Ramped therapeutic signals for modulating inhibitory interneurons, and associated systems and methods

Description

TECHNICAL FIELD

The present technology is directed generally to ramped therapeutic signals for modulating inhibitory interneurons, and associated systems and methods.

BACKGROUND

Neurological stimulators have been developed to treat pain, movement disorders, functional disorders, spasticity, cancer, cardiac disorders, and various other medical conditions. Implantable neurological stimulation systems generally have an implantable pulse generator and one or more leads that deliver electrical pulses to neurological tissue or muscle tissue. For example, several neurological stimulation systems for spinal cord stimulation (SCS) have cylindrical or paddle leads that include a lead body with a circular or rectangular/triangular/trapezoidal cross-sectional shape and multiple conductive rings or materials spaced apart from each other at the distal end of the lead body. The conductive rings and/or materials operate as individual electrodes or contacts, and the SCS leads are typically implanted either surgically or externally through a needle inserted into the epidural space, often with the assistance of a stylet.

Once implanted, the pulse generator applies electrical pulses to the electrodes, which in turn modify the function of or information transmitted by the patient's nervous system, such as by altering the patient's responsiveness to sensory stimuli and/or altering the patient's motor circuit and/or internal neural circuit output. The electrical pulses can generate sensations that mask or otherwise alter the patient's sensation of pain. For example, in many cases, patients report a tingling or paresthesia that is perceived as more pleasant and/or less uncomfortable than the underlying pain sensation. In other cases, the patients can receive pain relief without paresthesia or other sensations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a partially schematic illustration of an implantable spinal cord modulation system positioned at a patient's spine to deliver therapeutic signals in accordance with some embodiments of the present technology.

FIG. 1B is a partially schematic, cross-sectional illustration of a patient's spine, illustrating representative locations for implanted lead bodies in accordance with some embodiments of the present technology.

FIG. 2B is a series of charts illustrating certain recordings derived from the arrangement illustrated in FIG. 2A in accordance with some embodiments of the present technology.

FIG. 2C is a partially schematic illustration of a rat's foot illustrating a stimulation technique and certain neuronal responses thereto in accordance with the present technology.

FIG. 3A is a schematic illustration of neural circuits in the patient's spinal cord in accordance with some embodiments of the present technology.

FIG. 3B includes two charts illustrating mean firing rates of excitatory interneurons and inhibitory interneurons in accordance with the present technology.

FIG. 4 is a chart illustrating activation of inhibitory interneurons and excitatory interneurons relative to therapeutic signals having various percentages of a patient's motor threshold in accordance with some embodiments of the present technology.

FIG. 5A is an illustration of pulses and telemetry windows in a therapeutic signal in accordance with some embodiments of the present technology.

FIG. 5B includes two charts illustrating firing patterns of inhibitory interneurons and excitatory interneurons in response to the therapeutic signal illustrated in FIG. 5A in accordance with some embodiments of the present technology.

FIG. 6A is an illustration of pulses and telemetry windows in another therapeutic signal, and representative firings of inhibitory interneurons and excitatory interneurons in accordance with some embodiments of the present technology.

FIG. 6B is an illustration of pulses and telemetry windows in yet another therapeutic signal, and representative firings of inhibitory interneurons and excitatory interneurons in accordance with some embodiments of the present technology.

FIG. 6C is an illustration of pulses and telemetry windows in still another therapeutic signal, and representative firings of inhibitory interneurons and excitatory interneurons in accordance with some embodiments of the present technology.

FIG. 7A is an illustration of pulses and telemetry windows in a ramped-up therapeutic signal in accordance with some embodiments of the present technology.

FIG. 7B is an illustration of pulses and telemetry windows a ramped-down therapeutic signal in accordance with some embodiments of the present technology.

FIG. 7C is an illustration of pulses and telemetry windows in a ramped-up and ramped-down therapeutic signal in accordance with some embodiments of the present technology.

FIG. 7D is an illustration of pulses and telemetry windows in a ramped-down and ramped-up therapeutic signal in accordance with some embodiments of the present technology.

FIG. 8A is a chart illustrating mean firing rates of excitatory interneurons and inhibitory interneurons in response to the therapeutic signal illustrated in FIG. 6A in accordance with embodiments of the present technology.

FIG. 8B is a chart illustrating mean firing rates of excitatory interneurons and inhibitory interneurons in response to the therapeutic signal illustrated in FIG. 6B in accordance with embodiments of the present technology.

FIG. 8C is a chart illustrating mean firing rates of excitatory interneurons and inhibitory interneurons in response to the therapeutic signal illustrated in FIG. 6C in accordance with embodiments of the present technology.

DETAILED DESCRIPTION

Definitions of selected terms are provided under heading 1.0 (“Definitions”). General aspects of the anatomical and physiological environment in which the disclosed technology operates are described below under heading 2.0 (“Introduction”). Representative treatment systems their characteristics are described under heading 3.0 (“System Characteristics”) with reference to FIGS. 1A and 1B. Representative therapeutic signals for activating inhibitory interneurons are described under heading 4.0 (“Representative Therapeutic Signals”) with reference to FIGS. 2A-8C. Representative examples are described under heading 5.0 (“Representative Examples”).

1.0 Definitions

As used herein, the terms “therapeutic signal,” “electrical therapy signal,” “electrical signal,” “therapeutic electrical stimulation,” “therapeutic modulation,” “therapeutic modulation signal,” and “TS” refer to an electrical signal having (1) a frequency of from about 1 kHz to about 100 kHz, or from about 1.2 kHz to about 100 kHz, or from about 1.5 kHz to about 100 kHz, or from about 2 kHz to about 50 kHz, or from 2 kHz to 25 kHz, or from about 3 kHz to about 20 kHz, or from about 3 kHz to about 15 kHz, or from about 5 kHz to about 15 kHz, or from about 3 kHz to about 10 kHz, or 1 kHz, 2 kHz, 3 kHz, 4 kHz, 5 kHz, 10 kHz, 15 kHz, 20 kHz, 25 kHz, 30 kHz, 40, kHz, 50 kHz, or 100 kHz; (2) an amplitude within an amplitude range of about 0.1 mA to about 20 mA, about 0.5 mA to about 10 mA, about 0.5 mA to about 7 mA, about 0.5 mA to about 5 mA, about 0.5 mA to about 4 mA, about 0.5 mA to about 2.5 mA; (3) a pulse width in a pulse width range of from about 1 microsecond to about 20 microseconds, from about 5 microseconds to about 10 microseconds, from about 1 microseconds to about 500 microseconds, from about 1 microseconds to about 400 microseconds, from about 1 microseconds to about 333 microseconds, from about 1 microseconds to about 166 microseconds, from about 25 microseconds to about 166 microseconds, from about 25 microseconds to about 100 microseconds, from about 30 microseconds to about 100 microseconds, from about 33 microseconds to about 100 microseconds, from about 50 microseconds to about 166 microseconds; and (4) a telemetry window including a 30-microsecond cathodic pulse followed by a 20-microsecond telemetry window followed by a 30-microsecond anodic pulse followed by another 20-microsecond telemetry window, unless otherwise stated, that is delivered for therapeutic purposes.

Unless otherwise stated, the term “about” refers to values within 10% of a stated value.

As used herein, and unless otherwise stated, the TS can be a “first therapeutic signal,” and “a second therapeutic signal” refers to a frequency less than 1 kHz.

As used herein, and unless otherwise noted, the terms “modulate,” “modulation,” “stimulate,” and “stimulation” refer generally to signals that have any of the foregoing effects. Accordingly, a spinal cord “stimulator” can have an inhibitory effect on certain neural populations and an excitatory effect on other neural populations.

As used herein, and unless otherwise noted, the term “pulse” refers to a electrical pulse (e.g., a mono-phasic pulse of a bi-phasic pulse pair), and the term “pulse train” refers to a plurality of pulses.

As used herein, and unless otherwise noted, the terms “telemetry window” and “off period” are used interchangeably throughout the application and refer to periods of time where the TS is not being delivered and/or to pauses within the TS itself (e.g., between pulse widths and/or pulse trains). Stimulated neurons can recover from fatigue (e.g., synaptic fatigue) during these telemetry windows and off periods.

The following terms are used interchangeably throughout the present disclosure: “electrical signal,” “therapeutic modulation signal,” “therapeutic signal,” “electrical pulse,” “signal,” therapeutic signal,” “modulation signal,” “modulation,” “neural modulation signal,” and “therapeutic electrical signal.”

2.0 Introduction

The present technology is directed generally to treating a patient's condition (e.g., pain) by delivering a therapeutic signal that activates the patient's inhibitory interneurons and associated systems and methods. In some embodiments, the therapeutic signal includes one or more pulses, each pulse having a pulse width. The therapeutic signal can include pulses having pulse widths that are generally similar or different, such as a first pulse width, a second pulse width, a third pulse width, a fourth pulse width, and so on. Each pulse can also have one or more parameters, such as an amplitude, and multiple pulses can define a signal frequency.

In some embodiments, one or more parameters can be increased (e.g, ramped-up) and/or decreased (e.g., ramped-down) from a first value (e.g., the value when the pulse was initiated) to a second value, a third value, etc. during delivery of the pulse. In other embodiments, while the therapeutic signal is being delivered, the increase or decrease occurs from one pulse to the next. For example, the first pulse can be delivered at a first parameter, the second pulse at a second parameter, the third pulse at a third parameter, the fourth pulse at a fourth parameter, and so on. The first parameter can be less than the second parameter, which is less than the third, and so on, or the first parameter can be greater than the second parameter, which is greater than the third, and so on. For example, the first pulse can be delivered at a first amplitude and, during delivery, one or more pulses can be increased to a second amplitude, which is then increased to a third amplitude, to a fourth amplitude, and so on. It is thought that increasing one or more parameters of one or more pulses (e.g., amplitudes) activates inhibitory interneurons to a greater extent than excitatory interneurons. It is also thought that by activating inhibitory interneurons and preventing activation of excitatory interneurons, transmission of a pain signal can be inhibited. Treating a patient's pain using one or more of the ramped therapeutic signals of the present technology can prevent activating excitatory interneurons, and as such, are expected to have an improved outcome compared to therapeutic signals which are not ramped-up, and those which are ramped-down (e.g., for which the first frequency is decreased to a second frequency, and so on).

Specific details of some embodiments of the present technology are described below with reference to representative therapeutic signals to provide a thorough understanding of these embodiments, but some embodiments can have other features. Several details describing structures or processes that are well-known and often associated with delivery of therapeutic signals to treat patient pain, and associated devices, but that may unnecessarily obscure some significant aspects of the disclosure, are not set forth in the following description for purposes of clarity. Moreover, although the following disclosure sets forth some embodiments of different aspects of the technology, some embodiments of the technology can have different configurations, different components, and/or different procedures than those described below. Some embodiments may eliminate particular components and/or procedures. A person of ordinary skill in the relevant art, therefore, will understand that the present technology, which includes associated devices, systems, and procedures, may include some embodiments with additional elements or steps, and/or may include some embodiments without several of the features or steps shown and described below with reference to FIGS. 1A-8C. Several aspects of overall systems in accordance with the disclosed technology are described with reference to FIGS. 1A and 1B, and features specific to leads having sidewall openings are then discussed with reference to FIGS. 2A-8C.

Unless otherwise specified, the specific embodiments discussed are not to be construed as limitations on the scope of the disclosed technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the disclosed technology, and it is understood that such equivalent embodiments are to be included herein.

It is expected that the techniques described below with reference to FIGS. 1A-8C can produce more effective, more robust, less complicated, and/or otherwise more desirable results than can existing stimulation therapies. In particular, these techniques can produce results that activate inhibitory interneurons as opposed to excitatory interneurons, and/or persist after the modulation signal ceases. These techniques can be performed by delivering modulation signals continuously or intermittently (e.g., on a schedule) to obtain a beneficial effect with respect to treating the patient's pain.

In some embodiments, therapeutic modulation signals are directed to the target location which generally includes the patient's spinal cord, e.g., the dorsal column of the patient's spinal cord. More specifically, the modulation signals can be directed to the dorsal horn, dorsal root, dorsal root ganglion, dorsal root entry zone, and/or other areas at or in close proximity to the spinal cord itself. The foregoing areas are referred to herein collectively as the “spinal cord region.” In still further embodiments, the modulation signals may be directed to other neurological structures and/or target neural populations. For example, a device that is used for applying an electrical signal to the spinal cord may be repurposed with or without modifications to administer an electrical signal to another target tissue or organ, e.g., a spinal cord region, or a cortical, sub-cortical, intra-cortical, or peripheral target. As such, any of the herein described systems, sub-systems, and/or sub-components serve as means for performing any of the herein described methods.

Without being bound by any of the following theories, or any other theories, it is expected that the therapy signals act to treat the patient's pain and/or other indications via one or both of two mechanisms: (1) by activating at least one of the patient's inhibitory interneurons, and/or (2) by preventing activation of at least one of the patient's excitatory interneurons. The presently disclosed therapy is expected to treat the patient's pain without the side effects generally associated with standard SCS therapies e.g., including but not limited to, paresthesia. Many standard SCS therapies are discussed further in U.S. Pat. No. 8,170,675, incorporated herein by reference. These and other advantages associated with embodiments of the presently disclosed technology are described further below.

3.0 System Characteristics

FIG. 1A schematically illustrates a representative patient therapy system 100 for treating a patient's pain, arranged relative to the general anatomy of the patient's spinal column 191. The system 100 can include a signal generator 101 (e.g., an implanted or implantable pulse generator), which may be implanted subcutaneously within a patient 190 and coupled to one or more signal delivery elements or devices 110. The signal delivery elements or devices 110 may be implanted within the patient 190, at or off the patient's spinal cord midline 189. The signal delivery elements 110 carry features for delivering therapy to the patient 190 after implantation. The signal generator 101 can be connected directly to the signal delivery devices 110, or it can be coupled to the signal delivery devices 110 via a signal link, e.g., a lead extension 102. In some embodiments, the signal delivery devices 110 can include one or more elongated lead(s) or lead body or bodies 111 (identified individually as a first lead 111a and a second lead 111b). As used herein, the terms “signal delivery device,” “lead,” and/or “lead body” include any of a number of suitable substrates and/or supporting members that carry electrodes/devices for providing therapy signals to the patient 190. For example, the lead or leads 111 can include one or more electrodes or electrical contacts that direct electrical signals into the patient's tissue, e.g., to provide for therapeutic relief. In some embodiments, the signal delivery elements 110 can include structures other than a lead body (e.g., a paddle) that also direct electrical signals and/or other types of signals to the patient 190, e.g., as disclosed in U.S. Patent Application Publication No. 2018/0256892, which is incorporated herein by reference in its entirety.

In some embodiments, one signal delivery device may be implanted on one side of the spinal cord midline 189, and a second signal delivery device may be implanted on the other side of the spinal cord midline 189. For example, the first and second leads 111a and 111b shown in FIG. 1A may be positioned just off the spinal cord midline 189 (e.g., about 1 mm offset) in opposing lateral directions so that the two leads 111a and 111b are spaced apart from each other by about 2 mm. In some embodiments, the lead or leads 111 may be implanted at a vertebral level ranging from, for example, about T4 to about T12. In some embodiments, one or more signal delivery devices 110 can be implanted at other vertebral levels, e.g., as disclosed in U.S. Pat. No. 9,327,121, which is incorporated herein by reference in its entirety. For example, the one or more signal delivery devices can be implanted using methods and at locations suitable for deep brain stimulation, peripheral nerve stimulation, and/or other types of direct organ stimulation involving implantable leads.

The signal generator 101 can transmit signals (e.g., electrical signals) to the signal delivery elements 110 that excite and/or suppress target nerves (e.g., sympathetic nerves). The signal generator 101 can include a machine-readable (e.g., computer-readable) or controller-readable medium containing instructions for generating and transmitting suitable therapy signals. The signal generator 101 and/or other elements of the system 100 can include one or more processor(s) 107, memory unit(s) 108, and/or input/output device(s) 112. Accordingly, the process of providing modulation signals, providing guidance information for positioning the signal delivery devices 110, establishing battery charging and/or discharging parameters, and/or executing other associated functions can be performed by computer-executable instructions contained by, on or in computer-readable media located at the pulse generator 101 and/or other system components. Further, the pulse generator 101 and/or other system components may include dedicated hardware, firmware, and/or software for executing computer-executable instructions that, when executed, perform any one or more methods, processes, and/or sub-processes described in the materials incorporated herein by reference. The dedicated hardware, firmware, and/or software also serve as “means for” performing the methods, processes, and/or sub-processes described herein. The signal generator 101 can also include multiple portions, elements, and/or subsystems (e.g., for directing signals in accordance with multiple signal delivery parameters), carried in a single housing as shown in FIG. 1A, or in multiple housings (not shown).

The signal generator 101 can also receive and respond to an input signal received from one or more sources. The input signals can direct or influence the manner in which the therapy, charging, and/or process instructions are selected, executed, updated, and/or otherwise performed. The input signals can be received from one or more sensors (e.g., an input device 112 shown schematically in FIG. 1A for purposes of illustration) that are carried by the signal generator 101 and/or distributed outside the signal generator 101 (e.g., at other patient locations) while still communicating with the signal generator 101. The sensors and/or other input devices 112 can provide inputs that depend on or reflect patient state (e.g., patient position, patient posture, and/or patient activity level), and/or inputs that are patient-independent (e.g., time). Still further details are included in U.S. Pat. No. 8,355,797, incorporated herein by reference in its entirety.

In some embodiments, the signal generator 101 and/or signal delivery devices 110 can obtain power to generate the therapy signals from an external power source 103. For example, the external power source 103 can bypass an implanted signal generator and generate a therapy signal directly at the signal delivery devices 110 (or via signal relay components). The external power source 103 can transmit power to the implanted signal generator 101 and/or directly to the signal delivery devices 110 using electromagnetic induction (e.g., RF signals). For example, the external power source 103 can include an external coil 104 that communicates with a corresponding internal coil (not shown) within the implantable signal generator 101, signal delivery devices 110, and/or a power relay component (not shown). The external power source 103 can be portable for ease of use.

In some embodiments, the signal generator 101 can obtain the power to generate therapy signals from an internal power source, in addition to or in lieu of the external power source 103. For example, the implanted signal generator 101 can include a non-rechargeable battery or a rechargeable battery to provide such power. When the internal power source includes a rechargeable battery, the external power source 103 can be used to recharge the battery. The external power source 103 can in turn be recharged from a suitable power source (e.g., conventional wall power).

