Multi-modal stimulation for treating tremor

Abstract

The invention relates to multi-modal stimulation for treating tremor. A peripheral nerve stimulator is provided that stimulates the peripheral nerve to treat idiopathic tremor and other dyskinesia as well as overactive bladder, cardiac dysfunction, and neurotransmitter dysfunction. The peripheral nerve stimulator may be a non-invasive surface stimulator that provides multi-modal optimized therapy. The stimulation may be vibratory, electromechanical, thermal, radiant, electrical, magnetic, electromagnetic, optical, mechanical, chemical, thermal, ultrasonic, radio frequency (RF), acoustic, infrared, ultraviolet, X-ray, and / or microwave. Stimulation may be delivered using an open loop system and / or a closed loop system with feedback. Stimulation may be for one site or several sites.

Description

[0001] This application is a divisional application of Chinese patent application 201980055793.8, filed on June 26, 2019, entitled "Multimodal stimulation for the treatment of tremor".

[0002] Cross-reference to related applications This application is a continuation of U.S. Patent Application No. 16 / 020,876, filed June 27, 2018. U.S. Patent Application No. 16 / 020,876 is a partial continuation of U.S. Patent Application No. 15 / 277,946, filed September 27, 2016. U.S. Patent Application No. 15 / 277,946 is a continuation of U.S. Patent Application No. 14 / 805,385, filed July 21, 2015 (now U.S. Patent No. 9,452,287). U.S. Patent Application No. 14 / 805,385 is a continuation of International Patent Application No. PCT / US2014 / 012388, filed January 21, 2014. International Patent Application No. PCT / US2014 / 012388 claims U.S. Provisional Patent Application No., filed January 21, 2013. Priority is claimed in each of the following: U.S. Provisional Patent Application No. 61 / 754,945, filed March 15, 2013; U.S. Provisional Patent Application No. 61 / 786,549, filed April 25, 2013; U.S. Provisional Patent Application No. 61 / 815,919, filed May 10, 2013; and U.S. Provisional Patent Application No. 61 / 822,215, filed July 23, 2013; each of these patent applications is incorporated herein by reference in its entirety for all purposes (including under 37 CFR § 1.57). All patent publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual patent publication or patent application were specifically and individually indicated to be incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] Essential tremor (ET) is the most common movement disorder, affecting an estimated 10 million people in the United States, and the number is increasing due to an aging population. The prevalence of ET increases with age, rising from 6.3% in the population aged 65 and older to over 20% in the population aged 95 and older. ET is characterized by involuntary oscillatory movements, typically between 4 and 12 Hz. It (ET) produces vocal oscillations as well as involuntary movements of the head and limbs. Tremors are particularly common in the hands and forearms, and can cause problems by making writing, typing, eating, and drinking difficult. Unlike Parkinson's tremor, which is present at rest, essential tremor is postural and kinetic, meaning the tremor is caused by holding the limbs individually under the influence of gravity or during movement.

[0004] The disabilities associated with tremor tremor are varied and range from embarrassing to an inability to live independently, such as when tasks like writing and feeding oneself are impossible due to uncontrolled movements of the hands and arms. Despite the high prevalence and severe disability among many tremor patients, there are still insufficient treatment options to address the tremor.

[0005] It has been found that medications used to treat tremor (e.g., propranolol and primidone) are effective in reducing tremor amplitude by 50% in only 60% of patients. The side effects of these medications can be severe, and many ET patients cannot tolerate them. An alternative therapy involves surgically implanting a stimulant in the brain using deep brain stimulation (DBS), which can effectively reduce tremor amplitude by 90%. However, this is a highly invasive surgical procedure with significant risks, and many ET patients cannot tolerate it. Therefore, there is an urgent need for alternative therapies for ET patients that can reduce tremor without the side effects of medication or the risks of brain surgery.

[0006] Tremor is also a significant issue for patients with orthostatic tremor, multiple sclerosis, and Parkinson's disease. A variety of neurological disorders include tremor (e.g., stroke, alcoholism, alcohol withdrawal, peripheral neuropathy, Wilson's disease, Creutzfeldt-Jakob disease, Guillain-Barré syndrome, and Fragile X syndrome) as well as brain tumors, hypoglycemia, hyperthyroidism, hypoparathyroidism, insulinoma, normal aging, and traumatic brain injury. Stuttering or stammering is also a form of tremor. The underlying causes of tremor in these cases may differ from those in ET; however, treatment options are often limited in some of these cases, requiring alternative therapies. Summary of the Invention

[0007] Tremor tremor (ET) is thought to be caused by abnormalities in the dynamics of the circuits associated with movement generation and control. Previous work has shown that cooling, local analgesics, and vibration can temporarily alter these circuit dynamics. Previous work reported that electrical stimulation using transcutaneous electrical nerve stimulation (TENS) did not improve tremor (Munhoz 2003). Therefore, it is surprising that in our clinical study we found that the circuit dynamics associated with ET could be altered by peripheral nerve stimulation, resulting in a significant reduction in tremor in individuals with ET.

[0008] Several embodiments include novel peripheral stimulation devices that send signals along sensory nerves to the central nervous system to modify aberrant network dynamics. Over time, this stimulation normalizes neural firing in the aberrant network and reduces tremor. While DBS directly stimulates the brain, our peripheral stimulation influences aberrant brain circuit dynamics by sending signals along sensory nerves that connect the peripheral nervous system to the brain. This approach is non-invasive and promises to avoid the surgical risks of DBS and the problems associated with cognitive, declarative, and spatial memory dysarthria, ataxia, or gait disturbances. Peripheral nerve stimulation can effectively treat tremor by dephase, covering, or masking aberrant brain circuit dynamics. Following the assumptions of traditional DBS mechanisms, the brain is covered, masked, or trained to ignore aberrant brain circuit dynamics.

[0009] Perhaps the technique most closely related to our approach is transcutaneous electrical nerve stimulation (TENS). High-frequency TENS (50 to 250 Hz) is commonly used to treat pain, based on the assumption that activation of large, myelinated peripheral proprioceptive fibers (A-β) blocks incoming pain signals. Although inconsistent clinical results obtained using TENS for pain control have led many to question its use in pain management, there is ample evidence that surface electrical stimulation activates A-β neurons. A-β neurons transmit proprioceptive sensory information to the same brain circuits that are abnormal in diseases including ET and Parkinson's disease. Unrestricted by any proposed mechanism of action, this leads us to propose that nerve stimulation can be used to activate A-β neurons and thereby improve tremor. This proposal is particularly surprising because previous studies by Munhoz et al. failed to find any significant improvement in any tremor parameters tested after TENS application. See Munhoz et al., “Acute Effect of Transcutaneous Electrical Nerve Stimulation on Tremor”, published in Movement Disorders (2003, 18(2): 191-194).

[0010] Several embodiments disclosed herein relate to systems, devices, and methods for treating tremor, and more specifically to systems, devices, and methods for treating tremor by stimulating peripheral nerves.

[0011] In some embodiments, a method for reducing tremor in a patient is provided. The method includes placing a first peripheral nerve effector at a first location relative to a first peripheral nerve; delivering a first stimulus to the first peripheral nerve via the first peripheral nerve effector; and reducing the amplitude of the tremor by modifying the patient's neural network dynamics.

[0012] In some embodiments, the placement step includes placing a first peripheral nerve effector on the patient's skin, and the first stimulation is an electrical stimulation applied to the skin surface. In some embodiments, the first stimulation has an amplitude of about 0.1 mA to 10 mA or higher (e.g., 15 mA) and a frequency of about 10 to 5000 Hz or higher. In some embodiments, the first stimulation has an amplitude less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mA (e.g., between about 0.1 mA and about 1 mA, between about 0.1 mA and about 2 mA, between about 0.1 mA and about 3 mA, between about 0.1 mA and about 4 mA, between about 0.1 mA and about 5 mA, between about 0.1 mA and about 6 mA, etc.). Between approximately 0.1 mA and approximately 7 mA, between approximately 0.1 mA and approximately 8 mA, between approximately 0.1 mA and approximately 9 mA, between approximately 0.1 mA and approximately 10 mA, between approximately 0.1 mA and approximately 11 mA, between approximately 0.1 mA and approximately 12 mA, between approximately 0.1 mA and approximately 13 mA, between approximately 0.1 mA and approximately 14 mA, between approximately 0.1 mA and approximately 15 mA, or other ranges between such values. In some embodiments, the first stimulus has a frequency between about 10 Hz and about 20 kHz (e.g., about 10 Hz, about 20 Hz, about 30 Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 100 Hz, about 250 Hz, about 500 Hz, about 1000 Hz, about 2500 Hz, about 5000 Hz, about 10 kHz, about 15 kHz, about 20 kHz, and ranges between such values).

[0013] In some embodiments, the placement step includes implanting a first peripheral nerve effector into the patient, and the first stimulation is electrical stimulation. In some embodiments, the implantation step includes injecting the first peripheral nerve effector into the patient. In some embodiments, the first stimulation has an amplitude of less than about 3 mA and a frequency of about 10 to 5000 Hz. In some embodiments, the first stimulation has an amplitude of less than about 5, 4, 3, 2, or 1 mA (e.g., between about 0.1 mA and about 1 mA, between about 0.1 mA and about 2 mA, between about 0.1 mA and about 3 mA, between about 0.1 mA and about 4 mA, between about 0.1 mA and about 5 mA, or in other ranges between such values). In some embodiments, the first stimulus has a frequency between about 10 Hz and about 20 kHz (e.g., about 10 Hz, about 20 Hz, about 30 Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 100 Hz, about 250 Hz, about 500 Hz, about 1000 Hz, about 2500 Hz, about 5000 Hz, about 10 kHz, about 15 kHz, about 20 kHz, and ranges between such values).

[0014] In some embodiments, the peripheral nerve effector includes a power source. In some embodiments, the method further includes wirelessly powering the first peripheral nerve effector via an externally located power source.

[0015] In some embodiments, the first stimulus includes vibratory tactile stimulation. In some embodiments, the first stimulus includes chemical stimulation. In some embodiments, the first stimulus includes mechanical, vibratory, electromechanical, thermal, radiative, electrical, magnetic, electromagnetic, optical, acoustic, ultrasonic (e.g., focused ultrasound), chemical, infrared, radio frequency (RF), ultraviolet, X-ray, or microwave stimulation. In some embodiments, the second or third stimulus is the same as the first stimulus but at a different location on the body. In other embodiments, the second or third stimulus is different from the first stimulus and at the same or different locations on the body. For example, the first stimulus is applied to the wrist and different second stimuli are applied to different locations. Alternatively, the first stimulus is applied to a first location (e.g., the wrist) and different second stimuli are applied to the same first location. The same or different nerves may be stimulated at the first location. For example, in some embodiments, different nerves (or multiple location points) in a region may be stimulated. In several embodiments, instead of or in addition to being applied to the skin surface, stimulation or other neuromodulation may be applied internally (e.g., partial or complete implantation of a device, oral delivery, etc.).

[0016] In some embodiments, a multimodal approach (whether or not it involves multiple locations, multiple types of the same stimulus, or multiple stimuli, or combinations thereof) is beneficial by reducing habituation, improving efficacy, enhancing the specificity of preferentially stimulated nerve fibers, utilizing other non-energy-based therapies (e.g., pharmacological therapies) to produce synergistic effects, increasing stimulation efficiency to influence neural circuits, and / or reducing the amount or duration of at least one stimulus) can be employed. For example, treatment performed on the wrist and second locations (e.g., ankle, ear, finger, etc.) may result in faster reduction of tremor, longer duration of tremor reduction, delivery of stimulation with an overall reduction in stimulus amount, improved patient compliance, etc. In another example, using different points in the same region can provide similar beneficial results (e.g., different points on the wrist). In one embodiment, the distance between different points in the same region is within approximately 5 mm, 25 mm, 50 mm, 100 mm, and 200 mm (e.g., on the wrist or ankle). In other embodiments, the distance between different points in the same region is within approximately 0.25 feet to 4 feet (e.g., on the leg).

[0017] In many embodiments, a multimodal approach is used to treat essential tremor. In some embodiments, a multimodal approach is used to treat dystonia, Parkinson's disease, and other movement disorders. In several embodiments, tremors of the hands, legs, head, neck, and / or voice are treated in the same individual. In other embodiments, a patient with hand tremors or leg tremors is treated.

[0018] In some embodiments, compared to a single-modal approach or no treatment, a multimodal approach reduces the time required to achieve efficacy (e.g., tremor reduction) by 10-75% or increases the duration of therapeutic effect by 10-75%. For example, in some embodiments, a multimodal approach can reduce tremor during stimulation and at time points 30 minutes, 1-2 hours, and 6 hours or longer after stimulation. In some embodiments, stimulation is provided once, twice, three times, four times, five times, or more per day. In several embodiments, a multimodal optimization method using feedback is provided.

[0019] In some embodiments, the method further includes: using a measurement unit to sense movement of the patient's limbs to generate motion data; and determining tremor information from the motion data. In some embodiments, delivery includes delivering a first stimulus based on tremor (or other) information. In some embodiments, the information (e.g., tremor information) includes the maximum deviation from the resting position of the patient's limbs. In some embodiments, the information (e.g., tremor information) includes the resting position of the patient's limbs. In some embodiments, the tremor information includes tremor frequency, phase, and amplitude.

[0020] In some embodiments, delivering the first stimulus includes delivering a plurality of stimulus bursts with a variable time delay between the stimulus bursts.

[0021] In some embodiments, the method further includes: placing a second peripheral nerve effector at a second location relative to a second peripheral nerve; and delivering a second stimulus to the second peripheral nerve via the second peripheral nerve effector. According to several embodiments, the effector is placed at two or more points on the same general area (e.g., the wrist), or at two or more locations (e.g., the wrist and ankle).

[0022] In some embodiments, the method further includes determining a time period of tremor or other dysfunction in the patient, wherein delivering the second stimulus includes offsetting the delivery of the second stimulus from the delivery of the first stimulus by a predetermined fraction or multiple of the time period of tremor or other dysfunction. In some embodiments, the method further includes synchronizing the neural networks in the patient's brain. In some embodiments, the second stimulus is positioned at the same location as or different from the first stimulus. The second stimulus may be the same as the first stimulus (e.g., both are electrical or mechanical) or different. The second stimulus may be the same as the first stimulus but have different parameters (e.g., different amplitude, duration, frequency, etc.).

[0023] In some embodiments, the first and second locations are on adjacent fingers. In some embodiments, the first and second peripheral nerves are adjacent nerves. In some embodiments, the first peripheral nerve is the median nerve and the second peripheral nerve is the ulnar or radial nerve. In some embodiments, the first and second peripheral nerves are adjacent in body position.

[0024] In some embodiments, the first stimulus has an amplitude below a sensory threshold. In some embodiments, the first stimulus is greater than 15 Hz. In some embodiments, a first peripheral nerve carries proprioceptive information from the patient's limbs. In some embodiments, the method further includes: determining the duration of the effect of the first stimulus on reducing the amplitude of tremor; and delivering a second stimulus before the duration of the effect expires.

[0025] In some embodiments, determining the duration of an effect includes analyzing multiple stimulation applications applied over a predetermined time period. Stimuli may be applied sequentially (e.g., serially or one after another) and / or at least partially overlapping (e.g., in parallel).

[0026] In some embodiments, determining the duration of efficacy further includes determining a profile of the patient's activity. In some embodiments, determining the duration of efficacy further includes determining a profile of tremor or other functional impairment. In some embodiments, the activity profile includes data on caffeine and alcohol consumption. In some embodiments, the method further includes placing a conduction pathway enhancer on a first peripheral nerve. In some embodiments, the conduction pathway enhancer is a conductive tattoo. In some embodiments, the conduction pathway enhancer includes one or more conductive strips.

[0027] In some embodiments, the first position is selected from the group consisting of the wrist, forearm, carpal tunnel, fingers, and upper arm.

[0028] In some embodiments, a system for treating tremor or other functional impairment in a patient is provided. The device may include: a decision unit; and an interface unit adapted to deliver electrical stimulation to a peripheral nerve, the interface unit including a first peripheral nerve effector in communication with the decision unit, the first peripheral nerve effector including at least one electrode; wherein the decision unit includes a processor and a memory storing instructions, which, when executed by the processor, cause the decision unit to: deliver a first electrical stimulation to a first peripheral nerve via the first peripheral nerve effector, the electrical stimulation being configured by a controller to reduce tremor or other functional impairment in the patient's limbs by modifying the patient's neural network dynamics.

[0029] In some embodiments, the first electrical stimulation has an amplitude of less than about 10 mA or higher (e.g., 15 mA) and a frequency of about 10 to 5000 Hz. In some embodiments, the amplitude is less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mA (e.g., between about 0.1 mA and about 1 mA, between about 0.1 mA and about 2 mA, between about 0.1 mA and about 3 mA, between about 0.1 mA and about 4 mA, between about 0.1 mA and about 5 mA, between about 0.1 mA and about 6 mA, or between about 0.1 mA and about 10 mA). Between mA and about 7 mA, between about 0.1 mA and about 8 mA, between about 0.1 mA and about 9 mA, between about 0.1 mA and about 10 mA, between about 0.1 mA and about 11 mA, between about 0.1 mA and about 12 mA, between about 0.1 mA and about 13 mA, between about 0.1 mA and about 14 mA, between about 0.1 mA and about 15 mA, or other ranges between such values. In some embodiments, the first electrical stimulation has a frequency between about 10 Hz and about 20 kHz (e.g., about 10 Hz, about 20 Hz, about 30 Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 100 Hz, about 250 Hz, about 500 Hz, about 1000 Hz, about 2500 Hz, about 5000 Hz, about 10 kHz, about 15 kHz, about 20 kHz, and ranges between such values).

[0030] In some embodiments, the interface unit further includes a second peripheral nerve effector that communicates with the decision unit. The second peripheral nerve effector includes at least one electrode, wherein the memory stores instructions that, when executed by the processor, further instruct the decision unit to deliver a second electrical stimulation to a second peripheral nerve in the patient's limbs via the second peripheral nerve effector.

[0031] In some embodiments, when the instruction is executed by the processor, the decision unit delivers a second electrical stimulus, the second electrical stimulus being offset from the first electrical stimulus in time by a predetermined fraction or multiple of the time period of tremor or other dysfunction.

[0032] In some embodiments, a first peripheral nerve effector is adapted to be placed on a first finger, and a second peripheral nerve effector is adapted to be placed on a second finger.

[0033] In some embodiments, the first peripheral nerve effector includes a plurality of electrodes arranged in a linear array. In some embodiments, the plurality of electrodes are spaced apart by about 1 to 100 mm. In some embodiments, the first peripheral nerve effector includes a plurality of electrodes arranged in a two-dimensional array. In some embodiments, a memory stores instructions that, when executed by a processor, further cause a decision unit to select a subset of the plurality of electrodes based on the position of the first peripheral nerve effector on a patient's limbs, wherein the selection of a subset of the plurality of electrodes occurs whenever the first peripheral nerve effector is positioned or repositioned on the limbs. In some embodiments, the plurality of electrodes are spaced apart by about 1 to 100 mm along a first axis and by about 1 to 100 mm along a second axis perpendicular to the first axis. In some embodiments, some of the electrodes are adjacent to each other to form a band. In some embodiments, the spacing can be less than about 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2 or 1 mm (e.g., between about 0.1 mm and about 1 mm, between about 1 mm and about 2 mm, between about 1 mm and about 3 mm, between about 1 mm and about 4 mm, between about 1 mm and about 5 mm, between about 1 mm and about 10 mm, between about 1 mm and about 20 mm, between about 1 mm and about 30 mm, between about 1 mm and about 40 mm, between about 1 mm and about 50 mm, between about 1 mm and about 60 mm, between about 1 mm and about 70 mm, between about 1 mm and about 80 mm, between about 1 mm and 90 mm, between about 1 mm and about 100 mm or other ranges between such values).

[0034] In some embodiments, the system further includes a measurement unit, wherein the memory stores instructions that, when executed by a processor, further instruct the decision unit to: use the measurement unit to measure the movement of the patient's limbs to generate motion data; and determine the tremor frequency and magnitude (or other parameters) based on the analysis of the motion data.

[0035] In some embodiments, the analysis of motion data includes frequency analysis of the spectral power of the motion data. In some embodiments, the frequency analysis is limited to about 4 to 12 Hz. In some embodiments, the frequency analysis is limited to about one or more expected frequency ranges of the tremor of interest. In some embodiments, the analysis of motion data is performed within a predetermined time length of the motion data. In some embodiments, the decision unit is also adapted to determine tremor phase information based on the motion data and to deliver a first electrical stimulus based on the tremor phase information. In some embodiments, the tremor phase information includes a peak tremor deviation, and the decision unit is also adapted to deliver the first electrical stimulus at a time corresponding to the peak tremor deviation.

[0036] In some embodiments, for tremor and other indications, the memory stores instructions that, when executed by a processor, further instruct a decision unit to deliver the first electrical stimulation as a plurality of electrical stimulation bursts with a variable time delay between the electrical stimulation bursts. In some embodiments, the memory stores instructions that, when executed by a processor, further instruct the decision unit to set parameters of the first electrical stimulation based on a determined tremor frequency. In some embodiments, the memory stores instructions that, when executed by a processor, further instruct the decision unit to set parameters of the first electrical stimulation based on a determined tremor magnitude value. In some embodiments, the memory stores instructions that, when executed by a processor, further instruct the decision unit to compare the determined tremor magnitude value (or other data) with a predetermined threshold; and wherein the first electrical stimulation is delivered when the determined tremor magnitude value (or other data) exceeds the predetermined threshold. In some embodiments, the electrode is adapted to deliver the first electrical stimulation through the patient's skin. In some embodiments, the electrode is adapted to be implanted and deliver electricity. In some embodiments, the decision unit includes a user interface adapted to receive input from a user for adjusting parameters of the first electrical stimulation. In some embodiments, the memory also stores a library of one or more predetermined stimulation protocols. In some embodiments, the interface unit is integrated with the decision unit. In some embodiments, the interface unit and the decision unit are separate from each other and have separate housings. In some embodiments, the decision unit is configured to wirelessly provide power to or communicate with the interface unit. In some embodiments, the system further includes a measurement unit located in the decision unit. In some embodiments, the system further includes a measurement unit located in the interface unit. In some embodiments, the decision unit is a computing device selected from the group consisting of smartphones, tablets, and laptops. In some embodiments, the system further includes a server communicating with the computing device, the server being configured to receive motion data and a history of electrical stimulation delivered to a patient from the computing device. In some embodiments, the server is programmed to: add the received motion data and the history of electrical stimulation delivered to a patient to a database storing data from multiple patients. In some embodiments, the server is programmed to: compare the received motion data and the history of electrical stimulation delivered to a patient with data stored in the database; determine a modified electrical stimulation protocol based on the comparison of the received motion data and the history of electrical stimulation delivered to a patient with data stored in the database; and transmit the modified electrical stimulation protocol to the computing device. In some embodiments, the electronics are flexible and disposed on a flexible substrate, which may be a sleeve, pad, strap, or other housing.

[0037] In some embodiments, a system for monitoring tremors or other functional impairments in the limbs of a patient is provided. The system may include: an interface unit having an inertial motion unit for capturing motion data, a power supply, and a wireless transmitter and receiver, the interface unit being adapted to be worn on the patient's limbs; and a processing unit communicating with the interface unit, the processing unit being configured to receive motion data from the interface unit. In one embodiment, the processing unit is programmed to determine a tremor signature and profile over a predetermined time period based on analysis of the motion data. In another embodiment, the processing unit is programmed to determine a neural or motor signature and profile over a predetermined time period based on data analysis. In yet another embodiment, the processing unit is disposed in a device or on a remote processor wirelessly communicating with the device, and is programmed to analyze predetermined characteristics of the neural or motor data.

[0038] In several embodiments, the multimodal approach is based on monitoring, wherein a second mode (e.g., the same or different stimulus at a second body position, different stimulus at the same or different body positions, etc.) is provided based on feedback received after a first mode is activated. In some embodiments, the second mode may be a different type of energy (e.g., thermal, mechanical, chemical, etc.) or the same type of energy with different stimulation parameters (e.g., frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, burst, etc.). In some embodiments, a device is provided that adjusts the stimulation modality to enhance efficacy based on predetermined characteristics or features of the subject's previous responses and / or neural or motor data measured from sensors. In some embodiments, one or more sensors are provided to adjust the parameters of the second (or third or more) mode. In some embodiments, this is advantageous in reducing the time required to achieve a therapeutic effect (e.g., reducing it by at least 10%, 25%, 50% or more, or reducing the overlap therein) or prolonging the therapeutic effect (e.g., prolonging it by at least 10%, 20%, 40% or more, or increasing the overlap therein), or improving overall benefit (e.g., a greater reduction in hand tremor levels).

[0039] In some embodiments, the processing unit is a mobile phone. In some embodiments, the system further includes a server communicating with the mobile phone, the server being configured to receive motion data from the mobile phone. In some embodiments, the processing unit is also programmed to compare tremor magnitude or other data with a predetermined threshold. In some embodiments, the processing unit is also programmed to generate an alarm when the tremor magnitude or other factor exceeds the predetermined threshold. In some embodiments, the predetermined threshold may be adjustable by the patient. In some embodiments, the processing unit is programmed to prompt the patient to input activity data, which includes a description of the activity and the time the activity occurred. In some embodiments, the processing unit is programmed to correlate the activity data with determined tremor frequency and magnitude. In some embodiments, the activity data includes caffeine or alcohol consumption. In some embodiments, the activity data includes medication consumption.

[0040] Different stimulation patterns or multimodal stimulation may include stimulation at different locations. Different stimulation patterns or multimodal stimulation may include different types of energy and energy modalities combined with non-energy-based therapies (e.g., pharmacological therapy). Different stimulation patterns or multimodal stimulation may include different stimulation parameters of the same type of energy (e.g., frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, and / or burst). Different stimulation patterns or multimodal stimulation may include different types of stimulation to selectively or preferentially stimulate unique fiber and / or nerve types, including afferent and efferent stimuli. Different stimulation patterns or multimodal stimulation may include several stimulation targets or parameters to preferentially affect one of the limbs of the autonomic nervous system. Different stimulation patterns or multimodal stimulation may include several durations. Different stimulation patterns or multimodal stimulation may include applying different patterns to an array of devices (e.g., a linear array of paired electrodes). Different stimulation patterns or multimodal stimulation may include combinations of two or more of the different patterns described above. In some embodiments, a multimodal system may include multiple stimuli that wirelessly communicate with each other and provide synchronized, patterned stimulation. In some embodiments, several stimuli may be connected to several effectors to simultaneously stimulate several nerves. In one embodiment, a system may include a stimuli targeting the median nerve on the wrist and a stimuli targeting the auricular branch of the vagus nerve in the ear.

[0041] In some embodiments, a system for treating conditions (including but not limited to tremor) is provided, the system comprising: a first stimulator configured to apply a first stimulation pattern to a first peripheral nerve (e.g., a proprioceptor, afferent nerve, A fiber, B fiber, C fiber, etc.); a second stimulator configured to apply a second stimulation pattern to a second peripheral nerve (e.g., a proprioceptor, afferent nerve, A fiber, B fiber, C fiber, etc.); and a control module communicating with the first and second stimulators. In one embodiment, the second stimulation pattern is different from the first stimulation pattern. In another embodiment, the two patterns are identical (e.g., at the same location, both are electrical stimulations, both are excitatory, both are inhibitory, etc.). In some embodiments, three, four, or more patterns may be used. In addition to tremor, overactive bladder and cardiac dysfunction are also treated. In one embodiment, mental illnesses (e.g., neurotransmission dysfunction) are treated.

[0042] In some embodiments, at least one of the first or second stimulus actuators may include an electrical actuator (e.g., a means for delivering electrical stimulation, including, for example, an element, device, mechanism, component, part (e.g., an electrode), influencer, or the like). The electrical part may be transdermal. The electrical part may be subcutaneous. The first stimulus actuator may include a first electrical part. The second stimulus actuator may include a second electrical part.

[0043] The first stimulus pattern may include a first value of the parameter. The second stimulus pattern may include a second value of the parameter that is different from the first value of the parameter.

