Variable waveforms and neuromodulation devices capable of implementing the same for comfortable electrical stimulation

Abstract

A device may include a first electrode configured to be worn on the skin of a living body at a first location. A device may include a second electrode configured to be worn on the skin of the living body at a second location. A device may include a controller configured to transmit, to the living body via the first electrode and the second electrode, a pulse waveform that includes a plurality of pulses in sequence, wherein: frequencies of the plurality of pulses are modulated based on a Brownian noise distribution, and amplitudes of the plurality of pulses are modulated in accordance with a sinusoidal pattern.

Description

PATENT Attorney Docket No. 125847.8041.WO01VARIABLE WAVEFORMS AND NEUROMODULATION DEVICES CAPABLE OF IMPLEMENTING THE SAME FOR COMFORTABLE ELECTRICAL STIMULATION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Application No. 63 / 603,493, titled “Variable Waveforms and Neuromodulation Devices Capable of Implementing the Same for Comfortable Electrical Stimulation” and filed on November 28, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] Various embodiments relate to electrical neuromodulation. More particularly, methods and devices herein provide electrical neuromodulation for treating symptoms of chronic and acute pain as well as other conditions. BACKGROUND

[0003] Pain is the mental manifestation of a neurological response to various physiological and psychological ailments. Pain serves as a warning of physical injury or biological dysfunction. Sometimes pain persists much longer than it takes for the healing of the initial injury to occur, and may be very difficult to alleviate. The most common pain relief methods employ drugs (e.g., opioids) that act to block neurotransmission pathways within the body. Often such drugs are not effective for pain relief over the long term, or produce unacceptable side effects. Consequently, various forms of electrical stimulation such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) have also been employed to alleviate pain.

[0004] SCS is effective but is an invasive procedure and has all the typical risks associated with implantable devices, as well as the risk of serious damage to the spinal cord. Meanwhile, conventional TENS is not effective in all patients due to the difficulty in picking effective settings and it may produce effects which only last during stimulation and do not produce long-term pain relief. Moreover, many patients find conventional TENS at therapeutically effective levels to be uncomfortable. 1 168329102.1PATENT Attorney Docket No. 125847.8041.WO01BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1 illustrates a conventional example of a neuromodulation device for applying TENS.

[0006] Figure 2 is a block diagram illustrating modules of a neuromodulation device, according to some embodiments.

[0007] Figure 3 is a block diagram illustrating phases of an electrical pulse output from a neuromodulation device, according to some embodiments.

[0008] Figure 4 is a pulse waveform diagram illustrating phases of one variation of an electrical pulse output by a neuromodulation device as a simplified waveform, according to some embodiments.

[0009] Figure 5 is a diagram illustrating an exemplary Brownian noise distribution for modulation of a waveform, according to some embodiments.

[0010] Figure 6 is a diagram illustrating an exemplary oscillating pattern modulation of a pulse waveform, according to some embodiments.

[0011] Figure 7 illustrates a neuromodulation device for applying TENS, according to some embodiments.

[0012] Figure 8 is a flow diagram for a method of operating a neuromodulation device, according to some embodiments.

[0013] Figure 9 is a flow diagram for a method of operating a neuromodulation device, according to some embodiments.

[0014] Various features of the technology described herein will become more apparent to those skilled in the art from a study of the Detailed Description in conjunction with the drawings. Various embodiments are depicted in the drawings for the purpose of illustration. However, those skilled in the art will recognize that alternative embodiments may be employed without departing from the principles of the technology. Accordingly, although specific embodiments are shown in the drawings, the technology is amenable to various modifications. 2 168329102.1PATENT Attorney Docket No. 125847.8041.WO01DETAILED DESCRIPTION

[0015] Many conventional neuromodulation devices for applying transcutaneous electrical nerve stimulation (TENS) offer limited effectiveness in patients for a variety of reasons. One reason is that the physical construction of many neuromodulation devices means that the neuromodulation devices are not effective in offering a user pain relief while also remaining comfortable and not interfering with daily activities. For example, many conventional neuromodulation devices are bulky or difficult to wear. Another reason is that neuromodulation devices typically are configured to apply constant electrical signals to a user, with limited adjustability. Accordingly, many users find conventional neuromodulation devices to be uncomfortable or irritating when signals are applied at a current level proven to be therapeutically effective. While some neuromodulation devices allow a user to reduce the amplitude of the signal, conventional modifications of a neuromodulation signal result in less effectiveness for therapeutic treatment. These constant signals applied by conventional neuromodulation devices are not able to be tailored or personalized to particular sensitivities. Moreover, such constant signals cannot be tailored based on an underlying type of ailment or the severity of the ailment.

[0016] Introduced here are neuromodulation devices that overcome the deficiencies of conventional neuromodulation devices to provide effective pain relief while avoiding many of the downsides of conventional neuromodulation devices. That is, neuromodulation devices – and methods of operating the same – according to exemplary embodiments herein are configured to improve pain relief while avoiding user discomfort.

[0017] In addition to the above, many conventional neuromodulation devices for applying TENS utilize relatively low intensity (e.g., measured in current delivered to a living body) in an effort to maintain user comfort during treatment. However, therapeutic efficacy from TENS treatments is largely dependent on the intensity of the waveform delivered to a living body, notwithstanding user discomfort at higher intensities. Conventional neuromodulation devices and conventional methods of TENS treatments therefore frequently “under-dose” by applying less current to a living body, 3 168329102.1PATENT Attorney Docket No. 125847.8041.WO01resulting in inadequate relief provided for long term pain relief. Accordingly, there is a need for a neuromodulation device and method of TENS treatment that increases the intensity of applied electrical signals to a living body or more effective therapeutic treatment while avoiding the typical corresponding increase of user discomfort from irritation caused by the increased intensity.

[0018] In further addition to the above, many conventional neuromodulation devices are unsuitable for treatment of certain body areas and pain types at therapeutically effective levels. At therapeutically effective levels, conventional neuromodulation devices may cause significant prolonged muscle contractions. These muscle contractions are less comfortable in areas of the body with smaller muscle groups, for example, around joints such as the knee, elbow, shoulder, and wrist. Additionally, these muscle contractions may be particularly uncomfortable for some injuries or types of pain, including, strain injuries, menstrual pain, temporomandibular joint (TMJ) pain, and migraines. Accordingly, there is a need for a neuromodulation device and method of TENS treatment that is therapeutically effective on areas of a living body sensitive to muscle contractions. Additionally, there is a need for a neuromodulation device and method of TENS treatment that is therapeutically effective for types of pain and injuries that are not able to be treated with conventional neuromodulation devices because of prolonged muscle contractions.

