Apparatus and method for suppressing tremor

Abstract

To provide a device for suppressing tremor.SOLUTION: A system for treating tremor in a patient, the system comprising: a transcutaneous wearable device comprising: a determination unit; and a first peripheral nerve effector comprising at least one stimulation electrode configured to be positioned to modulate an afferent nerve pathway; A communication device configured to communicate with and receive data from the wearable device, the communication device comprising: a processor; and a memory storing instructions which, when executed by the processor, cause the device to perform an electrical stimulation of a first afferent nerve via the first peripheral effector to reduce tremor of a limb of the patient, wherein: Wherein the communication device is further configured to transmit the data to a remote computing system for storage and / or data processing.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61 / 754,945, filed January 21, 2013, U.S. Provisional Patent Application No. 61 / 786,549, filed March 15, 2013, U.S. Provisional Patent Application No. 61 / 815,919, filed April 25, 2013, U.S. Provisional Patent Application No. 61 / 822,215, filed May 10, 2013, and U.S. Provisional Patent Application No. 61 / 857,248, filed July 23, 2013, each of which is incorporated herein by reference in its entirety. Literature citations

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0003] Embodiments of the present invention relate generally to systems, devices, and methods for treating tremor, and more particularly to systems, devices, and methods for treating tremor through peripheral nerve stimulation. [Background technology]

[0004] Essential tremor (ET) is the most common movement disorder, affecting an estimated 10 million people in the United States, with prevalence increasing with the aging population. The prevalence of ET increases with age, from 6.3% in those over 65 years of age to over 20% in those over 95 years of age. ET is characterized by involuntary oscillatory movements, typically between 4 and 12 Hz. ET can cause vocal tremors and unwanted movements of the head and limbs. Tremors in the hands and forearms are particularly prevalent and problematic, making writing, typing, eating, and drinking difficult. Unlike Parkinson's tremor, which occurs at rest, essential tremor is either postural or kinetic; postural tremor is triggered by holding a limb against gravity, while kinetic tremor is triggered by movement.

[0005] Disability caused by ET is diverse and ranges from embarrassment to inability to live independently when uncontrolled hand and arm movements prevent tasks such as writing or self-feeding. Despite the high prevalence of ET and the significant disability experienced by many patients with ET, treatment options to address tremor are inadequate.

[0006] Medications used to treat tremor (e.g., propranolol and primidone) have been shown to be effective in reducing tremor amplitude by 50% in only 60% of patients. These medications can have severe side effects and are unacceptable to many ET patients. An alternative treatment, deep brain stimulation (DBS), involves surgically implanting a stimulator into the brain. This can be effective in reducing tremor amplitude by 90%, but it is a highly invasive surgical procedure with significant risks that are unacceptable to many ET patients. Therefore, there is a great need for alternative tremor-reducing treatments for ET patients that do not involve the side effects of medications or the risks of brain surgery.

[0007] Tremor is also a significant problem for patients with orthostatic tremor, multiple sclerosis, or Parkinson's disease. Various neurological disorders include tremor due to stroke, alcoholism, alcohol withdrawal, peripheral neuropathy, Wilson's disease, Creutzfeldt-Jakob disease, Guillain-Barré syndrome, and fragile X syndrome, as well as brain tumors, hypoglycemia, hyperthyroidism, hypoparathyroidism, insulinoma, normal aging, and traumatic brain injury. Stuttering and stammering may also be forms of tremor. While the underlying etiology of tremor in these conditions may differ from that in ET, treatment options for some of these conditions are limited, and alternative therapies are needed.

[0008] ET is thought to be caused by abnormalities in the circuit dynamics associated with movement generation and control. Previous studies have shown that these circuit dynamics can be temporarily altered by cooling, topical analgesics, or vibration. Previous studies have shown that electrical stimulation using transcutaneous electrical nerve stimulation (TENS) did not improve tremor (Munhoz, 2003). Therefore, it was surprising to discover in our clinical studies that peripheral nerve stimulation can alter the circuit dynamics associated with ET, resulting in a significant reduction in tremor in patients with ET.

[0009] The present invention is a novel peripheral stimulation device that sends signals along sensory nerves to the central nervous system to correct abnormal network dynamics. Over time, this stimulation normalizes neural firing in the abnormal network, reducing tremor. While DBS directly stimulates the brain, our peripheral stimulation affects abnormal brain circuit dynamics by sending signals along the sensory nerves connecting the periphery to the brain. This approach is non-invasive and anticipates avoiding the surgical risks of DBS and the associated problems with cognitive, declarative, spatial memory, articulation, movement, or gait impairments. Peripheral nerve stimulation can effectively treat tremor by dephasing, counteracting, or obscuring abnormal brain circuit dynamics. Counteracting, obscuring, or training the brain to ignore abnormal brain circuit dynamics is based on the conventional DBS mechanism hypothesis.

[0010] Perhaps the technology most closely related to our approach is transcutaneous electrical nerve stimulation (TENS). High-frequency TENS (50–250 Hz) is often used to treat pain, based on the hypothesis that excitation of large, myelinated peripheral proprioceptive fibers (Aβ) blocks incoming pain signals. While the inconsistent clinical results achieved with TENS for pain management have led many to question its use in pain treatment, there is ample evidence that surface electrical stimulation excites Aβ neurons. In diseases including ET and Parkinson's disease, multiple Aβ neurons transmit proprioceptive information to the same abnormal brain circuits. This led us to propose, without being limited by any proposed mechanism of action, that neurostimulation may be used to excite Aβ neurons to improve tremor. Our proposal is particularly surprising because a previous study by Munhoz et al. failed to show any significant improvement in any of the tremor parameters tested after TENS application. See Munhoz et al., Acute Effect of Transcutaneous Electrical Nerve Stimulation on Tremor, Movement Disorders, 18(2), pp. 191-194 (2003). Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention relates to systems, devices, and methods for treating tremor, and more particularly to systems, devices, and methods for treating tremor through peripheral nerve stimulation. [Means for solving the problem]

[0012]

[0006] In some embodiments, a method of reducing tremor in a patient is provided comprising: placing a first peripheral nerve effector at a first location relative to a first peripheral nerve, delivering a first stimulus to the first peripheral nerve through the first peripheral nerve effector, and reducing tremor amplitude by modifying the patient's neural network dynamics.

[0013]

[00030] In some embodiments, the placing step comprises placing the first peripheral nerve effector on the patient's skin and the first stimulus is an electrical stimulus applied to the skin surface.

[0014]

[0006] In some embodiments, the first stimulus has an amplitude of about 0.1 mA to about 10 mA and a frequency of about 10 Hz to about 5000 Hz. In some embodiments, the first stimulus has an amplitude of less than about 15 mA, less than about 14 mA, less than about 13 mA, less than about 12 mA, less than about 11 mA, less than about 10 mA, less than about 9 mA, less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA, less than about 4 mA, less than about 3 mA, less than about 2 mA, or less than about 1 mA.

[0015]

[00030] In some embodiments, the placing step comprises implanting a first peripheral nerve effector in the patient and the first stimulus is an electrical stimulus.

[0016]

[0006] In some embodiments, the implanting step comprises injecting the first peripheral nerve effector into the patient.

[0007] In some embodiments, the first stimulus has an amplitude less than about 3 mA and a frequency from about 10 Hz to about 5000 Hz.

[0008] In some embodiments, the first stimulus has an amplitude less than about 5 mA, less than about 4 mA, less than about 3 mA, less than about 2 mA, or less than about 1 mA.

[0017]

[00030] In some embodiments, the peripheral nerve effector comprises a power source.

[0018]

[0006] In some embodiments, the method further includes wirelessly powering the first peripheral nerve effector from an externally located power source.

[0019]

[00030] In some embodiments, the first stimulus is vibrotactile.

[0020]

[00030] In some embodiments, the first stimulus is a chemical formula.

[0021]

[0006] In some embodiments, the method further includes sensing movement of the patient's extremity with a measurement unit to generate movement data; and determining tremor information from the movement data.

[0022]

[0006] In some embodiments, the delivering step comprises delivering the first stimulus based on the tremor information.

[0023]

[0006] In some embodiments, the tremor information comprises a maximum deviation from a resting position of the patient's extremity.

[0024]

[0006] In some embodiments, the tremor information includes a resting position of the patient's extremity.

[0025]

[0003] In some embodiments, the tremor information includes tremor frequency, phase, and amplitude.

[0026]

[0006] In some embodiments, delivering the first stimulus comprises delivering a plurality of bursts of stimulation having a variable time delay between the bursts of stimulation.

[0027]

[0006] In some embodiments, the method further includes positioning a second peripheral nerve effector at a second location relative to the second peripheral nerve and delivering a second stimulus to the second peripheral nerve through the second peripheral nerve effector.

[0028]

[0006] In some embodiments, the method further includes determining a period of the patient's tremor, and wherein delivering the second stimulus includes offsetting delivery of the second stimulus from the delivery of the first stimulus by a predetermined fraction or multiple of a period of the tremor.

[0029]

[00036] In some embodiments, the method further comprises dephasing the synchronicity of neural networks in the patient's brain.

[0030] In some embodiments, the first location and second location are located on adjacent fingers.

[0031]

[0003] In some embodiments, the first peripheral nerve and the second peripheral nerve are adjacent nerves.

[0032] In some embodiments, the first peripheral nerve is the median nerve and the second peripheral nerve is the ulnar nerve or the radial nerve.

[0033]

[0003] In some embodiments, the first peripheral nerve and the second peripheral nerve are somatotopically adjacent.

[0034]

[00030] In some embodiments, the first stimulus has an amplitude below a sensory threshold.

[0035]

[0006] In some embodiments, the first stimulus is greater than 15 Hz.

[0036]

[0003] In some embodiments, the first peripheral nerve carries proprioceptive information from the patient's extremity.

[0037]

[0006] In some embodiments, the method further includes determining a duration of effectiveness of the first stimulus on reducing the tremor amplitude; and delivering a second stimulus before the duration of effectiveness expires.

[0038]

[00030] In some embodiments, determining the duration of effectiveness comprises analyzing multiple stimulation applications over a predetermined period of time.

[0039]

[00036] In some embodiments, determining the duration of efficacy further comprises determining an activity profile of the patient.

[0040]

[0006] In some embodiments, determining the duration of efficacy further comprises determining a tremor profile.

[0041]

[00030] In some embodiments, the activity profile includes data regarding caffeine and alcohol consumption.

[0042]

[0006] In some embodiments, the method further comprises placing a conduction pathway enhancer over the first peripheral nerve.

[0043]

[0003] In some embodiments, the conduction pathway enhancer is a conductive tattoo.

[0044]

[0003] In some embodiments, the conduction pathway enhancer comprises one or more conductive strips.

[0045]

[0003] In some embodiments, the first location is selected from the group consisting of a wrist, a forearm, a carpal tunnel, a finger, and an upper arm.

[0046]

[0009] In some embodiments, a system for treating tremor in a patient is provided. The device may include a decision unit and an interface unit adapted to deliver electrical stimuli to a peripheral nerve, the interface unit including a first peripheral nerve effector in communication with the decision unit, the first peripheral nerve effector comprising at least one electrode, the decision unit comprising a processor and a memory storing instructions that, when executed by the processor, cause the decision unit to deliver a first electrical stimulus through the first peripheral nerve effector to a first peripheral nerve, the electrical stimulus configured by the controller to reduce tremor in the patient's extremity by modifying the patient's neural network dynamics.

[0047]

[0006] In some embodiments, the first electrical stimulus has an amplitude less than about 10 mA and a frequency from about 10 Hz to about 5000 Hz. In some embodiments, the amplitude is less than about 15 mA, less than about 14 mA, less than about 13 mA, less than about 12 mA, less than about 11 mA, less than about 10 mA, less than about 9 mA, less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA, less than about 4 mA, less than about 3 mA, less than about 2 mA, or less than about 1 mA.

[0048]

[0006] 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; and the memory storing instructions that, when executed by the processor, further cause the decision unit to deliver a second electrical stimulus through the second peripheral nerve effector to a second peripheral nerve in the patient's extremity.

[0049]

[00030] In some embodiments, the instructions, when executed by the processor, cause the decision unit to deliver the second electrical stimulus offset in time from the first electrical stimulus by a predetermined fraction or multiple of a period of the tremor.

[0050]

[0006] In some embodiments, the first peripheral nerve effector is adapted to be placed on a first finger and the second peripheral nerve effector is adapted to be placed on a second finger.

[0051]

[0006] In some embodiments, the first peripheral nerve effector comprises a plurality of electrodes arranged in a linear array, the plurality of electrodes being spaced apart by about 1 mm to about 100 mm.

[0052]

[00030] In some embodiments, the first peripheral nerve effector comprises a plurality of electrodes arranged in a two-dimensional array.

[0053]

[0006] In some embodiments, the memory storing instructions that, when executed by the processor, further cause the decision unit to select a subset of the plurality of electrodes based on a position of a first peripheral nerve effector on the patient's extremity, wherein the selection of the subset of the plurality of electrodes occurs each time the first peripheral nerve effector is positioned or repositioned on the extremity.