[0044] Parameters may include at least one of stimulation frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, or burst. Parameters may include stimulation continuity. A first stimulation mode may include bursts. A second stimulation mode may include continuous stimulation. Parameters may include stimulation frequency. A first stimulation mode may include frequencies between 10 Hz and 30 Hz (e.g., 20 Hz). A second stimulation mode may include frequencies between 30 Hz and 50 Hz (e.g., 40 Hz). A first stimulation mode may include frequencies between 100 Hz and 200 Hz (e.g., 150 Hz). A second stimulation mode may include frequencies between 50 Hz and 150 Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be burst-on / off at a frequency between 4 and 12 Hz in an alternating pattern, such as in a burst mode (e.g., 10 Hz). Parameters may include stimulation waveforms. A first stimulation mode may include a first stimulation waveform. A second stimulation mode may include a second stimulation waveform different from the first stimulation waveform.

[0045] At least one of the first or second stimulus actuators may include a thermal device, component, actuator, or portion that increases and / or decreases the internal temperature of adjacent tissue (such as a device for heating and / or cooling (e.g., a resistance heater, piezoelectric cooler, fluid-based temperature space), including, for example, elements, devices, mechanisms, components, portions, influencers, or the like). The thermal device may be configured to apply a cooling effect. The thermal device may be configured to apply a heating effect. A temperature sensor may also be included and provide communication with a processor or control module, with or without feedback influencing cooling or heating.

[0046] At least one of the first or second stimulator actuators may include a vibratory or mechanically actuated actuator (such as a device for vibrating, generating vibrations, and transmitting vibrations to, for example, the skin (e.g., a vibrator, acoustic system, solenoid, bias motor), including, for example, elements, devices, mechanisms, components, or partial influencers, or the like). In some embodiments, a mechanical actuator configured to apply non-vibratory mechanical energy may be activated to apply pressure at a specific location, such as an acupoint. In some embodiments, a pin having a rounded end or other shaped element may be driven by a motor or solenoid to extend from a band worn around a body part into the skin to apply pressure to a nerve (e.g., the median nerve in the case of a wristband). In some embodiments, a band worn around a body part may be driven by a motor or solenoid to increase tension or tighten the band to apply pressure to a nerve (e.g., the median nerve in the case of a wristband). At least one of the first or second stimulator actuators may include a magnetic actuator (such as a device for generating a magnetic field (e.g., a magnet, electromagnet), including, for example, elements, devices, mechanisms, components, partial influencers, or the like). At least one of the first or second stimulus actuators may include a chemical substance (e.g., a drug treatment or lidocaine). At least one of the first or second stimulus actuators may include an ultrasonic (e.g., focused ultrasound) actuator (such as a device for generating ultrasonic energy (e.g., a transducer, piezoelectric element, coupling fluid), including elements, devices, mechanisms, components, parts, influencers, or the like). At least one of the first or second stimulus actuators may include a microwave actuator (such as a device for generating microwave energy (e.g., a microwave generator), including elements, devices, mechanisms, components, or parts, influencers, or the like). In some embodiments, at least one of the first or second stimulus actuators includes an electromagnetic actuator for generating electromagnetic energy, waves, fields, etc. In some embodiments, a third, fourth, or additional stimulus actuator is used in addition to the second stimulus actuator.

[0047] A first stimulus actuator may be configured to be positioned on the subject's wrist. A second stimulus actuator may be configured to be positioned on the subject's fingers. A second stimulus actuator may be configured to be positioned on the subject's ankle. The first position may include the body's arm, while the second position may include the body's leg. The first position may be the body's left arm or left leg, while the second position may be the body's right arm or right leg, to provide bilateral stimulation.

[0048] The system may also include sensors. The control module can be configured to activate at least one of a first stimulation mode or a second stimulation mode when an event is detected.

[0049] In some embodiments, a system for treating a subject's tremor may include a first stimulator actuator and a control module in communication with the first stimulator actuator. The first stimulator actuator is configured to apply a first stimulation pattern and a second stimulation pattern to a first peripheral nerve (e.g., a proprioceptor, afferent nerve, A fiber, B fiber, C fiber, etc.), the first stimulation pattern including a first value of a parameter, and the second stimulation pattern including a second value of the parameter different from the first value of the parameter.

[0050] The first stimulus actuator may include electrodes (e.g., 1-6 or more electrodes). The electrodes may be transdermal or subcutaneous.

[0051] Parameters may include at least one of stimulation frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, or burst. Parameters may include stimulation continuity. A first stimulation mode may include bursts. A second stimulation mode may include continuous stimulation. Parameters may include stimulation frequency. A first stimulation mode may include frequencies between 10 Hz and 30 Hz (e.g., 20 Hz). A second stimulation mode may include frequencies between 30 Hz and 50 Hz (e.g., 40 Hz). A first stimulation mode may include frequencies between 100 Hz and 200 Hz (e.g., 150 Hz). A second stimulation mode may include frequencies between 50 Hz and 150 Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be burst-on / off at a frequency between 4 and 12 Hz in an alternating pattern, such as in a burst mode (e.g., 10 Hz). Parameters may include stimulation waveforms. A first stimulation mode may include a first stimulation waveform. A second stimulation mode may include a second stimulation waveform different from the first stimulation waveform.

[0052] The system may also include a second stimulator actuator. The second stimulator actuator may include electrodes. The second stimulator actuator may include a thermal actuator. The stimulator actuator may be mechanical, vibratory, electromechanical, thermal, radiative, electrical, magnetic, electromagnetic, optical, acoustic, chemical, ultrasonic (e.g., focused ultrasound), infrared, radio frequency (RF), ultraviolet, X-ray, or microwave actuator. Optionally, a sensor may be included, which can alter the neural modulation of various actuators.

[0053] A first stimulator may be configured to be positioned on the subject's wrist. A second stimulator may be configured to be positioned on the subject's fingers or ankle. In one embodiment (e.g., at various points around the wrist, fingers, ankle, etc.), circumferential stimulation is provided using, for example, a bandage, cuff, etc. In some embodiments, the foot, ankle, knee, thigh, back, sacral region, lumbar region, ear, head and / or neck and / or nerve-targeted locations (including the tibial nerve, saphenous nerve, sacral nerve, peroneal nerve, sural nerve, and / or vagus nerve) may be beneficial for treating overactive bladder.

[0054] In some embodiments, a system and method for treating a subject's tremor or other indication includes applying a first stimulus to a first peripheral body site and applying a second stimulus to a second peripheral body site different from the first peripheral body site. The first stimulus includes at least one of electrical stimulation, vibrational stimulation, thermal stimulation, or chemical stimulation. The second stimulus includes at least one of electrical stimulation, vibrational stimulation, thermal stimulation, or chemical stimulation. The second stimulus is different from the first stimulus.

[0055] In some embodiments, a system and method for treating a subject's tremor or other indications includes applying a first stimulus to a first peripheral nerve (e.g., a proprioceptor, afferent nerve, A fiber, B fiber, C fiber, etc.) and applying a second stimulus to a second peripheral nerve (e.g., a proprioceptor, afferent nerve, A fiber, B fiber, C fiber, etc.). The first stimulus includes at least one of electrical stimulation, vibration stimulation, thermal stimulation, or chemical stimulation. The second stimulus includes at least one of electrical stimulation, vibration stimulation, thermal stimulation, or chemical stimulation. In one embodiment, the second stimulus is different from the first stimulus, but in other embodiments it may be the same. In some embodiments, the first stimulus includes at least one of electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibration stimulation, ultrasound stimulation (e.g., focused ultrasound), radiofrequency stimulation, or microwave stimulation, while the second or additional stimulus includes at least one of electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibration stimulation, ultrasound stimulation (e.g., focused ultrasound), radiofrequency stimulation, or microwave stimulation.

[0056] In some embodiments, the first and second (and optionally third, fourth or more) stimuli comprise electrical stimulation. The first stimulus may include a first value of a parameter. The second (and any additional) stimulus may include a second value of the parameter that differs from the first value of the parameter. Parameters may include at least one of stimulation frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, or burst. Parameters may include stimulation continuity. The first stimulation pattern may include bursts. The second stimulation pattern may include continuity. Parameters may include stimulation frequencies. The first stimulation pattern may include frequencies between 10 Hz and 30 Hz (e.g., 20 Hz). The second stimulation pattern may include frequencies between 30 Hz and 50 Hz (e.g., 40 Hz). In one embodiment, the first stimulus is less than 40 Hz and the second stimulus is 40 Hz or higher. In another embodiment, the first stimulus is less than 20 Hz and the second stimulus is 20 Hz or higher. The first stimulation pattern may include frequencies between 100 Hz and 200 Hz (e.g., 150 Hz). The second stimulation pattern may include frequencies between 50 Hz and 150 Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be switched on / off alternately at a frequency between 4 and 12 Hz, such as in a burst mode (e.g., 10 Hz). Parameters may include stimulation waveforms. The first stimulation mode may include a first stimulation waveform. The second stimulation mode may include a second stimulation waveform different from the first stimulation waveform.

[0057] In some embodiments, the first and second (and optionally third, fourth or more) stimuli include chemical stimuli. The first stimulus may include a first neuromodulatory chemical substance. The second (and any additional) stimulus may include a second neuromodulatory chemical substance that is different from the first neuromodulatory chemical substance.

[0058] In some embodiments, the first and second (and optionally third, fourth or more) stimuli comprise mechanical stimulation. In one embodiment, the stimulation has different vibration durations and / or frequencies. In another embodiment, a mechanical actuator is activated to apply controlled pressure to a specific location, such as a target nerve or acupoint. The mechanical actuator may include a linear actuator or a rotary actuator that displaces tissue near the nerve to apply pressure in order to activate proprioceptors in the target area or target nerve.

[0059] In some embodiments, the first and second (and optionally third, fourth or more) stimuli comprise different stimuli at different points in the same region. For example, electrical stimulation of a certain frequency, duration and / or amplitude is applied at the first point, and electrical stimulation of a different frequency, duration and / or amplitude is applied at the second point. These two points may be located at different positions on the wrist and may stimulate the same or different nerves. The stimulation may be simultaneous and / or sequential or overlapping. The stimulation may be patterned from one side to the other from multiple electrodes arranged linearly or circumferentially in a band or on a skin interface. A trimodal approach is also used in one embodiment, wherein, for example, three points on the wrist are stimulated. Instead of the wrist or other locations, treatment points (whether two, three or more) may be located on the ankle, knee, thigh, upper arm, fingers, toes, ear, chest, back, shoulder, head, neck, etc.

[0060] In one embodiment, electrical and mechanical (e.g., vibration) stimulation is provided sequentially and / or simultaneously using a multimodal dual approach. In one embodiment, dual stimulation is provided at the same location (e.g., the same point on the wrist). In another embodiment, dual stimulation is provided in the same region but at different points (e.g., different points on the wrist). In yet another embodiment, dual stimulation is provided in different regions (e.g., the wrist and the ankle). In some embodiments, a third, fourth, or additional stimulation is provided.

[0061] In some embodiments, a first stimulus is applied to a first location, a second stimulus is applied to a second location, and optionally a third stimulus is applied to a third location, and a fourth stimulus is applied to a fourth location. In one embodiment, one or more locations are different from the others.

[0062] In one embodiment, the first, second, third, or additional locations are selected from the wrist, fingers, toes, ears, ankles, knees, thighs, upper arms, backs, chests, hands, feet, heads, necks, etc. Cuffs or bandages may be used, and they may be flexible to fit the subject. Patches may also be used. In some embodiments, 1-12 (or more) electrodes (such as 2, 4, 6, 8, 10, and ranges thereof) may be used. The electrodes may be arranged in an array (e.g., a linear array).

[0063] In some embodiments, a method of treating a subject's tremor includes applying a first stimulus from a first actuator to a first location on the subject's body, and applying a second stimulus from a second actuator. The first stimulus includes electrical stimulation. The first actuator includes electrodes. The second stimulus includes vibrational stimulation. The first and second actuators are coupled to one of an arm, wrist, leg, knee, or ankle using a flexible cuff. Applying at least one of the first or second stimulus is responsive to a controller in a smart device and based on the sensing of a disease and predetermined characteristics. After applying the first and second stimuli, the symptoms of the disease are relieved.

[0064] A second stimulus from a second actuator is applied to a second position on the body. The second position may be spaced apart from the first position.

[0065] In some embodiments, the system and method may involve a combination of afferent (sensory) stimulation with motor (efferent) stimulation of nerves, muscles, or both, including but not limited to functional electrical stimulation (FES). In some cases, FES can piezotropically activate tremor-inducing muscles to reduce tremor. In other embodiments, tremor can be mechanically damped using tools such as gyroscopes (e.g., rotating eccentric blocks) in combination with neural stimulation utilizing energy or other modalities as described elsewhere herein. In some embodiments, the controller is capable of receiving real-time or near-real-time feedback from one or more sensors configured to measure patient parameters (e.g., tremor amplitude) and applying FES and / or mechanical damping when the tremor amplitude is measured to be above a predetermined threshold level.

[0066] We have invented a peripheral nerve stimulation device and method that effectively reduces tremor without the side effects of medication or the risks of brain surgery. Our method is safe and, in some embodiments, non-invasive, and effective in reducing tremor. In some embodiments, the device works by altering the neural circuit dynamics associated with essential tremor, Parkinson's tremor, and other tremors. The device is easy to use, comfortable, and adjustable to provide optimal treatment for each patient. In some embodiments, the multimodal device and method disclosed herein can also be used for a variety of other non-limiting indications. Such indications may include, but are not limited to, cardiac dysfunctions (e.g., arrhythmias such as atrial fibrillation, atrial flutter, ventricular tachycardia, etc.) and abnormal blood pressure (hypertension and hypotension). Other non-limiting indications include urinary and / or gastrointestinal dysfunctions (including overactive bladder, nocturia, and / or stress and urge incontinence) and fecal incontinence. In some embodiments, it can be used to treat mental illnesses with a neurological component (such as neurotransmitter dysfunction). It can also be used to treat migraines.

[0067] In one embodiment, overactive bladder is treated in a multimodal manner using first electrical stimulation and second vibrational stimulation at locations including the feet, ankles, knees, thighs, back, sacrum, lumbar region, ears, head and / or neck, and / or nerve-targeted locations including the tibial nerve, saphenous nerve, sacral nerve, peroneal nerve, sural nerve and / or vagus nerve. In some embodiments, electrical stimulation is provided at two or more different locations.

[0068] In one embodiment, a first electrical stimulation and a second vibrational stimulation are used in a multimodal manner to treat cardiac dysfunction at locations including the wrist, arm, fingers, shoulder, neck, head, transcranial, ear, inner ear, tragus, concha, back, or chest, and / or nerve-targeting locations including the median nerve, radial nerve, ulnar nerve, vagus nerve, auricular vagus nerve, or trigeminal nerve, median nerve, radial nerve, ulnar nerve, peroneal nerve, saphenous nerve, tibial nerve, and / or other palpable nerves or meridians on the limb. In some embodiments, electrical stimulation is provided at two or more different locations.

[0069] In one embodiment, a first electrical stimulation and a second vibrational stimulation are used in a multimodal manner to treat neurotransmitter dysfunction (e.g., depression, anxiety, and other mental illnesses) at locations including the wrist, arm, fingers, shoulder, neck, head, transcranial, ear, inner ear, tragus, concha, back, or chest, and / or nerve-targeting locations including the median nerve, radial nerve, ulnar nerve, vagus nerve, auricular vagus nerve, or trigeminal nerve, median nerve, radial nerve, ulnar nerve, peroneal nerve, saphenous nerve, tibial nerve, and / or other palpable nerves or meridians on the limb. In some embodiments, electrical stimulation is provided at two or more different locations.

[0070] For indications such as overactive bladder, cardiac dysfunction, mental illness, and others, electrical and vibrational modulation are non-limiting examples of multimodal methods. Other modulation modalities include, but are not limited to, magnetic, chemical (pharmacological), thermal, ultrasound (e.g., focused ultrasound), sound waves, radio frequency, and microwaves. According to several embodiments, the multimodal method also includes using the same modality at different locations on the body or at different points in the same region. The multimodal method also includes using the same modality with different parameters at the same or different locations on the body or at the same or different points in the same region, and / or using different stimulation patterns.

[0071] In several embodiments, when two or more devices are used in different locations, the devices can communicate with each other via a wired connection or via standard wireless communication protocols such as RF, WiFi, Bluetooth, cellular, or Zigbee. In another embodiment, several devices communicate to synchronize stimulation among multiple devices in the same or different locations. Feedback from a sensor can be used to adjust the stimulation of the devices at different locations.

[0072] In some embodiments, a wearable device for treating tremor includes: a processing unit; a first peripheral nerve effector including at least one stimulation source configured to modulate a first peripheral nerve pathway; a second peripheral nerve effector including at least one stimulation source configured to modulate a second peripheral nerve pathway; and at least one sensor configured to measure characteristics of a disease state. The processing unit includes a controller and a memory for storing instructions, which, when executed, cause the device to apply a first stimulus from the first actuator to a first location on the body and to apply a second stimulus from the second actuator. The first stimulus includes electrical or vibrational stimulation. The second stimulus may include a stimulus of a different type than the first stimulus. The second stimulus may include a stimulus of the same type as the first stimulus but with different stimulation parameters, including at least one of frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duty cycle, on / off time, burst pattern, or stimulus duration. Applying at least one of the first stimulus or the second stimulus is in response to the controller and based on the sensed characteristics of the disease state. After applying the first stimulus and the second stimulus, the characteristics of the disease state are alleviated.

[0073] The second actuator can be configured to be applied to a second position on the body, spaced a distance from the first position. The first stimulus can be configured for afferent nerve stimulation, while the second stimulus can be configured for functional electrical stimulation. Attached Figure Description

[0074] Several novel features of the embodiments are particularly set forth in the claims, detailed descriptions, and accompanying drawings. The detailed descriptions illustrate illustrative (non-limiting) embodiments in which the principles described herein are utilized, wherein: Figure 1 An example of delivering stimulation to the median nerve, where the tremor is to be relieved, is shown.

[0075] Figure 2A-2C It shows that in mild ( Figure 2A ), moderate ( Figure 2B ) and severe ( Figure 2CThe therapeutic effect of peripheral nerve stimulation in patients with essential tremor (ET) is illustrated by an example. It presents the results of a clinical study in which patients with ET experienced a reduction in tremor amplitude through a stimulation configuration with a stimulation on-time duration of 150 Hz, 300 µs, and 40 minutes. A reduction in tremor was observed immediately after stimulation was turned off, as shown by comparing the ability of ET patients to draw spirals.

[0076] Figures 3A-3C It shows according to Figure 2A-2C Wrist flexion and extension were calculated from gyroscope data in subject B. Figure 3A The tremor was shown before treatment; Figure 3B It showed an immediate reduction in tremor after treatment; Figure 3C The study showed that the tremor reduction lasted for twenty minutes after treatment.

[0077] Figure 4 An example of ineffective treatment for a patient with moderate ET is shown.

[0078] Figure 5A This shows the various locations where the tremor alteration system can be located in a patient.

[0079] Figure 6A and Figure 6B The main nerves controlling the hand and their terminal branches are shown.

[0080] Figures 7A-7D This is a block diagram illustrating various embodiments of a vibration alteration system.

[0081] Figure 8A An embodiment of an electrode pair for stimulating nerves in different fingers is shown, wherein both electrodes are positioned on the finger.

[0082] Figure 8B A device for stimulating nerves in different fingers is shown, with a second electrode positioned at the wrist.

[0083] Figure 8C An embodiment is shown in which electrodes are placed on the wrist to target different potential nerves.

[0084] Figure 8D and Figure 8E Various stimulation sites are shown.

[0085] Figure 9A This is a diagram illustrating an embodiment of a stimulation scheme for phasing brain regions that receive sensory input from two fingers.

[0086] Figure 9B This is a diagram illustrating an embodiment of a stimulation scheme for phasing brain regions that receive sensory input from four fingers.

[0087] Figures 10A-10CAn example is shown in which the position of the hand can determine the optimal stimulus duty cycle and timing.

[0088] Figure 11 An example of a variable stimulus whose frequency changes over time is shown.

[0089] Figure 12 This is a diagram illustrating an embodiment in which the stimulant is chemical and two neuromodulatory chemicals can be mixed to provide a customized chemical stimulus.

[0090] Figure 13A and Figure 13B Various forms of user controls are shown.

[0091] Figure 14A-14M Various non-invasive or invasive embodiments of the tremor alteration system are shown. Figure 14E This is a diagram illustrating an embodiment where the stimulus is mechanical. Figure 14H An embodiment of a device having the shape factor of a wristwatch is shown. Figure 14I It shows Figure 14H The back of the device shown displays the electrodes for the user interface. Figure 14J and Figure 14K An embodiment of a disposable electrode interface is shown, which snaps into a suitable position in the wristwatch shape factor of the device housing. Figure 14L An embodiment of a self-aligning snap-fit ​​feature is shown, which allows a disposable electrode interface to snap into the housing of a device with a wristwatch shape factor. Figure 14M This is a diagram illustrating the possible placement of electrodes along the spine in an embodiment of a device where the effector is electrical.

[0092] Figures 15A-15C Various embodiments of the electrode array are shown.

[0093] Figures 16A-16D Various embodiments of conductive ink tattoos are shown.

[0094] Figures 17A-17B This is a diagram illustrating an embodiment of positioning an accelerometer on the hand or wrist for measuring a patient's activity and tremor.

[0095] Figure 18A and Figure 18B An example of spectral analysis of gyroscopic motion data from a patient with a tremor centered at 6.5 Hz is shown.

[0096] Figure 19 The correlation between postural tremor and kinetic tremor was shown.

[0097] Figure 20An embodiment of a stimulation device is shown that is capable of recording data (such as tremor characteristics and stimulation history) and transmitting the data to a data portal device (such as a smartphone), which in turn transmits the data to a cloud-based server.

[0098] Figures 21A-21D It is a flowchart illustrating the monitoring, integration, analysis, and display of data used to notify users or improve stimuli.

[0099] Figure 22 This is a flowchart illustrating the feedback logic.

[0100] Figure 23 This is a diagram illustrating an embodiment in which the stimulant is an electrode implanted at least partially subcutaneously.

[0101] Figures 24A-24D Various embodiments of implantable and skin surface devices that allow for wireless power supply and control are shown.

[0102] Figure 25A-25F Various geometries for electrodes used for implanted electrical stimulation are shown.

[0103] Figures 26A-26B Two preferred embodiments of the control module for interacting with the device are shown. The control system of the tremor device utilizes feedback to modify the stimulus. This is a closed loop, where the stimulus is adjusted based on measurements of activity and tremor.

[0104] Figure 27A An embodiment of a system capable of being configured to stimulate multiple skin patches in a timed manner is shown.

[0105] Figure 27B An example of an electrode queue for selective or preferential activation of nerve fibers is shown.

[0106] The figures shown above may be used in conjunction with other figures and descriptions provided in this document. Detailed Implementation

[0107] As used herein, the terms “stimulus” and “stimulant” generally refer to neural tissue that delivers signals, stimuli, or impulses to a target area. The effect of such stimulation on neuronal activity is called “modulation”; however, for simplicity, the terms “stimulus” and “modulation” and their variations are sometimes used interchangeably herein. The effect of signal delivery to neural tissue can be excitatory or inhibitory and may enhance acute and / or long-term changes in neuronal activity. For example, the effects of “stimulating” or “modulating” neural tissue may include one or more of the following: (a) depolarizing neurons to induce action potentials, (b) hyperpolarizing neurons to inhibit action potentials, (c) depleting neuronal ion stores to inhibit action potential activation, (d) altering with proprioceptive input, (e) influencing muscle contraction, (f) influencing changes in neurotransmitter release or uptake, or (g) inhibiting activation. “Proprioception” refers to the sense of the relative position of a person’s body parts or the effort made to move them. Proprioception may also be referred to as somatosensory, kinesthetic, or tactile sensation. "Proprioceptors" are receptors that provide proprioceptive information to the nervous system, and include stretch receptors in muscles, joints, ligaments, and tendons, as well as receptors for pressure, temperature, light, and sound. "Effectors" are the mechanisms by which devices modulate target nerves. For example, an "effector" can be electrical stimulation of a nerve or mechanical stimulation of a proprioceptor.

[0108] "Electrical stimulation" refers to the application of electrical signals to soft tissues and nerves in a target area. "Vibrational tactile stimulation" refers to the stimulation of proprioceptors by applying biomechanical loads to soft tissues and nerves in a target area. "Thermal stimulation" refers to the resulting cooling or heating of a target area. "Chemical stimulation" refers to the delivery of chemicals, drugs, or pharmaceutical preparations that stimulate neuronal activity in nerves or nerve tissue exposed to the preparation. This includes local anesthetics that affect the release or uptake of neurotransmitters in neurons (electroexcitable cells that process and transmit information via electrical and chemical signals). "Cloud" refers to a network that uses real-time protocols, such as the Internet, to analyze and display data in distributed devices and the computers that communicate with them.

[0109] Equipment location The device stimulates sensory nerves to modify the dynamics of aberrant networks. Over time, this stimulation can normalize neural firing in the aberrant network and reduce tremors. Preferably, the stimulated nerves are those carrying proprioceptive information from the tremor-affected limb. The nerves can be modulated directly (e.g., by electrical stimulation) anywhere along or adjacent to the nerves carrying proprioceptive information. In some embodiments, the target nerve can be modulated indirectly, such as by stimulating the activation of proprioceptors of the target nerve. Figure 5AAccess points for nerves carrying proprioceptive information from a limb, vocal cord, or larynx are shown. These access points may include, but are not limited to: fingers 510 including one or more fingers and / or thumbs, hands 520, wrists 530, forearms or lower arms 540, elbows 550, upper arms 560, shoulders 570, spine 580 or neck 590, feet (e.g., including one or more toes), ankles, lower legs or calves, knees and / or upper legs or thighs. In some embodiments, these access points may be used for direct stimulation. In other embodiments, these access points may be used for indirect stimulation. Indirect and direct stimulation are provided in several embodiments. In some embodiments, two, three, or more access points are provided.

[0110] Nerves affecting proprioception may include, for example, the median, ulnar, radial, or other nerves located in or along muscles or joints in the hand, arm, and spinal region. These regions targeting nerves may include the brachial plexus, medial nerve, radial and ulnar nerves, cutaneous nerves, or interarticular nerves. These regions may also target muscular tissue, including muscles of the shoulder, arm, and forearm, hand, or fingers. As a non-limiting example, shoulder muscles may include the deltoid, triceps major, and supraspinatus. Arm muscles may include the coracobrachialis and triceps brachii. Forearm muscles may include the extensor carpi radialis longus, abductor pollicis longus, extensor carpi ulnaris, and flexor carpi ulnaris. In some embodiments, one, two, three, or more of these regions may be stimulated (directly and / or indirectly).

[0111] Some examples of device locations or treatment sites that can be used in combination include two or more of the following: wrist, hand, fingers, forearm, upper arm, elbow, shoulder, arm, ankle, foot, toes, calf, lower leg, thigh, upper leg, knee, leg, upper body appendages, upper body, lower body appendages, lower body, spine, neck, head, or a portion of any of these. Multiple sites can be combined with multiple modalities and / or patterns, each modality having multiple patterns or one or more modalities having different patterns. For example, a first stimulation modality and / or pattern can be applied to the wrist 530, and a second stimulation modality and / or pattern can be applied to the fingers 510. For another example, a first stimulation modality and / or pattern can be applied to the wrist 530, and a second stimulation modality and / or pattern can be applied to the ankle. For yet another example, a first stimulation modality and / or pattern can be applied to the arm, and a second stimulation modality and / or pattern can be applied to the leg. In yet another example, a first stimulation modality and / or pattern can be applied to the upper body, and a second stimulation modality and / or pattern can be applied to the lower body. Stimulants can be implanted (e.g., subcutaneously and / or percutaneously) at various sites.

[0112] In some embodiments, a vibration or tactile motor is disposed in the device and located near a target area or nerve, such that the vibrational energy is directed towards the target nerve. For example, in a wrist-worn device, a vibration motor may be disposed in a strap positioned on the palmar side of the wrist, directly adjacent to the median nerve. The movement of the vibration motor may be oriented such that it is orthogonal and / or tilted to the target nerve or skin surface. The movement of the motor may be, for example, linear or rotational with eccentric mass.

