Neuromodulation of two or more neuron targets in treatment of medical conditions

Abstract

The present disclosure relates to neuromodulation of two or more neuron targets in the treatment of medical conditions. The neuron target may be a sympathetic nerve, a parasympathetic nerve, or a combination of a sympathetic nerve and a parasympathetic nerve. Neuromodulation of the neuronal target may include stimulation of the neuronal target, conduction blocking of the neuronal target, or a combination of stimulation and conduction blocking of the neuronal target. The neuromodulation is performed by one or more neuromodulators, which may include electrical or non-electrical neuromodulators. The neuromodulation of each neuron target may include the same or different start / end times, the same or different durations, and / or the same or different neuromodulation patterns. Neuromodulation of the first neuron target cooperates with neuromodulation of the second neuron target to treat a medical condition.

Description

Technical Field

[0001] The present disclosure relates to neuromodulation, and more particularly, to neuromodulation of two or more neuronal targets in the treatment of medical conditions. Background Art

[0002] The peripheral nervous system consists of two main branches, the somatic sensory branch transmits information such as touch and pain to the central nervous system (CNS). Another branch consists of the autonomic nervous system, which carries information about the status of internal organs to the CNS and carries information from the CNS to control internal organs. The autonomic nervous system can be further divided into two parts: the sympathetic nervous system and the parasympathetic nervous system. They work in an antagonistic manner. The sympathetic nerves put the body in a "flight or fight" mode. For example, activation of the sympathetic nervous system takes blood away from the stomach and directs it to the muscles, slowing digestion and increasing the release of adrenaline. The parasympathetic nervous system puts the body into a "rest and digest" mode. For example, its activation directs blood to the stomach and promotes the digestion process. Most, if not all, internal organs are governed by both the sympathetic and parasympathetic nervous systems.

[0003] In the case of neuromodulation (stimulation or blockade) aimed at controlling the function of internal organs, modulating only one arm of the autonomic nervous system may not produce optimal or even minimal results. This is because when one arm is modulated, the other arm may compensate for the exogenous upregulation or downregulation of the nerves innervating that organ. Therefore, neuromodulation of a single neuronal target often fails to produce an effect sufficient to treat many medical conditions. Summary of the invention

[0004] The present disclosure relates to neuromodulation (stimulation or conduction blockade) of two or more neuron targets in the treatment of a medical condition. The neuron target may be a sympathetic nerve, a parasympathetic nerve, or a combination of a sympathetic nerve and a parasympathetic nerve. Neuromodulation of a neuron target may include stimulation of a neuron target, a conduction blockade of a neuron target, or a combination of stimulation and conduction blockade of a neuron target. Neuromodulation is performed by one or more neuromodulators, which may include electrical neuromodulators or non-electrical neuromodulators. Neuromodulation of each neuron target may include the same or different start / end times, the same or different durations, and / or the same or different neuromodulation modes. Neuromodulation of a first neuron target cooperates with neuromodulation of a second neuron target to treat a medical condition.

[0005] One aspect of the present disclosure relates to a system for regulating at least two neuron targets. The system comprises a first neuroregulator and a second neuroregulator. The first neuroregulator applies stimulation or conduction block to the first neuron target. The second neuroregulator applies a stimulator or conduction block to a second neuron target different from the first neuron target. The stimulation or conduction block to the first neuron target acts in conjunction with the stimulation or conduction block to the second neuron target to treat a medical condition. In certain embodiments, the first and second neuroregulators are both electrical neuroregulators, non-electrical neuroregulators, or a combination of electrical and non-electrical neuroregulators.

[0006] Another aspect of the disclosure relates to a method of treating a medical condition. The method comprises: (a) neuromodulating a first neuronal target using stimulation or conduction blockade; and (b) neuromodulating a second neuronal target using stimulation or conduction blockade, wherein the second neuronal target is different from the first neuronal target, and wherein the neuromodulation of the first neuronal target acts in conjunction with the neuromodulation of the second neuronal target to treat the medical condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 is an exemplary schematic diagram of a neuromodulation system for neuromodulating two or more neuronal targets according to the present disclosure.

[0008] Figure 2 is an exemplary schematic diagram of another neuromodulation system for neuromodulating two or more neuronal targets according to the present disclosure.

[0009] Figure 3 is an exemplary schematic diagram of another neuromodulation system for neuromodulating two or more neuronal targets according to the present disclosure.

[0010] Figure 4 is the time course of various conditions in Experimental Group 2 relevant to the Type II diabetes rat model studies described herein.

[0011] Figure 5 is a graph relating to the Type II diabetic rat model studies described herein showing the percent change in blood glucose concentrations in sham surgery or celiac branch stimulation and hepatic nerve vagotomy (Experimental Group 1) prior to glucose challenge.

[0012] Figure 6 is a graph relating to the Type II diabetic rat model studies described herein, showing the time course of percent change in blood glucose concentration following glucose challenge with sham surgery, celiac branch stimulation and hepatic nerve vagotomy (Experimental Group 1), and celiac branch stimulation with simultaneous delivery of 5000 Hz to the hepatic nerve arm (Experimental Group 2).

[0013] Figure 7 is a bar graph relating to the Type II diabetes rat model studies described herein and illustrates peak glucose concentrations following a glucose challenge (measured as percent change from baseline) for each experimental condition.

[0014] Figure 8 is a graph relating to the Type II diabetic rat model studies described herein, wherein the percent change in blood glucose versus time was obtained with celiac branch stimulation and simultaneous delivery of 5000 Hz to the hepatic nerve arm (experimental group 2) prior to a glucose tolerance test.

[0015] Fig. 9 is a graph relating to the type II diabetes rat model studies described herein, where the percentage change in blood glucose concentration over time during two glucose challenges was plotted with stimulation of the celiac rami and simultaneous delivery of 5000 Hz (dashed line) to the hepatic nerve.

[0016] Fig.10 is a flow chart showing the treatment process for controlling blood sugar levels.

[0017] Fig.11 is an illustrative depiction of exemplary neural innervation locations for altering blood glucose levels.

[0018] Fig.12 is a graphic illustration of an example of blood sugar levels over a 24 hour period.

[0019] Fig.13 is a graph relating to the Type II diabetes study described herein, where blood glucose concentration (mg / dL) is plotted over time (min) with stimulation of the celiac rami and simultaneous delivery of 5000 Hz to the hepatic nerve 5 minutes after an OGTT.

