WO2022212646A1

WO2022212646A1 - Neuromodulation system and methods for the treatment of a hypoglycemic state

Info

Publication number: WO2022212646A1
Application number: PCT/US2022/022746
Authority: WO
Inventors: Jonathan J. Waataja; Raj Nihalani
Original assignee: Reshape Lifesciences, Inc.
Priority date: 2021-04-01
Filing date: 2022-03-31
Publication date: 2022-10-06
Also published as: EP4313273A1

Abstract

Neuroregulation systems and methods for treatment or control of hypoglycemia are provided. In one example, a method of treating hypoglycemia in a subject comprises: applying a first electrical signal to a first nerve or organ of the subject using a neuroregulation system, wherein the first electrical signal initiates a neural stimulation or a neural block on the first nerve or organ of the subject; and optionally applying a second electrical signal to a second nerve or organ of the subject, wherein the second electrical signal initiates a neural stimulation or a neural block on the second nerve or organ of the subject.

Description

NEUROMODULATION SYSTEM AND METHODS FOR THE TREATMENT

OF A HYPOGLYCEMIC STATE

CROSS-REFERENCE TO RELATED APPLICATION

This application is being filed on March 31, 2022, as a PCT Patent International Application that claims priority to and the benefit of U.S. Provisional Application No. 63/169,554 filed April 1, 2021, the disclosure of which is hereby incorporated in its entirety.

INTRODUCTION

Over thirty (30.3) million Americans are diabetic with 1.5 million new cases per year. Hypoglycemia negatively affects diabetics. The average Type 1 diabetic experiences two episodes of symptomatic hypoglycemia per week. Severe hypoglycemia (need for a 3^rd party assistance) has an annual incidence of 1.0 - 1.7 episodes per patient per year. Every year 73% of insulin dependent Type 2 diabetics experience hypoglycemic episodes and 15% have severe episodes. Hypoglycemia can cause loss of consciousness, stroke, coma or death. Repeated hypoglycemic episodes have been linked to cardiovascular disease. There are about 235,000 emergency department visits/year to treat diabetic hypoglycemia that cost the health care system is about $120M/yr. Severe nocturnal hypoglycemia is suspected to contribute to an estimated 6% of all deaths in patients with diabetes below 40 years of age, which can lead to high levels of anxiety. Recent reports indicate that 10% of deaths of patients with Type 1 diabetes were caused by hypoglycemia. For diabetics hypoglycemia primarily results from diabetic medications such as sulfonylureas and more commonly insulin treatment.

With the increasing proportion of the population suffering from Type 2 diabetes mellitus (T2DM), hypoglycemia is becoming a problem in this diabetic segment.

Insulin therapy in Type 2 diabetes is mainly prescribed at the later stages of the disease (HbAlc about 9% or greater). This segment of T2DM population is large and growing with a totaling of 80 million patients worldwide. Henderson et al reported that 73% of insulin dependent T2DM subjects experience hypoglycemic episodes each year and 15% have severe episodes (Henderson, 2003). Treatments for hypoglycemia typically involve injection of dextrose or glucagon and/or consumption of a fast-acting carbohydrate. However, these treatments are not ideal for nocturnal hypoglycemia and/or contraindicated for severe hypoglycemic episodes. Insulin pump therapy in conjunction with glucose sensor technology decreases the risk of hypoglycemia, but still remains a meaningful problem (Guzman, 2020; A1 Hayek, 2018). Less than 1% of insulin dependent diabetics use insulin pumps with issues of maintenance and tolerance required by the continuous use of an external device (Schade, 2006; Walsh, 2015; Bonfanti, 2016).

Therefore, there is need for new systems and methods for treatment of hypoglycemia.

NEUROMODULATION SYSTEM AND METHODS FOR THE TREATMENT OF THE HYPOGLYCEMIC STATE

The present disclosure provides neuromodulation/neuroregulation systems and methods for treating hypoglycemia.

It has been found that stimulation of various segments of the vagal nerve may increase plasma glucose (Ahren, 1986; Adrian, 1983; Meyers, 2016). These included stimulation of cervical and thoracic segments. However, there are inherent problems with stimulation at these sites including changes in cardiac output. Meyer et al. demonstrated a significant increase in glucose and glucagon with cervical stimulation, however, throughout the stimulation period there was a significant decrease in heart rate (Meyers, 2016).

A likely mechanism behind increased glucose during vagal nerve stimulation is pancreatic release of glucagon (Ahren, 1986; Meyers, 2016). This endocrine hormone is a member of the secretin family of hormones and acts on the liver to induce glycogenolysis and glucose release into the circulatory system. Glucagon producing alpha cells of the islet are preserved, or even augmented, in Type 1 diabetics (Seiron, 2019). Without wishing to be bond to any particular theory, it is believed that vagal nerve stimulation in diabetics may have a profound effect of increasing glucose then in non-diabetics in that endocrine hormone release would be primarily glucagon and not insulin due to beta cell destruction.

The present systems and methods have shown efficacy of treating a hypoglycemic condition. In particular, it was found that application of HVNS signals to the vagal nerve is found to effectively increase plasma glucose (PG) in diabetic animals to a safe level and/or increase glucagon release in the diabetic animals during hypoglycemia or following insulin injection.

The present systems and methods advantageously employ continuous glucose monitoring (CGM) technology to trigger sub-diaphragmatic posterior vagus nerve (PVN) stimulation when plasma glucose falls below a pre-determined threshold. The stimulation site on the PVN is located cranial to the celiac vagal nerve branch which innervates the pancreas. This is a clinical paradigm shift, such that HVNS therapy presents an innovative approach to treat hypoglycemia by challenging methodologies that are ineffective to treat nocturnal and sever hypoglycemia by offering at least one the following features: (1) A closed loop system to complement CGM technology, which triggers vagal nerve stimulation during hypoglycemia; (2) Fast increase of plasma glucose with HVNS; (3) Personalized medicine by external re-programmability of HVNS therapy parameters to meet the glycemic control needs of individual patients; (4) An on-demand autonomous system using the patient’s endogenous organ systems to increase glucose; (5) Cost effective in preventing emergency room visits; (6) Decrease co-morbidities associated with repeated hypoglycemic episodes; and (7) Enhance patient experience.

Summary of Disclosure

In some aspects, the present disclosure provides systems and methods for hypoglycemia vagal nerve stimulation (HVNS). In particular embodiments, the present HVNS system comprises an implantable pulse generator (IPG) in a closed loop with a continuous glucose monitor (CGM), stimulation electrodes/leads attachable to posterior vagus nerve (PVN) cranial to the celiac branch, a programmer to alter settings for therapeutic customization.

In some aspects, the present disclosure also provides a minimally invasive electrode implantation method. In particular embodiments, the present method includes implanting electrodes in a subject to be treated using a less invasive laparoscopic technique for optimal electrode placement with enhanced visualization of the posterior vagus nerve and celiac branch. This can be achieved by reliably locating the celiac branch laparoscopically for correct electrode placement on the PVN. In some aspects, the present disclosure provides various operating parameters for HVNS. In particular embodiments, implementation of the present method using selected operating parameters is effective to increase plasma glucose by at least about 20 mg/dL within about 30 min after treatment in a subject from a controlled clamped glucose level of 50 mg/dL.

In some aspects, the present disclosure provides the safety of stimulation on vagal nerve and end organs. From animal studies presented in the Examples of this disclosure, little-to-no adverse behavior or organ damage is observed as a result of stimulation or gross necropsy.

In some aspects, a system for treating hypoglycemia in a subject comprises: (1) at least one electrode adapted to be placed on and deliver electrical signal to a posterior vagus nerve (PVN) of the subject or the celiac vagus nerve branch of the PVN; (2) an implantable pulse generator operably connected to the at least one electrode, wherein the implantable pulse generator comprises a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program, wherein the at least one therapy program comprises at least one electrical signal treatment applied to the PVN through the at least one electrode, (3) an external component comprising a communication system and a programmable storage and communication module, wherein programmable storage and communication module are configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator, and (4) a glucose sensor operably connected to the implantable pulse generator and the external component, wherein the glucose sensor is configured to continuously monitor plasma glucose of the subject and to detect an increase or decrease of plasma glucose from a pre-determined threshold level, wherein, the implantable pulse generator is triggered to deliver the at least one electrical signal treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, wherein the implantable pulse generator ceases to deliver the at least one electrical signal treatment when the plasma glucose of the subject is of or above a second pre-determined threshold, wherein the at least one electrical signal treatment comprises an electrical signal pattern having a frequency from about 1 Hz to about 200 Hz, a pulse width from about 0.1 microseconds (ms) to about 10 ms in about 0.1 ms steps, a pulse amplitude from about 0.1 mA to about 12 mA in about 0.1 mA steps, and wherein the electrical signal treatment is configured to initiate neural stimulation on PVN of the subject.

In some embodiments, a method of treating hypoglycemia in a subject comprises: applying the at least one electrical signal treatment to a posterior vagus nerve (PVN) of a subject or the celiac vagus nerve branch of the PVN of the subject using the present system.

In another example, a system for treating hypoglycemia in a subject comprises: (1) a first electrode adapted to be placed on and deliver electrical signal to a first nerve or organ; (2) optionally a second electrode adapted to be placed on and deliver electrical signal to a second nerve or organ; (3) an implantable pulse generator operably connected to the first and/or the second electrode, wherein the implantable pulse generator comprises a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program comprising a first therapy program and optionally a second therapy program, wherein the first therapy program comprises a first electrical signal treatment applied to the first nerve or organ through the first electrode, wherein the second therapy program comprises a second electrical signal treatment applied to the second nerve or organ through the second electrode, and wherein the first and/or the second electrical signal are each configured to initiate activity on the first and/or the second nerve or organ respectively, and wherein the activity is a neural stimulation or a neural block; and (4) an external component comprising a communication system and a programmable storage and communication module, wherein programmable storage and communication module are configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

In some embodiments, a method of treating hypoglycemia in a subject, the method comprising: (1) applying a first electrical signal to a first nerve or organ of the subject using the system of claim 1, wherein the first electrical signal initiates a neural stimulation or a neural block; and (2) optionally applying a second electrical signal to a second nerve or organ of the subject using the system of claim 1, wherein the second electrical signal initiates a neural stimulation or a neural block.

In some embodiments, the first and/or the second electrical signal are each independently configured to upregulate or downregulate activity respectively on the first and/or second target nerve or organ. In some embodiments, the first and the second electrical signals are applied concurrently, or simultaneously, or intermittently, or during substantially the same times, or during substantially different times, or in a coordinated fashion. In some embodiments, the first and/or the second electrical signal treatments are each continuously applied to the first target nerve or organ and/or the second target nerve or organ respectively. In certain embodiments, the first electrical signal is an upregulation or stimulation signal.

In some embodiments, the method further comprises a glucose sensor configured to continuously monitor plasma glucose of the subject, wherein the glucose sensor is operably connected to the implantable pulse generator and the external component. In some embodiments, the glucose sensor is configured to detect an increase or decrease of plasma glucose from a pre-determined threshold level. In some embodiments, the implantable pulse generator is triggered to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, and wherein the implantable pulse generator ceases to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or above a second pre-determined threshold.

In some embodiments, the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof. In particular embodiments, the first nerve or organ is celiac branch of posterior vagus nerve.

In some embodiments, the first nerve or organ and the second nerve or organ are different. In some embodiments, the first electrical signal is applied on a hepatic branch of a vagus nerve or a ventral vagus nerve central to a branching point of a hepatic nerve. In some embodiments, the first electrical signal is applied on a celiac branch of a vagus nerve, or a ventral vagus nerve central to a branching point of a celiac nerve, or liver, pancreas, or both.

In some embodiments, the first and/or the second electrical signals each have an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first and/or the second nerve or organ. In some embodiments, the on time is configured to commence upon the detection of plasma glucose level of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL. In some embodiments, the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 5 mg/dL in about 10 minutes. In some embodiments, the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 10 mg/dL in about 20 minutes. In some embodiments, the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 20 mg/dL in about 30 minutes.

In some embodiments, the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, from about 0.1 Hz to about 100 Hz, or from about 1 Hz to about 20 Hz. In other embodiments, the first electrical signal has a frequency of about 200 Hz to about 10k Hz.

In some embodiments, the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz, from about 0.1 Hz to about 100 Hz, or from about 1 Hz to about 20 Hz. In other embodiments, the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

In some embodiments, the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

In some embodiments, the first electrical signal and/or the second electrical signal each independently comprise a signal pattern, wherein each signal pattern comprises a pulse having a pulse width from about 10 microseconds to about 10,000 microseconds.

In some embodiments, the pulse of the first and/or the second electrical signal is monophasic pulse, or biphasic pulse, or combinations thereof. In some embodiments, the first and/or the second electrical signal each independently have an on time of about 30 seconds to about 30 minutes. In some embodiments, the first and/or the second electrical signal each independently have a current amplitude in a range from about 0.01 mAmps to about 20 mAmps. In some embodiments, the first and/or the second electrical signal each independently comprise an abrupt start of pulses, or a ramp up of current/voltage amplitude, or a ramp up of frequency, or a ramping up of pulse widths, or combination thereof at or near initiation of applying the first and/or the second electrical signal.

In some embodiments, the first and/or the second electrical signal treatments are configured to be applied intermittently multiple times in a day and over multiple days, wherein the first and/or the second electrical signal each have a frequency selected to upregulate activity on the first nerve or organ and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first nerve or organ.

In some embodiments, the programmable storage and communication module are configured to store and communicate more than one therapy program, wherein each therapy program is different from one another, and is configured to be selected for communication.

In some embodiments, the system further comprises a transmitter operably connected to the glucose sensor, wherein the transmitter is configured to communicate data generated by the glucose sensor to an external communication device.

In some embodiments, the communication system is selected from a group consisting of an antenna, blue tooth technology, radio frequency, WIFI, light, sound and combinations thereof, and wherein the communication system is configured to communicate parameters of the at least one therapy program to an external communication device.

In some embodiments, a method of making a system for treating hypoglycemia in a subject comprises: (1) connecting a first electrode to an implantable pulse generator and placing the first electrode to a first nerve or organ; (2) optionally connecting a second electrode to the implantable pulse generator and placing the second electrode to a second nerve or organ; (3) configuring a programmable therapy delivery module of the implantable pulse generator to deliver at least one therapy program comprising a first electrical signal treatment and optionally a second electrical signal treatment, wherein the first electrical signal treatment is configured to be applied to the first nerve or organ through the first electrode, and the second electrical signal treatment is configured to be applied to the second nerve or organ through the second electrode, and wherein the first and/or the second electrical signal each initiate a neural stimulation or a neural block; and (4) configuring a programmable storage and communication module of an external component to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

Definition and Interpretation of Selected Terms

The term “about” is not intended to either expand or limit the degree of equivalents which may otherwise be afforded a particular value. The term “about” in the context of the present disclosure means a value within 10 % (±10 %) of the value recited immediately after the term “about,” including any numeric value within this range, the value equal to the upper limit (i.e., + 10 %) and the value equal to the lower limit (i.e., -10 %) of this range. For example, the value "100" encompasses any numeric value that is between 90 and 110, including 90 and 110 (with the exception of “100 %,” which always has an upper limit of 100 %).

In some instances, one or more components may be referred to herein as “configured to,” “configurable to,” “operable/operative to,” “adapted/adaptable,” “able to,” “conformable/conformed to,” etc. Those skilled in the art will recognize that such terms (e.g., “configured to”) can generally encompass active-state components and/or inactive-state components and/or standby-state components, unless context requires otherwise.

“Cycle” as used herein means one repetition of a repetitive pattern of electrical signals. “Stimulation cycle” particularly refers to low frequency stimulation signal.