[0054] In some embodiments, the electrodes are spaced apart from each other by about 1 mm to about 100 mm along a first axis and from about 1 mm to about 100 mm along a second axis perpendicular to the first axis. In some embodiments, some of the electrodes are adjacent to each other to form strips. In some embodiments, the spacing may be less than about 100 mm, less than about 90 mm, less than about 80 mm, less than about 70 mm, less than about 60 mm, less than about 50 mm, less than about 40 mm, less than about 30 mm, less than about 20 mm, less than about 10 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm, less than about 2 mm, or less than about 1 mm.

[0055]

[0006] In some embodiments, the system further includes a measurement unit, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to measure movement of the patient's extremity using the measurement unit to generate motion data, and determine tremor frequency and magnitude based on analysis of the motion data.

[0056] In some embodiments, the analysis of the motion data comprises a frequency analysis of the spectral power of the motion data.

[0057]

[0006] In some embodiments, the frequency analysis is limited to between about 4 Hz and about 12 Hz.

[0007] In some embodiments, the frequency analysis is limited to approximately the expected frequency range of the tremor or tremors of interest.

[0058] In some embodiments, the analysis of the motion data is performed on a predetermined length of time of the motion data.

[0059]

[0006] In some embodiments, the decision unit is further adapted to determine tremor phase information based on the motion data and deliver the first electrical stimulus based on the tremor phase information.

[0060]

[0006] 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.

[0061]

[0006] In some embodiments, the memory storing instructions that, when executed by the processor, further cause the decision unit to deliver the first electrical stimulus as a plurality of bursts of electrical stimulation having a variable temporal delay between the bursts of electrical stimulation.

[0062]

[0006] In some embodiments, the memory storing instructions that, when executed by the processor, further cause the decision unit to set parameters of the first electrical stimulus based on the determined tremor frequency.

[0063]

[0006] In some embodiments, the memory storing instructions that, when executed by the processor, further cause the decision unit to set parameters of the first electrical stimulus based on the determined tremor magnitude.

[0064]

[0006] In some embodiments, the memory storing instructions that, when executed by the processor, further cause the decision unit to compare the determined tremor magnitude with a predetermined threshold; and wherein the first electrical stimulus is delivered when the determined tremor magnitude exceeds the predetermined threshold.

[0065]

[0006] In some embodiments, the electrode is adapted to deliver the first electrical stimulus through the patient's skin.

[0066]

[0006] In some embodiments, the electrode is adapted to be implanted and deliver the electrical stimulus to the nerve.

[0007] In some embodiments, the decision unit comprises a user interface adapted to accept input from a user to adjust parameters of the first electrical stimulus.

[0067]

[0006] In some embodiments, the memory further stores a library of one or more predetermined stimulation protocols.

[0068]

[0006] In some embodiments, the interface unit is integrated with the decision unit.

[0069]

[0006] In some embodiments, the interface unit and the decision unit are separate from each other and have separate housings.

[0070]

[0006] In some embodiments, the decision unit is configured to wirelessly provide power to or communicate with the interface unit.

[0071]

[0006] In some embodiments, the system further comprises a measurement unit located within the decision unit.

[0072]

[0006] In some embodiments, the system further includes a measurement unit located within the interface unit.

[0073]

[0006] In some embodiments, the decision unit is a computing device selected from the group consisting of a smartphone, a tablet, and a laptop.

[0074]

[0006] In some embodiments, the system further includes a server in communication with the computing device, the server configured to receive the motion data from the computing device along with a history of electrical stimuli delivered to the patient.

[0075]

[0006] In some embodiments, the server is programmed to add the received motion data and the history of electrical stimuli delivered to the patient to a database storing data from multiple patients.

[0076]

[0006] In some embodiments, the server is programmed to compare the received motion data and the history of electrical stimuli delivered to the patient with data stored in the database; determine a modified electrical stimulation protocol based on the comparison of the received motion data and the history of electrical stimuli delivered to the patient with the data stored in the database; and transmit the modified electrical stimulation protocol to the computing device.

[0077] In some embodiments, the electronic device is flexible and is disposed on a flexible substrate, which may be a sleeve, pad, band, or other housing.

[0078]

[0003] In some embodiments, a system for monitoring tremor in a patient's extremity is provided. The system may include an Interface Unit having an inertial motion unit for capturing motion data, a power source, and a wireless transceiver, the Interface Unit adapted to be worn on the patient's extremity, and a processor in communication with the Interface Unit, the processor configured to receive the motion data from the Interface Unit, the processor being programmed to determine a tremor signature and profile over a predetermined period of time based on analysis of the motion data.

[0079] In some embodiments, the processing unit is a mobile phone.

[0080]

[00030] 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.

[0081]

[0006] In some embodiments, the processing unit is further programmed to compare the tremor magnitude to a predetermined threshold.

[0082]

[0006] In some embodiments, the processing unit is further programmed to issue an alert if the tremor magnitude exceeds a predetermined threshold.

[0083] In some embodiments, the predetermined threshold is patient adjustable.

[0084]

[00036] In some embodiments, the processing unit is programmed to prompt the patient to enter activity data, the activity data including a description of the activity and the time the activity occurred.

[0085]

[0006] In some embodiments, the processing unit is programmed to correlate the activity data with the determined tremor frequency and magnitude.

[0086]

[00030] In some embodiments, the activity data includes caffeine or alcohol consumption.

[0087]

[0006] In some embodiments, the activity data includes medication consumption.

[0088] The inventors have invented a peripheral nerve stimulation device and method that effectively reduces tremors without the side effects of drugs or the risks of brain surgery. Our approach is safe, non-invasive in some embodiments, and effective in reducing tremors. In some embodiments, the device works by altering the neural circuit dynamics associated with essential tremor, Parkinson's tremor, and other tremors. The device is easy to use, comfortable, and adjustable to achieve optimal treatment for each individual patient.

[0089] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0090] [Figure 1] FIG. 1 illustrates one embodiment of delivering stimulation to the located median nerve to reduce tremor. [Figure 2] 1 illustrates the therapeutic effect of one embodiment of peripheral nerve stimulation in patients with (A) mild, (B) moderate, and (C) severe ET. This figure shows the results of a clinical study in which a stimulation configuration of 150 Hz frequency, 300 microseconds, and 40 minutes of stimulation on-time reduced tremor amplitude in patients with essential tremor. This tremor reduction, demonstrated by comparing the ET patients' ability to draw a spiral, was observed immediately after stimulation was turned off. [Figure 3A] ~ [Figure 3C] Figure 3 shows wrist flexion-extension calculated from gyroscope data for subject B from Figure 2. Figure 3A shows the tremor before treatment. Figure 3B shows the tremor reduction immediately after treatment. Figure 3C shows that tremor reduction is maintained 20 minutes after treatment. [Figure 4] FIG. 1 shows an example of treatment ineffectiveness in a patient with moderate ET. [Figure 5] FIG. 10 illustrates various locations on a patient where the tremor altering system can be placed. [Figure 6] FIG. 1 shows the major nerves innervating the hand and their distal branches. [Figure 7A] ~ [Figure 7D] 1A-1C are block diagrams illustrating various embodiments of a tremor altering system. [Figure 8A] FIG. 1 illustrates one embodiment of an electrode pair used to excite nerves in different fingers, where both electrodes are placed on the fingers. [Figure 8B] FIG. 10 illustrates an alternative means of exciting nerves in separate fingers, where a second electrode is placed on the wrist. [Figure 8C] FIG. 10 illustrates one embodiment of placing electrodes on the wrist to target different underlying nerves. [Figure 8D] FIG. 1 illustrates various stimulation sites. [Figure 9A] FIG. 1 illustrates one embodiment of an excitation scheme that dephases brain regions receiving sensory input from two fingers. [Figure 9B] FIG. 1 illustrates one embodiment of an excitation scheme that dephases brain regions that receive sensory input from four fingers. [Figure 10A] ~ [Figure 10C] FIG. 1 illustrates an embodiment in which hand position can determine optimal stimulation duty cycle and timing. [Figure 11] FIG. 1 illustrates an embodiment of a variable stimulus that changes frequency over time. [Figure 12] FIG. 1 illustrates an embodiment in which the stimulator is chemical and the chemical stimulation can be tuned by mixing two neuromodulating chemicals. [Figure 13] FIG. 1 illustrates various forms of user control. [Figure 14A] ~ [Figure 14L]

[0014] Figures 14E and 14H illustrate various non-invasive and invasive embodiments of the tremor altering system. Figure 14E illustrates an embodiment in which the stimulator is mechanical. Figure 14H illustrates an embodiment of a device with a wristwatch form factor. Figure 14I illustrates the back of the device shown in Figure 14H, showing the electrodes that interface with the user. Figure 14J illustrates an embodiment of a disposable electrode interface that snaps into place in a wristwatch form factor device housing. Figure 14K illustrates an embodiment of a self-aligning snap feature that allows the disposable electrode interface to snap into the wristwatch form factor device housing. Figure 15L illustrates the possibility of placing electrodes along the spine in an embodiment of a device in which the effector is electrical. [Figure 15A] ~ [Figure 15C] 1A-1C illustrate various embodiments of electrode arrays. [Figure 16A] ~ [Figure 16D] 1A-1C illustrate various embodiments of conductive ink tattoos. [Figure 17] FIG. 1 illustrates an embodiment of placing an accelerometer on the hand or wrist to measure patient activity and tremor. [Figure 18] FIG. 1 shows an example of a spectral analysis of gyroscope motion data for a patient with a tremor centered at 6.5 Hz. [Figure 19] FIG. 1 illustrates the correlation between postural and kinetic tremors. [Figure 20] FIG. 1 illustrates an embodiment of a stimulation device that can record and transmit data, such as tremor characteristics and stimulation history, to a data portal device, such as a smartphone, which transmits the data to a cloud-based server. [Figure 21] 1 is a flowchart illustrating the monitoring, integration, analysis, and display of data used to inform the user or improve stimulation. [Figure 22] 10 is a flowchart illustrating feedback logic. [Figure 23] FIG. 1 illustrates an embodiment in which the stimulator is an electrode that is implanted at least in part subcutaneously. [Figure 24A] ~ [Figure 24D] 1A-1C illustrate various embodiments of implantable and skin surface devices that allow for wireless powering and control. [Figure 25A] ~ [Figure 25F] 1A-1C illustrate various electrode shapes for implant electrical stimulation. [Figure 26A] ~ [Figure 26B]

[0013] Figure 1 illustrates two preferred embodiments of the control module used to interact with the device. The control system for the tremor device uses feedback to modify stimulation. The system is closed loop, with stimulation adjusted based on activity and tremor measurements. DETAILED DESCRIPTION OF THE INVENTION

[0091] Definition of Terms

[0092] As used herein, the terms "stimulate" and "stimulator" generally refer to the delivery of a signal, stimulus, or impulse to neural tissue in a target region. The effect of such stimulation on neuronal activity is referred to as "modulation," but for simplicity, the terms "stimulate" and "modulate," as well as variations thereof, may be used interchangeably herein. The effect of delivering a signal to neural tissue may be excitatory or inhibitory and may promote 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: (a) depolarizing neurons so that they fire action potentials; (b) hyperpolarizing neurons so that they suppress action potentials; (c) depleting neuronal ion reserves so that they suppress action potential firing; (d) altering proprioceptive input; (e) affecting muscle contraction; (f) altering neurotransmitter release or uptake; or (g) suppressing firing. "Proprioception" refers to the sense of awareness of the relative positions of one's body parts or the awareness of the effort required to move one's body parts. Proprioception is also sometimes referred to as somatosensation, kinesthetic sensation, or touch. "Proprioceptors" are receptors that provide proprioceptive information to the nervous system, including stretch receptors in muscles, joints, ligaments, and tendons, as well as pressure, temperature, light, and sound receptors. "Effector" is the mechanism by which the device modulates the target nerve. For example, an "effector" can be electrical stimulation of a nerve or mechanical stimulation of proprioception.

[0093] "Electrical stimulation" means applying electrical signals to soft tissue or nerves in a target area. "Vibrotactile stimulation" means exciting proprioceptors, such as by applying biomechanical loads to soft tissue and nerves in a target area. Applying "thermal stimulation" means causing cooling or heating of a target area. Applying "chemical stimulation" means exposing nerves or nerve tissue to chemical, drug, or pharmaceutical agents to deliver such agents capable of stimulating neuronal activity therein. This includes local anesthetics that affect the release or uptake of neurotransmitters in neurons, electrically excitable cells that process and transmit information through electrical and chemical signals. "Cloud" means a computer communication network (e.g., the Internet) using real-time protocols for analyzing, displaying, and interacting with data across distributed devices.

[0094] clinical research

[0095] The inventors evaluated the use of peripheral nerve stimulation to alter circuit dynamics associated with ET in a clinical study. As shown in FIG. 1 , a device 100 delivering transcutaneous electrical nerve stimulation (TENS) using surface electrodes 102 placed on the volar side of the wrist was used to stimulate the median nerve 104 with a square wave at a frequency of 150 Hz and a pulse width of 300 microseconds for 40 minutes. In this embodiment, wires 106 were used to connect the device 100 to the electrodes 102. Finding tremor reduction was surprising, as previous studies (Munhoz, 2003, cited above) have not shown improvement with peripheral nerve stimulation using TENS.

