WO2016137926A1 - Topical nerve stimulator and sensor for control of autonomic function - Google Patents

Topical nerve stimulator and sensor for control of autonomic function Download PDF

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Publication number
WO2016137926A1
WO2016137926A1 PCT/US2016/019032 US2016019032W WO2016137926A1 WO 2016137926 A1 WO2016137926 A1 WO 2016137926A1 US 2016019032 W US2016019032 W US 2016019032W WO 2016137926 A1 WO2016137926 A1 WO 2016137926A1
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Prior art keywords
stimulation
vagus nerve
nerve
method
axon
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PCT/US2016/019032
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French (fr)
Inventor
Graham H. Creasey
Hoo-Min Toong
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Creasey Graham H
Hoo-Min Toong
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Priority to US62/119,863 priority
Application filed by Creasey Graham H, Hoo-Min Toong filed Critical Creasey Graham H
Publication of WO2016137926A1 publication Critical patent/WO2016137926A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/0404Electrodes for external use
    • A61N1/0472Structure-related aspects
    • A61N1/0492Patch electrodes

Abstract

What is provided is an apparatus and method of modifying a nervous system signal by selectively electrically stimulating a mammalian nerve comprising: applying a dermal patch having an integral electrode in proximity to an axon in a vagus nerve or one or more of its branches or tributaries: determining a stimulation corresponding to the axon in the vagus nerve or the branch or tributary, by logic of the dermal patch; applying the stimulation by the electrodes and a stimulator integral to the dermal patch to produce an electric field; and selectively activating the axon in the vagus nerve or the branch or tributary by the electric field.

Description

Topical Nerve Stimulator and Sensor for Control of Autonomic Function

Related Applications and Claim of Priority

[0001] This application claims priority to and the benefit of the filing date of United States provisional patent application serial no. 62/119863, filed February 24, 2015. This application also claims priority to and the benefit of the filing date as a continuation-in-part application of U.S. utility patent application 14 893946 filed 1 1/25/2015, whic claims priority to and the benefit of the filing date as a national stage application of PCT patent application serial no. PCT/US 14/40240, filed May 30, 2014, which in turn claims priority to United States provisional patent application serial no. 61/828,981 , filed May 30, 2013.

Technical Problem

[0002] Mammalian and human nerves control organs and muscles. Artificially stimulating the nerves elicits desired organ and muscle responses. Accessing the nerves to selectively control these responses from outside the body, without invasive implants or needles penetrating the dermis, muscle or fat tissue is desired.

[0003] A Topical Nerve Stimulator and Sensor (TNSS) device described in the related United States Patent Application Serial No. PCT/US 14/40240 filed May 30, 2014 is used to stimulate nerves. A TNSS may apply electrode generated electric field(s) in a low frequency to dermis in the proximity of a nerve. The TNSS also includes hardware and logic for high frequency (GHz) communication to mobile devices.

[0004] A wireless system including a TNSS device is described herein. Its components, features and performance characteristics are set forth in the following technical description. Advantages of a wireless TNSS system over existing transcutaneous electrical nerve stimulation devices are;

[0005] fine control of all stimulation parameters from a remote device such as a smartphone, either directly by the user or by stored programs;

[0006] multiple electrodes of a TNSS can form an array to shape an electric field in the tissues;

[0007] multiple TNSS devices can form an array to shape an electric field in the tissues;

[0008] multiple TNSS devices can stimulate multiple structures, coordinated by a smartphone; [0009} selective stimulation of nerves and other structures at different locations and depths in a volume of tissue;

[0010] mechanical, acoustic or optical stimulation in addition to electrical stimulation;

[0011 ] transmitting antenna of TNSS device can focus beam of electromagnetic energy within tissues in short bursts to activate nerves directly without implanted devices;

[0012] inclusion of multiple sensors of multiple modalities, including but not limited to position, orientation, force, distance, acceleration, pressure, temperature, voltage, light and other electromagnetic radiation, sound, ions or chemical compounds, making it possible to sense electrical activities of muscles (EMG, EKG), mechanical effects of muscle contraction, chemical composition of body fluids, location or dimensions or shape of an organ or tissue by transmission and receiving of ultrasound;

[0013] TNSS devices are expected to have service lifetimes of days to weeks and their disposability places less demand on power sources and battery

requirements;

