signal may be configured such that any block of on- target neural components that may result from the first electrical signal is below a threshold amount. In this way, activation of on-target neural components (e.g., via the second electrical signal) is still sufficient to achieve clinically beneficial effects, such as improved cardiac function. On-target neural components can include small-diameter myelinated fibers and / or non-myelinated fibers (e.g., A-delta fibers and / or B fibers).

[0305] The first target electrically excitable tissue may be the vagus nerve. In some embodiments, the first target electrically excitable tissue may be the vagus trunk. In some embodiments, the first target electrically excitable tissue may be another neural target, such as electrically excitable tissue outside of the vagus nerve and / or outside of the vagus trunk. This can include (but is not limited to) the superior laryngeal nerve (including the external laryngeal nerve and the internal laryngeal nerve), the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve. In some embodiments, the first target electrically excitable tissue may be any other neural target described elsewhere herein.

[0306] The first electrical signal, at block 904, may be a direct current (DC) waveform. For example, the first electrical signal can include one or more features and / or functions similar or identical to any of those described with reference to DC waveforms (e.g., waveforms 500, 500(a), 500(b)), such as discussed elsewhere herein. The first electrical signal can include ananodic phase and a cathodic phase. In some embodiments, either of the anodic phase or the cathodic phase (or both the anodic and cathodic phases) can deliver charge suitable to cause partial or full block of action potential initiation and / or conduction in the off-target neural components. In some embodiments, the first electrical signal can include a slew rate sufficient to activate on-target neural components. For example, the first electrical signal can have a rise time and / or fall time of 0.1 seconds to 0.2 seconds. In some examples, the first electrical signal can have a different rise / fall time, such as any rise / fall time described elsewhere herein. However, the slew rate may not be so great so as to activate off-target neural components. In some embodiments, the off-target neural components may remain suppressed after delivery of anodic and / or cathodic charge such that the transition of the first electrical signal from anodic to cathodic and / or cathodic to anodic (e.g., slew rate) does not activate the off-target neural components.

[0307] The first electrical signal can have a frequency of 0.1 Hz to 10 Hz. In some embodiments, the first electrical signal can have another frequency, such as any frequency described elsewhere herein. The first electrical signal can have a current magnitude of 1 mA to 6mA. In some embodiments, the first electrical signal can have another current magnitude, such as any current magnitude described elsewhere herein. The first electrical signal can have a pulse width of 0.1 seconds to 100 seconds. In some embodiments, the first electrical signal can have another pulse width, such as any pulse width described elsewhere herein. The first electrical signal may have a longer pulse width than the second electrical signal.

[0308] At block 906, the controller can cause generation of a second electrical signal. For example, the controller may send one or more control signals to the signal generator to cause the signal generator to generate the second electrical signal. The second electrical signal may have a shorter pulse width than the first electrical signal. The second electrical signal can be configured to activate an on-target neural component of a second electrically excitable tissue. The second electrically excitable tissue may be the vagus nerve. In some embodiments, the second target electrically excitable tissue may be the vagus trunk. In some embodiments, the second electrically excitable tissue may be the same at the first electrically excitable tissue. The second electrical signal may be a vagus nerve stimulation (VNS) waveform, such as described herein. The second electrical signal can have a frequency of 1 Hz to 100 Hz. In some embodiments, the second electrical signal can have another frequency, such as a frequencygreater than 100 Hz. The second electrical signal can have a current magnitude of 1 mA to 10 mA. In some embodiments, the second electrical signal can have another current magnitude, such as any current magnitude described elsewhere herein. In some embodiments, the second electrical signal can have a greater slew rate than the first electrical signal. For example, the second electrical signal can have shorter rise time and / or fall time than the first electrical signal.

[0309] In some embodiments, at block 908, the controller can cause generation and delivery of the first electrical signal concurrently with generation and delivery of the second electrical signal. For example, the controller can send one or more control signals to the signal generator to cause the signal generator to generate the first electrical signal while also generating the second electrical signal. In some embodiments, the controller can send one or more control signals to the signal generator to cause the signal generator to deliver the first electrical signal to the implantable electrode while also delivering the second electrical signal to the implantable electrode.