“Concurrently” used here in generally means that in situations where multiple electrical signals are applied, in at least one time period, the multiple electrical signals are applied simultaneously or about the same time.

“Duty Cycle” as used herein means the percentage of time charge is delivered to the nerve in one cycle. In embodiments, duty cycle can be modified by decreasing pulse width and/or by adding inactive phases between pulses or both.

“Frequency” as used herein means the reciprocal of the period measured in

Hertz.

“High Duty Cycle” as used herein refers to a pattern of electrical signals with a duty cycle of about 76% or greater.

“Low Duty Cycle” as used herein refers to a pattern of signals with a duty cycle of about 75% or less. “High frequency” as used herein generally refers to a frequency of about 200 Hz or more. “High frequency signal” as used herein generally refers to HFAC or HFAV having a frequency of about 200 Hz or more. High frequency signal is particularly used to downregulate or block nerve activity.

“Low frequency” as used herein generally refers to a frequency of about 200 Hz or less.

“Low frequency signal” or “low frequency stimulation signal” as used herein generally refers to stimulation signal having a frequency of 199 Hz or less. Stimulation signal is particularly used to upregulate or stimulate nerve activity.

“HFAC” as used herein refers to high frequency alternating current.

“HFAV” as used herein refers to high frequency alternating voltage.

“Hz” as used herein refers to Hertz.

“Off Time” as used herein refers to a period when no charge is being delivered to the nerve. In embodiments, off time is on the order of seconds and/or minutes.

“On Time” refers to a period of time in which multiple micro and/or millisecond cycles and/or stimulation cycle and/or stimulation active phase are applied to the nerve. In embodiments, on time is on the order of seconds and/or minutes.

“Period” refers to the length of time of one charge phase and one recharge phase, which can include one or more pulse delays. “Stimulation period” particularly refers to the length of time of one charge phase and one recharge phase in a low frequency stimulation signal. Stimulation period can also include one or more pulse delays.

“Pulse Amplitude” is the height of the pulse in amperes or voltage relative to the baseline.

“Pulse Delay” as used herein refers to an aspect of the period wherein the impedance across a parallel electrical path with the nerve is at or close to 0 Ohms, with the intention of avoiding any unwanted electrical signals being delivered to the nerve.

“Pulse Width” as used herein refers to the length of time of the pulse.

“Ramp Down” as used herein refers to the period at the end of the application of an electrical signal, or between different patterns of electrical signals, to a nerve of a patient where the pulse amplitude of the signal decreases.

“Ramp Up” as used herein refers to increasing the pulse amplitude until the amplitude desired for therapy is reached at the start of an applied electrical signal or between different patterns of electrical signals. The starting amplitude of ramping may be below the current/voltage threshold of blocking.

“Therapy Cycle” as used herein refers to a discrete period of time that contains one or more on times and off times. The pattern of on and off times within the therapy cycle can be repetitive, non-fixed or randomized throughout a therapy schedule.

“Therapy Parameters” as used herein includes, but is not limited to, frequency, pulse width, pulse amplitude, on time, off time and pattern of electrical signals.

“Therapy Schedule” as used herein refers to the time of day when therapy cycles start, the number of therapy cycles, timing of therapy cycles and duration of the delivery of therapy cycles for at least one day of the week.

“Nerve” used herein generally encompasses a nerve or any part thereof, including but not limited to nerve branch, nerve fiber, trunk, branching point.

“Anterior vagus nerve (AVN)” or “anterior vagus trunk” distributes fibers on the anterior surface of the esophagus, and consists primarily of fibers from the left vagus. “Posterior vagus nerve (PVN)” or “posterior vagus trunk” consists primarily of fibers from the right vagal nerve distributed on the posterior surface of the esophagus. Anterior vagus nerve and posterior vagus nerve are two different and separate nerves.

“Hepatic branch” used herein refers to a nerve branch of the anterior vagus nerve below the diaphragm. Hepatic branch encompasses any segment of the anterior vagus nerve cranial to the hepatic branch. In particular, Hepatic branch carries afferent information from the pancreas to the brain and efferent information from the brain to the pancreas.

“Celiac branch” used herein generally refers to a nerve branch of the posterior vagus nerve below the diaphragm. Celiac branch encompasses any segment of the posterior vagus nerve cranial to celiac branch. In particular, celiac branch carries afferent information from the pancreas to the brain and efferent information from the brain to the pancreas.

“Celiac fiber” used herein refers to an afferent or efferent axon that travels within the length of the vagal nerve between the pancreas and the brain. The afferent axon travels from the pancreas through the celiac branch of the vagal nerve where it then travels into the posterior vagus below the level of the diaphragm. The afferent axon next enters the thoracic cavity and primarily into the right cervical segment. The afferent axon then enters the brainstem and form a synaptic connection. The efferent fiber is a part of the parasympathetic nervous system. The preganglionic cell body of the efferent fiber is in the brain stem and travels the length of the vagal nerve (similar to the afferent fiber) to its postganglionic neuron in close proximity to the pancreas.

“Hepatic fiber” used herein refers to an afferent or efferent axon that travels within the length of the vagal nerve between the liver and the brain. The afferent axon travels from the liver through the hepatic branch of the vagal nerve where it then travels into the anterior vagus below the level of the diaphragm. The afferent axon next enters the thoracic cavity and primarily into the left cervical segment. The afferent axon then enters the brainstem and form a synaptic connection. The efferent fiber is a part of the parasympathetic nervous system. The preganglionic cell body of the efferent fiber is in the brain stem and travels the length of the vagal nerve (similar to the afferent fiber) to its postganglionic neuron in close proximity to the liver.

When ranges are provided, the range includes both endpoint numbers as well as all real numbers in between. For example, a range of 200 Hz to 25kHz includes, for example, 201 to 25kHz, 202 to 25kHz, as well as 24,999 Hz to 200 Hz, 24,998 Hz to 200 Hz, and 201 Hz to 24,999 Hz, 202 Hz to 24,998 Hz.

With reference now to the various drawing figures in which identical elements are numbered identically throughout, a description of embodiments of the present disclosure will now be described.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. illustrates a schematic representation of an exemplary system comprising a pulse generator and leads comprising electrodes placed on an anterior vagus nerve (AVN) and posterior vagus nerve (PVN).

FIG. 2 illustrates a schematic representative of another exemplary system, in accordance with various embodiments of the present disclosure.

FIG. 3 illustrates an exemplary architecture of a computing device that can be used to implement aspects of the present disclosure.

FIG. 4 is a flowchart illustrating an exemplary method of operating the present system.

FIG. 5 illustrates another exemplary HVNS system in a disassembled configuration with individual components thereof, according to Example 1. FIG. 6 shows a schematic of system in which an implantable glucose sensor communicates with a pulse generator to initiate vagus nerve stimulation.

FIG. 7 shows a schematic of system in which an implantable glucose sensor communicates first with an external device attached to the outside of the skin which then communicates with the pulse generator to initiate vagus nerve stimulation.

FIG. 8 shows the change of plasma glucose level as a result of stimulation of the celiac branch of the vagus nerve in rat, according to Example 2. Stimulation started about 30 seconds following baseline measurement at time = 0.

FIG. 9 A illustrates an example of Type 1 diabetic swine with j acket to hold MC during charging session, according to Example 3.

FIG. 9B illustrates the change of plasma glucose level of the test swine, according to Example 3.

FIG. 10A illustrates an example of the test pig with subcostal incision, according to Example 4. FIG. 10B illustrates the relative position of PVN (yellow) and the celiac branch

(green, first major branching point of the PVN) in the test pig of FIG. 10A, according to Example 4.

FIG. 11 illustrates a flow chart of an experiment treatment for hypoglycemia, according to Example 5. A total of 30 minutes of stimulation is applied with the illustrated frequencies. DESCRIPTION

The particulars shown herein are by way of example and for purposes of illustrative discussion of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the disclosure, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

Therapy System In some aspects, the present disclosure provides systems and devices for treating a condition associated with hypoglycemia. The system generally includes a pulse generator that provides signals to modulate neural activity on a target nerve or organ.

In some embodiments, a system according to the present disclosure comprises at least one electrode operably connected to an implantable pulse generator, wherein the electrode is adapted to be placed on a target nerve and/or a target organ of a subject; an implantable pulse generator that comprises a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program comprising an electrical signal treatment applied intermittently multiple times in a day and over multiple days to the target nerve, wherein the electrical signal has a frequency selected to upregulate (for neural stimulation) nerve activity and/or downregulate (for neural block) on the target nerve and/or organ and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the target nerve or organ; and an external component comprising an antenna and a programmable storage and communication module, wherein programmable storage and communication module is configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

In some embodiments, the system may include two electrodes, e.g., a first electrode and a second electrode, each operably connected to the implantable pulse generator. The first electrode is adapted to be placed on and deliver electrical signal to a first nerve or organ of the subject. The second electrode is adapted to be placed on and deliver electrical signal to a second nerve or organ of the subject. The system may comprise at least two therapy program, e.g., a first therapy program and optionally a second therapy program. The first therapy program comprises a first electrical signal treatment applied to the first nerve or organ through the first electrode, and the second therapy program comprises a second electrical signal treatment applied to the second nerve or organ through the second electrode. The first and/or the second electrical signal are each configured to initiate activity on the first and/or the second nerve or organ respectively, and wherein the activity is a neural stimulation or a neural block.

Now referring to FIG. 1, one example system according to the present disclosure and various aspects thereof will be described. In the illustrated example, a system for treating hypoglycemia or a condition associated with hypoglycemia includes a pulse generator 104, an external mobile charger 101, and two electrical lead assemblies 106, 106a. The pulse generator 104 is adapted for implantation within a subject to be treated. In some embodiments, the pulse generator 104 is implanted just beneath a skin layer 103 of the subject. In related embodiments the system includes 1 or more pulse generators 104.

In some embodiments, the lead assemblies 106, 106a are electrically connected to the circuitry of the pulse generator 104 by conductors 114, 114a. Industry standard connectors 122, 122a are provided for connecting the lead assemblies 106, 106a to the conductors 114, 114a. As a result, leads 116, 116a and the pulse generator 104 may be separately implanted. Also, following implantation, lead 116, 116a may be left in place while the originally placed pulse generator 104 is replaced by a different pulse generator.

The lead assemblies 106, 106a upregulate and/or downregulate nerves of the subject based on the therapy signals provided by the neuroregulator 104. In one embodiment, the lead assemblies 106, 106a include distal electrodes 212, 212a, which are placed on one or more target nerves or target organs of the subject. For example, the electrodes 212, 212a may be individually placed on the celiac nerve, the vagal nerve, the celiac branches of the vagal nerve, the hepatic branches of the vagal nerve, or some combination of these, respectively, of the subject to be treated. For example, the leads 106, 106a have distal electrodes 212, 212a which are individually placed on the PVN and AVN, respectively, of the subject, for example, just below the patient’s diaphragm. Fewer or more electrodes can be placed on or near fewer or more nerves.

In some embodiments, only one electrode is placed on the PVN of the subject, and no more electrode is placed on any other nerve or organ of the same subject. In some embodiments, the electrodes are cuff electrodes.

The external mobile charger 101 includes circuitry for communicating with the implanted neuroregulator (pulse generator) 104. In some embodiments, the communication is a two-way radiofrequency (RF) signal path across the skin 103 as indicated by arrows A. Example communication signals transmitted between the external charger 101 and the neuroregulator 104 include treatment instructions, patient data, and other signals as will be described herein. Energy or power also can be transmitted from the external charger 101 to the neuroregulator 104 as will be described herein. In the example shown, the external charger 101 can communicate with the implanted neuroregulator 104 via bidirectional telemetry (e.g. via radiofrequency (RF) signals). The external charger 101 shown in FIG. 1 includes a coil 102, which can send and receive RF signals. A similar coil 105 can be implanted within the patient and coupled to the neuroregulator 104. In an embodiment, the coil 105 is integral with the neuroregulator 104. The coil 105 serves to receive and transmit signals from and to the coil 102 of the external charger 101.

For example, the external charger 101 can encode the information as a bit stream by amplitude modulating or frequency modulating an RF carrier wave. The signals transmitted between the coils 102, 105 preferably have a carrier frequency of about 6.78 MHz. For example, during an information communication phase, the value of a parameter can be transmitted by toggling a rectification level between half-wave rectification and no rectification. In other embodiments, however, higher or lower carrier wave frequencies may be used.

In one embodiment, the neuroregulator 104 communicates with the external charger 101 using load shifting (e.g., modification of the load induced on the external charger 101). This change in the load can be sensed by the inductively coupled external charger 101. In other embodiments, however, the neuroregulator 104 and external charger 101 can communicate using other types of signals.

In an embodiment, the neuroregulator 104 receives power to generate the therapy signals from an implantable power source 151 such as a battery. In a preferred embodiment, the power source 151 is a rechargeable battery. In some embodiments, the power source 151 can provide power to the implanted neuroregulator 104 when the external charger 101 is not connected. In other embodiments, the external charger 101 also can be configured to provide for periodic recharging of the internal power source 151 of the neuroregulator 104. In an alternative embodiment, however, the neuroregulator 104 can entirely depend upon power received from an external source. For example, the external charger 101 can transmit power to the neuroregulator 104 via the RF link (e.g., between coils 102, 105). In a further embodiment, charging of the rechargeable battery 151 in the neuroregulator 104, can be achieved by application of remote wireless energy. (Grajski et al, IEEE Microwave Workshop series on Innovative Wireless Power Transmission: Technology, Systems, and Applications, 2012 published on a4wp.org). In some embodiments, the neuroregulator 104 initiates the generation and transmission of therapy signals to the lead assemblies 106, 106a. In an embodiment, the neuroregulator 104 initiates therapy when powered by the internal battery 151. In other embodiments, however, the external charger 101 triggers the neuroregulator 104 to begin generating therapy signals. After receiving initiation signals from the external charger 101, the neuroregulator 104 generates the therapy signals (e.g., pacing signals) and transmits the therapy signals to the lead assemblies 106, 106a.

In other embodiments, the external charger 101 also can provide the instructions according to which the therapy signals are generated (e.g., pulse-width, amplitude, frequency, wave phase, and other such parameters). In some embodiments, the external component comprises an communication system and a programmable storage and communication module. Instructions for one or more therapy programs can be stored in the programmable storage and communication module. In a preferred embodiment, the external charger 101 includes memory in which several predetermined programs/therapy schedules can be stored for transmission to the neuroregulator 104. The external charger 101 also can enable a user to select a therapy program/therapy schedule stored in memory for transmission to the neuroregulator 104. In another embodiment, the external charger 101 can provide treatment instructions with each initiation signal.

Typically, each of the therapy programs/therapy schedules stored on the external charger 101 can be adjusted by an operator (such as a physician) to suit the individual needs of the subject (e.g., a patient to be treated). For example, a computing device (e.g., a notebook computer, a personal computer, etc.) 100 can be communicatively connected to the external charger 101. With such a connection established, an operator can use the computing device 107 to program therapies into the external charger 101 for either storage or transmission to the neuroregulator 104.

The neuroregulator 104 also may include memory in which treatment instructions and/or patient data can be stored. In some embodiments, the neuroregulator comprises a power module and a programmable therapy delivery module. For example, the neuroregulator 104 can store one or more therapy programs in the programmable therapy delivery module indicating what therapy should be delivered to the subject. The neuroregulator 104 also can store therapy/treatment/patient data indicating how the patient utilized the therapy system and/or reacted to the delivered therapy.