[0019] As further discussed below, the neuromodulation devices introduced here can overcome the deficiencies of conventional neuromodulation devices that implement low intensity electrical stimulation with prolonged muscle contraction. Neuromodulation devices herein may be configured to apply a plurality of pulse waveforms in sequence to form an overall waveform. The pulse waveforms may differ from one another in amplitude (e.g., peak or average current) and / or frequency. In some embodiments, the amplitudes of sequential pulse waveforms may be modulated according to a first pattern. The first pattern may be a sinusoidal pattern, parabolic pattern, noise distribution pattern, or curved rise and fall pattern. In some embodiments, the frequencies of sequential pulse waveforms may be modulated according to a second pattern. The second pattern may be a sinusoidal pattern, parabolic pattern, 4 168329102.1PATENT Attorney Docket No. 125847.8041.WO01noise pattern, or curved rise and fall pattern. The second pattern may be different than the first pattern. In some embodiments, a pattern for modulation as described herein may be oscillating (e.g., sinusoidal, parabolic, etc.) or may be nonlinear (e.g., noise). The modulation of frequency and / or amplitude according to oscillating or nonlinear patterns may create an irregular “breathing” sensation compared to conventional neuromodulation devices. Accordingly, waveforms described herein may avoid prolonged muscle contractions while delivering a greater amount of current compared to conventionally applied electrical signals. As a result, neuromodulation devices described herein may be more therapeutically effective than conventional neuromodulation devices with increased user comfort compared to those devices.

[0020] Waveforms according to exemplary embodiments herein have parameters that greatly influence both the therapeutic effectiveness and the comfort of a user receiving the waveform. As discussed further below, these parameters include, but are not limited to, peak amplitude, pattern of modulation, oscillation period for a pattern of modulation, total period of a waveform pulse, period of different phases of a pulse, modulation amplitude, and mean frequency. Examples of values and ranges for these parameters described herein have been shown to provide enhanced therapeutic effectiveness with increased comfort. In some cases, exemplary ranges described herein may provide enhanced therapeutic effectiveness and comfort independently of other parameters. In other cases, exemplary ranges described herein may provide enhanced therapeutic effectiveness and comfort when employed in combination with other parameters.

[0021] Given a neuromodulation device that applies pulse waveforms implementing frequency and / or amplitude modulation and having specific parameters, a neuromodulation device according to embodiments herein can: Effectively treat different body parts or nerve types in a living body to reduce pain; Transmit waveforms to a user that are therapeutically effective and conform to user tolerance; 5 168329102.1PATENT Attorney Docket No. 125847.8041.WO01Transmit waveforms to a user that are therapeutically effective while improving user comfort and reducing irritation compared to conventional neuromodulation devices; Provide pain relief via TENS treatments at areas of a living body with small muscle groups currently unsuitable for conventional neuromodulation devices, for example, at the knee, shoulder, wrist, and elbow; and Provide pain relief via TENS treatments for pain types currently unsuitable for conventional neuromodulation devices, for example, for strain injuries, menstrual pain, temporomandibular joint (TMJ) pain, and migraines.

[0022] In some embodiments, a waveform applied by a neuromodulation device may include a plurality of pulses applied in sequence. In some embodiments, amplitudes of the sequential pulses may be modulated according to a sinusoidal, parabolic, or otherwise curved rise / fall oscillating pattern. As a part of the modulation, the amplitude of a pulse may be different than an amplitude of the preceding pulse, as well as the amplitude of the succeeding pulse. For example, a first peak amplitude of a first pulse may be less than or greater than a second peak amplitude of a succeeding second pulse. As a part of the amplitude modulation, the peak current may be oscillated across the plurality of pulses between a peak current and between about 30% and 70% of the peak current. In some embodiments, a peak current may be oscillated between about 80% and 100% of the peak current. In some embodiments, the peak current may be oscillated across the plurality of pulses between the peak current and about half of the peak current. In some embodiments, a peak current of a waveform may be between about 1 and 150 milliamps (mA). In some embodiments, a peak current of a waveform may be between about 1 and 100 mA. In some embodiments, the modulation of amplitude may have a period of oscillation between about 1 and 10 seconds.

[0023] In some embodiments, a waveform applied by a neuromodulation device may include a plurality of pulses applied in sequence. In some embodiments, frequencies of sequential pulses may be modulated according 6 168329102.1PATENT Attorney Docket No. 125847.8041.WO01to a sinusoidal, noise, or oscillating modulation pattern. In some embodiments, the frequency may be modulated according to a Brownian noise frequency distribution. As a part of the modulation, the frequency of a pulse may be different than a frequency of the preceding pulse, as well as the frequency of the succeeding pulse. For example, a first frequency of a first pulse may be less than or greater than a second frequency of a succeeding second pulse. As a part of the frequency modulation, a mean frequency of the pulses may be between 1 and 200 Hz. In some embodiments, the frequency of the plurality of pulses may vary between a minimum frequency of about 1 Hz and a maximum frequency of about 200 Hz over a cycle of the pattern. It has been shown that a wide frequency range for modulation provides enhanced effectiveness for TENS treatments. In some embodiments, the modulation of frequency may have a period of oscillation between about 1 and 10 seconds.

[0024] According to exemplary embodiments herein, a modulation pattern may be a noise modulation pattern. In a noise modulation pattern, the modulation may occur randomly according to a noise distribution. That is, the pattern may not be cyclical, but rather a randomized signal according to a particular distribution of values, for example, of frequencies in the case of phase modulation, or of amplitudes in the case of amplitude modulation. In some embodiments, a noise distribution may have a dispersion of values from a mean value. For example, in some embodiments, a noise distribution may be measured in standard deviations of a Gaussian distribution as sigma. In some embodiments, a noise modulation pattern may be a Brownian noise modulation pattern, which is discussed further below with reference to Figure 5. In some embodiments, a modulation of frequency according to the Brownian noise modulation pattern may be based on a Brownian noise frequency distribution with a dispersion of frequencies between 0.05 and 0.25 sigma. In some embodiments, a modulation according to a noise pattern may be based on a mathematical operation including a randomized component. Optionally, in some embodiments, the mathematical operation may be applied to the preceding parameter value to obtain the succeeding parameter value. In some embodiments, the modulation according to noise pattern may be limited to 7 168329102.1PATENT Attorney Docket No. 125847.8041.WO01within a specific range. For example, in the case of frequency modulation, a maximum frequency may be about 200 Hz, and a minimum frequency may be about 1 Hz. In some embodiments, a maximum frequency may be no more than 250 Hz, 200 Hz, 150 Hz, or 100 Hz. In some embodiments, a minimum frequency may be no less than 0.5 Hz, 1 Hz, 25 Hz, 50 Hz, or 100 Hz. In some embodiments, a mean frequency may be between about 1 Hz and about 200 Hz. In some embodiments, a mean frequency may be between 50 and 150 Hz, 50 and 200 Hz, 1 and 100 Hz, or 100 and 200 Hz. Modulation according to a noise frequency may generate an irregular pattern which is less irritating for a user while maintaining efficacy of the waveform.