[0113] In some embodiments, a hydrogel or water-based component (e.g., a hydrogel patch having lidocaine or another chemical substance suspended in the gel, via electrodes stimulated by electrical energy) may embed a chemical or pharmacological agent (such as lidocaine). The electrodes may be placed on a skin surface, and the chemical substance is released at a predetermined rate proportional to the concentration of the chemical substance in the electrodes. In conjunction with the chemical substance suspended in the hydrogel, the electrodes may provide electrical stimulation or not. In some embodiments, the agent may be placed on the skin, and electrical energy may synergistically stimulate one, two, or more target areas or nerves, and assist in driving one, two, or more agents through the skin (e.g., via iontophoresis). In some embodiments, the iontophoresis device may be modified to promote skin penetration of the agent and enhancement of electrical stimulation via the electrodes (e.g., in some cases, alternating between a first stimulation mode that promotes iontophoresis and a second stimulation mode that promotes nerve stimulation). The mode may involve different frequencies, amplitudes, waveforms, and / or other parameters disclosed elsewhere herein.

[0114] In some embodiments, thermal energy in the surrounding tissue in contact with the device increases or decreases. Thermal energy in the tissue in contact with the device can be increased by a thermoelectric heating element (e.g., a battery disposed in a device with a resistive element). Heat can be transferred to a specific target location in the strap, for example, having a conductive element that transfers thermal energy to the tissue in contact with that conductive element. Thermal energy in the tissue in contact with the device can be reduced by a thermoelectric cooling element (e.g., a Peltier device or a solid-state refrigerator) or by circulating coolant or coolant through a portion of the device in contact with the target tissue area (e.g., in a wrist-worn device, the strap may be provided with tubing to circulate coolant through the strap). In some embodiments, the device may have a pump for circulating coolant. The device may have heat transfer elements (such as a radiator or an electric fan) to transfer thermal energy from the surrounding tissue to the surrounding air or environment (e.g., areas of the device not in contact with tissue).

[0115] In a preferred location in several embodiments, the device engages with the skin surface of the user's tremoring upper limb and applies neuromodulation signals to nerve bundles selected from the group consisting of the brachial plexus, medial nerve, radial nerve, and ulnar nerve, or excitable structures in the muscle tissue of the upper limb (on the skin or within the joint). In some embodiments, neuromodulation signals are provided to one, two, or three or more nerve bundles.

[0116] According to several embodiments, when stimuli or other neuromodulation signals are provided to two, three or more locations, the signals are provided simultaneously, sequentially or overlappingly.

[0117] Proprioceptors can be found in, for example, muscles, tendons, joints, skin, and the inner ear. Criteria for defining candidate nerves for direct modulation include the location of the tremor to be reduced, the proximity of the nerve to the skin surface, the density of proprioceptive fibers, and the distance from stimulating pain receptors or muscles. Based on these criteria, the median nerve for the wrist and the ulnar nerve for the elbow rank highly. Criteria for defining candidate locations for indirect proprioceptive modulation include the density and type of proprioceptors. Pacinian corpora provide information about touch; muscle spindles provide information about changes in muscle length by triggering action potentials in the muscle spindle afferent nerves when mechanically gated ion channels open due to muscle stretching. Golgi tendon organs provide information about muscle tension. Stimulation of these structures can also alter circuit dynamics and reduce tremors.

[0118] The device targets specific nerves that form synapses on abnormal brain circuits. These synapses can be direct synapses or synapses via multiple relay synapses. Figure 6A and Figure 6B A representative set of nerves that transmit proprioceptive information to the olive-cerebellar network (an aberrant network in ET) is shown. These nerves include the 610 distal and major branches of the 620 median nerve and the 630 ulnar nerve, and the 640 distal and major branches of the 650 radial nerve. In a preferred embodiment, the device targets the nerves that input proprioceptive information from the hand, wrist, and forearm.

[0119] In another embodiment, any combination of the parts described herein may be used to affect nerves associated with voice tremor, including but not limited to branches of the vagus nerve, such as the superior laryngeal nerve or the recurrent laryngeal nerve.

[0120] Equipment components: Various embodiments Figures 7A-7DThis is a conceptual diagram illustrating some embodiments of a tremor alteration system 700. System 700 includes a housing 720, one or more effectors 730, one or more controls 740 electrically connected to the effectors 730, and one or more power sources 750. In some embodiments, housing 720 may include an interface 760. The interface facilitates coupling the effector to a patient. For example, the interface may provide a physical, electrical, chemical, thermal, or magnetic connection between the device and the patient's nerves. In some embodiments, housing 720 may also include a sensor 780 for detecting tremor, a memory 770, a display 790, and a processor 797. The device in this embodiment may include a processor 797 coupled to the effector, which performs calculations and control of other components. The device may also include a digital library stored on the processor 797 or memory 770, which may contain pre-loaded modulation protocols. The device may include a control module 740 that communicates with the processor 797 and can be used by a user to control stimulation parameters. These controls allow the user to adjust the operation of the device. For example, the controls may be configured to turn the device on, turn the device off, and adjust the effector (such as intensity). The device may include a sensor 780 connected to a processor 797, which can detect information of predefined parameters and transmit the parameter information to the processor 797. The device may include a data storage unit 770 connected to the sensor 780 and the processor 797; and a power supply 750 may be connected to the processor.

[0121] The device may also include a display or indicator 790 for communicating with the user and reporting the device's status. In some embodiments, the indicator is preferably a light-emitting diode (LED) or some kind of visual indicator, but may be an audio indicator. The information may include battery level or stimulus status.

[0122] The device may lack or omit effector 730. It can be a diagnostic, non-therapeutic device. In a preferred embodiment, interface unit 704 will be worn on the tremor limb to track the tremor over time. Providing feedback to the user of the device allows them to become aware of their tremor and monitor it over time. Even without therapeutic stimulation, this biofeedback can help some individuals reduce their tremor. The device may lack or omit sensor 780. It can be a therapeutic, non-diagnostic device.

[0123] To keep the device small and simple, many of these components can be housed in a single unit. Processing, control, and potentially sensing can be performed remotely from the decision unit 702, making the interface unit 704, which provides therapeutic contact with the patient for various applications, compact, simple, and flexible. Figures 7B-7D The decision unit 702 can be a new device designed for this application, or it can be integrated into existing technologies such as smartphones. This would allow the system to be a robust, handheld form factor with reduced cost and size.

[0124] exist Figure 7B In the illustrated embodiment, the interface unit 704 is an implant; the effector 730 provides electrical stimulation of the nerve; and the instruction set and power are wirelessly transmitted from an external device. The implanted interface unit 704 may be powered by an onboard battery. The implanted interface unit 704 may include a sensor 780 for directly detecting tremors or neuromuscular activity detected by electroencephalography (ENG) or electromyography (EMG).

[0125] exist Figure 7C In the illustrated embodiment, the interface unit 704 is worn on the surface of the body; the effector 730 provides electrical stimulation to underlying nerves or vibratory tactile stimulation to nearby proprioceptors. The sensor 780 may include a motion sensor comprising an accelerometer, a gyroscope, and a magnetometer.

[0126] exist Figure 7D In the illustrated embodiment, one or more sensor units 780 that sense motion, temperature, etc., can be worn at different locations on the body. The effector 730 and decision unit 702 are separate entities worn on the body at locations different from the sensor 780. This is useful if nerve stimulation occurs at locations where tremors cannot be easily or accurately measured. For example, a stimulation device 700 placed on the underside of the wrist to reduce hand tremors is highly effective. However, measuring hand tremors from the wrist using an accelerometer or gyroscope proves more difficult; sensor units placed separately on the palm or back of the hand within a glove or worn as a ring on one of the fingers will show greater sensitivity to hand tremors due to their location outside the wrist joint.

[0127] Effector: Conventional Effectors can be used to modulate neural tissue in an upper limb region targeted by a stimulus. For example, an effector can modify neuronal signaling in a nerve and / or modify the flow or content of proprioceptive information. Effectors can be delivered percutaneously or subcutaneously. One or more effectors can be used to influence nerves. In some embodiments, the effector can be excitatory to the nerve. In other embodiments, the effector can be inhibitory to the nerve. In some embodiments, the system can be used to stimulate nerves during some portions of treatment and inhibit nerves during other portions of treatment.

[0128] Effector: Electrical stimulation In some embodiments, the effector may be an electrical stimulator. An electrical effector may include electrodes, electrode pairs, electrode arrays, or any device capable of delivering electrical stimulation to a desired location. The electrical stimulation may be percutaneous or subcutaneous. For example, percutaneous electrical stimulation can be achieved by electrodes placed on the skin surface, while subcutaneous electrical stimulation can be achieved by implanted electrodes positioned close to nerves.

[0129] Stimulation parameters can be adjusted automatically or controlled by the user. Stimulation parameters may include on / off state, duration, intensity, pulse rate, pulse width, waveform shape, and the slope of the pulse on and off. In a preferred embodiment, the pulse rate may be about 50 to 5000 Hz, and the preferred frequency is about 50 Hz to 300 Hz or 150 Hz. For example, the frequency may be between about 10 Hz and about 20 kHz (e.g., about 10 Hz, about 20 Hz, about 30 Hz, about 40 Hz, about 50 Hz, about 60 Hz, about 100 Hz, about 250 Hz, about 500 Hz, about 1000 Hz, about 2500 Hz, about 5000 Hz, about 10 kHz, about 15 kHz, about 20 kHz, and ranges between such values). The preferred pulse width is in the range of 50 to 500 μs (microseconds), and more preferably, the pulse width is about 300 μs (e.g., about 50 μs, about 100 μs, about 150 μs, about 200 μs, about 250 μs, about 300 μs, about 350 μs, about 400 μs, about 450 μs, about 500 μs, and ranges between such values). The intensity or amplitude of the electrical stimulation can vary from 0 mA to 500 mA, and the preferred current is about 1 mA to 6 mA (e.g., about 0 mA, about 0.1 mA, about 1 mA, about 6 mA, about 10 mA, about 20 mA, about 30 mA, about 40 mA, about 50 mA, about 100 mA, about 200 mA, about 300 mA, about 400 mA, about 500 mA, and ranges between such values). Certain preferred settings are derived from the aforementioned clinical studies, which demonstrated valuable reduction in tremor over a sustained period of time. Stimulation can be adjusted in different patients and through different stimulation modulation methods. These preferred settings are non-limiting examples. Increments in intensity adjustment can range from 0.1 mA to 1.0 mA (e.g., 0.1-3 mA, 3-6 mA, 6-10 mA, and overlapping ranges therewith). In a preferred embodiment, stimulation can last from approximately 10 minutes to 1 hour (e.g., 10-20 minutes, 20-40 minutes, 40-60 minutes, and overlapping ranges therewith).

[0130] In a preferred embodiment, the electrode may contact the user at the surface of the skin above one or more nerves, including the medial, radial, and ulnar nerves. The electrode may be configured with an electrode pair, one electrode proximal (near the elbow) and the other distal (near the hand). The electrode may be in communication with the opposing electrode. The electrode pair may have positive or negative polarity through which an electric current flows.

[0131] The effector may include two electrodes, each having either a positive or negative polarity, or the electrode array may include multiple electrode pairs, wherein each electrode pair is programmed independently or in relation to other electrode pairs. As an example, the program may allow cyclic stimulation of different nerves (such as the ulnar nerve, then the median nerve, then the radial nerve, or any combination thereof) at different times.

[0132] Electrical stimulation can be designed to suppress tremors by interfering with proprioceptive input, inducing compensatory muscle contractions, or a combination of both. Electrodes can be replaced by any equivalent material capable of conducting electrical signals through a stimulation interface with the skin surface of the upper limb. Electrodes can be attached to a control unit 740, which can apply electrical stimulation via the electrodes to soft tissue and nerves in the area where the electrodes are placed and in adjacent areas. In another variation of this embodiment, a combination of electrodes can be placed in the target area.

[0133] A function generator connected to and controlled by a processor can be used to adjust electrical stimulation parameters. The function generator is preferably an arbitrary waveform generator that uses direct digital synthesis technology to produce any waveform that can be described by an amplitude table. These parameters are selected from, but are not limited to, frequency, intensity, pulse width or pulse duration, and total duration. Preferably, the output has a power limit set by the maximum output voltage. In a preferred embodiment, a digitally stored protocol is cycled through various stimulation parameters to prevent patient adaptation to the environment. Variations in electrical stimulation are achieved through the function generator.

[0134] In some embodiments, electrical stimulation includes a combination of one or more single frequencies and one or more scanning frequencies (e.g., continuously changing from a lower frequency to a higher frequency). For example, a first single frequency may be applied for a first duration, and a first scanning frequency may be applied for a second duration. The second duration may follow the first duration (e.g., immediately after it, after a pause duration). The second duration may at least partially overlap with the first duration. Continuing this example, a second single frequency different from the second frequency may be applied for a third duration. The third duration may follow the second duration (e.g., immediately after it, after a pause duration). The third duration may at least partially overlap with the second duration. Continuing this example, a second scanning frequency different from the first scanning frequency (e.g., having different low frequencies, high frequencies, and / or rates of frequency change) may be applied for a fourth duration. The fourth duration may follow the third duration (e.g., immediately after it, after a pause duration). The fourth duration may at least partially overlap with the third duration. This example may continue within additional durations of single frequencies and / or scanning frequencies. Different frequencies may be applied to the same vibratory stimuli or different electrical stimuli (e.g., on the same body site, on different body sites). Electrical stimulation applied to different body parts can converge at a point between the body parts and may form a standing wave. In some embodiments, the convergence point can be the target body part (e.g., the elbow and fingers converge at the wrist). The amplitude of the scan can be enclosed by other waveforms (such as sine or Gaussian curves), or the parameters can be varied randomly or pseudo-randomly. The discussion above regarding different frequencies can also be applied to other parameters, such as frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, or burst, or combinations thereof.

[0135] Optimized stimulus: phase shift In a preferred embodiment, the stimulation is designed to phase-shift synchronicity in the brain. The concept of phase-shifting aberrant circuits follows recent work suggesting that neural retraining reduces the network's tendency to fall into aberrant rhythms. Interestingly, movement disorders are often associated with aberrant periodic synchronous discharges in brain circuits. In Parkinson's disease, this circuit is located in the basal ganglia. In ET, it is the olive-cerebellar circuit. These aberrant oscillations are thought to drive tremors, as supported by numerous studies showing that tremors observed in the muscles of the hand and forearm are synchronized with pathological rhythmic discharges in the brain. Recent DBS studies have shown that low-voltage phase-shift bursts on adjacent electrode pairs (called coordinated resets) reduce synchronicity in aberrant brain networks and this reduces Parkinson's tremors. The application of coordinated reset theory in the treatment of tinnitus supports the concept of using synaptic excitation to retrain neural networks.

[0136] The device disclosed herein offers several advantages over high-frequency TENS stimulation, including the use of lower power (leading to longer battery life, reduced discomfort from motor growth and contraction, and reduced discomfort from sensory excitation), less inhibition of discharges in adjacent nerve activity (through depletion or other mechanisms), and longer-lasting effects, requiring only intermittent use of the device to train or maintain training of neural circuit dynamics. The device stimulates neural clusters in a manner that targets neural subgroups to reduce group synchronization. For example, this can be achieved by stimulating different fingers on the hand.

[0137] Figure 8A This is a schematic diagram of a preferred embodiment of the device, wherein an anode 810 and a cathode 820 electrode pair on a finger are used to stimulate branches of proprioceptive nerves (median, radial, and ulnar nerves) in each finger. This arrangement, with the anode 810 distal and the cathode 820 proximal, is designed to induce nerve impulses to travel toward the brain. Due to the somatic organization of the brain, the unique stimulation pattern on each finger can send unique signals to specific subpopulations of neurons in the brain, where signals from different adjacent or nearby body parts form synapses at nearby locations in the brain. Stimulation using multiple unique patterns is an example of multimodal stimulation, where multiple patterns of the same type of stimulation (with at least one different parameter) are used. In some embodiments, the positions of the anode 810 and cathode 820 may be reversed to inhibit the transmission of sensory impulses toward the brain (reverse collision). Stimulation of multiple fingers is an example of multimodal stimulation, where several sites of the same type of stimulation are used. Combining unique stimulation patterns, such stimulation is an example of multimodal stimulation, where several sites and multiple patterns of the same type of stimulation are used. In several embodiments, different kinds of stimulation are also provided (e.g., electrical stimulation on one or more fingers and vibratory tactile stimulation on one or more other fingers).

[0138] Figure 8B An arrangement is shown in which electrode 830 is positioned on a finger and second electrode 840 is positioned on the wrist. In one embodiment, only a single electrode 830 is present on the finger, and the second electrode 840 is positioned on the wrist. The finger represents only one set of possible targets, and similarly, different locations can be used as targets for neighboring neuronal subpopulations. In some embodiments, the electrodes on one or more fingers may include an anode and a cathode, for example, as relative to... Figure 8BThe anode and cathode may be positioned on the wrist. Stimulation of one or more fingers and the wrist is another example of multimodal stimulation using multiple sites. In some embodiments, the electrodes on one or more fingers may be percutaneous, and the electrodes on the wrist may be subcutaneous. Placing electrodes at different locations on the skin is an example of multimodal stimulation. In some embodiments, multimodal therapy is provided on one finger (including the thumb) of one hand and another finger (including the thumb) of the other hand.

[0139] exist Figure 8C In the illustrated embodiment, electrodes are positioned at different locations 850, 860, and 870 on the wrist to target the median nerve (near location 850), ulnar nerve (near location 860), and radial nerve (near location 870). Those skilled in the art will recognize that the input may be located at other locations or branches of the nerves that supply the aberrant brain circuit. Locations may be on the same side or opposite side of the tremor limb. Locations may be on the surface of the skin, through the skin, and / or implanted.

[0140] Figure 8D Various stimulation sites are shown, which can be stimulated by a delay or shift of a predetermined fraction or multiple of the tremor cycle T, for example... Figure 9A and Figure 9B As shown. These sites are close to the median and ulnar nerves. Figure 8E The stimulation site near the radial nerve is shown. The first side of the wrist (e.g., Figure 8D ) and the second side of the wrist (e.g., Figure 8E The stimulus of ) is another example of multimodal stimulation using several sites.

[0141] The equipment uses stimulation schemes designed to phase-shift, cover, or mask anomalous networks. Figure 9A This is a conceptual diagram illustrating a sample activation scheme used to phase-shift brain regions receiving sensory input from two sites. For example, the two sites could be... Figures 8A-8E The two fingers are shown in the diagram. Stimulation at the second site is delayed by time T / 2 after stimulation at the first site, where T is the period of the natural tremor. For example, if the tremor is at 8 Hz and the period T is 125 ms, stimulation at the second site will be delayed by 62.5 ms. The stimulation is designed to reset the phase of the neuron, which can be achieved using high-frequency stimulation (above 100 Hz) or DC pulses.

[0142] Figure 9BThis is a conceptual diagram illustrating a sample activation scheme used to phase brain regions receiving sensory input from four sites, with subsequent sites delayed by T / 4. In another embodiment, the stimulation at different locations is variable in parameters other than timing, such as frequency or pulse width, or combinations thereof. These variations are similarly designed to retrain the brain by eliminating, covering, or masking aberrant network dynamics. In yet another embodiment, the stimulus may appear at a single location, but its parameters vary over time. For example, its frequency may change every few seconds, or it may be turned on and off. In yet another embodiment, the stimulus is constant and at a single location. In these preferred embodiments, the location is near the median nerve at the wrist.

[0143] Optimized Stimulus: Secondary Sensation Stimulating at an intensity below the sensory threshold will avoid discomfort (tingling, numbness, pain) that may be associated with peripheral nerve stimulation. Because the exact electrode location, size, and surface contact have a significant impact on the stimulation level and the anatomy receiving the stimulation, it may be necessary to calibrate the sensory threshold for each patient and even for each phase. This calibration can be done by the user manually setting the stimulation parameters or otherwise indicating their sensory threshold. Another possible mechanism of the device is to automatically scan a series of stimulation parameters, with the patient selecting a set of values ​​that are most comfortable. Another possible mechanism is to allow the patient to choose from a set of previously selected parameter values, thereby providing effective and comfortable stimulation. In some embodiments, the electrode pads may include a local analgesic such as lidocaine to reduce the discomfort of stimulation, thereby increasing the patient's tolerable sensory threshold. In some embodiments, a controlled-release form may be used to deliver the local analgesic to provide pain relief for the duration the electrode pads will be worn (which could be days, weeks, or months). Such an approach can provide greater comfort or greater therapeutic effect due to the greater stimulation intensity and / or the synergistic effect with the local analgesic, thereby reducing tremor in some patients.

[0144] Optimized stimulation: high frequency Alternatively or additionally, the stimulation waveform may be of a very high frequency (typically in kHz or higher), such that the user feels little or no stimulation. It is thought that very high-frequency stimulation would cause conduction blockade. However, prior to blockade, there is an initiation response including strong neural depolarization. To effectively achieve very high-frequency stimulation without causing discomfort to the patient, it is preferable to eliminate this initiation response. This can be accomplished by cooling the nerve during the initial stimulation. Motor nerves are typically activated by stimulation at about 15 Hz and below, while sensory nerves are typically activated by stimulation at about 50 Hz and above. In some embodiments, it may be desirable to specifically stimulate above the 15 Hz threshold for motor neuron stimulation to avoid inducing muscle contraction.

[0145] Optimize stimulus: trigger Alternatively or additionally, stimulation triggered by the tremor phase can improve effectiveness. The purpose of this stimulation is to break the rhythmic entrainment of the motor unit. More effective treatment may allow stimulation at lower levels to achieve similar therapeutic benefits with less discomfort. Essentially, tremor is a problem of feedback in a resonant circuit. Stimulation that is out of phase with the tremor can reduce tremor by altering the circuit dynamics, e.g., by changing the gain in the feedback loop.

[0146] like Figure 10B As shown, when the wrist is in its maximum flexion or extension ( Figure 10A ), which may cause sudden bursts of high-frequency stimuli at regular intervals. In the example ( Figure 10C In this context, the burst has been moved to a random phase. The position of the hand ( Figure 10A This can determine the optimal stimulus duty cycle and timing, such as ( Figure 10B ) through maximum tremor deviation or ( Figure 10C ) Use bursts with variable time delay to stimulate non-resonance to avoid resonance with tremor.

[0147] In some embodiments, the first stimulus may include a burst stimulus (e.g., a stimulus having a specified on-off cycle and an off-off cycle) and the second stimulus may include a continuous stimulus. The first stimulus may be applied before, during, and / or after the second stimulus. The first stimulus may be applied by the same electrode or electrode group as the second stimulus, or by a different electrode or electrode group than the second stimulus. In some embodiments, the burst stimulus may be applied to a first location on the body, and the continuous stimulus may be applied to a second location (simultaneously or sequentially).

[0148] Alternatively or additionally, the stimulus can be chaotic or variable. The goal of chaotic, random, or variable stimuli is to inhibit or prevent habituation and reduce resonance in the circuit. This can be achieved, for example, by changing the stimulus frequency over time and / or by superimposing higher and lower frequency components, such as... Figure 11 As shown.

[0149] Alternatively or additionally, the stimulus can be a high-frequency alternating current. This indicates that the action potential can be blocked as it propagates along the axon and that the loop dynamics can be tuned.

[0150] In some embodiments, the stimulation parameters described above can be cycled in a predetermined order to determine the optimal stimulation parameters. In some embodiments, the effectiveness of the stimulation parameters can be monitored over time to determine whether a particular set of stimulation parameters is losing effectiveness. In some embodiments, when the effectiveness of a particular set of stimulation parameters has decreased by a predetermined amount, the stimulation parameters can be changed or cycled in a predetermined order. For example, if stimulation is triggered for a tremor phase, the stimulation can be delivered with a random or variable time delay, or if the stimulation uses a set amplitude and / or frequency, the stimulation can be changed to a chaotic, random, or variable modality to prevent or disrupt habituation. In some embodiments, random or variable types of stimulation parameters can be used according to a predetermined routine, such as a predetermined number of hours per day, a predetermined number of days per week, or at some other predetermined interval (including time of day).

[0151] Effector: Vibratory tactile stimulation Effectors can mechanically stimulate proprioceptors by including vibratory tactile sensation or tactile sensation. Mechanical stimuli may include force, vibration, and / or motion. Effectors induce action potentials in target nerves by stimulating the Golgi tendon organ (GTO) or Pacinian corpuscles. Mechanical effectors may include, for example, small motors; piezoelectric elements; one or more vibratory tactile units consisting of a mass and an effector for moving the mass to apply a vibratory stimulus to the body; eccentric mass mounted on an axis to generate a vibratory stimulus when the axis rotates; ultrasonic motors; magnetorheological fluid (MRF) effectors or electroactive polymer (EAP) effectors; and / or loudspeakers (e.g., tactile loudspeakers, piezoelectric loudspeakers, electroactive polymer transducers, electromagnetic coil loudspeakers).

[0152] In some embodiments, the vibrational stimulation may be 250 Hz, corresponding to the optimal sensitivity of the Pacinian bodies (also known as lamellar bodies). Pacinian bodies are nerve endings in the skin that sense touch and vibration. Deformation of the bodies opens pressure-sensitive sodium ion channels to induce action potentials. In one embodiment, the vibration may be below 50 Hz to excite the touch-sensitive Meissner bodies (also known as tactile bodies) in the fingers. In some embodiments, the vibrational stimulation may be, for example, at least about, approximately, or no more than about 10 Hz, 20 Hz, 30 Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 110 Hz, 120 Hz, 130 Hz, 140 Hz, 150 Hz, 160 Hz, 170 Hz, 180 Hz, 190 Hz, 200 Hz, 210 Hz, 220 Hz, 230 Hz, 240 Hz, 250 Hz, 260 Hz, 270 Hz, 280 Hz, 290 Hz, 300 Hz, 350 Hz, 400 Hz, 450 Hz, 500 Hz, or higher or lower, or a range including any two of the foregoing parameters.

[0153] In some embodiments, the vibrational stimulus comprises a combination of one or more single frequencies. For example, a first single frequency may be applied for a first duration, and a second single frequency may be applied for a second duration. The second duration may follow the first duration (e.g., immediately after it, after a pause duration). The second duration may at least partially overlap with the first duration. Continuing this example, a third single frequency, different from the second frequency, may be applied for a third duration. The third duration may follow the second duration (e.g., immediately after it, after a pause duration). The third duration may at least partially overlap with the second duration. The third duration may at least partially overlap with the first duration. The third duration may at least partially overlap with both the first and second durations. This example may continue within additional durations of single frequencies. Different frequencies may be applied to the same vibrational stimulus or different vibrational stimuli (e.g., on the same body part, on different body parts). Vibrational stimuli applied to different body parts may converge at a point between the body parts and may form a standing wave. In some embodiments, the convergence point may be a target body part (e.g., the elbow and fingers converge at the wrist).

[0154] In some embodiments, the vibration stimulation comprises a combination of one or more single frequencies and one or more scanning frequencies (e.g., continuously changing from a lower frequency to a higher frequency). For example, a first single frequency may be applied for a first duration, and a first scanning frequency may be applied for a second duration. The second duration may follow the first duration (e.g., immediately after it, after a pause duration). The second duration may at least partially overlap with the first duration. Continuing this example, a second single frequency different from the second frequency may be applied for a third duration. The third duration may follow the second duration (e.g., immediately after it, after a pause duration). The third duration may at least partially overlap with the second duration. Continuing this example, a second scanning frequency different from the first scanning frequency (e.g., having different low frequencies, high frequencies, and / or rates of frequency change) may be applied for a fourth duration. The fourth duration may follow the third duration (e.g., immediately after it, after a pause duration). The fourth duration may at least partially overlap with the third duration. This example may continue within additional durations of single frequencies and / or scanning frequencies. Different frequencies may be applied to the same vibration stimulus or different vibration stimuli (e.g., on the same body part, on different body parts). Vibrational stimuli applied to different body parts may converge at a point between the body parts and potentially form standing waves. In some embodiments, the convergence point may be the target body part (e.g., the elbow and fingers converge at the wrist). The amplitude of the scan may be encapsulated by other waveforms (such as sine or Gaussian curves), or the parameters may be varied randomly or pseudo-randomly.

[0155] The above discussion on different frequencies can also be applied to other parameters, such as frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, or burst, or combinations thereof. In several applicable embodiments, the above discussion on vibrational stimulation is also applicable to other modes and their combinations.

