CN112601488A

CN112601488A - Multimodal stimulation for treating tremor

Info

Publication number: CN112601488A
Application number: CN201980055793.8A
Authority: CN
Inventors: K·H·罗森布卢特; S·L·德尔普; J·帕德里; V·拉贾塞哈尔; T·阿尔特曼; S·R·哈姆纳; E·K·罗斯
Original assignee: Cala Health Inc
Current assignee: Cala Health Inc
Priority date: 2018-06-27
Filing date: 2019-06-26
Publication date: 2021-04-02
Also published as: EP3813647A4; EP3813647A1; WO2020006048A1

Abstract

A peripheral nerve stimulator for stimulating peripheral nerves for the treatment of essential tremor and other movement disorders, as well as overactive bladder, cardiac dysfunction and neurotransmitter dysfunction is provided. The peripheral nerve stimulator may be a non-invasive surface stimulator providing a multimodal optimization therapy. The stimulus may be vibrational, electromechanical, thermal, radiative, 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 to one site or several sites.

Description

Multimodal stimulation for treating tremor

Cross Reference to Related Applications

This application is a continuation of U.S. patent application No.16/020,876 filed on day 27/6/2018, U.S. patent application No.16/020,876 is a continuation of U.S. patent application No.15/277,946 filed on day 27/9/2016, U.S. patent application No.15/277,946 is a continuation of U.S. patent application No.14/805,385 (now U.S. patent No.9,452,287) filed on day 21/7/2015, U.S. patent application No.14/805,385 is a continuation of international patent application No. pct/US2014/012388 filed on day 21/1/2014/012388, international patent application No. pct/US2014/012388 requires U.S. provisional patent application No.61/754,945 filed on day 21/2013, U.S. provisional patent application No.61/786,549 filed on day 15/3/2013, U.S. provisional patent application No.61/815,919 filed on day 25/4/2013, U.S. provisional patent application No.61/822,215 filed on day 5/10/2013, and U.S. provisional patent application No.61 filed on day 7/2013/7/61 857,248; each of these patent applications is incorporated herein by reference in its entirety for all purposes (including under 37c.f.r. § 1.57). All patent publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Background

Essential Tremor (ET) is the most common dyskinesia, estimated to affect 1000 million patients in the united states, and is growing due to an aging population. The prevalence of ET increases with age, from 6.3% in the population over 65 years to 20% in the population over 95 years. The ET is characterized by involuntary oscillatory motion, typically between 4-12 Hz. It (ET) produces acoustic oscillations and unwanted movements of the head and limbs. Tremor of the hands and forearms is particularly prevalent and problematic as it makes writing, typing, eating and drinking difficult. Unlike parkinsonian tremor, which occurs at rest, essential tremor is postural and motor, meaning that tremor is caused by holding the limb under gravity or during movement, respectively.

ET accompanying disabilities are variable and range from embarrassment to inability to live independently, for example when the task of writing and self-feeding is disabled due to uncontrolled movements of the hands and arms. Despite the high prevalence and high disability of many ET patients, there are still insufficient treatment options to address tremor.

It has been found that drugs 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 drugs can be severe and are not tolerated by many ET patients. An alternative therapy is surgical implantation of stimulators in the brain using Deep Brain Stimulation (DBS), which can effectively reduce tremor amplitude by 90%, but it is a highly invasive surgical procedure with great risk and intolerant to many ET patients. Therefore, there is an urgent need for alternative therapies for ET patients that reduce tremor without producing drug side effects and without risking brain surgery.

Tremor is also a significant problem in patients with standing 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-barre syndrome, and fragile X syndrome), as well as brain tumors, hypoglycemia, hyperthyroidism, hypoparathyroidism, insulinoma, normal aging, and traumatic brain injury. Stuttering or crusting is also a form of tremor. The underlying cause of tremor in these cases may be different from ET; however, treatment options for some of these conditions are also limited, and alternative therapies are required.

Disclosure of Invention

ET is believed to be caused by anomalies in the loop dynamics associated with motion generation and control. Previous work has shown that cooling, local analgesics, and vibrations may temporarily alter these circuit dynamics. Previous work reported that electrical stimulation using Transcutaneous Electrical Nerve Stimulation (TENS) did not improve tremor (Munhoz 2003). Thus, surprisingly, it was found in our clinical studies that the circuit dynamics associated with ET can be altered by peripheral nerve stimulation, resulting in a substantial reduction in tremor in individuals with ET.

Several embodiments include novel peripheral stimulation devices for signaling the central nervous system along sensory nerves to modify abnormal network dynamics. Over time, this stimulation normalizes nerve discharges in the abnormal network and reduces tremors. When DBS directly stimulates the brain, our peripheral stimulation will affect abnormal brain circuit dynamics by sending signals along the sensory nerves connecting the peripheral nerves to the brain. This approach is non-invasive and is expected to avoid surgical risks of DBS and problems associated with cognitive, declarative and spatial memory dysarthria, ataxia or gait disorders. Peripheral nerve stimulation can effectively treat tremors by shifting phase (phase), covering or masking abnormal brain circuit dynamics. Following the assumptions of traditional DBS mechanisms, the brain is covered, masked, or trained to ignore abnormal brain circuit dynamics.

Perhaps the most closely related technique to our approach is Transcutaneous Electrical Nerve Stimulation (TENS). High frequency TENS (50 to 250Hz) is commonly used to treat pain, assuming that excitation of large, myelinated peripheral proprioceptive fibers (a- β) would block afferent pain signals. Although inconsistent clinical outcomes from pain management using TENS have prompted many to question their use in pain management, there is ample evidence that surface electrical stimulation can excite a- β neurons. A- β neurons carry proprioceptive sensory information into the same brain circuits that are abnormal in diseases including ET and parkinson's disease. Without being limited by any proposed mechanism of action, this has led us to the idea that neurostimulation can be used to excite the a- β nerve and thereby improve tremor. This proposal is particularly surprising since previous studies by Munhoz et al failed to find any significant improvement in any tremor parameters tested after the application of TENS. See Munhoz et al, Acute Effect of Transcutaneous Electrical Nerve Stimulation on Tremor, published in Movement Disorders (2003, 18 (2): 191-194).

Several embodiments disclosed herein relate to systems, devices, and methods for treating tremors, and more particularly to systems, devices, and methods for treating tremors by stimulating peripheral nerves.

In some embodiments, a method of 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 a first peripheral nerve through a first peripheral nerve effector; and reducing the tremor amplitude by modifying the patient's neural network dynamics.

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

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

In some embodiments, the peripheral nerve effector comprises a power source. In some embodiments, the method further comprises wirelessly powering the first peripheral nerve effector by an externally located power source.

In some embodiments, the first stimulus comprises vibrotactile. In some embodiments, the first stimulus comprises chemical. In some embodiments, the first stimulus comprises mechanical, vibrational, electromechanical, thermal, radiative, electrical, magnetic, electromagnetic, optical, acoustic, ultrasonic (e.g., focused ultrasound), chemical, infrared, Radio Frequency (RF), ultraviolet, X-ray, or microwave. 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 location on the body. For example, a first stimulus is applied to the wrist and a different second stimulus is applied at a different location. Alternatively, a first stimulus is applied to a first location (e.g., the wrist) and a different second stimulus is applied to the same first location. The same or different nerves can be stimulated at the first location. For example, in some embodiments, different nerves (or multiple location points) in a region are stimulated. In several embodiments, stimulation or other neuromodulation may be applied within the body instead of or in addition to on the skin surface (e.g., partial or complete implantation of the device, oral delivery, etc.).

It may be beneficial in some embodiments to use multimodal methods (whether such methods include multiple locations, multiple types or multiple stimuli of the same stimulus, or the like, or combinations thereof) by reducing habituation, increasing efficacy, improving specificity of preferentially stimulating nerve fibers, creating a synergistic effect with other non-energy based therapies (e.g., drug therapies), increasing stimulation efficiency to affect neural circuits, and/or reducing the amount or duration of at least one stimulus, or the like. For example, treatment performed on the wrist and second location (e.g., ankle, ear, finger, etc.) may result in a faster reduction in tremor, a longer duration of tremor reduction, delivery of an overall reduced amount of stimulation, increased patient compliance, and the like. In another example, using different points in the same area may provide similar beneficial results (e.g., different points on the wrist). In one embodiment, different points in the same area are within a distance of about 5mm, 25mm, 50mm, 100mm, and 200mm from each other (e.g., on the wrist or ankle). In other embodiments, different points in the same area are within about 0.25 feet to 4 feet of each other (e.g., on a leg).

In many embodiments, multiple modality approaches are 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, hand, leg, head, neck, and/or sound tremor are treated in the same person. In other embodiments, a patient suffering from hand tremor or leg tremor is treated.

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

In some embodiments, the method further comprises: sensing movement of a patient extremity using a measurement unit to generate motion data; and determining tremor information from the motion data. In some embodiments, delivering comprises delivering the first stimulation based on tremor (or other) information. In some embodiments, the information (e.g., tremor information) includes a maximum deviation from a resting position of a patient's limb. In some embodiments, the information (e.g., tremor information) includes a resting position of a patient's limb. In some embodiments, the tremor information includes tremor frequency, phase, and amplitude.

In some embodiments, delivering the first stimulation includes delivering a plurality of stimulation bursts with variable time delays between the stimulation bursts.

In some embodiments, the method further comprises: placing a second peripherical nerve effector at a second location relative to a second peripherical nerve; and delivering a second stimulation to a second peripheral nerve through a second peripheral nerve effector. According to several embodiments, effectors are placed on two or more points on the same general area (e.g., the wrist) or on two or more locations (e.g., the wrist and ankle).

In some embodiments, the method further comprises determining a period of time for tremor or other dysfunction in the patient, wherein delivering the second stimulation comprises offsetting the delivery of the second stimulation from the delivery of the first stimulation by a predetermined fraction or multiple of the period of time for tremor or other dysfunction. In some embodiments, the method further comprises dephasing the synchronicity of the neural network in the brain of the patient. In some embodiments, the second stimulus is disposed at the same location or a different location than the first stimulus. The second stimulus may be the same (e.g., both electrical or mechanical) or different from the first stimulus. The second stimulus may be the same as the first stimulus, but with different parameters (e.g., different amplitude, duration, frequency, etc.).

In some embodiments, the first location and the second location are located on adjacent fingers. In some embodiments, the first peripheral nerve and the second peripheral nerve are adjacent nerves. In some embodiments, the first peripheral nerve is the median nerve and the second peripheral nerve is the ulnar nerve or the radial nerve. In some embodiments, the first peripheral nerve and the second peripheral nerve are orthotopically adjacent.

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, the first peripheral nerve carries proprioceptive information from a limb of the patient. In some embodiments, the method further comprises: determining a duration of efficacy of the first stimulus to reduce tremor amplitude; and delivering the second stimulus before the duration of efficacy expires.

In some embodiments, determining the duration of the effect comprises analyzing a plurality of stimulation applications applied over a predetermined period of time. The stimuli may be applied sequentially (e.g., serially or one after the other) and/or at least partially overlapping (e.g., in parallel).

In some embodiments, determining the duration of efficacy further comprises determining an activity profile of the patient. In some embodiments, determining the duration of efficacy further comprises determining a profile of tremors or other dysfunctions. In some embodiments, the activity profile includes data regarding caffeine and alcohol consumption. In some embodiments, the method further comprises placing a conduction pathway enhancer on the first peripheral nerve. In some embodiments, the conduction path enhancer is a conductive tattoo. In some embodiments, the conduction path enhancer includes one or more conductive strips.

In some embodiments, the first location is selected from the group consisting of a wrist, forearm, carpal tunnel, finger, and upper arm.

In some embodiments, a system for treating tremors or other dysfunctions in a patient is provided. The apparatus may comprise: a decision unit; and an interface unit adapted to deliver electrical stimulation to the peripheral nerve, the interface unit comprising a first peripheral nerve effector in communication with the decision unit, the first peripheral nerve effector comprising at least one electrode; wherein the decision unit comprises a processor and a memory storing instructions that, when executed by the processor, cause the decision unit to: delivering first electrical stimulation to the first peripheral nerve through the first peripheral nerve effector, the electrical stimulation configured by the controller to reduce tremor or other dysfunction of the patient's limb by modifying the patient's neural network dynamics.

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

In some embodiments, the interface unit further comprises a second peripheral nerve effector in communication with the decision unit, the second peripheral nerve effector comprising at least one electrode, wherein the memory stores instructions that, when executed by the processor, further cause the decision unit to deliver a second electrical stimulation to a second peripheral nerve in the limb of the patient through the second peripheral nerve effector.

In some embodiments, the instructions, when executed by the processor, cause the decision unit to deliver a second electrical stimulus offset in time from the first electrical stimulus by a predetermined fraction or multiple of the time period of tremor or other dysfunction.

In some embodiments, the first circumferential neuroeffector is adapted for placement on a first finger and the second circumferential neuroeffector is adapted for placement on a second finger.

In some embodiments, the first peripheral nerve effector comprises 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 comprises a plurality of electrodes arranged in a two-dimensional array. In some embodiments, the memory stores instructions that, when executed by the processor, further cause the decision unit to select a subset of the plurality of electrodes based on a location of the first peripheral neuroeffector on the limb of the patient, wherein the selection of the subset of the plurality of electrodes occurs each time the first peripheral neuroeffector is positioned or repositioned on the limb. In some embodiments, the plurality of electrodes are spaced apart about 1 to 100mm along a first axis and about 1 to 100mm along a second axis perpendicular to the first axis. In some embodiments, some of the electrodes are adjacent to each other to form a strip. 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 1mm (e.g., between about 0.1mm and about 1mm, between about 1mm and about 2mm, between about 1mm and about 3mm, between about 1mm and about 4mm, between about 1mm and about 5mm, between about 1mm and about 10mm, between about 1mm and about 20mm, between about 1mm and about 30mm, between about 1mm and about 40mm, between about 1mm and about 50mm, between about 1mm and about 60mm, between about 1mm and about 70mm, between about 1mm and about 80mm, between about 1mm and 90mm, between about 1mm and about 100mm, or other ranges between such values).

In some embodiments, the system further comprises a measurement unit, wherein the memory stores instructions that, when executed by the processor, further cause the decision unit to: measuring the movement of the patient's limb using a measurement unit to produce movement data; and determining tremor frequency and magnitude (or other parameters) based on analysis of the motion data.

In some embodiments, the analysis of the motion data includes a frequency analysis of the spectral power of the movement data. In some embodiments, the frequency analysis is limited to between about 4 to 12 Hz. In some embodiments, the frequency analysis is limited to approximately the expected frequency range of one or more tremors of interest. In some embodiments, the analysis of the motion data is done within a predetermined length of time of the motion data. In some embodiments, the decision unit is further adapted to determine tremor phase information based on the motion data and to deliver the first electrical stimulation based on the tremor phase information. In some embodiments, the tremor phase information includes a peak tremor deviation, and the decision unit is further adapted to deliver the first electrical stimulus at a time corresponding to the peak tremor deviation.

In some embodiments, for tremor and other indications, the memory stores instructions that, when executed by the processor, further cause the decision unit to deliver the first electrical stimulation as a plurality of electrical stimulation bursts with variable time delays between the electrical stimulation bursts. In some embodiments, the memory stores instructions that, when executed by the processor, further cause the decision unit to set parameters of the first electrical stimulation based on the determined tremor frequency. In some embodiments, the memory stores instructions that, when executed by the processor, further cause the decision unit to set a parameter of the first electrical stimulation based on the determined tremor magnitude. In some embodiments, the memory stores instructions that, when executed by the processor, further cause the decision unit to compare the determined tremor magnitude (or other data) to a predetermined threshold; and wherein the first electrical stimulation is delivered when the determined tremor magnitude (or other data) exceeds a predetermined threshold. In some embodiments, the electrode is adapted to deliver the first electrical stimulus through the skin of the patient. In some embodiments, the electrode is adapted to be implanted and deliver electricity. In some embodiments, the decision unit comprises a user interface adapted to receive input from a user to adjust a parameter of the first electrical stimulation. In some embodiments, the memory further 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 comprises a measurement unit located in the decision unit. In some embodiments, the system further comprises a measurement unit located in the interface unit. In some embodiments, the decision unit is a computing device selected from the group consisting of a smartphone, a tablet, and a laptop. In some embodiments, the system further includes a server in communication with the computing device, the server configured to receive the motion data and a history of electrical stimulation delivered to the patient from the computing device. In some embodiments, the server is programmed to: the received motion data and history of electrical stimulation delivered to the patient are added to a database storing data from a plurality of patients. In some embodiments, the server is programmed to: comparing the received motion data and the history of electrical stimulation delivered to the patient to data stored in a database; determining a modified electrical stimulation protocol based on a comparison of the received motion data and the history of electrical stimulation delivered to the patient with data stored in a database; and transmitting the modified electrostimulation 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.

In some embodiments, a system for monitoring tremors or other dysfunctions of a patient's extremities is provided. The system may include: an interface unit having an inertial motion unit for capturing motion data, a power source, and a wireless transmitter and receiver, the interface unit adapted to be worn on a patient extremity; and a processing unit in communication with the interface unit, the processing unit configured to receive the motion data from the interface unit. In one embodiment, the processing unit is programmed to determine tremor signatures and profiles (signatures and profiles) over a predetermined period of time based on analysis of the motion data. In another embodiment, the processing unit is programmed to determine a neural or movement signature and profile over a predetermined period of time based on the data analysis. In another embodiment, the processing unit is disposed in the device or on a remote processor in wireless communication with the device and programmed to analyze predetermined characteristics of the neural or movement data.

In several embodiments, the multimodal approach is based on monitoring, wherein a second mode (e.g., the same or different stimulation at a second body location, a different stimulation at the same or different body location, etc.) is provided based on feedback received after the first mode is activated. In some embodiments, the second pattern 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 a stimulation modality to enhance efficacy based on a predetermined characteristic or feature of a subject's prior response and/or measured neural or movement data from a sensor. 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 beneficial to reduce the time required to achieve a therapeutic effect (e.g., by at least 10%, 25%, 50% or more, or by reducing the range of overlap therein) or to prolong the therapeutic effect (e.g., by at least 10%, 20%, 40% or more, or by increasing the range of overlap therein), or to improve overall benefit (e.g., by reducing hand tremor levels to a greater extent).

In some embodiments, the processing unit is a mobile phone. In some embodiments, the system further includes a server in communication with the mobile phone, the server configured to receive the motion data from the mobile phone. In some embodiments, the processing unit is further programmed to compare the tremor magnitude or other data to a predetermined threshold. In some embodiments, the processing unit is further programmed to generate an alarm when the tremor magnitude or other factor exceeds a 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 for activity data including a description of the activity and a time at which the activity occurred. In some embodiments, the processing unit is programmed to correlate the activity data with the determined tremor frequency and magnitude. In some embodiments, the activity data comprises consumption of caffeine or alcohol. In some embodiments, the activity data comprises consumption of a medication.

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

In some embodiments, there is provided a system for treating a condition (including, but not limited to, tremor), the system comprising: a first stimulation actuator configured to apply a first pattern of stimulation to a first peripheral nerve (e.g., a proprioceptor, an afferent nerve, a fiber, B fiber, C fiber, etc.); a second stimulation actuator configured to apply a second pattern of stimulation to a second peripheral nerve (e.g., a proprioceptor, an afferent nerve, a fiber, B fiber, C fiber, etc.); and a control module in communication with the first stimulation actuator and the second stimulation actuator. In one embodiment, the second stimulation pattern is different from the first stimulation pattern. In another embodiment, the two patterns are the same (e.g., the same location, both electrical stimulation, both excitatory, both inhibitory, etc.). In some embodiments, three, four, or more modes may be used. In addition to tremor, overactive bladder and cardiac dysfunction are also treated. In one embodiment, a psychiatric disorder (e.g., suffering from neurotransmission dysfunction) is treated.

In some embodiments, at least one of the first or second stimulation actuators may comprise an electrical actuator (e.g., an apparatus for delivering electrical stimulation comprising, for example, an element, device, mechanism, component, portion (e.g., electrode), affector, or the like). The electrical portion may be transcutaneous. The electrical portion may be subcutaneous. The first stimulation actuator may include a first electrical portion. The second stimulation actuator may include a second electrical portion.

The first stimulation pattern may include a first value of a parameter. The second stimulation pattern may include a second value of the parameter that is different from the first value of the parameter.

The 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. The parameter may include stimulation continuity. The first stimulation pattern may comprise bursts. The second stimulation pattern may include continuous. The parameter may include stimulation frequency. The first stimulation pattern may include between 10Hz and 30Hz (e.g., 20 Hz). The second stimulation pattern may include between 30Hz and 50Hz (e.g., 40 Hz). The first stimulation mode may include between 100Hz and 200Hz (e.g., 150 Hz). The second stimulation pattern may include between 50Hz and 150Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be pulsed on/off in an alternating pattern at a frequency between 4-12Hz, such as in a burst mode (e.g., 10 Hz). The parameters may include a stimulation waveform. The first stimulation pattern may include a first stimulation waveform. The second stimulation pattern may include a second stimulation waveform that is different from the first stimulation waveform.

At least one of the first or second stimulation actuators may include a thermal device, component, actuator, or portion that increases and/or decreases the internal temperature of the collateral tissue (such as a means for heating and/or cooling (e.g., a resistive heater, a piezoelectric cooler, a fluid-based temperature space), including, for example, an element, device, mechanism, component, portion, influencer, 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. Temperature sensors may also be included and provide communication with the processor or control module, with or without feedback to affect cooling or heating.

At least one of the first or second stimulation actuators may comprise a vibrating or mechanically actuated actuator (such as a device for vibrating, generating vibrations and transmitting the vibrations to, for example, the skin (e.g., vibrator, sonic system, solenoid, biased motor), including, for example, an element, device, mechanism, component, or partial influencer, or the like). In some embodiments, a mechanical actuator configured to apply non-vibratory mechanical energy may be activated to apply pressure at a particular location, such as a pocket site. In some embodiments, a staple 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 for 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 for a wrist band). At least one of the first or second stimulation actuators may comprise a magnetic actuator (such as a means for generating a magnetic field (e.g., a magnet, an electromagnet), e.g., comprising an element, device, mechanism, component, portion, influencer, or the like). At least one of the first or second stimulation actuators may include a chemical (e.g., a medication or lidocaine). At least one of the first or second stimulation actuators may comprise an ultrasound (e.g., focused ultrasound) actuator (such as a means for generating ultrasound energy (e.g., a transducer, a piezoelectric element, a coupling fluid), e.g., comprising an element, a device, a mechanism, a component, a portion, an influencer, or the like). At least one of the first or second stimulation actuators may comprise a microwave actuator (such as a device for generating microwave energy (e.g., a microwave generator), e.g., comprising an element, device, mechanism, component, or partial influencer, or the like). In some embodiments, at least one of the first or second stimulation actuators comprises an electromagnetic actuator for generating electromagnetic energy, waves, fields, or the like. In some embodiments, a third, fourth, or additional stimulation actuator is used in addition to the second stimulation actuator.

The first stimulation actuator may be configured to be positioned on a wrist of a subject. The second stimulation actuator may be configured to be positioned on a finger of the subject. The second stimulation actuator may be configured to be positioned on an ankle of the subject. The first location may comprise an arm of the body and the second location may comprise a leg of the body. The first location may be the left arm or leg of the body and the second location may be the right arm or leg of the body to provide bilateral stimulation.

The system may also include a sensor. The control module may be configured to initiate at least one of the first stimulation mode or the second stimulation mode upon detecting the event.

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

The first stimulation actuator may include electrodes (e.g., 1-6 or more electrodes). The electrodes may be percutaneous or subcutaneous.