[0025] In some embodiments, a waveform may be composed of a plurality of pulses. In some embodiments, each pulse may include a spike and a primary phase following the spike. The spike may represent a maximum amplitude of the pulse. In some embodiments, the primary phase may have a lesser amplitude than the spike. In some embodiments, the spike may have an amplitude sufficient to induce an electric field with a strength sufficient to induce conformational change in a tissue region through which the spike current is applied. An electric field of the primary phase may have a strength sufficient to maintain the conformational change induced by the electric field of the spike. Conformational change may refer a change in the shape of a macromolecule induced by the electric field, for example, because of electrostatic forces acting on the macromolecule. Inducing and maintaining conformational changes may modulate the physiological function of the target cellular components or molecules to reduce pain.

[0026] According to embodiments herein, a pulse overall duration, as well as the duration of a spike and primary phase of a pulse, may influence the comfort of an overall waveform when applied to a living body. An overall period of a pulse may affect user comfort as a longer pulse may generate correspondingly longer contractions which may be uncomfortable. Similarly, a duration of a spike and a primary phase (e.g., a “pulse width”) may affect the comfort of a user because of the length of time conformational change is induced within tissue. In some embodiments, a pulse may have an overall 8 168329102.1PATENT Attorney Docket No. 125847.8041.WO01period between 9 ms and 12.5 ms, which has been shown to increase comfort without reducing overall waveform efficacy for TENS treatment. In some embodiments, an overall period of a pulse may be between 1-25 ms, 5-20 ms, 10-15 ms, 5-10 ms, or 10-12 ms. In some embodiments, an overall period of a pulse may be at least 1 ms, 5 ms, 9 ms, or 12 ms. In some embodiments, an overall period of a pulse may be no more than 25 ms, 20 ms, 15 ms, or 10 ms. Smaller periods (e.g., between about 1 and about 15 ms) may be useful for delivering interneuron effects that cause electrical sensations that mask pain. Greater periods (e.g., no less than about 20 ms) may target neurotransmitter release or release of endorphins to reduce pain. In some embodiments, a spike and primary phase of a pulse together may have a period (e.g., pulse width) between 30 s and 90 s, which has been shown to increase comfort without reducing overall waveform efficacy for TENS treatment. In some embodiments, a period of spike and primary phase of a pulse may be between 10-200 s, 20- 150 s, 30-100 s, or 40-60 s. In some embodiments, a period of spike and primary phase of a pulse may be at least 20 s, 30 s, or 50 s. In some embodiments, a period of spike and primary phase of a pulse may be no more than 60 s, 100 s, or 200 s. The pulse width is related to the amount of sensory and motor nerve activation delivered by a neuromodulation device. Higher pulse widths cause more muscle contractions, whereas lower pulse widths cause fewer muscle contractions. In many cases, causing fewer muscle contractions is more comfortable for a user receiving the waveform including the pulse width.

[0027] Embodiments herein may be described in the context of a “user.” A “user” may be a living body receiving electrical signals from an electrode or transmitting signals to an electrode. While embodiments are generally described in the context of human bodies, aspects of those embodiments may be similarly applicable if the living bodies being treated are animal bodies. Accordingly, electrodes and neuromodulation devices according to embodiments herein may be used in connection with any living body.

[0028] In some embodiments herein, a neuromodulation device may be a self-contained device. For example, in some embodiments, a neuromodulation 9 168329102.1PATENT Attorney Docket No. 125847.8041.WO01device may include a housing that houses a first electrode and a second electrode. In some embodiments, a first electrode and second electrode may have a fixed relationship to one another. In other embodiments, a first electrode and a second electrode may be independent from one another, such that the first electrode and the second electrode are able to be independently positioned on a user’s skin. In some embodiment embodiments, a first electrode and a second electrode may be connected to a controller via respective flexible wires.

[0029] Some embodiments herein are discussed with reference to a flow of current from a first electrode to a second electrode. In other embodiments, current may flow from a second electrode to a first electrode. As a part of TENS treatment, a direction of current flow may be reversed during a treatment session. Accordingly, electrodes described herein may be employed interchangeably as a source electrode or a sink electrode.

[0030] Embodiments may be described in the context of computer- executable instructions for the purpose of illustration. However, aspects of the approach could be implemented via hardware or firmware instead of, or in addition to, software. Terminology

[0031] References in the present disclosure to “an embodiment” or “some embodiments” mean that the feature, function, structure, or characteristic being described is included in at least one embodiment. Occurrences of such phrases do not necessarily refer to the same embodiment, nor are they necessarily referring to alternative embodiments that are mutually exclusive of one another.

[0032] Unless the context clearly requires otherwise, the terms “comprise,” “comprising,” and “comprised of” are to be construed in an inclusive sense rather than an exclusive or exhaustive sense. That is, in the sense of “including but not limited to.” The term “based on” is also to be construed in an inclusive sense. Thus, the term “based on” is intended to mean “based at least in part on.”

[0033] The terms “connected,” “coupled,” and variants thereof are intended to include any connection or coupling between two or more elements, either 10 168329102.1PATENT Attorney Docket No. 125847.8041.WO01direct or indirect. The connection or coupling can be physical, logical, or a combination thereof. For example, elements may be electrically or communicatively coupled to one another despite not sharing a physical connection.

[0034] The term “module” may refer broadly to software, firmware, hardware, or combinations thereof. Modules are typically functional components that generate one or more outputs based on one or more inputs. A computer program may include or utilize one or more modules. For example, a computer program may utilize multiple modules that are responsible for completing different tasks, or a computer program may utilize a single module that is responsible for completing all tasks.

[0035] When used in reference to a list of multiple items, the word “or” is intended to cover all of the following interpretations: any of the items in the list, all of the items in the list, and any combination of items in the list.

[0036] When used in reference to a numerical range, the word “about” refers to a value within 10% of the recited value. For example, “about” 50 refers to an inclusive range between 45 and 55. As another example, “about” 1 refers to an inclusive range between 0.90 and 1.10. Overview of Conventional Neuromodulation Device

[0037] Figure 1 illustrates a conventional example of a neuromodulation device 100. The neuromodulation device 100 is configured to apply an electrical signal to a user of the neuromodulation device to inhibit transmission of pain signals through the nervous system to the brain. The neuromodulation device 100 is configured as a patch 102 configured to be worn on the skin of a user. The patch 102 may include an adhesive material allowing the device 100 to adhere to the skin. The neuromodulation device 100 includes a controller 104 configured to control generation of the electrical signal. The controller 104 may be powered by an onboard power source, such as a battery.

[0038] As shown in Figure 1, the neuromodulation device 100 includes a first electrode 106 disposed in a first gel pad 108. Electrical current is configured to flow through the first electrode 106, through the gel pad 108, and into the 11 168329102.1PATENT Attorney Docket No. 125847.8041.WO01skin of the user of the neuromodulation device 100. The neuromodulation device 100 also includes a second electrode 110 disposed in a second gel pad 112. Current is configured to flow from the first electrode 106, into a user’s skin, and to the second electrode 110. The passage of this electrical current is configured to disrupt pain signals in the neurological system of the user, thereby alleviating pain. The first gel pad 108 and the second gel pad 112 are configured to distribute the current over a wider area than the point input / output provided by the first electrode 106 and the point input / output provided by the second electrode 110.