[0156] In some embodiments, electrical stimulation is applied to a first location on the body while vibrational stimulation is applied to a second location (e.g., wrist and ankle, wrist and ear, ankle and ear, arm and leg, etc.). Instead of the second location, or in addition to the second location, electrical and vibrational stimulation are applied simultaneously or sequentially at the first location. For example, a band (or other device) providing electrical and vibrational stimulation is used for the wrist, and a band (or other device) providing electrical and vibrational stimulation is used for the ear, ankle, leg, arm, etc. In one embodiment, electrical and vibrational stimulation are applied to both locations. Third, fourth, or other locations may also be stimulated. Although stimulation is disclosed in several embodiments, neural modulation including stimulation or inhibition is contemplated in many embodiments.

[0157] Stimuli of this mechanical type (e.g., vibration) can reduce tremors through several methods. One method is to transmit proprioceptive signals to the brain that mask or modify the proprioceptive signals driving the tremor from the muscles. Another method is impedance control. Joint impedance can alter co-contracting muscles through transcutaneous nerve stimulation, thereby affecting muscle stiffness and consequently muscle contraction. Another method is to generate compensatory muscle contractions against the tremor by stimulating the nerves. In some embodiments, the stimuli are preferably secured against the skin surface, for example, by an elastic or Velcro band (or other adjustable, adaptable band).

[0158] Effectors: Chemical, Thermal and Other The examples in this article primarily describe the stimulation as electrical or vibratory tactile. However, other effectors may be used alternatively to achieve stimulation, which can offer significant benefits in terms of patient comfort, portability, safety, or cost.

[0159] In another variation of this embodiment, the effector may be a neuromodulatory chemical that raises or lowers the neuronal firing threshold. In some embodiments, the chemical used may be a local anesthetic, including but not limited to the "caine" family. Anesthetics of the "caine" family may include, but are not limited to, benzocaine, bupivacaine, tetracaine, carbivacaine, chloroprocaine, cicaprocaine, diclofenac, etolacaine, heptane, levobupivacaine, lidocaine, lidocaine hydrochloride, propivacaine, micaine, procaine, micaine, procaine, and tetracaine. Other chemical families may include those of the menthol family, or α-hydroxycapsaicin or capsaicin from Sichuan pepper, all of which are known to affect peripheral sensory nerves.

[0160] Figure 12 Chemical stimuli can be delivered percutaneously via patches and / or microinjection. The pre-loaded protocol may preferably be a predetermined composition of one or more chemical substances. In several embodiments, the local anesthetic may be known for other indications. The recommended stimulation dose may have been tested and approved for the treatment of other indications. For example, the local anesthetic lidocaine may be administered at 2-10% by weight. Lidocaine may be administered in combination with other anesthetics. Figure 12 As shown, two neuromodulatory chemicals 1202 and 1204 are mixed to provide a customized composition. A chemical stimulant can be administered as a composition comprising 2.5 wt% lidocaine as the first chemical 1202 and 2.5 wt% prilocaine as the second chemical 1204. Alternatively, a chemical stimulant can be administered as a composition comprising 0.1-5 wt% lidocaine as the first chemical 1202 and 0.1-5 wt% prilocaine as the second chemical 1204.

[0161] The chemical stimulant may include α-hydroxycapsaicin from Sichuan pepper. α-hydroxycapsaicin may be contained in an excipient or carrier. The excipient may include a gel, cream, oil, or other liquid. If the delivery method is a percutaneous patch, the chemical agent is preferably in the form of a cream or gel. The user can select the composition via a control module (e.g., control module 740 of Figure 7). If the delivery method is microinjection, the form is preferably a solution.

[0162] In some embodiments, the effector may be a temperature or thermal effector that causes cooling and / or heating (e.g., temperature effector 732 of Figure 7). The effector may modulate neuronal firing directly by cooling nerves or indirectly by cooling adjacent muscles, skin, or other components of the arm. Temperature effectors may include, for example, piezoelectric materials (e.g., Peltier cooling bricks), circulating fluids, compressible expandable gases, cooling or heating solid materials, or evaporative materials. An example of a cooling effector may be disclosed as in U.S. Publication No. 2010 / 0107657, which is incorporated herein by reference. Heating and / or cooling may be applied as a patch that is attached to the skin surface by an attachment (such as an armband) or by an implant.

[0163] In embodiments with a thermal stimulus, the pre-loaded protocol may preferably be a predetermined temperature of stimulation and an associated duration of stimulation. Preferably, the pre-loaded protocol may require a 15-minute duration of thermal cooling and a cooling temperature in the range of 15-25°C (e.g., about 15°C, about 17.5°C, about 20°C, about 22.5°C, about 25°C, and such ranges). The duration of stimulation may be pre-programmed (but not limited to) about 5 minutes to about 30 minutes (e.g., about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, and such ranges). The maximum length of stimulation should be well tolerated by the user and should not cause any muscle or nerve damage. In embodiments where the stimulus is a thermal stimulus, a temperature sensor may be used to detect the effective cooling temperature. The effective cooling or heating temperature may be the temperature felt by the user, and this is not necessarily the same as the applied temperature. If the temperature sensor determines that the effective temperature has reached a threshold (which may be 5°C greater or less than the applied temperature of a particular protocol), the processor 797 (from Figure 7) may modify the protocol to cool or heat more than initially programmed in order to compensate for the difference between the effective cooling and the expected cooling.

[0164] In some embodiments, the effector may be a phased array ultrasound (e.g., focused ultrasound) effector. For example, a phased array ultrasound effector may include multiple ultrasound transducer elements. Each element may have a width and a thickness. The thickness may be related to the width (e.g., the thickness is a fraction of the width (e.g., 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, a range of such values, etc.) or a multiple (e.g., 2×, 3×, 4×, 5×, 10×, a range of such values, etc.)). Each element may have a width, and the space between elements may be related to that width (e.g., the same as the width, half the width, twice the width). The spacing between elements may be adjustable. In some embodiments, the elements have a width between about 0.5 mm and about 2 mm and a spacing between about 0.1 mm and about 2 mm. The elements may be arranged in a one-dimensional or two-dimensional array. The elements may be cuboids, rectangles, cylinders, prisms, pyramids, or any suitable shape. For example, the ultrasonic signal can be between about 20 kHz and about 2 GHz or higher (e.g., a range between about 20 kHz, about 50 kHz, about 100 kHz, about 500 kHz, about 1 MHz, about 1.5 MHz, about 2 MHz, etc.). At least one of the elements can transmit different frequencies. Each element can transmit different frequencies. Each element can transmit the same frequency. In some embodiments, the dose level applied by the ultrasonic effector is between about 0 W / cm². 2 Approximately 2W / cm 2 Between (e.g., approximately 0 W / cm) 2 Approximately 0.1 W / cm 2 Approximately 0.25 W / cm 2 Approximately 0.5 W / cm 2 Approximately 1W / cm 2 Approximately 1.5 W / cm 2 Approximately 2W / cm 2 (e.g., the range between such values). One, some, or all of the ultrasound transducer elements can be divergent, focused, scattering, planar, etc. In some embodiments, the transducer elements can be arranged below the skin surface near the target nerve or tissue region in a manner that is used to focus energy (e.g., energy from different elements causes constructive interference).

[0165] Ultrasonic transducer elements can be arranged on a printed circuit board. Ultrasonic transducer elements can also be arranged on flexible circuitry. Flexible circuitry may include, for example, ultrasonic transducer elements and one or more other types of effectors. Certain circuit boards, flexible circuits, etc., may include other combinations of effectors.

[0166] In some embodiments, the effector can be one or more magnets. For example, a first magnet having a first polarity can be applied to a first site, and a first magnet having a second polarity can be applied to a second site. The first polarity may be the same as the second polarity (e.g., positive-positive, negative-negative). The first polarity may be different from the second polarity (e.g., positive-negative, negative-positive). The first site may be close to the second site (e.g., within about 10 cm, about 8 cm, about 6 cm, about 5 cm, about 4 cm, about 3 cm, about 2 cm, about 1 cm, or closer). The first magnet may comprise the same material as the second magnet. The first magnet may comprise a different material than the second magnet. The first magnet may have the same dimensions as the second magnet (e.g., thickness, length, width diameter). The first magnet may have at least one dimension different from the second magnet (e.g., thickness, length, width diameter). The first magnet may have the same mass as the second magnet. The first magnet may have a different mass than the second magnet.

[0167] The magnet may include an electromagnet, the material of which becomes magnetic only when an electric current is applied to a wire wound around the magnet, thereby generating a magnetic field that can multiply the strength of the magnetic field in the material. In embodiments including an electromagnet, the magnetic effector can be turned on and off without moving the effector.

[0168] In some embodiments, a mini-TMS coil orthogonally oriented to the target nerve can be used to apply magnetic energy to deliver a burst of electromagnetic energy near the target nerve. The transcranial magnetic stimulation (TMS) coil comprises a loop shape containing multiple windings of wire. When a current is applied to the wire, a magnetic field is formed in a plane orthogonal to the loop coil. The current can vary over time, such as when connected to a stimuli. The magnetic field causes the current to flow in regions of the body adjacent to the TMS. The mini-TMS can be a smaller version of a TMS configured to penetrate tissue, such as opposite the skull.

[0169] Several embodiments may alternatively employ other effectors, including acoustic (using ultrasonic excitation to stimulate sensory nerves at the fingertips), vibratory, tactile, luminescent (e.g., exposure in optogenetically modified nerves), magnetic (e.g., by rapidly switching RF fields), or combinations of mechanisms. Some examples of modalities that can be used in combination include two, three, or more of the following: electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation (hot and / or cold), mechanical (e.g., vibratory tactile) stimulation, focused ultrasound (focused, high and / or low intensity, phased array), radiofrequency stimulation, or microwave stimulation. Such modalities may be used in the same or different regions. In some embodiments, different modalities are used to treat tremor or achieve other neuromodulations targeting a single region, even if two or more body regions are modulated. For example, the wrist and forearm may be modulated to synergistically reduce hand tremor. In other embodiments, different modalities are used to treat tremor or achieve other neuromodulations targeting multiple regions. For example, the wrist and ankle may be modulated to reduce both hand and leg tremors. In addition to tremor, the device described herein is also used to treat other indications, including but not limited to: cardiac dysfunction (e.g., cardiac arrhythmias such as atrial fibrillation, atrial flutter, ventricular tachycardia, etc.), blood pressure abnormalities (hypertension and hypotension), urinary and / or gastrointestinal dysfunction (including overactive bladder, nocturia and / or stress and urge incontinence), and fecal incontinence, as well as mental illnesses involving neurological components (such as neurotransmitter dysfunction).

[0170] In some embodiments, vibrational stimulation is used in combination with electrical stimulation. In some embodiments, the vibrational stimulation and electrical stimulation are located at the same location or at different locations. In some embodiments, the vibrational stimulation is used to preferentially stimulate proprioceptors (e.g., A fibers), and the electrical stimulation is used to preferentially stimulate different types of sensory fibers, such as pain or tactile sensory fibers (e.g., C fibers), or vice versa.

[0171] In some embodiments, chemical stimulation is used in combination with electrical stimulation. In some embodiments, the chemical stimulation and electrical stimulation are located at the same location or at different locations. In some embodiments, electrical stimulation is used to preferentially stimulate proprioceptors (e.g., A fibers), and chemical stimulation is used to preferentially stimulate different types of sensory fibers, such as pain or tactile sensory fibers (e.g., C fibers), or vice versa.

[0172] Events that alter the pattern may include biomarkers of the disease state (e.g., patient-reported symptoms, activity levels, tremor motor characteristics, neurological integrity). The pattern can be controlled by the prescribing physician. The pattern can be controlled by the end-user or the patient. The pattern can be pre-programmed for specific times of day. The pattern can be controlled by measures of voluntary activity, including HRV, GSR, MSNA, etc.

[0173] Some examples of patterns that can be used in combination include two or more different stimulation parameters (e.g., frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, burst, etc.). Multiple patterns can be combined with multiple modalities, each modality having multiple patterns or one or more modalities having different patterns. The first stimulus may include a burst stimulus and the second stimulus may include a continuous stimulus. The first stimulus may include a first frequency (e.g., about 20 Hz) and the second stimulus may include a second frequency (e.g., about 40 Hz). The first stimulus pattern may include between 100 Hz and 200 Hz (e.g., 150 Hz). The second stimulus pattern may include between 50 Hz and 150 Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be burst-on / off at frequencies between 4 and 12 Hz in an alternating pattern, such as in a burst pattern (e.g., 10 Hz). The first stimulus may include a first waveform and the second stimulus may include a second waveform different from the first waveform. In some embodiments, different stimulation parameters are used in the same region at the same nerve bundle, in the same region but in different nerve bundles (e.g., different points), and / or at different locations.

[0174] Shape factor: Universal wearable stimuli Reference Figures 14A-14E The system 700 from Figure 7 can be non-invasive, fully implantable, or partially implantable. For example, a non-invasive embodiment may include a non-invasive housing, such as a sleeve 1400, a patch 1410, or a glove. In such a non-invasive embodiment, the housing interface communicates with an external portion of the patient. In some embodiments, one or more of the system components may be implanted 1420. For example, when the power source is external to the patient, at least a portion of the effector and / or housing interface may be implanted into the patient at a contact point.

[0175] The non-invasive system housing facilitates maintaining the interface and / or effector near the patient. The sleeve may cover a long segment of the arm or may be a narrow band. The sleeve may cover at least a portion of the circumference of any part of the limb, or the sleeve may cover the entire circumference of any part of the limb. The function of the sleeve may be to maintain the position of the external device relative to the implant. The purpose of maintaining position may include achieving good power transmission, reliable communication, or other purposes.

[0176] The housing can be made of any material suitable for achieving the desired performance. For example, the housing material can be a flexible and / or stretchable material, polymer, or fabric. The housing may include fasteners such as Velcro, ties, elbows, and / or cable ties to secure the device to the patient. The housing may include multiple layers and / or pockets configured to hold various components of the system disclosed herein.

[0177] The system can be positioned by a patient with or without caregiver assistance. In some embodiments, the system may have assistive mechanisms for positioning it on the arm, such as pressure-responsive snaps and / or self-aligning magnets. In some embodiments, such as sleeve 1400, the system may slide on the end of the limb (similar to a motion sleeve) or wrap around or self-wrap around the arm (similar to a snap-on strap).

[0178] In some embodiments, the housing may take the form of a patch 1410. For example, the housing patch 1410 may be attached to the patient's skin using a removable or biodegradable adhesive. The patch may be worn multiple times, including but not limited to patches worn only during a stimulation cycle and patches left in place for days, weeks, or months. The patch may also be mechanically, chemically, or electrically attached. Such embodiments include, but are not limited to, pins, wires, or magnets for securing the patch in a desired location.

[0179] In some embodiments, the non-invasive system may include an interface that communicates with a patient but is not attached to the housing. For example, the system may be an external device with which the patient interacts. For instance, the housing may be an open or closed tubular structure in which the patient can place a limb. Figure 14D As shown, another example includes an external device similar to the pad 1430 or a support structure such as a wrist pad or support, on which a patient can place at least a portion of a limb.

[0180] In one embodiment, the housing 1450 may be configured as a watch worn on a user's wrist or arm, such as Figure 14H-14LAs shown. Housing 1450 may include interface 1452, which is detachable, partially detachable, or connected to housing and can interact with a user. Interface 1452 may be connected to housing 1450 and may be discarded after a period of use. Electrodes 1454 of the interface may be arranged in a strip and may be arranged as an anode / cathode pair. Other electrode configurations described herein may also be used. The period of use may be after a single use, or after multiple uses within a period of minutes, hours, days, weeks, or months. The interface itself may be an entire part of the wristband, or may be part of the wristband or attached to the wristband. The wristband itself may be part of the interface, or may be part of the housing, or may be both. In one example, a wristband with or without an interface may fasten around the wrist by including a feature of an elastic material that is slightly curved so that the wristband wraps around the wrist in a circular shape when moved. In another example, a temperature-sensitive material with shape memory (e.g., nitinol) is present, such that when the device comes into contact with the skin, the wristband with or without an interface may change shape to wrap around the patient's wrist. In another example, the wristband, with or without an interface, has one or more metal wires inside or outside the wristband that maintain a new shape during movement to allow the user to place the device on their wrist and apply force to shape the wristband into the user's unique anatomy. In yet another example, the wristband, with or without an interface, partially or completely wraps around the wrist. This wrapping can be on the same axis or can be helical.

[0181] Disposable or non-disposable interfaces can be attached to the housing in a variety of different ways, including but not limited to snap-fit ​​features, Velcro, press-fit, magnets, temperature sensors, and adhesives, and may or may not include self-aligning features. The connection can be on one or more dimensions or axes. As an example, Figure 14J-14L One possible embodiment is shown, in which a self-aligning element, which may be a magnet, connects the interface to the body in three dimensions. The circular shape of the alignment element allows for alignment in a first dimension within a plane. A rod-shaped portion of the alignment element, offset from the circular feature, allows for alignment of the interface along a suitable axis. The overall shape of the alignment element allows for alignment of the interface in a final dimension, which in this particular example of the embodiment is depth. The housing may have a matching feature of this shape, to which a connecting portion can be attached. It is possible that the connecting feature is reversible, and the alignment element can be placed on the housing, and the matching feature of the shape can be placed on the interface. These connecting portions of the alignment element may or may not have magnets on one or both of the housing or interface components.

[0182] In some embodiments, the external device may be an object not worn on the body. For example, it may have the shape factor of a mobile phone and be carried by the patient in their pocket, bag, hand, or in other ways that transport and support the phone, such as on a table. It may be designed to sit on a furniture surface in a location where the patient wants to control their tremors, such as at a dining table, in a kitchen, or in their dressing room.

[0183] like Figure 14M As shown, another preferred embodiment may include a stimulation device having one or more electrodes 1460 applied along the spine. The stimulation device can be used to stimulate the release of neurotransmitters and reduce tremors by neuromodulation of nerves located along the spine. Stimulation can affect the release and uptake of neurotransmitters, thereby affecting the nerve-innervated area of ​​the tremor. The electrodes are preferably placed on the skin surface at the base of the cervical vertebrae, preferably from C1 to C8, but most preferably between C5 and C8. The electrodes are preferably patch electrodes. The operating unit is preferably attachable to a user, and the leads connecting the electrodes to the operating unit are preferably magnetized for easy connection. The operating unit can be connected to and controlled by a processor. Because the electrodes are preferably placed along the spine (behind the user), a separate and portable control module is more convenient for user operation.

[0184] In some embodiments, neurotransmitters such as dopamine, serotonin, GABA, etc., are increased or decreased via neuromodulation devices described herein (e.g., electrical, vibrational, ultrasonic (e.g., focused ultrasound), radiofrequency, etc.) to treat tremors, overactive bladder, cardiac dysfunction, depression, anxiety, migraines, and other conditions. While the spine can be one location, other locations include the wrist, hand (including fingers), upper arm, head (including scalp, ears, face, temples), leg, foot (including toes), and other locations. Two, three, or more locations can be used to produce synergistic therapeutic effects.

[0185] In one embodiment, electrodes may be placed near the C2 to C8 regions of the neck and shoulder on either side of the spine. The electrodes may be placed approximately 100 cm to 1 cm from the spine and spaced 200 cm to 5 cm apart. Stimulation parameters may include a phase duration between 500 and 30 μs, preferably 300-60 μs (microseconds). The pulse rate may range from 10 Hz to 5000 Hz or higher (e.g., 20 kHz), and a preferred range is 50 Hz to 200 Hz or 150 Hz. The cycle time may be continuous or range from 5 seconds to 1 hour. A preferred cycle time is approximately 5 seconds to 20 seconds or 10 seconds. The duration of electrical stimulation may range from 5 minutes to 24 hours per day. A preferred range may include 30 to 60 minutes repeated approximately 10 times per day, or a preferred range may be approximately 40 minutes to 1 hour per day, repeated weekly to daily. The amplitude (which can be used interchangeably with intensity) can range from 0.1 mA to 200 mA, and a preferred range can include 1 mA to 10 mA. The duration for which the device can be used by the user before it affects the user's tremor can range from one day to one month, or preferably from two days to four days.

[0186] Shape factor: for electrical stimulation Conventional TENS devices are often difficult to position, bulky, and uncomfortable. The following innovations offer a solution that allows for easy and rapid application and adjustment of stimuli to control ET, enabling patients to use it independently and comfortably.

[0187] Using conventional TENS devices, it is difficult to correctly set the size and position of the adhesive electrodes to optimally target the desired nerve. Smaller electrodes increase the current density at the target nerve, but with smaller pads, they are likely to miss the nerve, and the higher current density from smaller electrodes can cause discomfort. Larger pads are easier to place, but require more power and are more likely to unintentionally stimulate adjacent tissues. The following innovations address these challenges and achieve consistent, effective, comfortable, and safe stimulation.

[0188] like Figures 15A-15CAs shown, the device may include an array of electrodes 1500, rather than using only a single electrode as a cathode and a single electrode as an anode. Although the electrodes are shown individually on the patient's skin for clarity, in practice, the electrode array may be integrated into a sleeve, flexible pad, or substrate, or other form factor described herein. An appropriate combination of electrodes will be selected each time the device is repositioned or based on the detected stimulation requirements. Stimulation may use a single electrode as both anode and cathode, or a combination of electrodes may be used to shape the stimulation field. Electrode selection may be automated based on feedback from sensors within the device (see below). In some embodiments, electrode selection may be performed manually by the user. For example, the user may cycle through electrode combinations until they find an alternative combination that provides optimal tremor reduction or achieves proper placement, such as the tingling sensation in the first (index) and second fingers accompanying median nerve sensory stimulation. Figure 15A A two-dimensional array of discrete electrodes 1500 is shown. In some embodiments, some electrodes may be combined into linear rows, such that the two-dimensional array is formed by multiple rows of electrodes. Figure 15B A linear array of electrodes 1500 is shown, which can be worn as straps, patches, pads, sleeves, etc., as shown in the figure. Figure 15C A housing 1502 is shown that can be used to hold an array of electrodes 1500.

[0189] In some embodiments, electrical stimulation from a poorly localized electrode can be redirected to the target nerve by modifying the conduction pathway between the electrode and the target nerve. For example, a conduction pathway enhancer 1600, which may be made of a conductive material, may be placed on the patient's skin, embedded in the skin, implanted, or a combination of the above methods to enhance the conduction of electrical stimulation from electrode 1602 to target nerve 1604, such as... Figures 16A-16D As shown. Conductivity enhancers can be placed above and / or across a nerve. For example, in one embodiment, a conductive ink tattoo can redirect stimuli deviating from the target to the median nerve. A tattoo with higher conductivity than adjacent structures (e.g., blood vessels, nerves) will provide a path of minimum resistance and redirect current. To place or position a conductive tattoo, the target nerve must first be actively identified. The conductive tattoo is then placed on the target nerve. Figures 16A-16D As shown, a conductive tattoo may include multiple conductive strips that cross a nerve. In some embodiments, the strips may be parallel to each other and cross the nerve laterally. In other embodiments, the strips may be formed as a star-shaped or crosshair pattern with their center located above the nerve. In still other embodiments, the strips may also be placed above and parallel to the nerve (not shown).

[0190] For user adoption, wearable devices should be discrete and comfortable. Figure 14B and Figure 14FIn the preferred embodiment shown, for example, the effector is electrical, and the skin patch has an electronic device (similar to a band-aid) with a single or multiple electrodes printed in a predetermined pattern onto a flexible substrate to form a "second skin." For optimal comfort and surface adhesion, mechanical properties such as elasticity and stiffness should match the skin. Circuitry and wiring for surface electrical stimulation can be printed or etched into a flexible material so that the device conforms to the body or tissue within the body. For example, it can be copper printed on a flexible substrate such as plastic.

[0191] In such Figure 14G In another embodiment shown, the device may be positioned on a body surface but includes percutaneous penetrating elements 1470 to improve effects on nerves. These elements may be microneedles, which are used to improve stimulation and / or drug delivery. In some embodiments, the percutaneous penetrating elements may form a microelectrode array that is placed on the skin surface and penetrates the skin. The microelectrode array can function like microneedles and can improve signal transmission from the electrodes to nerves and improve skin permeability, thereby improving local drug delivery.

[0192] Sensor: Sensor Type The device or system may include sensors. Sensors used to monitor tremor may include combinations of the following: single-axis or multi-axis accelerometers, gyroscopes, tiltmeters (for measuring and correcting for changes in the gravitational field caused by slow changes in device orientation), magnetometers; fiber optic goniometers, optical tracking, or electromagnetic tracking; electromyography (EMG) for detecting tremor muscles; electroneurography (ENG) signals; cortical recordings via techniques such as electroencephalography (EEG), or direct neural recordings on implants adjacent to nerves. Figures 17A to 17B The image shows a representative location of the motion sensor on the 1710 hand or 1720 wrist. Other tracking locations may include fingers or other body parts.

[0193] Data from these tremor sensors are used to measure a patient’s current and historical tremor characteristics (such as amplitude, frequency, and phase). These sensors can also be used to determine the presence or absence of tremor in activities such as distinguishing involuntary movements (e.g., tremor) from voluntary movements (e.g., drinking water, writing) or relative to the time of day or other detected activities (such as sleep / wake cycles).

[0194] The device may also include sensors for providing performance and usage data, including when the device is worn (e.g., from a temperature sensor), the device's location (e.g., from GPS), battery level, or video recording. In another embodiment, the sensor is a temperature sensor for measuring the temperature of a cooled limb. In another embodiment, the sensor includes video recording. In yet another embodiment, a sensor from existing hardware such as a smartphone is used. For example, an accelerometer on a smartphone or engaging the patient in a tremor-inducing writing task (by analyzing lines drawn on the smartphone screen) can be used to measure tremor.

[0195] Sensors: Algorithms used to extract tremors In several embodiments, the algorithm will be used to extract information about tremors from the data stream provided by the sensor. Tremors can be identified based on their time-domain signal, frequency-domain signal, amplitude, or discharge pattern (e.g., bursts, spikes). For example, in Figures 18A to 18B In the analysis of the spectral power of the gyroscope motion data, the frequency analysis indicates that the center of the jitter is at approximately 6.5 Hz (see the maximum power in the graph below).

[0196] Motion data can be acquired as a single raw sensor channel or by fusing raw signals from multiple sensors. As an example, multi-axis accelerometer data can be combined into a single value for analysis. The algorithm extracts motion data in the 4 to 12 Hz range to remove motion not attributable to tremor. This can be done using any combination of notch filters, low-pass filters, weighted frequency Fourier linear combiners, or wavelet filters. Since each patient has a dominant tremor frequency, this range can be narrowed based on a specific understanding of the patient's tremor or tremor history. For example, for a patient with a 6 Hz tremor, the analysis algorithm might extract motion data only in the 5 to 7 Hz range. If the patient's tremor is known to cause a maximum of 5 degrees of wrist flexion and extension, the analysis algorithm will determine that a measured movement at 45 degrees of wrist flexion is likely due to intentional overall movement rather than tremor. In some embodiments, the algorithm samples motion data by identifying time periods that may correspond to posture maintenance or fine motor tasks.

[0197] Once the appropriate motion data has been extracted, the algorithm will analyze the key characteristics of the tremor, including amplitude, center frequency, spread spectrum, amplitude, phase, and spectral power.

[0198] Sensor fusion technology can also be used to analyze different aspects of tremor. For example, multi-axis accelerometers and gyroscopes attached to the back of the hand can be combined to reduce noise and drift and determine the hand's accurate orientation in space. If a second pair of multi-axis accelerometers and gyroscopes is used on the wrist, the joint angle and position of the wrist can be determined during tremor. This can isolate which nerve stimuli and which types of stimulation cause damping in the different muscle groups that control tremor.

[0199] Patients with ET have two components of their tremor. Kinetic tremor is present during intentional movement and has a significant impact on quality of life because it affects a person's ability to perform daily tasks such as drinking, eating, writing, and dressing. Postural tremor is present during static positions maintained against gravity. Although they have a smaller impact on quality of life, they can be embarrassing. Postural tremor is usually present earlier in the disease progression and is thought to cause kinetic tremor. Both components are typically in the range of 4 to 12 Hz, with older patients experiencing lower frequency tremors.

[0200] Detecting postural and kinetic tremors is more challenging than detecting resting tremors. Resting tremors are present in other movement disorders, including Parkinson's disease, and can be easily identified by analyzing tremors that are present only when the limb is at rest. Extracting kinetic tremors from motion data is challenging because it is necessary to distinguish between movements caused by tremors and movements caused by tasks.

