Electrical metabolics

Abstract

A system, device, and method for treating a diabetic condition are provided. An illustrative device includes: a lead connectable to a signal generator and including a plurality of electrodes, wherein the plurality of electrodes generate a stimulation signal according to an input received from the signal generator and deliver the stimulation signal to one or more anatomical elements of a patient to treat at least one aspect of a diabetic condition based on a closed feedback loop.

Description

A0013966WO01ELECTRICAL METABOLICSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 777,545, filed March 25, 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Nerve stimulation is used to treat various conditions, such as pain, by stimulating the nerve with contacts or electrodes. When treating for example, pain, the contacts send an electrical signal generated by an implantable pulse generator to the nerve, which blocks the pain signal from the nerve to the brain.BRIEF SUMMARY

[0003] An estimated 6.3% of the world’s population has type 2 diabetes (DMT2), with a prevalence rate of 6,059 cases per 100,000 people. The number is projected to rise to 7,079 individuals per 100,000 people by 2030. Patients with DMT2 are at risk for heart disease, stroke, nerve damage, foot complications, vision loss and blindness, kidney disease, and dental issues. The management of DMT2 involves several key components: lifestyle modifications, weight loss, a healthy diet, and pharmacotherapy. Although effective, medical therapy often has side effects and poor tolerance, particularly in individuals with gastrointestinal problems and pregnant women. Therefore, a device-based therapy may be more desirable to optimize DMT2 patients' treatment.

[0004] The successful modulation of sensory nerve activity from the kidney has been demonstrated through dorsal root nerve stimulation using a dorsal root ganglion lead and a lateral epidural stimulation (LES) lead affecting dorsal roots at the T11 and T12 levels, which influenced diuresis. It is also contemplated that increasing sensory nerve traffic from the liver to the brain can affect nerve traffic to the liver, pancreas, and kidneys at T9-T10.

[0005] An increased glucose level in the portal vein activates afferent nerve traffic. This results in feedback to down-regulate glucose via activation of vagal nerve activity to the pancreas to stimulate insulin production, leading to a decrease in blood glucose levels on a systemic level. Embodiments of the present disclosure, therefore, propose that increased dorsal root nerve activity in nerves derived from the liver affects the release of insulin in pancreas, which indirectly decreases glucose levels.

[0006] Embodiments of the present disclosure further propose Dorsal Root Ganglion (DRG) stimulation via dorsal root ganglion stimulation leads and dorsal root stimulation via LES leadsA0013966WO01to inhibit sympathetic nerves and to activate the vagal nerve. Such an approach may, therefore, lower glucose production and increase glycogenesis, increase storage of glucose, and limit food intake.

[0007] According to some embodiments, DRG or LES may be implemented at various vertebra levels to influence insulin secretion and subsequent glucose blood level by affecting afferent sensory fibers derived from the liver, which in return modulates autonomic input to the pancreas. After finding the optimal stimulation site, glucose tolerance tests may be performed to study the effect of DRG or LES on glucose and insulin before and during these tests.

[0008] Embodiments of the present disclosure contemplate various types of metabolic treatment(s) in which DRG or LES is utilized. As some examples, LES may be utilized to target blood insulin and / or blood glucose.

[0009] In at least some embodiments, LES may be used to decrease glucose levels in diabetes 2 patients that: (1) insulin response plateaus after at least 90 minutes on LES at T9-T10 and (2) blood glucose only responds to LES in a hyperglycemic state. In a normoglycemic state it is possible to deactivate LES so that battery life is saved and the pancreas is not stimulated, preventing depletion of insulin producing cells in the pancreas. Furthermore, according to at least some embodiments, it may be beneficial to increase LES activation 90 minutes before a meal so that insulin is already higher when glucose starts to peak and the glucose peak can be lowered. During normoglycemic conditions not just before a meal, LES can be de-activated. According to some embodiments, it may also be beneficial to deactivate LES during the night, further helping to preserve battery life. A closed loop approach is provided in accordance with at least some embodiments to support the intelligent and beneficial treatment for diabetes and other related conditions. Instead of LES leads, it may also be beneficial to utilize DRG stimulation leads to be more effective and be able to use ECAPS between two electrodes to titrate current.

[0010] According to at least some embodiments, a system for treating a microvascular disease is provided that includes: a device comprising: a signal generator configured to generate an electrical signal; and at least one processor configured to: monitor a value of at least one parameter of a patient that is associated with diabetes; and control the signal generator using a closed feedback loop based on a threshold value and the value of the at least one parameter; and one or more electrodes coupled to the signal generator to stimulate at least one dorsal root nerve or dorsal root ganglion based on the electrical signal which causes a response by at least one anatomical element of the patient that changes the value of the at least one parameter of the patient.A0013966WO01

[0011] According to at least some aspects, the at least one processor is configured to control the signal generator to generate the electrical signal when the value of the at least one parameter exceeds the threshold value.

[0012] According to at least some aspects, the signal generator is controlled to generate the electrical signal in a manner that keeps the value of the at least one parameter above a second threshold value that is less than the threshold value.

[0013] According to at least some aspects, the at least one parameter comprises a blood glucose level of the patient or a metric calculated from the blood glucose level of the patient.

[0014] According to at least some aspects, the at least one processor is further configured to: determine that the patient is eating or is about to eat.

[0015] According to at least some aspects, an accelerometer is used to determine that the patient is eating.

[0016] According to at least some aspects, the at least one processor is further configured to: determine that a current time corresponds to nighttime; and control the signal generator based on determining that the current time corresponds to the nighttime.

[0017] According to at least some aspects, an accelerometer is used to determine that the patient is sleeping.

[0018] According to at least some aspects, the one or more electrodes apply a lateral epidural stimulation to the at least one dorsal root nerve.

[0019] According to at least some aspects, the one or more electrodes apply a dorsal root ganglion stimulation to the at least one dorsal root ganglion.

[0020] According to at least some aspects, the sympathetic activity level of the patient’s kidney is assessed by monitoring a celiac ganglion by monitoring sympathetic skin activity in the area of the kidney.

[0021] According to at least some aspects, the sympathetic activity level of the patient is assessed in the area of the heart.

[0022] According to at least some aspects, the sympathetic activity level of the patient’s kidney is assessed by monitoring heart rate variability in the frequency spectrum.

[0023] According to at least some aspects, the sympathetic activity level of the patient’s kidney is assessed by monitoring heart rate.

[0024] According to at least some aspects, the system further includes: at least one lead comprising the one or more electrodes.

[0025] According to at least some aspects, the one or more electrodes are located at or near aA0013966WO01

[0026] According to at least some aspects, the one or more electrodes target a pancreas function of the patient.

[0027] According to at least some aspects, the system further includes: a monitoring device configured to continuously provide data that enables the at least one processor to monitor the value of the at least one parameter.

[0028] According to at least some aspects, the data comprises the value of the at least one parameter.

[0029] According to at least some aspects, the at least one processor processes the data to determine the value of the at least one parameter.

[0030] According to at least some aspects, at least one of the one or more electrodes corresponds to a sensing electrode and wherein the monitoring device receives the data from the sensing electrode.

[0031] According to at least some aspects, the monitoring device comprises a continuous glucose monitor.

[0032] According to at least some aspects, the monitoring device comprises a glucose sensor.

[0033] According to at least some aspects, the monitoring device comprises an accelerometer.

[0034] According to at least some aspects, the monitoring device comprises an impedance measure to assess lead dislodgement.

[0035] According to at least some aspects, the monitoring device comprises a Controller Area Network (CAN).

[0036] In accordance with at least some embodiments of the present disclosure, an implantable device is provided that includes: a lead connectable to a signal generator and including a plurality of electrodes, where the plurality of electrodes generate a stimulation signal according to an input received from the signal generator and deliver the stimulation signal to one or more anatomical elements of a patient to treat at least one aspect of a diabetic condition based on a closed feedback loop.

[0037] According to at least some aspects, the electrode pair is positioned proximate T9 and / or T10 of the patient.

[0038] According to at least some aspects, the one or more feedback signals include a measure of glucose levels in the patient or a metric calculated from the blood glucose level of the patient.

[0039] In accordance with at least some embodiments of the present disclosure a method is provided that includes: monitoring a parameter associated with a diabetic condition of a patient; determining the parameter exceeds an upper limit threshold value; and generating an electrical signal for one or more electrodes to stimulate at least one dorsal root nerve of the patient to cause a response by the patient that at least includes minimizing glucose peaks.A0013966WO01

[0040] According to at least some aspects, the parameters are increased in case the time before a meal is 90 minutes or less.

[0041] According to at least some aspects, the parameters are pulse width, frequency, ECAP based current or duty cycling.

[0042] According to at least some aspects, termination criteria to stimulate are exercise as indicated by accelerometer, lead dislodgement or glucose being below a threshold.

[0043] Any aspect in combination with any one or more other aspects.

