Devices, systems, and methods for therapeutic muscle stimulation

Abstract

To provide devices and methods for electrical modulation of nervous tissue.SOLUTION: Devices, systems and methods are described for providing muscle contraction stimulation therapy to treat myriad diseases, including heart failure, Type 2 diabetes and peripheral vascular disease using a skin patch or implantable stimulator that includes a multiplicity of electrodes, a processor 13, a stimulation circuit, one or more sensors 15, and programming for a patient interface unit 16, where the processor 13 is programmed to control selection of a subset of the multiplicity of electrodes and of operation of the stimulation circuit responsive to an indication of an adverse physiologic response. The indication of patient discomfort may be determined by monitoring a physiologic parameter of the subject using the one or more sensors 15, by direct input from the subject via the patient interface unit programming, or a combination thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 607,297, filed December 18, 2017, the entire contents of which are incorporated herein by reference.

[0002] This application relates to medical devices and methods for stimulating muscles in the legs and other limbs to improve muscle tone, reduce atrophy, improve glucose uptake rates in type 2 diabetes, and provide other health benefits. More particularly, this application relates to devices and methods for the electrical modulation of nerve tissue to produce muscle contractions in skeletal muscles while reducing patient discomfort and improving patient safety. [Background technology]

[0003] The overwhelming number of health problems worldwide stems from several general societal trends: an increasingly elderly population, an increasingly sedentary population, and an increasingly obese population. More and more people in modern society are far from obtaining sufficient amounts of physical exercise, and this lack of exercise leads to a myriad of health problems, including obesity, nonalcoholic fatty liver disease, type 2 diabetes, metabolic syndrome, heart disease, heart failure, stroke, hypertension, joint disease, arthritis, certain forms of cancer, and likely many other highly significant health problems. Despite these epidemics, many people choose not to exercise, believe they cannot exercise, or are actually unable to exercise adequately due to time constraints, lack of motivation, or physical limitations.

[0004] Skeletal muscle is the largest organ in the human body. Of the many benefits that exercise provides, one important set of benefits arises simply from the contraction of the skeletal muscles in the body, particularly the large muscles of the lower extremities, such as the gluteus, quadriceps, hamstrings, and gastrocnemius. Skeletal muscle contraction plays many roles within the skeletal system, including bone movement, joint stabilization, and remodeling of bone, cartilage, ligaments, and tendons. Chronic muscle contraction can also increase muscle strength, endurance, neural drive, motor control, and proprioception.

[0005] In addition, skeletal muscle plays an important role in the physiology of other organ systems. For example, contracting skeletal muscles improves cardiac endurance, affects temperature, pumps blood from the periphery to the trunk, helps circulate lymph, reduces lipid tissue mass, regulates metabolism, and secretes various proteins called myokines. Some of these myokines primarily affect muscle physiology, while others additionally affect other tissues and organs. Through the secretion of myokines, skeletal muscle communicates with tissues throughout the body, such as the liver, fat, heart, brain, and vasculature. Contracting leg muscles actively pump blood back to the heart, which then pumps blood through the pulmonary artery to the lungs and through the aorta to the rest of the body. The sedentary lifestyle adopted by so many people in modern society, whether by choice or due to physical limitations, reduces muscle mass and muscle contraction.

[0006] Furthermore, many chronic medical conditions are associated with decreased muscle mass, strength, and functional capacity, including type 1 diabetes, type 2 diabetes, obesity, male hypogonadism, growth hormone deficiency, hyperthyroidism, neurodegenerative diseases, hypercortisolism, vitamin D deficiency, osteoporosis, rheumatoid arthritis, peripheral arterial disease, COPD, congestive heart failure, advanced renal disease, cirrhosis of the liver, cancer, and HIV.

[0007] One method being investigated for producing muscle contractions in subjects is neuromuscular electrical stimulation (NMES). NMES involves stimulating nerves located near or embedded within muscles to produce muscle contractions. Researchers have found that using NMES devices to stimulate contractions in lower limb muscles can have significant positive health effects. The patent literature describes several previously known NMES systems that attempt to provide these benefits to patients. For example, U.S. Patent No. 7,257,448 to Crowe et al. describes an apparatus and method for stimulating muscles such as the hamstrings and quadriceps to increase calorie expenditure and improve endurance, in which individual electrodes in an array are selectively energized to induce muscle tremors, and the operation of the device is controlled by monitoring the patient's cardiovascular response. While the patent acknowledges that patient pain and discomfort may limit the usefulness of the described system, it does not address how to set the dose of applied pulses to achieve sufficient muscle activation while avoiding patient discomfort.

[0008] U.S. Patent No. 8,145,318 to Van Herk describes a device having an array of selectable electrodes coupled to a stimulation signal generator via a cross switch, including a sensor for detecting muscle activity, the output of which can be used by the patient to confirm electrode positioning and measure muscle tissue activity. U.S. Patent No. 8,909,334 to Kolen et al. describes a similar system in which a feedback system is used to assess the suitability of electrical stimulation points and provide pain control via stimulation. Neither patent addresses reducing patient discomfort caused by stimulation or methods for reducing such pain and improving patient compliance.

[0009] U.S. Patent No. 8,209,030 to Minogue et al. describes a garment having a set of fixed-sized, replaceable, selectively actuatable electrodes that is configured to provide reproducible positioning when placed on a patient's legs. U.S. Patent No. 8,620,439 to Lee et al. describes an abdominal muscle stimulation system that includes an EMG sensor and other sensors whose output is used to calculate a fatigue index for adjusting a stimulation regimen.

[0010] U.S. Patent No. 8,285,381 to Fahey describes a muscle stimulation system having an array of selectable electrodes coupled to a stimulation generator and further including multiple sensors that provide feedback to assist in electrode selection, adjust stimulation parameters, and prevent undesirable conditions such as hot spots that may lead to burns in comatose or sedated patients. U.S. Patent Nos. 8,892,210 and 9,302,104, both to Fahey, describe improvements to the systems of prior patents, including methods and apparatus for optimizing stimulation parameters and / or stimulation location. Similarly, U.S. Patent No. 9,126,039 to Fahey describes a muscle stimulation system that includes a switching cooling or analgesia system whereby the impedance of the patient's tissue is modified to adjust current density, thereby reducing patient discomfort.

[0011] Although the benefits of NMES have been recognized in the literature, previously known systems have not overcome the perceived disadvantages of NMES systems, which are the production of patient discomfort, which adversely affects patient compliance and widespread use of such systems.

[0012] For example, an article by Giggins et al. titled "Neuromuscular Electrical Stimulation Exercise: A Potential Alternative to Conventional Exercise in the Management of Type 2 Diabetes" (British Journal of Diabetes (2017) 17(2):46-51) describes the results of a study in which NMES stimulation was used as a substitute for physical exercise for relatively healthy patients with type 2 diabetes, resulting in significant improvements in body composition and fasting blood glucose levels. However, as shown in this article, only male participants were recruited for the study because a pilot study demonstrated that NMES was not widely accepted by overweight / obese female patients. Therefore, the aforementioned article indicates that while NMES holds promise for treating type 2 diabetes, the disadvantages of previously known NMES systems make such systems unsuitable for the large segment of the intended target population that may benefit from such treatment.

[0013] Similarly, an article by Maffiuletti et al., entitled "Effect Of Gender And Obesity On Electrical Current Thresholds" (Muscle & Nerve, (2011) 8:1-6), describes the influence of gender and obesity on the effectiveness of neuromuscular stimulation, noting that women tend to experience pain and discomfort at lower thresholds than men, that the current threshold required to activate muscles is higher in obese subjects than in non-obese subjects, and that obese subjects tend to have reduced current tolerance. These findings highlight the disadvantages of previously known muscle stimulation systems and emphasize the need for improved NMES systems that address such shortcomings, improve patient compliance, and expand the target population for NMES systems.

[0014] Finally, an article by Nosaka et al. entitled "Muscle Damage Induced By Electrical Stimulation" (Eur J Appl Physiol (2011) 111:2427-2437) describes the potential for NMES to cause muscle injury, including rhabdomyolysis, and notes that suitable NMES regimens for frail or elderly patients must be carefully dosed and monitored to obtain benefit as opposed to inducing injury.

[0015] Although the aforementioned research is very promising, previously known muscle stimulation devices and techniques have several drawbacks. One significant drawback, as mentioned above, is the discomfort caused by electrical stimulation. To reduce this discomfort, clinicians typically first locate the motor point on the patient (where the motor nerves transmit to the muscle) to direct the electrical stimulation toward its target, thereby using the lowest stimulation amplitude required to produce muscle contraction. However, patient discomfort from sensory nerves within the skin layer typically requires a trade-off between placing electrodes near the motor point and avoiding stimulation of painful sensory nerves. Therefore, properly stimulating the motor point to achieve full muscle contraction without causing pain to the patient can be very difficult. Furthermore, as documented, this situation can be particularly challenging for overweight patients, obese patients, patients suffering from limb swelling from chronic venous insufficiency or fluid retention, anxiety patients, or patients suffering from peripheral or central nervous system hypersensitivity.

[0016] Existing approaches to transepidermal electrical stimulation often require relatively high current intensities (amplitudes) to penetrate the skin and subcutaneous fat layers. Conventional NMES can cause discomfort or even significant pain at the high current intensities required to generate strong muscle contractions in many individuals. This is due to the inadvertent activation of sensory and muscle pain receptors and fibers located between the skin surface and the muscle innervation. The degree of current intensity that can be used is limited by patient discomfort. For some patients, the sensation of electrical stimulation is intolerable, leading them to completely reject NMES as a treatment option. Others may have a low tolerance for optimal amplitude or treatment duration, resulting in suboptimal treatment, which can limit the effectiveness of the therapy.

[0017] Another drawback of currently available techniques is that treatment sessions are typically limited to 30–60 minutes per session, three times per week for 4–8 weeks. In other words, NMES is not used for extended periods. In addition to pain, NMES can also produce other undesirable side effects, such as stimulation-related skin irritation, galvanic skin injury, muscle damage, renal damage, and / or physiological decompensation, especially in ill or elderly patients.

[0018] NMES may work well for certain subsets of patients. However, each patient's physiology differs, sometimes dramatically, from one another. NMES typically involves delivering energy through multiple tissue layers to reach the target neural tissue, and patients vary widely in skin impedance, weight, height, body composition, body fat percentage, muscle mass, water content, and many other physical characteristics. For example, if the goal is to transcutaneously modulate the neural tissue directly beneath the muscle, the energy must pass through the epidermis, dermis, subcutaneous fat, fascia, and muscle. The distance between the skin surface and the target neural tissue can vary from patient to patient, and for a given patient, depending on the degree of tissue edema, the presence of muscle contractions (which shorten and thicken the muscle), limb position, and the location of the electrodes on the skin surface. For example, subcutaneous fat thickness varies from individual to individual. Overweight or obese patients will have a thicker layer of subcutaneous fat than lean or normal-weight patients. Additionally, patients with variable levels of tissue edema (e.g., interstitial fluid due to heart failure, "third interstitial space" fluid, renal failure, malnutrition, iatrogenic volume overload from IV fluids, lethargy, etc.) will have different distances from the skin surface to the target nerve tissue. Patient-to-patient variability also exists in the anatomical dimensions, location, and branching of nerves. Furthermore, nerve diameter, location, branching, myelination, and density also vary from person to person. Sensory and motor thresholds are affected by age and gender. Nerve function also varies from patient to patient and from one part of a patient's body to another due to a given patient's state of health. Chronic immunological disorders such as multiple sclerosis, diabetes, Guillain-Barré syndrome, and cancer can lead to nerve dysfunction, as can acute nerve injury from trauma, inflammation, or compression syndromes. Due to these many variables, each patient's energy delivery treatment must be tailored to their specific physiology to most effectively produce tolerable yet effective muscle contractions. Currently available NMES devices and methods do not account for this variability.

[0019] It would therefore be advantageous to have improved devices, systems, and methods for stimulating muscle contractions in patients, ideally configured to be safe for use by patients at home and elsewhere.

[0020] It would also be desirable to provide systems and methods for performing muscle contraction therapy that can be safely implemented over extended durations so that patients can benefit from longer-term, continuous muscle contraction therapy. Furthermore, it would be desirable to provide systems and methods for inducing muscle contractions that are highly customizable so that patients with a variety of body types, compositions, physical illnesses or disorders, and the like, can receive therapy safely and with little or no pain or other side effects. Ideally, such devices, systems, and methods would be able to adapt to the changing position of the patient so that motor points are stimulated in an acceptable manner, even as that position changes during therapy. [Prior art documents] [Patent documents]

[0021] [Patent Document 1] U.S. Patent No. 7,257,448 [Patent Document 2] U.S. Patent No. 8,145,318 Summary of the Invention [Means for solving the problem]

[0022] This application describes devices, systems, and methods for stimulating muscle contraction in a patient to achieve or preserve one or more health benefits. As used in this disclosure, the word "patient" refers to any human or animal subject. According to the principles of the present invention, muscle contraction is induced by stimulating nerve tissue, which in various embodiments may be a nerve trunk, nerve branch, nerve terminal, motor point, Golgi receptor, Golgi tendon organ, muscle spindle, or any other nerve tissue. The nerve tissue may be embedded within other tissues, such as connective tissue, fascia, ligament, muscle, cartilage, periosteum, and bone. Generally, the embodiments described herein include one or more stimulators, one or more sensors, one or more patient interface units, and at least one processor for processing data from the signals and providing the signals to other components.

[0023] The stimulator may take the form of, for example, an electrode located on a patch applied to the skin or on a garment, one or more implantable electrodes, a percutaneous lead with electrodes, a magnetic nerve stimulator, an ultrasonic nerve stimulator, or similar structure. The sensors may include a muscle contraction sensor, a muscle condition sensor, a vital sign sensor, a skin contact sensor, a therapy endpoint sensor, a motion sensor, and / or the like. Exemplary embodiments constructed according to the principles of the present invention may include at least a muscle contraction sensor and at least one other sensor for sensing a patient parameter, e.g., muscle fatigue, pain, etc.

[0024] In some embodiments, the stimulator, sensor, processor, and / or patient interface unit may be combined together in one device. For example, in one embodiment, multiple stimulators, sensors, and processors may be included in a skin patch, and the patient interface unit may communicate wirelessly with the skin patch. Such an embodiment may also include one or more separate sensors, such as an electrocardiogram (ECG) device or an electromyogram (EMG) device, located remotely from the skin patch, configured to be attached to other areas on the body.