[0096] This electrical stimulation effectively reduced tremors in subjects with mild to severe tremor severity. Kinetic tremor was assessed using the Archimedes spiral drawing task of the Fahn-Trossa-Marin test, a widely used measure of kinetic tremor. Postural tremor was assessed by measuring the angular velocity of a gyroscope worn on the back of the hand.

[0097] Figure 2 shows spirals drawn by three patients, designated as subjects A, B, and C, with mild, moderate, and severe ET before and after stimulation. Postural tremor reduction was 70%, 78%, and 92%, respectively, in the mild, moderate, and severe subjects. Postural tremor reduction was also possible with electrical stimulation, and this effect was maintained for up to 45 minutes after treatment ended. Figures 3A–3C show, as a representative example, the effect on wrist flexion-extension determined from gyroscope data for subject B in Figure 2. After 15 minutes of treatment, tremor amplitude was reduced from 0.9 degrees (Figure 3A) to 0.2 degrees (Figure 3B). This reduction in tremor amplitude was maintained even after 40 minutes of treatment. Measurements taken 20 minutes after treatment showed a continued reduction in tremor amplitude, maintained at 0.2 degrees (Figure 3C). Tremor reduction varied between subjects. As shown in Figure 4, some subjects did not benefit from treatment.

[0098] Remarkable therapeutic results have been achieved by reducing tremors in ET patients through the application of electrical stimulation. The stimulation was able to reduce tremors during the procedure, immediately after the procedure, and up to 20 minutes after the procedure. To enable chronic use of the system and enable ET patients to integrate the treatment into their lives, it is important to make the system easy to use and effective over the long term. This goal is achieved through the following innovations and devices:

[0099] Device placement

[0100] The device stimulates sensory nerves to correct abnormal network dynamics. Over time, this stimulation normalizes neural firing in the abnormal network, reducing tremor. The stimulated nerves are preferentially nerves carrying sensory proprioceptive information from the limb affected by tremor. The nerves may be directly modulated, for example, by electrically stimulating anywhere along or adjacent to the nerve carrying proprioceptive information. Alternatively, the target nerve may be indirectly modulated, for example, by exciting proprioceptors that stimulate the target nerve. Figure 5 illustrates access points to nerves carrying proprioceptive information from the limbs, vocal cords, or larynx. Such access points may include, but are not limited to, the fingers (510), hand (520), wrist (530), forearm (540), elbow (550), upper arm (560), shoulder (570), spine (580), or neck (590), foot, ankle, lower leg, knee, or thigh. Nerves affecting proprioception include, for example, the median, ulnar, and radial nerves in the hand, arm, or spinal area, along muscles, or within joints. Nerves targeted by these regions may include the brachial plexus, medial nerve, radial nerve, and ulnar, cutaneous, or joint spatial sensory nerves. These regions may also target musculature including shoulder muscles, arm muscles, and muscles of the forearm, hand, or fingers. Shoulder muscles may include, by way of non-limiting example, the deltoid, teres major, and supraspinatus. Arm muscles may include the coracobrachialis and triceps brachii. Forearm muscles may include the extensor carpi radialis longus, abductor pollicis longus, extensor carpi ulnaris, and flexor carpi ulnaris.

[0101] The device interfaces with the skin surface of the user's tremulous upper extremity at a preferred location and applies neuromodulation signals to nerve bundles selected from the group consisting of the brachial plexus, medial nerve, radial nerve, and ulnar nerve, or excitable structures in the cutaneous or intra-articular musculature of the upper extremity.

[0102] Proprioceptors are found, for example, in muscles, tendons, joints, skin, and the inner ear. Criteria for determining candidate nerves for direct modulation include the location of the tremor to be reduced, the nerve's proximity to the skin surface, a high density of proprioceptive fibers, and distance from excitable pain receptors or muscles. The median nerve, targeted in the forearm, and the ulnar nerve, targeted in the elbow, rank highly based on these criteria. Criteria for determining candidate locations for indirect proprioceptive modulation include the density and type of proprioceptors. Pacinian corpuscles provide information about the sense of touch. Muscle spindles provide information about changes in muscle length by triggering action potentials in muscle spindle afferents when mechano-gated ion channels open upon muscle stretch. Golgi tendon spindles provide information about muscle tone. Stimulating these structures can also alter circuit dynamics and reduce tremor.

[0103] The device targets specific nerves that synapse into abnormal brain circuits. This synapse may be direct or via multiple relay synapses. Figure 6 shows a representative set of nerves that transmit proprioceptive information to the olivocerebellar circuit, a circuit abnormal in ET. These nerves include the distal and main branches (610) of the median nerve (620) and ulnar nerve (630), and the distal and main branches (640) of the radial nerve (650). In a preferred embodiment, the device targets nerves that input proprioceptive information from the hand, wrist, and forearm.

[0104] In another embodiment, any combination of elements described herein can be used to affect nerves associated with vocal tremor, including but not limited to branches of the vagus nerve, such as the superior laryngeal nerve or the recurrent laryngeal nerve.

[0105] Device Components: Various Embodiments

[0106] 7A-7D are conceptual diagrams illustrating some embodiments of a tremor altering system 700. The system 700 includes a housing 720, one or more effectors 730, one or more controls 740 in electrical communication with the effector 730, and one or more power sources 750. The housing 720, in some embodiments, can include an interface unit 760. The interface unit facilitates coupling the effector to the patient. For example, the interface unit can provide a physical, electrical, chemical, thermal, or magnetic connection between the device and the patient's nerves. In some embodiments, the housing 720 can include a tremor detection sensor 780, a memory 770, a display 790, and a processor 797. The device in this embodiment can include a processor 797 coupled to the effector and capable of performing computations and controlling other components. The device can also include a digital library stored on the processor 797 or memory 770 that can contain pre-loaded modulation protocols. The device may include a control module 740 in communication with a processor 797, which may be used by a user to control stimulation parameters. The user may adjust the operation of the device through the control. For example, the control may be configured to turn the device on, turn the device off, or adjust effector parameters (e.g., intensity). The device may include a sensor 780 connected to the processor 797, which may detect information of predefined parameters and transmit the parameter information to the processor 797. The device may include a data storage unit 770 connected to the sensor 780 and the processor 797, which may be connected to a power source 750.

[0107] The device may further include a display or indicator 790 to communicate with the user and report the status of the device. The indicator is preferably a light emitting diode (LED) or some other visual indicator, but may also be an audio indicator. Information may include battery power and stimulation status.

[0108] The device may not have an Effector 730. The device may be a diagnostic, not a therapeutic, device. In a preferred embodiment, the Interface Unit 704 is worn on the tremor-affected limb to track the tremor over time. Providing feedback to the user of the device allows the user to become aware of their tremor and monitor it over time. Even in the absence of therapeutic stimulation, this biofeedback may help an individual reduce their tremor. Alternatively, the device may not have a Sensor 780. The device may be a therapeutic, not a diagnostic, device.

[0109] To make the device small and simple, many of these components may be housed in separate units. Processing, control, and possibly sensing may be performed in a remote Decision Unit 702, allowing the Interface Unit 704, which provides therapeutic contact with the patient, to be small, simple, and flexible for a variety of applications (FIGS. 7B-7D). This Decision Unit 702 may be a newly designed device for this application or may be integrated into existing technology, such as a smartphone. This allows the system to be in a robust handheld form factor, reducing cost and size.

[0110] In a preferred embodiment shown in Figure 7B, the Interface Unit 704 is an implant, the Effector 730 provides electrical stimulation of the nerve, and the instruction set and power are transmitted wirelessly from an external device. Alternatively, the implanted Interface Unit 704 may be powered by an on-board battery. Alternatively, the implanted Interface Unit 704 may house a sensor 780 for direct detection of tremor or neuromuscular activity detected by electroneurography (ENG) or electromyography (EMG).

[0111] In a preferred embodiment shown in Figure 7C, the Interface Unit 704 is worn on the body surface and the Effector 730 provides electrical stimulation to the underlying nerves or vibrotactile stimulation to nearby proprioceptors. The Sensors 780 may include motion sensors including accelerometers, gyroscopes, and magnetometers.

[0112] In the preferred embodiment shown in FIG. 7D , one or more sensor units 780 for sensing motion, temperature, etc. may be worn at various locations on the body. The effector 730 and decision unit 702 are separate entities worn at different locations on the body from the sensors 780. This is useful when nerve stimulation occurs in a location where tremor is not easily or accurately measured. For example, placing the stimulation device 700 on the underside of the wrist to reduce hand tremor can be very effective. However, measuring hand tremor at the wrist using an accelerometer or gyroscope can be difficult. In contrast, placing the sensor unit separately on the palm or back of the hand in a glove, or worn as a ring on one of the fingers, can improve sensitivity to hand tremor. This is because the sensor unit is located away from the wrist joint.

[0113] Effector: Overview

[0114] The effector is operable to modulate neural tissue in the region of the upper extremity where stimulation is applied. For example, the effector can modify neuronal signals within the nerve and / or modify the flow or content of proprioceptive information. The effector can act transcutaneously or subcutaneously. One or more effectors can be used to affect the nerve. In some embodiments, the effector can be excitatory to the nerve. In other embodiments, the effector can be inhibitory to the nerve. In some embodiments, the system can be used to excite the nerve for some portions of treatment and inhibit the nerve for other portions of treatment.

[0115] Effector: Electrical stimulation

[0116] In some embodiments, the effector may be an electrical stimulator. An electrical effector may include an electrode, an electrode pair, an electrode array, or any device capable of delivering electrical stimulation to a desired location. The electrical stimulation may be transcutaneous or subcutaneous. For example, transcutaneous electrical stimulation may be achieved by electrodes placed on the skin surface, while subcutaneous electrical stimulation may be achieved by implanted electrodes placed near a nerve.

[0117] Stimulation parameters may be adjusted automatically or controlled by the user. Stimulation parameters may include on / off, duration, intensity, pulse rate, pulse width, waveform shape, and pulse on / off slope. In a preferred embodiment, the pulse rate may be approximately 50-5000 Hz, with a preferred frequency of approximately 50-300 Hz or 150 Hz. A preferred pulse width may be in the range of 50-500 μs (microseconds), with a preferred pulse width of approximately 300 μs. The intensity of the electrical stimulation may vary from 0 mA to 500 mA, with a preferred current of approximately 1-6 mA. These preferred settings were derived from the clinical study described above, which demonstrated that they provided significant and sustained tremor reduction over a sustained period of time. Note that electrical stimulation can be adjusted for different patients and different electrical stimulation methods; therefore, these preferred settings are non-limiting examples. Intensity adjustment may be in increments of 0.1-1.0 mA. In a preferred embodiment, stimulation may last from approximately 10 minutes to approximately 1 hour.

[0118] In a preferred embodiment, the electrodes may contact the user at the skin surface above one or more nerves, which may include the medial, radial, and ulnar nerves. The electrodes may be configured in an electrode pair with one electrode proximal (closer to the elbow) and another electrode distal (closer to the hand). These electrodes may be in communication with the opposing electrode. The electrode pairs may have a positive or negative charge polarity through which current passes.

[0119] The effector may include two electrodes, each with a positive or negative polarity, or the electrode array may include multiple electrode pairs, each of which is programmed independently or depending on its relationship to the other electrode pairs. As an example, the program may allow for cyclic stimulation of different nerves at different times, such as first ulnar, then median, then radial, or any combination thereof.

[0120] Electrical stimulation may be designed to suppress tremor by interfering with proprioceptive input, by causing compensatory muscle contractions, or by a combination of both methods. The electrodes may be replaced with any equivalent material capable of conducting electrical signals through a stimulator that interfaces with the skin surface of the upper extremity. The electrodes may be connected to a control panel 740, which can apply electrical stimulation via the electrodes to the soft tissue and nerves in the area where the electrodes are placed and in the area immediately surrounding the area. In another variation of this embodiment, multiple electrodes may be placed over a combination of multiple target areas.

[0121] A function generator connected to and controlled by the processor may operate to modulate electrical stimulation parameters. The function generator is preferably an arbitrary waveform generator that utilizes direct digital synthesis techniques to generate any waveform that can be described in a table of amplitudes. The parameters are selected from a group including, but not limited to, frequency, intensity, pulse width or duration, and overall duration. The output preferably has a power limit set by a maximum output voltage. In a preferred embodiment, a digitally stored protocol cycles through various stimulation parameters to prevent patient habituation. The variation in electrical stimulation is achieved by the function generator.

[0122] Stimulation optimization: dephasing

[0123] In a preferred embodiment, stimulation is designed to dephasize synchronicity in the brain. The concept of dephasing abnormal circuits is based on recent research showing that neural retraining reduces the tendency of circuits to fall into abnormal rhythms. Interestingly, movement disorders are often associated with abnormalities in periodic synchronous firing in brain circuits. In Parkinson's disease, this circuit resides in the basal ganglia. In ET, this circuit is the olivocerebellar circuit. These abnormal oscillations are thought to drive tremors, supported by numerous studies showing that tremors observed in hand and forearm muscles are synchronized with abnormal rhythmic discharges in the brain. Recent DBS studies have shown that low-voltage, phase-shifted bursts between adjacent electrode pairs (called coordinated resetting) can reduce synchronization in abnormal brain circuits, thereby reducing Parkinson's tremors. The application of coordinated resetting theory to the treatment of tinnitus supports the concept of using synaptic excitation to retrain neural networks.

