Methods and apparatus for multi-modal or multiplexed electrical modulation of pain using complex electromagnetic fields

Abstract

Apparatus and methods for controlling pain use multiplexed / multimodal modulation / stimulation signals to provide pain relief during spinal cord stimulation or peripheral nerve stimulation. A glial stimulation signal is provided to a first subset of electrodes and a neuronal stimulation signal is concurrently provided to a second subset of the electrodes. At least one of the glial stimulation signal and the neuronal stimulation signal includes a plurality of component signals that are multiplexed to a respective electrode array provided with the glial stimulation signal and the neuronal stimulation signal.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 62 / 843,757, filed May 6, 2019, entitled “Method and Apparatus for Modulating Cellular Activity in Neural Tissue Using Multiplexed Electrical Signals with Relative to Differential Targets,” the entire contents of which are specifically incorporated herein by reference.

[0003] This application also claims priority and benefit to U.S. Provisional Application No. 62 / 964,281, filed January 22, 2020, entitled “Method and Apparatus for Multimodal Electrical Modulation of Pain Using a Composite Electromagnetic Field,” the entire contents of which are specifically incorporated herein by reference. Technical Field

[0004] This disclosure relates to systems and methods for providing multimodal or multiplexed stimulation of neural structures, and more specifically, to systems and methods for controlling pain with electromagnetic signals of multiple components having characteristic parameters. Background Technology

[0005] The term spinal cord stimulation (SCS) is used to describe advanced control therapy for chronic pain, in which a varying electric field is applied to the dorsal segment (DC) of the spinal cord via an array (or multiple arrays) of electrodes implanted in the epidural space. Traditional SCS, also known as rigidity, conventionally utilizes an electric field varying between 40 and 250 Hz to target the pain location by covering it with a sensory tingling sensation called paresthesia induced by the stimulating electric field. This therapy has been used clinically for approximately half a century. The primary mode of action is based on the gate control theory developed by Melzack and Wall, although a full understanding of the mechanism is not yet fully elucidated. The concept behind rigidity SCS is to shield pain signals traveling to the brain through the sensory paresthesia induced by the applied varying electric field, or "gate the pain signal off," however, the relationship between frequency, waveform shape, amplitude, and pulse width and the mechanism by which SCS provides analgesic effects is not fully understood. Summary of the Invention

[0006] This document discloses apparatus and methods for controlling patient pain by using multimodal stimulation of neural structures with multiple components in which electromagnetic signals have characteristic frequencies, amplitudes, and phase polarities. According to this disclosure, multimodal modulation for pain control contemplates the use of oscillating electromagnetic fields applied to specific neural structures via an array of electrodes (referred to as contacts or wires) using time and amplitude characteristics to modulate glial and neuronal interactions as a mechanism for relieving chronic pain. More specifically, an exemplary aspect provides an apparatus and method for modulating the expression of genes involved in multiple pathways including inflammatory / immune system mediators, ion channels, and neurotransmitters in both the spinal cord (SC) and dorsal root ganglia (DRG). In one exemplary embodiment, such expression modulation is induced by spinal cord stimulation or peripheral nerve stimulation. In one embodiment, the amplitude and frequency of one or more signals used to generate multimodal stimulation of neural structures may be optimized for pain relief and low-power applications in implantable multimodal signal generators, as described herein.

[0007] According to one exemplary embodiment, an apparatus and method are provided for controlling patient pain by targeting different neural structures with multiplexed stimulation signals, such that multiple stimulation signals are multiplexed in the time domain, hereinafter referred to as "differential target multiplexed stimulation". For example, a signal generator can multiplex signals that may have different signal characteristics (e.g., pulse frequency, amplitude, or pulse duration) to generate differential target multiplexed stimulation for pain control. According to aspects of this disclosure, the output of the signal generator can be used to generate individual oscillating electromagnetic fields (stimulation signals) that can be applied to different sets of multiple electrodes (also referred to as contacts). The electrodes may be portions of wires designed to apply corresponding stimulation signals to different parts of a specific neural structure.

[0008] Various aspects of this disclosure relate to the use of multiple temporal and amplitude characteristics to modulate glial-neuronal interactions as a mechanism for relieving chronic pain. Multiplexed stimulation signals have the property of allowing differentially synergistic targeting of glial cells and neurons. For example, embodiments of devices and methods relating to modulating the expression of genes and proteins involved in multiple pathways associated with interactions between glial cells and neurons in neural tissue, including inflammatory / immune system mediators, ion channels, and neurotransmitters, are disclosed. In embodiments, such expression modulation can be induced by any of spinal cord stimulation, dorsal root ganglion stimulation, brain stimulation, or peripheral nerve stimulation. In embodiments, the amplitude, phase polarity, waveform, and frequency of the signals combined to generate differentially targeted multiplexed stimulations of neural structures can be optimized for pain relief and low-power applications in implantable signal generators, as described herein.

[0009] In embodiments of differential target multiplexing stimulation therapy, a high-frequency charge-balanced biphasic pulse signal set is utilized, wherein the polarity of the first phase of the high-frequency signal can be cathode or anode. In embodiments, a low-frequency signal set is used, which may have waveform characteristics different from those of the high-frequency signal. The polarity of the first phase of the biphasic charge-balanced low-frequency signal can be cathode or anode. The high-frequency and low-frequency stimulation signals can be delivered to nerve tissue via corresponding electrode sets by multiplexing individual pulses from each electrode. In some embodiments, the corresponding electrode sets may be co-located very close to the same nerve tissue (e.g., near the same vertebra).

[0010] According to one aspect of this disclosure, a method for controlling pain in a subject includes modulating the activity of glial cells in stimulated neural tissue by regulating any one of genes and proteins involved in calcium binding, cytokines, cell adhesion, or specific immune responses. In one embodiment, modulating glial cell activity includes exposing glial cells to a stimulus comprising multiple signaling components. The method also includes synchronous modulation of neuronal genes and proteins associated with the regulation of neuronal activity, such as ion channels, neurotransmitter release, or intracellular calcium regulation. In an embodiment, modulating neuronal activity includes exposing neurons to a stimulus comprising multiple signaling components. Without being bound by theory, it is thought that targeted modulation of different types of target cells (glial cells and neurons) helps to normalize glial cell interactions that have been affected by the development of chronic pain conditions due to sensitization of the nervous system.

[0011] According to an aspect of this disclosure, a method for controlling pain in a subject by delivering differentially targeted multiplexed stimulation to various neural tissue locations using multiple electrodes within one or more electrode arrays, the electrodes being located in relevant anatomical locations within the central or peripheral nervous system, suitable for pain in various body parts. In embodiments, the electrode arrays are positioned intraspinally within the epidural space to access different aspects of the spinal cord, or in the foramen of the dorsal root ganglion, or in the lateral spaces above and below the conus medullaris to stimulate the dorsal nerve roots. Stimulation of neural tissue in these anatomical locations with differentially targeted multiplexed signals can relieve chronic pain in the neck, upper limbs, trunk, lower back, and lower limbs associated with various pathological conditions. In another embodiment, the electrode arrays may be positioned to access injured peripheral nerves in different anatomical locations. The electrode arrays may also be placed in the motor cortex or deep brain structures to deliver differentially targeted multiplexed stimulation and provide relief for various pathological conditions.

[0012] According to another aspect of this disclosure, a differentially targeted multiplexed stimulation system includes: a memory for storing a plurality of signal parameter programs; a selection device for selecting one of the plurality of signal parameter programs; a signal generator controllable by the selected one of the plurality of signal parameter programs; and an output unit for connection to at least one electrode array; wherein the stimulation system is configured to provide a plurality of electrical signals having at least one glial stimulation signal and at least one neuronal stimulation signal to the at least one electrode array via the output unit. Each of the glial stimulation signal and the neuronal stimulation signal may be the result of combining a plurality of pulsed electrical signals having different parameters. Such parameters may include any one of pulse frequency, pulse width, pulse amplitude, active or passive charge balance mode, duty cycle, etc. In an embodiment, the system further includes a housing of biocompatible material surrounding the differentially targeted multiplexed signal generator and the output unit. In another embodiment, the selection device is configured to receive a user-definable instruction for modifying any one of the corresponding electrical parameters of the plurality of signals constituting the differentially targeted multiplexed stimulation signal.

[0013] According to another aspect of this disclosure, a method for controlling pain in a subject includes modulating the activation of neurons in stimulated neural tissue using one or more electrical signals. Modulation of neurons may include lowering the neuronal depolarization threshold and activating or deactivating neurotransmission in the subject's neural tissue using differentially targeted multiplexed signals. Simultaneously, the method may include using one or more electrical signals to modulate the activation of glial cells in stimulated neural tissue. Modulation of glial cells may include reducing the activation of microglia, oligodendrocytes, and astrocytes, increasing the neuroprotective effects of glial cells, modulating neurotransmitters associated with glial activation, and modulating cellular communication processes controlled by glial cells. In embodiments, the electrical signals provided by differentially targeted multiplexed stimulation of neurons and glial cells in the subject's neural tissue have characteristics of any one of the following: corresponding pulse frequency, pulse amplitude, pulse width, charge balance pattern, duty cycle, interphase delay, and phase polarity. In another embodiment, each of the multiplexed signals that differentially target neurons and glial cells in a neural tissue region may be provided by a single electrical pulse signal or by a combination of two or more different electrical pulse signals.

[0014] According to another aspect of this disclosure, a method for controlling pain in a subject includes modulating neuronal activity by lowering the depolarization threshold of neurons and activating or deactivating neurotransmission in the subject's neural tissue using differentially targeted multiplexed signals; and modulating glial cell activity by reducing the activation of microglia, oligodendrocytes, and astrocytes, increasing the neuroprotective effects of glial cells, modulating neurotransmitters associated with glial activation, and modulating cellular communication processes controlled by glial cells. Modulation of neuronal and glial cell activity is achieved using pulsed electrical signals with unique characteristics, such as frequency, amplitude, pulse width, charge balance pattern, phase polarity, duty cycle, and interphase delay, and these pulsed electrical signals may be delivered synchronously or at two different time intervals; wherein these differentially targeted multiplexed stimulation signals alter the synaptic plasticity of neurons and glial cells within the neural structure and re-establish the balance required for glial interactions present in non-chronic pain states.

[0015] According to another aspect, this disclosure provides a method for controlling pain in a subject, comprising modulating neuronal activity by lowering the depolarization threshold of neurons and activating or deactivating neurotransmission in the subject's neural tissue using differentially targeted multiplexed signals; and modulating glial cell activity by reducing the activation of microglia, oligodendrocytes, and astrocytes, increasing the neuroprotective effects of glial cells, regulating neurotransmitters associated with glial activation, and regulating cellular communication processes controlled by glial cells; wherein the manipulation of corresponding characteristics of the multiplexed signals alters the synaptic plasticity of neurons and glial cells within the subject's neural tissue.

[0016] This paper also discloses a device comprising a multiplexed signal generation module configured to be electrically coupled to one or more electrode arrays to differentially target neurons and glial cells in neural tissue.

[0017] Optionally, the differential target multiplexed signal generation module is arranged to generate multiple electrical signals, which can be combined into a multiplexed signal that can be delivered to one or more electrode arrays.

[0018] Optionally, the differential target multiplexed signal generation module includes various electrical signal sources or terminals, wherein one or more electrode arrays include at least a first subgroup and a second subgroup of electrodes. In one embodiment, the first subgroup of electrodes may be electrically coupled to a first electrical signal source and / or terminal, and the second subgroup of electrodes may be electrically coupled to a second electrical signal source and / or terminal. Multiple subgroups of electrodes may be electrically coupled to multiple electrical signal sources and / or terminals.

[0019] Optionally, the differential target multiplexed signal generation module is configured to have an operating mode for providing pulsed electrical signals corresponding to glial stimulation signals and neuronal stimulation signals as described herein. Optionally, such pulsed electrical signals are charge-balanced and may have different characteristic parameters, such as pulse frequency, pulse amplitude, pulse width, leader phase polarity, charge balance mode, interphase delay, and duty cycle.

[0020] Optionally, the differential target multiplexed signal generation module is configured for operation in a mode having a subgroup of electrodes in an electrode array that correspond to a stimulus in any of the methods described herein for providing electrical signals.

[0021] Optionally, the differential target multiplexing signal generation module can be configured to have an operating mode for providing pulsed electrical signals between 20 Hz and 1,500 Hz. The frequency of the electrical signal targeting glial cells may differ from the frequency of the electrical signal targeting neurons. Other characteristics of these electrical signals, such as pulse width, charge balance mode (active or passive), phase delay, and / or amplitude, may also differ. The glial stimulation signal and the neuronal stimulation signal can be multiplexed in a manner that allows for simultaneous delivery of stimuli without requiring pulse overlap between the corresponding signals.

[0022] As used herein, a differential target multiplexed signal generation module configured to have operating modes may include a memory module containing instructions defining at least the operating modes as described, wherein the operating modes are optionally user-selectable operating modes and the memory module optionally includes instructions for additional operating modes. In some embodiments, the differential target multiplexed signal generation module is configured to deliver electrical signals to one or more subgroups of electrodes within one or more specified electrode arrays.

[0023] Optionally, the differential target multiplexed signal generation module includes two or more electrical signal sources, such as signal generators, which can be independently controlled and configured to deliver electrical signals having parameters that can be set individually for each of the electrical signal sources.

[0024] Optionally, the device is non-implantable, such as a dialing system, which includes a signal generation module comprising at least one signal generator configured to deliver a plurality of electrical signals having parameters that can be individually set for each of the signals.

[0025] Optionally, the implantable differential target multiplexer signal generator module is adapted for electrical coupling to one or more electrode arrays, or optionally to one or more electrode arrays. The implantable differential target multiplexer module includes a generator circuitry and a housing. The housing hermetically seals the generator circuitry and may be made of a durable, biocompatible material. The differential target multiplexer signal generator module has an output interface for establishing electrical connections to electrodes implemented in one or more electrode arrays, such as two or more terminals for electrical coupling to two or more subgroups of electrodes implemented on one or more electrode arrays.

[0026] Optionally, the implantable differential target multiplexed signal generator module includes two or more signal generators and a timer electronic circuit system, the timer electronic circuit system being able to subordinate one of the signal generators to another, such that a delay can be generated between signals generated by at least two signal generators.

[0027] According to another aspect of this disclosure, a differential target multiplexing stimulation device includes an output unit for connection to at least one electrode array, and at least one signal generator, wherein the stimulation device is arranged to provide a differential target multiplexing stimulation signal to the at least one electrode array via the output unit. At least one electrode within the electrode array is configured to expose neural tissue and its constituent glial cells and neurons to the differential target multiplexing stimulation signal. The differential target multiplexing stimulation device may be a pain treatment device.

[0028] Optionally, the differential target multiplexing stimulation device is arranged to generate differential target multiplexing electrical signals that can be provided to at least one specific electrode array referred to as stimulation leads.