The 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. The parameter may include stimulation continuity. The first stimulation pattern may comprise bursts. The second stimulation pattern may include continuous. The parameter may include stimulation frequency. The first stimulation pattern may include between 10Hz and 30Hz (e.g., 20 Hz). The second stimulation pattern may include 30Hz to 50Hz (e.g., 40 Hz). The first stimulation mode may include between 100Hz and 200Hz (e.g., 150 Hz). The second stimulation pattern may include between 50Hz and 150Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be pulsed on/off in an alternating pattern at a frequency between 4-12Hz, such as in a burst mode (e.g., 10 Hz). The parameters may include a stimulation waveform. The first stimulation pattern may include a first stimulation waveform. The second stimulation pattern may include a second stimulation waveform that is different from the first stimulation waveform.

The system may also include a second stimulation actuator. The second stimulation actuator may include an electrode. The second stimulation actuator may comprise a thermal actuator. The stimulation actuators may include mechanical, vibratory, electromechanical, thermal, radiative, electrical, magnetic, electromagnetic, optical, acoustical, chemical, ultrasonic (e.g., focused ultrasound), infrared, Radio Frequency (RF), ultraviolet, X-ray, or microwave actuators. Sensors are optionally included and may alter the neuromodulation of the various actuators.

The first stimulation actuator may be configured to be positioned on a wrist of a subject. The second stimulation actuator may be configured to be positioned on a finger or ankle of the subject. In one embodiment (e.g., at various points around the wrist, finger, ankle, etc.) circumferential stimulation is provided using, for example, a belt, 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.

In some embodiments, a system and method for treating tremors or other indications in a subject 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 an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus. The second stimulus includes at least one of an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus. The second stimulus is different from the first stimulus.

In some embodiments, a system and method for treating tremor or other indications in a subject includes applying a first stimulus to a first peripheral nerve (e.g., a proprioceptor, an afferent nerve, a fiber, B fiber, C fiber, etc.), and applying a second stimulus to a second peripheral nerve (e.g., a proprioceptor, an afferent nerve, a fiber, B fiber, C fiber, etc.). The first stimulus includes at least one of an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus. The second stimulus includes at least one of an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus. In one embodiment, the second stimulus is different from the first stimulus, but may be the same in other embodiments. In some embodiments, the first stimulus comprises at least one of an electrical stimulus, a magnetic stimulus, a chemical stimulus, a thermal stimulus, a vibratory stimulus, an ultrasonic stimulus (e.g., focused ultrasound), a radiofrequency stimulus, or a microwave stimulus, and the second or additional stimulus comprises at least one of an electrical stimulus, a magnetic stimulus, a chemical stimulus, a thermal stimulus, a vibratory stimulus, an ultrasonic stimulus (e.g., focused ultrasound), a radiofrequency stimulus, or a microwave stimulus.

In some embodiments, the first and second (and optionally third, fourth, or more) stimuli comprise electrical stimulation. The first stimulus may comprise a first value of a parameter. The second (and any additional) stimulus may comprise a second value of the parameter different from the first value of the parameter. The 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. The parameter may include stimulation continuity. The first stimulation pattern may comprise bursts. The second stimulation pattern may include continuous. The parameter may include stimulation frequency. The first stimulation pattern may include between 10Hz and 30Hz (e.g., 20 Hz). The second stimulation pattern may include between 30Hz and 50Hz (e.g., 40 Hz). In one embodiment, the first stimulus is less than 40Hz and the second stimulus is 40Hz or higher. In another embodiment, the first stimulus is less than 20Hz and the second stimulus is 20Hz or higher. The first stimulation mode may include between 100Hz and 200Hz (e.g., 150 Hz). The second stimulation pattern may include between 50Hz and 150Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be pulsed on/off in an alternating pattern at a frequency between 4-12Hz, such as in a burst mode (e.g., 10 Hz). The parameters may include a stimulation waveform. The first stimulation pattern may include a first stimulation waveform. The second stimulation pattern may include a second stimulation waveform that is different from the first stimulation waveform.

In some embodiments, the first and second (and optionally third, fourth, or more) stimuli comprise chemical stimuli. The first stimulus may include a first neuromodulation chemistry. The second (and any additional) stimuli may include a second neuromodulation chemistry that is different from the first neuromodulation chemistry.

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

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 a first point, and electrical stimulation of a different frequency, duration and/or amplitude is applied at a second point. The two points may be at different locations on the wrist and may stimulate the same or different nerves. The stimulation may be simultaneous and/or sequential or overlapping. Stimulation may be patterned from side to side of a plurality of electrodes arranged linearly or circumferentially in a band or at a skin interface. In one embodiment a tri-modal approach is also used, where, for example, three points on the wrist are stimulated. Instead of or in addition to the wrist, the treatment points (whether two, three, or more points) may be located on the ankle, knee, thigh, upper arm, finger, toe, ear, chest, back, shoulder, head, neck, etc.

In one embodiment, electrical and mechanical (e.g., vibration) is provided sequentially and/or simultaneously in a multi-modal 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 area but at different points (e.g., different points on the wrist). In yet another embodiment, dual stimulation is provided at different areas (e.g., wrist and ankle). In some embodiments, a third, fourth or additional stimulus is provided.

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 other locations.

In one embodiment, the first, second, third or additional location is selected from the group consisting of wrist, finger, toe, ear, ankle, knee, thigh, upper arm, back, chest, hand, foot, head, neck, and the like. A cuff or band may be used, and may be flexible to accommodate a subject. Patches may also be used. In some embodiments, 1-12 (or more) electrodes may be used (such as 2, 4, 6, 8, 10, and ranges therein). The electrodes may be arranged in an array (e.g., a linear array).

In some embodiments, a method of treating tremor in a subject 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 comprises an electrical stimulus. The first actuator includes an electrode. The second stimulus comprises a vibrational stimulus. The first and second actuators are coupled to one of an arm, a wrist, a leg, a knee, or an ankle using a flexible cuff. At least one of applying the first stimulus or applying the second stimulus is responsive to a controller in the smart device and is based on the sensing of the disease and the predetermined characteristic. After applying the first stimulus and applying the second stimulus, symptoms of the disease are reduced.

A second stimulus from a second actuator is applied to a second location on the body. The second position may be spaced a distance from the first position.

In some embodiments, the systems and methods may involve the combination of afferent (sensory) stimulation with motor (efferent) stimulation of the nerve, muscle, or both, including but not limited to functional electrical stimulation. In some cases, Functional Electrical Stimulation (FES) can activate the tremor muscles out of phase to reduce the tremor. In other embodiments, a tool such as a gyroscope (e.g., a rotating eccentric mass) may be used in combination with nerve stimulation using energy or other modalities as described elsewhere herein to mechanically dampen (damper) tremors. In some embodiments, the controller can receive real-time or near real-time feedback from one or more sensors configured to measure a parameter of the patient (e.g., tremor amplitude), and apply FES and/or mechanical damping when the tremor amplitude is measured to be above a predetermined threshold level.

We have invented a peripheral nerve stimulation device and method that effectively reduces tremor without drug side effects and without the risk of brain surgery. Our method is safe and in some embodiments non-invasive and effective in reducing tremor. In some embodiments, the device may function 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 devices and methods disclosed herein can also be used for a variety of other non-limiting indications. Such indications may include, but are not limited to, cardiac dysfunction (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 dysfunction (including overactive bladder, nocturia and/or stress and urge incontinence) and fecal incontinence. In some embodiments, mental disorders having a neurological component (such as neurotransmitter dysfunction) may be treated. Also can be used for treating migraine.

In one embodiment, overactive bladder is treated in a multimodal manner using the first electrical stimulation and the second vibrational stimulation at one of: including the position of the foot, ankle, knee, thigh, back, sacral region, lumbar region, ear, head, and/or neck, and/or the position targeted for nerves, including the tibial nerve, saphenous nerve, sacral nerve, sural nerve, and/or vagus nerve. In some embodiments, electrical stimulation is provided at two or more different locations.

In one embodiment, cardiac dysfunction is treated in a multimodal manner using the first electrical stimulation and the second vibrational stimulation at one of: including locations of the wrist, arm, finger, shoulder, neck, head, transcranial, ear, in the ear, tragus, turbinate, back or chest, and/or locations targeted for nerves, 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 nerves or channels and collaterals accessible on the limbs. In some embodiments, electrical stimulation is provided at two or more different locations.

In one embodiment, neurotransmitter dysfunction (e.g., depression, anxiety, and other mental disorders) is treated in a multimodal manner using a first electrical stimulus and a second vibratory stimulus at one of: including locations of the wrist, arm, finger, shoulder, neck, head, transcranial, ear, in the ear, tragus, turbinate, back or chest, and/or locations targeted for nerves, 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 nerves or channels and collaterals accessible on the limbs. In some embodiments, electrical stimulation is provided at two or more different locations.

For indications such as overactive bladder, cardiac dysfunction, psychiatric disorders, and other indications, electrical and vibration modulation are non-limiting examples of multimodal approaches. Other modulation modalities include, but are not limited to, magnetic, chemical (pharmacological), thermal, ultrasound (e.g., focused ultrasound), acoustic, radio frequency, and microwave. According to several embodiments, the multimodal method further comprises using the same modality at different locations on the body or at different points in the same region. The multimodal methods also include using the same modality with different parameters, and/or using different stimulation patterns, at the same or different locations of the body or at the same or different points in the same region.

In several embodiments, when two or more devices are used in different locations, the devices may communicate with each other, communicate via a wired connection, or communicate wirelessly via a standard wireless communication protocol (such as RF, WiFi, bluetooth, cellular, or Zigbee). In another embodiment, several devices communicate to synchronize stimulation between multiple devices in the same or different locations. Feedback from one sensor can be used to adjust the stimulation of the device at different locations.

In some embodiments, a wearable device for treating tremor comprises: a processing unit; a first peripheral nerve effector comprising at least one stimulation source configured to be positioned to modulate a first peripheral nerve pathway; a second peripherical nerve effector comprising at least one stimulation source configured to be positioned to modulate a second peripherical nerve pathway; and at least one sensor configured to measure a characteristic of the disease state. The processing unit includes a controller and a memory for storing instructions that, when executed, cause the device to apply a first stimulus from a first actuator to a first location on the body and to apply a second stimulus from a second actuator. The first stimulus comprises an electrical stimulus or a vibrational stimulus. The second stimulus may comprise a different type of stimulus than the first stimulus. The second stimulation may include the same type of stimulation as the first stimulation and 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 stimulation duration. At least one of applying the first stimulus or applying the second stimulus is responsive to the controller and is based on the sensed characteristic of the disease state. After applying the first stimulus and applying the second stimulus, the characteristic of the disease state is reduced.

The second actuator may be configured to be applied to a second location on the body that is spaced a distance from the first location. The first stimulation can be configured for afferent nerve stimulation, while the second stimulation is configured for functional electrical stimulation.

Drawings

The novel features of several embodiments are set forth with particularity in the claims and the detailed description and the accompanying drawings, which set forth illustrative (non-limiting) embodiments, and in which the principles described herein are utilized, wherein:

figure 1 illustrates one embodiment of delivering stimulation to the median nerve found to reduce tremors.

Fig. 2A-2C show therapeutic effects of embodiments of peripheral nerve stimulation in mild (fig. 2A), moderate (fig. 2B), and severe (fig. 2C) ET patients. It demonstrates the results of a clinical study in which patients with essential tremor have reduced tremor amplitude by stimulation profiles at 150Hz frequency, 300 μ s and 40 min stimulation on-duration. Reduction in tremor was observed immediately after stimulation was turned off, as shown by comparing the ability of ET patients to draw a helix.

Figures 3A-3C show calculated wrist flexion from gyroscope data in subject B of figures 2A-2C. Figure 3A shows tremor prior to treatment; figure 3B shows immediate tremor reduction after treatment; figure 3C shows that tremor reduction was maintained for twenty minutes following treatment.

Figure 4 shows an example of ineffective treatment for moderate ET patients.

Figure 5A illustrates various locations on a patient where the tremor modification system can be located.

Fig. 6A and 6B show the major nerves of the branch hands and their peripheral branches.

Figures 7A-7D are block diagrams illustrating various embodiments of a tremor change system.

Fig. 8A shows an embodiment of an electrode pair for exciting nerves in different fingers, where both electrodes are positioned on the finger.

Fig. 8B shows a device exciting nerves in different fingers, where the second electrode is positioned at the wrist.

Figure 8C shows an embodiment where electrodes are placed on the wrist to target different potential nerves.

Fig. 8D and 8E show various stimulation sites.

FIG. 9A is a diagram illustrating an embodiment of an excitation scheme for phase shifting a brain region receiving sensory input from two fingers.

FIG. 9B is a diagram illustrating an embodiment of an excitation scheme for phase shifting a brain region receiving sensory input from four fingers.

Fig. 10A-10C illustrate embodiments in which the position of the hand may determine the optimal stimulation duty cycle and timing.

Fig. 11 shows an embodiment of a variable stimulus that varies in frequency over time.

Fig. 12 is a diagram illustrating an embodiment in which the stimulus is chemical and two neuromodulation chemicals can be mixed to provide a customized chemical stimulus.

Fig. 13A and 13B illustrate various forms of user controls.

Figures 14A-14M illustrate various non-invasive or invasive embodiments of a tremor modification system. Fig. 14E is a diagram illustrating an embodiment in which the stimulus is mechanical. Fig. 14H illustrates an embodiment of a device having a form factor of a wristwatch. FIG. 14I shows the back of the device shown in FIG. 14H, showing the electrodes interfacing with the user. Fig. 14J and 14K illustrate an embodiment of a disposable electrode interface that snaps into place in a wristwatch form factor of the device housing. Fig. 14L illustrates an embodiment of a self-aligning snap feature that allows a disposable electrode interface to be snapped into a housing of a device having a wristwatch form factor. Fig. 14M is a diagram illustrating the possible placement of electrodes along the spine in an embodiment of the device in which the effector is electrical.

Figures 15A-15C illustrate various embodiments of electrode arrays.

Fig. 16A-16D illustrate various embodiments of conductive ink tattoos.

17A-17B are diagrams illustrating an embodiment of positioning an accelerometer on the hand or wrist for measuring patient activity and tremor.

Fig. 18A and 18B show examples of spectral analysis of gyroscopic motion data for a patient with tremor centered at 6.5 Hz.

Fig. 19 shows the correlation of postural tremor and kinetic tremor.

Fig. 20 shows an embodiment of a stimulation device capable of recording data (such as tremor characteristics and stimulation history) and transmitting the data to a data portal device (such as a smartphone) that transmits the data to a cloud-based server.

21A-21D are flow diagrams illustrating the monitoring, integration, analysis, and display of data for notifying a user or improving a stimulus.

Fig. 22 is a flow chart illustrating feedback logic.

Fig. 23 is a diagram illustrating an embodiment in which the stimulus is an electrode implanted at least partially subcutaneously.

Fig. 24A-24D illustrate various embodiments of implantable devices and skin surface devices that allow for wireless power and control.

Fig. 25A-25F illustrate various geometries of electrodes for implanted electrical stimulation.

26A-26B illustrate two preferred embodiments of a control module for interacting with a device. The control system of the tremor device uses feedback to modify the stimulation. This is a closed loop in which the stimulation is adjusted based on the measurement of activity and tremor.

Fig. 27A illustrates an embodiment of a system that can be configured to stimulate several skin patches in a timed manner.

Fig. 27B illustrates an embodiment of an electrode alignment (electrode alignment) for selective or preferential activation of nerve fibers.

The figures identified above can be used in conjunction with other figures and descriptions provided herein.

Detailed Description

As used herein, the terms "stimulation" and "stimulus" generally refer to the delivery of a signal, stimulus, or pulse to neural tissue of a target area. The effect of such stimulation on neuronal activity is called "modulation"; however, for simplicity, the terms "stimulating" and "modulating" and variants thereof are sometimes used interchangeably herein. The effect of signal delivery to neural tissue may be excitatory or inhibitory and may enhance acute and/or long-term changes in neuronal activity. For example, the effect of "stimulating" or "modulating" neural tissue may include one or more of the following effects: (a) depolarizing the neuron such that the neuron fires an action potential, (b) hyperpolarizes the neuron to inhibit the action potential, (c) depletes the neuron ion store to inhibit firing the action potential, (d) varies with proprioceptive input; (e) affect muscle contraction, (f) affect changes in neurotransmitter release or uptake, or (g) inhibit firing. "proprioception" refers to the feeling of a person's relative position to their body parts or the effort employed to move their body parts. Proprioception may alternatively 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. An "effector" is a mechanism by which a device modulates a target nerve. For example, an "effector" may be an electrical stimulation of a nerve or a mechanical stimulation of proprioceptors.

"Electrical stimulation" refers to the application of electrical signals to soft tissue and nerves of a target area. "vibrotactile stimulation" refers to the excitation of proprioceptors by applying biomechanical loads to the soft tissues and nerves of a target area. Applying a "thermal stimulus" refers to the induced cooling or heating of the target area. The use of "chemical stimulation" refers to the delivery of a chemical, drug, or pharmaceutical agent that is capable of stimulating neuronal activity in a nerve or nerve tissue exposed to the agent. This includes local anesthetics that affect neurotransmitter release or uptake in neurons (electrically excitable cells that process and transmit information through electrical and chemical signals). "cloud" refers to a network of computers communicating with using real-time protocols, such as the internet, to analyze, display, and interact with data in distributed devices.

Device location

The device stimulates sensory nerves in order to modify abnormal network dynamics. Over time, the stimulation can normalize nerve discharges in abnormal networks and reduce tremor. Preferably, the stimulated nerve is a nerve that carries sensory proprioceptive information from a limb affected by tremors. The nerve may be directly modulated anywhere along or adjacent to the nerve carrying proprioceptive information (such as by electrical stimulation). In some embodiments, the target nerve may be modulated indirectly, such as by stimulation of a proprioceptor that stimulates the target nerve. Fig. 5A shows an access point of a nerve carrying proprioceptive information from a limb or vocal cords or throat. These access points may include, but are not limited to: fingers 510 including one or more fingers and/or thumbs, a hand 520, a wrist 530, a lower or forearm 540, an elbow 550, an upper arm 560, a shoulder 570, a spine 580 or neck 590, a foot (e.g., including one or more toes), an ankle, a lower or lower leg, a knee, and/or an upper or upper leg. In some embodiments, these access points may be used for direct stimulation. In other embodiments, these access points are used for indirect stimulation. Indirect and direct stimulation is provided in several embodiments. In some embodiments, two, three or more access points are provided.

Nerves that affect proprioception can include, for example, the median, ulnar, radial, or other nerves in the hand, arm, and spinal regions or along muscles or within joints. These areas for nerves may include the brachial plexus, medial, radial and ulnar nerves, cutaneous nerves, or the interarticular nerve. These areas may also be directed to muscle tissue, including muscles of the shoulder, muscles of the arm, and muscles of the forearm, hand, or finger. As a non-limiting example, shoulder muscles may include deltoid, large triceps, and supraspinatus. The muscles of the arm may include the brachiocephalic muscle and the triceps brachii muscle. The muscles of the forearm may include the extensor carpi radialis, extensor hallucis, extensor carpi ulnaris, and flexor carpi ulnaris. In some embodiments, one, two, three, or more of these regions are stimulated (directly and/or indirectly).

Some examples of device locations or treatment sites that may be used in combination include two or more of the following: a wrist, a hand, a finger, a forearm, an upper arm, an elbow, a shoulder, an arm, an ankle, a foot, a toe, a lower leg, a thigh, an upper leg, a knee, a leg, an upper body appendage, an upper body, a lower body appendage, a lower body, a spine, a neck, a head, or a portion of any of these. The multiple sites may be combined with multiple modalities and/or multiple modes, each modality having multiple modes or one or more modalities having different modes. For example, a first stimulation modality and/or pattern may be applied to the wrist 530 and a second stimulation modality and/or pattern may be applied to the finger 510. For another example, a first stimulation modality and/or mode may be applied to the wrist 530 and a second stimulation modality and/or mode may be applied to the ankle. For yet another example, a first stimulation modality and/or pattern may be applied to an arm and a second stimulation modality and/or pattern may be applied to a leg. For yet another example, the first stimulation modality and/or pattern may be applied to the upper body and the second stimulation modality and/or pattern may be applied to the lower body. A stimulator may be implanted (e.g., subcutaneously and/or transdermally) at various sites.

In some embodiments, a vibration or haptic motor is disposed in the device and positioned near the target area or nerve such that the vibrational energy is directed at the target nerve. For example, in a wrist-worn device, the vibration motor may be disposed in the band such that it is located on the palm side of the wrist, directly adjacent to the median nerve. The motion of the vibration motor may be oriented such that it is normal and/or oblique to the target nerve or skin surface. The movement of the motor may be, for example, linear or rotary with an eccentric mass.

In some embodiments, a hydrogel or water-based component (e.g., a hydrogel patch with lidocaine or another chemical suspended in a gel, electrodes stimulated via electrical energy) may be embedded with a chemical or pharmacological agent (such as lidocaine). The electrodes may be placed on the skin surface and the chemical released at a predetermined rate proportional to the concentration of the chemical in the electrodes. The electrodes may or may not provide electrical stimulation in combination with chemicals suspended in the hydrogel. In some embodiments, the agents may be placed on the skin, and the electrical energy may synergistically stimulate one, two, or more target areas or nerves, as well as 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 facilitate 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 facilitates iontophoresis and a second stimulation mode that facilitates neural stimulation). The patterns may relate to different frequencies, amplitudes, waveforms, and/or other parameters disclosed elsewhere herein.

In some embodiments, the thermal energy in the surrounding tissue in contact with the device is increased or decreased. Thermal energy may be added to tissue in contact with the device by a thermoelectric heating element (e.g., a battery disposed in the device having a resistive element). Heat can be transferred to a specific target location in the band, for example, having a conductive element that transfers thermal energy to tissue in contact with the conductive element. Thermal energy in tissue in contact with the device may be reduced by thermoelectric cooling elements (e.g., peltier devices or solid state refrigerators) or by circulating a coolant or cooling fluid through a portion of the device in contact with the target tissue area (e.g., in wrist worn devices, the band may be provided with tubing to circulate cooling fluid through the band). In some embodiments, the apparatus may have a pump to circulate the coolant. The device may have a heat transfer element (such as a heat sink or an electrically powered fan) to transfer thermal energy from the surrounding tissue to the surrounding air or environment (e.g., areas on the device not in contact with the tissue).

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

According to several embodiments, where stimulation or other neuromodulation signals are provided to two, three, or more locations, the signals are provided simultaneously, sequentially, or overlapping.

Proprioceptors are found in, for example, muscles, tendons, joints, skin and the inner ear. Criteria defining candidate nerves for direct modulation include the location of tremors to be reduced, as well as the proximity of the nerves to the skin surface, high density of proprioceptive fibers, and distance from excitable pain receptors or muscles. According to these criteria, the median nerve for the wrist and the ulnar nerve for the elbow are ranked higher. Criteria defining candidate locations for indirect proprioceptive modulation include the density and type of proprioceptors. Pacinian corpuscles provide information about touch; when the mechanically gated ion channel opens due to muscle stretching, the muscle spindles provide information about the change in muscle length by triggering the action potential in the muscle spindle afferent nerves. The golgi tendon organs provide information about muscle tone. These structures can also be stimulated to alter circuit dynamics and reduce tremor.

The device is directed to a specific nerve that forms synapses on an abnormal brain circuit. The synapse may be a direct synapse or through a plurality of relay synapses. Fig. 6A and 6B show a representative set of nerves that deliver proprioceptive information to the olive-cerebellar network (the network that is abnormal in ET). These nerves include the 610 distal and major branches of the 620 median and 630 ulnar nerves, and the 640 distal and major branches of the 650 radial nerve. In a preferred embodiment, the device is directed to nerves that input proprioceptive information from the hand, wrist and forearm.

In another embodiment, a combination of any of the portions described herein may be used to affect a nerve associated with speech tremor, including but not limited to a branch of the vagus nerve, such as the superior laryngeal nerve or the recurrent laryngeal nerve.