[0310] In some embodiments, at block 910, the controller can determine a measure of neural inhibition of the off-target neural component. For example, the controller may receive or access a neural signal (or neural data) indicative of a level of neural inhibition of the off- target neural component, such as from a sensor (e.g., sensor(s) 110). In some embodiments, the sensor may be a sensing reference electrode. The neural signal may be associated with one or more biomarkers, such as electrically evoked compound action potentials (ECAP), EMG recording of off-target muscles, and / or the like. The controller may be configured to determine a level of neural inhibition of the off-target neural component based on the received neural signal, such as based on one or more detected biomarkers.

[0311] At block 910, in some embodiments, the controller may be configured to cause generation of a test pulse. For example, the controller may send one or more control signals to the controller to cause the signal generator to generate a test pulse. The test pulse can be configured to cause detectable changes in the off-target neural component. For example, the test pulse may be an electrical signal that is configured to active the off-target neural component. In some examples, the test pulse may be an electrical signal that is configured to invoke a compound action potential in the off-target neural component. The first electrical signal may be configured to interfere with the neural activation caused by the test pulse. The controller may be configured to determine a measure of this interference.

[0312] In some embodiments, at block 912, the controller may be configured to adjust (e.g., increase or decrease) one or more signal parameters of the first electrical signal. Signal parameters can include any of the waveform parameters described elsewhere herein. For example, the controller may be configured to adjust one or more of a frequency of the first electrical signal; a current amplitude of the first electrical signal; a current magnitude of the first electrical signal; a phase of the first electrical signal; a duty cycle of the first electrical signal; a slew rate of the first electrical signal; and / or the like. The controller may be configured to adjust one or more signal parameters of the first electrical signal based at least in part on the determined level of neural inhibition associated with the off-target neural component. In some embodiments, at block 912, the controller may be configured to adjust the one or more signal components based on whether the determined level of neural inhibition satisfies a threshold condition (e g., is greater than a threshold value, greater than or equal to a threshold value, less than a threshold value, less than or equal to a threshold value, and / or the like).

[0313] Based on a determination that the determined level of neural inhibition does not satisfy a threshold condition, in some embodiments, the controller may be configured to increase one or more signal parameters. Based on a determination that the determination level of neural inhibition satisfies a threshold condition, in some embodiments, the controller may be configured to decrease one or more signal parameters.

[0001] At block 912, the threshold condition(s) can include limits such as lower and upper limits. In some embodiments, the controller can determine a change in the neural data (e.g., relating to the biomarkers) between a first time and a second time. In some embodiments, at block 912, the controller can determine whether the neural data satisfies a threshold condition and / or whether the neural data satisfies a threshold condition more than a certain number of times. In some embodiments, at block 912, the controller can determine whether a value associated with the neural data satisfies a threshold condition. In some embodiments, the controller can determine whether a change in the neural data satisfies a threshold condition. In some embodiments, the controller can determine whether a rate of change of the neural data satisfies a threshold condition. In some embodiments, at block 912, the controller can determine whether a change in the rate of change of the neural data satisfies a threshold condition. In some embodiments, the controller can determine whether the neural data is changing in a certain direction (e.g., positive change or negative change). In someembodiments, at block 912, the controller may make a determination based on any combination of the foregoing examples.

[0314] At block 912, threshold condition(s) may be fixed or programmable. In some embodiments, the biomarker threshold condition(s) may be based at least on part on a history of sensor data such as relating to average of historical sensor data.

[0315] The controller, at block 912, may be configured to implement and consume one or more closed-loop feedback algorithms. In some embodiments, the controller may monitor neural signals and adjust one or more signal parameters using a closed-loop feedback system, including but not limited to: a fuzzy logic control system; a proportional-integral-drive (PID) control system; a linear control system; and / or any other available type of closed-loop control system.Additional Example Implementations and Details