During at least some procedures, an external stimulator or trial modulator 105 can be coupled to the signal delivery elements 110 during an initial procedure, prior to implanting the signal generator 101. For example, a practitioner (e.g., a physician and/or a company representative) can use the trial modulator 105 to vary the modulation parameters provided to the signal delivery elements 110 in real time and select optimal or particularly efficacious parameters. These parameters can include the location from which the electrical signals are emitted, as well as the characteristics of the electrical signals provided to the signal delivery devices 110. In some embodiments, input is collected via the external stimulator or trial modulator and can be used by the practitioner to help determine what parameters to vary. In a typical process, the practitioner uses a cable assembly 120 to temporarily connect the trial modulator 105 to the signal delivery device 110. The practitioner can test the efficacy of the signal delivery devices 110 in an initial position. The practitioner can then disconnect the cable assembly 120 (e.g., at a connector 122), reposition the signal delivery devices 110, and reapply the electrical signals. This process can be performed iteratively until the practitioner obtains the desired position for the signal delivery devices 110. Optionally, the practitioner may move the partially implanted signal delivery devices 110 without disconnecting the cable assembly 120. Furthermore, in some embodiments, the iterative process of repositioning the signal delivery devices 110 and/or varying the therapy parameters can be eliminated.

The signal generator 101, the lead extension 102, the trial modulator 105, and/or the connector 122 can each include a receiving element 109. Accordingly, the receiving elements 109 can be patient-implantable elements, or the receiving elements 109 can be integral with an external patient treatment element, device, or component (e.g., the trial modulator 105 and/or the connector 122). The receiving elements 109 can be configured to facilitate a simple coupling and decoupling procedure between the signal delivery devices 110, the lead extension 102, the pulse generator 101, the trial modulator 105, and/or the connector 122. The receiving elements 109 can be at least generally similar in structure and function to those described in U.S. Patent Application Publication No. 2011/0071593, which is incorporated by reference herein in its entirety.

After the signal delivery elements 110 are implanted, the patient 190 can receive therapy via signals generated by the trial modulator 105, generally for a limited period of time. During this time, the patient wears the cable assembly 120 and the trial modulator 105 outside the body. Assuming the trial therapy is effective or shows the promise of being effective, the practitioner then replaces the trial modulator 105 with the implanted signal generator 101, and programs the signal generator 101 with therapy programs selected based on the experience gained during the trial period. Optionally, the practitioner can also replace the signal delivery elements 110. Once the implantable signal generator 101 has been positioned within the patient 190, the therapy programs provided by the signal generator 101 can be updated remotely via a wireless physician programmer (e.g., a physician's laptop, a physician's remote or remote device, etc.) 117 and/or a wireless patient programmer 106 (e.g., a patient's laptop, patient's remote or remote device, etc.). Generally, the patient 190 has control over fewer parameters than the practitioner. For example, the capability of the patient programmer 106 may be limited to starting and/or stopping the signal generator 101 and/or adjusting the signal amplitude. The patient programmer 106 may be configured to accept pain relief input as well as other variables, such as medication use.

In some embodiments, the present technology includes receiving patient feedback, via a sensor, that is indicative of, or otherwise corresponds to, the patient's response to the signal. Feedback includes, but is not limited to, motor, sensory, and verbal feedback. In response to the patient feedback, one or more signal parameters can be adjusted, such as frequency, pulse width, amplitude, or delivery location.

FIG. 1B is a cross-sectional illustration of the spinal cord 191 and an adjacent vertebra 195 (based generally on information from Crossman and Neary, Neuroanatomy, 1995 (published by Churchill Livingstone)), along with multiple leads 111 (shown as leads 111a-111e) implanted at representative locations. For purposes of illustration, multiple leads 111 are shown in FIG. 1B implanted in a single patient. In addition, for purposes of illustration, the leads 111 are shown as elongated leads; however, the leads 111 can be paddle leads. In actual use, any given patient will likely receive fewer than all the leads 111 shown in FIG. 1B.

The spinal cord 191 is situated within a vertebral foramen 188, between a ventrally located ventral body 196 and a dorsally located transverse process 198 and spinous process 197. Arrows V and D identify the ventral and dorsal directions, respectively. The spinal cord 191 itself is located within the dura mater 199, which also surrounds portions of the nerves exiting the spinal cord 191, including the ventral roots 192, dorsal roots 193 and dorsal root ganglia 194. The dorsal roots 193 enter the spinal cord 191 at the dorsal root entry portion 187, and communicate with dorsal horn neurons located at the dorsal horn 186. In some embodiments, the first and second leads 111a and 111b are positioned just off the spinal cord midline 189 (e.g., about 1 mm offset) in opposing lateral directions so that the two leads 111a and 111b are spaced apart from each other by about 2 mm, as discussed above. In some embodiments, a lead or pairs of leads 111 can be positioned at other locations, e.g., toward the outer edge of the dorsal root entry portion 187 as shown by a third lead 111c, or at the dorsal root ganglia 194, as shown by a fourth lead 111d, or approximately at the spinal cord midline 189, as shown by a fifth lead 111e.

Several aspects of the technology are embodied in computing devices, e.g., programmed/programmable pulse generators, controllers, and/or other devices. The computing devices on/in which the described technology can be implemented may include one or more central processing units, memory, input devices (e.g., input ports), output devices (e.g., display devices), storage devices, and network devices (e.g., network interfaces). The memory and storage devices are computer-readable media that may store instructions that implement the technology. In some embodiments, the computer-readable media are tangible media. In some embodiments, the data structures and message structures may be stored or transmitted via an intangible data transmission medium, such as a signal on a communications link. Various suitable communications links may be used, including but not limited to a local area network and/or a wide-area network.

In some embodiments, it is important that the signal delivery device 110 and, in particular, the therapy or electrical contacts of the device, be placed at or proximate to a target location that is expected (e.g., by a practitioner) to produce efficacious results in the patient when the device 110 is activated. Section 4.0 describes ramped therapeutic signals for activating inhibitory interneurons that can be delivered to the patient's spinal cord to treat pain.

4.0 Representative Therapeutic Signals

A. Pertinent Neuronal Physiology and/or Pathophysiology

The following discussion provides further details regarding pertinent physiology and/or pathophysiology for the technology disclosed herein. This section is intended to provide additional context regarding the disclosed technology and the cellular effects associated with neuronal stimulation. The technology disclosed herein is not limited to any particular mechanism of action, and both known and unknown mechanisms of action may be relevant to this technology, including direct effects at the cellular membrane, among others.

Conventional SCS (e.g., SCS at frequencies of 1000 Hz or less, which use paresthesia to mask patient pain), cause direct and indirect effects that ultimately result in pain relief. The direct effects include activation of the subject's dorsal column whereas the indirect effects include propagation of the orthodromic and antidromic action potential (AP), the latter of which results in inhibitory interneuron activation, and ultimately results in inhibition of wide dynamic range (pain-mediating) projection neurons. In addition, antidromic AP propagation may also activate terminal C-fibers, resulting in release of calcitonin gene-related peptide (CGRP).

One possible mechanism of action by which therapeutic signals are expected to treat pain is to reduce the excitability of wide dynamic range (WDR) neurons. It is believed that therapeutic signals can operate in a similar and/or analogous manner as pain treatment to inhibit at least a portion of the patient's sympathetic system. The effect of therapeutic modulation signals on WDR neurons is described in U.S. Pat. No. 9,833,614, previously incorporated by reference herein in its entirety. Specific design requirements and treatment parameters may include determining alternative lead placement within a patient, the type of neuron to target, the frequency of energy delivery, the pulse width, amplitude and combinations thereof, ramping one or more of the frequency of energy delivery, the pulse width, and amplitude up and/or down during delivery of the therapeutic signal, delivery of an alternative number of pulses, and/or prolonging or shortening the length of one or more telemetry windows between one or more pulses of the therapeutic signal.

i. Representative Experiments

FIG. 2A is a partially schematic illustration of a rat's spinal column illustrating an arrangement for recording neuronal responses to various types of stimulation during therapeutic stimulation. Experiments were designed to allow for systematic recording of neural responses from the rat spinal cord following stimulation with either a brush 230 or a Von Frey (VF) pin 240. The therapeutic signal was applied from the lead 111 positioned near the dorsal root entry zone. The lead 111 includes electrodes (not shown) and was placed near the dorsal root and the dorsal lamina II to generate a therapeutic electrical field having a pulse width of about 30 μs and a frequency of 1 kHz to 10 kHz. For illustration purposes, the dorsal root 210 and three lumbar vertebrae (L4 209, L5 208, and L6 205) are shown.

A data acquisition system (including Plexon to record extracellular potential and pClamp9 for whole-patch configured to record 40,000 samples per second for extracellular recording(s) and 100,000 samples per second in a whole-patch technique) was used to record the cellular responses to electrical fields having kHz magnitudes. The recording occurred at a target recording site, or more than one target recording site, located within or near the dorsal lamina II. Recordings were performed using a recording setup 220 having 16 distal recording electrodes 225. Cells were identified as single units according the action potential morphology of their firing rates, response to Von Frey (VF) stimulation and relative location of the cell. The data shown in FIG. 2B represent each of the 16 channels. These responses were sorted based on channel and compared between responses to stimulation with a brush 230 and VF pin 240.

B. Inhibitory Interneurons and Excitatory Interneurons

i. Representative Experimental Data

There are at least two different types of interneurons in the dorsal horn of the spinal cord. These include the inhibitory (e.g., non-adapting) interneurons and the excitatory (e.g., adapting) interneurons. As shown in FIG. 2C, the inhibitory interneurons and the excitatory interneurons responded differently to three-zone stimulation via the pin 240. The firing pattern of inhibitory interneurons fired continuously and at a reduced pace compared to excitatory interneurons, which initially fired but ceased.

FIG. 3A is a schematic illustration of a neural circuit in the patient's spinal cord. As shown, this neural circuit includes inhibitory neurons 330, excitatory interneurons 340, projection neurons 320, and the brain 310. The projection neurons 320 consolidate the effect of the inhibitory interneurons 330 and the excitatory interneurons 340, and transmit a consolidated output to the brain 310. The firing pattern from FIG. 2C, as an example, is also shown in FIG. 3A, for reference.

FIG. 3B includes two charts which illustrate the effect of different frequencies on superficial dorsal horn neurons (e.g., those located in the outer layer, close to the skin surface) at the spinal cord. The effect is shown as the mean firing rates of excitatory interneurons (left) and inhibitory interneurons (right) in response to therapeutic stimulation at four different frequencies (1 kHz, 5 kHz, 8 kHz, and 10 kHz) and at an amplitude of either 10% or 30% of the subject's motor threshold. The mean firing rates were obtained during kHz stimulation and were normalized to the brush response firing rates shown in FIG. 2B. As shown in FIG. 3B, the inhibitory interneurons responded with high mean firing rates in response to a 10 kHz therapeutic signal delivered at 30% of the subject's motor threshold, whereas the excitatory interneurons had a minor response at these stimulation signal parameters. Otherwise, the inhibitory interneurons had lower mean firing rates compared to the excitatory interneurons at all frequencies across both motor thresholds.

FIG. 4 illustrates activation of inhibitory interneurons and excitatory interneurons in response to a 10 kHz therapeutic signal having various motor threshold levels. The activation levels were computed as firings per second (e.g., Hz, y-axis). In general, interneuron activity increased as the percentage of the subject's motor threshold increased. However, inhibitory interneurons were activated to a greater extent than excitatory interneurons. For example, when the amplitude of the 10 kHz therapeutic signal was at about 10% of the subject's perception threshold, the therapeutic signal did not activate excitatory interneurons or inhibitory interneurons. However, when the amplitude increased to about 30% of the subject's motor threshold, the therapeutic signal activated inhibitory interneurons, but not excitatory interneurons. At 60% of the subject's motor threshold, both excitatory interneurons and inhibitory interneurons increased activities. When the amplitude was increased to 90% of the subject's motor threshold, the inhibitory interneurons were activated to a greater extent than the excitatory interneurons. Clinically, optimal therapeutic outcomes were observed at about 30% of motor threshold (data not shown). Although, in the animal study, higher amplitudes were associated with a larger difference in activation between inhibitory and excitatory neurons (e.g., 60% and 90% of the subject's motor threshold). Without intending to be bound by any particular theory, it is believed that small activations (e.g., more than about 60% of the subject's motor threshold) of excitatory interneurons cancel the pain relief effect provided by activation of inhibitory neurons. Selective activation of inhibitory interneurons at relatively high amplitudes (e.g., greater than about 30% of the subject's motor threshold) without activation of excitatory interneurons may provide significant pain relief.

As shown in FIG. 5A, therapeutic signals of the present technology are not continuous, but rather, include pulse trains, e.g., a series of electrical stimulation signals each followed by a period of no signal delivery. Depending upon the embodiment, the amplitude of individual pulses can be ramped over the time period defined by the pulse width, and/or the ramping can by increasing (or decreasing) the amplitude of one pulse relative to the next pulse. The period of no signal delivery can serve as a telemetry window during which data are exchanged with the signal generator and/or other devices. In the illustrated embodiment, the therapeutic signal of FIG. 5A includes pulse trains having a duration of about 200 milliseconds (ms) followed by a telemetry window of about 15 ms to about 40 ms. In other embodiments, the pulse trains each have a duration of about 500 ms, about 450 ms, about 300 ms, about 250 ms, or about 200 ms.

FIG. 5B illustrates firing patterns of inhibitory interneurons (left) and excitatory interneurons (right) in response to step pulses at different level(s) of current injections. Without intending to be bound by any particular theory, it is thought that inhibitory interneurons integrate the input signals while excitatory interneurons are sensitive to the difference in the input signals. For example, inhibitory interneurons fire continuously during stimulation, while excitatory interneurons responded with action potentials at the beginning of stimulation.

Without intending to be bound by any particular theory, it is thought that the inhibitory (e.g., non-adapting) interneurons suppress activity of the neural circuit illustrated in FIG. 3A. This neural circuit is thought to increase a patient's pain and as such, activating the inhibitory interneurons may suppress the patient's pain. Similarly, it is thought that, when activated, excitatory interneurons may increase a patient's perception of pain. Accordingly, the therapeutic signals of the present disclosure can have one or more parameters, such as amplitude, that activate an inhibitory interneuron and/or inhibit an excitatory interneuron to treat the patient's pain. For example, it is thought that delivering pulsed therapeutic signals having a ramped amplitude (e.g., an amplitude ramped across a single pulse) affects the response (e.g., firing rates) of interneurons. As shown in FIG. 5B, the inhibitory interneurons (left) fired continuously during delivery of the therapeutic signal (e.g., during delivery of more than one pulse), whereas excitatory neurons fired during an initial portion of a pulse rather than continuously during the therapeutic signal. As such, each pulse of the therapeutic signal activates excitatory interneurons during the initial phase of each pulse (e.g., when the pulse begins).

One approach to reduce activity of the excitatory interneurons is to gradually increase one or more parameters of the therapeutic signal at the beginning of and/or throughout one or more of the pulses, such as ramping one or more of the parameters. It is thought that continuously ramping one or more parameters up during one or more of the pulses (e.g., a ramped stimulation amplitude of the therapeutic signal) can result in greater activation of inhibitory interneurons compared to excitatory interneurons. For example, a ramped therapeutic signal can result in a greater delta (e.g., difference) between activation of inhibitory interneurons and excitatory interneurons.

ii. Representative Ramped Therapeutic Signals

Therapeutic signals of the present technology can be delivered to the target location to treat the patient's pain using one or more motor thresholds. It is thought that increasing the amplitude of the therapeutic signal relative to the patient's motor threshold allows neurons further away from the target location to respond to the therapeutic signal. For example, other SCS therapeutic signals having a frequency in a frequency range of 1 kHz to 100 kHz (or similar SCS therapeutic signals) and which do not generate paresthesia, are delivered up to about 20% of the patient's perception threshold (e.g., about 10% to about 30% of the patient's perception threshold). In some embodiments, the ramped therapeutic signals of the present technology can be delivered at about 10% to about 30% of a patient's perception threshold and using one or more pulse widths having a ramped amplitude.

FIG. 6A illustrates another representative therapeutic signal of the present technology having a series of pulses (e.g., pulse trains) and telemetry windows (top). The firing rates of inhibitory interneurons (middle) and excitatory interneurons (bottom), which correspond to the illustrated pulse trains, are also shown. In response to a continuous therapeutic signal (e.g., pulse trains having pulses with unramped amplitudes), the inhibitory interneurons fired continuously whereas the excitatory interneurons fired only initially. As such, excitatory interneurons respond to the initial portion of each of the pulse trains and the transition from a telemetry window to the next pulse train may activate the excitatory interneurons.

FIG. 6B illustrates yet another therapeutic signal of the present technology having a series of pulses trains interleaved with telemetry windows (top). In contrast to FIG. 6A, the therapeutic signal of FIG. 6B is a ramped up therapeutic signal and includes pulses having amplitudes that are ramped-up (e.g., increased) over the course of the pulse train. Predicted firing rates of inhibitory interneurons (middle) and excitatory interneurons (bottom), which correspond to the illustrated ramped-up therapeutic signal, are also shown. While it is expected that the inhibitory interneurons will fire continuously in response to the continuous therapeutic signal of FIG. 6A, it is thought that the magnitude of these firing rates may be lower than those of FIG. 6A. In addition, it is thought that ramping therapeutic signals may prevent activation (e.g., firing) of excitatory interneurons. Similar to FIG. 6A, the ramped-up therapeutic signal of FIG. 6B includes telemetry windows and it is thought that ramping up a parameter (e.g., amplitude) of the therapeutic signal during over the course of multiple pulses, may prevent activation of the excitatory interneurons despite the presence of the telemetry window.

FIG. 6C illustrates still another representative therapeutic signal of the present technology having a series of pulses (pulse trains) and telemetry windows (top). In contrast to FIG. 6B, the signal of FIG. 6C includes pulses having one or more parameters (e.g., amplitude) that are ramped down (e.g., decreased) during delivery of the pulse train. Predicted firing rates of inhibitory interneurons (middle) and excitatory interneurons (bottom), which correspond to the illustrated pulses, are also shown. As illustrated in FIG. 6C, the excitatory interneurons are thought to activate in response to the initial phase of the signal (e.g., where the parameter is at a maximum value relative to the parameter during a remainder of the pulse train) but cease firing as the parameter is ramped down. While not illustrated in FIG. 6C, the inhibitory interneurons may fire at the end or near the end of the pulse train.

