Methods for non-invasive spinal neuromodulation for treating diabetes and systems for same

Abstract

Aspects of the present disclosure include methods for treating a subject having a metabolic disorder by neuromodulation. Methods according to certain embodiments include applying electrical stimulation to the spinal cord of a subject (e.g., a subject diagnosed as having or determined to have diabetes or prediabetes) in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject. In some embodiments, neuromodulation is sufficient to treat one or more symptoms of diabetes or prediabetes such as fasting plasma glucose concentration, non-fasting plasma glucose concentration, elevated hbA1c, glucose tolerance and insulin secretion by the subject. Systems having one or more electrodes configured for applying electrical stimulation to the spinal cord of the subject suitable for practicing the subject methods are also described.

Description

Atty Dkt No.: SPNX-002WOMETHODS FOR NON-INVASIVE SPINAL NEUROMODULATION FOR TREATING DIABETES AND SYSTEMS FOR SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 722,906, filed November 20, 2024, the disclosure of which is incorporated herein by reference in its entirety.INTRODUCTION

[0002] Hyperglycemia is a condition characterized by elevated blood glucose concentration. An elevated blood glucose concentration may result from impaired insulin secretion from the pancreas or glucose may not be fully metabolized by the secreted insulin. Excessive glucose release from the kidneys and the liver can also contribute to hyperglycemia. Insulin provides for glucose uptake into a variety of tissues and decreases production of glucose by the liver and kidneys. Insulin resistance results in reduced peripheral glucose uptake and increased endogenous glucose output.

[0003] Diabetes mellitus that can be categorized as Type 1 which results from autoimmune destruction of pancreatic beta cells causing insufficient insulin production or as Type 2 which is a chronic metabolic disorder that develops due to a combination of insufficient insulin production as well as cellular resistance to the action of insulin.

[0004] Medication, diet, and exercise, seek to control blood glucose levels in subjects with metabolic disorders. Patients with type 1 diabetes mellitus and type 2 diabetes mellitus are often treated by injections of insulin. Effective treatment with insulin can be complicated by lack of efficacy, metabolic changes or poor compliance.SUMMARY

[0005] Aspects of the present disclosure include methods for treating a subject having a metabolic-disorders such as diabetes by neuromodulation. Methods according to certain embodiments include applying electrical stimulation waveforms to the spinal cord of a subjectAtty Dkt No.: SPNX-002WO(e.g., a subject diagnosed as having or determined to have diabetes or prediabetes) in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject. In some embodiments, neuromodulation is sufficient to treat one or more symptoms of diabetes or prediabetes such as fasting plasma glucose concentration, non-fasting plasma glucose concentration, elevated hbAlc, glucose tolerance and insulin secretion by the subject. Systems having one or more electrodes configured for applying electrical stimulation to the spinal cord of the subject suitable for practicing the subject methods are also described.

[0006] In embodiments, methods include applying electrical stimulation to a subject diagnosed as having diabetes, such as Type I diabetes, Type II diabetes mellitus, insulin resistance or prediabetes. In some embodiments, methods include modulating one or more of fasting plasma glucose concentration and non-fasting plasma glucose concentration in the subject. In some instances, methods include treating elevated hbAlc in the subject. In some instances, methods include modulating glucose tolerance. In some instances, methods include modulating insulin secretion by the subject. In some embodiments, the subject exhibits hyperglycemia after consumption of glucose.

[0007] In some embodiments methods include applying electrical stimulation to a subject diagnosed as having high cholesterol including high triglyceride levels, high LDL cholesterol, low HDL cholesterol and fatty buildups within the artery walls resulting in increased risk of heart attack and stroke.

[0008] In some embodiments, the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to reduce blood glucose concentration in the subject by 5% or more, such as by 10% or more. In some instances, the electrical stimulation is applied to the spinal cord of the subject in manner sufficient to reduce blood glucose concentration in the subject by 10 mg / dL or more, such as by 25 mg / dL or more. In some embodiments, the electrical stimulation is applied in a manner sufficient to immediately reduce blood glucose concentration in the subject. In some instances, the reduced blood glucose concentration in the subject is maintained for the duration of the electrical stimulation. In some instances, the electrical stimulation is applied to maintain a reduced blood glucose concentration in the subject for a predetermined duration after the applied electrical stimulation. In certainAtty Dkt No.: SPNX-002WO instances, the reduced blood glucose is maintained for 1 hour or more after the applied electrical stimulation, such as for 6 hours or more, 12 hours or more and including being maintained for 24 hours or more after the applied electrical stimulation. In some embodiments, the electrical stimulation is applied over a region of the spinal cord of the subject comprising T6-T10 or a region therein. In some instances, the electrical stimulation is applied to a first region between T6-T7 of the spinal cord of the subject and a second region between T9-T10 of the spinal cord of the subject. In certain instances, the electrical stimulation is applied to T6 of the spinal cord of the subject. In certain instances, the electrical stimulation is applied to T10 of the spinal cord of the subject. In some embodiments, methods include applying electrical stimulation to the spinal cord of the subject for 1 hour or more. In certain embodiments, methods include applying electrical stimulation to the spinal cord of the subject for 2 hours or more. In some instances, the electrical stimulation is applied to the spinal cord of the subject at predetermined time intervals, such as 1-2 hours after the consumption of food or fluids by the subject. In certain instances, the electrical stimulation is applied to the spinal cord of the subject immediately after the consumption of food or fluids by the subject. In certain instances, the electrical stimulation is applied to the spinal cord of the subject concurrently with the consumption of food or fluids by the subject.

[0009] In practicing methods according to embodiments, electrical stimulation is applied to the spinal cord of the subject, where in certain instances, the electrical stimulation is applied having a waveform selected from the group of: one or more a trapezoidal monophasic waveform and a trapezoidal biphasic waveform; one or more of a triangular monophasic waveform and triangular biphasic waveform; an asymmetrical biphasic waveform; a delayed biphasic waveform; a double monophasic waveform; and a monophasic waveform. In some instances, the one or more applied waveform further includes a DC (direct current) offset. In certain instances, the DC offset is an applied current that is sufficient to compensate for each applied electrical stimulation pulse. In some embodiments, methods include applying the electrical stimulation from two or more channels of a transcutaneous or epidural electrical spinal cord stimulator. In some instances, each channel of the transcutaneous or epidural electrical spinal cord stimulator independently applies a different waveform of electricalAtty Dkt No.: SPNX-002WO stimulation. In certain instances, the applied electrical stimulation includes a plurality of different waveforms from the same electrode, where in some embodiments each waveform is applied sequentially and in other embodiments waveforms are applied simultaneously.

[0010] In some embodiments, methods further include assessing blood glucose concentration of the subject after applying the electrical stimulation. In some instances, the blood glucose concentration of the subject is measured 1 hour or more after applying the electrical stimulation, such as 2 hours or more after applying the electrical stimulation. In certain instances, one or more parameters of the electrical stimulation is modified based on the assessed blood glucose concentration of the subject. In some instances, methods include changing the waveform of the applied electrical stimulation in response to the measured blood glucose concentration. In some instances, methods include changing the frequency of the applied waveform in response to the measured blood glucose concentration. In some instances, methods including changing the amplitude of the applied electrical stimulation in response to the measured blood glucose concentration.

[0011] Aspects of the disclosure also include systems for practicing the subject methods. Systems according to certain embodiments include an electrical stimulator that is configured to apply electrical stimulation to the spinal cord of a subject in a manner sufficient to treat at least one symptom of a metabolic disorder in the subject, such as Type 1 diabetes, Type 2 diabetes, prediabetes or insulin resistance. In some embodiments, the subject systems are configured to modulate one or more of fasting plasma glucose concentration and non-fasting plasma glucose concentration. In some instances, systems are configured to treat elevated hbAlc in a subject. In some instances, systems are configured to modulate glucose tolerance. In some instances, systems are configured to modulate insulin secretion by the subject.

[0012] In some embodiments, systems include a wearable electrical stimulator device. In some instances, the wearable device includes a single use battery. In other instances, the wearable device includes a rechargeable battery. In certain instances, the wearable device is disposable.

[0013] In some embodiments, the electrical stimulator is configured to apply electrical stimulation to the spinal cord of the subject having a waveform selected from the group of: oneAtty Dkt No.: SPNX-002WO or more a trapezoidal monophasic waveform and a trapezoidal biphasic waveform; one or more of a triangular monophasic waveform and triangular biphasic waveform; an asymmetrical biphasic waveform; a double monophasic waveform; and a monophasic waveform. In some instances, the electrical stimulator is configured to apply one or more of the waveforms with a DC offset. In certain instances, the DC offset is an applied voltage that is sufficient to compensate for each applied electrical stimulation pulse. In some embodiments, systems include a transcutaneous or epidural electrical spinal cord stimulator that is configured to apply electrical stimulation from two or more channels. In some instances, each channel of the transcutaneous or epidural electrical spinal cord stimulator independently applies a different waveform of electrical stimulation. In certain instances, the transcutaneous or epidural electrical spinal cord stimulator applies a plurality of different waveforms from the same electrode, where in some embodiments each waveform is applied sequentially and in other embodiments waveforms are applied simultaneously.BRIEF DESCRIPTION OF THE FIGURE

[0014] FIG. 1 depicts the placement of electrodes on the skin surface of the subject with reference to the position on the spinal cord according to certain embodiments.

[0015] FIG. 2 depicts the blood glucose concentration of a subject with electrical stimulation and without electrical stimulation according to certain embodiments.

[0016] Fig. 3 depicts blood glucose levels in a pre-diabetic and non-diabetic individuals without and with stimulation (SCONE) after consuming a meal at the start.