[0020] Fig.14 is an illustration of an example of lead placement and neuromodulator control.

[0021] Fig.15 is a table showing complications associated with diabetes. DETAILED DESCRIPTION

[0022] The present disclosure relates to neuromodulation (stimulation or conduction blockade) of two or more neuronal targets in the treatment of medical conditions. Neuronal targets typically include sympathetic and / or parasympathetic nerves, which typically innervate visceral organs. One or more neuromodulators provide the desired stimulation or conduction blockade to the neuronal targets, working in conjunction to treat the medical condition. In certain embodiments, two or more neuronal targets: (a) are neuromodulated in a common time period; (b) are neuromodulated in overlapping time periods; (c) are neuromodulated in different non-overlapping time periods; and / or (d) are neuromodulated in any combination of (a), (b), and (c). Neuromodulation of each neuronal target can include the same or different start / end times, the same or different durations, and / or the same or different neuromodulation patterns.

[0023] Stimulating neuromodulators may include, for example, electrical stimulators or chemical reagent stimulators. Conduction blocking neuromodulators may include, for example, physical partial (e.g., ablation) conduction blocking, electrical conduction blocking, electrical high-frequency conduction blocking, chemical conduction blocking, or optogenetic conduction blocking obtained by delivering inhibitory opsins or excitatory opsins through high-frequency light flashes. Of the neuromodulators mentioned, electrical stimulators, electrical conduction blocking, and electrical high-frequency conduction blocking may be considered electrical neuromodulators, while all other mentioned neuromodulators may be considered non-electrical neuromodulators.

[0024] Medical conditions that can be treated by coordinated neuromodulation of two or more neuronal targets include, but are not limited to: (a) heart failure; (b) inflammation; (c) hypertension; (d) pancreatitis; (e) refractory asthma; (f) urinary incontinence; (g) erectile dysfunction; (h) type II diabetes; (i) obesity; (j) Parkinson's disease; (k) refractory depression; (l) refractory epilepsy; and (m) cluster headache.

[0025] Figure 1 A simplified schematic diagram of a neuromodulation system 10 is illustrated in which a single neuromodulator 12 is used to neuromodulate multiple neuronal targets 14a, 14b ... 14(n). Figure 2 A simplified schematic diagram of a neuromodulation system 10 is illustrated, wherein each neuron target 14a, 14b ... 14(n) is neuromodulated by a corresponding neuromodulator 12a, 12b ... 12(n). Other combinations of neuromodulators and neuron targets within a neuromodulation system are also possible. Neuromodulation of a neuron target acts in conjunction with neuromodulation of another of two or more neuron targets to treat a medical condition.

[0026] Figure 3A schematic diagram of an exemplary neuromodulation system 100 is provided, the system having a first neuromodulator 102 for neuromodulating a first neuron target and a second neuromodulator 104 for neuromodulating a second neuron target. In this example, each of the first neuromodulator 102 and the second neuromodulator 104 comprises an electrical neuromodulator that can provide electrical stimulation and / or electrical conduction blocking. In other examples, the first neuromodulator of the neuromodulation system can include an electrical neuromodulator, and the second neuromodulator of the neuromodulation system can include a non-electrical neuromodulator, such as the non-electrical stimulation and / or conduction blocking neuromodulators described in the above paragraphs.

[0027] continue Figure 3 In an example of a neuromodulation system 100, a neuromodulation system 100 generally includes an external component 106 located outside the body 108 and an internal component 110 implanted beneath the dermis within the body 108. The external component 106 includes a charger 112, which is coupled to a battery 114 and a transmitting coil 116 via a connector 113. The charger 112 is also communicatively coupled to a programming device 118 via a communication port 117. The internal component 110 includes a first neuroregulator 102 and a second neuroregulator 104, each of which is coupled to one or more electrodes 122 via one or more wires 120, and the electrodes 122 are placed on neuronal targets. Each of the neuroregulators 102, 104 includes a rechargeable battery 124 and a receiving antenna 126. In some examples, the neuroregulators 102, 104 share a common battery 124 and a common receiving antenna 126.

[0028] exist Figure 3 In examples of the invention, the leads 120 include bipolar leads, each of which is connected to a first electrode 122a and a second electrode 122b. However, other lead and electrode configurations may be used depending on the particular application. In some examples, each of the neuroregulators 102, 104 includes an implantable component that is independent of the other, while in other examples, the first neuroregulator 102 and the second neuroregulator 104 are combined within a single implantable component. In some examples, each of the neuroregulators 102, 104 is configured to interact with a common external component 106, while in other examples, each of the neuroregulators 102, 104 interacts with its own corresponding external component 106.

[0029] In operation, the first neuroregulator 102 and the second neuroregulator 104 of the neuromodulation system 100 generate electrical pulses that are delivered to their respective first and second neuronal targets via the conductive wires 120 and electrodes 122. In addition to delivering electrical pulses, each of the neuroregulators 102, 104 also receives wireless command signals from the programming device 118 and can wirelessly upload data to the programming device 118 via the charger 112. Each of the neuroregulators 102, 104 is powered by its internal battery 124; in some examples, the neuroregulators 102, 104 share a common internal battery 124. The internal battery 124 is periodically recharged by RF power radiated by the transmitting coil 116 and picked up by the receiving antenna 126. The charger 112 provides the electrical excitation of the transmitting coil 116 required to deliver RF power to the neuroregulators 102, 104. In addition, the charger 112 acts as an interface for communication between the neuroregulators 102, 104 and the programming device 118. In some examples, a rechargeable battery (not shown) powers the charger 112. The transmitting coil 116 is used to transmit RF power from the charger 112 percutaneously to the neuroregulators 102, 104. The transmitting coil 116 further facilitates bidirectional RF communication between the neuroregulators 102, 104 and the charger 112. The programming device 118 enables a clinician to program each neuroregulator 102, 104 using a treatment plan and using treatment parameters to deliver stimulation or conduction blockade to its respective neuronal target.