[0316] Although this disclosure has been described in the context of certain aspects and examples, it will be understood by those skilled in the art that the disclosure extends beyond the specifically disclosed aspects to other alternative aspects and / or uses and obvious modifications and equivalents thereof. In addition, while several variations of the aspects of the disclosure have been shown and described in detail, other modifications, which are within the scope of this disclosure, will be readily apparent to those of skill in the art. It is also contemplated that various combinations or sub-combinations of the specific features and aspects of the aspects may be made and still fall within the scope of the disclosure. For example, features described above in connection with one aspect can be used with a different aspect described herein and the combination still fall within the scope of the disclosure. It should be understood that various features and aspects of the disclosed aspects can be combined with, or substituted for, one another in order to form varying modes of the aspects of the disclosure. Thus, it is intended that the scope of the disclosure herein should not be limited by the particular aspects described above. Accordingly, unless otherwise stated, or unless clearly incompatible, each aspect of this invention may comprise, additional to its essential features described herein, one or more features as described herein from each other aspect of the invention disclosed herein.

[0317] It should be emphasized that many variations and modifications may be made to the herein-described implementations, the elements of which are to be understood as beingamong other acceptable examples. All such modifications and variations are intended to be included herein within the scope of this disclosure. The section headings used herein are merely provided to enhance readability and are not intended to limit the scope of the implementations disclosed in a particular section to the features or elements disclosed in that section. The foregoing description details certain implementations. It will be appreciated, however, that no matter how detailed the foregoing appears in text, the systems and methods can be practiced in many ways. As is also stated herein, it should be noted that the use of particular terminology when describing certain features or aspects of the systems and methods should not be taken to imply that the terminology is being re-defined herein to be restricted to including any specific characteristics of the features or aspects of the systems and methods with which that terminology is associated.

[0318] The various features and processes described herein may be used independently of one another, or may be combined in various ways. Features, materials, characteristics, or groups described in conjunction with a particular aspect, embodiment, implementation, example, and / or the like, are to be understood to be applicable to any other aspect, embodiment, implementation, example, and / or the like, described in this section or elsewhere in this specification unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The protection is not restricted to the details of any foregoing aspects. The protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0319] Furthermore, certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can, in some cases, be excised from the combination, and the combination may be claimed as a sub-combination orvariation of a sub-combination. All possible combinations and sub-combinations are intended to fall within the scope of this disclosure.

[0320] Moreover, while operations may be depicted in the drawings or described in the specification in a particular order, such operations need not be performed in the particular order shown or in sequential order, or that all operations be performed, to achieve desirable results. For example, in some embodiments, certain acts, events, functions, operations, or method or process blocks of any of the algorithms described herein can be performed in a different sequence than that specifically disclosed, can be added, merged, rearranged, or left out altogether (for example, not all described acts or events are necessary for the practice of the algorithms). Moreover, in certain implementations, acts, events, functions, operations, or method or process blocks can be performed concurrently, for example, through multi-threaded processing, interrupt processing, or multiple processors or processor cores or on other parallel architectures, rather than sequentially. In addition, different tasks or processes can be performed by different machines and / or computing systems that can function together. Other operations that are not depicted or described can be incorporated in the example methods and processes. For example, one or more additional operations can be performed before, after, simultaneously, or between any of the described operations. Furthermore, the features and attributes of the specific aspects disclosed above may be combined in different ways to form additional aspects, all of which fall within the scope of the present disclosure. Also, the separation of various system components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described components and systems can generally be integrated together in a single product or packaged into multiple products.

[0321] Any process, descriptions, elements, or blocks in the flow diagrams described herein and / or depicted in the attached figures should be understood as potentially representing modules, segments, or portions of code which include one or more executable instructions for implementing specific logical functions or steps in the process. Alternate implementations are included within the scope of the implementations described herein in which elements or functions may be deleted, executed out of order from that shown or discussed, including substantially concurrently or in reverse order, depending on the functionality involved, as would be understood by those skilled in the art.

[0322] Each of the processes, methods, and algorithms described in the preceding sections may be embodied in, and fully or partially automated by, code modules executed by one or more computer systems or computer processors including computer hardware. The code modules may be stored on any type of non-transitory computer-readable medium or computer storage component, such as hard drives, solid state memory, optical disc, and / or the like. The systems and modules may also be transmitted as generated data signals (for example, as part of a carrier wave or other analog or digital propagated signal) on a variety of computer-readable transmission mediums, including wireless-based and wired / cable-based mediums, and may take a variety of forms (for example, as part of a single or multiplexed analog signal, or as multiple discrete digital packets or frames). The processes and algorithms may be implemented partially or wholly in application-specific circuitry. The results of the disclosed processes and process steps may be stored, persistently or otherwise, in any type of non-transitory computer storage such as, for example, volatile or non-volatile storage.