In some embodiments, the external component and/or the neuroregulator, are programmed with one or more therapy programs. One therapy program may comprise an electrical signal treatment applied intermittently multiple times in a day and over multiple days, wherein the electrical signal has a frequency selected to downregulate and/or upregulate activity on a first target nerve and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first target nerve. Another therapy program may comprise an electrical signal treatment applied continuously over multiple days, wherein the electrical signal has a frequency selected to downregulate and/or upregulate activity on the first target nerve or organ. A second therapy program may comprise an electrical signal treatment applied intermittently multiple times in a day and over multiple days, wherein the electrical signal has a frequency selected to upregulate or downregulate activity on a second target nerve or organ, and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the second target nerve.

The first and/or second therapy programs may be applied at the same time, at different times, or at overlapping times. The first and/or second therapy programs may be delivered at specific times of the day, and or in response to a signal from a sensor. In some embodiments the sensor is designed to measure the plasma glucose level of a patient. In some embodiments the off time is configured to commence upon the detection of plasma glucose levels between 80 mg/dL and 110 mg/dL. In some embodiment the on time is configured to commence upon the detection of plasma glucose levels below 80 mg/mL, below 70 mg/dL, below 60 mg/dL, below 50 mg/dL, below 40 mg/dL, below 30 mg/dL, below 20 mg/dL, or below 10 mg/dL.

In some embodiments, the present system further comprises a biological sensor (not shown). The biological sensor may be an independent unit integrated into the therapy system, or be otherwise operatively coupled to the system. In embodiments, the biological sensor is electrically connected to the system. In embodiments, the biological sensor is in wireless communication with the therapy system. In embodiments, the biological sensor is operatively coupled to the neuroregulator of the therapy system. For example, a sensing electrode SE of the biological sensor can be added to monitor neural activity as a way to determine how to modulate the neural activity and/or the duty cycle. While sensing electrode can be an additional electrode to blocking electrode, it will be appreciated a single electrode could perform both functions. The sensing and blocking electrodes can be connected to a controller as shown in FIG. 1. Such a controller is the same as controller 102 previously described with the additive function of receiving a signal from sensing electrode.

In some embodiments, the sensor can be a sensing electrode, a glucose sensor, or sensor that senses other biological molecules or hormones of interest. When the sensing electrode SE yields a signal representing a targeted maximum vagal activity or tone, the controller with the additive function of receiving a signal from sensing electrode functions to change and/or maintain the signals delivered to the electrode(s) placed on nerve branches/fibers. As described with reference to controller 102, controller with the additive function of receiving a signal from sensing electrode can be remotely programmed as to parameters of blocking/stimulating duration and no blocking/stimulation duration as well as targets for initiating, or maintaining, or ceasing, or terminating, or otherwise manipulating the blocking signal and/or upregulating signal.

In practicing the therapy system, depending upon the glucose value of the subject indicated by the glucose sensor, the system can apply responsive changes to the first and/or the second electrical signal to control/maintain the plasma glucose at a demanded level.

In one particular embodiment, system 100 includes a glucose sensor configured to continuously monitor plasma glucose of the subject, wherein the glucose sensor is operably connected to the implantable pulse generator 104 and the external component. The glucose sensor is configured to detect an increase or decrease of plasma glucose from a pre-determined threshold level. The implantable pulse generator 104 is triggered to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, and wherein the implantable pulse generator ceases to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or above a second pre-determined threshold. The pre-determined threshold of the plasma glucose is about 80 mg/mL, about 70 mg/dL, about 60 mg/dL, about 50 mg/dL, about 40 mg/dL, about 30 mg/dL, about 20 mg/dL, or about 10 mg/dL. The circuitry 170 of the external mobile charger 101 can be connected to an external coil 102. The coil 102 communicates with a similar coil 105 implanted within the subject and connected to the circuitry 150 of the pulse generator 104. Communication between the external mobile charger 101 and the pulse generator 104 includes transmission of pacing parameters and other signals as will be described.

Having been programmed by signals from the external mobile charger 101, the pulse generator 104 generates upregulating signals and/or downregulating signals to the leads 106, 106a. As will be described, the external mobile charger 101 may have additional functions in that it may provide for periodic recharging of batteries within the pulse generator 104, and also allow record keeping and monitoring.

While an implantable (rechargeable) power source for the pulse generator 104 is preferred, an alternative design could utilize an external source of power, the power being transmitted to an implanted module via the RF link (i.e., between coils 102, 105). In this alternative configuration, while powered externally, the source of the specific electrical signals could originate either in the external power source unit, or in the implanted module.

The electronic energization package may, if desired, be primarily external to the body. An RF power device can provide the necessary energy level. The implanted components could be limited to the lead/electrode assembly, a coil and a DC rectifier. With such an arrangement, pulses programmed with the desired parameters are transmitted through the skin with an RF carrier, and the signal is thereafter rectified to regenerate a pulsed signal for application as the stimulus to the vagal nerve to modulate vagal activity. This would virtually eliminate the need for battery changes.

However, the external transmitter must be carried on the subject (e.g., the person of the patient), which is inconvenient. Also, detection is more difficult with a simple rectification system, and greater power is required for activation than if the system were totally implanted. In any event, a totally implanted system is expected to exhibit a relatively long service lifetime, amounting potentially to several years, because of the relatively small power requirements for most treatment applications. Also, as noted earlier herein, it is possible, although considerably less desirable, to employ an external pulse generator with leads extending percutaneously to the implanted nerve electrode set. The major problem encountered with the latter technique is the potential for infection. Its advantage is that the patient can undergo a relatively simple procedure to allow short term tests to determine whether the condition associated with excess weight of this particular patient is amenable to successful treatment. If it is, a more permanent implant may be provided.

In some embodiments, the present system is configured to apply an electrical signal to an internal anatomical feature of a subject. The system includes at least one electrode for implantation within the subject and placement at the anatomical feature (e.g., a nerve) for applying the signal to the feature upon application of the signal to the electrode. An implantable component is placed in the subject’s body beneath a skin layer and having an implanted circuit connected to the electrode. The implanted circuit includes an implanted communication system. An external component has an external circuit with an external communication system for placement above the skin and adapted to be electrically coupled to the implanted communication system across the skin through radiofrequency transmission. The external circuit has a plurality of user interfaces including an information interface for providing information to a user and an input interface for receiving inputs from the user.

In some embodiments, the present system is configured to apply electrical signals to different vagal nerve branches. For example, the esophagus passes through the diaphragm at an opening or hiatus. In the region where the esophagus passes through the diaphragm, trunks of the vagal nerve (e.g., AVN or PVN) are disposed on opposite sides of the esophagus. It will be appreciated that the precise location of the AVN and PVN relative to one another and to the esophagus are subject to a wide degree of variation within a patient population. However, for many subjects, the AVN and PVN are in close proximity to the esophagus at the hiatus where the esophagus passes through the diaphragm. The AVN and PVN may divide into a plurality of trunks that innervate organs such as the pancreas, gallbladder, liver, stomach, and intestines. Commonly, the AVN and PVN are still in close proximity to the esophagus and stomach (and not yet extensively branched out) at the region of the junction of the esophagus and stomach.

Now referring to FIG. 2, another example of the present system useful in treating a condition associated with hypoglycemia will be illustrated and described. With reference to FIG. 2, a device comprises an implantable component comprising an electronic assembly 210 (“hybrid circuit”) and a receiving coil 216; standard connectors 217 (e.g. IS-1 connectors) for attachment to electrode leads. Two leads are connected to the IS-1 connectors for connection to the implanted circuit. Both have a tip electrode for placement on a nerve. Set screws are shown in 214 and allow for adjustment of the placement of the electrodes. In some embodiments, a marker 213 to indicate the dorsal or ventral lead is provided. Suture tabs 211 are provided to provide for implantation at a suitable site. In some embodiments, strain relief 215 is provided. The subject to be treated receives an external controller comprising an communication system connected to control circuitry. The external control unit can be programmed for various signal parameters including options for frequency selection, pulse width, pulse amplitude, duty cycle, etc.

In some embodiment, the nerves AVN and/or PVN are indirectly stimulated by passing electrical signals through the tissue surrounding the nerves. In some embodiments, the electrodes are bipolar pairs (i.e. alternating anode and cathode electrodes). In some embodiments, a plurality of electrodes may be placed overlying the AVN and/or PVN. As a result, energizing the plurality of electrodes will result in application of a signal to the AVN and/or PVN and/or their branches. In some therapeutic applications, some of the electrodes may be connected to a upregulating electrical signal source (e.g., with a low frequency and other suitable parameters as described below) and other electrodes may apply a downregulating signal (e.g., with a high frequency and/or other suitable parameters as described below). In some embodiments, only a single array of electrodes could be used with all electrodes connected to a upregulating or a downregulating signal. In some therapeutic applications, some of the electrodes may be connected to an upregulating electrical signal source (with a suitable frequency and other parameters as described below).

In other embodiments, a plurality of electrodes are placed overlying the hepatic and/or celiac branches of the AVN and/or PVN nerves. In some therapeutic applications some of the electrodes may be connected to a upregulating electrical signal source (with a low frequency and other suitable parameters described below) and other electrodes may apply a downregulating signal. In some therapeutic application an electrode connected to a blocking electrical signal is placed on the hepatic branch of the vagal nerve. In other therapeutic applications an electrode connected to an upregulating signal is placed on the celiac branch of the vagal nerve. In still yet other therapeutic applications a first electrode connected to an upregulating signal is placed on the hepatic branch and a second electrode, connected to an downregulating signal is place on the celiac branch.

The electrical connection of the electrodes to an pulse generator may be as previously described by having a leads (e.g. 106,106a) connecting the electrodes directly to an implantable pulse generator (eg.104). Alternatively and as previously described, electrodes may be connected to an implanted communication system for receiving a signal to energize the electrodes.

Two paired electrodes may connect to a pulse generator for bi-polar signal. In other embodiments, a portion of the vagal nerve is dissected away from the esophagus. An electrode is placed between the nerve and the esophagus. Another electrode is placed overlying the vagal nerve on a side of the nerve opposite the first electrode and with electrodes axially aligned (i.e., directly across from one another). Not shown for ease of illustration, the electrodes may be carried on a common carrier (e.g., a PTFE or silicone cuff) surrounding the nerve VN. Other possible placements of electrodes are described herein U.S. 20050131485, the disclosure of which is hereby incorporated by reference in its entirety.

While any of the foregoing electrodes could be flat metal pads (e.g., platinum), the electrodes can be configured for various purposes. In an embodiment, an electrode is carried on a patch. In other embodiments, the electrode is segmented into two portions both connected to a common lead and both connected to a common patch. In some embodiments, each electrode is connected to a lead and placed to deliver a therapy from one electrode to another. A flexible patch permits articulation of the portions of the electrodes to relieve stresses on the nerve.

The present system may contain software to permit use of the system 100 in a programmable variety of therapy schedules, electrical signal delivery, therapy programs, operational modes, system monitoring and interfaces as will be described herein. In embodiments, system software can be stored on a variety of computer devices, such as an external smartphone or tablet, external programmer, the neuroregulator, and/or external charger.

Now referring to FIG. 3, an exemplary architecture of a computing device that can be used to implement aspects of the present disclosure is illustrated. For example, the external charger 101, the neuroregulator 104, an external programmer, an external smartphone of tablet, or various systems and devices of the therapy system 100 can be implemented with at least some of the components of the computing device as illustrated in FIG. 3. Such a computing device is designated herein as reference numeral 300. The computing device 300 is used to execute the operating system, application programs, and software modules (including the software engines) described herein.

The computing device 300 includes, in some embodiments, at least one processing device 302, such as a central processing unit (CPU). A variety of processing devices are available from a variety of manufacturers, for example, Intel or Advanced Micro Devices. In this example, the computing device 300 also includes a system memory 304, and a system bus 306 that couples various system components including the system memory 304 to the processing device 302. The system bus 306 is one of any number of types of bus structures including a memory bus, or memory controller; a peripheral bus; and a local bus using any of a variety of bus architectures.

Examples of computing devices suitable for the computing device 300 include a desktop computer, a laptop computer, a tablet computer, a mobile device (such as a smart phone, an iPod® mobile digital device, or other mobile devices), or other devices configured to process digital instructions.

The system memory 304 includes read only memory 308 and random access memory 310. A basic input/output system 312 containing the basic routines that act to transfer information within computing device 300, such as during start up, is typically stored in the read only memory 308.

The computing device 300 also includes a secondary storage device 314 in some embodiments, such as a hard disk drive, for storing digital data. The secondary storage device 314 is connected to the system bus 306 by a secondary storage interface 316. The secondary storage devices and their associated computer readable media provide nonvolatile storage of computer readable instructions (including application programs and program modules), data structures, and other data for the computing device 300.

Although the exemplary environment described herein employs a hard disk drive as a secondary storage device, other types of computer readable storage media are used in other embodiments. Examples of these other types of computer readable storage media include magnetic cassettes, flash memory cards, digital video disks, Bernoulli cartridges, compact disc read only memories, digital versatile disk read only memories, random access memories, or read only memories. Some embodiments include non- transitory media.

A number of program modules can be stored in secondary storage device 314 or memory 304, including an operating system 318, one or more application programs 320, other program modules 322, and program data 324.

In some embodiments, computing device 300 includes input devices to enable a user to provide inputs to the computing device 300. Examples of input devices 326 include a keyboard 328, pointer input device 330, microphone 332, and touch sensitive display 340. Other embodiments include other input devices 326. The input devices are often connected to the processing device 302 through an input/output interface 338 that is coupled to the system bus 306. These input devices 326 can be connected by any number of input/output interfaces, such as a parallel port, serial port, game port, or a universal serial bus. Wireless communication between input devices and interface 338 is possible as well, and includes infrared, BLUETOOTH® wireless technology, WiFi technology (802.11a/b/g/n etc.), cellular, or other radio frequency communication systems in some possible embodiments.

In this example embodiment, a touch sensitive display device 340 is also connected to the system bus 306 via an interface, such as a video adapter 342. The touch sensitive display device 340 includes touch sensors for receiving input from a user when the user touches the display. Such sensors can be capacitive sensors, pressure sensors, or other touch sensors. The sensors not only detect contact with the display, but also the location of the contact and movement of the contact over time. For example, a user can move a finger or stylus across the screen to provide written inputs. The written inputs are evaluated and, in some embodiments, converted into text inputs.

In addition to the display device 340, the computing device 300 can include various other peripheral devices (not shown), such as speakers or a printer.

The computing device 300 further includes a communication device 346 configured to establish communication across the network. In some embodiments, when used in a local area networking environment or a wide area networking environment (such as the Internet), the computing device 300 is typically connected to the network through a network interface, such as a wireless network interface 348. Other possible embodiments use other wired and/or wireless communication devices. For example, some embodiments of the computing device 300 include an Ethernet network interface, or a modem for communicating across the network. In yet other embodiments, the communication device 346 is capable of short-range wireless communication. Short-range wireless communication is one-way or two-way short- range to medium-range wireless communication. Short-range wireless communication can be established according to various technologies and protocols. Examples of short- range wireless communication include a radio frequency identification (RFID), a near field communication (NFC), a Bluetooth technology, and a Wi-Fi technology.

The computing device 300 typically includes at least some form of computer- readable media. Computer readable media includes any available media that can be accessed by the computing device 300. By way of example, computer-readable media include computer readable storage media and computer readable communication media.

Computer readable storage media includes volatile and nonvolatile, removable and non-removable media implemented in any device configured to store information such as computer readable instructions, data structures, program modules or other data. Computer readable storage media includes, but is not limited to, random access memory, read only memory, electrically erasable programmable read only memory, flash memory or other memory technology, compact disc read only memory, digital versatile disks or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by the computing device 300.