[0044] Any one or more of the features disclosed herein.

[0045] Any one or more of the features as substantially disclosed herein.

[0046] Any one or more of the features as substantially disclosed herein in combination with any one or more other features as substantially disclosed herein.

[0047] Any one of the aspects / features / embodiments in combination with any one or more other aspects / features / embodiments.

[0048] Use of any one or more of the aspects or features as disclosed herein.

[0049] It is to be appreciated that any feature described herein can be claimed in combination with any other feature(s) as described herein, regardless of whether the features come from the same described embodiment.

[0050] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.

[0051] The phrases “at least one”, “one or more”, and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and / or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. When each one of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or class of elements, such as X1-Xn, Y1-Ym, and Z1-Zo, the phrase is intended to refer to a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., X1 and X2) as well as a combination of elements selected from two or more classes (e.g., Y1 and Zo).

[0052] The term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0053] The preceding is a simplified summary of the disclosure to provide an understanding of some aspects of the disclosure. This summary is neither an extensive nor exhaustive overview ofA0013966WO01the disclosure and its various aspects, embodiments, and configurations. It is intended neither to identify key or critical elements of the disclosure nor to delineate the scope of the disclosure but to present selected concepts of the disclosure in a simplified form as an introduction to the more detailed description presented below. As will be appreciated, other aspects, embodiments, and configurations of the disclosure are possible utilizing, alone or in combination, one or more of the features set forth above or described in detail below.

[0054] Numerous additional features and advantages of the present disclosure will become apparent to those skilled in the art upon consideration of the embodiment descriptions provided hereinbelow.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0055] The accompanying drawings are incorporated into and form a part of the specification to illustrate several examples of the present disclosure. These drawings, together with the description, explain the principles of the disclosure. The drawings simply illustrate preferred and alternative examples of how the disclosure can be made and used and are not to be construed as limiting the disclosure to only the illustrated and described examples. Further features and advantages will become apparent from the following, more detailed, description of the various aspects, embodiments, and configurations of the disclosure, as illustrated by the drawings referenced below.

[0056] Fig. 1 is a diagram of a system according to at least one embodiment of the present disclosure;

[0057] Fig. 2 is a diagram of another system according to at least one embodiment of the present disclosure;

[0058] Fig. 3A depicts a schematic illustration of a lead according to at least one embodiment of the present disclosure;

[0059] Fig. 3B depicts a schematic illustration of a lead according to at least one embodiment of the present disclosure;

[0060] Figs. 4A to 4E illustrate various views of spinal anatomy for explaining nerve stimulation along with various potential configurations of a lead according to at least one embodiment of the present disclosure;

[0061] Fig. 5 is a diagram that illustrates various physiological effects / relationships for certain anatomical elements according to at least one embodiment of the present disclosure;

[0062] Fig. 6 is a block diagram of a system according to at least one embodiment of the present disclosure;

[0063] Fig. 7 is a flowchart illustrating a first method according to at least one embodiment of the present disclosure; andA0013966WO01

[0064] Fig. 8 is a flowchart illustrating a second method according to at least one embodiment of the present disclosure.DETAILED DESCRIPTION

[0065] It should be understood that various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example or embodiment, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, and / or may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the disclosed techniques according to different embodiments of the present disclosure). In addition, while certain aspects of this disclosure are described as being performed by a single module or unit for purposes of clarity, it should be understood that the techniques of this disclosure may be performed by a combination of units or modules associated with, for example, a computing device and / or a medical device.

[0066] In one or more examples, the described methods, processes, and techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware -based processing unit. Alternatively or additionally, functions may be implemented using machine learning models, neural networks, artificial neural networks, or combinations thereof (alone or in combination with instructions). Computer-readable media may include non-transitory computer-readable media, which corresponds to a tangible medium such as data storage media (e.g., random-access memory (RAM), read-only memory (ROM), electrically erasable programmable ROM (EEPROM), flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and that can be accessed by a computer).

[0067] Instructions may be executed by one or more processing circuits or one or more processors, such as one or more digital signal processors (DSPs), general purpose microprocessors (e.g., Intel Core i3, i5, i7, or i9 processors; Intel Celeron processors; Intel Xeon processors; Intel Pentium processors; AMD Ryzen processors; AMD Athlon processors; AMD Phenom processors; Apple A10 or 10X Fusion processors; Apple A11, A12, A12X, A12Z, or A13 Bionic processors; or any other general purpose microprocessors), graphics processing units (e.g., Nvidia GeForce RTX 2000-series processors, Nvidia GeForce RTX 3000-series processors, AMD Radeon RX 5000-series processors, AMD Radeon RX 6000-series processors, or any other graphics processing units), application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry. Accordingly, the term “processor” as used herein may refer to any of the foregoing structure or any other physicalA0013966WO01structure suitable for implementation of the described techniques. Also, the techniques could be fully implemented in one or more circuits or logic elements.

[0068] Before any embodiments of the disclosure are explained in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Further, the present disclosure may use examples to illustrate one or more aspects thereof. Unless explicitly stated otherwise, the use or listing of one or more examples (which may be denoted by “for example,” “by way of example,” “e.g.,” “such as,” or similar language) is not intended to and does not limit the scope of the present disclosure.

[0069] Embodiments of the present disclosure contemplate technical solutions in which one or two leads (e.g., left and right leads) are used to deliver an electronic metabolic therapy.Embodiments of the present disclosure also contemplate solutions in which an automatic closed feedback loop is created for both controlling insulin and for controlling Hypertension / Diuresis. It should be appreciated, however, that an open feedback loop may also be utilized without departing from the scope of the present disclosure.

[0070] Fig. 1 illustrates a diagram of aspects of a system 100 according to at least one embodiment of the present disclosure. The system 100 may be used to provide electrical signals for a patient and / or carry out one or more other aspects of one or more of the methods disclosed herein. For example, the system 100 may include at least a device 104 that may be configured to generate a current or electrical signal, such as a signal capable of stimulating one or more nerves (e.g., dorsal root nerves). In some examples, the device 104 may be referred to as an implantable device. Additionally, the system 100 may include one or more wires or leads 108 that provide a connection between the device 104 and nerves of the patient for enabling nerve stimulation / blocking.

[0071] Neuromodulation techniques (e.g., technologies that act directly upon nerves of a patient, such as the alteration, or “modulation,” of nerve activity by delivering electrical pulses or pharmaceutical agents to a target area) may be used for assisting in treatments for different diseases, disorders, or ailments of a patient. As described herein, neuromodulation techniques may be used to stimulate one or more nerves which causes a response in one or more anatomical elements of the patient that treats diabetes or contributing factors thereof. For example, theA0013966W001device 104 may provide electrical stimulation to one or more nerves in the spinal cord of the patient (e.g., via the one or more leads 108) to cause the brain and subsequently the spleen, pancreas, and / or kidney to respond in a manner that treats diabetes by managing insulin levels and therefore glucose peaks or, for example. The response by the anatomical element may be directly caused by the stimulation (e.g., stimulation of a nerve causes stimulation of the anatomical element that produces the response) and / or may be indirectly caused the stimulation (e.g., stimulation of a nerve causes the brain to send and / or block signals to an anatomical element that produces the response based on the signals). In one embodiment, stimulating dorsal roots or dorsal root ganglions at one or more spinal levels at T6-T12 may cause desirable responses in the patient.

[0072] In some examples, as shown in Fig. 1, the one or more leads 108 include a single lead 108. In other embodiments, as will be described in Fig. 2, the one or more leads 108 may include multiple leads 208A, 208B. The lead 108 may be implanted on or near a target anatomical element, such as implanted in a location that enables stimulation of one or more dorsal roots or dorsal root ganglion at one or more spinal levels (e.g., at one or more thoracic levels Tl, T2, T3, T4, T5, T6, T7, T8, T9, T10, Tl 1, and / or T12), of the patient. Stated another way, one or more dorsal roots or dorsal root ganglion at a single one of the above spinal levels may be stimulated or one or more dorsal roots at multiple ones of the above spinal levels may be stimulated. In some examples, the lead 108 is implanted near the spinal cord and more specifically, in the epidural space between the spinal cord and the vertebrae. Once implanted, the lead 108 may provide an electrical signal (whether stimulating or blocking) from the device 104 to the target anatomical element (e.g., one or more nerves in the spinal cord, the brain, etc.). The device 104 in some embodiments, may be implanted in the patient, though in other embodiments - such as during testing of the lead 108 - the device 104 may be external to the patient’s body.

[0073] In some examples, the lead 108 may provide the electrical signals to the respective nerves via electrodes that are connected to the nerves (e.g., sutured in place, wrapped around the nerves, etc.). In some examples, the lead 108 include cuff electrodes (e.g., at an end of the lead 108 not connected or plugged into the device 104). Additionally or alternatively, while shown as physical wires that provide the connection between the device 104 and the one or more nerves, the electrodes may provide the electrical signals to the one or more nerves wirelessly (e.g., with or without the device 104).