[0323] The various illustrative logical blocks, modules, and algorithm elements described in connection with the implementations disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, and elements have been described herein generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.

[0324] The various illustrative logical blocks and modules described in connection with the implementations disclosed herein can be implemented or performed by a machine, such as a general purpose processor, a digital signal processor (“DSP”), an application specific integrated circuit (“ASIC”), a field programmable gate array (“FPGA”) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A processor can include electrical circuitry configured to process computer-executable instructions. In anotherimplementation, a processor includes an FPGA or other programmable devices that performs logic operations without processing computer-executable instructions. A processor can also be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Although described herein primarily with respect to digital technology, a processor may also include primarily analog components. For example, some, or all, of the signal processing algorithms described herein may be implemented in analog circuitry or mixed analog and digital circuitry. A computing environment can include any type of computer system, including, but not limited to, a computer system based on a microprocessor, a mainframe computer, a digital signal processor, a portable computing device, a device controller, or a computational engine within an appliance, to name a few.

[0325] Where the computer system includes multiple computing devices, these devices may, but need not, be co-located. The results of the disclosed methods and tasks may be persistently stored by transforming physical storage devices, such as solid-state memory chips and / or magnetic disks, into a different state. In some embodiments, the computer system may be a cloud-based computing system whose processing resources are shared by multiple distinct business entities or other users.

[0326] The elements of a method, process, or algorithm described in connection with the implementations disclosed herein can be embodied directly in hardware, in a software module stored in one or more memory devices and executed by one or more processors, or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD- ROM, or any other form of non-transitory computer-readable storage medium, media, or physical computer storage known in the art. An example storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. The storage medium can be volatile or nonvolatile. The processor and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. In the alternative, the processor and the storage medium can reside as discrete components in a user terminal.

[0327] For purposes of this disclosure, certain aspects, advantages, and novel features are described herein. Not necessarily all such advantages may be achieved in accordance with any particular aspect described herein. Thus, for example, those skilled in the art will recognize that certain aspects may be configured to operate in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein.

[0328] As used herein, “system,” “instrument,” “apparatus,” and “device” generally encompass both the hardware (for example, mechanical and electronic) and, in some embodiments, associated software (for example, specialized computer programs for graphics control) components.

[0329] Conditional language, such as, among others, “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain implementations include, while other implementations do not include, certain features, elements and / or steps. Thus, such conditional language is not generally intended to imply that features, elements and / or steps are in any way required for one or more implementations or that one or more implementations necessarily include logic for deciding, with or without user input or prompting, whether these features, elements and / or steps are included or are to be performed in any particular implementation.

[0330] Conjunctive language such as the phrase “at least one of X, Y, and Z,” or disjunctive language such as the phrase “at least one of X, Y, or Z,” unless specifically stated otherwise, is to be understood with the context as used in general to convey that an item, term, and / or the like may be either X, Y, or Z, or any combination thereof (for example, X, Y, and / or Z). For example, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Thus, such conjunctive or disjunctive language is not generally intended to imply that certain implementations require at least one of X, at least one of Y, and at least one of Z to each be present.

[0331] Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially” as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms “approximately,” “about,” “generally,” and“ substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount. As another example, in certain implementations, the terms “generally parallel” and “substantially parallel” refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 10 degrees, 5 degrees, 3 degrees, or 1 degree. As another example, in certain implementations, the terms “generally perpendicular” and “substantially perpendicular” refer to a value, amount, or characteristic that departs from exactly perpendicular by less than or equal to 10 degrees, 5 degrees, 3 degrees, or 1 degree.

[0332] The term “substantially” when used in conjunction with the term “real-time” forms a phrase that will be readily understood by a person of ordinary skill in the art. For example, it is readily understood that such language will include speeds in which no or little delay or waiting is discernible, or where such delay is sufficiently short so as not to be disruptive, irritating, or otherwise vexing to a user.