[0039] Conventional neuromodulation devices like that of Figure 1 are configured to apply fixed frequency waveforms, usually at a constant current. Accordingly, conventional neuromodulation devices frequently under-dose the current applied to a living body to avoid user discomfort. However, reducing the current applied to improve user comfort results in a less therapeutically effective waveform.

[0040] As discussed further below, devices and methods described with reference to embodiments herein may address the deficiencies of conventional neuromodulation devices like those shown in Figure 1. Accordingly, neuromodulation devices and methods described herein may not only provide for more therapeutically effective treatments, but may also increase user comfort during treatments by reducing irritation caused by application of waveforms with constant current. Overview of Neuromodulation Device and Method of Operation

[0041] Figure 2 is a block diagram illustrating modules of a neuromodulation device 200, according to some embodiments. The control electronics module 202 generally comprises a microcontroller which may be programmable to provide the desired pulse signals to the patient. The control electronics module 202 may also include the various electronics that are used to effect the treatment and control the output on / off state, pulse amplitude, timing, modulation, and other pulse parameters. Examples of such electronics include timers, clocks, DACs, processing units, and the like. In some embodiments, the 12 168329102.1PATENT Attorney Docket No. 125847.8041.WO01control electronics module 202 may include a memory storing a plurality of waveforms. In order to actuate and / or interface with the control electronics module 202, a controls module 204 may be in communication with the control electronics module 202 through any number of interface mechanisms, such as, buttons, knobs, sliders, capacitive touch sensors, and the like, through which a user can turn the device on / off, adjust amplitude or other settings, etc. The control electronics module 202 may receive input indicative of a request to initiate an electrical neuromodulation operation, in some embodiments. Additionally, the controls module 204 or other controller may communicate locally or remotely with the control electronics module 202 through a communication interface module 208 which may include any number of various wired communication mechanisms and / or wireless communication mechanisms. Examples of wireless communication mechanisms (also called “wireless communication protocols”) include Bluetooth®, Bluetooth® Low Energy or Bluetooth® Smart (Bluetooth SIG, Inc., Kirkland, Wash.), ANT, ZigBee, Wi-Fi, near field communication (NFC), infrared (e.g., Infrared Data Association (IrDA) associated wireless communications), etc. The communication interface module 208 may allow a neuromodulation device to access waveform files stored on remote devices, such as a mobile phone or remote server.

[0042] The control electronics module 202 may provide any number of details, feedback, or information about its operation through an indicator module 206 which may include any variety of indicators or displays that may be positioned directly upon the neuromodulation device or separately in communication with the control electronics module 202. Generally, the term “indicator” is used to refer to one or more illuminants that visually provide information (e.g., regarding power status, connectivity status, program, etc.) through illumination. Meanwhile, the term “display” is generally used to refer to a panel of illuminants that are collectively controlled to visually present information. Displays may comprise liquid crystal display (LCD) elements, light- emitting diodes (LEDs), organic LEDs (OLEDs), electrophoretic elements, and the like. 13 168329102.1PATENT Attorney Docket No. 125847.8041.WO01

[0043] In order for the neuromodulation device to provide the electrical stimulation to the patient's body, the control electronics module 202 may be in communication with a pulse generating electronics module 210 which is in communication with electrodes 214 through connecting elements 212. The control electronics module 202 and pulse generating electronics module 210 may be in communication with a power supply module 216 which supplies the power for the electrical stimulation. The power supply module 216 may include a battery such as a lithium-ion battery with associated circuits such as voltage regulators, LDOs, boost or buck converters, etc. The device output may utilize a voltage which is much higher than that available from the battery, and therefore the power supply may optionally include a generating mechanism for providing the high voltage as well as regulated low voltages for the other internal circuits.

[0044] The pulse generating electronics module 210 may include various components, including, but not limited to, switching circuits, digital-to-analog convertors (DACs), switches, and registers, which are configured to produce the electric pulses with controlled shape and amplitude as described herein.

[0045] Each of the various components may be in electrical communication through the connecting elements 212. The connecting elements used may comprise any number of electrically conductive elements, such as connectors, printed conductive traces, flex circuit boards, and the like, which provide electrical connection from the electronics to the electrodes or between any number of electrical components.

[0046] The electrodes 214 electrically coupled to the pulse generating electronics module 210 may be shaped in various configurations for facilitating placement upon the patient depending upon the region of the body to be treated. Accordingly, the electrodes may be external for providing an electrical connection from the device output to the body through the skin, particularly to the target tissues or nerves.

[0047] External electrodes, in one variation, may be constructed of a conductive current-distributing element (such as a silver chloride coated silver, 14 168329102.1PATENT Attorney Docket No. 125847.8041.WO01stainless steel, graphite, etc.) and a hydrogel (such as polyacrylamide or other stable and biocompatible gel with good adhesion) which contains a conductive solution (typically sodium chloride). The electrodes may be a driven as a pair of electrodes where the current flows from a first electrode to a second electrode, or as a more complex multi-polar setup, for example, in a quadrupolar setup, with four electrodes driven as any one of six alternating pairs. Exemplary electrode configurations will be discussed further with reference to Figure 7.

[0048] In other variations, the neuromodulation device may additionally and / or optionally include additional features or elements. For example, in one variation, the device may be controlled entirely via a communication interface using, for example, wireless communication from a controller located remotely from the neuromodulation device. Such remotely located controllers may include, for example, smartphones or other programmable devices, which may communicate via any number of wireless communication protocols (e.g., Bluetooth® Low Energy). Such a variation may remove the need for any controls or indicators on the device itself as the controls module 204 may be located remotely. In yet another alternative, the device may directly incorporate the controls module 204 upon the neuromodulation device itself so that it may be controlled entirely through an interface located upon the device.

[0049] Additionally, and / or alternatively, the control electronics module 202 and power supply module 216 may be packaged as a compact device that may be removably attached as a unit upon electrodes 214. For example, the electrodes 214 may be embedded, suspended, or otherwise situated in polyacrylamide hydrogel with silver ink conductive traces printed on a polymer film base. The electrodes 214 may be placed upon the region of interest upon the patient body and the device may be temporarily coupled to an engagement mechanism which also allows for the electrical communication between the pulse generating electronics module 210 and the electrodes 214 to effect treatment upon the patient. This variation as well as others described may be combined in any number of combinations as practicable. 15 168329102.1PATENT Attorney Docket No. 125847.8041.WO01

[0050] Figure 3 is a block diagram illustrating phases of an electrical pulse output from a neuromodulation device, according to some embodiments. Specifically, Figure 3 shows a block diagram of a representative pulse waveform 300 illustrating the major phases of an electrical pulse output. Using the neuromodulation device 200 of Figure 2, the control electronics module 202 may be programmed to effect a specified pulse waveform generated by the pulse generating electronics module 210 and transmitted through the electrodes 214 and to the area of the patient's body upon which the electrodes 214 are positioned for treatment. Generally, the pulse waveform 300 may have a primary phase 306 followed by an optional dead time 308 period and then a secondary phase 310. Initiating the primary phase 306 is a leading edge 302 having a relatively fast rise time which leads to a spike 304 having an intensity greater than an average intensity of the primary phase 306. The remainder of the primary phase 306 may have an intensity which is lower than the intensity of the spike 304. In some embodiments, the remainder of the primary phase 306 may have an intensity approximately half intensity of the spike 304.