The ramped up and ramped down signals were described above with reference to FIGS. 6A-6C as occurring over multiple pulses, e.g. over the course of a pulse train, with individual pulse trains separated by a telemetry window. In other embodiments, the parameter can be varied over the course of a single pulse (e.g., within the duration of a single pulse width), in addition to or in lieu of ramping over the course of multiple pulses. Further examples are provided below with reference to FIGS. 7A-7D

FIG. 7A illustrates the ramped-up therapeutic signal 710 of the present technology having a series of pulses with generally similar pulse widths. As shown, the ramped-up therapeutic signal 710 has an amplitude of a first pulse that increases from a first baseline amplitude across a first portion of a first pulse width to a first maximum amplitude. The amplitude of the first pulse then decreases to a first minimum amplitude before returning to the first baseline amplitude. The amplitude of a second pulse increases from a second baseline amplitude across a second portion of a second pulse width to a second maximum amplitude. The amplitude of the second pulse then decreases to a second minimum amplitude before returning to the second baseline amplitude. This pattern can continue with a third pulse width, a fourth pulse width, a fifth pulse width, and so on (not shown).

FIG. 7B illustrates a ramped-down therapeutic signal 730 of the present technology having a series of pulses. As shown, the ramped-down therapeutic signal 730 has an amplitude of a first pulse that decreases from a first maximum amplitude across a first portion of a first pulse width to a first baseline amplitude. The amplitude of the first pulse then decreases to a first minimum amplitude before returning to the first baseline amplitude. The amplitude of a second pulse decreases from a second maximum amplitude across a second portion of a second pulse width to a second baseline amplitude. The amplitude of the second pulse then decreases to a second minimum amplitude before returning to the second baseline amplitude. This pattern can continue with a third pulse, a fourth pulse, a fifth pulse, and so on (not shown).

FIG. 7C illustrates the ramped-up and ramped-down therapeutic signal of the present technology having a series of pulses. As shown, the ramped-up and ramped-down therapeutic signal 760 has an amplitude of a first pulse that increases from a first baseline amplitude across a first portion of a first pulse width to a first maximum amplitude. The amplitude of the first pulse then decreases to the first baseline amplitude, and further to the first minimum amplitude before returning to the first baseline amplitude. The amplitude of a second pulse increases from a second baseline amplitude across a second portion of a second pulse to a second maximum amplitude. The amplitude of the second pulse then decreases to a second baseline amplitude before decreasing further to a second minimum amplitude before returning to the second baseline amplitude. This pattern can continue with a third pulse, a fourth pulse, a fifth pulse, and so on (not shown).

FIG. 7D illustrates a ramped-down and ramped-up therapeutic signal of the present technology having a series of pulses. As shown, the ramped-down and ramped-up therapeutic signal 780 has an amplitude of a first pulse that begins at a first maximum amplitude during a first portion of a first pulse width and decreases to a first baseline amplitude. The amplitude of the first pulse returns to the first baseline and continues to decrease to the first minimum amplitude before returning to the first baseline amplitude. The amplitude of a second pulse begins at a second maximum amplitude during a second portion of a second pulse width and decreases to a second baseline amplitude. The second pulse continues to decrease to a second minimum amplitude before returning to the second baseline amplitude. This pattern can continue with a third pulse, a fourth pulse, a fifth pulse, and so on (not shown).

FIG. 8A illustrates mean firing rates of inhibitory interneurons (top) and excitatory interneurons (bottom) in response to the therapeutic signal illustrated in FIG. 6A having pulses with one or more continuous (e.g., non-ramped) parameters (e.g., amplitude) and a 200-millisecond pulse train. As shown, the continuous therapeutic signal activates both inhibitory interneurons and excitatory interneurons; however, the excitatory interneurons are activated to a lesser extent than the inhibitory interneurons. The mean firing rates were computed after discharge (e.g., discharge of the neural impulse from the ganglion cell).

FIG. 8B illustrates mean firing rates of inhibitory interneurons (top) and excitatory interneurons (bottom) in response to the ramped-up therapeutic signal illustrated in FIG. 6B having pulses with one or more ramped-up parameters (e.g., amplitude) and a 200-millisecond pulse train. As shown, the ramped-up therapeutic signal activates inhibitory interneurons to a greater extent than excitatory interneurons. Similar to FIG. 8A, the mean firing rates were computed after discharge. In some embodiments, the ramped-up therapeutic signal of FIG. 8B preferentially activates inhibitory interneurons compared to excitatory interneurons, which may or may not be activated by the ramped-up therapeutic signal. For example, when the ramped-up therapeutic signal activates the excitatory interneurons, it does so to a lesser extent than the inhibitory interneurons. In some embodiments, the ramped-up therapeutic signal is delivered to a patient to treat the patient's pain for a time period extending between minutes and hours per day. In some embodiments, the ramped-up therapeutic signal is delivered to the patient at a first peak amplitude, a second peak amplitude, and a third amplitude throughout the day.

FIG. 8C illustrates mean firing rates of inhibitory interneurons (top) and excitatory interneurons (bottom) in response to the therapeutic signal illustrated in FIG. 6C having pulses with one or more ramped-down parameters (e.g., amplitude) and a 200-millisecond pulse train. As shown, the ramped-down therapeutic signal activates excitatory interneurons to a greater extent and more rapidly than inhibitory interneurons. In addition, the ramped-down therapeutic signal activates excitatory interneurons to a greater extent than the continuous therapeutic signal (e.g., FIGS. 6A and 8A) or ramped-up therapeutic signal (e.g., FIGS. 6B and 8B). However, the excitatory interneurons are largely inactive and not firing once delivery of the ramped-down therapeutic signal has ceased. Unlike the interneurons of FIGS. 8A and 8B, the interneurons of FIG. 8C did not exhibit an after-discharge and, as such, the mean firing rates were computed during stimulation after any stimulation artifacts (e.g., short-duration high-amplitude spikes) had been removed from the data set.

In some embodiments, therapeutic signals in accordance with embodiments of the present technology treat a patient's pain, and associated methods of treating the patient's pain include positioning an implantable signal delivery device proximate to a target location at or near the patient's spinal cord and delivering an electrical therapy signal having at least one parameter (e.g., amplitude) that is increased from a first value to a second value (e.g., ramped) during delivery of one or more pulses. In some embodiments, the parameter is an amplitude of one or more pulses. In some embodiments, the therapeutic signal has a frequency in a frequency range of from 1 kHz to 100 kHz, the amplitude is within an amplitude range of from 0.1 mA to 20 mA, and/or a pulse width within a pulse width range of from 3 microseconds (μs) to 500 μs (e.g., 3 μs to 100 μs).

In some embodiments, ramped therapeutic signals of the present technology include one or more pulse trains, such as a first pulse train and a second pulse train separated from the first pulse train by a telemetry window or a rest period. In some embodiments, the telemetry window has a length of time within a time range of about 15 milliseconds to about 40 milliseconds. In addition, the parameters described herein can be ramped over a pulse train having a time period of from 5 milliseconds to 1000 milliseconds. In some embodiments, the ramped therapeutic signals of the present technology can be delivered to a target location, such as the patient's spinal cord (e.g., along the patient's dorsal column and superior to the patient's sacral region). In some embodiments, the signal delivery device is implanted in the patient's epidural space proximate to the target location.

In some embodiments, the methods described herein include monitoring the patient's pain, and in response to results obtained from monitoring the patient's pain, adjusting at least one signal delivery parameter in accordance with which the electrical signal is applied to the target location.

While embodiments of the present technology may create some effect on normal motor and/or sensory signals, the effect is below a level that the patient can reliably detect intrinsically, e.g., without the aid of external assistance via instruments or other devices. Accordingly, the patient's levels of motor signaling and other sensory signaling (other than signaling associated with pain) can be maintained at pre-treatment levels. For example, the patient can experience a significant reduction in pain largely independent of the patient's movement and/or position. In particular, the patient can assume a variety of positions, consume various amounts of food and liquid, and/or undertake a variety of movements associated with activities of daily living and/or other activities, without the need to adjust the parameters in accordance with which the therapy is applied to the patient (e.g., the signal amplitude). This result can greatly simplify the patient's life and reduce the effort required by the patient to undergo pain treatment (or treatment for corresponding symptoms) while engaging in a variety of activities. This result can also provide an improved lifestyle for patients who experience symptoms associated with pain during sleep.

In some embodiments, patients can choose from a number of signal delivery programs (e.g., two, three, four, five, or six), each with a different amplitude and/or other signal delivery parameter(s), to treat the patient's pain. In some embodiments, the patient activates one program before sleeping and another after waking, or the patient activates one program before sleeping, a second program after waking, and a third program before engaging in particular activities that would trigger, enhance, or otherwise exacerbate the patient's pain. This reduced set of patient options can greatly simplify the patient's ability to easily manage pain, without reducing (and, in fact, increasing) the circumstances under which the therapy effectively addresses the patient's pain. In some embodiments that include multiple programs, the patient's workload can be further reduced by automatically detecting a change in patient circumstance, and automatically identifying and delivering the appropriate therapy regimen. Additional details of such techniques and associated systems are disclosed in U.S. Pat. No. 8,355,797, incorporated herein by reference.

In some embodiments, electrical stimulation may be administered on a pre-determined schedule or on an as-needed basis. Administration may continue for a pre-determined amount of time, or it may continue indefinitely until a specific therapeutic benchmark is reached, e.g., until an acceptable reduction in one or more symptoms is achieved. In some embodiments, electrical stimulation may be administered one or more times per day, one or more times per week, once a week, once a month, or once every several months. Because electrical stimulation is thought to improve the patient's pain over time with repeated use of TS therapy, the patient is expected to need less frequent TS therapy. In some embodiments, the TS therapy can be delivered when the patient's pain recurs or increases in severity. Administration frequency may also change over the course of treatment. For example, a patient may receive less frequent administrations over the course of treatment as certain therapeutic benchmarks are met. The duration of each administration (e.g., the actual time during which a subject is receiving electrical stimulation) may remain constant throughout the course of treatment, or it may vary depending on factors such as patient health, internal pathophysiological measures, or symptom severity. In some embodiments, the duration of each administration may range from 1 to 4 hours, 4 to 12 hours, 12 to 24 hours, 1 day to 4 days, or 4 days or greater.

In some embodiments, therapeutic electrical stimulation to treat a patient's pain is performed with at least a portion of the therapy signal at amplitudes within amplitude ranges of: about 0.1 mA to about 20 mA; about 0.5 mA to about 10 mA; about 0.5 mA to about 7 mA; about 0.5 mA to about 5 mA; about 0.5 mA to about 4 mA; about 0.5 mA to about 2.5 mA; and in some embodiments, surprisingly effective results have been found when treating certain medical conditions with amplitudes below 7 mA.

In some embodiments, therapeutic electrical stimulation to treat a patient's pain is performed with at least a portion of the therapy signal having a pulse width in a pulse width range of from about 1 microseconds to about 500 microseconds; about 1 microsecond to about 400 microseconds; about 1 microsecond to about 333 microseconds; from about 1 microsecond to about 166 microseconds; from about 25 microseconds to about 166 microseconds; from about 25 microseconds to about 100 microseconds; from about 30 microseconds to about 100 microseconds (e.g., less than 100 microseconds); from about 33 microseconds to about 100 microseconds; from about 50 microseconds to about 166 microseconds; and in some embodiments, surprisingly effective results have been found when treating certain medical conditions with pulse widths from about 25 microseconds to about 100 microseconds; and from about 30 microseconds to about 40 microseconds.

In some embodiments, the therapeutic modulation signal may be delivered to a patient having pain at a frequency in a frequency range of 1 kHz to 100 kHz, a pulse width in a pulse width range of 1 microseconds to 333 microseconds, and an amplitude in an amplitude range of 0.1 mA to 20 mA in some embodiments in accordance with the present technology. In addition, the therapy signal can be applied at a duty cycle of 5% to 75%, and can be applied to locations within a patient's spinal cord region to treat the patient's pain.

In some embodiments, therapeutic electrical stimulation to treat a patient's pain is performed with at least a portion of the therapy signal having a telemetry window including a 30-microsecond cathodic pulse followed by a 20-microsecond telemetry window followed by a 30-microsecond anodic pulse followed by another 20-microsecond telemetry window.

Patients can receive multiple signals in accordance with some embodiments, such as two or more signals, each with different signal delivery parameters. For example, the signals can be interleaved with each other, such as 5 kHz pulses interleaved with 10 kHz pulses. In some embodiments, patients can receive sequential “packets” of pulses at different frequencies, with each packet having a duration of less than one second, several seconds, several minutes, or longer depending on the particular patient and indication.

Aspects of the therapy provided to the patient may be varied while still obtaining beneficial results. For example, the location of the lead body (and, in particular, the lead body electrodes or contacts) can be varied throughout and/or across the target location(s) described above, such as target locations proximate to or at various vertebral locations within the patient's spine, and/or other organs, tissues, and/or neurological structures. Other characteristics of the applied signal can also be varied. In some embodiments, the amplitude of the applied signal can be ramped up and/or down and/or the amplitude can be increased or set at an initial level to establish a therapeutic effect, and then reduced to a lower level to save power without forsaking efficacy, as is disclosed in U.S. Patent Publication No. 2009/0204173, which is incorporated herein by reference. The signal amplitude may refer to the electrical current level, e.g., for current-controlled systems, or to the electrical voltage level, e.g., for voltage-controlled systems. The specific values selected for the foregoing parameters may vary from patient to patient and/or from indication to indication and/or on the basis of the selected electrical stimulation location, e.g., the sacral region. The present technology also may make use of other parameters, in addition to or in lieu of those described above, to monitor and/or control patient therapy. For example, in cases for which the pulse generator includes a constant voltage arrangement rather than a constant current arrangement, the current values described above may be replaced with corresponding voltage values.

In some embodiments, the parameters in accordance with which the pulse generator provides signals can be modulated during portions of the therapy regimen. For example, the frequency, amplitude, pulse width, pulse train, and/or signal delivery location can be modulated in accordance with a preset program, patient and/or physician inputs, and/or in a random or pseudorandom manner. Such parameter variations can be used to address a number of potential clinical situations, including changes in the patient's perception of one or more symptoms associated with the condition being treated, changes in the preferred target neural population, and/or patient accommodation or habituation.

Electrical stimulation may be applied directly to the spinal cord region, an organ, and/or another target tissue, or it may be applied in close proximity to the spinal cord region, an organ, and/or another target tissue (i.e., close enough to the spinal cord region, the spinal cord region, an organ, and/or another target tissue to receive the electrical signal). For example, electrical stimulation can be applied at or proximate to a target location in the spinal cord region. As another example, the electrical stimulation is applied to other neural tissue such as peripheral nerves corresponding to the spinal cord region (e.g., sympathetic nerves and/or the parasympathetic nerves)

A variety of suitable devices for administering an electrical signal to the spinal cord region, an organ, and/or another target tissue are described in greater detail above in Section 3.0 and may also be described in the references incorporated by reference herein. Examples of devices for administering an electrical signal that can treat pain are disclosed in U.S. Pat. Nos. 8,694,108 and 8,355,797, both of which are incorporated herein by reference in their entireties, and attached as Appendices H and D, respectively. For example, applying electrical stimulation can be carried out using suitable devices and programming modules specifically programmed to carry out any of the methods described herein. For example, the device can comprise a lead, wherein the lead in turn comprises an electrode. In some embodiments, administration of electrical stimulation comprises a positioning step (e.g., placing the lead such that an electrode is in proximity to the spinal cord, sacral region, an organ, and/or another target tissue) and a stimulation step (e.g., transmitting an electrical therapy signal through the electrode). In some embodiments, a device that is used for applying an electrical signal to the spinal cord may be repurposed with or without modifications to administer an electrical signal to another target tissue or organ, e.g., a spinal cord region or a cortical, sub-cortical, intra-cortical, or peripheral target. As such, any of the herein described systems, sub-systems, and/or sub-components serve as means for performing any of the herein described methods.

Many of the embodiments described above are described in the context of treating pain with modulation signals applied to the spinal cord at various vertebral levels. Pain represents an example indication that is expected to be treatable with modulation applied at this location. In some embodiments, modulation signals having parameters (e.g., frequency, pulse width, amplitude, and/or duty cycle) generally similar to those described above can be applied to other patient locations to address other indications, such as those having corresponding abnormal neural system activity (e.g., epilepsy, Parkinson's disease, mood disorders, obesity, and dystonia).

The methods disclosed herein include and encompass, in addition to methods of making and using the disclosed devices and systems, methods of instructing others to make and use the disclosed devices and systems. For example, a method in accordance with some embodiments includes treating a patient's pain by applying a therapeutic signal to the patient's spinal cord region, with the electrical signal being one or more pulse trains, each pulse train having a pulse train duration range from about 3 milliseconds to about 5 seconds and having more than one pulse width. A duration of one or more pulse widths within the pulse train can differ from a duration of one or more other pulse widths within the same pulse train. For example, a first pulse width can be longer or shorter than a second pulse width which can be longer or shorter than a third pulse width, and so on. Likewise, the first pulse width can be associated with a first frequency that differs from a second frequency associated with the second pulse width and/or a third frequency associated with the third pulse width. The electrical signal has a frequency in a range of from about 1 kHz to about 100 kHz, a pulse width in a pulse width range of 1 microseconds to 333 microseconds across a single phase or a single bi-phasic set of pulses, an amplitude in an amplitude range of 0.1 mA to 20 mA, and/or a duty cycle of 1% to 99%, where at least one of these parameters of the electrical signal is ramped up at least during one of the pulse widths, such as amplitude.

A method in accordance with another embodiment includes programming a device and/or system to deliver such a method, instructing or directing such a method. Accordingly, any and all methods of use and manufacture disclosed herein also fully disclose and enable corresponding methods of instructing such methods of use and manufacture.

From the foregoing, it will be appreciated that some embodiments of the present technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. As described above, signals having the foregoing characteristics are expected to provide therapeutic benefits for patients having pain when stimulation is applied at the patient's spinal cord region. In some embodiments, the present technology can be used to address one or more pain indications, such as those described in the references incorporated by reference, besides and/or in addition to those described herein.