[0074] Electrodes of a lead 108 may comprise stimulating electrodes (e.g., electrodes configured to stimulate a target anatomical element). In some embodiments, electrodes of a lead 108 may further comprise recording electrodes (e.g., electrodes configured to record a physiological response to the stimulation). The stimulating electrodes may stimulate a targetA0013966WO01anatomical element such as a nerve and the recording electrodes may record a physiological response to the stimulation. More specifically in closed loop stimulation, the recording electrode may record or measure electrically evoked compound action potential (ECAP), which may be used to regulate or adjust the electrical signal generated by the device 104. For example, as a patient bends over, a distance between the lead 108 and the spinal cord (or other target anatomical element) may change, thus the resulting stimulation may be weaker or stronger based on the change in the distance. The recording electrode may measure and record the ECAPs and a processor may determine a difference in the ECAP. The difference may be used to adjust the electrical signal to cause an amplitude of the ECAP to remain within a range that is comfortable for the patient while still treating a condition of DIABETES.

[0075] Additionally, while not shown, the system 100 may include one or more processors (e.g., one or more DSPs, general purpose microprocessors, graphics processing units, ASICs, FPGAs, or other equivalent integrated or discrete logic circuitry) that are programmed to carry out one or more aspects of the present disclosure. In some examples, the one or more processors may be used to drive a feedback loop in a closed-loop stimulation system or an open-loop stimulation system, as will be discussed in detail with reference to the remaining figures and description. In other examples, the at least one processing circuit may include a memory or may be otherwise configured to perform aspects of the present disclosure. For example, the one or more processors may provide instructions to the device 104, the electrodes, or other components of the system 100 not explicitly shown or described with reference to Fig. 1 for treating diabetes or aspects thereof as described herein. In some examples, the one or more processors may be part of the device 104 or part of a control unit for the system 100 (e.g., where the control unit is in communication with the device 104 and / or other components of the system 100 - see, for example, processor 604 in Fig. 6).

[0076] The system 100 or similar systems may be used, for example, to carry out one or more aspects of any of the methods described herein. The system 100 or similar systems may also be used for other purposes. It will be appreciated that the human body has many nerves and the stimulation / blocking treatments described herein may be applied to any one or more nerves, which may reside at a suitable location of a patient (e.g., cervical, lumbar, thoracic, etc.) affecting the function of an organ connected.

[0077] Fig. 2 depicts a system 200 according to at least one embodiment of the present disclosure is shown. The system 200 is the same as or similar to the system 100 and comprises a device 204 which may be the same as or similar to the device 104. The system 200 also includes a lead that comprises a first lead 208A and a second lead 208B. The first lead 208A may comprise stimulating electrodes configured to stimulate a target anatomical element or elementsA0013966W001(e.g., dorsal roots at one side of a spinal cord) and the second lead 208B may comprise additional stimulating electrodes configured to stimulate another target anatomical element or elements (e.g., dorsal roots at the other side of the spinal cord). The first lead 208A and the second lead 208B may be implanted near each other in in the same space (for example, the epidural space), or may be implanted in separate spaces. It will be appreciated that in some embodiments, the leads 108, 208A, 208B may comprise one lead, two leads, or more than two leads.

[0078] Fig. 3A and Fig. 3B depict a schematic illustration of a first lead 300 and a second lead 302, respectively. The first lead 300, as illustrated, comprises a paddle lead 304 and the second lead 302 comprises a cylindrical lead 306. It will be appreciated that while a paddle lead and a cylindrical lead are shown and described, any type of lead may be used to carry out inventive concepts.

[0079] The paddle lead 304 may enable directional stimulation such that stimulation can be directed in a target direction. For example, the paddle lead 304 may be implanted above the spinal cord such that electrodes 308 on the paddle lead 304 face the spinal cord. During stimulation, the electrodes 308 direct the stimulation in the direction of the spinal cord.

[0080] The cylindrical lead 306 may also provide directional stimulation when the cylindrical lead 306 is segmented, as described in detail below. Further, the cylindrical lead 306 may be beneficially implanted using a minimally invasive surgical procedure (as opposed to forming an incision to implant the lead). During such procedures, the cylindrical lead 306 can be inserted into the epidural space using an epidural needle.

[0081] In the illustrated embodiments, the paddle lead 304 comprises sixteen electrodes 308 and the cylindrical lead 306 comprises eight electrodes 310. It will be appreciated that in other embodiments, the paddle lead 304 may comprise less than or more than sixteen electrodes and the cylindrical lead 306 may comprise less than or more than eight electrodes. Though the electrodes 308 of the paddle lead 304 are shown as ovals, the electrodes 308 (and / or the electrodes 310 of the cylindrical lead 306) may be any shape or size and may be spaced from each other at any distance. Each electrode may also be a different shape or size than another electrode and each electrode may be spaced a different distance from adjacent electrodes.Further, though the electrodes 310 of the cylindrical lead are shown as ring electrodes, the cylindrical lead 306 may be segmented such that the electrodes 310 do not wrap around the entire cylindrical lead 306. More specifically, the cylindrical lead 306 can be segmented into any number of segments. For example, the cylindrical lead 306 can be bi-segmented or tri-segmented. In a segmented cylindrical lead 306, the electrode can be positioned in a segment such that the electrode will direct the stimulation in the direction that the electrode is facing. In other words, aA0013966W001segmented cylindrical lead 306 may enable directional stimulation in a target direction toward a target nerve.

[0082] Fig. 4A illustrates a cross-sectional view of a spine that shows possible stimulated regions of a nerve according to at least one example embodiment. The view in Fig. 4A may correspond to a cross-section taken at thoracic level T10 from below. Meanwhile, Fig. 4B illustrates a view showing a pair of epidural leads 108 implanted at the left and right sides of a patient’s spine, where each lead 108 includes a pair of stimulating electrodes 400. Figs. 4A and 4B illustrate various anatomical elements of the spine including a vertebral body, epidural space, transverse processes, spinal cord, superior facets, sympathetic ganglions, a spinal nerve, ventral roots, and dorsal roots (also called dorsal root nerves). Fig. 4A further illustrates stimulated regions on a right-side R of the vertebral body. Although not explicitly shown, it should be appreciated that the stimulated regions exist in the same corresponding locations at a left-side L of the vertebral body. A stimulation location in Fig. 4B may correspond to a location at which or near which one or more electrodes are implanted. As shown, the stimulation location corresponds to or is proximate to the dorsal root while the stimulated regions correspond to the dorsal root and / or the dorsal root.

[0083] Fig. 4B shows a set of electrodes that includes two pairs of stimulating electrodes 400 on two leads 108 that are positioned in a location that enables injection of an electrical signal at or near the stimulation location of the left and right sides of the vertebral body. Each pair of stimulating electrodes 400 may receive the electrical signal from a signal generator (e.g., signal generator 616 in Fig. 6) of the device 104 which in turn stimulates the dorsal root at the left and right sides of the vertebral body. In the example shown in Fig. 4B, each pair of stimulating electrodes 400 comprises one electrode at a top side of the dorsal root and one electrode at a bottom side of the dorsal root with each electrode receiving an electrical signal from a signal generator of the device 104. As shown, the stimulation location in Fig. 4B may be under or directly adjacent to a lead 108 between a pair of stimulating electrodes 400 in a lengthwise direction of the lead 108. In at least one embodiment, each stimulating electrode 400 may be about 1.5mm in size and be within about 5mm (+ / - 20%) of the dorsal root. Using an electrode configuration with pairs of stimulating electrodes 400 as shown in Fig. 4B may assist with focusing electrical energy to the stimulation location between a pair of stimulating electrodes 400. However, example embodiments are not limited to using pairs of electrodes to stimulate a dorsal root, and a single stimulating electrode on each lead 108 may be placed at or near the stimulation location on each side of the vertebral body to stimulate a respective dorsal root. Notably, the stimulating electrodes 400 may be passively held in place by surrounding tissue of the patient and should be located at a position that does not accidently stimulate the ventral rootA0013966W001(which may cause negative side effects for the patient). As may be appreciated, remaining electrodes (i.e., non-stimulating electrodes) of each lead 108 do not receive the electrical signal for the purpose of treating one or more conditions of metabolic syndrome. However, depending on locations of the remaining electrodes, the remaining electrodes may receive electrical signals for other purposes (e.g., for treating another condition, like pain).