[0017] Fig. 4 depicts the neuronal mapping of the spinal nerves to the pancreas and a mechanism of action resulting in increased insulin secretion and reduced blood glucose levels.DETAILED DESCRIPTION

[0018] Aspects of the present disclosure include methods for treating a subject having a metabolic disorder by neuromodulation. Methods according to certain embodiments include applying electrical stimulation to the spinal cord of a subject (e.g., a subject diagnosed as having or determined to have diabetes or prediabetes) in a manner sufficient to treat at least oneAtty Dkt No.: SPNX-002WO symptom of the metabolic disorder in the subject. In some embodiments, neuromodulation is sufficient to treat one or more symptoms of diabetes or prediabetes such as fasting plasma glucose concentration, non-fasting plasma glucose concentration, elevated hbAlc, glucose tolerance and insulin secretion by the subject. Systems having one or more electrodes configured for applying electrical stimulation to the spinal cord of the subject suitable for practicing the subject methods are also described.

[0019] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0020] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0021] Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to thoseAtty Dkt No.: SPNX-002WO described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

[0023] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0024] It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0025] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0026] While the apparatus and method has or will be described for the sake of grammatical fluidity with functional explanations, it is to be expressly understood that the claims, unless expressly formulated under 35 U.S.C. §112, are not to be construed as necessarily limited in any way by the construction of "means" or "steps" limitations, but are to be accorded the full scope of the meaning and equivalents of the definition provided by the claims under the judicial doctrine of equivalents, and in the case where the claims are expressly formulated under 35 U.S.C. §112 are to be accorded full statutory equivalents under 35 U.S.C. §112.Atty Dkt No.: SPNX-002WO

[0027] As summarized above, the present disclosure provides methods for treating a subject having a metabolic disorder by neuromodulation. In further describing embodiments of the disclosure, methods for applying electrical stimulation in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject are first described in greater detail. Next, systems including an electrical stimulator (e.g., a transcutaneous or epidural electrical spinal cord stimulator) are described. Wearable devices and systems integrating the subject electrical stimulators are also provided.METHODS FOR TREATING A METABOLIC DISORDER BY NEUROMODULATION

[0028] Aspects of the present disclosure include treating a metabolic disorder by neuromodulation in a subject. Methods according to certain embodiments include applying electrical stimulation to the spinal cord of a subject (e.g., a subject diagnosed as having or determined to have diabetes or prediabetes) in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject. The term metabolic disorder is used herein in its conventional sense to refer to conditions that negatively alters a subject's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the normal metabolic process. In certain embodiments, the metabolic disorder is a disorder of the pancreas. In certain embodiments, the metabolic disorder is a disorder of the liver. In some instances, the metabolic disorder includes one or more a glucose tolerance disorder, insulin resistance, diabetes or prediabetes. As described herein, electrical stimulation is applied to the spinal cord of a subject in need thereof. In some instances, the subjects are humans. The methods may be applied to human subjects of both genders and at any stage of development (e.g., neonate, infant, juvenile, adolescent, adult, geriatric, etc.), where in certain embodiments the human subject is a juvenile, adolescent or adult.

[0029] In some cases, the subject is a subject that exhibits at least one symptom of having Type 1 diabetes. In some cases, the subject is diagnosed as having Type 1 diabetes. In some cases, the subject is a subject that exhibits at least one symptom of having Type 2 diabetes. In some cases, the subject is diagnosed as having Type 2 diabetes. In some cases, the subject is aAtty Dkt No.: SPNX-002WO subject that exhibits at least one symptom of having gestational diabetes. In some cases, the subject is diagnosed as having gestational diabetes. In some cases, the subject is a subject that exhibits at least one symptom of having prediabetes. In some cases, the subject is diagnosed as having prediabetes. In certain cases, methods include diagnosing the subject as having insulin resistance, Type 1 diabetes, Type 2 diabetes, gestational diabetes or prediabetes. In some cases, the subject is a subject that exhibits at least one symptom of having a glucose tolerance disorder. In some cases, the subject is a subject that is diagnosed as having a glucose tolerance disorder. The subject may be diagnosed by any convenient clinical protocol, such as by blood sugar analysis, analysis of glycated hemoglobin (A1C) or some other laboratory analysis.

[0030] In some cases, neuromodulation by electrical stimulation as described herein is applied in conjunction with other treatment modalities such as various pain relief medications, anti-arthritis agents, chemotherapeutic agents, antibiotic agents, anti-neurodegeneration agents, anti-addiction agents, other diabetes agents, and the like, depending on the malady that is afflicting the subject. In some cases, methods for electrical stimulation described herein are applied while the subject is taking at least one of insulin, inhaled insulin, insulin analogs, insulin aspart, insulin degludec, insulin glargine, insulin isophane, insulin lispro, metformin, a glitazone, GLP-1, GLP-1 analogs, exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, GLP-l / glucagon agonists, GLP-l / GCGR agonists, FGF-21 / GLP-1 dual agonists, GIP / GLP-1 dual agonists, GLP-l / GIP / glucagon triple agonists, SGLT-2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sulfonylureas, glyburide, glipizide, glimepiride, pramlinitide, glinides, repaglinide, nateglinide, thiazolidinediones, rosiglitazone, glibenclamide, pioglitazone, glucagon, DDP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, vildagliptin, acarbose, a Ibigl utide, alogliptin, bromocriptine mesylate, miglitol, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, or further comprising administering to the subject at least one of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In some cases, methods and compositions described herein are administered while the subject is taking a lipid lowering drug, such as at least one of a statin, fenofibrate, omega-3 fatty acid, icosapent ethyl, and fish oil, or further comprising administering a lipid lowering drug, such as at least one of a statin, fenofibrate, omega-3 fatty acid, icosapent ethyl,Atty Dkt No.: SPNX-002WO and fish oil. In some cases, methods for electrical stimulation described herein are applied while the subject is receiving statin therapy. In some cases, the phrase "is taking" or "is receiving" refers to the administration of these supplemental treatment modalities to the subject while the subject is undergoing.

[0031] In embodiments, electrical stimulation is administered to the central nervous system, e.g., to the spinal cord of a subject. In some embodiments, the electrical stimulation is applied in a manner sufficient to increase activity by one or more internal organs of the subject. In some embodiments, the electrical stimulation is applied in a manner sufficient to increase activity of the pancreas by the subject.

[0032] In some embodiments, the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to reduce blood glucose concentration in the subject, such as where the blood glucose concentration measured is reduced by 0.1% or more, such as by 0.5% or more, such as by 1% or more, such as by 2% or more, such as by 3% or more, such as by 4% or more, such as by 5% or more, such as by 6% or more, such as by 7% or more, such as by 8% or more, such as by 9% or more, such as by 10% or more, such as by 11% or more, such as by 12% or more, such as by 13% or more, such as by 14% or more, such as by 15% or more, such as by 16% or more, such as by 17% or more, such as by 18% or more, such as by 19% or more and including by 20% or more. For example, the electrical stimulation applied to the spinal cord of the subject may be sufficient to reduce blood sugar concentration in the subject by 0.5 mg / dL or more, such as by 1 mg / dL or more, such as by 2 mg / dL or more, such as by 3 mg / dL or more, such as by 4 mg / dL or more, such as by 5 mg / dL or more, such as by 6 mg / dL or more, such as by 7 mg / dL or more, such as by 8 mg / dL or more, such as by 9 mg / dL or more, such as by 10 mg / dL or more, such as by 11 mg / dL or more, such as by 12 mg / dL or more, such as by 13 mg / dL or more, such as by 14 mg / dL or more, such as by 15 mg / dL or more, such as by 16 mg / dL or more, such as by 17 mg / dL or more, such as by 18 mg / dL or more, such as by 19 mg / dL or more, such as by 20 mg / dL or more, such as by 21 mg / dL or more, such as by 22 mg / dL or more, such as by 23 mg / dL or more, such as by 24 mg / dL or more, such as by 25 mg / dL or more, such as by 26 mg / dL or more, such as by 27 mg / dL or more, such as by 28Atty Dkt No.: SPNX-002WO mg / dL or more, such as by 29 mg / dL or more and including by reducing blood glucose concentration by 30 mg / dL or more.

[0033] In some embodiments, methods include modulating one or more of fasting plasma glucose concentration and non-fasting plasma glucose concentration in the subject. In some instances, the subject methods reduce the fasting plasma glucose concentration, such as by 0.5 mg / dL or more, such as by 1 mg / dL or more, such as by 2 mg / dL or more, such as by 3 mg / dL or more, such as by 4 mg / dL or more, such as by 5 mg / dL or more, such as by 6 mg / dL or more, such as by 7 mg / dL or more, such as by 8 mg / dL or more, such as by 9 mg / dL or more, such as by 10 mg / dL or more, such as by 11 mg / dL or more, such as by 12 mg / dL or more, such as by 13 mg / dL or more, such as by 14 mg / dL or more, such as by 15 mg / dL or more, such as by 16 mg / dL or more, such as by 17 mg / dL or more, such as by 18 mg / dL or more, such as by 19 mg / dL or more, such as by 20 mg / dL or more, such as by 21 mg / dL or more, such as by 22 mg / dL or more, such as by 23 mg / dL or more, such as by 24 mg / dL or more, such as by 25 mg / dL or more, such as by 26 mg / dL or more, such as by 27 mg / dL or more, such as by 28 mg / dL or more, such as by 29 mg / dL or more and including by reducing plasma glucose concentration by 30 mg / dL or more. In certain embodiments, the subject methods are sufficient to reduce the fasting plasma glucose concentration in the subject to a normal range for fasting plasma glucose concentration, such as to a level from 70 mg / dL and 100 mg / dL.