[0025] These and other aspects of systems and devices constructed in accordance with the present invention and methods of using them are described in further detail below with reference to the accompanying drawings. The present invention provides, for example, the following items. (Item 1) 1. A system for stimulating nervous tissue associated with one or more skeletal muscles of a subject, comprising: A number of electrodes; a switching circuit coupled to the plurality of electrodes; a stimulation circuit operably coupled to the switching circuit; a processor operatively coupled to the stimulation circuitry and the switching circuitry, the processor programmed to configure the switching circuitry to select a subset of the number of electrodes and provide electrical stimulation to neural tissue associated with one or more skeletal muscles to ameliorate a disorder selected from the group consisting of insulin resistance, fatty liver disease, obesity, osteoarthritis, sarcopenia, limb weakness, aerobic insufficiency, cancer, heart failure, chronic venous insufficiency, deep vein thrombosis, peripheral arterial disease, lymphedema, or hypertension, the processor programmed to respond to an indication of an adverse physiological response suffered by the subject; a non-transitory medium containing patient interface unit programming, the patient interface unit programming configured for use with the patient interface unit to control operation of the processor, switching circuitry, and stimulation circuitry; A system comprising: (Item 2) Item 10. The system of item 1, further comprising a sensor coupled to the processor. (Item 3) 3. The system of claim 2, wherein the sensor monitors a physiological parameter and generates an output, and the processor analyzes the output to determine an indication of the adverse physiological response. (Item 4) 3. The system of claim 2, wherein the sensor monitors a physiological parameter and generates an output, and the processor analyzes the output and controls operation of the stimulation circuit. (Item 5) 5. The system of claim 4, wherein the physiological parameter is indicative of muscle fatigue, and the processor adjusts operation of the stimulation circuit in response to the output. (Item 6) 5. The system of claim 4, wherein the sensor generates an ECG signal, and the processor controls application of electrical stimulation to a subset of the multiple electrodes by the stimulation circuit in response to the ECG signal. (Item 7) Item 3. The system of item 2, wherein the sensor is selected from the group consisting of an EMG device, an infrared sensor, an MMG device, an impedance device, and a vital signs monitor. (Item 8) 10. The system of claim 1, wherein the patient interface unit programming provides a patient input interface, and the indication of the adverse physiological response is input by the subject through the patient input interface. (Item 9) Item 10. The system of item 1, wherein the multiple electrodes, stimulation circuitry, and processor are mounted on a skin patch comprising a substrate having a skin-contacting surface. (Item 10) 10. The system of claim 9, further comprising a biocompatible gel disposed on the skin-contacting surface. (Item 11) 10. The system of claim 9, wherein the substrate comprises a disposable portion including the plurality of electrodes and a reusable portion supporting the switching circuitry, the stimulation circuitry, and the processor, the disposable portion and the reusable portion being configured to be removably coupled together. (Item 12) Item 12. The system of item 11, further comprising an RFID component disposed on the disposable portion. (Item 13) 10. The system of claim 9, wherein the multiple electrodes are arranged on the skin contact surface in two groups spaced apart from each other. (Item 14) Item 14. The system of item 13, wherein the first group and the second group each contain 3 to 5 electrodes. (Item 15) 15. The system of claim 14, wherein the processor varies current paths established between individual electrodes of the first group and the second group during application of electrical stimulation during selection of a subset of the multiple electrodes. (Item 16) Item 10. The system of item 1, wherein the stimulation circuit applies an alternating voltage to the multiple electrodes. (Item 17) Item 17. The system of item 16, wherein the stimulation circuit provides stimulation at a frequency of 50 to 150 Hz and a voltage of 3 to 35 volts. (Item 18) 10. The system of claim 9, wherein the skin patch further comprises a transceiver, and the processor is programmed to control operation of the transceiver and to wirelessly communicate with the smart device when the smart device activates the patient interface unit programming. (Item 19) Item 10. The system of item 9, wherein the skin patch further comprises an inductive circuit for wirelessly receiving energy from an external source. (Item 20) 2. The system of claim 1, wherein the processor is programmed to automatically determine an optimal set of stimulation values ​​for use with the stimulation circuit in response to the indication of the adverse physiological response. (Item 21) 10. The system of claim 9, wherein the multiple electrodes are configured to penetrate the stratum corneum of the subject when the skin patch is applied to the skin of the subject. (Item 22) 10. The system of claim 9, further comprising a standalone sensor configured to be positioned on the patient spaced apart from the skin patch, the standalone sensor configured to communicate with the processor or the smart device when the smart device is activating the patient interface unit programming. (Item 23) 10. The system of claim 9, wherein the system includes two or more skin patches, and the patient interface unit programming, when executed on the smart device, is configured to coordinate the application of the electrical stimuli by the two or more skin patches. (Item 24) Item 10. The system of item 9, wherein the substrate is configured to flexibly conform to the subject's anatomy. (Item 25) 1. A system for stimulating nervous tissue associated with one or more skeletal muscles of a subject, comprising: 1. An implantable stimulation device comprising: an elongate member configured to be implanted subcutaneously near neural tissue associated with one or more skeletal muscles; a number of electrodes mounted on the elongate member; a switching circuit coupled to the plurality of electrodes; a stimulation circuit operably coupled to the switching circuit; a processor disposed within the elongate member and operably coupled to the stimulation circuit and the switching circuit, the processor programmed to configure the switching circuit to select a subset of the number of electrodes and provide electrical stimulation to ameliorate a disorder selected from the group consisting of insulin resistance, fatty liver disease, obesity, osteoarthritis, sarcopenia, limb weakness, aerobic insufficiency, cancer, heart failure, chronic venous insufficiency, deep vein thrombosis, peripheral arterial disease, lymphedema, or hypertension, the processor programmed to respond to an indication of an adverse physiological response suffered by the subject; a non-transitory medium containing patient interface unit programming, the patient interface unit programming configured for use with a smart device for controlling operation of the implantable stimulator; an implantable stimulation device comprising: A system comprising: (Item 26) 26. The system of claim 25, wherein the implantable stimulator further comprises a sensor coupled to the processor. (Item 27) 27. The system of claim 26, wherein the sensor monitors a physiological parameter and generates an output, and the processor analyzes the output to determine an indication of the adverse physiological response. (Item 28) 27. The system of claim 26, wherein the sensor monitors a physiological parameter and generates an output, and the processor analyzes the output and controls operation of the stimulation circuit. (Item 29) 29. The system of claim 28, wherein the physiological parameter is indicative of muscle fatigue, and the processor adjusts operation of the stimulation circuit in response to the output. (Item 30) 30. The system of claim 28, wherein the sensor generates an ECG signal, and the processor controls application of electrical stimulation to a subset of the multiple electrodes by the stimulation circuit in response to the ECG signal. (Item 31) 27. The system of claim 26, wherein the sensor is selected from the group consisting of an EMG device, an infrared sensor, an MMG device, an impedance device, and a vital signs monitor. (Item 32) 26. The system of claim 25, wherein the patient interface unit programming provides a patient input interface, and wherein the indication of the adverse physiological response is input by the subject through the patient input interface. (Item 33) 26. The system of claim 25, further comprising a plurality of anchors configured to hold the implantable stimulation device in place. (Item 34) Item 26. The system of item 25, wherein the elongate member is flexible. (Item 35) 26. The system of claim 25, further comprising a battery disposed within the implantable stimulator. (Item 36) Item 26. The system of item 25, wherein the multiple electrodes are arranged on the exterior of the elongate member in two groups spaced apart from each other. (Item 37) 26. The system of claim 25, wherein the first group and the second group each contain 3 to 5 electrodes. (Item 38) 26. The system of claim 25, wherein the processor varies current paths established between individual electrodes of the first group and the second group during application of electrical stimulation during selection of a subset of the multiple electrodes. (Item 39) Item 39. The system of item 38, wherein a first group of the multiple electrodes functions as an anode and a second group of the multiple electrodes functions as a cathode. (Item 40) 26. The system of claim 25, wherein the stimulation circuit applies an alternating voltage to the multiple electrodes. (Item 41) 41. The system of claim 40, wherein the stimulation circuit provides stimulation at a frequency of 50 to 150 Hz and a voltage of 3 to 35 volts. (Item 42) 26. The system of claim 25, wherein the implantable stimulator further comprises a transceiver, and wherein the processor is programmed to control operation of the transceiver and to wirelessly communicate with the smart device when the smart device activates the patient interface unit programming. (Item 43) 26. The system of claim 25, wherein the implantable stimulator further comprises an inductive circuit for wirelessly receiving energy from an external source. (Item 44) Item 44. The system of item 43, wherein the implantable stimulator includes a capacitor for storing energy that is wirelessly transferred to the implantable stimulator via the inductive circuit. (Item 45) Item 44. The system of item 43, wherein the external source is positioned within a surface that allows the subject to rest against. (Item 46) 26. The system of claim 25, wherein the processor is programmed to automatically determine an optimal set of stimulation values ​​for use with the stimulation circuit in response to an indication of discomfort. (Item 47) 26. The system of claim 25, further comprising a standalone sensor configured to be positioned on the patient at a location remote from the implantable stimulator, the standalone sensor configured to communicate with the processor or the smart device when the smart device activates the patient interface unit programming. (Item 48) 26. The system of claim 25, wherein the system includes two or more implantable stimulators, and the patient interface unit programming, when executed on the smart device, is configured to coordinate the application of the electrical stimuli by the two or more implantable stimulators. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 is a schematic diagram of components of a muscle contraction stimulation system, according to one embodiment.

[0027] [Figure 2] FIG. 2 is a schematic illustration of a patient wearing a skin patch embodiment of a muscle contraction stimulation system constructed in accordance with the principles of the present invention.

[0028] [Figure 3]3 is a perspective view of the internal components and patient interface unit of a skin patch embodiment of the muscle contraction stimulation system of FIG. 2. FIG.

[0029] [Figure 4] 4A and 4B are bottom perspective views of two alternative embodiments of disposable skin-contact electrode pads, either of which may be part of the skin patch portion of a muscle contraction stimulation system.

[0030] [Figure 5] FIG. 5 is a bottom perspective view of a skin-contact electrode pad and external housing, according to one embodiment.

[0031] [Figure 6] FIG. 6 is an illustration of an electrode design with electrodes designed to penetrate the stratum corneum of the skin epidermis.

[0032] [Figure 7] FIG. 7 is a diagram of the display screen of the patient interface unit showing the controls and parameter settings used for the processor of the muscle stimulation system.

[0033] [Figure 8] FIG. 8 is an illustration of an alternative embodiment of a muscle stimulation skin patch in which an RFID system is used for trademark protection and security.

[0034] [Figure 9] FIG. 9 is a plan view of the layout of electronic components on a skin patch of a muscle contraction stimulation system, according to one embodiment of the present invention.

[0035] [Figure 10] FIG. 10 is a schematic diagram illustrating the flow of electrical signals between the electronic components of the skin patch portion of the muscle contraction stimulation system.

[0036] [Figure 11]FIG. 11 is a flow chart illustrating a method for delivering muscle contraction stimulation therapy according to one aspect of the present invention.

[0037] [Figure 12] 12A and 12B are schematic perspective views of an electrode pad illustrating the path of electrical current traveling between a set of electrodes on the pad, where the current path changes as a result of the elimination of some electrodes employed in the stimulation regimen.

[0038] [Figure 13] FIG. 13 is a flow chart illustrating an alternative muscle contraction stimulation method of the present invention.

[0039] [Figure 14] FIG. 14 is a flow chart illustrating a further alternative muscle contraction stimulation method of the present invention.

[0040] [Figure 15] FIG. 15 is a simplified circuit diagram of an electrical stimulation unit of a muscle contraction stimulation system constructed in accordance with one aspect of the present invention.

[0041] [Figure 16] 16A and 16B are simplified circuit diagrams of the first stage (FIG. 16A) and second stage (FIG. 16B), respectively, of an electrode set and its associated switch suitable for use in the muscle contraction stimulation system of the present invention.

[0042] [Figure 17] FIG. 17 is a graph illustrating details of an electrical stimulation waveform suitable for use with the muscle stimulation system of the present invention.

[0043] [Figure 18] FIG. 18 is a graph illustrating timing signals for electrical stimulation therapy.

[0044] [Figure 19]FIG. 19 is a graph illustrating the muscle forces resulting from the application of electrical stimulation shown in the upper portion of the figure.

[0045] [Figure 20] FIG. 20 is a diagram illustrating a wireless connectivity configuration between a patient user interface and multiple muscle contraction stimulation patches.

[0046] [Figure 21] 21A and 21B are a lateral view of a patient having multiple muscle contraction stimulating skin patches applied to their lower extremities, along with an ECG tracing and a chart illustrating the timing of muscle contraction therapy, respectively.

[0047] [Figure 22] FIG. 22 is an ECG tracing and ballistocardiogram curve illustrating timing windows for muscle contraction stimulation in accordance with aspects of the present invention.

[0048] [Figure 23] 23A-23D are ECG tracings and muscle contraction stimulation therapy timing for a program of contraction stimulation that is adjusted over time to the physiological needs of the patient.

[0049] [Figure 24] FIG. 24 is a chart illustrating a muscle contraction stimulation therapy timeline in accordance with the present invention.

[0050] [Figure 25A] 25A and 25B are frontal views of a patient with a muscle contraction stimulation patch placed to target the femoral nerve and a schematic diagram of the location of the skin patch in relation to the underlying anatomy, respectively. [Figure 25B] 25A and 25B are frontal views of a patient with a muscle contraction stimulation patch placed to target the femoral nerve and a schematic diagram of the location of the skin patch in relation to the underlying anatomy, respectively.

[0051] [Figure 26] FIG. 26 is an illustration of an approximate model of tissue that has been simulated based on electrical circuit theory.

[0052] [Figure 27] 27A-27C illustrate a simplified version of an approximation model of tissue being stimulated based on electrical circuit theory.

[0053] [Figure 28] 28A and 28B are contour plots of the normalized intensity of current density in tissue when two pairs of electrodes are positioned symmetrically and when two pairs of electrodes are positioned with an offset, respectively, and the data was obtained using a computerized model.

[0054] [Figure 29] FIG. 29 is a two-dimensional plot of the maximum current density in tissue when two pairs of electrodes are positioned symmetrically or with an offset, the data being obtained using a computerized model.

[0055] [Figure 30] Figure 30 is a two-dimensional plot of maximum current density in tissue obtained using a computerized model and superimposed over a schematic cross-section of the leg when two pairs of electrodes are positioned symmetrically or with an offset.

[0056] [Figure 31] 31A and 31B are contour plots of the normalized intensity of current density in tissue when two pairs of electrodes are positioned symmetrically and when two pairs of electrodes are positioned with an offset, respectively, data obtained using an in vitro model.

[0057] [Figure 32]FIG. 32 is a schematic diagram showing electrode placement during an in vivo study conducted to demonstrate the utility of one of the methodologies for reducing pain associated with the application of electrical stimulation.

[0058] [Figure 33] FIG. 33 is a side view of a patient with a muscle contraction stimulation patch containing a mechanomyogram ("MMG") sensor placed to target leg muscles, according to one embodiment.

[0059] [Figure 34] FIG. 34 is an illustrative time-domain plot of MMG signals collected from a human leg muscle during a single stimulation session using a system such as that depicted in FIG.

[0060] [Figure 35] FIG. 35 is a frequency domain plot of MMG signals collected from a human leg muscle during a single stimulation session corresponding to the time domain plot of FIG.

[0061] [Figure 36] FIG. 36 is a plot depicting the root mean square (“RMS”) values ​​of MMG signals collected from a person's leg muscles during a prolonged stimulation session during which the stimulation amplitude was kept below that required for maximal contraction.

[0062] [Figure 37] FIG. 37 is a plot depicting the power content of MMG signals at three different frequencies, where the MMG signals were collected from a human leg muscle during a prolonged stimulation session, and the stimulation amplitude was kept below that required for maximal contraction.

[0063] [Figure 38] FIG. 38 shows the RMS values ​​of MMG signals collected from a human leg muscle during a prolonged stimulation session, where the stimulation amplitude was kept above that required for maximal contraction.

[0064] [Figure 39] Figure 39 shows the power content of MMG signals at three different frequencies collected from a human leg muscle during a prolonged stimulation session, where the stimulation amplitude was kept above that required for maximal contraction.

[0065] [Figure 40] FIG. 40 is an axial cross-sectional view of an implantable muscle contraction stimulator of the present invention.

[0066] [Figure 41A] FIG. 41A is a cross-sectional view of the anatomy of a human leg, while FIG. 41B is a cross-sectional view of a leg implanted with a muscle contraction stimulator configured to be wirelessly coupled to an external electronic controller. [Figure 41B] FIG. 41A is a cross-sectional view of the anatomy of a human leg, while FIG. 41B is a cross-sectional view of a leg implanted with a muscle contraction stimulator configured to be wirelessly coupled to an external electronic controller.

[0067] [Figure 42] 42 is a side view of a leg showing an external controller for activating the implantable muscle contraction stimulator of FIG. 40 in accordance with the principles of the present invention.

[0068] [Figure 43] FIG. 43 is a side view of an alternative system for controlling and powering the implantable muscle stimulator system of FIG.

[0069] [Figure 44] FIG. 44 is an axial cross-sectional view of a flexible implantable muscle contraction stimulator having components similar to those of the implantable muscle stimulator of FIG.

[0070] [Figure 45] FIG. 45 is an axial cross-sectional view showing the implantation of the muscle contraction stimulator depicted in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0071] Unless defined otherwise, all technical and scientific terms commonly used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art.

[0072] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0073] The term "comprising" includes, but is not limited to, whatever follows the word "comprising." Use of this term indicates that the listed elements are required or mandatory, but other elements are optional and may or may not be present.

[0074] The term "consisting of" includes and is limited to whatever follows the phrase "consisting of." This phrase indicates that the specified elements are required or essential, and that no other elements may be present.

[0075] The term "set" means one or more items from the same category.

[0076] A "microprocessor" is an electronic device that can be programmed to perform certain tasks, including generating signals, collecting inputs, making decisions based on the inputs, and communicating with other devices in a system.

[0077] A "patient" is a human or animal subject. A patient can obviously be a healthy individual, an individual suffering from a disease, or an individual being treated for an acute condition or a chronic disease.

[0078] The term "electronic devices" refers to a set of electronic components, including passive components such as resistors, capacitors, inductors, and crystals, active components such as amplifiers and transistors, and connectors, conductors, and antennas.

[0079] An "electromyogram" or EMG is the electrical signal generated by skeletal muscles during contraction, evoked either by voluntary action or by electrical stimulation.

[0080] An "electrocardiogram" or ECG is the electrical signal produced by cardiac muscle during contraction, evoked either by voluntary action or by electrical stimulation.

[0081] "Electroencephalograms" or EEG are electrical signals generated by the brain during its normal functioning.

[0082] A "mechanomyogram" or MMG is an electrical signal proportional to the physical movement produced by a muscle.

[0083] A "ballistocardiogram" is an electrical signal proportional to the physical movement of tissue in various parts of the body resulting from pulsatile blood flow following the heartbeat.

[0084] "Electrodes" are conductive or semi-conductive elements used for the delivery of electrical current to human and animal tissue and / or for sensing electrical signals generated by human and animal tissue, such as electrocardiograms, electromyograms, and electroencephalograms.

[0085] "Electrical noise" or "noise" is an unwanted signal that is superimposed on another signal of interest.

[0086] An "accelerometer" is a device that produces an electrical signal proportional to the physical acceleration of the device. Such a device may respond to physical activity in one, two, or three dimensions, or rotation about any or all three axes.

[0087] A "temperature sensor" is a device that produces an electrical signal proportional to the physical temperature of the device. It can be a semiconducting body, a thermocouple, a resistance temperature detector ("RTD"), or a thermistor.

[0088] "Tissue impedance" is a measure of the resistance that tissue presents when an electrical signal is drawn across it. Impedance consists of a complex quantity, including real and imaginary components, corresponding to in-phase and out-of-phase components, respectively.

[0089] As explained above, neuromuscular electrical stimulation (NMES) has several disadvantages as a treatment modality because it can produce any number of adverse physiological responses. NMES treatment can be painful, and it can be difficult to stimulate significant muscle contraction without also inducing pain in the patient. Patients may have delicate skin that may be inflamed, burned, or otherwise compromised. Patients are often elderly and / or have illnesses that may be exacerbated by NMES. Excessive NMES can cause muscle ischemia, edema, or breakdown (rhabdomyolysis). Therefore, current systems and methods for delivering NMES are typically not self-administered by patients for extended periods or used at home or outside of a clinic or hospital by individuals with co-morbidities because any of several side effects may occur. Examples of side effects that can result from unsupervised NMES include physiological decompensation (arrhythmia, hypotension, hypertension, tachycardia, bradycardia, tachypnea, hypoventilation, fever, hypothermia), skin damage, hypoglycemia, hyperkalemia, rhabdomyolysis, renal damage, and unwanted muscle contractions while walking, driving, or performing other activities in which muscle contractions may interfere. Long-term NMES will also eventually lead to muscle fatigue and weakness. In summary, adverse physiological responses may include one or more of the following: pain, muscle pain, skin pain, nerve pain, skin inflammation, skin burns, skin injuries, hypoactive skin, exacerbation of a chronic disease or diseases, exacerbation of a comorbidity or diseases, muscle ischemia, muscle edema, muscle fatigue, muscle weakness, rhabdomyolysis, physiological decompensation, arrhythmia, hypotension, hypertension, tachycardia, bradycardia, tachypnea, hypoventilation, fever, hypothermia, hypoglycemia, hyperkalemia, hypocalcemia, serum electrolyte disturbances, renal impairment, cardiac ischemia, decreased cardiac output, shortness of breath, sleep disturbances, or unwanted muscle contractions during the performance of other activities with which muscle contraction may interfere.

[0090] This application describes devices, systems, and methods for stimulating muscle contractions in a patient by stimulating one or more target nerve tissues that innervate one or more target muscles. The embodiments described herein generally include a stimulator, a sensor, a patient interface unit, and a processor. Each of these four components is described in more detail below with respect to several alternative embodiments, including devices that are applied externally to the skin and / or include implantable components. Generally, the devices, systems, and methods described herein provide muscle contraction therapy that is applied over an extended period (e.g., 1-8 hours) per therapy session, and is administered and / or controlled, at least in part, by the patient, e.g., in their home or other convenient location, which may allow for more frequent therapy sessions, longer therapy courses, and more convenient therapy. This expedient, longer and therefore more effective treatment regimen is achieved by targeting stimulation, minimizing patient pain, providing more effective nerve tissue stimulation and therefore muscle contraction, modifying the shape of the electric field, adjusting for patient movement, monitoring side effects and adverse events, automatically adjusting the electric field shape, pausing stimulation or shutting off the system as needed, and building in features to promote safety.

[0091] For use in the NMES system of the present invention, anticipated stimulation parameters include the use of frequencies in the range of 2-10 Hz for non-convulsive pulse trains, or 20-100 Hz for convulsive pulse trains, with amplitudes sufficient to induce muscle contractions and pulse durations of 0.2-1 ms. It is contemplated that preferred pulse shapes should be either sinusoidal or square wave, charge-balanced, and include a duty cycle selected to achieve the desired pulse contraction goal without excessive fatigue or muscle damage.

[0092] Voluntary contractions of skeletal muscles are induced when an electrical impulse travels through a nerve to reach the neuromuscular junction between the nerve and the target muscle. Involuntary contractions of skeletal muscles can be induced by using electronic circuitry to deliver electrical pulses to the same neuromuscular junction. To produce such involuntary contractions, electrodes attached to a pulse generator are used to deliver pulses to the target tissue.