[0201] Identifying postural tremor may be easier than kinetic tremor because accelerometer / gyroscope data during kinetic tasks can be corrupted by the movement during the task. Postural tremor is thought to cause kinetic tremor because people typically develop postural tremor earlier in life and they occur at approximately the same frequency. Figure 19 As shown, the correlation between postural tremor and kinetic tremor that we found in our clinical studies supports the theory of using postural tremor data to analyze or treat kinetic tremor.

[0202] Custom processing based on feedback and / or algorithms is provided in several embodiments.

[0203] Sensors: Data Storage and Use like Figure 20 As shown, the stimulation device 2000 may include hardware, software, and firmware to record data (such as tremor characteristics, stimulation history, device performance, use, and / or control) and transmit it to a data portal device 2002 (such as a smartphone, mobile phone, tablet computer, laptop computer, desktop computer, or other electronic device using a wireless communication protocol such as Bluetooth).

[0204] Data recorded using devices used by ET patients can be stored on a smartphone, which then transmits the data to a cloud-based database / server 2004. Alternatively, the devices used by ET patients can directly transmit data to the cloud-based database / server 2004, enabling numerous activities including tremor tracking, stimulation optimization, sharing with caregivers and physicians, and community building. The data can inform controllers, provide real-time feedback to patients, caregivers, and / or clinicians, or be stored to provide historical data to patients, caregivers, and clinicians. Data stored in the cloud 2004 can be viewed by multiple users 2008 on multiple platforms 2006. Furthermore, data in the cloud 2004 can be pooled and analyzed by computing devices 2010.

[0205] Tremors are typically monitored every few months or once a year during a patient's doctor's visit. This monitoring is usually highly subjective. Furthermore, the severity of tremors can be significantly influenced by many factors, including sleep patterns, emotional state, prior physical activity, caffeine intake, food, and medications.

[0206] This infrequent and inaccurate monitoring limits the ability of patients, their caregivers, and physicians to understand the severity and progression of a patient's tremor, as well as the impact of various treatments and behaviors. These factors can interact with the effects of the stimulation provided by the device, and these interactions can be difficult to detect. Identifying these interactions can optimize treatment and help patients better understand how their behavior affects their tremor.

[0207] exist Figure 21A In one embodiment shown, tremors are monitored 2100 using sensors, which may be an IMU, electrodes, or any other sensors previously discussed. Monitoring may be continuous or over discrete time periods. 2110 Data from these sensors is analyzed to identify changes in tremor characteristics (amplitude, frequency, etc.) over time. The results are recorded and displayed to the user 2120. Analysis 2110 and / or display 2120 may be performed on the stimulation device itself or by transmitting the raw or analyzed data to an auxiliary device such as a smartphone or computer.

[0208] In another embodiment, behavioral data (2101) may also be collected, allowing analysis to examine the relationship between tremor history and user behavior. Behavioral data may include caffeine, alcohol, medication consumption, and anxiety levels. The system can then alert the patient to the interaction between behavior and tremor.

[0209] In another embodiment where the device is therapeutic (e.g., if it has an effector), a stimulation history can be collected, allowing analysis to examine the relationship between the stimulation history and tremor characteristics.

[0210] Figure 21B The illustrated embodiment adds an upload 2140 to the cloud. The order of the upload 2140 and analysis 2110 can be interchanged, allowing analysis (not shown) to be completed on a machine before uploading. The use of the cloud enables the display of results 2120 to a user on various networked devices, including smartphones, tablets, laptops, and desktop computers; the display of results 2150 to other users such as physicians or caregivers; or pooled analysis 2160 for multiple patients.

[0211] Figure 21C Some potential uses of pooled data are shown, including connecting patients with similar patients based on features such as the patient's tremor characteristics, geography, age, and gender 2170, or improving stimulation algorithms 2180.

[0212] Figure 21D This demonstrates how it can be used in a closed loop. Figure 21A -C indicates that data monitoring and analysis are used to adjust stimulation parameters. In this way, the algorithm detects the interactions between variables to optimize treatment.

[0213] The device may include closed-loop control of stimulation to adaptively respond to the detected tremor or activity level. The device achieves tremor sensation through activity sensors, data recording, and systematic tuning of stimulation parameters to achieve optimal tremor reduction. Figure 26A This is a control diagram illustrating the basic components of the detection and response system. Target 2650 defines the expected profile. For example, in ET patients, this profile might be the absence of tremor, and in PD patients, it might be the absence of tremor or rigidity. The error 2670 between target 2650 and detection 2660 is fed to controller 2680, which modifies output 2690. Controller 2680 may include a processor and memory. In addition to the error and measurement, the algorithm of controller 2680 may also incorporate measurement history, stimuli, and activity inputs. Output 2690 modifies the stimulus. If the effector is electrical, this may include modifying the waveform, frequency, phase, position, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, burst, and / or amplitude of the stimulus. In a preferred embodiment (Figure 15), the device comprises an array of small electrodes and the output modifies the selection of electrodes to be used as anode and cathode. The effect of the modification 2660 is then detected by a measuring device, and the process is repeated. Modifications to detection 2660 and / or output 2690 can occur continuously in real time, with periodic delays between predefined time intervals (e.g., hourly or daily), or in response to user-generated signals such as a predefined sequence of motion or button presses. In some embodiments, the controller can alert the patient to manually modify the stimulation parameters. This closed loop can be used for automatic self-calibration.

[0214] Figure 26B A control diagram showing the basic components of this detection and response system is shown, which is similar to... Figure 26A The description shown is now about the components located inside and outside.

[0215] The control can also take into account other behavioral patterns, more like a feedforward controller 2640. For example, typical patterns of eating times can cause effectors to fire more actively at specific times to reduce tremors during these activities. Furthermore, people can be instructed in their schedules based on their daily activities, such as whether they wish to increase treatment during certain time periods, for example, whether they have given a speech or other anxiety-inducing events. This type of information can also be acquired and learned by the control unit over time. Other data collected through other mobile technologies and applications (such as Azumio, Jawbone, Fitbit, etc.) such as sleep, food intake (especially alcohol and caffeine intake), exercise history, emotional state (especially anxiety levels), and medication use can be integrated into a cloud-based patient database, such as… Figure 20 As shown in Figure 21, users can be prompted to input data such as using an imaging processing application to take photos of meals to determine food intake. The database combines discrete events (e.g., the time and amount of caffeine intake) with time-series data (e.g., tremor measurements). The algorithm will examine the relationship between patient behavior, stimuli, and tremor. These will optimize stimuli and alert the patient to behaviors that affect tremor. This will allow for individually optimized treatments for tremor and feed them forward into the system.

[0216] In some embodiments, the device or mobile phone may prompt the user to perform a specific task at a predetermined time. This task may be tailored to the type of tremor afflicting the patient, such as holding the arm in a specific posture for ET or keeping the arm in a static position for Parkinson's disease. During this time, sensors may record the tremor. In some embodiments, the patient may be additionally or alternatively instructed to drink caffeine or the time elapsed since their last caffeine consumption may be recorded. This data can be used to determine how caffeine affects the tremor, the effectiveness of treatment regimens and stimulation parameters, the duration of effectiveness, etc. In some embodiments, the patient may be prompted at a predetermined amount of time after stimulation, such as 10 minutes, 20 minutes, 30 minutes, and / or 60 minutes. The timing may be adjusted depending on the duration of the measured reduction in tremor after stimulation.

[0217] The device will have onboard data logging capabilities and can transmit this information to external data portal devices, such as smartphones or internet-enabled charging and sync stations. This transmission can be wireless or direct. External devices will have greater storage capacity and allow transmission to databases in the cloud. The external device can analyze this data on the machine and present the information on a screen or using indicators such as LED lights, or it can display the data on the device itself.

[0218] Data in the cloud can be viewed on multiple platforms, including smartphones, tablets, and computers. The data can be viewed by multiple people, including the user, their physician, caregiver, or family member. This allows for a more comprehensive understanding of the patient's tremor and enables optimized treatment. In some embodiments, users viewing the data can also add comments and annotations, which can be tagged with the identity of the user making the comment or annotation and the time when the comment or annotation was made. In some embodiments, the ability to annotate may be limited to healthcare providers (such as the patient's physician) and the patient.

[0219] In some embodiments, access to the data is limited to healthcare providers and patients. Access can be restricted by requiring users to set secure usernames and passwords to access the data. In some embodiments, patients may also grant access to the data to others, such as family and friends.

[0220] Algorithms for optimization Our data indicate that stimulation using the TENS device is highly effective in some patients, slightly effective in others, and ineffective in still others. However, optimization of stimulation parameters (stimulation intensity (e.g., amplitude), frequency, phase, waveform (e.g., shape, symmetry), duty cycle, phasing, pulse width, pulse interval, duration, on / off time, bursts, etc.) allows the device to achieve maximum tremor reduction with maximum comfort in each patient and allows the device to adjust over time in response to changes in circuit dynamics, device position, patient status, etc. Figure 22 The decision-making algorithm / controller used for the device is shown.

[0221] In one embodiment, the optimization algorithm begins by initializing one or more parameters 2200, which may include stimulus amplitude, expected frequency, on-time duration, off-time duration, and expected stimulus effect delay time. Next, the sensor detects 2202 and records tremor characteristics, including tremor amplitude, frequency, phase, and other characteristics described herein. The detected tremor characteristics 2202 are compared with a desired target tremor characteristic 2204, which may be no tremor or reduced tremor. A comparison step 2206 determines the error or difference between the detected tremor characteristics and the target tremor characteristics, and determines whether tremor or reduced tremor exists 2208, or in other words, whether the detected tremor meets or exceeds the target condition. If no tremor is detected, or more generally, if the predetermined target tremor condition is not exceeded, the algorithm loops back to detection step 2202. If tremor is detected, or more generally, if the predetermined target tremor condition is exceeded, stimulation 2210 can be activated. Once the stimulation has exceeded the set on-time duration 2212, the stimulation is turned off 2214, and the algorithm proceeds to the detection step 2202. When the stimulation is on, the device can upload the recorded data 2218 to the cloud or another device for further processing. Once the stimulation 2214 has been turned off, the algorithm can monitor the off-time duration 2216 and continue uploading data 2218 once the off-time duration has elapsed. In some embodiments, data can be uploaded even before the off-time has elapsed. User-reported events 2220 (which may include caffeine or alcohol intake, anxiety, and other events that may affect tremor) can also be input into the system and sent to the cloud. The data can be processed by a controller 2222, which can use various algorithms, including machine learning algorithms, to optimize the stimulation parameters. Once the parameters are optimized, new stimulation parameters are set 2224. A report 2226 can also be sent to the patient, highlighting or correlating various behaviors identified in the user-reported events with the measured tremor.

[0222] In one embodiment, the stimulation algorithm is designed to optimize the timing of the therapy “on”. The optimization algorithm can find the best solution for the output, including but not limited to controlling tremor during a specific task, at a specific time of day, at a specific location, or simply optimizing the overall daily minimization of tremor. The algorithm can be self-calibrated to adjust stimulation parameters, including but not limited to frequency, amplitude, pulse width, electrode selection for the cathode and anode, and / or the timing of turning stimulation on and off. The algorithm can respond to user input or can be fully pre-programmed. The algorithm can be a learning algorithm for customizing stimulation over time to adjust in real time according to the patient’s tremor or patient-defined needs. The on / off stimulation can be triggered in response to input, including but not limited to user input (e.g., turning the device on or off), time since last use, time of day, tremor detection (e.g., via an accelerometer), electronic recording, or an algorithm based on previously described or other inputs. For example, a user can use voice activation to turn off the device to utilize a treatment window (e.g., the time of tremor reduction after stimulation is turned off) to provide the stable time intervals required for intentional movement. In another example, the user bites down or uses the tongue muscles (detected by an external device placed inside or outside the mouth), which signals to shut off the stimulation and allows the user to stabilize their arm, thus enabling them to perform intentional movements stably. In some embodiments, the system and algorithm may detect the type of tremor based on analysis of tremor parameters and measured patient activity, such as distinguishing between postural and kinetic tremors. In some embodiments, stimulation parameters may be determined in part based on the type of tremor detected.

[0223] In some embodiments, the system may be controlled by an event trigger. The event trigger may include defined motion, temperature, voice activation, GPS location, or data received by sensors, or any combination thereof. For example, the device may be turned on or off during intentional motion prior to the onset or end of tremor. In another example, the device may be turned on or off when a specified temperature is reached. The system may function to achieve a desired tremor suppression profile. For example, control may be applied during the desired tremor suppression period; its effect may persist beyond device use prior to the desired tremor suppression period; and / or the device may be activated in response to tremor detection.

[0224] According to several embodiments, the system may use sensors to determine whether a modality, combination of modalities, or modal setting is effective and adjust one or more modal parameters to improve the response. For example, if a wearable device includes an electrical effector and a vibration effector, but the setting is not effective (e.g., due to tolerance accumulation), parameters of the electrical stimulation (e.g., frequency, amplitude, pulse width, duty cycle, phase, waveform shape, waveform symmetry, pulse interval, duration, on / off time, burst, etc.) may be modified, and / or parameters of the vibration stimulation (e.g., frequency, amplitude, pulse width, duty cycle, waveform shape, phase, waveform symmetry, pulse interval, duration, on / off time, burst, etc.) may be modified. In some embodiments, a modality may be deactivated. In some embodiments, a new modality may be added (e.g., replacing a deactivated modality or adding it to one or more existing modalities).

[0225] Optimization based on community data Currently, little is known about the time course of tremor. While creating a database for a single patient would improve our ability to reduce that patient's tremor, combining individual patient data into a database that includes records from many patients would allow for the application of more powerful statistical methods to identify optimal stimulation parameters. In some embodiments, data from patients with the same type of tremor may be combined. In some embodiments, tremor data from each patient may include searchable and categorizable metadata, which allows data to be collected in a database for categorization, searching, and / or reorganization as needed. Metadata may include the type of tremor (tremor amplitude, tremor frequency, tremor temporality, etc.), name, age, ethnicity, sex, location, time, food and beverage consumption (especially for caffeine and alcohol), activity history (exercise, sleep, etc.), medications, past treatments, and current treatments.

[0226] The above is for Figure 20 The system described in Figure 21 is applicable to data from many patients entering the database, and the algorithm can operate on large datasets.

[0227] Community building Individuals with ET often feel isolated due to the disability associated with their tremor. Therefore, they are very proactive in connecting with others who have ET. There is an active and growing collection of support groups that organize meetings and allow ET patients to talk about their problems and discuss possible solutions. Attending these meetings can be challenging because some ET patients have difficulty driving. Similarly, individuals attending support groups within a specific geographical area may have different symptoms from each other, and they may lack the ability to identify other patients who are most similar to them.

[0228] Algorithms can help individuals find members of ET communities with similar profiles. For example, an algorithm can characterize a patient based on their age, tremor severity, tremor characteristics, treatment success, type of treatment, type of medication, location (based on address or GPS), and other characteristics. This will help them communicate with each other and share information from a central community website tailored to specific individuals with ET or their caregivers. For example, the system can identify patients within a geographic location or other patients within a predetermined distance of a specific patient. Patients can choose to join an online ET community and make their location searchable on the system. The system can also identify existing ET community support groups within a predetermined distance for the patient.

[0229] Other processors, libraries, data storage devices For example, such as Figures 7A-7D As shown, processor 797 can manipulate data, perform calculations, and control other components of the tremor reduction device. It is preferably a microprocessor or microcontroller with peripheral devices. For example, the processor can receive input from the user via control module 740 and can control the execution of stimuli selected by the user. In another embodiment, processor 797 can execute predefined stimulation protocols selected by the user. These stimulation protocols can be found in a digital library 798 of stimulation protocols, which can be loaded into processor 797 or stored in external memory (such as EEPROM, SD card, etc.). Processor 797 can also receive information from sensor 780 and process that information on the machine, adjusting the stimulation accordingly. The choice of processor is determined by the degree of signal processing it needs to perform and the number and type of peripheral devices that need to be controlled. For example, communication with peripheral devices can be performed via any well-known standard such as USB, UART, SPI, I2C / TWI. The processor can also communicate wirelessly with other device components using Bluetooth, Wi-Fi, etc. The processor can transmit tremor data on the device or via a wireless link between the processing unit and the stimulation unit.

[0230] In embodiments with electrical stimulant 730, the preloading protocol 798 may be electrical stimulation or an electrical stimulation sequence. Electrical stimulation or an electrical signal refers to an electrical pulse or a pattern of electrical pulses. Electrical stimulation may include parameters such as pulse frequency, amplitude, phase, pulse width or duration, duty cycle, waveform shape, waveform symmetry, pulse interval, on / off time, or bursts of electrical stimulation. These parameters may be predefined or controlled by the user.

[0231] The data storage unit 770 can be used to store, preferably, operational statistics and usage statistics of the device in a NAND flash memory. NAND flash memory is a non-volatile data storage device that does not require power to retain stored information and can be electrically erased and rewritten. In some cases, it may be advantageous to be able to remove this memory in the form of a micro-SD card.

[0232] power supply The effector can be electrically coupled to one or more power sources, for example, such as Figures 7A-7D As shown. Power supply 750 is used to power the device. Power supply 750 can be connected to processor 797 and provide power for processor operation. The power supply is preferably rechargeable and removable, as this allows for reuse of the device. The power supply is preferably a battery. Several different chemical combinations are typically used, including lead-acid, nickel-cadmium (NiCd), nickel metal hydride (NiMH), lithium-ion (Li-ion), and lithium-ion polymer (Li-ion polymer). Methods for recharging the battery are preferably attached to a wall socket or other power source, solar, radio frequency, and electrochemical. In some embodiments, the power supply is a supercapacitor. Supercapacitors can be classified into three different series—double-layer capacitors, pseudo-capacitors, and hybrid capacitors. Supercapacitors are preferably made of nanoporous materials, including activated carbon, graphene, carbon nanotubes, carbide-derived carbon, carbon aerogels, solid activated carbon, tunable nanoporous carbon, and mineral-based carbon. The advantages of supercapacitors are faster charging than batteries and greater tolerance to charge and discharge cycles. Batteries and supercapacitors can be used in combination because the tolerance of supercapacitors to numerous charge-discharge cycles makes them ideal for parallel connection with batteries and can improve battery performance in terms of power density. In some embodiments, the power source can utilize energy from the body. In some embodiments, electricity can be utilized via kinetic energy, thermal energy, and / or sound. In some embodiments, the power source may include a plug leading to an external source, such as a general utility. Two, three, or more power sources may be provided for a single device. In some embodiments, low-profile and lightweight devices are used to increase patient compliance. In some embodiments, water-resistant or waterproof devices are provided.

[0233] In one embodiment, a dedicated charging station or docking station can be used to recharge the device. The advantage of a dedicated charging station is that it also facilitates uploading data from the device to the Web via Wi-Fi or other communication protocols.

[0234] implants In some embodiments, at least a portion of the system is implantable. Implanted stimuli offer better control and comfort compared to surface stimuli because they are located closer to nerves and avoid stimulating afferent sensations through the skin.

[0235] Methods for stimulating peripheral nerves to control hand tremors set specific requirements for suitable implantable stimuli. First, the implant should be small to minimize invasiveness in the process of positioning and fitting it into place. Second, because stimulation may respond to detected tremors or user input, the implant should be able to receive communication from external devices. Third, the device should tolerate changes in the position of external devices.

[0236] Any number of system components disclosed herein can be implanted. In some embodiments, a housing, interface, effector, and power supply are implanted, and the controller is external to the patient. In such embodiments, the controller may, for example, communicate wirelessly with the effector. In other embodiments, the power supply is external to the patient.

[0237] The device can be implanted subcutaneously, partially, or percutaneously (through the skin), on the surface of the skin, or without contact with the body. It may be a component of these devices, such as a surface part that communicates with or powers the implanted part. If the device is implanted, it can be placed in or around nerves, muscles, bones, ligaments, or other tissues.

[0238] In one embodiment, the implant is positioned within or near the carpal tunnel to affect the nerves passing through it. In another embodiment, the implant is located on or near the median nerve in the upper arm between the biceps brachii muscles. In another embodiment, the implant is positioned on or near the median, radial, or ulnar nerves in the forearm or wrist. In yet another embodiment, the implant is positioned on or near the brachial plexus to affect proprioceptive nerves transmitting signals from the arm toward the central nervous system.

[0239] The implant can be placed or delivered intravascularly to affect nerves in the area within the implant's effective range. In one example, the device is placed within or through the subclavian artery or vein to affect the brachial plexus.

[0240] like Figure 23As shown, a preferred embodiment of a controllable device for reducing a user's basic tremor includes: an electrode 2310 made of a biocompatible material, at least partially implanted subcutaneously to stimulate a target nerve; and an external operating unit 2320 containing a user control interface connected via wires to the implanted electrode 2310. The device may include additional components, such as: a processor 797 that performs calculations and controls other components; a processor-controlled function generator; a digital library 799 stored in the processor or memory containing pre-loaded conditioning protocols; a sensor 780 connected to or communicating with the processor 797 that detects predefined parameters and transmits that parameter information to the processor; a data storage unit 770 connected to the sensor and the processor; and a power supply 750.

[0241] In this embodiment, the implanted electrode 2310 can be used to deliver direct electrical stimulation to a target nerve. Since the electrode is at least partially implanted in the body and will remain there for an extended period (preferably several years), it can be made of a material with suitable electrical properties and biocompatibility. The material of electrode 2310 is preferably selected from the group consisting of silicone, PTFE, parylene, polyimide, polyesterimide, platinum, ceramic, and gold, or natural materials such as collagen or hyaluronic acid. Electrode 2310 can have varying shapes and sizes, but it is important to contact the nerve of interest. Electrode shapes include planar stalks, simple and uniform microfilaments, and probes that taper from a wider base to a narrower tip. The electrode may have a proximal end and a distal end. The distal end is contacting the nerve and adapted to deliver nerve stimulation pulses to the selected nerve. The proximal end of the lead can be adapted to connect to an external operating unit operated by processor 797.

[0242] In a variation of the embodiment, multiple leads may be connected to different nerve bundles. In another variation, such as Figures 24A-24D As shown, the implant can communicate wirelessly. The implant 2400, which may be a microelectrode or microstimulator, can be inserted near a nerve using a needle. A needle 2402 can be inserted into the patient to approach or be near the target nerve 2404, and the implant can then be ejected from the needle. The implant 2400 can communicate with, transmit and receive data from, and be powered by an externally located device 2406 (such as the decision unit described herein).

[0243] In one embodiment, the interface may be an implanted neural cuff. The cuff may completely or partially encircle the nerve. The cuff may be attached to the nerve via a closed butterfly arm electrode. In another embodiment, the interface may be a neural bridging platform. The bridging platform may be positioned close to or along the nerve. The function of the cuff may be to provide good contact or close proximity between the device and the nerve. In another embodiment, the interface may be anchored to the nerve or a sheath surrounding the nerve. For example, the device may be wrapped around the nerve or nerve sheath, bound to the nerve or nerve sheath, clamped to the nerve or nerve sheath, tethered with small hooks, or chemically fused to the nerve or nerve sheath. The function of the cuff, coil, bridging platform, or anchor is to provide good contact or close proximity between the device and the nerve. Figure 25A-25F Some embodiments of these embodiments are depicted. The cuff or strap can be used on the wrist, fingers, ankle, leg, arm, ear, and other locations.

[0244] For example, Figures 25A-25C An embodiment of a coil electrode interface is shown, which may be a multi-coil electrode or a single-coil electrode as shown. In some embodiments, the coil electrode 2500 may be made of a shape memory material such as nitinol and may have a relaxed straight configuration before insertion and implantation, and a curled configuration after exposure to body temperature. Figure 25D and Figure 25E An embodiment of a butterfly-shaped cuff electrode 2510 is shown, which may at least partially surround a nerve. As in other embodiments, the interface may include one or more electrodes and may be made of shape memory material to have an open configuration during delivery and a closed configuration that wraps around the nerve after implantation. Figure 25F An embodiment of an interface with a linear array of electrodes 2520 is shown, the linear array of electrodes being positioned abutting against and along a nerve.

[0245] Methods of inserting an implant may involve local or general anesthesia. The implant may be delivered through one or more perforations in the skin, such as needles or sutures, or it may be an open incision made in the skin to access the target area, or it may include both methods. In one embodiment, the device may be implanted by inserting all or part of the device around a nerve and / or surrounding tissue, such as a blood vessel or tendon.

[0246] In one embodiment, the implant may include two electrodes placed along a vascular pathway. The pathway may be along the palmar arch and the electrodes may be located in the brachial and axillary arteries. A fluid column between the electrodes may carry electricity and stimulate adjacent nerves. The electrodes may be internal to the vascular pathway (e.g., a stent) or external to the vascular pathway (e.g., a vascular wrap). In one embodiment, the device may be an implant capable of bidirectional communication with an external device. Embodiments may include memory. The external "listener" device may also be a power source. The implant may transmit information such as its power reserve or usage history to the "listener." In another embodiment, the device is an implant capable of sensing activity on a nerve or adjacent nerve and reporting that information to the listener.

[0247] In another embodiment, one or more devices for placing the device may be guided by ultrasound. Ultrasound can be used to measure proximity to blood vessels, nerves, or other tissues, or to characterize the type and location of adjacent tissues.

[0248] In another embodiment, the electrode for stimulation may be injected as a liquid. In another embodiment, the electrode may be flexible and delivered in a viscous medium such as hyaluronic acid. In yet another embodiment, the electrode may be made of nitinol, which is shaped at 37 degrees Celsius. This would allow the electrode to be injected or inserted in a configuration such as an elongated configuration to fit within a needle, and then shaped upon heating to body temperature. Some examples of these examples are depicted in Figure 25.

[0249] The implant may include necessary components for one-way or two-way communication between the implant, external power transmission, communication system, and / or electronic equipment to store programmable stimulation parameters. The device may include a wireless micromodule that receives command and electrical signals via radio frequency inductive coupling from an external antenna. If the effector is electrical, the incoming communication channel may contain information including stimulation frequency, delay, pulse width, and on / off interval.

[0250] Percutaneous charging or power supply can reduce implant size by eliminating the need for large power sources (such as batteries) and eliminate the need for repeated surgeries to replace the power source. External components can be used to wirelessly power internal components, such as through radio frequency (RF) power transmission. For example, the external device can transmit RF power received by the internal component via a resonant coil. Power can be transmitted at various wavelengths, including but not limited to the radio frequency and microwave spectrum, ranging from 3 kHz to 300 GHz. In some embodiments, the internal device may contain a battery. The external device can be worn or carried on the body, or it can be in the nearby surrounding environment, such as on a nearby table or wall. It can be portable or fixed. The device may contain capacitive energy storage module electrodes that stimulate upon discharge. Powering the electronics to drive the stimulation profile can significantly simplify the electronics. The capacitor blocks direct current but allows alternating current to pass through. When the capacitor reaches its insulation breakdown voltage, it discharges and releases a stimulation pulse.

[0251] The implant can also directly sense tremors, such as by using electroencephalography (ENG) or electromyography (EMG) signals or an accelerometer, or a combination thereof. In this case, the implant may include multiple electrodes, as microelectrodes and macroelectrodes are preferably used for sensing and stimulation, respectively. The device may also include an outgoing communication channel to transmit the detected events.

[0252] Other embodiments for multimodal treatment of urinary and / or gastrointestinal dysfunction. In some embodiments, the multimodal approach may involve restoring a balance of autonomic (sympathetic and parasympathetic) nervous system activity, including but not limited to reducing sympathetic and / or parasympathetic nervous system activation associated with the neurobladder circuit. Some embodiments may utilize any of the multimodal methods disclosed herein and may be used or modified for use with the systems and methods for treating bladder disorders in PCT disclosure WO2017 / 132067 by Wong et al., which is incorporated herein by reference in its entirety.

[0253] In some embodiments, this document discloses multimodal peripheral nerve stimuli for improving conditions, including but not limited to urinary and / or gastrointestinal dysfunction. Stimulation may target one, two, three, or more nerves associated with bladder function. Nerves may include, for example, the tibial nerve or posterior tibial nerve (which may branch into medial and lateral plantar nerve branches) and the calcaneal nerve. The saphenous nerve is a cutaneous branch of the femoral nerve. Other nerves include, for example, the pudendal nerve, pelvic nerve, dorsal genital nerve, external anal sphincter nerve, and dorsal genital nerve. In some embodiments, the tibial (e.g., posterior tibial) nerve may be stimulated percutaneously in a manner similar to percutaneous tibial nerve stimulation, but in a non-invasive and more prolonged manner. In some embodiments, the system and method comprise only percutaneous elements without any implanted and / or percutaneous components. In some embodiments, the nerve to be stimulated is only a peripheral afferent nerve of the lower extremity, rather than a spinal nerve.