[0034] In certain instances, the subject methods reduce the non-fasting plasma glucose concentration (e.g., after a meal or consuming a sugar containing fluid), such as by 0.5 mg / dL or more, such as by 1 mg / dL or more, such as by 2 mg / dL or more, such as by 3 mg / dL or more, such as by 4 mg / dL or more, such as by 5 mg / dL or more, such as by 6 mg / dL or more, such as by 7 mg / dL or more, such as by 8 mg / dL or more, such as by 9 mg / dL or more, such as by 10 mg / dL or more, such as by 11 mg / dL or more, such as by 12 mg / dL or more, such as by 13 mg / dL or more, such as by 14 mg / dL or more, such as by 15 mg / dL or more, such as by 16 mg / dL or more, such as by 17 mg / dL or more, such as by 18 mg / dL or more, such as by 19 mg / dL or more, such as by 20 mg / dL or more, such as by 21 mg / dL or more, such as by 22 mg / dL or more, such as by 23 mg / dL or more, such as by 24 mg / dL or more, such as by 25 mg / dL or more, such as by 26 mg / dL or more, such as by 27 mg / dL or more, such as by 28Atty Dkt No.: SPNX-002WO mg / dL or more, such as by 29 mg / dL or more and including by reducing plasma glucose concentration by 30 mg / dL or more. In certain embodiments, the subject methods are sufficient to reduce the non-fasting plasma glucose concentration in the subject to a normal range for non-fasting plasma glucose concentration, such as to a level from 140 mg / dL and 180 mg / dL.

[0035] In some embodiments, methods include treating elevated hemoglobin Ale (hbAlc) levels in the subject. In some instances, the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to reduce the hemoglobin Ale (hbAlc) in the subject by 0.1% or more, such as by 0.5% or more, such as by 1% or more, such as by 2% or more, such as by 3% or more, such as by 4% or more, such as by 5% or more and including by 6% or more. In certain embodiments, the subject methods are sufficient to reduce the hemoglobin Ale (hbAlc) levels in the subject to a normal range for hemoglobin Ale, such as to a level from 4% to 5.6%.

[0036] In some instances, methods include modulating glucose tolerance. In some instances, the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to reduce the glucose levels in the body by lOmg / dL or more such as by 20mg / dL or more, such as by 40mg / dL or more upon consumption of solid food or fluids consisting of glucose.

[0037] In some instances, methods include modulating insulin secretion by the subject. In some instances, the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to increase secretion of insulin resulting in decrease of glucose levels in the body by lOmg / dL or more such as by 20mg / dL or more, such as by 40mg / dL or more upon consumption of solid food or fluids consisting of glucose.

[0038] In some embodiments, the electrical stimulation is applied in a manner sufficient to immediately reduce blood glucose concentration in the subject. In some instances, the electrical stimulation applied to the subject reduces the blood glucose concentration in the subject after a predetermined duration, such as from 0.1 hours to 12 hours after the electrical stimulation is applied to the subject, such as from 0.5 hours to 11.5 hours after the electrical stimulation is applied to the subject, such as from 1 hour to 11 hours after the electricalAtty Dkt No.: SPNX-002WO stimulation is applied to the subject, such as from 1.5 hours to 10.5 hours after the electrical stimulation is applied to the subject, such as from 2 hours to 10 hours after the electrical stimulation is applied to the subject, such as from 2.5 hours to 9.5 hours after the electrical stimulation is applied to the subject, and including from 3 hours to 9 hours after the electrical stimulation is applied to the subject.

[0039] In some instances, the reduced blood glucose concentration in the subject is maintained for the duration of the electrical stimulation. In some instances, the electrical stimulation applied to the subject is sufficient to maintain a reduced blood glucose concentration in the subject for a predetermined duration after the applied electrical stimulation, such as where the reduced blood glucose concentration is maintained for 1 hour or more after the applied electrical stimulation, such as for 6 hours or more, 12 hours or more and including being maintained for 24 hours or more after the applied electrical stimulation. In certain instances, the applied electrical stimulation is sufficient to chronically reduce blood glucose concentration, such as where the reduced blood glucose concentration is maintained for 2 days or more, such as for 3 days or more, such as for 4 days or more, such as for 5 days or more, such as for 6 days or more, such as for 7 days or more, such as for 2 weeks or more, such as for 3 weeks or more, such as for 4 weeks or more, such as for 2 months or more and including where electrical stimulation is sufficient to reduce blood glucose concentration that is maintained for 3 months or more.

[0040] In certain embodiments, at least one channel of the transcutaneous and / or epidural stimulation is applied over the thoracic spinal cord or a region thereof. In certain embodiments at least one channel of the transcutaneous and / or epidural stimulation is applied over or more regions straddling or spanning a region selected from the group consisting of Tl-Tl, T1-T2, TITS, T1-T4, T1-T5, T1-T6, T1-T7, T1-T8, T1-T9, T1-T10, Tl-Tll, T1-T12, T2-T2, T2-T3, T2-T4, T2-T5, T2-T6, T2-T7, T2-T8, T2-T9, T2-T10, T2-T11, T2-T12, T3-T3, T3-T4, T3-T5, T3-T6, T3-T7, T3-T8, T3- T9, T3-T10, T3-T11, T3-T12, T4-T4, T4-T5, T4-T6, T4-T7, T4-T8, T4-T9, T4-T10, T4-T11, T4-T12, T5-T5, T5-T6, T5-T7, T5-T8, T5-T9, T5-T10, T5-T11, T5-T12, T6-T6, T6-T7, T6-T8, T6-T9, T6-T10, T6-T11, T6-T12, T7-T7, T7-T8, T7-T9, T7-T10, T7-T11, T7-T12, T8-T8, T8-T9, T8-T10, T8-T11, T8- T12, T9-T9, T9-T10, T9-T11, T9-T12, T10-T10, T10-T11, T10-T12, Tll-Tll, T11-T12, and T12-T12.Atty Dkt No.: SPNX-002WOIn some embodiments, the electrical stimulation is applied over a region of the spinal cord of the subject comprising T6-T10 or a region therein. In some instances, the electrical stimulation is applied to a first region between T6-T7 of the spinal cord of the subject and a second region between T9-T10 of the spinal cord of the subject. In certain instances, the electrical stimulation is applied to T6 of the spinal cord of the subject. In certain instances, the electrical stimulation is applied to T10 of the spinal cord of the subject.

[0041] In certain embodiments, at least one channel of the electrical stimulation is applied over or more regions straddling or spanning a region selected from the group consisting of the brainstem, C0-C1, C0-C2, C0-C3, C0-C4, C0-C5, C0-C6, C0-C7, C0-T1, Cl-Cl, C1-C2, C1-C3, C1-C4, C1-C7, C1-C6, C1-C7, Cl-Tl, C2-C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-T1, C3-C3, C3-C4, C3- C5, C3-C6, C3-C7, C3-T1, C4-C4, C4-C5, C4-C6, C4-C7, C4-T1, C5-C5, C5-C6, C5-C7, C5-T1, C6-C6, C6-C7, C6-T1, C7-C7, and C7-T1. In certain embodiments at least one channel of the electrical stimulation is applied over a region comprising or consisting of C2-C3 or a region therein. In certain embodiments at least one channel of the electrical stimulation is applied at or about C3.

[0042] In certain embodiments, at least one channel of the electrical stimulation is applied over the lumbar spinal cord or a region thereof. In certain embodiments at least one channel of the electrical stimulation stimulation is applied over or more regions straddling or spanning a region selected from the group consisting of Ll-Ll, L1-L2 , L1-L3, L1-L4, L1-L5, Ll-Sl, L1-S2, LISS, L1-S4, L1-S5, L2-L2 , L2-L3, L2-L4, L2-L5, L2-S1, L2-S2, L2-S3, L2-S4, L2-S5, L3-L3, L3-L4, L3-L5, L3-S1, L3-S2, L3-S3, L3-S4, L3-S5, L4-L4, L4-L5, L4-S1, L4-S2, L4-S3, L4-S4, L4-S5, L5-L5 , L5-S1, L5- S2, L5-S3, L5-S4, L5-S5, Sl-Sl, S1-S2, S1-S3, S1-S4, S1-S5, S2-S2, S2-S3, S2-S4, S2-S5, S3-S3, S3- S4, S3-S5, S4-S4, S4-S5, and S5-S6. In certain embodiments at least one channel of the the electrical stimulation is applied over the coccyx.

[0043] In embodiments, the electrical stimulation is applied to the spinal cord of the subject for 0.1 hours or more, such as for 0.5 hours or more, such as for 1 hour or more, such as for 2 hours or more, such as for 3 hours or more, such as for 4 hours or more, such as for 5 hours or more, such as for 6 hours or more, such as for 7 hours or more, such as for 8 hours or more, such as for 9 hours or more, such as for 10 hours or more, such as for 11 hours or more and including applying the electrical stimulation to the spinal cord of the subject for 12 hours orAtty Dkt No.: SPNX-002WO more. In some instances, the electrical stimulation is applied to the spinal cord of the subject at predetermined time intervals, such as 0.1 hours or more after the consumption of food or fluids by the subject, such as 0.5 hours or more, such as 1 hour or more, such as 2 hours or more and including 3 hours or more after the consumption of food or fluids by the subject. In certain instances, the electrical stimulation is applied to the spinal cord of the subject immediately after the consumption of food or fluids by the subject. In certain instances, the electrical stimulation is applied to the spinal cord of the subject concurrently with the consumption of food or fluids by the subject.

[0044] In practicing the subject methods, electrodes are contacted with the subject. In some instances, the electrodes are contacted with the skin surface of the subject, such as over a region of the spinal cord of the subject comprising T6-T10 or a region therein, e.g., at or about T6 and T10. In certain embodiments, the subject methods include applying electrical stimulation to a subject, where the method involves providing an electrical stimulator as described herein where the stimulator stores (transiently or non-transiently) one or more stimulation programs and one or more channels of the stimulator are electrically coupled to one or more transcutaneous stimulation electrodes contact with the subject (e.g., the skin surface of the subject's body) and operating the stimulator according to one or more programs to provide transcutaneous electrical stimulation to the subject. In certain embodiments the subject include applying epidural electrical stimulation to a subject, where the method involves providing an electrical stimulator where the stimulator stores (transiently or non-transiently) one or more stimulation programs and one or more channels of the stimulator are electrically coupled to one or more epidural stimulation electrodes contacted with the subject; and operating the stimulator according to one or more programs to provide epidural electrical stimulation to said subject. In certain embodiments the stimulator is configured to provide transcutaneous stimulation at one location, or at two or more locations, or at three or more locations, or at four or more locations on the subject and / or the stimulator is configured to provide epidural stimulation at one location, or at two or more locations, or at three or more locations, or at four or more locations on the subject. In certain embodiments all of the active channels of the stimulator provide transcutaneous electrical stimulation. In certainAtty Dkt No.: SPNX-002WO embodiments all of the active channels of the stimulator provide epidural stimulation. In certain embodiments one or more stimulator channels are configured to provide transcutaneous electrical stimulation, while other channels are configured to provide epidural electrical stimulation.