[0051] The dead time 308 period, if included, may have an output amplitude of zero. If the dead time 308 period is omitted, the secondary phase 310 may follow immediately after the primary phase 306 where the secondary phase 310 may have a polarity opposite to that of the primary phase 306. Like the dead time 308 period, the secondary phase 310 may be optionally omitted entirely from the pulse waveform 300. The presence and duration of the secondary phase may also affect the perceived intensity of a paresthesia sensation in a user receiving the pulse. The treatment pulses having the pulse waveform 300 may be repeated during a treatment where a specified time interval period 312 may be present between each individual pulse waveform 300.

[0052] While the output is described here in terms of amplitude, this may include a measure of either current or voltage. In one embodiment, the pulse waveforms 300 may be produced by a circuit which is a voltage-limited current source, and the amplitudes may comprise current amplitudes. Using a current control allows for the effective movement of charges to be less dependent on the electrode impedance (which may change with skin condition or over time) 16 168329102.1PATENT Attorney Docket No. 125847.8041.WO01and less dependent on the tissue impedance (which may change with placement or individually).

[0053] In another embodiment, the output may also comprise a voltage source or current-limited voltage source, since in the short term the tissue and electrode impedances are relatively constant and so the current is approximately equal to the voltage times a constant factor. In this case, the output may require more frequent adjustments. However, controlled or produced, the amplitude pattern shown describes the variation in electrical field strength independent of the effects of variation in electrode impedance or the specifics of the control circuit.

[0054] If any parameters (such as timings or amplitude) of the output electrical pulses depend on the load impedance, they may be measured using a resistive-capacitive test load simulating the electrodes and human body.

[0055] Figure 4 graphically illustrates an individual representative pulse waveform 300 described in Figure 3 with each of the major phases of an electrical pulse output. The primary phase 306 is shown including the leading edge 302 of spike 304 over a relatively short rise time and the remainder of the primary phase 306 where the intensity of the spike 304 is significantly greater than an average intensity of the primary phase 306 and where the intensity of the remainder is significantly lower than the intensity of the spike 304, for example, about half the intensity. This may then be followed by the secondary phase 310 which may have its polarity opposite to that of the primary phase 306, as shown.

[0056] The transition or edge rise and fall times are measured as the time from, for example, 10% to 90% of the change from initial to final level. Widths are measured as the time from, for example, the 10% level on the rising edge to the 10% level on the falling edge. The illustration of the pulse waveform 300 is intended to be illustrative of the relative shape of the waveform with its timing measurements. Hence, the amplitudes during the spike 304, primary phase 306 and secondary phase 310 of the pulse waveform 300 do not need to be held constant as shown in Figure 4. Any pulse shape such that the spike 304 has a 17 168329102.1PATENT Attorney Docket No. 125847.8041.WO01relatively fast rise time and high peak amplitude 410, and the typical amplitude during the remainder of the primary phase 306 after the spike 304 is significantly less than the spike 304, may provide an effective pulse waveform 300. For example, if it is easier for the pulse generating or control electronics to produce, the primary phase 306 and secondary phase 310 may be comprised of, for example, piecewise segments of exponentially decaying waveforms (e.g., due to capacitor discharge or inductor decay), piecewise linear, trapezoidal, or any other shape. The spike 304 itself may be shaped as, for example, a half-sine wave, sine, parabolic, or similar waveform, as it is not necessary for it to have a constant level (e.g., “flat top”).

[0057] Additionally, the transitions between the spike 304, primary phase 306, optional dead time, secondary phase 310, and interval period 312 do not need to have rapid rise and fall times, or in any case the rapid rise and fall times are not necessary for effectiveness. However, it may be desirable to have a relatively rapid and / or fall time 404 at the end of the spike 304 to increase patient comfort. Once the brief time at maximum amplitude 402 during the spike 304 has passed, it is unlikely that any high but sub-maximum amplitude would have a physiological effect; however, it may cause greater charging of the skin capacitance and thus skin discomfort and for that reason it is desirable for the spike 304 to transition to the lower level during the remainder of the primary phase 306 relatively quickly. The fall time 406 at the end of the primary phase 306 and the fall time 408 from secondary phase 310 to the interval period 312 state or inter-pulse interval may be implemented in different ways while still having a therapeutically effective pulse shape as described herein. For example, as shown in Figure 4, the fall time 406 may be stepwise, and the fall time 408 may be exponential decay. Other arrangements may be implemented, in other embodiments. The spike 304 and the primary phase 306 may have a pulse width 412. The overall pulse may have an overall pulse period 414.

[0058] Turning now to the individual portions of the pulse waveform 300, the spike 304 is comprised of a relatively high amplitude 410, short duration spike which has a leading edge 302 with a fast rise time. In some embodiments, the amplitude 410 may be between about 1 mA and about 150 mA. The amplitude 18 168329102.1PATENT Attorney Docket No. 125847.8041.WO01410 may affect inhibition of nerve ion channels that produce effects through the skin. Additionally, the amplitude 410 may change based on a distance between electrodes. The rise time of the spike may affect the targeting of specific nerve cell membrane components. The effective electric field during the spike 304 is expected to be high enough to be able to drive conformational changes of the cellular components which are targeted therapeutically directly, by the electrostatic forces acting on fixed charges or dipoles therein. A relatively high electric field strength is desirable in order to produce conformational changes and thereby modulate the physiological function of the target cellular components or molecules in a target tissue region; hence, an initial spike 304 with an amplitude 402 which is significantly higher than the average amplitude during the primary phase 306. In some embodiments, the spike 304 may be repeated. Such repetition may affect the strength of nerve ion channel inhibition.

[0059] The transition between spike 304 and primary phase 306 may not be as fast as the leading edge 302 of the spike 304. In one embodiment, the transition is a rapid linear transition with a controlled fall time equal to the rise time of the leading edge 302 of the spike 304, but this is not required. Many variations in the transition between the spike 304 and primary phase 306 are possible which accomplish the same goal of relatively rapid transition using different profiles.