[0084] Figs. 4C - 4E illustrate other example configurations for leads 108 according to at least some example embodiments. As shown in Fig. 4C, each lead 108 may have a substantially straight or linear configuration. Each lead 108, in some embodiments, may include a plurality of electrodes 400. Electrodes 400 may be configured to deliver a stimulation signal to an adjacent stimulation location. The leads 108 of Figs. 4C, 4D, and 4E are shown to have a different number of electrodes 400. It should be appreciated that the number of electrodes 400 provided on a lead 108 does not have to be limited to the particular number of electrodes 400 illustrated in the figures. For instance, a lead 108 may be provided with any suitable number of electrodes that is greater than one and less than twenty. In the embodiment of Fig. 4C, each lead 108 is shown to include eight (8) electrodes 400. A first set of electrodes 404a may be configured to deliver a stimulation signal to a first set of vertebral locations (e.g., T6-T9), a second set of electrodes 404b may be configured to deliver a stimulation signal to a second set of vertebral locations (e.g., T9-T10), and a third set of electrodes 404c may be configured to deliver a stimulation signal to a third set of vertebral locations (e.g., T11-T12). The stimulation signal delivered by the various sets of electrodes 404a, 404b, 404c may be the same or different. The collection of electrodes 400 on both leads 108 may be configured to treat various aspects of diabetes or related conditions. As a non-limiting example, each set of electrodes 404a, 404b, 404c may be configured to deliver a stimulation signal to a corresponding stimulation location. As an example, a stimulation signal having a current between approximately 0.1mA and 0.4mA may be delivered with a pulse width between approximately 80mics and 500mics. The stimulation signal may be delivered with a frequency of approximately 15Hz.

[0085] In some embodiments, electrode pairs from the first set of electrodes 404a (e.g., electrodes 1-4 and / or electrodes 9-12) may be used to provide anti-inflammatory treatments to a patient, electrode pairs from the second set of electrodes 404b (e.g., electrodes 5-6 and / or electrodes 13-14) may be used to provide metabolic treatments to a patient, and / or electrode pairs from the third set of electrodes 404c (e.g., electrodes 7-8 and / or electrodes 15-16) may be used to provide diuretic treatments to a patient. By segmenting the leads 108 into different sets of electrodes 404a, 404b, 404c, various aspects of diabetes may be treated with minimal invasiveness.A0013966W001

[0086] As can be seen in Fig. 4D, a spacing between electrodes 400 may be provided such that each pair of electrodes 400 on a lead 108 is spaced apart from other pairs of electrodes 400 according to a potential or actual vertebral spacing. For instance, first and second electrodes 400 may be spaced apart from the third and fourth electrodes 400 by approximately 18mm. In other words, electrode 400 spacing between two vertebral levels may be approximately 18mm to ensure that each pair of electrodes is not inadvertently stimulating the same nerves. Each electrode 400 may itself have a length of approximately 3mm and the distance between adjacent electrodes 400 in a pair of electrodes (e.g., the first and second electrodes 400) may be in the order of approximately 4mm.

[0087] Fig. 4E illustrates leads 108 with a different number of electrodes 400 than the leads 108 illustrated in Figs. 4C or 4D. In some embodiments, the leads 108 may be provided with two or four electrodes 400, where one or more electrodes 400 on each lead 108 is positioned on or near the patient’s celiac ganglia 408. Such electrodes 400 may be configured to deliver a stimulation signal if the patient’s sympathetic drive is above a predetermined threshold for a predetermined amount of time and / or if the patient’s blood pressure exceeds a predetermined threshold and / or if the patient is retaining fluids.

[0088] While illustrated as straight or linear leads 108, it should be appreciated that non-linear or curved leads may be used without departing from the scope of the present disclosure. For instance, curved leads 108 may be designed to conform to or partially conform to a shape of a respective dorsal root so that one end of each lead 108 terminates at an outer part of the respective dorsal root while a section of the lead 108 curves around one edge of the respective dorsal root.

[0089] Although Figs. 4A - 4E have been described with reference to implantation at or near the thoracic level (e.g., levels T6-T12), additional leads 108 with pairs of stimulating electrodes 400 may be implanted at the same or similar locations to achieve the same or similar stimulation effects at one or more other spinal levels, for example, at one more other thoracic levels, one or more lumbar levels, and / or one or more cervical levels.

[0090] Fig. 5 is a diagram that illustrates various physiological effects / relationships for certain anatomical elements. As shown, activation of the vagal (or vagus) nerve increases insulin production decreases glucose production in the pancreas. In some embodiments, activation of the vagal nerve increases glycogenesis and reduces glucose production in the liver. Meanwhile, activation of sympathetic nerves may increase sodium resorption and reduces urinary excretion by the kidneys while also decreasing glycogenesis and increasing glucose production by the liver. As may be appreciated, dorsal root stimulation according to example embodiments inhibits sympathetic nerves and activates the vagal nerve, which results in lower glucose production andA0013966W001increased glycogenesis while limiting food intake. In addition, dorsal root stimulation may cause release of a hepatic insulin sensitizing substance (HISS) from the liver to increase glucose storage in muscle. In one embodiment, dorsal root stimulation at one or more of spinal levels T12, LI, and L2 may affect feedback.

[0091] Fig. 6 depicts a block diagram of a system 600 according to at least one embodiment of the present disclosure. In some examples, the system 600 may implement aspects of or may be implemented by aspects of Figs. 1-5 as described herein. For example, the system 600 may include a computing device 602, a monitoring device 614, and a stimulating / blocking system 612 with a signal generator 616 and / or one or more lead(s) 622 to carry out one or more aspects of one or more of the methods disclosed herein. A device 104, 204 as described with reference to Figs. 1 and 2 may include aspects of the system 600, such as the signal generator 616, the computing device 602, and / or the monitoring device 614. In this case, the signal generator 616 and the computing device 602 may be integrated with one another in the same implantable device 104, 204. The lead(s) 622 may represent an example of the lead(s) 108, 208, 300, and / or 302 from Figs. 1-3B. The system 600 may further comprise a database 630, and / or a cloud or other network 634. Systems according to other embodiments of the present disclosure may comprise more or fewer components than the system 600. For example, the system 600 may not include one or more components of the computing device 602, the database 630, and / or the cloud 634.

[0092] The stimulating / blocking system 612 may comprise the signal generator 616 and the lead(s) 622. As previously described, the signal generator 616 may be configured to generate an electrical signal, and the lead 622 may comprise a plurality of electrodes 618 configured to apply the electrical signal to a target anatomical element (e.g., dorsal root(s)). The electrodes 618 may correspond to electrodes of leads 108 described herein and may include stimulating electrodes and, in some cases, non-stimulating electrodes. The stimulating / blocking system 612 may communicate with the computing device 602 to receive instructions such as instructions 624 for applying the electrical signal to the target anatomical element, where the electrical signal is intended to stimulate one or more dorsal roots at one or more spinal levels of the patient to thereby generate a response by at least one anatomical element such as the spleen, pancreas, and / or kidney(s), with a particular purpose of treating diabetes or aspects thereof.

[0093] The computing device 602 is illustrated to include a processor 604, a memory 606, a communication interface 608, and a user interface 610. Computing devices according to other embodiments of the present disclosure may comprise more or fewer components than the computing device 602.

[0094] The processor 604 of the computing device 602 may comprise one or more suitable processing circuits such as one or more suitable processors described herein or any similarA0013966W001suitable processor. The processor 604 may be configured to execute instructions 624 stored in the memory 606, which instructions may cause the processor 604 to carry out one or more methods described herein. For example, as described in more detail below, the processor 604 may execute instructions 624 to monitor a parameter of a patient, such as a blood glucose level (or a metric calculated from a blood glucose level), and to control generation of the electrical signal by the signal generator 616 based on the monitored parameter and a threshold associated with the monitored parameter (e.g., a threshold blood glucose level). Other examples of a monitored parameter may exist. For instance, and without limitation, embodiments of the present disclosure contemplate that the monitored parameter comprises one or more of: a glucose level; an insulin level; a heart rate; a general sympathetic activity level of the patient as assessed by heart rate variability in a frequency domain, a time-based domain, a non-linear calculation on the heart rate signal; and / or an inflammation marker of the patient.

[0095] The memory 606 may be or comprise RAM, DRAM, SDRAM, other solid-state memory, any memory described herein, or any other tangible, non-transitory memory for storing computer-readable data and / or instructions. The memory 606 may store information or data useful for completing, for example, any steps of the method 700 described herein, or of any other methods. The memory 606 may store, for example, instructions and / or machine learning models that support one or more functions of the stimulating / blocking system 612. For instance, the memory 606 may store content (e.g., instructions 624 and / or machine learning models) that, when executed by the processor 604, cause the signal generator 616 to generate an electrical signal for lead(s) 622 which apply the electrical signal to a respective target anatomical element such as a dorsal root to cause a response in one or more anatomical elements that changes a value of the parameter being monitored to treat a condition, such as diabetes.