[0045] In certain embodiments, the transcutaneous and / or epidural stimulation is provided by one or more of the following stimulation patterns on one or more independently controlled channels: i) one or more of a trapezoidal monophasic waveform and a trapezoidal biphasic waveform. In some instances, the ramp rate for the trapezoidal waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; ii) one or more of a triangular monophasic waveform and triangular biphasic waveform. In some instances, the ramp rate for the triangular waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; iii) an asymmetrical biphasic waveform. In some instances, the ramp rate for the asymmetrical biphasic waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; iv) a double monophasic waveform. In some instances, the ramp rate for the double monophasic waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; and a v) a monophasic waveform. In some instances, the ramp rate for the monophasic waveform varies from 0.001 ms to 0.1 ms. In some instances, the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms. In certain embodiments the stimulator provides the same stimulation modality and stimulation parameters on 2 or more different channels or on 3 or more different channels, or on 4 or more different channels. In certain embodiments the stimulator provides a different stimulation modality and / or different stimulation parameters on 2 or more different channels or on 3 or more different channels, or on 4 or more different channels. In certain embodiments, pulsing is integrated into the same electrode and pulsed simultaneously. In some instances, positive and negative waveforms are pulsed simultaneously through the same electrode and stitched together to generate a unique user defined waveform.Atty Dkt No.: SPNX-002WO

[0046] In some embodiments, the transcutaneous and / or epidural stimulation is provided with one or more of the aforementioned waveform patterns in a manner sufficient to achieve a predetermined threshold intensity. In some instances, the predetermined threshold intensity is a preset pulse amplitude, such as a pulse amplitude of from 1 mA to 500 mA, such as from 10 mA to 490 mA, such as from 20 mA to 480 mA, such as from 30 mA to 470 mA, such as from 40 mA to 460 mA, such as from 50 mA to 450 mA, such as from 60 mA to 440 mA, such as from 70 mA to 430 mA, such as from 80 mA to 420 mA, such as from 90 mA to 410 mA and including from 100 mA to 400 mA. In certain instances, predetermined threshold intensity is a pulse amplitude of about 100 mA. In some instances, the predetermined threshold intensity is an intensity that is determined based on a particular goal such as where some functional goal is achieved (e.g., reduced plasma glucose concentration, increase in activity of the pancreas, increase in the activity of the liver).

[0047] In some instances, the transcutaneous and / or epidural stimulation is provided at a rate where the maximum intensity of each waveform is applied for a duration of from 0.001 ms to 0.1 ms, such as from 0.002 ms to 0.09 ms, such as from 0.003 ms to 0.08 ms, such as from 0.004 ms to 0.07 ms, such as from 0.005 ms to 0.06 ms, such as from 0.007 ms to 0.05 ms, such as from 0.008 ms to 0.04 ms, such as from 0.009 ms to 0.05 ms and including from 0.01 ms to 0.04 ms.

[0048] In some embodiments, the one or more applied waveforms further includes a DC offset. In some instances, the DC offset is continuously applied in simultaneously with the applied waveforms of transcutaneous and / or epidural stimulation. In other instances, the DC offset is applied at a predetermined time after the applied waveforms of transcutaneous and / or epidural stimulation, such as 0.001 milliseconds or more after the waveforms of transcutaneous and / or epidural stimulation are applied, such as 0.005 milliseconds or more, such as 0.01 milliseconds or more, such as 0.05 milliseconds or more, such as 0.1 milliseconds or more, such as 0.5 milliseconds or more, such as 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more and including 10 milliseconds or more after theAtty Dkt No.: SPNX-002WO waveforms of transcutaneous and / or epidural stimulation are applied. In certain instances, the DC offset is applied in predetermined intervals where the DC offset is on for a predetermined period of time followed by a period of time where the DC is off. In some instances, intervals of applying the DC offset include where the DC offset is on for a duration of 0.001 milliseconds or more, such as 0.005 milliseconds or more, such as 0.01 milliseconds or more, such as 0.05 milliseconds or more, such as 0.1 milliseconds or more, such as 0.5 milliseconds or more, such as 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more and including 10 milliseconds or more. In some instances, intervals of applying the DC offset include where the DC offset is off for 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more, such as 10 milliseconds or more, such as 15 milliseconds or more, such as 20 milliseconds or more, such as 25 milliseconds or more, such as 30 milliseconds or more, such as 35 milliseconds or more, such as 40 milliseconds or more, such as 45 milliseconds or more, such as 50 milliseconds or more and including intervals where the DC offset is off for 100 milliseconds or more.

[0049] In certain embodiments, the DC offset is constantly on and a second electrode is used to remove charge from the applied electrical stimulation. In some instances, the applied DC offset has a pulse amplitude that is proportional to the amplitude of the waveform of electrical stimulation. In some instances, the pulse amplitude of the DC offset is proportional in an amount sufficient to compensate for the amplitude of the waveform of the electrical stimulation.

[0050] In some embodiments, the electrical stimulation is applied to the spinal cord of the subject at a pulse frequency of 5 Hz or more, such as at a pulse frequency of 25 Hz or more and including about a pulse frequency of about 30 Hz. In some embodiments, the electrical stimulation is applied to the spinal cord of the subject with a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. In someAtty Dkt No.: SPNX-002WO embodiments, the electrical stimulation has a positive phase having a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. In some instances, the electrical stimulation has a negative phase having a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. As described above, in some instances, the electrical stimulation has an asymmetrical biphasic waveform where the positive phase has a different amplitude from the negative phase. In certain instances, where the positive phase and the negative phase have different amplitudes, the positive phase may have an amplitude that is greater than the negative phase by 1 mA or more, such as by 2 mA or more, such as by 3 mA or more, such as by 4 mA or more, such as by 5 mA or more, such as by 10 mA or more, such as by 25 mA or more, such as by 50 mA or more and including by 100 mA or more. In other instances, where the positive phase and the negative phase have different amplitudes, the negative phase may have an amplitude that is greater than the positivce phase by 1 mA or more, such as by 2 mA or more, such as by 3 mA or more, such as by 4 mA or more, such as by 5 mA or more, such as by 10 mA or more, such as by 25 mA or more, such as by 50 mA or more and including by 100 mA or more. When a DC offset is applied, the DC offset amplitude may be from 0.1 mA to 10 mA, such as from 0.5 mA to 2.5 mA, including a DC offset amplitude of about 1.5 mA. The applied DC offset may be a pulsed DC offset or a continuously applied DC offset.

[0051] In some embodiments, each waveform has a high frequency component and a low frequency component. In some instances, the high frequency component has a frequency of from 1 KHz to 100 KHz, such as fro 2 KHz to 75 KHz, such as from 3 KHz to 50 KHz, such as from 4 KHz to 25 KHz, such as from 5 KHz to 15 KHz, including a high frequency component of about 10 KHz. For example, the high frequency component may have a frequency that ranges from 1 KHz to 25 KHz. In some instances, the high frequency component is the same during each interval of applied electrical stimulation. In other instances, the high frequency component is varied during each interval of applied electrical stimulation. In some instances, the low frequency component has a frequency of from 1 Hz to 500 Hz, such as from 2 Hz to 450 Hz, such as from 3 Hz to 400 Hz, such as from 4 Hz to 350 Hz, such as from 5 Hz to 300 Hz, such as from 10 Hz to 250 Hz, such as from 25 Hz to 200 Hz and including from 50 Hz to 150 Hz. ForAtty Dkt No.: SPNX-002WO example, the low frequency component may be about 100 Hz. In some embodiments, each applied waveform has a high frequency component and a low frequency component where the high frequency component provides an analgesic effect and the low frequency component provides for the neuromodulation of the nervous system as described herein. In certain instances, the high frequency component is sufficient to provide an analgesic effect to the skin of the subject and the low frequency component is sufficient to tune spinal cord neurons to achieve the desired functional goals (i.e., the functional goals of neuromodulation).

[0052] In certain embodiments one or more channels of the electrical stimulator provide amplitude modulated dynamic stimulation. In certain embodiments one or more channels of the electrical stimulator provides frequency modulated dynamic stimulation. In certain embodiments the frequency modulated dynamic stimulation ranges in frequency from about 1Hz to about 1000Hz. In certain embodiments the dynamic stimulation is sourced from a biosignal (e.g., a signal derived from an EMG, and EEG, or an EKG). In certain embodiments the biosignal is recorded from a mammal (e.g., from a human or from a non-human primate).

[0053] In embodiments, the electrical stimulation may be applied to the spinal cord of the subject in intervals of 0.001 hours or more, such as 0.005 hours or more, such as 0.01 hours or more, such as 0.05 hours or more, such as 0.1 hours or more, such as 0.5 hours or more, such as 1 hour or more, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 12 hours or more and including intervals of 16 hours or more. In some instances, each interval of applied electrical stimulation is a duration that ranges from 0.1 hours to 12 hours, such as from 0.5 hours to 11.5 hours, such as from 1 hour to 11 hours, such as from 2 hours to 10 hours, such as from 3 hours to 9 hours and including from 4 hours to 8 hours.