[0093] Electrodes used for muscle stimulation can be implantable, i.e., placed percutaneously or subcutaneously via electrical leads so that the electrodes of the leads are positioned within the tissue, preferably near the targeted neuromuscular junction. Alternatively, the electrodes can be external and applied to the skin. In the latter case, stimulation current enters the tissue from one or more electrodes, flows through the tissue so that at least a portion of the current reaches the neuromuscular junction, and exits the tissue via another electrode or electrodes, returning to the stimulator to complete the electrical circuit.

[0094] Delivery of direct current, or DC, can damage tissue. Even charge-balanced, pulsed current is known to be harmful because the resulting net charge left on the tissue creates ionic imbalance, harming the tissue near the electrode and the target tissue itself. Therefore, charge-balanced, i.e., pulsed, or AC, current with alternating polarity is generally preferred for stimulation of excitable tissue.

[0095] Stimulation pulses may have any form, however, those with a sinusoidal or square wave shape are generally preferred. The tissue response to individual stimulation pulses tends to be binary; i.e., subthreshold stimulation does not usually result in muscle contraction. The intensity of individual stimulation pulses can be increased by either increasing the pulse amplitude, extending its duration, or both. The repeated application of pulses forms a pattern known as a pulse train.

[0096] Pulse trains suitable for tissue stimulation can have a number of pulses ranging from 1 to 25 or more. Typically, each phase of a pulse, i.e., a positive and negative pulse, lasts for 50 microseconds to 2 milliseconds, although most pulses used in NMES systems generally have a duration of 200 microseconds to 1 millisecond. To generate a biphasic stimulation pattern, the first pulse is immediately followed by another pulse of equal amplitude but of opposite polarity. In some implementations, the amplitudes of the two phases, i.e., the positive and negative pulses, are unequal. In that case, the durations of these pulses are adjusted to maintain charge balance, such that the pulse with the lower amplitude has a longer duration, and vice versa.

[0097] Pulse pairs repeated at a rate of 2-10 Hz within a train can create non-convulsive wave-like contractions, and the individual contractions of the muscle resulting from the application of each pulse pair can be felt by the patient. At higher rates, the muscle generally does not have enough time to relax between pulse pairs within a train, and the contractions begin to overlap. When stimulation is applied at a rate of 20 Hz or greater, the individual contractions of most muscles merge to form convulsive wave-like contractions. The muscle will remain contracted as long as the train of stimulation pulses continues to be applied, but after a few seconds, fatigue sets in and the stimulation intensity may need to be increased to maintain the contraction.

[0098] Electrodes used for the delivery of electrical stimuli to tissue may be either polarizable or non-polarizable. Electrodes in which no net current is released into the tissue are ideally referred to as polarizable electrodes. Such electrodes can be modeled as simple capacitors. Typically, the capacitance of an ideal polarizable electrode is between 10 and 30 microfarads / cm. 2Polarizable electrodes act as capacitors, building up a voltage at the tissue-electrode interface as current is injected into the tissue. On the other hand, an ideal non-polarizable electrode allows current to flow unimpeded, and the injected electrical charge is accommodated by ions in the tissue. With non-polarizable electrodes, no change in voltage across the tissue-electrode interface occurs in response to the passage of current, and therefore the electrode remains insensitive to the amount of current being delivered to the tissue. Due to this property, non-polarizable electrodes are generally used in NMES systems for the delivery of electrical stimulation to tissue and are preferred for use with the present invention.

[0099] As discussed below, electrode types suitable for use in the systems of the present invention should generally be made from biocompatible materials, metals, or metal alloys that are suitable for prolonged (1-8 hours) contact with the skin without causing irritation, or suitable for implantation for those embodiments requiring implantable electrodes. For transepidermal stimulation, the electrodes are preferably disposed on a flexible substrate that conforms to the patient's anatomy and may include a biocompatible surrounding gel that promotes electrical coupling to the patient's skin without excessive crosstalk between adjacent electrodes.

[0100] Transcutaneous muscle contraction simulator, system, and method Referring now to FIG. 1 , a first embodiment of a muscle contraction stimulation system 10 constructed in accordance with the principles of the present invention includes a stimulator 11, a processor 13, a sensor 15, and a patient interface unit. While these components, i.e., stimulator 11, processor 13, sensor 15, and patient interface unit 16, are frequently referred to herein in the singular, systems of the present invention may include multiple such components. In some embodiments, stimulator 11, processor 13, sensor 15, and / or patient interface unit 16 may be combined together in a single device. For example, in one preferred embodiment, multiple stimulators 11, processors 13, and sensors 15 may be included in a skin patch 12. Such an embodiment may also include one or more separate sensor devices for attachment to other areas on the body, such as an electrocardiogram (ECG), electromyogram (EMG), or mechanomyogram (MMG) device, located spaced apart from the skin patch. Many different combinations and configurations are possible, some of which are discussed further below.

[0101] The patient interface unit 16 includes suitable programming or software loaded onto any device, such as a smartphone, tablet device, laptop computer, or desktop computer, that allows the patient to communicate with one or more other components of the system. Alternatively, the patient interface unit 16 may be a dedicated device programmed solely for use with the muscle contraction stimulation system 10. In a preferred embodiment, the patient interface unit 16 may be used to provide input by the patient indicating whether pain is felt during or after stimulation of neural tissue. For example, the patient may be prompted to confirm discomfort after detection of a marker of pain, such as tachycardia, heart rate variability, blood pressure, or sympathetic activity. Alternatively, the patient may indicate a sense of discomfort, which is used by the processor 13 to adjust the applied stimulation regimen. The patient interface unit 16 may be configured for other uses as well, such as allowing the patient to input other information into the system 10, turn the system on and off, adjust the amount of stimulation current provided by the stimulator 11, view the patient's vital signs and / or other physiological information, and / or view information about the therapy being delivered by the system 10. The processor 13 receives signals from the sensor 15 and the patient interface unit 16, processes those signals, and provides signals to the stimulator 11 regarding when and how to stimulate the nerve tissue and promote muscle contraction.

[0102] The system 10 of the present invention offers several unique improvements over previous and currently available NMES devices. For example, the system 10 is configured to receive input from the patient interface unit 16 indicative of the patient's sensation of pain and use that information to customize nerve tissue stimulation using its stimulator 11 for the specific patient's anatomy and physiology. The system 10 also includes a sensor 15 that can sense not only when (and the amount of) a target muscle contracts, but also a combination of sensors that sense at least one other parameter of the patient, the output of which is utilized to improve the safety and / or effectiveness of muscle contraction therapy. For example, in various embodiments, the sensor 15 may be used to sense the patient's vital signs, muscle fatigue or injury, the reaching of a physiological sign indicative of a clinical endpoint, and / or the like. A sensor, such as an accelerometer, may be used to detect whether the patient is attempting to change position, such as moving from a reclining position to a sitting position or from a sitting position to a standing position. The sensed data may then be used by the system 10 to automatically pause, adjust, or shut off muscle contraction therapy. Thus, system 10 provides customized muscle contraction stimulation therapy for each patient, with safety and efficacy features designed to allow muscle contraction therapy to be used safely in hospital or out-of-clinic or clinical settings with reduced direct monitoring over longer time periods and over longer treatment courses.

[0103] Another advantage of system 10 is that it can be used to treat multiple muscle groups on the same patient during a therapy session. Conventional NMES systems are known to target a single muscle group, such as the quadriceps. To stimulate four large muscles, such as two quadriceps and two hamstrings, using a conventional NMES system, the patient would typically need to be wired with at least eight wires and eight separate electrodes, making the initial wiring process and maintenance of such a system difficult, time-consuming, and cumbersome (thus restricting such treatment to medical facilities only). In contrast, system 10 of the present invention is configured for use on one muscle group or multiple muscle groups, for example, in a sequential distal / proximal stimulation pattern, to help pump blood from the legs to the trunk. In some embodiments, system 10 accomplishes this by providing all electronic components within a skin patch and having the skin patch communicate wirelessly with patient interface unit 16.

[0104] Two common problems associated with the use of transepidermal electrical stimulation of skeletal muscles are inadvertent stimulation of sensory nerves close to the skin surface (resulting in pain) and difficulty in determining correct electrode placement for capturing / stimulating motor points. This is particularly relevant in patients who are not sedated with medications. System 10 solves these problems by allowing the patient to input feedback into system 10, which automatically turns off certain stimulating electrodes within system 10 until the desired combination of pain reduction and clinically significant muscle contraction is achieved. Alternatively, other embodiments may provide one or more sensors that detect noxious stimulation and, in response to such sensor output, automatically turns off certain stimulating electrodes within system 10 until the desired combination of pain reduction and clinically significant muscle contraction is achieved.

[0105] System 10 also addresses the safety of long-term unsupervised electrical stimulation for muscle contraction therapy. In a preferred embodiment, system 10 uses information provided by sensors 15 to determine muscle fatigue, muscle damage, and the like, and alters or terminates the stimulation regimen in response to such sensor output. Sensors 15 such as, but not limited to, accelerometers, EMG sensors, pressure sensors, impedance sensors, or mechanomyogram sensors (such as vibration detectors, microphones, or ultrasonic sensors) may be used for this purpose.

[0106] Thus, muscle contraction stimulation embodiments of system 10 constructed according to the principles of the present invention may be used for longer time periods than conventional systems, e.g., 1 to 8 hours or more at a time, while the patient is eating, reading, watching television, resting, sleeping, and / or the like. Preferably, muscle contraction stimulation system 10 is self-administered by the patient, or at least configured to be turned off and on by the patient, thereby facilitating home use over the course of long-term treatment to more effectively achieve desired health benefits compared to previously known NMES systems. System 10 may not only sense muscle contractions and parameters indicative of unsafe conditions, but may also sense that one or more treatment objectives have been achieved over an individual treatment session. For example, if the system is used to treat type 2 diabetes in a patient, the system may automatically stop stimulating muscle contractions once it senses that the patient's glucose level has reached a target level. In some embodiments, the system may detect muscle fatigue and pause stimulation or change stimulation parameters to allow the muscle to recover. Alternatively or additionally, some embodiments may vary the site of stimulation, resting one set of muscle fibers while stimulating a different set of fibers. In patients suffering from impaired blood supply to stimulated muscles, ischemia may occur in tissue distal to the impaired blood supply as oxygen demand may exceed supply. To address this, embodiments of system 10 may include an ischemia sensor that continuously or intermittently measures oxygen saturation changes (SpO2) using LED light in the infrared and near-infrared spectrum. Based on the sensor's output, the system may pause muscle contraction stimulation in response to detecting muscle ischemia. Alternatively, the system may include a lactate sensor such that the system pauses muscle contraction stimulation when lactate levels begin to rise above baseline (i.e., when lactate is produced faster than the body can eliminate it). In yet another embodiment, EMG may be used to determine muscle ischemia and lactate accumulation for the same purpose.

[0107] Referring now to FIG. 2 , an exemplary embodiment of a muscle contraction stimulation system 10 applied to a patient P is described. The system 10 includes a stimulation / sensing patch 12 applied to the patient's skin, at least one sensor 14 separate from and spaced apart from the patch 12, and a patient interface unit 16 that allows the patient P to communicate with other components of the system 10. The patch 12 is shown applied over the patient P's quadriceps (on the skin of the thigh), and the sensor 14 may be shown applied over the patient's chest, for example, in a location suitable for placing electrodes of an ECG monitor. Preferably, the patch 12 is positioned at a location on the patient's body such that it can be used to stimulate underlying nerve tissue. In some embodiments, this nerve tissue may be a motor point where the nerve penetrates muscle tissue. In other embodiments, the target nerve tissue may be more proximal along the nerve, such as a nerve root, a dorsal root ganglion (DRG), a nerve trunk, a nerve branch, or multiple nerve branches. In still other embodiments, patch 12 may be applied across any muscle group or groups of the body to target one or more specific nerve tissues.

[0108] As mentioned above, it may often be advantageous to stimulate contraction of one or more muscles of the lower extremities, such as the gluteus, quadriceps, hamstrings, and / or gastrocnemius. In such cases, multiple patches may be applied individually over any of these muscle groups or muscles. For example, a patient may simultaneously wear multiple skin patches 12, one positioned over each of the gluteus, quadriceps, hamstrings, and gastrocnemius muscles on both limbs, i.e., a total of eight skin patches 12. In other embodiments, it may be advantageous to stimulate contraction of these or other muscles by placing one or more patches 12 over nerve trunks, for example, in the groin area over the femoral nerve, over the buttocks to target the sciatic nerve, or over other muscle / nerve trunk targets. In still other embodiments, larger patch devices may be provided, each configured to cover more than one muscle group and more than one target nerve tissue. Patches 12 may be provided individually or as a kit of multiple patches 12, according to various embodiments. Multiple patches may be connected, for example, via a wireless network, as described below with respect to Figure 20. Thus, although Figure 2 shows only one skin patch 12 applied across one quadriceps muscle of patient P, it should be understood that any number, configuration, and placement of one or more skin devices 12 may be used.

[0109] Many of the exemplary embodiments described herein below involve systems that include one or more skin patches. However, in alternative embodiments, neural tissue stimulation may be achieved using different types of stimulation devices, such as, but not limited to, one or more implantable electrodes, percutaneous leads with electrodes, magnetic nerve stimulators, and ultrasonic nerve stimulators, and / or the like. In some embodiments, the implantable device may include one or more sensors and possibly one or more other features contained within the skin patch 12.

[0110] 3 , the skin patch 12 having the sensor 15 and the patient interface unit 16 will be described in more detail. The system 10 may include one or more additional sensors 14 suitable for detecting any of several physiological parameters of the patient P, as depicted in FIG. 2 , which communicate with the processor of the skin patch 12, the patient interface unit 16, or both. As described in this disclosure, various combinations of sensors 15 and separate sensor devices 14 may be provided within the system 10. Thus, if in one embodiment a sensor is described as a possible sensor 14, in alternative embodiments, that sensor may be included as a sensor 15 of the skin patch 12. The opposite may be true in other embodiments; in general, any given embodiment may include any number, type, and combination of sensors 15 in the skin patch 12 and separate sensors 14.

[0111] One preferred type of sensor 14 may be a muscle condition sensor, which allows system 10 to pause stimulation of neural tissue when muscle condition drops from a baseline state. Examples of muscle condition sensors may include EMG devices (which may be used to detect muscle fatigue, ischemia, or lactate), infrared sensors (which may be used to detect lactate in the blood), and muscle impedance devices for detecting ECG, MMG, or markers of rhabdomyolysis. Another example of a separate sensor device 14 may include any type of vital sign sensor, which may be used by system 10 to pause stimulation if patient P becomes physiologically unstable. Such sensors include, but are not limited to, ECG devices, pulse oximeters, blood pressure monitors, transthoracic impedance monitors, inductance plethysmography devices, thermistors / thermometers, basic vital sign monitoring devices such as pulse counters, and the like. Such devices may be used to monitor, for example, heart rate, cardiac rhythm, arrhythmia, blood pressure, systemic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure, venous pressure, cardiac ischemia, respiratory rate, and / or temperature. Yet another example of a separate sensor device 14 may include a therapy achievement (or “therapy endpoint”) sensor, which detects one or more physiological signs or parameters that can be used by system 10 to determine when a predetermined amount of stimulation time or clinical efficacy endpoint is reached. For example, such sensors may measure insulin sensitivity, blood glucose level, sympathetic activity, vagal tone, sympathetic drive, heart rate variability, blood pressure, tissue edema, or the like. As can be seen from these examples, separate sensor device 14 may include any suitable patient sensor or combination of sensors configured for placement anywhere on the body.

[0112] The patient interface unit 16 may include hardware components, software components, or both. In particular, the patient interface unit of the present invention need not include hardware but may instead consist of a suitable application program that can be downloaded for use with a conventional smartphone, tablet, laptop, desktop, or other programmable device that provides wireless connectivity. In alternative embodiments, the patient interface unit 16 may be a dedicated device configured for use solely with the system 10, or may include one or more other hardware components. Thus, in general, the patient interface unit 16 may be any hardware, software, or combination thereof that allows the patient P to input information into, and in some embodiments, receive information from, the system 10. The patient interface unit 16 preferably communicates with the skin patch 12 via a wireless connection. However, in alternative embodiments, the patient interface unit 16 may connect to the skin patch 12 via a wire or may be plugged into the skin patch 12 via a docking station. In yet another alternative embodiment, patient interface unit 16 may simply be a button (or multiple buttons) on the outer surface of skin patch 12, such as a button that patient P may press each time he or she experiences pain in response to neural stimulation. In most embodiments, patient interface unit 16 at least allows patient P to inform system 10 that he or she experiences pain during or after neural stimulation or contraction of stimulated muscles. System 10 may then use that information to customize a stimulation regimen to reduce or eliminate the pain felt by patient P.

[0113] In some embodiments, long-duration electrodes may be used to deliver therapy. In this case, the electrodes are reusable, so there is rarely a reason to discard the skin patch. However, the patient interface unit may maintain a log of the therapy being delivered, and that information may be retrieved directly or remotely from the patient interface unit's memory. The therapy log retrieved from the patient interface unit may be used to determine an individual's compliance with a predefined therapy regimen and make any necessary corrections to improve outcomes. The therapy log information may also be used to enable a "pay-per-click" business model, in which the patient, family, physician, payer, or employer periodically adds funds to the patient's therapy account, against which there would be a debit or credit for each therapy session.

[0114] In some embodiments involving reusable electrodes, various payment methods can be used to purchase treatment session credits, including credit cards, debit cards, checking accounts, gift cards, mobile phone bills, Paypal, online banking, or online retail payment methods such as Apple ID, Amazon ID, or Skype ID. To encourage compliance, patients can also be offered discounts for purchasing treatment sessions in bulk. Patients can also be charged daily, weekly, monthly, quarterly, or annually instead of on a pay-per-click basis. A recurring time-based fee (similar to a monthly health club membership or cable TV subscription) may encourage some patients to use the device regularly without creating a financial disincentive to regular use. Once funds in a patient's account for treatment sessions are depleted, the interface unit will become unavailable until additional funds are added to the account. Payment mechanisms can also include pay-per-click and subscription models, or a combination of models that start with one payment plan and then switch to another based on patient compliance or individual, family, clinician, employer, or payer preferences. The system may also be leased to patients in a manner similar to durable medical equipment.

[0115] Referring again to FIG. 3 , patch 12 includes an outer substrate 18, a tissue-contacting substrate 20, and multiple components coupled thereto. In alternative embodiments, outer substrate 18 and tissue-contacting substrate 20 may be combined into a single monolithic substrate. In other words, while patch 12 is often described herein as a two-piece substrate embodiment, in alternative embodiments, the patch may include a one-piece substrate. In some embodiments, outer substrate 18 is designed to be reusable, while tissue-contacting substrate 20 contacts the patient's skin and is designed to be disposable (after one or more uses). In this case, the two substrates 18, 20 may be removably coupled to one another so that they can be easily separated by the patient for disposal of tissue-contacting substrate 20. Alternatively, both substrates 18, 20 may be reusable, or both substrates 18, 20 may be disposable. In one preferred embodiment, the outer substrate 18 houses a power source 22, a control unit 24, a communications unit 26, a signal processor 28, sensors 15, and an electrical stimulation unit 32. The tissue-contacting substrate 20 includes multiple electrode sets 34a and 34b, which in this embodiment include four electrodes each. All of these components may be attached to the substrates 18 and 20 in any suitable manner, such as by embedding the components between layers of the substrates 18, 20 or by attaching them to the substrates 18, 20 with an adhesive.