[0096] The memory 606 may also store data for electrical signal optimization 620. Data for electrical signal optimization 220 may correspond to a routine executed by the processor 604 to optimize the electrical signal used in an electrical stimulation. Optimization may be achieved by adjusting signal current, adjusting signal amplitude, adjusting signal frequency, adjusting signal type (e.g., square wave, sinusoidal wave, triangle wave, etc.), adjusting duty cycle, adjusting treatment duration, electrode combination (e.g., which electrodes are stimulating), signal polarity (positive or negative), and / or the like. More specifically, the electrical signal optimization 620 may enable the processor 604 to determine one or more parameters of the electrical signal. Data for electrical signal optimization 620 may also enable the processor 604 to determine or adjust one or more parameters of the electrical signal based on a physiological response recorded during stimulation of the target anatomical element. The one or more parameters of the electrical signal may be adjusted to, for example, maintain one or more monitored parameters of the patientA0013966W001within an acceptable range. For example, as discussed in more detail below, current of the electrical signal may be gradually increased over time to bring a patient parameter (e.g., blood glucose) below a threshold value to treat diabetes.

[0097] The data for electrical signal optimization 620 may be preprogrammed before or shortly after implantation of a device 104, 204, but may change as the computing device 602 learns more about which parameters of the electrical signal and / or other parameters of the treatment process result in better treatment of metabolic syndrome for a particular patient. For example, parameters related to treatment duration, current of the electrical signal, pulse width of the electrical signal, and / or frequency of the electrical signal may have initial values that are adjusted overtime to better treat diabetes and saved as data for electrical signal optimization 620 (see, e.g., step 724 below). In addition, parameters may be optimized in a way that prevents undesired side-effects, such as sweating, dangerously low blood pressure, and the like.

[0098] Content stored in the memory 606, if provided as instructions, may be organized into one or more applications, modules, packages, layers, or engines. Alternatively or additionally, the memory 606 may store other types of content or data (e.g., machine learning models, artificial neural networks, deep neural networks, etc.) that can be processed by the processor 604 to carry out the various method and features described herein. Thus, although various contents of memory 606 may be described as instructions, it should be appreciated that functionality described herein can be achieved through use of instructions, algorithms, and / or machine learning models (e.g., for electrical signal optimization). The data, algorithms, and / or instructions may cause the processor 604 to manipulate data stored in the memory 606 and / or received from or via the stimulating / blocking system 612, the database 630, and / or the cloud 634.

[0099] The computing device 602 may also comprise a communication interface 608. The communication interface 608 may be used for receiving data (for example, data from a recording electrodes capable of recording data) or other information from an external source (such as the stimulating / blocking system 612, the database 630, the cloud 634, and / or any other system or component not part of the system 600), and / or for transmitting instructions, images, or other information to an external system or device (e.g., another computing device 602, the stimulating / blocking system 612, the database 630, the cloud 634, and / or any other system or component not part of the system 600). The communication interface 608 may comprise one or more wired interfaces (e.g., a USB port, an Ethernet port, a Firewire port) and / or one or more wireless transceivers or interfaces (configured, for example, to transmit and / or receive information via one or more wireless communication protocols such as 802.11a / b / g / n, Bluetooth, NFC, ZigBee, and so forth). In some embodiments, the communication interface 608 may be useful for enabling the device 602 to communicate with one or more other processors 604 orA0013966W001computing devices 602, whether to reduce the time needed to accomplish a computing-intensive task or for any other suitable reason.

[0100] The computing device 602 may also comprise one or more (optional) user interfaces 610. The user interface 610 may be or comprise a keyboard, mouse, trackball, monitor, television, screen, touchscreen, and / or any other device for receiving information from a user and / or for providing information to a user. The user interface 610 may be used, for example, to receive a user selection or other user input regarding any step of any method described herein. In some embodiments, the user interface 610 may be used to select one or more parameters for the electrodes including, but not limited to, selecting whether an electrode is active or inactive. For example, the user interface 610 may receive input to select a first electrode as active and to select a second and a third electrode as inactive. Notwithstanding the foregoing, any required input for steps of methods described herein may be generated automatically by the system 600 (e.g., by the processor 604 or another component of the system 600) or received by the system 600 from a source external to the system 600. In some embodiments, the user interface 610 may be useful to allow a surgeon or other user to modify instructions to be executed by the processor 604 according to one or more embodiments of the present disclosure, and / or to modify or adjust a setting of other information displayed on the user interface 610 or corresponding thereto.

[0101] Although the user interface 610 is shown as part of the computing device 602, in some embodiments, the computing device 602 may utilize a user interface 610 that is housed separately from one or more remaining components of the computing device 602. In some embodiments, the user interface 610 may be located proximate one or more other components of the computing device 602, while in other embodiments, the user interface 610 may be located remotely from one or more other components of the computer device 602. In this case, the communication interface 608 may enable communication between the computing device 102 and the user interface 610.

[0102] The monitoring device 614 may include suitable hardware and / or software for monitoring at least one parameter of a patient that is useful for determining whether dorsal root stimulation is effectively treating one or more conditions of metabolic syndrome. The monitoring device 614 may continuously provide data that enables the processor 604 to monitor the value of the at least one parameter of the patient. The monitoring device 614 may be attachable to and / or or at least partially implanted in a patient. In one non-limiting example, the monitoring device 614 comprises a blood glucose monitor or continuous glucose monitor (CGM) that monitors a blood glucose level of the patient. The monitoring device 614 may also be a part of a CAN and may be implanted cranially (e.g., above) the patient’s heart.A0013966W001

[0103] Another non-limiting example of a monitoring device 614 may include a blood pressure monitor, which may be incorporated into a wearable such as a fitness tracker or fitness watch. In other embodiments, the monitoring device 614 may include a device that monitors the patient’s cholesterol levels, and / or triglyceride levels. Still further, the monitoring device 614 may comprise a device that monitors the status of (e.g., the amount of) body fluids, for example, with a suitable impedance sensor because stimulating dorsal roots may affect the splanchnic bed which, in turn, affects body fluid status and / or blood pressure. The monitoring device 614 may include additional or alternative devices that monitor any suitable parameter useful for determining whether dorsal root stimulation is successfully treating a condition of metabolic syndrome in the patient. The monitoring device 614 may be separate from the device 104, 204 in Figs. 1 and 2 while being in wired or wireless communication with the computing device 602. In one embodiment, the monitoring device 614 is integrated with the device 104, 204 along with the stimulating / blocking system 612 and / or the computing device 602.

[0104] The database 630 may store information such as patient data, results of a stimulation and / or blocking procedure, stimulation and / or blocking parameters, electrical signal parameters, electrode parameters, electrode configurations and / or the like. The database 630 may be configured to provide any such information to the computing device 602 or to any other device of the system 600 or external to the system 600, whether directly or via the cloud 634. In some embodiments, the database 630 may be or comprise part of a hospital image storage system, such as a picture archiving and communication system (PACS), a health information system (HIS), and / or another system for collecting, storing, managing, and / or transmitting electronic medical records.

[0105] The cloud 634 may be or represent the Internet or any other wide area network. The computing device 602 may be connected to the cloud 634 via the communication interface 608, using a wired connection, a wireless connection, or both. In some embodiments, the computing device 602 may communicate with the database 630 and / or an external device (e.g., a computing device) via the cloud 634.

[0106] The system 600 or similar systems may be used, for example, to carry out one or more aspects of any of the method 700 or method 800 as described herein. The system 600 or similar systems may also be used for other purposes.

[0107] Fig. 7 depicts a method 700 that may be used, for example, to perform neuromodulation techniques (e.g., a stimulation / block therapy) to treat diabetes (e.g., type 1 and / or type 2) and / or at least one condition of metabolic syndrome for a patient.

[0108] The method 700 (and / or one or more steps thereof) may be carried out or otherwise performed, for example, by at least one processor. The at least one processor may be the same asA0013966W001or similar to the processor 604 or the processor(s) of the device 104 or 204 described above. The at least one processor may be part of the device 104 or 204 (such as an implantable pulse generator) or part of a control unit in communication with the device 104 or 204. A processor other than any processor described herein may also be used to execute the method 700. The at least one processor may perform the method 700 by executing elements stored in a memory (such as a memory 606 in the device 104 as described above). The elements stored in the memory and executed by the processor may cause the processor to execute one or more steps of a function as shown in method 700. One or more portions of a method 700 may be performed by the processor executing any of the contents of memory, such as providing stimulation to a nerve with an electrical signal.

[0109] The method 700 is shown to include an initialization step in which an LES is implanted at or near T9 - T10 (step 704). The initialization step may include determining an ECAP threshold, setting a starting pulse width (PW), setting a starting frequency, and setting a starting current. The illustrative, but non-limiting example, may include a starting PW of 210 mics, a starting frequency of 15Hz, and a starting current of 0.9 of an ECAP threshold.

[0110] The method 700 may then include determining if the current time is nighttime (step 708). This particular step may be determined with the input from one or more accelerometers that are on a device that is carried and / or worn by a patient (e.g., a mobile phone, a wearable device, etc.).[oni] If the analysis of step 708 is answered affirmatively, then the LES may be turned OFF (step 712). The LES may be turned OFF and remain OFF until the accelerometer data indicates that the patient is moving (e.g., it is no longer nighttime).