[0124] The devices disclosed herein offer several advantages over high-frequency TENS stimulation, including reduced power usage (leading to longer battery life, less discomfort from motor recruitment and contraction, and less discomfort from sensory arousal), less suppression of activity firing in adjacent nerves (through depletion or other mechanisms), and longer-lasting effects such that the device only needs to be used intermittently to train or maintain neural circuit dynamics. The devices stimulate a range of nerves in a manner that targets subpopulations to reduce synchronization of neural populations. For example, this can be achieved by stimulating separate fingers on a hand. Figure 8A shows a preferred embodiment of the device, in which anode (810) and cathode (820) electrode pairs attached to the fingers are used to excite branches of the proprioceptive nerves (median, radial, and ulnar nerves) in each finger. This arrangement of anodes (distal) and cathodes (proximal) is intended to induce nerve pulses directed toward the brain. A unique stimulation pattern for each finger sends unique signals to specific neuronal subpopulations in the brain. This is due to the brain's somatotopic nature, where signals from different adjacent or nearby body parts synapse in close proximity to each other in the brain. In an alternative embodiment, the anode and cathode locations may be reversed to prevent sensory impulses from passing through to the brain (antidromic collisions). Figure 8B shows an alternative configuration in which only a single electrode (830) is attached to the finger, and a second electrode (840) is placed on the wrist. Those skilled in the art will appreciate that the finger represents only one possible set of targets, and other locations may similarly be used to target adjacent neuronal subpopulations. In an alternative embodiment shown in Figure 8C, electrodes are placed at different locations on the wrist, targeting the median nerve (850), ulnar nerve (860), and radial nerve (870), respectively. Those skilled in the art will appreciate that the input may be placed at another location or branch of the nerve that feeds into the abnormal brain circuit, this location may be on the same side as the tremoring limb or on the opposite side, this location may be on the surface of the skin, transcutaneous, or implanted.FIG. 8D illustrates various stimulation sites that may be targeted with stimulation delayed or offset by a predetermined fraction or multiple of the tremor period, T, as shown in FIG. 9, for example.

[0125] The device uses a stimulation scheme designed to dephase, cancel, or obscure abnormal networks. Figure 9A is a conceptual diagram illustrating an example of an excitation scheme to dephase brain regions receiving sensory input from two sites. For example, these two sites may be two of the fingers shown in Figures 8A-8D. Stimulation at Site 2 is delayed by a time T / 2 after stimulation at Site 1, where T is the period of the native tremor. For example, if the tremor frequency is 8 Hz, the period is 125 ms, and stimulation at Site 2 would be delayed by 62.5 ms. Stimulation is designed to reset the phase of neurons, which may be achieved using high-frequency stimulation (above 100 Hz) or DC pulses. Figure 9B is a conceptual diagram illustrating an example of an excitation scheme to dephase brain regions receiving sensory input from four sites, with a delay of T / 4 between successive sites. In another embodiment, parameters of stimulation other than timing, such as frequency or pulse width, or a combination thereof, are variable by location. This variability is similarly intended to retrain the brain by dephasing, counteracting, or obscuring abnormal network dynamics. In yet another embodiment, stimulation may be performed at a single location with parameters varied over time. For example, the frequency of stimulation may be varied every few seconds, or stimulation may be turned on and off. In yet another embodiment, stimulation is constant and performed at a single location. In a preferred embodiment of these, the location is the median nerve near the wrist.

[0126] Optimizing stimulation: Subsensory

[0127] Stimulation intensity below the sensory threshold avoids discomfort (tingling, numbness, pain) that can be associated with peripheral nerve stimulation. Because the precise location, size, and surface contact of the electrode significantly affect the stimulation level and the anatomical structures stimulated, it may be necessary to calibrate the sensory threshold for each patient and even each session. This calibration may be performed by the user manually setting stimulation parameters or by otherwise specifying their individual sensory threshold. Another possible mechanism is for the device to automatically sweep through a range of stimulation parameters and for the patient to select the set of parameter values ​​that is least uncomfortable. Another possible mechanism is for the patient to select from a preselected set of parameter values ​​that was effective and comfortable. In some embodiments, the electrode pad may contain a topical analgesic, such as lidocaine, to reduce stimulation discomfort and increase the patient's tolerance of the sensory threshold. In some embodiments, the topical analgesic can be delivered in a controlled-release format to provide pain relief for the duration the electrode pad is worn, which may be several days, weeks, or even months. Such methods may be less uncomfortable or more therapeutically effective due to higher stimulation intensities and / or synergistic effects with topical analgesics, which may reduce tremor in some patients.

[0128] Optimizing stimulation: High frequency

[0129] Alternatively or additionally, the stimulation waveform may be very high frequency, typically kHz or higher, resulting in little or no stimulation felt by the user. Very high frequency stimulation is believed to cause conduction blockages. However, this blockage is preceded by an onset response that includes a strong depolarization of the nerve. To effectively implement very high frequency stimulation without causing discomfort to the patient, it may be desirable to eliminate this onset response. This can be achieved by cooling the nerve during the initial stimulation. Motor nerves are generally excited by stimulation at approximately 15 Hz or below, while sensory nerves are generally excited by stimulation at approximately 50 Hz or above. In some embodiments, it may be desirable to stimulate clearly above the 15 Hz threshold for motor neuron stimulation to avoid inducing muscle contraction.

[0130] Optimizing stimulation: triggered

[0131] Alternatively or additionally, efficacy can be enhanced by triggering stimulation according to the phase of the tremor. The goal of such stimulation is to disrupt the rhythmic synchronization of motor units. A more effective treatment would allow for a lower level of stimulation to achieve the same therapeutic effect with less discomfort. Essential tremor is essentially a feedback problem in a resonant circuit. By implementing stimulation at a timing that is out of phase with the tremor, tremor can be reduced by changing the circuit dynamics, for example, by shifting the gain of the feedback loop.

[0132] As shown in Figure 10B, bursts of high-frequency stimulation may be timed to occur at maximum wrist flexion or extension (Figure 10A). In the example (Figure 10C), the bursts are randomly phase shifted. The hand position (Figure 10A) may determine the optimal duty cycle and timing of stimulation, such as stimulating off-resonance when the tremor deviation is greatest (Figure 10B) or using variable time-delay bursts to avoid resonance with the tremor (Figure 10C).

[0133] Alternatively or additionally, the stimulation may be chaotic or variable. The goal of chaotic, random, or variable stimulation is to prevent habituation and reduce circuit resonance. For example, this may be done by varying the frequency of the stimulation over time and / or by superimposing higher and lower frequency components, as shown in FIG. 11.

[0134] Alternatively or additionally, the stimulus may be a high frequency alternating current, which has been shown to block action potentials as they propagate along axons, and can modulate circuit dynamics.

[0135] In some embodiments, the stimulation parameters may be cycled through in a predetermined order to determine optimal stimulation parameters. In some embodiments, the effectiveness of stimulation parameters may be monitored over time to determine if a particular set of stimulation parameters is losing effectiveness. In some embodiments, when the effectiveness of a particular set of stimulation parameters decreases by a predetermined amount, the stimulation parameters may be changed or cycled through in a predetermined order. For example, if stimulation is being triggered according to the phase of the tremor, stimulation may be delivered with a random or variable time delay, or if stimulation is using a set of amplitudes and / or frequencies, stimulation may be changed to a chaotic, random, or variable modality to prevent or disrupt habituation. In some embodiments, random or variable types of stimulation parameters may be utilized in accordance with a predetermined routine, such as daily for a predetermined number of hours, weekly for a predetermined number of days, or some other predetermined interval, including time of day.

[0136] Effector: Vibrotactile stimulation

[0137] The effector can mechanically excite proprioceptors by means such as vibrotactile or tactile stimulation. The mechanical stimulation can include force, vibration, and / or motion. The effector induces action potentials in the target nerve by exciting the Golgi tendon organ (GTO) or Pacinian corpuscles. The mechanical effector can be, for example, a miniature motor, a piezoelectric material, one or more vibrotactile units consisting of a mass and an effector that moves the mass to apply a vibratory stimulus to the body, an eccentric mass attached to a shaft that generates a vibratory stimulus when the shaft is rotated, or an ultrasonic motor, but it can also be a magnetorheological fluid (MRF) effector or an electroactive polymer (EAP) effector.

[0138] Vibration stimulation is optimal at 250 Hz, which corresponds to the optimal sensitivity of Pacinian corpuscles (also called lamellar corpuscles). Pacinian corpuscles are nerve endings in the skin that detect touch and vibration. Deformation of the corpuscles opens pressure-sensitive sodium ion channels, generating action potentials. Alternatively, vibration can be below 50 Hz to excite Meissner's corpuscles (also called tactile corpuscles), which are located in the fingers and are sensitive to light touch.

[0139] This mechanical stimulator can operate to reduce tremor in several ways. One method may be to send proprioceptive signals to the brain that obscure or modify the proprioceptive drive signals sent from the trembling muscles. Another method may be to control impedance. Joint impedance can affect muscle stiffness and consequently muscle contraction by altering co-contracting muscles with transcutaneous nerve stimulation. Another method may be to generate compensatory muscle contractions that counter the trembling contractions with nerve stimulation. The stimulator is preferably firmly attached to the skin surface, for example with an elastic or Velcro band.

[0140] Effector: Chemical, Thermal, Other

[0141] In the examples described herein, stimulation has primarily been described as electrical or vibrotactile, however, stimulation may also be performed using other effectors that may offer significant advantages in terms of patient comfort, portability, safety, or cost.

[0142] In another variation of this embodiment, the effector may be a neuromodulatory chemical that increases or decreases the neural firing threshold. The chemical used in the present invention may be a local anesthetic, including, but not limited to, the "caine" family. The "caine" family of anesthetics may include, but is not limited to, benzocaine, bupivacaine, butacaine, carbisocaine, chloroprocaine, ciprocaine, dibucaine, etidocaine, heptacaine, levobupivacaine, lidocaine, lidocaine hydrochloride, mepivacaine, mesocaine, prilocaine, procaine, propanocaine, ropivacaine, and tetracaine. Other chemicals may include menthol-family chemicals, alpha-hydroxysanshool from Sichuan peppercorns, or capsaicin, all of which are known to affect peripheral sensory nerves.

[0143] Figure 12 shows a chemical stimulator capable of delivering chemical stimulation transdermally through a patch or via microinjection. The preloaded protocol preferably includes a predetermined composition of one or more chemicals. The local anesthetic in the present invention may be known for other conditions, and the recommended dosage for stimulation may be one that has been tested and approved for the treatment of other conditions. For example, the local anesthetic lidocaine may be administered at 2-10% by weight. Alternatively, lidocaine may be administered with other anesthetics. As shown in Figure 12, two neuromodulatory chemicals are mixed to provide the desired composition. The chemical stimulator may be administered in a composition containing 2.5% by weight lidocaine and 2.5% by weight prilocaine. Alternatively, the chemical stimulator may be administered in a composition containing 0.1-5% by weight lidocaine and 0.1-5% by weight prilocaine.

[0144] The chemical stimulator may be alpha-hydroxy sanshool from Sichuan peppercorns. The alpha-hydroxy sanshool may be contained in an excipient or carrier. The excipient may be a liquid such as a gel, cream, or oil. If the delivery method is a transdermal patch, the chemical formulation may preferably be a cream or gel. The composition may be selected by the user in the control panel module 740 (of FIG. 7). If the delivery method is a microinjection, the formulation may preferably be a solution.

[0145] In some embodiments, the effector may be a temperature effector 732 (of FIG. 7) that induces cooling or heating. This effector can modulate neural firing by directly cooling the nerve or indirectly cooling adjacent arm muscle, skin, or other components. Temperature effectors may include, for example, piezoelectric materials (e.g., Peltier cooling tiles), circulating fluids, compressed expandable gases, cooled or heated solid materials, or evaporative materials. An example of a cooling effector may be as disclosed in U.S. Patent Publication No. 2010 / 0107657, which is incorporated herein by reference. Heating or cooling may be in the form of a patch that adheres to the skin surface, which may be provided by a device (e.g., a wristband) that attaches the stimulator to the skin surface, or by an implant.

[0146] In one embodiment involving a thermal stimulator, a preloaded protocol may preferably have a predetermined stimulation temperature and associated stimulation duration. Preferably, the preloaded protocol may call for a thermal cooling duration of 15 minutes and a cooling temperature range of 15-25°C. The stimulation duration may be preprogrammed to be (but is not limited to) about 5 to about 30 minutes. The maximum length of stimulation must be well tolerated by the user and not cause any damage to muscles or nerves. The temperature sensor is operable to detect the effective cooling temperature in embodiments where the stimulator is a thermal stimulator. The effective cooling or heating temperature may be the temperature felt by the user, which is not necessarily the same as the applied temperature. If the temperature sensor detects that the effective temperature has reached a threshold value, which may be within ±5°C of the applied temperature for a particular protocol, the processing unit 797 (of FIG. 7) can modify the protocol to provide more cooling or heating than originally programmed to compensate for the discrepancy between the effective cooling and the intended cooling.