[0116] The tissue-contacting substrate 20 is preferably flexible and stretchable so that it can conform to the patient's skin over the target muscle and move with the muscle as it contracts. The tissue-contacting substrate 20 may be made from one or more generally non-conductive polymeric materials, such as, for example, but not limited to, rubber, polyethylene, polypropylene, or any other insulating material, including cellulose. The outer substrate 18 may also be flexible and stretchable, but in some embodiments may be somewhat stiffer, thicker, and / or more durable than the tissue-contacting substrate 20. The tissue-contacting substrate 20 also typically includes a biocompatible adhesive surface for adhering the patch 12 to the patient's skin, which will be covered with a protective cover until ready for use. Such adhesive surfaces are well known. The tissue-contacting substrate 20 may also have two adhesive surfaces: one side for attachment to the skin and the other side for attachment to the outer substrate 18. Ideally, all of the skin patches 12 may be worn for extended periods, for example, a day or more. In some embodiments, the skin patches 12 may be worn in the shower or bathtub. In other embodiments, only the tissue-contacting substrate 20 may be worn in the shower or bathtub, with the outer substrate 18 being removed for bathing.

[0117] Each of the electrode sets 34a and 34b illustratively includes four transepidermal electrodes 36. While two electrode sets 34a, 34b, each with four electrodes 36, are shown in this embodiment, alternative embodiments may have more than two electrode sets and / or more or fewer than four electrodes per set. Providing two electrode sets 34a, 34b per patch may have some advantages in terms of simplicity and controllability of stimulation current, although any other suitable alternative embodiment is also contemplated within the scope of the present invention. In general, the overall area of ​​one electrode set 34a, 34b may be large enough to deliver sufficient current to stimulate the neural tissue innervating one or more skeletal muscles being targeted for therapeutic use. To minimize the applied current density, and therefore discomfort to the patient, each electrode set 34a, 34b should be at least approximately 20 cm². 2 , preferably at least about 30 cm 2 may have a total active surface area of

[0118] 4A and 4B, two alternative embodiments of tissue-contacting substrates with alternative electrode sets are described. Substrates 120 and 220 of FIGS. 4A and 4B include corresponding alternative configurations of electrode sets 134a, 134b, 234a, and 234b, respectively. In some embodiments, some of the individual electrodes may need to be turned off during therapy to redirect stimulation current within the tissue to minimize pain sensation. In such cases, it may be preferable for the total surface area of ​​the electrode set at the time of stimulation to be greater than the minimum surface area required for stimulation of the motor point or innervation for the target muscle. For example, in the embodiment of FIG. 4B, each electrode set 234a, 234b on tissue-contacting substrate 220 may include nine electrodes 36, each measuring 4 cm. 2 36 cm per electrode set 234a 23 and 234a and 234b in FIG. 8B are arrayed in a square pattern, in alternative embodiments, the electrodes may be arranged in any other regular pattern or asymmetric arrangement. For example, as shown in FIG. 4A, two electrode sets 134a, 134b of five electrodes each may be provided on the tissue-contacting substrate 120. In other alternative embodiments, any orientation, number, shape, and spacing of electrodes within a given electrode set may be used.

[0119] 3 and 4 may be made from any suitable conductive material, such as, but not limited to, carbon black. In some embodiments, the electrodes 36 may be coated with a conductive gel, such as silver chloride gel. In alternative embodiments, where the electrodes are implantable, such electrodes may be constructed from metals such as gold or silver, or metal alloys such as platinum-iridium, or conductive polymers, such as those containing carbon black, or combinations of carbon and graphite. Each electrode 36 is approximately 2 mm in size. 2 ~approx. 6cm 2 In addition, the electrodes 36 may have any suitable shape, such as, but not limited to, a square (as shown), a circle, an ellipse, an oval, a curved triangle, a quad lobe, or any polygon, such as a triangle, a rectangle, a parallelogram, a trapezoid, a rhombus, a pentagon, a hexagon, etc. To prevent unintended stimulation via disconnected electrodes 36, the minimum separation between electrodes 36 in a given electrode set 34a, 34b on the tissue-contacting substrate 20 may be about 0.5 mm. To provide the desired stimulation of neural tissue beneath the skin surface and facilitate muscle contraction, the electrode sets 34a, 34b will typically be spaced at least about 3 cm from each other, as measured from the center of each set 34a, 34b.

[0120] 5, each electrode 36 of the tissue-contacting substrate 20 may be coupled to electronics disposed on the outer substrate 18 via a separate electrode connector 100. In various embodiments, the electrode connector 100 may be a snap-fit ​​connector, a mini-banana connector, or other suitable connector. Alternatively, the skin patch 12 may include one monolithic substrate rather than separate tissue-contacting substrate 20 and outer substrate 18. In such embodiments, the entire skin patch 12 may be either reusable or disposable, and the electrodes 36 may be permanently attached to the electronics disposed on the patch.

[0121] Referring to Figure 6, in some embodiments, the electrodes may consist of multiple conductive segments protruding from the skin-contacting surface of the patch. This design allows the electrodes to penetrate through the epidermal layer instead of simply contacting the stratum corneum of the skin. In addition to providing better contact with the conductive tissue, the design of Figure 6 is expected to provide a more uniform delivery of electrical stimulation. The electrodes may optionally be pre-coated with a liquid or gel to deliver an analgesic or antibiotic, such as neomycin or polymyxin.

[0122] Referring again to FIG. 3 , the power source 22 may be attached to / embedded in the outer housing 18, or alternatively, attached to / embedded in the tissue-contacting substrate 20. For example, the power source 22 may be a 9-volt battery, a button cell, a rechargeable battery, or any other type of battery. In other embodiments, the power source 22 may be one or more photovoltaic panels positioned on the outer surface of the outer housing 18. In yet another embodiment, the outer housing 18 may include a plug for attaching a smartphone (or other power source) to the skin patch 12, which may be used to charge the power source 22 or may even be used as the power source 22. In yet another embodiment, a magnetic coupling may be used as the power source 22. In that embodiment, a transmitter coil may be placed across or at a distance from the outer substrate 18 to power the skin patch 12. In yet another embodiment, power may be generated by converting kinetic energy into an electric current, which may be stored on a capacitor. As a further alternative, the skin patch 22 may be powered by plugging the power cord attached thereto into a power source, such as an electrical outlet or a separate power source.

[0123] The sensor 15 disposed on the patch 12 may be one or more devices. By way of example, the sensor 15 is described as being disposed on the skin patch 12, however, in alternative embodiments, the sensor 15 may be configured for placement in a separate location on the patient, spaced apart from the skin patch 12 (i.e., a separate sensor device 14 in FIG. 2). Most, if not all, of the sensors described below may be included in the system 10 as part of the skin patch 12, as one or more separate sensors 14, or as both. In any given embodiment, any combination of sensors 15 and separate sensor devices 14 may be used. For ease of description and understanding, the sensor devices will be referred to below as sensors 15. Any of the specific embodiments described below may be combined in any suitable combination in the muscle contraction stimulation system 10.

[0124] As mentioned above, a preferred sensor 15 disposed on the skin patch 12 is a muscle contraction sensor. This may be, for example, an accelerometer for sensing movement associated with muscle contraction. Another type of sensor 15 is a muscle integrity sensor, which may sense when muscle begins to break down, such as during rhabdomyolysis. Markers of rhabdomyolysis, any of which may be sensed by one or more sensors 15, include hyperkalemia (which may be sensed via ECG), hypocalcemia (which may be sensed via ECG), muscle edema (which may be sensed via muscle impedance), elevated creatine phosphokinase (CPK) levels (CPK released from damaged muscle), or EMG or MMG readings indicating muscle damage. Another exemplary type of sensor 15 is a muscle fatigue sensor. Sensor 15 may alternatively include one or more vital signs sensors, which monitor respiratory rate, heart rate, blood pressure, or temperature. Physiological parameters may also be used to guide therapy or for safety purposes. For example, ECG signals may be used to synchronize the timing of skeletal muscle contractions with the cardiac cycle, e.g., in heart failure therapy. Alternatively, therapy may be automatically turned off for safety whenever the heart rate falls outside predetermined limits. Other physiological parameters include markers of sympathetic drive, such as heart rate variability, piloerection (goosebumps), sweating, and muscle sympathetic nerve activity.

[0125] The sensor 15 may also include a skin contact sensor. Such a sensor 15 may be located on the skin-contacting surface of the patch 12 near one or more electrodes 36 and configured to detect whether proper contact is made between the tissue-contacting substrate 20 / electrodes 36 and the patient's skin. If proper contact is achieved, therapy can begin; however, if proper contact is not established, the patient may receive a message on the patient interface unit 16 indicating that the skin patch 12 needs to be repositioned, pressure applied thereto, or adjusted.

[0126] In other embodiments, sensor 15 may be used to sense one or more metabolic parameters, such as glucose levels detected via an implantable, transdermal, transepidermal, or corneal glucose monitor. For therapies designed to treat diabetes, it may be important to detect changes in glucose levels so that the therapy can be set based on glucose levels and / or terminated once an end goal is reached. Therapies may be integrated with various insulin delivery methods, including injections, pump-based delivery, and inhaled and oral formulations. Furthermore, such information may be provided to healthcare professionals to help them personalize therapy for each individual based on their specific needs. In some embodiments, the "end goal" of diabetes therapy may be achieved when glucose falls below a set level (e.g., 100 mg / dL) or once a threshold for insulin sensitivity is reached. Markers of insulin sensitivity include skin sympathetic nerve activity, motor nerve conduction velocity, RR interval (which is inversely correlated with HOMA-IR (homeostasis model assessment of insulin resistance)), and muscle capture threshold (which increases with increasing blood insulin).

[0127] The sensor 15 may also include one or more sensing devices that detect biomechanical parameters, such as position and activity-related measurements. For example, if the sensor 15 detects that the patient is walking, the system 10 may be programmed to suspend muscle contraction stimulation so as not to interfere with the act of walking. A local ballistocardiogram may be used to detect the arrival of blood pressure in the extremities. A goniometer may be used to measure the angles of joints (e.g., knees, hips, etc.).

[0128] Any of several different types of sensors 15 may be used to detect one or more of the patient parameters described above. An impedance sensor, for example, uses electrical impedance measured between a set of electrodes to ensure the electrodes are in electrical contact with the skin and detect changes in tissue volume and composition. During muscle contraction, both the muscle's shape and composition change, which in turn alters the impedance signal. For example, when contracted, the muscle contains little blood, which can be detected as a decrease in overall conductivity because blood's electrical conductivity is approximately 0.8 siemens / meter, while muscle's electrical conductivity is approximately 0.1 siemens / meter. Similarly, a sudden increase in electrical impedance may indicate that electrode contact with the tissue is too weak. When impedance sensing is performed using electrodes near the chest area, such as when using an ECG sensor, the resulting change in transthoracic impedance measurement may be used to determine the patient's respiratory rate.

[0129] The temperature sensor may be used to measure ambient temperature and / or estimate caloric heat produced by stimulated muscles. Additionally, changes in local temperature may result from local heating beneath the electrodes 36, which may result from loss of conductive gel and indicate the need for replacement of the skin patch 12.

[0130] An EMG sensor uses electrodes to detect signals produced by skeletal muscles as they contract. An electromyogram (EMG) not only indicates that a muscle is contracting, but also indicates the strength of the muscle contraction resulting from the application of an electrical stimulus. The evoked response of skeletal muscles exhibits two distinct characteristics known as the M-wave and the H-wave. The M-wave arrives within 5 milliseconds after the application of an electrical stimulus, and its amplitude is proportional to the strength of the muscle contraction. The H-wave appears 20 milliseconds after the application of an electrical stimulus, and its amplitude decreases as the strength of the muscle contraction increases. In one embodiment, the amplitude of the M-wave is used to estimate the strength of the skeletal muscle contraction. In another embodiment, the ratio of the M-wave amplitude to the H-wave amplitude is used to measure muscle contraction.

[0131] An ECG sensor may be used to detect cardiac electrical activity, particularly P, QRS, and T waves, using two or three electrodes. In some embodiments, skin patch 12 may include an ECG sensor to detect cardiac signals so that system 10 will know when a patient may accidentally place skin patch 12 over the heart. In such cases, system 10 will detect the proximity of the heart and will not allow itself to activate / stimulate. An ECG monitor may also be an example of a separate sensor device 14, as previously described.

[0132] Pressure sensors may also be used in some embodiments to measure changes in external pressure. If the outer substrate 18 is held in place, for example, with an elastic bandage covering the entire limb, muscle contraction will result in an increase in measured pressure. Goniometers may be used in some embodiments to measure joint flexion or extension angles, such as the angles of the elbow, shoulder, wrist, ankle, hip, or knee. Based on the joint angle, the control unit 24 may adjust stimulation amplitude or instruct the patient to change the joint angle.

[0133] Accelerometers may be used to monitor movement and produce signals useful for detecting muscle contractions. For example, in response to contraction, skeletal muscles pack together, resulting in radial expansion of the muscle. Thus, the stronger the contraction, the stronger the signal produced by the accelerometer. In various embodiments, one-dimensional, two-dimensional, or three-dimensional accelerometers, and any combination thereof, may be used.

[0134] Any other suitable sensors 15 may be used in system 10, according to various alternative embodiments. For example, blood flow within a muscle may be measured using an ultrasound or ultrasonic sensor, which will indicate not only the immediate change in blood volume within the muscle resulting from contraction, but also the change in resistance of the vascular bed following prolonged contraction of the muscle. Similarly, electrical activity of afferent and efferent nerves may be monitored to assess the results of electrical stimulation applied to the muscle proximal and distal to the sensing location. Signals resulting from the sensors are processed by signal processing unit 28 before being presented to control unit 24.

[0135] One of the sensors that the present invention may advantageously use is a mechanomyogram (MMG) sensor, which detects the mechanical movement of muscles during contraction. The MMG sensor can be of the microphone or accelerometer type. Generally, it is placed over the muscle to be stimulated so that the contraction can be detected and recorded by the MMG sensor. The signal from the MMG sensor may be processed by a signal processor to extract root mean square (RMS) and frequency domain power information, which may be interpreted by the control unit 24. The MMG sensor may provide multiple types of feedback to the control unit, including the strength of the contraction and muscle fatigue status.

[0136] The signal processing unit 28 extracts information from signals originating from the sensor 15 and the separate sensor device 14 and presents the resulting data to the control unit 24. The signal processing unit 28 represents one embodiment of the processor 16, which was generally described above with reference to FIG. 1. Alternatively, the signal processing unit 28 and the controller 24 together may be considered to correspond to the processor 16 of FIG. 1. The signal processing unit 28 may use an impedance sensor to extract the absolute value of the electrical impedance, which may be used to confirm muscle contraction and to assess the strength of a given muscle contraction. This information may also be used to estimate the tissue volume that changes during muscle contraction (plethysmography). Alternatively, the signal processing unit 28 may use the tissue impedance signal to determine the tissue content producing the impedance signal. Because tissue conductivity varies depending on tissue type, changes in tissue composition can be determined. For example, approximate values ​​for tissue conductivity are: blood 0.8 siemens / meter, bone 0.02 siemens / meter, fat 0.05 siemens / meter, cardiac muscle 0.1 siemens / meter, and skeletal muscle 0.1 siemens / meter. During muscle contraction, the amount of blood in the muscle is reduced, thereby resulting in a decrease in tissue conductivity or an increase in impedance.

[0137] The signal processing unit 28 may also perform additional functions. It may extract temperature information from the temperature sensor and present it to the control unit 24 after low-pass filtering. The signal processing unit 28 may process signals from the EMG sensor and spectroscopically analyze the signals so that the resulting frequency-domain signals can be used to detect the onset of fatigue. For example, as muscles fatigue, the center frequency shifts, which can be interpreted as a condition requiring the end of therapy or a change in stimulation frequency to extend the therapy session. The signal processing unit 28 may also process signals from the EMG sensor and calculate estimates of multiple EMG cross-correlations, EMG autocorrelations and spectral densities, and EMG repetition frequency spectral densities. Information from these measurements may be used by the control unit 24 to infer the fatigue status of the skeletal muscles being stimulated.

[0138] The signal processing unit 28 may also be used to process signals from the ECG sensor and extract information used by the system 10, such as heart rate. Heart rate detection may be performed by measuring the RR interval of the electrocardiogram. If the heart rate is determined to be outside a predetermined range, a risk condition is assumed to exist, and therapy is preferably discontinued by the control unit 24. The signal processing unit 28 may also detect "peaked" T waves and shortened QT intervals, prolonged PR intervals and loss of P waves, followed by widening of the QRS complex, and extremes of a "sine wave" morphology, all of which may be signs of hyperkalemia resulting from rhabdomyolysis. The signal processing unit 28 may also detect narrowing of the QRS complex, reduced PR intervals, T-wave flattening and inversions, prolonged QT intervals, the appearance of prominent U-waves, and prolonged ST duration and ST depression, all of which may be signs of hypocalcemia resulting from rhabdomyolysis.

[0139] The signal processing unit 28 may extract information from the strain gauge pressure sensors and present it to the control unit 24 after low-pass filtering so that the strength of the contraction can be inferred. The signal processing unit 28 may also extract joint angle information from the goniometers and present it to the control unit 24 after low-pass filtering so that the angle of joint flexion or extension can be calculated. The signal processing unit 28 may also extract acceleration information from the accelerometers and present it to the control unit 24 after low-pass filtering so that the strength of muscle contraction can be calculated from the peak values ​​of the resulting traces. The signal processing unit 28 may extract fatigue information from the MMG signals and present it to the control unit 24 so that the therapy session can be terminated before any damage to the muscles occurs. Furthermore, the rate of contraction may be used to assess the state of muscle fatigue.

[0140] The communications unit 26 provides bidirectional communication between the control unit 24 and the patient interface unit 16. Such communication may be achieved using wired techniques such as USB, I2C, SPI, or RS-232, or wirelessly. Wireless connections may be established using techniques such as, but not limited to, WiFi, Bluetooth, or Zigbee, or by other radio frequency (RF), optical, or acoustic electrical communication methods.

[0141] The control unit 24 is responsible for coordinating the operation of the other components of the skin patch 12, such as the electrical stimulation unit 32 and the communication unit 26. It also governs the execution of the therapy protocol. The control unit 24 may include combinatorial logic or microprocessor circuitry, such as a PIC16F690, along with other components, such as memory chips. The control unit 24 generates the logic signals necessary to govern the operation of the switches, shown in subsequent figures, that interconnect the electrodes to the stimulation unit 32.