[0030] An example of a neuromodulation system similar to the one described above is provided by ReShape Lifesciences, Inc. (St. Paul, MN) A rechargeable system, although only one neuroregulator, is described in detail in the following U.S. Patent Publication No. Rechargeable systems: US 7,489,969; US 7,167,750; US 7,444,183; US 7,613,515; US 7,720,540; US 7,630,769; US 7,693,577; US 7,729,771; US ​​7,844,338; US 8,046,085; US 7,986,995; US 8,010,204; US 8,369,952; US 8,538,542; US 9,174,040; US 8,538,533; US 9,162,062, US 8,862,233; US 7,672,727;US 8,103,349; US 7,822,486; US 8,140,167; US 8,532,787; US 8,068,918; US 8,521,299; US 7,917,226; US 8,483,838; US 8,326,426; US 9,186,502; US 8,483,830; US 9,333,340; US 6,699,275; US 6,860,851; US ​​8,825,164; US2014 / 0214129; US 9,393,420; US 8,101,204; US 8,768,469; US 9,095,711; and US2013 / 0237948. Each of the patent publications mentioned is incorporated herein by reference in its entirety.

[0031] How to use

[0032] It is preferred to use an implantable pulse generator to perform the methods of the present invention, but it is also contemplated that the treatment may be administered on an outpatient basis using an external device, although this is only slightly more convenient than full hospitalization. Of course, implantation of one or more pulse generators allows the patient to be fully ambulatory, so that normal daily activities (including work performance) are not affected.

[0033] The pulse generator can be programmed using a programming stick and a personal computer using appropriate programming software developed based on the programming needs and signal parameters already described herein. Of course, the purpose is to allow non-invasive communication with the electronic assembly after the electronic assembly is implanted to achieve both monitoring and programming functions. In addition to the basic functions, the programming software should be organized to provide simple, menu-driven operation, help functions, prompts and messages to facilitate simple and fast programming while allowing the user to fully understand all that occurs at each step of the sequence. Programming capabilities should include the ability to modify adjustable parameters of the electronic assembly, test device diagnostics, and store and retrieve data obtained and transmitted from a distance. It is expected that when the implanted unit is interrogated, the current status of the adjustable parameters is displayed on the PC monitor so that the programmer can then conveniently change any or all of these parameters at the same time; and, if a specific parameter is chosen to be changed, all the allowed values ​​of the parameter are displayed so that the programmer can select the appropriate desired value to enter the pulse generator.

[0034] Other desirable features of suitable software and associated electronics include the ability to store and retrieve historical data including patient code, device serial number, battery run hours, output hours and number of magnetic activations (referring to patient mediations) for displaying on screen the date and time information of the last activation or activations.

[0035] Diagnostic tests should be performed to verify that the device is functioning properly and to indicate if there are problems such as communications, battery, or lead / electrode impedance. For example, a low battery reading would indicate that the battery life is coming to an end and a new device needs to be implanted. However, because the pulse generator of the present invention requires activation relatively infrequently, its battery life should significantly exceed that of other implantable medical devices, such as pacemakers. In any case, if no signs of problems with the neural electrodes are observed during diagnostic testing, they can be used indefinitely.

[0036] The device may also utilize circadian rhythm or other programming so that activation occurs automatically at the patient's normal mealtimes. This may be in addition to the manual, periodic between-meal, and sensor-triggered activations described above.

[0037] The patient can also manually activate the pulse generator by any of a number of means through appropriate settings of the device. These techniques include the patient using an external magnet or external radio frequency signal generator, or tapping a surface above the pulse generator, to activate the pulse generator, thereby applying the desired modulation signal to the electrodes. Another form of treatment can be achieved by programming the pulse generator to periodically deliver vagal nerve activity modulation that produces glycemic control at programmed intervals.

[0038] In some embodiments, the system can include one or more sensors that can provide a signal to initiate a therapeutic signal to one or more electrodes. For example, a sensor can measure the amount of biological activity in the blood and initiate a signal to a nerve or organ if the amount exceeds or falls below a predetermined threshold.

[0039] As described herein, the method involves modifying a biological activity selected from the group consisting of blood glucose, heart rate, blood pressure, respiration, movement, CNS neuron electrical signals, peripheral nerve signals, and combinations thereof. In some example embodiments, the method of modifying the amount of biological activity comprises: applying a first intermittent (or continuous) electrical signal to a target nerve (or organ), wherein the first electrical signal is selected to block or stimulate neural activity on the nerve, and restore neural activity on the nerve when the signal stops, wherein the electrical signal is selected to modify the amount of biological activity measured by the sensor.

[0040] In some embodiments, the method further includes intermittently (or continuously) applying a second electrical signal treatment to a second target nerve or organ, wherein the frequency of the second electrical signal is selected to block or stimulate activity on the target nerve or organ and restore neural activity of the second target nerve (or organ) to restore the activity of the target to baseline levels.

[0041] In another aspect of the present disclosure, a system for treating a patient is provided. In some embodiments, the system comprises: at least one electrode operably connected to an implantable pulse generator, wherein one of the electrodes is adapted to be placed on a target nerve; an implantable pulse generator comprising a power module and a programmable therapy delivery module, wherein the programmable therapy delivery module is configured to deliver at least one therapy program, the therapy program comprising applying an electrical signal therapy to the target nerve multiple times within a day and multiple days intermittently (or continuously), wherein the frequency of the electrical signal is selected to change the activity on the target nerve and has an on time and an off time, wherein the off time is selected to allow at least partial recovery of the activity of the target nerve; and an external component, which comprises a communication system and a programmable storage and communication module, wherein the programmable storage and communication module is configured to store at least one therapy program and transmit at least one therapy program to the implantable pulse generator.

[0042] In some embodiments, the programmable therapy delivery module is configured to deliver a second therapy program to a second target nerve or organ, the second therapy program comprising applying an electrical signal therapy to the second target nerve multiple times within a day and intermittently over multiple days, wherein the frequency of the electrical signal is selected to upregulate or downregulate activity on the target nerve and has an on time and an off time, wherein the off time is selected to allow at least partial recovery of activity of the target nerve or organ. In other related embodiments, the communication module is configured to store at least one therapy program and transmit at least one therapy program to the implantable pulse generator using a communication system selected from the group consisting of an antenna, Bluetooth technology, radio frequency, WIFI, light, sound, and combinations thereof, such as Bluetooth technology, radio frequency, WIFI, light, or sound.