Computer readable communication media typically embodies computer readable instructions, data structures, program modules or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term “modulated data signal” refers to a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, computer readable communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, radio frequency, infrared, and other wireless media. Combinations of any of the above are also included within the scope of computer readable media.

As described above, the computing device typically includes at least some form of computer-readable media. Computer readable media includes any available media that can be accessed by the computing device. By way of example, computer-readable media include computer readable storage media and computer readable communication media.

The computer implemented methods as described herein are implemented by storing a series of instructions on the neuroregulator, external programmer, and/or the external charger. In embodiments, a user may select parameters of the electrical signal therapy and upon selection, selects a combination of electrical signal treatments for the therapy program(s).

Now referring to FIG. 4, an example method 400 of operating the therapy system 100 is illustrated. At operation 402, the system 100 generates a user interface configured to receive various inputs from a user, such as one or more parameters, therapy programs, schedules, and any other information usable for system operation. At operation 404, the system 100 receives a user input of a therapy program via the user interface. As described herein, the system 100 is configured to provide a plurality of therapy programs, and the user can select one of the therapy programs available through the user interface. At operation 406, the system 100 receives a user input of one or more parameters that determine the characteristics of a therapy program.

At operation 408, the system 100 generates electrical signals based on the selected parameters, which implement the therapy program selected by the user. At operation 410, it is determined whether the on-time has lapsed. If so (“YES” at the operation 410), the system 100 stops the therapy program. If not (“NO” at the operation 410), the system 100 determines if there is any input for changing one or more of the parameters, at operation 412. If so (“YES” at the operation 412), the system 100 modifies the parameters based on the input, and continues the operation 408 and the subsequent operations. If not (“NO” at the operation 412), the system 100 continues the operation 408 and the subsequent operations.

As illustrated in FIG. 4, the system 100 receives and utilizes a plurality of parameters to generate various patterns of electrical signals for different therapy programs. Examples of the parameters are described as follows:

Parameters that are selected by a user include type of nerve or organ. In embodiments, the type of nerve is selected from vagal nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagal nerve, celiac branch of vagal nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

In embodiments, a user can select parameters that feature a high frequency signal or a high frequency low duty cycle signal for downregulating/blocking nerve activity. A user can also select parameters that feature a low frequency stimulation signal for upregulating/stimulating nerve activity. A user can select parameters to independently and separately apply multiple electrical signals applied to multiple nerves or nerve branches/fibers. A user can also select parameters to concurrently or simultaneously apply multiple electrical signals applied to multiple nerves or nerve branches/fibers, or otherwise apply the multiple signals in a coordinated fashion.

Additional examples of the neuroregulator, pulse generator, electrode, biological sensor, therapy program, therapy schedule, electrical signal pattern, treatment parameters, etc., are described in US20210146136 and WO2020214982, the disclosure of which are hereby incorporated by reference in their entirety.

In some aspects, the present disclosure provides a method for making or assembling the system described herein for treating a condition associated with hypoglycemia in a subject. In one example, a method comprises: (1) connecting a first electrode to an implantable pulse generator and placing the first electrode to a first nerve or organ; (2) optionally connecting a second electrode to the implantable pulse generator and placing the second electrode to a second nerve or organ; (3) configuring a programmable therapy delivery module of the implantable pulse generator to deliver at least one therapy program comprising a first electrical signal treatment and optionally a second electrical signal treatment, wherein the first electrical signal treatment is configured to be applied to the first nerve or organ through the first electrode, and the second electrical signal treatment is configured to be applied to the second nerve or organ through the second electrode, and wherein the first and/or the second electrical signal each initiate a neural stimulation or a neural block; and (4) configuring a programmable storage and communication module of an external component to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

In some embodiments, the first and/or the second electrical signal each have a frequency selected to initiate activity respectively on the first and/or the second target nerve or organ, and wherein the activity is an upregulation or downregulation of neural activity.

In some embodiments, the method further comprises connecting a glucose sensor to the implantable pulse generator; and monitoring or detecting plasma glucose level of the subject using the glucose sensor.

In some embodiments, the method further comprises configuring a communication system of the external component to communicate parameters of the at least one therapy program to an external communication device.

In some embodiments, the method further comprises connecting a transmitter to the glucose sensor to communicate data generated by the glucose sensor to an external communication device.

In some embodiments, the first and/or the second electrode are placed on the nerve or organ via a laparoscopic approach.

Methods

In some aspects, the disclosure provides methods of treating a subject for a condition associated with impaired glucose regulation, in particular, a hypoglycemic condition, or hypoglycemia in Type 1 and/or Type 2 diabetics. The subject may be a patient having a diabetic or non-diabetic condition.

It should be noted that hypoglycemia is not only observed in diabetics but also arises from other diseases such as, but not limited to, kidney failure, certain tumors, liver disease, hypothyroidism, inborn errors of metabolism, severe infections, reactive hypoglycemia, and a number of drugs including alcohol use. The proposed device may help treat hypoglycemia in patents with these medical conditions.

In some embodiments, a method comprises: applying an intermittent (or continuous) electrical signal to a target nerve or a target organ of a subject at a site with said electrical signal selected to upregulate and/or downregulate neural activity on the nerve or organ and with normal or baseline neural activity restoring upon discontinuance of said upregulation and/or downregulation. In embodiments, the method provides for an decrease in secretion of insulin and/or an increase in secretion of glucagon, or both. In some embodiments, the method provides for an increase in glucose concentration of the treated subject. In some embodiments, the methods further comprise administering a composition to the subject comprising an effective amount of an agent that increases glycemic control. In some embodiments, the electrical signal is applied to the nerve or organ by implanting a device or system as described herein.

In some embodiments, a method of treating a condition associated with hypoglycemia in a subject in need thereof comprises applying an intermittent (or continuous) neural stimulation signal to a target nerve of the subject having a hypoglycemic condition at a stimulating site with said neural stimulation signal selected to upregulate neural activity on the nerve and to restore neural activity on the nerve upon discontinuance of said stimulation.

In some embodiments methods include, treating a patient for hypoglycemia with a concurrent treatment comprising: a) applying an intermittent (or continuous) neural stimulation signal to a target nerve or organ of the patient at multiple times per day and over multiple days with the stimulation signal selected to upregulate afferent and/or efferent neural activity on the nerve and with neural activity restoring upon discontinuance of said stimulation signal; and b) applying an intermittent (or continuous) neural block signal to a target nerve of the patient at multiple times per day and over multiple days with the stimulation selected to downregulate afferent and/or efferent neural activity on the nerve with neural activity restoring upon discontinuance of said block signal.

In some embodiments, a method of achieving glucose regulation in a patient comprises positioning an electrode on or near a vagal nerve branch, and an anodic electrode in contact with adjacent tissue; implanting a neurostimulator coupled to the electrodes into the patient, applying electrical pulses with defined characteristics of amplitude, pulse width, frequency and duty cycle to the vagal nerve branch wherein the defined characteristics are selected to improve glucose regulation or restoring the glucose level to a normal or desired level in the patient.

In some embodiments, a method comprises: applying an intermittent (or continuous) electrical signal to a target nerve or organ, with said electrical signal selected to upregulate or downregulate neural activity on the nerve or organ and to restore neural activity on the nerve upon discontinuance of said signal, wherein the electrical signal is selected to perform at least one of: increasing or modifying the amount of glucagon, decreasing or modifying the amount of insulin, or increasing the glucose level to reach or exceed a pre-determined level. In some embodiments, the electrical signal is selected for frequency, pulse width, amplitude, and timing to upregulate neural activity as described herein. In some embodiments, the electrical signal is selected for frequency, pulse width, amplitude and timing to downregulate neural activity as described herein. In some embodiments, the electrical signal is selected to increase or modify release of glucagon and/or to decrease or modify insulin by the pancreas, especially when plasma glucose is below a pre-determined threshold level. In some embodiments, the electrical signal is selected to modify liver sensitivity to glucagon.

In embodiments, the electrical signal is applied intermittently in a cycle including an on time of application of the signal followed by an off time during which the signal is not applied to the nerve, wherein the on and off times are applied multiple times per day over multiple days. In some embodiments, the on time is selected to have a duration of about 30 seconds to about 5 minutes. When the signal is selected to downregulate activity on the nerve, the electrical signal is applied at a frequency of about 200 Hz to about 10,000 Hz. When the signal is selected to upregulate activity on the nerve, the electrical signal is applied at a frequency of about 0.01 Hz up to about 200 Hz.

In embodiments, the electrical signal is applied to an electrode positioned on the vagal nerve. In some cases, the electrical signal is applied on the hepatic branch of the vagal nerve. In other cases, the electrical signal is applied on the celiac branch of the vagal nerve. In some embodiments, the electrical signal is applied to an organ involved in glucose regulation such as the liver, pancreas, duodenum, jejunum, or ileum.

In embodiments, downregulating and upregulating signals are both applied. In some cases, the signals are applied at the same time, different times, or overlapping times. In some embodiments, a downregulating signal is applied to a vagal nerve near the liver, and an upregulating signal is applied to a vagal nerve near the pancreas. In some embodiments, a downregulating signal is applied to the hepatic branch of the vagal nerve, and an upregulating signal is applied to the celiac branch of the vagal nerve.

In some embodiments, a method of treating a condition associated with hypoglycemia in a subject comprises measuring plasma glucose levels following an intravenous (IV) glucose tolerance test (IVGTT) during stimulation of the celiac branch of the vagal nerve and with ligation, or high frequency alternating current (HFAC) blockade, of the vagal nerve hepatic branch.

In some embodiments, the method further comprises detecting the level of plasma glucose or glucagon or insulin to determine whether to apply an electrical signal treatment. If the levels of plasma glucose and/or glucagon are decreased to or below normal or baseline levels expected in a control sample from a subject having diabetes, treatment to increase glucagon and/or decreased insulin may by triggered until the plasma glucose levels rise to the expected levels required to maintain adequate hypoglycemia control. Such levels are known or can be determined using methods known to those of skill in the art.

In some embodiments, the method further comprises administering an amount of an agent such as glucose, glucagon, or dextrose to facilitate the alleviation of hypoglycemia.

In some embodiments, the method comprises applying a reversible intermittent (or continuous) modulating signal to a target nerve or organ of the subject in order to downregulate and/or upregulate neural activity on the nerve.

In some cases, the nerve is a nerve that innervates one or more alimentary organs, including but not limited to the vagal nerve, celiac nerves, hepatic branch of the vagal nerve, and splanchnic nerve. The signal applied may upregulate and/or downregulate neural activity on one or more of the nerves.

In some embodiments, said modulating signal comprises applying an electrical signal. The signal is selected to upregulate or downregulate neural activity and allow for restoration of the neural activity upon discontinuance of the modulating signal. A pulse generator, as described above, can be employed to regulate the application of the signal in order to alter the characteristic of the signal to provide a reversible intermittent (or continuous) signal. The characteristics of the signal include location of the signal, frequency of the signal, amplitude of the signal, pulse width of the signal, and the administration cycle of the signal. In some embodiments, the signal characteristics are selected to provide for treating a condition associated with hypoglycemia.

In embodiments of the methods described herein a signal is applied to a target nerve at a site with said signal selected to upregulate neural activity on the nerve and with neural activity restoring upon discontinuance of said signal. In some embodiments, an upregulating signal may be applied to a first nerve or organ in combination with a down regulating signal applied to a second nerve or organ in order to improve glucose regulation.

The signal is selected to upregulate neural activity and allow for restoration of the neural activity upon discontinuance of the signal. A pulse generator, as described above, is employed to regulate the application of the signal in order to alter the characteristic of the signal to provide a reversible intermittent (or continuous) signal. The characteristics of the signal include frequency of the signal, location of the signal, and the administration cycle of the signal.

In some embodiments, electrodes applied to a target nerve are energized with an upregulating signal. The signal is applied for a limited time (e.g., 5 minutes). The speed of neural activity recovery varies from subject to subject. However, 20 minutes is a reasonable example of the time needed to recover to baseline. After recovery, application of an up signal again upregulates neural activity which can then recover after cessation of the signal. Renewed application of the signal can be applied before full recovery. For example, after a limited time period (e.g., 10 minutes) upregulating signal can be renewed.

In some embodiments, an upregulating signal may be applied in combination with a downregulating signal in order to improve glucose regulation, increase/modify the amount of secretion of glucagon, decrease/modify the amount of insulin, and/or increase the amount of plasma glucose. The neural regulation signals can influence the sensitivity to glucagon by the liver, the amount of glucose absorbed from food, and the amount of glucagon and/or insulin secreted from the pancreas. The neural regulation provides for a decrease in the amount of insulin required by the subject.

The upregulating and downregulating signals may be applied to different nerves at the same time, applied to the same nerve at different times, or applied to different nerves at different times. In embodiments, an upregulating signal may be applied to a celiac nerve or splanchnic nerve. In other embodiments, an upregulating or downregulating signal may be applied to a hepatic branch of the vagal nerve or the signal may be applied to increase or control the amount of glucose secreted from the liver.

In some embodiments, a upregulating signal is applied to a vagal nerve branch intermittently multiple times in a day and over multiple days in combination with an downregulating signal applied intermittently multiple times in a day and over multiple days to a different nerve or organ. In some embodiments, the upregulating signal is applied due to a sensed event such as the amount of plasma glucose present. In other embodiments, an upregulating signal applied to the splanchnic nerve or the celiac nerve can be applied during a time period after normal meal times for the subject typically 15 to 30 minutes after mealtimes or times when plasma glucose levels decrease.

In some cases, signals are applied at specific times. For example, a downregulating signal may be applied before and during meal, followed by a stimulatory signal about 30 to 90 minutes after eating. In another example, an upregulating signal may be applied to the vagal nerve or the celiac branch of the vagal nerve late in the evening when the glucose is decreasing.

In some embodiments, a stimulation signal is applied to the celiac branch of the vagal nerve when a monitor detects low plasma glucose levels. In other embodiments, a downregulating signal is continuously delivered to the hepatic branch of the vagal nerve, or the ventral vagal trunk above the branching point of the hepatic nerve, along with stimulation of the celiac branch, or the dorsal vagal trunk above the branching point of the celiac nerve. However, if an internal monitor detected plasma glucose reaching an undesirable hypoglycemic state the blocking signal would cease and stimulation would continue alone.

Modulation of neural activity can be achieved by upregulating and/or down regulating neural activity of one or more target nerves or organs.

In some embodiments, electrodes can be positioned at a number of different sites and locations on or near a target nerve. Target vagal nerve branches include the celiac nerve, the hepatic nerve, the vagal nerve, the splanchnic nerve, or some combination of these, respectively, of a subject. The electrode may also be positioned to apply a signal to an organ in proximity to the vagal nerve such as the liver, duodenum, jejunum, ileum, spleen, pancreas, esophagus, or stomach. In some embodiments, the electrode is positioned to apply an electrical signal to the nerve at a location distal to the diaphragm of the subject.

Electrodes may be positioned on different nerves to apply a downregulating signal as opposed to an upregulating signal. For example, a down regulating signal can be applied on the hepatic nerve and an upregulating signal applied to the celiac nerve.

In some embodiments, the signals may be applied to reduce the neurally mediated reflex secretion by blocking the vagal nerves to the liver, and concurrently or subsequently, stimulate the celiac to inhibit insulin secretion and/or upregulate the celiac nerve to stimulate glucagon production.

In some embodiments, the electrode is positioned to apply a signal to a branch or trunk of the vagal nerve. In other embodiments, the electrode is positioned to apply a signal to a ventral trunk, dorsal trunk or both. In some embodiments, the electrodes may be positioned at two different locations at or near the same nerve or on the nerve and on an alimentary tract organ.