[0254] Unrestricted by theory, voluntary control of the bladder can be largely mediated by the autonomic nervous system (ANS). The ANS maintains balance, which can be important for the normal functioning of bodily organs. For example, the hypogastric nerve (sympathetic nerve) and the pelvic nerve (parasympathetic nerve) both carry information about bladder fullness to the brain and work together to achieve the relaxation-contraction mechanism that controls urination.

[0255] Activation of the pontine voiding center (PMC) leads to activation of the parasympathetic nervous system of the bladder. This, in turn, causes the muscles in the bladder to contract and the muscles in the urethra to relax. The urination command stops when the CNS structures, including the periaqueductal gray (PAG), receive a signal that the bladder is no longer full.

[0256] Inappropriate activation and inhibition of the parasympathetic and sympathetic nervous systems can lead to bladder fullness, urgency, discomfort, and / or involuntary urination. Peripheral stimuli affecting autonomic activity can be used to modulate or interrupt the micturition reflex circuit to correct aberrant bladder function. Such modulation can be achieved through multimodal stimulation, for example, of the saphenous nerve, tibial nerve, or a combination of both. In some embodiments, systems and methods use multimodal stimulation protocols designed to phase-shift, cover, or obscure aberrant networks. In some embodiments, systems and methods use multimodal stimulation protocols designed to restore the balance of sympathetic and parasympathetic activity in the micturition reflex circuit. Advantageously, some embodiments utilize multimodal percutaneous afferent stimulation of one, two, or more peripheral nerves to modulate brain or spinal pathways associated with bladder function and / or organs or targets distant from the stimulation site.

[0257] In some embodiments, the system and method involve multimodal stimulation parameters, including frequency and spatial selectivity on distal limb surfaces, to selectively or preferentially modulate and balance the sympathetic and parasympathetic nervous systems.

[0258] Unrestricted by theory, stimulation of a first target nerve (such as the saphenous nerve) can provide sympathetic modulation of the bladder circuit. Specifically, stimulation of the large myelinated fibers in a target nerve (e.g., the saphenous nerve) provides somatic input to the lumbar plexus, thereby mediated by the hypogastric nerve to the sympathetic input to the bladder circuit. The sympathetic nervous system relaxes the detrusor muscle of the bladder by releasing norepinephrine, thereby activating β-adrenergic receptors, and by activating α-adrenergic receptors, thereby contracting the intrinsic urethral sphincter. Relaxation of the bladder and contraction of the intrinsic sphincter provide comfort during the filling and storage phases of the bladder cycle. Stimulation of a second target nerve (e.g., the tibial nerve) can provide parasympathetic modulation of the bladder circuit. Specifically, stimulation of the large myelinated fibers in the tibial nerve provides somatic input to the nerve plexus (sacral voiding center), and by releasing cholinergic neurotransmitters, mediated by the pelvic nerve to the parasympathetic input to the bladder circuit. Somatic effusors from the pelvic floor may also feed into the external urethral sphincter and modulate the afferent sensation of bladder fullness. Due to the extensive connectivity of these circuits and the circuit-based mechanisms, in some embodiments, all of the above mechanisms can modulate the central cortex and pontine voiding centers that coordinate and time signals.

[0259] The system can run on a series of pre-defined programs that alter stimulation parameters and target one or more nerves, individually or in combination, to improve symptoms of overactive bladder in a particular patient, whether the challenge is primarily daytime urgency, nocturnal awakenings (nappy), or incontinence and / or gastrointestinal dysfunction. Alternatively, the system can be closed-loop on a number of parameters, including: the subject’s symptom history, including nocturnal awakening events, or manual input voiding indicated by the device or assistive devices; direct detection of sympathetic and parasympathetic nerve tension in the bladder or general circuit, including HRV and electrodermal response; and / or closed-loop based on prior use of the device.

[0260] In some embodiments, multimodal neural stimulation may be combined in synergistic with one or more pharmacological treatments for overactive bladder, including but not limited to anticholinergics (e.g., oxybutynin, tolterodine, trocechloramine, dafenapyridine, sofenapyridine and / or fesorodine), β-3-adrenergics (e.g., mirabezon), antispasmodics (e.g., flavonoids) and / or antidepressants (e.g., tricyclic antidepressants such as desipramine or imipramine), hormones (e.g., estrogen and / or progesterone) or botulinum toxin.

[0261] In some embodiments, the effector may be excitatory to the nerve. In other embodiments, the effector may be inhibitory to the nerve. In some embodiments, the system may be used to stimulate the nerve during some portions of the treatment and inhibit the nerve during other portions of the treatment.

[0262] In some embodiments, waveforms including those described herein can be modified over time to minimize certain effects, such as habituation. One way to reduce habituation is to modify the frequency, pulse width, amplitude, duty cycle, phase, waveform, waveform symmetry, pulse interval, duration, on / off time, or burst pattern of the stimulus. For example, randomization or pseudo-randomization parameters (e.g., frequency or pulse width) can reduce habituation. Using a Gaussian distribution for randomization may be effective in some cases and can be used in waveforms such as random waveforms. Another way to reduce habituation is to reduce the frequency below a certain threshold, for example, no more than about 60 Hz, 55 Hz, 50 Hz, 45 Hz, or 40 Hz, where humans tend not to habituate.

[0263] Changing other parameters, such as amplitude, can be a way to improve waveform comfort. For example, the amplitude of the stimulus can be adjusted based on the threshold necessary to produce strong sensory perception and paresthesia without inducing motor contraction. In some embodiments, stimulation of muscles can lead to unpleasant spasmodic sensations. This amplitude can also be adjusted to an appropriate comfortable value throughout the phase, depending on the person's position or movement.

[0264] For example, the stimulation waveforms described herein can be continuously applied to target nerves (such as the tibial nerve and / or saphenous nerve), or can be provided in a manner adapted to the application of stimulation for various durations or by adjusting the characteristics of the stimulation waveforms (including, but not limited to, amplitude, frequency, pulse width, duty cycle, phase, waveform shape, waveform symmetry, pulse interval, duration, on / off time, and burst) in response to different inputs into the system. In some embodiments, the system may include closed-loop control that modulates the stimulation to improve efficacy using one or more signals measured by the device or feedback input to the device by the patient or physician. Signals or inputs may include, for example, any number of the following: sensors on the device or connected to a digital ecosystem; using heart rate variability to assess autonomic function, reflex circuit integrity, or excitability; measuring muscle sympathetic activity (MSNA); and / or measuring h-reflexes by sending stimulation signals and using EMG to measure responses. In some embodiments, signals or inputs may also include a set of sleep sensors (including, but not limited to, accelerometers, gyroscopes, infrared-based motion sensors, and / or pressure sensors under the mattress) to measure nocturnal movement as a measure of nocturia. For example, patients may wear stimulants while sleeping, and nocturnal restlessness may trigger treatment; nocturnal restlessness is an indicator of an impending nocturia event. A set of motion sensors (e.g., accelerometers, IR-based motion sensors, etc.) can measure rapid back-and-forth leg movements typically seen when a person experiences urgency. An EEG headband can be used to measure different sleep states. Patient and / or physician input can provide feedback to the device or another connected device regarding treatment effectiveness and / or satisfaction. Similarly, the use of the stimulation device can be tracked; and specific stimulation patterns (e.g., a specified set of stimulation parameters) can be changed based on patient symptoms or treatment outcomes. Multiple patterns can be triggered sequentially and / or simultaneously or overlappingly.

[0265] In some embodiments, the stimuli may be part of a sensor-equipped system to assess sleep state and adjust the stimulation according to the wearer's sleep state. Sensors may include motion sensors (e.g., wearable accelerometers and gyroscopes, or wireless motion tracking via video or infrared), temperature sensors for measuring body temperature, pressure sensors under the mattress for measuring motion, heart rate sensors for measuring HRV, other sensors for measuring sympathetic and parasympathetic activity, and / or EEG sensors for measuring brain activity to assess the wearer's sleep state. For example, if nocturia occurs during slow-wave sleep (when parasympathetic activity may be elevated), stimulation parameters are adjusted to influence parasympathetic activity, and vice versa.

[0266] In some embodiments, multimodal stimulation may be a first stimulation frequency that provides short-term benefit and a second stimulation frequency that provides long-term benefit, which differs from the first stimulation frequency (e.g., higher or lower). For example, in some cases, 10Hz stimulation may provide short-term benefit and 20Hz stimulation may provide long-term benefit. As an example, 10Hz stimulation may be provided in the initial cycle of treatment (e.g., 3 weeks) for acute treatment, while 20Hz stimulation may be provided for long-term maintenance or condition treatment, or vice versa, depending on the desired clinical outcome. In some embodiments, specific sympathetic and / or parasympathetic targets and circuits may be specifically used to modulate up or down sympathetic and / or parasympathetic activity, depending on the patient’s underlying autonomic nervous system activity. Data and / or the use of sensors that directly or indirectly measure sympathetic and / or parasympathetic activity (e.g., disclosed elsewhere herein) may be used as closed-loop feedback inputs to hardware and / or software controllers to modify stimulation parameters, including on a real-time basis.

[0267] In some embodiments, treatment (e.g., stimulation) may be applied for about, at least about, or no more than about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more than one day. In some embodiments, such as during sleep and / or during wakefulness, the patient may be treated at night. Depending on the desired clinical outcome, treatment may be repeated 1, 2, 3, 4, 5, or more times daily or weekly, every other day, every three days, weekly, or at other intervals.

[0268] In some embodiments, responsiveness may vary depending on the time of day. For example, a patient or physician (or algorithm) may pre-schedule different phases of treatment throughout the day, and the device may provide therapeutic stimulation at those different times of day. In one example, treatment may be applied at regular or irregular intervals throughout the day and at a frequency related to typical urination volume. In the treatment of nocturia, stimulation may be timed to regular intervals during human sleep. In some embodiments, stimulation protocols are applied based on the natural diurnal patterns of sympathetic and parasympathetic activity to restore autonomic regulation. Treatment may also be administered at irregular intervals, which may be manually input or predicted by machine learning from urination events over the previous few days. In some embodiments, a first frequency (e.g., 10 Hz or 20 Hz) of treatment may be applied in the morning for acute daytime relief, and a second, different higher or lower frequency (e.g., 20 Hz or 10 Hz) of treatment may be provided before bedtime for longer nighttime relief.

[0269] In some embodiments, responsiveness may depend on activity. For example, in nocturia, motion sensors such as accelerometers or gyroscopes can sense whether a person is making micro-movements, which can indicate a potential need for urination. During this time, the device may be turned on to provide appropriate stimulation. In some embodiments, the device may be turned off once urination is complete.

[0270] In some embodiments, the responsiveness to stimuli may depend on one, two, or more sensors encapsulated in the device to collect, store, and analyze biological metrics about the wearer, including but not limited to motion (e.g., accelerometers, gyroscopes, magnetometers, bending sensors), ground reaction forces or foot pressure (e.g., force sensors or pressure insoles), muscle activity (e.g., EMG), cardiovascular measurements (e.g., heart rate, HRV), skin conductance (e.g., skin conductance response, skin conductance response), respiratory rate, skin temperature, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM sleep). Using standard statistical analysis techniques (such as logistic regression or Naive Bayes classifiers), these biological metrics can be analyzed to assess the wearer's activity status, such as sedentary versus active status, stress levels, and / or bladder fluid volume, which can then be used as predictors of increased urinary and / or gastrointestinal urgency.

[0271] Sympathetic and parasympathetic activity can be measured using several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or skin conductance. HRV provides a quick and effective approximation of voluntary activity in the body. HRV is determined by analyzing the time intervals between heartbeats (also known as RR intervals). For example, heart rate can be accurately captured using recording devices such as chest straps or finger sensors. The differences between consecutive RR intervals provide an image of a person's heart health and voluntary activity. Generally, a healthier heart exhibits greater variability between consecutive RR intervals. This heartbeat data can also be used to represent an individual's levels of sympathetic and parasympathetic activity. Through frequency domain analysis, heartbeat frequencies can be divided into different frequency bands. High-frequency signals (approximately 0.15–0.4 Hz) almost entirely reflect parasympathetic activity, while low-frequency signals (approximately 0.04–0.15 Hz) represent a mixture of sympathetic and parasympathetic activity. Therefore, obtaining the ratio of high-frequency (HF) to low-frequency (LF) signals can produce an approximation of a person's sympathetic nervous system activity. In some embodiments, HRV can be analyzed, for example, in the time domain or geometric domain, in addition to frequency domain methods. In some embodiments, increased heart rate variability may represent increased parasympathetic response and / or decreased sympathetic response. Decreased heart rate variability may represent decreased parasympathetic response and / or increased sympathetic response. In some embodiments, the system can sense an increase or decrease in HRV of approximately or more than a baseline value (or target desired HRV value) of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, 100%, or higher, and accordingly establish one, two, or more changes in stimulation modality parameters. In some embodiments, one, two, or more stimulation modalities may be configured to modulate (e.g., increase or decrease) stimulation of one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and the response to treatment may be confirmed by sensing an increase or decrease in parasympathetic or sympathetic tone, including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency HRV. In some embodiments, the balance of parasympathetic and sympathetic activity in the bladder reflex circuit may be assessed by frequency analysis of heart rate variability measured using pulse plethysmography, which utilizes an LED light source and an optical sensor disposed in the device to measure fluctuations in light levels due to blood flow to one of the major vessels around the knee, which may include one or more of the following: femoral, popliteal, tibial, posterior tibial, anterior tibial, and / or descending genicular artery or vein.

[0272] In some embodiments, systems or methods for noninvasively measuring extraocular muscle movements and / or blink reflexes can serve as biomarkers for the diagnosis of overactive bladder or other conditions (e.g., biomarkers that can be used to inform the diagnosis of a disease state), for monitoring the progress or efficacy of treatment for overactive bladder or other conditions, and / or as feedback parameters for closed-loop adjustments to treatment. Without being theoretically limited, the centers involved in voiding control (such as the medial and lateral regions of the pontine voiding center) are located in the reticular formation of the pontine tegmentum and are anatomically very close to the areas controlling extraocular muscle movements and / or coordinating the blink reflex. Therefore, such biomarkers can be used to assess functions integrated into or mediated by the pontine structures. For example, an increase in blink delay time compared to reference values ​​(such as approximately or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or higher) may be associated with symptoms of overactive bladder in some cases. In some embodiments, a patient's baseline extraocular muscle movement parameters, such as blink time, can be compared to the patient's parameters / times during or after treatment for comparison. Some embodiments may involve, for example: video eye tracking or blinking (e.g., via a camera, including a webcam, tablet or smartphone camera, or a wearable device including a camera, such as a headwear such as a hat, glasses such as a modified Google Glass, etc.); eye dipole-based electrooculography (EOG) recording of eye muscles; EMG of head muscles that control blinking (such as the orbicularis oculi and levator palpebrae superioris); systems for inducing blinking (such as light entering the eye or air expulsion) and then using a camera or EMG to measure the duration of blinking; and / or measuring blink reflexes and recording neural activity of the orbicularis oculi muscle by means of active stimulation signals (such as percutaneous application to the supraorbital nerve).

[0273] In some embodiments, stimulation of any form as disclosed herein may be used to apply stimulation to one, two, or more acupoints. In some embodiments, the acupoints to be stimulated may include any one, two, three, four, five, six, seven, eight, nine, ten, or any other number of the following: BL18 (Ganshu), BL23 (Shenshu), BL27 (Xiaochangshu); BL28 (Pangguangshu); BL32 (Ciliao); BL33 (Zhongliao); BL53 (Baohuang); CV2 (Qugu); CV3 (Zhongji); CV4 (Guanyuan); CV5 (Shinen); CV6 (Qihai); GB34 (Yanglingquan); KI7 (Fuliu); KI10 (Yingu); LR1 (Dadun); LR2 (Xingjian); LR8 (Quan); N-BW-38 (Xiajiaoshu); SP6 (Sanyinjiao); SP9 (Yinlingquan); and / or ST28 (Shuidao). In some embodiments, the acupoints to be stimulated include BL18, BL23, BL28, and CV2. In some embodiments, the points to be stimulated include ST28, SP6, BL23, BL28, BL32, BL33, BL53, CV3, and N-BW-38. In some embodiments, the acupoints to be stimulated include SP6, BL23, BL27, BL28, BL33, and CV4. In some embodiments, the acupoints to be stimulated include SP9, LR1, LR2, CV4, and CV6. In some embodiments, the acupoints to be stimulated include SP6, SP9, BL23, CV3, and CV6. In some embodiments, the acupoints to be stimulated include SP9 and GB34. In some embodiments, the acupoints to be stimulated include SP9, KI7, KI10, and LR8. In some embodiments, the acupoint to be stimulated is CV5 alone or BL39 alone, or a combination thereof. Other arrangements of the stimulation points are also possible, depending on the desired clinical outcome.

[0274] A major source of error in optical heart rate measurement is motion artifacts, caused by the relative motion between the optical sensor and the blood vessel being measured. In some embodiments, the optical heart rate sensor has an adhesive on one side of the housing that contacts the wearer's skin to reduce the relative motion between the sensor and the target blood vessel.

[0275] In some embodiments, the device includes one, two or more additional sensors, including electrical sensors that contact the wearer’s skin to measure cardiac activity or pressure sensors for measuring changes in blood vessels. These sensors are used in conjunction with optical sensors to improve the fidelity of heart rate measurements.

[0276] In some embodiments, the system and device have a memory and a processor to extract RR intervals from sensor data, calculate the variability of RR intervals, transform the data to the frequency domain, and calculate high-frequency signals, low-frequency signals, and high-frequency ratios of high-frequency and low-frequency signals.

[0277] In some embodiments, the heart rate sensor may store data collected over a specified time period to collect sufficient data for heart rate variability calculations. In some cases, the specified time period may range from 1 to 60 seconds and may be extended to 10 minutes or longer.

[0278] In some embodiments, sensors, such as electrodes, can be used to measure electrical skin activity (also known as electroskin response or skin conductance response). The skin conductance response is a change in skin resistance caused by emotional stress and can be measured, for example, with a sensitive galvanometer. Without being theoretically limited, skin resistance varies with the state of sweat glands in the skin. Sweating is controlled by the sympathetic nervous system, and skin conductance can be an indicator of psychological or physiological stimuli. If the sympathetic nervous system is highly aroused, sweat gland activity also increases, which in turn increases skin conductance. In this way, skin conductance can be a measurable measure of emotional and sympathetic responses, and feedback data can be sent to a controller that will then modulate the stimulation to, for example, reduce sympathetic nervous system activity. Other non-limiting parameters associated with sensed sympathetic and / or parasympathetic nervous system activity include, for example, sweating during specific times of day and / or night, sleep states detected, for example by an EEG headband (to determine when sympathetic and / or parasympathetic activity is particularly high or low, and may associate sleep states such as stage 1, 2, 3, 4, or REM with nocturia), and / or movement. In some embodiments, diagnostic and / or combined diagnostic / stimulation devices may be configured to measure a person's heart rate and electrodermal response to improve estimates of a person's voluntary activities. In some embodiments, wearable devices (such as wrist-worn devices) may include an electrodermal activity (EDA) sensor and an optical heart rate sensor. In some embodiments, such data combination may advantageously and synergistically provide improved estimates of sympathetic and parasympathetic activity compared to individual measurements alone. In some embodiments, the system may include multiple sensors to combine heart rate and HRV to measure EDA. Data from multiple sensors may be analyzed by a hardware or software processor and combined to provide a more accurate estimate of sympathetic and / or parasympathetic activity. In some embodiments, EDA and HR sensors may be placed in a wrist-worn device that communicates with the stimulus via a wired or wireless connection or transmits data to a centralized remote server (e.g., the cloud). Stimulation parameters, nerve target location (e.g., the tibial nerve and / or the saphenous nerve), or dosing regimen (e.g., the duration or frequency of the stimulation phase) may be adjusted based on estimates of sympathetic and / or parasympathetic activity. Adjustments may be made in real time or in subsequent stimulation phases. In some embodiments, the stimulation frequency may be adjusted to increase or decrease voluntary activity modulated by a single specific nerve or multiple nerves. For example, in some embodiments, relatively low-frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5 Hz)) may potentially inhibit the nerve and thus reduce sympathetic activity, while higher-frequency stimulation (e.g., above a threshold (e.g., about 5 Hz)) may potentially excite the nerve and thus increase sympathetic activity. The same action may be performed with respect to the same or other target nerves to modulate parasympathetic activity.In other words, in some embodiments, relatively low-frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5 Hz)) may potentially inhibit the nerve and thus reduce parasympathetic activity, while higher-frequency stimulation (e.g., above a threshold (e.g., about 5 Hz)) may potentially excite the nerve and thus increase parasympathetic activity. Not limited by theory, but depending on the stimulation parameters, in some cases, stimulation of the target nerve may increase or decrease sympathetic activity, parasympathetic activity, or both. In some embodiments, stimulation of the saphenous nerve may affect sympathetic activity, and stimulation of the tibial nerve may affect parasympathetic activity.

[0279] Multimodal devices may also respond to the number of symptom episodes, including overactive bladder. If more episodes occur during the day, treatment can be increased, for example, by increasing the intensity of stimulation, the duration of stimulation, or the number of treatment phases.

[0280] The number of symptom episodes (such as overactive bladder) can be detected in various ways to control the stimulation applied by the system and device. In some embodiments, the patient can input events related to the symptoms of overactive bladder on a mobile device, including but not limited to bladder voiding events, urinary urgency events, or urinary incontinence events. In some embodiments, location services (such as GPS) on the device can detect when a person enters a building or bathroom.

[0281] In some embodiments, this document discloses multimodal wearable systems and methods that can utilize transcutaneous sensory stimulation in the form of burst patterns (e.g., theta burst patterns) to improve symptoms of overactive bladder and various other conditions, including but not limited to those described herein (e.g., tremor and other movement disorders, hypertension, cardiac arrhythmias, and inflammatory bowel diseases (e.g., Crohn's disease)). Non-invasive peripheral nerve theta burst stimulation can effectively promote cortical or spinal cord plasticity to reduce symptoms and improve individual quality of life.

[0282] In some embodiments, multimodal stimulation involves patterns of electromagnetic stimulation of the peripheral nerves. Patterned stimulation can be sudden, such as an on / off pattern repeated at regular intervals (e.g., on for 10 ms, off for 20 ms, etc.), or in some embodiments, more complex non-sudden patterned stimulation, such as a random pattern or a sinusoidal envelope. Electromagnetic stimulation can include, for example, electrical energy, mechanical energy (e.g., vibration), magnetic energy, ultrasonic energy (e.g., focused ultrasound), radiofrequency energy, thermal energy, optical energy (e.g., such as infrared or ultraviolet energy), and / or microwave energy, or combinations thereof. In some embodiments, stimulation is limited to electrical energy or electrical and mechanical energy (e.g., no magnetic energy or other types of energy are applied). Peripheral stimulation can include percutaneous, transdermal, and / or implanted stimulation.

[0283] In some embodiments, multimodal stimulation involves non-invasive, percutaneous patterned or abrupt stimulation of peripheral nerves, including afferent and / or efferent nerves. Not limited by theory, abrupt stimulation of peripheral nerves may unexpectedly result in one or more of the following compared to conventional or continuous stimulation: greater efficacy; greater plasticity; increased tolerance or forbearance; reduced habituation effects; increased comfort; and / or reduced treatment time required to achieve the same beneficial effects. In some cases, abrupt stimulation of peripheral nerves, including afferent nerves, can deliver more effective treatment by remotely accelerating the plasticity of one or more central nervous system (e.g., brain and / or spinal cord) circuits. In other words, this plasticity in the neural circuits persists for a period of time far longer than the duration of the stimulation phase, such as approximately or at least about 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, or longer. In some cases, peripheral stimulation is more convenient and comfortable for the user than central stimulation (e.g., transcranial and / or spinal stimulation) and may be more suitable for home and non-hospital use.

[0284] In some embodiments, the burst stimulus includes theta burst stimulation. Theta burst stimulation (TBS) is a patterned form of repetitive stimulation that uses high-frequency pulses separated by varying burst intervals. Originally used in hippocampal learning and memory studies to induce long-term potentiation, theta burst stimulation in the form of repetitive magnetic stimulation (rTMS) has been shown to non-invasively induce plasticity in the motor, sensory, and visual cortices of humans. Long-term potentiation or inhibition (LTP / LTD) effects, which are surrogate measures of synaptic efficacy, can be observed depending on various parameters, including the duration and continuity of the stimulus. The number of stages of stimulation and the interval between individual stages can also influence the duration of the induced response. The level of muscle relaxation before or during stimulation can also affect the direction or amplitude of the outcome induced by plasticity, suggesting the existence of homeostatic mechanisms that adjust the plasticity threshold based on prior synaptic activity. The effective modulation of neural plasticity demonstrated by theta burst stimulation has great potential for treating a variety of neurological disorders and can also influence other central neural circuits.

[0285] In some embodiments, theta burst stimulation may take the form of intermittent theta burst stimulation (iTBS), continuous theta burst stimulation (cTBS), and intermediate theta burst stimulation (imTBS). The burst pattern (or a combination of two or more burst patterns) may be selected depending on the desired clinical outcome. In some cases, cTBS may be inhibitory, iTBS may be excitatory, and imTBS may be neither excitatory nor inhibitory, but this may vary depending on parameters. In some embodiments, inhibitory stimulation of a first nerve (e.g., the saphenous nerve or the tibial nerve) may be used alone or in combination with excitatory stimulation of a second nerve (e.g., the saphenous nerve or the tibial nerve), such as to restore or improve the balance of the sympathetic and parasympathetic nervous systems. In some embodiments, the inhibitory or excitatory stimulation of a nerve can be controlled by adjusting the frequency or pulse width of the stimulation waveform.

[0286] In some embodiments, each burst may include multiple stimuli, such as approximately or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more stimuli. Each burst may have the same or a variable number of stimuli.

[0287] In some embodiments, the intra-burst frequency may be approximately or at least about 10 Hz, 20 Hz, 30 Hz, 40 Hz, 50 Hz, 100 Hz, 250 Hz, 500 Hz, 1 kHz, or higher. In some embodiments, the intra-burst frequency may vary between about 10 Hz and about 20 kHz. The intra-burst frequency may also vary randomly or pseudo-randomly during a burst to reduce habituation and / or increase comfort. In other embodiments, the intra-burst frequency may be between about 10 Hz and about 250 Hz, between about 50 Hz and about 150 Hz, between about 10 Hz and about 100 Hz, between about 100 Hz and about 150 Hz, between about 50 Hz and about 250 Hz, or between about 50 Hz and about 1000 Hz to minimize tremor reduction, improve comfort, reduce habituation, and / or reduce the power consumption of the stimulus device.

[0288] In some embodiments, the burst frequency may be between about 1 Hz and about 20 Hz, such as between about 4 Hz (250 ms between the start of each burst) and about 12 Hz (83 ms), such as between about 4 Hz (250 ms) and about 8 Hz (142 ms) (which is generally considered to be the θ band frequency, including about 5 Hz (200 ms)), or between about 3.5 Hz and about 7.5 Hz in some embodiments, or between about 6 Hz and about 10 Hz.

[0289] In some embodiments, the inter-stage frequency may be between about 1 minute and about 12 hours, such as between about 5 minutes and about 120 minutes, between about 5 minutes and about 60 minutes, between about 10 minutes and about 30 minutes, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660 or 720 minutes, or a range combining any two of the above values.

[0290] In some embodiments, a repetitive patterned stimulus known as a four-pulse stimulus may be used, comprising four pulses repeated at a short interval (1.5 ms between excitations) at approximately 0.2 Hz over a period of time (e.g., about 30 minutes). Four-pulse stimulation has been shown to induce prolonged plasticity. Variations in the frequency within the burst using this paradigm can influence the direction of the induced plasticity. These repetitive small pulses can be located anywhere between 2 and 10 pulses or more.