[0147] The present invention may alternatively employ other effectors, including acoustic (ultrasound excitation to excite sensory nerves in the fingertip), vibratory, tactile, light-emitting (e.g., light exposure in optogenetically modified nerves), magnetic (e.g., by rapidly switching RF fields), or a combination of each mechanism.

[0148] Form factor: Typical wearable stimulator

[0149] 14A-E, the system 700 of FIG. 7 may be non-invasive, fully implantable, or partially implantable. For example, a non-invasive embodiment may include a non-invasive housing, such as a sleeve 1400, patch 1410, or glove. In such non-invasive embodiments, the housing interface is in communication with an exterior portion of the patient. In some embodiments, one or more system components may be implanted 1420. For example, the power source may be external to the patient, and the effector and / or at least a portion of the housing interface may be implanted within the patient at the point of contact.

[0150] The non-invasive system housing can facilitate maintaining the interface and / or effector in close proximity to the patient. The sleeve can cover the full length of the arm or can be a thin band. The sleeve can cover at least a portion of the circumference of any portion of the limb, or the sleeve can cover the entire circumference of any portion of the limb. The function of the sleeve can be to maintain the position of the external device relative to the implant. The purpose of maintaining this position can include achieving good power transfer, reliable communication, or other purposes.

[0151] The housing may be made of any material suitable to achieve the desired properties. For example, the housing material may be a flexible and / or stretchable material, a polymer, or a fabric. The housing may include fasteners, such as Velcro, laces, toggles, and / or tethers, 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.

[0152] The system may be positioned by the patient with or without the assistance of a caregiver. In some embodiments, the system may have an assistive mechanism for positioning on the arm, such as pressure-responsive snaps and / or self-aligning magnets. In some embodiments, such as sleeve 1400, the system may be slipped over the end of the limb (similar to a sports sleeve), wrapped around the arm, or automatically wrapped around the arm (similar to a snap band). In some embodiments, the housing may be in the form of a patch 1410. For example, housing patch 1410 may be secured to the patient's skin with a removable or degradable adhesive. The patch may be worn for a variety of lengths of time, including, but not limited to, patches worn only for the stimulation period or patches that remain in place for days, weeks, or months. The patch may be attached mechanically, chemically, or electrically. Such embodiments include, but are not limited to, staples, strings, or magnets that secure the patch in the desired location.

[0153] In some embodiments, a non-invasive system may include an interface that is in communication with the patient but where 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 housing may be an open or closed tubular structure within which the patient can place a limb. As shown in FIG. 14D, another example is an external device similar to a pad 1430 or support structure, such as a wrist pad or support, within which the patient can place at least a portion of a limb.

[0154] In one embodiment, the housing 1450 may have a watch configuration, as shown in FIGS. 14H-K, worn on a user's wrist or arm. The housing 1450 may include a contact surface 1452 that is separate, partially separate, or connected to the housing, allowing for user interaction. The contact surface 1452 may be connectable to the housing 1450 and disposable after a period of use. The electrodes 1454 on the contact surface may be arranged in strips or in anode-cathode pairs. Other electrode configurations described herein may also be used. The period of time may be after a single use or after multiple uses over a period of minutes, hours, days, weeks, or months. The contact surface itself may be the entire wristband, a portion of the wristband, or attached to the wristband. The wristband itself may be a portion of the contact surface, a portion of the housing, or both. In one example, the wristband, with or without a contact surface, can snap around the wrist by having a slightly curved elastic material feature that allows the wristband to circularize and wrap around the wrist when moved. Another example is a temperature-sensitive material, such as Nitinol, that has shape memory, so that when the device comes into contact with the skin, the wristband, with or without a contact surface, changes shape and wraps around the patient's wrist. In another example, the wristband, with or without a contact surface, has one or more metal wires on the inside or outside of the wristband, which retains a new shape when moved, allowing the user to place the device on their wrist and apply force to shape the wristband to the user's unique anatomy. In another example, the wristband, with or without a contact surface, wraps around part or all of the wrist. This wrapping may be on the same axis or may be spiral.

[0155] The disposable or non-disposable interface may be connected to the housing in a variety of ways, including but not limited to snap features, Velcro, press-fit, magnets, temperature, adhesives, etc., which may or may not include a self-aligning feature. This connection may be made in one or more dimensions or axes. As an example, FIGS. 14J and 14K show one possible embodiment with a self-aligning component, which may be a magnet that connects the interface to the body in three dimensions. The circular shape of the alignment component may allow for alignment in the first dimension in one plane. The bar-shaped portion of the alignment component may be offset from the circular outline of the alignment component, allowing the interface to align to the proper axis. The overall shape of the alignment component allows for alignment of the interface in the final dimension, which in this particular example is depth. The housing may have a matching contour, and the connection may be made to this contour. The connection function may be reversed, with the alignment component placed on the housing and the matching contour placed on the interface. These alignment piece connections may involve magnets in one or both of the housing or interface components, or neither.

[0156] Alternatively, the external device may be an object not worn on the body. For example, the external device may have the form factor of a cell phone, and the patient may carry the external device in a pocket, bag, hand, or other manner in which a cell phone is transported and supported (e.g., placed on a table). The external device may be designed to be placed on a furniture surface in the location where the patient wants to reduce the tremor, such as a dining room table, kitchen, or dressing room.

[0157] As shown in FIG. 14L, another preferred embodiment of the present invention may include a stimulation device with one or more electrodes 1460 attached along the spine. The stimulation device is operable to reduce tremor by neuromodulating nerves located along the spine, stimulating the release of neurotransmitters. Stimulation can affect nerves innervating tremor regions by affecting the release and uptake of neurotransmitters. The electrodes are preferably placed on the skin surface of the cervical spine roots, preferably from C1 to C8, and most preferably between C5 and C8. These electrodes are preferably patch electrodes. The control unit is preferably attachable to the user, and the leads connecting the electrodes to the control unit are preferably magnetized for easy connection. The control unit may be connected to and controlled by the processor. Because the electrodes are preferably placed along the spine (on the user's back), a detachable and portable control panel module may be more convenient for user operation.

[0158] In one embodiment, electrodes may be placed on either side of the spine around the C2 to C8 region of the neck and shoulders. The electrodes may be placed approximately 100 cm to 1 cm apart from the spine and 200 cm to 5 cm apart from each other. Stimulation parameters may include a phase duration between 500 microseconds and 30 microseconds, with 300 to 60 microseconds being preferred. The pulse rate may range from 10 Hz to 5000 Hz, with preferred ranges being 50 Hz to 200 Hz or 150 Hz. The cycle time may be continuous or may range from 5 seconds to 1 hour. Preferred cycle times may be approximately 5 seconds to 20 seconds or 10 seconds. The duration of electrical stimulation may range from 5 minutes to 24 hours per day. A preferred range may include 30 to 60 minutes repeated approximately 10 times per day, or a preferred range may be approximately 40 minutes to 1 hour per day, repeated once per week to once daily. Amplitude (which may be used interchangeably with intensity) may range from 0.1 mA to 200 mA, with a preferred range including 1 mA to 10 mA. The length of time a user can use the device before experiencing an effect on their tremor may range from 1 day to 1 month, or preferably 2 to 4 days.

[0159] Form Factor: For Electrical Stimulation

[0160] Traditional TENS devices are often difficult to position, bulky, and uncomfortable. The innovation described below is a solution that makes it easy to quickly apply and adjust the stimulator that suppresses ET, and allows patients to use the stimulator as a standalone device without discomfort.

[0161] With conventional TENS devices, it is difficult to properly size and position the applied electrodes to optimally target the desired nerve. Smaller electrodes result in greater current density at the target nerve, but smaller pads increase the chance of missing the nerve, and higher current densities from smaller electrodes can cause discomfort. Larger pads are easier to position but require more power and are more likely to unintentionally stimulate adjacent tissue. The innovations described below address these challenges and achieve consistent, effective, comfortable, and safe stimulation.

[0162] Instead of using only one electrode as the cathode and only one electrode as the anode, the device may include an array of electrodes 1500, as shown in FIGS. 15A-15C. For simplicity, these electrodes are shown individually on the patient's skin; however, in practice, the array of electrodes may be incorporated into a sleeve, flexible pad, or substrate, or other form factor described herein. The appropriate combination of electrodes is selected each time the device is repositioned or based on the detected stimulation needs. Stimulation may be performed using one electrode as the anode and one as the cathode, or a combination of electrodes may determine the shape of the stimulation field. Electrode selection may be performed automatically based on feedback from sensors within the device (described below). Alternatively, electrode selection may be performed manually by the user. For example, the user may cycle through multiple electrode combinations until they find a combination that provides optimal tremor reduction or a symptom indicative of correct placement (e.g., tingling in the first and second fingers following median nerve sensory stimulation). Figure 15A shows a two-dimensional array 1500 of individual electrodes. Alternatively, some of these electrodes may be combined into multiple linear rows, with the two-dimensional array being formed from multiple rows of electrodes. Figure 15B shows a linear array 1500 of electrodes, which may be worn as a band as shown, or as a patch, pad, sleeve, etc. Figure 15C shows a housing 1502 that may be used to hold the electrode array 1500.

[0163] Alternatively, electrical stimulation from a poorly positioned electrode may be redirected to the target nerve by modifying the conduction pathway between the electrode and the target nerve. For example, as shown in FIGS. 16A-16D, a conduction pathway enhancer 1600, which may be made of a conductive material, may be placed on the patient's skin, embedded in the skin, implanted, or a combination thereof, to enhance conduction of electrical stimulation from the electrode 1602 to the target nerve 1604. The conduction pathway enhancer may be placed over the nerve and / or across the nerve. For example, in one embodiment, a conductive ink tattoo can redirect off-target stimulation toward the median nerve. A tattoo that is more conductive than adjacent structures (i.e., blood vessels, nerves) provides a path of least resistance to redirect the current. To place or position a conductive tattoo, the target nerve is first clearly identified. Then, the conductive tattoo is placed over the target nerve. As shown in Figures 16A-16D, the conductive tattoo may include multiple conductive stripes that cross the nerve. In some embodiments, these stripes may be parallel to each other and cross the nerve. In other embodiments, the stripes may be formed in a star or cross-hatch pattern with the center over the nerve. In other embodiments, the stripes may be positioned over and parallel to the nerve (not shown).

[0164] To be acceptable to users, wearable devices must be discrete and comfortable. In the preferred embodiment shown in Figures 14B and 14F, for example, the effector is electrical, and the skin patch has single- or multi-electrode electronics printed in a predetermined pattern on a flexible substrate, forming a "second skin" similar to a band-aid. Mechanical properties such as elasticity and stiffness must be comparable to skin for optimal comfort and surface adhesion. Circuitry and wiring for surface electrical stimulation may be printed or etched into flexible materials to allow the device to conform to the body or tissue within the body. For example, the circuitry and wiring may be copper printed on a flexible substrate such as plastic.

[0165] In another embodiment, shown in FIG. 14G, the device may be placed on the surface of the body but includes transdermal penetrating elements 1470 to enhance neural influence. These elements may be microneedles and may be used for improved stimulation and / or drug delivery. In some embodiments, the transdermal penetrating elements may form a microelectrode array that is placed on the skin surface and penetrates the skin. The microelectrode array can act like a microneedle, both improving signal transmission from the electrode to the nerve and increasing skin permeability for improved local drug delivery.

[0166] Sensor: Type of sensor

[0167] The device or system may include sensors. Tremor monitoring sensors may include a combination of single- or multi-axis accelerometers, gyroscopes, inclinometers (which measure and correct for changes in the gravitational field as a result of slow changes in the device's orientation), magnetometers, fiber optic electrogoniometers, optical or electromagnetic tracking, electromyography (EMG) to detect trembling muscle firing, electroneurography (ENG) signals, cortical recording using techniques such as electroencephalography (EEG), or direct neural recording with implants in close proximity to nerves. Figure 17 shows representative placement of motion sensors on the hand (1710) or wrist (1720). Other tracking locations may include the fingers or other body parts.

[0168] Data from these tremor sensors is used to measure a patient's current and historical tremor characteristics, such as amplitude, frequency, and phase. These sensors may be used to identify activity, for example, to distinguish involuntary movements (e.g., tremor) from voluntary movements (e.g., drinking or writing), or to identify the presence or absence of tremor relative to time of day or other detected activities (e.g., sleep / wake cycles).

[0169] The device may include sensors that provide performance and usage data, including when the device was worn (e.g., from a temperature sensor), the device's location (e.g., from GPS), battery level, or video recording. In another embodiment, the sensor is a temperature sensor that measures the temperature of a cooled limb. In another embodiment, the sensor includes video recording. In another embodiment, sensors found in existing hardware, such as a smartphone, are used. For example, tremor may be measured by analyzing a line traced on a smartphone screen using an accelerometer found on the smartphone or attached to the patient while they perform a tremor-inducing writing task.