In some embodiments, a downregulating signal has a frequency of at least 200 Hz and up to 5000 Hz. In other embodiments, the signal is applied at a frequency of about 500 to 5000 Hz. In some embodiments, a downregulating signal has a frequency of 3,000 Hz to 5,000 Hz or greater when applied by two or more bi-polar electrodes. Such a signal has a preferred pulse width of 100 micro-seconds (associated with a frequency of 5,000 Hz). A short "off time in the pulse cycle (e.g., between cycles or within a cycle) could be acceptable as long as it is short enough to avoid nerve repolarization. The waveform may be a square or sinusoidal waveform or other shape. The higher frequencies of 5,000 Hz or more have been found, in porcine studies, to result in more consistent neural conduction block. Preferably, the signal is bi-polar, bi- phasic delivered to two or more electrodes on a nerve.

In some embodiments, a signal amplitude of 0.01 to 20.0 mA is adequate for blocking. In other embodiments a signal amplitude of 0.01 to 10 mA is adequate for blocking. In still yet other embodiments a signal amplitude of 0.01 to 8 mA is adequate for blocking. Other amplitudes may suffice. Other signal attributes can be varied to reduce the likelihood of accommodation by the nerve or an organ. These include altering the power, waveform or pulse width.

Upregulating signals typically comprise signals of a frequency of less than 200 Hz, more preferably between 0.01 to 200 Hz, more preferably 10 to 50 Hz, more preferably 5 to 20 Hz, more preferably 5 to 10 Hz, more preferably 1 to 5 Hz, preferably 0.1 to 2 Hz, most preferably 1 Hz. Such a signal has a preferred pulse width of 0.1-10 microseconds. In some embodiments, a signal amplitude of 0.1 to 12 mA is adequate for stimulating. Other amplitudes may suffice. Other signal attributes can be varied to reduce the likelihood of accommodation by the nerve or an organ. These include altering the power, waveform or pulse width. Selection of a signal that upregulates and/or downregulates neural activity and/ or allows for recovery of neural activity can involve selecting signal type and timing of the application of the signal. For example, with an electrode conduction block, the block parameters (signal type and timing) can be altered by the pulse generator and can be coordinated with the stimulating signals. The precise signal to achieve blocking may vary from patient to patient and nerve site. The precise parameters can be individually tuned to achieve neural transmission blocking at the blocking site.

In some embodiments, the signal has a duty cycle including an ON time during which the signal is applied to the nerve followed by an OFF time during which the signal is not applied to the nerve. For example, the on time and off times may be adjusted to allow for partial recovery of the nerve. In some cases, the downregulating and upregulating signals can be coordinated so that the upregulating signals are applied when down regulating signals are not being applied such as when the upregulating signals are applied at specific times or due to sensed events. In some embodiments, a sensed event indicates that an upregulating signal is applied and a down regulating signal is not applied for a time period relating to the sensed event, e.g. plasma glucose is below a certain threshold. In preferred embodiments, the signal is continuously being applied.

In some embodiments, subjects receive an implantable component 104. (FIG.

1). The electrodes 212, 212a are placed on the AVN and/or PVN just below the patient’s diaphragm. The external antenna (coil 102) (or other communication system) is placed on the patient’s skin overlying the implanted receiving coil 105. The external control unit 101 can be programmed for various signal parameters including options for frequency selection, pulse amplitude and duty cycle. For stimulating signals, a frequency is selected of less than about 200 Hz. For blocking signals, the frequency options includes about 200 Hz to about 5,000 Hz. The amplitude options are 0 - 10 mA.

In some embodiments, an upregulating signal may be applied in combination with a down regulating signal in order to improve glucose regulation.

Normally a patient would only use the device while awake. The hours of therapy delivery can be programmed into the device by the clinician (e.g., automatically turns on at 7:00 AM and automatically turns off at 9:00 PM). In some cases, the hours of therapy would be modified to correspond to times when blood sugar fluctuates such as before a meal and 30-90 minutes after eating. For example, the hours of therapy may be adjusted to start at 5:00 AM before breakfast and end at 9:00 PM or later depending on when the last meal or snack is consumed. In the RF -powered version of the pulse generator, use of the device is subject to patient control. For example, a patient may elect to not wear the external antenna. The device keeps track of usage by noting times when the receiving antenna is coupled to the external antenna through radio-frequency (RF) coupling through the patient’s skin.

In some embodiments, the external component 101 can interrogate the pulse generator component 104 for a variety of information. In some embodiments, therapy times of 30 seconds to 180 seconds per duty cycle are preferred to therapy times of less than 30 seconds per duty cycle or greater than 180 seconds per duty cycle.

During a 10 minute duty cycle (i.e., intended 5 minutes of therapy followed by a 5 minute OFF time), a patient can have multiple treatment initiations. For example, if, within any given 5-minute intended ON time, a patient experienced a 35-second ON time and 1.5 minute actual ON time (with the remainder of the 5 -minute intended ON time being a period of no therapy due to signal interruption), the patient could have two actual treatment initiations even though only one was intended. The number of treatment initiations varies inversely with length of ON times experienced by a patient.

In some embodiments, a sensor may be employed. A sensing electrode SE can be added to monitor neural activity as a way to determine how to modulate the neural activity and the duty cycle. While sensing electrode can be an additional electrode to stimulating electrode, it will be appreciated a single electrode could perform both functions. The sensing and stimulating electrodes can be connected to a controller as shown in FIG. 1. Such a controller is the same as controller 102 previously described with the additive function of receiving a signal from sensing electrode.

In some embodiments, the sensor can be a sensing electrode, a glucose sensor, or sensor that senses other biological molecules or hormones of interest. When the sensing electrode SE yields a signal representing a targeted minimum vagal activity or tone, the controller with the additive function of receiving a signal from sensing electrode energizes the stimulating electrode BE with a upregulating signal. As described with reference to controller 102 (FIG. 1), controller with the additive function of receiving a signal from sensing electrode can be remotely programmed as to parameters of stimulation duration and no stimulation duration as well as targets for initiating an upregulating or downregulating signal.

EXAMPLES

Example 1- Implantable HVNS System

A particular example system is described in accordance with the present disclosure. FIG. 5 illustrates individual components of an example HVNS system. In the illustrated example, an implantable HVNS system comprises a Rechargeable Neuroregulator (RNR) pulse generator in combination with a Guardian™ Connect CGM system for glucose monitoring glucose. The HVNS system further includes two electrical leads with platinum-iridium electrodes which connect to the Rechargeable Neuroregulator (RNR) implantable pulse generator, a transmit coil, which is positioned over the RNR, outside the layer of the skin and communicates with the RNR through an antenna using a 6.73 MHz radio-frequency signal. The signal from the coil is used to charge the RNR as well as to program stimulation parameters. A mobile charger (MC) is connected to the transmit coil for charging and programming and a clinician programmer, which is connected to the MC for programming stimulation parameters. The Mobile Charger is recharged when connected to the AC Recharger. The Guardian™ Connect system includes a sensor inserted underneath the skin to measure glucose in the interstitial fluid. A transmitter is connected to the sensor and sends this information to the transmitter. The transmitter then wirelessly sends this data out to a smart device (e.g., iPhone or iPad) via blue-tooth technology, which displays plasma glucose levels.

Referring to FIGS. 6-7, wherein the HVNS system would include a pulse generator, leads that are placed on the vagus nerve and an implantable glucose sensor (to monitor plasma glucose levels). The sensor sampling rate would be from about 1 second to 10 min. FIG. 6 shows a schematic of system in which an implantable glucose sensor communicates with a pulse generator to initiate vagus nerve stimulation. The implantable sensor would detect low plasma glucose levels and send a signal to turn the pulse generator on. FIG. 7 shows a schematic of system in which an implantable glucose sensor communicates first with an external device attached to the outside of the skin which then communicates with the pulse generator to initiate vagus nerve stimulation. The communication between the pulse generator and the glucose sensor can be through, but not limited to, blue tooth technology, radio frequency, WIFI, light or sound. In some embodiments the glucose sensor would be below the layer of the skin and communicate to a device outside of the skin with a battery to power wireless communication. The communication between the glucose sensor and the device outside the body can be through, but not limited to, blue tooth technology, radio frequency, WIFI, light or sound. The device outside of the skin would then communicate with the pulse generator through, but not limited to, blue tooth technology, radio frequency, WIFI, light or sound. The implantable glucose sensor, or the external device that communicates with the implantable glucose sensor, could also communicate with a smart device (such as a phone running an app) to display plasma glucose levels and send an alarm when plasma glucose reaches an unsafe low level.

The communication to the smart device can be through, but not limited to, blue tooth technology, radio frequency, WIFI, light or sound. Stimulation parameters include a frequency range between 0.01 Hz to 200 Hz, current or voltage amplitude range: 0.1 mA to 12 mA or 0.1 to 12 volts, pulse width range: 0.1 ms to 10 ms. Stimulation can be continuous or bursting with inter-burst intervals ranging from milliseconds, seconds to minuets.

Site of stimulation include any segment of the vagus nerve. This includes sub- diaphragmatic anterior or posterior vagus trunks and branches of the sub-diaphragmatic vagal trunks such as the celiac branch originating from the posterior vagus trunk, the accessory celiac branch, originating from the anterior vagus trunk or the hepatic branch, originating from the anterior vagus trunk. Sites of stimulation also include the anterior or posterior thoracic vagus, or the left or right cervical vagus. Any combination of vagus nerve stimulation sites is included.

An implant procedure is performed as follows: the RNR is implanted in a subcutaneous pocket along the thorax mid-axillary line. Leads are routed to the sub- diaphragmatic posterior nerve cranial to the celiac branching point via intra-abdominal laparoscopy (see Example 4). Nerve electrodes are placed on nerve, separated by 1-2 cm and sutured to the esophagus to maintain position. An additional suture tab, proximal to the electrode, is sutured to the stomach to create a strain relief preventing nerve damage due to abdominal movement. The RNR is programmed to provide charge balanced biphasic square waves with pulse widths programmable from about 0.1 ms to about 10 ms in about 0.1 ms steps and current amplitudes of about 0.1 mA to about 12 mA in about 0.1 mA steps. Frequency can be programmable from about 0.01 Hz to about 200 Hz. At a typical therapy level of about 6 mA, the 2.6 Ah lithium-ion battery draws about 13 mA at an impedance of about 1500 Ohms. The batery life with 12 hours a day of stimulation requires a 1-hour recharge approximately every 3 months.

The HVNS system works in conjunction with the Guardian™ Connect system as follows: the Guardian™ smart device monitors plasma glucose levels in a patient. When glucose reaches a predetermined threshold the clinician programmer instructs the RNR to initiate stimulation. Glucose level is then be monitored with the smart device and stimulation can then be turned off by the same procedure as stimulation initiation.

In other embodiments, the HVNS system is entirely closed looped with the primary cell RNR incorporating blue-tooth capability to directly communicate with the glucose transmiter. Low duty cycle on demand stimulation may facilitate use of a small primary cell device without the need for recharging. The CGM transmiter may communicate with a smart device allowing physicians to optimize therapy parameters during a controlled hypoglycemic trial.

Example 2-Zucker Diabetic Rat Study

Previous experiments involving vagal nerve stimulation induced glucose release have been conducted in non-diabetic model systems. To test if vagal nerve stimulation increased glucose in a diabetic model system, a well-established rodent model of diabetes, the Zucker obese diabetic rats (ZDF fa/fa) (Apweiler, 1993; Corseti, 2000; Friedman, 1991; Schmidt, 2003; Sparks, 1998), was utilized in this study.

Experiments were acute with the rat under anesthesia and the celiac branch of the vagal nerve suspended on bipolar hook electrodes. An electrical signal patern comprising negative square wave pulses was used to stimulate the celiac branch of the vagal nerve at an amplitude of 4 mA and 0.25 ms pulse width with a frequency of 1 Hz.

The statistics for analysis of the experiments are provided as follows: The analysis normalized plasma glucose levels at time t for each rat by log-transforming the ratio between the plasma glucose at time t and the plasma glucose at time 0. The effect of stimulation was assessed through a linear mixed model with no intercept, fixed effects for time and the interaction between time and group (stimulation vs. sham operation), and a random time slope. A P-value of 0.05 for the group by time interaction represents a significant difference in slopes between the two groups. Data were presented as mean ± SEM.

Following 15 min of stimulation there was a significant increase in glucose concentration (27±12 mg/dL) compared to sham control rats (FIG. 8, n=6 for stim and 4 for sham p<0.05). This significant increase continued for the course of the experiment with an increase of 75±24 mg/dL at 1 hr. Due to the length of the rats being under anesthesia (surgical procedure and time of stimulation), the experiment ended at 1 hour post stimulation.

The above results support that stimulation of the celiac branch of the vagal nerve could increase glucose in a rodent model of diabetes.

Example 3-Type 1 Diabetic Swine Study

To rule out the effects of anesthesia on plasma glucose levels (Behdad, 2014; Chen, 2015), vagal nerve stimulation in chronic experiments on an alloxan treated Type 1 diabetic swine model was studied. This model was widely used in the field (Emmrich, 1982; Badin, 2019; Badin, 2018; Phillips, 1980). Swine were given 10 days to recover from surgery.

Test pigs (n=3, FIG. 9A) were implanted with an RNR and two leads with electrodes placed on the posterior vagus trunk just cranial to the celiac branch. This site served as an ideal segment to suture the lead tips to the esophagus and still capture celiac axons. This implant procedure is similar to the FDA approved vBloc implant.

Experimental procedure for the treatment of hypoglycemia consisted of a subcutaneous bolus injection of fast acting Humalog insulin. Since there was variability in baseline glucose (up to 100 mg/dL) and that each pig responded to Humalog differently a percentage drop was used to determine when stimulation was initiated. A 36% decrease was chosen due to its clinical significance (Mo, 2020; Rodbard, 2018; Lee, 2017; Marchand, 2019). An increase of 20 mg/dL by 30 min was considered a successful experiment similar to Rickels et al. The average baseline glucose for the swine was about 300 mg/dL. In the first set of experiments, stimulation was delivered at a frequency of 1 Hz with no change in glucose. Next, the frequency was increased to 5 Hz or 10 Hz. One of the test pigs responded to a 5 Hz and had an increase of 40 mg/dL by 5 min. The other two test pigs responded to 10 Hz with an increase of 27 mg/dL by 15 min and the other with an increase of 42 mg/dL in 5 min. With all three test pigs achieving an increase in glucose by 20 mg/dL by 15 min (average of 45 ±20 mg/dL at the 15 min time point, FIG. 9B), which supports the efficiency and efficacy of the treatment. Following experiments the pigs were offered food; plasma glucose then increased and stabilized at about 175 mg/dL.

The above results support that stimulation of the posterior vagus nerve cranial to the celiac branch could increase glucose following an insulin injection in a diabetic pig model of diabetes.

Example 4-Swine Anatomy and Implantation of the HVNS System

Dissections were undertaken to expose the celiac branch of the Vagal nerve and mark its location to surrounding organs and distances from the hiatus in juvenile swine. It was determined that a surgical incision of the left abdominal wall just behind the costal arch, subcostal incision (FIG. 10A), was the preferred method to visualize the PVN. The PVN was located along the dorsal side of the esophagus. The celiac branching point was measured from the hiatus in three swine with the following distances: 5.8 cm, 6.2 cm, and 5.9 cm. An example of the branching point can be seen in FIG. 10B.

In alternative embodiments, minimally invasive electrodes implantation technique may be used. In preliminary experiments electrodes were implanted using laparotomy. This procedure has greater chances of complications than a minimally invasive laparoscopic surgery. Furthermore, it is challenging to locate the celiac branching point with a laparotomy surgical approach. A less invasive laparoscopic technique for optimal electrode placement with enhanced visualization of the PVN and celiac branch may be employed in the study. In addition, electrode(s) may be placed as close as possible to the celiac branch to decrease undesired non-specific stimulation effects.