The device component: various embodiments

Fig. 7A-7D are conceptual diagrams illustrating some embodiments of a tremor modification system 700. The system 700 includes a housing 720, one or more effectors 730, one or more controls 740 in electrical communication with the effectors 730, and one or more power sources 750. In some embodiments, the housing 720 may include an interface 760. The interface facilitates coupling the effector to the 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, memory 770, display 790 and processor 797. The apparatus in this embodiment may include a processor 797 coupled to the effector, which may perform calculations and control of other components. The device may also include a digital library stored on the processor 797 or memory 770 that may contain preloaded adjustment protocols. The device may include a control module 740 in communication with the processor 797 and usable by the 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 effectors (such as intensity). The device may include a sensor 780 connected to the processor 797 that may detect information for predefined parameters and transmit the parameter information to the processor 797. The device may include a data storage unit 770 connected to sensor 780 and processor 797; and a power supply 750 may be connected to the processor.

The device may also contain a display or indicator 790 to communicate with the user and report the status of the device. In some embodiments, the indicator is preferably a Light Emitting Diode (LED) or some sort of visual indicator, but may be an audio indicator. The information may include battery power or stimulation status.

The device may lack or be devoid of effectors 730. It may be a diagnostic non-therapeutic device. In a preferred embodiment, the interface unit 704 will be worn on a tremor limb to track tremors over time. Providing feedback to the user of the device may make them aware of their tremor and may monitor over time. This biofeedback may help some individuals reduce their tremor even in the absence of therapeutic stimulation. The device may lack or be devoid of sensors 780. It may be a therapeutic, non-diagnostic device.

Many of these components may be housed in separate units in order to make the device small and simple. The processing, control, and possibly sensing may be done remotely in the decision unit 702, so that the interface unit 704, which provides therapeutic contact with the patient for a variety of applications, is compact, simple, and flexible (fig. 7B-7D). The decision unit 702 may be a new device designed for this application or it may be integrated into existing technology such as smart phones. This would allow the system to be a robust hand-held form factor with reduced cost and size.

In the embodiment shown in fig. 7B, the interface unit 704 is an implant; effector 730 provides electrical stimulation of the nerve; the instruction set and power are wirelessly transmitted from an external device. The implanted interface unit 704 may be powered by an on-board battery. The implanted interface unit 704 may include sensors 780 for directly detecting tremor or neuromuscular activity detected by Electrography (ENG) or Electromyography (EMG).

In the embodiment shown in fig. 7C, the interface unit 704 is worn on the surface of the body; effector 730 provides electrical stimulation of the underlying nerve or vibrotactile stimulation of nearby proprioceptors. Sensor 780 may include a motion sensor including an accelerometer, a gyroscope, and a magnetometer.

In the embodiment shown in fig. 7D, one or more sensor units 780 that sense motion, temperature, etc. may be worn at different locations in the body. The effector 730 and the decision unit 702 are separate entities worn on the body at different locations than the sensor 780. This is useful if the stimulation of the nerve occurs at a location where tremor cannot be easily or accurately measured. For example, a stimulation device 700 placed on the underside of the wrist for reducing hand tremors is highly effective. However, measuring hand tremor from the wrist using an accelerometer or gyroscope can prove more difficult; a sensor unit placed alone in a glove on the palm or back of the hand or worn as a ring on one of the fingers will show a higher sensitivity to hand tremor due to its location outside the wrist joints.

An effector: general of

Effectors may be used to modulate neural tissue in the upper limb region to which stimulation is directed. For example, the effector may modify neuronal signals in the nerve and/or modify the flow or content of proprioceptive information. The effector may be delivered transdermally or subcutaneously. One or more effectors may be used to affect a nerve. 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 excite nerves during some portions of treatment and to inhibit nerves during other portions of treatment.

An effector: electrical stimulation

In some embodiments, the effector may be an electrical stimulus. The electrical effect may include electrodes, electrode pairs, electrode arrays, or any device capable of delivering electrical stimulation to a desired location. The electrical stimulation may be transdermal or subcutaneous. For example, transcutaneous electrical stimulation may be achieved by electrodes placed on the surface of the skin, whereas subcutaneous electrical stimulation may be achieved by implanted electrodes positioned close to the nerve.

The stimulation parameters may be automatically adjusted or controlled by the user. Stimulation parameters may include on/off, duration, intensity, pulse rate, pulse width, waveform shape, and slope of the pulses on and off. In a preferred embodiment, the pulse rate may be about 50 to 5000Hz, and the preferred frequency is about 50Hz to 300Hz or 150 Hz. For example, the frequency may be between about 10Hz and about 20kHz (e.g., about 10Hz, about 20Hz, about 30Hz, about 40Hz, about 50Hz, about 60Hz, about 100Hz, about 250Hz, about 500Hz, about 1000Hz, about 2500Hz, about 5000Hz, about 10kHz, about 15kHz, about 20kHz, and ranges between such values). Preferred pulse widths may be in the range of 50 to 500 μ s (microseconds), and preferred pulse widths may be about 300 μ s (e.g., about 50 μ s, about 100 μ s, about 150 μ s, about 200 μ s, about 250 μ s, about 300 μ s, about 350 μ s, about 400 μ s, about 450 μ s, about 500 μ s, and ranges between such values). The intensity or amplitude of the electrical stimulation may vary from 0mA to 500mA, and preferably the current may be about 1mA to 6mA (e.g., about 0mA, about 0.1mA, about 1mA, about 6mA, about 10mA, about 20mA, about 30mA, about 40mA, about 50mA, about 100mA, about 200mA, about 300mA, about 400mA, about 500mA, and ranges between such values). Certain preferred settings are derived from the above-described clinical study, which provides a valuable reduction in tremor for a period of time. The stimulation may be adjusted in different patients and by different stimulation modulation methods. These preferred settings are non-limiting examples. The increment of intensity adjustment may be 0.1mA to 1.0mA (e.g., 0.1-3mA, 3-6mA, 6-10mA, and overlapping ranges therein). In a preferred embodiment, stimulation may last for about 10 minutes to 1 hour (e.g., 10-20 minutes, 20-40 minutes, 40-60 minutes, and overlapping ranges therein).

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

The effector may comprise two electrodes, each electrode having a positive or negative polarity, or the electrode array may comprise a plurality of electrode pairs, wherein each electrode pair is programmed independently or relatively with respect to the other electrode pairs. As an example, the program may allow for 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.

Electrical stimulation can be designed to suppress tremor by interfering with proprioceptive input, causing compensatory muscle contraction, or a combination of both approaches. The electrodes may be replaced by any equivalent material capable of conducting electrical signals through a stimulator interface with the skin surface of the upper limb. The electrodes may be attached to a control unit 740, which may apply electrical stimulation via the electrodes to soft tissue and nerves in the area where the electrodes are placed and in the immediate vicinity. In another variation of this embodiment, several electrodes may be placed to a combination of target areas.

A function generator connected to and controlled by the processor may be used to adjust the electrical stimulation parameters. The function generator is preferably an arbitrary waveform generator using direct digital synthesis techniques to generate any waveform that can be described by an amplitude table. These parameters are selected from the group including, but not limited to, frequency, intensity, pulse width or pulse duration, and total duration. Preferably, the output has a power limit set by a maximum output voltage. In a preferred embodiment, the digitally stored protocol cycles through various stimulation parameters to prevent the patient from adapting to the environment. The variation of the electrical stimulation is achieved by a function generator.

In some embodiments, the electrical stimulation includes a combination of one or more single frequencies and one or more sweep 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 be subsequent to the first duration (e.g., immediately thereafter, subsequent to the pause duration). The second duration may at least partially overlap the first duration. Continuing with the example, a second single frequency different from the second frequency may be applied for a third duration. The third duration may be subsequent to the second duration (e.g., immediately thereafter, subsequent to the pause duration). The third duration may at least partially overlap with the second duration. Continuing with the example, a second scanning frequency different from the first scanning frequency (e.g., having a different low frequency, high frequency, and/or rate of change in frequency) may be applied for a fourth duration. The fourth duration may be after the third duration (e.g., immediately thereafter, after the pause duration). The fourth duration may at least partially overlap with the third duration. This example may continue for additional durations of single frequencies and/or scanning frequencies. Different frequencies may be applied to the same vibratory stimulus or different electrical stimuli (e.g., on the same body part, on different body parts). Electrical stimuli applied to different body parts may converge at some point between the body parts and may form a standing wave. In some embodiments, the junction may be a target body part (e.g., where an elbow and a finger meet at a wrist). The amplitude of the sweep may be enveloped by other waveforms, such as sinusoids or gaussian, or the parameters may be varied randomly or pseudo-randomly. The above discussion of different frequencies may also apply to other parameters such as frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on/off time, or burst, combinations thereof, and the like.

And (3) optimizing stimulation: phase shifting

In a preferred embodiment, the stimulation is designed to dephasise synchronicity in the brain. The concept of phase shifting the abnormal loop followed closely by recent work, which suggests that neural retraining reduces the tendency of the network to fall into an abnormal rhythm. Interestingly, dyskinesias are often associated with abnormally periodic synchronous discharges in the brain circuits. In Parkinson's disease, the circuit is located in the basal ganglia. In ET, it is the olive-cerebellar circuit. These abnormal oscillations are thought to drive tremors as supported by many studies that suggest that tremors observed in the hand and forearm muscles are synchronized with pathologically rhythmic discharges in the brain. Recent studies of DBS have shown that low voltage phase shift bursts on adjacent electrode pairs (known as coordinated resets) can reduce synchronization in abnormal brain networks and this can reduce parkinson's tremor. The application of the coordination reset theory in the treatment of tinnitus supports the concept of using synaptic excitations to retrain neural networks.

The devices disclosed herein have several advantages over high frequency TENS stimulation, including using lower power (resulting in extended battery life, reduced discomfort due to motion growth and contraction, reduced discomfort due to sensory excitation), less suppression of discharges in the activity of adjacent nerves (through depletion or other mechanisms), and maintaining a more sustained action so that only intermittent use of the device is required to train or maintain training on neural circuit dynamics. The device stimulates the neural ensemble in such a way that it targets a neural subpopulation to reduce synchronization of the populations. This may be achieved, for example, by stimulating different fingers on the hand.

Fig. 8A is a schematic diagram of a preferred embodiment of the device in which pairs of anode 810 and cathode 820 electrodes on the fingers are used to excite branches of the 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 cause nerve pulses to travel toward the brain. Due to the body tissue of the brain, the unique stimulation pattern on each finger may send a unique signal to a specific subset 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 multi-modal stimulation, where multiple patterns (with at least one different parameter) of the same type of stimulation are used. In some embodiments, the positions of the anode 810 and cathode 820 may be reversed to inhibit the transfer of sensory impulses toward the brain (retrograde collisions). Stimulation of multiple fingers is an example of multi-modal stimulation, where several sites of the same type of stimulation are used. In combination with unique stimulation patterns, such stimulation is an example of multi-modal stimulation, where several sites and multiple patterns of the same type of stimulation are used. Different kinds of stimulation are also provided in several embodiments (e.g., electrical stimulation on one or more fingers and vibrotactile stimulation on one or more other fingers).

Fig. 8B shows an arrangement in which electrode 830 is positioned on the finger and second electrode 840 is positioned on the wrist. In one embodiment, there is only 830 single electrodes on the finger, and 840 the second electrode is positioned on the wrist. The fingers represent only one set of possible targets, and similarly different locations may be used as targets for a subset of adjacent neurons. In some embodiments, the electrodes on one or more fingers may include an anode and a cathode, e.g., as described with respect to fig. 8B, and the anode and cathode may be positioned on the wrist. Stimulation of one or more fingers and wrists is another example of multimodal stimulation using several 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 of the skin is an example of multi-modal stimulation. In some embodiments, the multimodal treatment is provided on one finger (including the thumb) on one hand and additionally on one finger (including the thumb) on the other hand.

In the embodiment shown in fig. 8C, the electrodes are located at

different locations

850, 860, 870 on the wrist to target the median nerve (near location 850), the ulnar nerve (near location 860), and the radial nerve (near location 870). Those skilled in the art will recognize that the input may be located on other locations or branches of the nerves that input the abnormal brain circuit. The locations may be on the same or opposite sides of the tremor of the limb. The site may be on the surface of the skin, through the skin, and/or implanted.

Fig. 8D illustrates various stimulation sites that may be subjected to stimulation that is delayed or shifted by a predetermined fraction or multiple of the tremor period T, such as shown in fig. 9A and 9B. These sites are near the median and ulnar nerves. Fig. 8E shows the stimulation site near the radial nerve. Stimulation of the first side of the wrist (e.g., fig. 8D) and the second side of the wrist (e.g., fig. 8E) is another example of multi-modal stimulation in which several sites are used.

The device uses a stimulation scheme designed to phase shift, cover or mask the abnormal network. Fig. 9A is a conceptual diagram illustrating a sample excitation scheme for dephasing a region of the brain that receives sensory input from two sites. For example, the two sites may be two fingers as shown in FIGS. 8A-8E. Stimulation at the second site is delayed by a time T/2 after stimulation at the first site, where T is the period of natural tremor. For example, if tremor is at 8Hz and the period T is 125ms, stimulation of the second site will be delayed by 62.5 ms. Stimulation is designed to reset the phase of the neuron, which can be achieved using high frequency stimulation (above 100Hz) or DC pulses.

Fig. 9B is a conceptual diagram illustrating a sample excitation scheme for dephasing a region of the brain receiving sensory input from four sites, with a delay of T/4 for subsequent sites. In another embodiment, the stimulation at different locations is variable in parameters other than timing, such as frequency or pulse width or a combination thereof. These changes are similarly designed to retrain the brain by eliminating, covering or masking abnormal network dynamics. In yet another embodiment, the stimulus may appear at a single location, but its parameters change over time. For example, its frequency may change every few seconds or it may be turned on and off. In yet another embodiment, the stimulation is constant and at a single location. In preferred embodiments of these, the location is near the median nerve of the wrist.

And (3) optimizing stimulation: secondary feeling

Stimulation at an intensity below the sensory threshold will avoid discomfort (stinging, numbness, pain) that may be associated with peripheral nerve stimulation. Because the exact electrode position, size and surface contact have a large impact on the stimulation level and the anatomy receiving the stimulation, it may be necessary to calibrate the sensory thresholds for each patient and even each stage. This calibration may be accomplished by the user manually setting stimulation parameters or otherwise indicating their sensory thresholds. Another possible mechanism of the device is to automatically sweep through a series of stimulation parameters and the patient selects the most comfortable set of parameter values. Another possible mechanism is for the patient to select from a set of previously selected parameter values, thereby providing an effective and comfortable stimulation. In some embodiments, the electrode pad may include a local analgesic such as lidocaine to reduce discomfort from stimulation, thereby increasing the sensory threshold of patient tolerance. In some embodiments, the local analgesic may be delivered using a controlled release form to provide pain relief for the duration of time (which may be days, weeks, or months) that the electrode pad is about to be worn. Such methods may provide greater comfort or greater therapeutic effect due to greater stimulation intensity and/or synergy with local analgesics, which may reduce tremor in some patients.

And (3) optimizing 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 no or little stimulation. It is believed that very high frequency stimulation results in conduction blockages. However, prior to blockade, there is an onset response that includes a strong nerve depolarization. In order to effectively achieve very high frequency stimulation without causing discomfort to the patient, it is preferable to eliminate this onset response. This can be done by cooling the nerve during the initial stimulation. Motor nerves are typically stimulated by stimulation at about 15Hz and below, while sensory nerves are typically stimulated by stimulation at about 50Hz and above. In some embodiments, it may be desirable to stimulate specifically above the 15Hz threshold of motor neuron stimulation to avoid causing muscle contraction.

And (3) optimizing stimulation: touch and touchHair-like device

Alternatively or additionally, triggering stimulation for the tremor stage may improve effectiveness. The purpose of this stimulation is to break the rhythmic entrainment of the motor units. More effective treatment may allow stimulation at lower levels to achieve similar therapeutic benefits, with less discomfort. Essentially, chattering is a problem of feedback in the resonant tank. Stimulation timed out of phase with tremor can reduce tremor by altering the loop dynamics (e.g., by changing the gain on the feedback loop).

As shown in FIG. 10B, bursts of high frequency stimulation may occur periodically when the wrist is at its maximum flexion or extension (FIG. 10A). In the example (fig. 10C), the burst has been shifted to a random phase. The position of the hand (fig. 10A) may determine the optimal stimulation duty cycle and timing, such as stimulating non-resonance with maximum tremor deviation (fig. 10B) or stimulating non-resonance with variable time delayed bursts (fig. 10C) to avoid resonance with tremor.

In some embodiments, the first stimulus may comprise a burst stimulus (e.g., a stimulus having specified on and off periods) and the second stimulus may comprise a continuous stimulus. The first stimulus may be before, during and/or after the second stimulus. The first stimulus may be applied by the same electrode or set of electrodes as the second stimulus, or by a different electrode or set of electrodes than the second stimulus. In some embodiments, a burst of stimulation may be applied to a first location on the body, and a continuous stimulation may be applied to a second location (simultaneously or sequentially).

Alternatively or additionally, the stimulus may be chaotic or variable. The goal of chaotic, random or variable stimulation is to suppress or prevent habituation and reduce resonance in the circuit. This may be achieved, for example, by varying the stimulation frequency over time and/or by superimposing higher and lower frequency components, as shown in fig. 11.

Alternatively or additionally, the stimulus may be a high frequency alternating current. This indicates that the action potential is blocked and the loop dynamics can be adjusted as it passes along the axon.

In some embodiments, the stimulation parameters described above may be cycled according to a predetermined sequence to determine optimal stimulation parameters. In some embodiments, the effectiveness of stimulation parameters may 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 may be changed or cycled according to a predetermined sequence. For example, if stimulation is triggered for the tremor stage, stimulation may be delivered with a random or variable time delay, or if stimulation uses a set amplitude and/or frequency, stimulation may be changed to a chaotic, random, or variable modality to prevent or disrupt habituation. In some embodiments, a random or variable type of stimulation parameter may be utilized according to a predetermined routine, such as for a predetermined number of hours per day, or for a predetermined number of days per week, or at some other predetermined interval (including time of day).

An effector: vibrotactile stimulation

Effectors may mechanically excite proprioceptors by sensations that include vibrotactile or haptic sensations. The mechanical stimulus may include force, vibration, and/or motion. The effector elicits action potentials in the target nerve by firing the Golgi Tendon Organ (GTO) or pacinian corpuscles. The mechanical effector may include, for example, a small motor; a piezoelectric body; one or more vibrotactile units consisting of a mass and an effector for moving the mass such that a vibratory stimulus is applied to the body; an eccentric mass mounted on the shaft such that a vibrational stimulus is generated when the shaft rotates; an ultrasonic motor; a magnetorheological fluid (MRF) effector or an electroactive polymer (EAP) effector; and/or a speaker (e.g., a haptic speaker, a piezoelectric speaker, an electroactive polymer transducer, a solenoid speaker).

In some embodiments, the vibrational stimulus may be 250Hz, corresponding to the best sensitivity of pacinian corpuscles (also known as zonal corpuscles). Pacinian corpuscles are nerve endings in the skin that sense touch and vibration. Deformation of the capsule opens pressure sensitive sodium ion channels to elicit action potentials. In one embodiment, the vibration may be below 50Hz to excite a meissner corpuscle (also called a haptic corpuscle) in the finger that is sensitive to a tap. In some embodiments, the vibrational stimulus can be, for example, at least about, or no more than about 10Hz, 20Hz, 30Hz, 40Hz, 50Hz, 60Hz, 70Hz, 80Hz, 90Hz, 100Hz, 110Hz, 120Hz, 130Hz, 140Hz, 150Hz, 160Hz, 170Hz, 180Hz, 190Hz, 200Hz, 210Hz, 220Hz, 230Hz, 240Hz, 250Hz, 260Hz, 270Hz, 280Hz, 290Hz, 300Hz, 350Hz, 400Hz, 450Hz, 500Hz, or higher or lower, or a range including any two of the foregoing parameters.

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 be subsequent to the first duration (e.g., immediately thereafter, subsequent to the pause duration). The second duration may at least partially overlap the first duration. Continuing with the example, a third single frequency different from the second frequency may be applied for a third duration. The third duration may be subsequent to the second duration (e.g., immediately thereafter, subsequent to the pause duration). The third duration may at least partially overlap with the second duration. The third duration may at least partially overlap the first duration. The third duration may at least partially overlap with the first duration and the second duration. This example may continue for an additional duration of a single frequency. Different frequencies may be applied to the same vibratory stimulus or different vibratory stimuli (e.g., on the same body part, on different body parts). Vibratory stimuli applied to different body parts may converge at some point between the body parts and may form a standing wave. In some embodiments, the junction may be a target body part (e.g., where an elbow and a finger meet at a wrist).

In some embodiments, the vibrational stimulus comprises a combination of one or more single frequencies and one or more sweep 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 be subsequent to the first duration (e.g., immediately thereafter, subsequent to the pause duration). The second duration may at least partially overlap the first duration. Continuing with the example, a second single frequency different from the second frequency may be applied for a third duration. The third duration may be subsequent to the second duration (e.g., immediately thereafter, subsequent to the pause duration). The third duration may at least partially overlap with the second duration. Continuing with the example, a second scanning frequency different from the first scanning frequency (e.g., having a different low frequency, high frequency, and/or rate of change in frequency) may be applied for a fourth duration. The fourth duration may be after the third duration (e.g., immediately thereafter, after the pause duration). The fourth duration may at least partially overlap with the third duration. This example may continue for additional durations of single frequencies and/or scanning frequencies. Different frequencies may be applied to the same vibratory stimulus or different vibratory stimuli (e.g., on the same body part, on different body parts). Vibratory stimuli applied to different body parts may converge at some point between the body parts and may form a standing wave. In some embodiments, the junction may be a target body part (e.g., where an elbow and a finger meet at a wrist). The amplitude of the sweep may be enveloped by other waveforms, such as sinusoids or gaussian, or the parameters may be varied randomly or pseudo-randomly.

The above discussion of different frequencies may also apply to other parameters such as frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duration, duty cycle, on/off time, or burst, combinations thereof, and the like. In several applicable embodiments, the above discussion of vibrational stimulation is also applicable to other modalities and combinations thereof.

In some embodiments, electrical stimulation is applied to a first location on the body while vibratory stimulation is provided to a second location (e.g., wrist and ankle, wrist and ear, ankle and ear, arm and leg, etc.). Electrical and vibrational stimulation are provided (simultaneously or sequentially) at the first location instead of, or in addition to, the second location. For example, a belt (or other device) that provides electrical and vibratory stimulation is used for the wrist, and a belt (or other device) that provides electrical and vibratory stimulation is used for the ear, ankle, leg, arm, etc. In one embodiment, both locations provide electrical stimulation and vibrational stimulation. Third, fourth or other locations may also be stimulated. While stimulation is disclosed in several embodiments, neuromodulation, including stimulation or inhibition, is contemplated in various embodiments.

This mechanical type (e.g., vibration) of stimulus can reduce tremor by several methods. One approach may be to transmit proprioceptive signals to the brain that mask or modify the driving proprioceptive signals transmitted from the tremor muscles. Another method may be impedance control. Joint impedance can alter co-contracting muscles by transcutaneous nerve stimulation, thereby affecting the degree of stiffness of the muscles and in turn affecting the contraction of the muscles. Another approach may be to generate compensatory muscle contractions that oppose the tremor contraction by neural stimulation. In some embodiments, the stimulus is preferably securely held against the skin surface, for example by an elastic or Velcro strap (or other adjustable, adaptable strap).

An effector: chemical, thermal and other

Examples herein primarily describe the stimulation as electrical or vibrotactile. However, stimulation may alternatively be achieved using other effectors that may bring significant benefits in terms of patient comfort, portability, safety, or cost.

In another variation of this embodiment, the effector may be a neuromodulation chemical that increases or decreases a neuron firing threshold. The chemical used in some embodiments may be a local anesthetic, including but not limited to the "caine" family. The anesthetic of the "caine" family may include, but is not limited to, benzocaine, bupivacaine, tetracaine, carbicaine, chloroprocaine, cicadine, dibucaine, etocaine, heptane, levobupivacaine, lidocaine hydrochloride, propivacaine, mecaine, procaine, mecaine, proparacaine, and tetracaine. Other chemical families may include those of the menthol family, or alpha-hydroxy capsaicin from zanthoxylum bungeanum, or capsaicin, all of which are known to affect peripheral sensory nerves.