In any of the foregoing embodiments, aspects of the therapy provided to the patient may be varied within or outside the parameters used during the experimental testing and computational models described above, while still obtaining beneficial results for patients suffering neurogenic and/or other disorders. For example, the location of the lead body (and, in particular, the lead body electrodes) can be varied over the significant lateral and/or axial ranges described above. Other characteristics of the applied signal can also be varied and or ramped in a manner different than those described herein. The specific values selected for the foregoing parameters may vary from patient to patient and/or from indication to indication and/or on the basis of the selected vertebral location. In addition, the methodology may make use of other parameters, in addition to or in lieu of those described above, to monitor and/or control patient therapy. For example, in cases for which the pulse generator includes a constant voltage arrangement rather than a constant current arrangement, the current values described above may be replaced with corresponding voltage values.

In some embodiments, the duty cycle may be varied from the ranges of values described above, as can the lengths of the on/off periods. For example, it has been observed that patients can have therapeutic effects (e.g., pain reduction) that persist for significant periods after the stimulation has been halted. In some embodiments, the beneficial effects can persist for 10 to 20 minutes in some cases, and up to several hours or even days in others. Accordingly, the simulator can be programmed to halt stimulation for periods of up to several hours, with appropriate allowances for the time necessary to re-start the beneficial effects. This arrangement can significantly reduce system power consumption, compared to systems with higher-duty cycles, and compared to systems that have shorter on/off periods.

In any of the foregoing embodiments, the parameters in accordance with which the signal generator 102 in FIG. 1A provides signals can be adjusted during portions of the therapy regimen. For example, the frequency, amplitude, pulse width, and/or signal delivery location can be adjusted in accordance with a pre-set therapy program, patient and/or physician inputs, and/or in a random or pseudorandom manner. Such parameter variations can be used to address a number of potential clinical situations. Some embodiments of the foregoing systems and methods may be simplified or eliminated in some embodiments of the present disclosure.

Some embodiments of the disclosure described in the context of some embodiments may be combined or eliminated in other embodiments. For example, as described above, the trial period, operating room mapping process, and/or external stimulator may be eliminated or simplified in some embodiments. Therapies directed to some indications may be combined in still further embodiments. Further, while advantages associated with some embodiments have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the present disclosure. The following examples provide additional embodiments of the disclosure.

Several of the embodiments described above include modifying cell membrane potentials to achieve a therapeutic result. The result can be identified on a larger scale by observing and/or recording a change in the patient's condition (e.g., a reduction in symptoms resulting from the target indication). The result can be identified on a smaller scale by conducting tissue-level and/or cellular-level testing. Representative techniques include electrophysiological and/or electromyographical testing to demonstrate changes in the activation threshold of some cells and/or groups of cells.

To the extent the foregoing materials and/or any other materials incorporated herein by reference conflict with the present disclosure, the present disclosure controls.

Claims

1. A method for treating a patient's pain, comprising delivering an electrical therapy signal to a target location via a signal delivery device; wherein the electrical therapy signal has multiple pulses at a frequency in a frequency range of from 1.2 kHz to 100 kHz,an amplitude of an individual pulse of the multiple pulses is ramped in only a single direction from a first value to a second value over the individual pulse's duration,the individual pulse is at a single polarity over the individual pulse's duration, andthe electrical therapy signal preferentially activates inhibitory interneurons.
2. The method of claim 1 wherein the amplitude is within an amplitude range of from 2 mA to 20 mA.
3. The method of claim 2 wherein the amplitude is ramped across more than one individual pulse.
4. The method of claim 1 wherein the target location includes a target nerve fiber.
5. The method of claim 4 wherein the target location is in the patient's spinal cord.
6. The method of claim 5 wherein the target location is along the patient's dorsal column and superior to the patient's sacral region.
7. The method of claim 1 wherein the electrical therapy signal treats the patient's pain without relying on paresthesia or tingling to mask the patient's sensation of the pain.
8. The method of claim 1 wherein the multiple pulses are configured in a first pulse train and a second pulse train separated from the first pulse by a telemetry window.
9. The method of claim 8 wherein the first pulse train and/or the second pulse train have a duration of from about 3 microseconds to about 5 seconds.
10. The method of claim 1 wherein the amplitude is increased over a period of from one microsecond to 333 microseconds.
11. The method of claim 10 wherein the amplitude is increased over a period of less than 100 microseconds.
12. The method of claim 11 wherein the amplitude is increased over a period of from 1 microsecond to 400 microseconds.
13. The method of claim 1, further comprising positioning the signal delivery device proximate to the target location at or near the patient's spinal cord.
14. The method of claim 13 wherein the signal delivery device is implanted in the patient's epidural space proximate to the target location.
15. The method of claim 1, further comprising: monitoring the patient's pain; andin response to results obtained from monitoring the patient's pain; adjusting at least one signal delivery parameter in accordance with which the electrical signal is applied to the target location, orterminating delivery of the electrical therapy signal.
16. A method for alleviating a patient's pain, comprising: programming a signal generator to generate and deliver an electrical therapy signal to a target location, via at least one implanted electrode electrically coupled to the signal generator, to alleviate the patient's pain; whereinthe electrical therapy signal has multiple pulses at a frequency in a frequency range of from 1.2 kHz to 100 kHz,the signal generator is programmed to ramp an amplitude of an individual pulse of the multiple pulses in only a single direction from a first value to a second value over the individual pulse's duration, the individual pulse being at a single polarity over the individual pulse's duration, andthe electrical therapy signal preferentially activates inhibitory interneurons.
17. The method of claim 16 wherein the signal generator is programmed to ramp the amplitude over a time period of from 1 microsecond to 400 microseconds.
18. The method of claim 16, wherein the amplitude is between 2 mA and 20 mA.
19. The method of claim 16 wherein the electrical therapy signal alleviates the patient's pain without relying on paresthesia or tingling to mask the patient's sensation of the pain.
20. The method of claim 16 wherein the signal delivery device is implanted in the patient's epidural space proximate to the target location.
21. A system for alleviating a patient's pain, comprising: a signal delivery device carrying at least one electrode, the at least one electrode being positionable at or near a target location within the patient; anda signal generator coupleable to the at least one electrode and programmed to: generate an electrical therapy signal having multiple pulses at a frequency in a frequency range of from 1.2 kHz to 100 kHz,ramp an amplitude of an individual pulse of the multiple pulses in only a single direction from a first value to a second value over the individual pulse's duration, wherein the individual pulse is at a single polarity over the individual pulse's duration, anddeliver the electrical therapy signal having the ramped amplitude to the target location via the at least one electrode to preferentially activate inhibitory interneurons and alleviate the patient's pain.
22. The system of claim 21 wherein the signal generator is programmed to ramp the amplitude over a time period in a range of from about 1 microsecond to about 400 microseconds.
23. The system of claim 21 wherein the electrode is implantable.
24. The system of claim 21 wherein the electrical therapy signal remains on for a period of at least a few milliseconds at a time.
25. A method for treating a patient's pain, comprising: programming a signal delivery device to deliver an electrical therapy signal to a target location, wherein the electrical therapy signal includes multiple pulses at a frequency in a frequency range of from 1.2 kHz to 100 kHz,an amplitude of an individual pulse of the multiple pulses is ramped in only a single direction from a first value to a second value over the individual pulse's duration, andthe individual pulse is at a single polarity over the individual pulse's duration.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims priority to pending U.S. Provisional Application No. 62/798,334, filed on Jan. 29, 2019, and are incorporated herein by reference.

US Referenced Citations (769)