[0029] Optionally, the differential target multiplexing stimulation device may have an output unit comprising a first output for connection to a first stimulation lead and a second output for connection to a second stimulation lead. The first stimulation lead comprises a first electrode array. The second stimulation lead comprises a second electrode array.

[0030] Optionally, the differential target multiplexed stimulation device is arranged to provide at least a first multiplexed electrical signal to a first output and at least a second multiplexed electrical signal to at least a second output. The first multiplexed electrical signal and the other multiplexed electrical signals may differ in one or more parameters, such as amplitude, frequency, phase polarity, waveform shape, width, duty cycle, and interphase delay. In some embodiments, some of the multiplexed electrical signals may have the same set of parameters, while one or more of the other multiplexed electrical signals may have at least one different parameter.

[0031] According to another aspect of this disclosure, a method for operating a differential target multiplexed signal generation module includes connecting the signal generation module to one or more stimulation leads provided to the body of a subject. The method includes using the differential target multiplexed signal generation module to generate a first multiplexed signal for at least one of the one or more stimulation leads, and using the differential target multiplexed signal generation module to generate a second multiplexed signal for at least one of the one or more stimulation leads. At least one of the first multiplexed signal and the other multiplexed signals may have at least one uncommon parameter therebetween.

[0032] According to another aspect of this disclosure, a conductive material, such as a metal or a conductive polymer, is provided, for example in the form of an electrode, for applying a differentially targeted multiplexed stimulation signal to a subject to treat pain. The differentially targeted multiplexed stimulation signal may have at least one uncommon parameter therebetween.

[0033] Optionally, the first multiplexed stimulation signal is a glial stimulation signal and the second multiplexed stimulation signal is a neuronal stimulation signal. The first multiplexed stimulation signal may be a single electrical signal or a combination of two or more electrical signals having a frequency between 100 Hz and 100 kHz. The second multiplexed stimulation signal may be a single electrical signal or a combination of two or more electrical signals having a frequency lower than that of the first multiplexed stimulation signal, for example, between 20 Hz and 500 Hz. The frequency ratio between the first multiplexed stimulation signal and the second multiplexed stimulation signal is in the range of 5:1 to 5,000:1.

[0034] According to another aspect of this disclosure, a differential target multiplexing stimulation system includes: a memory for storing a plurality of differential target multiplexing signal parameter programs; a selection device for selecting one of the plurality of differential target multiplexing signal parameter programs; a differential target multiplexing signal generator device controllable by selection from the plurality of differential target multiplexing signal parameter programs; and an output unit for connection to at least one stimulation lead composed of an electrode array; wherein the stimulation device is configured to provide a differential target multiplexing stimulation signal generated by the differential target multiplexing signal generator according to the selection of the differential target multiplexing signal parameter programs to the at least one stimulation lead via the output unit. The differential target multiplexing stimulation system may further include a housing of biocompatible material surrounding the differential target multiplexing stimulation signal generator device and the output unit. In one embodiment, the differential target multiplexing stimulation signal generator device generates two or more multiplexed electrical signals in its operating mode. In one embodiment, the differential target multiplexing stimulation system may be combined with at least one stimulation lead comprising a subgroup of electrodes, wherein the subgroup of electrodes is electrically coupled to two or more multiplexed stimulation signals.

[0035] According to another aspect of this disclosure, optimization of differentially targeted multiplexed stimulation therapy includes the systematic selection of differentially targeted multiplexed stimulation signals and corresponding characteristic parameters suitable for the needs of the treated subject. This can include combinations of components in a manner described herein. In one embodiment, differentially targeted multiplexed stimulation can also be optimized by setting an optimal electric field, which modulates glial interactions in stimulated neural structures by selecting monopolar, bipolar, tripolar, shielded cathode, shielded anode, or any other multi-level arrangement of one or more stimulation leads positioned near the dorsal column of the spinal cord, adjacent to any other aspect of the spinal cord, in the intervertebral foramen, or adjacent to the dorsal nerve root corresponding to a specific anatomical region of the body in which the patient experiences pain, or in intracranial structures targeted to provide relief for various pathological conditions. In another embodiment, differential target multiplexing stimulation can also be optimized by setting an optimal electric field by modulating glial interactions in the stimulated neural structures through a selection of monopolar, bipolar, tripolar, shielded cathode, shielded anode, or any other multi-level arrangement of one or more stimulation leads positioned near one or more peripheral nerves associated with a specific anatomical region of the body where the patient experiences pain.

[0036] According to another exemplary aspect, this disclosure provides an electromagnetic stimulation system comprising: a memory for storing a plurality of multimodal signal parameter programs; a selection device for selecting one of the plurality of multimodal signal parameter programs; a signal generator controllable by the selected one of the plurality of multimodal signal parameter programs; and an output unit for connection to at least one electrode; wherein the stimulation system is configured to provide a composite electrical signal having an initiation phase signal segment and a hysteresis phase signal segment to the at least one electrode via the output unit. In one embodiment, the system further comprises a housing of biocompatible material surrounding the multimodal signal generator and the output unit. In another embodiment, the selection device is configured to receive a user-definable instruction for modifying any one of the respective amplitudes, relative phases, waveform shapes, and widths of the initiation phase signal segment and the hysteresis phase signal segment of the composite electrical signal. In another embodiment, the selection device is configured to receive a user-definable instruction for modifying any one of the amplitude and frequency of the composite electrical signal.

[0037] According to yet another exemplary aspect, this disclosure provides a method for controlling pain in a subject, comprising: A) lowering the depolarization threshold of nerve fibers in the subject with a component of a composite electromagnetic field; and B) simultaneously activating glial cells with a second component of the composite electromagnetic field; without administering a pharmacological compound to the subject. In one embodiment, the components of the composite electromagnetic field have any of a corresponding frequency, amplitude, phase, or harmonic content. In another embodiment, the composite electromagnetic field can be provided by a single electromagnetic signal or by a combination of two or more different electromagnetic signals.

[0038] According to another exemplary aspect, a method for controlling pain in a subject includes: A) reducing the depolarization threshold of nerve fibers of the subject with a first component of a composite electromagnetic field during a first time period; and B) simultaneously modulating glial cell activity with a second component of the composite electromagnetic field during a second time period different from the first time period; wherein the composite electromagnetic field alters the synaptic plasticity of neurons and glial cells within the neural structure.

[0039] According to another exemplary aspect, this disclosure provides a method for controlling pain in a subject, comprising: A) lowering the depolarization threshold of a subject's nerve fibers with a first phase segment of a biphasic signal; and B) modulating the glial cell activity of a subject with a second phase segment of a biphasic signal; wherein the manipulation of the biphasic signal alters the synaptic plasticity of neurons and glial cells within the nerve fibers.

[0040] According to another exemplary aspect, this disclosure provides a method for controlling pain in a subject, comprising: A) activating glial cells by multimodal electromagnetic stimulation through modulation of any one of the genes of calcium-binding proteins, cytokines, cell adhesion, or specific immune response proteins; and B) administering a pharmacological substance to the subject systemically, epidurally, or intrathecally over a period of time. In one embodiment, such a pharmacological substance may be injected via a stimulation lead having a port for direct delivery of the pharmacological agent into the epidural or intrathecal lumen. Optionally, a sustained-release formulation may be used to impregnate the pharmacological agent onto the stimulation lead to slowly elute the pharmacological substance into the nerve tissue surrounding the lead.

[0041] According to yet another exemplary aspect, this disclosure provides a method for controlling pain in a subject, comprising: A) lowering the depolarization threshold of nerve fibers in the subject with a component of a composite electromagnetic field; and B) simultaneously modulating glial cell activity with other components of the composite electromagnetic field; wherein the components of the composite electromagnetic field control the balance of glutamate and glutamine within the modulated glial cells in a calcium-dependent manner. In one embodiment, the components of the composite electromagnetic field have any one of a corresponding frequency, amplitude, phase, harmonic content, or width of a rectangular waveform. In another embodiment, the components of the composite electromagnetic field may be provided by a single electrical signal or by more than one different electrical signal.

[0042] According to another exemplary aspect, a method for controlling pain in a subject includes: A) modulating glial cells with an asymmetric biphasic electromagnetic signal having a variable duration having an anodic phase, the variable duration being selected to modulate the amount of glutamate released from the glial cells; and B) modulating glial cells with an asymmetric biphasic electromagnetic signal having a variable duration having a cathodic phase, the variable duration being selected to modulate the amount of glutamate released from the glial cells.

[0043] According to another aspect, a method for controlling pain in a subject includes: A) modulating glial cells with an asymmetric biphasic electromagnetic signal having a variable duration having cathode and anode phases thereon, the variable duration being selected to modulate the amount of glutamate released from the glial cells, wherein the electromagnetic field controls the balance of glutamate and glutamine within the modulated glial cells in a calcium-dependent manner.

[0044] This document also discloses a device including a signal generation module configured for electrical coupling with one or more wires.

[0045] Optionally, the signal generation module is arranged to generate a composite electrical signal. The composite electrical signal may be a sum of multiple electrical signals. Optionally, the signal generation module is arranged to generate a multimode signal, such as a frequency-modulated signal. The composite signal and / or multimode signal can be provided to one or more conductors.

[0046] Optionally, the signal generation module includes at least first and second electrical signal sources or terminals, and one or more wires include at least a first subgroup and a second subgroup of electrodes. The first subgroup of electrodes may be electrically coupled to the first electrical signal source and / or terminal, and the second subgroup of electrodes may be electrically coupled to the second electrical signal source and / or terminal.

[0047] Optionally, the signal generation module is configured to have an operating mode for providing at least first and second electrical signals corresponding to the first and second electromagnetic stimuli as described herein. Optionally, the first and second electrical signals have different frequency, amplitude, and phase polarity characteristics.

[0048] Optionally, the signal generation module is configured to operate in a mode having electrodes for providing electrical signals to electromagnetic stimulation corresponding to any of the methods described herein.

[0049] Optionally, the signal generation module can be configured to have an operating mode for providing a first subgroup of electrodes with a first electrical signal having a frequency to a second subgroup of electrodes and providing at least a second electrical signal having the same frequency to a second subgroup of electrodes. The frequency may be between 500 Hz and 1,500 Hz. Other parameters of the first and second electrical signals may differ, such as pulse width and / or amplitude. The first electrical signal may be excited synchronously (i.e., simultaneously) with the second electric field, or asynchronously (e.g., with a given time delay) relative to the first electrical signal.

[0050] As used herein, a signal generation module configured to have operating modes may include a memory module containing at least the operating modes defined as described, wherein the operating modes are optionally user-selectable operating modes and the memory module optionally includes instructions for additional operating modes. In some embodiments, the signal generation module is configured to deliver electrical signals to one or more wires as specified.

[0051] Optionally, the device is non-implantable, for example, a dialing system that includes a signal generation module comprising at least two signal generators configured to deliver electrical signals having parameters that can be individually set for each of the signal generators, such as a start signal and a shunt signal.

[0052] Optionally, an implantable multimodal generator is provided, adapted for electrical coupling to one or more wires, or optionally to one or more wires. The implantable multimodal generator includes a generator circuitry and a housing. The housing hermetically seals the generator circuitry and may be made of a durable, biocompatible material. The generator has an output interface for establishing electrical connections to electrodes implemented on one or more wires, such as at least a first terminal and a second terminal for electrical coupling to a first subgroup and a second subgroup of electrodes implemented on one or more wires.

[0053] According to another exemplary aspect of this disclosure, an electromagnetic stimulation device is provided, comprising an output unit for connection to at least one electrode, and a signal generator, wherein the stimulation device is arranged to provide a multimodal stimulation signal to the at least one electrode via the output unit. The multimodal stimulation signal may be an electromagnetic signal. The at least one electrode is configured to expose glial cells and neurons to the multimodal stimulation signal. At least one wire may comprise an electrode array or multiple electrode arrays.

[0054] Optionally, the signal generator is arranged to generate a multimode electrical signal, such as a frequency-modulated signal or an amplitude-modulated signal. The multimode electrical signal can be provided to at least one conductor.

[0055] Optionally, the signal generator is arranged to provide a first electrical signal to a first output and at least a second electrical signal to at least a second output. The first electrical signal and other electrical signals may differ in parameters such as amplitude, frequency, phase, phase polarity, waveform shape, and width. The first electrical signal and other electrical signals may correspond in parameters such as amplitude, frequency, phase, phase polarity, waveform shape, and width. At least the second electrical signal may be a tetanic stimulus signal, and the first electrical signal may have a frequency higher than that of the tetanic stimulus signal.

[0056] According to another exemplary aspect of this disclosure, a method for operating a signal generation module is provided. The method includes connecting the signal generation module to one or more wires. The wires may have been provided to the body of a subject. The method includes using the signal generation module to generate a first oscillating electromagnetic field in at least one of the one or more wires, and using the signal generation module to generate a second oscillating electromagnetic field in at least one of the one or more wires. The first oscillating electromagnetic field and at least one of the other oscillating electromagnetic fields may have at least one uncommon parameter therebetween.

[0057] Optionally, the first component of the composite signal is a activation signal, and the second component is a tonic signal. The first component may have a frequency between 200 Hz and 100 kHz. The second component may have a frequency lower than that of the first stimulus, for example, between 10 Hz and 500 Hz. In an exemplary embodiment, the frequencies of the first and second stimuli have a ratio within the range of 2:1 to 40:1, 4:1 to 40:1, 10:1 to 40:1, 20:1 to 40:1, up to 70:1, up to 140:1, etc.

[0058] According to another exemplary aspect of this disclosure, an electromagnetic stimulation system includes: a memory for storing a plurality of multimodal signal parameter programs; a selection device for selecting one of the plurality of multimodal signal parameter programs; a multimodal signal generator controllable by the selected one of the plurality of multimodal signal parameter programs; and an output unit for connection to at least one electrode; wherein the stimulation device is configured to provide a multimodal stimulation signal generated by the multimodal signal generator according to the selected one of the multimodal signal parameter programs to at least one electrode via the output unit.

[0059] According to another exemplary aspect of this disclosure, the optimization of the therapy includes the systematic selection of multimodal stimulation waveforms and parameters suitable for the needs of the patient being treated. This may include combinations of components in a manner described herein.

[0060] According to another exemplary aspect of this disclosure, a method for controlling pain in a subject includes: lowering the depolarization threshold of the subject's nerve fibers using a first phase segment of a biphasic signal; and modulating the glial cell activity of the subject using a second phase segment of a biphasic signal.

[0061] In an exemplary embodiment, the first phase segment of the biphasic signal is derived from a first electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's priming perception threshold (PPT), and the second phase segment of the biphasic signal is derived from a second electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's tetanic perception threshold (TPT). As used herein, the term perception threshold or sensory abnormality threshold (PT) relates to any type of stimulus, including priming stimuli and tetanic stimuli.