[001 ] combination of stimulation with feedback from artificial or natural sensors for closed loop control of muscle contraction and force, position or orientation of parts of the body, pressure within organs, and concentrations of ions and chemical compounds in the tissues;

[0015] multiple TNSS devices can form a network with each other, with remote controllers, with other devices, with the internet and with other users;

[0016} collection of large amounts of data from one or many TNSS devices and one or many users regarding sensing and stimulation, collected and stored locally or through the internet;

[0017] analysis of large amounts of data to detect patterns of sensing and stimulation, apply machine learning, and improve algorithms and functions;

[00 8] creation of databases and knowledge bases of value;

[0019] convenience;

absence of wires to become entangled in clothing

showerproof and sweat proof

low profile, flexible, camouflaged or skin colored

integrated power, communications, sensing and stimulating

inexpensive

disposable TNSS, consumable electronics

[0020] power management that utilizes both hardware and software functions will be critical to the convenience factor and widespread deployment of T SS device. Description of Action Potentials and Nerve Physiology

[0021] Referring to Figure 1, a nerve cell normally has a voltage across the cell membrane of 70 millivolts with the interior of the cell at a negative voltage with respect to the exterior of the cell . This is kno wn as the resting potential and it is normally maintained by metabolic reactions which maintain different

concentrations of electrical ions in the inside of the cell compared to the outside. Ions can be actively "pumped" across the cell membrane through ion channels in the membrane that are selective for different types, of ion, such as sodium and potassium. The channels are voltage sensitive and can be opened or closed depending on the voltage across the membrane. A electric field produced within the tissues by a stimulator can change the normal resting voltage across the membrane, either increasing or decreasing the voltage from its resting voltage.

[00223 Referring- to Figure 2, a decrease in voltage across the cell membrane to about 55 millivolts opens certai ion channels, allowing ions to flow through the membrane in a self-catalyzing but self-limited process which results in a transient decrease of the trans membrane potential to zero, and even positive, known as depolarization followed by a rapid restoration of the resti ng potential as a result of acti ve pumping of ions across the membrane to restore the resting situation which is known as repolarization. This transient change of voltage is known as an action potential and it typically spreads over the entire surface of the cell. If the shape of the cell is such that it has a long extension known as an axon, the action potential spreads along the length of the axon. Axons that have insulating myelin sheaths propagate action potentials at much higher speeds than those axons without myelin sheaths or with damaged myelin sheaths.

[0023] If the action potential reaches a junction, known as a synapse, wit another nerve cell, the transient change in membrane voltage results in the release of chemicals known as neurotransmitters that can initiate an action potential in the other cell. This provides a means of rapid electrical communication 'between cells, analogous to passing a digital pulse from one cell to another.

[0024] If the action potential reaches a synapse with a muscle cell it can initiate an action potential that spreads over the surface of th muscle ceil. This voltage change across the membrane of the musc le cell opens ion channels in the membrane that allow ions such as sodium, potassium and calcium to flow across the membrane, and ca result in contraction of the muscle cell.

[0025] Increasing the voltage across the membrane of a ceil belo -70 milli volts is known as hyper-polarization and reduces the probability of an action potential being generated in the cell. This can be useful for reducing nerve activit and thereby reducing unwanted symptoms such as pain and spasticity

[0026] The voltage across the membrane of a cell can be changed by creating an electric field in the tissues with a stimulator. It is important to note that action potentials are created within the mammalian nervous system by the brain, the sensory nervous system or other internal means. These action potentials travel along the body's nerve "highways". The TNSS creates an action potential through an externally applied electric field from outside the body. This is very different than how action potentials are naturally created within the body.

Electric Fields that can cause Action Potentials

[0027} Referring to Figure 2, electric fields capable of causing action potentials can be generated by electronic stimulators connected to electrodes that are implanted surgically in close pro imity to the target nerves. To avoid the many issues associated with implanted devices, it is desirable to generate the required electric fields by electron ic devices located on the surface of the skin. Such devices typically use square wave pulse trains of the form shown in Figure 3. Such devices ma be used instead of implants and/or with implants such as reflectors, conductors, refractors, or markers for tagging target nerves and the like, so as to shape electric fields to enhance nerve targeting and/or selectivity.

