Neuromodulatory systems for inducing changes in the plasticity of the blood glucose regulatory system

Abstract

Current treatments for type 2 diabetes include lifestyle management and medications, and may include bariatric surgery for morbidly obese individuals. However, issues with medication compliance, side effects, and permanent anatomical changes provide a need for alternative therapies to modulate peripheral nerves (e.g., the vagus nerve) in a manner that induces plastic changes in the blood glucose regulatory system, thereby altering organ activity, with or without central nervous system (CNS) involvement. Low-energy vagus nerve neuromodulation has potential as a novel treatment for type 2 diabetes by inducing plasticity in the body's blood glucose regulatory system with low-energy, transient stimulation. This allows for the effective use of small, implantable pulse generators that require infrequent or no charging over the device's lifetime.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application was filed as a PCT international patent application on December 29, 2023, and claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 477,996, filed on December 30, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Introduction) It is within the scope of the present invention to excite peripheral nerves in a manner that causes plastic changes in the blood glucose regulatory system, including but not limited to, involvement of the central nervous system (CNS), that alter the activity of one or more organs involved in maintaining blood glucose control. [Background technology]

[0003] (overview) Diabetes is the seventh leading cause of death in the United States, with 252,000 deaths directly or indirectly attributable to the disease. Approximately 31 million Americans have type 2 diabetes mellitus (T2DM), with 1.5 million new cases diagnosed each year. Diabetic comorbidities impose a significant burden on public healthcare due to long-term adverse effects on the heart, blood vessels, eyes, kidneys, and nerves. 97.5% of people with diabetes have at least one comorbid condition, and 88.5% have at least two comorbid conditions.

[0004] The annual economic burden of T2DM in the United States is $237 billion in direct treatment costs, with individuals spending $9,600 annually directly attributable to the disease.

[0005] Metformin is the first-line pharmacotherapy. Other medications include sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor antagonists. Treatment persistence decreased by 21% to 34% over 5 years. 5, requiring the addition of a second or third drug. Drug therapy can induce side effects such as hypoglycemia, heart failure, ketoacidosis, diarrhea, nausea, abdominal pain, and orthopedic fractures. Furthermore, the incidence of medication compliance is also a major problem, as approximately 50% of patients do not take medication as prescribed (including 33% of patients taking GLP-1 receptor antagonists once every two weeks).

[0006] Insulin may be prescribed for type 2 diabetes patients who progress to glycated hemoglobin (HbA1c) ≥ 10% and / or blood glucose levels ≥ 300 mg / dL. Although insulin therapy is a tool for reducing blood glucose, there is a risk of hypoglycemia, and most diabetic patients fear insulin injections. A study by Stotland et al. found that 45% of diabetic subjects avoided injections due to anxiety, fear, and dread. Injection anxiety has been associated with poorer treatment adherence, greater psychological distress, a greater incidence of diabetes-related hospitalizations, and a higher risk of retinopathy and neuropathy.

[0007] Remission of T2DM has been observed in obese diabetic patients after metabolic surgery, but it is recommended only for adults with a BMI of 30.0–34.9 kg / m² when medical therapy is ineffective. However, remission rates are as high as 26% after 5 years, raising doubts about their durability. Common risks of metabolic surgery include intestinal obstruction, GERD, gallstones, hernias, hypoglycemia, malnutrition, and dumping syndrome. Nutritional deficiencies leading to hematologic, metabolic, and neurological disorders have been reported.

[0008] Stand-alone vagus nerve stimulation or vagus nerve blockade has shown increased glycemic control but only in the setting of significant and sustained weight loss, which is not realistic for many patients with type 2 diabetes. Hepatic branch ligation has been proposed as a method for increasing glycemic control, but this may cause negative changes in feeding behavior, increase hypoglycemic episodes, affect liver regeneration, and increase metastasis during liver cancer.

[0009] Optogenetic and chemogenetic vagal manipulation, currently under investigation, offers impressive neuronal specificity and may affect glycemic control, but viral vector-mediated gene regulation is not currently clinically feasible. Electrical vagal stimulation has a proven clinical safety and efficacy profile for other indications (e.g., epilepsy) and may be a practical method of vagal modulation for glycemic control.

[0010] Induction of long-term potentiation or long-term depression of autonomic reflex arcs for the treatment of disease may also be a potential therapeutic approach. The reflex arc between sensory autonomic afferents and autonomic efferents that drive visceral organ activity is a therapeutic approach that offers more promise than currently widely used therapies.

[0011] Therefore, there is a need for a long-term T2DM therapy that provides a long-term therapy that can be modified in real time to reduce glucose levels in patients while also reducing non-compliance with the therapeutic treatment. Summary of the Invention [Means for solving the problem]

[0012] Neuromodulatory system for inducing changes in the plasticity of the blood glucose regulation system The inventions described herein include alternative therapeutic approaches for modulating peripheral nerves (e.g., the vagus nerve) in a manner that induces plastic changes in the blood glucose regulatory system, thereby altering organ activity, with or without central nervous system (CNS) involvement. Low-energy vagal neuromodulation has potential as a novel treatment for type 2 diabetes by inducing plasticity in the body's blood glucose regulatory system with low-energy, transient stimulation. This allows for the effective use of small, implantable pulse generators that require infrequent or no charging over the life of the device. [Brief explanation of the drawings]

[0013] [Figure 1AB] Figure 1(A) is a diagram of the hepatic branch of the vagus nerve resulting in a decrease in pancreatic insulin release. Figure 1(B) is a diagram of increased portal vein glucose concentration inducing a decrease in afferent hepatic axon activity. Figure 1(C) is a diagram of block conduction through the hepatic branch of the vagus nerve. Figure 1(D) is a diagram of combined stimulation of the celiac branch of the vagus nerve. [Figure 1CD] Figure 1(A) is a diagram of the hepatic branch of the vagus nerve resulting in a decrease in pancreatic insulin release. Figure 1(B) is a diagram of increased portal vein glucose concentration inducing a decrease in afferent hepatic axon activity. Figure 1(C) is a diagram of block conduction through the hepatic branch of the vagus nerve. Figure 1(D) is a diagram of combined stimulation of the celiac branch of the vagus nerve.

[0014] [Figure 2] Figure 2 is a diagram of five possible sites of neuroplasticity in the glucose regulatory reflex arc.

[0015] [Figure 3] FIG. 3 is a graphical representation of the increased glycemic control during an oral glucose tolerance test (OGTT) compared to sham, where HFAC delivered at the hepatic branch point and concomitant co-stimulation at the celiac branch point.

[0016] [Figure 4] FIG. 4 is a schematic diagram of a burst stimulus containing two pulses in one burst.

[0017] [Figure 5] FIG. 5 is a schematic diagram of burst stimulation using multiple pulses in one burst and two bursts.

[0018] [Figure 6] FIG. 6 is a schematic diagram of burst stimulation using multiple pulses and multiple bursts.

[0019] [Figure 7] FIG. 7 is a schematic diagram of burst stimulation with variable interburst intervals.

[0020] [Figure 8] FIG. 8 is a schematic diagram of burst stimulation with variable interburst intervals.

[0021] [Figure 9] FIG. 9 is a diagram of various neuromodulatory sites on the vagus nerve.

[0022] [Figure 10] Figure 10 (A) is a graphical representation of the intravenous glucose tolerance test (IVGTT) in pigs before and after alloxan treatment, including absolute plasma glucose values ​​expressed in mg / dL. (B) is a bar graph showing the area under the curve (AUC) of the graph in Figure A. **p<0.05 (Mann-Whitney U test).