[0062] It should be understood that any of the aspects, features, and options described in the method are equally applicable to the system, signal generation module, and stimulation device. It should be understood that any one or more of the above aspects, features, and options as described herein can be combined. Attached Figure Description

[0063] The various features and advantages of the invention can be more readily understood by referring to the following detailed description in conjunction with the accompanying drawings, wherein like reference numerals refer to like structural elements, and wherein: Figure 1 A schematic diagram illustrating a device for pain control according to an embodiment of the present disclosure; Figure 2 A schematic circuit diagram illustrating an implantable multimodal modulation device that can be used with a system according to an embodiment of the present disclosure; Figure 3A and Figure 3B A conceptual illustration of an electrode array used in conjunction with a system according to an embodiment of this disclosure; Figure 4 Conceptually, this describes a pair of traces of a signal that can be used in an example of primary multimodal modulation according to embodiments of the present disclosure; Figure 5 Conceptually, this describes a pair of traces of a signal that can be used in an example of primary multimodal modulation according to embodiments of the present disclosure; Figure 6 Conceptually, this describes a pair of traces of a signal that can be used in an example of primary multimodal modulation according to embodiments of the present disclosure; Figure 7 Conceptually, this describes a frequency-modulated signal having a carrier frequency greater than the modulation frequency that can be used for multimodal modulation according to embodiments of this disclosure. Figure 8 Conceptually, this describes a frequency-modulated signal having a carrier frequency less than the modulation frequency that can be used for multimodal modulation according to embodiments of this disclosure; Figure 9 This section illustrates, conceptually, examples of biphasic pulses of composite signals that can be used for multimodal modulation according to embodiments of the present disclosure; Figure 10 Conceptually illustrating a composite signal having a rectangular biphase initiation component and an asymmetric biphase kinetic component that can be used for multimodal modulation according to embodiments of the present disclosure; Figure 11 Conceptually illustrating a composite signal with continuously changing frequencies that can be used for multimodal modulation according to embodiments of the present disclosure; Figure 12 Conceptually, this describes a composite signal having a white noise initiation component added to a symmetrical biphasic strong component, which can be used for multimodal modulation according to embodiments of the present disclosure. Figure 13 This conceptually illustrates the placement of an implantable system in a human subject according to embodiments of the present disclosure; Figure 14 This conceptually illustrates the placement of an implantable system in a human subject according to embodiments of the present disclosure; Figure 15 A diagram that conceptually illustrates the results obtained in preclinical animal studies utilizing the systems and methods according to this disclosure; Figure 16A and 16B A graph conceptually illustrating the results obtained during a short-term pilot clinical trial utilizing the systems and methods according to this disclosure; Figures 17A-17E A diagram illustrating the experimental results that conceptually demonstrate how the polarity of an electromagnetic field signal used to instruct a stimulus affects gene expression; Figure 18 This describes an exemplary patient adaptation / setup workflow; Figure 19 The illustration describes a trace of differentially multiplexed signals comprising four different signals according to an exemplary aspect of the present disclosure, wherein signals 1, 2 and 3 are multiplexed in at least one of an electrode array to target a specific type of nerve cell, while signal 4 is multiplexed at a different frequency with the other three signals using the same or another electrode array to target another type of nerve cell, wherein two signals, namely 2 and 4, have different intensities than the other two signals. Figure 20 The illustration describes a trace of differentially multiplexed signals comprising four different signals according to an exemplary aspect of the present disclosure, wherein signals 1, 2 and 3 are multiplexed in at least one of an electrode array to target a specific type of nerve cell, while signal 4 is multiplexed at a different frequency with the other three signals using the same or another electrode array to target another type of nerve cell, and all the multiplexed signals have different intensities. Figure 21 The illustration describes a trace of differentially multiplexed signals comprising four different signals according to an exemplary aspect of the present disclosure, wherein signals 1, 2 and 3 are multiplexed in at least one of an electrode array to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at a different frequency using the same or another electrode array to target another type of nerve cell, all multiplexed signals having different intensities, while signal 2 has a different pulse width. Figure 22 The illustration describes a trace of differentially multiplexed signals comprising four different signals according to an exemplary aspect of the present disclosure, wherein signals 1, 2 and 3 are multiplexed in at least one of an electrode array to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at a different frequency using the same or another electrode array to target another type of nerve cell, all multiplexed signals having different intensities, while the signals having different pulse widths and signal 3 having a different pulse frequency; Figure 23 The illustration describes a trace of differentially multiplexed signals comprising four different signals according to an exemplary aspect of this disclosure, wherein signals 1, 2, and 3 are multiplexed in an electrode array to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at different frequencies using the same or another electrode array to target another type of nerve cell, signal 2 has a different pulse width, and all signals differ in pulse frequency and intensity; and Figure 24 A grayscale image according to an exemplary aspect of this disclosure, showing the effect of differentially targeted multiplexing therapy on gene expression relative to the primary color (white) and the fold change caused by a pain model, wherein darker gray indicates larger changes in expression that are regulated up or down. Detailed Implementation

[0064] This application claims priority and benefit to U.S. Provisional Application No. 62 / 843,757, filed May 6, 2019, entitled “Method and Apparatus for Modulating Cellular Activity in Nerve Tissue Using Multiplexed Electrical Signals with Relative to Differential Targets”. This application also claims priority and benefit to U.S. Provisional Application No. 62 / 964,281, filed January 22, 2020, entitled “Method and Apparatus for Multimodal Electrical Modulation of Pain Using Composite Electromagnetic Fields”, the contents of all these applications are incorporated herein by reference in their entirety for all purposes.

[0065] This disclosure will be more fully understood through the following description, which should be read in conjunction with the drawings. In this description, the same numbers refer to similar elements within various embodiments of this disclosure. Those skilled in the art will readily appreciate that the methods, apparatus, and systems described herein are merely exemplary and variations may be made without departing from the spirit and scope of this disclosure.

[0066] Oscillating electromagnetic fields applied to neural structures induce alterations in synaptic plasticity when modulating two distinct cell populations: neurons and glial cells. This occurs simultaneously with effects on neurons, such as the generation or blocking of action potentials by stimulating mechanosensitive fibers to shield against (or gate) nociceptive signals traveling to the brain. Additionally, glial cells, being immune-active cells, constitute the most common cell population in the nervous system and play a crucial role in the development and maintenance of chronic neuropathic pain. Glial cells are responsible for monitoring the state of the nervous system through constant chemical communication with neurons and other glial cells. Microglia are glial cells responsible for monitoring the brain and spinal cord. Following nerve (or brain) injury, these cells are activated and respond to any stimuli deemed to threaten central nervous system (CNS) homeostasis. This activation involves morphological changes in microglia, accompanied by alterations in chemotactic and phagocytic activity, and the release of chemokines and cytokines that induce immune system responses. Microglia have been demonstrated as direct responders to CNS injury. Damage also triggers the activation of astrocytes, glial cells that monitor the synaptic cleft and thus participate in synaptic plasticity by regulating neuronal and glial neurotransmitter molecules and immune cells involved in synaptic pruning. Astrocyte activation and regulation persist for a longer period, and therefore it can be hypothesized that astrocytes play a significant role in alterations to synaptic plasticity influencing chronic pain. Experimental evidence supports this hypothesis. Notably, in the peripheral nervous system (PNS), astrocyte-like oligodendrocytes, Schwann cells, and satellite glial cells play important roles.

[0067] ATP-mediated calcium ion and phosphorylation processes play a crucial role in the glial response to injury. Electrical impulses induce changes in calcium ion concentration in astrocytes, which propagate between astrocytes via calcium waves. This, in turn, signals the release of neurotransmitters such as glutamate, adenosine, and ATP, even after sodium channel blockade that modulates both neuronal excitability and synaptic transmission. The presence of an external oscillating electric field then stimulates glial cells to affect synapses negatively impacted by injury. The electric field provides an initiation response, shifting synaptic function back to a normal state.

[0068] Without being bound by theory, it is possible to electrically stimulate glial cells because their responses (glial depolarization, ion release / capture, glial neurotransmitter release) depend on specific parameters, such as the amplitude, frequency, phase polarity, waveform shape, and width (in the case of rectangular waveforms). For example, the release of glutamate from astrocytes can be modulated proportionally to the amount of anodic current applied during biphasic pulse stimulation. Monophasic cathodic stimulation of hippocampal astrocytes promotes glutamate release. The introduction of the anodic component reduces the amount of glutamate released. Given that glial cells and neurons respond differently to electric fields, it is then possible to modulate the responses of these cell populations differentially with significantly different electrical parameters. This theory lays the mechanistic foundation for multimodal stimulation. Subthreshold stimulation with an electromagnetic field set at optimal frequency, amplitude, waveform, width, and phase can modulate the behavior of glial cells and how they interact with neurons at the synaptic level. Therefore, multimodal modulation provides the ability to control the glutamate and glutamine balance in a calcium-dependent manner, and the possibility of modulating such a balance with an electromagnetic field in an appropriate way.

[0069] Electromagnetic fields modulate the expression of genes and proteins involved in numerous processes related to synaptic plasticity, neuroprotection, neurogenesis, and inflammation. Genome-wide expression analysis of ipsilateral DC and DRG tissues obtained from an animal model of chronic neuropathic pain, with continuous SCS application up to 72 hours, provides findings that inform the development of the multimodal approach described below. Without wishing to be bound by theory, gene expression results indicate that analgesic effects may be induced at the molecular level, either in addition to or independently of electric field blocking or shielding of nerve conduction. For example, SCS was identified as an upregulated gene for calcium-binding protein (Cabp), cytokines (Tnf, 116, 111b, Cxcl16, lfg), cell adhesion (ltgb), and specific immune-reactive proteins (Cd68, Tlr2), all of which are associated with glial activation. Modulation parameters, particularly oscillation frequency and amplitude, can play a crucial role in the mode of action.

[0070] Multimodal modulation method

[0071] According to an exemplary aspect of this disclosure, a method for multimodal modulation utilizes a composite electric field in which at least one component oscillates at a higher frequency than that of the other component. This composite electric field is intended to provide pain relief exceeding that provided by either of its own electric fields alone. The electric field of the higher-frequency “activating” component provides a sustained electrochemical potential, which can promote the stimulation of nerves by the other component oscillating at a lower frequency. Without being bound by theory, the activating component lowers the depolarization threshold of nerve fibers, synchronously modulating glial activation. The activating component can also reduce the impedance of the stimulated tissue, which allows the electric field to penetrate the nerve tissue better. The frequent pulses of the activating component also contribute to the lower threshold of depolarization of membrane-integrated nerve fibers via electrical stimulation. In addition, the activating component can promote neuronal desynchronization, which is a mechanism that helps to reconstruct neuronal circuits that are no longer naturally synchronized to maintain nociceptive input to the brain.

[0072] In the disclosed main multimodal modulation techniques, depolarization mechanisms are combined with amplitudes below or slightly above the sensory abnormality threshold (PT), so that even with tetanic stimulation, the patient may or may not feel tingling. In some embodiments, a complex signal comprising a major component providing electrical stimulation at a frequency above the tetanic frequency can activate a state that allows synaptic plasticity to be reverted to a state closer to that prior to central sensitization caused by injury, thereby providing a mechanism for long-lasting pain relief.

[0073] In some embodiments, the activation frequency (PF) can be set to any frequency between 200 Hz and 100 kHz. When using charge-balanced pulsed rectangular electrical components (e.g., biphasic symmetric, biphasic asymmetric, capacitor-coupled monophasic), the pulse width (PW) of the activation component can be set as low as 10 µs and as high as allowed by the activation frequency. For example, the maximum PW of a biphasic component with equal PW per phase and a 20 µs interphase delay is 395 µs at PF = 1,200 Hz or 980 µs at PF = 500 Hz. Voltage- or current-controlled composite signals can be used, although current-controlled signals may be more desirable because such signals are independent of changes in temporal impedance in the stimulated tissue.

[0074] In some embodiments, the first or activation frequency is between 1000 Hz and 1400 Hz (burst), or between 750 Hz and 1050 Hz (average). According to embodiments, multiple signals can be multiplexed within a repetitive set of N pulse spaces. Each pulse space within the mode can correspond to a different electrical signal with corresponding parameters. A lower average frequency can be generated by multiplexing a second strong DC signal component in one of the N pulses. According to embodiments, the burst frequency of the activation frequency signal component can be an integer multiple (M) of the strong DC signal frequency, such that the strong DC pulse space contains only pulses from a set of N pulse spaces repeated every M times. Blank pulse spaces result in a burst of N-1 pulses at the “burst” frequency, followed by “missed” pulses, resulting in a lower “average” frequency in the set of N pulses. As used herein, the average frequency of the activation signal is calculated separately without including pulses associated with the strong DC signal. In some embodiments, different sets of electrodes relative to the strong DC signal are used to deliver the activation signal to different physical locations. In another exemplary embodiment, the first or start frequency is set to 1200 Hz (burst) or 900 Hz (average). In some embodiments, each pulse within a burst can be provided on separate programs for different electrode groups, wherein the configuration is set to allow individual amplitude variability.

[0075] In other exemplary embodiments, the second or tetanic component is set at a frequency of about 50 Hz and interleaved into the treatment to account for the average initiation frequency, although other tetanic values ​​and ranges, such as 20 Hz to 200 Hz, 20 Hz to 100 Hz, 30 Hz to 80 Hz, etc., are considered herein.

[0076] Multiplexing modulation method

[0077] In other exemplary embodiments, this disclosure recognizes that different glial cells and neurons in neural tissue respond to electric fields in different ways, and it is possible to modulate the responses of these cell populations differentially with significantly different electrical signals containing parameters characteristic of targeting and modulating the activity of specific cell types. The disclosed systems and methods are based on delivering such signals in this multiplexed manner to modulate the activity of glial cells and neurons in neural tissue in order to balance glial interactions away from states that cause pain sensation in a subject. The multiplexed signal affects the expression of genes and proteins associated with relevant biological processes that have been identified as being affected by chronic pain. Applying differentially targeted multiplexed SCS signals to a live model of neuropathic pain normalizes the expression of such genes and, consequently, normalizes the associated biological processes toward those found in healthy animals, referred to herein as primitive animals.

[0078] RNA sequencing has been used to investigate the effects of differentially targeted multiplexing (SCS) on the aggregation of mRNAs associated with various biological processes in a rodent model of neuropathic pain. Weighted Gene Association Network Analysis (WGCNA) aggregated more than 9,000 RNA transcripts into forty-one modules, which aggregated these RNA transcripts according to their expression patterns. WGCNA was complemented by Gene Ontology Enrichment Analysis (GOEA), which identified the biological processes involved in the gene transcripts aggregated in the modules. WGCNA allowed comparisons of the effects of the treatment on a group of subjects relative to a control group of untreated subjects and a control group of the original subjects. WGCNA demonstrated that the expression patterns of genes in twenty-four modules significantly affected the original animal pain model. Continuous application of differentially targeted multiplexing-based therapy for up to 48 hours reversed the expression patterns in twelve of these modules back to their original patterns. Table 1 illustrates the biological processes associated with modules whose effects of differentially targeted multiplexing (SCS) therapy were significantly reversed relative to chronic pain, with GOEA identifying the enriched biological processes. Figure 24 The diagram illustrates a grayscale image where key genes in relevant biological processes are grouped by the fold change ratio of their expression levels relative to the original (healthy) level under chronic pain. The image also illustrates the effects of differentially targeted multiplex therapy, where the expression of most genes folds towards the levels of the original subjects.