[0060] As discussed above, the pulse width 412 (e.g., a duration of a spike and a primary phase) may affect the comfort of a user because of the length of time conformational change is induced within tissue. For example, the duration of the spike and the primary phase may affect the intensity of paresthesia sensation caused by the waveform. Additionally, the pulse width 412 may affect the intensity of motor effects (e.g., muscle contractions) caused by a waveform. In some embodiments, the pulse width 412 may be between 30 s and 90 s, which has been shown to increase comfort without reducing overall waveform efficacy for TENS treatment. In some embodiments, the pulse width 412 may be between 10-200 s, 20-150 s, 30-100 s, or 40-60 s. In some embodiments, the pulse width 412 may be at least 20 s, 30 s, or 50 s. In 19 168329102.1PATENT Attorney Docket No. 125847.8041.WO01some embodiments, the pulse width 412 may be no more than 60 s, 100 s, or 200 s.

[0061] As discussed above, the overall pulse period 414 may also affect the comfort of a user because of the length of time muscle contractions are induced (e.g., during the spike 304, the primary phase 306, and secondary phase 310) and the length of time muscles are allowed to relax (e.g., during the interval period 312). The overall pulse period may affect the repetition rate of the pulse, which affects the quality of the paresthesia sensation (e.g., tingling, massaging, etc.). In some embodiments, the overall pulse period 414 may be between 9 ms and 12.5 ms, which has been shown to increase comfort without reducing overall waveform efficacy for TENS treatment. In some embodiments, the overall pulse period 414 may be between 1-25 ms, 5-20 ms, 10-15 ms, 5-10 ms, or 10-12 ms. In some embodiments, the overall pulse period 414 may be at least 1 ms, 5 ms, 9 ms, or 12 ms. In some embodiments, the overall pulse period 414 of a pulse may be no more than 25 ms, 20 ms, 15 ms, or 10 ms.

[0062] According to some embodiments herein, a plurality of pulse waveforms as shown in the example of Figure 4 may be applied in sequence to form an overall waveform. In some embodiments, one or more parameters of a pulse waveform may be varied as the pulse waveforms are applied. For example, a pulse width 412 and / or pulse period 414 may be varied to change a frequency of the overall waveform. In some embodiments, a pulse width and / or pulse period may be modulated according to a sinusoidal, noise, or other oscillating pattern, examples of which will be discussed with reference to Figures 5-6. In some embodiments, a first pulse of a plurality of pulses may have a first frequency, and a second pulse of the plurality of pulses following the first pulse may have a second frequency that is a modulation of the first frequency. As another example, an amplitude 410 of the spike 304 and / or an amplitude of the primary phase 306 may be varied between sequential pulse waveforms. In some embodiments, an amplitude 410 of the spike 304 and / or an amplitude of the primary phase 306 maybe modulated according to a sinusoidal, parabolic, or otherwise curved rise and fall pattern. In some embodiments, a first pulse of a plurality of pulses may have a first peak 20 168329102.1PATENT Attorney Docket No. 125847.8041.WO01amplitude, and a second pulse of the plurality of pulses following the first pulse may have a second peak amplitude that is a modulation of the first peak amplitude.

[0063] Figure 5 is a diagram illustrating an exemplary Brownian noise distribution 500 for frequency and / or amplitude modulation of a waveform, according to some embodiments. As discussed above, in some cases a frequency of a plurality of pulses may be modulated according to a noise frequency distribution. In some embodiments, the noise frequency distribution may be a Brownian noise frequency distribution. Brownian modulation may mimic a Brownian pattern, which may be obtained as the integral of a white noise signal. For example, Brownian noise modulation may be obtained by adding a random offset to each preceding value to obtain the next value. In this manner, Brownian noise is also known as “random walk” noise, as the value will walk randomly over time. In some embodiments, an upper and lower bound for the modulation may be set. For example, for a modulation of waveform frequency, a lower bound may be set at 1 Hz, and an upper bound may be set at 200 Hz in some embodiments.

[0064] As shown in Figure 5, an amplitude 502 of the modulation may be greater at lower frequencies 504. In some embodiments, the amplitude 502 may decrease in intensity by 20 dB per decade. In general, a Brownian noise modulation pattern may cause a waveform to feel more intense in a pulsing yet irregular manner, which has been shown to be more comfortable when higher intensities are applied compared to constant frequency waveforms. In some embodiments, a dispersion of frequencies 504 for Brownian noise modulation may be between 0.05 sigma and 0.25 sigma.

[0065] While in some embodiments a Brownian noise modulation may be employed based on a Brownian noise frequency distribution like that shown in Figure 5, in other embodiments other noise modulation patterns may be employed, including, but not limited to, white noise or pink noise.

[0066] Figure 6 is a diagram 600 illustrating an exemplary modulation of a pulse waveform, according to some embodiments. In the example of Figure 6, 21 168329102.1PATENT Attorney Docket No. 125847.8041.WO01the modulation is a sinusoidal oscillating pattern 602. An applied waveform 604 representative of a waveform formed by a plurality of pulses is shown in Figure 6 as modified by the sinusoidal oscillating pattern 602. In the example of Figure 6, the sinusoidal oscillating pattern 602 may modify the amplitude of the applied waveform 604.

[0067] As shown in Figure 6, the sinusoidal oscillating pattern has a period 606. In some embodiments, the period 606 of the sinusoidal oscillating pattern 602 may be between 1 and 10 seconds, which may provide a more comfortable sensation while the waveform 604 is applied to tissue. In other embodiments, the period 606 of the sinusoidal oscillating pattern may be between 0.5 and 5 seconds, 5 and 15 seconds, or 2 and 8 seconds. In some embodiments, the period 606 may be no more than 15 seconds, 10 seconds, 8 seconds, or 5 seconds. In some embodiments, the period 606 may be no less than 0.5 seconds, 1 second, 2 seconds, or 5 seconds. While a sinusoidal oscillating pattern is shown in Figure 6, in other embodiments other patterns may be employed to modulate a waveform 604. In some such embodiments, the period of the pattern may be like that of the sinusoidal oscillating pattern, for example, between 1 and 10 seconds.

[0068] As shown in Figure 6, the sinusoidal oscillating pattern 602 has an amplitude 608. The amplitude 608 of the sinusoidal oscillating pattern 602 may change the amplitude of the waveform 604. In the example of Figure 6, the sinusoidal oscillating pattern 602 may limit the amplitude of the waveform 604. Accordingly, the sinusoidal oscillating pattern 602 may cyclically modulate the amplitude of the waveform 604 from a peak amplitude to another amplitude less than the peak amplitude. Such a modulation may allow more intense, therapeutically effective pulses to be interspersed with less intense, less uncomfortable pulses. In this manner, therapeutic effectiveness may be maintained, while reducing or eliminating the discomfort usually associated with pulses having the peak amplitude. In some embodiments, the sinusoidal oscillating pattern 602 may modify the amplitude of the waveform 604 from a peak amplitude to between 30% and 70% of the peak amplitude. In some 22 168329102.1PATENT Attorney Docket No. 125847.8041.WO01embodiments, the sinusoidal oscillating pattern 602 may modify the amplitude of the waveform 604 from a peak amplitude to about half of the peak amplitude.