Number	Name	Date	Kind
1597061	Cultra	Aug 1926	A
2622601	Nemec	Dec 1952	A
3195540	Waller	Jul 1965	A
3279468	Vine	Oct 1966	A
3449768	Doyle	Jun 1969	A
3646940	Timm et al.	Mar 1972	A
3724467	Avery et al.	Apr 1973	A
3727616	Lenzkes	Apr 1973	A
3774618	Avery	Nov 1973	A
3817254	Maurer	Jun 1974	A
3822708	Zilber	Jul 1974	A
3893463	Williams	Jul 1975	A
4014347	Halleck et al.	Mar 1977	A
4023574	Nemec	May 1977	A
4055190	Tany et al.	Oct 1977	A
4096866	Fischell	Jun 1978	A
4148321	Wyss et al.	Apr 1979	A
4155366	Di Mucci	May 1979	A
4289136	Rienzo, Sr.	Sep 1981	A
4315503	Ryaby et al.	Feb 1982	A
4379462	Borkan et al.	Apr 1983	A
4414986	Dickhudt et al.	Nov 1983	A
4459989	Borkan	Jul 1984	A
4535777	Castel	Aug 1985	A
4541432	Molina-Negro et al.	Sep 1985	A
4550733	Liss et al.	Nov 1985	A
4607639	Tanagho	Aug 1986	A
4608985	Crish et al.	Sep 1986	A
4612934	Borkan et al.	Sep 1986	A
4649935	Charmillot et al.	Mar 1987	A
4702254	Zabara	Oct 1987	A
4735204	Sussman et al.	Apr 1988	A
4739764	Lue et al.	Apr 1988	A
4764132	Stutz, Jr.	Aug 1988	A
4784142	Liss et al.	Nov 1988	A
4793353	Borkan et al.	Dec 1988	A
4841973	Stecker	Jun 1989	A
RE33420	Sussman et al.	Nov 1990	E
4989605	Rossen	Feb 1991	A
5002053	Garcia-Rill	Mar 1991	A
5042486	Pfeiler et al.	Aug 1991	A
5052375	Stark et al.	Oct 1991	A
5078140	Kwoh	Jan 1992	A
5188104	Wernicke et al.	Feb 1993	A
5211165	Dumoulin et al.	May 1993	A
5257636	White	Nov 1993	A
5284153	Raymond et al.	Feb 1994	A
5306291	Kroll et al.	Apr 1994	A
5325873	Hirschi et al.	Jul 1994	A
5330515	Rutecki et al.	Jul 1994	A
5335657	Terry, Jr. et al.	Aug 1994	A
5354320	Schaldach et al.	Oct 1994	A
5375596	Twiss et al.	Dec 1994	A
5417719	Hull	May 1995	A
5425367	Shapiro et al.	Jun 1995	A
5501703	Holsheimer et al.	Mar 1996	A
5514175	Kim et al.	May 1996	A
5531774	Schulman et al.	Jul 1996	A
5540730	Terry, Jr. et al.	Jul 1996	A
5540734	Zabara	Jul 1996	A
5562717	Tippey et al.	Oct 1996	A
5573552	Hansjurgens et al.	Nov 1996	A
5643330	Holsheimer et al.	Jul 1997	A
5702428	Tippey et al.	Dec 1997	A
5707396	Benabid	Jan 1998	A
5716377	Rise	Feb 1998	A
5727553	Saad	Mar 1998	A
5755758	Wolozko	May 1998	A
5776170	MacDonald et al.	Jul 1998	A
5792187	Adams	Aug 1998	A
5806522	Katims	Sep 1998	A
5830151	Hadzic et al.	Nov 1998	A
5833709	Rise	Nov 1998	A
5853373	Griffith et al.	Dec 1998	A
5871487	Warner et al.	Feb 1999	A
5893883	Torgerson	Apr 1999	A
5895416	Barreras	Apr 1999	A
5925070	King	Jul 1999	A
5938690	Law	Aug 1999	A
5948007	Starkebaum et al.	Sep 1999	A
5976110	Greengrass et al.	Nov 1999	A
5983141	Sluijter et al.	Nov 1999	A
5995872	Bourgeois	Nov 1999	A
6002964	Feler et al.	Dec 1999	A
6014588	Fitz	Jan 2000	A
6027456	Feler et al.	Feb 2000	A
6049701	Sparksman	Apr 2000	A
6104957	Alo et al.	Aug 2000	A
6159163	Strauss et al.	Dec 2000	A
6161044	Silverstone	Dec 2000	A
6161048	Sluijter et al.	Dec 2000	A
6167305	Cammilli et al.	Dec 2000	A
6167311	Rezai	Dec 2000	A
6176242	Rise	Jan 2001	B1
6192278	Werner et al.	Feb 2001	B1
6198963	Haim et al.	Mar 2001	B1
6233488	Hess	May 2001	B1
6236892	Feler et al.	May 2001	B1
6238423	Bardy	May 2001	B1
6246912	Sluijter et al.	Jun 2001	B1
6259952	Sluijter et al.	Jul 2001	B1
6314325	Fitz	Nov 2001	B1
6319241	King et al.	Nov 2001	B1
6341236	Osorio et al.	Jan 2002	B1
6356786	Rezai et al.	Mar 2002	B1
6366814	Boveja	Apr 2002	B1
6381496	Meadows et al.	Apr 2002	B1
6393325	Mann et al.	May 2002	B1
6397108	Camps et al.	May 2002	B1
6405079	Ansarinia	Jun 2002	B1
6421566	Holsheimer	Jul 2002	B1
6438418	Swerdlow et al.	Aug 2002	B1
6440090	Schallhorn	Aug 2002	B1
6473644	Terry, Jr. et al.	Oct 2002	B1
6474341	Hunter et al.	Nov 2002	B1
6487446	Hill et al.	Nov 2002	B1
6505074	Boveja et al.	Jan 2003	B2
6505078	King et al.	Jan 2003	B1
6510347	Borkan	Jan 2003	B2
6516227	Meadows et al.	Feb 2003	B1
6526318	Ansarinia	Feb 2003	B1
6571127	Ben-Haim et al.	May 2003	B1
6584358	Carter et al.	Jun 2003	B2
6587724	Mann	Jul 2003	B2
6587727	Osorio et al.	Jul 2003	B2
6600954	Cohen et al.	Jul 2003	B2
6609030	Rezai et al.	Aug 2003	B1
6609031	Law et al.	Aug 2003	B1
6610713	Tracey	Aug 2003	B2
6622047	Barrett et al.	Sep 2003	B2
6622048	Mann	Sep 2003	B1
6659968	McClure	Dec 2003	B1
6662051	Eraker et al.	Dec 2003	B1
6671556	Osorio et al.	Dec 2003	B2
6671557	Gliner	Dec 2003	B1
6675046	Holsheimer	Jan 2004	B2
6684105	Cohen et al.	Jan 2004	B2
6687538	Hrdlicka et al.	Feb 2004	B1
6701190	Gliner	Mar 2004	B2
6712753	Manne	Mar 2004	B2
6712772	Cohen et al.	Mar 2004	B2
6714822	King et al.	Mar 2004	B2
6721603	Zabara et al.	Apr 2004	B2
6757561	Rubin et al.	Jun 2004	B2
6795737	Gielen et al.	Sep 2004	B2
6836685	Fitz	Dec 2004	B1
6856315	Eberlein	Feb 2005	B2
6862480	Cohen et al.	Mar 2005	B2
6871090	He et al.	Mar 2005	B1
6871099	Whitehurst et al.	Mar 2005	B1
6875571	Crabtree et al.	Apr 2005	B2
6885888	Rezai	Apr 2005	B2
6892097	Holsheimer et al.	May 2005	B2
6895280	Meadows et al.	May 2005	B2
6907293	Grill et al.	Jun 2005	B2
6907295	Gross et al.	Jun 2005	B2
6920357	Osorio et al.	Jul 2005	B2
6923784	Stein	Aug 2005	B2
6928320	King	Aug 2005	B2
6941173	Nachum	Sep 2005	B2
6950707	Whitehurst	Sep 2005	B2
6961618	Osorio et al.	Nov 2005	B2
6968237	Doan et al.	Nov 2005	B2
6973346	Hafer et al.	Dec 2005	B2
6988006	King et al.	Jan 2006	B2
6990376	Tanagho et al.	Jan 2006	B2
7020523	Lu et al.	Mar 2006	B1
7024246	Acosta et al.	Apr 2006	B2
7024247	Gliner et al.	Apr 2006	B2
7047079	Erickson	May 2006	B2
7047084	Erickson et al.	May 2006	B2
7054686	MacDonald	May 2006	B2
7076307	Boveja et al.	Jul 2006	B2
7082333	Bauhahn et al.	Jul 2006	B1
7117034	Kronberg	Oct 2006	B2
7127297	Law et al.	Oct 2006	B2
7146224	King	Dec 2006	B2
7149574	Yun et al.	Dec 2006	B2
7158826	Kroll et al.	Jan 2007	B1
7162303	Levin et al.	Jan 2007	B2
7162304	Bradley	Jan 2007	B1
7167750	Knudson et al.	Jan 2007	B2
7174215	Bradley	Feb 2007	B2
7177690	Woods	Feb 2007	B2
7177702	Wallace et al.	Feb 2007	B2
7180760	Varrichio et al.	Feb 2007	B2
7206632	King	Apr 2007	B2
7206640	Overstreet	Apr 2007	B1
7206642	Pardo et al.	Apr 2007	B2
7212865	Cory	May 2007	B2
7212867	Van Venrooij et al.	May 2007	B2
7225035	Brabec et al.	May 2007	B2
7228179	Campen et al.	Jun 2007	B2
7231254	DiLorenzo	Jun 2007	B2
7236822	Dobak, III	Jun 2007	B2
7236830	Gliner	Jun 2007	B2
7236834	Christopherson et al.	Jun 2007	B2
7239912	Dobak, III	Jul 2007	B2
7241283	Putz	Jul 2007	B2
7242984	DiLorenzo	Jul 2007	B2
7244150	Brase et al.	Jul 2007	B1
7251529	Greenwood-Van Meerveld	Jul 2007	B2
7252090	Goetz	Aug 2007	B2
7254445	Law et al.	Aug 2007	B2
7260436	Kilgore et al.	Aug 2007	B2
7266412	Stypulkowski	Sep 2007	B2
7276057	Gerber	Oct 2007	B2
7288062	Spiegel	Oct 2007	B2
7313440	Miesel	Dec 2007	B2
7324852	Barolat et al.	Jan 2008	B2
7326181	Katims	Feb 2008	B2
7328068	Spinelli et al.	Feb 2008	B2
7329262	Gill	Feb 2008	B2
7333857	Campbell	Feb 2008	B2
7337005	Kim et al.	Feb 2008	B2
7337006	Kim et al.	Feb 2008	B2
7343200	Litvak et al.	Mar 2008	B2
7346398	Gross et al.	Mar 2008	B2
7349743	Tadlock	Mar 2008	B2
RE40279	Sluijter et al.	Apr 2008	E
7359751	Erickson et al.	Apr 2008	B1
7363076	Yun et al.	Apr 2008	B2
7381441	Leung et al.	Jun 2008	B2
7386341	Hafer et al.	Jun 2008	B2
7389145	Kilgore et al.	Jun 2008	B2
7393351	Woloszko et al.	Jul 2008	B2
7425142	Putz	Sep 2008	B1
7433734	King	Oct 2008	B2
7444181	Shi et al.	Oct 2008	B2
7444183	Knudson et al.	Oct 2008	B2
7444184	Boveja et al.	Oct 2008	B2
7447546	Kim et al.	Nov 2008	B2
7450993	Kim et al.	Nov 2008	B2
7452335	Wells et al.	Nov 2008	B2
7463927	Chaouat	Dec 2008	B1
7483747	Gliner et al.	Jan 2009	B2
7489969	Knudson et al.	Feb 2009	B2
7493172	Whitehurst et al.	Feb 2009	B2
7496404	Meadows et al.	Feb 2009	B2
7502651	Kim et al.	Mar 2009	B2
7502652	Gaunt et al.	Mar 2009	B2
7551964	Dobak, III	Jun 2009	B2
7571007	Erickson et al.	Aug 2009	B2
7580753	Kim et al.	Aug 2009	B2
7599737	Yomtov et al.	Oct 2009	B2
7606622	Reeve	Oct 2009	B2
7610096	McDonald, III	Oct 2009	B2
7613520	De Ridder	Nov 2009	B2
7634317	Ben-David et al.	Dec 2009	B2
7676269	Yun et al.	Mar 2010	B2
7689276	Dobak	Mar 2010	B2
7689289	King	Mar 2010	B2
7702379	Avinash et al.	Apr 2010	B2
7711432	Thimineur et al.	May 2010	B2
7715915	Rye et al.	May 2010	B1
7734340	De Ridder	Jun 2010	B2
7734352	Greenberg et al.	Jun 2010	B2
7734355	Cohen et al.	Jun 2010	B2
7742810	Moffitt et al.	Jun 2010	B2
7761166	Giftakis et al.	Jul 2010	B2
7761168	Gross	Jul 2010	B2
7761170	Kaplan et al.	Jul 2010	B2
7769463	Katsnelson	Aug 2010	B2
7778704	Rezai	Aug 2010	B2
7792591	Rooney et al.	Sep 2010	B2
7801601	Maschino et al.	Sep 2010	B2
7801604	Brockway et al.	Sep 2010	B2
7805197	Bradley	Sep 2010	B2
7809443	Giftakis et al.	Oct 2010	B2
7813803	Heruth et al.	Oct 2010	B2
7813804	Jaax	Oct 2010	B1
7826901	Lee et al.	Nov 2010	B2
7831306	Finch et al.	Nov 2010	B2
7844338	Knudson et al.	Nov 2010	B2
7848818	Barolat et al.	Dec 2010	B2
7853322	Bourget et al.	Dec 2010	B2
7856277	Thacker et al.	Dec 2010	B1
7860570	Whitehurst et al.	Dec 2010	B2
7865243	Whitehurst et al.	Jan 2011	B1
7877136	Moffitt et al.	Jan 2011	B1
7877146	Rezai	Jan 2011	B2
7881805	Bradley	Feb 2011	B2
7890163	Belalcazar	Feb 2011	B2
7890166	Heruth et al.	Feb 2011	B2
7890176	Jaax et al.	Feb 2011	B2
7890182	Parramon et al.	Feb 2011	B2
7890185	Cohen et al.	Feb 2011	B2
7894907	Cowan et al.	Feb 2011	B2
7899542	Cowan et al.	Mar 2011	B2
7914452	Hartley et al.	Mar 2011	B2
7933654	Merfeld et al.	Apr 2011	B2
7937145	Dobak	May 2011	B2
7957797	Bourget et al.	Jun 2011	B2
7957809	Bourget et al.	Jun 2011	B2
7979133	Feler et al.	Jul 2011	B2
7996055	Hauck et al.	Aug 2011	B2
8000794	Lozano	Aug 2011	B2
8010198	Libbus et al.	Aug 2011	B2
8016776	Bourget et al.	Sep 2011	B2
8019423	Possover	Sep 2011	B2
8027718	Spinner et al.	Sep 2011	B2
8046075	Rezai	Oct 2011	B2
8060208	Kilgore et al.	Nov 2011	B2
8082038	Simon et al.	Dec 2011	B2
8082039	Kim et al.	Dec 2011	B2
8086318	Strother et al.	Dec 2011	B2
8128600	Gill	Mar 2012	B2
8131357	Bradley et al.	Mar 2012	B2
8150531	Skelton	Apr 2012	B2
8170658	Dacey et al.	May 2012	B2
8170675	Alataris et al.	May 2012	B2
8180445	Moffitt	May 2012	B1
8197494	Jaggi et al.	Jun 2012	B2
8204607	Rooney et al.	Jun 2012	B2
8209021	Alataris et al.	Jun 2012	B2
8209028	Skelton et al.	Jun 2012	B2
8214047	Pyles et al.	Jul 2012	B2
8224453	De Ridder	Jul 2012	B2
8224459	Pianca et al.	Jul 2012	B1
8255048	Dal Molin et al.	Aug 2012	B2
8255057	Fang et al.	Aug 2012	B2
8280515	Greenspan	Oct 2012	B2
8301241	Ternes et al.	Oct 2012	B2
8340775	Cullen et al.	Dec 2012	B1
8355791	Moffitt	Jan 2013	B2
8355792	Alataris et al.	Jan 2013	B2
8355797	Caparso	Jan 2013	B2
8359102	Alataris et al.	Jan 2013	B2
8359103	Alataris et al.	Jan 2013	B2
8364271	De Ridder	Jan 2013	B2
8364273	De Ridder	Jan 2013	B2
8380318	Kishawi et al.	Feb 2013	B2
8396559	Alataris et al.	Mar 2013	B2
8412338	Faltys	Apr 2013	B2
8423147	Alataris et al.	Apr 2013	B2
8428735	Littlewood et al.	Apr 2013	B2
8428748	Alataris et al.	Apr 2013	B2
8467875	Bennett et al.	Jun 2013	B2
8483830	Tweden	Jul 2013	B2
8509905	Alataris et al.	Aug 2013	B2
8509906	Walker et al.	Aug 2013	B2
8554326	Alataris et al.	Oct 2013	B2
8569935	Kosierkiewicz	Oct 2013	B1
8577458	Libbus et al.	Nov 2013	B1
8612018	Gillbe	Dec 2013	B2
8649874	Alataris et al.	Feb 2014	B2
8666506	King	Mar 2014	B2
8676331	Parker	Mar 2014	B2
8688212	Libbus et al.	Apr 2014	B2
8691877	Yun et al.	Apr 2014	B2
8694109	Alataris et al.	Apr 2014	B2
8712533	Alataris et al.	Apr 2014	B2
8712534	Wei	Apr 2014	B2
8718781	Alataris et al.	May 2014	B2
8718782	Alataris et al.	May 2014	B2
8751009	Wacnik	Jun 2014	B2
8768469	Tweden et al.	Jul 2014	B2
8768472	Fang et al.	Jul 2014	B2
8774926	Alataris et al.	Jul 2014	B2
8805512	Greiner et al.	Aug 2014	B1
8825164	Tweden et al.	Sep 2014	B2
8825166	John	Sep 2014	B2
8874217	Alataris et al.	Oct 2014	B2
8874221	Alataris et al.	Oct 2014	B2
8886326	Alataris et al.	Nov 2014	B2
8886328	Alataris et al.	Nov 2014	B2
8892209	Alataris et al.	Nov 2014	B2
8918172	Moffitt et al.	Dec 2014	B2
8918190	Libbus et al.	Dec 2014	B2
8918191	Libbus et al.	Dec 2014	B2
8923964	Libbus et al.	Dec 2014	B2
8923990	Libbus et al.	Dec 2014	B2
8965521	Birkholz et al.	Feb 2015	B2
8996125	Greiner et al.	Mar 2015	B2
9002457	Hamann et al.	Apr 2015	B2
9002459	Lee et al.	Apr 2015	B2
9026214	Ternes et al.	May 2015	B2
9026215	Rossing	May 2015	B2
9026226	Gerber et al.	May 2015	B2
9067076	Nolan et al.	Jun 2015	B2
9101770	Arcot-Krishnamurthy et al.	Aug 2015	B2
9126044	Kramer et al.	Sep 2015	B2
9132272	Alves et al.	Sep 2015	B2
9180298	Alataris et al.	Nov 2015	B2
9205258	Simon et al.	Dec 2015	B2
9211410	Levine et al.	Dec 2015	B2
9220889	Carlton et al.	Dec 2015	B2
9278215	Thacker et al.	Mar 2016	B2
9283387	Thacker et al.	Mar 2016	B2
9283388	Thacker et al.	Mar 2016	B2
9295840	Thacker	Mar 2016	B1
9308370	Lima et al.	Apr 2016	B2
9327127	Alataris et al.	May 2016	B2
9370659	Franke et al.	Jun 2016	B2
9381356	Parker	Jul 2016	B2
9403007	Moekelke et al.	Aug 2016	B2
9421355	Colborn	Aug 2016	B2
9440074	Ternes et al.	Sep 2016	B2
9480846	Strother	Nov 2016	B2
9533153	Libbus et al.	Jan 2017	B2
9561366	Wei et al.	Feb 2017	B2
9561370	Rezai	Feb 2017	B2
9572983	Levine et al.	Feb 2017	B2
9694183	Grandhe	Jul 2017	B2
9700724	Liu et al.	Jul 2017	B2
9724509	Su et al.	Aug 2017	B2
9724511	Wei et al.	Aug 2017	B2
9789313	Lipani	Oct 2017	B2
9833614	Gliner	Dec 2017	B1
9895532	Kaula et al.	Feb 2018	B2
9895539	Heit et al.	Feb 2018	B1
9913980	Ostroff et al.	Mar 2018	B2
9950173	Doan	Apr 2018	B2
9968732	Drew et al.	May 2018	B2
10149978	Park	Dec 2018	B1
10188856	Libbus et al.	Jan 2019	B1
10207109	Zhu et al.	Feb 2019	B2
10220205	Bhadra et al.	Mar 2019	B2
10328264	Hamann et al.	Jun 2019	B2
10420935	Illegems	Sep 2019	B2
10485975	Greiner et al.	Nov 2019	B2
10537740	Cabunaru	Jan 2020	B2
10561845	Giftakis et al.	Feb 2020	B2
10632300	Wagenbach et al.	Apr 2020	B2
10675468	Torgerson	Jun 2020	B2
10799701	Lee	Oct 2020	B2
10898714	Libbus et al.	Jan 2021	B2
11045649	Wei et al.	Jun 2021	B2
11058875	Zinner	Jul 2021	B1
11235153	Kibler et al.	Feb 2022	B2
20020055779	Andrews	May 2002	A1
20020087201	Firlik et al.	Jul 2002	A1
20020128700	Cross	Sep 2002	A1
20020198572	Weiner	Dec 2002	A1
20030018368	Ansarinia	Jan 2003	A1
20030100931	Mullett	May 2003	A1
20030120323	Meadows et al.	Jun 2003	A1
20030135241	Leonard et al.	Jul 2003	A1
20030135248	Stypulkowski	Jul 2003	A1
20030181958	Dobak	Sep 2003	A1
20030199952	Stolz et al.	Oct 2003	A1
20030204221	Rodriguez	Oct 2003	A1
20030208244	Stein et al.	Nov 2003	A1
20030212440	Boveja	Nov 2003	A1
20030236558	Whitehurst	Dec 2003	A1
20040015202	Chandler et al.	Jan 2004	A1
20040034394	Woods et al.	Feb 2004	A1
20040039425	Greenwood-Van Meerveld	Feb 2004	A1
20040059395	North et al.	Mar 2004	A1
20040073273	Gluckman et al.	Apr 2004	A1
20040093093	Andrews	May 2004	A1
20040116977	Finch et al.	Jun 2004	A1
20040122477	Whitehorse	Jun 2004	A1
20040158119	Osorio et al.	Aug 2004	A1
20040158298	Gliner	Aug 2004	A1
20040158839	Gliner et al.	Aug 2004	A1
20040162590	Whitehurst et al.	Aug 2004	A1
20040167584	Carroll et al.	Aug 2004	A1
20040172085	Knudson et al.	Sep 2004	A1
20040176812	Knudson et al.	Sep 2004	A1
20040186532	Tadlock	Sep 2004	A1
20040186544	King	Sep 2004	A1
20040193228	Gerber	Sep 2004	A1
20040193230	Overstreet	Sep 2004	A1
20040199214	Merfeld et al.	Oct 2004	A1
20040210270	Erickson	Oct 2004	A1
20040210271	Campen et al.	Oct 2004	A1
20040210290	Omar-Pasha	Oct 2004	A1
20040267330	Lee et al.	Dec 2004	A1
20050004417	Nelson et al.	Jan 2005	A1
20050004638	Cross	Jan 2005	A1
20050021104	DiLorenzo	Jan 2005	A1
20050033381	Carter et al.	Feb 2005	A1
20050038489	Grill	Feb 2005	A1
20050049664	Harris et al.	Mar 2005	A1
20050060001	Singhal et al.	Mar 2005	A1
20050070982	Heruth et al.	Mar 2005	A1
20050113877	Spinelli et al.	May 2005	A1
20050113878	Gerber	May 2005	A1
20050113882	Cameron et al.	May 2005	A1
20050119713	Whitehurst et al.	Jun 2005	A1
20050143783	Boveja	Jun 2005	A1
20050143789	Whitehurst et al.	Jun 2005	A1
20050149148	King	Jul 2005	A1
20050153885	Yun et al.	Jul 2005	A1
20050154435	Stern et al.	Jul 2005	A1
20050182453	Whitehurst et al.	Aug 2005	A1
20050187591	Carter et al.	Aug 2005	A1
20050222641	Pless	Oct 2005	A1
20050228451	Jaax et al.	Oct 2005	A1
20050240241	Yun et al.	Oct 2005	A1
20050245978	Varrichio et al.	Nov 2005	A1
20050245987	Woods	Nov 2005	A1
20050246006	Daniels	Nov 2005	A1
20050267545	Cory	Dec 2005	A1
20050278000	Strother et al.	Dec 2005	A1
20050288721	Girouard	Dec 2005	A1
20060004422	De Ridder	Jan 2006	A1
20060009820	Royle	Jan 2006	A1
20060015153	Gliner et al.	Jan 2006	A1
20060025832	O'Keeffe et al.	Feb 2006	A1
20060030895	Simon et al.	Feb 2006	A1
20060030899	O'Keeffe et al.	Feb 2006	A1
20060041285	Johnson	Feb 2006	A1
20060052836	Kim et al.	Mar 2006	A1
20060069415	Cameron et al.	Mar 2006	A1
20060074450	Boveja et al.	Apr 2006	A1
20060074456	Pyles et al.	Apr 2006	A1
20060079936	Boveja et al.	Apr 2006	A1
20060079937	King et al.	Apr 2006	A1
20060089697	Cross et al.	Apr 2006	A1
20060095088	De Ridder	May 2006	A1
20060100671	Ridder	May 2006	A1
20060149337	John	Jul 2006	A1
20060161219	Mock et al.	Jul 2006	A1
20060161235	King	Jul 2006	A1
20060167498	DiLorenzo	Jul 2006	A1
20060167512	Ross et al.	Jul 2006	A1
20060167525	King	Jul 2006	A1
20060168805	Hegland et al.	Aug 2006	A1
20060190044	Libbus et al.	Aug 2006	A1
20060190048	Gerber	Aug 2006	A1
20060206166	Weiner	Sep 2006	A1
20060224187	Bradley et al.	Oct 2006	A1
20060229687	Goetz et al.	Oct 2006	A1
20060253174	King	Nov 2006	A1
20060253182	King	Nov 2006	A1
20060271108	Libbus et al.	Nov 2006	A1
20070021801	Heruth et al.	Jan 2007	A1
20070021803	Deem et al.	Jan 2007	A1
20070025608	Armstrong	Feb 2007	A1
20070027486	Armstrong	Feb 2007	A1
20070032827	Katims	Feb 2007	A1
20070039625	Heruth et al.	Feb 2007	A1
20070043400	Donders et al.	Feb 2007	A1
20070049988	Carbunaru	Mar 2007	A1
20070049991	Klostermann et al.	Mar 2007	A1
20070060954	Cameron et al.	Mar 2007	A1
20070060955	Strother et al.	Mar 2007	A1
20070066995	Strother et al.	Mar 2007	A1
20070066997	He et al.	Mar 2007	A1
20070073353	Rooney et al.	Mar 2007	A1
20070073354	Knudson et al.	Mar 2007	A1
20070083240	Peterson et al.	Apr 2007	A1
20070100388	Gerber	May 2007	A1
20070106337	Errico et al.	May 2007	A1
20070106342	Schumann	May 2007	A1
20070142863	Bradley	Jun 2007	A1
20070142874	John	Jun 2007	A1
20070150029	Bourget et al.	Jun 2007	A1
20070150034	Rooney et al.	Jun 2007	A1
20070156183	Rhodes	Jul 2007	A1
20070156207	Kothandaraman et al.	Jul 2007	A1
20070162088	Chen et al.	Jul 2007	A1
20070167992	Carley	Jul 2007	A1
20070179558	Gliner et al.	Aug 2007	A1
20070179559	Giftakis et al.	Aug 2007	A1
20070179579	Feler et al.	Aug 2007	A1
20070191902	Errico	Aug 2007	A1
20070191906	Iyer et al.	Aug 2007	A1
20070203537	Goetz et al.	Aug 2007	A1
20070208381	Hill et al.	Sep 2007	A1
20070208394	King et al.	Sep 2007	A1
20070213789	Nolan et al.	Sep 2007	A1
20070233194	Craig	Oct 2007	A1
20070239226	Overstreet	Oct 2007	A1
20070244522	Overstreet	Oct 2007	A1
20070255118	Miesel et al.	Nov 2007	A1
20070255333	Giftakis et al.	Nov 2007	A1
20070255340	Giftakis et al.	Nov 2007	A1
20070255341	Giftakis et al.	Nov 2007	A1
20070265675	Lund	Nov 2007	A1
20070265681	Gerber et al.	Nov 2007	A1
20070282376	Shuros et al.	Dec 2007	A1
20070293893	Stolen et al.	Dec 2007	A1
20070293915	Kilgore et al.	Dec 2007	A1
20070299482	Littlewood et al.	Dec 2007	A1
20080033511	Dobak	Feb 2008	A1
20080051839	Libbus et al.	Feb 2008	A1
20080058871	Libbus et al.	Mar 2008	A1
20080058878	King	Mar 2008	A1
20080058888	King	Mar 2008	A1
20080065158	Ben-Ezra	Mar 2008	A1
20080086036	Hartley	Apr 2008	A1
20080103570	Gerber	May 2008	A1
20080109045	Gross et al.	May 2008	A1
20080140153	Burdulis	Jun 2008	A1
20080154329	Pyles et al.	Jun 2008	A1
20080154333	Knudson et al.	Jun 2008	A1
20080167697	Johnson	Jul 2008	A1
20080183259	Bly et al.	Jul 2008	A1
20080234791	Arie et al.	Sep 2008	A1
20080262411	Dobak	Oct 2008	A1
20080269854	Hegland et al.	Oct 2008	A1
20080281381	Gerber et al.	Nov 2008	A1
20080300449	Gerber	Dec 2008	A1
20080319511	Pless	Dec 2008	A1
20080319514	Shi et al.	Dec 2008	A1
20090018617	Skelton et al.	Jan 2009	A1
20090024186	Brockway et al.	Jan 2009	A1
20090024187	Erickson et al.	Jan 2009	A1
20090036945	Chancellor et al.	Feb 2009	A1
20090048643	Erickson	Feb 2009	A1
20090054950	Stephens	Feb 2009	A1
20090054962	Lefler et al.	Feb 2009	A1
20090069803	Starkebaum	Mar 2009	A1
20090076565	Surwit	Mar 2009	A1
20090083070	Giftakis	Mar 2009	A1
20090112282	Kast et al.	Apr 2009	A1
20090118777	Iki	May 2009	A1
20090125079	Armstrong et al.	May 2009	A1
20090132010	Kronberg	May 2009	A1
20090132016	Putz	May 2009	A1
20090157141	Chiao et al.	Jun 2009	A1
20090157149	Wahlgren et al.	Jun 2009	A1
20090157183	Song	Jun 2009	A1
20090196472	Goetz et al.	Aug 2009	A1
20090198306	Goetz et al.	Aug 2009	A1
20090204173	Fang	Aug 2009	A1
20090204192	Carlton et al.	Aug 2009	A1
20090264959	Lange	Oct 2009	A1
20090264973	Boling et al.	Oct 2009	A1
20090281595	King et al.	Nov 2009	A1
20090281596	King	Nov 2009	A1
20090287035	Dietrich et al.	Nov 2009	A1
20090287274	De Ridder	Nov 2009	A1
20090287279	Parramon et al.	Nov 2009	A1
20090326611	Gillbe	Dec 2009	A1
20100010567	Deem et al.	Jan 2010	A1
20100016929	Prochazka	Jan 2010	A1
20100023103	Elborno	Jan 2010	A1
20100036454	Bennett et al.	Feb 2010	A1
20100042170	Shuros et al.	Feb 2010	A1
20100042193	Slavin	Feb 2010	A1
20100057178	Simon	Mar 2010	A1
20100094375	Donders et al.	Apr 2010	A1
20100125313	Lee et al.	May 2010	A1
20100137938	Kishawi et al.	Jun 2010	A1
20100152817	Gillbe	Jun 2010	A1
20100191307	Fang et al.	Jul 2010	A1
20100228310	Shuros et al.	Sep 2010	A1
20100241190	Kilgore et al.	Sep 2010	A1
20100249876	Giftakis et al.	Sep 2010	A1
20100256696	Schleicher et al.	Oct 2010	A1
20100262205	De Ridder	Oct 2010	A1
20100274312	Alataris	Oct 2010	A1
20100274314	Alataris et al.	Oct 2010	A1
20100274315	Alataris et al.	Oct 2010	A1
20100274316	Alataris et al.	Oct 2010	A1
20100274317	Parker et al.	Oct 2010	A1
20100274318	Walker et al.	Oct 2010	A1
20100274320	Torgerson	Oct 2010	A1
20100274326	Chitre et al.	Oct 2010	A1
20100318157	Giftakis et al.	Dec 2010	A1
20100324630	Lee et al.	Dec 2010	A1
20100331916	Parramon et al.	Dec 2010	A1
20100331920	DiGiore et al.	Dec 2010	A1
20110009919	Carbunaru et al.	Jan 2011	A1
20110009923	Lee	Jan 2011	A1
20110009927	Parker et al.	Jan 2011	A1
20110022114	Navarro	Jan 2011	A1
20110040291	Weissenrieder-Norlin et al.	Feb 2011	A1
20110040362	Godara et al.	Feb 2011	A1
20110046696	Barolat et al.	Feb 2011	A1
20110071589	Starkebaum et al.	Mar 2011	A1
20110077721	Whitehurst et al.	Mar 2011	A1
20110093042	Torgerson et al.	Apr 2011	A1
20110106208	Faltys et al.	May 2011	A1
20110184301	Holmstrom et al.	Jul 2011	A1
20110184486	De Ridder	Jul 2011	A1
20110184488	De Ridder	Jul 2011	A1
20110201977	Tass	Aug 2011	A1
20110276107	Simon et al.	Nov 2011	A1
20110282412	Glukhovsky et al.	Nov 2011	A1
20110301679	Rezai	Dec 2011	A1
20120010680	Wei	Jan 2012	A1
20120089200	Ranu et al.	Apr 2012	A1
20120150252	Feldman et al.	Jun 2012	A1
20120172946	Alataris et al.	Jul 2012	A1
20120083857	Bradley	Aug 2012	A1
20120277833	Gerber et al.	Nov 2012	A1
20120283797	De Ridder	Nov 2012	A1
20130006325	Woods et al.	Jan 2013	A1
20130023951	Greenspan	Jan 2013	A1
20130035740	Sharma et al.	Feb 2013	A1
20130041425	Fang et al.	Feb 2013	A1
20130066411	Thacker et al.	Mar 2013	A1
20130079841	Su	Mar 2013	A1
20130096643	Fang et al.	Apr 2013	A1
20130096644	Fang et al.	Apr 2013	A1
20130110194	Wei	May 2013	A1
20130110196	Alataris et al.	May 2013	A1
20130116754	Sharma et al.	May 2013	A1
20130123879	Alataris et al.	May 2013	A1
20130172955	Alataris et al.	Jul 2013	A1
20130204173	Kelly et al.	Aug 2013	A1
20130204321	Alataris et al.	Aug 2013	A1
20130204323	Thacker et al.	Aug 2013	A1
20130204324	Thacker et al.	Aug 2013	A1
20130204338	Alataris et al.	Aug 2013	A1
20130211487	Fang et al.	Aug 2013	A1
20130237948	Donders	Sep 2013	A1
20130261695	Thacker	Oct 2013	A1
20130261696	Thacker	Oct 2013	A1
20130282078	Wacnik	Oct 2013	A1
20130289659	Nelson	Oct 2013	A1
20140031896	Alataris et al.	Jan 2014	A1
20140180361	Burdick et al.	Jan 2014	A1
20140067016	Kaula	Mar 2014	A1
20140081350	Zhu	Mar 2014	A1
20140142656	Alataris et al.	May 2014	A1
20140142657	Alataris et al.	May 2014	A1
20140142658	Alataris et al.	May 2014	A1
20140142659	Alataris et al.	May 2014	A1
20140142673	Alataris et al.	May 2014	A1
20140276549	Osorio	Sep 2014	A1
20140316484	Edgerton	Oct 2014	A1
20140343622	Alataris	Nov 2014	A1
20140379044	Walker et al.	Dec 2014	A1
20150012079	Goroszeniuk et al.	Jan 2015	A1
20150018896	Alataris et al.	Jan 2015	A1
20150032181	Baynham	Jan 2015	A1
20150032182	Alataris et al.	Jan 2015	A1
20150032183	Alataris et al.	Jan 2015	A1
20150039049	Alataris et al.	Feb 2015	A1
20150039050	Alataris et al.	Feb 2015	A1
20150045853	Alataris et al.	Feb 2015	A1
20150045854	Alataris et al.	Feb 2015	A1
20150051664	Alataris et al.	Feb 2015	A1
20150051665	Hershey et al.	Feb 2015	A1
20150073510	Perryman	Mar 2015	A1
20150151125	Zhu	Jun 2015	A1
20150165209	Grandhe	Jun 2015	A1
20150217116	Parramon et al.	Aug 2015	A1
20150321000	Rosenbluth	Nov 2015	A1
20150343220	Alataris et al.	Dec 2015	A1
20160082252	Hershey et al.	Mar 2016	A1
20160114165	Levine	Apr 2016	A1
20160121119	Alataris et al.	May 2016	A1
20160158551	Kent	Jun 2016	A1
20160175594	Min et al.	Jun 2016	A1
20160256689	Vallejo et al.	Sep 2016	A1
20160263376	Yoo et al.	Sep 2016	A1
20160271392	Vallejo et al.	Sep 2016	A1
20160287872	Alataris et al.	Oct 2016	A1
20160287873	Alataris et al.	Oct 2016	A1
20160287874	Alataris et al.	Oct 2016	A1
20160287875	Thacker et al.	Oct 2016	A1
20160287888	Alataris et al.	Oct 2016	A1
20160303374	Alataris et al.	Oct 2016	A1
20160339239	Yoo et al.	Nov 2016	A1
20170036023	Parker	Feb 2017	A1
20170050021	Cosman, Sr.	Feb 2017	A1
20170087369	Bokil	Mar 2017	A1
20170095669	Libbus et al.	Apr 2017	A1
20170165485	Sullivan et al.	Jun 2017	A1
20170189686	Steinke et al.	Jul 2017	A1
20170216602	Waataja et al.	Aug 2017	A1
20170239470	Wei et al.	Aug 2017	A1
20170274209	Edgerton	Sep 2017	A1
20170348526	Southwell	Dec 2017	A1
20180256906	Pivonka	Sep 2018	A1
20180272132	Subbaroyan	Sep 2018	A1
20180345022	Steinke et al.	Dec 2018	A1
20190022382	Gerasimenko et al.	Jan 2019	A1
20190232064	Parker	Aug 2019	A1
20190321641	Baldoni	Oct 2019	A1
20200139138	Sit	May 2020	A1
20200254255	Lee	Aug 2020	A1