[0079] Table 1. The WGCNA module is significantly affected by differential target multiplexing relative to the effects on chronic pain and related biological processes obtained via GOEA.

[0080] In an exemplary embodiment, the signal processor receives signals from one or more signal generator modules and is programmable to execute various algorithms for combining individual signals into a single composite signal, including any one of amplitude modulation, frequency modulation, signal summation, signal synchronization, phase modulation, convolution, etc., or any combination thereof, and to generate custom signals from a wavetable or digital oscillator in real time in response to user input data. The signal processor, combined with a tap delay module, facilitates the multiplexing of various signals supplied to the electrode array.

[0081] In other exemplary embodiments, the central processing unit (CPU) module of the differential target multiplexing device can access stored digital data that mathematically describes the waveforms of one or more signals, and can generate analog signals at different frequencies from such data step functions. The processor performs algorithmic manipulation on such data to obtain the desired signal processing result. A digital-to-analog converter associated with the CPU module can convert the processed signal into a single output with the correct amplitude for coupling to one or more electrode arrays. In this way, the interaction of the multiplexed individual signals can be achieved through a single electrical complex signal capable of stimulating / modulating the interaction between glial cells and neurons in a manner that simulates the use of the multiplexed individual signals.

[0082] In other exemplary embodiments, the systems and apparatus described herein can be used to generate various differentially targeted multiplexed electrically modulated signals, such as Figure 19-23 The signals described herein. Those skilled in the art will understand that other different target multiplexed electrical modulation signals can be conceived based on this disclosure.

[0083] Figure 19 The description includes traces of differentially multiplexed signals of four different signals, wherein signals 1, 2 and 3 are multiplexed in at least one of the electrode arrays to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at a different frequency using the same or another electrode array to target another type of nerve cell, and signals 2 and 4 have different intensities (amplitudes) than the other two signals.

[0084] like Figure 19 As shown, signals 1, 2, and 3 repeat together at a frequency higher than that of interleaved signal 4. Therefore, the burst frequencies of signals 1, 2, and 3 are ¾ of the average frequency (ignoring interleaved signal 4). According to various embodiments, a combination of signals 1, 2, and 3 can be provided to a first electrode set, while interleaved signal 4 can be provided to a second electrode set. As used herein, the terminology applies simultaneously to signals 1-4 relative to each other. Specifically, individual pulses do not need to overlap to be considered synchronized, as the signals are constituted by multiple pulses forming the signal at corresponding frequencies.

[0085] Figure 20 The description includes traces of differentially multiplexed signals of four different signals, wherein signals 1, 2 and 3 are multiplexed in at least one of the electrode arrays to target a specific type of nerve cell, while signal 4 is multiplexed at a different frequency with the other three signals using the same or another electrode array to target another type of nerve cell, and each of the four multiplexed signals has a different intensity.

[0086] Figure 21The description includes traces of differentially multiplexed signals of four different signals, wherein signals 1, 2 and 3 are multiplexed in at least one of the electrode arrays to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at different frequencies using the same or another electrode array to target another type of nerve cell. All the multiplexed signals have different intensities, while signal 2 has a different pulse width.

[0087] Figure 22 The description includes traces of differentially multiplexed signals of four different signals, wherein signals 1, 2 and 3 are multiplexed in at least one of the electrode arrays to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at different frequencies using the same or another electrode array to target another type of nerve cell. All the multiplexed signals have different intensities, while signal 2 has a different pulse width and signal 3 has a different pulse frequency.

[0088] Figure 23 The description includes traces of differentially multiplexed signals of four different signals, wherein signals 1, 2 and 3 are multiplexed in at least one of the electrode arrays to target a specific type of nerve cell, while signal 4 is multiplexed with the other three signals at different frequencies using the same or another electrode array to target another type of nerve cell, signal 2 has a different pulse width, and all signals differ in pulse frequency and intensity.

[0089] Figure 24 The image is a grayscale image, showing the effect of differentially targeted multiplex therapy on gene expression relative to the original color (white) and the fold change caused by the pain model. Darker grayscale values ​​indicate larger changes in expression that are regulated upward or downward.

[0090] As will be discussed in more detail below, an exemplary process for programming can be configured to determine a program algorithm for one program, and then match or set the algorithms of other programs to be the same or adjusted based on the first program. Additionally, in an exemplary embodiment, multiple different activation frequencies can be used, where different selections are made of amplitude, pulse width, and frequency to alleviate pain.

[0091] The amplitude of the priming component can be set below the priming perception threshold (PPT), but is not excluded from being set at or above the PPT. The PPT can be found by slowly increasing the amplitude while receiving feedback from the subject. Once perception begins to be recorded, the amplitude of the priming component can be changed as a percentage of PPT (%PPT). In the case of an exemplary PF of 1500 Hz, the signal can then be set for a given time, for example, 10-30 minutes, before the electrical component set at a tetanic frequency below the PF (e.g., 10 Hz to 99 kHz) is independently applied to other electrodes in the lead. In one embodiment, for example, in the case of an exemplary PF of 200 Hz, the tetanic frequency can be in the range of approximately 10 Hz to 199 Hz. In the primary stimulation mode, the tetanic frequency will be below the priming frequency, but is not necessarily limited to a specific range of frequencies below the priming frequency.

[0092] For charge-balanced, such as two-phase symmetrical, two-phase asymmetrical, or capacitor-coupled single-phase pulse signals, the pulse width (PW) can be as low as 10 µs or as large as allowed by the set DC frequency. In exemplary embodiments, the pulse width can be between about 100 microseconds and 500 microseconds, between about 100 microseconds and 400 microseconds, between about 150 microseconds and 200 microseconds, or any different value, range, or combination of pulse widths.

[0093] The signal generation and delivery circuitry system also allows modification of the duty cycle of the pulse width signal and various schemes for altering the initial initiation time, as well as the on / off time of the initiation signal relative to the delivery of the tetanic signal. The amplitude of the tetanic electrical component, which can be controlled by voltage or current, can be set above, below, or at the tetanic sensing threshold (TPT). PT can be obtained by increasing the amplitude of the tetanic component while receiving feedback from the patient. The tetanic amplitude can then be set to a value corresponding to a percentage of TPT (%TPT). In one embodiment, in the primary multimodal modulation method described herein, both the initiation component and the tetanic component can be below 100 kHz. In another embodiment, the tetanic signal can be below 500 Hz. In yet another embodiment, the tetanic signal can be below 100 Hz. In one embodiment, depending on the specific value of the selected frequency, the ratio of the initiation component frequency to the tetanic component frequency can be in the range of 2:1 to 40:1, 4:1 to 40:1, 10:1 to 40:1, 20:1 to 40:1, up to 70:1, up to 140:1, etc.

[0094] In yet another embodiment of multimodal modulation therapy, the initiating component may be biphasic, wherein the polarity of the first phase of the biphasic initiating component may be cathode or anode. In this embodiment, the tetanic component may have properties different from those of the initiating component. The tetanic component may be biphasic, wherein the polarity of the first phase of the biphasic tetanic signal is cathode or anode.

[0095] In an exemplary embodiment of multimodal modulation therapy, an active recharge mode provides a recovery pulse that applies equal charge in the opposite direction to the input, thereby driving the waveform in each direction.

[0096] The techniques disclosed herein can be implemented using minimally invasive surgery, which is superior to those requiring extensive surgical intervention and medical expenses, but may require surgical implantation in special circumstances. Similar to... Figure 3A and Figure 3B The electrical stimulation wires described herein can be used, but other designs with different numbers of electrodes, sizes of electrical contacts, spacing between contacts, and geometric arrangements of electrodes within an array can be used to deliver electromagnetic stimulation to neural structures. In exemplary embodiments, various electrode and wire configurations provide spacing configured to modulate glial cells and neurons.

[0097] In embodiments, the lead includes a cylindrical arrangement of multiple electrodes, for example, the number of electrodes being between four and sixteen. The diameter of the lead may be small enough to allow percutaneous implantation into the spinal canal using an epidural needle under standard clinical practice. The electrodes are made of a biocompatible material that is also corrosion-resistant, such as an iridium-platinum alloy. For example, a 50 cm long lead implemented with eight electrodes may have a diameter of 1.35 mm, with each cylindrical electrode having a length of 3.0 mm and a spacing of 4.0 mm between the electrodes. Conductive metal wires may extend from the electrodes to the distal portion of the lead into a metal connector. The metal wires may be enclosed in a triple-insulated safety housing made of a biocompatible durable polymer.

[0098] In the context of multimodal modulation of the spinal cord, various multi-contact leads can be positioned in the epidural space to stimulate previously described cell populations. In a particular arrangement, the leads can be positioned parallel to each other, but not necessarily coplanar within the epidural space. Figure 3A This illustrates two eight-contact electrode arrays that can be used with the disclosed multimode modulation technique. It should be noted that the polarity of the wires can also be customized during the programming phase for bipolar, monopolar, or shielded cathode configurations. Another example of a possible electrode array arrangement is shown in... Figure 3B In this arrangement, the leads are staggered relative to each other. Customization and optimization of the therapy may include positioning the leads intradurally at the appropriate spinal segment in either type of lead arrangement.

[0099] Other arrangements can be used to stimulate different locations along the spinal canal; for example, the leads do not need to be parallel. In one arrangement, for instance, one lead may be dedicated to delivering a signal in the spinal cord at a given vertebral level, while another lead provides a signal more tail-like or head-like relative to the other lead. In principle, leads can be located in the spinal cord at any vertebral level, or they can be positioned peripherally, because the principles behind multimodal modulation are applicable to investigating peripheral glial cells of axons.

[0100] Furthermore, the location and penetration of multimodal stimulation electromagnetic fields can be used to customize and optimize therapies that deliver multimodal stimulation signals to specific electrode arrays within each lead by setting up monopolar, bipolar, or shielded cathode arrangements of such electrode arrays. For example, a therapy for a patient with lower back pain extending into one of the lower limbs might require positioning stimulation leads along the vertebral level at T8 (TS) and T12 (T12) within the epidural space in an alternating arrangement. The electrode array at the head of the lead can be configured as a monopolar, bipolar, or shielded cathode arrangement. Another electrode array at the tail of the lead can also be configured as a monopolar, bipolar, or shielded cathode arrangement. Clinicians will be able to customize electrode array settings in an organized manner, thereby optimizing therapy based on patient feedback.

[0101] Optionally, pain relief can also be achieved by positioning the lead near the peripheral nerve, such as... Figure 14 As explained in the text, peripheral nerve stimulation (PNS) is an alternative therapy for chronic pain, where the target nerve has been identified as the source of pain. Current understanding of the therapeutic effects of PNS is also based on the gate control theory. However, the axons of sensory neurons in the peripheral nerves are surrounded by glial cells that are known to respond accordingly to the frequency characteristics of stimuli.

[0102] Multimodal peripheral nerve stimulation involves positioning one or more stimulation leads around or near a target nerve. As described herein, the leads are connected to a signal generator with multimodal capacity. According to the principles and methods described in this application, multimodal stimulation is delivered to neural tissue composed of neuronal axons and their corresponding glial cells (Schwann cells). The leads can be implanted to position around the target nerve using an invasive surgical approach or percutaneously using a needle cannula.

[0103] Alternatively, in cases where stimulation is intended for target nerves close to the skin surface (e.g., the vagus nerve, nerves in limb joints, etc.), the wires can be positioned within a conductive biocompatible pad for transcutaneous delivery of multimodal electromagnetic fields. This embodiment constitutes transcutaneous electroneural multimodal stimulation (TENMS). In this embodiment, the initiation high-frequency component of the multimodal signal reduces the impedance of the skin and subcutaneous tissue and allows for better penetration of the tetanic signal. The initiation signal also provides a modulation signal to the perisynaptic glial cells in the neuromuscular joints. These cells are known to distinguish different stimulation modes and respond accordingly, thus allowing modulation of synapses with multimodal stimulation. The tetanic component of the multimodal signal is used to stimulate neuronal axons below a lower threshold.

[0104] System components

[0105] Figure 1 This document conceptually illustrates an embodiment of a multimodal stimulation system that can be used to perform the methods disclosed herein. As illustrated, the system includes a pair of electrical leads 30 and 32, each of which may be implemented as an array of electrode contacts, a junction box 18, and signal generators 17 and 19. The junction box 18 is electrically coupled to the leads 30 and 32 and the signal generators 17 and 19 via suitable connectors. The junction box 18 and the signal generators 17 and 19 may be housed in a housing referred to as an External Stimulator Unit (ESU) system 16. Each of the generators 17 and 19 delivers a specific signal having parameters that can be individually set for each other. Each of the generators 17 and 19 may have functional characteristics and architectural elements similar to those of the generator 20 described herein, without an external housing suitable for implantation into a patient. In one embodiment, the system 16 may also include the implantable multimodal generator 20 and [other components referenced herein]. Figure 2 One or more of the modules described.

[0106] The ESU system 16 is electrically coupled to electrical wires that can be implemented by an array of electrode contacts. In an embodiment, such as Figure 1 As illustrated, a pair of wires 30 and 32 are coupled to ESU 16 using appropriate connectors. In another embodiment, a single wire implemented as an electrode array can be used. In a configuration for performing primary multimode modulation, one of generators 17 or 19 can be configured to deliver a start-up component, such as 1,200 Hz, and the other generator can be configured to deliver a strong inflection component, such as 50 Hz. Tap cassette 18 can be used to reconfigure signal delivery to appropriate electrode contacts in wires 30 and 32. Figure 1In the embodiments described herein, electrode contacts 1-8 in electrode array 30 may be split such that electrode contacts 1-4 deliver a first signal, such as a shunt signal, different from a second signal delivered at electrode contacts 5-8, for example, a start signal. Similarly, electrode contacts 9-16 in electrode array 32 may be split such that electrode contacts 9-12 deliver signals similar to those delivered by electrode contacts 1-4 in electrode array 30, while electrode contacts 13-16 deliver signals similar to those delivered at electrode contacts 5-8 in electrode array 30, as described.

[0107] Implantable multimodal generator

[0108] Figure 2 A block diagram conceptually illustrates elements including an implantable multimodal generator (IMG) 20. The generator circuitry can be hermetically sealed within a housing made of a durable biocompatible material, such as stainless steel or titanium. The generator 20 has an output interface for establishing electrical connections with electrode arrays implemented within previously described leads 30 and 32 for delivering multimodal signals to glial cells and neurons. In one embodiment, the implantable multimodal generator 20 includes a central processing module 25, a memory module 28, a telemetry module 26, a power supply module 21, a signal generator module 23, a signal generator module 24, a tap and delay module 22, and a signal processor 27 containing its output interface. In embodiments, the elements of the implantable multimodal generator 20 can be as follows: Figure 2 The interconnections described herein may be connected via a central bus, depending on the implementation scheme, enabling all components to communicate with each other.