[0043] Signal frequency and timing

[0044] In some embodiments, the down-regulation signal frequency is at least 200Hz and up to 5000Hz. In other embodiments, the signal is applied at a frequency of about 500 to 5000Hz. The applicant has determined that the most preferred blocking signal frequency is 3,000Hz to 5,000Hz or higher applied by two or more bipolar electrodes. The preferred pulse width of such a signal is 100 microseconds (related to a frequency of 5,000Hz). It is believed that this frequency and pulse width can best avoid nerve recovery from blocking and avoid nerve repolarization by avoiding a phase without a signal in the pulse cycle. A short "off time" in the pulse cycle (e.g., between cycles or within a cycle) is acceptable as long as it is short enough to avoid nerve repolarization. The waveform can be a square wave or a sine wave or other shape. In pig studies, it was found that a higher frequency of 5,000Hz or higher can result in a more consistent nerve conduction blockade. Preferably, the signal is bipolar, biphasic, and is delivered to two or more electrodes on the nerve.

[0045] In some embodiments, a signal amplitude of 0.01 to 20.0 mA is sufficient for blocking. In other embodiments, a signal amplitude of 0.01 to 10 mA is sufficient for blocking. In yet other embodiments, a signal amplitude of 0.01 to 8 mA is sufficient for blocking. Other amplitudes may suffice. Other signal attributes may be changed to reduce the possibility of nerve or organ modulation. These include changing the power, waveform, or pulse width.

[0046] The up-regulating signal generally comprises a signal having a frequency of less than 200 Hz, more preferably 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. The preferred pulse width of such a signal is 0.1-10 microseconds. In some embodiments, a signal amplitude of 0.1 to 12 mA is sufficient for stimulation. Other amplitudes may suffice. Other signal attributes may be changed to reduce the possibility of nerve or organ regulation. These include changing power, waveform or pulse width.

[0047] Selecting signals that upregulate and / or downregulate neural activity and / or allow neural activity to resume can involve selecting the signal type and timing of signal application. For example, for electrode conduction blocking, the blocking parameters (signal type and timing) can be changed by the pulse generator and can be coordinated with the stimulation signal. The precise signal to achieve the blockade may vary from patient to patient and from nerve site to nerve site. The precise parameters can be adjusted individually to achieve neural transmission blockade at the blocking site.

[0048] In some embodiments, the signal has a duty cycle, comprising 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 time can be adjusted to allow the nerve to partially recover.

[0049] In some cases, the down-regulating and up-regulating signals can be coordinated so that the up-regulating signal is applied when the down-regulating signal is not applied, such as when the up-regulating signal is applied at a particular time or due to a sensed event. In some embodiments, the sensed event indicates that the up-regulating signal is applied, and the down-regulating signal is not applied during a time period associated with the sensed event, such as blood glucose exceeding a certain threshold. In preferred embodiments, the signal is applied continuously.

[0050] Many medical conditions can be treated by neuromodulation of two or more neuronal targets. Various neuromodulation systems (including the systems described herein) can be used to achieve the desired neuromodulation. Table 1 below provides only some examples of at least a first and a second neuronal target that can be neuromodulated (stimulated or blocked) to treat a medical condition.

[0051] Table 1.

[0052]

[0053]

[0054] *Third neuron target – Gallbladder for bile production (stimulation)

[0055] It should be understood that in other embodiments, the second target of electrical stimulation will be smooth muscle. Targets include, but are not limited to, the stomach, duodenum, small intestine, large intestine, intestines, and bladder for the treatment of medical conditions. For example, the antrum and / or duodenum can be stimulated to increase gastric emptying and reduce the absorption of monosaccharides and polysaccharides to treat type 2 diabetes. Antrum and / or duodenal stimulation can be combined with subdiaphragmatic vagus nerve stimulation to further increase gastric emptying. In addition, blocking fibers that innervate the liver will reduce insulin resistance and can be used together with antrum and / or duodenal stimulation.

[0056] Intestinal stimulation can be used to treat diseases such as, but not limited to, Crohn's disease, which can produce chronic intestinal obstruction. Stimulation of the nerves innervating the enteric nervous system and intestinal stimulation can be used to treat chronic intestinal obstruction.

[0057] Combination of neuromodulation with smooth muscle can also be used to treat disorders related to urination. Stimulation of the bladder combined with blockade of the pudendal nerve innervating the external ureteral sphincter can induce urination in patients with spinal cord injury. Stimulation of the colon combined with blockade of the inferior rectal nerve innervating the external anal sphincter can be used to increase stool output in patients with spinal cord injury. Pudendal nerve stimulation can be used to treat urinary incontinence, and stimulation of the inferior rectal nerve can be used to treat fecal incontinence.

[0058] The results of the study suggest that a device that uses high-frequency conduction to block the anterior subphrenic vagus nerve trunk above the level of the hepatic branch and low-frequency stimulation of the posterior subphrenic vagus nerve trunk above the level of the celiac branch may be an effective method for controlling blood sugar and treating type 2 diabetes.

[0059] It should be understood that aspects of the various embodiments disclosed herein can be combined in any manner to provide many additional embodiments. For the sake of brevity, these embodiments will not be described separately.

[0060] A specific example is provided below of treating a medical condition, such as type II diabetes, by neuromodulating two neuronal targets (eg, the celiac nerve and the hepatic nerve) using a neuromodulation system.

[0061] Example: Type II diabetes-rat model study results

[0062] The incidence of type II diabetes (90% of diabetes cases, World Health Organization (WHO)) is increasing, and the consequences are severe. In 2012, 1.5 million people died from diabetes, and 2.2 million died from hyperglycemia (WHO). In the United States, diabetes is the sixth leading cause of death. People who live with type II diabetes for many years may develop neuropathic pain, nerve degeneration, blindness, and amputations. Treatments are limited, and there is a large unmet need for new therapies.

[0063] Type II diabetes takes a great toll on the body due to the toxic effects of persistently high blood sugar concentrations. The pancreas is one such organ that plays a key role in stabilizing high blood sugar concentrations. With prolonged high blood sugar levels, the ability of the islet cells of the pancreas to produce insulin decreases, which further reduces the body's ability to cope with high glucose. Finding a way to stabilize blood sugar levels in people with type II diabetes would stop this harmful cycle.

[0064] In view of the above, a study was conducted to determine the possible effectiveness of controlling glucose levels by stimulating the posterior vagus nerve at the celiac level, as a first neuronal target, in combination with hepatic nerve blockade, as a second neuronal target. More specifically, the differential regulation procedure was tested in a rat model by using an intravenous glucose challenge (infusion of high concentrations of glucose into the circulation) with concurrent stimulation of the posterior vagus nerve at the level of the celiac rami following hepatic vagotomy or high-frequency alternating current conduction blockade.