Yorkshire swine cadavers (e.g., n=9) are used to develop the surgical technique. The Preliminary Swine Anatomy Study suggested that a laparoscopic approach with a subcostal incision could be an optimal method to locate the celiac branch. Abdominal navigation may be improved with the abdominal cavity filled with CCh and the liver retracted. The body could be titled with the legs & right side down to move the stomach and intestines for enhance navigation. The PVN could be located at the hiatus and followed down to its first major branching point; which would be the site of the celiac branch (Dixon, 2000). It is the site immediately cranial to the celiac branch in which electrodes may be placed in stimulation experiments. After the celiac branch has been located laparoscopically and electrodes placed on the PVN a suture could be placed around the branch and a necropsy could be performed to confirm the success of locating the celiac branch. A laparoscopic method is found feasible to locate the celiac branching point in 6 Yorkshire pig cadavers and to correct placement of electrodes on the PVN nerves.

Example 5-Optmization of HVNS Parameters

Optimal parameters for vagal nerve stimulation may be determined. In preliminary studies it was demonstrated that circulating plasma glucose in Type 1 diabetic swine could be increased by stimulation of the PVN following a glucose decrease of 36% after insulin injection. The stimulation parameter set was limited due to the exploratory purpose of the study and the glucose level in which stimulation was applied was variable. More optimal stimulation amplitude, pulse width and frequency were determined in this study.

In alternative embodiments, hypoglycemia may be induced by an infusion of insulin, titrating the dose from 1 mU/kg/min i.v., up to 3 mU/kg/min, as necessary to achieve a controlled decline in plasma glucose to 50 mg/dL (Rickels, 2016).

The stimulation parameters tested in the preliminary swine experiments included a charged balanced biphasic waveform with a current amplitude of 8 mA and 0.5 ms Pulse Width (PW). However, more energy efficient parameters may be used to produce similar outcomes. In the preliminary experiment a relatively high stimulation pulse energy was used to show proof of concept. However, in ideal laboratory conditions through isolated nerve electrophysiology, it is determined that lower energy could also stimulate the PVN. Different testing different combinations of pulse width and current amplitude may be used to optimize the stimulation condition and to produce similar results as observed in preliminary experiments.

The energy (in coulombs) of a pulse is calculated by multiplying the pulse width (in seconds) by the current amplitude (in amps). For example, the energy of the pulses used in the preliminary experiments was 0.0005 sec X 0.008 amps=0.000004 coulombs = 4 pC. In alternative embodiments, different combinations of pulse width and current amplitude could be combined to decrease the pulse energy. Non-limiting examples of combination are provided in Table 1.

Table 1. Non-limiting examples of the combination of pulse widths and pulse amplitudes for vagal nerve stimulation used to treat hypoglycemia.

Frequency of the electrical pattern for vagal nerve stimulation could also be optimized. In preliminary studies, it was found that 5 Hz had increased plasma glucose concentration by 20 mg/dL on one pig while 10 Hz had had similar effect other two pigs. In alternative embodiments, the frequency may be controlled to start with 5 Hz and increase to 10 Hz depending on the response. FIG. 11 shows a flow diagram of an example method for treating four swine having a hypoglycemic condition. In the illustrated example, the method includes treating the subject with a starting frequency of 5 Hz for 10 min, if there is an increase in glucose by 5 mg/dL then it is continued with 5 Hz for another 20 min. If there is no significant rise in glucose of 5 mg/dL with 5 Hz stimulation within 10 min, then stimulation is stopped for 10 min to rest the nerve. The rational to stop stimulation for 10 min is based on the observations from the preliminary experiments which demonstrated that the 10 min gap acted like a washout period with no effect on glucose levels. Thus, it is reasonable for a 10 min rest following 5 Hz before another stimulation test. Next, a frequency of 10 Hz is applied for 30 min following the rest. An indication of effective treatment may be supported by a rise of 20 mg/dL in glucose by 30 min in 75% of the swine post initiation (Rickels, 2016) of stimulation (at either the start of the 5 or 10 Hz). Following the experiment, the swine could be offered food for glucose stabilization and there may be a washout of one week following experiments. Further, optimized efficient stimulation conditions and parameters could be determined aiming at increasing glucose by 20 mg/dL by 30 min in 75% of the swine from a controlled clamped glucose level of 50 mg/dL (Rickels, 2016). Safety of stimulation on Vagal nerve and end organs could be determined.

Given the involvement of PVN with systems that have feedback between targeted peripheral organ and origins in the brain, whether HVNS therapy is safe on the organs innervated could be investigated. The fibers that are receiving HVNS innervate the pancreas and brain, and HVNS therapy could upregulate endogenous function.

Toxicity with histology testing could be done following the termination of the efficacy experiments. Since the metabolic processes may also be affected by the HVNS therapy, the histopathology could be performed on the liver. Histopathology could also be performed on the vagal nerve at the site of the stimulation electrode.

In alternative embodiments, electrodes are placed closer to the hiatus on the posterior nerve, a level that reliably is cranial to the Celiac branch (Dixon, 2000).

There could be a possibility for non-specific effects, however, the electrodes are still placed below the level of innervation of thoracic organs such as the heart. This avoids more sever non-specific effects seen in cervical vagal nerve stimulation (Meyers,

2016).

Preliminary in vivo experiments have shown a treatment effect with pulses with parameters of 8 mA 0.5 ms pulse. Combining a relatively low frequency, duty cycle, and on-demand stimulation, energy expenditure is expected to be relatively low, such that the battery is considerably smaller than batter sizes used in other stimulation devices, which typically continuously stimulate at a frequency of 40 Hz and above. If the treatment effect shown in preliminary in vivo experiments is not realized, other combinations of parameters could be tested, requiring energy expenditure that can be accommodated by an acceptably larger size battery.

Stimulating the Vagal nerve at locations cranial to HVNS and at higher frequencies has demonstrated a strong safety profile in humans with FDA approved devices. There was no adverse behavior during or following HVNS in the preliminary swine studies. These facts support the safety of HVNS. If there appears to be any issue with safety, current amplitude, pulse width or frequency can be changed demonstrating the concept of personalized medicine using HVSN.

Example 6-Trial HVNS Therapy Studies on Yucatan Swine

A trial HVNS Therapy study on Yucatan Swine is performed at American Preclinical Serves (APS, Minneapolis, MN). Deployment of Maestro™ Rechargeable Neuroregulator (4) device in domestic swine is performed by trained APS surgeons or consulting physicians using standard medications and anesthesia per protocol and APS SOP. Under the guidance and approval of the APS’s Institutional Animal Care and Use Committee (IACUC), the animals are induced with Ketamine / Midazolam, (2.5-4.0 mg/kg / 0.4-0.5 mg/kg, IM) and maintained on inhaled isoflurane (1-3% in 100% oxygen) for the duration of the surgery.

Adult female Yucatan swine (n=4) are procured at Sinclair Research Institute. Animals could be presented with alloxan to ablate beta cells. This established model by Sinclair Research Institute has been shown to cause insulin dependency. The swine model for Type 2 diabetes has been described in the scientific literature (Boullion, 2003; Dixon, 1999; Dyson, 2006; Laber-Laird, 1992; Mullen, 1989; Otis, 2003) and is available for purchase from a reputable laboratory animal supplier. The necessity for testing a diabetic model ensures proof of concept prior to testing in man. Additionally, regulatory authorities want to see the study performed in a clinically relevant disease state to ensure that adverse events related to the disease treatment do not occur.

Surgical methods

1. Use a standard laparoscopic technique. a. Identify the intra-abdominal anterior vagus trunk at the hepatic nerve branching point, place electrode, suture electrode tongue to the esophagus using 2-0 to 4-0 suture (e.g. ethibond, polyester) while ensuring that there is no visible tension on the nerve. b. Identify the intra-abdominal posterior vagus trunk at the branching point of the celiac nerve, place electrode , suture electrode tongue to the esophagus using 2-0 to 4-0 suture (e.g. ethibond, polyester) (suture tongue to the esophagus). c. Strain relief leads to the top of the stomach by suturing the proximal suture tab to the proximal pig stomach using the same suture type used above; ensure strain-relief is captured in video/photograph. d. The leads are tunneled out through the abdominal cavity to the animals left lateral aspect of the abdomen. e. Attach sterile adapters to lead ends.

2. Remove sterile adapters. 3. Observe that the neuroregulator IPG lead sockets are open.

4. Insert the lead connectors into the lead sockets. Verify that the posterior vagal nerve lead, with white stripe and white suture tab, is inserted into the lead socket with the white septum. Insert anterior vagal nerve lead into the lead socket with the clear septum.

5. Verify that the lead is fully inserted by visually identifying that the lead connector extends past each setscrew septum. Using the provided torque wrench tighten the two setscrews (1 setscrew per lead) until one or two clicks are heard. After the setscrews are tightened, gently pull back on each lead to verify they are both secured.

6. Perform the lead status (impedance) test.

7. Create a pocket for the neuroregulator subcutaneously using blunt dissection. The pocket should be large enough to accommodate the neuroregulator. a. Note: The neuroregulator should be implanted between 2 and 3 cm below, and parallel to, the surface of the skin.

8. Use medical adhesive to seal the two pressure relief holes and the two septums in the neuroregulator IPG header.

9. Use all three suture holes to secure the neuroregulator to the muscular fascia. This prevents device migration and helps to maintain position approximately parallel to the skin surface.

10. The leads should be routed straight out from the neuroregulator IPG and should exit the pocket without forming any loops around the neuroregulator. Do not leave any excess lead length in the pocket. This facilitates safe operation of the system during charging.

11. Closure of abdominal wall and neuroregulator pocket incision using suture as requested by the surgeon. Each layer is closed using running stitches. The abdominal incision is closed using a minimum of 3 layers. The IPG pocket incision is closed using a minimum of 2 layers.

12. At the first opportunity, the animal is weaned from the ventilator and, if necessary, receive oxygen either through the endotracheal tube or nasal cone (3 to 4 L/min).

Lead status test for the neuroregulator

1. Press the Animal-MC button and the coil position light begins to flash indicating that the animal-MC is in coil position mode. 2. Connect the clinician transmit coil to the Animal-MC and then connect to the Programmer with the programmer cable. The Animal-MC is in operating mode after the Animal-MC has been successfully connected to the clinician transmit coil and communication has been established with the neuroregulator.

3. Place the clinician transmit coil in a sterile sleeve or sterile surgical drape, and position coil over the neuroregulator.

4. Position the coil over the neuroregulator such that there is at least one centimeter distance between the coil and neuroregulator.

5. The flashing red light indicates a ‘find coil position’ setting.

6. The green light indicates current coil position.

7. Optimal position is indicated when the intensity of the green light is maximized. To optimize the transmit coil position over the neuroregulator, move the coil to the left or right as well as up or down from its initial position over the implanted neuroregulator.

8. To accept the coil position, swipe a magnet past the Animal-MC once again. Coil position settings are now ready.

9. Use the Programmer to perform lead status testing. The Diagnostic Screen displays the impedance values and a green checkmark if the lead impedance measurements are in the appropriate range.

10. If the lead status is not acceptable, the following should be considered: a. Check setscrew connections for each lead to the neuroregulator. b. Clear all fluids from nerve electrodes. c. Reposition, re-suture, or replace leads as appropriate.

Animals undergo deployment of the device on day 1 followed by regular daily instillation of fluid into the pleural space. The performance of the Maestro™ Rechargeable Neuroregulator Medical Device could be evaluated throughout the recovery period. The animals are monitored by APS Veterinarians and staff until fully recovered. The animals remain on the device for up to 100 days at which time they are euthanized and assessed for device performance and overall tissue response to the device and systemic toxicity. Justifications for use of animals & generation of Type I diabetic alloxan treated Yucatan swine

The Maestro™ Rechargeable Neuroregulator Medical Device requires evaluation using an in vivo model, as its anticipated use is in humans. No in vitro alternatives exist to the use of live animals in order to accomplish the goals of this study. Yucatan swine or other live large animals having similar anatomically sized target organs and tissues are essential for effective evaluation of the Maestro™ Rechargeable Neuroregulator Medical Device. Deployment of the device requires target organs and target space similar in size to that of human anatomy. In addition, the extended use of the Maestro™ Rechargeable Neuroregulator Medical Device requires all physiological components of the intact live animal cardiovascular and respiratory systems to suitably evaluate the ability of test article to function as expected. This study serves as a simulated use study, in accordance with FDA recommendation and approval, and is used to evaluate the residual device risks and evaluate performance in use and allows comparison to existing standard of care procedures. There are existing literature accounts indicating that the Yucatan swine model is an acceptable model for evaluation of the safety and performance of this system.

Adult female Yucatan swine (n=4) are procured at Sinclair Research Institute. Animals are presented with of Alloxan to ablate beta cells. This established model by Sinclair Research Institute has been shown to cause a decreases glycemic control and require daily insulin injections. Alloxan treatment is found in the scientific literature (Boullion, 2003; Dixon, 1999; Dyson, 2006; Laber-Laird, 1992; Mullen, 1989; Otis, 2003) and is available for purchase from a reputable laboratory animal supplier. The necessity for testing a diabetic model ensures proof of concept prior to testing in man. Additionally, regulatory authorities want to see the study performed in a clinically relevant disease state to ensure that adverse events related to the disease treatment do not occur.

Veterinary care of animals

All animals are maintained at American Preclinical Services, Inc (Minneapolis, MN). APS is a contract research organization with a facility over 130,000 square feet consisting of surgical procedure suites, animal housing rooms, and supporting in vitro and analytical laboratories. Veterinary medical care is available throughout working hours 6:30AM- 7:30PM and staff are on night-call evenings and weekends. This care program is patterned after the principles outlined in the NIH Guide for the Care and Use of Laboratory Animals. Veterinary care is executed by the animal facility staff following APS standard operating procedures (SOPs) that address issues such as sanitation, quarantine, necropsy and euthanasia procedures, monitoring physical environment, disease control procedures and surgical/interventional procedures. APS employs four full-time Veterinarians. Two veterinarians serve as ad hoc members of the Institutional Animal Care and Use Committee (IACUC). The Department employs 15 full time research technicians, a dedicated Large Animal Operations Supervisor, 20 large animal technicians and a Vivarium Supervisor to provide daily health monitoring and care for the animals. The APS animal research facility is registered with the USDA. APS has an institutional assurance with PHS and is accredited with AAALAC international.

Upon arrival at APS, animals have a minimum 7 day quarantine period. A health assessment by a veterinarian is performed for each animal prior to release. Per APS SOP, unless otherwise directed assessments are performed per:

• protocol specified postoperative clinical observations,

• other protocol requirements,

• by ad hoc Veterinarian order, or

• by ad hoc Study Director order.

The animals could be observed at a minimum of twice per day throughout the duration of the study for physical and behavioral ahributes including, but not limited to, the following:

• Interaction with pen-mates (if applicable).

• Elimination of urine & feces, discolored urine (if applicable), diarrhea, absence of feces (constipation).

• Signs of illness or injury, lethargy, vomiting, excessive salivation, abnormal posture, pain, lameness, discomfort, unwillingness or inability to move.

• Additional assessments are performed whenever warranted based on clinical observations.