[0054] In some embodiments, the electrical stimulation is applied to the spinal cord of the subject once per day or more, such as twice per day or more, such as 3 times per day or more, such as 4 times per day or more, such as 5 times per day or more, such as 6 times per day or more and including 7 times per day or more. In these embodiments, the total duration that the electrical stimulation is applied may be 1 hour or more, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more, suchAtty Dkt No.: SPNX-002WO as 7 hours or more, such as 8 hours or more, including a total duration of 12 hours or more. In some instances, the electrical stimulation is applied on 1 day per week or more, such as on 2 days per week or more, such as on 3 days per week or more, such as on 4 days per week or more, such as on 5 days per week or more, such as on 6 days per week or more and including on every day of the week. In some instance, the electrical stimulation is applied to the subject once or twice per day in a cycle for a duration of 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days or 2 days or 1 day. In some instance, the electrical stimulation is applied to the subject once or twice per week in a cycle for a duration of one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0055] Each cycle of applied electrical stimulation may include application of one or more of the above described waveforms of electrical stimulation. In some instances, each cycle of applied electrical stimulation may include two or more different waveforms. In some instance, the electrical stimulation is applied to the subject in cycles that are repeated for 2, 3, 4, 5, 6, 7, 8 or more cycles, for a total period of 1 month or longer, 2 months or longer, 3 months or longer, 4 months or longer, 5 months or longer, 6 months or longer, 1 year, 2 years, 3 years or 4 years or more.

[0056] In some embodiments, methods further include assessing one or more biological parameters of the subject, such as to determine whether there is a decrease in the severity / intensity of the symptom of the metabolic disorder. In some instances, methods include assessing the blood glucose concentration of the subject after applying the electrical stimulation. In some instances, the blood glucose concentration of the subject is measured 0.1 hours or more after applying the electrical stimulation, such as 0.2 hours or more, such as 0.3 hours or more, such as 0.4 hours or more, such as 0.5 hours or more, such as 1 hour or more, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more, such as 7 hours or more, such as 8 hours or more, such as 9 hours or more, such as 10 hours or more, such as 11 hours or more, such as 12 hours or more, such as 18 hours or more and including assessing the blood glucose concentration of theAtty Dkt No.: SPNX-002WO subject 24 hours or more after applying the electrical stimulation. In certain instances, one or more parameters of the electrical stimulation is modified based on the assessed blood glucose concentration of the subject. In some instances, methods include changing the waveform of the applied electrical stimulation in response to the measured blood glucose concentration. In some instances, methods include changing the frequency of the applied waveform in response to the measured blood glucose concentration. In some instances, methods including changing the amplitude of the applied electrical stimulation in response to the measured blood glucose concentration.SYSTEMS FOR TREATING A METABOLIC DISORDER BY NEUROMODULATIO

[0057] Aspects of the present disclosure include systems for practicing the subject methods described above for neuromodulation of a subject to treat a metabolic disorder (e.g., Type 1 diabetes, Type 2 diabetes, prediabetes or insulin resistance) in a manner sufficient to treat at least one symptom of the metabolic disorder. Systems according to certain embodiments include an electrical stimulator that is configured to apply electrical stimulation to the spinal cord of a subject in a manner sufficient to treat at least one symptom of the metabolic disorder. In some embodiments, systems include a wearable electrical stimulator device. In some instances, the wearable device includes a single use battery. In other instances, the wearable device includes a rechargeable battery. In certain instances, the wearable device is disposable. In some embodiments, the wearable device is configured to route wires under the clothing of the subject. In some instances, the electrical stimulator is integrated into clothing or furniture (e.g., chair or bed) or some other device which positions the electrical stimulator at a location along the spinal cord of the subject.

[0058] In certain embodiments, the electrical stimulator includes a set of spring-loaded electrodes that are configured to ensure hydrogel contact between the electrodes with the skin of the subject. For example, the electrical stimulator may be integrated into a belt or harness with worn springs.

[0059] In some embodiments, the electrical stimulator component of the subject systems include one or more channels where each channel provides a transcutaneous electricalAtty Dkt No.: SPNX-002WO stimulation signal or an epidural stimulation signal. In certain embodiments the electrical stimulator provides one or more independently controlled stimulation channel, such as 2 or more independently controllable (programmable) stimulation channels, such as 3 or more independently controllable (programmable) stimulation channels, such as 4 or more independently controllable (programmable) stimulation channels, such as 6 or more independently controllable (programmable) stimulation channels, such as 8 or more independently controllable (programmable) stimulation channels, such as 12 or more independently controllable (programmable) stimulation channels, such as 16 or more independently controllable (programmable) stimulation channels, such as 20 or more independently controllable (programmable) stimulation channels, such as 24 or more independently controllable (programmable) stimulation channels. In certain embodiments where there is more than one channel, multiple channels may provide stimulation signals with respect to a common (e.g., neutral or ground) lead. In certain embodiments where there is more than one channel, two or more different channels may provide stimulation signals with respect to a different leads. In certain embodiments, pulsing is integrated into the same electrode and pulsed simultaneously. In some instances, positive and negative waveforms are pulsed simultaneously through the same electrode and stitched together to generate a unique user defined waveform.

[0060] Where the electrical stimulator includes more than one channel, one or more of the channels may be configured to provide a transcutaneous electrical stimulation. In other instances, where the electrical stimulator includes more than one channel, one or more of the channels may be configured to provide an epidural stimulation signal. In yet other instances, where the electrical stimulator includes more than one channel, or one or more channels may be configured to provide a transcutaneous electrical stimulation signal, while one or more other channels are configured to provide an epidural stimulation signal.

[0061] As described above, in some instances, the electrical stimulator is configured to provide one or more of the following stimulation patterns on one or more independently controlled channels: i) one or more of a trapezoidal monophasic waveform and a trapezoidal biphasic waveform. In some instances, the ramp rate for the trapezoidal waveform varies fromAtty Dkt No.: SPNX-002WO0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; ii) one or more of a triangular monophasic waveform and triangular biphasic waveform. In some instances, the ramp rate for the triangular waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; iii) an asymmetrical biphasic waveform. In some instances, the ramp rate for the asymmetrical biphasic waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; iv) a double monophasic waveform. In some instances, the ramp rate for the double monophasic waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms; and a v) a monophasic waveform. In some instances, the ramp rate for the monophasic waveform varies from 0.001 ms to 0.1 ms. In some instances the duration for which the pulse is at the max varies from 0.01 ms to 0.1 ms. In certain embodiments the stimulator provides the same stimulation modality and stimulation parameters on 2 or more different channels or on 3 or more different channels, or on 4 or more different channels. In certain embodiments the stimulator provides a different stimulation modality and / or different stimulation parameters on 2 or more different channels or on 3 or more different channels, or on 4 or more different channels.

[0062] In some embodiments, the electrical stimulator is configured to provide transcutaneous and / or epidural stimulation with one or more of the aforementioned waveform patterns in a manner sufficient to achieve a predetermined threshold intensity. In some instances, the predetermined threshold intensity is a preset pulse amplitude, such as a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA as described in greater detail below. In some instances, the predetermined threshold intensity is an intensity that is determined based on a particular goal such as where some functional goal is achieved (e.g., reduced plasma glucose concentration, increase in activity of the pancreas, increase in the activity of the liver).

[0063] In some embodiments, systems include an electrical stimulator that is configured to apply one or more waveforms that further include a DC offset. In some instances, the electrical stimulator is configured to continuously apply the DC offset simultaneously with the appliedAtty Dkt No.: SPNX-002WO waveforms of transcutaneous and / or epidural stimulation. In other instances, the electrical stimulator is configured to apply the DC offset at a predetermined time after the applied waveforms of transcutaneous and / or epidural stimulation, such as 0.001 milliseconds or more after the waveforms of transcutaneous and / or epidural stimulation are applied, such as 0.005 milliseconds or more, such as 0.01 milliseconds or more, such as 0.05 milliseconds or more, such as 0.1 milliseconds or more, such as 0.5 milliseconds or more, such as 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more and including 10 milliseconds or more after the waveforms of transcutaneous and / or epidural stimulation are applied. In certain instances, the electrical stimulator is configured to apply the DC offset in predetermined intervals where the DC offset is on for a predetermined period of time followed by a period of time where the DC is off. In some instances, the electrical stimulator is configured to apply intervals of the DC offset where the DC offset is on for a duration of 0.001 milliseconds or more, such as 0.005 milliseconds or more, such as 0.01 milliseconds or more, such as 0.05 milliseconds or more, such as 0.1 milliseconds or more, such as 0.5 milliseconds or more, such as 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more and including 10 milliseconds or more. In some instances, the electrical stimulator is configured to apply intervals of the DC offset where the DC offset is off for 1 millisecond or more, such as 2 milliseconds or more, such as 3 milliseconds or more, such as 4 milliseconds or more, such as 5 milliseconds or more, such as 6 milliseconds or more, such as 7 milliseconds or more, such as 8 milliseconds or more, such as 9 milliseconds or more, such as 10 milliseconds or more, such as 15 milliseconds or more, such as 20 milliseconds or more, such as 25 milliseconds or more, such as 30 milliseconds or more, such as 35 milliseconds or more, such as 40 milliseconds or more, such as 45 milliseconds or more, such as 50 milliseconds or more and including intervals where the DC offset is off for 100 milliseconds or more.Atty Dkt No.: SPNX-002WO

[0064] In certain embodiments, the electrical stimulator is configured to have the DC offset constantly on and a second electrode to remove charge from the applied electrical stimulation. In some instances, the electrical stimulator is configured to apply a DC offset that has a pulse amplitude that is proportional to the amplitude of the waveform of electrical stimulation. In some instances, the pulse amplitude of the DC offset is proportional in an amount sufficient to compensate for the amplitude of the waveform of the electrical stimulation.