[0112] Following step 712, the method 700 may include a step of determining if the patient’s glucose level is at or above the glucose threshold determined in step 704 and / or if the glucose increase is above a corresponding glucose threshold (step 716). If the analysis of step 716 is answered affirmatively, then the LES may be turned ON (step 720).

[0113] Thereafter, the method 700 may proceed to determine if the current time is 90 minutes (e.g., a predetermined amount of time) or less before a meal (step 724). For example, step 724 may include using a glucose peak previous measure as a measure for an amount of minutes or using an ambulator intravenous glucose tolerance test (IVGT test) with and without LES. If the analysis of step 724 is answered negatively, then the parameters are kept constant for an additional amount of time (e.g., an additional 30 minutes) (step 744). The method 700 may then return to step 708.

[0114] If the analysis of step 724 is answered affirmatively, then the method 700 may include increasing the current applied to the patient with a 0.1 ECAP (e.g., for a DRG lead) or increasingA0013966W001the current by 0.1mA (e.g., for LES with SCS lead) or increasing the pulse width or frequency constant for at least a predetermined amount of time (e.g., 30 minutes) (step 728). This step may also include limiting the parameters determined in step 704 based on one or more ambulatory side effects.

[0115] The method 700 may then include determining if the patient’s glucose level is above the glucose threshold and / or if the glucose increase is above a corresponding glucose threshold (step 732). The analysis of step 732 may be the same or similar to the analysis of step 716.

[0116] The method 700 may then include determining if the glucose level has fallen below the predetermined threshold (step 736). If the analysis of step 736 is answered affirmatively, then the method returns to step 712 where the LES is turned OFF. If the analysis of step 736 is answered negatively, then the method proceeds to step 744.

[0117] Fig. 7 further illustrates that one or more termination criteria 748 may be provided for the method 700. As some non-limiting examples, the termination criteria 748 may include determining that exercise has been indicated by the accelerometer work or carried by the patient. The termination criteria 748 may alternatively or additionally include an analysis of a side effect, such as an HRV and / or high heart rate that shows an increase sympathetic drive. Other termination criteria may include that it is currently night or that not increase glucose levels have been detected or that the patient glucose levels are below a predetermined threshold.

[0118] Fig. 8 depicts another method 800 that may be used, for example, to perform neuromodulation techniques (e.g., a stimulation / block therapy) to treat diabetes (e.g., type 1 and / or type 2) and / or at least one condition of metabolic syndrome for a patient.

[0119] The method 800 (and / or one or more steps thereof) may be carried out or otherwise performed, for example, by at least one processor. The at least one processor may be the same as or similar to the processor 604 or the processor(s) of the device 104 or 204 described above. The at least one processor may be part of the device 104 or 204 (such as an implantable pulse generator) or part of a control unit in communication with the device 104 or 204. A processor other than any processor described herein may also be used to execute the method 800. The at least one processor may perform the method 800 by executing elements stored in a memory (such as a memory 606 in the device 104 as described above). The elements stored in the memory and executed by the processor may cause the processor to execute one or more steps of a function as shown in method 800. One or more portions of a method 800 may be performed by the processor executing any of the contents of memory, such as providing stimulation to a nerve with an electrical signal.

[0120] The method 800 may include determining if the patient’s parasympathetic drive has increased (step 804). The increase if parasympathetic drive may indicate that the patient isA0013966W001currently eating. In some embodiments, heart rate variability may be used in the frequency spectrum to assess the parasympathetic drive.

[0121] The method 800 may also include determining if the accelerometer carried or worn by the patient indicates that the patient is eating (step 808). For instance, the accelerometer may indicate that the patient is making one or more movements consistent with eating (e.g., moving a hand toward the mouth).

[0122] If the analysis of step 804 and / or 808 are answered affirmatively, then the method 800 may proceed by increasing the current with 0.1 ECAP or PW or frequency (step 812). Step 812 may also include keeping the current applied to the patient constant for at least a predetermined amount of time or proportional to a difference from a target value. In some embodiments, parameters may be limited based on ambulatory side effects.

[0123] It should be appreciated that example embodiments are shown and described with reference to specific values for various parameters (e.g., threshold values or levels, electrical signal characteristics, durations of iterations of a step, etc.), but that these values may vary or be adjusted based on empirical evidence and / or design preference.EXAMPLES

[0124] In one non-limiting example of the present disclosure, an experimental protocol is implemented once pressure, heart rates, and glucose levels of a subject animal (e.g., a female Landrace Yorkshire pig) are stabilized within 10% of baseline. To prevent unintentional stimulation of the ventral root linked to sympathetic activation, aortic pressure and heart rate were monitored every 5 minutes during the procedure to ensure stability in both measurements. The stimulation current used was 0.2mA, pulse width 210 ps and frequency 15 Hz. The cranial electrode was programmed as negative.

[0125] In a first experiment, the optimal vertebrae level to stimulate was determined. After a 1-hour baseline measurement, low energy stimulation (LES) was applied bilaterally at T7 and T8 for 1 hour. This was followed by 1 hour of stimulation at T9 and T10, then another hour at T11 and T12. Finally, there was 1 hour without any stimulation.

[0126] The primary endpoints are the effect on blood insulin and blood glucose using intravenous glucose tolerance test (IVGT) tests. C-peptide serves as a surrogate for insulin due to its stability. The half-life of C-peptide is approximately 30 minutes, compared to the 5-10 minutes half-life of insulin. Duplicate measurements were averaged.

[0127] In further experiments (e.g., experiments 2 and 3), after a period of baseline measurement, stimulation took place for 1 hour bilaterally at T9 and T10, followed by a recoveryA0013966W001period of 30 minutes. During these periods, glucose and C-peptide were assessed every 15 minutes.

[0128] Next, at the beginning of the baseline of 1.5 hours, an intravenous glucose tolerance test was given by a 600 mg / kg dose of 50% dextrose solution (or equivalent) over 30-60 seconds. After the infusion, C-peptide was assessed every 15 minutes, and glucose was assessed every 5 minutes. Similarly, during LES stimulation at T9-T10 an intravenous glucose tolerance test was given. Again, during this period C-peptide was assessed every 15 minutes and glucose was assessed every 5 minutes.

[0129] In another experiment (e.g., experiment 4), the order of the IVGT-test was changed and an IVGT-test during LES was started followed by an IVGTT test with LES deactivated.

[0130] In further experiments (e.g., experiments 5-7), the baseline was performed first and was followed by an IVGT-test taking 1.5 hour, which was repeated during LES. It was noted in experiments 2 and 3 that C-peptide did not increase instantaneously but was still increasing at the end of the IVGT-test. By changing the order of the protocol, i.e. moving a LES without IVGT-test before an IVGT-test with LES, LES was allowed more time to take effect on C-peptide. However, it appeared that the glucose levels did not recover enough before a baseline IVGT-test and therefore the order was optimized in experiment 5-7. Data for the experiments 1-7 is produced below for convenience and reference.

[0131] The above figure illustrates a protocol scheme. In the figure, blue arrows indicate C-Peptide + glucose measurements every 15 minutes and red only indicate glucose measurements every 5 minutes. If arrows are connected by a line, it means that the last measure of one series was used as the first measure of the subsequent series.

[0132] Based on insights from experiments 5 and 6, it was decided in experiment 7 to extend the LES T9-T10 stimulation period from 1 to 2 hours before starting the IVGT-test, allowing sufficient time for insulin to respond to LES.A0013966W001

[0133] Necroscopies were performed to check if the leads were positioned correctly at the dorsal roots or incorrectly at the ventral roots.

[0134] Repeated Measures Anova was used to test if glucose levels changed over time in multiple experiments during baseline conditions or during LES (no IVGT-test). During the IVGT-tests, the decay time constant was calculated using the glucose peak and values thereafter according to the formula: Glucose [mg / dl] = constant x Time [min]decay time constant. During the period of no stimulation, glucose data was fitted with two degrees of freedom (e.g., constant and decay time constant). For the measurements where LES was used, the constant was derived from the baseline measurement in the same experiment. Two-sided paired t-tests were used to calculate significant differences between the decay constants (p < 0.05).

[0135] In experiment 1, the optimal location of the electrode pairs to have the greatest affect on C-peptide was location T9-T10 (Fig.4A). As such, despite an increase in C-peptide, glucose values remained unchanged within 1 hour of normoglycemic conditions (see below).Figure 4: A) C-peptide (insulin marker) measured at baseline and multiple thoracic levels. B) Associated glucose levels measured withing 1 hour of baseline (no stimulation).