[0333] The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “approximately,” “about,” and “substantially” as used herein include the recited numbers (e.g., about 10% = 10%), and also represent an amount close to the stated amount that still performs a desired function or achieves a desired result. For example, the terms “approximately,” “about,” and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount.

[0334] Unless otherwise explicitly stated, articles such as “a” or “an” should generally be interpreted to include one or more described items. Accordingly, phrases such as “a device configured to” are intended to include one or more recited devices. Such one or more recited devices can also be collectively configured to carry out the stated recitations. For example, “a processor configured to carry out recitations A, B and C” can include a first processor configured to carry out recitation A working in conjunction with a second processor configured to carry out recitations B and C.

[0335] The term “comprising” as used herein should be given an inclusive rather than exclusive interpretation. For example, a general -purpose computer comprising one or moreprocessors should not be interpreted as excluding other computer components, and may possibly include such components as memory, input / output devices, and / or network interfaces, among others.

[0336] While the above detailed description has shown, described, and pointed out novel features as applied to various implementations, it may be understood that various omissions, substitutions, and changes in the form and details of the devices or processes illustrated may be made without departing from the spirit of the disclosure. As may be recognized, certain implementations of the inventions described herein may be embodied within a form that does not provide all of the features and benefits set forth herein, as some features may be used or practiced separately from others. The scope of the present disclosure is not intended to be limited by the specific disclosures of preferred aspects in this section or elsewhere in this specification. The scope of the present disclosure is indicated by the appended claims rather than by the foregoing description, and may be indicated by claims presented in the future. The language of the claims is to be interpreted broadly based on the language employed in the claims and not limited to the examples described in the present specification or during the prosecution of the application, which examples are to be construed as nonexclusive. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.Example Aspects

[0337] Examples of implementations of the present disclosure can be described in view of the following example aspects or aspects. The features recited in the below example implementations can be combined with additional features disclosed herein. Furthermore, additional inventive combinations of features are disclosed herein, which are not specifically recited in the below example implementations, and which do not include the same features as the specific implementations below. For sake of brevity, the below example implementations do not identify every inventive aspect of this disclosure. The below example implementations are not intended to identify key features or essential features of any subject matter described herein. Any of the example aspects below, or any features of the example aspects, can be combined with any one or more other example aspects, or features of the example aspects or other features of the present disclosure.

[0338] Aspect 1. A system for electrically modulating target electrically excitable tissue, the target electrically excitable tissue comprising an on-target neural component associated with a clinically beneficial therapy and an off-target neural component associated with a clinically undesirable side effect, comprising: a signal generator configured to be in electrical communication with at least one implantable electrode; and a controller in electrical communication with the signal generator, wherein the controller is configured to: cause the signal generator to generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and cause the signal generator to generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electrical signal is configured to activate an on-target neural component of a second target electrically excitable tissue.

[0339] Aspect 2. The system of Aspect 1, wherein the first target electrically excitable tissue comprises the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

[0340] Aspect 3. The system of Aspect 1, wherein the first target electrically excitable tissue is outside of the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

[0341] Aspect 4. The system of Aspect 3, wherein the first target electrically excitable tissue comprises at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

[0342] Aspect 5. The system of Aspect 1, wherein the first electrical signal is configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

[0343] Aspect 6. The system of Aspect 1, wherein the first electrical signal is configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

[0344] Aspect 7. The system of Aspect 1, wherein the implantable electrode is configured as a vagus nerve stimulation cuff electrode.

[0345] Aspect 8. The system of Aspect 1, wherein the implantable electrode is arranged on an implantable paddle lead.

[0346] Aspect 9. The system of Aspect 1, wherein the first electrical signal has a frequency of 0.01 Hz to 10 Hz.

[0347] Aspect 10. The system of Aspect 1, wherein the first electrical signal has a current magnitude of 1 mA to 6 mA.

[0348] Aspect 11. The system of Aspect 1, wherein the first electrical signal has a pulse width of 0.1 seconds to 100 seconds.

[0349] Aspect 12. The system of Aspect 1, wherein the second electrical signal has a frequency of 1 Hz to 150 Hz.