Foreign Referenced Citations (50)

Number	Date	Country
101175530	May 2008	CN
10318071	Nov 2004	DE
1181947	Feb 2002	EP
2243510	Oct 2010	EP
2243511	Oct 2010	EP
2448633	May 2012	EP
2630984	Aug 2013	EP
2586491	Aug 2016	EP
2449546	Nov 2008	GB
2002090196	Mar 2002	JP
2002200179	Jul 2002	JP
2007528774	Oct 2007	JP
2008500086	Jan 2008	JP
1512625	Oct 1989	SU
1690727	Nov 1991	SU
WO-02065896	Aug 2002	WO
WO-02085448	Oct 2002	WO
WO-02092165	Nov 2002	WO
WO-03015863	Feb 2003	WO
WO-03066154	Aug 2003	WO
WO-2004007018	Jan 2004	WO
WO-2005115532	Dec 2005	WO
WO-2006007048	Jan 2006	WO
WO-2006057734	Jun 2006	WO
WO-2006063458	Jun 2006	WO
WO-2006084635	Aug 2006	WO
WO-2006119046	Nov 2006	WO
WO-2007035925	Mar 2007	WO
WO-2007082382	Jul 2007	WO
WO-2007103324	Sep 2007	WO
WO-2007117232	Oct 2007	WO
WO-2008039982	Apr 2008	WO
WO-2008045434	Apr 2008	WO
WO-2008106174	Sep 2008	WO
WO-2008121891	Oct 2008	WO
WO-2008140940	Nov 2008	WO
WO-2008142402	Nov 2008	WO
WO-2008153726	Dec 2008	WO
WO-2009018518	Feb 2009	WO
WO-2009061813	May 2009	WO
WO-2009097224	Aug 2009	WO
WO-2009129329	Oct 2009	WO
WO-2010111358	Sep 2010	WO
WO-2011014570	Feb 2011	WO
WO-2012154985	Nov 2012	WO
WO-2013116368	Aug 2013	WO
WO-2016154091	Sep 2016	WO
WO-2017044904	Mar 2017	WO
WO-2017146658	Aug 2017	WO
WO-2020236946	Nov 2020	WO

Non-Patent Literature Citations (235)