[0136] For the next set of experiments, the optimal electrode placement (T9-T10) was repeated in multiple animals (n=6). During baseline, glucose remained relatively constant (Fig. 5 A, p = 0.51, Repeated Measures ANOVA). During LES, no effect on glucose was found (Figure 5B, p = 0.09, Repeated Measures ANOVA). In an analysis of a subset of the data obtained during LES, it appeared that there was a significant effect (p = 0.005) during hyperglycemic conditions (defined >150 mg / dl), but no effect during normoglycemic conditions (p = 0.33).

[0137] During baseline, C-peptide did not increase (Fig. 5C, p = 0.15, Repeated Measures ANOVA). When LES was applied during a 1-hour period, C-peptide increased (Fig. 5D, p = 0.001, Repeated Measures ANOVA). Measurement variance in C-peptide appeared to be presentA0013966W001(Fig. 5C-D). The increase in C-peptide in 1 hour appeared higher during LES than during baseline, although significance was not reached (p = 0.06, two-sided t-test).Figure 5: Effect of LES on glucose and C-peptide without IVGT test

[0138] Since the effect on glucose was not present in an euglycemic state, a hyperglycemic state was induced using an intravenous glucose tolerance test provoking a change in C-peptide (n=6). The increase in C-peptide during the first 90 minutes of the IVGT-test was greater during LES than during no stimulation (p = 0.024, two-sided paired t-test) (Figure 6, Table 1).A0013966W001Figure 6: Example readings of the IVGT test for a single animal.Change in C- peptide Change in C- from start IVGTT (no peptide from startLES) to maximum IVGTTfLESjtoExperiment wit in 90 minutes maximum within2 533 104 755 9G 1.356 21 1657 41 2SSaverage 32 121std 36 99Table 1: Maximum change in C-peptide after IVGT test for each experiment.

[0139] In Figure 7, IVGT-tests are shown with and without LES present. In experiment 2, the baseline shifted after the first IVGT-test and this shift was corrected to visualize the differences with and without LES stimulation. The decay time is not affected by an offset.

[0140] The glucose decay time constant was more negative during LES compared to no stimulation, i.e. glucose was eliminated faster from the blood stream (A= -0.03, p = 0.045, paired t-testtwo sided) (Table 2 and Figure 7).

[0141] In all experiments, necroscopy demonstrated that the leads were correctly positioned at the dorsal roots (Figure 8). In experiment 7 the heart rate suddenly increased when LES was ON for 1 hour from 86bpm to 104 bpm, coinciding with shivering of the upper body. In experiment 7, CRP were twice as high as in the previous experiments reaching 600 microgram / ml. In experiments 1-4, both aortic pressure and heart rate remained unchanged during periods of stimulation and no stimulation (see example Figure 9). In experiment 5, heart rate gradually rose from 82 to 96 bpm, with a slow increase during the first hour of LES stimulation. This increase in heart rate could not be attributed to LES. A decline in systolic aortic pressure from 115 to 98 mmHg during the experiment could explain the rise in heart rate. Similarly, experiment 6 showed a very gradual increase in heart rate from 82 to 99 bpm over the entire experiment duration, without an abrupt change or gradual change in pressure when LES was activated.A0013966W001Figure 7: Effect of LES on blood glucose during IVGT test.Experiment Constant decay time decay time differenceconstant no constant LESstim2 470 -0.15 -0.23 -0.083 599 -0.23 -0.23 04 520 -0.18 -0.23 -0.055 728 -0.29 -0.32 -0.032 638 -0.28 -0.30 -0.027 591 -0.29 -0.30 -0.01average -0.03sd0.03A0013966W001Table 2: Decay times glucose curves without and during LES.Figure 8: Example of a necroscopy image showing that leads are dorsally located. Green circles indicate electrode pairs from which is stimulated.Figure 9: Example of aorta pressure and heart rate remaining relatively constant over the experiment.A0013966W001

[0142] This study was performed to investigate the effect of LES on blood insulin and subsequently blood glucose as an alternate or supplemental therapy to pharmaceuticals for the treatment of DMT2. The change in C-peptide (insulin marker), during stimulation at T9-T10 with 2 leads during the IVGT-test was two to three times greater than the period without stimulation, as reflected by a significantly steeper decay of blood glucose. Furthermore, a glucose change due to LES was only noted during a hyperglycemic state and not during an euglycemic state, whereas C-peptide also increased during the euglycemic state. This indicates that this therapy may not result in hypoglycemia during fasting conditions.

[0143] As such, it was observed that the maximum change in C-peptide occurred in time >1 hour and was trending higher towards the end of the IVGT-test, where a plateau was noted around 90 minutes. It is plausible that if the euglycemic state was maintained for longer than 1 hour, the C-peptide would have increased more, and plasma glucose would have decreased during LES in the euglycemic condition as well. This can be verified in future work. In comparison to the earlier experiments (experiments 1-4), experiments 5-7 utilized longer testing time periods and recovery periods in between. This resulted in greater C-peptide changes during the IVGT-tests when applying LES in experiments 5-7, which were respectively 135, 165 and 288 ng / ml compared to 53, 75 and 10 in experiments 2-4. This difference between the earlier and later experiments was not observed for the IVGT-tests without stimulation. It is plausible that the greater C-peptide increases observed in experiments 5-7 caused the smaller glucose peaks during the IVGT-tests with LES, as compared to without LES. Therefore, it is concluded that LES optimally affects insulin and glucose levels after 90 minutes in a hyperglycemic state.

[0144] The LES therapy depends on the ability of the pancreas to create extra insulin. In a diabetes 1 patient or a diabetes 2 patient in which insulin injections are required this therapy is believed to be ineffective since there is a deterioration in [3 cell function.

[0145] In experiment 4 (Figure 6), the order of IVGT-tests was reversed compared to the other experiments, meaning that LES IVGT-test occurred first. The effect of LES on C-peptide during the IVGT-test with LES in the background might have induced some carry over effect to the IVGT-test without LES. Therefore, C-peptide was relatively high at the start of the IVGT-test with no stimulation, over-estimating glucose during the baseline IVGT-test and limiting the difference.

[0146] In experiment 7, a very small difference in decay time of glucose was found between IVGT-test without and with stimulation. During the stimulation, a sudden increase in heart rate was noted, reflecting a high sympathetic drive, which could have counter-acted a decrease in glucose. The increase in heart rate could have been due to the stimulation of sympathetic nerves in the adjacency of the dorsal roots even though the leads were correctly positioned. In that caseA0013966W001the current could have been lowered to 0.1mA to check if this would decrease heart rate. Another explanation is that the high sympathetic drive and heart rate could have been due to the animal having an infection as reflected by the high CRP in this farm animal.

[0147] The effect of LES on the storage of glucose in the liver in the form of glucagon has not been considered in this study and could be subject to future research. An increase in vagal activity and inhibition of sympathetic activity to the liver promotes glycogenesis (the process of converting glucose in glucagon), resulting in lowering of blood glucose level (Figure 1). The glucagon is stored in the liver and muscles. Potentially DRG stimulation at T9-T10 level decreases plasma glucose via promoting glucogenesis in the liver and insulin release in the pancreas (Figure 1). Furthermore, longer stimulation periods need to be considered and the chronic effect of the therapy in a diabetes model needs to be studied.

[0148] LES T9-T10 could potentially also be used to improve gastric emptying. It was found that SCS at T10 with 0.2ms (pulse width), 50Hz (frequency), 90% motor threshold, at 2s on / 3s off was able to enhance gastric motility and decrease sympathetic activity.

[0149] Pharmacological treatments for Type 2 Diabetes which are necessary for when exercise and diet fail, often cause side effects and are poorly tolerated by patients with gastrointestinal issues or those who are pregnant. Metformin, the most common and cost-effective drug, reduces glucose production but causes gastro-intestinal (GI) side effects in -25% of users. GLP-1 receptor agonists also cause GI side effects in up to 50% of users. Ozempic (semaglutide) is a GLP-1 receptor agonist, like Tirzepatide, which also target glucose-dependent insulinotropic polypeptide receptors. Tirzepatide, is discontinued by 6.3% of patients due to GI issues. DPP-4 inhibitors can cause joint pain and edema in 5-15% of patients and are costly. SGLT2 inhibitors lower blood sugar, support heart health, and promote weight loss but may cause infections and, rarely, diabetic ketoacidosis. The high cost Ozempic (up to $12k annually) and SGLT-2 can be cost prohibitive. About 50% of patients with chronic conditions do not adhere to prescribed medications. LES therapy might be a cost-effective alternative for patients facing side effects or non-compliance.

[0150] In conclusion, preclinical work has demonstrated that LES therapy could be promising to be used in non-compliant diabetes patients or those having side effects with conventional medications, to affect insulin secretion and subsequently glucose blood level when in a hyperglycemic state.