[0065] method

[0066] Rats (250-300 g) were divided into a control group (n=5) and two experimental groups (n=5 for stimulation / vagus nerve ablation and n=6 for stimulation / 5000 Hz). In all groups, rats were fasted for at least 18 hours, similar to other studies investigating changes in blood glucose concentrations (Lee and Miller, 1985). The control group underwent sham surgery. First, the rats were anesthetized by intramuscular injection of a combination of ketamine, xylazine, and acepromazine. Testicular reflex tests were performed regularly to determine that the rats were anesthetized, and ketamine was injected if the rats were slightly conscious. Next, the abdominal cavity was opened and the liver was retrieved. For the sham surgery, the hepatic nerve branch of the anterior vagus trunk (hereinafter referred to as the "hepatic branch") and the celiac nerve branch of the posterior vagus trunk (hereinafter referred to as the "celiac branch") were isolated and separated from the esophagus using gentle dissection. In the experimental groups, a surgical approach similar to the sham procedure was performed, but the celiac branch was placed on a bipolar platinum hook electrode for electrical stimulation in combination with hepatic branch vagotomy in the first experimental group, and electrodes were placed under the hepatic nerve to achieve conduction blockade combined with stimulation of the celiac branch in the second experimental group.

[0067] Blood samples were collected by wrapping a warm cloth around the rat's tail (to stimulate blood flow) and then cutting the end of the rat's tail. The tail was then "squeezed" by squeezing from the end of the tail where it was attached to the body to the cut end to ensure that a fresh systemic blood sample was collected. Blood glucose concentrations (mg / dl) squeezed from the rat's tail were measured using an AlphaTrak (Abbott Laboratories, North Chicago, IL, USA) blood glucose monitor.

[0068] Blood glucose measurement was performed at the beginning of the experiment and was regarded as baseline. In experimental group 1, the hepatic branch was cut and the celiac branch was stimulated at a rate of 1 Hz immediately after baseline sampling. A gauze soaked in synthetic interstitial fluid (SIF) was placed between the hooks of the stimulating electrodes to ensure that nerve dryness would not occur during the experiment. The square wave with a pulse width of 4 milliseconds generated by the grass s44 stimulator (Grass Medical Instruments, Quincy, Massachusetts, the United States) drives the stimulation isolation unit (Model A360, World Precision Instruments, Sarasota, Florida, the United States). The pulse amplitude is 9 mA. In experimental group 1, the stimulation scheme was continuously applied for 1 hour, and blood glucose concentration was sampled regularly. For the sham operation group, stimulation was not delivered to the celiac branch and the hepatic branch was not cut off, but blood samples were collected over the same time course as the experimental group.

[0069] In experimental group 2, the celiac ramus was stimulated using the same procedure as experimental group 1. However, rather than performing a hepatic nerve vagotomy, a 5000 Hz alternating current signal was applied to the hepatic ramus using a bipolar platinum-iridium hook electrode (“blocking electrode”). The device that delivered the 5000 Hz signal was a rechargeable neuroregulator (RNR), similar to the device used in EnteroMedics' rechargeable clinical studies. A piece of gauze soaked in SIF was placed between the hooks of the blocking electrode to ensure that nerve desiccation did not occur during the experiment. The soaked gauze also reduced the impedance between the bipolar blocking electrodes to a level within the safe range of the RNR. The current amplitude was 12 mA, and the typical impedance was 1000 ohms (measured at 3 mA, 1000 Hz). The voltage on the blocking electrode was measured using a portable fluke (Everett, WA, USA) oscilloscope and was typically about 7 volts. This is less than the 12 volts predicted by the impedance test. Previous experiments have determined that the difference between the expected and measured voltages is due to the difference in frequency and current amplitude between the impedance test and the blocking signal. After obtaining a baseline blood sample, celiac branch stimulation was initiated simultaneously and 5000 Hz was delivered to the hepatic nerve. Blood samples were then collected 5 and 15 minutes after the start of the experiment.

[0070] A blood glucose challenge was performed 1 hour after initiation of the experimental group 1 condition (and sham surgery) and 15 minutes after initiation of the experimental group 2 condition. The blood glucose challenge consisted of an intravenous injection of a 0.5 g / kg dose of glucose made up of 0.9% saline at a concentration of 20% weight / volume into the tail vein. Blood glucose samples were then collected within 30 minutes after the injection. Stimulation / vagus nerve ablation (experimental group 1) or stimulation / 5000 Hz (experimental group 2) was performed continuously during the glucose challenge and for the following 30 minutes. Four of the six rats in experimental group 2 underwent a second glucose challenge 15 minutes after termination of the stimulation / 5000 Hz procedure ( Figure 4 ).

[0071] Statistical analysis consisted of a two-tailed Student's t-test assuming unequal variances using Microsoft Excel software (Redmond, WA, USA). All data are presented as mean ± SEM. The percent change in glucose concentration was calculated using the following equation:

[0072] % change = ((blood glucose concentration at time x - baseline blood glucose concentration) / (baseline blood glucose concentration)) * 100

[0073] The area under the curve after glucose challenge was calculated by assuming linearity between the data points (% change in glucose concentration*time=area units). The area between the line connecting two consecutive data points and the x-axis was calculated as one segment. The total number of segments after glucose challenge was then summed.

[0074] result

[0075] Experimental Group 1

[0076] Effects of hepatic vagotomy and celiac branch stimulation before glucose challenge

[0077] Reference now Figure 5 , wherein the blood glucose concentration of the sham-operated group remained relatively constant within one hour before the glucose attack. In experimental group 1, 5 minutes after stimulation / vagus nerve ablation, glucose concentration did not change significantly. However, from 15 minutes on, blood glucose concentration slightly decreased and continued for 60 minutes before the glucose tolerance test. As described in the above method, rats are fasted and have a low initial blood glucose concentration (generally about 170 mg / dL), which may have caused a floor effect. Therefore, glucose attack is implemented to test whether the stimulation / vagus nerve ablation combination can give rats the ability to tolerate glucose push injection into their circulatory system.

[0078] Glucose tolerance test

[0079] See also Figure 6 , which showed that five minutes after glucose injection, the sham-operated group experienced a substantial increase in blood glucose concentration (60 ± 22%) on average. The time to peak glucose concentration was different between sham-operated rats. Figure 7 , where the peak glucose concentration in the sham operation increased by an average of 90±16%. Glucose concentration remained high within 30 minutes after intravenous glucose injection and then decreased significantly after 30 minutes.