[0170] Sensor: Tremor extraction algorithm

[0171] Algorithms are used to extract information about the tremor from the stream of data provided by the sensors. Tremor can be identified based on its time-domain signal, frequency-domain signal, amplitude, or firing pattern (e.g., bursts, spikes). For example, in Figure 18, frequency analysis of the spectral power of the gyroscope movement data shows that the tremor is centered at approximately 6.5 Hz (note the maximum power in the lower plot).

[0172] Motion data can be acquired as individual raw sensor channels or by fusing raw signals from multiple sensors. For example, multi-axis accelerometer data can be combined to generate a single numerical value for analysis. The algorithm extracts motion data in the 4-12 Hz range to remove motion not attributable to tremor. This can be done using some combination of notch filters, low-pass filters, weighted-frequency Fourier linear combiners, or wavelet filters. Because each patient has a dominant tremor frequency, this range can be narrowed based on specific information about the patient's tremor or tremor history. For example, for a patient with a 6 Hz tremor, the analysis algorithm may only extract motion data in the 5-7 Hz range. Alternatively, if a patient's tremor is known to flex and extend the wrist by up to 5 degrees, the analysis algorithm may determine that a 45-degree wrist extension is likely due to intentional gross movement rather than tremor. Alternatively, the algorithm samples motion data by identifying time periods that may correspond to postural control or fast-moving fine motor tasks.

[0173] Once appropriate motion data is extracted, the algorithm analyzes key characteristics of the tremor, such as amplitude, center frequency, frequency spread, amplitude, phase, and spectral power.

[0174] Sensor fusion techniques can be used to analyze various aspects of the tremor. For example, a multi-axis accelerometer and gyroscope attached to the back of the hand can be combined to reduce noise and drift and determine the exact orientation of the hand in space. If a second pair of multi-axis accelerometers and gyroscopes is also used on the wrist, the angle and position of the wrist joint can be determined during the tremor. This allows for the identification of which nerve excitations are causing the damping of the various muscle groups that control the tremor.

[0175] Tremor in patients with ET has two components. Kinetic tremor is present during purposeful movement and has a significant impact on quality of life, affecting the ability to perform daily tasks such as drinking, eating, writing, and dressing. Postural tremor is present during static posture against gravity. While it can be unsightly, it has a lesser impact on quality of life than kinetic tremor. Postural tremor typically presents earlier in the disease progression and is thought to cause kinetic tremor. Both components are typically in the 4-12 Hz range, with older patients experiencing lower tremor frequencies.

[0176] Detecting postural and kinetic tremors is more difficult than detecting resting tremors. Resting tremors are present in other movement disorders, including Parkinson's disease, and can be easily identified by analyzing tremors that are present only while the limb is at rest. Extracting kinetic tremors from motion data is difficult because tremor-induced motion must be separated from task-induced motion.

[0177] Identifying postural tremors can be easier than identifying kinetic tremors because accelerometer / gyroscope data during motor tasks is corrupted by task-related movements. Because postural tremors often occur earlier in life than kinetic tremors and have similar frequencies, it is believed that postural tremors may cause kinetic tremors. The correlation between postural and kinetic tremors discovered by the inventors in clinical studies, as shown in FIG. 19, supports the theory of using postural tremor data to analyze or treat kinetic tremors.

[0178] Sensors: Data storage and use

[0179] As shown in FIG. 20 , the stimulation device 2000 includes hardware, software, and firmware that can record and transmit data such as tremor characteristics, stimulation history, performance, usage, and / or control of the device to a data portal device 2002 (e.g., a smartphone, mobile phone, tablet computer, laptop computer, desktop computer, or other electronic device that uses a wireless communication protocol such as Bluetooth).

[0180] Data recorded using the device used by the ET patient may be stored on a smartphone, which transmits the data to a cloud-based database / server 2004. Alternatively, the device used by the ET patient can transmit data directly to the cloud-based database / server 2004. This enables many activities, including tremor tracking, stimulation optimization, sharing with caregivers and physicians, and community building. This data can inform the control unit, provide real-time feedback to the patient, caregiver, and / or clinician, or can be stored to provide historical data to the patient, caregiver, and clinician. Data stored in the cloud 2004 can be viewed by multiple users 2008 on multiple platforms 2006. Furthermore, data on the cloud 2004 can be aggregated and analyzed by a computing device 2010.

[0181] Patients typically visit their doctor every few months, or perhaps once a year, to have their tremor monitored. This monitoring is usually highly subjective. Furthermore, the severity of tremor can be dramatically affected by a variety of factors, including sleep patterns, emotional state, recent physical activity, caffeine intake, food, and medications.

[0182] Such infrequent and imprecise monitoring limits the ability of patients, caregivers, and physicians to understand the severity and progression of a patient's ET and the effectiveness of various treatments and behaviors. The above factors may interact with the effects of the stimulation provided by the device, but these interactions may be difficult to detect. Identifying these interactions may optimize treatment and help patients better understand how their behavior affects their tremor.

[0183]

[00023] In one embodiment shown in Figure 21A, the tremor is 2100 monitored using sensors, which may be IMUs, electrodes, or any of the other sensors previously described. Monitoring may occur continuously or over discrete time periods. Data from these sensors is 2110 analyzed to identify changes in tremor characteristics (amplitude, frequency, etc.) over time. The results are recorded and 2120 displayed to the user. The 2110 analysis and / or 2120 display may occur within the stimulation device itself or by transmitting raw data or analyzed data to a secondary device such as a smartphone or computer.

[0184] In another embodiment, 2101 behavioral data may be collected so that analysis can examine relationships between tremor history and user behavior. Behavioral data may include caffeine, alcohol, medication consumption, and anxiety levels. The system can then alert the patient to interactions between behavior and tremor.

[0185] In another embodiment where the device is therapeutic (i.e., the device has an effector), a stimulation history 2102 may be collected so that analysis can examine the relationship between stimulation history and tremor characteristics.

[0186] 21B adds upload to cloud 2140. The order of upload 2140 and analysis 2110 may be reversed so that analysis occurs on-board (not shown) before upload. Using the cloud allows results to be displayed 2120 to the user on a variety of network-connected devices, such as smartphones, tablets, laptops, and desktop computers, to other users such as physicians 2150 and caregivers, and for pooled analysis across multiple patients 2160.

[0187] FIG. 21C illustrates some of the potential uses of the integrated data, including matching patients with similar patients based on characteristics such as their tremor characteristics, geography, age, and gender 2170 and refining stimulation algorithms 2180.

[0188] Figure 21D shows how the monitoring and analysis of the data shown in Figures 21A-C can be used in a closed loop to adjust stimulation parameters. In this way, algorithms detect interactions between variables to optimize therapy.

[0189] The device may include closed-loop control of stimulation to adaptively respond to detected tremor or activity levels. The device senses tremor through activity sensors, performs data logging, and systematically adjusts stimulation parameters to achieve optimal tremor reduction. FIG. 26A is a control diagram illustrating the basic components of this detection and response system. The target (2650) defines the intended profile. For example, for an ET patient, this profile may be the absence of tremor, and for a PD patient, this profile may be the absence of tremor or rigidity. The error (2670) between the target (2650) and the detected result (2660) is fed to the controller (2680), which modifies the output (2690). The controller (2680) may include a processor and memory. The algorithm in the controller (2680) may input the measurement, stimulation, and activity history, in addition to the error and measurements, into its algorithm. The output (2690) modifies the stimulation. If the effector is electrical, this may include modifying the waveform, frequency, phase, location, and / or amplitude of the stimulation. In a preferred embodiment (FIG. 15), the device includes an array of small electrodes, and the output modifies the selection of which electrodes to use as anodes and cathodes. The effect of the modification is then detected (2660) by a measurement device, and the process is repeated. Modification of the detection (2660) and / or output (2690) may be performed continuously in real time, or with a periodic delay between predetermined times (e.g., hourly or daily), or in response to a user-generated signal, such as a predetermined sequence of movements or button presses. Alternatively, the controller may alert the patient to manually modify the stimulation parameters. This closed loop may be used for automatic self-calibration.

[0190] FIG. 26B is a control diagram showing the basic components of this detection and response system, similar to that shown in FIG. 26A, but now with internally located and externally located components.

[0191] This control may also take other behavioral patterns into account, more akin to a feedforward controller 2640. For example, for typical eating patterns, more aggressive effector firing at specific times can reduce tremor during those activities. A person can also schedule whether they want increased treatment at certain times based on their activities that day (e.g., whether there are anxiety-provoking events, such as speeches). This type of information may be acquired and learned over time by the controller. Other data, such as sleep, food intake (especially alcohol and caffeine consumption), exercise history, emotional state (especially anxiety levels), and medication use, may be collected by other mobile technologies and applications, such as Azumio, Jawbone, Fitbit, etc., and integrated into the cloud-based patient database shown in FIGS. 20 and 21. The user may be prompted to enter such data, for example, by taking photos of meals to track food intake using an image processing application. The database links discrete events (e.g., time and amount of caffeine intake) with time series data (e.g., tremor measurements). The relationship between the patient's behavior, stimulation, and tremor is examined by an algorithm. The algorithm optimizes stimulation and alerts the patient about behaviors that affect tremor. This allows for personalized optimization of tremor treatment and is fed forward to the system.

[0192] In some embodiments, the user may be prompted by the device or mobile phone at predetermined times to perform a specific task, which may be tailored to the type of tremor affecting the patient, such as holding the arm outstretched in a specific posture for ET or placing the arm in a resting position for Parkinson's disease. During this time, the sensor may record the tremor. In some embodiments, the patient may additionally or alternatively be instructed to consume caffeine or record the time since last consuming caffeine. This data may be used to determine how caffeine affects tremor, the effectiveness of treatment protocols and stimulation parameters, the duration of effectiveness, etc. In some embodiments, the patient may be instructed a predetermined time after stimulation, such as 10, 20, 30, and / or 60 minutes after stimulation. This time may be adjusted depending on the measured duration of tremor reduction after stimulation.

[0193] The device has on-board data logging and can transmit this information to an external data portal device, such as a smartphone or internet-enabled charging / sync station. This transmission can be wireless or direct. The external device has a larger storage capacity and can transmit to a database in the cloud. The external device can analyze this data on-board and present the information on a screen or using indicators such as LED lights, or this data can be displayed on the stimulator itself.

[0194] The data in the cloud can be viewed on multiple platforms, including smartphones, tablets, and computers. The data can be viewed by multiple people, including the user, their physician, caregivers, and family members. This can provide a better understanding of the patient's tremor status and allow for optimization of treatment. In some embodiments, users viewing the data can also add comments and notes to the data, which can be tagged with the identity of the user who created the comment or note and the date and time of its creation. In some embodiments, the ability to create notes can be restricted to healthcare providers, such as the patient's physician, and the patient.

[0195] In some embodiments, access to the data is restricted to healthcare providers and patients, which may be done by requiring users to set up secure usernames and passwords to access the data, and in some embodiments, patients may also allow others, such as family members or friends, to access the data.

[0196] Optimization algorithm:

[0197] Our data show that stimulation from a TENS device works well for some patients, moderately well for others, and not for others. However, by optimizing stimulation parameters (e.g., intensity, frequency, waveform, duty cycle, phasing) with the device, we can achieve maximum tremor reduction with optimal comfort for every patient, and adjust over time to accommodate changes in circuit dynamics, device positioning, and patient symptoms. Figure 22 shows the device's decision algorithm / controller.

[0198] In one embodiment, the optimization algorithm begins by initializing 2200 one or more parameters. The parameters may include stimulation amplitude, expected frequency, on-time duration, off-time duration, expected stimulation effect delay, etc. Next, a sensor detects 2202 and records tremor characteristics. Tremor characteristics include tremor amplitude, frequency, phase, and other characteristics described herein. The detected tremor characteristics 2202 are compared to desired target tremor characteristics 2204. The goal may be tremor elimination or reduction. In the comparison step 2206, an error or difference between the detected tremor characteristics and the target tremor characteristics may be calculated to determine whether tremor or reduced tremor is present 2208, or in other words, whether the detected tremor meets or exceeds a target condition. If no tremor is detected, or more generally, if a predetermined target tremor condition is not exceeded, the algorithm loops back to the detection step 2202. If a tremor is detected, or more generally, if a predetermined target tremor condition is exceeded, stimulation may be turned on 2210. If stimulation exceeds the set on-time duration 2212, stimulation is turned off 2214 and the algorithm returns to detection step 2212. While stimulation is on, the device can upload 2218 recorded data to the cloud or another device for further processing. Once stimulation is turned off 2214, the algorithm can monitor 2216 the duration of the off-time and continue uploading 2218 data once the off-time duration has elapsed. Alternatively, data can be uploaded before the off-time has elapsed. User-reported events 2220, which may include caffeine or alcohol intake, anxiety, and other events that may affect tremor, can also be entered into the system and sent to the cloud. This data can be processed by the controller 2222, which can optimize stimulation parameters using various algorithms, including machine learning algorithms. Once the parameters are optimized, new stimulation parameters are set 2224.A report 2226 may be sent to the patient that may highlight and correlate various behaviors identified in the user-reported events with the measured tremor.