[0028] Referring to Figure 3, the amplitude of the pulses, A, applied to the skin, may vary between 1 and 100 Volts, pulse width, t, between 100 microseconds and 10 milliseconds, duty cycle (t/T) between 0.1 % and 50%, the frequency of the pulses within a group between 1 and 100/sec, and the number of pulses per group, n, between 1 and several hundred. Typically, pulses applied to the skin will have an amplitude of up to 60 volts, a pulse width of 250 microseconds and a frequency of 20 per second, resulting in a duty cycle of 0.5%. In some cases balanced-charge biphasic pulses will be used to avoid net current flow. Referring to Figure 4, these pulses may be symmetrical, with the shape of the first part of the pulse similar to that of the second part of the pulse, or asymmetrical, in which the second part of the pulse has lower amplitude and a longer pulse width in order to avoid canceling the stimulatory effect of the first part of the pulse.

Formation of Electric Fields by Stimulators

[0029] The location and magn itude of the electric potential applied to the tissues by electrodes provides a method of shaping the electrical field. For example, applying two electrodes to the skin, one at positive electrical potential with respect to the other, can produce a field in the underlying tissues such as that shown in the cross-sectional diagram, Figure 5.

[0030] The diagram in Figure 5 assumes homogeneous tissue. The voltage gradient is highest close to the electrodes and lower at a distance from the electrodes. Nerves are more likely to be activated close to the electrodes than at a distance. For a given voltage gradient, nerves of large diameter are more likely to be activated than nerves of smaller diameter. Nerves whose long axis is aligned with the voltage gradient are more likely to be activated than nerves whose long axis is at right angles to the voltage gradient. [00311 Referring to Figure 6, applying similar electrodes to a part of the body in which there are two layers of tissue of different electrical, resistivity, such as fat and muscle, can produce a field such as that shown in Figure 6. Layers of different tissue may act to refract and direct energy waves and be used for beam aiming and steering. An individual's tissue parameters may be measured and used to

characterize the appropriate energy stimulation for a selected nerve.

[0032] Referring to Figure 7, when the stimulating pulse i s turned off the electric field will collapse and the fields will be absent as shown.

[0033] It is the change in electric field mat will cause an action potential to be created in a nerve cell, provided sufficient voltage and the correct orientation of the electric field occurs. More comple three-dimensional arrangements of tissues with different electrical properties can result in more complex three-dimensional electric fields, particularly since tissues have different electrical properties and these properties are different along the length of a tissue and across it, as shown in Table 1.

Table 1

Figure imgf000010_0001
Figure imgf000011_0001

Modification of Electric Fields by Tissue

[0034] An important factor in the formation of electric fields used to create action potentials in nerve cells is the medium through which, the electric fields must penetrate. For the human body this medium consists of various types of tissue including bone, fat, muscle, and skin. Each of these tissues possesses different electrical resistivity or conductivity and different capacitance and these properties are anisotropic. They are not unifonn in all directions within the tissues. For example, an axon has lower electrical resistivity along its axis than

perpendicular to its axis. The wide range of conductivities is shown in Table 1. The three-dimensional structure and resistivity of the tissues will therefore affect the orientation and magnitude of the electric field at any given point in the body. Modification of Electric Fields by Multiple Electrodes [0035] Applying a larger number of electrodes to the skin can also produce more complex three-dimensional electrical fields that can be shaped by the location of the electrodes and the potential applied to each of them. Referring to Figure 3, the pulse trains can differ from one another indicated by A, t/T, n, and f as well as have different phase relationships between the pulse trains. For example with an 8x8 array of electrodes, combinations of electrodes can be utilized ranging from simple dipoles, to quadripoles, to linear arrangements, to approximately circular configurations, to produce desired electric fields within tissues.

[0036] Applying multiple electrodes to a part of the body with complex tissue geometr will thus result in an electric field of a complex shape. The interaction of ■electrode arrangement and tissue geometry- can be modeled using Finite Element Modeling, which is a mathematical method of dividing the tissues into many small elements in order to calculate the shape of a complex electric field. This can be used to design an electric field of a desired shape and orientation to a particular nerve.