[0109] The central processing module 25 may be implemented using a microprocessor integrated circuit or may include a small-scale logic with reduced functionality, but in either implementation it includes a wireless transceiver function that enables bidirectional wireless communication of information with an external programmer unit (not shown) or a user-controlled remote controller 36.

[0110] A memory module 28, which may be implemented as RAM or ROM, can be used to store modulation programs that can be executed by a central processing module 25, which generates functional information for the generator 20. The central processing module 25 can store and retrieve information from the memory module 28 according to user commands.

[0111] Telemetry module 26 is used to communicate with an external programmer unit (or control remote controller) via a wireless protocol and includes a transceiver circuitry system for wireless communication with devices remote from generator 20 according to any number of established wireless protocols.

[0112] The power module 21 may include a rechargeable or non-rechargeable battery and electronic circuitry that distributes power from the battery to all other components of the implantable multimodal generator 20.

[0113] Signal generator module 23 includes an electronic circuit system that allows delivery of a charge-balanced waveform of any waveform, including, but not limited to, biphase or single-phase pulses, sine waves, sawtooth waves, triangular waves, and their pulse trains.

[0114] In one embodiment, the signal generator module 23 includes an electronic circuitry system that allows the delivery of a noise signal, such as white noise with a constant power spectral density, pink noise with equal energy in an octave interval, or other noise signals in which the energy within the signal spectrum is distributed in other patterns. In one embodiment, the noise signal may be used as a starting component in the techniques disclosed herein. The signal generator module 23 is capable of delivering these waveforms at frequencies ranging from 1 Hz to 100 kHz. For pulse delivery, depending on the frequency, the signal generator module 23 is capable of delivering rectangular pulse waves with widths ranging from, for example, 1 µs to 250 ms. The signal generator module 23 is further capable of generating a range of phase delays. The signal generator module 23 is designed to deliver signals with voltage-controlled or current-controlled amplitudes, respectively, in values ​​ranging from, for example, 0 V to 30 V or 0 mA to 30 mA. The signal generator module 23 is also capable of generating pulses with duty cycles. The signal generator module 23 is controlled by a central processing module 25 according to parameters selected by the user in an external programmer unit (or control remote). The signal generator module 23 can be implemented as an analog or digital circuit system or a combination thereof.

[0115] Signal generator module 24 may be structurally or functionally similar to signal generator module 23, and can be independently controlled and programmed.

[0116] Signal processor 27 may be implemented as a dedicated digital signal processor (DSP) or may include a programmable general-purpose DSP. Signal processor 27 may be implemented as any number of commercially available signal processing integrated circuit components having a dedicated instruction set and processor capable of performing algorithmic manipulation on one or more signals input thereto.

[0117] Signal processor 27 receives signals from signal generator modules 23 and 24 and is programmable to execute various algorithms for combining individual signals into a single composite signal, including any one of amplitude modulation, frequency modulation, signal summation, signal synchronization, phase modulation, convolution, etc., or any combination thereof, and to generate custom signals from a wavetable or digital oscillator in real time in response to user input data. Signal processor 27 may have associated temporary memory areas for locally storing data and program variables while performing signal processing or other tasks. Additionally, signal processor 27 may include dedicated analog circuitry systems, such as filters, control circuitry systems, and circuitry systems for generating composite signals from signals from signal generator modules 23 and 24. Depending on whether the output of the signals generated by signal generator modules 23 and 24 is analog or digital, signal processor 27 may also include its own analog-to-digital converter and digital-to-analog converters for converting any input signal into an appropriate format for processing and for outputting the signal to tap and delay module 22.

[0118] Tap and delay module 22 includes a precise timer electronics system that allows one of the signal generator modules 23 or 24 to be subordinate to the other, enabling a delay between signals generated therefrom, thus allowing the user to program the synchronous delivery of such signals. Tap and delay module 22 also incorporates an electronics system called a tap, which allows the user to select an option where output array 1 delivers signals to all the top (mouth) electrode contacts of a pair of electrode arrays (e.g., tetanic 50 Hz, 250 µs pulse width, 3.0 mA), while output array 2 delivers signals to all the bottom electrode contacts of a pair of electrode arrays (e.g., a start signal with 1,200 Hz, 100 µs pulse width, 3.5 mA). An example of this option is shown in... Figure 3A middle.

[0119] The other option is Figure 3B One option described herein is where the tapping option can be omitted. In this case, all contacts in a given electrode array will be set to the same modulation parameters as those delivered by, for example, signal generator module 23. All contacts in another electrode array will be set to the same modulation parameters as those provided by another signal generator module. In embodiments where the same composite signal is provided as output to arrays 1 and 2, the functionality of the tapping and delay module 22 can be entirely performed by the signal processor 27, thereby avoiding the need for the tapping and delay module 22, assuming a suitable output interface for properly coupling the output of the signal processor 27 to the electrode array.

[0120] In one embodiment, all or most of the functional blocks of generator 20 may be fabricated on a single integrated circuit chip, which includes a microprocessor and associated memory, a wireless transducer, and one or more digital oscillators. Alternatively, the digital oscillators may be replaced by wavetables in which mathematical descriptions of various waveform data values ​​are stored, which can be converted into analog signals using a digital-to-analog converter and integrated into or associated with processor module 25 or signal generator module 23 or 24, depending on the appropriate implementation. Such wavetables may be stored in processor module 25 or memory module 28.

[0121] In other embodiments, the various modules of the IMG 20 may communicate via a central bus within it, or may have dedicated direct connections between them, or any combination thereof.

[0122] In one embodiment, the IMG 20 or ESU 16 can be programmed by a clinician using software that allows control of all aspects of the system. This software is accessible through a computer-based interface known as Clinician Programmer (CP) software. The software can be implemented using a wireless communication protocol for remote access to the IMG 20 or ESU 16. The ESU 16 may also have a network port, such as a USB or micro USB port, for interacting with the CP. In the case of the IMG 20, the CP software enables the clinician to communicate with the central processing module 25 to define a set of parameters for the signals generated by the signal generator modules 23 or 24, such as amplitude, frequency, phase, phase polarity, waveform shape, and width (rectangular waveform), and further define the parameters of its relative timing by defining the operating parameters of the tap and delay modules 22. Such defined parameter sets may be stored as one or more configuration programs in the memory module 28 or in memory associated with the central processing module 25.

[0123] In one embodiment, one or more configuration programs may be stored in memory associated with the remote controller 36, and their parameters may be passed to the IMG 20 via the telemetry module 26 for controlling the generator module 23 or 24 and the tap and delay module 22. The CP software allows clinicians to further define which parameters a patient can control via the remote controller 36 and to define any limitations on such parameters.

[0124] For example, a clinician can set up and store a configuration program #1 with parameters that provides a primary multimodal stimulation consisting of a biphasic symmetrical rectangular pulse signal component set to 1,200 Hz, 150 µs PW, and a current-based amplitude set to %PPT, as well as a tonic signal component consisting of a biphasic asymmetric pulse (rectangular and exponentially decaying phases) with a current-based amplitude set to %PT, at 50 Hz, 400 µs PW. The composite signal can be delivered to a specific set of electrodes in the lead.

[0125] Clinicians can also set up and store configuration program #2, which provides primary multimodal stimulation consisting of an initiation signal component with a biphasic symmetrical rectangular pulse at 900 Hz and 300 µs PW, and a tetanic signal component delivering biphasic symmetrical rectangular pulses at 100 Hz and 400 µs PW, each set to its own current-based amplitude setting of a specific %PT. These signals can be delivered to a specific set of electrodes in a wire that may differ from the set of electrodes used in configuration program #1. The system allows additional configuration programs that clinicians deem necessary, depending on the storage capacity of memory module 28.

[0126] Limited control over the multimodal configuration program is available to the patient via the remote controller 36. In one embodiment, a clinician can use the CP to access one or more configuration programs to control any of the parameters of the configuration programs stored in the ESU 16 or IMG 20. The patient may be able to browse and / or select any available configuration program using the remote controller. For example, the patient may be able to change the current-based amplitude of any particular configuration program to a specific setting determined by the PPT or PT to optimize pain relief. It should be noted that the remote controller 36 may have a simple interface, such as a selector switch or dial pad, to select the appropriate configuration program, or a more complex user interface including a visual display with directional keys or touch-sensitive menus.

[0127] In the embodiments described herein, options exist for user feedback and control of the system via a programming device. As stated above, the initial settings for the initiation and tetanic frequencies are programmed by a physician or clinical domain engineer. Subsequently, the device allows the patient to change numerous settings, including the initiation and tetanic frequencies, and parameters of either frequency, such as amplitude, duty cycle, pulse width, or phase. In one embodiment, the patient will be able to adjust the tetanic stimulation frequency from its initial setting to 10 Hz with the initiation frequency. (fp) Any frequency between -1 and -1. In the example above using a startup frequency of 1,200 Hz, the shunt frequency can be adjusted between 10 Hz and 1,199 Hz.

[0128] In another embodiment, the patient will be able to change the amplitude of the tetanic stimulus, wherein the amplitude is limited to between zero and the amplitude of the initiating stimulus. When the stimulus waveform consists of discrete pulses separated by latency, the patient may also be able to change the pulse width and duty cycle of the initiating or tetanic stimulus. These values ​​will be limited by the selected frequency. The stimulation frequency determines the time between pulses (defined herein as the period). Due to charge balance requirements, the pulse width cannot be greater than the period divided by two. Therefore, the patient can shift the pulse width between a minimum of 10 µs and half the period.

[0129] The final aspect controlled by the patient is the phase of the waveform. In this embodiment, the patient will be able to shift the tetanic or initiating stimulus throughout its cycle. A zero phase will correspond to the pulse that appears at the start of the duty cycle, and the remainder of the cycle will be free of stimulation. The user can shift the position of the pulse along the duty cycle to any point where the phase is constrained to be equal to the maximum value of the cycle. The phase shift of the pulse within its cycle will produce different constructive effects on the electric field or the signal itself. This will produce a waveform specific to neural tissue, although it consists of the same initiation and tetanic frequencies. Allowing the patient to adjust these parameters aims to enable each patient to better control their pain relief.

[0130] Figure 4 Conceptually, this describes a pair of traces representing signals 40 and 45 used in an example of primary multimodal modulation. Signal 40 acts as the initiation electrical component and may include, for example, a biphasic rectangular pulse with a frequency of 1,200 Hz, PW = 200 µs, and an interphase delay of 20 µs (although other delays are considered herein, such as an 80 µs delay between the therapeutic pulse and the recharge / recovery pulse, where there is a 40 µs gap between the end of the recovery pulse and the next stimulation pulse (e.g., for an exponentially decaying recovery pulse)). Signal 45 acts as the tetanic component and may include, for example, a biphasic rectangular pulse with a frequency of 50 Hz, PW = 200 µs, and an interphase delay of 20 µs. In this example, the amplitude of the tetanic component is set to be greater than that of the initiation component. For visual clarity, signals 40 and 45 have been... Figure 4 Mid-offset. Signals 40 and 45 can be used to generate composite signals using the systems and techniques described herein.

[0131] Figure 5Conceptually, this describes a pair of traces of signals 50 and 55 used in an example of primary multimodal modulation. Signal 55 acts as the initiation electrical component and may include, for example, a biphase rectangular pulse with a frequency of 1,200 Hz, a pulse wave size (PW) of 150 µs, and an interphase delay of 20 µs. Signal 50 acts as the strong current component and may include, for example, a biphase asymmetric rectangular / exponentially decaying pulse with a frequency of 50 Hz, a pulse wave size (PW) of 400 µs, and an interphase delay of 20 µs. In this example, the amplitude of the strong current component is set to be greater than the amplitude of the initiation component. Signals 50 and 55 can be used to generate a composite signal using the systems and techniques described herein.

[0132] Figure 6 Conceptually, this illustrates a pair of traces representing signals 60 and 65 used in an example of primary multimodal modulation. Signal 60 acts as the initiation electrical component and may include, for example, white noise with a specific maximum amplitude. Signal 65 acts as the dynamometer component and may include, for example, a double-phase symmetrical rectangular pulse with a frequency of 50 Hz, PW = 400 µs, and an interphase delay of 20 µs. In this example, the amplitude of the dynamometer component is set to be greater than that of the initiation component. It should be noted that in Figure 4-6 In this document, for visual clarity, the signals representing the rigid waveform and the initiation waveform are offset; such offsets are not intended to be limiting in all cases. Signals 60 and 65 can be used to generate composite signals using the systems and techniques described herein.

[0133] The ESU 16 or IMG 20 can deliver multimodal stimulation using a single composite modulation / stimulation signal with rhythmically varying characteristics, and therefore with alternating magnetic field characteristics that yield the same results as when combining two individual signal components. In such embodiments, a composite signal characterized by typical alternating characteristics is used to obtain the same stimulation and modulation of the interaction between glial cells and neurons. Such composite signals can be generated by a signal processor 27 capable of executing various algorithms for combining individual signals into a single composite signal, including amplitude modulation, frequency modulation, signal summation, signal synchronization, phase modulation, or convolution or any combination thereof, as well as generating custom signals from wavetables or in real time, such composite signals having either periodic or aperiodic characteristics. Additionally, pulse width modulation can be used to generate composite signals with variablely varying harmonic energy content, which can be similarly utilized to obtain the desired multimodal stimulation of glial cells and neurons.

[0134] Figure 7-12 This section provides examples of multimodal composite signals that can be used for multimodal modulation, formed by combining frequency modulation, double-combined sine waves, double-combined biphase rectangular pulses, frequency-varying signals, and white noise with low-frequency pulses. Figure 7Conceptually, a frequency-modulated composite signal 70 is described, wherein its initiation signal component is delivered within a given time period preceding the delivery of its direct signal component, which is not necessarily equal to the time period for delivering the initiation component. In the illustrated embodiment, the composite signal 70 may be formed by delivering a 1,200 Hz sinusoidal initiation component for up to 1 ms followed by a 180 Hz sinusoidal direct signal component for up to 2 ms. Using the user interface described herein, a user may be able to control the frequency, amplitude, and duration of each initiation signal and direct signal component as described herein.

[0135] Figure 8 A dual-sinusoidal composite signal 80 is conceptually illustrated, wherein the initiation component has a low amplitude and is convolved into a strong linear component. In the illustrated embodiment, the composite signal 80 may be formed from a 100 Hz strong linear sinusoidal component and a 1,200 Hz initiation sinusoidal component, wherein the strong linear component has an amplitude eight times that of the initiation component. Using the user interface described herein, a user may be able to control the frequency, amplitude, and phase shift of each component as described herein.