[0350] Aspect 13. The system of Aspect 1, wherein the second electrical signal has a current magnitude of 1 mA to 10 mA.

[0351] Aspect 14. The system of Aspect 1, wherein the second electrical signal has a pulse width of 90 ps to 1,000 ps.

[0352] Aspect 15. The system of Aspect 1, wherein the first electrical signal is configured to activate the on-target neural component of the second target electrically excitable tissue

[0353] Aspect 16. The system of Aspect 15, wherein the first electrical signal has a rise time or fall time of 0.1 seconds to 0.7 seconds.

[0354] Aspect 17. The system of Aspect 1, wherein the second electrical signal has a greater slew rate than the first electrical signal.

[0355] Aspect 18. The system of Aspect 17, wherein the second electrical signal has a shorter rise time or shorter fall time than the first electrical signal.

[0356] Aspect 19. The system of Aspect 18, wherein the second electrical signal has a rise time or fall time of 0.1 ps to 15 ps.

[0357] Aspect 20. The system of Aspect 1, wherein the off-target neural component comprises a large-diameter myelinated fiber.

[0358] Aspect 21. The system of Aspect 20, wherein the large-diameter myelinated fiber comprises one or more of: an A-alpha fiber and an A-beta fiber.

[0359] Aspect 22. The system of Aspect 1, wherein the on-target neural component comprises a small-diameter myelinated fiber.

[0360] Aspect 23. The system of Aspect 22, wherein the small-diameter myelinated fiber comprises one or more of: an A-delta fiber and a B fiber.

[0361] Aspect 24. The system of Aspect 1, wherein the on-target neural component comprises a non-myelinated fiber.

[0362] Aspect 25. The system of Aspect 1, wherein the controller is further configured to cause the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

[0363] Aspect 26. The system of Aspect 1, wherein the controller is further configured to measure a level of neural inhibition of the off-target neural component using a closed-loop control system.

[0364] Aspect 27. The system of Aspect 26, wherein the controller is further configured to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.

[0365] Aspect 28. A method for electrically modulating electrically excitable tissue, the method comprising: providing a signal generator, wherein the signal generator configured to be in electrical communication with at least one implantable electrode; and signaling the signal generator to: generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electrical signal is configured to activate an on-target neural component of a second target electrically excitable tissue.

[0366] Aspect 29. The method of Aspect 28, wherein the first target electrically excitable tissue comprises the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

[0367] Aspect 30. The method of Aspect 28, wherein the first target electrically excitable tissue is outside of the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

[0368] Aspect 31. The method of Aspect 30, wherein the first target electrically excitable tissue comprises at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

[0369] Aspect 32. The method of Aspect 28, wherein the first electrical signal is configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

[0370] Aspect 33. The method of Aspect 28, wherein the first electrical signal is configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

[0371] Aspect 34. The method of Aspect 28, wherein the implantable electrode is configured as a vagus nerve stimulation cuff electrode.

[0372] Aspect 35. The method of Aspect 28, wherein the implantable electrode is arranged on an implantable paddle lead.

[0373] Aspect 36. The method of Aspect 28, wherein the first electrical signal has a frequency of 0.01 Hz to 10 Hz.

[0374] Aspect 37. The method of Aspect 28, wherein the first electrical signal has a current magnitude of 1 mA to 6 mA.

[0375] Aspect 38. The method of Aspect 28, wherein the first electrical signal has a pulse width of 0.1 seconds to 100 seconds.

[0376] Aspect 39. The method of Aspect 28, wherein the second electrical signal has a frequency of 1 Hz to 150 Hz.

[0377] Aspect 40. The method of Aspect 28, wherein the second electrical signal has a current magnitude of 1 mA to 10 mA.

[0378] Aspect 41. The method of Aspect 28, wherein the second electrical signal has a pulse width of 90 ps to 1,000 ps.

[0379] Aspect 42. The method of Aspect 28, wherein the first electrical signal is configured to activate the on-target neural component of the second target electrically excitable tissue.

[0380] Aspect 43. The method of Aspect 42, wherein the first electrical signal has a rise time or fall time of 0.1 seconds to 0.7 seconds.