[0142] In some embodiments, the control unit 24 may drive the electrical stimulation unit 32 to produce high-frequency stimulation for pain suppression. This stimulation may be distinct from stimulation used for motor point excitation of skeletal muscles. For example, the high-frequency stimulation may be applied at a frequency ranging from about 10 KHz to about 200 KHz. The electrical stimulation unit 32 may also deliver a combined waveform having a low-frequency square wave and a high-frequency sine wave burst, where the high-frequency sine wave burst penetrates deep into the tissue and causes motor point stimulation. In this case, the combined waveform may be periodically interrupted for sensing of EGM and ECG waveforms. In other embodiments, the control unit 24 may drive the electrical stimulation unit 32 to reduce the frequency of the electrical stimulation following stimulation at a higher frequency to reduce muscle fatigue. The control unit 24 may also cause the electrical stimulation unit 32 to reduce the amplitude of the stimulation after a period of time.

[0143] In some embodiments, the patient interface unit 16 may be an application downloaded for use on a smartphone, tablet, laptop computer, or other smart device. Other types and configurations of the patient interface unit 16, including dedicated devices, may also be used in alternative embodiments of the system 10. In its simplest form, the patient interface unit 16 may include a "pain" button 17a on a smartphone screen (or other touch screen), as depicted in FIG. 3, which is pressed by the patient whenever pain is felt in response to nerve stimulation by the system 10. The illustrated embodiment also includes a "painless" button 17b, which is optional. Alternative embodiments may include additional features that allow the patient to input further information and / or adjust therapy, such as turning the system 10 on and off, setting the timing of therapy, adjusting the intensity and / or frequency of contractions, pulse width, pulse shape, pulse frequency, pulse train rate, pulse train duration, duty cycle, waveform, voltage, etc. Some embodiments may also provide information to the patient, such as physiological information (pulse, blood pressure, muscle fatigue, etc.) and / or information about the therapy being received. However, all of these additional features are optional.

[0144] In some embodiments, the patient interface unit 16 may provide commands and questions to the patient on a digital display, audio channel, or illuminated sign, while patient responses are entered via electrical switches, a touchscreen, or speech recognition. In some embodiments, the patient interface unit 16 is capable of handling 16 external packages, i.e., patches 12 and / or sensors 14, at once, for example, using up to 16 unique codes. The patient interface unit 16 may collect data regarding system 10 operation, patient compliance, and / or patient outcomes, and may store such information. The patient interface unit 16 may also log the status of strength training, the amount and duration of applied stimulation, and / or patient compliance with treatment. Any of this logged information may be made available to medical personnel, either continuously or periodically, by downloading it via a wired or wireless network. Furthermore, the resulting data may be transmitted to a central location for comprehensive evaluation and eventual distribution to clinical facilities. Algorithms running on the central computing warehouse may be used to determine best practices for stimulation and patient outcomes for implementation in future versions of the medical device. The patient interface unit 16 may also be used to direct stimulation patterns for the patient based on a particular therapy prescription. All muscles may be stimulated simultaneously, sequentially, or randomly, as desired. Additionally, the stimulator may alternate the site of stimulation, such as alternating the leg being stimulated, to reduce fatigue, extend treatment duration, and / or adapt to the patient's physiological needs.In patients with cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT) devices, and combination devices such as CRT-Ds, or active medical devices such as insulin pumps or continuous glucose monitors, the patient interface unit 16 may be configured to communicate with the active medical devices to obtain vital information such as heart rate and ECG timing such as marker channels and blood glucose levels.

[0145] Referring now to FIG. 7 , the display 202 of another exemplary embodiment of a patient interface unit is described. The patient interface unit 200 is depicted as a traditional smartphone running an application loaded on the smartphone. In this embodiment, the display 202 includes a start button 204, a stop button 206, a proximal pain button 208, a distal pain button 210, a stimulation amplitude window 212, an accelerometer window 214, and a treatment status window 216. In this embodiment, the patient interface unit 200 thus allows the patient to stop and start a therapy session via buttons 204 and 206 and input pain feedback via buttons 208 and 210. The patient may also view information originating from the rest of the system 10 (such as the skin patch 12) regarding the current therapy session and the electrodes that are active at any given time. This example illustrates that any given embodiment of a patient interface device may include suitable mechanisms for receiving patient input and providing information to the patient.

[0146] The skin patch 12 of the system 10 may include additional electronic and / or mechanical features. For example, as described above, the skin patch 12 may include multiple sensors 15 of the same or different types. The skin patch 12 may also include a cooling device as part of the tissue-contacting substrate 20 to cool the skin during therapy. Such cooling may help to reduce pain and discomfort, induce vasoconstriction in the skin and reduce fluid content beneath the electrodes 36, or both. Cooling may be achieved using chemical compounds, such as ionic salts or urea or ammonium nitrate mixtures dissolved in water, or via mechanical devices, such as Peltier coolers or evaporative coolers. Cooling may also be delivered to a range of locations relative to the stimulating electrodes, including below, between, to the sides of, adjacent to, proximal to, and distal to the proximal electrode, distal to the distal electrode, and proximal to the proximal electrode.

[0147] Long-term use of skin patches is not recommended because the gel may be degraded over the course of a therapy session by dead skin cells or sweating, thus leading to suboptimal therapy when the skin patch is used for subsequent therapy sessions. Additionally, the use of non-genuine skin patches (e.g., counterfeit, i.e., those made by unauthorized third parties without proper quality control) may also compromise patient safety and reduce the effectiveness of the therapy being delivered. To address this concern, the embodiment disclosed in FIG. 8 includes an embedded RFID chip that prevents reuse of the skin patch while also eliminating the possibility of using a skin patch from an unauthorized source. In such an embodiment, the outer substrate may include an RFID reader that verifies whether the skin-contacting substrate is authentic and / or previously used. The connection between the RFID chip and the RFID reader may be a wired or wireless link. In either case, the control unit of the outer substrate may query the RFID chip of the skin patch to obtain a unique skin patch ID number or USPID. If the RFID is not detected, a report is sent to the patient interface unit, informing the patient to couple a new, unused, genuine skin patch to the outer substrate. If a USPID is present on the skin-contacting substrate and is read, the USPID is transmitted to the patient interface unit, where it undergoes a test, including the application of a mathematical formula, to determine whether the USPID is a valid number. If the USPID is a valid number, a therapy session is initiated and the USPID is stored in the non-volatile memory of the patient interface unit. If the USPID is not valid or is a number previously verified by the patient interface unit, the patient interface unit instructs the patient to replace the skin-contacting substrate.

[0148] 9, an exemplary detailed layout of the electronic components for the skin patch 12 of FIG. 3 is described. The various electronic components may include a power source 22 (e.g., a 9-volt battery), a control unit 24, a signal processor 28, a communication unit 26 (including an antenna), sensors 15 (such as accelerometers and / or other sensors discussed above), and electrical contacts for electrode sets 34a, 34b, each electrode set including six electrodes 36. The skin patch 12 may additionally include a voltage multiplier 90, a holding capacitor 92, coupling capacitors 94, 96, and two sets of switches 98a, 98b that control the delivery of signals to the electrode sets 34a, 34b.

[0149] 10 , the information flow within the skin patch 12 will be described. Information from the sensor 15 may be amplified by an amplifier 80, which together may be referred to as a sensory feedback unit 82. The sensed and amplified signal is passed to a signal processor 28, and the processed signal is then passed to the control unit 24. The control unit 24 may transmit signals to and receive signals from a communication unit 26, which in turn transmits signals to and receives signals from the patient interface unit 16 and the control unit 24. Based on various different inputs entered into the control unit 24, such as information identifying the patient, muscle fatigue level, whether to start or stop therapy, etc., the control unit sends a signal to the electrical stimulation unit 32, which provides a signal to the electrode sets 34 a, 34 b to stimulate the nervous tissue and therefore muscle contraction.

[0150] Referring now to FIG. 11 , a muscle contraction stimulation method in accordance with the principles of the present invention using muscle contraction system 10 is described. In the first step of method 40, system 10 is activated by entering a start command in step 42. In this embodiment, upon start-up of skin patch 12, all electrodes 36 of electrode sets 34a, 34b are activated and the stimulation voltage is set to a minimum value, such as 3 volts. Next, an initialization step 44 is performed, which may include test stimulation (delivery of current toward target neural tissue) to detect whether skin patch 12 is properly and correctly adhered to the patient's skin and capable of delivering stimulation therapy. The test stimulation also serves to determine whether the patient will experience pain during the stimulation therapy. If the test stimulation produces pain 46, the patient inputs feedback to that effect using patient interface unit 16. At that point, the control unit 24 will remove one electrode 36 from each of the two electrode sets 34a, 34b in step 48 and then deliver a new stimulation current to the revised electrode sets 34a, 34b. If the patient again reports pain in step 46, another electrode 36 is removed in step 48 and current is again delivered. This process continues until the patient no longer reports pain. If additional electrodes 36 cannot be removed and the patient still reports significant pain sensations, instructions may be provided to the patient via the patient interface unit 16 to reposition the skin patch 12. The method 40 then resumes from the beginning of initialization step 44.

[0151] In step 50, the muscle contraction stimulation system 10 determines whether the delivered current produces a satisfactory muscle contraction. This is done using a feedback signal originating from the signal processing unit 28, which in turn obtains its input from the sensor 15. If a satisfactory contraction is not achieved, the system 10 increases the stimulation voltage and repeats the current delivery in step 52. In some embodiments, the stimulation amplitude may be gradually increased until the strength of the muscle contraction is sufficient. In an alternative embodiment, a binary search algorithm may be used, in which the correct stimulation amplitude is found by continuously segmenting the stimulation range. Once sufficient current has been delivered to produce a satisfactory contraction and the patient no longer reports pain, the system 10 is ready to deliver therapy in step 54.

[0152] The system 10 then delivers muscle contraction stimulation therapy until an off condition is met in step 56 or the patient requests that therapy be stopped via the patient interface unit 16 in step 58. When either of these two conditions is reached, therapy stops (step 60). Any of several different conditions may trigger therapy to stop. For example, a predetermined end time for therapy may be reached, a therapy goal may be achieved, the patient may begin to move, such as walking or standing, or a danger condition may occur. Danger conditions include any damage to muscle, such as rhabdomyolysis, muscle fatigue, deteriorating vital signs, such as changes in blood pressure, heart rate, or respiratory rate, or other markers of altered sympathetic drive.

[0153] As part of initialization step 44 or as a separate process, method 40 may include one or more additional test stimuli. One purpose / type of test stimuli may be performed to verify that skin patch 12 is properly attached to the skin in the desired location for delivering therapy. Another purpose / type of test stimuli may be performed to verify that skin patch 12 is not positioned directly over or in close proximity to the heart, where the stimuli may affect cardiac function.

[0154] The control unit 24 plays a significant role in the operation of the muscle contraction stimulation system 10 and method 40. For example, in some embodiments, it may monitor the power supply 22 and issue an alert if the power level becomes too low. If the user does not take action, the control unit 24 automatically shuts off the system to prevent any erroneous operation. The control unit 24 may communicate with the patient interface unit 16 and prompt the user with questions such as "Tolerable pain?" The control unit 24 may also receive interrupts from the patient interface unit 16, such as a request to terminate therapy. Communication between the control unit 24 and the patient interface unit 16 is provided by the communication unit 26. The control unit 24 may also check the quality of the electrodes 36 to ensure an adequate safety margin. If the tissue-contact substrate 20 is not an original part or has been previously used (and is designed to be disposable), the control unit 24 may issue an alert to the patient via the patient interface unit 16 and request replacement of the tissue-contact substrate 20 with a new, original part. Control unit 24 may perform additional tasks related to the signals originating from sensor 15 and signal processing unit 28. For example, control unit 24 may calculate heart rate variability, as reduced heart rate variability may be undesirable for patients suffering from various pathological conditions.

[0155] 12A and 12B, simplified diagrams depicting a portion of method 40 are described. FIG. 12A shows the tissue-contacting substrate 20 with a current path 70 proceeding from the positive electrode set 34a to the negative electrode set 34b. In FIG. 12A, all four electrodes 36 in each electrode set 34a, 34b are activated. In this example, the current path 70 is too shallow and does not contact and stimulate the target neural tissue. Also (or alternatively), it may be the case that current delivered with all activated electrodes 36 causes pain to the patient. In FIG. 12B, as initiated by step 48, electrode 36a is turned off within each electrode set 34a, 34b, which changes the shape and trajectory of the current path 70, thus contacting and stimulating the target neural tissue N. If the current configuration depicted in FIG. 12B still causes pain to the patient, a new configuration of on and off electrodes 36 may then be tried. 11 , the process of delivering stimulation currents, receiving feedback regarding muscle contraction and patient pain, turning electrodes 36 of sets 34 a, 34 b on and off, and delivering new stimulation currents may be repeated as many times as necessary. By turning various electrodes 36 in electrode sets 34 a, 34 b on and off in this manner and delivering test stimulation currents with each new electrode configuration, a desired combination of electrodes 36 may be achieved based on effective stimulation of nerve tissue to produce muscle contraction and minimal pain felt by the patient. System 10 may use any suitable algorithm to select which electrodes 36 to turn off and / or on to reach the desired combination of electrodes 36.

[0156] According to another aspect of the invention with reference to FIG. 13, a more detailed muscle contraction stimulation method 500 is described. At the start of method 500, system 10 is in idle mode 502 (LOO). Once the user presses the start button on the patient interface unit 16, the system proceeds to path LOl in step 504. Initially, all electrode segments are included (all segments are active) in step 506, and system 10 proceeds to program path LO2. Stimulation amplitude is set to a minimum value, which is 10% of the maximum value, in step 516, and system 10 proceeds to path LO3. At this point, stimulation is delivered (step 518), and data from a sensor (e.g., a 3D accelerometer) is measured. Total acceleration may be determined from a low-pass filtered version of the original acceleration signal (X, Y, and Z) using an infinite impulse response (IIR) filter implemented in firmware. After stimulation is completed (path L04), the system 10 queries the patient interface unit 16 to see if the user pressed a button (see, e.g., patient interface unit 200 in FIG. 7) indicating a pain sensation associated with the proximal electrode set (step 522) or the distal electrode set (step 526). If the patient reports a pain sensation for the proximal electrode set in step 522 (path L05), the pattern of electrode segments in the proximal set is rearranged in step 520 (path L17), and the stimulation procedure resumes at step 516 (path L02). If all proximal segments have been tried at this point (step 512), a message is sent to the patient interface unit 16 instructing the user to reposition the device (at least its proximal section) (step 508), and the system returns to the idle state 502 (path L00) until the user again presses the start button 504 on the patient interface unit 16.

[0157] Similarly, if pain is reported as associated with the distal electrode set in step 526 (path L07), the pattern of electrode segments in the distal set is rearranged in step 524 (path L13) and the stimulation procedure is resumed from the programmed location in step 516 (path L02). If all proximal segments have now been tried (step 514), a message is sent to the patient interface unit 16 instructing the user to reposition the device (at least its distal section) in step 510, and the system returns to the idle state 502 (path L00) until the user again presses the start button 504 on the patient interface unit 16.

[0158] If no pain indication is received, the strength of the muscle contraction determined using the accelerometer is compared against a minimum value in step 528 (path L08). If the contraction is strong enough, it is concluded that the muscle is contracted (path L10). Otherwise (path L09), the stimulation amplitude is increased in step 530 (path L15). If the stimulation is already at the maximum available voltage, the proximal and distal electrode pattern is readjusted in step 536, and the system returns to step 516 (path L02). If the new stimulation amplitude is less than the maximum allowable value (path L10), the patient interface unit 16 is queried to determine whether the user has requested to end therapy (step 534). If a stop request is detected (path L11), the system returns to the idle state in step 502 (path L00). Otherwise, the method 500 returns to step 518 (path L03) for the next stimulation. Advantageously, the aforementioned algorithm automatically determines stimulation thresholds, allowing delivery of minimal energy to tissue to achieve the desired therapeutic outcome. By keeping stimulation energy to the minimum required to produce muscle contraction, battery life is extended and the likelihood of unintended stimulation of sensory nerves and motor nerves of non-target muscles is reduced.

[0159] Referring now to FIG. 14, a modified version of the method of operation is described, which provides advantages similar to those of method 500 of FIG. 13, but additionally eliminates the need for the patient to be involved in determining the optimal electrode pattern and current path. Instead, the method of FIG. 14 automatically determines the electrode pattern and stimulation amplitude. Method 550 begins in an idle state (step M00) and remains so until the start button is pressed. Once the start button is pressed (at step M01), the algorithm begins by including all electrodes and setting the stimulation amplitude to the lowest setting (step M02), followed by delivery of stimulation (step M03). In the next step, step M04, a marker of the patient's pain sensation is detected, as described below. Multiple markers of pain sensation may also be used. If sufficient pain is detected (step M05), the pattern of both electrodes is adjusted (step M10). If all electrodes have not yet been tried, the algorithm returns to stimulation, starting with the lowest amplitude (step M02). If all permutations of electrode patterns have been tried (step M11), the subject is instructed to reposition both electrodes, and the system returns to an idle state (step M00) until the subject restarts the search algorithm. If the pain indication is low (step M06), the muscle response is checked to determine whether the contraction is strong enough to produce a therapeutic effect. If the strength of the contraction is less than necessary for application, the stimulation amplitude is increased (step M08). At this point, if the stimulation amplitude has reached its maximum value, the pattern of both electrodes is readjusted (step M05). If the stimulation amplitude is still below the maximum allowable value (step M07), a check is made to determine whether the patient has requested that therapy be stopped. If there is a request to stop the session (step M09), the system returns to an idle state (step M00). If the patient has not requested that the session be ended, the algorithm continues to deliver stimulation (step M03).

[0160] The algorithm described above relies on the device's automatic detection of a pain marker or multiple pain markers. Various options for detecting pain are available, such as using sensors to detect increased sympathetic activity, which correlates with pain onset and severity. Measurements of sympathetic activity include heart rate variability, elevated heart rate, which can be detected via an ECG (electrocardiogram), and elevated respiratory rate. Respiratory rate may be measured via an ECG, using a skin patch accelerometer, chest wall electrical impedance, a microphone, or other techniques known in the art of respiratory monitoring. Other measurements of sympathetic activity include muscle sympathetic nerve activity or sympathetic nerve activity. Such sympathetic nerve activity may be measured via needle microneurography, or more preferably, via noninvasive measurement of sympathetic nerve activity using surface electrodes. Sympathetic activity is also known to affect sweat gland activity, which can be measured via variations in skin conductance via a skin patch. Increased sympathetic activity can also lead to piloerection (hair standing), which leads to "goosebumps" on the skin surface. Goosebumps may be detected via skin impedance. Electrical impedance also increases between the simulating electrode skin patch and the goosebump-affected skin surface. Other markers that correlate with sympathetic activity include blood pressure, mean arterial pressure, vascular tone, vascular stiffness, capillary vasoconstriction (e.g., detected as tissue pallor in the distal fingers or toes or via a skin perfusion sensor), and carotid-femoral pulse wave velocity.