[0136] Figure 9 Conceptually, a composite signal 90 is described, consisting of two biphasic rectangular signals. The initiation component has a lower amplitude than the kinetic component and is convolved with the kinetic signal. In the illustrated embodiment, the composite signal 90 may be formed by convolving a 10,000 Hz initiation signal with a 50 µs PW into a 250 Hz biphasic rectangular signal with a 900 µs PW, wherein the amplitude of the kinetic component is ten times that of the initiation component. Using the user interface described herein, the user will be able to control the frequency, amplitude, and phase shift of each component as described herein.

[0137] Figure 10 Conceptually, a composite signal 100 is described, consisting of two biphasic rectangular signals. The initiation component has a lower amplitude than the kinetic component and is convolved with the kinetic signal. In the illustrated embodiment, the composite signal 100 may be formed by convolving a 1,200 Hz initiation signal with a 150 µs PW into a 50 Hz biphasic asymmetric rectangular / exponentially decaying signal with a 400 µs PW, wherein the amplitude of the kinetic component is five times that of the initiation component. Using the user interface described herein, a user can control the frequency, amplitude, and phase shift of each component as described herein.

[0138] Figure 11Conceptually, a composite signal 110 with varying frequencies is described, wherein an initiation component is initially delivered at a frequency greater than that of the shunt component, and then decreases to the shunt component frequency within a given time before the start of a new signal cycle. An example may include an initiation frequency of 1,000 Hz, which rolls down to a shunt frequency of 200 Hz within a 50 ms period while maintaining a constant amplitude. In the illustrated embodiment, the composite signal 110 may be formed according to a linear or non-linear change in amplitude as the signal rolls down from the initiation frequency to the shunt frequency. Using the user interface described herein, a user may be able to control the frequency, amplitude, and roll-down time of each component as described herein.

[0139] Figure 12 Conceptually, a composite signal 120 is illustrated, wherein the initiating component is noise and convolved with a bi-symmetrical rectangular kinetic component. In the illustrated embodiment, the composite signal 110 may be formed from a noise amplitude equivalent to one-third of the kinetic component amplitude having a kinetic frequency of 100 Hz and a kinetic power of 200 µs PW. The kinetic component may be delivered randomly and non-linearly in the range of 10–500 Hz to generate a random resonance effect. In embodiments where random resonance is used for the kinetic component, pseudo-random signal generation techniques may be required. For example, randomization can be achieved using a series of Zener diodes and transistors to generate a pseudo-random signal based on the random movement of electrons through the circuit.

[0140] In some embodiments, randomization can be obtained from harmonic oscillations of a quartz oscillator and timing circuit configured with various pseudo-random counting parameters. In other embodiments, a Peltier-based thermocouple can be used to generate randomization based on thermal noise from the patient's body. Those skilled in the art will understand that many other configurations based on digital or analog circuitry can be used to obtain random numbers. Once obtained, the random numbers can be used to generate digital high or low signals, thereby producing a series of random tetanic pulses to be applied to nerve tissue. Such randomization circuits can also be used to generate noise that approximates true white noise, pink noise, blue noise, brown noise, gray noise, or any other energy distribution within the spectrum.

[0141] Using the user interface described herein, users will be able to control the frequency, amplitude, and phase shift of each component as described herein.

[0142] According to embodiments of this disclosure, the central processing unit module 25 of the multimodal generator 20 can access stored digital data that mathematically describes the waveforms of one or more signals, and analog signals of different frequencies can be generated from such data step functions. The processor performs algorithmic manipulation on such data to obtain the desired signal processing result. A digital-to-analog converter associated with the central processing module 25 can convert the processed signal into a single output with the correct amplitude for coupling to one or two electrode arrays 30 and 32. In this way, the interaction effect of two separate signals can be achieved using a single electrical complex signal capable of stimulating / modulating the interaction between glial cells and neurons in a manner that simulates the use of two separate signals.

[0143] In a composite signal simulating a frequency-modulated main multimode modulated signal, signal components, such as activation or transient signals, can function as program or carrier signals in a frequency modulation algorithm. For example, a frequency-modulated multimode signal can have a carrier frequency greater than the modulation frequency (e.g., 50 Hz) (e.g., 1,000 Hz), thereby obtaining... Figure 7 The stimulus signal described herein. In another example, the frequency-modulated multimodal signal may have a carrier frequency smaller than the modulation frequency (e.g., 50 Hz), thereby obtaining, as shown in the figure. Figure 8 The stimulation signal described herein. In these embodiments, a tetanic component may be delivered randomly and nonlinearly in the range of 10-500 Hz to produce a random resonance effect as described herein.

[0144] Figure 13 Another embodiment of an implantable system is conceptually illustrated in a prone position for a human subject. An example of an implantable system is shown where two leads 30 and 32 are positioned above the dorsal spinal cord at a specific vertebral level. A programmable implantable multimodal generator (IMG) 20 is attached to the leads using conductive cables and is powered by a rechargeable or non-rechargeable long-life battery contained within a power module 21. An external battery charger 34 can be used to recharge the generator using inductive (i.e., wireless) charging. A wireless remote control 36, which may include Bluetooth or any number of other wireless communication protocols, can be used to communicate with the IMG 20 to allow the patient to adjust parameters at the physician's discretion. The system can be programmed using an external programmer unit, which, for example, can transmit information to a computer (not shown) of the IMG 20 via a wireless communication protocol.

[0145] Figure 14 This section illustrates another embodiment of an implantable system conceptually designed for use in a prone position in a human subject. It demonstrates a system similar to those referenced herein. Figure 13 Examples of implantable systems described herein, in which the lead wire is positioned near a peripheral nerve.

[0146] According to another aspect of this disclosure, a method for controlling pain in a subject includes activating glial cells through multimodal electromagnetic stimulation by modulating genes for any one of calcium-binding proteins, cytokines, cell adhesion proteins, or specific immune response proteins, and administering a pharmacological substance to the subject systemically, epidurally, or intrathecally over a period of time. In other embodiments, such a pharmacological substance may be injected via a stimulation lead having a port for direct delivery of the pharmacological agent into the epidural or intrathecal lumen. Optionally, a sustained-release formulation may be used to impregnate the pharmacological agent onto the stimulation lead to slowly elute the pharmacological substance into the nerve tissue surrounding the lead.

[0147] Suitable pharmacological substances for use with the disclosed methods may include metabolitic or ionotropic glutamate receptor antagonists, such as (S)-4-carboxyphenylglycine (CPG), (RS)-α-methyl-4-carboxyphenylglycine (MCPG), or kynurenine (KYA). In another embodiment, suitable pharmacological substances may include potassium channel antagonists, such as 4-aminopyridine (4AP), or α-2-adrenergic receptor agonists, such as clonidine, or calcium channel agonists, such as β-conotoxin MVllC, NMDA receptor agonists, such as ketamine, or glial cell modulators, such as alendronate, cyclosporine A, cannabinoid receptor agonists (CB1R or CB2R), or monoclonal antibodies against at least one cytokine (such as tumor necrosis factor α, interleukin 1 or 6, etc.), or fusion proteins, such as etanercept or abatacept. These pharmacological substances can help activate or deactivate glial cells by modulating the release of glutamate, potassium, or calcium ions inside or outside glial cells.

[0148] In one embodiment, activating glial cells includes exposing them to a stimulus, which is a complex electromagnetic field. A multimodal signal generated by a single, two, or multiple synchronously applied electromagnetic fields can facilitate the targeted delivery of a pharmacological agent by reducing the resistance of the applied pharmacological agent to tissue penetration while simultaneously providing the electrical power to direct the pharmacological compound to the target neural tissue based on the electrical properties (polarity, polarizability) of such pharmacological agents (ionoosmotic effect). The stimulatory properties of the initiating components of the multimodal signal can reduce tissue resistance, thus allowing the pharmacological substance to penetrate better into the target neural tissue. Additionally, the polarity of the multimodal electric field can be optimized to direct the pharmacological substance to the aforementioned target neural tissue.

[0149] Example 1

[0150] refer to Figure 15An initial pilot study (n = 29) using an animal model of chronic neuropathic pain was conducted. In this study, peripheral nerve injury (a preservative nerve injury (SNI) model) was surgically induced by transecting the tibial and fibular branches of the sciatic nerve at the trigeminal junction while preserving the sural nerve. Four days after the transect, subjects exhibited mechanical and thermal hypersensitivity (abnormal pain), which was considered pain-like behavior. Small cylindrical four-contact wires were surgically implanted into the epidural space of the subjects at the vertebral level corresponding to the innervation of the sciatic nerve. On the fourth postoperative day, behavioral tests were performed on the subjects using von Frey wires. These wires, with varying tensile strengths, were used to measure the sensitivity of the affected skin area to mechanical stimulation. In the SNI model, the plantar region of the ipsilateral hind paw became hypersensitive. Hypersensitive subjects would withdraw their paw when stimulated with a wire of very low tensile strength. The ipsilateral hind paw exhibited significantly greater mechanical hypersensitivity compared to the contralateral hind paw, which served as a normal behavioral control.

[0151] In one specific instance of multimodal stimulation, electrodes implanted in the epidural space above the dorsal aspect of the rat spinal cord were connected to an electrical source delivering an initiation signal consisting of a charge-balanced biphasic symmetrical rectangular pulse oscillating at 1,200 Hz and 30 µs with an amplitude of 0.1 mA (33% motor threshold, MT). This was combined with a tetanic signal, which was a charge-balanced biphasic symmetrical rectangular pulse oscillating at 50 Hz, 50 µs with a 0.2 mA (66% MT) amplitude. Electrical stimulation was continuously applied for two hours, with mechanosensitivity behavioral tests performed every fifteen minutes while the subject was being stimulated. Behavioral testing continued every fifteen minutes after stimulation was stopped for one hour, and then hourly until three hours post-stimulation. Figure 16B The results are presented as averages of the various records obtained from them.

[0152] Behavioral data indicate that multimodal stimulation improved mechanical abnormal pain 15 minutes after stimulation, and the improvement lasted for more than an hour after stimulation was turned off, indicating residual effects of the applied field, which suggests modulation of the nervous system.

[0153] Example 2

[0154] In this example, the genome-wide expression effect of spinal cord stimulation (administered up to 72 hours) in ipsilateral dorsal spinal cord (DC) tissue was assessed in rats with chronic neuropathic pain induced following peripheral nerve injury. Specifically, in this example, genome-wide expression levels were compared between continuous SCS animals and sham-operated animals in a most commonly used rodent model of chronic neuropathic pain (sparing nerve injury, SNI), where the pain model was induced and implanted but not stimulated.

[0155] The commercially available whole-genome expression profiling microarrays from laboratory rats used in this study can investigate the expression of approximately 21,000 genes. Enrichment analysis based on cluster statistics (using weighted gene association network analysis (WGCNA)) allows for the identification of modules (or subsets) containing genes highly correlated with each other in terms of biological function. Gene ontology analysis allows for the grouping of genes within modules according to more specific biological processes and molecular functions. Further refinement is possible by identifying key genes within specific pathways.

[0156] As described in this article, by comparing the genomes of treated animals, it was found that SCS upregulated and downregulated genes associated with various related processes.

[0157] Comparative genomics of the spinal cord

[0158] Because the stimulation was performed at the top of the dorsal region of the spinal cord, differential expression in dorsal spinal cord cells was examined to indicate the role of these genes in the molecular and biological functions of this tissue. WGCNA identified that SCS significantly upregulated genes involved in immune system activation (false discovery rate (FDR) adjusted P = 0.016); while genes involved in phosphorylation and transmembrane transport-related activities (FDR P = 0.011) were downregulated, as were genes associated with the regulation of neuronal activity including regeneration and development. Data refinement identified 52 key genes. Among these key genes, the following were identified as particularly noteworthy because they were described as being involved in processes related to glial activation, immune responses, and neuronal activity: Calcium-binding protein (Cabp1): This gene was identified by SCS as significantly downregulated (i.e., reduced by 1.4 to 1.5 times). The encoded calcium-binding protein 1 regulates the calcium-dependent activity of the inositol 1,4,5-triphosphate (ITP) receptor. ITP receptors participate in inter-astrocyte communication via calcium waves, which are thought to play a role in propagating astrocyte activation. Downregulation of Cabp1 may reduce astrocyte activation, which is otherwise conducive to synaptic remodeling, thus contributing to chronic pain states.

[0159] Toll-like receptor 2 (Tlr2): This gene was identified by SCS as significantly upregulated (i.e., increased 2.4- to 2.8-fold). Tlr2 is expressed in activated glial cells, which contain both microglia and astrocytes; however, expression in activated microglia is greater than in astrocytes. The encoded Toll-like receptor 2 protein induces a series of events that may lead to the secretion of anti-inflammatory cytokines such as IL-10.

[0160] Chemokine Cxcl16: This gene was identified by SCS as significantly upregulated (i.e., increased 2.2-fold to 3.6-fold). This is a transmembrane chemokine that drives the interaction between glial cells and neurons by stimulation. Cxcl16 is expressed by microglia and astrocytes as a neuroprotective agent. The upregulation of this gene by SCS suggests that neuroprotective processes in the spinal cord may involve the modulation of microglia.

[0161] Glial maturation factor (Gmfg): This gene was identified by SCS as significantly upregulated (i.e., increased 2.1 to 2.3 times). This gene is thought to be involved in glial differentiation and neurogenesis. Little is known about this gene. The upregulation of it by SCS may be associated with glial activation processes that may lead to neuronal regeneration.

[0162] Other key genes identified as upregulated or downregulated by spinal cord stimulation are described in Table 2 below: Table 2

[0163] For the genes mentioned above, any change in expression level considered statistically significant can predict the outcome (e.g., the ability to manipulate biphasic signals over a sufficient duration to produce a statistically significant change in the expression of one or more such genes in modulated glial cells as an indication that the SCS has achieved the desired effect on the subject). The statistical significance level of the upregulation compared to an appropriate control (e.g., control cells, tissues, and / or values) may include at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1-9-fold, at least 2-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3-fold, at least 3.1-fold, at least 3.2-fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, at least 3.8-fold, at least 3.9-fold, at least 4-fold, at least 5-fold, etc. Similarly, the statistical significance level of the downregulation compared to an appropriate control (e.g., control cells, tissues, and / or values) may include at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1-9-fold, at least 2-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3-fold, at least 3.1-fold, at least 3.2-fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, at least 3.8-fold, at least 3.9-fold, at least 4-fold, at least 5-fold, etc.

[0164] Many genes involved in inflammatory and immune responses are associated with glial activity. Peripheral nerve injury is accompanied by the regulation of genes and proteins, not only at the site of injury but also in afferent ipsilateral CNS structures such as the DRG and spinal cord. Recent proteomic analyses were performed in the spinal cord and DRG of a neuropathic neuropathic pain animal model of spinal cord injury (SNI). This study indicated the observation of protein transport and translocation along axons to somatic cells, followed by mutual protein transport back to the periphery to induce axonal regeneration. Interestingly, the spinal cord exhibits neuroprotective proteins, some of which are associated with glial cell activation. Post-injury glial cell activation induces a series of events, including inflammatory and immune responses, which then develop into peripheral sensitization favoring ectopic neuronal firing. The alarm eventually extends to the CNS at the spinal cord level, where microglia apparently attempt to protect the integrity of the system. Ultimately, glial cells overreact and induce the release of factors that remodel synapses. These alterations in synaptic plasticity manifest as chronic pain.