[0080] In experimental group 1, 5 minutes after glucose injection, the average increase in glucose concentration was only 5 ± 14% (see Figure 6). Glucose concentrations remained relatively low for 30 minutes after the glucose challenge and reached an average peak (increase of 21 ± 13%) 15 minutes after injection. As in the sham group, the peak time of glucose concentration varied between rats. The average peak value of experimental group 1 (increase of 21 ± 14%) was significantly lower than that of the sham group (see Figure 7 , p=0.01).

[0081] The area under the curve of the % change in glucose concentration relative to time after the glucose challenge was calculated as a measure of the overall effect of the glucose tolerance test. This showed a significant difference between the two groups (1704 ± 553 area units in the sham group vs. 202 ± 322 area units in the stimulation / vagus nerve cut group). Therefore, not only were there differences in peak glucose concentrations between the groups, but the overall ability of experimental group 1 to tolerate glucose challenges over time was also significantly higher than that of the sham group.

[0082] Experimental Group 2

[0083] Experimental Group 2 received 5,000 Hz alternating current applied to the hepatic nerve and simultaneously stimulated the celiac branch. This delivery significantly improved the ability to cope with a glucose challenge.

[0084] Reference now Figure 8 , where a 5000 Hz AC signal will reversibly block conduction in the subdiaphragmatic vagus nerve of rats. Applying a 5000 Hz AC signal to the hepatic nerve while stimulating the celiac branch will have the same effect as the cut hepatic nerve tested (with stimulation of the celiac branch). Similar to Experimental Group 1, blood glucose concentration decreased slightly before glucose challenge (see Figure 8 ).

[0085] After glucose challenge, blood glucose concentrations remained similar to those in experimental group 1 and were significantly lower than those in the sham group (see Figure 6 The peak time of blood glucose concentration after challenge in experimental group 2 was similar to that in experimental group 1 and the sham operation group. Compared with the baseline, the average peak value had a change of 31±6%, which was significantly lower than that in the sham operation group (p=0.005, see Figure 7 The ability of rats in experimental group 2 to cope with glucose challenge compared to the sham group was also evident in their area under the curve values ​​(1704±553 area units for sham vs 418±140 area units for stimulation / 5000 Hz).

[0086] Reversibility of stimulation / 5000 Hz program

[0087] A major advantage of using 5000 Hz to block conduction through the hepatic nerve compared to complete hepatic vagotomy is that the 5000 Hz conduction block is reversible, allowing normal communication from the brain to the liver (and vice versa) to occur at a controlled time. To test whether delivery of 5000 Hz to the hepatic nerve and stimulation of the celiac branch is reversible, the signal was turned off 30 minutes after the glucose challenge and a subsequent glucose challenge was performed 15 minutes later, referring to Figure 4 Figure 2 shows the procedural timeline for the experiment in which 4 of 6 rats in Experimental Group 2 received this electro-delivery protocol.

[0088] Reference now Fig. 9 , where blood glucose concentration remained relatively stable 15 minutes after stimulation / 5000Hz blocking. After the second blood glucose attack 15 minutes after stimulation / blocking (all electrical signals were turned off), blood glucose concentration increased significantly. As with all other glucose attacks in this study, the time of peak blood glucose concentration was different between rats. The average peak increased by 130±42%, which was not significantly different from the sham group, but there was a slight significant increase. The area under the curve was also not significantly different from the sham group (1704±553 area units in the sham group vs. 2566±915 area units in the second glucose attack group). It should be noted that after the first glucose attack, the blood glucose concentration of 1 of the 6 rats in experimental group 2 increased significantly (similar to the sham group). However, it should be understood that the specific test animal in question may be due to the fact that in order to prevent nerve drying, gauze soaked in SIF was placed between the hooks of the stimulating electrode and the blocking electrode. SIF is conductive, and it is likely that the blocking electrode and / or the stimulating electrode will short-circuit during this experiment. Therefore, this abnormal data is considered an outlier and is not included in the data set.

[0089] The above data show that, compared with sham surgery, by blocking the neuronal information sent in and out of the liver, while stimulating the celiac nerve (at the branch point where the posterior vagus nerve starts), the blood glucose concentration after the glucose tolerance test can be significantly reduced. Further, by using 5000Hz to block the neuronal information under the hepatic nerve (relative to vagotomy), and stimulate the celiac branch, the procedure is reversible. The stimulation can be always turned off, and it is well known that high-frequency conduction block is reversible. After stopping the stimulation / 5000Hz program, the biological system performance of the rats is similar to that of the sham surgery group (blood glucose increases significantly after glucose attack), which proves this point.

[0090] See now Fig.10, wherein a flow chart depicts the need for alternative therapeutic approaches to stimulation and blocking in the treatment of hyperglycemia in type 2 diabetes. As shown, the various needs or problems that need to be addressed include, for example: type 2 diabetes patients no longer respond effectively to oral hypoglycemic therapy, particularly sulfonylureas (301) after 3-5 years, non-compliant type 2 diabetes patients receiving combination therapy (302), diet control and exercise still suffer from uncontrolled blood sugar and HbA1c greater than 8, type 2 diabetes patients receiving insulin therapy have beta cell function to produce endogenous insulin, but not enough to overcome insulin resistance, including many patients also suffer from non-alcoholic liver disease and hypoglycemia problems (303), and GLP1 agonists are expensive and have tolerance problems, such as nausea and gastrointestinal problems. Therefore, the solution is a new implantable bioelectronic device to control blood sugar and the body's natural insulin secretion (305). It is performed using stimulation (320) and / or blocking (330).

[0091] Reference now Fig.11 , wherein blockade and stimulation of the liver and pancreas, respectively, provide dual regulatory options that provide (1) pacing stimulation of the pancreas to release insulin; (2) resistive hepatic branch interruption to reduce glucose release from the liver; and (3) local, reversible, and customizable therapy. Reference now Fig.12 , which provides a graphic illustration of the harmful "glucose spikes" that patients with type 2 diabetes experience throughout the day that lead to vascular and microvascular complications.