[0023] [Figure 11] Figure 11(A) is a graphical representation of the same IVGTT as in Figure 10A in pigs before and after alloxan treatment, including the % change in plasma glucose. Figure (B) is a bar graph showing the AUC of the graph in Figure A.

[0024] [Figure 12] Figure 12(A) is a graphical representation of how HFAC delivered at the hepatic branch point with concomitant co-stimulation at the celiac branch point alters glycemic control during an OGTT compared to sham. Figure (B) is a bar graph showing the AUC from the experiment in Figure A.

[0025] [Figure 13] Figure 13(A) is a graphical representation of HFAC delivered at the hepatic branch point compared with co-stimulation at the celiac branch point during an OGTT, and Figure 13(B) is a bar graph representation of the AUC from the experiment in Figure 13(A).

[0026] [Figure 14] FIG. 14 is a graphical representation of HFAC delivered at the hepatic branch point with concomitant co-stimulation at the celiac branch point.

[0027] [Figure 15] FIG. 15 is a bar graph showing fasting plasma glucose (FGP) before 1 minute of HFAC delivered at the hepatic branch point and concomitant stimulation at the peritoneal branch point, and 1 day after termination of the signals.

[0028] [Figure 16] FIG. 16 is a graphical representation of the time course of the experiment in FIG.

[0029] [Figure 17] FIG. 17 is a graphical representation of (A) % change in plasma glucose, insulin, and heart rate (HR), (B) blood pressure, and (C) oxygen saturation. DETAILED DESCRIPTION OF THE INVENTION

[0030] (Detailed explanation) The body converts carbohydrates from food into glucose, a simple sugar that serves as an important energy source. The hormones insulin and glucagon play important roles in glucose regulation. The pancreas contains a collection of cells called the islets of Langerhans, which release both insulin and glucagon. If the body does not convert enough glucose, blood glucose levels remain high. The pancreas secretes insulin to help cells absorb glucose, reducing blood glucose and providing cells with glucose for energy. When blood glucose decreases, cells in the pancreas secrete glucagon. Glucagon signals the liver to convert stored glucose (i.e., glycogen) into glucose, making it more available in the bloodstream. Insulin and glucagon function in a cyclical manner: glucagon interacts with the liver to increase blood glucose, while insulin decreases it by helping cells use glucose. Conditions associated with impaired glucose regulation include type 2 diabetes, impaired glucose tolerance, impaired fasting glucose, gestational diabetes, and type 1 diabetes. "Glucose dysregulation" refers to alterations in one or more of glucose absorption, glucose production, insulin secretion, insulin sensitivity, GLP-1 regulation, and glucagon regulation.

[0031] Type 2 diabetes is a disease in which liver cells, muscle cells and fat cells do not use insulin properly to transport glucose into cells and provide cells with energy.When cells begin to run out of energy, a signal is sent to the pancreas to increase insulin production.In some cases, the pancreas eventually produces less insulin, worsening the symptoms of hyperglycemia.Patients with type 2 diabetes have a fasting blood (plasma) glucose level of 126 mg / dL or higher; an oral glucose load of 200 mg / dL or higher; and / or an HbAlC percentage of 6.5% or higher.

[0032] Despite the existence of treatments for type 2 diabetes, not all patients achieve or maintain glucose control. Patients who do not achieve glycemic control typically have an HbAlC greater than 7%. In some embodiments, patients who continue to have problems with glycemic control even with drug treatment are selected.

[0033] A patient with impaired glucose tolerance and / or impaired fasting glucose is one who has some minimal level of evidence of a lack of glucose control. The patient may be untreated, or the patient may be treated with one or more pharmaceutical treatments. "Prediabetes" is a term used by the American Diabetes Association to refer to people with blood glucose levels higher than normal but not high enough to meet the criteria for diabetes. Lack of blood glucose control can be determined by fasting plasma glucose test (FPG) and / or oral glucose tolerance test (OGTT). The blood glucose levels measured after these tests determine whether the patient has normal glucose metabolism, impaired glucose tolerance, impaired fasting glucose, or diabetes. If a patient's blood glucose level is abnormal within a specific range after FPG, it is called impaired fasting glucose (IFG); if a patient's glucose level is abnormal within a specific range after OGTT, it is called impaired glucose tolerance (IGT). Patients are identified as having impaired fasting glucose with an FPG of greater than or equal to 100 to less than 126 mg / dL and / or impaired glucose tolerance with an OGTT of greater than or equal to 140 to less than 200 mg / dL. Those with prediabetes may have IFG and / or IGT within these ranges. In some embodiments, patients with type 2 diabetes who are overweight but not obese (with a BMI of less than 30), overweight but not obese patients with prediabetes, or patients with type 2 diabetes who are neither overweight nor obese are selected. In some embodiments, patients with one or more risk factors for type 2 diabetes are selected. These risk factors include age over 30, family history, overweight, cardiovascular disease, high blood pressure, elevated triglycerides, a history of gestational diabetes, IFG, and / or IGT.

[0034] The present disclosure includes systems and methods for regulating glucose dysregulation in a subject.

[0035] In some embodiments, a method for treating a condition associated with glucose dysregulation in a subject includes applying an intermittent (or continuous) electrical signal to a target nerve of the subject, the electrical signal being selected to downregulate neural activity on the nerve and restore neural activity on the nerve when the blockade is discontinued. In some embodiments, the target nerve is the vagus nerve. In some embodiments, the site on the target nerve is located so as to avoid affecting heart rate (e.g., under vagal innervation of the heart). In some embodiments, the electrical signal is selected for frequency, amplitude, pulse width, and timing.

[0036] The electrical signal may also be further selected to improve glucose regulation. Improved glucose regulation may be determined by a change in any one of HbAlC %, fasting blood glucose, or an intravenous glucose tolerance test (IVGTT). In some embodiments, the method further comprises combining the application of the electrical signal treatment with the administration of an agent that affects glucose regulation. In some embodiments, the application of the electrical signal treatment excludes the application of the electrical signal treatment to other nerves or organs.

[0037] Referring now to FIG. 1, this diagram shows an example of an autonomic nervous system glycemic control reflex arc. Specifically, referring to FIG. 1A, this diagram illustrates how tonic activity of the hepatic branch of the vagus nerve decreases pancreatic insulin release. Increased hepatic branch activity excites inhibitory neurons in the nucleus tractus solitarius (NTS) in the brainstem. These neurons then project to the dorsal motor vagus (DMV) nucleus, also in the brainstem, resulting in decreased celiac branch efferent activity. Decreased celiac branch activity results in decreased tonic insulin release. Referring now to FIG. 1B, this diagram shows that portal vein glucose concentration induces a decrease in afferent hepatic axon activity, which results in upregulation of celiac axon activity. This celiac branch efferent activity induces pancreatic insulin release. In some embodiments, it is desirable to block conduction through the hepatic branch of the vagus nerve, which inhibits hepatic neuronal tone and, in turn, increases celiac efferent activity, as shown in FIG. 1C. In some embodiments, a combination of hepatic branch block with celiac branch stimulation of the vagus nerve, or alternatively, stimulation at any location on the posterior vagus nerve cranial to the celiac branch point, can be utilized to affect various physiological processes, resulting in increased glycemic control (see FIG. 1D). In an alternative embodiment, block at any location on the anterior vagus nerve cranial to the hepatic branch point can also be used to increase glycemic control. Referring now to FIG. 1D, this figure illustrates various mechanisms for how hepatic branch block and celiac branch stimulation of the vagus nerve can increase glycemic control. In one exemplary embodiment, hepatic branch block reduces hepatic tone, resulting in increased sustained insulin release (see FIG. 1D-1). In another embodiment, the hepatic branch is blocked, thereby decreasing hepatic sensitivity to glucagon (see FIG. 1D-2). In yet another embodiment, the hepatic branch is blocked, thereby increasing hepatic insulin receptor expression (see FIG. 1D-3). In another embodiment, celiac stimulation enhances pancreatic insulin release (see FIG. 1D-4).It should be understood that any of the four block protocols shown in Figure 1 may further include a step of delivering stimulation, in embodiments including that an additional celiac branch stimulation step may provide further glycemic control compared to block alone.