[0291] Alternatively or additionally, burst patterns other than theta bursts may be used. Some non-limiting examples include inter-burst frequencies of δ (0-4Hz), α (8-12Hz), β (12-30Hz), and γ (30-100Hz). In some embodiments, ambient burst stimuli may include sinusoidal, square, rectangular, triangular, sawtooth, or other waveforms.

[0292] In some embodiments, this document discloses a multimodal method for treating urinary and / or gastrointestinal symptoms in a patient through dual stimulation of the saphenous nerve and the posterior tibial nerve. In some embodiments, the method may include any number of the following: positioning a first peripheral nerve effector on the patient's skin to stimulate the patient's saphenous nerve; positioning a second peripheral nerve effector on the patient's skin to stimulate the patient's posterior tibial nerve; percutaneously delivering a first nerve stimulation signal to the saphenous nerve via the first peripheral nerve effector; percutaneously delivering a second nerve stimulation signal to the tibial nerve via the second peripheral nerve effector; receiving input related to the patient's autonomic nervous system activity; and modifying at least one brain or spinal cord autonomic feedback loop related to bladder function based on the input to balance the patient's parasympathetic and sympathetic nervous system activity. In some embodiments, the method does not utilize any implantable components and involves only percutaneous stimulation. Both the first and second peripheral nerve effectors may be located near the patient's knee. The first stimulation signal may differ from the second stimulation signal, including but not limited to different types of energy, stimulation parameters, burst patterns, waveform shapes, etc. The first stimulation signal may have a first frequency different from the second frequency of the second stimulation signal. The first stimulation signal may have an amplitude different from the second stimulation signal. The first or second frequency may be, for example, from about 10 Hz to about 20 Hz. The first or second frequency may be, for example, from about 5 Hz to about 30 Hz. Receiving input related to the patient's autonomic nervous system activity may include any number of the following: receiving data from sensors measuring the patient's autonomic nervous system activity; receiving data from sensors measuring the patient's heart rate variability; receiving heart rate variability data from optical sensors measuring blood flow characteristics and positioned near blood vessels close to the patient's knee; receiving data from sensors measuring the patient's skin conductance; receiving data related to the patient's urinary tract and / or gastrointestinal symptoms; and / or receiving data related to the patient's nocturia episodes.

[0293] This document also discloses a multimodal wearable device for dual stimulation of the saphenous nerve and posterior tibial nerve, and for treating urinary and / or gastrointestinal symptoms in patients. In some embodiments, the device may include any number of the following features: a controller; a first peripheral nerve effector configured to percutaneously modulate the saphenous nerve; a second peripheral nerve effector configured to percutaneously modulate the posterior tibial nerve; and at least one biomedical sensor or data input source configured to provide feedback information. The controller may include a processor and memory for receiving feedback information from the sensor, which, when executed by the processor, causes the device to adjust one or more parameters of the first and second stimuli based at least in part on the feedback information; and / or deliver the first stimulus to the saphenous nerve via the first peripheral nerve effector and the second stimulus to the posterior tibial nerve via the second peripheral nerve effector to reduce urinary and / or gastrointestinal symptoms by modifying the brain or spinal cord autonomic feedback loops related to bladder function and balancing sympathetic and parasympathetic activity. In some embodiments, the device is not configured for implantation in a patient. The feedback information may include real-time feedback information. The first stimulus may have a frequency, for example, between about 10 Hz and about 20 Hz. The second stimulus may have a frequency, for example, between approximately 5 Hz and approximately 30 Hz. Feedback information may include the patient's autonomic nervous system activity. Feedback information may include heart rate variability. Feedback information may also include information related to the patient's nocturia events. Feedback information may also include information related to the patient's sleep status.

[0294] Additional Examples of Multimodal Treatment for Cardiac Dysfunction In some embodiments, the multimodal approach may involve restoring a balance of autonomic (sympathetic and parasympathetic) nervous system activity, including but not limited to reducing sympathetic and / or parasympathetic nervous system activation associated with neural circuits affecting blood pressure and cardiac arrhythmias. Some embodiments may utilize any of the multimodal methods disclosed herein and may be used or modified for use with the systems and methods for treating cardiac disease in Hamner et al., PCT Publication WO 2018 / 039458, which is incorporated herein by reference in its entirety.

[0295] Imbalances in autonomic activity can lead to several heart conditions, such as high blood pressure and arrhythmia; these are imbalances in the activity of the sympathetic and parasympathetic nervous systems within the autonomic nervous system. This imbalance can result from overactivity or underactivity of the sympathetic and / or parasympathetic limbs of the autonomic nervous system. Multimodal stimulation of the autonomic nervous system, including the systems and methods disclosed herein, can provide therapeutic benefits by restoring the balance of the autonomic nervous system, thereby reducing the burden of symptoms associated with these heart conditions.

[0296] Autonomic nervous activity has been shown to be a significant contributing factor to cardiac arrhythmias. The skin is well innervated by the autonomic nervous system, and stimulation of nerves or meridians, as disclosed herein, may potentially aid in the treatment of cardiac arrhythmias. For example, afferent nerves in the peripheral or distal limbs (including, but not limited to, the median nerve) connect via neural circuits to the arcuate nucleus of the hypothalamus. Without being confined by theory, regulation of the arcuate nucleus reduces elevated sympathetic outflow through either or both of the following pathways: decremental input from the pituitary gland to the neuroendocrine or hormonal system, and decremental input via the ventrolateral periaqueductal gray matter and the suture nucleus pallidus of the medulla oblongata to the ventrolateral cephalic medulla oblongata (RVLM). This pathway may be mediated via cholinergic mu receptors.

[0297] Optionally or otherwise, stimulation of the peripheral cutaneous fibers of the arms, legs, neck, or tragus can modulate the activity of the stellate ganglia at the C8-T1 level of the spinal cord to reduce elevated sympathetic outflow and / or increase vagal tone via the carotid sinus nerve. Modulating peripheral nerves include the musculocutaneous nerve (innervating at C5-C7), radial nerve (innervating at C5-T1), median nerve (innervating at C5-T1), ulnar nerve (innervating at C8-T1), and medial cutaneous nerve (innervating at C8-T1). The medulla oblongata is operatively connected to the vagus nerve, which has a parasympathetic role in, for example, the SA and AV nodes of the heart. Cervical ganglia are paravertebral ganglia of the sympathetic nervous system. Preganglionic nerves from the thoracic spinal cord can enter the cervical ganglia and synapses containing their postganglionic fibers or nerves. The cervical ganglia consist of three paravertebral ganglia: the superior cervical ganglion, adjacent to C2 and C3; whose postganglionic axons project to targets (heart, head, neck) via pathways adjacent to the carotid arteries; the middle cervical ganglion (smallest), adjacent to C6; targeting the heart and neck; and the inferior cervical ganglion. The inferior ganglion can fuse with the first thoracic ganglion to form a single structure, the stellate ganglion—adjacent to C7; targeting the heart, lower neck, arm, and posterior cranial arteries. For example, nerves arising from the cervical sympathetic ganglia contribute to the cardiac plexus. The stellate ganglion (or cervicothoracic ganglion) is a sympathetic ganglion formed by the fusion of the inferior cervical ganglion and the first thoracic ganglion. From the thoracic ganglia arise the thoracic visceral ganglia (thoracic-pulmonary nerves, larger, smaller, and smallest visceral nerves), which contribute to the sympathetic innervation of abdominal structures.

[0298] Optionally or otherwise, and without being limited by theory, multimodal stimulation can invoke a neurohormonal response by stimulating myofascial or dermal acupressure points on the upper and lower extremities (such as Ht7, Pc6, Gb34, Sp6, Ki6, etc.). The neurohormonal response may include changes (increases or decreases) in the production of norepinephrine, epinephrine, acetylcholine, and / or inflammatory cytokines. Inflammatory cytokines may include interleukins, high-mobility group box B1, and / or tumor necrosis factor α. The neurohormonal response may also be induced by stimulation of the median, radial, ulnar, or vagus nerves, cutaneous nerves, or sympathetic nerves, either afferent or efferent. In one embodiment, following treatment with the device disclosed herein, one or more of norepinephrine, epinephrine, acetylcholine, and / or inflammatory cytokines are reduced by at least about 5%, 10-20%, 20-40%, 40-60%, or more (including overlap) compared to pre-treatment levels.

[0299] Optionally or otherwise, but not limited by theory, retrograde stimulation of autonomic or visceral efferent nerve fibers in the arms, legs, neck, or tragus can modulate sympathetic outflow and / or modulate vagal tone. Specifically, sympathetic outflow can be specifically stimulated by targeting C fibers in the periphery of the body.

[0300] Optionally or otherwise, and without being limited by theory, multimodal stimulation of somatic, autonomic, afferent, and / or efferent peripheral nerves can reduce sporadic electrical activity in pulmonary veins that trigger and maintain cardiac arrhythmias.

[0301] Some embodiments relate to multimodal devices and systems that provide peripheral nerve stimulation targeting individual nerves. Some embodiments relate to devices and systems that allow for customized and optimized treatment for an individual. Specifically, the device may be configured for multimodal stimulation of the median, radial, ulnar, peroneal, saphenous, tibial, and / or other palpable nerves or meridians on the limbs for the treatment of cardiac arrhythmias, including but not limited to atrial fibrillation (chronic or paroxysmal atrial fibrillation) and other arrhythmias, and / or to reduce cardiac dyssynchrony and / or hypertension. Other non-limiting examples of arrhythmias that can be treated using the systems and methods disclosed herein may include, for example, long QT syndrome, torsades de pointes, premature atrial contractions, wandering atrial pacemakers, multifocal atrial tachycardia, atrial flutter, supraventricular tachycardia (including PSVT), atrioventricular nodal reentrant tachycardia, junctional rhythms, junctional tachycardia, junctional premature contractions, premature ventricular contractions, accelerated ventricular voluntary rhythms, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, and ventricular fibrillation. Targeting specific nerves and using appropriately tailored stimulation results in more effective treatments (e.g., reduced episodes of arrhythmia, such as fibrillation or fibrillation episodes and / or shorter duration of fibrillation episodes; reduced sensation of palpitations / arrhythmias; improved rate control of arrhythmias compared to pre-treatment (with or without cessation of arrhythmias), such as a reduction in heart rate of approximately or at least about 10%, 20%, 30%, 40%, or higher; prevention or reduction of the incidence of embolic events associated with atrial fibrillation, such as stroke; and / or regulation, e.g., reduction of systolic blood pressure, diastolic blood pressure, and / or mean blood pressure). In some embodiments, treatment may prevent or reduce the recurrence rate of fibrillation in patients with persistent atrial fibrillation (AF) after medication or electrical cardioversion, or the number and duration of fibrillation episodes in patients with paroxysmal atrial fibrillation, including but not limited to reducing the number of recurrent episodes of rhythm completion after ablation procedures. In some embodiments, treatment may reduce or eliminate the amount, dosage, and / or frequency of medications that a patient may need to take for their underlying arrhythmias, thereby advantageously reducing side effects / potential toxicity. In some embodiments, treatment may have unexpected synergistic effects when combined with one, two, or more pharmacological agents, such as rate controllers (e.g., beta-blockers such as atenolol, metoprolol, propranolol, carvedilol; calcium channel blockers such as nifedipine, amlodipine, diltiazem, or verapamil; or cardiac glycosides such as digoxin), and / or antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, propafenone, sotalol, ibutilide, dofetilide, amiodarone, or dronedarone). In some embodiments, cardiac glycosides such as digoxin may be administered orally, intravenously, or by another route, in conjunction with peripheral nerve stimulation protocols such as those described herein, to have unexpected synergistic benefits in the treatment of arrhythmias, cardiac asynchrony, and / or hypertension.Unrestricted by theory, digitoxin and cardiac glycosides (sometimes also called digoxin or deslanoside) modulate the body's arterial baroreflex mechanism. A weakened baroreflex can lead to continuous and excessive sympathetic activity, which in turn can result in increased heart rate, increased blood pressure, and the initiation and maintenance of cardiac arrhythmias. Abnormal baroreceptor function can be associated with elevated activation of the sodium-potassium ATPase pump; digitoxin and cardiac glycosides reduce this elevated activation, leading to increased baroreceptor sensitivity, including sensitivity to stimuli. Therefore, multimodal stimulation of peripheral nerves that modulate baroreceptors (e.g., the median, radial, ulnar nerves, or skin fibers of the arm) can have unexpected synergistic effects with digitoxin and cardiac glycosides, thereby inhibiting elevated sympathetic activity; glycosides increase the sensitivity of the baroreceptor reflex and stimulate its activation. This synergistic effect can be advantageous by reducing the dose of glycoside required to treat cardiac dysfunctions such as hypertension or cardiac arrhythmias, because digoxin has a very narrow therapeutic target and can cause serious toxicity at plasma concentrations only twice the therapeutic range. In some embodiments, the dose of cardiac glycosides such as digoxin administered to the patient may be much smaller than the usual prescription, such as about 3, 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, or 0.2 mcg / kg per day. In some embodiments, the dose of cardiac glycosides may be titrated to below therapeutic blood levels, for example, about 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 ng / ml. In some embodiments, digoxin is provided in a single-dose administration form (e.g., tablets) of about or less than about 250 mcg, 125 mcg, 62.5 mcg, 31.25 mcg, 16 mcg, 8 mcg, 4 mcg, 2 mcg, 1 mcg or less.

[0302] In some embodiments, this document discloses multimodal device systems and methods for stimulating multiple nerves to treat cardiac dysfunction. Stimulation of two, three, or more nerves or skin flaps (such as the median nerve, median cutaneous nerve, radial nerve, and / or ulnar nerve) can be used to treat conditions such as arrhythmias. In some cases, dual-nerve stimulation can synergistically enhance therapeutic effects by acting on the brachial plexus (a proximal location where individual nerves converge near the spinal cord). For example, in one embodiment, the device disclosed herein is used to stimulate two nerves (including, but not limited to, the median, radial, ulnar, or median cutaneous nerves) located at a distance from the brachial plexus at two different times, wherein ultimately, the brachial plexus is stimulated substantially simultaneously by two signals from two or more nerves (e.g., less than about 2 ms, 1 ms, 0.5 ms, 0.4 ms, 0.3 ms, 0.2 ms, 0.1 ms, 0.09 ms, 0.08 ms, 0.07 ms, 0.06 ms, 0.05 ms, 0.04 ms, 0.03 ms, 0.02 ms, 0.01 ms or less), but may be higher in some cases. In one embodiment, the two nerves are offset (in terms of the timing of stimulation) by 0.1–3.0 ms. In one embodiment, two, three, four, or more nerves located at a distance from a target (including, but not limited to, the brachial plexus) are stimulated at different times to substantially simultaneously hit the target. In some embodiments, the system may be configured to independently control the stimulation of a first target nerve and a second target nerve (including stimulation parameters such as frequency and other parameters listed herein). In other words, the first and second target nerves may be stimulated with the same or different parameters, and may be stimulated simultaneously or alternately or otherwise. In some embodiments, the stimulation system may include multiple separate stimulation circuits, or a common circuit with a controller configured to switch the stimulation parameters of one, two, or more nerves.

[0303] Embodiments of the present invention may include devices, systems, and methods for performing the following operations: measuring and collecting biological data (e.g., heart rate, heart rate variability, ECG, skin conductance response, temperature, and blood pressure), analyzing the data to interpret how these measurements affect heart rhythm and / or blood pressure, and providing peripheral nerve stimulation to one or more nerves (such as the median nerve, ulnar nerve, and / or radial nerve) to treat or prevent cardiac arrhythmias, reduce cardiac dyssynchrony, and / or reduce blood pressure, wherein the applied stimulation may or may not be modified based on the measurement data.

[0304] In some embodiments, the multimodal system and method may include a monitor unit, which may be a wearable monitor with a housing having a user interface. The housing may use multiple sensors to collect, store, and analyze the wearer's biometrics, including but not limited to: blood pressure, motion (e.g., accelerometer, gyroscope, magnetometer, flexure sensor), muscle activity (e.g., EMG using electrodes), cardiovascular rhythm measurements (e.g., heart rate, heart rate variability, or ECG measurement using electrodes, ventricular and / or atrial dyssynchrony with arrhythmias), skin conductance (e.g., skin conductance response, skin conductance response, using electrodes), respiratory rate, skin temperature, pupil diameter, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM sleep). Heart rhythm measurements may be recorded using optical, electrical, and / or accelerometer-based sensors. Specifically, studies have shown that elevated stress levels can increase blood pressure. Activities such as exercise can also affect heart rate and / or rhythm, and / or blood pressure—measuring acceleration (exercise), heart rate, etc., can help identify these activities and standardize measurements through similar activities. Furthermore, hypertension is associated with heart failure—measuring ventricular dyssynchrony via ECG sensors can help identify the long-term effectiveness of stimulation in reducing hypertension. Therefore, these biological measures can be analyzed using standard statistical analysis, machine learning, deep learning, or big data techniques (such as logistic regression or Naive Bayes classifiers) to assess a person's condition (such as stress levels), which can then serve as predictors of cardiac arrhythmias, dyssynchrony, and / or increased blood pressure. In some embodiments, the device may deliver stimulation based on measurements of one or more biological measures, determination of a person's condition, and / or prediction of changes in cardiac arrhythmias, dyssynchrony, and / or blood pressure.

[0305] In some embodiments, responsiveness may depend on activity. For example, in cases of heart rhythm irregularities that may be exacerbated by exercise, motion sensors, such as accelerometers or gyroscopes, can sense whether a person is exercising. During this time, the device may be turned on to provide appropriate stimulation. In some embodiments, the device may be turned off once the activity is complete. In some embodiments, the sensor may activate stimulation during periods of inactivity, such as when the subject is sleeping.

[0306] In some embodiments, the responsiveness to stimuli may depend on one, two, or more sensors encapsulated in the device to collect, store, and analyze biological metrics about the wearer, including but not limited to motion (e.g., accelerometers, gyroscopes, magnetometers, bending sensors), ground reaction forces or foot pressure (e.g., force sensors or pressure insoles), muscle activity (e.g., EMG), cardiovascular measurements (e.g., heart rate, heart rate variability (HRV), photoplethysmography (PPG), or using electrodes to measure ECG and / or ventricular and / or atrial dyssynchrony with arrhythmias), skin conductance (e.g., skin conductance response, skin conductance response), respiratory rate, skin temperature, pupil diameter, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM sleep). These biological metrics can be analyzed using standard statistical analysis, machine learning, deep learning, or big data techniques (such as logistic regression or Naive Bayes classifiers) to assess the wearer's activity status (e.g., sedentary vs. active, stress levels, etc.), which can then be used as predictors of changes in blood pressure, cardiac arrhythmias, or cardiac dyssynchrony.

[0307] Sympathetic and parasympathetic activity can be measured by several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or skin conductance, as described elsewhere in this article.

[0308] HRV measurements may differ significantly in patients with cardiovascular disease compared to controls. Through frequency domain analysis, heart rate can be segmented into different frequency bands. High-frequency signals (between approximately 0.15 Hz and approximately 0.4 Hz) almost entirely reflect parasympathetic activity, while low-frequency signals (between approximately 0.04 Hz and approximately 0.15 Hz) represent a mixture of sympathetic and parasympathetic activity. In some embodiments, acquiring the ratio of high-frequency (HF) to low-frequency (LF) signals provides an approximation of a person's sympathetic tone. Very low frequency (VLF) signals (between approximately 0.004 Hz and approximately 0.040 Hz) can also be assessed to evaluate parasympathetic activity. The total power of HRV in the frequency domain can also be evaluated to assess voluntary activity.

[0309] Sympathetic and parasympathetic function can also be assessed, for example, by analyzing the mean normal-normal intervals, such as all intervals between adjacent QRS complexes of the measured heart rhythm, including the interval difference of NN consecutive intervals greater than 50 milliseconds; the square root of the mean square of the NN consecutive intervals; and the standard deviation of the NN intervals.

[0310] In some embodiments, more conventional techniques may also be used to assess sympathetic activity: such as measuring blood pressure changes before release and before initiating grip exercises, or measuring blood pressure changes before and after immersing the hand in a cold water bath (e.g., cold pressure test). Parasympathetic activity can be assessed by measuring heart rate responses during deep breathing or when standing up from a lying or sitting position (or in an upright position), or by changing the orientation of the body using a tilted table. Both sympathetic and parasympathetic activity can be assessed during Vascular manipulation (e.g., blowing into a mercury manometer and maintaining a pressure of about or at least about 40 mmHg) or in an upright position (e.g., standing up from a lying or sitting position).

[0311] In some embodiments, the device includes one, two or more additional sensors, including electrical and / or accelerometer sensors that contact the wearer's skin to measure cardiac activity or pressure sensors for measuring changes in blood vessels. These sensors are used in conjunction with optical sensors to improve the fidelity of heart rate measurements.

[0312] In some embodiments, the system and device have a memory and a processor to extract RR intervals from sensor data, calculate the variability of RR intervals, transform the data to the frequency domain, and calculate high-frequency signals, low-frequency signals, and the ratio of high-frequency signals to low-frequency signals. In some embodiments, the system may store cardiac events such as arrhythmias, tachycardia, bradycardia, etc.

[0313] In some embodiments, the heart rate sensor may store data collected over a specified time period to collect sufficient data for heart rate variability calculations. In some cases, the specified time period may range from 1 to 60 seconds and may be extended to 10 minutes or longer.

[0314] In some embodiments, such as those disclosed elsewhere herein, electrical skin activity (also known as electroskin response or skin conductance response) can be measured. In some embodiments, significant changes in sympathetic and / or parasympathetic activity can be used to predict the onset of ventricular and / or atrial dyssynchrony or arrhythmias, and the device can initiate stimulation to prevent or reduce the duration of dyssynchronous events. Adjustments can be made in real time or in subsequent stimulation phases. In some embodiments, the stimulation frequency can be adjusted to increase or decrease voluntary activity modulated by a single specific nerve or multiple nerves. For example, in some embodiments, relatively low-frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5 Hz)) can potentially inhibit the nerve and thus reduce sympathetic activity, while higher-frequency stimulation (e.g., above a threshold (e.g., about 5 Hz)) can potentially excite the nerve and thus increase sympathetic activity. Additionally, the pulse width of the stimulation waveform can be adjusted to recruit more or fewer specific fiber types, including skin fibers, which can inhibit sympathetic activity. The same action can be performed with respect to the same or other target nerves to modulate parasympathetic activity. In other words, in some embodiments, relatively low-frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5 Hz)) may potentially inhibit the nerve and thus reduce parasympathetic activity, while higher-frequency stimulation (e.g., above a threshold (e.g., about 5 Hz)) may potentially excite the nerve and thus increase parasympathetic activity. Not limited by theory, but depending on the stimulation parameters, in some cases, stimulation of the target nerve may increase or decrease sympathetic activity, parasympathetic activity, or both. In some embodiments, stimulation of the saphenous nerve may affect sympathetic activity, and stimulation of the tibial nerve may affect parasympathetic activity.

[0315] Unrestricted by theory, simultaneous firing of vagal and sympathetic nerve activity can trigger several arrhythmias, including atrial fibrillation, leading to an imbalance in the two arms of the autonomic nervous system. In some embodiments, systems and methods may include measurements of heart rate variability / skin conductance response and arrhythmia (e.g., atrial fibrillation) events to assess sympathetic balance and determine the likelihood of a response to peripheral stimuli. For example, a device worn on the wrist may combine sensors for measuring heart rate (such as optically based sensors) and / or sensors for measuring skin conductance response to assess sympathetic-vagal balance and detect arrhythmias (e.g., atrial fibrillation events) with a stimulation device. The device may measure HRV and / or GSR and detect atrial fibrillation events over a specified time period (such as 1–3 days or 1 week) to adjust stimulation parameters (e.g., stimulation frequency, alternation frequency, stimulation duration, stimulation time of day, pulse width, amplitude, duty cycle, phase, waveform shape, waveform symmetry, pulse interval, on / off time, burst) based on the assessment of sympathetic-vagal balance and the detection of arrhythmia events. In some embodiments, stimulation of one, two or more nerves in the upper and / or lower limbs may be combined with stimulation of the auricular branches of the vagus nerve (such as through the tragus) to modulate vagus nerve activity and restore the balance of the autonomic nervous system.

[0316] In some embodiments, a multimodal system may include multiple stimuli that wirelessly communicate with each other and provide synchronized, patterned stimulation. In some embodiments, the multiple stimuli may be connected to multiple effectors to simultaneously stimulate multiple nerves. In one embodiment, a system may include a wrist-based stimuli targeting the median nerve and an ear-based stimuli targeting an auricular branch of the vagus nerve. Each stimuli in the system may communicate with each other via wired or wireless connections. The multiple stimuli may provide synchronized stimulation to multiple nerves. The stimulation may be, for example, bursts, shifts, or alternations between multiple nerves.

[0317] In some cases, the device can also respond to a variety of symptom episodes, including chest pain, shortness of breath, dizziness, and / or palpitations, indicating an irregular heartbeat, cardiac asynchrony, and / or abnormal blood pressure. If more episodes occur during the day, treatment can be increased, for example, by increasing the amplitude of the stimulation, the duration of the stimulation, or the number of treatment phases.

[0318] The number of symptom episodes can be detected in a variety of ways to control the stimulation applied by the system and device. In some embodiments, the patient can input events related to cardiac symptoms on a mobile device, including but not limited to chest pain, shortness of breath, dizziness, and / or palpitations.

[0319] One embodiment of the system can centrally store biological metrics from multiple wearers, along with other relevant demographic data about each user (including age, weight, height, sex, ethnicity, etc.), on a server system (e.g., the cloud). Standard statistical analysis, machine learning, deep learning, or big data techniques (such as logistic regression or Naive Bayes classifiers (or other classifiers)) can be used to analyze the data collected from multiple wearers to improve predictions of arrhythmias, heart asynchrony, or blood pressure changes by determining the correlation between biological metrics and other recorded events with cardiac arrhythmias, cardiac dyssynchrony, and / or increased blood pressure. These correlations can be used to set parameters for the stimulation waveform applied by the treatment unit, determine the optimal time to apply stimulation therapy, and / or adjust the stimulation waveform applied by the treatment unit in real time.

[0320] In some embodiments, the wearable monitor may have visual, auditory, tactile (e.g., squeeze band) or vibratory haptic cues to notify the wearer of critical events based on biological metric analysis, including but not limited to predictions of cardiac arrhythmias, cardiac dyssynchrony, blood pressure or increased blood pressure and / or stress levels, heart rate, heart rate variability or other parameters. The cueing system may also notify the wearer of other predetermined events or reminders set by the wearer. The cueing system is intended to deliver information (such as the presence of arrhythmias such as atrial fibrillation, hypertension or other predetermined events) to the wearer in a more discreet and personalized manner without drawing the attention of others in social situations.

[0321] In some embodiments, the wearable monitor and / or treatment unit may take the form of a wristband or watch, ring, glove, arm sleeve or arm strap or cuff, knee strap, sock, leg sleeve or cuff, earplug / earphone, head strap, necklace or neck strap, or compatible patch that fits multiple locations on the body.

[0322] In some embodiments, specific fiber types within one or more nerves may be selectively or preferentially activated (e.g., action potentials are generated in such specific fiber types) to restore voluntary balance by specifically modulating the sympathetic and parasympathetic limbs of the autonomic nervous system (e.g., selectively or preferentially modulating only or more of A-α, A-β, A-δ, B, and / or C fibers). In some embodiments, the system and method do not stimulate or substantially do not stimulate A-α, A-β, A-δ, B, or C fibers.

[0323] Unrestricted by theory, stimulation of superficial and / or cutaneous afferent and / or afferent nerves can prevent arrhythmia by inhibiting the nuclei of solitary tract cells and the vagus nerve nucleus, inhibiting the aortic depressor nerve, and thereby inhibiting parasympathetic input; stimulation of deep afferent and / or efferent nerves can prevent arrhythmia by stimulating the arcuate nucleus-ventral aqueduct perigravimetric suture pathway, thereby inhibiting the rostral ventrolateral medulla oblongata (rVLM) and thus inhibiting sympathetic input. Superficial fibers are thinner (e.g., smaller diameter) afferent nerves that transmit sensory information to the superficial dorsal horn, a prominent region of the dorsal horn and spinal cord gray matter; deeper fibers are thicker (e.g., larger diameter) afferent nerves that transmit sensory information to the deep dorsal horn.