[0381] Aspect 44. The method of Aspect 28, wherein the second electrical signal has a greater slew rate than the first electrical signal.

[0382] Aspect 45. The method of Aspect 44, wherein the second electrical signal has a shorter rise time or fall time than the first electrical signal.

[0383] Aspect 46. The method of Aspect 45, wherein the second electrical signal has a rise time or fall time of 0.1 ps to 15 ps.

[0384] Aspect 47. The method of Aspect 28, wherein the off-target neural component comprises a large-diameter myelinated fiber.

[0385] Aspect 48. The method of Aspect 47, wherein the large-diameter myelinated fiber includes one or more of: an A-alpha fiber and an A-beta fiber.

[0386] Aspect 49. The method of Aspect 28, wherein the on-target neural component comprises a small-diameter myelinated fiber.

[0387] Aspect 50. The method of Aspect 49, wherein the small-diameter myelinated fiber comprises one or more of: an A-delta fiber and a B fiber.

[0388] Aspect 51. The method of Aspect 28, wherein the on-target neural component comprises a non-myelinated fiber.

[0389] Aspect 52. The method of Aspect 28, the method further comprising: signaling the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

[0390] Aspect 53. The method of Aspect 28, the method further comprising: measuring a level of neural inhibition of the off-target neural component using a closed-loop control system.

[0391] Aspect 54. The method of Aspect 53, the method further comprising: signaling the signal generator to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.

Claims

WHAT IS CLAIMED IS:

1. A system for electrically modulating target electrically excitable tissue, the target electrically excitable tissue comprising an on-target neural component associated with a clinically beneficial therapy and an off-target neural component associated with a clinically undesirable side effect, comprising: a signal generator configured to be in electrical communication with at least one implantable electrode; and a controller in electrical communication with the signal generator, wherein the controller is configured to: cause the signal generator to generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and cause the signal generator to generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electrical signal is configured to activate an on-target neural component of a second target electrically excitable tissue.

2. The system of Claim 1, wherein the first target electrically excitable tissue comprises the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

3. The system of Claim 1, wherein the first target electrically excitable tissue is outside of the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

4. The system of Claim 3, wherein the first target electrically excitable tissue comprises at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

5. The system of Claim 1, wherein the first electrical signal is configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

6. The system of Claim 1, wherein the first electrical signal is configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

7. The system of Claim 1 , wherein the implantable electrode is configured as a vagus nerve stimulation cuff electrode.

8. The system of Claim 1, wherein the implantable electrode is arranged on an implantable paddle lead.

9. The system of Claim 1, wherein the first electrical signal has a frequency of 0.01 Hz to 10 Hz.

10. The system of Claim 1, wherein the first electrical signal has a current magnitude of 1 mA to 6 mA.

11. The system of Claim 1, wherein the first electrical signal has a pulse width of 0.1 seconds to 100 seconds.

12. The system of Claim 1, wherein the second electrical signal has a frequency of 1 Hz to 150 Hz.

13. The system of Claim 1 , wherein the second electrical signal has a current magnitude of 1 mA to 10 mA.

14. The system of Claim 1, wherein the second electrical signal has a pulse width of 90 ps to 1,000 ps.

15. The system of Claim 1, wherein the first electrical signal is configured to activate the on-target neural component of the second target electrically excitable tissue16. The system of Claim 15, wherein the first electrical signal has a rise time or fall time of 0.1 seconds to 0.7 seconds.

17. The system of Claim 1, wherein the second electrical signal has a greater slew rate than the first electrical signal.

18. The system of Claim 17, wherein the second electrical signal has a shorter rise time or shorter fall time than the first electrical signal.

19. The system of Claim 18, wherein the second electrical signal has a rise time or fall time of 0.1 ps to 15 ps.

20. The system of Claim 1, wherein the off-target neural component comprises a large- diameter myelinated fiber.

21. The system of Claim 20, wherein the large-diameter myelinated fiber comprises one or more of: an A-alpha fiber and an A-beta fiber.

22. The system of Claim 1, wherein the on-target neural component comprises a smalldiameter myelinated fiber.

23. The system of Claim 22, wherein the small-diameter myelinated fiber comprises one or more of an A-delta fiber and a B fiber.