Entry
U.S. Appl. No. 15/606,869, filed May 26, 2017, Lee.
Alo et al., “New Trends in Neuromodulation for the Management of Neuropathic Pain,” Neurosurgery, vol. 50, No. 4, Apr. 2002, 15 pages.
Bahdra et al., Stimulation of High-Frequency Sinusoidal Electrical Block of Mammalian Myelinated Axons, J Comput Neurosco, 22:313-326, 2007.
Barolat et al., “Multifactorial Analysis of Epidural Spinal Cord Stimulation,” Sterotactic and Functional Neurosurgery, 1991; 56: 77-103.
Bhadra et al., “High Frequency electrical conduction block of the pudendal nerve,” Journal of Neural Engineering—Institute of Physics Publishing, 2006, 8 pages.
Bhadra MD, Niloy et al., “High-Frequency Electrical Conduction Block of Mammalian Peripheral Motor Nerve,” Muscle and Nerve, Dec. 2005, 9 pages.
Boger et al., “Bladder Voiding by Combined High Frequency Electrical Pudendal Nerve Block and Sacral Root Stimulation,” Neurourology and Urodynamics, 27, 2008, 5 pages.
Bowman and McNeal, Response of Single Alpha Motoneurons to High-Frequency Pulse Trains, Appl. Neurophysiol. 49, p. 121-138, 1986, 10 pages.
Burton, Charles, “Dorsal Column Stimulation: Optimization of Application,” Surgical Neurology, vol. 4, No. 1, Jul. 1975, 10 pages.
Cuellar et al., “Effect of High Frequency Alternating Current on Spinal Afferent Nociceptive Transmission,” Neuromodulation: Technology at the Neural Interface, 2012, 10 pages.
DeRidder et al., “Are Paresthesias necessary for pain suppression in SCS—Burst Stimulation,” Brain, Brain Research Center Antwerp of Innovative and Interdisciplinary Neuromodulation, 2010, 27 pages.
DeRidder et al., “Burst Spinal Cord Stimulation: Toward Paresthesia-Free Pain Suppression,” www.neurosurgery-online.com, vol. 66, Nos. 5, May 2010, 5 pages.
Grill, Warren et al., “Stimulus Waveforms for Selective Neural Stimulation,” IEEE Engineering in Medicine and Biology, Jul./Aug. 1995, pp. 375-385.
Holsheimer—Effectiveness of Spinal Cord Stimulation in the Management of Chronic Pain: Analysis of Technical Drawbacks and Solutions, Neurosurgery, vol. 40, No. 5, May 1997, pp. 990-999.
Hopp et al., “Effect of anodal blockade of myelinated fibers on vagal c-fiber afferents,” American Journal Physiological Society, Nov. 1980; 239(5), 9 pages.
Hoppenstein, Reuben, “Electrical Stimulation of the Ventral and Dorsal Columns of the Spinal Cord for Relief of Chronic Intractable Pain: Preliminary Report,” Surgical Neurology, vol. 4, No. 1, Jul. 1975, 9 pages.
Huxely et al., “Excitation and Conduction in Nerve: Quantitative Analysis,” Science, Sep. 11, 1964; 145: 1154-9.
Jang et al., “Analysis of Failed Spinal Cord Stimulation Trails in the Treatment of Intractable Chronic Pain,” J. Korean Neurosurg Soc 43, 2008, 5 pages.
Kilgore et al. “Nerve Conduction Block Utilizing High-Frequency Alternating Current” Medical & Biology Engineering and Computing, 2004, vol. 24, pp. 394-406.
Kilgore et al. “Reversible Nerve Conduction Block Using Kilohertz Frequency Alternating Current,” Neuromodulation Technology at the Neural Interface, International Neuromodulation Society, 2013, 13 pages.
Kumar et al., “Spinal Cord Stimulation in Treatment of Chronic Benign Pain: Challenges in Treatment Planning and Present Status, a 22-Year Experience,” Neurosurgery, vol. 58, No. 3, Mar. 2006, 16 pages.
Lachance et al., “Stimulation-induced ectopicity and propagation windows in model damaged axons,” J. Comput Neurosci, 2014, 9 pages.
Linderoth et al., “Mechanisms of Spinal Cord Stimulation in Painful Syndromes: Role of Animal Models,” Pain Medicine, vol. 7, No. S1, 2006, 13 pages.
Linderoth et al., “Physiology of Spinal Cord Stimulation: Review and Update,” Neuromodulation, vol. 2, No. 3, 1999, 15 pages.
Mediati, R.D., , “Mechanisms of Spinal Cord Stimulation,” Florence, Oct. 2, 2002, 31 pages.
Melzack, Ronald et al., “Pain Mechanisms: A New Theory,” Science, vol. 150, No. 3699, Nov. 19, 1965, 9 pages.
Muller and Hunsperger, “Helvetica Physiologica Acta—Reversible Blockierung der Erregungsleitung im Nerven durch Mittelfrequenz—Daverstrom,” Schwabe & Co. Basel, vol. 25, Fasc. 1, 1967, 4 pages.
North et al., “Failed Back Surgery Syndrome: 5-year Follow-Up after Spinal Cord Stimulator Implantation,” Neurosurgery, Official Journal of the Congress of Neurological Surgeons, vol. 28, No. 5, May 1991, 9 pages.
North et al., “Spinal Cord Stimulation for Axial Low Back Pain,” SPINE, vol. 30, No. 12, 2005, 7 pages.
North et al., “Spinal Cord Stimulation for Chronic, Intractable Pain: Experience over Two Decades,” Neurosurgery, vol. 32, No. 2, Mar. 1993, 12 pages.
Oakley, John C., “Spinal Cord Stimulation Mechanisms of Action,” SPINE vol. 27, No. 22, copyright 2002, 10 pages.
Perruchoud et al., “Analgesic Efficacy of High-Frequency Spinal Cord Stimulation: A Randomized Double-Blind Placebo-Controlled Study,” Neuromodulation: Technology at Neural Interface, International Neuromodulation Society, 2013, 7 pages.
Shealy MD, C. Norman et al., “Electrical Inhibition of Pain by Stimulation of the Dorsal Columns: Preliminary Clinical Report,” Anesthesia and Analgesia . . . Current Researches, vol. 446, No. 4, Jul.-Aug. 1967, 3 pages.
Simpson, BA, “Spinal Cord Stimulation in 60 cases of Intractable Pain.” Journal of Neurology, Neurosurgery and Psychiatry, 1991; 54 pages 196-199.
Simpson, BA, “Spinal Cord Stimulation.” British Journal of Neurosurgery, 1997, Feb. 11 (1), 5-11, 7 pages.
Solomonow et al., “Control of Muscle Contractile Force through Indirect High-Frequency Stimulation,” AM Journal of Physical Medicine, 1983, vol. 62, No. 3, pp. 71-82.
Tanner, J.A., “Reversible blocking of nerve conduction by alternating-current excitation,” Nature, Aug. 18, 1962; 195: 712-3.
Tiede et al., “Novel Spinal Cord Stimulation Parameters in Patients with Predominate Back Pain,” Neuromodulation: Technology at the Neural Interface, 2013, 6 pages.
Urban et al., “Percutaneous epidural stimulation of the spinal cord for relief of pain—Long Term Results,” Journal of Neurosurgery, vol. 48, Mar. 1978, 7 pages.
Van Butyen et al., “High Frequency Spinal Cord Stimulation for the Treatment of Chronic Back Pain Patients: Results of a Prospective Multicenter European Clinical Study,” Neuromodulation Technology at the Neural Interface, International Neuromodulation Society, 2012, 8 pages.
Van Den Honert, Mortimer JT, “A Technique for Collision Block of Peripheral Nerve: Frequency Dependence,” MP-11 IEEE Trans. Biomed, Eng. 28: 379-382, 1981.
Wallin et al., “Spinal Cord Stimulation inhibits long-term potentiation of spinal wide dynamic range neurons,” Elsevier Science B.V., Brain Research, 5 pages 2003.
Wolter et al., “Continuous Versus Intermittent Spinal Cord Stimulation: An Analysis of Factors Influencing Clinical Efficacy,” Neuromodulation: Technology at Neural Interface, www.neuromodulationjournal.com, 2011, 8 pages.
Woo MY, Campbell B. “Asynchronous Firing and Block of Peripheral Nerve Conduction by 20KC Alternating Current,” Los Angeles Neuro Society, Jun. 1964; 87-94, 5 pages.
Zhang et al., “Simulation Analysis of Conduction Block in Myelinated Axons Induced by High-Frequency Biphasic Rectangular Pulses,” IEEE Transactions on Biomedical Engineering, vol. 53., No. 7, Jul. 2006, 4 pages.
Zhu et al., “Changes in functional properties of A-type but not C-type sensory neurons in vivo in a rat model of peripheral neuropathy,” Journal of Pain Research, Dovepress, 2012, 18 pages.
Zhu et al., “Early Demyelination of Primary A-Fibers Induces a Rapid-Onset of Neuropathic Pain in Rat,” Neuroscience 200, 2012, 13 pages.
Zhu et al., “Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy,” BMC Neuroscience, 13:15, 2012, 15 pages.
“The Need for Mechanism-Based Medicine in Neuromodulation,” Neuromodulation: Technology at the Neural Interface, 2012, 7 pages.
Acticare.com website, http://web.archive.org/web/*/acticare.com, Internet Archive Way Back Machine, 2012, 22 pages.
Advanced Neuromodulation Systems, Compustim SCS Systems, Clinical Manual, 1997, 52 pages.
Agnew et al., “Considerations for safety with chronically implanted nerve electrodes,” Epilepsia, 31.s2, 1990, 6 pages.
Al-Kaisy et al., “10 kHz High-Frequency Spinal Cord Stimulation for Chronic Axial Low Back Pain in Patients With No History of Spinal Surgery: A Preliminary, Prospective, Open Label and Proof-of-Concept Study,” Neuromodulation: Technology at the Neural Interface, 2016, 8 pages.
Al-Kaisy et al., “Sustained Effectiveness of 10kHz High-Frequency Spinal Cord Stimulation for Patients with Chronic, Low Back Pain: 24-month Results of Prospective Multicenter Study,” Pain Medicine, 2014, 8 pages.
Al-Kaisy et al., “The Use of 10-Kilohertz Spinal Cord Stimulation in a Cohort of Patients with Chronic Neuropathic Limb Pain Refractory to Medical Management,” Neuromodulation Technology at the Neural Interface, 2015, 6 pages.
Al-Kaisy et al., Poster: “High-Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Chronic Back Pain Patients without Prior Back Surgery,” 2013, 1 page.
Al-Kaisy., “The use of 10-kilohertz spinal cord stimulation in a cohort of patients with chronic neuropathic limb pain refactory to medical management,” Neuromodulation: Technology at the Neural Interface, 18.1, 2015, 6 pages.
Augustinsson et al., “Spinal Cord Stimulation in Cardiovascular Disease,” Functional Neurosurgery, vol. 6, No. 1, Jan. 1995, 10 pages.
Bara et al., Poster re: High Frequency Spinal Cord Stimulation for Dominant Back Pain—1 year follow up, 2013, 1 page.
Barolat et al., “Multifactorial Analysis of Epidural Spinal Cord Stimulation,” Stereotactic and Functional Neurosurgery, 1991 56: 77-103.
Barolat et al., “Spinal Cord Stimulation for Chronic Pain Management,” Seminars in Neurosurgery, vol. 15, Nos. 2/3, 2004, 26 pages.
Barolat et al., “Surgical Management of Pain—Spinal Cord Stimulation: Equipment and Implantation Techniques,” Chapter 41, Thieme Medical Publishers, New York, 2002, 11 pages.
Bennett et al., “Spinal Cord Stimulation for Complex regional pain syndrome \| [RSD]: a Retrospective Multicenter Experience from 1995 to 1998 of 101 patients.” Neuromodulation, vol. 2, No. 3, 1999, 9 pages.
Benyamin et al., “A Case of Spinal Cord Stimulation in Raynaud's Phenomenon: Can Subthreshold Sensory Stimulation Have an Effect?” Pain Physician www.painphysicianjournal.com, 2007, 6 pages.
Bhadra et al., Stimulation of High-Frequency Sinusoidal Electrical Block of Mammalian Myelinated Axons, J Comput Neurosco, 22:313-326, 2007.
BionicNAVIGATOR Software Guide, Part MP9055261-001, 2004, 58 pages.
Boston Scientific “Precision™ Spinal Cord Stimulator System Clinician Manual—Directions for Use,” Clinician Manual, 2015, 74 pages (pp. I, 9-10).
Boston Scientific, News Release: “New Data Presented at NANS 2014 Demonstrate Long-Term, Low Back Pain Relief with Boston Scientific Precision Spectra™ Spinal Cord Stimulator System,” Dec. 12, 2014, 8 pages.
Broseta et al., “High-Frequency cervical spinal cord stimulation in spasticity and motor disorders,” Advances in Stereotactic and Functional Neurosurgery 7. Springer Viennam 1987, 6 pages.
Butt et al., “Histological Findings Using Novel Stimulation Parameters in a Caprine Model,” European Journal of Pain Supplements, 2011, 2 pages.
Cahana et al., “Acute Differential Modulation of Synaptic Transmission and Cell Suvival During Exposure to Pulsed and Continuous Radiofrequency Energy,” Journal of Pain, vol. 4, No. 4, May 2003, 6 pages.
Cameron et al., “Effects of posture on stimulation parameters in spinal cord stimulation,” Neuromodulation: Technology at the Neural Interface 1.4, 1998, 8 pages.
Camilleri et al., “Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device,” Surgery 143.6, 2008, 9 pages.
ClinicalTrials.Gov, “Safety and Effectiveness Study of the Precision SCS System Adapted for High-Rate Spinal Cord Stimulation (ACCELERATE),” https://clinicaltrials.gov/ct2/show/NCT02093793?term=boston+scientific&recr=Open&cond=%22Pain%22&rank=3, Feb. 2015, 3 pages.
Crapanzano et al., “High Frequency Spinal Cord Stimulation for Complex Regional Pain Syndrome: A Case Report,” Pain Physician, 2017, 6 pages.
Crosby et al., “Stimulation Parameters Define the Effectiveness of Burst Spinal Cord Stimulation in a Rat Model of Neuropathic Pain,” Neuromodulation Technology at the Neural Interface, International Neuromodulation Society, 2014, 8 pages.
De Carolis et al., Poster: “Efficacy of Spinal Cord Stimulation (SCS) in the Treatment of Failed Back Surgery Syndrome (FBSS): a comparative study,” 2013, 1 page.
Dorland's Illustrated Medical Dictionary, Twenty-sixth Edition, “Paresthesia,” 1981, 4 pages.
Doug Atkins of Medtronic Neurological, “Medtronic Neurostimulation Leads, 510(k) Summary,” Submission Prepared: Feb. 27, 2004, 6 pages.
Duyvendak et al., “Spinal Cord Stimulation With a Dual Quadripolar Surgical Lead Placed in General Anesthesia is Effective in Treating Intractable Low Back and Leg Pain,” Neuromodulation: Technology at the Neural Interface, vol. 10, No. 2, 2007, 7 pages.
Eddicks et al., “Thoracic Spinal Cord Stimulation Improves Functional Status and Relieves Symptoms in Patients with Refractory Angina Pectoris: The First Placebo-Controlled Randomised Study,” Heart Journal, 2007, 6 pages.
Feeling vs. Function Poster, Mager and Associates Consulting, 2009, 1 page.
Geddes, “A Short History of the electrical stimulation of excitable tissue—Including Electrotherapeutic Applications,” The Physiologist, vol. 27, No. 1, Feb. 1984, 51 pages.
Gulve et al., Poster: “10kHz High Frequency Spinal Cord Stimulation: Middlesbrough Experience,” 2013, 1 page.
Guo et al., “Design and Implement of a Mini-Instrument for Rehabilitation with Transcutaneous Electrical Nerve Stimulation,” School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai China, Mar. 31, 2007, 5 pages.
Hefferman et al., “Efficacy of Transcutaneous Spinal Electroanalgesia in Acute Postoperative Pain Management,” Anesthesiology, 2001, 2 pages.
Higuchi et al., “Exposure of the Dorsal Root Ganglion in Rats to Pulsed Radiofrequency Currents Activates Dorsal Horn Lamina I and II Neurons,” Neurosurgery, vol. 50, No. 4, Apr. 2002, 7 pages.
Hilberstadt et al., “The Effect of Transcutaneous Spinal Electroanalgesia upon Chronic Pain: A single case study,” Physiotherapy, vol. 86 No. 3, Mar. 2000, 2 pages.
House et al., “Safety and Efficacy of the House/3M Cochlear Implant in Profoundly Deaf Adults,” Otolaryngologic Clinics of North America, vol. 19, No. 2, May 1986, 12 pages.
International Neuromodulation Society 10th World Congress, Neuromodulation: Technology that Improves Patient Care, London, England, May 21-26, 2011, 385 pages.
J.P. Morgan North America Equity Research, “Nevro—Let the Launch Begin: Senza Approved, Raising PT to $54,” www.jpmorganmarkets.com, May 10, 2015, 8 pages.
J.P. Morgan North America Equity Research, “Nevro—Welcome to the Future of Spinal Cord Stimulation Initiating at OW with $34 Price Target,” www.jpmorganmarkets.com, Dec. 1, 2014, 39 pages.
Jacques et al., “Development of a New Implantable Bio-Telestimulator,” Surg. Neurol., vol. 13, May 1980, 2 pages.
Jain et al., Abstract—“Accelerate: A Prospective Multicenter Trial Evaluating the Use of High-Rate Spinal Cord Stimulation in the Management of Chronic Intractable Pain,” The American Academy of Pain Medicine, 2015, 1 page.
Jezernik et al., “Electrical Stimulation for the Treatment of Bladder Dysfunction: Current Status and Future Possibilities,” Neurological Research, vol. 24, Jul. 2002, 18 pages.
JMP Securities, “Nevro Corp. (NVRO) Initiating Coverage on Nevro Corp. with a Market Outperform Rating—Investment Highlights,” Dec. 1, 2014, 42 pages.
Kapural et al., “Comparison of 10-kHz High Frequency and Traditional Low-Frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: 24-Month Results From a Multicenter, Randomized, Controlled Pivotal Trial,” Neurosurgery, vol. 79, No. 5, Nov. 2016, 11 pages.
Kapural et al., “Novel 10-Khz High Frequency Therapy (HF10 Therapy) is Superior to Traditional Low-Frequency Spinal Cord Stimulation for Treatment of Chronic Back and Leg Pain,” Anesthesiology The Journal of American Society of Anesthesiologists, Inc., 2005, 11 pages.
Kilgore et al. “Nerve Conduction Block Utilizing High-Frequency Alternating Current” Medical & Biology Engineering and Computing, 2004, vol. 42, pp. 394-406.
Kreitler et al., “Chapter 15: Implantable Devices and Drug Delivery Systems—The Handbook for Chronic Pain,” NOVA Biomedical Books, New York, 2007, 17 pages.
Krista Oakes of Neuromed, Inc., “Implanted Spinal Cord Stimulator Lead 510(k) Summary of Safety and Effectiveness,” Submission Prepared Feb. 21, 1996, 3 pages.
Kuechmann et al., Abstract #853: “Could Automatic Position Adaptive Stimulation Be Useful in Spinal Cord Stimulation?” Medtronic, Inc., Minneapolis, MN, European Journal of Pain 13, 2009, 1 page.
Kumar et al., “The Effects of Spinal Cord Stimulation in Neuropathic Pain Are Sustained: A 24-month Follow-Up of the Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation,” www.neurosurgery-online.com, vol. 63, No. 4, Oct. 2008, 9 pages.
Lambru et al., “Safety and Efficacy of Cervical 10 kHz Spinal Cord Stimulation in Chronic Refactory Primary Headaches: A Retrospective Case Series,” The Journal of Headache and Pain, 2016, 8 pages.
Lempka et al., “Computational Analysis of Kilohertz Frequency Spinal Cord Stimulation for Chronic Pain Management,” Anesthesiology, vol. 122, No. 6, Jun. 2015, 15 pages.
Linderoth et al., “Mechanisms of Spinal Cord Stimulation in Neuropathic and Ischemic Pain Syndromes,” Neuromodulation, Chapter 25, 2009, 19 pages.
MacDonald, Alexander J. R, and Coates, Tim W., “The Discovery of Transcutaneous Spinal Electroanalgesia and Its Relief of Chronic Pain,” Physiotherapy, vol. 81. No. 11, Nov. 1995, 9 pages.
Manola et al., “Technical Performance of Percutaneous Leads for Spinal Cord Stimulation: A Modeling Study,” International Neuromodulation Society, 2005, 12 pages.
Mavoori et al., “An Autonomous implantable computer for neural recording and stimulation in unrestrained primates,” Journal of Neuroscience Methods, 2005, 7 pages.
Medtronic—Neurological Division, QuadPlus, Model 3888, Lead Kit for Spinal Cord Stimulation (SCS) Implant Manual, 1996, 33 pages.
Medtronic—Neurological Division, Resume II, Model 3587A, Lead Kit for Spinal Cord Stimulation (SCS) and Peripheral Nerve Stimulation (PNS), Implant Manual, 1996, 32 pages.
Medtronic—Neurological Division, Resume TL, Model 3986, Lead Kit for Spinal Cord Stimulation (SCS) and Peripheral Nerve Stimulation (PNS), Implant Manual, 1996, 27 pages.
Medtronic—Neurostimulation Systems: Expanding the Array of Pain Control Solutions, 1999, 6 pages.