[0092] Reference now Fig.13 , which shows the type II diabetes study described herein, in which the change in blood glucose concentration (mg / dL) over time (min) was observed when the celiac branch was stimulated 5 minutes after an oral glucose tolerance test (OGTT) and 5000Hz was delivered to the hepatic nerve at the same time. The specific blood glucose values ​​are shown in the square brackets "[]" in the figure. The data show that 5 minutes after the start of the OGTT, the feasibility of the technology is proven to be discontinuous operation but using a continuous blood glucose monitoring system. This also shows that the algorithm-based technology can provide predictive blocking and / or stimulation therapy based on blood glucose data received in a closed-loop system.

[0093] Reference now Fig.14 , which shows the anatomical placement of a system (410) for modifying biological activity. The system includes a charging coil (416) and a neuroregulator system (402), which is shown as having a battery (430). As shown, the charging coil (416) is connected to a mobile charger (412). At least in this example embodiment, the system provides a radio frequency signal carrying energy to the patient to allow periodic charging without the need for a transdermal charging port. Now see Fig.15 , which shows a table of complications of diabetes. Fig.15 The percentages shown are from the CDC's 2020 National Diabetes Statistics Report.

[0094] Although the present invention is described above mainly with reference to the accompanying drawings, it should be understood that the present invention is not limited to the embodiments shown; on the contrary, these embodiments are intended to disclose the present invention to those skilled in the art. In the accompanying drawings, the same reference numerals always represent the same elements.

[0095] It should be understood that although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another element. For example, the first element may be referred to as the second element, and similarly, the second element may be referred to as the first element without departing from the scope of the present invention.

[0096] For brevity and / or clarity, well-known functions or constructions may not be described in detail.As used herein, the expression "and / or" includes any and all combinations of one or more of the associated listed items.

[0097] The terms used herein are only used to describe specific embodiments and are not intended to limit the present invention. As used herein, the singular forms "a", "an" and "the" are also intended to include the plural forms, unless the context clearly indicates otherwise. It should also be understood that the terms "comprises, comprising" and / or "includes, including" used in this specification specify the presence of the features, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, operations, elements, components and / or combinations thereof.

[0098] Herein, unless otherwise stated, the terms "attached," "coupled," "connected," "interconnected," "contact," "mounted," etc. may mean a direct or indirect attachment or contact between elements.

[0099] Non-limiting aspects of the invention are described herein by the following numbered clauses.

[0100] 1. A system for modulating at least two neuronal targets:

[0101] A first neuromodulator that applies stimulation or conduction blockade to a first neuronal target; and

[0102] A second neuromodulator applies stimulation or conduction blockade to a second neuronal target different from the first neuronal target, wherein the stimulation or conduction blockade of the first neuronal target acts in conjunction with the stimulation or conduction blockade of the second neuronal target to treat a medical condition.

[0103] 2. The system of clause 1, wherein the first neuron target and the second neuron target each comprise one or more sympathetic nerves.

[0104] 3. A system according to any of clauses 1-2, wherein the first neuron target and the second neuron target each include one or more parasympathetic nerves.

[0105] 4. A system according to any of clauses 1-3, wherein the first neuronal target comprises one or more sympathetic nerves, and wherein the second neuronal target comprises one or more parasympathetic nerves.

[0106] 5. A system according to any of clauses 1-4, wherein the stimulation or conduction block applied to the first neuronal target has a different duration than the stimulation or conduction block applied to the second neuronal target.

[0107] 6. A system according to any of clauses 1-5, wherein the first neuroregulator applies stimulation to the first neuronal target and the second neuroregulator applies stimulation to the second neuronal target.

[0108] 7. A system according to any of clauses 1-6, wherein the first neuroregulator applies a conduction block to the first neuronal target, and wherein the second neuroregulator applies a conduction block to the second neuronal target.

[0109] 8. A system according to any of clauses 1-7, wherein the first neuroregulator applies the conduction block to the first neuronal target, and wherein the second neuroregulator applies a stimulator to the second neuronal target.

[0110] 9. The system of clause 8, wherein the first neuronal target comprises a hepatic nerve and the second neuronal target comprises the celiac branch of the posterior vagus nerve.

[0111] 10. The system of any one of clauses 1-9, wherein the first neuroregulator is an electrical neuroregulator.

[0112] 11. The system of clause 10, wherein the second neuroregulator is an electrical neuroregulator.

[0113] 12. The system of clause 10, wherein the second neuroregulator is a non-electrical neuroregulator.

[0114] 13. A method of treating a medical condition comprising:

[0115] neuromodulating the first neuronal target using stimulation or conduction blockade; and

[0116] Stimulation or conduction blockade is used to neuromodulate a second neuronal target, wherein the second neuronal target is different from the first neuronal target, and wherein neuromodulation of the first neuronal target acts in conjunction with neuromodulation of the second neuronal target to treat a medical condition.

[0117] 14. The method of clause 13, wherein the first neuron target and the second neuron target each comprise one or more sympathetic nerves.

[0118] 15. A method according to any of clauses 13-14, wherein the first neuronal target and the second neuronal target each comprise one or more parasympathetic nerves.

[0119] 16. A method according to any of clauses 13-15, wherein the first neuronal target comprises one or more sympathetic nerves, and wherein the second neuronal target comprises one or more parasympathetic nerves.

[0120] 17. The method of any of clauses 13-16, wherein neuromodulating a first neuronal target comprises neuromodulating using stimulation, and wherein neuromodulating a second neuronal target comprises neuromodulating using stimulation.

[0121] 18. The method of any of clauses 13-17, wherein neuromodulating a first neuronal target comprises neuromodulating using stimulation, and wherein neuromodulating a second neuronal target comprises neuromodulating using conduction blockade.

[0122] 19. The method of any of clauses 13-18, wherein neuromodulating a first neuronal target comprises neuromodulating using a conduction block, and wherein neuromodulating a second neuronal target comprises neuromodulating using a conduction block.

[0123] 20. A system for modulating at least two neuronal targets:

[0124] a first implantable electrical neuromodulator that applies stimulation or conduction block to a first neuronal target; and

[0125] A second implantable neuromodulator applies stimulation or conduction blockade to a second neuronal target different from the first neuronal target, wherein the stimulation or conduction blockade of the first neuronal target acts in conjunction with the stimulation or conduction blockade of the second neuronal target to treat a medical condition.

[0126] 21. A method for sensing biological activity to trigger neuromodulation, the method comprising the steps of:

[0127] Obtain changes in biological activity from sensors;

[0128] The neuromodulator is activated to initiate at least one signal to a target nerve, target organ, or target tissue to alter the biological activity to a predetermined level where the signal ceases.