[0037] High frequency techniques known for modifying an electric field, such as the relation between phases of a beam, cancelling and reinforcing by using phase shifts, may not apply to application of electric fields by TNSSs because they use low frequencies. Instead, the present system uses beam selection to mov e or shift or shape an electric field, also described as field steering or field shaping, by activating different electrodes, such as from an array of electrodes, to move the field. Selecting different combinations of electrodes from an array may result in beam or field steering. A particular combination of electrodes may shape a beam and or change the direction of a beam by steering. This may shape the electric field to reach a target nerve selected for stimulation.

Activation of Nerves by Electric Fields

[0038] Usually in. the past selectivity in activating nerves has required electrodes to be implanted surgically on or near nerves. Using electrodes on the surface of the skin to focus activation selectively on nerves deep in the tissues has many advantages. These include avoidance of surgery, avoidance of the cost of developing complex implants and gaining regulatory approval for them, and avoidance of the risks of long-term implants.

[0039] The features of the electric field that determine whether a nerve will be activated to produce an action potential can be modeled mathematically by the Activating Function described by Rattay (Rattay F. The basic mechanism for the electrical stimulation of the nervous system. Neuroseience Vol. 89, No. 2, pp. 335- 346, 1999). The electric field can produce a voltage, or extracellular potential, within the tissues that varies along the l ength of a nerve. If the voltage is

proportional to distance along the nerve, the first order spatial derivative will be constant and the second order spatial derivative will be zero. If the voltage is not proportional to distance along the nerv e, the first order spatial derivative will not be constant and the second order spatial derivative will not be zero. The Activating Function is proportional to the second-order spatial derivative of the extracellular potential along the nerve. If it is sufficiently greater than zero at a given point it predicts whether the electric field will produce an action potential in the nerve at that point. This prediction may be input to a nerve signature.

[0040] In practice this means that electric fields that are varying sufficiently greatly in space or time can produce action potentials in nerves. These action potentials are also most likely to be produced where the orientation of the nerves to the fields change, either because the nerve or the field changes direction. The direction of the nerve ca be determined from anatomical studies and imaging studies such as MRI scans. The direction of the field can be determined by the positions and configurations of electrodes and the voltages applied to them, together with the electrical properties of the tissues.

[0041] As a result it is possible to activate certain nerves at certain tissue locations selectively while not activating others.

[0042] To accurately control an organ or muscle, the nerve to be activated must be accurately selected. This selectivity may be improved by using the system described herein, and described herein as a nerve signature, in several ways, as follows: [0043] Improved algorithms to control the effects when a nerve is stimulated, for example, by measuring the resulting electrical or mechanical activity of muscles and feeding back this information to modify the stimulation and measuring the effects again. Repeated iterations of this process can result in optimizing the selectivity of the sti mulation, either by classical closed loop control or by machine learning techniques such as pattern recognition and artificial intelligence;

[0044] Improving nerve selectivity by labeling or tagging nerves chemically; for example, introduction of genes into some nerves to render them responsive to light or other electromagnetic radiation can result in the ability to activate these nerves and not others when light or electromagnetic radiation is applied from outside the body;

[0045] Improving nerve selectivity by the use of electrical conductors to focus an electric field on a nerve; these conductors might be implanted, but could be passive and much simpler than the active implantable medical devices currently used;

[0046] Improving nerve selectivity by the use of reflectors or refractors, either outside or inside the body, to focus a beam of electromagnetic radiation on a nerve. If these reflectors or refractors are implanted, they may be passive and much simpler than the active implantable medical devices currently used; [0047] Improving nerve selectivity by the use of feedback from the person upon whom the stimulation is being performed; this may be an action taken by the person in response to a physical indication such as a muscle activation or a feeling from one or more nerve activations;

[0048] Improving nerve selectivity by the use of feedback from sensors associated with the TNSS, or separately from other sensors, that monitor electrical activity associated with the stimulation; and

[0049] improving nerve selectivity by the combination of feedback from both the person or sensors and the TNSS that may be used to create a unique profile of the user's nerve physiology for selected nerve stimulation.

[0050] Potential applications of electrical stimulation to the body are shown in Figure 8.

LOGIC COMPONENTS

[0051] Referring to Figure 9 A, the TNSS 934 human and mammalian interface and its method of operation and supporting system are managed by a Master Control Program (MCP) 910 represented in function format as block diagrams. It provides the logic for the nerve stimulator system.