[0038] Still referring to Figure 1, Figure 1(A) shows how tonic activation of the hepatic branch of the vagus nerve reduces pancreatic insulin release. Figure 1(B) shows how an increase in portal vein glucose concentration induces a decrease in afferent hepatic axon activity, which leads to upregulation of celiac axon activity. Figure 1(C) shows how block conduction through the hepatic branch of the vagus nerve inhibits hepatic neuronal tone, which in turn increases celiac efferent nerve activity. Figure 1(D) shows that the combination of stimulation of the celiac branch of the vagus nerve and hepatic branch block to affect various physiological processes results in increased glycemic control (Figure 1(D)).

[0039] Referring now to Figure 2, five potential sites of neuroplasticity in the glucose regulatory reflex arc are shown: 1) between hepatic afferents and their targets in the nucleus tractus solitarius (NTS), 2) between projection neurons from the NTS to the hypothalamus, 3) between the internal hypothalamic nuclei, 4) between excitatory synaptic projections between the NTS and DMV, and 5) between projections from the hypothalamus to the NTS. It should be understood that plasticity can also occur in higher brain regions influenced by vagal activity.

[0040] Referring now to Figure 3, HFAC delivered at the hepatic branch point and concomitant stimulation at the celiac branch point increased glycemic control during OGTT compared to sham. HFAC and stimulation signals were delivered continuously during the 4-hour OGTT experiment. As shown, plasma glucose levels remained below 100 mg / dL from 0 to 250 minutes, whereas the sham group showed a steady increase to above 250 mg / dL between 0 and 125 minutes, returning to just above 100 mg / dL between 125 and 250 minutes.

[0041] Referring now to Figure 4, one protocol includes burst stimulation with two pulses in a burst. Referring now to Figure 5, the burst stimulation protocol includes multiple pulses in a burst and two bursts. Referring now to Figure 6, the burst stimulation includes multiple pulses and multiple bursts. Figure 7 includes burst stimulation with a variable intra-burst interval. Referring now to Figure 8, the burst stimulation includes delivery of a variable inter-burst interval.

[0042] Referring now to Figure 9, a diagram shows various sites of vagal neuromodulation. Sites 4 and 5 have similar effects. Referring now to Figure 10, this figure shows IVGTTs in pigs before and after alloxan treatment, including absolute values ​​of plasma glucose in mg / dL (Figure 10A). Figure 10B is a bar graph that is an analysis of Figure 10A, where the area under the curve is ** *p<0.05 (Mann-Whitney U test). Referring now to Figure 11, in this figure, the same IVGTT protocol was performed as in Figure 10, here pre- and post-alloxan treatment, including the % change in plasma glucose. Figure 11B is a bar graph of the analysis of the experiment performed in Figure 11A, where the analysis is shown: **are indicated with a p-value of p<0.05 using the Mann-Whitney U test.

[0043] Referring now to Figure 12A, HFAC delivered at the hepatic branch point with simultaneous stimulation at the celiac branch point increased glycemic control during OGTT compared to sham. Data are expressed as absolute plasma glucose levels (mg / dL). HFAC and stimulation signals were delivered sequentially during the 4-hour OGTT experiment. Figure 12B is a graphical analysis using area under the curve for the experiment in Figure 12A, and the analysis was ** The results are performed with a p-value of p<0.05 (Mann-Whitney U test).

[0044] Referring now to Figure 13, this figure shows that HFAC delivered at the hepatic branch point with concomitant stimulation at the celiac branch point increased glycemic control during an OGTT compared to sham. This is the same experiment as in Figure 12, except the data is expressed as % change from baseline. The HFAC signal and stimulation signal were delivered sequentially during the 4 hour OGTT experiment. Figure 13B shows ** Analysis using the AUC of the graph for the data in Figure 13A is provided with p<0.05 (Mann-Whitney U test).

[0045] Referring now to Figure 14, this figure shows that HFAC delivered at the hepatic branch point with concomitant co-stimulation at the celiac branch point increased glycemic control during an OGTT, with the signal delivered either continuously throughout the 4 hour OGTT or intermittently during the first 30 minutes of the OGTT.

[0046] Referring to Figure 15, this figure shows FPGs before 1 minute of HFAC delivered at the hepatic branch point and concomitant stimulation at the celiac branch point, and 1 day after the termination of these signals. *The p-value (Student's t-test) was p=0.00092. The data were normally distributed (Shapiro-Wilk test). The sample contained an n-value of 4. A boxplot was used, where whiskers = minimum and maximum values, boxes = 1st and 3rd quartiles, line = median, and x = mean.

[0047] Referring to FIG. 16, this is a graphical representation of the time course carried out during the experiment in FIG.

[0048] Figure 17A shows the % change in plasma glucose, insulin, and heart rate (HR) during 5 Hz stimulation of the celiac branch in a pig. Figure 17B shows the change in blood pressure during delivery of 5 Hz stimulation of the celiac branch in a pig. Figure 17C shows the oxygen saturation during delivery of 5 Hz stimulation of the celiac branch.

[0049] It should be understood that changes in the synapses of nerves to which signals (blocking and / or stimulating) are delivered are plastic. This phenomenon is based on the fact that activation of a presynaptic neuron induces either long-term potentiation (LTP) or long-term depression (LTD) of the synapse between the presynaptic neuron and the postsynaptic neuron. The pattern of activity of the presynaptic neuron induces either LTP or LTD.

[0050] LTP induces a larger postsynaptic depolarization followed by presynaptic release of neurotransmitters. This larger postsynaptic depolarization increases the likelihood of action potential generation by the postsynaptic neuron. LTD has the opposite effect to LTP. LTD is followed by a smaller postsynaptic depolarization followed by presynaptic release of neurotransmitters. This decreases the likelihood of action potential generation by the postsynaptic neuron. Most, if not all, LTP and LTD events occur at glutamatergic synapses.

[0051] Multiple plastic glutamatergic synapses exist in the glycemic reflex arc, providing numerous opportunities for long-lasting activity-induced changes to increase glycemic control. Figure 2 labels five such synapses: 1) between hepatic afferents and their targets in the nucleus tractus solitarius (NTS), 2) between projection neurons from the NTS to the hypothalamus, 3) between the interhypothalamic nuclei, 4) between excitatory synaptic projections between the NTS and DMV, and 5) between projections from the hypothalamus to the NTS. It is important to note that plasticity can also occur in higher brain regions influenced by vagal activity.

[0052] It is within the scope of this disclosure to modulate peripheral nerves (e.g., the vagus nerve) in a manner that causes plastic changes in the glycemic control system, with or without central nervous system (CNS) involvement. These plastic changes result in organ activity. Plasticity, as defined within the scope of this disclosure, is defined as a change in a physiological process that lasts longer than the end of the applied electrical signal. Plasticity can occur at the level of the CNS or in peripheral organs (not involving the CNS) involved in glycemic control, such as, but not limited to, the liver, pancreas, duodenum, skeletal muscle, or adipose tissue, or a combination thereof. This can be achieved either through application of brief low-frequency nerve stimulation or high-frequency alternating current (HFAC), or through burst stimulation, or any combination thereof.