[0199] In one embodiment, the stimulation algorithm is designed to optimize therapeutic "on" time. The optimization algorithm can find the best solution for output, which may include, but is not limited to, suppressing tremor during a specific task, at a specific time of day, in a specific location, or simply optimizing for overall minimization of tremor throughout the day. The algorithm may self-calibrate to adjust stimulation parameters, including, but not limited to, frequency, amplitude, pulse width, cathode and anode electrode selection, and / or timing of stimulation on and off. The algorithm may be responsive to user input or may be fully pre-programmed. The algorithm may be a learning algorithm that adjusts stimulation over time to adapt in real time to the patient's tremor or patient-defined needs. Stimulation may be triggered on or off in response to inputs, including, but not limited to, user input (e.g., turning the device on and / or off), timing since last use, time of day, tremor detection (e.g., by an accelerometer), electrical recordings, or algorithms based on the above or other inputs. As one example, a user can use voice activation to turn off the device, utilizing a therapeutic window (i.e., the time period during which tremor is reduced after stimulation is turned off) to provide the necessary time for stabilization for intentional movements. In another example, when a user's clenching or use of the tongue muscles is detected by an external device placed inside or outside the oral cavity, the external device outputs a signal to turn off stimulation, allowing the user to stabilize their arm and perform the intended movement. In some embodiments, the system and algorithm can detect the type of tremor, for example, by distinguishing between postural and kinetic tremors based on an analysis of tremor parameters and the patient's measured activity. In some embodiments, stimulation parameters may be determined, in part, based on the type of tremor detected.

[0200] In some embodiments, the system may be controlled by an event trigger. Event triggers may include defined movement, temperature, voice activation, GPS location, or may be based on data received by a sensor, or any combination thereof. For example, the device may be turned on or off during intentional movement, such as before a tremor begins or before a tremor ends. In another example, the device may be turned on or off when a specified temperature is reached. The system may operate to achieve a desired tremor suppression profile. For example, a control may activate the device during a time period when tremor suppression is desired, activate the device before a time period when tremor suppression is desired so that the effect continues after use of the device, and / or activate the device when a tremor is detected.

[0201] Optimization based on community data

[0202] The time course of tremor is currently poorly understood. While creating a database for a single patient enhances our ability to reduce that patient's tremor, combining individual patient data into a database containing records from multiple patients allows for more powerful statistical methods to be applied to identify optimal stimulation parameters. In some embodiments, data from patients suffering from the same type of tremor can be combined. In some embodiments, the tremor data from each patient can include searchable and sortable metadata that allows for on-demand sorting, searching, and / or reorganization of the collection of data in the database. The metadata may include tremor type (e.g., tremor amplitude, tremor frequency, temporal presence of tremor), name, age, race, sex, location, date and time, food and beverage consumption (e.g., caffeine and alcohol consumption), activity history (e.g., exercise, sleep), medications, past treatments, and current treatments.

[0203] The systems described above with respect to Figures 20 and 21 can be adapted to data from a large number of patients entering the database, and the algorithms can operate on large data sets.

[0204] Building a community

[0205] People with ET feel isolated because of their tremor-related disabilities. As a result, they are very motivated to meet with other people with ET. Several active and growing support groups organize meetings that allow people with ET to talk about their problems and discuss possible solutions. Attending these meetings can be challenging because some people with ET have difficulty driving. Also, people who attend support groups in a particular physical area may have symptoms that are different from each other, and they may not have the resources to identify other patients who are most similar to each other.

[0206] Algorithms can help people find members of the ET community with similar profiles. For example, an algorithm could characterize each patient based on age, tremor severity, tremor characteristics, treatment success, type of treatment, type of medication, location (based on address or GPS), and other characteristics. This helps them communicate with each other and ET share information from a central community website customized for a particular individual or caregiver. For example, the system could find patients within a geographic area or find other patients within a specified distance of a particular patient. Patients could have the option to join an online ET community or make their location searchable on the system. The system could find and inform patients of existing ET community support groups within a specified distance.

[0207] Other Processing Units, Libraries, and Data Storage Devices

[0208] For example, the processor 797 shown in FIGS. 7A-7D is operable to process data, perform calculations, and control other components of the tremor reduction device. It may preferably be a microprocessor with peripherals or a microcontroller. For example, the processor may receive input from a user via a control panel module 740 and control the delivery of stimulation as selected by the user. In another embodiment, the processor 797 may execute predefined stimulation protocols selected by the user. These stimulation protocols may be found in a digital library of stimulation protocols 798, which may be loaded into the processor 797 or stored in external memory such as an EEPROM, SD card, etc. The processor 797 may also receive information from the sensors 780, process the information on-board, and adjust the stimulation accordingly. The choice of processor is determined by the degree of signal processing that needs to be performed and the number and type of peripherals that need to be controlled. Communication with peripherals may be performed via any of the well-known standards, such as USB, UART, SPI, I2C / TWI, etc. The processor may also communicate wirelessly with other device components using Bluetooth, Wi-Fi, etc. The processor may be an on-board device, or the tremor data may be transmitted over a wireless link between the processor and stimulator.

[0209] In one embodiment with an electrical stimulator 730, the preloaded protocol 798 may be an electrical stimulus or a sequence of electrical stimuli. An electrical stimulus or electrical signal refers to an electrical pulse or pattern of electrical pulses. The electrical stimulus may include parameters such as pulse frequency, amplitude, phase, pulse width, or duration of the electrical stimulus. These parameters may be predefined or controlled by the user.

[0210] The data storage unit 770 is operable to store operational statistics about the device and usage statistics about the device, preferably in NAND flash memory. NAND flash memory is a non-volatile data storage device that does not require power to retain stored information and can be electrically erased and rewritten. In some cases, it may be advantageous for this memory to be removable in the form of a micro-SD card.

[0211] Power:

[0212] For example, as shown in Figures 7A-7D, the effector may be electrically coupled to one or more power sources. The power source 750 operates to power the device. The power source 750 may be connected to the processor 797 and provide energy for the processor to operate. The power source may preferably be rechargeable and removable, allowing the device to be reused. The power source may preferably be a battery. Various combinations of chemistries 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 battery is preferably recharged by connecting it to a wall socket or other powered device, solar power, radio frequency, or electrochemical power. One alternative power source is an ultracapacitor. Ultracapacitors may be classified into three different families: double-layer capacitors, pseudocapacitors, and hybrid capacitors. The ultracapacitor may preferably be made of nanoporous materials, such as activated carbon, graphene, carbon nanotubes, carbide-derived carbon, carbon aerogel, solid activated carbon, tunable nanoporous carbon, and mineral-based carbon. Ultracapacitors have the advantage of charging faster than batteries and allowing a greater number of charge-discharge cycles. Alternatively, batteries and ultracapacitors may be used together, as their large number of charge-discharge cycles makes them suitable for parallel connection with batteries and may improve battery performance in terms of current density. Alternatively, the power source may utilize energy from the body. In some embodiments, power may be derived from kinetic motion, thermal energy, and / or sound. Alternatively, the power source may include a plug to an external power source (e.g., a general-purpose appliance).

[0213] In one embodiment, a dedicated charging station or dongle may be used to recharge the device. An advantage of a dedicated charging station is that it may also facilitate uploading data from the device to the web via Wi-Fi or another communication protocol.

[0214] Implants:

[0215] In some embodiments, at least a portion of the system is implantable. An implanted stimulator may offer better control and comfort than surface stimulation because it is located closer to the nerve and does not excite cutaneous afferents.

[0216] Methods for stimulating peripheral nerves to suppress hand tremors impose certain requirements on the suitability of an implanted stimulator. First, the implant must be small to minimize the invasiveness of the procedure for placing and qualifying the implant. Second, the implant must be capable of receiving communication from an external device, as stimulation may be sensitive to detected tremor or user input. Third, the device must tolerate variable positioning of the external device.

[0217] Any number of the system components disclosed herein may be implanted. In some embodiments, the housing, interface, effector, and 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.

[0218] The device may be implanted subcutaneously, partially implanted, transcutaneous (through the skin), placed on the surface of the skin, or not in contact with the body. The device may be a collection of these devices, for example, a surface component that communicates with or powers the implant component, and an implant component. If implanted, the device may be implanted in or around nerves, muscles, bones, ligaments, or other tissue.

[0219] In one embodiment, the implant is placed in or near the carpal tunnel to affect the nerves that pass through it. In another embodiment, the implant is placed on or near the median nerve between the biceps muscles in the upper arm. In another embodiment, the implant is placed on or near the median, radial, or ulnar nerve in the forearm or wrist. In another embodiment, the implant is placed on or near the brachial plexus to affect the proprioceptive nerves that pass from the arm to the central nervous system.

[0220] The implanted portion may be placed or delivered intravascularly to affect nerves within the implant's range of effect. In one example, a device is placed in or through the subclavian artery or vein to affect the nerves of the brachial plexus.

[0221] 23, a preferred embodiment of a controllable device for a user to reduce essential tremor includes an electrode 2310 made of a biocompatible material and implanted at least in part subcutaneously to stimulate a target nerve, and an external operating panel 2320, which includes a user control interface and is connected by leads to the implanted electrode 2310. The device may include additional elements such as a processor 797 that performs calculations and controls other components, a function generator controlled by the processor, a digital library 799 stored in the processor or memory and containing preloaded modulation protocols, a sensor 780 connected to or in communication with the processor 797 to detect predefined parameters and send the parameter information to the processor, a data storage device 770 connected to the sensor and processor, and a power source 750.

[0222] In this embodiment, the implanted electrode 2310 is operable to provide electrical stimulation directly to the target nerve. Because these electrodes are at least partially implanted within the body and remain in place for an extended period of time (preferably several years), they may be made from a material that has suitable electrical properties and is biocompatible. The electrode 2310 material is preferably selected from a group including silicone, PTFE, parylene, polyimide, polyesterimide, platinum, ceramic, and gold, or natural materials such as collagen and hyaluronic acid. The electrode 2310 may be of various shapes and sizes, but it is important that it contacts the target nerve. Electrode shapes include flat shanks, simple uniform microwires, and probes that taper from a wide base to a thin tip. The electrode may have a proximal end and a distal end. The distal end may contact the nerve and be adapted to deliver neural stimulation pulses to the selected nerve. The proximal end of the lead may be adapted to connect to an external console operated by the processor 797.

[0223] In one variation of this embodiment, multiple leads may be connected to different nerve bundles. In another variation, wireless communication with the implant may occur, as shown in FIGS. 24A-24D. The implant 2400 may be a microelectrode or microstimulator and may be inserted in close proximity to the nerve by needle insertion. A needle 2402 may be inserted next to or near the target nerve 2404 in the patient, after which the implant may be ejected from the needle. The implant 2400 may communicate with, exchange data with, and be powered by an externally located device 2406 (e.g., a decision unit described herein).

[0224] In one embodiment, the interface may be an implanted nerve cuff. The nerve cuff may completely or partially encircle the nerve. The nerve cuff may be attached to the nerve by closing butterfly arm electrodes. In another embodiment, the interface may be a nerve abutment. The abutment may be adjacent to or positioned along the nerve. The function of the cuff may be to provide good contact or proximity between the device and the nerve. In another embodiment, the interface may be anchored to the nerve or nerve sheath. For example, the device may be wrapped, tied, clamped, tethered with small barbs, or chemically fused to the nerve or nerve sheath. The function of the cuff, coil, abutment, or anchor is to provide good contact or proximity between the device and the nerve. Some of these embodiments are shown in Figures 25A-25F.

[0225] For example, FIGS. 25A-25C show one embodiment 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 before insertion and implantation, and a coiled configuration after exposure to body temperature. FIGS. 25D and 25E show an embodiment of a butterfly cuff electrode 2510, which can encircle at least a portion of a nerve. As with other embodiments, the interface may include a single electrode or multiple electrodes and may be made of a shape-memory material so that it is in an open configuration during delivery and in a closed configuration wrapped around the nerve after implantation. FIG. 25F shows one embodiment of an interface having a linear array of electrodes 2520 that can abut against and lie along the nerve.

[0226] The method of inserting the implant may involve local or general anesthesia. The implant may be delivered through one or more punctures in the skin, such as with a needle or suture, or an incision may be made in the skin to access the target area, or both methods may be used in combination. In one embodiment, the device may be implanted by wrapping all or part of the device around a nerve and / or surrounding tissue (e.g., a blood vessel or tendon).

[0227] In one embodiment, the implant may include two electrodes positioned along a vascular pathway. The pathway may be along the palmar arch, and the electrodes may be positioned 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 pathway, like a stent, or external to the vascular pathway, like a vascular wrap. In one embodiment, the device may be an implant capable of two-way communication with an external device. This embodiment may include memory. The external "listener" device may be a power source. The implant may communicate information to the "listener," such as its power reserve and usage history. In another embodiment, the device is an implant capable of sensing activity on the nerve or adjacent nerves and reporting this information to the listener.

[0228] In another embodiment, the device, or a device used to position the device, may use ultrasound for guidance, which may be used to measure proximity to blood vessels, nerves, or other tissue, or to characterize the type and location of adjacent tissue.