A variety of agents are available for the management of pain and distress in domestic and Yucatan swine, typically APS staff Veterinarians recommend Buprenorphine Sustained Release (SR), (dosed at 0.12-0.24 mg/kg, SQ, q 72 hour). Other pain management techniques can be administered with veterinarian order. All methods used are in agreement with the recommendations of the AVMA Colloquium on Recognition and Alleviation of Animal Pain and Distress. Per APS SOP, emergency treatments not specified in the protocol may be administered by veterinarian order, or other trained personnel, in consultation with the Study Director. If necessary, emergency treatment may also preclude approval by the Study Director prior to drug administration. Any commercially available medication not contraindicated in this protocol may be administered. The reason for treatment, description of treatment, date(s) of treatment, and resolution are documented in the animal’s records, preferably in SOAP (subjective, objective, assessment, plan) format. The Study Director determines the overall impact of all treatments on the study objectives.

All attempts are made to avoid treatments that may interfere with study endpoints. If treatment(s) have the potential to interfere with study endpoints, animals may be euthanized in lieu of treatments.

Insulin treatment

1. Plasma glucose Monitoring and Insulin Therapy: a) Plasma glucose monitoring occurs as often as needed but at a minimum of three times daily. The morning and afternoon plasma glucose should be collected just prior to feeding and insulin administration. In the evening plasma glucose may be measured with the CGM. b) The preferred method of testing is ear stick with a 25-gauge needle along the edge of the ear. A lancet may also be used. Rotate testing locations as needed. c) Plasma glucose are monitored via glucose sensor and phone app.

Glucose sensors may be replaced as needed.

(1) Animals are monitored via sensor during monitors (at a minimum) or for the duration of the study (preferred). d) VAP’s must be accessed aseptically at all times. Aseptic preparation and use of sterile gloves are mandatory. e) Positive reinforcement should be provided to facilitate the blood sampling process. When entering the kennel, first sit down in the front of the kennel and wait for the pig to come to you. Then scratch the pig either behind the ear or under the belly, depending on the animal’s preference. Only after this should you proceed with blood sampling or other interventions.

1) Target plasma glucose levels should be maintained between 100-350 mg/dL (normal clinical lab values 85-150 mg/dL). Target values are reached and maintained by following the Diabetic Pig Insulin Adjustment Rules document during mealtimes. If values outside of veterinary ordered limits occur, another sample may be sent to the clinical laboratory for value confirmation. g) Type of insulin (Humalog, Lantus, etc.) is per vet directives. Insulin dosage depends on the pig’s daily feed amount, weight, hydration status, individual insulin sensitivity, and prior treatment. Dose and frequency are adjusted according to the Diabetic Pig Insulin Adjustment Rules document or per veterinary discretion. h) Dextrose infusions [20 ml of 50% dextrose given slowly over 10 minutes (IV), or as directed by vet] or orogastric tubing of 1-2 bottles of Ensure may be used in the case of accidental overdose of insulin or severe hypoglycemia.

Additionally, Nutri-Cal® (applied to gums) or 50 ml of 50% dextrose given orally with a syringe may be administered per veterinarian discretion. i) A veterinarian is contacted if:

(1) Clinical signs of hyper or hypoglycemia are noted, including but not limited to lethargy/depression, poor responsiveness, incoordination, head pressing, seizing, or convulsions.

(2) Plasma glucose values are below 60 mg/dL or above 500 mg/dL.

2. Feeding Requirements: a) Animals are fed twice per day. b) Insulin is administered at feeding time after the animal has eaten. c) When fasting the pigs, if a meal is skipped insulin is not given.

3. Weekly Weight: a) Animals are weighed weekly. If the weight has increased or decreased by 10% or more, a veterinarian is contacted.

Provisions to minimize discomfort, distress, pain, and injury:

Per APS SOP, routine medical or emergency treatments not specified in this protocol may be administered by veterinarian order in consultation with the Study Director. In the event that the Study Director cannot be reached, the veterinarian may act in the best interest of the animal’s welfare and, if deemed necessary in accordance with the Animal Welfare Act, the veterinarian may authorize treatment to mitigate pain/distress up to and including euthanasia (as long as treatments are not contraindicated by the protocol). The reason for treatment, description of treatment, date(s) of treatment, and resolution are documented in the animal’s records, preferably in SOAP (subjective, objective, assessment, plan) format. The Study Director may determine the overall impact of all medical treatments on the study objectives.

Postoperative pain is managed in all animal species with the administration of local anesthetics prior to surgery and with buprenorphine, an opioid narcotic agent, or NSAIDS unless contraindicated by the study protocol with appropriate scientific rationale and IACUC approval. Animals are group housed if appropriate to study endpoints. All attempts are made to avoid treatments that may interfere with study endpoints. If treatment(s) have the potential to interfere with study endpoints, animals may be euthanized in lieu of treatments.

Euthanasia

All animals are euthanized per protocol at the end of their protocol specified in- life period. The proposed method is according to the AVMA Guidelines for the Euthanasia of Animals, 2013 Edition. At the completion of the final procedure, intravenous (IV) administration of a commercially available barbiturate euthanasia solution (Euthasol or equivalent) are performed (typically doses at 1 mL/4.5 kg IV). Death is confirmed by absence of cardiac function as determined by: auscultation, palpation, or cardiac visualization.

Modifications and equivalents of disclosed concepts such as those which might readily occur to one skilled in the art are intended to be included in the scope of the claims which are appended hereto. In addition, this disclosure contemplates application of a combination of electrical signal treatment by placement of electrodes on one or more nerves. Any publications referred to herein are hereby incorporated by reference. Non-Patent References

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NUMBERED CLAUSES

The following numbered clauses define further example aspects and features of the compositions, methods, and techniques of the present disclosure:

1. A system for treating hypoglycemia in a subject, the system comprising: a first electrode adapted to be placed on and deliver electrical signal to a first nerve or organ; optionally a second electrode adapted to be placed on and deliver electrical signal to a second nerve or organ; an implantable pulse generator operably connected to the first and/or the second electrode, wherein the implantable pulse generator comprises a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program comprising a first therapy program and optionally a second therapy program, wherein the first therapy program comprises a first electrical signal treatment applied to the first nerve or organ through the first electrode, wherein the second therapy program comprises a second electrical signal treatment applied to the second nerve or organ through the second electrode, and wherein the first and/or the second electrical signal are each configured to initiate activity on the first and/or the second nerve or organ respectively, and wherein the activity is a neural stimulation or a neural block; and an external component comprising a communication system and a programmable storage and communication module, wherein programmable storage and communication module are configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

2. The system of clause 1, wherein the first and/or the second electrical signal are each independently configured to upregulate or down-regulate activity respectively on the first and/or second target nerve or organ. 3. The system of any one of clauses 1-2, wherein the first and the second electrical signals are applied concurrently, or simultaneously, or intermittently, or during substantially the same times, or during substantially different times, or in a coordinated fashion.

4. The system of any one of clauses 1-3, wherein the first and/or the second electrical signal treatments are each continuously applied to the first target nerve or organ and/or the second target nerve or organ respectively.

5. The system of any one of clauses 1-4, further comprising a glucose sensor configured to continuously monitor plasma glucose of the subject, wherein the glucose sensor is operably connected to the implantable pulse generator and the external component.

6. The system of any one of clauses 1-5, wherein the glucose sensor is configured to detect an increase or decrease of plasma glucose from a pre-determined threshold level.

7. The system of clause 6, wherein the implantable pulse generator is triggered to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, and wherein the implantable pulse generator ceases to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or above a second pre-determined threshold.

8. The system of any one of clauses 1-7, wherein the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof. 9. The system of any one of clauses 1-8, wherein the first and/or the second electrical signals each have an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first and/or the second nerve or organ.

10. The system of clauses 9, wherein the on time is configured to commence upon the detection of plasma glucose level of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL.

11. The system of any one of clauses 1-10, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 5 mg/dL in about 10 minutes.

12. The system of any one of clauses 1-11, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 10 mg/dL in about 20 minutes.

13. The system of any one of clauses 1-12, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 20 mg/dL in about 30 minutes.

14. The system of any one of clauses 1-13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

15. The system of any one of clauses 1-13, wherein the first electrical signal has a frequency of about 200 Hz to about 10k Hz.

16. The system of any one of clauses 1-15, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

17. The system of any one of clauses 1-15, wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz. 18. The system of any one of clauses 1-13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

19. The system of any one of clauses 1-18, wherein the first electrical signal and/or the second electrical signal each independently comprise a signal pattern, wherein each signal pattern comprises a pulse having a pulse width from about 0.1 microseconds to about 10,000 microseconds.

20. The system of any one of clauses 1-19, wherein the pulse of the first and/or the second electrical signal is monophasic pulse, or biphasic pulse, or combinations thereof.

21. The system of any one of clauses 1-20, wherein the first and/or the second electrical signal each independently have an on time of about 30 seconds to about 30 minutes.

22. The system of any one of clauses 1-21, wherein the first and/or the second electrical signal each independently have a current amplitude in a range from about 0.01 mAmps to about 20 mAmps.

23. The system of any one of clauses 1-22, wherein the first and/or the second electrical signal each independently comprise an abrupt start of pulses, or a ramp up of current/voltage amplitude, or a ramp up of frequency, or a ramping up of pulse widths, or combination thereof at or near initiation of applying the first and/or the second electrical signal.

24. The system of any one of clauses 1-23, wherein the first and/or the second electrical signal treatments are configured to be applied intermittently multiple times in a day and over multiple days, wherein the first and/or the second electrical signal each have a frequency selected to upregulate activity on the first nerve or organ and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first nerve or organ. 25. The system of any one of clauses 1-24, wherein the programmable storage and communication module are configured to store and communicate more than one therapy program, wherein each therapy program is different from one another, and is configured to be selected for communication.

26. The system of any one of clauses 1-25, further comprising a transmitter operably connected to the glucose sensor, wherein the transmitter is configured to communicate data generated by the glucose sensor to an external communication device.

27. The system of any one of clauses 1-26, wherein the communication system is selected from a group consisting of an antenna, blue tooth technology, radio frequency, WIFI, light, sound and combinations thereof, and wherein the communication system is configured to communicate parameters of the at least one therapy program to an external communication device.

28. A method of treating hypoglycemia in a subject, the method comprising: applying a first electrical signal to a first nerve or organ of the subject using the system of clause 1, wherein the first electrical signal initiates a neural stimulation or a neural block; and optionally applying a second electrical signal to a second nerve or organ of the subject using the system of clause 1, wherein the second electrical signal initiates a neural stimulation or a neural block.

29. The method of clause 28, wherein the first and the second electrical signals are applied concurrently, or simultaneously, or intermittently, or during substantially the same times, or during substantially different times, or in a coordinated fashion.

30. The method of any one of clauses 28-29, wherein the first and/or the second electrical signal are configured to increase plasma glucose of the subject by at least about 5 mg/dL in about 10 minutes. 31. The method of any one of clauses 28-30, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 10 mg/dL in about 20 minutes.

32. The system of any one of clauses 28-31, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 20 mg/dL in about 30 minutes.

33. The method of any one of clauses 28-32, wherein the first and/or the second electrical signal are each applied continuously during an on time followed by an off time during which the signal is not applied to the nerve or organ.

34. The method of any one of clauses 28-33, wherein the on times are applied multiple times per day when plasma glucose level is of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL.

35. The method of any one of clauses 28-34, wherein the off times are applied multiple times per day when plasma glucose level is of or above about 80 mg/dL, of or above about 90 mg/dL, of or above about 100 mg/dL, of or above about 110 mg/dL.

36. The method of any one of clauses 28-35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

37. The method of any one of clauses 28-35, wherein the first electrical signal has a frequency of about 200 Hz to about 10k Hz.

38. The method of any one of clauses 28-37, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

39. The method of any one of clauses 28-37, wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz. 40. The method of any one of clauses 28-35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

41. The method of any one of clauses 28-40, wherein the first nerve or organ and the second nerve or organ are independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

42. The method of any one of clauses 28-41, wherein the first nerve or organ and the second nerve or organ are different.

43. The method of any one of clauses 28-42, wherein the first electrical signal is applied on a hepatic branch of a vagus nerve or a ventral vagus nerve central to a branching point of a hepatic nerve.

44. The method of any one of clauses 28-42, wherein the first electrical signal is applied on a celiac branch of a vagus nerve or a ventral vagus nerve central to a branching point of a celiac nerve.

45. The method of any one of clauses 28-42, wherein the first electrical signal is applied to liver, pancreas or both.

46. The method of any one of clauses 28-45, wherein the second electrical signal is applied to a splanchnic nerve or a celiac branch of a vagus nerve, or pancreas.

47. The method of any one of clauses 28-45, wherein the second electrical signal is not involved in the method. 48. The method of any one of clauses 28-47, further comprising administering an agent that improves glucose control.

49. The method of clause 48, wherein the agent decreases the amount of insulin and/or decreases the sensitivity of cells to insulin.

50. A method of making a system for treating hypoglycemia in a subject, the method comprising: connecting a first electrode to an implantable pulse generator and placing the first electrode to a first nerve or organ; optionally connecting a second electrode to the implantable pulse generator and placing the second electrode to a second nerve or organ; configuring a programmable therapy delivery module of the implantable pulse generator to deliver at least one therapy program comprising a first electrical signal treatment and optionally a second electrical signal treatment, wherein the first electrical signal treatment is configured to be applied to the first nerve or organ through the first electrode, and the second electrical signal treatment is configured to be applied to the second nerve or organ through the second electrode, and wherein the first and/or the second electrical signal each initiate a neural stimulation or a neural block; and configuring a programmable storage and communication module of an external component to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

51. The method of clause 50, wherein the first and/or the second electrical signal each have a frequency selected to initiate activity respectively on the first and/or the second target nerve or organ, and wherein the activity is an upregulation or down- regulation of neural activity.

52. The method of any one of clauses 50-51, further comprising connecting a glucose sensor to the implantable pulse generator; and monitoring or detecting plasma glucose level of the subject using the glucose sensor. 53. The method of any one of clauses 50-52, further comprising configuring a communication system of the external component to communicate parameters of the at least one therapy program to an external communication device.

54. The method of any one of clauses 50-53, further comprising connecting a transmitter to the glucose sensor to communicate data generated by the glucose sensor to an external communication device.

55. The method of any one of clauses 50-54, wherein the first and/or the second electrode are placed on the nerve or organ via a laparoscopic approach.

56. A system for treating hypoglycemia in a subject, the system comprising: at least one electrode adapted to be placed on and deliver electrical signal to a nerve or organ of the subject; an implantable pulse generator operably connected to the at least one electrode, wherein the implantable pulse generator comprises a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program, wherein the at least one therapy program comprises at least one electrical signal treatment applied to the nerve or organ through the at least one electrode, an external component comprising a communication system and a programmable storage and communication module, wherein programmable storage and communication module are configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator, and a glucose sensor operably connected and to and in communication with the implantable pulse generator and the external component, wherein the glucose sensor is configured to continuously monitor plasma glucose of the subject and to detect an increase or decrease of plasma glucose from a pre-determined threshold level, wherein, the implantable pulse generator is triggered to deliver the at least one electrical signal treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, and wherein the implantable pulse generator ceases to deliver the at least one electrical signal treatment when the plasma glucose of the subject is of or above a second pre-determined threshold, wherein the at least one electrical signal treatment is configured to initiate neural stimulation on the nerve or organ of the subject.

57. The system of clause 56, wherein the nerve or organ is selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

58. The system of any one of clauses 56-57, wherein the nerve is posterior vagus nerve (PVN) of the subject or the celiac vagus nerve branch of the PVN.

59. The system of any one of clauses 56-58, wherein the electrical signal has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the nerve or organ.

60. The system of clause 59, wherein the on time is configured to commence upon the detection of plasma glucose level of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL in the subject.