Fig. 12 illustrates that chemical stimuli can be delivered transdermally through a patch and/or by microinjection. The pre-loaded protocol may preferably be a predetermined composition of one or more chemicals. In several embodiments, local anesthetics may be known for other indications. The recommended stimulation dose may have been tested and approved for treatment of other indications. For example, the local anesthetic lidocaine can be administered at 2-10% by weight. Lidocaine can be administered in combination with other anesthetics. As shown in fig. 12, two

neuromodulation chemistries

1202, 1204 are mixed to provide a customized composition. The chemical irritant may be administered as a composition comprising 2.5% lidocaine by weight as the first chemical 1202 and 2.5% prilocaine by weight as the second chemical 1204. The chemical irritant may be administered as a composition comprising 0.1-5% by weight lidocaine as the first chemical 1202 and 0.1-5% by weight prilocaine as the second chemical 1204.

The chemical irritant may comprise alpha-hydroxy capsaicin from Zanthoxylum bungeanum. The alpha hydroxy capsaicin can be included in an excipient or carrier. Excipients may include gels, creams, oils, or other liquids. If the method of delivery is a transdermal patch, the form of the chemical agent may preferably be a cream or gel. The user may select the composition via a control module (e.g., control module 740 of fig. 7). If the method of delivery is microinjection, the form may preferably be a solution.

In some embodiments, the effector may be a temperature or thermoeffector (e.g., temperature effector 732 of fig. 7) that causes cooling and/or heating. Effectors may modulate neuronal firing directly by cooling nerves or indirectly by cooling adjacent muscle, skin, or other components of the arm. The temperature effectors may include, for example, piezoelectric materials (e.g., peltier cooling tiles), circulating fluids, compressed expandable gases, cooled or heated solid materials, or vaporized materials. One example of a cooling effector may be as disclosed in U.S. publication No. 2010/0107657, which is incorporated herein by reference. The heating and/or cooling may be applied as a patch that is attached to the skin surface by an attachment (such as an armband) that attaches the stimulus to the skin surface or by an implant.

In embodiments with thermal stimuli, the pre-loaded protocol may preferably be a predetermined temperature of the stimulus and an associated stimulus duration. Preferably, the pre-loaded protocol may require a 15 minute duration of thermal cooling and a cooling temperature in the range of 15-25 ℃ (e.g., about 15 ℃, about 17.5 ℃, about 20 ℃, about 22.5 ℃, about 25 ℃, a range between such values, etc.). The duration of stimulation may be preprogrammed to be, but is not limited to, about 5 minutes to about 30 minutes (e.g., about 5min, about 10min, about 15min, about 20min, about 25min, about 30min, ranges between such values, etc.). The maximum length of stimulation should be well tolerated by the user and not cause any muscle or neurological 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 reaches a threshold (which may range 5 deg.C greater or less than the applied temperature for a particular protocol), the processor 797 (from FIG. 7) may modify the protocol to cool or heat more than originally programmed in order to compensate for the difference between the effective cooling and the expected cooling.

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 a plurality of ultrasound transducer elements. The elements may each have a width and a thickness. The thickness can be related to the width (e.g., the thickness is a fraction (e.g., 1/2, 1/3, 1/4, 1/5, 1/10, ranges between such values, etc.) or multiple (e.g., 2 x, 3 x, 4 x, 5 x, 10 x, ranges between such values, etc.) of the width). Each element may have a width, and the space between elements may be related to the width (e.g., the same as the width, half the width, twice the width). The spacing between the elements may be adjustable. In some embodiments, the elements have a width of between about 0.5mm and about 2mmDegrees and a spacing between about 0.1mm and about 2 mm. The elements may be arranged in a one-dimensional array or a two-dimensional array. The elements may be rectangular, cylindrical, prismatic, pyramidal or any suitable shape. For example, the ultrasonic signal can be between about 20kHz and about 2GHz or higher (e.g., about 20kHz, about 50kHz, about 100kHz, about 500kHz, about 1MHz, about 1.5MHz, about 2MHz, ranges between such values, etc.). At least one of the elements may transmit different frequencies. Each element may transmit a different frequency. Each element may transmit the same frequency. In some embodiments, the dose level applied by the ultrasound effector is between about 0W/cm ²And about 2W/cm²Between (e.g., about 0W/cm)²About 0.1W/cm²About 0.25W/cm²About 0.5W/cm²About 1W/cm²About 1.5W/cm²About 2W/cm²Ranges between such values, etc.). One, some, or all of the ultrasound transducer elements may be diverging, focused, scattering, flat, etc. In some embodiments, the transducer elements may be disposed below the skin surface in a manner for focusing energy (e.g., energy from different elements causing constructive interference) proximate to a target nerve or tissue region.

The ultrasound transducer elements may be arranged on a printed circuit board. The ultrasound transducer elements may be arranged on a flexible circuit. The flexible circuit may include, for example, an ultrasound transducer element and one or more other types of effectors. Some circuit boards, flexible circuits, etc. may include other combinations of effectors.

In some embodiments, the effector may be a magnet or a plurality of magnets. For example, a first magnet having a first polarity may be applied to a first site, and a first magnet having a second polarity may 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 location may be proximate to the second location (e.g., within about 10cm, within about 8cm, within about 6cm, within about 5cm, within about 4cm, within about 3cm, within about 2cm, within about 1cm, or more). 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 (e.g., thickness, length, width diameter) as the second magnet. The first magnet may have at least one dimension (e.g., thickness, length, width diameter) that is different from the second magnet. The first magnet may have the same mass as the second magnet. The first magnet may have a different mass than the second magnet.

The magnet may comprise an electromagnet whose material becomes magnetic only when a current is applied to a wire wrapped around the magnet to produce a magnetic field that multiplies the magnetic field strength of the material. In embodiments including electromagnets, the magnetic effectors may be turned on and off without moving the effectors.

In some embodiments, magnetic energy may be applied using a mini-TMS coil oriented orthogonally to the target nerve to deliver bursts of electromagnetic energy near the target nerve. A Transcranial Magnetic Stimulation (TMS) coil includes a ring shape containing a plurality of windings of a lead. When current is applied to the wire, a magnetic field is formed normal to the plane of the toroidal coil. The current may change over time, for example when connected to a stimulus. The magnetic field causes a current to flow in a region of the body adjacent to the TMS. The mini-TMS may be a smaller version of TMS configured to penetrate tissue, e.g. as opposed to the skull.

Several embodiments may alternatively apply other effectors, including acoustics (using ultrasound excitation to excite sensory nerves at the tips of fingers), vibration, touch, luminescence (e.g., exposure in optogenetically modified nerves), magnetism (e.g., by rapidly switching RF fields), or a combination of mechanisms. Some examples of modes that may be used in combination include two, three, or more of the following: electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation (heat and/or cold), mechanical (e.g., vibrotactile) stimulation, focused ultrasound (focused, high and/or low intensity, phased array), radiofrequency stimulation, or microwave stimulation. Such modalities may be used in the same region or in different regions. In some embodiments, different modalities are used to treat tremors or achieve other neuromodulations for a single region, even if two or more body regions are modulated. For example, the wrist and forearm may be adjusted to synergistically reduce hand tremor. In other embodiments, different modalities are used to treat tremor or achieve other neuromodulation for multiple regions. For example, the wrist and ankle may be adjusted to reduce both hand tremor and leg tremor. In addition to tremor, other indications are treated using the devices described herein, 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 tract dysfunction (including overactive bladder, nocturia and/or stress and urge incontinence), and fecal incontinence, as well as psychiatric disorders related to neurological components (such as neurotransmitter dysfunction).

In some embodiments, vibratory stimulation is used in conjunction with electrical stimulation. In some embodiments, the vibrational stimulus and the electrical stimulus are located at the same location or different locations. In some embodiments, vibratory stimulation is used to preferentially stimulate proprioceptors (e.g., a-fibers), and 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.

In some embodiments, chemical stimulation is used in conjunction with electrical stimulation. In some embodiments, the chemical 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.

Events that change patterns can include biomarkers of the disease state (e.g., patient reported symptoms, activity level, tremor motor characteristics, neural integrity). The mode may be controlled by the prescribing physician. The modes may be controlled by the end user or the patient. The pattern may be pre-programmed for a particular time of day. The pattern may be controlled by measures of autonomic activity, including HRV, GSR, MSNA, etc.

Some examples of patterns that may be used in conjunction 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.). The multiple modes may be combined with multiple modalities, each with multiple modes or one or more modalities with different modes. The first stimulation may comprise a burst stimulation and the second stimulation may comprise a continuous stimulation. The first stimulus may include a first frequency (e.g., about 20Hz) and the second stimulus may include a second frequency (e.g., about 40 Hz). The first stimulation mode may include between 100Hz and 200Hz (e.g., 150 Hz). The second stimulation pattern may include between 50Hz and 150Hz (e.g., 100 Hz). In some embodiments, the first and second stimuli may be pulsed on/off in an alternating pattern at a frequency between 4-12Hz, such as in a burst mode (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 at the same nerve bundle in the same region, in the same region but at different nerve bundles (e.g., different points), and/or at different locations.

Form factor: universal wearable irritant

Referring to fig. 14A-14E, the system 700 from fig. 7 may be non-invasive, fully implantable, or partially implantable. For example, non-invasive embodiments may include a non-invasive housing, such as sleeve 1400, or patch 1410 or glove. In such non-invasive embodiments, the interface of the housing 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 the housing interface may be implanted within the patient at the contact point.

The non-invasive system housing may facilitate maintaining the interface and/or effector in proximity to the patient. The sleeve may cover a long arm or may be a narrow band. The sleeve may cover at least a portion of the circumference of any portion of the limb, or the sleeve may cover the entire circumference of any portion 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 the position may include achieving good power transfer, reliable communication, or other purposes.

The housing may be made of any material suitable to achieve the desired performance. For example, the shell material may be a flexible and/or stretchable material, polymer, or fabric. The housing may include fasteners such as Velcro, ties, toggles, and/or straps to secure the device to the patient. The housing may include multiple layers and/or pockets configured to hold various components of the systems disclosed herein.

The system may be positioned by the patient with or without assistance from a caregiver. In some embodiments, the system may have an auxiliary mechanism for positioning it on the arm, such as a pressure-responsive clasp and/or a self-aligning magnet. In some embodiments, such as sleeve 1400, the system may be slid over the end of the limb (similar to a sports sleeve) or wrapped around the arm or self-wrapped around the arm (similar to a snap-fit strap).

In some embodiments, the housing may take the form of a patch 1410. For example, the housing patch 1410 may be secured to the skin of the patient using a removable or degradable adhesive. The patch may be worn multiple times, including but not limited to patches that are worn only during the stimulation period and patches that are left in place for days, weeks, or months. The patch may also be mechanically attached, chemically attached, or electrically attached. Such embodiments include, but are not limited to, staples, wires, or magnets to secure the patch in the desired position.

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

In one embodiment, housing 1450 may have the configuration of a watch worn on the wrist or arm of the user, as shown in fig. 14H-14L. The housing 1450 may contain an interface 1452 that is separate from, partially separate from, or connected to the housing and that may interact with a user. The interface 1452 may be connected to the housing 1450 and may be disposable after a certain period of use. The electrodes 1454 of the interface may be arranged in strips and may be arranged in an anode/cathode pair. Other electrode configurations described herein may also be used. A time period may be after a single use, or after multiple uses over a period of minutes, hours, days, weeks, or months. The interface itself may be an entire portion of the wristband or may be a portion of the wristband or may be 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 be snapped around a wrist by including features of elastic material that are slightly curved so that when moved, the wristband wraps around the wrist in a circular shape. In another example, there is a temperature sensitive material (e.g., nitinol) with shape memory such that when the device is in contact with the skin, the wristband, with or without an interface, may change shape to wrap around the patient's wrist. In another example, a wristband, with or without an interface, has one or more wires inside or outside the wristband that remain in a new shape when moved to allow the user to place the device on the wrist and add strength to shape the wristband onto the user's unique anatomy. In another example, a wristband with or without an interface wraps partially or completely around the wrist. The windings may be on the same axis or may be helical windings.

The disposable or non-disposable interface may be connected to the housing in a number of different ways, including but not limited to snap features, velcro, press fit, magnets, temperature, adhesives, which may or may not include self-aligning features. The connection may be in one or more dimensions or axes. By way of example, fig. 14J-14L illustrate one possible embodiment in which there is a self-aligning piece, which may be a magnet, that connects the interface to the body in 3 dimensions. The circular shape of the alignment member may allow for alignment of the first dimension in one plane. The shaft portion of the alignment member, which may be offset from the circular feature of the alignment member, may align the interface along the appropriate axis. The overall shape of the alignment member may allow for alignment of the interface in the final dimension, which in this particular example of embodiment is the depth. The housing may have a matching feature of this shape to which the connection may be connected. It is possible that the connection features may be reversed and the alignment member may be placed on the housing and the shaped mating feature may be placed on the interface. These connections of the alignment member may or may not have magnets on one or both or either of the housing or the interface member.

In some embodiments, the external device may be an object that is not worn on the body. For example, it may have the form factor of a cell phone, and the patient carries the device in his pocket, bag, hand, or in other ways of transporting and supporting the cell 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 table, in a kitchen, or in their dressing room.

As shown in fig. 14M, another preferred embodiment may include a stimulation device having one or more electrodes 1460 applied along the spinal column. Stimulation devices can be used to stimulate the release of neurotransmitters and reduce tremor by neuromodulation of nerves located along the spine. Stimulation can affect the release and uptake of neurotransmitters, thereby affecting the innervated tremor region. The electrodes are preferably placed on the skin surface at the root of the cervical spine, 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 lead connecting the electrode to the operating unit is preferably magnetized to facilitate the connection. The operating unit may be connected to and controlled by the processor. Since the electrodes are preferably placed along the spine (the back side of the user), separate and portable control modules may be more convenient for the user to operate.

In some embodiments, neurotransmitters (such as dopamine, serotonin, GABA, etc.) are increased or decreased via neuromodulation devices described herein (e.g., electricity, vibration, ultrasound (e.g., focused ultrasound), radiofrequency, etc.) to treat tremor, overactive bladder, cardiac dysfunction, depression, anxiety, migraine, and other diseases. While the spine may be one location, other locations include the wrist, hand (including fingers), upper arm, head (including scalp, ears, face, temple), legs, feet (including toes), and other locations. Two, three or more positions may be used to produce a synergistic therapeutic effect.

In one embodiment, electrodes may be placed near the C2 to C8 regions of the neck and shoulders on either side of the spine. The electrodes may be placed about 100cm to 1cm from the spine and may be placed 200cm to 5cm from each other. The stimulation parameters may comprise a phase duration between 500 and 30 μ s, which may preferably be 300-60 μ s (microseconds). The pulse rate may range from 10Hz to 5000Hz or higher (e.g., 20kHz), and a preferred range may be from 50Hz to 200Hz or 150 Hz. The cycle time may be continuous or may be in the range of 5 seconds to 1 hour. Preferred cycle times may be about 5 seconds to 20 seconds or 10 seconds. The duration of the electrical stimulation may range from 5 minutes to 24 hours per day. The preferred range may include 30 minutes to 60 minutes repeated about 10 times per day, or the preferred range may be about 40 minutes to 1 hour per day and repeated once per week to once per day. The amplitude (which may be used interchangeably with intensity) may range from 0.1mA to 200mA, and preferred ranges may include 1mA to 10 mA. The length of time that the user can use the device before it affects the user's tremor may be one day to one month, or may preferably be 2 days to 4 days.

Form factor: for electrical stimulation

Conventional TENS devices are often difficult to locate, cumbersome and uncomfortable. The following innovation is a solution that can easily and quickly apply, adjust stimuli to control ET and enable the patient to use it comfortably on his own.

With conventional TENS devices, it is difficult to properly size and position the pasted 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 higher current densities from smaller electrodes can cause discomfort. Larger pads are easier to place, but require more power and are more likely to inadvertently stimulate adjacent tissue. The following innovations address these challenges and achieve consistent, effective, comfortable, and safe stimulation.

As shown in fig. 15A-15C, the apparatus may comprise 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 separately on the patient's skin for clarity, in practice, the electrode array may be integrated into the sleeve, flexible pad or substrate, or other form factor as described herein. The appropriate electrode combination will be selected each time the device is repositioned or based on the detected stimulation requirements. Stimulation may use a single electrode as an anode and cathode, or a combination of electrodes may be used to shape the stimulation field. The selection of the electrodes may be made automatically based on feedback from sensors in the device (see below). In some embodiments, electrode selection may be done manually by a user. For example, the user may cycle through electrode combinations until they find an alternative combination that provides the best tremor reduction or obtains proper placement, such as tingling in the 1 st finger (index finger) and the 2 nd finger that occurs with the median nerve sensory stimulation. Fig. 15A shows a two-dimensional array of discrete electrodes 1500. In some embodiments, some electrodes may be combined into linear rows, such that a two-dimensional array is formed from multiple rows of electrodes. Fig. 15B shows a linear array of electrodes 1500 that may be worn as a belt or patch, pad, sleeve, etc., as shown. Fig. 15C shows a housing 1502 that can be used to hold an array of electrodes 1500.

In some embodiments, electrical stimulation from poorly positioned electrodes may be redirected to the target nerve by modifying the conduction pathway between the electrode and the target nerve. For example, the conduction pathway enhancer 1600, which may be made of an electrically conductive material, may be placed on the skin of a patient, embedded in the skin, implanted, or a combination thereof, in order to enhance the conduction of electrical stimulation from the electrodes 1602 to the target nerve 1604, as shown in fig. 16A-16D. The conduction pathway enhancer may be placed over and/or across a nerve. For example, in one embodiment, a tattoo of conductive ink may direct off-target stimulation to the median nerve. A tattoo that is more conductive than adjacent structures (e.g., blood vessels, nerves) will provide the path of least resistance and redirect current. In order to place or locate the conductive tattoo, the target nerve is first actively identified. A conductive tattoo is then placed on the target nerve. As shown in fig. 16A-16D, a conductive tattoo may include a plurality of conductive strips spanning a nerve. In some embodiments, the strips may be parallel to each other and traverse across the nerve. In other embodiments, the strips may be formed in a star or cross-hatched pattern with the center located over the nerve. In other embodiments, the strips may also be placed over and parallel to the nerve (not shown).

For adoption by a user, the wearable device should be discrete and comfortable. In the preferred embodiment shown in fig. 14B and 14F, for example, the effector is electrical and the skin patch has electronics (similar to a woundplast) of a single electrode or multiple electrodes printed onto the flexible substrate in a predetermined pattern to form a "second skin". For optimal comfort and surface adherence, mechanical properties such as elasticity and stiffness should be matched to the skin. The circuitry and wiring for surface electrical stimulation may be printed or etched into the flexible material so that the device conforms to the body or tissues within the body. For example, it may be copper printed on a flexible substrate (such as plastic).

In another embodiment as shown in fig. 14G, the device may be positioned on the surface of the body, but contain a transcutaneous penetrating element 1470 to improve the impact on the nerve. These elements may be microneedles for improved stimulation and/or drug delivery. In some embodiments, the transcutaneous penetration elements may form a microelectrode array, which is placed on the surface of the skin and penetrates the skin. Microelectrode arrays can function like microneedles and can improve signal transmission from the electrodes to the nerves and improve the permeability of the skin, thereby improving local drug delivery.

A sensor: sensor type

The device or system may include a sensor. The sensors for monitoring tremor may include a combination of: single or multi-axis accelerometers, gyroscopes, inclinometers (for measuring and correcting for gravitational field changes caused by slow changes in the orientation of the device), magnetometers; fiber optic electrical goniometers, optical tracking or electromagnetic tracking; electromyography (EMG) for detecting tremor muscles; an Electrical Neurograph (ENG) signal; by cortical recordings, such as electroencephalography (EEG) techniques, or direct nerve recordings on implants in close proximity to the nerve. Fig. 17A-17B show representative positions of motion sensors on 1710 hands or 1720 wrists. Other tracked locations may include fingers or other body parts.

Data from these tremor sensors is used to measure the patient's current and historical tremor characteristics (such as amplitude, frequency and phase). These sensors may also be used to determine activity, such as for distinguishing involuntary movements (e.g., tremor) from voluntary movements (e.g., drinking water, writing) or the presence or absence of tremor relative to the time of day or other detected activity (such as sleep/wake cycles).

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 location of the device (e.g., from GPS), battery power, or video recordings. In another embodiment, the sensor is a temperature sensor for measuring the temperature of the cooled limb. In another embodiment, the sensor comprises a video recording. In another embodiment, sensors from existing hardware, such as a smart phone, are used. For example, tremors can be measured using an accelerometer on a smartphone or engaging the patient in a writing task that induces tremors (by analyzing lines drawn on the smartphone screen).

A sensor: algorithm for extracting tremor

In several embodiments, an algorithm will be used to extract information about tremor from the data stream provided by the sensor. Tremors may be identified based on their time domain signal, frequency domain signal, amplitude, or discharge pattern (e.g., bursts, spikes). For example, in fig. 18A-18B, frequency analysis of the spectral power of the gyroscopic motion data indicates that the center of tremor is at about 6.5Hz (see maximum power in the lower graph).

The motion data may be acquired as each raw sensor channel, or by fusing the raw signals of multiple sensors together. As one example, multi-axis accelerometer data may be combined into a single value for analysis. The algorithm will extract motion data in the range of 4 to 12Hz to remove motion not attributed to tremor. This may be done using any combination of notch filters, low pass filters, weighted frequency fourier linear combiners, or wavelet filters. Since each patient has a predominant 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 6Hz tremor, the analysis algorithm may only extract motion data in the range of 5 to 7 Hz. If the patient's tremor is known to be 5 degrees maximum in wrist flexion and extension, the analysis algorithm will determine that the measured motion of 45 degrees of wrist flexion is likely due to an intentional gross motion rather than tremor. In some embodiments, the algorithm will sample the motion data by identifying time periods that may correspond to a gesture-hold or motor fine motion task.

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

Sensor fusion techniques can also be used to analyze different aspects of tremor. For example, a multi-axis accelerometer and gyroscope attached to the back of the hand may be combined to reduce noise and drift, and to determine the exact orientation of the hand in space. If a second pair of multi-axis accelerometers and gyroscopes are also used on the wrist, the joint angle and position of the wrist can be determined during tremor. This can isolate which stimulation of which nerves causes damping of the different muscle groups that control tremors.

ET patients have two components of their tremor. Motor tremor are present during intentional exercise and have a significant impact on quality of life as they affect a person's ability to perform daily tasks such as drinking, eating, writing and dressing. Postural tremor exists during a static position held against gravity. Although they have less of an impact on quality of life, they can be embarrassing. Postural tremor is often present early in the disease process and is thought to cause motor tremor. Both components are typically in the range of 4 to 12Hz, with elderly patients experiencing lower frequency tremors.

Detecting postural tremor and kinetic tremor is more challenging than detecting resting tremor. Resting tremor is present in other movement disorders, including parkinson's disease, and can be easily identified by analyzing tremor that is present only when the limb is at rest. Extracting motor tremor from the motion data is challenging because it is necessary to distinguish motion due to tremor from motion due to the task.

It may be easier to identify postural tremor than kinetic tremor because accelerometer/gyroscope data during a kinetic task may be corrupted by motion in the task. Postural tremor is thought to result in kinetic tremor because people often suffer from postural tremor earlier in life than kinetic tremor and they are at about the same frequency. As shown in fig. 19, our findings of association of postural tremor and kinetic tremor in clinical studies support this theory of using postural tremor data to analyze or treat kinetic tremor.

Feedback and/or algorithm based customization processing is provided in several embodiments.