Medtronic commercial leaflet entitled: Surgical Lead Comparison, 1999, 4 pages.
Medtronic, “Medtronic Pain Therapy—Using Neurostimulation for Chronic Pain, Information for Prescribers” 2007, 29 pages.
Medtronic, Pain Therapy Product Guide, Dec. 2008, 31 pages.
Medtronic, Pisces Quad 3487A, Pisces Quad Compact model 3887, Pisces Quad Plus 3888 Lead Kit, Implant Manual, 2008, 16 pages.
Medtronic: Spinal Cord Stimulation Systems, 2013, 4 pages.
Merriam Webster's Collegiate Dictionary, Tenth Edition, definition of “Implantable,” 1995, 3 pages.
Meyerson et al., Mechanisms of spinal cord stimulation in neuropathic pain, Neurological Research, vol. 22, Apr. 2000, 5 pages.
Miller, Jonathan, “Neurosurgery Survival Guide—A Comprehensive Guide to Neurosurgical Diagnosis and Treatment,” http://d3jonline.tripod.com/neurosurgery/, Nov. 14, 2016, 4 pages.
Miller, Jonathan, “Parameters of Spinal Cord Stimulation and Their Role in Electrical Charge Delivery: A Review,” Neuromodulation: Technology at the Neural Interface, 2016, 12 pages.
Morgan Stanley Research North America, “Nevro Corp—There's Something Happening Here,” Dec. 15, 2014, 12 pages.
Mosby's Medical Dictionary, 8th Edition, “Paresthesia,” 2009, 3 pages.
Mounaïm et al., “New Neurostimulation Strategy and Corresponding Implantable Device to Enhance Bladder Functions,” Biomedical Engineering Trends in Electronics, Communications and Software, Chapter 5, 2011, 15 pages.
Mueller et al., “The MED-EL SONATATI 100 Cochlear Implant: An evaluation of its safety in adults and children,” Acta Oto-Laryngologica, vol. 131, No. 5, 2011, 8 pages.
Munglani, Rajesh, “The Longer Term Effect of Pulsed Radiofrequency for Neuropathic Pain,” PAIN 80, 1999, 3 pages.
Nashold et al., “Dorsal Column Stimulation for Control Pain—Preliminary Report on 30 Patients,” J. Neurosurg., vol. 36, May 1972, 8 pages.
Nevro—Chronic Pain and Treatments, http://www.nevro.com/English/Patients/Chronic-Pain-and-Treatments/default.aspx2016, 3 pages.
Nevro—Clinical Evidence www.nevro.com/English/Physicians/Clinical-Evidence/default.aspx, 2016, 2 pages.
Nevro—HF10™ Therapy Fact Sheet, http://www.nevro.com/English/Newsroom/Resources/default.aspx, 2015, 4 pages.
Nevro—Physician Overview www.nevro.com/English/Physicians/Physician-Overview/default.aspx, 2016, 5 pages.
Nevro—Senza System http://www.nevro.com/English/Physicians/Senza-System/default.aspx, 2016, 3 pages.
Nevro HF10 Therapy—New Hope for Chronic Back Pain and Leg Pain Sufferers, http://s21.q4cdn.com/478267292/files/doc_downloads/HF10-Therapy-New-Hope-for-Chronic-Pain.pdf, 2016, 2 pages.
Nevro Senza Patient Manual, Jan. 16, 2015, 53 pages.
Nevro Senza Physician Implant Manual, Jan. 16, 2015, 31 pages.
Nevro website: HF10 Therapy Advantages, www.nevro.com/English/Patients/HF10-Therapy-Advantages/default.aspx, 2016, 3 pages.
Nevro, PMA Approval Letter and Referenced Summary of Safety and Effectiveness Data (SSED) May 8, 2015, 60 pages.
Nevro's presentation of HF10 therapy on Nevro's website, http://www.nevro.com/English/Home/default.aspx, 2016, 2 pages.
News Release Details, “Nevro Corp. Announces Pricing of Initial Public Offering,” 2014, 1 page.
NIDCD-NIH 2011, Cochlear Implant Brochure, http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx, Jun. 29, 2012, 2 pages.
North American Neuromodulation Society—14th Annual Meeting, “Neuromodulation: Vision 2010,” Dec. 2-5, 2010, 9 pages.
North American Neuromodulation Society—16th Annual Meeting, “From Innovation to Reality Syllabus,” Dec. 6-9, 2012, 198 pages.
North American Neuromodulation Society—Celebrating 20 years, 1 8th Annual Meeting Program Book, Dec. 11-14, 2014, 28 pages.
North American Neuromodulation Society, “Today's Vision, Tomorrow's Reality—17th Annual Meeting,” Dec. 5-8, 2013, 12 pages.
North American Neuromodulation, “15th Annual Meeting, Our Crystal Anniversary,” Dec. 8-11, 2011, 8 pages.
North et al., “Spinal Cord Stimulation With Interleaved Pulses: A Randomized, Controlled Trial,” vol. 10, No. 4, 2007, 9 pages.
Oakley et al., “A New Spinal Cord Stimulation System Effectively Relieves Chronic, Intractable Pain: A Multicenter Prospective Clinical Study,” Neuromodulation: Technology at the Neural Interface, vol. 10, No. 3, 2007, 17 pages.
Oakley, John C., “Spinal Cord Stimulation in Axial Low Back Pain: Solving the Dilemma,” Pain Medicine, vol. 7, No. S1, 2006, 6 pages.
OHSIPP Summer Newsletter, The Official Newsletter for the Ohio Society of Interventional Pain Physicians, vol. 1 Ed. 2, Summer 2010, 8 pages.
Paicius et al., “Peripheral Nerve Field Stimulation for the Treatment of Chronic Low Back Pain: Preliminary Results of Long-Term Follow-up: A Case Series,” Neuromodulation: Technology at the Neural Interface, vol. 10, No. 3, 2007, 12 pages.
Palmer et al., “Transcutaneous electrical nerve stimulation and transcutaneous spinal electroanalgesia: A preliminary efficacy and mechanisms-based investigation,” Physiotherapy, 95, 2009, 7 pages.
Prausnitz et al., “The Effects of Electric Current Applied to Skin: A Review for Transdermal Drug Delivery,” Advanced Drug Delivery Reviews 18, 1996, 31 pages.
Precision—Charging System, Advanced Bionic Corporation, Part 9055259-0001, 2005, 2 pages.
Precision—Physician System Handbook, Advanced Bionic Corporation, Part 9055253-0001, 2005, 92 pages.
Precision—Physician Trail Kit Insert, Advanced Bionic Corporation, Part 9055258-0001, 2005, 2 pages.
Precision Spinal Cord Stimulation—Charging System Insert, Advanced Bionic Corporation, Part 9055074-0001, 2004, 2 pages.
Precision Spinal Cord Stimulation—Patienet Trial Journal, Advanced Bionic Corporation, Part 9055260-0001, 2004, 10 pages.
Precision Spinal Cord Stimulation—Patient System Handbook, Advanced Bionic Corporation, Part 9055072-0001, 2004, 93 pages.
Precision Spinal Cord Stimulation—Physician Implant Manual, Advanced Bionic Corporation, Part 9055100, 2004, 62 pages.
Precision Spinal Cord Stimulation—Physician Implant Manual, Advanced Bionic Corporation, Part 9055255-0001, 2005, 70 pages.
Precision Spinal Cord Stimulation—Physician Lead Manual, Advanced Bionic Corporation, Part No. 9055183-001, May 2004, 31 pages.
Precision Spinal Cord Stimulation—Physician Lead Manual, Advanced Bionic Corporation, Part 9055095, 2004, 62 pages.
Precision Spinal Cord Stimulation—Physician Lead Manual, Advanced Bionic Corporation, Part 9055256-0001, 2005, 56 pages.
Precision Spinal Cord Stimulation—Physician Trail Handbook, Advanced Bionic Corporation, Part 9055254-0001, 2005, 66 pages.
Precision Spinal Cord Stimulation—Physician Trail Kit Model SC-7005, Part 9055066-001, Advanced Bionic Corporation, 2004, 2 pages.
Precision Spinal Cord Stimulation—Remote Control Model SC-5200, Part 9055107-001, 2004, Advanced Bionic Corporation, 2 pages.
Precision Spinal Cord Stimulation—Remote Control Model SC-5210, Advanced Bionic Corporation, Part 9055257-001, 2005, 2 pages.
Precision Spinal Cord Stimulation System—Patient System Handbook, Advanced Bionic Corporation, Part No. 9055184-001, May 2004, 86 pages.
Precision Spinal Cord Stimulation System, Patient Trial Handbook, Part 9055078, 2004, 74 pages.
Pudenz et al., “Development of an Implantable Telestimulator,” Proc. 4th Ann. Nat'l Conf. Neuroelectric Soc., Mar. 10-12, 1971, 111-12 ( Wulfsohn, Norman L. and Anthony Sances, Jr. (eds.) 1971, 4 pages.
Pudenz et al., “Neural Stimulation: Clinical and Laboratory Experiences,” Surg. Neurol, 39:235-242 (1993).
Rapcan et al., Clinical Study, “High-Frequency—Spinal Cord Stimulation,” Indexed and Abstracted in Science Citation Index Expanded and in Journal Citation Reports, 2015, 3 pages.
Reddy et al., “Comparison of Conventional and Kilohertz Frequency Epidural Stimulation in Patients Undergoing Trailing for Spinal Cord Stimulation: Clinical Considerations,” World Neurosurgery, www.sciencedirect.com, 6 pages, 2015.
Remedi Pain Relief—ENM (Electronic Nerve Modulation), https://web.archive.org/web/20050906181041/http://www.remediuk.com/trials.htm, 2005, 5 pages.
Robb et al., “Transcutaneous Electrical Nerve Stimulation vs. Transcutaneous Spinal Electroanalgesia for Chronic Pain Associated with Breast Cancer Treatments,” Journal of Pain and Symptom Management, vol. 33, No. 4, Apr. 2007, 10 pages.
Royle, John., “Transcutaneous Spinal Electroanalgesia and Chronic Pain,” Physiotherapy, vol. 86, No. 5, May 2000, 1 page.
Schulman et al., “Battery Powered BION FES Network,” Proceedings of the 26th Annual Conference of the IEEE EMBS, San Francisco, CA., Sep. 1-5, 2004, 4 pages.
Science Daily, “Chronic Pain Costs U.S. upto $635 billion, study shows,” www.sciencedaily.com/releases/2012/09/120911091100.htm, Sep. 11, 2012, 2 pages.
Senza Spinal Cord Stimulation (SCS) System—P130022, http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm449963.htm Oct. 14, 2016, 2 pages.
Sharan et al., “Evolving Patterns of Spinal Cord Stimulation in Patients Implanted for Intractable Low Back and Leg Pain,” International Neuromodulation Society, vol. 5, No. 3, 2002, 13 pages.
Shealy et al., “Dorsal Column Electrohypalgesia,” Jul. 1969, 8 pages.
Shelden et al., “Depolarization in the Treatment of Trigeminal Neuralgia,” Evaluation of Compression and Electrical Methods Clinical Concept of Neurophysiological Mechanism, 1966, 8 pages.
Shelden et al., “Development and Clinical Capabilities of a New Implantable Biostimulator,” The American J. of Surgery, vol. 124, Aug. 1972, 6 pages.
Shelden et al., Electrical Control of Facial Pain, Am. J. of Surgery, vol. 114, Aug. 1967, 4 pages.
Shelden et al., “Electrical stimulation of the nervous system,” Surg. Neurol. vol. 4, No. 1, Jul. 1975, 6 pages.
Simpson et al., “A Randomized, Double-Blind, Crossover Study of the Use of Transcutaneous Spinal Electroanalgesia in Patients with Pain from Chronic Critical Limb Ischemia,” Journal of Pain and Symptom Management, vol. 28, No. 5, Nov. 2004, 6 pages.
Simpson, BA, “Spinal Cord Stimulation in 60 cases of Intractable Pain.” Journal of Neurology, Neurosurgery and Psychiatry, 1991 54 pp. 196-199.
Sluijter et al., “The Effects of Pulsed Radiofrequency Fields Applied to the Dorsal Root Ganglion—A Preliminary Report,” The Pain Clinic, vol. 11, No. 2, 1998, 12 pages.
Smet et al,., “Successful Treatment of Low Back Pain with a Novel Neuromodulation Device,” AZ Nikolaas, 2010, 12 pages.
Smet et al., Poster: “High-Frequency Spinal Cord Stimulation at 10 kHz after Failed Traditional Spinal Cord Stimulation,” NANS, 2013, 1 page.
St. Jude Medical, “Eon Mini™ Rechargeable IPG, The smallest, longest lasting IPG for enhanced patient satisfaction, ”Apr. 29, 2013, 3 pages.
St. Jude Medical, “Individualized Therapy through Diverse Lead Options,” 2008, 6 pages.
Stimwave, News Release: Stimwave Receives FDA Approval for High Frequency IDE, http://stimwave.com/newsroom/latest-news, Jun. 9, 2015, 2 pages.
Struijk et al., “Recruitment of Dorsal Column Fibers in Spinal Cord Stimulation: Influence of Collateral Branching,” IEEE Transactions on Biomedical Engineering, vol. 39, No. 9, Sep. 1992, 10 pages.
Sweet et al., “Paresthesia-Free High Density Spinal Cord Stimulation for Postlaminectomy Syndrome in a Prescreened Population: A Prospective Case Series,” Neuromodulation: Technology at the Neural Interface, 2015, 7 pages.
Swigris et al., “Implantable Spinal Cord Stimulator to Treat the Ischemic Manifestations of Thromboangiitis Obliterans (Buerger's disease),” Journal of Vascular Surgery, vol. 29, No. 5, 1998, 8 pages.
Tan et al., “Intensity Modulation: A Novel Approach to Percept Control in Spinal Cord Stimulation,” Neuromodulation Technology at the Neural Interface, International Neuromodulation Society 2015, 6 pages.
Taylor et al., “The Cost Effectiveness of Spinal Cord Stimulation in the Treatment of Pain: A Systematic Review of the Literature,” Journal of Pain and Symptom Management, vol. 27, No. 4., Apr. 2001, 9 pages.
Tesfaye et al., “Electrical Spinal Cord Stimulation for Painful Diabetic Peripheral Neuropathy,” The Lancet, vol. 348, Dec. 21-28, 1996, 4 pages.
Thompson et al., “A double blind randomised controlled clinical trial on the effect of transcutaneous spinal electroanalgesia (TSE) on low back pain,” European Journal of Pain, vol. 12, Issue 3, Apr. 2008, 6 pages.
Tollison et al., “Practical Pain Management Neurostimulation Techniques,” Chapter 12, Lippincott Williams and Wilkins, Third Edition, 2002, 13 pages.
Towell et al., “High Frequency non-invasive stimulation over the spine: Effects on mood and mechanical pain tolerance in normal subjects,” Behavioral Neurology, vol. 10, 1997, 6 pages.
Van Buyten et al., “Pain Relief for Axial Back Pain Patients,” INS Meeting Poster, 2011, 1 page.
Van Havenbergh et al., “Spinal Cord Stimulation for the Treatment of Chronic Back Pain Patients: 500-Hz vs. 1000-Hz Burst Stimulation,” Neuromodulation: Technology at the Neural Interface, International Neuromodulation Society, 2014, 4 pages.
Verrills et al., “Peripheral Nerve Field Stimulation for Chronic Pain: 100 Cases and Review of the Literature,” Pain Medicine, 2011, 11 pages.
Verrills et al., “Salvaging Failed Neuromodulation Implants with Nevro High Frequency Spinal Cord System,” NANS Poster, 2013, 1 page.
Von Korff et al., “Assessing Global Pain Severity by Self-Report in Clinical and Health Services Research,” SPINE, vol. 25, No. 24, 2000, 12 pages.
Wallace et al., Poster: “Accelerate: A Prospective Multicenter Trial Evaluating the Use of High-Rate Spinal Cord Stimulation in the Management of Chronic Intractable Pain,” Boston Scientific Corporation, 2015, 1 page.
Ward et al., “Variation in Motor Theshold with Frequency Using kHz Frequency Alternating Current,” Muscle and Nerve, Oct. 2001, 9 pages.
Webster's Third New International Dictionary of the English Language Unabridge, “Paresthesia,” 1993, 3 pages.
Weinberg et al., “Increasing the oscillation frequency of strong magnetic fields above 101 kHz significantly raises peripheral nerve excitation thresholds,” Medical Physics Letter, May 2012, 6 pages.
Woo MY, Campbell B. “Asynchronous Firing and Block of Peripheral Nerve Conduction by 20KC Alternating Current,” Los Angeles Neuro Society, 1964, June 87-94, 5 pages.
Yearwood et al., “A Prospective Comparison of Spinal Cord Stimulation (SCS) Using Dorsal Column Stimulation (DCS), Intraspinal Nerve Root Stimulation (INRS), and Varying Pulse Width in the Treatment of Chronic Low Back Pain,” Congress of Neurological Surgeons 56th Annual Meeting, Oct. 7-12, 2006, 2 pages.
Yearwood et al., “Pulse Width Programming in Spinal Cord Stimulation: A Clinical Study,” Pain Physician Journal, Jul./Aug. 2010, 16 pages.
Yearwood et al., Case Reports: “A Prospective Comparison of Spinal Cord Stimulation (SCS) Using Dorsal Column Stimulation (DCS), Intraspinal Nerve Root Stimulation (INRS), and Varying Pulse Width in the Treatment of Chronic Low Back Pain,” Presented at the Congress of Neurological Surgeons 56th Annual Meeting, Oct. 7-12, 2006, 7 pages.
Zhang et al., Changes Across Time in Spike Rate and Spike Amplitude of Auditory Nerve Fibers Stimulated by Electric Pulse Trains, Journal of the Association for Research of Otolaryngology, 2007, 17 pages.
Abejon et al., “Is Impedance a Parameter to be Taken into Account in Spinal Cord Stimulation?” Pain Physician, 2007, 8 pages.
Alo et al., “Factors Affecting Impedance of Percutaneous Leads in Spinal Cord Stimulation,” International Neuromodulation Society, vol. 9, No. 2, 2006, 8 pages.
Al-Kaisy et al., “Prospective, Randomized, Sham-Control, Double Blind, Crossover Trial of Subthreshold Spinal Cord Stimulation at Various Kilohertz Frequencies in Subjects Suffering from Failed Back Surgery Syndrome,” International Neuromodulation Society, Jan. 2018, 9 pages.
Bronstein et al., “The Rationale Driving the Evolution of Deep Brain Stimulation of Constant-Current Devices,” International Neuromodulation Society 2014, 5 pages.
McCreery et al., “Charge Density and Charge Per Phase as Cofactors in Neural Injury Induced by Electrical Stimulation,” IEEE Transactions on Biomedical Engineering, vol. 37, No. 10, Oct. 1990, 6 pages.
McCreery et al., “Damage in Peripheral Nerve from Continuous Electrical Stimulation: Comparison of Two Stimulus Waveforms,” Medical and Biological Engineering and Computing, Jan. 1992, 6 pages.
McCreery et al., “Relationship between Stimulus Amplitude, Stimulus Frequency and Neural Damage During Electrical Stimulation of Sciatic Nerve of a Cat,” Medical and Biological Engineering and Computing, May 1995, 4 pages.
Nevro—Leadership Through Innovation, J. P. Morgan 36th Annual Healthcare Conference, Jan. 8, 2018, 21 pages.
Renew Neurostimulation System—Clinician's Manual—Advanced Neuromodulation Systems, Life Gets Better, 2000, 77 pages.
Rosenblueth et al., “The Blocking and Deblocking Effects of Alternating Currents on Nerve,” Department of Physiology in Harvard Medical School, Nov. 1938, 13 pages.
St. Jude Medical, “Clinician's Manual—Percutaneous Lead Kit, Models 3143, 3146, 3149, 3153, 3156, 3159, 3183, 3186, 3189,” 2016, 24 pages.
Thomson et al., “Effects of Rate on Analgesia in Kilohertz Frequency Spinal Cord Stimulation: Results of the PROCO Randomized Controlled Trial,” Neuromodulation: Technology at the Neural Interface, 2017, 10 pages.
Wesselink et al., Analysis of Current Density and Related Parameters in Spinal Cord Stimulation, IEEE Transaction on Rehabilitation Engineering vol. 6, No. 2, Jun. 1998, 8 pages.
Siegel et al., “Prospective Randomized Feasibility Study Assessing the Effect of Cyclic Sacral Neuromodulation on Urinary Urge Incontinence in Women,” Female Pelvic Med Reconstr Surg. 2018, 5 pages.
Cadish, “Stimulation Latency and Comparison of Cycling Regimens in Women Using Sacral Neuromodulation,” Feb. 1, 2016, 4 pages.
Ward et al., “Electrical Stimulation Using Kilohertz-Frequency Alternating Current,” Journal of the American Physical Therapy Association, vol. 89, No. 2, Feb. 2009, 12 pages.
Cappaert et al., “Efficacy of a New Charge-Balanced Biphasic Electrical Stimulus in the Isolated Sciatic Nerve and the Hippocampal Slice,” International Journal of Neural Systems, vol. 23, No. 1, 2013, 16 pages.
Hofmann et al., “Modified Pulse Shapes for Effective Neural Stimulation,” Frontiers in Neuroengineering, Sep. 28, 2011, 10 pages.

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	Number	Date	Country
	20200269051 A1	Aug 2020	US

Provisional Applications (1)

	Number	Date	Country
	62798334	Jan 2019	US

Ramped therapeutic signals for modulating inhibitory interneurons, and associated systems and methods

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