24. The system of Claim 1, wherein the on-target neural component comprises a nonmyelinated fiber.

25. The system of Claim 1, wherein the controller is further configured to cause the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

26. The system of Claim 1, wherein the controller is further configured to measure a level of neural inhibition of the off-target neural component using a closed-loop control system.

27. The system of Claim 26, wherein the controller is further configured to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.

28. A method for electrically modulating electrically excitable tissue, the method comprising: providing a signal generator, wherein the signal generator configured to be in electrical communication with at least one implantable electrode; and signaling the signal generator to: generate a first electrical signal configured to cause partial or full block of action potential conduction and / or initiation in an off-target neural component of a first target electrically excitable tissue; and generate a second electrical signal having a shorter pulse width than the first electrical signal, wherein the second electrical signal is configured to activate an on-target neural component of a second target electrically excitable tissue.

29. The method of Claim 28, wherein the first target electrically excitable tissue comprises the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.-HO-30. The method of Claim 28, wherein the first target electrically excitable tissue is outside of the vagus nerve, and wherein the second target electrically excitable tissue comprises the vagus nerve.

31. The method of Claim 30, wherein the first target electrically excitable tissue comprises at least one of: the superior laryngeal nerve, the left recurrent laryngeal nerve, and the right recurrent laryngeal nerve.

32. The method of Claim 28, wherein the first electrical signal is configured to not cause partial or full block of action potential conduction and / or initiation in the on-target neural component of the target electrically excitable tissue.

33. The method of Claim 28, wherein the first electrical signal is configured to cause partial or full block of only stimulation-evoked action potential initiation and / or conduction of the off-target neural component.

34. The method of Claim 28, wherein the implantable electrode is configured as a vagus nerve stimulation cuff electrode.

35. The method of Claim 28, wherein the implantable electrode is arranged on an implantable paddle lead.

36. The method of Claim 28, wherein the first electrical signal has a frequency of 0.01 Hz to 10 Hz.

37. The method of Claim 28, wherein the first electrical signal has a current magnitude of 1 mA to 6 mA.

38. The method of Claim 28, wherein the first electrical signal has a pulse width of 0.1 seconds to 100 seconds.

39. The method of Claim 28, wherein the second electrical signal has a frequency of 1 Hz to 150 Hz.

40. The method of Claim 28, wherein the second electrical signal has a current magnitude of 1 mA to 10 mA.

41. The method of Claim 28, wherein the second electrical signal has a pulse width of 90 ps to 1,000 ps.

42. The method of Claim 28, wherein the first electrical signal is configured to activate the on-target neural component of the second target electrically excitable tissue.

43. The method of Claim 42, wherein the first electrical signal has a rise time or fall time of 0.1 seconds to 0.7 seconds.

44. The method of Claim 28, wherein the second electrical signal has a greater slew rate than the first electrical signal.

45. The method of Claim 44, wherein the second electrical signal has a shorter rise time or fall time than the first electrical signal.

46. The method of Claim 45, wherein the second electrical signal has a rise time or fall time of 0.1 ps to 15 ps.

47. The method of Claim 28, wherein the off-target neural component comprises a large-diameter myelinated fiber.

48. The method of Claim 47, wherein the large-diameter myelinated fiber includes one or more of an A-alpha fiber and an A-beta fiber.

49. The method of Claim 28, wherein the on-target neural component comprises a small-diameter myelinated fiber.

50. The method of Claim 49, wherein the small-diameter myelinated fiber comprises one or more of: an A-delta fiber and a B fiber.

51. The method of Claim 28, wherein the on-target neural component comprises a nonmyelinated fiber.

52. The method of Claim 28, the method further comprising: signaling the signal generator to generate and deliver the second electrical signal while also generating and delivering the first electrical signal.

53. The method of Claim 28, the method further comprising: measuring a level of neural inhibition of the off-target neural component using a closed-loop control system.

54. The method of Claim 53, the method further comprising: signaling the signal generator to adjust a signal parameter of the first electrical signal based at least in part on the measured level of neural inhibition of the off-target neural component.

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