A sensor: data storage and use

As shown in fig. 20, the stimulation device 2000 may contain hardware, software, and firmware to record and transmit data (such as tremor characteristics, stimulation history, performance, usage, and/or control of the device) to a data portal device 2002 (such as a smartphone, cell phone, tablet, laptop, desktop computer, or other electronic device using a wireless communication protocol (such as bluetooth)).

Data recorded using the device used by the ET patient may be stored on a smartphone, which then transmits the data to the cloud-based database/server 2004, or the device used by the ET patient may transmit the data directly to the cloud-based database/server 2004, enabling a number of activities, including tracking tremors, optimizing stimuli, sharing with caregivers and physicians, and establishing a community. The data may provide information to the controller, real-time feedback to the patient, caregiver, and/or clinician, or the data may be stored to provide historical data to the patient, caregiver, and clinician. Data stored on the cloud 2004 may be viewed by multiple users 2008 on multiple platforms 2006. Further, data on the cloud 2004 may be pooled and analyzed by the computing device 2010.

Patient tremor is monitored when the patient visits a physician, usually every few months, or once a year. Such monitoring is typically highly subjective. In addition, tremor severity can be significantly affected by many factors, including sleep patterns, emotional state, previous physical exercise, caffeine intake, food, drugs, and the like.

Such infrequent and inaccurate monitoring limits the ability of the patient, their caregiver and physician to understand the severity and progression of the patient's ET as well as the effects of various treatments and behaviors. These factors may interact with the effects of the stimulus provided by the device, and these interactions may be difficult to detect. These interactions can be identified to optimize treatment and help patients better understand how their behavior affects their tremor.

In one embodiment shown in FIG. 21A, 2100 tremor is monitored using a sensor that may be an IMU, an electrode, or any other sensor previously discussed. The monitoring may be continuous or during discrete time periods. The data from these sensors is analyzed 2110 to identify changes in tremor characteristics (amplitude, frequency, etc.) over time. The results are recorded and displayed 2120 to the user. The analysis 2110 and/or display 2120 may be done on the stimulation device itself, or by transmitting the raw or analyzed data to an auxiliary device such as a smartphone or computer.

In another embodiment, behavior data may also be collected 2101 so that the analysis may examine the relationship between tremor history and user behavior. Behavioral data may include caffeine, alcohol, drug consumption, and anxiety levels. The system may then alert the patient to the interaction between the behavior and tremor.

In another embodiment where the device is therapeutic (e.g., if it has effectors), stimulation history may be collected 2102 so that the analysis may examine the relationship between stimulation history and tremor characteristics.

The embodiment shown in fig. 21B adds an upload 2140 to the cloud. The order of upload 2140 and analysis 2110 may be switched so that the analysis is done on the machine before uploading (not shown). The use of the cloud enables display 2120 results to the user on various networked devices (including smart phones, tablets, laptops, and desktop computers); displaying 2150 the results to other users, such as physicians or caregivers; or pooling analysis for multiple patients 2160.

Figure 21C illustrates some potential uses of pooling data, including connecting 2170 patients to similar patients based on characteristics such as tremor characteristics, geography, age, and gender of the patients, or improving 2180 stimulation algorithms.

Fig. 21D illustrates how the data monitoring and analysis shown in fig. 21A-C can be used in a closed loop to adjust stimulation parameters. In this way, the algorithm detects interactions between variables to optimize treatment.

The device may include closed loop control of stimulation to adaptively respond to detected tremor or activity levels. The device achieves the sensation of tremor through activity sensors, data recording and systematic adjustment of stimulation parameters to achieve optimal tremor reduction. Fig. 26A is a control diagram showing the basic components of the detection and response system. Goal 2650 defines an expected profile. For example, in ET patients, the profile may be no tremor, and in PD patients, the profile may be no tremor or rigidity. The error 2670 between the target 2650 and the detection 2660 is fed to a controller 2680 which modifies the output 2690. The controller 2680 may include a processor and a memory. In addition to the errors and measurements, the algorithm of the controller 2680 may also input measurement history, stimuli, and activities into its algorithm. 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 stimulation. In a preferred embodiment (fig. 15), the device contains an array of small electrodes and the output modifies the selection of electrodes to be used as anodes and cathodes. The effect of the modification is then detected 2660 by the measurement device and the process is repeated. The detection 2660 and/or output 2690 modification may occur continuously in real-time, with periodic delays between predefined times (e.g., hourly or daily), or in response to a user-generated signal, such as a predefined sequence of motions or button presses. In some embodiments, the controller may alert the patient to manually modify the stimulation parameters. The closed loop may be used for automatic self-calibration.

FIG. 26B shows a control diagram showing the basic components of this detection and response system, similar to that described in FIG. 26A, but now with respect to the components located inside and outside.

Control may also consider other modes of behavior, much like the feedforward controller 2640. For example, a typical pattern of eating times may cause the effector to discharge more aggressively at specific times to reduce tremor of these activities. Also, a person may indicate in a schedule whether they wish to add therapy for certain periods of time based on their activities of the day, e.g., whether they have a lecture or other anxiety-causing event. Over time, this type of information may also be obtained and learned by the control unit. Other data (such as sleep, food intake (especially alcohol and caffeine intake), exercise history, emotional state (especially anxiety levels), and drug use) collected by other mobile technologies and applications (such as Azumio, Jawbone, Fitbit, etc.) can be integrated into the cloud-based patient database, as shown in fig. 20 and 21. The user may be prompted to enter such data, such as taking a picture of a meal using an imaging processing application to determine the amount of food intake. The database combines discrete events (e.g., time and amount of caffeine intake) with time series data (e.g., tremor measurements). The algorithm will examine the relationship between patient behavior, stimulation and tremor. These will optimize stimulation and alert the patient to the action affecting tremors. This would allow for an individually optimized treatment of tremor and feed forward into the system.

In some embodiments, the device or cell phone may prompt the user at predetermined times to perform specific tasks that may be tailored to the type of tremor afflicting the patient, such as holding the arm in a specific posture for ET, or placing the arm in a stationary position for parkinson's disease. During this time, the sensor may record tremor. In some embodiments, patients may additionally or alternatively be instructed to drink caffeine or to record the period of time that has elapsed since they last drunk caffeine. This data can be used to determine how caffeine affects tremor, the effectiveness of the treatment regimen and stimulation parameters, the duration of effectiveness, and the like. In some embodiments, the patient may be prompted for a predetermined amount of time after stimulation (such as 10 minutes, 20 minutes, 30 minutes, and/or 60 minutes). The time may be adjusted depending on the measured duration of tremor reduction after stimulation.

The device will have an onboard data record and can transmit this information to an external data portal device, such as a smart phone or internet-enabled charging and synchronization station. The transmission may be wireless or direct. The external device will have a larger storage capacity and allow for transmission to the database in the cloud. The external device may analyze this data on the machine and present the information on a screen or using an indicator such as an LED light, or may show the data on the stimulation device itself.

Data in the cloud can be viewed on multiple platforms, including smartphones, tablets, and computers. The data will be viewable by a number of people including the user, his or her physician, a caregiver, or a family member. This will give a more complete understanding of the patient's tremor and achieve an optimization of the treatment. In some embodiments, a user viewing the data may also add comments and annotations to the data, which may be tagged with the identity of the user making the comments or annotations and the time at which the comments or annotations were made. In some embodiments, the ability to make annotations may be limited to the healthcare provider (such as the patient's physician) and the patient.

In some embodiments, access to the data is limited to healthcare providers and patients. Access may be restricted by requiring the user to set a secure username and password to access the data. In some embodiments, the patient may also provide access to the data to other people, such as family and friends.

Algorithm for optimization

Our data indicate that stimulation using TENS devices is highly effective in some patients, slightly effective in others, and ineffective in others. However, optimization of the 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, burst, etc.) allows the device to achieve maximum tremor reduction in each patient with maximum comfort and allows the device to adjust over time in response to changes in circuit dynamics, device position, patient state, etc. Fig. 22 shows a decision algorithm/controller for a device.

In one embodiment, the optimization algorithm begins by initializing one or more parameters 2200, which may include stimulation amplitude, desired frequency, on-time duration, off-time duration, and desired stimulation 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 characteristic 2202 is compared to a desired target tremor characteristic 2204, which may be no tremor or reduced tremor. The comparison step 2206 may determine an error or difference between the detected tremor characteristic and the target tremor characteristic, and determine whether there is a tremor or reduced tremor 2208, or in other words, whether the detected tremor meets or exceeds the target condition. If tremor is not detected, or more generally, if the predetermined target tremor condition is not exceeded, the algorithm loops back to the detection step 2202. Stimulation 2210 may be turned on if tremor is detected, or more generally, if a predetermined target tremor condition is exceeded. Once the stimulus has exceeded the set on-time duration 2212, the stimulus 2214 is turned off and the algorithm proceeds back to the detection step 2202. When the stimulus is turned on, the device can upload the recorded data 2218 to the cloud or another device for further processing. Once the stimulus 2214 has been turned off, the algorithm may monitor the off-time duration 2216 and may continue to upload data 2218 once the off-time duration has elapsed. In some embodiments, data may be uploaded even before the shutdown time has elapsed. User-reported events 2220 (which may include caffeine or alcohol intake, anxiety, and other events that may affect tremor) may also be entered into the system and sent to the cloud. The data may be processed by a controller 2222, which may 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 may also be sent to the patient that may highlight or otherwise correlate the various behaviors identified in the user reported event with the measured tremor.

In one embodiment, the stimulation algorithm is designed to optimize the treatment "on" time. The optimization algorithm may find the best solution for the output, including but not limited to controlling tremor at specific locations during specific tasks, at specific times of the day, or optimizing only the overall daily minimization of tremor. The algorithm may be self-calibrating to adjust stimulation parameters including, but not limited to, frequency, amplitude, pulse width, electrode selection for the cathode and anode, and/or timing of on and off stimulation. The algorithm may be responsive to user input or may be fully preprogrammed. The algorithm may be a learning algorithm for customizing the stimulation over time to adjust in real time according to the patient's tremor or patient-defined needs. The switch stimulus may be triggered in response to an input including, but not limited to, a user input (e.g., turning the device on or off), a time since last use, a time of day, detection of tremor (e.g., via an accelerometer), electronic recording, or an algorithm based on the previously described or other inputs. For example, the user may turn off the device using voice activation to provide a stable time interval needed for intentional motion with a therapeutic window (e.g., turn off time for tremor reduction after stimulation). In another example, the user bites or uses the tongue muscle (detected by an external device placed inside or outside the mouth), which will signal to turn off the stimulus and allow the user to stabilize the arm, thereby being able to stably perform the intended action. In some embodiments, the system and algorithm may detect the type of tremor based on an analysis of the tremor parameters and the measured patient activity, such as distinguishing between postural tremor and kinetic tremor. In some embodiments, the stimulation parameters may be determined based in part on the type of tremor detected.

In some embodiments, the system may be controlled by an event trigger. Event triggers may include defined motion, temperature, voice activation, GPS location, or based on data received by the sensor, or any combination thereof. For example, the device may be turned on or off, such as during intentional motion before tremor has started or ended, respectively. In another example, the device is 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 during a period of desired tremor suppression; the effect may continue to outweigh the use of the device until the desired period of tremor suppression; and/or activating the device in response to detection of tremor.

According to several embodiments, the system may use sensors to determine whether a modality, combination of modalities, or setting of modalities is valid and adjust one or more modality parameters to improve response. For example, if the wearable device includes electrical and vibration effectors, but the settings are not valid (e.g., due to tolerance accumulation), parameters of the electrical stimulation (e.g., one or more of 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., one or more of 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, the modality may be taken out of service. In some embodiments, new modalities may be added (e.g., instead of a stopped modality or in addition to one or more existing modalities).

Community data based optimization

At present, the time course of tremor is poorly understood. While creating a database for a single patient would improve our ability to reduce tremor in that patient, combining individual patient data into a database comprising records from many patients may enable more powerful statistical methods to be applied 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 classifiable metadata that allows the data to be collected in a database for classification, searching, and/or reorganization as desired. The metadata may include the type of tremor (tremor amplitude, tremor frequency, temporary presence of tremor, etc.), name, age, race, gender, location, time, food and beverage consumption (especially for caffeine and alcohol), activity history (exercise, sleep, etc.), medications, past treatments, and current treatment methods.

The systems described above with respect to fig. 20 and 21 may be applicable to data from many patients entering a database, and the algorithms may operate on large data sets.

Community construction

Individuals with ET feel isolated due to the disability associated with their tremor. Thus, they are very active in recognizing others who suffer from ET. There is an active and growing set of support teams that organize meetings and allow ET patients to converse with their problems and discuss possible solutions. Attending these meetings can be challenging because some ET patients are difficult to drive. Also, individuals within a particular geographic location participating in the support panel may present symptoms that are different from one another, and they lack the ability to identify other patients that are most similar to one another.

The algorithm may help individuals find members of the ET community with similar profiles. For example, the algorithm may characterize the patient based on the patient's age, tremor severity, tremor characteristics, success of the treatment, type of medication, location (address or GPS based), and other characteristics. This will help them to communicate with each other and share information from a central community website that is tailored to the particular individual or caregiver with the ET. For example, the system may identify patients within a geographic location or identify other patients within a predetermined distance from a particular patient. The patient may choose to join the online ET community and make their location searchable on the system. The system may identify to the patient existing ET community support groups within a predetermined distance.

Other processors, libraries, data storage devices

For example, as shown in fig. 7A-7D, the processor 797 may be employed to operate on data, perform calculations, and control other components of the tremor reduction device. It may preferably be a microprocessor or microcontroller with peripherals. For example, the processor may receive input from a user via control module 740, and may control the execution of the stimulus selected by the user. In another embodiment, the processor 797 may execute a predefined stimulation protocol selected by the user. These stimulation protocols may be found in a digital library 798 of stimulation protocols, which may be loaded in the processor 797 or stored in external memory (e.g., EEPROM, SD card, etc.). Processor 797 may also receive information from sensor 780 and process the information on the machine and adjust 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 it needs to control. For example, communication with the peripheral device may be performed over any well-known standard such as USB, UART, SPI, I2C/TWI. The processor may also communicate wirelessly with other device components using bluetooth, Wifi, etc. The processor may transmit tremor data on the device, or via a wireless link between the processing unit and the stimulation unit.

In embodiments with electrostimulation 730, the pre-loaded protocol 798 may be an electrostimulation or an electrostimulation sequence. Electrical stimulation or signal refers to an electrical pulse or pattern of electrical pulses. The 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 electrical stimulation burst. These parameters may be predefined or controlled by the user.

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

Power supply

The effectors may be electrically coupled to one or more power sources, for example, as shown in fig. 7A-7D. Power supply 750 is used to power the device. A power supply 750 may be coupled to the processor 797 and provide power for processor operations. The power source may preferably be rechargeable and detachable as this allows the device to be reused. The power source may preferably be a battery. Several different chemical combinations are commonly used, including lead-acid, nickel cadmium (NiCd), nickel metal hydride (NiMH), lithium ion (Li-ion), and lithium ion polymer (Li-ion polymer). The method of recharging the battery is preferably attached to a wall outlet or other powered device, solar, radio frequency and electrochemical. In some embodiments, the power source is a supercapacitor. Supercapacitors can be divided into three distinct families-double layer capacitors, pseudo-capacitors and hybrid capacitors. The supercapacitor may preferably be 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 more tolerance to charge and discharge cycles. Batteries and supercapacitors can be used in combination because the tolerance of supercapacitors to a large number of charge-discharge cycles makes them well suited for connection in parallel with batteries and can improve battery performance in terms of power density. In some embodiments, the power source may utilize energy from the body. In some embodiments, electricity may be utilized through kinetic energy, through thermal energy, and/or through sound. In some embodiments, the power source may include a plug to an external source (such as a utility). Two, three or more power supplies may be provided for a single device. In some embodiments, a low profile and lightweight device is used to increase patient compliance. In some embodiments, a water resistant or waterproof device is provided.

In one embodiment, a dedicated charging station or docking station may be used to recharge the device. A benefit of a dedicated charging station is that it may also facilitate uploading data from the device to the Web via Wifi or other communication protocols.

Implant and method of manufacturing the same

In some embodiments, at least a portion of the system is implantable. The implanted stimulus may provide better control and comfort than surface stimulation because it is located closer to the nerve and avoids stimulating cutaneous afferent sensations.

The method of stimulating peripheral nerves to control hand tremor presents specific requirements for a suitable implantable stimulator. First, the implant should be small to minimize the invasiveness of the procedure for positioning and adapting the implant to implantation. Second, because the stimulation may be responsive to detected tremors or user input, the implant should be able to receive communication from an external device. Third, the device should tolerate variability in the location of the external device.

Any number of the system components disclosed herein may be implanted. In some embodiments, the housing, the interface, the effector, and the power source 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 source is external to the patient.

The device may be implanted subcutaneously, partially, or transdermally (through the skin), may be on the surface of the skin, or may not be in contact with the body. It may be a component of these devices, such as a surface component that communicates with or powers an implanted component. If a device is implanted, the device may be implanted in or around a nerve, muscle, bone, ligament, or other tissue.

In one embodiment, the implant is positioned within or near the carpal tunnel to affect a nerve traversing the carpal tunnel. In another embodiment, the implant is located on or near the median nerve in the upper arm between the biceps. In another embodiment, the implant is positioned on or near the median, radial or ulnar nerve in the forearm or wrist. In another embodiment, the implant is positioned on or near the brachial plexus to affect the proprioceptive nerve which passes from the arm toward the central nervous system.

The implant portion may be placed or delivered within a vessel to affect nerves in an area within the reach of the implant. In one example, the device is placed within or through a subclavian artery or vein to affect the brachial plexus.

As shown in FIG. 23, a preselected embodiment of a controllable device for enabling a user to reduce essential tremor includes: an electrode 2310 made of a biocompatible material that is at least partially subcutaneously implanted to stimulate a target nerve; an external operation unit 2320 including a user control interface connected to the implant electrode 2310 through a wire. The apparatus may comprise further elements, which may comprise: a processor 797 that performs calculations and controls other components; a processor-controlled function generator; a digital library 799 stored in a processor or memory that contains preloaded adjustment protocols; a sensor 780 connected to or in communication with the processor 797 that detects a predefined parameter and transmits the parameter information to the processor; a data storage unit 770 connected to the sensors and the processor; and a power supply 750.

In this embodiment, the implanted electrode 2310 may be used to provide direct electrical stimulation to the target nerve. Since the electrodes are at least partially implanted in the body and will remain for an extended period of time, preferably several years, the electrodes may be made of a material having suitable electrical properties and being biocompatible. The material of the 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. The electrodes 2310 may have varying shapes and sizes, but are in significant contact with the nerve of interest. The electrode shape includes a planar handle, simple and uniform microwires, and a probe that tapers from a wider base to a narrow tip. The electrode may have a proximal end and a distal end. The distal end may contact a nerve and be adapted to deliver a nerve stimulation pulse to a selected nerve. The proximal end of the lead may be adapted to connect to an external operating unit operated by the processor 797.

In variations of the embodiments, there may be multiple leads connected to different nerve bundles. In another variation, as shown in fig. 24A-24D, wireless communication with the implant may be possible. Implant 2400, which may be a microelectrode or a microstimulator, may be inserted near a nerve using needle insertion. The needle 2402 can be inserted into the patient so as to be proximate to or near the target nerve 2404, and the implant can then be ejected from the needle. Implant 2400 may communicate with, transmit and receive data to and be powered by an externally located device 2406, such as the decision making unit described herein.

In one embodiment, the interface may be an implanted nerve cuff. The cuff may completely or partially surround the nerve. The cuff may be attached to the nerve by closing a butterfly arm electrode. In another embodiment, the interface may be a neural abutment. The abutment may be placed against the nerve or may be placed 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 hub may be anchored to the nerve or to a sheath surrounding the nerve. For example, the device may be wrapped around, bound to, clamped to, tethered with a small barb, or chemically fused to a nerve or nerve sheath. The function of the cuff, coil, abutment or anchor is to provide good contact or close proximity between the device and the nerve. Some of these embodiments are depicted in fig. 25A-25F. Cuffs or bands may be used on the wrist, fingers, ankle, leg, arm, ear, and other locations.

For example, fig. 25A-25C illustrate embodiments of a coil electrode interface, which may be a multi-coil electrode as shown or a single coil electrode. 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 prior to insertion and implantation, and a coiled configuration after exposure to body temperature. Fig. 25D and 25E illustrate an embodiment of a butterfly cuff-type electrode 2510 that may at least partially encircle a nerve. As in other embodiments, the interface may include a single or multiple electrodes, and may be made of a shape memory material to have an open configuration during delivery and a closed configuration wrapped around the nerve after implantation. Fig. 25F shows an embodiment of an interface having a linear array of electrodes 2520 that can be abutted against and placed along a nerve.

The method of inserting the implant may involve local or general anesthesia. The implant may be delivered through one or more perforations in the skin, such as a needle or suture, 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 penetrating all or part of the device around a nerve and/or surrounding tissue (such as a blood vessel or tendon).

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

In another embodiment, one or more devices used to place the devices may be guided using ultrasound. Ultrasound can be used to measure proximity to blood vessels, nerves, or other tissue, or to characterize the type and location of adjacent tissue.

In another embodiment, the electrodes used for stimulation may be injected as a liquid. In another embodiment, the electrodes may be flexible and delivered in a viscous medium such as hyaluronic acid. In another embodiment, the electrodes may be made of nitinol, which is shaped at 37 degrees celsius. This would allow the electrode to be injected or inserted in one configuration, such as an elongate configuration to fit in a needle, and then shaped when heated to body temperature. Some of these examples are described in fig. 25.

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

Transcutaneous charging or powering may reduce implant size by eliminating the need for a large power source (e.g., a battery) and may not require replacement of the power source by repeated surgery. The external components may be used to wirelessly power the internal components, such as by Radio Frequency (RF) power transmission. For example, the external device may transmit RF power that the internal components receive through the resonant coil. Power may be transmitted at various wavelengths including, but not limited to, radio frequency and microwave spectrum, ranging from 3kHz to 300 GHz. In some embodiments, the internal device may include a battery. The external device may be wearable or carried on the body, or it may be in a nearby ambient environment, such as on a nearby desk or wall. It may be portable or stationary. The device may contain capacitive energy storage module electrodes that stimulate upon discharge. The electronics can be significantly simplified if the electronics are powered to drive the stimulation profile. The capacitor blocks the passage of direct current but allows the passage of alternating current. When the capacitor reaches its dielectric breakdown voltage, it discharges and releases the stimulus pulse.

The implant may also sense tremors directly, such as by using an Electronic Neuroelectrogram (ENG) or Electromyogram (EMG) signal or an accelerometer or a combination of the above. In this case, the implant may comprise a plurality of electrodes, as micro-electrodes and large electrodes are preferred for sensing and stimulation, respectively. The device may also include an outgoing communication channel to communicate the detected event.

Other embodiments for multimodal treatment of urinary and/or gastrointestinal dysfunction

In some embodiments, the multimodal methods 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 disease in WO ng et al, PCT publication WO 2017/132067, which is incorporated herein by reference in its entirety.

In some embodiments, disclosed herein are multi-modal peripheral nerve stimulators for improving conditions, including but not limited to urinary and/or gastrointestinal tract dysfunction. The stimulation may be directed to one, two, three or more nerves associated with bladder function. Nerves may include, for example, the tibial 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, genital dorsal nerve, external anal sphincter nerve, and genital dorsal 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 manner and in a more permanent manner. In some embodiments, the systems and methods include only the transcutaneous member without any implanted and/or transcutaneous components. In some embodiments, the nerve to be stimulated is only a peripheral afferent nerve of the lower limb, not a spinal nerve.

Without being limited by theory, voluntary control of the bladder can be mediated to a large extent by the Autonomic Nervous System (ANS). The ANS maintains balance, which can be important for the proper functioning of the body organs. For example, both the lower abdominal (sympathetic) and pelvic (parasympathetic) nerves carry information about bladder fullness to the brain, and also work together to achieve a relaxation-contraction mechanism that controls urination.