[0324] Some embodiments may include preferential stimulation of cutaneous fibers (e.g., A-α, A-β, A-δ, and / or C) to inhibit sympathetic activity via the stellate ganglion. At the wrist, stimulation of selected cutaneous fibers carries sensory information via the medial cutaneous nerve and the medial cord of the brachial plexus, which innervates the spinal cord at the C8-T1 level; stimulation then modulates cardiac sympathetic activity via the stellate or cervicothoracic ganglia, which are collections of sympathetic nerves at the C7-T1 level. In some embodiments, a peripheral nerve effector may be located, for example, on the patient's skin, such as on the medial aspect of the forearm, to stimulate the median cutaneous nerve but not, or substantially not, the median / radial or ulnar nerves, or at least preferentially stimulate the median cutaneous nerve. In some embodiments, the lateral cutaneous nerve and / or myocutaneous nerve, or specific fibers thereof, may be preferentially or specifically stimulated. In some embodiments, only one type of nerve fiber is activated, while other types of nerve fibers are not activated. For example, in one embodiment, only A-α fibers are activated, but B fibers are not activated. In one embodiment, 1-5 fiber types are activated, while one or more fiber types are deactivated (or functionally unstimulated). In some embodiments, the deactivated fibers do not discharge or carry action potentials. In some embodiments, one or more of A-α, A-β, A-δ, B fibers, or C fibers are activated or not activated. In some embodiments, one or more fibers are preferentially activated such that a greater number or fraction of one or more fiber types of a particular peripheral nerve are stimulated relative to other fibers of that peripheral nerve and / or other peripheral nerves adjacent to the target peripheral nerve. In some embodiments, more than about 50%, 60%, 70%, 80%, 90%, 95%, or substantially all of the fibers of one or more fiber types of a nerve are activated, while less than about 50%, 40%, 30%, 20%, 10%, 5%, or less of another fiber type are activated, such that one or more fiber types are preferentially activated relative to one or more different fiber types of other peripheral nerves of the same nerve and / or adjacent to the target peripheral nerve.

[0325] Selective or preferential activation of various nerve fiber types can be accomplished in a variety of ways. In some embodiments, stimulation parameters of the biphasic square wave, such as pulse width, can be controlled to selectively or preferentially activate specific fiber types (e.g., without activating other fiber types). For example, a pulse width of about 50–100 µs can selectively or preferentially stimulate larger A-α fibers; a pulse width of about 150–200 µs can selectively or preferentially stimulate smaller A fibers; and a pulse width of about 300–400 µs can selectively or preferentially stimulate even smaller C fibers.

[0326] In some embodiments, the frequency of the sinusoidal mode can be controlled to selectively or preferentially activate specific fiber types. For example, frequencies of about 2000 Hz, about 250 Hz, and about 5 Hz can selectively or preferentially activate A-β, A-δ, and C afferent fibers, respectively.

[0327] In some embodiments, the device may include a peripheral nerve effector configured to selectively or preferentially stimulate superficial nerve fibers (e.g., fibers closer to the skin surface) by aligning the effector along the length of a nerve axon.

[0328] Some embodiments may involve one or more multimodal stimulation patterns (e.g., burst, pulse, random, pseudo-random, or noise) to improve the efficiency and effectiveness of stimulation. In some embodiments, stimulation may be provided in a burst pattern, wherein the bursts may be rhythmic (e.g., at regular intervals) or pseudo-random. In some embodiments, stimulation waveforms may be provided that combine ultra-low stimulation frequencies (0.01-0.1 Hz) with higher frequency stimuli (1-200 Hz) or combine lower frequencies (1-200 Hz) with very high frequencies (1000-10 kHz).

[0329] In some embodiments, this document discloses wearable systems and methods that can utilize transcutaneous sensory stimulation in burst modes, such as theta burst modes, to improve cardiac arrhythmias, cardiac dyssynchrony, hypertension, and / or a variety of other conditions, including but not limited to those disclosed herein. In some cases, noninvasive peripheral nerve theta burst stimulation can more effectively promote cortical or spinal cord plasticity to reduce symptoms and improve individual quality of life than continuous stimulation. Additional details regarding non-restrictive burst parameters are disclosed elsewhere herein.

[0330] In some embodiments, multimodal stimulation involves non-invasive, transcutaneous patterned or abrupt stimulation of peripheral nerves (including afferent and / or efferent nerves), as described elsewhere herein.

[0331] Unrestricted by theory, alternating bursts of stimulation on the median, radial, and / or ulnar nerves can prevent arrhythmias by producing a synergistic effect that increases input to the stellate ganglion via the brachial plexus to inhibit sympathetic activity or modulates vagal tone via the carotid sinus nerve.

[0332] In some embodiments, stimulation of the median, radial, and / or ulnar nerves may be combined for synergistic effects at the brachial plexus. The median, radial, and ulnar nerves innervate different levels of the spinal cord at the brachial plexus, with pathways leading to different target locations and organs. Some embodiments may provide timed stimulation of the median, radial, and / or ulnar nerves simultaneously or with delay to control targeting within the brachial plexus, thereby providing synergistic neural activation at the brachial plexus, leading to the stellate ganglion and the sympathetic chain. This synergy can provide greater therapeutic benefits with less discomfort and less current (e.g., less power to extend battery life). The timing of stimulation may be synchronous or delayed to accommodate differences in conduction velocities among the different nerves, allowing signals to arrive at the brachial plexus simultaneously. Not limited by theory, simultaneous or near-simultaneous activation of the brachial plexus can enhance stimulation to the stellate ganglion through pathway enhancement and increase the effects of the sympathetic nervous system (e.g., inhibition). For example, the mean conduction velocities of the sensory nerves of the radial, median, and ulnar nerves are approximately 51 m / s, 60 m / s, and 63 m / s, respectively. Based on the variation in nerve length from the wrist to the brachial plexus (ranging from 1% in women to 99% in men), this requires a stimulation delay of approximately 1.3 to approximately 1.7 milliseconds between the median and radial nerves, approximately 0.3 and approximately 0.4 milliseconds between the median and ulnar nerves, and approximately 1.6 and approximately 2.1 milliseconds between the radial and ulnar nerves. In some embodiments, the stimulation delay between the first and second nerves may be between approximately 0.3 ms and approximately 1.7 ms, or between approximately 0.2 ms and approximately 2.0 ms, between approximately 1.2 ms and approximately 2.1 ms, or between approximately 1 ms and approximately 2 ms. Lower threshold stimulation on the median, radial, and / or ulnar nerves can advantageously require lower threshold stimulation on individual nerves, thereby producing a synergistic effect on the brachial plexus. In some embodiments, the system may include a nerve conduction velocity measurement (which measures an individual's nerve conduction velocity by applying a stimulation source to the distal portion of the nerve and measuring electrodes to the proximal portion of the nerve) and modify the timing delay based on the individualized measurement.

[0333] In some embodiments, the system may include a peripheral nerve effector configuration to stimulate nerves (e.g., radial, median, and / or ulnar nerves) in alternating patterns that may be rhythmic or pseudo-random. For rhythmic alternating patterns, the alternation frequency may be in the range of 1-100 Hz, which can improve therapeutic efficacy by promoting the plasticity of corticospinal circuits. In some embodiments, device embodiments may include an effector configuration for stimulating alternating nerves (e.g., radial, median, and / or ulnar nerves) and adjusting stimulation parameters (e.g., stimulation frequency, alternation frequency, stimulation duration, stimulation time of day, pulse width, amplitude, duty cycle, phase, waveform shape, waveform symmetry, pulse interval, on / off time, or bursts) based on an assessment of autonomic balance, for example by measuring heart rate variability (HRV) and analyzing sympathetic balance, such as the ratio of absolute low frequency (LF) to absolute high frequency (HF) power or the measured HRV LF / HF, as described elsewhere herein.

[0334] In some embodiments, a multimodal method for treating arrhythmia or hypertension is disclosed herein. The method may include any number of the following: positioning a first peripheral nerve effector on the patient's skin in the upper limb to stimulate a first peripheral nerve selected from a group consisting of one of the patient's median, radial, and ulnar nerves; positioning a second peripheral nerve effector on the patient's ear or the tragus of the vagus nerve (e.g., via the cymba conchae) to stimulate a second peripheral nerve associated with the patient's parasympathetic pathway; delivering a first nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve, which is sufficient to modify at least one cerebral or spinal cord autonomic feedback loop associated with arrhythmia or hypertension; and delivering a second nerve stimulation signal to the second peripheral nerve effector to stimulate the second peripheral nerve, which is sufficient to modify at least one cerebral or spinal cord autonomic feedback loop associated with arrhythmia or hypertension. The second nerve stimulation signal may have the same or different stimulation parameters as the first nerve stimulation signal. The first and second nerve stimulation signals may be configured to balance the patient's parasympathetic and sympathetic nervous system activity. The method may also include monitoring sympathetic and parasympathetic activity in the patient. The method may further include adjusting the first neural stimulation signal when identifying abnormal sympathetic activity in the patient. The method may also include adjusting the second neural stimulation signal when identifying abnormal parasympathetic activity in the patient.

[0335] In some embodiments, this document also discloses a multimodal wearable system for treating arrhythmias or hypertension. The system may include any number of the following features, or other features disclosed elsewhere in the specification. The system may include: a first peripheral nerve effector configured to be positioned on the patient's skin in a patient's limb; a second peripheral nerve effector configured to be positioned on the patient's ear or the tragus of the vagus nerve (e.g., via the cymba conchae); and / or at least one biomedical sensor or data input source configured to provide feedback information. A controller may be configured to generate a first neural stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve, sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with arrhythmias or hypertension. The controller may also be configured to generate a second neural stimulation signal to the second peripheral nerve effector to stimulate a second peripheral nerve associated with the patient's parasympathetic pathways to modify at least one brain or spinal cord autonomic feedback loop associated with arrhythmias or hypertension. The controller may also be configured to adjust the first and second neural stimulation signals to balance the patient's parasympathetic and sympathetic nervous system activity. The controller can be configured to adjust the first nerve stimulation signal when abnormal sympathetic and / or parasympathetic nerve activity is identified in a patient.

[0336] This article also discloses a multimodal method for treating arrhythmias or hypertension. The method may include any number of the following: assessing at least one of the sympathetic and parasympathetic activity in a subject and determining the presence of abnormal sympathetic and parasympathetic activity in the subject; if abnormal sympathetic activity is present, stimulating a first nerve operatively connected to the brachial plexus sufficient to have a therapeutic effect on the arrhythmia or hypertension; and if abnormal parasympathetic activity is present, stimulating the tragus of the ear or auricular vagus nerve (e.g., via the cymba conchae) sufficient to have a therapeutic effect on the arrhythmia or hypertension. In some cases, stimulation may be transcutaneous only and may include activating or inhibiting the neural activity of the first nerve. If both abnormal sympathetic and abnormal parasympathetic activity are present, stimulation may involve the first nerve and the tragus of the ear or auricular vagus nerve (e.g., via the cymba conchae). Assessing at least one of the sympathetic and parasympathetic activity in a subject includes, for example, measuring HRV in the subject using a wrist-worn device, and also includes measuring heart rate and / or electrodermal activity. The primary nerve can be, for example, the median nerve, radial nerve, ulnar nerve, median cutaneous nerve, lateral cutaneous nerve, or other nerves discussed herein. Adjustments may include energy type, stimulation parameters (e.g., frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on / off time, burst, etc.), and time of day during which stimulation is applied.

[0337] This article also discloses a multimodal approach for treating arrhythmias or hypertension, which may involve stimulating a first peripheral nerve; assessing at least one of the sympathetic and parasympathetic nerve activity in the subject and identifying abnormal sympathetic and parasympathetic nerve activity in the subject; and adjusting the stimulation after assessing at least one of the sympathetic and parasympathetic nerve activity. Adjusting the stimulation may include identifying abnormal sympathetic and parasympathetic nerve activity in the patient and adjusting the stimulation frequency of the first nerve, and / or interrupting the stimulation of the first nerve; and initiating stimulation of a second nerve.

[0338] In some embodiments, the embodiments described herein, which include multiple peripheral nerve stimulations to promote sympathetic balance by modulating at least one peripheral nerve of the sympathetic nervous system and at least one peripheral nerve of the parasympathetic nervous system, may advantageously have the ability to selectively or preferentially modulate the sympathetic and / or parasympathetic arms of the autonomic nervous system in response to detected sympathetic and / or parasympathetic overactivity.

[0339] For essential tremor and other movement disorders, cardiac dysfunction, overactive bladder, gastrointestinal disorders, inflammatory bowel disease, psychosis, and other indications, the first stimulant may include an electrical stimulant and the second stimulant may include a magnetic stimulant. The first stimulant may include an electrical stimulant and the second stimulant may include a chemical stimulant. The first stimulant may include an electrical stimulant and the second stimulant may include a thermal stimulant. The first stimulant may include an electrical stimulant and the second stimulant may include a mechanical stimulant. The first stimulant may include an electrical stimulant and the second stimulant may include an ultrasound stimulant (e.g., focused ultrasound). The first stimulant may include an electrical stimulant and the second stimulant may include a radiofrequency stimulant. The first stimulant may include an electrical stimulant and the second stimulant may include a microwave stimulant. The first stimulant may include a magnetic stimulant and the second stimulant may include a chemical stimulant. The first stimulant may include a magnetic stimulant and the second stimulant may include a thermal stimulant. The first stimulant may include a magnetic stimulant and the second stimulant may include a mechanical stimulant. The first stimulant may include a magnetic stimulant and the second stimulant may include an ultrasound stimulant, such as a focused ultrasound stimulant (e.g., focused ultrasound). The first stimulant may include a magnetic stimulant and the second stimulant may include a radiofrequency stimulant. The first stimulant may include a magnetic stimulant and the second stimulant may include a microwave stimulant. The first stimulant may include a chemical stimulant and the second stimulant may include a thermal stimulant. The first stimulant may include a chemical stimulant and the second stimulant may include a mechanical stimulant. The first stimulant may include a chemical stimulant and the second stimulant may include a focused ultrasound stimulant (e.g., focused ultrasound). The first stimulant may include a chemical stimulant and the second stimulant may include a radiofrequency stimulant. The first stimulant may include a chemical stimulant and the second stimulant may include a microwave stimulant. The first stimulant may include a thermal stimulant and the second stimulant may include a mechanical stimulant. The first stimulant may include a thermal stimulant and the second stimulant may include a focused ultrasound stimulant (e.g., focused ultrasound). The first stimulant may include a mechanical stimulant and the second stimulant may include a radiofrequency stimulant. The first stimulant may include a mechanical stimulant and the second stimulant may include a microwave stimulant. The first stimulant may include a focused ultrasound stimulant (e.g., focused ultrasound) and the second stimulant may include a radiofrequency stimulant. The first stimulant may include an ultrasound (e.g., focused ultrasound) stimulant and the second stimulant may include a microwave stimulant. The first stimulant may include a radiofrequency stimulant and the second stimulant may include a microwave stimulant.

[0340] Figure 27AA system is illustrated that can be configured to periodically stimulate multiple skin patches (using an electrode array embedded in a sleeve across the arm) by stimulating adjacent electrode pairs at regular intervals, such that specific points along a nerve are stimulated. The electrodes can be arranged in a linear array, for example, to provide spatially patterned stimulation. Multimodal stimulation may include applying different patterns to the electrode array (e.g., a linear array of electrode pairs). Skin patches in the arm that can be stimulated and carry sensory information include, for example, C5 (lateral aspect of the upper limb above the elbow); C6 (forearm and radial side of the hand); C7 (middle finger); C8 (skin on the little finger and medial aspect of each hand); T1 (medial aspect of the forearm); and T2 (medial and upper aspect of the arm and axillary region).

[0341] Some embodiments may involve stimulation patterns (e.g., burst, pulse, random, pseudo-random, or noise) to improve the efficiency and effectiveness of stimulation. In some embodiments, such as... Figure 27A As schematically illustrated, an electrode array can be aligned along the axons of a nerve and can stimulate adjacent electrode pairs at regular intervals, such that specific points along the nerve are stimulated at speeds, for example, between about 1 cm / s and about 10 cm / s (e.g., about 1 cm / s, about 2 cm / s, about 3 cm / s, about 4 cm / s, about 5 cm / s, about 6 cm / s, about 7 cm / s, about 8 cm / s, about 9 cm / s, about 10 cm / s, and ranges between such values). In some embodiments, stimulation can be provided in a burst pattern, wherein the bursts can be rhythmic (e.g., at regular intervals) or pseudo-random. In some embodiments, stimulation waveforms combining ultra-low stimulation frequencies (0.01-0.1 Hz) with higher frequency stimulation (1-200 Hz) or combining lower frequencies (1-200 Hz) with very high frequencies (1000-10 kHz) can be provided.

[0342] Lateral electrode configurations can deliver disruptive stimulation below the skin surface. Multiple modes can be used to create different interference patterns. The interference can be constructive or destructive. Each electrode pair can have the same or different stimulation parameters. For example, different stimulation frequencies can produce destructive interference, which stimulates at a new beat frequency (e.g., the difference between two different frequencies).

[0343] In some embodiments, the electrode pairs may be spaced apart on the limb, such as Figure 27BAs shown, stimulation waveforms are combined at specific crossover points to target deep fibers by generating an interference pattern of stimulation with a frequency equal to the difference between the frequencies of the two waveforms, for example, frequencies between approximately 2 Hz and approximately 20 kHz (e.g., approximately 2 Hz, approximately 4 Hz, approximately 6 Hz, approximately 8 Hz, approximately 10 Hz, approximately 12 Hz, approximately 15 Hz, approximately 20 Hz, approximately 30 Hz, approximately 40 Hz, approximately 50 Hz, approximately 60 Hz, approximately 100 Hz, approximately 250 Hz, approximately 500 Hz, approximately 1000 Hz, approximately 2500 Hz, approximately 5 kHz, approximately 10 kHz, approximately 15 kHz, approximately 20 kHz, and ranges between such values). Higher and lower frequencies are also possible.

[0344] Example The following examples are merely illustrative and are not intended to limit the scope of the invention.

[0345] We evaluated a method for using peripheral nerve stimulation to alter the circuit dynamics associated with ET in a clinical study. A device 100 for delivering transcutaneous electrical nerve stimulation (TENS) using a surface electrode 102 located on the palmar side of the wrist was used to stimulate the median nerve 104 with a square wave at a frequency of 150 Hz and a pulse width of 300 microseconds for 40 minutes. Figure 1 As shown. In this embodiment, wire 106 is used to connect device 100 to electrode 102. Surprisingly, a reduction in tremor was found, as previous studies reported that peripheral nerve stimulation using TENS did not improve tremor.

[0346] This electrical stimulation effectively reduced tremor in subjects with mild to severe tremor. Kinetic tremor was assessed using widely used measurement methods for kinetic tremor: the Archimedes spiral drawing task of the Fahn-Tolosa-Marin test. Postural tremor was assessed by measuring the angular velocity of a gyroscope worn on the back of the hand.

[0347] Three patients (represented as subjects A, B, and C in Figure 2) are shown with spirals drawn by subjects with mild, moderate, and severe ET before and after stimulation. In subjects with mild, moderate, and severe tremor, postural tremor was reduced by 70%, 78%, and 92%, respectively. Postural tremor was also reduced by electrical stimulation, and this effect lasted for up to 45 minutes after treatment. Figures 3A-3C The effect on wrist flexion and extension, determined by gyroscope data from subject B in Figure 2, is shown as a representative example. Fifteen minutes of treatment reduced the tremor amplitude from 0.9 degrees ( Figure 3A Reduced to 0.2 degrees ( Figure 3B The reduction in tremor amplitude was maintained for 40 minutes of treatment. Measurements taken 20 minutes after treatment showed that the tremor amplitude continued to decrease and remained at 0.2 degrees. Figure 3C The reduction in tremor is variable among subjects. (e.g.) Figure 4 As shown, some subjects did not respond to the treatment.

[0348] Excellent therapeutic outcomes were achieved by reducing tremors in subjects with ET through the application of electrical stimulation. The stimulation reduced tremors during treatment, immediately after treatment, and for up to twenty minutes post-treatment. To enable long-term use and allow patients with ET to integrate treatment into their lives, the system is made easy to use and effective over a long period in many embodiments. In several embodiments, the innovations and devices described herein are used to achieve this goal.

[0349] In another example, a multimodal approach will be used, which in some embodiments will employ algorithmic learning and / or feedback. At least two stimuli will be selected from the group consisting of vibratory tactile, chemical, mechanical, thermal, electrical, ultrasonic (e.g., ultrasound, focused ultrasound), RF, and microwave, and applied to the same or different locations on or within the body. For example, a first stimulus may be applied to the wrist, and different second stimuli may be applied to different locations (ankle, finger, ear, leg, arm, etc.). Alternatively, a first stimulus may be applied to a first location (e.g., the wrist), and different second stimuli may be applied to the same first location. In another example, using different points within the same region may also provide synergy (e.g., different points on the wrist). The same or different nerves may be stimulated at the first location. For example, in some embodiments, different nerves (or multiple location points) within a region will be stimulated.

[0350] Various embodiments of disease-modifying devices and methods thereof have been disclosed above, including but not limited to tremor-modifying devices and methods of use thereof. These various embodiments may be used alone or in combination, and various changes may be made to individual features of the embodiments without departing from the scope of the invention. For example, in some cases, the order of various method steps may be changed, and / or one or more optional features may be added to or removed from the described device. Therefore, the description of the embodiments provided above should not be construed as an undue limitation of the scope of the invention as set forth in the claims.

[0351] In the context of a single embodiment, some functions described herein may also be implemented in combination in a single embodiment. Conversely, various features described in the context of a single embodiment may also be implemented individually or in any suitable sub-combination in multiple embodiments. Moreover, although features may be described above as functioning in certain combinations and even initially claimed in this way, in some cases one or more features in the claimed combination may be removed from the combination, and the claimed combination may be for sub-combinations or variations thereof.

[0352] The foregoing descriptions and examples have been set forth to illustrate the invention according to various embodiments and are not intended to be unduly limiting. The headings provided herein are for organizational purposes only and are not intended to limit the embodiments. Each aspect and example of this disclosure may be considered alone or in combination with other aspects, examples, and variations of this disclosure. Furthermore, unless otherwise stated, the steps of the methods of this disclosure are not limited to any particular order of execution. References cited herein are incorporated herein by reference in their entirety. Describing embodiments as “preferred” does not limit the use or scope of alternative embodiments.

[0353] While the methods and apparatus described herein are readily subject to various modifications and substitutions, specific examples have been shown in the accompanying drawings and described in detail herein. However, it should be understood that the disclosed embodiments are intended to cover modifications, equivalents, and alternatives falling within the spirit and scope of the various embodiments described herein and in the appended claims.

[0354] Depending on the implementation, one or more actions, events, or functions of any algorithm, method, or process described herein may be performed in a different order, and may be added, combined, or omitted (e.g., not all of the described actions or events are necessary for the implementation of the algorithm). In some examples, actions or events may be performed concurrently, for example, through multithreading, interrupt handling, or on multiple processors or processor cores or other parallel architectures, rather than sequentially.

[0355] Unless otherwise explicitly stated or understood in the context in which they are used, the use of sequential or chronological language such as “then,” “next,” “after,” “following,” etc., is generally intended to facilitate the transmission of text and not to restrict the order of operations performed.

[0356] The various illustrative logic blocks, modules, processes, methods, and algorithms described in conjunction with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this interchangeability between hardware and software, various illustrative components, blocks, modules, operations, and steps have been described above generally according to their functionality. Whether this functionality is implemented as hardware or software depends on the specific application and the design constraints imposed on the system as a whole. The described functionality can be implemented in various ways for each specific application, but such implementation decisions should not be construed as departing from the scope of this disclosure.

[0357] The various illustrative logic blocks and modules described in conjunction with the embodiments disclosed herein can be implemented or executed by a machine, such as a general-purpose processor, a digital signal processor (DSP), an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but alternatively, the processor may be a controller, a microcontroller, or a state machine, a combination thereof, etc. The processor may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors combined with a DSP core, or any other such configuration.

[0358] The blocks, operations, or steps of the methods, processes, or algorithms described in conjunction with the embodiments disclosed herein may be directly embodied in hardware, in a software module executed by a processor, or a combination of both. The software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, removable disk, optical disk (e.g., CD-ROM or DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. The storage medium may be coupled to the processor, such that the processor can read information from and write information to the storage medium. Alternatively, the storage medium may be integrated with the processor. The processor and storage medium may reside in an ASIC. The ASIC may reside in a user terminal. Alternatively, the processor and storage medium may reside as discrete components in the user terminal.

[0359] Unless otherwise expressly stated or understood in the context in which they are used, the conditional language used herein (such as “may,” “possibly,” “can,” “for example,” etc.) is generally intended to convey that some examples include certain features, elements, and / or states, but some examples do not include them. Therefore, such conditional language is not generally intended to imply that one or more examples require features, elements, boxes, and / or states in any way, or that one or more examples must include logic for determining (with or without author input or prompts) whether such features, elements, and / or states are included or will be performed in any particular embodiment.

[0360] The methods disclosed herein may include certain actions taken by practitioners; however, these methods may also include any third-party instructions regarding these actions, whether explicit or implicit. For example, actions such as “positioning electrodes” include “indicating the positioning of electrodes.”

[0361] The scope disclosed herein also covers any and all overlaps, subranges, and combinations thereof. Language such as “at most,” “at least,” “greater than,” “less than,” “between,” etc., includes the listed numbers. Numbers previously referred to as “about” or “approximately” include the listed numbers and should be interpreted on a case-by-case basis (e.g., as reasonably accurate as possible in this context, such as ±5%, ±10%, ±15%, etc.). For example, “about 1 hour” includes “1 hour.” Phrases previously referred to as “substantially” include the cited phrase and should be interpreted on a case-by-case basis (e.g., as reasonably accurate as possible in this context). For example, “substantially vertical” includes “vertical.” Unless otherwise stated, all measurements are performed under standard conditions, including temperature and pressure. The phrase “at least one” is intended to require at least one item from the subsequent list, not every item of a certain type in each of the subsequent lists. For example, “at least one of A, B, and C” may include A, B, C, A and B, A and C, B and C, or A, B, and C.

Claims

1. A method for treating tremor in a subject, the method comprising: A first stimulus from the first actuator is applied to a first location on the subject's body. The first stimulation includes electrical stimulation, wherein the first actuator includes electrodes, and wherein the first location is the wrist of the body; A second stimulus from the second actuator is applied to a second location on the body. The second stimulus includes vibrational stimulation, wherein the second location is the wrist of the body, the second location is spaced apart from the first location, and wherein a flexible cuff is used to couple the first actuator and the second actuator to the wrist. The application of at least one of the first stimulus or the application of the second stimulus is responded to by a controller in the smart device and based on the sensed amplitude of the tremor. The amplitude of the tremor decreases after the first stimulus and the second stimulus are applied.

2. The method of claim 1, further comprising applying a third stimulus from a third actuator to a third location on the body, the third stimulus including magnetic stimulation, electromagnetic stimulation, chemical stimulation, thermal stimulation, ultrasonic stimulation, radio frequency stimulation, light stimulation, or microwave stimulation.

3. A method for treating tremor in a subject, the method comprising: A first stimulus from the first actuator is applied to a first location on the subject's body. The first stimulus includes electrical stimulation or vibrational stimulation; and A second stimulus from the second actuator is applied to a second location on the body. The second stimulus includes vibrational stimulation. The application of the first stimulus or the application of the second stimulus is in response to a controller in a smart device and is based on the sensing amplitude of the tremor; The amplitude of the tremor decreases after the first stimulus and the second stimulus are applied.

4. The method of claim 3, wherein the second stimulus comprises electrical stimulation or vibrational stimulation, and the second stimulus is different from the first stimulus.

5. The method according to claim 3, wherein the second stimulation includes electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibration stimulation, ultrasonic stimulation, radio frequency stimulation, or microwave stimulation.

6. The method of claim 5, wherein the second stimulus is different from the first stimulus.

7. The method of claim 3, further comprising applying a third stimulus from a third actuator to a third location on the body, the third stimulus including electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibration stimulation, ultrasonic stimulation, radio frequency stimulation, or microwave stimulation.

8. The method of claim 7, wherein the second stimulus is different from the first stimulus, and wherein the third stimulus is different from the second stimulus.

9. The method of claim 3, wherein the first position includes the wrist of the body and the second position includes the wrist of the body.

10. The method of claim 3, wherein the first position includes an arm of the body and the second position includes a leg of the body.

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