[0229] In another embodiment, the stimulation electrodes 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 from nitinol, which assumes its shape at 37°C. This allows the electrodes to be injected or inserted in one configuration, e.g., an elongated configuration suitable for passing through a needle, and then assume their respective shape when warmed to body temperature. Some of these examples are shown in FIG. 25.

[0230] The implant may include the necessary components for unidirectional or bidirectional communication between the implant, an external power transmission, a communication system, and / or an electronic device that stores programmable stimulation parameters. The device may include a wireless micromodule that receives command and power signals from an external antenna by radio frequency inductive coupling. If the effector is electrical, the incoming communication channel may contain information including stimulation frequency, delay, pulse width, and on-off interval.

[0231] Transcutaneous charging or powering reduces the implant size by eliminating the need for a large power source (e.g., a battery) and eliminates the need for power source replacement during repeated surgeries. An external component may be used to wirelessly power the internal component (e.g., via radio frequency (RF) power transfer). For example, the external device may emit RF power, which the internal component receives with a resonant coil. This power may be transmitted at various wavelengths, for example, but not limited to, in the radio frequency and short wave spectrums ranging from 3 kHz to 300 GHz. Alternatively, the internal device may include a battery. The external device may be worn on the body, carried on the body, or in the nearby surroundings, such as on a nearby table or wall. The external device may be portable or fixed. The device may include a capacitive energy storage module electrode that stimulates when discharged. The electronics can be significantly simplified when the stimulation profile is driven by the power supply itself. The capacitor blocks direct current while passing alternating current. When the capacitor reaches its breakdown, it discharges, emitting a stimulation pulse.

[0232] The implant can also sense tremors directly, for example, using electroneurography (ENG) or electromyography (EMG) signals, or an accelerometer, or a combination thereof. In this case, the implant may include multiple electrodes, with microelectrodes and macroelectrodes being preferred for sensing and stimulating, respectively. The device may also include an outgoing communication channel to communicate detected events.

[0233] Various embodiments of tremor altering devices and methods of using the devices have been disclosed. These various embodiments may be used alone or in combination, and various modifications to individual features of these embodiments may be made without departing from the scope of the invention. For example, the order of various method steps may be changed in some cases, and / or one or more optional features may be added or removed from the described devices. Therefore, the description of the above embodiments should not be construed as unduly limiting the scope of the invention, which is set forth in the claims.

[0234] Certain features described herein in the context of separate embodiments may also be implemented in combination in a single embodiment. Conversely, various features described in the context of a single embodiment may also be implemented separately in multiple embodiments or in any suitable subcombination. Furthermore, while features may be described above as operating in particular combinations and may initially be claimed as such, one or more features within a claimed combination may be deleted from that combination, and the claimed combination may be directed to subcombinations or variations of subcombinations.

[0235] [Appendix 1] 1. A method of reducing tremor in a patient, comprising: placing a first peripheral nerve effector at a first location relative to a first peripheral nerve; delivering a first stimulus to the first peripheral nerve through the first peripheral nerve effector; reducing the tremor amplitude by modifying the patient's neural network dynamics; A method comprising: [Appendix 2] 10. The method of claim 1, wherein the placing step comprises placing the first peripheral nerve effector on the patient's skin and the first stimulus is an electrical stimulus applied to a skin surface. [Appendix 3] 3. The method of claim 2, wherein the first stimulus has an amplitude of about 0.1 mA to about 10 mA and a frequency of about 10 Hz to about 5000 Hz. [Appendix 4] 10. The method of claim 1, wherein the placing step comprises implanting the first peripheral nerve effector in the patient and the first stimulus is an electrical stimulus. [Appendix 5] 5. The method of claim 4, wherein the first stimulus has an amplitude less than about 3 mA and a frequency from about 10 Hz to about 5000 Hz. [Appendix 6] sensing movement of the patient's limbs with a measurement unit to generate movement data; determining tremor information from the motion data; 2. The method of claim 1, further comprising: [Appendix 7] 7. The method of claim 6, wherein the delivering step comprises delivering the first stimulus based on the tremor information. [Appendix 8] 8. The method of claim 7, wherein the tremor information comprises a maximum deviation from a resting position of the patient's extremity. [Appendix 9] 8. The method of claim 7, wherein the tremor information includes a resting position of the patient's extremity. [Appendix 10] 7. The method of claim 6, wherein the tremor information includes tremor frequency, phase, and amplitude. [Appendix 11] 10. The method of claim 1, wherein the step of delivering the first stimulus comprises delivering a plurality of stimulation bursts having a variable temporal delay between the stimulation bursts. [Appendix 12] placing a second peripheral nerve effector at a second location relative to a second peripheral nerve; delivering a second stimulus to the second peripheral nerve through the second peripheral nerve effector. 2. The method of claim 1, further comprising: [Appendix 13] 13. The method of claim 12, further comprising determining a period of the patient's tremor, wherein the step of delivering the second stimulus comprises offsetting delivery of the second stimulus from delivery of the first stimulus by a predetermined fraction or multiple of a period of the tremor. [Appendix 14] 13. The method of claim 12, further comprising dephasing synchronicity of neural networks in the patient's brain. [Appendix 15] 13. The method of claim 12, wherein the first location and the second location are located on adjacent fingers. [Appendix 16] 13. The method of claim 12, wherein the first peripheral nerve and the second peripheral nerve are adjacent nerves. [Appendix 17] 13. The method of claim 12, wherein the first peripheral nerve is the median nerve and the second peripheral nerve is the ulnar nerve or the radial nerve. [Appendix 18] 13. The method of claim 12, wherein the first peripheral nerve and the second peripheral nerve are somatotopically adjacent. [Appendix 19] 2. The method of claim 1, wherein the first stimulus has an amplitude below a sensory threshold. [Appendix 20] 2. The method of claim 1, wherein the first stimulus is greater than 15 Hz. [Appendix 21] 2. The method of claim 1, wherein the first peripheral nerve carries proprioceptive information from the patient's extremity. [Appendix 22] determining a duration of effectiveness of the first stimulus on reducing the tremor amplitude; and delivering a second stimulus before the expiration of the duration of efficacy; 2. The method of claim 1, comprising: [Appendix 23] 2. The method of claim 1, wherein determining the duration of effectiveness comprises analyzing multiple applications of the stimulus over a predetermined period of time. [Appendix 24] 24. The method of claim 23, wherein the step of determining the duration of efficacy further comprises determining an activity profile of the patient. [Appendix 25] 24. The method of claim 23, wherein the determining the duration of efficacy further comprises determining a profile of the tremor. [Appendix 26] 25. The method of claim 24, wherein the activity profile includes data regarding caffeine and alcohol consumption. [Appendix 27] 10. The method of claim 1, further comprising placing a conduction pathway enhancer over the first peripheral nerve. [Appendix 28] 28. The method of claim 27, wherein the conduction pathway enhancer is a conductive tattoo. [Appendix 29] 28. The method of claim 27, wherein the conduction pathway enhancer comprises one or more conductive strips. [Appendix 30] 2. The method of claim 1, wherein the first location is selected from the group consisting of a wrist, a forearm, a carpal tunnel, a finger, and an upper arm. [Appendix 31] 1. A system for treating tremor in a patient, comprising: a determination unit; and an interface unit adapted to deliver electrical stimulation to a 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; The decision unit includes a processor and a memory that stores instructions, the instructions, when executed by the processor, and causing the decision unit to deliver a first electrical stimulus to a first peripheral nerve through the first peripheral nerve effector, the electrical stimulus configured by the controller to reduce tremor in the patient's extremity by modifying the patient's neural network dynamics. system. [Appendix 32] 32. The method of claim 31, wherein the first electrical stimulus has an amplitude of less than about 10 mA and a frequency of about 10 Hz to about 5000 Hz. [Appendix 33] 32. The system of claim 31, wherein 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; and the memory storing instructions that, when executed by the processor, further cause the decision unit to deliver a second electrical stimulus through the second peripheral nerve effector to a second peripheral nerve in the patient's extremity. [Appendix 34] 31. The system of claim 30, wherein the instructions, when executed by the processor, cause the decision unit to deliver the second electrical stimulus offset in time from the first electrical stimulus by a predetermined fraction or multiple of a period of the tremor. [Appendix 35] 31. The system of claim 30, wherein the first peripheral nerve effector is adapted to be placed on a first finger and the second peripheral nerve effector is adapted to be placed on a second finger. [Appendix 36] 32. The system of claim 31, wherein the first peripheral nerve effector comprises a plurality of electrodes arranged in a linear array. [Appendix 37] 32. The system of claim 31, wherein the plurality of electrodes are spaced apart by about 1 mm to about 100 mm. [Appendix 38] 32. The system of claim 31, wherein the first peripheral nerve effector comprises a plurality of electrodes arranged in a two-dimensional array. [Appendix 39] 39. The system of claim 38, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to select a subset of the plurality of electrodes based on a position of a first peripheral nerve effector on the patient's extremity, wherein the selection of the subset of the plurality of electrodes occurs each time the first peripheral nerve effector is positioned or repositioned on the extremity. [Appendix 40] 39. The system of claim 38, wherein the plurality of electrodes are spaced apart by about 1 mm to about 100 mm along a first axis and by about 1 mm to about 100 mm along a second axis perpendicular to the first axis. [Appendix 41] a measurement unit, wherein the memory stores instructions that, when executed by the processor, measuring movement of the patient's limb using the measurement unit to generate movement data; determining tremor frequency and magnitude based on an analysis of the motion data; and 32. The system of claim 31, further causing the decision unit to: [Appendix 42] 42. The system of claim 41, wherein the analysis of the motion data includes a frequency analysis of spectral power of the motion data. [Appendix 43] 43. The system of claim 42, wherein the frequency analysis is limited to between about 4 Hz and about 12 Hz. [Appendix 44] 42. The system of claim 41, wherein the analysis of the motion data is performed on a predetermined length of time of the motion data. [Appendix 45] 42. The system of claim 41, wherein the decision unit is further adapted to determine tremor phase information based on the motion data and deliver the first electrical stimulus based on the tremor phase information. [Appendix 46] 46. ​​The system of claim 45, wherein the tremor phase information includes a peak tremor deviation, the decision unit being further adapted to deliver the first electrical stimulus at a time corresponding to the peak tremor deviation. [Appendix 47] 42. The system of claim 41, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to deliver the first electrical stimulus as a plurality of bursts of electrical stimulation having a variable temporal delay between the bursts of electrical stimulation. [Appendix 48] 42. The system of claim 41, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to set parameters of the first electrical stimulus based on the determined tremor frequency. [Appendix 49] 42. The system of claim 41, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to set parameters of the first electrical stimulus based on the determined tremor magnitude. [Appendix 50] 42. The system of claim 41, wherein the memory storing instructions that, when executed by the processor, further cause the decision unit to compare the determined tremor magnitude with a predetermined threshold; and wherein the first electrical stimulus is delivered when the determined tremor magnitude exceeds a predetermined threshold. [Appendix 51] 32. The system of claim 31, wherein the electrode is adapted to deliver the first electrical stimulus through the patient's skin. [Appendix 52] 32. The system of claim 31, wherein the electrode is adapted to be implanted and deliver the electrical stimulus to the nerve. [Appendix 53] 32. The system of claim 31, wherein the decision unit comprises a user interface adapted to accept input from a user to adjust parameters of the first electrical stimulus. [Appendix 54] 32. The system of claim 31, wherein the memory further stores a library of one or more predetermined stimulation protocols. [Appendix 55] 32. The system of claim 31, wherein the interface unit is integrated with the decision unit. [Appendix 56] 32. The system of claim 31, wherein the interface unit and the decision unit are separate from each other and have separate housings. [Appendix 57] 57. The system of claim 56, wherein the decision unit is configured to wirelessly provide power to or communicate with the interface unit. [Appendix 58] 57. The system of claim 56, further comprising a measurement unit located within the decision unit. [Appendix 59] 57. The system of claim 56, further comprising a measurement unit located within the interface unit. [Appendix 60] 57. The system of claim 56, wherein the decision unit is a computing device selected from the group consisting of a smartphone, a tablet, and a laptop. [Appendix 61] 61. The system of claim 60, further comprising a server in communication with the computing device, the server configured to receive motion data from the computing device along with a history of the electrical stimuli delivered to the patient. [Appendix 62] The server and adding the received motion data and the history of the electrical stimuli delivered to the patient to a database storing data from a plurality of patients. 62. The system of claim 61. [Appendix 63] The server comparing the received motion data and the history of the electrical stimuli delivered to the patient with data stored in the database; determining a modified electrical stimulation protocol based on a comparison of the received motion data and the history of the electrical stimuli delivered to the patient with data stored in the database; transmitting the modified electrical stimulus protocol to the computing device; 63. The system of claim 62, programmed to:

Claims

[Claim 1] 1. A system for treating tremor associated with a neurological disorder in a patient, comprising: a non-implantable wearable device having a first peripheral nerve effector; a determination unit; and at least one biomechanical sensor configured to measure movement of the patient's extremities to characterize one or more features of the tremor associated with the neurological disorder; the decision unit comprises a processor and a memory for storing instructions; The instructions, when executed by the processor, cause the device to: characterizing one or more features of the tremor associated with the neurological disorder; system.

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