[0053] A current amplitude of 0.1 mA to 20 mA may be desirable for HFAC signals, low-frequency stimulation signals, or burst stimulation signals. The pulse width for low-frequency stimulation signals or burst stimulation signals may be 0.01 ms to 10 ms. HFAC signals may have frequencies of 200 Hz or greater, more specifically, 500 Hz to 5 kHz, 1 kHz to 10 kHz, and 10 kHz to approximately 80 kHz. The frequency of the low-frequency stimulation signal may be 0.01 Hz to 199 Hz, 0.1 Hz to 10 Hz, 10 Hz to 30 Hz, 30 Hz to 100 Hz, or 100 Hz to 199 Hz.

[0054] The ability to induce long-lasting positive effects on glycemic control (e.g., reduction in fasting plasma glucose (FPG), reduction in HbA1c, reduction in the amplitude of plasma glucose spikes throughout the day (as measured by the standard deviation of plasma glucose (less than one-third of the mean glucose) or coefficient of variation (less than 33% variation)) with a minimal amount of energy is desirable for creating a small implantable pulse generator or implantable generator that requires infrequent charging (once per week to once per 12 months), an implantable pulse generator that is a primary battery device (does not require charging during the device's lifetime (typically 3-5 or 5-10 years)), or any combination of these properties. It should be understood that in some exemplary embodiments, a small implantable generator has a length not exceeding 1.5 inches. In other related embodiments, the total volume of the implantable pulse generator is less than 0.5 in. 3 , 1in. 3 , 1.5in. 3 , 1.75in. 3 , or 2.0in. 3The small size of the implantable pulse generator is such that it delivers electrical signals to target nerves while also requiring reduced energy to perform its function, thereby allowing for a longer period of use without the need for recharging. Furthermore, in embodiments in which the implantable pulse generator requires recharging, the amount of time to recharge the implantable pulse generator is also reduced compared to currently available pulse generators.

[0055] The amount of energy efficiency gained by requiring only a short period of HFAC (e.g., 1 minute) compared to longer periods of HFAC application can be seen, for example, in Figure 3, where increased glycemic control can be achieved when applied to the subdiaphragmatic vagus nerve branch and combined with low-frequency stimulation (see oral glucose tolerance test in alloxan-treated pigs). It should be understood that, using the present disclosure, calculation of the total charge to be delivered is performed by evaluating the area under the curve of the pulses during their delivery. For example, under 4 hours of application of a 5 kHz HFAC signal at 8 mA and 90 microsecond pulse width, the total charge is 0.000090 seconds (pulse width) x 5,000 (pulses / second) x 14,400 seconds (4 hours of signal delivery) x 0.008 (amplitude of signal) = 51.84 coulombs. For a 1 minute 5 kHz application with the same parameters, the total charge delivered is 0.000090 seconds (pulse width) x 5,000 (pulses / second) x 60 (seconds signal delivered per minute) x 0.008 (Amp) = 0.216 Coulombs. This equates to 96% less charge being delivered for a 1 minute 5 kHz signal compared to a 4 hour signal. In other alternative embodiments, the charge using the above short duration protocol is delivered using at least 60% less charge, at least 65% less charge, at least 70% less charge, at least 75% less charge, at least 80% less charge, at least 85% less charge, or at least 90% less charge.

[0056] The amount of energy efficiency gained by requiring only a 1-minute low-frequency signal compared to a 4-hour low-frequency application (which in our study was previously shown to increase glycemic control when combined with a high-frequency signal applied to the subdiaphragmatic vagal branch and combined with an HFAC signal (as demonstrated through oral glucose tolerance tests in alloxan-treated pigs) (Figure 3)) can be understood by calculating the total charge delivered (which is the area under the curve of the pulses during their delivery). For a 4-hour application of a 4-millisecond pulse width signal at 8 mA at 1 Hz, 0.004 seconds (pulse width) × 1 (pulses / second) × 14,400 seconds (for 4 hours of signal delivery) × 0.008 (Amp) = 0.4608 Coulombs. For a 1-minute application using the same parameters, 0.004 seconds (pulse width) × 1 (pulses / second) × 60 seconds (for 1 minute of signal delivery) × 0.008 (Amp) = 0.00192 Coulombs. This equates to 96% less charge delivered for 1 minute of a 1 Hz signal compared to a 4 hour signal. In other alternative embodiments, the charge using this low frequency protocol is delivered using at least 60% less charge, at least 65% less charge, at least 70% less charge, at least 75% less charge, at least 80% less charge, at least 85% less charge, or at least 90% less charge.

[0057] The combined total charge for 4 hours of HFAC and 1 Hz signal delivery = 51.84 coulombs + 0.4608 coulombs = 52.3008 coulombs. The combined total charge for 1 minute of HFAC and 1 Hz signal delivery = 0.216 coulombs + 0.00192 coulombs = 0.21792 coulombs. This equates to 96% less charge delivered for 1 minute of 5 kHz and 1 Hz signal compared to 4 hours of 5 kHz and 1 Hz signal.

[0058] The long-lasting effects of enhanced glycemic control achieved by 1-minute delivery of 5 kHz and 1 Hz to the subdiaphragmatic vagus nerve trunk are an example of plasticity in the glycemic control system, which can be used as a method to substantially increase the efficiency of neuromodulation to improve glycemic control in patients in need thereof. Plasticity can occur through neural or extraneural activity, where examples of extraneural activity are physiological processes within or between visceral organs that regulate plasma glucose concentrations. Examples of organs that regulate plasma glucose concentrations are the liver, pancreas, duodenum, skeletal muscle, or adipose tissue. Plastic changes can occur in one or more organs.

[0059] The electrical signal can be characterized by a plurality of stimulation waveform pulses or by the total charge delivered during application of the electrical signal. The waveform pulses can consist of a fixed frequency of pulses or a burst of pulses. A burst of pulses consists of at least two pulses followed by the delivery of at least two more pulses separated by an inter-burst interval (see FIG. 4).

[0060] As shown in FIG. 4, the inter-burst interval is greater than the time separating the two or more pulses. The time separating the two or more pulses is called the intra-burst interval. The intra-burst interval is less than the inter-burst interval. A burst containing multiple pulses is shown in FIG. 5. An example of burst stimulation using multiple pulses and multiple bursts is shown in FIG. 6. The burst stimulation may not have a fixed intra-burst interval (see FIG. 7). The burst stimulation may not have a fixed inter-burst interval (FIG. 8). The frequency of the intra-burst interval may range from 1 to 199 Hz. The inter-burst interval may range from 1 second to 20 seconds. The duration of the burst stimulation may last from about 10 seconds to about 30 minutes.

[0061] The electrical signal may be delivered at a fixed, continuous frequency. The frequency may range from 0.01 Hz to 199 Hz. The duration of application of the electrical signal delivered at a fixed frequency may last from about 1 second to about 1 hour.

[0062] The waveform characteristics may consist of a square wave monophasic pulse, a square wave biphasic pulse, a sine wave pulse, a triangular wave pulse, or a sawtooth wave pulse with a base-peak amplitude of 0.01 mA to 20 mA. The square wave pulse width may range from 0.01 msec to 20 msec.

[0063] The electrical signal can be characterized by the total charge delivered, regardless of waveform characteristics or pulse delivery pattern (bursting frequency or fixed continuous frequency application). Charge ranges include 1.25×10 -6 ~286 coulombs, 2.5 x 10 -5 ~0.288 coulombs, 3.2 × 10 -3 ~0.16 coulombs, or about 1.28×10 -2 Coulomb, 9.38 x 10 -5 ~0.144 coulombs, 9.6 x 10 -3 ~4.8×10 -2 Coulombs, or approximately 1.2 x 10 -2 Coulomb is one example.