[0069] Figure 7 illustrates a neuromodulation device 700 for applying waveforms according to exemplary embodiments described herein. The neuromodulation device 700 is configured to apply an electrical signal to a user of the neuromodulation device to inhibit transmission of pain signals through the nervous system to the brain. The neuromodulation device 700 is configured as a patch 702 configured to be worn on the skin of a user. The patch 702 may include an adhesive material allowing the device 700 to adhere to the skin. In some embodiments, the patch 702 may include one or more gel pads configured to adhere to the skin. The neuromodulation device 700 includes a controller 703 configured to control generation of the electrical signal. The controller 703 may be powered by an onboard power source, such as a battery. In other embodiments, the controller 703 may be powered by an external power source. In some embodiments, the controller 703 may be proximate a geometric center of the neuromodulation device 700.

[0070] As shown in Figure 7, the neuromodulation device 700 includes a first controller input / output 704 and a second controller input / output 706 for providing electrical connections to a first electrode 705 and a second electrode 707, respectively. The first electrode 705 includes a first conductive trace mesh 708 connected to the first controller input / output 704 via traces 710. The second electrode 707 includes a second conductive trace mesh 712 connected to the second controller input / output 706 via traces 714. The first trace mesh 708 and the second trace mesh 712 are configured to assist in spreading current across a greater area of each respective electrode.

[0071] The neuromodulation device 700 differs from the conventional neuromodulation device 100 of Figure 1 in the process of applying the electrical signals to the user. Specifically, the neuromodulation device 700 of Figure 7 is configured to modulate an amplitude and / or frequency of a waveform according to one or more patterns. Additionally, the neuromodulation device is configured to apply waveforms having specific parameters that have been shown to 23 168329102.1PATENT Attorney Docket No. 125847.8041.WO01improve user comfort while remaining therapeutically effective for TENS treatments.

[0072] In the example of Figure 7, the neuromodulation device 700 is self- contained. That is, the first electrode 705 and the second electrode 707 form portions of the same patch 702. Accordingly, the relative spacing and positions of the first electrode 705 is fixed relative to the second electrode 707. In other embodiments, the first electrode 705 and the second electrode 707 may be separate from one another, for example, as separate patches. In some such embodiments, the first electrode 705 and the second electrode 707 may be independently positioned relative to one another. In some such embodiments, a controller of the neuromodulation device may also be independently positioned relative to one or both of the electrodes. For example, a controller may be integrated with one or more electrodes of a neuromodulation device or may be disposed in an independent housing.

[0073] Figure 8 is a flow diagram for a method 800 of operating a neuromodulation device, according to some embodiments. The method 800 may be a method for providing a TENS treatment, in some embodiments. In act 802, the method includes generating a first waveform portion, where the first waveform portion has a first amplitude and a first frequency. In some embodiments, the first waveform portion may be a first pulse waveform. In other embodiments, the first waveform portion may be a section of an overall waveform, for example, representing one period of the overall waveform. The overall waveform may be formed of a plurality of waveform portions, in which the first waveform portion is included. In act 804, the first waveform portion is applied to a pair of electrodes. In some embodiments, applying the first waveform portion to the pair of electrodes may include transmitting the first waveform portion to a living body in contact with the pair electrodes.

[0074] In act 806, the method 800 includes generating a second waveform portion (e.g., a second pulse waveform), where the second waveform portion has a second amplitude and a second frequency different from the first amplitude and the first frequency, respectively. In some embodiments, the second waveform portion may be generated according to a modulation of the 24 168329102.1PATENT Attorney Docket No. 125847.8041.WO01first waveform portion. For example, the second amplitude may be a modulation of the first amplitude, and accordingly may be greater than or less than the first amplitude. In some embodiments, the second amplitude may be based on a sinusoidal, parabolic, or other curved rise and fall oscillating pattern applied to the first amplitude. As another example, the second frequency may be a modulation of the first frequency and may be greater than or less than the first frequency. In some embodiments, the second frequency may be based on a sinusoidal, noise, or other oscillating pattern applied to the first frequency. In act 808, the second waveform portion is applied to the pair of electrodes. In some embodiments, the second waveform portion may be applied to the pair of electrodes immediately following the first waveform portion, such that together the first waveform portion and the second waveform portion form an overall waveform.

[0075] Figure 9 is a flow diagram for a method 900 of operating a neuromodulation device, according to some embodiments. The method 900 may be a method for providing a TENS treatment, in some embodiments. In act 902, the method includes generating a waveform of pulses over an interval of time. In act 904, the method includes transmitting the waveform to a pair of electrodes. In some embodiments, transmitting the waveform to the pair of electrodes may include transmitting the waveform to a living body in contact with the pair electrodes. In act 906, the method includes modulating a frequency of the pulses over the interval of time according to a first pattern. In some embodiments, the first pattern may be a sinusoidal, noise, or other oscillating pattern. In act 908, the method includes modulating an amplitude of the pulses over the interval of time according to a second pattern. The second pattern may be different than the first pattern. Such a difference in pattern may yield more a more comfortable waveform while retaining effectiveness. In some embodiments, the second pattern may be a sinusoidal, parabolic, or otherwise curved rise and fall pattern.

[0076] In the embodiment of Figure 9, both amplitude and frequency are modulated, which provides benefits in efficacy and comfort as described herein. In some embodiments, either act 906 or 908 may be optional. That is, in some 25 168329102.1PATENT Attorney Docket No. 125847.8041.WO01embodiments, modulation of frequency may be optional, such that only amplitude is modulated in act 908. In other embodiments, modulation of amplitude may be optional, such that only frequency is modulated in act 906. Remarks

[0077] The foregoing description of various embodiments of the claimed subject matter has been provided for the purposes of illustration and description. It is not intended to be exhaustive or to limit the claimed subject matter to the precise forms disclosed. Many modifications and variations will be apparent to one skilled in the art. Embodiments were chosen and described in order to best describe the principles of the invention and its practical applications, thereby enabling those skilled in the relevant art to understand the claimed subject matter, the various embodiments, and the various modifications that are suited to the particular uses contemplated.

[0078] Although the Detailed Description describes certain embodiments and the best mode contemplated, the technology can be practiced in many ways no matter how detailed the Detailed Description appears. Embodiments can vary considerably in their implementation details, while still being encompassed by the specification. Particular terminology used when describing certain features or aspects of various embodiments should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the technology with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the technology to the specific embodiments disclosed in the specification, unless those terms are explicitly defined herein. Accordingly, the actual scope of the technology encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the embodiments.