[0165] The results indicate that electrical stimulation of the spinal cord triggers regulation of genes and proteins that modulate the interactions between glial cells and neurons. It is reasonable that these molecular events produce an analgesic effect.

[0166] Example 3

[0167] The effect of phase polarity on previously proposed gene modulation was investigated using an animal model of chronic neuropathic pain. In this example, spinal cord tissue was obtained from animals and stimulated with a rectangular waveform at a frequency of 50 Hz per phase and a pulse width of 200 µs. The waveform could be monophasic, monophasic anode, or symmetrical biphasic with an initial cathode polarity. RNA was extracted from the tissue and cDNA was prepared by reverse transcription. RNA expression levels were assessed using real-time PCR, and the levels were quantified and normalized. Based on the above experiment (Example 2), a set of genes containing markers for glial activation (tlr2, cxcl16), markers for calcium-dependent glial processes (Cabp1), markers for immune system activation (cd68), and opioid receptors (oprm1) were selected for analysis.

[0168] Figures 17A-17E A graph conceptually illustrating the observed expression levels of selected genes relative to the polarity of the phase used in the stimulation waveform is provided. These selected genes include a) calcium-binding protein (Cabp1); b) chemokine (Cxcl16); c) Toll-like receptor 2 (Tlr2); d) Cd68 molecule; and e) opioid receptor mu-1 (Oprm1). Clearly, the polarity of the signal phase influences the regulation of these genes. Biphasic stimulation, relative to anodic and cathodic stimulation, increased the levels of genes associated with glial activation (Tlr2 and Cxcl16) in response to glutamate release from astrocytes. Biphasic stimulation, relative to monophasic stimulation (cathode or anodic), increased the level of Cabp1. Both monophasic (cathode or anodic) and biphasic stimulation produced similar levels of the immune-related gene Cd68, as well as the gene encoding the opioid receptor Oprm1.

[0169] Example 4

[0170] The patient was a 65-year-old woman diagnosed with diabetic neuropathy syndrome, complaining of severe bilateral pain from the lower extremities to the feet. She had experienced multiple treatment failures, including physical therapy, medication, and surgical intervention.

[0171] The patient underwent a spinal cord stimulator trial based on the high-frequency, non-sensory SCS system. Two leads were positioned posteriorly in the epidural space, with one lead tipped at the top of the TS and the other at the top of the T9. The patient returned seven days later to conclude the high-frequency, non-sensory SCS trial, reporting only 30% pain relief.

[0172] At this point, the multimodal stimulation system of this disclosure was applied. The system uses two external generators reprogrammed to produce composite signals in neural tissue. One generator is set to tetany at 50 Hz and 400 µs pulses per second (PW). The other is set to initiation at either 900 Hz or 1200 Hz and 150 µs PW. Before the patient went home, the amplitude of the 50 Hz signal was initially set to 0.6 mA, and the amplitude of the 900 Hz signal was initially set to 2.2 mA. These amplitudes did not induce sensory abnormalities during treatment. Twenty hours after the therapy, the patient reported a 57% reduction in leg pain.

[0173] The patient was reprogrammed to receive a starting frequency of 1,200 Hz. Following reprogramming, the patient continued to experience pain relief without tingling. More importantly, 54 hours after reprogramming, the pain relief rate increased to 71%.

[0174] Experiment Summary: 1. During the four-day treatment period, the subjects did not experience any sensory abnormalities.

[0175] 2. Multimodal therapy with no reported sensory abnormalities is superior to high-frequency stimulation therapy.

[0176] 3. The patient reported a 71% reduction in pain in her legs and feet.

[0177] 4. The severe leg pain was significantly reduced.

[0178] 5. The burning sensation in the feet was relieved, allowing the patient to tolerate walking for longer periods than before the treatment.

[0179] Example 5

[0180] The subject was a 76-year-old woman diagnosed with failed back surgery syndrome. She presented with chronic pain in her lower back and legs. She had received standard treatment without clinical success. Prior to treatment, her pain numerical score was 8, and she experienced back pain radiating to her legs. A pair of SCS test leads were implanted using non-parallel alignment (i.e., they were offset from each other), and a high-frequency, non-abnormality program was set. The patient reported complete pain relief in her back and legs after high-frequency treatment. She also reported improved sleep and reduced vitolin intake. The patient was then reprogrammed using multimodal stimulation, with activation parameters set at 1,200 Hz, 150 µs PW, and 3 mA, and tetanic parameters set at 50 Hz, 400 µs PW, and 4.9 mA.

[0181] Over the next few days, under multimodal therapy, the patient experienced almost no pain in his back and legs (0-1 on a 0-10 numerical rating scale).

[0182] The patient also reported being able to increase her activity level and climb stairs (an activity she had previously avoided before SCS treatment). Since the start of the trial period, her family has been impressed with the improvements in her daily activities.

[0183] Summarize: 1. During the three-day multimodal SCS therapy, the patient did not experience any sensory abnormalities.

[0184] 2. Patients can reduce their intake of painkillers.

[0185] 3. The patient reported mild back and leg pain (mean value of 0.5 on a 0-10 scale).

[0186] 4. Patients reported significant improvements in their sleep habits.

[0187] 5. The patient reported a significant improvement in her ability to perform daily activities that she was unable to do before starting SCS therapy.

[0188] Example 6

[0189] refer to Figure 16A and 16BAn observational study using human volunteers (n = 22) was conducted. These participants were part of a trial period for a commercial spinal stimulation system controlled under standard clinical practice. Participants voluntarily underwent multimodal modulation upon completion of their trial period. A pain relief of 50% or higher relative to the numerical pain score (NRS) prior to the start of spinal stimulation therapy indicated trial success. All participants received two eight-electrode trial leads. Thirteen participants had their leads interleaved, and five had their leads parallel to each other. Nine participants tried a conventional paresthesia-based stimulation system (50–70 Hz), and thirteen tried a high-frequency system (10,000 Hz). Four participants failed the trial with the conventional paresthesia-based stimulation (50–70 Hz), and three participants failed the trial with the high-frequency non-paresthesia stimulation (10,000 Hz). Multimodal stimulation was attempted for periods ranging from three hours to four days. All but one of the 22 participants successfully attempted multimodal stimulation at either paresthesia or perceptual threshold (PT). The average pain relief rate among the participants was 72%, and all participants reported satisfaction with the multimodal stimulation therapy.

[0190] Exemplary embodiments describe various patient adaptation / configuration options. (Reference) Figure 18 At 1800, a workflow for fitting / setting up a patient is generally illustrated, and this workflow includes placing an electrode or electrode group at a neural region (spinal nerve, peripheral nerve, specific region or cluster, etc.), as shown in step 1802. For the electrode or electrode group placed at the neural region, the signal (including frequency and pulse width) ramps up in intensity / amplitude until it indicates a sensory abnormality (step 1804). Once a sensory abnormality is indicated, the intensity ramps up or ramps down to a level that no longer indicates a sensory abnormality. This provides an indication of a sensory abnormality threshold, which can be stored as a sensory abnormality threshold. Optionally, a reduction in signal intensity / amplitude can be performed at 1810. At 1812, an adjustment of intensity / amplitude (e.g., increasing over time) is performed until an optimal or preferred setting is established for the patient.

[0191] In an exemplary embodiment, after the procedure, the patient procedure can be set to one of a range of perceived percentages (%TPT or %PPT). In one exemplary embodiment, such a range is 65%–75% perceived. Other exemplary embodiments consider ranges between 20% and 90%, 30% and 80%, 40% and 80%, 50% and 80%, 60% and 80%, and so on. Additionally, %TPT and %PPT may differ, where the percentages between different frequency types or between electrodes or electrode groups may vary depending on the location or the desired effect.

[0192] In an exemplary embodiment, the signal strength / amplitude may be initially set to zero, then increased until the patient indicates a perception threshold, and then decreased to the PT percentage mentioned above. Furthermore, in an exemplary embodiment, the programming settings for each electrode or electrode group are individually adjustable.

[0193] Additionally, in an exemplary embodiment, programming efficiency can be improved by performing a pulse setting on the electrode group and then copying the program settings (matching settings) or by making certain changes to the program settings (different settings) before pasting these program settings into other electrode groups.

[0194] In an exemplary embodiment, the establishment of perception (TPT or PPT) can also be performed individually for each electrode group, thereby providing a relevant level for determining the effective level of each of the different desired effects (initiation and rigidity, positioning, etc.), or providing a baseline tailored to a specific patient that can be used to quickly find the optimal or preferred setting for said patient.

[0195] Furthermore, reducing the amplitude to a percentage or perceived level (TPT or PPT) and then increasing each or every type of electrode group (activation and stimulation / tetany) may be beneficial because: it facilitates a beneficial choice from both the perspective of pain relief and power expenditure (as also considered in this specification, relative to starting with perception and deceleration); it recognizes that even if there is a synergistic effect between different stimulation types (activation and tetany), the combination will be additionally effective when the amplitude of each group or type is set independently; and it recognizes that different stimulation types may be perceived differently by the patient, and that the patient may prefer one over another.

[0196] As already mentioned, additional exemplary embodiments include alternative methods for establishing a comfort level for the patient, such as establishing a perception and increasing it upwards or downwards rather than decreasing it to a percentage to find the comfort level. As before, this can be performed on one or more groups and replicated (or partially replicated), or it can be done individually without such replication.

[0197] The following is a description of an exemplary programming setup process that exemplarily improves programming efficiency.

[0198] Example 7

[0199] Select a specific spinal position to assign electrodes. For example, the electrode closest to the middle of T8 and T9 can be specified. For "Group A" Program 1, the cathode is placed / assigned to the electrode closest to T8. The anode is placed on the two electrodes below the cathode. Set the device rate to the desired frequency, for example, 300 Hz; and change the programming rate to a rate lower than the device rate, for example, 1 / 6 of the device rate, or 50 Hz. The pulse width can be set to the desired width, for example, 200 microseconds. Program 1 can be turned off. For Program 2 in Group A, the cathode can be placed on the electrode closest to T9, and the anode is placed on the two electrodes below the cathode. Some variations in the pulse width can be set, for example, PW = 170 microseconds. Program 2 can be turned off.

[0200] In the exemplary procedure setup, group B can be set up the same as group A, except that it is ½ vertebral segment lower (and on the second lead) than group A. Group B is activated and procedure 1 is selected. Procedure 1 is activated, and all electrodes are selected. The cathode and anode then slide down half a vertebral segment (where the cathode is now on the electrode closest to the top of T9). Procedure 2 is activated, all electrodes are selected; and the cathode and anode slide down half a vertebral segment (where the cathode is on the electrode closest to the T9 / T10 intervertebral disc space). The procedure is then deactivated.

[0201] In another exemplary “Group C” procedure setup, the electrode setup is the same as Group A, except that it is lower by a quarter vertebral segment, again on the second lead. Group C is activated, and Procedure 1 is selected. Procedure 1 is activated, and all electrodes are selected. Subsequently, the cathode and anode slide down a quarter vertebral segment (with the cathode positioned on the electrode closest to the bottom of T8). Subsequently, Procedure 2 is activated, all electrodes are selected, and the cathode and anode move down a quarter vertebral segment (with the cathode positioned on the electrode closest to the bottom of T9). The procedure is then closed.

[0202] In an exemplary embodiment, for the programmed amplitude, for group A, program 1 (A1), the intensity in program 1 is ramped up until a sensory abnormality is felt. It is then ramped down in individual increments until the patient loses the sensory abnormality. This is recorded as the LD sensory abnormality threshold. The intensity is then reduced to a PT percentage (e.g., 70%) as the final LD ​​amplitude, and the stimulation of program 1 continues.

[0203] The procedure was changed to Procedure 2 (A2) in Group A, where the intensity was increased gradually until the patient felt the paresthesia. Subsequently, the intensity was decreased gradually in individual increments until the patient lost the paresthesia. These values ​​were recorded as the HD paresthesia threshold. The intensity was reduced to a PT percentage (e.g., 65%) and recorded as the final HD amplitude. Stimulation in Procedure 2 continued.

[0204] For procedure 3 (A3) in group A, the intensity is increased to that of procedure 2 in group A. For procedure 4 (A4) in group A, the intensity is increased to that of procedure 2 in group A.

[0205] In an exemplary embodiment, for the programmed amplitude, for program 1 (B1) in group B, the intensity in program 1 is ramped up until a sensory abnormality is felt. It is then ramped down in individual increments until the patient loses the sensory abnormality. This is recorded as the LD sensory abnormality threshold. The intensity is then reduced to a PT percentage (e.g., 70%) as the final LD ​​amplitude, and the stimulation of program 1 continues.

[0206] The procedure was changed to Procedure 2 (B2) in Group B, where the intensity was increased gradually until the patient felt the paresthesia. Subsequently, the intensity was decreased gradually in individual increments until the patient lost the paresthesia. These values ​​were recorded as the HD paresthesia threshold. The intensity was reduced to a PT percentage (e.g., 65%) and recorded as the final HD amplitude. Stimulation in Procedure 2 continued.

[0207] For program 3 (B3) in group B, the intensity is increased to that of program 2 in group B. For program 4 (B4) in group B, the intensity is increased to that of program 2 in group B.

[0208] In an exemplary embodiment, for the programmed amplitude, for program 1 (C1) in group C, the intensity in program 1 is ramped up until a sensory abnormality is felt. It is then ramped down in individual increments until the patient loses the sensory abnormality. This is recorded as the LD sensory abnormality threshold. The intensity is then reduced to a PT percentage (e.g., 70%) as the final LD ​​amplitude, and the stimulation of program 1 continues.

[0209] The procedure was changed to Procedure 2 (C2) in Group C, where the intensity was increased gradually until the patient felt the paresthesia. The intensity was then decreased gradually in individual increments until the patient lost the paresthesia. These values ​​were recorded as the HD paresthesia threshold. The intensity was reduced to a PT percentage (e.g., 65%) and recorded as the final HD amplitude. Stimulation in Procedure 2 continued.

[0210] For program 3 (C3) in group C, the strength is increased to that of program 2 in group C. For program 4 (C4) in group C, the strength is increased to that of program 2 in group C.

[0211] In the exemplary program setup, program A2 is copied and pasted into A3 and A4. Similarly, program B2 is copied and pasted into B3 and B4. Finally, program C2 is copied and pasted into C3 and C4. Accordingly, in this exemplary embodiment, there are 4 programs in each group, creating 3 groups, all with a power consumption of 0.0 mA.