[0064] Delivery of the burst or fixed frequency electrical signal can occur one or more times per day, or once per week, or once per month. [Example]

[0065] (Example) Example 1

[0066] Blockade (at 5000 Hz) and stimulation (at 1 Hz) increased glycemic control in the Zucker rat model of type 2 diabetes.

[0067] Experiments were performed on a well-established Zucker rat model of type 2 diabetes. The experiments consisted of five conditions: sham operation (n = 6), vagotomy plus stimulation (vagotomy at site 3 on Figure 9, stimulation at site 4 on Figure 9 at 1 Hz) (n = 4), block of the hepatic vagus nerve branch (at site 3 on Figure 9) with simultaneous stimulation of the celiac branch of the vagus nerve (at 1 Hz, site 4 on Figure 9) (n = 5), hepatic vagotomy alone (at site 3 on Figure 9, n = 4), and celiac stimulation (site 4 on Figure 9, at 1 Hz) alone (n = 4). The area under the curve (AUC, area units = glucose) of the intravenous glucose tolerance test (IVGTT) was measured. * Glucose responses were quantified using established methods to calculate time (AU). Comparisons between the tested condition and sham consisted of Student's t-tests. A significance level of ≦0.5 was considered significant, and data are expressed as mean ± standard error of the mean (SEM).

[0068] To reduce the significant variability in fasting plasma glucose (FPG) between animals (ranging from approximately 200 mg / dL to approximately 300 mg / dL), changes in glucose were normalized to baseline glucose. One hour after these procedures, an IVGTT was administered as described by Nagase et al., the disclosure of which is incorporated herein in its entirety.

[0069] In the block and stimulation group (applied 15 minutes before and throughout the 30-minute IVGTT) and the vagotomy + stimulation group, there was a significant and sustained decrease in AUC compared to the sham group (sham = 1543 ± 257 AU; vagotomy + stimulation = 618 ± 111 AUC, p < 0.01; block and stimulation = 898 ± 68 AUC, p < 0.05). In the hepatic vagotomy alone group and the stimulation alone group, there was no significant difference in AUC compared to the sham group after challenge. 15 minutes after the cessation of block and stimulation, a second glucose injection induced a large increase in plasma glucose AUC, which was not significant compared to the subsequent glucose injection in the sham group (sham second injection, AUC = 2603 ± 310 AU; block and stimulation second injection, AUC = 1820 ± 301 AU, p = 0.15). This suggests functional recovery. The rats showed impaired glucose tolerance after cessation of block and stimulation. Furthermore, the increase in glycemic control in the block and stimulation group was similar to that in the vagotomy + stimulation group, indicating that 5000 Hz mimicked vagotomy and suggesting a reversible electrical conduction block.

[0070] Without wishing to be bound by any particular theory, mechanisms contributing to the effects of blockade and stimulation in these experiments may include, but are not limited to, the following: reduced insulin resistance (a key feature of type 2 diabetes). Second, liver blockade causing a decrease in PPARα expression. Third, release of peritoneal afferent axons from inhibition, resulting in increased insulin release. Fourth, decreased liver sensitivity to glucagon due to liver blockade. Fifth, insulin release due to peritoneal stimulation. It should be understood that any one or combination of the above mechanisms can be utilized to obtain effective blockade and / or stimulation. Regardless of the mechanism, the combination of stimulation and blockade appears to be superior to either condition alone in terms of increasing glycemic control (the ultimate goal of T2DM treatment).

[0071] Example 2

[0072] (Electrophysiological experiments on isolated porcine subdiaphragmatic vagus nerves)

[0073] In isolated subdiaphragmatic electrophysiology stimulation experiments (n = 3), pig vagus nerves were suspended over two electrodes in oil. One bipolar electrode was used for stimulation (biphasic square wave), and the other was used to record compound action potentials (CAPs, conduction velocity <1 m / s). The nerve was stimulated at 1 Hz, with the anode contact closest to the recording electrode. Strength-time curves were then generated using a chronaxie of 1.27 ± 0.24 m / s and a rheobase of 3.67 ± 0.72 mA. A current amplitude of 8 mA with a 4 ms pulse width maximized CAP amplitude. This combination was used in this pig experiment to demonstrate proof-of-concept and safety.

[0074] In an isolated subdiaphragmatic vagus nerve block experiment (n = 6), the vagus nerve was suspended over four electrodes in oil. These electrodes consisted of a distal stimulating electrode, an electrode delivering 5000 Hz HFAC, a proximal control electrode for testing stimulation, and a recording electrode. CAPs (conduction velocities <1 m / s) due to stimulation of the distal and proximal electrodes were detected by the recording electrode before and within 1 second after the 5000 Hz stimulation for 1 minute.

[0075] A decrease in CAP amplitude with proximal stimulation indicates stimulation induced by 5000 Hz, and a decrease in CAP with distal stimulation indicates conduction block induced by 5000 Hz. At 8 mA, complete conduction block was achieved with little to no stimulation, and this amplitude was used in the in vivo pig experiments. It should be noted that block may occur at current amplitudes other than 8 mA, depending on electrode geometry, electrode-nerve contact, and impedance.

[0076] Example 3

[0077] In alloxan-treated pigs, adding stimulation to the block was superior to the block alone.

[0078] There are mixed reports regarding whether hepatic vagotomy increases glycemic control. This raises the question of whether HFAC-induced blockade (at 5000 Hz) is sufficient to increase glycemic control, or whether additional stimulation is necessary to increase glycemic control. To address this, we evaluated HFAC in a porcine model of type 2 diabetes. An animal model of type 2 diabetes was created by alloxan treatment in Yucatan pigs. After alloxan, the pigs became glucose intolerant as indicated by impaired performance in an IVGTT (Figures 10A, 10B, 11A, and 11B), but the pigs were not insulin-dependent (indicating a type 2 diabetic state). Glycemic control was assessed using an oral glucose tolerance test (OGTT). The OGTT consisted of oral ingestion of 75 g of glucose dissolved in 100 mL of diet Gatorade. We found that there was no difference in glycemic control between sham and hepatic branch HFAC block alone (block applied at site 1 in Figure 9). There was a significant increase in glycemic control with block and stimulation (stimulation location shown at site 2 in Figure 9) compared with sham and block alone. Neuromodulation to enhance glycemic control may not be limited to the combination of block and stimulation. This example serves to demonstrate that neuromodulation of the subdiaphragmatic vagus trunk and branches retains the ability to affect glycemic control and that stimulation may enhance the effects of block under these conditions.

[0079] Example 4

[0080] (Safety on organ systems innervated by the celiac and hepatic branches of the vagus nerve has been successfully demonstrated after block and stimulation experiments).

[0081] After one month of block and stimulation in alloxan-treated type 2 diabetic pigs, brain, liver, and pancreas sections were prepared for histopathological analysis. No damage to the vagus nerve was observed at the site of the TDN-delivering electrode. Brain sections were considered within normal limits. Clear areas were present surrounding many of the cells and vasculature in the sections. This has been reported as a process artifact in neural tissue. While edema cannot be completely ruled out, it is considered unlikely given the absence of any other overt pathological changes. Liver sections showed mild changes (edematous changes, bile duct enlargement) that may be related to the alloxan-induced model. Two of the four animals had increases in gamma-glutamyltransferase (GGT) over the course of the study, which can be seen with bile duct enlargement. These increases were very mild and may not be clinically significant. There was also a gross and histopathological fibrous connective tissue reaction associated with the device leads. This is an expected reaction to a foreign body and may not be clinically significant. The most striking finding in this study was in the histological examination of the pancreatic tissue. Many of the changes may be associated with islet cell atrophy, vacuolation, necrosis, and apoptosis in the alloxan model, which have been reported in alloxan-treated animals. Similar findings, such as islet atrophy, vacuolation, necrosis, and apoptosis, were observed in the pancreases of control alloxan-treated pigs that did not receive the blocking or stimulating signals. Overall, the tissues were healthy or had mild changes. This may not be clinically significant.