[0161] In addition, other parameters can be measured to provide pain detection, including facial EMG electrodes or monitoring facial expressions via video screens (e.g., smartphones, iPhones, tablets, iPads, laptops, webcams, etc.). The occurrence of grimacing or frowning or clenching of the eyes can serve as markers for pain. Noxious stimuli can also cause pupil dilation, which is detectable via photographic or video images. Electroencephalography may also be used to detect pain, as the EEG power spectrum increases with pain and certain bandwidths, including the delta, theta, and alpha bandwidths, may be particularly sensitive to pain.

[0162] Referring now to FIG. 15, a simplified circuit diagram for an embodiment of the electrical stimulation unit 32 is illustrated. As described with respect to the layout of FIG. 9, the electrical stimulation unit 32 includes a holding capacitor 92, coupling capacitors 94, 96, and a set of switches 112a, 112b, all of which provide two currents 114a, 114b to the electrode sets. FIGS. 16A and 16B depict two final sets of switches 116a through which the voltage passes before reaching the electrodes 36 of electrode sets 34a, 34b. Switches 116a are used to control the subset of electrodes 36 that will be actively involved in stimulation.

[0163] Figure 17 depicts the pattern of stimulation provided by system 10 via electrical stimulation unit 32 to generate a desired muscle contraction waveform. Figure 18 depicts the pattern of signals provided to the system's electrodes 36 via switches 112a, 112b to achieve the desired waveform. Figure 19 illustrates the desired waveform.

[0164] In Figure 17, V P is the amplitude of the first pulse (Φ1), sometimes called the anodic pulse, while V N is the amplitude of the second pulse (Φ2), sometimes called the cathodic pulse. Usually, but not always, the amplitudes of the anodic and cathodic pulses are chosen to be equal, but their polarities are opposite to each other. V P-P is the peak-to-peak amplitude of the resulting waveform. The waveform generated by system 10 may be in the form of a pulse train, as shown in FIG. 17, which may work well for stimulating skeletal muscle contraction. T1 is the duration of the anodic pulse, T2 is the duration of the cathodic pulse, T3 is the total elapsed time between two subsequent anodic pulses, and T4 is the total elapsed time between two subsequent pulse trains. N is the total number of pulses in the pulse train.

[0165] 15 and 17, the first task performed by system 10 is to produce the required stimulation voltage as determined by control unit 24. For example, if the desired stimulation voltage is 15 volts, it is generated from power supply 22, which may be 3 volts, using voltage multiplier 90 (see FIG. 9). Voltage multiplier 90 may be a Villard cascade voltage multiplier, a Dickson charge pump, or any other type of voltage multiplier. The resulting voltage V S is the holding capacitor C H During the application of the anodic pulse, V S is the amplitude of the anodic pulse, i.e., V P Similarly, during the application of the cathodic pulse, V S is the amplitude of the cathode pulse, i.e., V N Coupling capacitors 94 and 96 ensure that the stimulation delivered to the patient is charge balanced and that no net charge is left on either of the electrode sets over time.

[0166] To generate the anode pulse, an electronic switch S 2P and S 1N While keeping open, electronic switch S 1P and S 2N is closed. To generate the cathode pulse, the electronic switch S 1N and S 2P is closed, while the electronic switch S 2N and S 1P is opened. At all other times, all four switches are kept open. This operation results in the formation of voltages V1 and V2, with a differential voltage V1-V2, as shown in Figure 17. The electronic switch S 1P , S 1N , S 2P , S 2N A timing diagram for the operation is shown in FIG.

[0167] Before voltages V1 and V2 are applied to electrode sets 34a, 34b, they pass through a final set of electronic switches 116a, 116b, as shown in Figures 16A and 16B. When all switches 116a shown on Figure 16A are closed (S 1A , S 1B , S 1C , S 1D ), all four electrodes 36 of electrode set 34a will be connected in parallel. Similarly, if all switches 116b shown on FIG. 16B are closed (S 2A , S 2B , S 2C , S 2D ), all four electrodes 36 of electrode set 34b will be connected in parallel. The resulting current flow in the tissue will be similar to that shown in FIG. 12A. However, if electronic switch S is turned on while all other switches 116a, 116b are kept closed, 1B and S 2B When the "B" electrode 36 is released, the "B" electrode 36 is removed from both electrode sets 34a, 34b, and the resulting current in the tissue will be similar to that shown in FIG. 12B. Again, this example and accompanying figures illustrate an embodiment with four electrodes 36 per electrode set 34a, 34b, but any other suitable number of electrodes may be used in each set 34a, 34b. Additionally, each electrode set 34a, 34b may have more or fewer than four electrodes 36, and / or different numbers of electrodes 36 may be turned on or off within a set. Additionally, the number and configuration of electrodes need not be symmetrical between the two sets 34a, 34b.

[0168] 20, another exemplary muscle contraction stimulation system 300 is described in which multiple skin patches 12a-12e are used and connected to each other via a multimodal wireless network. The skin patches 12a-12e may be wirelessly coupled together via a ZigBee® connection 334 or other wireless protocol. One or more of the patches 12a-12e may communicate with the patient interface unit 16 via a Bluetooth® link 332 or other wireless protocol. In the illustrated multimodal wireless network, the skin patches 12a-12e are all connected to each other using a ZigBee network 334. Additionally, the skin patch 12a acts as a ZigBee hub, echoing all communications to the patient interface unit 16 using the Bluetooth® link 332. To best communicate with the patient interface unit 16, one of the skin patches 12a preferably acts as the ZigBee hub and communicates with the patient interface unit 16, such as a smartphone. The ZigBee network 334 has the advantage of being capable of self-forming and self-repairing if one of the case skin patches 12a-12e is removed from the network.

[0169] Furthermore, ZigBee systems use low power and are suitable for low-data-rate applications. Each skin patch 12a-12e may report the timing of relevant events, such as the arrival of blood pressure pulses at the muscles and cardiac contractions from the ECG, all of which are relayed to the patient interface unit 16 via a Bluetooth® link 332 between the ZigBee hub 12a and the patient interface unit 16. The patient interface unit 16 then calculates the required timing of stimulation to be delivered to the muscles and communicates these values ​​via the Bluetooth® link 332 to the ZigBee hub 12a. The ZigBee hub distributes the parameters to the remaining units via a ZigBee network 334. Additional communication transceivers may be utilized to establish live links with implantable medical devices, such as pacemakers, defibrillators, and CRT / CRT-D devices, to coordinate stimulation timing with cardiac activity. Additionally, the patient interface unit may communicate with external medical devices such as wearable heart rate monitors, glucose sensors, or insulin pumps, and other stations over the Internet, such as electronic medical records (EMRs) and databases.

[0170] Therapeutic uses of the present invention The NMES system of the present invention is expected to find widespread application by making self-administered muscle contraction therapy simpler, safer, and associated with improved clinical outcomes. Some examples of potential clinical applications for embodiments of muscle contraction stimulation system 10 are provided below. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention as described by the claims. Additionally, while descriptions of several disorders that may be treated using the systems, devices, and methods of the present application are disclosed, these examples are not intended to be a comprehensive description of all possible applications. Many other disease states and disorders may also be treated using the systems, devices, and methods described herein.

[0171] A. Treatment of metabolic disorders It is contemplated that the systems of the present invention may be advantageously used by a large patient population suffering from metabolic disorders to either complement existing exercise programs or to provide muscle stimulation in patients who are otherwise not capable of routine or vigorous exercise. A non-limiting list of possible metabolic disorders for which the systems, devices, and methods of the present invention may provide treatment includes the following:

[0172] 1. Insulin Resistance. Insulin resistance affects millions of people worldwide. As a person becomes more obese, they gradually become more insulin resistant, leading to impaired glucose tolerance and often resulting in type 2 diabetes. As the disease progresses, individuals can develop complications such as retinopathy, nephropathy, peripheral neuropathy, vasculopathy, heart disease, and stroke. Exercise can benefit these individuals because acute muscle contractions effectively stimulate skeletal muscle glucose uptake rates, and regular exercise stimulates pancreatic insulin secretion. A therapeutic regimen of muscle contraction therapy using the muscle contraction stimulation system 10 can improve weight, HbA1c (a marker of long-term glycemic control), and overall health in patients with type 2 diabetes.

[0173] 2. Fatty Liver Disease. Nonalcoholic fatty liver disease (NAFLD) is an acquired metabolic liver disorder affecting 20-30% of the population in North America. NAFLD refers to a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), characterized by an inflammatory response accompanied by liver cell injury. 5-20% of patients with steatosis develop NASH, 10-20% develop fibrosis, and <5% progress to cirrhosis. Weight loss plays an important role in resolving NAFLD, and therefore, lifestyle modifications such as exercise and dietary control are recommended interventions for these individuals. For example, a therapeutic regimen of muscle contraction therapy using muscle contraction stimulation system 10 targeting any combination of gluteal, quadriceps, hamstrings, or gastrocnemius muscles may improve fatty liver and reduce insulin resistance and serum IL-6 levels in NAFLD patients who are resistant to lifestyle counseling or unable to exercise.

[0174] 3. Obesity. Obesity has serious physical, psychological, and economic implications for patients and presents a challenge to healthcare systems in many countries. Approximately 35% of adults in the United States are obese. Interventions to promote weight loss begin with behavior modification, including counseling, nutritional counseling, and exercise. Due to lack of motivation, lack of time, or reasons related to coexisting conditions, many obese individuals are unable to maintain a long-term exercise program. Given the muscle mass of the gluteal and leg muscles, it is expected that regular daily sessions of muscle contraction therapy using the muscle contraction stimulation system 10 will increase lipid tissue metabolism, reduce body weight, and help treat obesity in overweight patients.

[0175] B. Treatment of Skeletal Muscle Dysfunction 1. Osteoarthritis. The knee is the joint most commonly affected by osteoarthritis (OA). The prevalence of OA is expected to increase in the future due to an aging population and increasing rates of obesity. Patients with knee OA have decreased strength in the knee extensor muscles, as well as decreased muscle thickness and fiber bundle length. A therapeutic regimen of muscle contraction therapy using muscle contraction stimulation system 10 may reduce knee pain and improve muscle mass and function in patients with knee OA. Muscle contraction therapy using system 10 may also reduce hip pain and improve muscle mass and function in patients with hip OA.

[0176] 2. Sarcopenia. Aging is associated with a progressive loss of skeletal muscle mass. This loss of muscle mass reduces muscle strength and impairs functional capacity. Rapid muscle loss is a common problem in elderly individuals following limb immobilization or bed rest due to injury or illness. Maintaining some degree of physical activity during periods of disuse is required to mitigate muscle atrophy. Therefore, a regular, ongoing regimen of muscle contraction therapy using the muscle contraction stimulation system 10 may mitigate loss of muscle mass and / or strength in elderly patients, ICU patients, and patients recovering from surgery.

[0177] 3. Neuromuscular Training. NMES is a standard tool in physical therapy to improve limb weakness, for example, after stroke, head trauma, or surgery. Physical therapists may use the muscle contraction stimulation system 10 to treat muscle atrophy, increase muscle mass, improve muscle strength, and increase muscle endurance. The system 10 may also be used to increase neural drive to muscles, improve proprioception, improve motor control, and facilitate or retrain voluntary motor function.

[0178] C. Treatment to improve aerobic endurance 1. Aerobic Exercise. Aerobic exercise is an important component of maintaining health and improving cardiac function in patients with chronic illnesses such as COPD or coronary artery disease. If an individual is unable to perform aerobic exercise due to injury or illness, system 10 may be used as an exercise substitute to avoid or eliminate the ailments associated with aerobic inactivity. Indeed, muscle contraction stimulation system 10 may be used to induce oxygen uptake (VO2), increase heart rate, and increase blood lactate (all changes similar to those resulting from aerobic exercise).

[0179] 2. Cancer. Exercise may improve survival in patients with cancer for a variety of reasons. Patients in better physical condition are more likely to undergo second- and third-line treatment and are better able to tolerate and complete chemotherapy courses. Exercise may also enhance the effectiveness of cytotoxic chemotherapy through its effects on drug distribution, pharmacodynamics, and metabolism. Improvements in lean body mass and physical function may also have implications for disease risk and survival. System 10 may be advantageously used to improve function, and potentially survival, in cancer patients.

[0180] d. Treatment of cardiovascular disorders Counterpulsation is a method of circulatory system support to reduce cardiac workload. While intra-aortic balloon pumps ("IABPs") offer this benefit, IABP placement requires an invasive implant, limiting decompensated patients to the ICU. Non-invasive external counterpulsation systems are known that enclose the patient's legs in pneumatic cuffs, which provide sequential inflation (distal to proximal) during the diastolic phase of the cardiac cycle. External counterpulsation is an FDA-approved treatment for heart failure, unstable angina, acute myocardial infarction, and cardiogenic shock, and is performed in a hospital or physician's office. It includes a large table, hydraulic system, and computer interface. A therapeutic regimen for muscle contraction therapy using the muscle contraction stimulation system 10 may provide benefits similar to those of external counterpulsation.

[0181] e. Treatment of peripheral vascular disease 1. Chronic Venous Insufficiency (CVI). CVI occurs when venous valves in the leg veins do not function effectively, making it difficult for blood to return to the heart. Valve damage can occur as a result of aging, prolonged sitting or standing, or reduced mobility leading to deep vein thrombosis (DVT). Valve insufficiency leads to venous hypertension, which underlies most of the symptoms of CVI. Patients may develop swollen legs, leg pain, skin oozing, and ulceration. A therapeutic regimen of muscle contraction therapy using the muscle contraction stimulation system 10 may improve hemodynamic parameters, reduce leg edema, and improve blood supply to the skin of the feet.

[0182] 2. Prevention of Deep Vein Thrombosis (DVT). During prolonged immobilization, individuals are at risk of developing DVT, which is potentially life-threatening if it progresses to the lungs (pulmonary embolism). To prevent venous stasis, immobilized patients may have sequential compression devices (SCDs) placed around their legs, which are periodically inflated with air to direct venous blood from the legs to the trunk. A therapeutic regimen of muscle contraction therapy using the muscle contraction stimulation system 10, particularly of the gastrocnemius muscles, may be used to improve blood flow from the legs during bed rest and thus prevent DVT.

[0183] 3. Peripheral Arterial Disease (PAD). Over 8 million Americans and over 200 million people worldwide suffer from PAD, characterized by diseased, blocked, or partially blocked arteries in the legs. The incidence is likely to rise as the population ages. The classic symptom is claudication, discomfort during physical exertion in muscle groups distal to the affected artery. Primary treatment involves supervised walking until pain is felt, followed by rest until the pain subsides, and then walking again, repeating the sequence for 20 to 60 minutes per session at least three times per week. This exercise allows collateral vessels in the legs to form, which can compensate for the blocked artery. The average age at which people develop PAD is 70 years old. Some of these patients suffer from confounding illnesses, such as COPD, heart failure, arthritis, or other disorders, that make it difficult for them to participate in a walking exercise program. Furthermore, claudication discomfort can prevent them from maintaining a chronic exercise program. A therapeutic regimen of muscle contraction therapy using the muscle contraction stimulation system 10 may be used as a substitute for exercise in these PAD patients.

[0184] 4. Lymphedema. The lymphatic system circulates lymph through lymphatic vessels, which drain into lymph nodes. Removal, damage, or blockage of lymphatic vessels or lymph nodes from surgery, radiation, cancer, or infection can interfere with lymphatic fluid returning from the limbs, resulting in limb swelling. System 10, used in conjunction with one or more limbs, can help return lymphatic fluid from the limbs to the trunk, thereby reducing limb swelling.

[0185] F. Improved sympathetic drive Hypertension. Mechanically sensitive stretch receptors are located within the blood vessels of the heart, vena cava, aorta, and lungs. These stretch receptors sense changes in central blood volume and blood pressure. An increase in central blood volume (blood pressure) increases vagal afferent nerve firing, reflexly decreasing sympathetic nerve activity (SNA). This phenomenon is called the cardiopulmonary baroreflex. The increase in central blood volume associated with muscle contraction activates cardiopulmonary baroreceptors, inhibiting SNA. A therapeutic regimen of muscle contraction therapy using the muscle contraction stimulation system 10 can be used to reduce SNA and ameliorate various conditions associated with increased SNA, including hypertension.

[0186] As noted above, the muscle contraction stimulation systems and methods of the present invention may be used to treat any of a number of medical conditions, enhance physical therapy, act as a substitute for physical exercise and / or any other suitable therapy, and provide benefit to a given human or animal subject. Below are three exemplary therapeutic examples using system 10.

[0187] Example 1: Stimulating muscle contraction for the treatment of heart failure 21-24, an exemplary configuration and method of a muscle contraction stimulation system 400 suitable for treating heart failure is described. Heart failure is a condition in which the heart muscle is unable to pump a sufficient amount of blood to meet the body's physiological needs. It is a progressive disease with no known cure, affecting over 5 million individuals in the United States. The average expected survival time for a heart failure patient is approximately 5 years from the time of diagnosis. Conventional treatments aim to improve cardiac function by reducing afterload (e.g., reducing arterial pressure) and increasing myocardial contractility. Despite such treatments, heart failure patients eventually succumb to the disease.

[0188] The muscle contraction stimulation system 400 may be configured and used to treat heart failure patients by stimulating contractions in the muscles of the lower limbs, helping to pump blood back to the heart. This allows the heart to be acutely "rested." With chronic use, the muscle contraction stimulation system may potentially remodel the heart, thereby reducing end-diastolic volume and improving left ventricular ejection fraction. In one embodiment, skin patches 412a-412d may be placed over the gastrocnemius (patch 412a), hamstrings (patch 412b), gluteus maximus (patch 412c), and quadriceps (patch 412d). Electrical stimulation may be applied to these muscle groups sequentially by the system 400, starting with the gastrocnemius and moving up the limb toward the head, thus causing the muscles to pump blood upward toward the heart. The timing diagram in Figure 21B illustrates the patient's ECG signal 422 along with stimulation pulses 420 provided by system 400 to the patient's neural tissue, showing the approximate timing of stimulation of skin patches 412a-412d. Electrical stimulation applied to the gastrocnemius muscle is labeled "A" and occurs immediately after the T-wave of the ECG. Next, the hamstrings and quadriceps are stimulated, labeled "B." Finally, the gluteus maximus is stimulated, labeled "C."

[0189] The muscle contraction system 400 may use a variety of frequencies, including non-convulsive wave-like frequencies (4-12 Hz) that produce muscle spasms, and convulsive wave-like frequencies (20-100 Hz) that produce fusion contractions. For applications where the goal is to promote fluid circulation from the legs (e.g., heart failure, chronic venous insufficiency, prevention of deep vein thrombosis, and peripheral arterial disease), it is anticipated that a convulsive wave-like frequency of 20-75 Hz will preferably be used.

[0190] 22 , for the treatment of heart failure using electrical stimulation of leg muscles to be safe and effective, it is important that the application of electrical stimulation to the muscles be determined and applied correctly. For example, if skeletal muscle stimulation causes the muscle to contract shortly after ventricular systole, such stimulation will increase cardiac afterload, undesirably increasing the cardiac workload. Such stimulation timing may also result in mitral valve regurgitation. The task of determining the optimal timing of skeletal muscle stimulation is further complicated by patient-to-patient variability, its dependence on heart rate, and patient position.