[0065] In some embodiments, the electrical stimulator applies stimulation to the spinal cord of the subject at a pulse frequency of 5 Hz or more, such as at a pulse frequency of 25 Hz or more and including about a pulse frequency of about 30 Hz. In some embodiments, the electrical stimulator in configured to apply electrical stimulation to the spinal cord of the subject with a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. In some embodiments, the electrical stimulator in configured to apply electrical stimulation that has a positive phase having a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. In some instances, the electrical stimulator in configured to apply electrical stimulation that has a negative phase having a pulse amplitude of from 1 mA to 500 mA, such as from 50 mA to 200 mA, including a pulse amplitude of about 100 mA. As described above, in some instances, the electrical stimulation has an asymmetrical biphasic waveform where the positive phase has a different amplitude from the negative phase. In certain instances, where the positive phase and the negative phase have different amplitudes, the electrical stimulator in configured to apply electrical stimulation where the positive phase has an amplitude that is greater than the negative phase by 1 mA or more, such as by 2 mA or more, such as by 3 mA or more, such as by 4 mA or more, such as by 5 mA or more, such as by 10 mA or more, such as by 25 mA or more, such as by 50 mA or more and including by 100 mA or more. In other instances, where the positive phase and the negative phase have different amplitudes, the electrical stimulator in configured to apply electrical stimulation where the negative phase has an amplitude that is greater than the positivce phase by 1 mA or more, such as by 2 mA or more, such as by 3 mA or more, such as by 4 mA or more, such as by 5 mA or more, such as by 10 mA or more, such as by 25 mA or more, such as by 50 mA or more and including by 100 mA orAtty Dkt No.: SPNX-002WO more. When a DC offset is applied, the DC offset amplitude may be from 0.1 mA to 10 mA, such as from 0.5 mA to 2.5 mA, including a DC offset amplitude of about 1.5 mA. The applied DC offset may be a pulsed DC offset or a continuously applied DC offset.

[0066] In some embodiments, the electrical stimulator in configured to apply electrical stimulation where each waveform has a high frequency component and a low frequency component. In some instances, the high frequency component has a frequency of from 1 KHz to 100 KHz, such as fro 2 KHz to 75 KHz, such as from 3 KHz to 50 KHz, such as from 4 KHz to 25 KHz, such as from 5 KHz to 15 KHz, including a high frequency component of about 10 KHz. For example, the high frequency component may have a frequency that ranges from 1 KHz to 25 KHz. In some instances, the high frequency component is the same during each interval of applied electrical stimulation. In other instances, the electrical stimulator is configured to apply a high frequency component that is varied during each interval of applied electrical stimulation. In some instances, the low frequency component has a frequency of from 1 Hz to 500 Hz, such as from 2 Hz to 450 Hz, such as from 3 Hz to 400 Hz, such as from 4 Hz to 350 Hz, such as from 5 Hz to 300 Hz, such as from 10 Hz to 250 Hz, such as from 25 Hz to 200 Hz and including from 50 Hz to 150 Hz. For example, the low frequency component may be about 100 Hz. In some embodiments, the electrical stimulator is configured to provide a stimulation pulse (burst) width on one or more channels ranging from about 0.1 ms up to about 20 ms, or up to about 10 ms, or up to about 5 ms, or up to about 4 ms, or from about 0.2 ms up to about 3 ms. In certain embodiments the stimulator provides a pulse width fixed at 1 ms at stimulation frequencies over 10 kHz.

[0067] In certain embodiments, systems include a transcutaneous or epidural stimulator for applying electrical stimulation to the spinal cord having electrical stimulator components such as transcutaneous and epidural stimulation electrodes, electrical stimulator controller (e.g., microprocessors / microcontrollers), pulse generators, pulse modulating gating units, shift generators, charge balancers, DC current controllers, monitors and biometric input controllers.

[0068] In some instances, the subject systems are modular systems that include one or more subsystems. In certain instances, the waveform generator system includes an analog voltage measurement subsystem to measure the voltage and current levels at the outputAtty Dkt No.: SPNX-002WO channels. In some instnaces, the waveform generator includes a feedback system to control the output controls all bursts, current and bias settings per user settings.

[0069] In some instances, the subject systems include a display system. In certain instances, the display system includes a data storage subsystem to store the graphic data in a non-volatile fashion and a graphical display subsystem to output the graphics to a custom graphics display / OLED display module.

[0070] In some instances, the subject systems include a power supply. In some embodiments, the power supply includes a battery system. In certain embodiments, the battery system includes a battery charging subsystem which charges the battery and a fuel gauge subsystem which monitors the status of the battery.

[0071] In some instances, the subject systems include a safety monitor system. In certain instances, the safety monitor system includes an analog subsystem which monitors voltage values and a digital subsystem which monitors digital inputs. These subsystem inputs are then evaluated for validity and the system responds per SRS.

[0072] In certain embodiments, systems of interest include electrodes for contacting with the skin surface of the subject that are spring-loaded, such as where the electrode includes a spring to ensure sufficient contact between the electrode and the skin surface of the subject. In some instances, the spring loaded electrodes are sufficient to apply mechanical pressure to maintain contact between the electrodes and the spine of the subject. In some instances, the spring loaded electrodes are integrated in a harness device or a belt which can be worn by the subject. In other instances, the spring-loaded electrodes are integrated into the clothing worn by the subject. In other instances, the spring-loaded electrodes are integrated into a device which maintains contact with spine of the subject, such as for example a chair or a bed.

[0073] In some embodiments, the electrical stimulator is configured to deliver the electrical stimulation while the subject is seated. In some instances, the subject is in a supine position while the electrical stimulation is applied to the subject. In other instances, the subject is standing while the electrical stimulation is applied to the subject.Atty Dkt No.: SPNX-002WOEXPERIMENTALExample 1

[0074] A subject diagnosed as having diabetes consumed 75 grams of glucose after undergoing a fasting blood glucose test. Electrical stimulation was applied to the spinal cord of the subject between T6 and T10 (e.g., areas which map to the pancreas). Figure 1 depicts the placement of the electrodes on the skin surface of the subject, with reference being shown as to the position on the spinal cord.

[0075] FIG. 2 depicts the blood glucose concentration of the subjects that were either non-diabetic or diabetic with electrical stimulation and without electrical stimulation on two different days after consumption of the glucose. No other food or fluids was consumed by the subject and the subject performed routine activities. As shown in Figure 2, application of the electrical stimulation to the spinal cord according to embodiments described herein provided for a greater decrease in blood glucose 2 hours after consumption of the glucose, reducing the blood glucose of the subject.

[0076] FIG. 3 depicts the blood glucose concentration of the subjects that were either nondiabetic or pre-diabetic with electrical stimulation and without electrical stimulation on two different days after consumption of a regular meal. No other food or fluids was consumed by the subject and the subject performed routine activities. As shown in Figure 3, application of the electrical stimulation to the spinal cord according to embodiments described herein provided for a greater and faster decrease in blood glucose within 20mins of consumption of the mean with stimulation compared to without stimulation resulting in lowered blood glucose levels of the subject

[0077] FIG. 4 depicts the neuronal mapping of the spinal nerves to the pancreas and a mechanism of action resulting in increased insulin secretion and reduced blood glucose levels. Figure 4A) A schematic representation of the spinal activation of pancreas via increased parasympathetic activity and reduced sympathetic activity resulting in increase in insulin secretion and decrease in blood glucose levels and 4B) map demonstrating the spinal nerves mapped to the pancreasAtty Dkt No.: SPNX-002WOEMBODIMENTS