[0082] Example 5

[0083] One-minute block and stimulation experiments demonstrate plasticity of glycemic control by subphrenic nerve modulation in alloxan-treated pigs with type 2 diabetes.

[0084] Previous exemplary experiments showed that continuous HFAC (8 mA at 5000 Hz) delivery to the subdiaphragmatic hepatic branch of the vagus nerve (site of 5000 Hz block shown as site 1 on Figure 9) followed by simultaneous stimulation (8 mA at 1 Hz, 4 ms pulse width) to the subdiaphragmatic celiac branch of the vagus nerve (site of stimulation shown as site 2 on Figure 9) increased glycemic control during a 4-hour OGTT in alloxan-treated pigs (Figures 12A, 12B, 13A, and 13B). It was also shown that continuous HFAC (5000 Hz, 8 mA) delivery to the subdiaphragmatic hepatic branch of the vagus nerve, followed by simultaneous stimulation of the subdiaphragmatic celiac branch of the vagus nerve (1 Hz, 8 mA, 4 ms pulse width) during only the first 30 minutes of a 4-hour OGTT, increased glycemic control in alloxan-treated pigs (Figure 14). This indicates that intermittent delivery of block (5000 Hz) and stimulation (1 Hz) signals delivered to the subdiaphragmatic vagus nerve can blunt glucose spikes even without prolonged signal application. For example, a 30-minute delivery time was comparable to a 4-hour delivery time. This intermittent delivery reduces power consumption by 8-fold. Further experiments were performed to determine whether shorter durations of block and stimulation could increase glycemic control.

[0085] Delivery of HFAC (5000 Hz, 8 mA) for 1 minute to the subdiaphragmatic hepatic branch of the vagus nerve (site 1 in Figure 9) followed by simultaneous stimulation (1 Hz, 8 mA, 4 ms pulse width) to the subdiaphragmatic celiac branch of the vagus nerve (site 2 in Figure 9) significantly reduced glycemic control, as observed by a decrease in fasting plasma glucose (FPG). Fasting plasma glucose (FPG) before the 1-minute signal was 142 ± 12 mg / dL (range 117–207 mg / dL), which significantly decreased to 76 ± 6 mg / dL (range 63–91 mg / dL; Figure 15; p = 0.00092, Student's t-test, n = 4 pigs; data were normally distributed by the Shapiro-Wilk test) 1 day after the signal was terminated (see timeline shown in Figure 16). These results demonstrate two differentiation factors compared to previous experimental data, as well as the location of neuromodulation typically performed in the field of vagus nerve stimulation for the treatment of diseases (e.g., epilepsy and depression). The prolonged increase in glycemic control after the end of block and stimulation indicates plasticity of the glycemic control system induced by neuromodulation using only a 1-minute application (compared to the 30 minutes or 4 hours performed in previous experiments). This short-term neuromodulation is typically used to induce synaptic plasticity using bursty or fixed continuous frequencies.

[0086] Another differentiating feature of the present disclosure is reduced off-target effects compared to established vagus nerve stimulation paradigms. Clinically, vagus nerve stimulation is used to treat epilepsy and treatment-refractory depression using stimulation localized to the cervical region of the vagus nerve. This stimulation site causes unwanted off-target effects (e.g., effects on speech due to stimulation of laryngeal muscles caused by vagal currents, changes in heart rate, blood pressure, and respiration). Neuromodulation of the vagus nerve to limit (or neutralize) these off-target effects is desirable. In one set of experiments, we tested the hypothesis that subdiaphragmatic vagus nerve stimulation using our system can affect pancreatic activity and plasma glucose without inducing changes in heart rate, blood pressure, and respiration. In these experiments, 5 Hz stimulation was applied to the celiac branch of the vagus nerve in pigs (the site of stimulation shown as site 4 in Figure 9). This induced a decrease in plasma glucose and an increase in plasma insulin without causing changes in heart rate (Figure 17A). Furthermore, no changes in blood pressure or respiration (as assessed by changes in oxygen saturation) were observed during subdiaphragmatic stimulation (Figures 17B and 17C). Finally, because the stimulation was not performed in a cervical position, the expected laryngeal muscle stimulation would not have been present due to the distance from these muscles. The ability to influence blood glucose through vagal neuromodulation without off-target effects on the heart, blood pressure, or respiration, while simultaneously reducing or eliminating effects on speech, allows for greater flexibility in selecting stimulation parameters to induce the desired effect on blood glucose. These stimulation parameters include pulse amplitude, pulse width, duration of neuromodulation application, and type of neuromodulation (e.g., application of a burst frequency or a fixed continuous frequency).

[0087] Other diseases that can be treated by inducing plasticity with subdiaphragmatic stimulation include (but are not limited to) obesity, diseases caused by inflammation, autoimmune diseases, organ transplant rejection, pancreatitis, hypertension, and cancer.

[0088] Although the present disclosure has been described with respect to one or more particular embodiments, it will be understood that other embodiments of the present disclosure can be made without departing from the scope of the present disclosure.