Activation of the transcranial micturition center (PMC) leads to activation of the parasympathetic nerve of the bladder. This in turn causes the muscles in the bladder to contract and the muscles in the urethra to relax. Voiding orders cease when CNS structures, including periaqueductal gray (PAG), receive a signal that the bladder is no longer full.

Inappropriate activation and inhibition of the parasympathetic and sympathetic nervous systems can lead to bladder fullness, urge sensation, sensory discomfort, and/or involuntary urination. Peripheral stimuli affecting autonomic nerve activity may be used to modulate or interrupt the micturition reflex circuit to correct abnormal bladder function. Such modulation may be achieved by multi-modal stimulation of, for example, the saphenous nerve, the tibial nerve, or a combination of both. In some embodiments, the systems and methods use a multi-modal stimulation scheme designed to phase shift, overlay, or obscure an abnormal network. In some embodiments, the systems and methods use a multi-modal stimulation protocol designed to restore the balance of sympathetic and parasympathetic activity of the micturition reflex circuit. Advantageously, certain embodiments utilize multi-modal 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.

In some embodiments, the systems and methods relate to multi-modal stimulation parameters, including frequency and spatial selectivity on the distal limb surface, to selectively or preferentially modulate and balance the sympathetic and parasympathetic nervous systems.

Without being limited by theory, stimulation of a first target nerve (such as the saphenous nerve) may provide sympathetic modulation of the bladder circuit. In particular, stimulation tuned to excite large myelinated fibers in the target nerve (e.g., the saphenous nerve) may provide somatic afferent input to the lumbar plexus, mediating sympathetic input to the bladder circuit via the inferior abdominal nerve. Sympathetic nerves relax the detrusor muscle of the bladder by releasing noradrenaline, thereby activating beta adrenergic receptors, and constrict the intrinsic urethral sphincter by activating alpha adrenergic receptors. Relaxing the bladder and contracting the natural sphincter muscle can provide comfort during the filling and storage phases of the bladder cycle. Stimulation of the second target nerve (e.g., the tibial nerve) may provide parasympathetic modulation of the bladder circuit. In particular, stimulation tuned to stimulate large myelinated fibers in the tibial nerve provides somatic afferent input to the plexus (sacral micturition center) and parasympathetic input to the bladder circuit is mediated by the pelvic nerve via release of cholinergic transmitters. Somatic cell efferents of the pelvic floor may also be afferent to the external urethral sphincter and modulate the afferent sensation of bladder filling. Due to the extensive connection of these loops and the loop-based mechanisms, in some embodiments, all of the above mechanisms can regulate the central cortex and the pons micturition center that coordinates and times the signals.

The system may be run on a series of pre-specified programs that vary stimulation parameters and target one or more nerves individually or in combination to ameliorate the symptoms of overactive bladder in a particular patient, e.g., with the challenge of primarily daytime urgency, nighttime awakening (nocturia), or incontinence and/or gastrointestinal dysfunction. Alternatively, the system may be closed loop over a number of parameters, including: a history of symptoms of the subject, including a nighttime wake event, or a manually entered urination indicated on the device or accessory; direct detection of sympathetic and parasympathetic tone in the bladder or general circuit, including HRV and galvanic skin response; and/or closed loop based on previous use of the device.

In some embodiments, the multi-modal neurostimulation may be synergistically combined with one/two or more drug treatments for overactive bladder, including, but not limited to, anticholinergics (e.g., oxybutynin, tolterodine, trospium, darifenacin, solifenacin, and/or fesoterodine), beta-3 adrenergic drugs (e.g., mirabegron), antispasmodics (e.g., flavoxate), and/or antidepressants (e.g., tricyclic antidepressants such as desipramine or imipramine), hormones (such as estrogen and/or progesterone), or botulinum toxin.

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 excite nerves during some portions of treatment and to inhibit nerves during other portions of treatment.

In some embodiments, waveforms including those described herein may 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 symmetry, pulse interval, duration, on/off time, or burst pattern of stimulation. For example, randomization or pseudo-randomization parameters (e.g., frequency or pulse width) may reduce habituation. Using a gaussian distribution for randomization may be effective in some cases and may be used in waveforms such as random waveforms. Another way to reduce habituation is to lower the frequency below a certain threshold, for example, no more than about 60Hz, 55Hz, 50Hz, 45Hz, or 40Hz, where humans tend not to become habituated.

Varying other parameters such as amplitude may be a way to improve waveform comfort. For example, the amplitude of the stimulation may be adjusted based on the threshold necessary to produce strong sensory perception and paresthesia without causing motor contractions. In some embodiments, the excitation of the muscle may result in an unpleasant spastic sensation. This amplitude can also be adjusted to an appropriate comfort value throughout the phase, depending on the position or motion of the person.

For example, the stimulation waveforms described herein may be applied to a target nerve (such as the tibial nerve and/or the saphenous nerve) continuously, or may be provided in a manner that is adapted to apply stimulation of various durations, or by adjusting characteristics of the stimulation waveform (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 in the system. In some embodiments, the system may include a closed loop control that uses one or more signals measured by the device or feedback input to the device by the patient or physician to adjust the stimulation to improve efficacy. The signals or inputs may include, for example, any number of the following: sensors on the device or connected in the digital ecosystem; using heart rate variability to assess autonomic nerve function, reflex circuit integrity or excitability, measuring Muscle Sympathetic Nerve Activity (MSNA) and/or measuring h-reflex by sending stimulation signals and measuring responses using EMG. In some embodiments, the signals or inputs may also include a sleep sensor group (including but not limited to accelerometers, gyroscopes, infrared-based motion sensors, and/or pressure sensors under the mattress) to measure nocturnal motion as a measure of nocturnal enuresis events. For example, a patient may wear a stimulus while sleeping and night restlessness, which is an indicator of an impending nocturia event, may trigger treatment. A motion sensor group (e.g., accelerometer, IR-based motion sensor, etc.) may measure the rapid back and forth movement of the leg that is typically seen when a person is in a sense of urgency. EEG headstraps can be used to measure different sleep states. The patient and/or physician input may provide feedback to the device or another connected device regarding the effectiveness and/or satisfaction of the treatment. Also, the use of the stimulation device may be tracked; and the particular stimulation pattern (e.g., the specified stimulation parameter set) may be altered based on the symptoms presented by the patient or the outcome of the treatment. Multiple modes may be triggered sequentially and/or simultaneously or overlapping.

In some embodiments, the stimulus may be part of a system with sensors to assess sleep state and adjust the stimulus according to the wearer's sleep state. The sensors may include motion sensors (e.g., body worn 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 sleep state of the wearer. For example, if a nocturia event occurs during slow wave sleep (at which time parasympathetic activity may rise), the stimulation parameters are adjusted to affect parasympathetic activity, and vice versa.

In some embodiments, the multi-modal stimulation may be a first stimulation frequency that may provide for a short-term benefit, and a second stimulation frequency that may provide for a long-term benefit, the second stimulation frequency being different (e.g., higher or lower) than the first stimulation frequency. For example, in some cases, 10Hz stimulation may provide a short term benefit and 20Hz stimulation may provide a long term benefit. As one example, 10Hz stimulation may be provided in an initial period of treatment (e.g., 3 weeks) for acute treatment, whereas 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 nervous system targets and circuits may be used specifically to modulate sympathetic and/or parasympathetic nervous system activity, either upward or downward, depending on the patient's underlying autonomic nervous system activity. Utilization of data and/or sensors (e.g., disclosed elsewhere herein) that directly or indirectly measure sympathetic and/or parasympathetic nervous system activity may be used as closed loop feedback inputs into hardware and/or software controllers to modify stimulation parameters, including on a real-time basis.

In some embodiments, the 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, the patient is treated during the night, such as during sleep and/or during waking hours. Depending on the desired clinical outcome, 1, 2, 3, 4, 5 or more treatments may be repeated daily or weekly, every other day, every third day, weekly, or at other intervals.

In some embodiments, the responsiveness may depend on different times of day. For example, the patient or physician (or algorithm) may schedule different situational treatment sessions throughout the day in advance, and the device may provide treatment stimuli at those different times of the day. In one example, therapy is applied at regular or irregular intervals throughout the day and at a frequency related to typical urine output. In the treatment of nocturia, the stimulation may be timed to regular intervals during the person's sleep. In some embodiments, the stimulation regimen is applied to restore autonomic regulation based on the natural circadian pattern of sympathetic and parasympathetic activity. Treatment may also be performed at irregular intervals, either manually entered or predicted by machine learning from urination events over the previous days. In some embodiments, a first frequency (e.g., 10Hz or 20Hz) therapy may be applied in the morning for acute daytime relief, and a second, different, higher or lower frequency (e.g., 20Hz or 10Hz) therapy may be provided before sleep for longer nighttime relief.

In some embodiments, the responsiveness may be activity dependent. For example, in nocturia, a motion sensor such as an accelerometer or gyroscope may sense whether a person is jogging, which may indicate a desired potential urination. During this time, the device may be turned on to provide the appropriate stimulation. In some embodiments, once urination is complete, the device may be turned off.

In some embodiments, the responsiveness to a stimulus may depend on one, two, or more sensors packaged in the device to collect, store, and analyze biological metrics about the wearer, including, but not limited to, motion (e.g., accelerometer, gyroscope, magnetometer, bending sensor), ground reaction force or foot pressure (e.g., force sensor or pressure insole), muscle activity (e.g., EMG), cardiovascular measurements (e.g., heart rate, HRV), skin conductance (e.g., skin conductance response, galvanic skin response), respiration rate, skin temperature, and sleep state (e.g., awake, light sleep, deep sleep, REM). Using standard statistical analysis techniques (such as logistic regression or na iotave bayes classifiers), these biological metrics can be analyzed to assess the activity state of the wearer, such as sedentary versus activity state, pressure levels, and/or bladder fluid volumes, etc., which in turn can be used as predictors of increased urinary and/or gastrointestinal urgency.

Sympathetic and parasympathetic activity can be measured by several methods, including Microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response. HRV can provide a fast and efficient approximation of autonomic activity in the body. The HRV may be determined by analyzing the time interval between heartbeats (also referred to as the RR interval). For example, heart rate may be accurately captured by a recording device such as a chest strap or finger sensor. The difference between successive RR intervals may provide an image of a person's heart health and autonomic activity. Generally, a healthier heart has greater variability between successive RR intervals. Such heartbeat data may also be used to represent the level of sympathetic and parasympathetic activity of the individual. By frequency domain analysis, the heartbeat frequency can be divided into different frequency bands. The high frequency signal (about 0.15-0.4Hz) may almost completely reflect parasympathetic activity, and the low frequency signal (about 0.04-0.15Hz) may represent a mixture of sympathetic and parasympathetic activity. Thus, obtaining a ratio of a High Frequency (HF) signal to a Low Frequency (LF) signal may yield an approximation of a person's sympathetic tone. In some embodiments, the HRV may be analyzed, for example, under a time domain, geometric domain approach, in addition to a frequency domain approach. In some embodiments, increased heart rate variability may be indicative of increased parasympathetic response and/or decreased sympathetic response. Reduced heart rate variability may be indicative of reduced parasympathetic responses and/or increased sympathetic responses. In some embodiments, the system may sense an increase or decrease in HRV of about or above 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 establish a change in one, two or more stimulation modality parameters accordingly. In some embodiments, one, two, or more stimulation modalities may be configured to modulate (such as increase or decrease) stimulation of one or more nerves (e.g., peripheral nerves) associated with the sympathetic nervous system and/or the parasympathetic nervous system, and may confirm a response to treatment 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 the high frequency content to the low frequency content of HRV. In some embodiments, the balance of parasympathetic and sympathetic nerve activity of the bladder reflex circuit may be assessed by frequency analysis of heart rate variability measured with pulse plethysmography, which utilizes an LED light source and an optical sensor disposed in the device that measures fluctuations in light level due to blood flow for one of the primary blood vessels around the knee, which may include one or more of the following: the femoral, popliteal, tibial, posttibial, anterior tibial and/or knee descending arteries or veins.

In some embodiments, the systems or methods for non-invasively measuring eye muscle movement and/or blink reflex can be used as a biomarker for diagnosis of overactive bladder or other conditions (e.g., a biomarker that can be used to inform disease status diagnosis), monitoring the progress or efficacy of treatment of overactive bladder or other diseases, and/or as a feedback parameter regarding closed-loop adjustment of treatment. Without being limited by theory, the centers involved in voiding control (such as the medial and lateral regions of the center of pontocerebral voiding) are located in the meshwork of the pontocerebral cap and are anatomically close to the regions that control eye muscle movement and/or for coordinating blink reflex. Thus, such biomarkers can be used to assess function integrated in or mediated by a pons structure. For example, an increased blink delay time (such as about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or higher) compared to a reference value may in some cases be associated with a symptom of overactive bladder. In some embodiments, a baseline eye muscle movement parameter, such as blink time, of the patient may be compared to a parameter/time of the patient during or after treatment for comparison. Some embodiments may involve, for example: video eye tracking or blinking (such as via a camera, including a webcam, tablet or smartphone camera, or a wearable device including a camera, e.g., headwear such as a hat, glasses such as modified Google Glass, etc.); electrooculography based on the dipole of the eye; EMG to control blinking head muscles (such as orbicularis oculi and levator palpebrae superioris); systems for causing blinks (such as bright light entering the eye or air puffs) and then measuring the time of the blink using a camera or EMG; and/or measuring blink reflex and recording nerve activity of the orbicularis oculi muscles by an activity stimulating signal (such as applied percutaneously to the supraorbital nerve).

In some embodiments, any form of stimulation as disclosed herein may be used to apply stimulation to one, two, or more acupuncture points. In some embodiments, the acupuncture points 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(bao huang); 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 (Xiaoiaosashu); SP6 (Sanyinjiao); SP9 (yinglingquan); and/or ST28 (Shuidao). In some embodiments, the acupuncture points to be stimulated include BL18, BL23, BL28, and CV 2. 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 acupuncture points to be stimulated include SP6, BL23, BL27, BL28, BL33, and CV 4. In some embodiments, the acupuncture points to be stimulated include SP9, LR1, LR2, CV4, and CV 6. In some embodiments, the acupuncture points to be stimulated include SP6, SP9, BL23, CV3, and CV 6. In some embodiments, the acupoints to be stimulated include SP9 and GB 34. In some embodiments, the acupuncture points to be stimulated include SP9, KI7, KI10, and LR 8. In some embodiments, the acupoint to be stimulated is CV5 alone or BL39 alone, or a combination thereof. Other arrangements of stimulation points are also possible, depending on the desired clinical outcome.

A large source of error in the optical measurement of heart rate is motion artifacts due to relative motion between the optical sensor and the blood vessel under test. In some embodiments, the optical heart rate sensor has an adhesive on one side of the housing in contact with the wearer's skin to reduce relative motion between the sensor and the target blood vessel.

In some embodiments, one, two or more additional sensors are provided in the device, including electrical sensors in contact with the wearer's skin to measure heart activity or pressure sensors for measuring changes in blood vessels, which sensors are used in conjunction with optical sensors to improve the fidelity of heart rate measurements.

In some embodiments, the systems and devices have a memory and a processor to extract RR intervals from sensor data, calculate variability of the RR intervals, transform the data to the frequency domain, and calculate high frequency signals, low frequency signals, and high frequency ratio frequencies and low frequency signals.

In some embodiments, the heart rate sensor may store data collected over a specified period of time to collect sufficient data for a heart rate variability calculation. In some cases, the specified time period may range from 1-60 seconds, and may extend to 10 minutes or more.

In some embodiments, for example, electrodermal activity (also referred to as an electrical skin response or a skin conductance response) may be measured using sensors, such as electrodes. Galvanic skin response is a change in skin resistance caused by emotional stress and can be measured with, for example, a sensitive ammeter. Without being limited by theory, skin resistance varies with the state of sweat glands in the skin. Sweating is controlled by the sympathetic nervous system, and skin conductance may be indicative of psychological or physiological stimuli. If the sympathetic nervous system is highly evoked, sweat gland activity will also increase, which in turn increases skin conductance. In this way, skin conductance may be a measure of emotional and sympathetic responses that may be measured, and feedback data may be sent to a controller, which in turn will adjust stimulation to, for example, reduce sympathetic nervous system activity. Other non-limiting parameters associated with sympathetic and/or parasympathetic nervous system activity that may be sensed include, for example, sweating during specific times of day and/or night, sleep states detected, for example, by EEG headbands (to determine when sympathetic and/or parasympathetic activity is particularly high or low, and possibly to associate sleep states such as

stage

1, 2, 3, 4, or REM with nocturia), and/or exercise. In some embodiments, a diagnostic and/or combined diagnostic/stimulation device may be configured to measure a person's heart rate and galvanic skin response to improve an estimate of the person's autonomic activity. In some embodiments, a wearable device, such as a device worn with a wrist, 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 a single measurement alone. In some embodiments, the system may include multiple sensors to measure electrodermal activity in conjunction with heart rate and HRV. 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, the EDA and HR sensors may be placed in a wrist worn device that communicates with the stimulus via a wired or wireless connection or sends the data to a centralized remote server (e.g., the cloud). Stimulation parameters, neural target locations (e.g., tibial and/or saphenous nerves), or drug delivery regimens (e.g., duration or frequency of stimulation sessions) may be adjusted based on the estimates of sympathetic and/or parasympathetic activity. The adjustment may be made in real time or in a subsequent stimulation phase. In some embodiments, the stimulation frequency may be adjusted to increase or decrease autonomic activity modulated by a particular nerve or nerves. For example, in some embodiments, relatively low frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5Hz)) may potentially inhibit the nerve and thereby reduce sympathetic activity, while higher frequency stimulation (e.g., above a threshold (e.g., about 5Hz)) may potentially excite the nerve and thereby increase sympathetic activity. The same effect 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 5Hz)) may potentially inhibit the nerve and thereby reduce parasympathetic activity, while higher frequency stimulation (e.g., above a threshold (e.g., about 5Hz)) may potentially excite the nerve and thereby increase parasympathetic activity. Without being limited by theory, for example, depending on the stimulation parameters, in some cases, stimulating the target nerve may increase or decrease sympathetic activity, parasympathetic activity, or both. In some embodiments, stimulation of the saphenous nerve may affect sympathetic nerve activity, and stimulation of the tibial nerve may affect parasympathetic nerve activity.

The multimodal device may also react to the number of symptom episodes, including overactive bladder. If more episodes occur in a day, the treatment may be increased, for example, by increasing the amplitude of the stimulation, the duration of the stimulation, or the number of treatment sessions.

The number of episodes of a symptom (such as overactive bladder) can be detected in a variety of ways to control the stimulation applied by the system and device. In some embodiments, the patient may enter an event on the mobile device related to a symptom of overactive bladder, including but not limited to a bladder micturition event, an urgency event, or a urinary incontinence event. In some embodiments, a location service (such as GPS) on the device can detect when a person enters a building or bathroom.

In some embodiments, disclosed herein are multi-modal wearable systems and methods that can utilize transcutaneous sensory stimulation in burst mode (e.g., theta burst mode) 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 disease (e.g., crohn's disease)). Non-invasive peripheral nerve theta burst stimulation is effective in promoting cortical or spinal cord plasticity to reduce symptoms and improve the quality of life of an individual.

In some embodiments, the multi-modal stimulation involves patterns of electromagnetic stimulation of peripheral nerves. The patterned stimulus may be a burst stimulus, such as an on/off pattern that repeats at regular intervals (e.g., 10ms on, 20ms off, etc.), or may be a more complex non-burst patterned stimulus in some embodiments, such as a random pattern or sinusoidal envelope. The electromagnetic stimulus may include, for example, electrical energy, mechanical energy (e.g., vibration), magnetic energy, ultrasonic energy (e.g., focused ultrasound), radio frequency energy, thermal energy, optical energy (e.g., such as infrared or ultraviolet energy), and/or microwave energy, or a combination thereof. In some embodiments, stimulation is limited to electrical energy or electrical and mechanical energy (e.g., no magnetic or other type of energy is applied). The peripheral stimulation may include transcutaneous, transdermal and/or implanted stimulation.

In some embodiments, multimodal stimulation involves non-invasive percutaneous patterned or burst stimulation of peripheral nerves, including afferent and/or efferent nerves. Without being limited by theory, burst stimulation of peripheral nerves may unexpectedly result in one or more of the following, as compared to conventional or continuous stimulation: greater efficacy; greater plasticity; increased tolerance or tolerance; reduced habituation effects; increased comfort; and/or reduced treatment time required to achieve the same beneficial effect. In some cases, a sudden stimulation of peripheral nerves including afferent nerves can deliver a 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, creating plasticity in the neural circuits for a period of time that is much longer than the duration of the stimulation phase, e.g., about 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 stimulation and/or spinal stimulation), and may be more suitable for home and non-hospitalized use.

In some embodiments, the burst stimulus comprises a theta burst stimulus. The Theta Burst Stimulation (TBS) is a patterned form of repetitive stimulation that uses high frequency pulses separated by varying burst intervals. The onset of long-term potentiation, originally used for hippocampal learning and memory studies, theta burst stimulation in the form of repetitive magnetic stimulation (rTMS) has been shown to non-invasively induce plasticity in humans in the motor, sensory and visual cortex. Depending on various parameters, including duration and continuity of stimulation, a long-term potentiation or inhibition (LTP/LTD) effect can be observed, which is a surrogate measure of synaptic efficacy. The number of phases of stimulation and the interval between individual phases may also have an effect on the duration of the induced response. The level of muscle relaxation before or during stimulation may also affect the direction or magnitude of the result caused by plasticity, indicating the presence of homeostatic mechanisms that adjust the plasticity threshold depending on previous synaptic activity. Effective modulation of nervous system plasticity as demonstrated by theta burst stimulation may have great potential in treating various nervous system diseases, and may have effects on other central nervous circuits.

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

In some embodiments, each burst may include a plurality of stimuli, such as about 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.

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

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

In some embodiments, the inter-stage frequency can 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 that combines any two of the above.

In some embodiments, a repetitive patterned stimulation, referred to as a four-pulse stimulation, may be used, which includes four pulses at a short interval frequency (1.5 ms interval between excitations) repeated at about 0.2Hz for a certain period of time, such as about 30 minutes. Four-pulse stimulation has been shown to induce prolonged plasticity. Changes in frequency within a burst using this example may affect the direction of the induced plasticity. These repeated small pulses can be anywhere between 2-10 pulses or more.

Alternatively or additionally, other burst modes other than theta burst stimulation may also be used. Some non-limiting examples include delta (0-4Hz), alpha (8-12Hz), beta (12-30Hz), and gamma (30-100Hz) inter-burst frequencies. In some embodiments, the peripheral burst stimulation may include a sinusoidal, square, rectangular, triangular, saw tooth, or other waveform.

In some embodiments, disclosed herein is a multimodal method of treating urinary and/or gastrointestinal symptoms in a patient by 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 skin of a patient to stimulate a saphenous nerve of the patient; positioning a second peripherical nerve effector on the skin of the patient to stimulate a posterior tibial nerve of the patient; delivering a first neural stimulation signal transcutaneously to a saphenous nerve through a first peripheral nerve effector; delivering a second nerve stimulation signal percutaneously to the tibial nerve through a second peripheral nerve effector; receiving an input related to autonomic nervous system activity of a patient; and modifying at least one brain or spinal cord autonomic feedback loop related to bladder function based on the input to balance parasympathetic and sympathetic nervous system activity of the patient. In some embodiments, the methods do not utilize any implantable components and involve only transcutaneous stimulation. Both the first and second peripheral nerve effectors may be located near a knee of the patient. The first stimulation signal may be different from the second stimulation signal including, but not limited to, different types of energy, stimulation parameters, burst patterns, waveform shapes, and the like. The first stimulation signal may have a first frequency that is different from a second frequency of the second stimulation signal. The first stimulation signal may have a different amplitude than the second stimulation signal. The first frequency or the second frequency may be, for example, from about 10Hz to about 20 Hz. The first frequency or the second frequency may be, for example, from about 5Hz 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 a sensor measuring autonomic nervous system activity of a patient; receiving data from a sensor measuring heart rate variability of a patient; receiving heart rate variability data from an optical sensor measuring blood flow characteristics and disposed near a blood vessel near a knee of a patient; receiving data from a sensor measuring a patient's galvanic skin response; receiving data relating to urinary and/or gastrointestinal symptoms of a patient; and/or receiving data relating to the onset of nocturia in the patient.