[0078] Certain embodiments of the present disclosure are described in the clauses below. The clauses below are not intended to limit the scope of the invention disclosed herein.1. A method for treating a metabolic disorder comprising applying transcutaneous electrical stimulation waveform to the spinal cord of a subject, wherein the electrical stimulation is applied in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject.2. The method according to clause 1, wherein the subject is determined to have or is diagnosed as having diabetes.3. The method according to clause 2, wherein the subject is determined to have or is diagnosed as having Type 1 diabetes, Type 2 diabetes or prediabetes.4. The method according to any one of the clauses 1-3, wherein the method comprises normalizing function of the pancreas.5. The method according to any one of clauses 1-4, wherein the method comprises modulating one or more of fasting plasma glucose concentration and non-fasting plasma glucose concentration in the subject.6. The method according to any one of clauses 1-5, wherein the method comprises treating elevated hbAlc in the subject.7. The method according to any one of clauses 1-6, wherein the method comprises normalizing the hbAlc levels.8. The method according to any one of clauses 1-7, wherein the method comprises of increased secretion of insulin.9. The method according to any one of clauses 1-8, wherein the method comprises of increased processing of insulin.10. The method according to any one of clauses 1-9, wherein the method comprises of decreased insulin resistance.11. The method according to any one of clauses 1-10, wherein the method comprises of increased glucose uptake in skeletal musclesAtty Dkt No.: SPNX-002WO12. The method according to any one of clauses 1-11, wherein the method comprises of decreased pain and increases sleep, wherein the method further comprises increasing insulin indirectly.13. The method according to any one of clauses 1-12, wherein the method comprises of decreased symptoms of painful diabetic neuropathy.14. The method according to any one of clauses 1-13, wherein the method comprises of change which occurs within 1-2 hours of stimulation.15. The method according to any one of clauses 1-14, wherein the method comprises of stimulation that has an immediate effect on blood glucose and can be turned off or on.16. The method according to any one of clauses 1-15, wherein the method comprises of stimulating autonomic nerves which affects the islets hormone secretion.17. The method according to any one of clauses 1-16, wherein the method comprises of applying the electrical stimulation to a subject diagnosed as having pre-diabetes in a manner sufficient to reduce or prevent the subject from progressing to becoming diabetic.18. The method according to any one of clauses 1-17, wherein the method comprises of reduced glucose spikes.19. The method according to any one of clauses 1-18, wherein the method comprises of increased processing of food in the body.20. The method according to any one of clauses 1-19, wherein the method comprises of reduction of body weight.21. The method according to any one of clauses 1-20, wherein the method comprises of reduction of body fat.22. The method according to any one of clauses 1-21, wherein the method comprises of an increase in muscle mass in body.23. The method according to any one of clauses 1-22, wherein the method comprises of decrease in body mass index.24. The method according to any one of clauses 1-23, wherein the method comprises of decrease in body composition of one or more of body fat percentage, body fat mass, visceral fat, muscle mass and bone mass.Atty Dkt No.: SPNX-002WO25. The method according to any one of clauses 1-24, wherein the method comprises of decrease in the atherogenic index or ratio of total cholesterol to High Density Lipoprotein (HDL).26. The method according to any one of clauses 1-25, wherein the method comprises of change in Total Cholesterol over time.27. The method according to any one of clauses 1-26, wherein the method comprises of decrease in High Density Lipoprotein (HDL) over time.28. The method according to any one of clauses 1-27, wherein the method comprises of increase in Low Density Lipoprotein (LDL) over time.29. The method according to any one of clauses 1-28, wherein the method comprises of decrease in Triglycerides over time.30. The method according to any one of clauses 1-29, wherein the method comprises of decrease in Very-low-density lipoprotein (VLDL) over time.31. The method according to any one of clauses 1-30, wherein the method comprises of normalization in pulse rate over time.32. The method according to any one of clauses 1-31, wherein the method comprises of normalization in Mean arterial pressure (MAP).33. The method according to any one of clauses 1-32, wherein the method comprises of decrease in anti-diabetic medication.34. The method according to any one of clauses 1-33, wherein the method comprises of normalization in cardiovascular medication.35. The method according to any one of clauses 1-34, wherein the method comprises modulating glucose tolerance by the subject.36. The method according to any one of clauses 1-35, wherein the electrical stimulation is applied in a manner sufficient to modulate insulin secretion by the subject.37. The method according to any one of clauses 1-36, wherein the subject exhibits hyperglycemia after consumption of glucose.Atty Dkt No.: SPNX-002WO38. The method according to any one of clauses 1-37, wherein the electrical stimulation is applied in a manner sufficient to reduce blood glucose concentration in the subject by 5% or more.39. The method according to any one of clauses 1-38, wherein the electrical stimulation is applied in a manner sufficient to reduce blood sugar concentration in the subject by 10% or more.40. The method according to any one of clauses 1-39, wherein the electrical stimulation is applied in a manner sufficient to reduce blood sugar concentration in the subject by 10 mg / dL or more.41. The method according to any one of clauses 1-40, wherein the electrical stimulation is applied in a manner sufficient to reduce blood glucose concentration in the subject by 25 mg / dL or more.42. The method according to any one of clauses 1-41, wherein the electrical stimulation is applied in a manner sufficient to immediately reduce blood glucose concentration in the subject.43. The method according to any one of clauses 1-42, wherein the reduced blood glucose concentration in the subject is maintained for the duration of the electrical stimulation.44. The method according to any one of clauses 1-43, wherein the electrical stimulation is applied in a manner sufficient to maintain a reduced blood glucose concentration in the subject for a predetermined duration after the applied electrical stimulation.45. The method according to any one of clauses 1-44, wherein the electrical neuromodulation applied to the spinal cord is sufficient to induce neuroplasticity in the brain and spinal cord resulting in reduced blood glucose levels after the neuromodulation therapy has been turned off.46. The method according to any one of clauses 1-45, wherein the reduced blood glucose is maintained for 1 hour or more after the applied electrical stimulation.47. The method according to any one of clauses 1-46, wherein the reduced blood glucose is maintained for 6 hours or more after the applied electrical stimulation.Atty Dkt No.: SPNX-002WO48. The method according to any one of clauses 1-46, wherein the reduced blood glucose is maintained for 12 hours or more after the applied electrical stimulation.49. The method according to any one of clauses 1-48, wherein the reduced blood glucose is maintained for 24 hours or more after the applied electrical stimulation.50. The method according to any one of clauses 1-49, wherein the reduced blood glucose is maintained for 2 days or more after the applied electrical stimulation.51. The method according to any one of clauses 1-50, wherein the reduced blood glucose is maintained for 5 days or more after the applied electrical stimulation.52. The method according to any one of clauses 1-51, wherein the reduced blood glucose is maintained for 7 days or more after the applied electrical stimulation.53. The method according to any one of clauses 1-52, wherein the method comprises applying electrical stimulation to the spinal cord of the subject for 1 hour or more.54. The method according to any one of clauses 1-53, wherein the method comprises applying electrical stimulation to the spinal cord of the subject for 2 hours or more.55. The method according to any one of clauses 1-54, wherein the electrical stimulation is applied over a region of the spinal cord of the subject comprising T6-T10 or a region therein.56. The method according to any one of clauses 1-55, wherein the electrical stimulation is applied to a first region between T6-T7 of the spinal cord of the subject and a second region between T9-T10 of the spinal cord of the subject.57. The method according to any one of clauses 1-56, wherein the electrical stimulation is applied to T6 of the spinal cord of the subject.58. The method according to any one of clauses 1-57, wherein the electrical stimulation is applied to T10 of the spinal cord of the subject.59. The method according to any one of clauses 1-58, wherein the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to increase activity by the pancreas of the subject.60. The method according to any one of clauses 1-59, wherein the transcutaneous electrical neuromodulation is applied to the spinal cord of the subject in a manner sufficient to inhibitsAtty Dkt No.: SPNX-002WO the sympathetic innervation to the pancreas and excites the parasympathetic innervation to the pancreas.61. The method according to any one of clauses 1-60, wherein the electrical stimulation comprises applying at least one waveform selected from the group consisting of:62. The method according to any one of clauses 1-61, wherein the one or more applied waveforms further comprises: delayed and charge balanced biphasic waveform; one or more of a trapezoidal monophasic waveform and a trapezoidal biphasic waveform; one or more of a triangular monophasic waveform and triangular biphasic waveform; an asymmetrical biphasic waveform; a double monophasic waveform; or a monophasic waveform.63. The method according to clause 62, wherein the one or more applied waveforms further comprises a DC offset.64. The method according to clause 63, wherein the DC offset is an applied voltage that is sufficient to compensate for each applied electrical stimulation pulse.65. The method according to any one of clauses 1-64, wherein the method further comprises assessing blood glucose concentration of the subject after applying the electrical stimulation.66. The method according to any one of clauses 1-65, wherein the blood glucose concentration of the subject is measured 1 hour or more after applying the electrical stimulation.67. The method according to any one of clauses 1-66, wherein the blood glucose concentration of the subject is measured 2 hours or more after applying the electrical stimulation.68. The method according to any one of clauses 1-67, wherein the method further comprises modifying one or more parameters of the electrical stimulation based on the assessed blood glucose concentration of the subject.Atty Dkt No.: SPNX-002WO69. The method according to any one of clauses 1-68, wherein the method comprises of attaching the transcutaneous electrical neuromodulator system permanently or temporarily to the back of the subject70. The method according to any one of clauses 1-69, wherein the method comprises of the transcutaneous electrical neuromodulator capable of transmitting and receiving information to and from an external communication device such as a mobile phone71. The method according to any one of clauses 1-70, wherein the method comprises of the subject being able to manually control the transcutaneous electrical neuromodulation using their mobile phones72. The method according to any one of clauses 1-71, wherein the system and method consist of delivering or modifying the parameters of spinal neuromodulation or stopping the neuromodulation system using a closed loop algorithm based on the changes in glucose levels as recorded on a continuous glucose monitor to create a closed loop system.73. The method according to any one of clauses 1-72, wherein the method comprises changing the waveform of the applied electrical stimulation based on the measured blood glucose concentration of the subject.74. The method according to any one of clauses 1-73, wherein the method comprises changing the frequency of the applied waveform based on the measured blood glucose concentration of the subject.75. The method according to any one of clauses 1-74, wherein the method comprises changing the amplitude of the applied electrical stimulation based on the measured blood glucose concentration of the subject.76. The method according to any one of clauses 1-75, wherein the method comprises applying electrical stimulation to the spinal cord of the subject at predetermined time intervals to modulate blood glucose concentration in the subject.77. The method according to any one of clauses 1-76, wherein the method comprises applying electrical stimulation to the spinal cord of the subject 1-2 hours after the consumption of food or fluids by the subject.Atty Dkt No.: SPNX-002WO78. The method according to any one of clauses 1-77, wherein the method comprises applying electrical stimulation to the spinal cord of the subject immediately after the consumption of food or fluids by the subject.79. The method according to any one of clauses 1-78, wherein the electrical stimulation is applied to the spinal cord of the subject concurrently with the consumption of food or fluids by the subject.80. The method according to any one of clauses 1-79, wherein the electrical stimulation is applied to the spinal cord of the subject immediately before the consumption of food or fluids by the subject.

[0079] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0080] Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions.Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.Atty Dkt No.: SPNX-002WO

[0081] The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked.

Claims

Atty Dkt No.: SPNX-002WOWhat is claimed is:

1. A method for treating a metabolic disorder comprising applying transcutaneous electrical stimulation waveform to the spinal cord of a subject, wherein the electrical stimulation is applied in a manner sufficient to treat at least one symptom of the metabolic disorder in the subject.

2. The method according to claim 1, wherein the subject is determined to have or is diagnosed as having diabetes.

3. The method according to claim 2, wherein the subject is determined to have or is diagnosed as having Type 1 diabetes, Type 2 diabetes or prediabetes.

4. The method according to any one of claims 1-3, wherein the method comprises normalizing function of the pancreas.

5. The method according to any one of claims 1-4, wherein the method comprises modulating one or more of fasting plasma glucose concentration and non-fasting plasma glucose concentration in the subject.

6. The method according to any one of claims 1-5, wherein the method comprises treating elevated hbAlc in the subject.

7. The method according to any of claims 1-6, wherein the method comprises normalizing the hbAlc levels.

8. The method according to any of claims 1-7, wherein the method comprises of increased secretion of insulin.Atty Dkt No.: SPNX-002WO9. The method according to any one of claims 1-8, wherein the method comprises of increased processing of insulin.

10. The method according to any one of claims 1-9, wherein the method comprises of decreased insulin resistance.

11. The method according to any one of claims 1-10, wherein the method comprises of increased glucose uptake in skeletal muscles12. The method according to any one of claims 1-11, wherein the method comprises of decreased pain and increases sleep, wherein the method further comprises increasing insulin indirectly.