[0089] Further examples and embodiments of the present disclosure are disclosed in the following enumerated sections: 1. A system for altering plasticity in a target, comprising: At least two electrodes operably connected to an implantable pulse generator Equipped with At least one of the electrodes is adapted to be placed at a target to alter the plasticity. system. 2. The implantable pulse generator comprises: a power module and a programmable therapy delivery module configured to deliver at least one therapy program including an electrical signal treatment applied to the target, the electrical signal having a frequency selected to initiate activity in the target; and an external component comprising a communication system and a programmable storage and communication module, the programmable storage and communication module configured to store the at least one therapy program and communicate the at least one therapy program to the implantable pulse generator, the activity being nerve stimulation or nerve block; Equipped with Item 1 system. 3. The system of item 2, wherein the electrical signal treatment is applied continuously to the target nerve. 4. The system of item 2, wherein the electrical signal treatment is burst neuromodulation applied to the target. 5. The system of any one of items 1 to 4, wherein the electrical signal has an on time and an off time, the off time being selected to allow at least partial recovery of activity of the target nerve. 6. The system of any one of items 1 to 5, wherein the off time is configured to begin upon detecting a blood glucose level between 80 mg / dL and 110 mg / dL. 7. The system of any one of items 1 to 6, wherein the communication system is selected from the group consisting of antenna, Bluetooth® technology, radio frequency, WIFI, light, sound, and combinations thereof. 8. The system of any one of items 1 to 7, wherein the at least one electrode is adapted to be placed in an organ selected from the spleen, stomach, duodenum, pancreas, liver, and ileum. 9. The system of any one of items 1-8, wherein the at least one electrode is adapted to be placed on a target, and the target is a nerve selected from the group including the vagus nerve, a splanchnic nerve, a hepatic branch of the vagus nerve, a celiac branch of the vagus nerve, and combinations thereof. 10. The system of any one of items 1-9, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency of at least 200 Hz. 11. The system of any one of items 1-9, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency between 500 Hz and 5 kHz, between 1 kHz and 10 kHz, or between 10 kHz and about 80 kHz. 12. The system of any one of items 1-9, wherein the programmable therapy delivery module is configured to deliver HFAC, low frequency stimulation, or burst stimulation signals. 13. The system of item 12, wherein the current amplitude of the HFAC, low frequency stimulation, or burst stimulation signal is between 0.1 mA and 20 mA. 14. The system of any one of items 12 to 13, wherein the pulse width for the low frequency stimulation signal or burst stimulation signal is between 0.01 ms and 10 ms. 15. The system of any one of items 12 to 13, wherein the frequency of the low-frequency stimulation signal is 0.01 Hz to 199 Hz, 0.1 to 10 Hz, 10 Hz to 30 Hz, 30 Hz to 100 Hz, or 100 Hz to 199 Hz. 16. The total volume of the implantable pulse generator is 0.5 in. 3 , 1in. 3 , 1.5in. 3 , 1.75in. 3 , or 2.0in. 3 Not to exceed one system of items 1 to 15. 17. The system of any one of items 1-16, wherein the combined total charge of the HFAC and 1 Hz signal delivered over 1 minute is less than 0.40 coulombs. 18. A system of any one of items 1 through 16 in which the delivery of a 5 kHz signal over a 1-minute period is at least 90% less than the same 5 kHz signal delivered over a 4-hour period. 19. The system of any one of items 1 to 18, wherein the electrical signal is delivered for 1 second to 1 hour. 20. The system of any one of items 12 to 18, wherein the electrical signal is a burst signal, and the burst signal is delivered for about 10 seconds to about 30 minutes. 21. The system of any one of items 1 to 20, wherein the system for inducing plasticity is delivered to a subdiaphragmatic target. 22. The system of any one of items 1 to 21, wherein the system treats a disease selected from the group including obesity, inflammation, autoimmune disease, organ transplant rejection, pancreatitis, hypertension, cancer, and any combination thereof. 23. The system of any of items 1-22, wherein the programmable therapy delivery module is configured to deliver an electrical signal having an off time of at least 30 minutes between second electrical treatment applications. 24. The system of any of items 1 to 23, wherein the programmable storage and communication module is configured to store and communicate more than one treatment program, each treatment program being different from the others and configured to be selected for communication. 25. The system of any of items 1-24, wherein the programmable therapy delivery module is configured to deliver a second therapy program including an electrical signal treatment applied to a second target, the second target being a nerve or an organ. 26. The system of any of items 1 to 25, wherein the second target nerve is a splanchnic nerve or the celiac branch of the vagus nerve, or the dorsal vagus nerve central to the branching point of the celiac nerve. 27. Applying an electrical signal to a target nerve or organ using the system of any one of items 1 to 26. 10. A method for altering plasticity in a target, comprising: 28. Applying an electrical signal to a target nerve or organ in a subject having impaired glucose regulation using the system of any one of items 1 to 26. 10. A method for altering plasticity in a target, comprising: 29. Applying an electrical signal to a target nerve or organ in a subject with type 2 diabetes using the system of any one of items 1 to 26. 10. A method for altering plasticity in a target, comprising: 30. The method of any one of items 27 to 29, further comprising administering an agent that improves glucose control. 31. The method of item 30, wherein the agent increases the amount of insulin and / or increases the sensitivity of cells to insulin. 32. The method of item 31, wherein the agent that increases the amount of insulin is selected from the group consisting of insulin, insulin analogs, sulfonylureas, meglitinides, GLP-1 analogs, GLP-1 antagonists, and DPP4 inhibitors. 33. The method of item 32, wherein the agent that increases the sensitivity of cells to insulin is a PPAR α, γ, or δ agonist. 34. The method of any one of items 27-33, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency of at least 200 Hz. 35. The method of any one of items 27-33, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency between 500 Hz and 5 kHz, between 1 kHz and 10 kHz, or between 10 kHz and about 80 kHz. 36. The method of any one of items 27-33, wherein the programmable therapy delivery module is configured to deliver HFAC, low frequency stimulation, or burst stimulation signals. 37. The method of item 36, wherein the current amplitude of the HFAC, low frequency stimulation, or burst stimulation signal is between 0.1 mA and 20 mA. 38. The method of any one of items 36 to 37, wherein the pulse width for the low-frequency stimulation signal or burst stimulation signal is between 0.01 ms and 10 ms. 39. The method of any one of items 36 to 37, wherein the frequency of the low-frequency stimulation signal is 0.01 Hz to 199 Hz, 0.1 to 10 Hz, 10 Hz to 30 Hz, 30 Hz to 100 Hz, or 100 Hz to 199 Hz. 40. The total volume of the implantable pulse generator is 0.5 in. 3 , 1in. 3 , 1.5in. 3 , 1.75in. 3 , or 2.0in. 3 Any one of the methods from items 27 to 39, not exceeding 41. The method of any one of items 27-40, wherein the combined total charge of the delivery of the HFAC and 1 Hz signals for 1 minute is less than 0.40 coulombs. 42. Any one of the methods of items 27-41, in which the delivery of a 5 kHz signal over one minute is at least 90% less than the same 5 kHz signal delivered over a four-hour period. 43. The method of any one of items 27 to 42, wherein the electrical signal is delivered for 1 second to 1 hour. 44. The method of any one of items 27 to 43, wherein the electrical signal is a burst signal, and the burst signal is delivered for about 10 seconds to about 30 minutes. 45. The method of any one of items 27 to 44, wherein the system for inducing plasticity is delivered to a subdiaphragmatic target. 46. ​​The method of any one of items 27 to 45, wherein the system treats a disease selected from the group including obesity, inflammation, autoimmune disease, organ transplant rejection, pancreatitis, hypertension, cancer, and any combination thereof. 47. The method of any one of items 27-46, wherein the programmable therapy delivery module is configured to deliver an electrical signal having an off time of at least 30 minutes between second electrical treatment applications. 48. The method of any one of items 27 to 47, wherein the programmable storage and communication module is configured to store and communicate more than one treatment program, each treatment program being different from the others and configured to be selected for communication. 49. The method of any one of items 27-48, wherein the programmable therapy delivery module is configured to deliver a second therapy program including an electrical signal treatment applied to a second target, the second target being a nerve or an organ. 50. The method of any one of items 27 to 49, wherein the second target nerve is a splanchnic nerve or the celiac branch of the vagus nerve, or the dorsal vagus nerve central to the branching point of the celiac nerve. 51. The method of any one of items 27 to 50, wherein the system delivers a signal in a closed loop system.

Claims

1. 1. A system for altering plasticity in a target, comprising: At least two electrodes operably connected to an implantable pulse generator. Equipped with At least one of the electrodes is adapted to be placed at a target to alter the plasticity. system.

2. the implantable pulse generator comprising: a power module and a programmable therapy delivery module configured to deliver at least one therapy program including an electrical signal treatment applied to the target, the electrical signal having a frequency selected to initiate activity in the target; and an external component comprising a communication system and a programmable storage and communication module configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator, the activity being nerve stimulation or nerve block; Equipped with The system of claim 1 .

3. The system of claim 2 , wherein the electrical signal treatment is applied continuously to the target nerve.

4. The system of claim 2 , wherein the electrical signal treatment is burst neuromodulation applied to the target.

5. 5. The system of claim 1, wherein the electrical signal has an on time and an off time, the off time selected to allow at least partial recovery of activity of the target nerve.

6. The system of any one of claims 1 to 5, wherein the off time is configured to begin upon detecting a blood glucose level between 80 mg / dL and 110 mg / dL.

7. The system of any one of claims 1 to 6, wherein the communication system is selected from the group consisting of antenna, Bluetooth technology, radio frequency, WIFI, light, sound and combinations thereof.