[0151] The foregoing is not intended to limit the disclosure to the form or forms disclosed herein. In the foregoing Detailed Description, for example, various features of the disclosure are grouped together in one or more aspects, embodiments, and / or configurations for the purpose of streamlining the disclosure. The features of the aspects, embodiments, and / or configurations ofA0013966W001the disclosure may be combined in alternate aspects, embodiments, and / or configurations other than those discussed above. This method of disclosure is not to be interpreted as reflecting an intention that the claims require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed aspect, embodiment, and / or configuration. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the disclosure.

[0152] Moreover, though the foregoing has included description of one or more aspects, embodiments, and / or configurations and certain variations and modifications, other variations, combinations, and modifications are within the scope of the disclosure, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative aspects, embodiments, and / or configurations to the extent permitted, including alternate, interchangeable and / or equivalent structures, functions, ranges, or steps to those claimed, whether or not such alternate, interchangeable and / or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter.

[0153] The following examples are illustrative of the techniques described herein.

[0154] Example 1. A system for treating a microvascular disease, comprising: a device comprising: a signal generator configured to generate an electrical signal; and at least one processor configured to: monitor a value of at least one parameter of a patient that is associated with diabetes; and control the signal generator using a closed feedback loop based on a threshold value and the value of the at least one parameter; and one or more electrodes coupled to the signal generator to stimulate at least one dorsal root nerve or dorsal root ganglion based on the electrical signal which causes a response by at least one anatomical element of the patient that changes the value of the at least one parameter of the patient.

[0155] Example 2. The system according to example 1, wherein the at least one processor is configured to control the signal generator to generate the electrical signal when the value of the at least one parameter exceeds the threshold value.

[0156] Example 3. The system according to example 2, wherein the signal generator is controlled to generate the electrical signal in a manner that keeps the value of the at least one parameter above a second threshold value that is less than the threshold value.

[0157] Example 4. The system according to example 2 or 3, wherein the at least one parameter comprises a blood glucose level of the patient or a metric calculated from the blood glucose level of the patient.A0013966W001

[0158] Example 5. The system according to any preceding claim, wherein the at least one processor is further configured to: determine that the patient is eating or is about to eat.

[0159] Example 6. The system according to example 5, wherein an accelerometer is used to determine that the patient is eating.

[0160] Example 7. The system according to any preceding claim, wherein the at least one processor is further configured to: determine that a current time corresponds to nighttime; and control the signal generator based on determining that the current time corresponds to the nighttime.

[0161] Example 8. The system according to example 7, wherein an accelerometer is used to determine that the patient is sleeping.

[0162] Example 9. The system according to example 7, wherein the one or more electrodes apply a lateral epidural stimulation to the at least one dorsal root nerve.

[0163] Example 10. The system according to example 7, wherein the one or more electrodes apply a dorsal root ganglion stimulation to the at least one dorsal root ganglion.

[0164] Example 11. The system according to either example 9 or 10, wherein the sympathetic activity level of the patient’s kidney is assessed by monitoring a celiac ganglion by monitoring sympathetic skin activity in the area of the kidney.

[0165] Example 12. The system according to either example 9 or 10, wherein the sympathetic activity level of the patient is assessed in the area of the heart.

[0166] Example 13. The system according to example 9 or 10, wherein the sympathetic activity level of the patient’s kidney is assessed by monitoring heart rate variability in the frequency spectrum.

[0167] Example 14. The system according to example 9 or 10, wherein the sympathetic activity level of the patient’s kidney is assessed by monitoring heart rate.

[0168] Example 15. The system according to any preceding claim, further comprising: at least one lead comprising the one or more electrodes.

[0169] Example 16. The system according to example 15, wherein the one or more electrodes are located at or near a T9 - T10 of the patient.

[0170] Example 17. The system according to any preceding example, wherein the one or more electrodes target a pancreas function of the patient.

[0171] Example 18. The system according to any preceding example, further comprising: a monitoring device configured to continuously provide data that enables the at least one processor to monitor the value of the at least one parameter.

[0172] Example 19. The system according to example 18, wherein the data comprises the value of the at least one parameter.A0013966W001

[0173] Example 20. The system according to example 18 or 19, wherein the at least one processor processes the data to determine the value of the at least one parameter.

[0174] Example 21. The system according to any of example 18 through example 20, wherein at least one of the one or more electrodes corresponds to a sensing electrode and wherein the monitoring device receives the data from the sensing electrode.

[0175] Example 22. The system according to any of example 18 through example 21, wherein the monitoring device comprises a continuous glucose monitor.

[0176] Example 23. The system according to any of example 18 through example 22, wherein the monitoring device comprises a glucose sensor.

[0177] Example 24. The system according to any of example 18 through example 22, wherein the monitoring device comprises an accelerometer.

[0178] Example 25. The system according to any of example 18 through example 22, wherein the monitoring device comprises an impedance measure to assess lead dislodgement.

[0179] Example 26. The system according to any of example 18 through example 25, wherein the monitoring device comprises a Controller Area Network (CAN).

[0180] Example 27. An implantable device, comprising: a lead connectable to a signal generator and including a plurality of electrodes, wherein the plurality of electrodes generate a stimulation signal according to an input received from the signal generator and deliver the stimulation signal to one or more anatomical elements of a patient to treat at least one aspect of a diabetic condition based on a closed feedback loop.

[0181] Example 28. The implantable device according to example 27, wherein the electrode pair is positioned proximate T9 and / or T10 of the patient.

[0182] Example 29. The implantable device according to example 28, wherein the one or more feedback signals include a measure of glucose levels in the patient or a metric calculated from the blood glucose level of the patient.

[0183] Example 30. A method, comprising: monitoring a parameter associated with a diabetic condition of a patient; determining the parameter exceeds an upper limit threshold value; and generating an electrical signal for one or more electrodes to stimulate at least one dorsal root nerve of the patient to cause a response by the patient that at least includes minimizing glucose peaks.

[0184] Example 31. The method according to example 22, wherein the parameters are increased in case the time before a meal is 90 minutes or less.

[0185] Example 32. The method according to example 31, wherein the parameters are pulse width, frequency, ECAP based current or duty cycling.A0013966W001

[0186] Example 33. The method according to example 30, wherein termination criteria to stimulate are exercise as indicated by accelerometer, lead dislodgement or glucose being below a threshold.

Claims

1. A0013966W001CLAIMSWhat is claimed is:

1. A system for treating a microvascular disease, comprising:a device comprising:a signal generator configured to generate an electrical signal; andat least one processor configured to:monitor a value of at least one parameter of a patient that is associated with diabetes; andcontrol the signal generator using a closed feedback loop based on a threshold value and the value of the at least one parameter; andone or more electrodes coupled to the signal generator to stimulate at least one dorsal root nerve or dorsal root ganglion based on the electrical signal which causes a response by at least one anatomical element of the patient that changes the value of the at least one parameter of the patient.

2. The system according to claim 1, wherein the at least one processor is configured to control the signal generator to generate the electrical signal when the value of the at least one parameter exceeds the threshold value.

3. The system according to claim 2, wherein the signal generator is controlled to generate the electrical signal in a manner that keeps the value of the at least one parameter above a second threshold value that is less than the threshold value.

4. The system according to claim 2 or 3, wherein the at least one parameter comprises a blood glucose level of the patient or a metric calculated from the blood glucose level of the patient.

5. The system according to any preceding claim, wherein the at least one processor is further configured to:determine that the patient is eating or is about to eat.

6. The system according to claim 5, wherein an accelerometer is used to determine that the patient is eating.A0013966W0017. The system according to any preceding claim, wherein the at least one processor is further configured to:determine that a current time corresponds to nighttime; andcontrol the signal generator based on determining that the current time corresponds to the nighttime.

8. The system according to claim 7, wherein an accelerometer is used to determine that the patient is sleeping.

9. The system according to claim 7, wherein the one or more electrodes apply a lateral epidural stimulation to the at least one dorsal root nerve.

10. The system according to claim 7, wherein the one or more electrodes apply a dorsal root ganglion stimulation to the at least one dorsal root ganglion.

11. The system according to any preceding claim, further comprising:at least one lead comprising the one or more electrodes.

12. The system according to claim 11, wherein the one or more electrodes are located at or near a T9 - T10 of the patient.

13. The system according to any preceding claim, further comprising:a monitoring device configured to continuously provide data that enables the at least one processor to monitor the value of the at least one parameter.

14. An implantable device, comprising:a lead connectable to a signal generator and including a plurality of electrodes, wherein the plurality of electrodes generate a stimulation signal according to an input received from the signal generator and deliver the stimulation signal to one or more anatomical elements of a patient to treat at least one aspect of a diabetic condition based on a closed feedback loop.

15. A method, comprising:monitoring a parameter associated with a diabetic condition of a patient; determining the parameter exceeds an upper limit threshold value; andA0013966W001generating an electrical signal for one or more electrodes to stimulate at least one dorsal root nerve of the patient to cause a response by the patient that at least includes minimizing glucose peaks.

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