13. The method according to any one of claims 1-12, wherein the method comprises of decreased symptoms of painful diabetic neuropathy.

14. The method according to any one of claims 1-13, wherein the method comprises of change which occurs within 1-2 hours of stimulation.

15. The method according to any one of claims 1-14, wherein the method comprises of stimulation that has an immediate effect on blood glucose and can be turned off or on.

16. The method according to any one of claims 1-15, wherein the method comprises of stimulating autonomic nerves which affects the islets hormone secretion.

17. The method according to any one of claims 1-16, wherein the method comprises of applying the electrical stimulation to a subject diagnosed as having pre-diabetes in a manner sufficient to reduce or prevent the subject from progressing to becoming diabetic.Atty Dkt No.: SPNX-002WO18. The method according to any one of claims 1-17, wherein the method comprises of reduced glucose spikes.

19. The method according to any one of claims 1-18, wherein the method comprises of increased processing of food in the body.

20. The method according to any one of claims 1-19, wherein the method comprises of reduction of body weight.

21. The method according to any one of claims 1-20, wherein the method comprises of reduction of body fat.

22. The method according to any one of claims 1-21, wherein the method comprises of an increase in muscle mass in body.

23. The method according to any one of claims 1-22, wherein the method comprises of decrease in body mass index.

24. The method according to any one of claims 1-23, wherein the method comprises of decrease in body composition of one or more of body fat percentage, body fat mass, visceral fat, muscle mass and bone mass.

25. The method according to any one of claims 1-24, wherein the method comprises of decrease in the atherogenic index or ratio of total cholesterol to High Density Lipoprotein (HDL).

26. The method according to any one of claims 1-25, wherein the method comprises of change in Total Cholesterol over time.Atty Dkt No.: SPNX-002WO27. The method according to any one of claims 1-26, wherein the method comprises of decrease in High Density Lipoprotein (HDL) over time.

28. The method according to any one of claims 1-27, wherein the method comprises of increase in Low Density Lipoprotein (LDL) over time.

29. The method according to any one of claims 1-28, wherein the method comprises of decrease in Triglycerides over time.

30. The method according to any one of claims 1-29, wherein the method comprises of decrease in Very-low-density lipoprotein (VLDL) over time.

31. The method according to any one of claims 1-30, wherein the method comprises of normalization in pulse rate over time.

32. The method according to any one of claims 1-31, wherein the method comprises of normalization in Mean arterial pressure (MAP).

33. The method according to any one of claims 1-32, wherein the method comprises of decrease in anti-diabetic medication.

34. The method according to any one of claims 1-33, wherein the method comprises of normalization in cardiovascular medication.

35. The method according to any one of claims 1-34, wherein the method comprises modulating glucose tolerance by the subject.

36. The method according to any one of claims 1-35, wherein the electrical stimulation is applied in a manner sufficient to modulate insulin secretion by the subject.Atty Dkt No.: SPNX-002WO37. The method according to any one of claims 1-36, wherein the subject exhibits hyperglycemia after consumption of glucose.

38. The method according to any one of claims 1-37, wherein the electrical stimulation is applied in a manner sufficient to reduce blood glucose concentration in the subject by 5% or more.

39. The method according to any one of claims 1-38, wherein the electrical stimulation is applied in a manner sufficient to reduce blood sugar concentration in the subject by 10% or more.

40. The method according to any one of claims 1-39, wherein the electrical stimulation is applied in a manner sufficient to reduce blood sugar concentration in the subject by 10 mg / dL or more.

41. The method according to any one of claims 1-40, wherein the electrical stimulation is applied in a manner sufficient to reduce blood glucose concentration in the subject by 25 mg / dL or more.

42. The method according to any one of claims 1-41, wherein the electrical stimulation is applied in a manner sufficient to immediately reduce blood glucose concentration in the subject.

43. The method according to any one of claims 1-42, wherein the reduced blood glucose concentration in the subject is maintained for the duration of the electrical stimulation.Atty Dkt No.: SPNX-002WO44. The method according to any one of claims 1-43, wherein the electrical stimulation is applied in a manner sufficient to maintain a reduced blood glucose concentration in the subject for a predetermined duration after the applied electrical stimulation.

45. The method according to any one of claims 1-44, wherein the electrical neuromodulation applied to the spinal cord is sufficient to induce neuroplasticity in the brain and spinal cord resulting in reduced blood glucose levels after the neuromodulation therapy has been turned off.

46. The method according to any one of claims 1-45, wherein the reduced blood glucose is maintained for 1 hour or more after the applied electrical stimulation.

47. The method according to any one of claims 1-46, wherein the reduced blood glucose is maintained for 6 hours or more after the applied electrical stimulation.

48. The method according to any one of claims 1-46, wherein the reduced blood glucose is maintained for 12 hours or more after the applied electrical stimulation.

49. The method according to any one of claims 1-48, wherein the reduced blood glucose is maintained for 24 hours or more after the applied electrical stimulation.

50. The method according to any one of claims 1-49, wherein the reduced blood glucose is maintained for 2 days or more after the applied electrical stimulation.

51. The method according to any one of claims 1-50, wherein the reduced blood glucose is maintained for 5 days or more after the applied electrical stimulation.

52. The method according to any one of claims 1-51, wherein the reduced blood glucose is maintained for 7 days or more after the applied electrical stimulation.Atty Dkt No.: SPNX-002WO53. The method according to any one of claims 1-52, wherein the method comprises applying electrical stimulation to the spinal cord of the subject for 1 hour or more.

54. The method according to any one of claims 1-53, wherein the method comprises applying electrical stimulation to the spinal cord of the subject for 2 hours or more.

55. The method according to any one of claims 1-54, wherein the electrical stimulation is applied over a region of the spinal cord of the subject comprising T6-T10 or a region therein.

56. The method according to any one of claims 1-55, wherein the electrical stimulation is applied to a first region between T6-T7 of the spinal cord of the subject and a second region between T9-T10 of the spinal cord of the subject.

57. The method according to any one of claims 1-56, wherein the electrical stimulation is applied to T6 of the spinal cord of the subject.

58. The method according to any one of claims 1-57, wherein the electrical stimulation is applied to T10 of the spinal cord of the subject.

59. The method according to any one of claims 1-58, wherein the electrical stimulation is applied to the spinal cord of the subject in a manner sufficient to increase activity by the pancreas of the subject.

60. The method according to any one of claims 1-59, wherein the transcutaneous electrical neuromodulation is applied to the spinal cord of the subject in a manner sufficient to inhibits the sympathetic innervation to the pancreas and excites the parasympathetic innervation to the pancreas.Atty Dkt No.: SPNX-002WO61. The method according to any one of claims 1-60, wherein the electrical stimulation comprises applying at least one waveform selected from the group consisting of:

62. The method according to any one of claims 1-61, wherein the one or more applied waveforms further comprises:Delayed and charge balanced biphasic waveform; one or more of a trapezoidal monophasic waveform and a trapezoidal biphasic waveform; one or more of a triangular monophasic waveform and triangular biphasic waveform; an asymmetrical biphasic waveform; a double monophasic waveform; or a monophasic waveform.

63. The method according to claim 62, wherein the one or more applied waveforms further comprises a DC offset.

64. The method according to claim 63, wherein the DC offset is an applied voltage that is sufficient to compensate for each applied electrical stimulation pulse.

65. The method according to any one of claims 1-64, wherein the method further comprises assessing blood glucose concentration of the subject after applying the electrical stimulation.

66. The method according to any one of claims 1-65, wherein the blood glucose concentration of the subject is measured 1 hour or more after applying the electrical stimulation.

67. The method according to any one of claims 1-66, wherein the blood glucose concentration of the subject is measured 2 hours or more after applying the electrical stimulation.Atty Dkt No.: SPNX-002WO68. The method according to any one of claims 1-67, wherein the method further comprises modifying one or more parameters of the electrical stimulation based on the assessed blood glucose concentration of the subject.

69. The method according to any one of claims 1-68, wherein the method comprises of attaching the transcutaneous electrical neuromodulator system permanently or temporarily to the back of the subject70. The method according to any one of claims 1-69, wherein the method comprises of the transcutaneous electrical neuromodulator capable of transmitting and receiving information to and from an external communication device such as a mobile phone71. The method according to any one of claims 1-70, wherein the method comprises of the subject being able to manually control the transcutaneous electrical neuromodulation using their mobile phones72. The method according to any one of the claims 1-71, wherein the system and method consist of delivering or modifying the parameters of spinal neuromodulation or stopping the neuromodulation system using a closed loop algorithm based on the changes in glucose levels as recorded on a continuous glucose monitor to create a closed loop system.

73. The method according to any one of claims 1-72, wherein the method comprises changing the waveform of the applied electrical stimulation based on the measured blood glucose concentration of the subject.

74. The method according to any one of claims 1-73, wherein the method comprises changing the frequency of the applied waveform based on the measured blood glucose concentration of the subject.Atty Dkt No.: SPNX-002WO75. The method according to any one of claims 1-74, wherein the method comprises changing the amplitude of the applied electrical stimulation based on the measured blood glucose concentration of the subject.

76. The method according to any one of claims 1-75, wherein the method comprises applying electrical stimulation to the spinal cord of the subject at predetermined time intervals to modulate blood glucose concentration in the subject.

77. The method according to any one of claims 1-76, wherein the method comprises applying electrical stimulation to the spinal cord of the subject 1-2 hours after the consumption of food or fluids by the subject.

78. The method according to any one of claims 1-77, wherein the method comprises applying electrical stimulation to the spinal cord of the subject immediately after the consumption of food or fluids by the subject.

79. The method according to any one of claims 1-78, wherein the electrical stimulation is applied to the spinal cord of the subject concurrently with the consumption of food or fluids by the subject.

80. The method according to any one of claims 1-79, wherein the electrical stimulation is applied to the spinal cord of the subject immediately before the consumption of food or fluids by the subject.

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