8. The system of any one of claims 1 to 7, wherein the at least one electrode is adapted to be placed in an organ selected from the spleen, stomach, duodenum, pancreas, liver and ileum.

9. 9. The system of claim 1, wherein the at least one electrode is adapted to be placed on a target, the target being a nerve selected from the group including the vagus nerve, a splanchnic nerve, a hepatic branch of the vagus nerve, a celiac branch of the vagus nerve, and combinations thereof.

10. The system of any one of claims 1 to 9, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency of at least 200 Hz.

11. 10. The system of any one of claims 1 to 9, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency between 500 Hz and 5 kHz, between 1 kHz and 10 kHz, or between 10 kHz and about 80 kHz.

12. The system of any one of claims 1 to 9, wherein the programmable therapy delivery module is configured to deliver HFAC, low frequency stimulation, or burst stimulation signals.

13. 13. The system of claim 12, wherein the current amplitude of the HFAC, low frequency stimulation or burst stimulation signal is between 0.1 mA and 20 mA.

14. The system of any one of claims 12 to 13, wherein the pulse width for the low frequency stimulation signal or burst stimulation signal is between 0.01 ms and 10 ms.

15. 14. The system of claim 12, wherein the low-frequency stimulation signal has a frequency of 0.01 Hz to 199 Hz, 0.1 to 10 Hz, 10 Hz to 30 Hz, 30 Hz to 100 Hz, or 100 Hz to 199 Hz.

16. The implantable pulse generator has a total volume of 0.5 in. ３ , 1 in. ３ , 1.5 in. ３ , 1.75 in. ３ , or 2.0 in. ３ The system according to any one of claims 1 to 15, wherein the

17. 17. The system of any one of claims 1 to 16, wherein the combined total charge of the HFAC and 1 Hz signal delivered over 1 minute is less than 0.40 coulombs.

18. 17. A system according to any preceding claim, wherein delivery of a 5 kHz signal for 1 minute is at least 90% less than the same 5 kHz signal delivered for 4 hours.

19. The system of any one of claims 1 to 18, wherein the electrical signal is delivered for a period of between 1 second and 1 hour.

20. 19. The system of any one of claims 12 to 18, wherein the electrical signal is a burst signal, and the burst signal is delivered for about 10 seconds to about 30 minutes.

21. The system of any one of claims 1 to 20, wherein the system for inducing plasticity is delivered to a subdiaphragmatic target.

22. 22. The system of any one of claims 1 to 21, wherein the system treats a disease selected from the group comprising obesity, inflammation, autoimmune diseases, organ transplant rejection, pancreatitis, hypertension, cancer, and any combination thereof.

23. 23. The system of any of claims 1-22, wherein the programmable therapy delivery module is configured to deliver an electrical signal having an off time of at least 30 minutes between second electrical treatment applications.

24. 24. The system of any of claims 1-23, wherein the programmable storage and communication module is configured to store and communicate more than one treatment program, each treatment program being different from the others and configured to be selected for communication.

25. 25. The system of any of claims 1-24, wherein the programmable therapy delivery module is configured to deliver a second therapy program comprising an electrical signal treatment applied to a second target, the second target being a nerve or an organ.

26. 26. The system of claim 1, wherein the second target nerve is a splanchnic nerve or the celiac branch of the vagus nerve, or the dorsal vagus nerve central to a branching point of the celiac nerve.

27. Applying an electrical signal to a target nerve or organ using a system according to any one of claims 1 to 26.

10. A method for altering plasticity in a target, comprising:

28. Applying an electrical signal to a target nerve or organ in a subject with impaired glucose regulation using the system of any one of claims 1 to 26.

10. A method for altering plasticity in a target, comprising:

29. Applying an electrical signal to a target nerve or organ in a subject with type 2 diabetes using a system according to any one of claims 1 to 26.

10. A method for altering plasticity in a target, comprising:

30. 30. The method of any one of claims 27 to 29, further comprising administering an agent that improves glucose control.

31. 31. The method of claim 30, wherein the agent increases the amount of insulin and / or increases the sensitivity of cells to insulin.

32. 32. The method of claim 31, wherein the agent that increases the amount of insulin is selected from the group consisting of insulin, insulin analogs, sulfonylureas, meglitinides, GLP-1 analogs, GLP-1 antagonists, and DPP4 inhibitors.

33. 33. The method of claim 32, wherein the agent that increases the sensitivity of a cell to insulin is a PPAR alpha, gamma, or delta agonist.

34. 34. The method of any one of claims 27 to 33, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency of at least 200 Hz.

35. 34. The method of any one of claims 27 to 33, wherein the programmable therapy delivery module is configured to deliver an electrical signal having a frequency between 500 Hz and 5 kHz, between 1 kHz and 10 kHz, or between 10 kHz and about 80 kHz.

36. 34. The method of any one of claims 27 to 33, wherein the programmable therapy delivery module is configured to deliver HFAC, low frequency stimulation, or burst stimulation signals.

37. 37. The method of claim 36, wherein the current amplitude of the HFAC, low frequency stimulation or burst stimulation signal is between 0.1 mA and 20 mA.

38. 38. The method of any one of claims 36 to 37, wherein the pulse width for the low frequency stimulation signal or burst stimulation signal is between 0.01 ms and 10 ms.

39. 38. The method of any one of claims 36 to 37, wherein the frequency of the low frequency stimulation signal is 0.01 Hz to 199 Hz, 0.1 to 10 Hz, 10 Hz to 30 Hz, 30 Hz to 100 Hz, or 100 Hz to 199 Hz.

40. The implantable pulse generator has a total volume of 0.5 in. ３ , 1 in. ３ , 1.5 in. ３ , 1.75 in. ３ , or 2.0 in. ３ The method of any one of claims 27 to 39, wherein the total amount of

41. 41. The method of any one of claims 27 to 40, wherein the combined total charge of the delivery of the HFAC and 1 Hz signals for 1 minute is less than 0.40 coulombs.

42. 42. The method of any one of claims 27 to 41, wherein delivery of a 5 kHz signal for 1 minute is at least 90% less than the same 5 kHz signal delivered for 4 hours.

43. 43. The method of any one of claims 27 to 42, wherein the electrical signal is delivered for a period of between 1 second and 1 hour.

44. 44. The method of any one of claims 27 to 43, wherein the electrical signal is a burst signal, and the burst signal is delivered for about 10 seconds to about 30 minutes.

45. 45. The method of any one of claims 27 to 44, wherein the system for inducing plasticity is delivered to a subdiaphragmatic target.

46. 46. ​​The method of any one of claims 27 to 45, wherein the system treats a disease selected from the group comprising obesity, inflammation, autoimmune diseases, organ transplant rejection, pancreatitis, hypertension, cancer, and any combination thereof.

47. 47. The method of any one of claims 27 to 46, wherein the programmable therapy delivery module is configured to deliver an electrical signal having an off time of at least 30 minutes between second electrical treatment applications.

48. 48. The method of any one of claims 27 to 47, wherein the programmable storage and communication module is configured to store and communicate more than one treatment program, each treatment program being different from the others and configured to be selected for communication.

49. 49. The method of any one of claims 27-48, wherein the programmable therapy delivery module is configured to deliver a second therapy program comprising an electrical signal treatment applied to a second target, the second target being a nerve or an organ.

50. 50. The method of any one of claims 27 to 49, wherein the second target nerve is a splanchnic nerve or the celiac branch of the vagus nerve, or the dorsal vagus nerve central to a branching point of the celiac nerve.

51. The method of any one of claims 27 to 50, wherein the system delivers the signal in a closed loop system.

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