Also disclosed herein is a multi-modal wearable device for dual stimulation of the saphenous nerve and the posterior tibial nerve and for treating urinary and/or gastrointestinal symptoms in a patient. In some embodiments, the device may include any number of the following features: a controller; a first peripheral nerve effector configured to transcutaneously modulate a saphenous nerve; a second peripheral nerve effector configured to transcutaneously modulate a 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 a memory for receiving feedback information from the sensor, the feedback information, when executed by the processor, causing 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 delivering a first stimulus to the saphenous nerve through a first peripheral nerve effector and delivering a second stimulus to the posterior tibial nerve through a second peripheral nerve effector to reduce urinary and/or gastrointestinal symptoms by modifying 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 within a patient. The feedback information may include real-time feedback information. The first stimulus may have a frequency of, for example, between about 10Hz and about 20 Hz. The second stimulus may have a frequency of, for example, between about 5Hz and about 30 Hz. The feedback information may include autonomic nervous system activity of the patient. The feedback information may include heart rate variability. The feedback information may also include information related to the patient's nocturia events. The feedback information may also include information related to the sleep state of the patient.

Additional embodiments of multimodal treatment of cardiac dysfunction

In some embodiments, the multimodal methods may involve restoring 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 dysrhythmias. 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 heart disease in PCT publication WO2018/039458 to Hamner et al, which is incorporated by reference herein in its entirety.

Imbalances in autonomic activity can lead to certain heart diseases, such as hypertension and cardiac arrhythmias; this is an imbalance of sympathetic and parasympathetic activity within the autonomic nervous system. This imbalance may be due to over-or under-activation 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 diseases.

Autonomic nerve activity has been shown to be a significant cause of cardiac dysrhythmia. Human skin is well innervated by autonomic nerves, and neural or meridian stimulation as disclosed herein can potentially help treat cardiac arrhythmias. For example, afferent nerves in the peripheral or distal limb (including but not limited to the median nerve) are connected to the arcuate nucleus of the hypothalamus by neural circuits. Without being limited by theory, modulation of the arcuate nucleus reduces elevated sympathetic outflow through either or both of the following pathways: descending entry from the pituitary into the neuroendocrine or hormonal system, and descending entry to the ventral lateral medullary head (RVLM) via the pallor nuclei of the periencephalic grey matter and medulla oblongata in the ventral lateral middle aqueducts. This pathway may be via cholinergic mu receptors.

Alternatively or in addition, stimulation of peripheral skin fibers of the arm, leg, neck, or tragus can modulate stellate ganglion activity at the level of spinal cord C8-T1 to reduce elevated sympathetic outflow and/or increase vagal tone via the carotid sinus nerves. The peripheral nerves that can be accommodated include the musculocutaneous nerve (innervated at C5-C7), the radial nerve (innervated at C5-T1), the median nerve (innervated at C5-T1), the ulnar nerve (innervated at C8-T1), and the medial cutaneous nerve (innervated at C8-T1). The medulla oblongata is operatively connected to the vagus nerve, which has parasympathetic effects in, for example, the SA and AV nodes of the heart. The cervical ganglion is the paraspinal ganglion of the sympathetic nervous system. The preganglionic nerve from the thoracic spinal cord may enter the cervical ganglia and synapses with their postganglionic fibers or nerves. The cervical ganglion has three paraspinal ganglia: the upper cervical ganglion adjacent to C2 and C3; postganglionic axons protrude to target: (heart, head, neck) via access adjacent the carotid artery; the middle cervical ganglion (minimum) -adjacent to C6; for the heart and neck; and the cervical ganglia. The lower ganglion may fuse with the first thoracic ganglion to form a single structure, the stellate ganglion — adjacent to C7; for the heart, lower neck, arms, posterior cranial arteries. For example, nerves emerging from the cervical sympathetic ganglion contribute to the cardiac plexus. The stellate ganglion (or cervicothoracic ganglion) is the sympathetic ganglion formed by the fusion of the lower cervical ganglion and the first thoracic ganglion. The thoracic visceral ganglia (pectoral pulmonary nerves, major, minor and minor visceral nerves) emerge from the thoracic ganglia and help provide sympathetic innervation to the abdominal structures.

Alternatively or additionally, and without being limited by theory, multi-modal stimulation may invoke neurohormonal responses through muscle fascia or skin stimulation of the upper and lower limb finger pressure points (such as Ht7, Pc6, Gb34, Sp6, Ki6, etc.). The neurohormonal response may include a change (increase or decrease) in the production of norepinephrine, epinephrine, acetylcholine, and/or inflammatory cytokines. Inflammatory cytokines may include interleukins, high mobility group proteins B1 and/or tumor necrosis factor alpha. Neurohormonal responses may also be caused by afferent and/or efferent neural stimulation of the median, radial, ulnar or vagus nerves, cutaneous nerves or sympathetic nerves. In one embodiment, after treatment with the device disclosed herein, one or more of norepinephrine, epinephrine, acetylcholine, and/or inflammatory cytokine is reduced by at least about 5%, 10-20%, 20-40%, 40-60%, or more (including overlapping ranges) as compared to pre-treatment.

Alternatively or additionally, but not limited by theory, retrograde stimulation of autonomic or visceral efferent fibers in the arm, leg, neck or tragus may modulate sympathetic outflow and/or modulate vagal tone. Specifically, by targeting the c-fibers around the body, sympathetic efferents can be specifically stimulated.

Alternatively or additionally, and without being limited by theory, multi-modal stimulation of somatic, autonomic, afferent, and/or efferent peripheral nerves can reduce sporadic electrical activity of the pulmonary veins that trigger and sustain cardiac dysrhythmia.

Some embodiments relate to multimodal devices and systems that provide peripheral nerve stimulation for individual nerves. Some embodiments relate to devices and systems that allow customization and optimization of therapy for an individual. In particular, the device may be configured for multimodal stimulation of the median nerve, radial nerve, ulnar nerve, or, peroneal nerve, saphenous nerve, tibial nerve, and/or other nerves or channels and collaterals accessible on the limb for treating cardiac arrhythmias, including but not limited to atrial fibrillation (chronic such as or paroxysmal atrial fibrillation) and other arrhythmias, and/or reducing cardiac dyssynchrony and/or hypertension. Other non-limiting examples of cardiac arrhythmias that may be treated using the systems and methods disclosed herein may include: for example, long QT syndrome, torsade de pointes ventricular velocity, atrial premature beats, migratory atrial pacing points, multifocal atrial tachycardia, atrial flutter, supraventricular tachycardia (including PSVT), atrioventricular nodal reentrant tachycardia, junctional zone heart rhythm, junctional zone tachycardia, junctional extra-systolic contraction, premature ventricular contraction, accelerated ventricular autonomic rhythm, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia and ventricular fibrillation. The use of appropriately tailored stimulation for those particular nerves results in a more effective treatment (e.g., reduced arrhythmia episodes, such as fibrillation or fibrillation episodes and/or shorter durations of fibrillation episodes, reduced feelings of palpitations/arrhythmias, improved rate control of arrhythmias such as about or at least about 10%, 20%, 30%, 40% or more reduction of heart rate compared to pre-treatment (with or without cessation of arrhythmia), prevention or reduction of the incidence of embolic events associated with atrial fibrillation, such as stroke, and/or modulation, e.g., reduction of systolic, diastolic, 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 drug or 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 cardiac arrhythmia after ablative surgery. In some embodiments, treatment may reduce or eliminate the amount, dose, and/or frequency of medications that a patient may need to take for their potential arrhythmia, thereby advantageously reducing side effects/potential toxicity. In some embodiments, the treatment can have an unexpected synergistic effect when combined with one, two, or more pharmacological agents, such as a rate control agent (e.g., a beta receptor blocker such as atenolol, metoprolol, propranolol, carvedilol; a calcium channel blocker such as nifedipine, amlodipine, diltiazem, or verapamil, or a cardiac glycoside such as digoxin), and/or an antiarrhythmic agent (e.g., quinidine, procainamide, propranamide, lidocaine, mexiletine, flecainide, propafenone, sotalol, ibutilide, dofetilide, amiodarone, or dronedarone). In some embodiments, a cardiac glycoside such as digoxin may be administered orally, intravenously, or by another route, along with a peripheral nerve stimulation protocol such as described herein, to have an unexpected synergistic beneficial effect in treating cardiac arrhythmias, cardiac dyssynchrony, and/or hypertension. Without being limited by theory, digitonin and cardiac glycosides (also sometimes referred to as digoxin or desacetyleriocitrin) can modulate arterial baroreflex mechanisms in humans. Attenuation of the baroreceptor reflex can lead to continuous and excessive sympathetic nerve activity, which in turn can lead to an increase in heart rhythm, blood pressure, and the initiation and maintenance of cardiac arrhythmias. Aberrant baroreceptor function may be associated with elevated activation of the sodium potassium ATPase pump; the effect of digitonin and cardiac glycosides is to reduce this elevated activation, resulting in increased sensitivity of baroreceptors, including sensitivity to stimuli. Thus, multi-modal stimulation of peripheral nerves that regulate baroreceptors (e.g., the median biblical, neural, ulnar, or skin fibers of the arm) can have an unexpected synergistic effect with digitoxin and cardiac glycosides, thereby inhibiting elevated sympathetic activity; the glycoside increases the sensitivity of the baroreceptor reflex and stimulates activation of the baroreceptor reflex. This synergy can be advantageous by reducing the glycoside dose required to treat cardiac dysfunction (such as hypertension or cardiac arrhythmias), since digoxin is very narrow in therapeutic index and produces severe toxic effects at plasma concentrations only twice as high as the therapeutic plasma concentration range. In some embodiments, the dose of cardiac glycoside, such as digoxin, administered to the patient may be much smaller than conventionally prescribed, such as about or less than 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 0.2mcg/kg per day. In some embodiments, the dose of cardiac glycoside may be titrated to less than a therapeutic blood level, e.g., about or less than 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., a tablet) of about or less than about 250mcg, 125mcg, 62.5mcg, 31.25mcg, 16mcg, 8mcg, 4mcg, 2mcg, 1mcg, or less.

In some embodiments, disclosed herein are multimodal device systems and methods for stimulating a plurality of nerves to treat cardiac dysfunction. 2. Stimulation of 3 or more nerves or flaps (such as the median nerve, median cutaneous nerve, radial nerve, and/or ulnar nerve) may be used to treat conditions such as cardiac arrhythmias. In some cases, bichannel stimulation can synergistically enhance therapeutic efficacy through action on the brachial plexus (the 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 located at a distance from the brachial plexus (including, but not limited to, the median nerve, radial nerve, ulnar nerve, or median cutaneous nerve) at two different times, wherein, ultimately, the brachial plexus is stimulated substantially simultaneously (e.g., less than about 2ms, 1ms, 0.5ms, 0.4ms, 0.3ms, 0.2ms, 0.1ms, 0.09ms, 0.08ms, 0.07ms, 0.06ms, 0.05ms, 0.04ms, 0.03ms, 0.02ms, 0.01ms, or less) by two signals from two or more nerves, but may be higher in some cases. In one embodiment, the two nerves are offset (in terms of timing of stimulation) by 0.1-3.0 ms. In one embodiment, two, three, four or more nerves located at a distance from the target (including but not limited to the brachial plexus) are stimulated at different times so as to hit the target substantially simultaneously. In some embodiments, the system may be configured to independently control stimulation of the first and second target nerves (including stimulation parameters such as frequency and other parameters listed herein), respectively. In other words, the first target nerve and the second target nerve may be stimulated with the same or different parameters, and the first target nerve and the second target nerve may be stimulated simultaneously or in an alternating or other manner. In some embodiments, the stimulation system may include a plurality of individual stimulation circuits, or a common circuit having a controller configured to switch stimulation parameters of one, two, or more nerves.

Embodiments of the invention may include apparatuses and systems and methods for: measuring and collecting biological data (e.g., heart rate variability, ECG, galvanic skin response, temperature, and blood pressure), analyzing the data to interpret how these metrics affect heart rhythm and/or blood pressure, and providing peripheral nerve stimulation to one or more nerves (such as the median nerve, the ulnar nerve, and/or the 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 measured data.

In some embodiments, the multimodal systems and methods may include a monitor unit, which may be a wearable monitor having a housing with a user interface. The housing may use a plurality of sensors to collect, store and analyze biometric metrics of the wearer, including but not limited to: blood pressure, motion (e.g., accelerometer, gyroscope, magnetometer, bending sensor), muscle activity (e.g., EMG using electrodes), cardiovascular rhythm metrics (e.g., heart rate variability, or using electrodes to measure ECG, abnormal ventricular and/or atrial dyssynchrony with heart rhythm), skin conductance (e.g., skin conductance response, galvanic skin response, using electrodes), respiration rate, skin temperature, pupil diameter, and sleep state (e.g., awake, light sleep, deep sleep, REM). The cardiac rhythm metric may be recorded by optical, electrical and/or accelerometer based sensors. In particular, studies have shown that elevated pressure levels can increase blood pressure. Activities such as exercise may also affect heart rate and/or rhythm, and/or blood pressure — measuring acceleration (motion), heart rate, etc. may help to identify these activities and normalize the measurements by similar activities. Furthermore, hypertension is associated with heart failure-measuring ventricular dyssynchrony via ECG sensors can help identify the effectiveness of stimulation to reduce hypertension over the long term. Thus, using standard statistical analysis, machine learning, deep learning, or big data techniques (such as logistic regression or na iotave bayes classifiers), these biological metrics can be analyzed to assess a person's state (such as stress level), which in turn can serve as a predictor of cardiac arrhythmia, cardiac dyssynchrony, and/or an increase in blood pressure. In some embodiments, the device may provide stimulation based on measurements of one or more biological metrics, a determination of a human state, and/or a prediction of cardiac dysrhythmia, cardiac dyssynchrony, and/or blood pressure changes.

In some embodiments, the responsiveness may be activity dependent. For example, in arrhythmias that may be exacerbated by motion, for example, a motion sensor such as an accelerometer or gyroscope may sense whether a person is exercising. During this time, the device may be turned on to provide the appropriate stimulation. In some embodiments, once the activity is complete, the device may shut down. In some embodiments, the sensor may activate the stimulation during periods of inactivity (e.g., when the subject is sleeping).

In some embodiments, the responsive capability of the stimulus may depend on one, two, or more sensors packaged in the device to collect, store, and analyze biological metrics about the wearer, including, but not limited to, motion (e.g., accelerometer, gyroscope, magnetometer, bending sensor), ground reaction force or foot pressure (e.g., force sensor or pressure insole), muscle activity (e.g., EMG), cardiovascular measurements (e.g., Heart Rate Variability (HRV), photoplethysmography (PPG), or ventricular and/or atrial dyssynchrony using electrodes to measure ECG and/or arrhythmia), skin conductance (e.g., skin conductance response), respiration rate, skin temperature, pupil diameter, and sleep state (e.g., awake, light sleep, deep sleep, REM). 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 classifier) to assess the activity state of the wearer (such as sedentary versus active, stress level, etc.), which in turn can be used as predictors of changes in blood pressure, cardiac arrhythmias, or cardiac dyssynchrony.

Sympathetic and parasympathetic activity can be measured by several methods, including Microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response, as described elsewhere herein.

HRV measurements of patients with cardiovascular disease may differ significantly compared to controls. By frequency domain analysis, the heartbeat frequency can be divided into different frequency bands. The high frequency signal (between about 0.15Hz and about 0.4 Hz) may almost completely reflect parasympathetic activity, and the low frequency signal (between about 0.04Hz and about 0.15 Hz) may represent a mixture of sympathetic and parasympathetic activity. In some embodiments, obtaining a ratio of a High Frequency (HF) signal to a Low Frequency (LF) signal produces an approximation of a person's sympathetic tone. Very Low Frequency (VLF) signals (between about 0.004Hz and about 0.040 Hz) can also be evaluated to assess parasympathetic activity. The total power of the HRV in the frequency domain may also be evaluated to evaluate autonomous activity.

Sympathetic and parasympathetic function can also be assessed by, for example, analyzing the average normal-normal interval, e.g., all intervals between adjacent QRS complexes of the measured heart rhythm, including interval differences of consecutive NN intervals of greater than 50 milliseconds; the square root of the mean square error of consecutive NN intervals and the standard deviation of the NN intervals.

In some embodiments, sympathetic activity may also be assessed using more traditional techniques: such as measuring blood pressure changes before release and before beginning a grip exercise, 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 response during deep breathing or when standing from a lying or sitting position (upright position) or by changing the orientation of the human body using a tilting table. Both sympathetic and parasympathetic activity can be assessed during a watt's maneuver (e.g., insufflating a mercury manometer and maintaining a pressure of about or at least about 40 mmHg), or an orthostatic cardiac rhythm response (e.g., standing from a lying or sitting position).

In some embodiments, one, two or more additional sensors are provided in the device, including electrical and/or accelerometer sensors that contact the wearer's skin to measure heart activity or pressure sensors for measuring vascular changes, which sensors are used in conjunction with optical sensors to improve the fidelity of heart rate measurements.

In some embodiments, the systems and devices have a memory and a processor to extract RR intervals from sensor data, calculate variability of the RR intervals, transform the data to a frequency domain, and calculate high frequency signals, low frequency signals, and ratios of the high frequency signals and the low frequency signals. In some embodiments, the system may store cardiac events such as arrhythmias, tachycardia, bradycardia, and the like.

In some embodiments, for example, as disclosed elsewhere herein, electrodermal activity (also referred to as an electrical skin response or a skin conductance response) may be measured. In some embodiments, significant changes in sympathetic and/or parasympathetic activity may be used to predict the onset of ventricular and/or atrial dyssynchrony or abnormal heart rhythm, and the device may begin stimulation to prevent or reduce the duration of the dyssynchrony event. The adjustment may be made in real time or in a subsequent stimulation phase. In some embodiments, the stimulation frequency may be adjusted to increase or decrease autonomic activity modulated by a particular nerve or nerves. For example, in some embodiments, relatively low frequency stimulation of the target nerve (e.g., below a threshold (e.g., about 5Hz)) may potentially inhibit the nerve and thereby reduce sympathetic activity, while higher frequency stimulation (e.g., above a threshold (e.g., about 5Hz)) may potentially excite the nerve and thereby increase sympathetic activity. In addition, 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 effect 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 5Hz)) may potentially inhibit the nerve and thereby reduce parasympathetic activity, while higher frequency stimulation (e.g., above a threshold (e.g., about 5Hz)) may potentially excite the nerve and thereby increase parasympathetic activity. Without being limited by theory, for example, depending on the stimulation parameters, in some cases, stimulating the target nerve may increase or decrease sympathetic activity, parasympathetic activity, or both. In some embodiments, stimulation of the saphenous nerve may affect sympathetic nerve activity, and stimulation of the tibial nerve may affect parasympathetic nerve activity.

Without being limited by theory, the simultaneous firing of vagal and sympathetic activities may trigger some arrhythmias, including atrial fibrillation, which leads to an imbalance in the two arms of the autonomic nervous system. In some embodiments, the systems and methods may include using measurements of heart rate variability/galvanic skin response and arrhythmia (e.g., atrial fibrillation) events to assess sympathetic balance to determine the likelihood of response to peripheral stimulation. For example, a device may be worn on the wrist that incorporates sensors for measuring heart rate (such as optical-based sensors) and/or sensors and stimulation devices that measure galvanic skin response to assess sympathetic fan balance and detect arrhythmias (e.g., atrial fibrillation events). The device may measure HRV and/or GSR and detect atrial fibrillation events over a specified period of time, 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 walking balance and the detection of arrhythmic events. In some embodiments, stimulation of one, two, or more nerves in the upper and/or lower extremities may be combined with stimulation of the ear branches of the vagus nerve (such as through the tragus) to modulate vagal nerve activity and restore balance of the autonomic nervous system.

In some embodiments, the multimodal system may include multiple stimuli that wirelessly communicate with each other and provide synchronized patterned stimulation. In some embodiments, multiple stimulators may be connected with multiple effectors to stimulate multiple nerves simultaneously. In one embodiment, a system may include a stimulus on a wrist for a median nerve and a stimulus in an ear for an ear branch of a vagus nerve. Each stimulus in the system may communicate with each other via a wired or wireless connection. Multiple stimuli may provide synchronized stimulation to multiple nerves. The stimulation may be, for example, bursts, shifts or alternates between multiple nerves.

In some cases, the device may also respond to the onset of a variety of symptoms, including chest pain, dyspnea, dizziness, and/or palpitations, which indicate the presence of an arrhythmia, cardiac dyssynchrony, and/or blood pressure abnormalities. If more episodes occur in a day, the treatment may be increased, for example, by increasing the amplitude of the stimulation, the duration of the stimulation, or the number of treatment sessions.

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

One embodiment of the system may centrally store the biological metrics from multiple wearers on a server system (e.g., the cloud) along with other relevant demographic data about each user, including age, weight, height, gender, race, etc. Data collected from multiple wearers may be analyzed using standard statistical analysis, machine learning, deep learning, or big data techniques, such as logistic regression or naive bayes classifiers (or other classifiers), to improve the prediction of cardiac arrhythmia, cardiac dyssynchrony, blood pressure, or blood pressure changes by determining correlations between biological metrics and other recorded events and cardiac arrhythmia, cardiac dyssynchrony, and/or increased blood pressure. These correlations may be used to set parameters of the stimulation waveform applied by the therapy unit, determine an optimal time to apply the stimulation therapy, and/or adjust the stimulation waveform applied by the therapy unit in real-time.

In some embodiments, the wearable monitor may have visual, audible, tactile (e.g., squeezing a belt), or vibrotactile cues to notify the wearer of critical events based on analysis of biological metrics, including but not limited to predicting cardiac arrhythmia, cardiac dyssynchrony, prediction of blood pressure or increased blood pressure, and/or an increase in stress level, heart rate variability, or other parameters. The reminder system may also notify the wearer of other predetermined events or reminders set by the wearer. The reminder system is used to convey information (such as the presence of cardiac arrhythmias such as atrial fibrillation, hypertension, or other predetermined events) to the wearer in a more discreet, personalized manner without drawing the attention of others in the social setting.

In some embodiments, the wearable monitor and/or therapy unit may be in the form of a wrist or watch, ring, glove, arm or arm band or cuff, knee band, sock, leg sleeve or cuff, ear plug/earpiece, head band, necklace or neck band, or a compatible patch that conforms to multiple locations on the body.

In some embodiments, a particular fiber type within one or more nerves can be selectively or preferentially activated (e.g., an action potential is generated in such particular fiber type) to restore autonomic balance by specifically modulating the sympathetic and parasympathetic limbs of the autonomic nervous system (e.g., selectively or preferentially modulating only one or more of the a- α, a- β, a- δ, B, and/or C fibers). In some embodiments, the systems and methods do not stimulate or substantially stimulate A-alpha, A-beta, A-delta, B fibers, or C fibers.

Without being limited by theory, stimulation of superficial and/or cutaneous afferents and/or afferents may prevent arrhythmias by inhibiting the nucleus solitary tract and the vagus nerve nucleus, inhibiting the aortic hypotensive nerve and thereby inhibiting parasympathetic input; stimulation of the deep afferent and/or efferent nerves can prevent arrhythmias by stimulating the peri-arcual nuchal-ventral aqueduct grey nuclear suture pathway, thereby inhibiting medullary cephalic-ventral lateral (rVLM) and thereby inhibiting sympathetic input. Superficial fibers are relatively thin (e.g., small diameter) afferent nerves that convey sensory information to the superficial dorsal horn, which is a distinct region of the dorsal horn and gray matter; deeper fibers are thicker (e.g., larger diameter) afferent nerves that convey sensory information to the deep dorsal horn.