[0191] The system 400 may use one or more sensors 15 in the skin patch 12, a separate sensor 14, and the signal processing unit 28, as described above, to determine the correct timing of skeletal muscle stimulation relative to the cardiac cycle. For example, an ECG device, a blood pressure measurement device, and / or an accelerometer may be used to monitor the patient's ECG signal 422 and local ballistocardiogram signal 424. The ECG signal 422 may be used as a reference for the timing occurrence of all subsequent events, such as stimulation pulses A, B, and C in FIG. 21B. First, the delay between the QRS or T-wave and the peak of the local ballistocardiogram 424 may be measured while the patient is at rest and no pressure is applied to the leg muscles (T10 on FIG. 22). The peak of the local ballistocardiogram 424 indicates the arrival of the systolic pressure wave at a local location, e.g., the upper thigh. Muscle stimulation should begin only in the period T11 after this peak, but before T12, as shown in FIG. 22. Skeletal muscle can be safely stimulated within the time interval T11-T12.

[0192] The exact time to stimulate within the time interval T11-T12 may be determined using additional information from sensors 14 and 15. Once therapy is effective, both heart rate and arterial blood pressure will decrease. Thus, control unit 24 may sweep the time at which electrical stimulation is applied within the time interval T11-T12 while monitoring blood pressure or heart rate. The delay that produces the greatest drop in heart rate or blood pressure may then be selected as the preferred delay for stimulating skeletal muscle.

[0193] In a preferred embodiment, skeletal muscle stimulation can be timed to occur at the onset of diastole and cease at the onset of systole, providing counterpulsation support. This stimulation regimen is expected to increase diastolic pressure, decrease left ventricular afterload, and increase venous return. The increase in diastolic pressure displaces blood volume back into the coronary arteries during diastole, when the heart is in a relaxed state and resistance within the coronary arteries is minimal. The resulting increase in coronary perfusion pressure may increase blood flow through or enhance the development of coronary collateral vessels. Additionally, as the left ventricle contracts, counterpulsation will contribute to emptying blood volume from the aorta, thus working against the reduced afterload. Clinical applications for this embodiment would include angina pectoris, heart failure, ischemic stroke, erectile dysfunction, and acute myocardial infarction.

[0194] In another embodiment, skeletal muscle stimulation may be timed to occur during systole and terminate during diastole of the same or subsequent cardiac cycle to direct blood flow to organs of the head and trunk. Such a stimulation regimen is expected to be beneficial for patients requiring increased intravascular fluid volume, including conditions such as inferior myocardial infarction, hemorrhage, dehydration, sepsis, etc.

[0195] 23A-23D and 24, the control unit 24 may also determine the rate at which the skeletal muscles of the lower extremities are stimulated. For example, a training regimen may be used on the patient over time to help slowly condition the muscles. Such training may be highly beneficial for heart failure patients, who are typically not accustomed to any exercise or who exercise only minimally. In one training regimen, illustrated in FIGS. 23A-23D, the control unit 24 determines whether stimulation should be applied during any given cardiac cycle. During the initial cycle of therapy, illustrated in FIG. 23A, electrical stimulation is applied for only one out of four consecutive cardiac cycles. Later, as the patient's muscles condition, muscle contractions may be stimulated for one out of three consecutive cardiac cycles (FIG. 23B), then every other cardiac cycle (FIG. 23C), and finally once every cardiac cycle (FIG. 23D). The decision to accelerate the timing of stimulation may be made by the control unit 24 based on programmed parameters, parameters entered by a physician, decisions made by the patient, a programmed treatment algorithm, and / or muscle fatigue sensed by one or more sensors 14, 15 of the system 400.

[0196] FIG. 24 illustrates a second exemplary treatment regimen for a heart failure patient. In this case, electrical stimulation is applied to skeletal muscle during every other cardiac cycle throughout the regimen (rows 1-4 of the table in FIG. 24 ), but the number of stimulation pulses per cardiac cycle increases over time. During the early periods of the training regimen, such as the first two weeks, only a single pulse is applied. This is illustrated in the first row of the table in FIG. 24 and would correspond to N=1 for the waveform shown in FIG. 17 . As the skeletal muscle transforms and becomes less susceptible to fatigue, the number of pulses (N) is increased, creating a stronger and more sustained contraction. Furthermore, when there is a strong demand for increased cardiac output, as indicated by a sudden increase in heart rate, control unit 24 may switch to a stimulation pattern in which skeletal muscle is stimulated during each cardiac cycle, as depicted in the bottom row of FIG. 24 .

[0197] Example 2: Treatment of Type 2 Diabetes Insulin resistance refers to impaired insulin action in tissues such as skeletal muscle, adipocytes, and the liver. In insulin-resistant states, insulin-stimulated glucose uptake into skeletal muscle is both reduced and delayed. Insulin resistance in skeletal muscle is associated with many disease states, including heart failure, dyslipidemia, chronic renal failure, normal aging, obesity, and type 2 diabetes. Diabetes is a complex disease affecting millions of people worldwide. It is predicted that one in three adults in the United States will have diabetes by 2050. Obesity plays a role in the majority of cases. As a person becomes more obese, they become more insulin-resistant, leading to impaired glucose tolerance, which can lead to the development of type 2 diabetes. As the disease progresses, the risk of complications increases. Complications include retinopathy, nephropathy, peripheral neuropathy, and vasculopathy, leading to heart disease and stroke.

[0198] Exercise is considered a primary treatment for individuals with type 2 diabetes because it increases the sensitivity of the glucose transport process to insulin in skeletal muscle. Muscle contraction during exercise is a more effective stimulus of skeletal muscle glucose uptake than insulin. Regular regular exercise leads to an adaptive response of increased muscle mass, which affects glucose metabolism. Regular exercise also affects glucose-stimulated pancreatic insulin secretion. Exercise guidelines for type 2 diabetes recommend regular, moderate-intensity, endurance-type physical activity for 30 to 60 minutes per day, approximately every week. However, patients' motivation to adhere to exercise programs is low. Approximately 70% of the adult population fails to achieve the recommended 30-minute goal of regular exercise, and approximately 40% do not engage in any type of physical activity. Individuals with type 2 diabetes are typically overweight, suffer from arthritis, embarrassment, or lack motivation to go outside or head to the gym for outdoor exercise. They may also be elderly or disabled.

[0199] The muscle contraction stimulation method, device, and system of the present invention may be used to treat patients with type 2 diabetes by simulating exercise through stimulated muscle contractions. As discussed above, the muscle contraction system of the present invention may use various frequencies. The use of non-convulsive wave-like frequencies (4-12 Hz) produces muscle twitches, while convulsive wave-like frequencies (20-100 Hz) produce fusion contractions. Stimulation at 5 Hz will allow complete relaxation between muscle twitches. Relaxation between muscle twitches is important for achieving maximal energy expenditure because muscle fiber shortening (actin / myosin cross-bridge cycling) consumes more ATP than sustaining a shortened muscle length. Additionally, non-convulsive wave-like stimulation is less fatiguing than convulsive wave-like stimulation at comparable levels of oxygen consumption. To maximize metabolic benefits and energy expenditure in disorders such as type 2 diabetes, fatty liver disease, and obesity, the muscle contractile system should be stimulated at a frequency of 4-6 Hz over long treatment sessions (greater than 60 minutes), with a training frequency of 5-7 times per week, involving multiple large muscle groups, to maximize muscle mass.

[0200] An additional consideration is the inherent safety issues associated with the treatment of type 2 diabetes. The muscle contraction stimulation system of the present invention is uniquely configured to help manage these issues. For example, when blood glucose concentrations fall below 70 mg / dL, a condition known as hypoglycemia occurs, typically accompanied by a condition known as tachycardia, which is also characterized by an increased heart rate. System 10 may be configured to monitor a subject's heart rate using an ECG device; if the heart rate rises above a certain value, the increase in heart rate may be interpreted as an indicator of hypoglycemia, which may then be used to terminate therapy. Increased values ​​of the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index are associated with significantly higher blood pressure levels and reduced RR interval, stroke index, cardiac index, pre-ejection period, and left ventricular ejection time across different categories of body mass index and blood pressure. Thus, a therapy session may be terminated upon detection of a decrease in blood pressure or an increase in the RR interval, stroke index, cardiac index, pre-ejection period, and left ventricular ejection time.

[0201] Another feedback mechanism available for monitoring safety operation is the use of the capacitive component of skin impedance to provide a measure of changes in blood glucose concentration. Again, any significant drop in skin capacitance, measured within the 20 KHz to 100 KHz frequency range, can be interpreted as indicating the onset of hypoglycemia and the need to terminate therapy. This type of measurement is best performed using interdigitating electrodes placed over a superficial vessel, such as the cephalic vein. A baseline capacitance value of 35 picofarads (pF) can generally be expected. During a treatment cycle, blood glucose levels are expected to decrease for patients with type 2 diabetes. Typically, a decrease in blood glucose levels of 2 mmol / L is indicated by a capacitance drop of 3.5 pF. Thus, in one embodiment, the system is configured to monitor changes in capacitance values ​​and interpret a decrease in skin capacitance as a decrease in blood glucose levels. Once the capacitance value has decreased by a desired amount, for example 3.5 pF, it may be assumed that the blood glucose level has decreased by 2 mmol / L and the therapy session may be terminated.

[0202] In another embodiment, the control unit may be configured to terminate stimulation being delivered to the fatigued muscle group but simultaneously communicate this information to the patient interface unit. If time remains in the planned therapy duration or the therapy goal has not yet been achieved, stimulation of another muscle group may be initiated. This transition between stimulated muscle groups may be accomplished in any one of several ways. If the patch is positioned to cover both the fatigued muscle group and the new muscle group, the electrodes in the patch may be electrically reconfigured to capture the new muscle group instead of the previous one. Alternatively, the patient interface unit may instruct the patient to reposition the skin patch closer to the new muscle group, and a new threshold determination process is initiated as discussed above. Finally, the patient may initially place multiple skin patches at the beginning of a training session so that the patient interface unit can automatically switch from one muscle group to the next when a fatigue condition is detected in the first muscle group. Certain embodiments of the present invention utilize fatigue sensors, as described above.

[0203] If the patient also has a cardiac stimulating device, such as a pacemaker, ICD, CRT, CRT-D, or subcutaneous ICD, changes in the pacing threshold may be used as a detector of the blood glucose level. In this case, the patient interface unit 16 may communicate with the cardiac stimulating device, obtain the pacing threshold information, and interpret any increase in the capture threshold as a drop in the glucose level.

[0204] A feedback system incorporated into a system constructed according to the principles of the present invention also allows a medical professional to determine whether a given therapy session is effective. For example, if there is no change in heart rate, blood pressure, or the volumetric component of skin resistance throughout a given therapy session, blood glucose levels are likely not changing significantly either, which in turn indicates that insulin resistance has not been significantly reduced. Based on this type of data report, a medical professional may choose to increase the number of muscles or muscle fiber bundles being stimulated, increase the pre-specified therapy duration, or switch to a more intensive stimulation regimen.

[0205] The feedback system described above also allows for optimal delivery of therapy specific to the treatment of a given disease state. For example, to reduce insulin resistance, it may be possible to use submaximal contractions of skeletal muscles, which would delay the onset of fatigue in the muscle, increase overall therapeutic benefit, and reduce patient discomfort. However, it may be necessary to periodically add maximal contractions to the submaximal contractions to have therapeutic benefit. All of this can be accomplished through the use of sensors such as accelerometers or MMG sensors, with the aid of a signal processing unit, allowing the control unit to regulate the entire therapy session. For example, the control unit may be programmed to increase the intensity of the applied stimulation while monitoring the intensity of the muscle contraction. This can be done by measuring the RMS value of the MMG signal or its power at 50 Hz to determine the intensity of the contraction. When an increase in stimulation amplitude does not result in a further increase in muscle contraction intensity, the control unit may determine that maximal contraction has been achieved. At this point, the stimulation amplitude can be reduced to decrease the intensity of the muscle contraction, which would in turn delay the onset of fatigue. To ensure optimal therapy benefit and test muscle fatigue status, the control unit periodically, for example, every 15 minutes, increases the stimulation intensity to that required for maximum contraction, measures the intensity of the contraction, and subsequently decreases the stimulation intensity. The control unit may terminate therapy when any of the following occurs: the preprogrammed therapy duration is completed, muscle fatigue is detected, a safety concern is detected (as described elsewhere herein), the patient becomes ambulatory, or the patient types in a request to end the session.

[0206] Example 3: Stimulating muscle contraction for the treatment of arthritis Osteoarthritis (OA) of the knee is a progressive, age-related condition that can lead to pain, disability, and ultimately, knee replacement surgery. It is the leading cause of chronic disability in people over the age of 50, leading to a cycle of increasing pain, weakness, and more pain. Knee OA carries a heavier burden than any other disease, as it results in the inability to walk, climb stairs, and perform household chores.

[0207] In addition to the effects on the skeletal structure, OA also affects the neuromuscular system. Patients often suffer from quadriceps weakness, i.e., knee extensor muscles. Muscle weakness can be associated with decreased muscle mass and / or reduced neural drive to the quadriceps. Quadriceps weakness is associated with decreased proprioception, joint stability, and shock absorption, leading to further joint degeneration and subsequent pain.

[0208] Treatment for knee osteoarthritis aims to relieve pain and improve functional measures such as strength, neuromotor control, and range of joint motion. Primary therapy is exercise or supervised physical therapy, aimed at improving knee extensor muscle strength. However, pain and joint stiffness can make it difficult for patients to participate in traditional strength training and physical therapy programs. Pain can lead to an inadequate amount of strength training. In addition, supervised exercise therapy is labor-intensive, time-consuming, expensive, and often difficult for patients to travel to. Many patients with osteoarthritis are largely sedentary and are reluctant or unable to maintain a long-term physical therapy program.

[0209] The muscle contraction stimulation system 10 and method described herein may be used to treat OA in many patients. The system 10 and method 40 may be used to increase strength, endurance, neural drive, activation time, proprioception, muscle architecture, muscle thickness, cross-sectional area, fiber bundle length, biomechanics, and strength of tendons, ligaments, fascia, connective tissue, and soft tissue. Treatment with the system 10 may increase muscle strength, promote faster walking, and make it easier for individuals to perform daily activities, such as rising from a seated position or climbing stairs, without worsening knee pain. Stronger knee extensors are believed to reduce force exertion at the knee joint, which may reduce mechanical stimulation associated with pain.

[0210] The effectiveness of exercise (and NMES) in treating OA is related to frequency, intensity, and program duration. Poor compliance, shorter treatment sessions, reduced repetitions, or suboptimal levels of muscle contraction will reduce the effectiveness of the exercise program. The system 10 and method 40 are configured to enable longer treatment sessions, longer overall treatment program duration, and simpler and easier prescription regimens for patients to follow and adhere to. When used for OA therapy, the system 10 may include one or more sensors 15, 14 specific to joint measurements, such as a goniometer. In some embodiments, the system 10 may be used to determine target joint flexion and / or extension before or during therapy. A stimulator 11, such as a skin patch 12, may be placed on any or all of the major muscle groups of the lower extremity. In some embodiments, it may be advantageous to stimulate antagonist muscles, such as the hamstrings, to balance quadriceps muscle contraction.

[0211] One embodiment of a contraction stimulation system for OA would use a 20-75 Hz twitch wave frequency with an on-time of 4-10 seconds and an off-time of 4-10 seconds. For hip OA or rehabilitation after hip surgery, the gluteal muscles would be stimulated. For knee OA or rehabilitation after knee surgery, the quadriceps or both the quadriceps and hamstrings would be stimulated.

[0212] The simulator 11 may also, in alternative embodiments, include a single femoral nerve stimulator or one or more implanted electrodes, for example, anchored to the inguinal ligament or positioned in the femoral vein near the femoral nerve. Because the femoral nerve innervates muscles that extend the knee, the femoral nerve may be stimulated to directly capture multiple muscles instead of stimulating their individual neuromuscular junctions. Because the nerve is positioned closer to the skin near the groin area, a stimulator patch may be placed there, as shown in FIGS. 25A and 25B. In particular, in FIG. 25A, a skin patch 12 constructed in accordance with the present invention is positioned near the groin area. FIG. 25B depicts the underlying anatomy of the skin S, on which the skin patch 12 is placed, including the femoral nerve FN, femoral artery FA, ​​femoral vein FV, femoral sheath FS, fat pad F, inguinal ligament IL, fascia iliaca FI, iliopsoas muscle IM, and pubic muscle PM. Nerve depth within this region is known to be between 2 and 7 cm, depending on the individual's body mass index (BMI), with most of the variation due to the thickness of the fat layer beneath the skin.

[0213] Stimulation may also be applied to different muscles and coordinated to minimize lateral and rotational forces on the knee joint, for example, using feedback from one or more accelerometers. Any of the safety features and sensors described above may be employed, including an automatic shut-off function that stops stimulation when the patient stands or walks, for example. Some embodiments may use electrical impedance spectroscopy to measure the extent of swelling in and around the knee joint, which may be used as feedback to determine when to terminate, pause, or adjust therapy. These and other features of system 10 and method 40 may be applied not only to the treatment of knee OA, but also to the treatment of any other joint, such as, but not limited to, the shoulder, elbow, hip, and ankle joint.

[0214] Theoretical modeling and experimental results A series of studies were conducted to assess the feasibility of the muscle contraction stimulation system and method of the present invention, including theoretical analysis of current distribution in tissue, finite element analysis, in vitro studies using physical models, and in vivo experiments in human subjects. These studies are described below.

[0215] To determine the potential for reducing inadvertent stimulation of sensory nerves by reconfiguring the stimulation electrode to a laterally adjacent position, a mathematical model of current transmission within tissue was developed, which is depicted in FIG. 26. In this model, the lateral impedance parallel to the skin surface is represented using a resistor labeled R1, while the impedance normal to the skin surface is modeled as a resistor labeled R2. A current source 421 is assumed to inject current into a node labeled V1, and the node to be avoided is labeled V2. For this study, the return electrode is positioned away from node V1; therefore, current flow is assumed to flow primarily into the tissue. The ratio V2 / V1 therefore corresponds to the reduction in stimulation amplitude as one moves laterally away from the node to be avoided.