[0079] The language used in the specification has been principally selected for readability and instructional purposes. It may not have been selected to delineate or circumscribe the subject matter. It is therefore intended that the scope of the technology be limited not by this Detailed Description, but rather 26 168329102.1PATENT Attorney Docket No. 125847.8041.WO01by any claims that issue on an application based hereon. Accordingly, the disclosure of various embodiments is intended to be illustrative, but not limiting, of the scope of the technology as set forth in the following claims. 27 168329102.1

Claims

PATENT Attorney Docket No. 125847.8041.WO01CLAIMS What is claimed is:

1. A neuromodulation device comprising: a first electrode configured to be worn on the skin of a living body at a first location; a second electrode configured to be worn on the skin of the living body at a second location; and a controller configured to transmit, to the living body via the first electrode and the second electrode, a pulse waveform that includes a plurality of pulses in sequence, wherein: frequencies of the plurality of pulses are modulated based on a Brownian noise distribution, and amplitudes of the plurality of pulses are modulated in accordance with a sinusoidal pattern.

2. The neuromodulation device of claim 1, wherein for each pulse of the plurality of pulses, a frequency and / or amplitude is different from a frequency and / or amplitude of a preceding pulse in the sequence and a frequency and / or amplitude of a succeeding pulse in the sequence.

3. The neuromodulation device of claim 1, wherein each pulse of the plurality of pulses includes a spike and a primary phase following the spike.

4. The neuromodulation device of claim 3, wherein the spike and the primary phase together have a period between 30 s and 90 s.

5. The neuromodulation device of claim 3, wherein an electric field of the spike has a strength sufficient to produce a conformational change in cellular components of a tissue region of interest, and an electric field of the primary phase has a strength sufficient to maintain the conformational change induced by the electric field of the spike. 28 168329102.1PATENT Attorney Docket No. 125847.8041.WO016. The neuromodulation device of claim 1, wherein each pulse of the plurality of pulses has a total period between 9 ms and 12.5 ms.

7. The neuromodulation device of claim 1, wherein the modulation of the amplitudes is between a peak amplitude and about half of the peak amplitude.

8. The neuromodulation device of claim 7, wherein the modulation of the amplitudes has an oscillation period between 1 and 10 seconds.

9. The neuromodulation device of claim 1, wherein the Brownian noise distribution has a dispersion of frequencies between 0.05 and 0.25 sigma.

10. The neuromodulation device of claim 9, wherein a mean frequency of the plurality of pulses is between 1 and 200 Hz.

11. A neuromodulation device comprising: a first electrode configured to be worn on the skin of a living body at a first location; a second electrode configured to be worn on the skin of the living body at a second location; and a controller programmed to transmit, to the living body via the first electrode and the second electrode, a pulse waveform that includes a plurality of pulses in sequence, wherein: each pulse of the plurality of pulses includes a spike and a primary phase, the spike and the primary phase together have a period between 30 s and 90 s, each pulse of the plurality of pulses has a total period between 9 ms and 12.5 ms, and 29 168329102.1PATENT Attorney Docket No. 125847.8041.WO01a mean frequency of the plurality of pulses is between 1 and 200 Hz.

12. The neuromodulation device of claim 11, wherein amplitudes of sequential pulses are modulated by a sinusoidal pattern, a parabolic pattern, or a curved rise and fall pattern.

13. The neuromodulation device of claim 12, wherein the modulation of the amplitudes is between a peak amplitude and between 30% and 70% of the peak amplitude.

14. The neuromodulation device of claim 13, wherein the modulation of the amplitudes has an oscillation period between 1 and 10 seconds.

15. The neuromodulation device of claim 11, wherein frequencies of sequential pulses are modulated based on a Brownian noise distribution.

16. The neuromodulation device of claim 15, wherein the Brownian noise distribution has a dispersion of frequencies between 0.05 and 0.25 sigma.

17. The neuromodulation device of claim 11, wherein an electric field of the spike has a strength sufficient to produce a conformational change in cellular components of a tissue region of interest, and an electric field of the primary phase has a strength sufficient to maintain the conformational change induced by the electric field of the spike.

18. A neuromodulation device comprising: a first electrode configured to be worn on the skin of a living body at a first location; a second electrode configured to be worn on the skin of the living body at a second location; and 30 168329102.1PATENT Attorney Docket No. 125847.8041.WO01a controller programmed to transmit a pulse waveform to the living body via the first electrode and the second electrode, wherein: the pulse waveform includes a first pulse and a second pulse in sequence, the first pulse has a first frequency and a first amplitude, the second pulse has a second frequency that is different than the first frequency and based on a modulation of the first frequency according to a noise frequency distribution or a frequency oscillating pattern, and the second pulse has a second amplitude that is different than the first amplitude and based on a modulation of the first amplitude according to an amplitude oscillating pattern.

19. The neuromodulation device of claim 18, wherein the first pulse includes a first spike and a first primary phase, and wherein the second pulse includes a second spike and a second primary phase.

20. The neuromodulation device of claim 19, wherein the first spike and the first primary phase together have a period between 30 s and 90 s, and wherein the second spike and the second primary phase together have a period between 30 s and 90 s.

21. The neuromodulation device of claim 19, wherein electric fields of the first spike and the second spike have a strength sufficient to produce a conformational change in cellular components of a tissue region of interest, and electric fields of the first primary phase and the second primary phase have a strength sufficient to maintain the conformational change induced by the electric fields of the first spike and the second spike.

22. The neuromodulation device of claim 18, wherein the first pulse has a total period between 9 ms and 12.5 ms, and wherein the second pulse has a total period between 9 ms and 12.5 ms. 31 168329102.1PATENT Attorney Docket No. 125847.8041.WO0123. The neuromodulation device of claim 18, wherein the second frequency is based on a modulation of the first frequency according to a noise frequency distribution, wherein the noise frequency distribution is a Brownian noise frequency distribution with a dispersion of frequencies between 0.05 and 0.25 sigma.

24. The neuromodulation device of claim 18, wherein the amplitude oscillating pattern is a sinusoidal pattern.

25. The neuromodulation device of claim 18, wherein the first amplitude is a peak amplitude, and wherein the second amplitude is between the peak amplitude and about half of the peak amplitude.

26. The neuromodulation device of claim 25, wherein the amplitude oscillating pattern has an oscillation period between 1 and 10 seconds.

27. The neuromodulation device of claim 18, wherein a mean frequency of the first pulse and the second pulse is between 1 and 200 Hz.

28. A device for treating a tissue region of a living body through electrical neuromodulation, the device comprising: a pair of electrodes that are to be positioned proximate to the tissue region; and a controller that is configured to transmit, through the pair of electrodes, a waveform of pulses over an interval of time, wherein over the interval of time, amplitude and frequency of the pulses are modulated in accordance with different patterns.

29. The device of claim 28, wherein the amplitude is modulated in accordance with a nonlinear pattern. 32 168329102.1PATENT Attorney Docket No. 125847.8041.WO0130. The device of claim 28, wherein the frequency is modulated in accordance with a noise distribution pattern.

31. The device of claim 28, wherein for each of the pulses, a corresponding amplitude differs from a preceding amplitude of a preceding pulse and a succeeding amplitude of a succeeding pulse, and a corresponding frequency differs from a preceding frequency of the preceding pulse and a succeeding frequency of the succeeding pulse. 33 168329102.1

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