61. The system of any one of clauses 59-60, wherein the on time is about 30 seconds to about 30 minutes.

62. The system of any one of clauses 56-61, wherein the at least one electrical signal treatment comprises an electrical signal pattern having a frequency from about 1 Hz to about 200 Hz, or from about 1 Hz to about 50 Hz, or from about 1 Hz to about 20 Hz, or from about 1 Hz to about 10 Hz, or from about 1 Hz to about 5 Hz, or from about 1 Hz to about 2 Hz.

63. The system of any one of clauses 56-62, wherein the electrical signal pattern has a pulse width from about 0.1 microseconds to about 10 microseconds in about 0.1 microseconds steps. 64. The system of any one of clauses 56-63, wherein the electrical signal pattern has a pulse amplitude from about 0.1 mA to about 12 mA in about 0.1 mA steps.

65. The system of any one of clauses 56-64, wherein the pulse of the at least one electrical signal is monophasic pulse, or biphasic pulse, or combinations thereof.

66. The system of any one of clauses 56-65, wherein the at least one electrical signal further comprises an abrupt start of pulses, or a ramp up of current/voltage amplitude, or a ramp up of frequency, or a ramping up of pulse widths, or combination thereof at or near initiation of applying the electrical signal.

67. The system of any one of clauses 56-66, wherein at least one electrical signal treatment is configured to be applied intermittently multiple times in a day and over multiple days.

68. The system of any one of clauses 56-67, wherein the at least one electrical signal treatment is configured to causes increase of the plasma glucose of the subject by at least about 5 mg/dL in about 10 minutes, or by at least about 10 mg/dL in about 20 minutes, by at least about 20 mg/dL in about 30 minutes, or by at least about 30 mg/dL in about 45 minutes, or by at least about 40 mg/dL in about 60 minutes.

69. The system of any one of clauses 56-68, wherein the at least one electrical signal treatment is configured to cause an increase of glucagon secretion in the subject.

70. The system of any one of clauses 56-69, wherein application of the at least one electrical signal treatment is configured to cause an decrease of insulin secretion in the subject.

71. The system of any one of clauses 56-70, further comprising a transmitter operably connected to the glucose sensor, wherein the transmitter is configured to communicate data generated by the glucose sensor to an external communication device. 72. The system of any one of clauses 56-71, wherein the communication system is selected from a group consisting of an antenna, blue tooth technology, radio frequency, WIFI, light, sound and combinations thereof, and wherein the communication system is configured to communicate parameters of the at least one therapy program to an external communication device.

73. A method of treating hypoglycemia in a subject in need thereof, the method comprising: applying the at least one electrical signal treatment to a posterior vagus nerve (PVN) of a subject or the celiac vagus nerve branch of the PVN of the subject using the system of any one of clauses 56-72.

74. The method of clause 73, wherein the electrical signal pattern applied to the has a frequency from about 1 Hz to about 20 Hz, a pulse width from about 0.1 microseconds to about 10 microseconds in about 0.1 microseconds steps, and a pulse amplitude from about 0.1 mA to about 12 mA in about 0.1 mA steps.

75. The method of any one of clauses 73-74, wherein application of the at least one electrical signal treatment causes increase of the plasma glucose of the subject by at least about 5 mg/dL, at least about 10 mg/dL, at least about 20 mg/dL, at least about 30 mg/dL, at least about 40 mg/dL, at least about 50 mg/dL, at least about 60 mg/dL, at least about 70 mg/dL, at least about 80 mg/dL, at least about 90 mg/dL, or at least about 100 mg/dL, in about 60 minutes.

76. The method of any one of clauses 73-75, wherein application of the at least one electrical signal treatment causes increase of glucagon secretion in the subject.

77. The method of any one of clauses 73-76, wherein application of the at least one electrical signal treatment causes decrease of insulin secretion in the subject.

78. The method of any one of clauses 73-77, further comprising: placing the at least one electrode on the nerve or organ via a laparoscopic approach. The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

Claims

CLAIMS What is claimed is:

2. The system of claim 1, wherein the first and/or the second electrical signal are each independently configured to upregulate or down-regulate activity respectively on the first and/or second target nerve or organ.

3. The system of any one of claims 1-2, wherein the first and the second electrical signals are applied concurrently, or simultaneously, or intermittently, or during substantially the same times, or during substantially different times, or in a coordinated fashion.

4. The system of any one of claims 1-3, wherein the first and/or the second electrical signal treatments are each continuously applied to the first target nerve or organ and/or the second target nerve or organ respectively.

5. The system of any one of claims 1-4, further comprising a glucose sensor configured to continuously monitor plasma glucose of the subject, wherein the glucose sensor is operably connected to the implantable pulse generator and the external component.

6. The system of any one of claims 1-5, wherein the glucose sensor is configured to detect an increase or decrease of plasma glucose from a pre-determined threshold level.

7. The system of claim 6, wherein the implantable pulse generator is triggered to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or below a first pre-determined threshold, and wherein the implantable pulse generator ceases to deliver the first and/or the second electrical treatment when the plasma glucose of the subject is of or above a second pre-determined threshold.

8. The system of any one of claims 1-7, wherein the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

9. The system of any one of claims 1-8, wherein the first and/or the second electrical signals each have an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first and/or the second nerve or organ.

10. The system of claims 9, wherein the on time is configured to commence upon the detection of plasma glucose level of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL.

11. The system of any one of claims 1-10, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 5 mg/dL in about 10 minutes.

12. The system of any one of claims 1-11, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 10 mg/dL in about 20 minutes.

13. The system of any one of claims 1-12, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 20 mg/dL in about 30 minutes.

14. The system of any one of claims 1-13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

15. The system of any one of claims 1-13, wherein the first electrical signal has a frequency of about 200 Hz to about 10k Hz.

16. The system of any one of claims 1-15, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

17. The system of any one of claims 1-15, wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

18. The system of any one of claims 1-13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

19. The system of any one of claims 1-18, wherein the first electrical signal and/or the second electrical signal each independently comprise a signal pattern, wherein each signal pattern comprises a pulse having a pulse width from about 0.1 microseconds to about 10,000 microseconds.

20. The system of any one of claims 1-19, wherein the pulse of the first and/or the second electrical signal is monophasic pulse, or biphasic pulse, or combinations thereof.

21. The system of any one of claims 1-20, wherein the first and/or the second electrical signal each independently have an on time of about 30 seconds to about 30 minutes.

22. The system of any one of claims 1-21, wherein the first and/or the second electrical signal each independently have a current amplitude in a range from about 0.01 mAmps to about 20 mAmps.

23. The system of any one of claims 1-22, wherein the first and/or the second electrical signal each independently comprise an abrupt start of pulses, or a ramp up of current/voltage amplitude, or a ramp up of frequency, or a ramping up of pulse widths, or combination thereof at or near initiation of applying the first and/or the second electrical signal.

24. The system of any one of claims 1-23, wherein the first and/or the second electrical signal treatments are configured to be applied intermittently multiple times in a day and over multiple days, wherein the first and/or the second electrical signal each have a frequency selected to upregulate activity on the first nerve or organ and has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the first nerve or organ.

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

26. The system of any one of claims 1-25, further comprising a transmitter operably connected to the glucose sensor, wherein the transmitter is configured to communicate data generated by the glucose sensor to an external communication device.

27. The system of any one of claims 1-26, wherein the communication system is selected from a group consisting of an antenna, blue tooth technology, radio frequency, WIFI, light, sound and combinations thereof, and wherein the communication system is configured to communicate parameters of the at least one therapy program to an external communication device.

28. A method of treating hypoglycemia in a subject, the method comprising: applying a first electrical signal to a first nerve or organ of the subject using the system of claim 1, wherein the first electrical signal initiates a neural stimulation or a neural block; and optionally applying a second electrical signal to a second nerve or organ of the subject using the system of claim 1, wherein the second electrical signal initiates a neural stimulation or a neural block.

29. The method of claim 28, wherein the first and the second electrical signals are applied concurrently, or simultaneously, or intermittently, or during substantially the same times, or during substantially different times, or in a coordinated fashion.

30. The method of any one of claims 28-29, wherein the first and/or the second electrical signal are configured to increase plasma glucose of the subject by at least about 5 mg/dL in about 10 minutes.

31. The method of any one of claims 28-30, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 10 mg/dL in about 20 minutes.

32. The system of any one of claims 28-31, wherein the first and/or the second electrical signal treatment are configured to increase the plasma glucose level by at least about 20 mg/dL in about 30 minutes.

33. The method of any one of claims 28-32, wherein the first and/or the second electrical signal are each applied continuously during an on time followed by an off time during which the signal is not applied to the nerve or organ.

34. The method of any one of claims 28-33, wherein the on times are applied multiple times per day when plasma glucose level is of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL.

35. The method of any one of claims 28-34, wherein the off times are applied multiple times per day when plasma glucose level is of or above about 80 mg/dL, of or above about 90 mg/dL, of or above about 100 mg/dL, of or above about 110 mg/dL.

36. The method of any one of claims 28-35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

37. The method of any one of claims 28-35, wherein the first electrical signal has a frequency of about 200 Hz to about 10k Hz.

38. The method of any one of claims 28-37, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

39. The method of any one of claims 28-37, wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

40. The method of any one of claims 28-35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and wherein the second electrical signal has a frequency of about 200 Hz to about 10k Hz.

41. The method of any one of claims 28-40, wherein the first nerve or organ and the second nerve or organ are independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

42. The method of any one of claims 28-41, wherein the first nerve or organ and the second nerve or organ are different.

43. The method of any one of claims 28-42, wherein the first electrical signal is applied on a hepatic branch of a vagus nerve or a ventral vagus nerve central to a branching point of a hepatic nerve.

44. The method of any one of claims 28-42, wherein the first electrical signal is applied on a celiac branch of a vagus nerve or a ventral vagus nerve central to a branching point of a celiac nerve.

45. The method of any one of claims 28-42, wherein the first electrical signal is applied to liver, pancreas or both.

46. The method of any one of claims 28-45, wherein the second electrical signal is applied to a splanchnic nerve or a celiac branch of a vagus nerve, or pancreas.

47. The method of any one of claims 28-45, wherein the second electrical signal is not involved in the method.

48. The method of any one of claims 28-47, further comprising administering an agent that improves glucose control.

49. The method of claim 48, wherein the agent decreases the amount of insulin and/or decreases the sensitivity of cells to insulin.

51. The method of claim 50, wherein the first and/or the second electrical signal each have a frequency selected to initiate activity respectively on the first and/or the second target nerve or organ, and wherein the activity is an upregulation or down- regulation of neural activity.

52. The method of any one of claims 50-51, further comprising connecting a glucose sensor to the implantable pulse generator; and monitoring or detecting plasma glucose level of the subject using the glucose sensor.

53. The method of any one of claims 50-52, further comprising configuring a communication system of the external component to communicate parameters of the at least one therapy program to an external communication device.

54. The method of any one of claims 50-53, further comprising connecting a transmitter to the glucose sensor to communicate data generated by the glucose sensor to an external communication device.

55. The method of any one of claims 50-54, wherein the first and/or the second electrode are placed on the nerve or organ via a laparoscopic approach.

57. The system of claim 56, wherein the nerve or organ is selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus on posterior nerve, hepatic branch of vagus nerve, celiac branch of vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerves, baroreceptors, glossopharyngeal nerve, duodenum, jejunum, ileum, small bowel, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

58. The system of any one of claims 56-57, wherein the nerve is posterior vagus nerve (PVN) of the subject or the celiac vagus nerve branch of the PVN.

59. The system of any one of claims 56-58, wherein the electrical signal has an on time and an off time, wherein the off time is selected to allow at least a partial recovery of the activity of the nerve or organ.

60. The system of claim 59, wherein the on time is configured to commence upon the detection of plasma glucose level of or below about 50 mg/dL, of or below about 60 mg/dL, of or below about 70 mg/dL, of or below about 80 mg/dL in the subject.

61. The system of any one of claims 59-60, wherein the on time is about 30 seconds to about 30 minutes.

62. The system of any one of claims 56-61, wherein the at least one electrical signal treatment comprises an electrical signal pattern having a frequency from about 1 Hz to about 200 Hz, or from about 1 Hz to about 50 Hz, or from about 1 Hz to about 20 Hz, or from about 1 Hz to about 10 Hz, or from about 1 Hz to about 5 Hz, or from about 1 Hz to about 2 Hz.

63. The system of any one of claims 56-62, wherein the electrical signal pattern has a pulse width from about 0.1 microseconds to about 10 microseconds in about 0.1 microseconds steps.

64. The system of any one of claims 56-63, wherein the electrical signal pattern has a pulse amplitude from about 0.1 mA to about 12 mA in about 0.1 mA steps.

65. The system of any one of claims 56-64, wherein the pulse of the at least one electrical signal is monophasic pulse, or biphasic pulse, or combinations thereof.

66. The system of any one of claims 56-65, wherein the at least one electrical signal further comprises an abrupt start of pulses, or a ramp up of current/voltage amplitude, or a ramp up of frequency, or a ramping up of pulse widths, or combination thereof at or near initiation of applying the electrical signal.

67. The system of any one of claims 56-66, wherein at least one electrical signal treatment is configured to be applied intermittently multiple times in a day and over multiple days.

68. The system of any one of claims 56-67, wherein the at least one electrical signal treatment is configured to causes increase of the plasma glucose of the subject by at least about 5 mg/dL in about 10 minutes, or by at least about 10 mg/dL in about 20 minutes, by at least about 20 mg/dL in about 30 minutes, or by at least about 30 mg/dL in about 45 minutes, or by at least about 40 mg/dL in about 60 minutes.

69. The system of any one of claims 56-68, wherein the at least one electrical signal treatment is configured to cause an increase of glucagon secretion in the subject.

70. The system of any one of claims 56-69, wherein application of the at least one electrical signal treatment is configured to cause an decrease of insulin secretion in the subject.

71. The system of any one of claims 56-70, further comprising a transmitter operably connected to the glucose sensor, wherein the transmitter is configured to communicate data generated by the glucose sensor to an external communication device.

72. The system of any one of claims 56-71, wherein the communication system is selected from a group consisting of an antenna, blue tooth technology, radio frequency, WIFI, light, sound and combinations thereof, and wherein the communication system is configured to communicate parameters of the at least one therapy program to an external communication device.

73. A method of treating hypoglycemia in a subject in need thereof, the method comprising: applying the at least one electrical signal treatment to a posterior vagus nerve (PVN) of a subject or the celiac vagus nerve branch of the PVN of the subject using the system of any one of claims 56-72.

74. The method of claim 73, wherein the electrical signal pattern applied to the has a frequency from about 1 Hz to about 20 Hz, a pulse width from about 0.1 microseconds to about 10 microseconds in about 0.1 microseconds steps, and a pulse amplitude from about 0.1 mA to about 12 mA in about 0.1 mA steps.

75. The method of any one of claims 73-74, wherein application of the at least one electrical signal treatment causes increase of the plasma glucose of the subject by at least about 5 mg/dL, at least about 10 mg/dL, at least about 20 mg/dL, at least about 30 mg/dL, at least about 40 mg/dL, at least about 50 mg/dL, at least about 60 mg/dL, at least about 70 mg/dL, at least about 80 mg/dL, at least about 90 mg/dL, or at least about 100 mg/dL, in about 60 minutes.

76. The method of any one of claims 73-75, wherein application of the at least one electrical signal treatment causes increase of glucagon secretion in the subject.

77. The method of any one of claims 73-76, wherein application of the at least one electrical signal treatment causes decrease of insulin secretion in the subject.

78. The method of any one of claims 73-77, further comprising: placing the at least one electrode on the nerve or organ via a laparoscopic approach.