[0129] 22. The method of clause 21, wherein the method is a closed loop system.

[0130] 23. The method of clause 21, wherein the method is an open loop system.

[0131] 24. A method according to any of clauses 21-23, wherein the signal comes from at least two electrodes.

[0132] 25. A method according to any of clauses 21-24, wherein the at least two electrodes are activated simultaneously.

[0133] 26. A method according to any of clauses 21-24, wherein the at least two electrodes are activated at different times.

[0134] 27. A method according to any of clauses 21-24, wherein the at least two electrodes are activated with one electrical signal initiating blocking and the other electrical signal initiating stimulation.

[0135] 28. A method according to any of clauses 21-24, wherein the at least two electrodes are activated with one electrical signal initiating blocking and the other electrical signal initiating blocking.

[0136] 29. A method according to any of clauses 21-24, wherein the at least two electrodes are activated with one electrical signal initiating stimulation and the other electrical signal initiating stimulation.

[0137] 30. A method according to any one of clauses 21-29, wherein the sensor detects changes in biological activity, the biological activity being selected from the group consisting of blood glucose, heart rate, blood pressure, respiration, movement, CNS neuron electrical signals, peripheral nerve signals, and combinations thereof.

[0138] Although exemplary embodiments of the present invention have been described, those skilled in the art will readily appreciate that many modifications may be made to the exemplary embodiments and methods without materially departing from the novel teachings and advantages of the present invention. Therefore, all such modifications are intended to be included within the scope of the present invention as defined by the claims. The present invention is defined by the appended claims, and equivalents of the claims are also included therein.

Claims

1. A system for modulating at least two neuronal targets: A first neuromodulator that applies stimulation or conduction blockade to a first neuronal target; and A second neuromodulator applies stimulation or conduction blockade to a second neuronal target different from the first neuronal target, wherein the stimulation or conduction blockade of the first neuronal target acts in conjunction with the stimulation or conduction blockade of the second neuronal target to treat a medical condition.

2. The system of claim 1, wherein the first neuron target and the second neuron target each comprise one or more sympathetic nerves.

3. The system of claim 1, wherein the first neuron target and the second neuron target each comprise one or more parasympathetic nerves.

4. The system of claim 1, wherein the first neuronal target comprises one or more sympathetic nerves, and wherein the second neuronal target comprises one or more parasympathetic nerves.

5. The system of claim 1, wherein the stimulation or conduction block applied to the first neuronal target has a different duration than the stimulation or conduction block applied to the second neuronal target.

6. The system of claim 1, wherein the first neuroregulator applies the stimulation to the first neuronal target and the second neuroregulator applies the stimulation to the second neuronal target.

7. The system of claim 1, wherein the first neuroregulator applies the conduction block to the first neuronal target, and wherein the second neuroregulator applies the conduction block to the second neuronal target.

8. The system of claim 1, wherein the first neuroregulator applies the conduction block to the first neuronal target, and wherein the second neuroregulator applies a stimulator to the second neuronal target.

9. The system of claim 8, wherein the first neuronal target comprises a hepatic nerve and the second neuronal target comprises the celiac branch of the posterior vagus nerve.

10. The system of claim 1, wherein the first neuroregulator is an electrical neuroregulator.

11. The system of claim 10, wherein the second neuroregulator is an electrical neuroregulator.

12. The system of claim 10, wherein the second neuroregulator is a non-electrical neuroregulator.

13. A method of treating a medical condition comprising: neuromodulating the first neuronal target using stimulation or conduction blockade; and Stimulation or conduction blockade is used to neuromodulate a second neuronal target, wherein the second neuronal target is different from the first neuronal target, and wherein neuromodulation of the first neuronal target acts in conjunction with neuromodulation of the second neuronal target to treat a medical condition.

14. The method of claim 13, wherein the first neuronal target and the second neuronal target each comprise one or more sympathetic nerves.

15. The method of claim 13, wherein the first neuronal target and the second neuronal target each comprise one or more parasympathetic nerves.

16. The method of claim 13, wherein the first neuronal target comprises one or more sympathetic nerves, and wherein the second neuronal target comprises one or more parasympathetic nerves.

17. The method of claim 13, wherein neuromodulating the first neuronal target comprises neuromodulating using the stimulation, and wherein neuromodulating the second neuronal target comprises neuromodulating using the stimulation.

18. The method of claim 13, wherein neuromodulating the first neuronal target comprises neuromodulating using the stimulation, and wherein neuromodulating the second neuronal target comprises neuromodulating using the conduction block.

19. The method of claim 13, wherein neuromodulating the first neuronal target comprises neuromodulating using the conduction block, and wherein neuromodulating the second neuronal target comprises neuromodulating using the conduction block.

20. A system for modulating at least two neuronal targets: a first implantable electrical neuromodulator that applies stimulation or conduction block to a first neuronal target; and A second implantable neuromodulator applies stimulation or conduction blockade to a second neuronal target different from the first neuronal target, wherein the stimulation or conduction blockade of the first neuronal target acts in conjunction with the stimulation or conduction blockade of the second neuronal target to treat a medical condition.

21. A method for sensing biological activity to trigger neuromodulation, the method comprising the steps of: Obtain changes in biological activity from sensors; The neuroregulator is activated to initiate at least one signal to a target nerve, target organ, or target tissue to alter the biological activity to a predetermined level wherein the signal ceases.

22. The method of claim 21, wherein the method is a closed loop system.

23. The method of claim 21, wherein the method is an open loop system.

24. The method of any one of claims 21-23, wherein the signal comes from at least two electrodes.

25. The method of any one of claims 21-24, wherein the at least two electrodes are activated simultaneously.

26. The method of any one of claims 21-24, wherein the at least two electrodes are activated at different times.

27. The method of any one of claims 21-24, wherein the at least two electrodes are activated with one electrical signal initiating blocking and another electrical signal initiating stimulation.

28. The method of any one of claims 21-24, wherein the at least two electrodes are activated with one electrical signal initiating blocking and the other electrical signal initiating blocking.

29. The method of any one of claims 21-24, wherein the at least two electrodes are activated with one electrical signal initiating stimulation and the other electrical signal initiating stimulation.

30. The method of any one of claims 21-29, wherein the sensor detects changes in biological activity selected from the group consisting of blood glucose, heart rate, blood pressure, respiration, movement, CNS neuron electrical signals, peripheral nerve signals, and combinations thereof.

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