[0212] In an exemplary embodiment, after initial setup, the patient can adjust the frequency upwards toward the PT in spaced increments, for example, with a 4-hour waiting period between adjustments to facilitate accurate assessment of pain relief improvement. Exemplary embodiments record and / or adjust such adjustments, waiting times, and assessments. In other exemplary embodiments, objective feedback from the patient may be incorporated into such adjustment considerations, for example, using an informed loop via sensing changes in patient aspects, conditions, or parameters through sensing the patient's posture or other physically sensed changes.

[0213] Readers should understand that the multimodal modulation techniques described herein, achieved through composite signals modulated, for example by frequency, amplitude, or pulse width modulation, can be used to modulate genes and proteins that modulate the interaction between glial cells and neurons, as described herein. Furthermore, as described herein, multiplexing techniques can also be used to modulate genes and proteins that modulate the interaction between glial cells and neurons.

[0214] Other exemplary embodiments provide a method for controlling pain in a subject, comprising: applying a first phase segment of a biphasic signal to a nerve region via at least one electrode, the first phase segment having a frequency between 750 Hz and 1400 Hz; and applying a second phase segment of the biphasic signal to the nerve region via said at least one electrode, the second phase segment having a frequency lower than that of the first phase segment. In other exemplary embodiments, the first phase segment has frequencies of approximately 1200 Hz (burst) and 900 Hz (average). In other exemplary embodiments, the second phase segment has a frequency of approximately 50 Hz.

[0215] In other exemplary embodiments, the first phase segment and the second phase segment have different corresponding amplitudes, waveform shapes, widths, phase polarities, and phases relative to each other.

[0216] In other exemplary embodiments, the biphasic signal is an asymmetric biphasic signal. In other exemplary embodiments, the biphasic signal is a frequency-modulated signal. In other exemplary embodiments, the biphasic signal is a phase-modulated signal. In other exemplary embodiments, the biphasic signal is a pulse-width modulated signal. In other exemplary embodiments, the application of the biphasic signal is performed without administering any pharmacological substance to the subject.

[0217] In other exemplary embodiments, the pulse width of the first phase segment is between approximately 170 microseconds and 400 microseconds.

[0218] In other exemplary embodiments, the biphasic signal is derived from a first electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's perception threshold.

[0219] In other exemplary embodiments, the amplitude of the signal is initially set to zero, then increased until the patient indicates a perception threshold, and then decreased to a predetermined perception percentage. In other exemplary embodiments, the perception percentage is between 20% and 90%. In other exemplary embodiments, the perception percentage is between 65% and 75%.

[0220] Other exemplary embodiments include a procedure for generating the biphasic signal as a first pulse on at least one electrode, and further include generating an exact or modified copy of the procedure for a single electrode or group of electrodes.

[0221] Other exemplary embodiments include the biphasic signal generation procedure as a first pulse on at least one electrode, and further include the generation procedure individually for at least one individual electrode or group of electrodes, including independently assessing the patient’s perception and adjusting the amplitude of the signal upward or downward based on the perception.

[0222] In other exemplary embodiments, the neural region includes a spinal nerve region. In other exemplary embodiments, the neural region includes a peripheral nerve region. In other exemplary embodiments, the neural region includes a nerve cluster.

[0223] In other exemplary embodiments, the first phase segment includes an initiation component. In other exemplary embodiments, the second phase segment includes a tetanic component.

[0224] In other exemplary embodiments, the biphasic signal is derived from: a first electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's activation perception threshold (PPT); and a second electrical signal having a current amplitude set to a value corresponding to a percentage of the tetanic perception threshold (TPT).

[0225] As used herein, the term "pharmacological substance" means any tangible chemical substance, drug, medicine, or therapeutic substance, whether synthetic or naturally occurring, regardless of the form of administration to the subject, which is applied to the subject's body.

[0226] Numerical values ​​are disclosed in various places throughout this specification in the form of groups or ranges. The description is specifically intended to include each individual sub-combination of the members of such groups and ranges, as well as any combination of the various endpoints of such groups or ranges. For example, integers in the range 0 to 40 are specifically intended to be individually disclosed as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range 1 to 20 are specifically intended to be individually disclosed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0227] For the purposes of clarity and concise description, features are described herein as parts of the same or separate embodiments; however, it should be understood that the scope of the concept may include embodiments having a combination of all or some of the features described herein.

[0228] It will be apparent to those skilled in the art that modifications can be made to the apparatus and processes disclosed herein, including replacing various component values ​​or connection nodes, without departing from the true spirit and scope of this disclosure as defined by the claims set forth herein. For example, although the embodiments described herein primarily disclose the use of a pulsed rectangular signal, other waveform shapes can be similarly used to achieve the same effect. For instance, any of the following can be used as the stimulation waveform in the multimodal modulation techniques described herein: a single-phase pulse wave, a charge-balanced biphase pulse wave, a charge-unbalanced biphase pulse wave, a charge-balanced biphase wave with a delayed pulse, a charge-balanced biphase fast-reversal wave, and a charge-balanced biphase slow-reversal wave. Additionally, other varying electromagnetic fields defined by periodic electrical signals with different waveform shapes, as well as noise signals and even non-periodic electrical signals with irregular, non-repetitive shapes, can be used.

Claims

1. A medical system comprising: Signal generation module, and One or more electrodes are configured to expose a subject's glial cells to one or more electromagnetic stimuli and simultaneously expose the subject's neurons to a second electromagnetic stimulus. The signal generation module is configured to: Glial stimulation signals are generated by multiplexing multiple signals with at least one different corresponding parameter in the time domain. Generate neuronal stimulation signals, which are used to modulate the activity of neurons in the subject; as well as The glial stimulation signal is provided to the first subgroup of the electrodes, and the neuronal stimulation signal is simultaneously provided to the second subgroup of the electrodes.

2. The medical system of claim 1, wherein the at least one different corresponding parameter includes at least one of amplitude, frequency, relative phase, waveform shape, pulse width, charge balance, or duty cycle.

3. The medical system according to claim 1, wherein the glial stimulation signal has a burst frequency of 1200 Hz and an average frequency of 900 Hz.

4. The medical system of claim 1, wherein the neuronal stimulation signal has a frequency of 50 Hz.

5. The medical system according to claim 1, wherein the pulse width of the glial stimulation signal is between 170 microseconds and 400 microseconds.

6. The medical system of claim 1, wherein the glial stimulation signal and the neuronal stimulation signal are derived from a first electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's perception threshold, wherein the amplitude of the signal is initially set to zero, then increases until the patient indicates a perception threshold, then decreases to a predetermined percentage of the perception threshold, and wherein the predetermined percentage is between 20% and 90%.

7. The medical system of claim 6, wherein the predetermined percentage is between 65% and 75%.

8. The medical system of claim 1, wherein the glial stimulation signal and the neuronal stimulation signal are derived from a first electrical signal having a current amplitude set to a value corresponding to a percentage of the subject's perception threshold, the system further comprising a signal generation procedure as a first pulse on at least one electrode, and further comprising a separate generation procedure for at least one individual electrode or group of electrodes, comprising independently assessing the patient's perception and adjusting the amplitude of the signal upward or downward based on the perception.

9. The medical system of claim 1, wherein the signal generation module is further configured to generate the neuronal stimulation signal by multiplexing a plurality of signals having at least one different corresponding parameter, wherein the at least one different parameter includes one or more of amplitude, frequency, waveform shape, pulse width, charge balance, duty cycle, or phase relative to each other.

10. The medical system of claim 9, wherein the neuronal stimulation signal comprises a plurality of component signals, and the system is configured to provide a first component signal and other component signals of the neuronal stimulation signal to the same electrodes in the second subgroup of electrodes.

11. The medical system of claim 9, wherein the neuronal stimulation signal comprises a plurality of component signals, and the system is configured to provide a first component signal and other component signals of the neuronal stimulation signal to different electrodes in a second subgroup of electrodes.

12. A stimulation device comprising a signal generation module connected to one or more electrode arrays provided to a subject, wherein the signal generation module is configured to: A first varying electromagnetic field is generated at one or more electrodes in one or more of the electrode arrays to expose the subject's glial cells to the first varying electromagnetic field; and A second varying electromagnetic field is synchronously generated at one or more electrodes in the one or more electrode arrays to expose the subject's neurons to the second varying electromagnetic field. One of the first and second varying electromagnetic fields includes multiple component signals that are multiplexed to the one or more electrode arrays in the time domain.

13. An electromagnetic stimulation system, comprising: A memory used to store multiple signal parameter programs; A selection device for selecting one of the plurality of signal parameter programs; A signal generator, which can be controlled by one of the plurality of signal parameter programs and configured to synchronously generate at least one glial stimulation signal and at least one neuronal stimulation signal different from the at least one glial stimulation signal; as well as An output unit is configured to connect the glial stimulation signal and the neuronal stimulation signal to a first electrode array and a second electrode array, respectively, provided to the subject. The electromagnetic stimulation system is configured to simultaneously provide, via the output unit, at least one glial stimulation signal and at least one neuronal stimulation signal generated by the signal generator according to one of the signal parameter programs to the first electrode array and the second electrode array, respectively, for modulating the activity of the subject's glial cells with the at least one glial stimulation electrical signal and for modulating the activity of the subject's neurons with the at least one neuronal stimulation electric field. One of the glial stimulation electrical signal and the neuron stimulation electrical signal includes multiple component signals, which are multiplexed in the time domain to corresponding electrode arrays providing the glial stimulation signal and the neuron stimulation signal.

14. The electromagnetic stimulation system of claim 13, wherein the at least one glial stimulation signal comprises a first subgroup of component signals multiplexed to the first electrode array, and The at least one glial stimulation signal further includes at least one other component signal, the at least one other component signal having any one of the following different amplitudes, frequencies, relative phases, waveform shapes, pulse widths, charge balances, or duty cycles from one of the first subgroups of component signals.

15. The electromagnetic stimulation system of claim 14, wherein the first electrode array comprises a first subgroup of electrodes, and the at least one other component signal is provided to at least one electrode in the first subgroup of electrodes, the at least one electrode being different from the electrode in the first subgroup of electrodes to which the first subgroup of component signals is multiplexed.

16. The electromagnetic stimulation system of claim 13, wherein the at least one neuron stimulation signal comprises at least a first component signal and other component signals, the first component signal and the other component signals having any one of corresponding amplitude, frequency, waveform shape, pulse width, charge balance, duty cycle or phase relative to each other.

17. The electromagnetic stimulation system of claim 16, wherein the second electrode array comprises a second subgroup of electrodes, and the first component signal and the other component signals are provided to the same electrodes in the second subgroup of electrodes.

18. The electromagnetic stimulation system of claim 16, wherein the second electrode array comprises a second subgroup of electrodes, and the first component signal and the other component signals are provided to different electrodes in the second subgroup of electrodes.

19. A medical system comprising: Signal generation module, and One or more electrodes are configured to expose a subject's glial cells to a first electromagnetic stimulus and simultaneously expose the subject's neurons to a second electromagnetic stimulus. The signal generation module is configured to have an operating mode for providing a start signal to a first subgroup of the electrodes and simultaneously providing a strong convective signal to a second subgroup of the electrodes. The activation signal and the strong current signal include a plurality of component signals, which are multiplexed in the time domain to at least one electrode in a corresponding subgroup of electrodes to which the activation signal or the strong current signal is provided.

20. The medical system of claim 19, wherein the activation signal comprises a first subgroup of component signals multiplexed to at least one electrode in the first subgroup of electrodes, and The activation signal further includes at least one other component signal, which has any one of the following characteristics different from one of the first subgroup of component signals: amplitude, frequency, relative phase, waveform shape, pulse width, charge balance, or duty cycle.

21. The medical system of claim 20, wherein the at least one other component signal is provided to an electrode in the first subgroup of electrodes, the electrode being different from the at least one electrode in the first subgroup of electrodes to which the first subgroup of component signals is multiplexed.

22. The medical system of claim 19, wherein the rigid signal comprises at least a first component signal and a second component signal, the first component signal and the second component signal having any one of corresponding amplitude, frequency, waveform shape, pulse width, charge balance, duty cycle or phase relative to each other.

23. The medical system of claim 22, wherein the first component signal and the second component signal are provided to the same electrode in the second subgroup of electrodes.

24. The medical system of claim 22, wherein the first component signal and the second component signal are provided to different electrodes in the second subgroup of electrodes.

25. A stimulation device comprising a signal generation module connected to one or more leads provided to a subject, wherein the signal generation module is configured to: A first changing electromagnetic field is generated at one point in the conductor to expose the subject's glial cells to the first changing electromagnetic field; and A second, varying electromagnetic field is synchronously generated at different points in the conductor to expose the subject's neurons to the second, varying electromagnetic field. One of the first changing electromagnetic field and the second changing electromagnetic field includes multiple component signals that are multiplexed to the one or more conductors in the time domain.

26. An electromagnetic stimulation system, comprising: A memory used to store multiple signal parameter programs; A selection device for selecting one of the plurality of signal parameter programs; A signal generator, which can be controlled by one of the plurality of signal parameter programs and configured to synchronously generate a first electrical signal and a second electrical signal different from the first electrical signal; as well as An output unit is configured to connect the first electrical signal and the second electrical signal to the first electrode and the second electrode provided to the subject, respectively. The electromagnetic stimulation system is configured to simultaneously provide a first electrical signal and a second electrical signal, generated by the signal generator according to one of the signal parameter programs, to the first electrode and the second electrode via the output unit, respectively, for exposing the subject's glial cells to the first electrical signal and for exposing the subject's neurons to the second electrical signal. One of the first electrical signal and the second electrical signal includes multiple component signals, which are multiplexed in the time domain to the electrode providing the first electrical signal and the second electrical signal.

27. The electromagnetic stimulation system of claim 26, wherein the first electrical signal comprises a first subgroup of component signals multiplexed to the first electrode, and The first electrical signal further includes at least one other component signal, which has any one of the following different amplitudes, frequencies, relative phases, waveform shapes, pulse widths, charge balances, or duty cycles from one of the first subgroups of component signals.

28. The electromagnetic stimulation system of claim 27, wherein the first electrode comprises a first subgroup of electrodes, and the at least one other component signal is provided to an electrode in the first subgroup of electrodes, the electrode being different from the electrode in the first subgroup of electrodes to which the component signal is provided.

29. The electromagnetic stimulation system of claim 26, wherein the second electrical signal comprises at least a first component signal and a second component signal, the first component signal and the second component signal having any one of corresponding amplitude, frequency, waveform shape, pulse width, charge balance, duty cycle or phase relative to each other.

30. The electromagnetic stimulation system of claim 29, wherein the second electrode comprises a second subgroup of electrodes, and the first component signal and the second component signal are provided to the same electrodes in the second subgroup of electrodes.

31. The electromagnetic stimulation system of claim 29, wherein the second electrode comprises a second subgroup of electrodes, wherein the first component signal and the second component signal are provided to different electrodes in the second subgroup of electrodes.

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