[0216] The geometry of the model shown in FIG. 26 is symmetric and can be simplified to the model shown in FIG. 27A, where R Y The resistors labeled as represent the impedance experienced by the current as it progresses downward into the tissue. Because a single node V2 is of interest, only half of the resistor ladder need be studied without loss of accuracy, as shown in FIG. 27B. The resistor ladder in FIG. 27B is infinite, meaning it spans infinity. At each step of the ladder, there is another infinite resistor ladder extending to the right of the diagram. Furthermore, the infinite resistor ladder seen at each step of the ladder is the same, R X It can be expressed as R X The value of may be determined as follows:

[0217] [ka]

[0218] [ka]

[0219] [ka]

[0220] [ka]

[0221] [ka]

[0222] R X When solved, we get the following:

[0223] [ka]

[0224] or

[0225] [ka]

[0226] Negative resistance is not possible, so:

[0227] [ka]

[0228] Once R X Once the value of V is determined using the above equation, the model can be further simplified as depicted in Figure 27C. The ratio V / V can then be calculated as follows:

[0229] [ka]

[0230] Inspection of the above equation shows that the ratio V2 / V1 is always less than 1, indicating that the excitation at the node to be avoided, i.e., V2, will always be less than that at the node of stimulation, i.e., V1. To estimate the numerical value of the reduction, the resistance in all directions can be assumed to be constant, i.e.,

[0231] [ka]

[0232] Equations 8 and 10 can then be combined to give:

[0233] [ka]

[0234] and

[0235] [ka]

[0236] Combining equations 9 and 11 gives:

[0237] [ka]

[0238] Thus, the numbers produced by Equation 13 show that displacement of the electrode from a single node to another node reduces the excitation amplitude to less than 40 percent of its original value.

[0239] Based on the results of the aforementioned theoretical analysis, a numerical simulation using a computerized model was performed to evaluate the usefulness of modifying the electrode segment pattern and altering the path taken by the current. The results of the simulation are depicted in Figures 28A and 28B, which were generated using a custom finite-difference program to solve the 2D Laplace equation using the calculus of variations. The computerized simulation was performed using a 70 x 70 grid, resulting in 4,900 equally spaced nodes encompassing 9,522 triangular elements. Figure 28A depicts the current density lines for a pair of electrode elements A and B used to deliver current into the tissue, while C and D formed the counterelectrode. As shown in Figure 28A, the electrode and counterelectrode were positioned symmetrically and formed mirror images across the vertical axis. The outer circle represents the skin surface for the simulated tissue. The curve within the circle, along with scaled values, represents the region where the current density is uniform. The letter "T" within the circle represents the location of the target motor nerve. As can be observed from Figure 28A, a stimulation current with a relative amplitude of 100 reaches the target location "T." The letter "S" represents a sensory nerve that, when stimulated, results in an unacceptable pain sensation. As shown in Figure 28A, the amplitude of the current intensity at sensory nerve location S is approximately 300 units, corresponding to an unacceptably high pain level.

[0240] Referring now to FIG. 28B, electrode element C is turned off and electrode element D is paired with E. In this case, the electrode pair is no longer positioned symmetrically across the vertical axis, and the resulting current path is altered. Target location "T" still receives stimulation at an amplitude of 100 relative units. However, sensory nerve "S" now receives stimulation at an amplitude of less than 200 relative units, far below the amount of excitation at that location compared to the electrode arrangement of FIG. 28A.

[0241] FIG. 29 depicts the variation of the maximum current path for the electrode arrangements of FIGS. 28A and 28B. Again, for both cases, current enters the tissue from the electrodes formed by the elements of the pair labeled A and B. For the return electrode formed by electrode pair C and D, the maximum current path is depicted by a gray square. For the return electrode formed by electrode pair D and E, the maximum current path is depicted by a black diamond. As explained above, the current path is shaped by the selection of the active electrode. FIG. 30 graphically depicts the advantage of the ability to modify the maximum current path when applied to a human leg and includes an image of the maximum current path calculated using finite difference methods superimposed over a cross-section of a human leg.

[0242] The results from the computational study were further evaluated using an in vitro model. This saline model allowed measurements to be made using an 18 x 18 grid resulting in 158 elements, using a conductive material to represent tissue. Data collected during the in vitro study are presented in Figures 31A and 31B. Again, a trace of uniform current intensity was plotted inside the test area, demonstrating that the current path could be modified as predicted during the computational study of Figures 28A and 28B.

[0243] To further demonstrate the usefulness of current path shaping, an in vivo study was conducted. In this case, two sets of electrodes, four in each set, were positioned on the left leg of an experimental subject, as shown in FIG. 32. Four electrodes 431, 432, 433, and 434 were located near the knee and connected in parallel to form one polarity for stimulation. The remaining four electrodes, 436, 437, 438, and 439, were employed to form the opposing polarity. Once the stimulation voltage rose above 22 volts, the subject reported a pain sensation near the knee. Then, the electrodes near the knee, i.e., 431, 432, 433, and 434, were each disconnected one at a time, and the subject was asked to describe their level of pain each time. When electrode 434 was disconnected, the discomfort was eliminated, and the stimulation amplitude was increased until a tetani muscle contraction could be observed without any pain perceived by the subject.

[0244] The experiments described above, i.e., theoretical analysis of current distribution in tissue, finite element analysis on a digital computer, in vitro studies using physical models, and acute in vivo studies using eight electrodes, all demonstrate the feasibility of shaping tissue and current pathways and steering stimulation to neuromuscular targets while avoiding stimulation of pain sensors.

[0245] In a further investigation of functional outcomes, two healthy Caucasian adult men consumed a prescribed diet for two consecutive nights and fasted overnight. The following morning, blood samples were taken to measure fasting plasma insulin (FPI) and fasting plasma glucose (FPG) concentrations, which were then used to calculate a baseline HOMA-IR score as follows:

[0246] HOMA-IR=(FPI(mU / L)×FPG(mmol / L)) / 22.5[Equation 14]

[0247] where FPI is the fasting plasma insulin concentration and FPG is the fasting plasma glucose concentration, both measured from blood samples.

[0248] The HOMA-IR score can be interpreted as follows:

[0249] A HOMA-IR<2 indicates normal insulin resistance.

[0250] HOMA-IR2-3 is an indicator of early insulin resistance.

[0251] HOMA-IR3-5 is an indicator of moderate insulin resistance.

[0252] A HOMA-IR>5.0 is an indicator of severe insulin resistance.

[0253] Two days later, both subjects were implanted into the Empi Continuum via separate lead wires. TM Two 1-inch square saline-soaked sponges connected to a neuromuscular stimulator were used to identify motor points for acceptable transcutaneous muscle stimulation of the quadriceps. The areas were dried and marked with ink, and adhesive electrodes were then applied to these locations. Motor points were also identified on the hamstrings, and electrodes were placed. Neuromuscular electrical stimulation was applied overnight to the quadriceps and hamstrings of both legs while the subjects slept. A second venous blood draw was performed the following morning for measurement of FPI and FPG concentrations and calculation of HOMA-IR scores, producing the results listed in Table 1. These study data demonstrate that, for healthy subjects, neuromuscular electrical stimulation reduced the subjects' HOMA-IR scores from baseline. It is expected that HOMA-IR score improvement will be similar to or better than that for subjects with moderate or severe baseline insulin resistance. [Table 1]

[0254] In another study conducted by the inventors, two electrodes were placed across the quadriceps muscle of a male subject's left leg, as depicted in FIG. 33. The subject was seated on the floor with his leg extended so that all contractions were isovolumic, i.e., contractions did not result in significant muscle shortening. The stimulator was programmed to produce biphasic pulses lasting 400 microseconds at 50 Hz. Between pulse trains, stimulation was turned off for 2 seconds, and then the amplitude of the stimulation pulses increased for 2 seconds. Stimulation was then kept on for a total of 3 seconds before being decreased for a 1-second interval, which in turn was followed by another 2-second interval of off time before the start of the next stimulation cycle.

[0255] It was noted that stimulation with an amplitude of 30 volts produced muscle tremors, indicating that stimulation at 30 volts was below that required for maximal contraction. Full-strength contractions were observed when the stimulation amplitude was increased to 35 volts. Figure 34 shows a time-domain trace of the MMG signal over a portion of a single cycle, while Figure 35 shows the corresponding frequency-domain trace. It can be observed that the dominant power in the MMG signal remains at the stimulation frequency, 50 Hz, with harmonic integer multiples of 50 Hz, i.e., 100 Hz, 150 Hz, 200 Hz, etc.

[0256] 36 and 37, the signal from the MMG sensor, applied as shown in Fig. 33, increases as the strength of the contraction increases. Thus, the control unit may be programmed to increase the stimulation amplitude until there is no corresponding increase in the MMG signal, indicating that the maximum contraction condition has been reached.

[0257] More specifically, Figure 36 shows the root mean square (RMS) values ​​of the MMG signal for each cycle of the stimulation experiment when the stimulation amplitude was increased to 30 volts, resulting in tremor but not full muscle contraction. Figure 37 shows the power values ​​of the MMG signal during each cycle. Three traces, one for 50 Hz, one for 100 Hz, and one for 150 Hz, were generated by adding the power values ​​for all frequencies within + / - 5 Hz of the selected frequency. For example, the trace for 50 Hz shows the total power within the range of 45 Hz to 55 Hz. From the traces shown in Figures 36 and 37, it can be observed that the submaximal contractions do not show a clear trend over time.

[0258] 38 and 39 show that the signal from the MMG sensor decreased as the strength of the contraction decreased as a result of muscle fatigue. This information is processed by the control unit, and therapy can be paused or terminated when a muscle fatigue condition is detected. More specifically, FIG. 38 shows the root mean square (RMS) values ​​of the MMG signal in each cycle of the stimulation experiment when the stimulation amplitude is increased up to 35 volts, resulting in full muscle contraction, as described above. FIG. 39 shows the power values ​​of the MMG signal during each cycle. As can be observed from the traces shown in FIGS. 38 and 39, the maximum contraction exhibits a decay function, reaching a steady state within approximately 2 minutes of repeated contractions as the muscle fatigues.

[0259] IMPLANTABLE MUSCLE STIMULATION SYSTEM AND METHODS The muscle contraction stimulation systems of the foregoing embodiments are generally directed to transepidermal stimulation, in which a skin patch is applied to the patient's skin. In alternative embodiments constructed in accordance with the principles of the present invention, pain sensations may be alleviated by subcutaneously implanting the electrodes used to stimulate the muscles, with power supplied either via an implantable power source or wirelessly, for example, by inductive energy transfer.

[0260] Referring now to FIG. 40 , an implantable device 600 is described. The implantable device 600 includes four electrodes 604a, 604b, 604c, and 604d and may be powered using a battery or via an externally applied radio frequency (RF) signal received by a circuit 630 with coils T1 and T2. Coils T1 and T2 may also be for communication with an external device, such as a patient interface unit. Coils T1 and T2 may be constructed on different planes, preferably positioned orthogonally, to form a diversity receiver, which improves communication with external devices positioned along different planes. Energy received by the coils is stored on a capacitor 628 until needed to generate stimulation to be delivered to tissue. A processor 624 controls the operation of the implantable device 600 and communication with external devices. Once implanted in tissue, the device 600 remains anchored to the targeted tissue using hooks 622a, 622b, 622c, and 622d.

[0261] In one preferred embodiment, implantable device 600 has a 4 mm (12 French) diameter and a 4 cm length, although other external dimensions may also be used. Implantable device 600 advantageously positions the electrodes in proximity to the target motor nerve, thereby reducing the risk of unintentional stimulation of sensory nerves. Furthermore, because migration of implantable device 600 is minimized by the presence of hooks 622 a, 622 b, 622 c, and 622 d, potential errors caused by mispositioning the electrodes are significantly reduced.

[0262] FIG. 41A depicts a radial cross-section of a human leg, while FIG. 41B depicts the same radial cross-section with multiple implanted devices 600. For this embodiment, an external coil used to energize and communicate with implantable device 600 is secured on clothing 610 worn by the patient. The external coil is controlled by an external controller 612, which communicates with the implantable device's controller 624 via a receiver 630. FIG. 42 illustrates a patient's leg into which implantable device 600 is implanted and a transceiver coil 602, which may be held in place by gravity, a strap, or suitable clothing. The transceiver coil 602 is coupled to the external controller 612, which may provide stimulation parameters, operational control, or energy for implantable device 600.

[0263] Referring now to FIG. 43 , an alternative mode of activation of a muscle contraction stimulator 600 implanted within a patient P using an external electronic controller is described. In this example, the patient is reclining on a bed 618 that includes an external coil 620 that couples to a receiver 630 of the implantable device 600. This particular arrangement allows a patient with the implantable device 600 to receive therapy benefits while resting or sleeping. While FIG. 43 shows the external coil 630 positioned within a bed, it should be understood that the external coil may be contained within any other structure that allows the patient to lie down or sit, including, but not limited to, chairs and couches.

[0264] 44 shows an alternative implantable device embodiment. Implantable device 700 has two ends interconnected by flexible section 701. Flexible section 701 may also be longitudinally extensible, thereby allowing movement of the device anchored therein with the tissue. Implantable device 700 also reduces the potential for hooks 622a, 622b, 622c, and 622d to be subjected to excessive force and breakage or to protrude implantable device 700 through the skin due to unexpected movement effects after implantation.

[0265] 45 depicts a method of implanting implantable device 600. Implantable device 600 is first loaded into a syringe-type deployment device 802, which has a distal opening port 803. Once a medical professional determines that distal opening port 803 is located in the desired location, piston 804 is depressed, expelling implantable device 600 from deployment device 802. Once positioned within tissue, hooks 622a, 622b, 622c, and 622d expand, securing implantable device 600 in place and preventing subsequent migration.

[0266] The foregoing detailed description provides several different embodiments and features of muscle contraction stimulation systems, devices, and methods constructed in accordance with the principles of the present invention. The description of exemplary embodiments is provided for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims. Various modifications, such as, for example, rearrangements of parts, different combinations of components, or the like, may be made to a given embodiment without departing from the scope thereof.

Claims

1. 1. A system for stimulating neural tissue associated with one or more skeletal muscles of a subject, the system comprising: A number of electrodes; switching circuitry coupled to the plurality of electrodes; a stimulation circuit operably coupled to the switching circuit; a physiological sensor device configured to generate an output indication of a physiological parameter based on monitoring by the physiological sensor device of the subject's physiological parameter corresponding to a stimulation treatment session; a processor operatively and communicatively coupled to the stimulation circuit, the switching circuit, and the physiological sensor device, the processor being programmed to configure the switching circuit to provide electrical stimulation for excitation of skeletal muscles of the subject by selecting a subset of the number of electrodes, the electrical stimulation being provided to neural tissue associated with one or more skeletal muscles; the processor being programmed to automatically determine whether the output indication from the physiological sensor device indicates an adverse physiological response to the stimulation by analyzing the output indication from the physiological sensor device to apply one or more criteria; and to respond to the output indication of the adverse physiological response to the stimulation when the output indication from the physiological sensor device indicates the adverse physiological response to the stimulation; a patient interface unit configured to allow the subject to provide input to the processor, switching circuitry, and stimulation circuitry; and A system comprising:

2. 10. The system of claim 1, further comprising a physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus comprising at least one of hypoglycemia, skeletal muscle dysfunction, cardiovascular dysfunction, tissue ischemia, or lactate accumulation.

3. 2. The system of claim 1, wherein the physiological sensor device comprises an ECG sensor that provides the output indication, and wherein the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication based on at least one of an elevated heart rate, a shortened QT interval, a "peaked" T wave, a narrowed QRS complex, a prolonged PR interval, a loss of P waves, a widened QRS complex, a characteristic morphology of an ECG signal, a "sine wave" morphology, T-wave flattening, T-wave inversion, the appearance of U-waves, a long ST interval duration, ST depression, or at least one ECG indication of hyperkalemia, rhabdomyolysis, hypocalcemia, or ischemia.

4. 2. The system of claim 1, wherein the physiological sensor device comprises a lactate sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication based on at least one of a lactate level or a lactate level rising above a specified threshold level.

5. 2. The system of claim 1, wherein the physiological sensor device comprises a muscle fatigue sensor that provides the output indication, the processor is configured to automatically determine the adverse physiological response to stimulation from the output indication based on a physiological parameter indicative of muscle fatigue, and the processor adjusts operation of the stimulation circuit in response to the output indication of muscle fatigue.

6. 2. The system of claim 1, wherein the physiological sensor device provides the output indication to the processor, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

7. 2. The system of claim 1, wherein the physiological sensor device comprises a vital signs monitor that provides the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

8. 2. The system of claim 1, wherein the physiological sensor device comprises a glucose sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication based on a change in glucose.

9. 10. The system of claim 1, wherein the processor is programmed to automatically determine an adjusted set of stimulation values ​​for use with the stimulation circuit in response to the adverse physiological response to the stimulation.

10. 2. The system of claim 1, wherein the physiological sensor device comprises an ischemia sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication based on an indication of muscle ischemia.

11. 2. The system of claim 1, wherein the physiological sensor device comprises an oxygen sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication based on an in vivo indication of oxygen.

12. 2. The system of claim 1, wherein the physiological sensor device comprises a blood pressure sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response from the output indication based on a change in blood pressure.

13. 10. The system of claim 1, wherein the physiological sensor device comprises a temperature sensor providing the output indication, and the processor is configured to automatically determine the adverse physiological response from the output indication based on a change in body temperature.

14. 2. The system of claim 1, wherein the physiological sensor device is configured to generate the output indication of the subject's physiological parameter based on monitoring the subject's physiological parameter corresponding to a stimulation therapy session, the physiological parameter being correlated with insulin sensitivity and including an indication of at least one of skin sympathetic nerve activity, motor nerve conduction velocity, R-R interval, homeostasis model assessment of insulin resistance, or muscle capture threshold.

15. The system of claim 1 , further comprising the physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus, including hypoglycemia.

16. The system of claim 1 , further comprising the physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus including muscle dysfunction.

17. The system of claim 1 , further comprising the physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus comprising cardiovascular dysfunction.

18. The system of claim 1 , further comprising a physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus comprising tissue ischemia.

19. The system described in claim 1, further comprising a physiological sensor device coupled to the processor for monitoring or detecting the adverse physiological response to a stimulus including lactic acid accumulation.

20. 2. The system of claim 1, wherein the physiological sensor device comprises an impedance device that provides the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

21. 2. The system of claim 1, wherein the physiological sensor device comprises an MMG device that provides the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

22. 2. The system of claim 1, wherein the physiological sensor device comprises an infrared sensor that provides the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

23. 2. The system of claim 1, wherein the physiological sensor device comprises an EMG device that provides the output indication, and the processor is configured to automatically determine the adverse physiological response to the stimulus from the output indication and to control application of the electrical stimulus by the stimulation circuit in response to the output indication of the adverse physiological response to the stimulus.

24. 1. A system for stimulating neural tissue associated with one or more skeletal muscles of a subject, the system comprising: A number of electrodes; switching circuitry coupled to the plurality of electrodes; a stimulation circuit operably coupled to the switching circuit; a physiological sensor device configured to generate an output indication of an adverse physiological response corresponding to the stimulation treatment session; a processor operatively and communicatively coupled to the stimulation circuitry, the switching circuitry, and the physiological sensor device, the processor being programmed to analyze the output indication and respond to the output indication of the adverse physiological response to the stimulation by terminating or otherwise adjusting the stimulation therapy session when the output indication from the physiological sensor device indicates the adverse physiological response to the stimulation; a patient interface unit configured to allow the subject to provide input to the processor, switching circuitry, and stimulation circuitry; and A system comprising:

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