Some embodiments may include preferential stimulation of skin fibers (e.g., A-alpha, A-beta, A-delta, and/or C) to inhibit sympathetic nerve activity via the stellate ganglion. At the wrist, stimulation of selected skin fibers can carry sensory information through the medial cutaneous nerve and the medial cord of the brachial plexus, which innervates the spinal cord at the level of C8-T1; stimulation in turn modulates cardiac sympathetic nerve activity through the stellate or cervicothoracic ganglion, which is a collection of sympathetic nerves at the C7-T1 level. In some embodiments, the peripheral nerve effector may be located on the patient's skin, such as on the medial forearm, for example, to stimulate the median cutaneous nerve, but not or substantially not, or at least preferentially, the median/radial or ulnar nerve. In some embodiments, the lateral cutaneous nerves and/or the musculocutaneous nerves, or specific fibers thereof, may be stimulated preferentially or specifically. In some embodiments, only one type of nerve fiber is activated, while the other type of nerve fiber is not activated. For example, in one embodiment, only a- α fibers are activated, but B fibers are not activated. In one embodiment, 1-5 types of fibers are activated, while one or more fiber types are inactivated (or functionally unstimulated). In some embodiments, the deactivated fibers do not discharge or carry an action potential. In some embodiments, one or more of the 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 is 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 the same nerve and/or other peripheral nerves adjacent to the target peripheral nerve.

Selective or preferential activation of various nerve fiber types can be accomplished in a variety of ways. In some embodiments, a stimulation parameter of the biphasic square wave, such as pulse width, may be controlled to selectively or preferentially activate particular fiber types (e.g., without activating other fiber types). For example, a pulse width of about 50-100 μ s may selectively or preferentially stimulate larger A- α fibers; pulse widths of about 150-; and a pulse width of about 300-.

In some embodiments, the frequency of the sinusoidal wave pattern may be controlled to selectively or preferentially activate particular fiber types. For example, frequencies of about 2000Hz, about 250Hz, and about 5Hz may selectively or preferentially activate the A- β, A- δ, and C afferent fibers, respectively.

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

Some embodiments may involve one or more multi-modal stimulation patterns (e.g., burst, pulse pattern, random, pseudo-random, or noise) to improve the efficiency and efficacy of stimulation. In some embodiments, the stimulation may be provided in a burst mode, where 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 (0.01-0.1Hz) with higher frequency stimulation (1-200Hz) or lower frequencies (1-200Hz) with very high frequencies (1000-10 kHz).

In some embodiments, disclosed herein are wearable systems and methods that may utilize transcutaneous sensory stimulation in the form of burst patterns, e.g., theta burst patterns, to ameliorate cardiac arrhythmias, cardiac dyssynchrony, hypertension, and/or a variety of other conditions, including but not limited to those disclosed herein. In some cases, non-invasive peripheral nerve theta burst stimulation may promote cortical or spinal cord plasticity more effectively than continuous stimulation to reduce symptoms and improve the quality of life of the individual. Additional details regarding non-limiting burst parameters are disclosed elsewhere herein.

In some embodiments, multimodal stimulation involves non-invasive percutaneous patterned or burst stimulation of peripheral nerves (including afferent and/or efferent nerves), as described elsewhere herein.

Without being limited 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 through the stellate ganglion of the brachial plexus to inhibit sympathetic activity or modulate vagal tone through the carotid sinus nerve.

In some embodiments, median, radial and/or ulnar nerve stimulation may be combined for synergistic effects at the brachial plexus. The median, radial and ulnar nerves innervate the different levels of the spinal cord at the brachial plexus with access to different target locations and organs. Some embodiments may provide timed stimulation to the median, radial and/or ulnar nerves simultaneously or with delay to control targeting within the brachial plexus to provide a synergistic effect of nerve activation at the brachial plexus, which leads to the stellate ganglion and sympathetic nerve chain. This synergy may provide greater therapeutic benefit with less discomfort and less current (e.g., less power to extend battery life). The timing of stimulation may be synchronized, or have a delay, to account for differences in conduction velocity of different nerves, so that signals arrive at the brachial plexus simultaneously. Without being limited by theory, simultaneous or near-simultaneous activation of the brachial plexus may enhance stimulation to the stellate ganglion through the pathway and increase the effect (e.g., inhibition) of the sympathetic nervous system. For example, the mean conduction velocities of the sensory nerves of the radial, median and ulnar nerves are about 51, 60 and 63m/s, respectively. Based on the change in nerve length from the wrist to the brachial plexus (from 1% in women to 99% in men), this requires a stimulation delay between the median and radial nerves of about 1.3 to about 1.7 milliseconds, a stimulation delay between the median and ulnar nerves of about 0.3 to about 0.4 milliseconds, and a stimulation delay between the radial and ulnar nerves of about 1.6 milliseconds and about 2.1 milliseconds. In some embodiments, the stimulation delay between the first nerve and the second nerve may be between about 0.3ms and about 1.7ms, or between about 0.2ms and about 2.0ms, between about 1.2ms and about 2.1ms, or between about 1ms and about 2 ms. Lower threshold stimulation on the median, radial and/or ulnar nerve may advantageously require lower threshold stimulation on individual nerves, resulting in synergy on the brachial plexus. In some embodiments, the system can include nerve conduction velocity measurement (which measures nerve conduction velocity of the individual by applying a stimulation source at a distal portion of the nerve and a measurement electrode at a proximal portion of the nerve), and modify the timing delay based on the individualized measurements.

In some embodiments, the system may include a peripheral nerve effector configuration to stimulate a nerve (e.g., the radial, median, and/or ulnar nerves) in an alternating pattern that may be rhythmic or pseudo-random. For a rhythmic alternating pattern, the alternating frequency may be in the range of 1-100Hz, which may improve the therapeutic efficacy by promoting plasticity in the corticospinal circuit. In some embodiments, device embodiments may include an effector configuration for stimulation of an alternating nerve (e.g., radial, median, and/or ulnar nerves) and adjusting stimulation parameters (e.g., stimulation frequency, alternating frequency, stimulation duration, stimulation time of day, pulse width, amplitude, duty cycle, phase, waveform shape, waveform symmetry, pulse interval, on/off time, or burst) based on an assessment of autonomic balance, e.g., by measuring Heart Rate Variability (HRV) and analyzing sympathetic nerve balance, such as a ratio of absolute Low Frequency (LF) to absolute High Frequency (HF) power or measuring LF/HF of HRV, as described elsewhere herein.

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

In some embodiments, a multimodal wearable system for treating arrhythmia or hypertension is also disclosed herein. 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 a patient's skin of a patient's limb; a second peripherical nerve effector configured to be positioned on a tragus of an ear or vagus nerve of the ear of the patient (e.g., via a cymba concha); and/or at least one biomedical sensor or data input source configured to provide feedback information. The controller may be configured to generate a first nerve stimulation signal to a first peripheral nerve effector to stimulate a first peripheral nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with arrhythmia or hypertension. The controller may also be configured to generate a second nerve stimulation signal to a second peripheral nerve effector to stimulate a second peripheral nerve associated with a parasympathetic pathway of the patient to modify at least one brain or spinal cord autonomic feedback loop related to arrhythmia or hypertension. The controller may also be configured to adjust the first and second neural stimulation signals to balance parasympathetic and sympathetic nervous system activity of the patient. The controller may be configured to adjust the first neural stimulation signal when identifying abnormal sympathetic and/or parasympathetic activity in the patient.

Also disclosed herein is a multimodal method for treating arrhythmia or hypertension. The method may include any number of the following: assessing at least one of sympathetic and parasympathetic activity of the subject and determining whether abnormal sympathetic and parasympathetic activity is present in the subject; stimulating a first nerve operably connected to the brachial plexus sufficient to produce a therapeutic effect on arrhythmia or hypertension if abnormal sympathetic nerve activity is present; and stimulating the tragus of the ear or the vagus nerve of the ear (e.g., via the cymba concha) sufficient to produce a therapeutic effect on arrhythmia or hypertension if abnormal parasympathetic activity is present. In some cases, the stimulation may be transdermal only stimulation, which may include stimulating or inhibiting neural activity of the first nerve. If both abnormal sympathetic and parasympathetic activity are present, the stimulation may involve the first nerve and the tragus of the ear or vagus nerve of the ear (e.g., via a cymba concha). Assessing at least one of sympathetic and parasympathetic activity of the subject includes measuring HRV in the subject, such as with a device worn by the wrist, and also includes measuring heart rate and/or electrodermal activity. The first nerve may be, for example, the median nerve, radial nerve, ulnar nerve, median cutaneous nerve, lateral cutaneous nerve, or other nerves discussed herein. The 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.), time of day of stimulation application, etc.

Also disclosed herein are multimodal methods of treating arrhythmia or hypertension, which may involve stimulating a first peripheral nerve; assessing at least one of sympathetic and parasympathetic activity of the subject and determining abnormal sympathetic and parasympathetic activity in the subject; and adjusting the stimulation after assessing at least one of sympathetic and parasympathetic activity. Adjusting the stimulation may include identifying abnormal sympathetic and parasympathetic activity in the patient, and adjusting a frequency of stimulation of the first nerve, and/or interrupting stimulation of the first nerve; and initiating stimulation of the second nerve.

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

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

Fig. 27A illustrates a system that can be configured to stimulate multiple flaps in a timed manner (with an electrode array embedded in a sleeve across the arm) by stimulating adjacent pairs of electrodes at regular intervals, such that a particular point along the nerve is stimulated. The electrodes may be arranged in a linear array, for example to provide spatially patterned stimulation. Multi-modal stimulation may include applying different patterns to an electrode array (e.g., a linear array of electrode pairs). The skin pieces in the arm that can be stimulated to carry sensory information include, for example, C5 (outside of the upper limb above and at the elbow); c6 (forearm and radius side of hand); c7 (middle finger); c8 (skin on little finger and inside of each hand); t1 (inner forearm); and T2 (medial and superior arm and axillary region).

Some embodiments may involve stimulation patterns (e.g., bursts, pulse patterns, random, pseudorandom, or noise) to improve the efficiency and efficacy of stimulation. In some embodiments, for example as schematically shown in fig. 27A, the electrode array may be aligned along the axon of the nerve and may stimulate adjacent pairs of electrodes at regular intervals such that specific points along the nerve are stimulated at a speed of, for example, between about 1cm/s and about 10cm/s (e.g., about 1cm/s, about 2cm/s, about 3cm/s, about 4cm/s, about 5cm/s, about 6cm/s, about 7cm/s, about 8cm/s, about 9cm/s, about 10cm/s, and ranges between such values). In some embodiments, the stimulation may be provided in a burst mode, where 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 (0.01-0.1Hz) with higher frequency stimulation (1-200Hz) or lower frequencies (1-200Hz) with very high frequencies (1000-10 kHz).

The lateral electrode configuration may provide interfering stimulation at a location below the skin surface. Multiple modes may be used to create different interference patterns. The interference may be constructive or destructive. Each electrode pair may have the same stimulation parameters or different parameters. For example, different stimulation frequencies may produce destructive interference, which stimulates at a new beat frequency (e.g., the difference between two different frequencies).

In some embodiments, the electrode pairs may be spaced on the limb, as shown in fig. 27B, such that the stimulation waveforms combine at specific intersections to target deep fibers by producing an interference pattern of stimulation having a frequency that is the difference between the two waveform frequencies, e.g., a frequency between about 2Hz and about 20kHz (e.g., about 2Hz, about 4Hz, about 6Hz, about 8Hz, about 10Hz, about 12Hz, about 15Hz, about 20Hz, about 30Hz, about 40Hz, about 50Hz, about 60Hz, about 100Hz, about 250Hz, about 500Hz, about 1000Hz, about 2500Hz, about 5kHz, about 10kHz, about 15kHz, about 20kHz, and ranges between such values). Higher and lower frequencies are also possible.

Examples of the invention

The following examples are illustrative only and are not intended to limit the present invention.

We evaluated methods of using peripheral nerve stimulation to alter the circuit dynamics associated with ET in clinical studies. A device 100 for delivering Transcutaneous Electrical Nerve Stimulation (TENS) using surface electrodes 102 located on the volar side of the wrist is used to stimulate the median nerve 104 for 40 minutes with a square wave at a frequency of 150Hz and having a pulse width of 300 microseconds, as shown in fig. 1. In this embodiment, a wire 106 is used to connect the device 100 to the electrode 102. Surprisingly, it was found that tremor was reduced, as previous studies reported that peripheral nerve stimulation using TENS did not improve tremor.

Such electrical stimulation is effective to reduce tremors in subjects with mild to severe tremors. Kinetic tremor was assessed using a widely used measurement of kinetic tremor: archimedean spiral drawing task for Fahn Tolosa Marin test. Postural tremor was assessed by measuring the angular velocity of a gyroscope worn on the back of the hand.

Three patients (represented as subjects A, B and C, respectively, in fig. 2) showed spirals drawn by subjects with mild, moderate and severe ET before and after stimulation. In subjects with mild, moderate and severe tremor, reductions in postural tremor were 70%, 78% and 92%, respectively. Postural tremor may also be reduced by electrical stimulation and this effect is maintained for up to 45 minutes after treatment is complete. Fig. 3A-3C show the effect on wrist flexion and extension, as determined from gyroscope data in subject B of fig. 2, as a representative example. Fifteen minutes of treatment reduced the tremor amplitude from 0.9 degrees (fig. 3A) to 0.2 degrees (fig. 3B). This reduction in tremor amplitude was maintained over 40 minutes of treatment. Measurements taken 20 minutes after treatment showed that the tremor amplitude continued to decrease and remain at 0.2 degrees (fig. 3C). Tremor reduction was variable between subjects. As shown in fig. 4, some subjects did not respond to treatment.

Tremors in subjects with ET were reduced by applying electrical stimulation, thereby achieving excellent therapeutic results. Stimulation can reduce tremor during, immediately after, and up to twenty minutes after treatment. To achieve long-term use and allow patients with ET to integrate therapy into their lives, in many embodiments, the system is made easy to use and long-term effective. In several embodiments, the innovations and devices described herein are used to achieve this goal.

In another example, a multi-modal approach would be used, which in some embodiments would use algorithmic learning and/or feedback. At least two stimuli will be selected from the following group: vibrotactile, chemical, mechanical, thermal, electrical, ultrasound (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 is to be applied to the wrist and a different second stimulus is to be applied at a different location (ankle, finger, ear, leg, arm, etc.). Alternatively, a first stimulus is to be applied to a first location (e.g., the wrist) and a different second stimulus is to be applied to the same first location. In another example, using different points in the same area may also provide synergy (e.g., different points on the wrist). The same or different nerves can be stimulated at the first location. For example, in some embodiments, different nerves (or multiple location points) in a region will be stimulated.

Various embodiments of various 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 present 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 eliminated from the described apparatus. Accordingly, the description of the embodiments provided above should not be construed as unduly limiting the scope of the invention as set forth in the claims.

Certain functions described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination.

The foregoing description 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 to be construed as limiting the embodiments. Each disclosed aspect and example of the disclosure may be considered alone or in combination with other aspects, examples, and variations of the disclosure. Moreover, unless otherwise indicated, the steps of the methods of the present disclosure are not limited to any particular order of execution. The references cited herein are incorporated by reference in their entirety. Describing an embodiment as "preferred" does not limit the use or scope of alternative embodiments.

While the methods and apparatus described herein are susceptible to various modifications and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, 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.

Depending on the embodiment, one or more acts, events or functions of any algorithm, method or process described herein can be performed in a different order, may be added, merged, or left out (e.g., not all described acts or events are necessary for the implementation of the algorithm). In some examples, acts or events may be performed concurrently, e.g., through multi-threaded processing, interrupt processing, or multiple processors or processor cores, or on other parallel architectures, rather than sequentially.

The use of sequential or chronological languages such as "then," "next," "after," "then," etc. is generally intended to facilitate the transfer of text and is not intended to limit the order of operations performed, unless otherwise explicitly stated or otherwise understood in the context of use.

The various illustrative logical blocks, modules, processes, methods, and algorithms described in connection with the embodiments disclosed herein may be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, operations, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality may be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present disclosure.

The various illustrative logical blocks and modules described in connection with the embodiments disclosed herein may be implemented or performed with 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 in the alternative, the processor may be a controller, microcontroller, or state machine, combinations of these, or the like. A processor may also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

The blocks, operations, or steps of a method, process, or algorithm described in connection with the embodiments disclosed herein may be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, an optical disk (e.g., a CD-ROM or DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. A storage medium may be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium may be integral to the processor. The processor and the storage medium may reside in an ASIC. The ASIC may reside in a user terminal. In the alternative, the processor and the storage medium may reside as discrete components in a user terminal.

Conditional language (such as "may," "e.g.," and the like) used herein is generally intended to convey that some examples include certain features, elements, and/or states, but some examples do not include them, unless expressly stated otherwise or understood otherwise in the context of the use. Thus, such conditional language is not generally intended to imply that features, elements, blocks, and/or states are in any way required for one or more examples or that one or more examples necessarily include logic for deciding (with or without author input or prompting) whether these features, elements, and/or states are included or are to be performed in any particular embodiment.

The methods disclosed herein may include certain actions taken by a practitioner; however, the methods may also include any third party description of the actions, whether explicit or implicit. For example, actions such as "positioning an electrode" include "indicating the positioning of an electrode".

The ranges disclosed herein also encompass any and all overlaps, sub-ranges, and combinations thereof. Language such as "at most," "at least," "greater than," "less than," "between," and the like includes the recited number. Numerals preceded by a term such as "about" or "approximately" include the enumerated numbers, and should be interpreted on a case-by-case basis (e.g., as reasonably accurate as possible in this case, e.g., ± 5%, ± 10%, ± 15%, etc.). For example, "about 1 hour" includes "1 hour". A phrase preceded by a term such as "substantially" includes the referenced phrase and should be interpreted as appropriate (e.g., as reasonably possible in such a case). For example, "substantially vertical" includes "vertical". Unless otherwise indicated, all measurements were made under standard conditions, including temperature and pressure. The phrase "at least one" is intended to require at least one item in the subsequent list, rather than each item of one type in each item in the subsequent list. 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 of treating tremor in a subject, the method comprising:

applying a first stimulus from a first actuator to a first location on the subject's body,

wherein the first stimulation comprises electrical stimulation, wherein the first actuator comprises an electrode, and

wherein the first location is a wrist of the body;

applying a second stimulus from a second actuator to a second location on the body,

wherein the second stimulus comprises a vibrational stimulus, wherein the second location is the wrist of the body, the second location is spaced a distance from the first location, and wherein the first and second actuators are coupled to the wrist using a flexible cuff,

wherein at least one of applying the first stimulus or applying the second stimulus is responsive to a controller in a smart device and based on the sensed amplitude of tremors,

wherein the amplitude of the tremor decreases after the application of the first and second stimuli.

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 comprising a magnetic stimulus, an electromagnetic stimulus, a chemical stimulus, a thermal stimulus, an ultrasonic stimulus, a radio frequency stimulus, a light stimulus, or a microwave stimulus.

3. A method of treating tremor in a subject, the method comprising:

wherein the first stimulus comprises an electrical or vibrational stimulus; and

wherein the second stimulus comprises a vibration stimulus,

wherein at least one of applying the first stimulus or applying the second stimulus is responsive to a controller in a smart device and is based on the sensed amplitude of tremors;

4. The method of claim 3, wherein the second stimulation comprises an electrical or vibrational stimulation, the second stimulation being different from the first stimulation.

5. The method of claim 3, wherein the second stimulation comprises electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibrational 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 comprising an electrical stimulus, a magnetic stimulus, a chemical stimulus, a thermal stimulus, a vibratory stimulus, an ultrasonic stimulus, a radio frequency stimulus, or a microwave stimulus.

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 location comprises a wrist of the body and the second location comprises the wrist of the body.

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

11. The method of claim 3, wherein the first location is a left arm or leg of the body and the second location is a right arm or leg of the body to provide bilateral stimulation.

12. The method of claim 3, wherein the first location comprises a wrist of the body and the second location comprises an ankle of the body.

13. The method of claim 3, wherein the first location comprises a wrist of the body and the second location comprises an ankle of the body.

14. A method of treating tremor in a subject, the method comprising:

applying a first stimulus from a first actuator to a first location on the subject's body; and

wherein the amplitude of the tremor decreases after the application of the first and second stimuli,

the first stimulus comprises at least one of an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus; and

applying a second stimulus to a second peripheral body site different from the first peripheral body site, the second stimulus comprising at least one of an electrical stimulus, a vibrational stimulus, a thermal stimulus, or a chemical stimulus, the second stimulus different from the first stimulus.

15. The method of claim 14, wherein the first stimulus comprises an electrical stimulus, a magnetic stimulus, a chemical stimulus, a thermal stimulus, a vibratory stimulus, an ultrasonic stimulus, a radio frequency stimulus, or a microwave stimulus.

16. The method of claim 15, wherein the second stimulation comprises electrical stimulation, magnetic stimulation, chemical stimulation, thermal stimulation, vibrational stimulation, ultrasonic stimulation, radio frequency stimulation, or microwave stimulation.

17. The method of claim 16, wherein the second stimulus is different from the first stimulus.

18. The method of claim 14, further comprising applying a third stimulus from a third actuator to a third location on the body, the third stimulus comprising an electrical stimulus, a magnetic stimulus, a chemical stimulus, a thermal stimulus, a vibratory stimulus, an ultrasonic stimulus, a radio frequency stimulus, or a microwave stimulus.

19. The method of claim 18, wherein the second stimulus is different from the first stimulus, and wherein the third stimulus is different from the second stimulus.

20. The method of claim 14, wherein the first location comprises a wrist of the body and the second location comprises the wrist of the body.

21. The method of claim 14, wherein the first location comprises an ankle wrist of the body and the second location comprises the ankle of the body.

22. The method of claim 14, wherein the first location comprises a wrist of the body and the second location comprises an ankle of the body.

23. A method of treating tremor in a subject, the method comprising:

wherein the first stimulation comprises electrical stimulation, and wherein the first actuator comprises an electrode;

applying a second stimulus from a second actuator,

wherein the second stimulus comprises a vibratory stimulus, and wherein the first and second actuators are coupled to one of an arm, a wrist, a leg, a knee, or an ankle using a flexible cuff,

wherein at least one of applying the first stimulus or applying the second stimulus is responsive to a controller in a smart device and based on a sensed and predetermined characteristic of a disease,

wherein symptoms of the disease are reduced after applying the first stimulus and applying the second stimulus.

24. The method of claim 23, wherein the second stimulus from the second actuator is applied to a second location on the body, the second location being spaced a distance from the first location.

25. A wearable device for treating tremor, the device comprising:

a processing unit;

A first peripheral nerve effector comprising at least one stimulation source configured to be positioned to modulate a first peripheral nerve pathway;

a second peripherical nerve effector comprising at least one stimulation source configured to be positioned to modulate a second peripherical nerve pathway; and

at least one sensor configured to measure a characteristic of a disease state,

wherein the processing unit comprises a controller and a memory to store instructions that, when executed, cause the apparatus to:

a first stimulus from a first actuator is applied to a first location on the body,

wherein the first stimulus comprises an electrical or vibrational stimulus; and

applying a second stimulus from a second actuator,

wherein the second stimulation comprises a different type of stimulation than the first stimulation, or wherein the second stimulation comprises the same type of stimulation as the first stimulation and a different stimulation parameter comprising at least one of frequency, amplitude, pulse width, pulse interval, phase, waveform shape, waveform symmetry, duty cycle, on/off time, burst pattern, or stimulation duration,

wherein at least one of applying the first stimulus or applying the second stimulus is responsive to the controller and is based on a sensed characteristic of the disease state, and

Wherein the characteristic of the disease state decreases after the application of the first stimulus and the application of the second stimulus.

26. The apparatus of claim 25, wherein the second actuator is configured to be applied to a second location on the body that is spaced a distance from the first location.

27. The device of claim 25, wherein the first stimulation is configured for afferent nerve stimulation and the second stimulation is configured for functional electrical stimulation.