Master Control Program

[0052] The primary responsibility of the MCP 910 is to coordinate the activities and communications among the various control programs, the Data Manager 920, the User 932, and the external ecosystem and to execute the appropriate response algorithms in each situation. The MCP 910 accomplishes electric field shaping and/or beam steering by providing an electrode activation pattern to the TNSS device 934 to selectively stimulate a target nerve. For example, upon notification by the Communications Controller 930 of an external event or request, the MCP 910 is responsible for executing the appropriate response, working with the Data Manager 920 to formulate the correct response and actions. It integrates data from various sources such as Sensors 938 and external inputs such as TNSS devices 934, and applies the correct security and pri vacy policies, such as encryption and HIPAA required protocols. It will also manage the User Interface (UI) 912 and the various Application Program Interfaces (APIs) 914 that provide access to external programs.

[0053] The MCP is also responsible for effectively managing power

consumption by the TNSS device through a combination of software algorithms and hardware components that may include, among other things: computing, communications, and stimulating electronics, antenna, electrodes, sensors, and power sources in the form of conventional or printed batteries.

Communications Controller

[0054] The communications controller is responsible for receiving inputs from the User 932, from a plurality of TNSS devices 934, and from 3rd party apps 936 via communications sources such as Internet or cellular networks. The format of such inputs' will vary by source and must be recei ved, consolidated, possibly reformatted, and packaged for the Data Manager 920.

{0055] User inputs may consist of simple requests for acti vation of TNSS devices 934 to status and information concerning the User's 932 situation or needs. TNSS devices 934 will provide signaling data that may consist of voltage readings, TNSS 934 status data, responses to control program inquiries, and other signals. The Communications Controller 930 is also responsible for sending data and control requests to the plurality of TNSS devices 934. 3rd party applications 936 can send data, requests, or mstructions for the Master Control Program 910 or User 932 via Internet or cellular networks. The Communications Controller 930 is also responsible for communications via the cloud where various software applications reside.

Data Manager

[0056] The Data Manager (DM) 920 has primary responsibility for the storage and movement of data to and from the Communications Controller 930, Sensors 938, Actuators 940, and the Master Control Program 910. The DM 920 has the capability to analyze and correlate any of the data under its control. It provides logic to select and activate nerves. Examples of such operations upon the data include: statistical analysis and trend identification; machine learning algorithms; signature analysis and pattern recognition, correlations among the data within the Data Warehouse 926, the Therapy Library 922, the Tissue Models 924, and the Electrode Placement Models 928, and other operations. There are several components to the data that is under its control as described in the following paragraphs.

[0057] The Data Warehouse (DW) 926 is where incoming data is stored;

examples of this data can be real-time measurements from TNSS devices 934 or from Sensors (938), data streams from the Internet, or control and instructional data from various sources. The DM 920 will analyze data, as specified above, that is held in the DW 926 and cause actions, including the export of data, under MCP 910 control. Certain decision making processes implemented by the DM 920 will identify data patterns both in time, frequency, and spatial domains and store them as signatures for reference by other programs. Techniques like EMG, even multi- electrode EMG, gather a lot of data that is the sum of hundreds to thousands of individual motor units and the normal procedure is to perform complex

decomposition analysis on the total signal to attempt to tease out individual motor units and their behavior. The DM 920 will perform big data analysis over the total signal and recognize patterns that relate to specific actions or even individual nerves or motor units. This analysis can be performed over data gathered in time from an individual, or over a population of TNSS Users. [0058] The Therapy Library 922 contains various control regimens for the TNSS devices 934. Regimens specify the parameters and patterns of pulses to be applied by the TNSS devices 934. The width and amplitude of individual pulses may be specified to stimulate nerve axons of a particula size selectively without

stimulating nerve axons of other sizes. The frequency of pulses applied may be specified to modulate some reflexes selectively without modulating other reflexes. There are preset regimens that may be loaded from the Cloud 942 or 3rd party apps 936. The regimens may be static read-only as well as adaptive with read-write capabilities so they can be modified in real-time responding to control signals or feedback signals or software updates. Referring to Figure 3 one such embodiment of a regimen has parameters A = 40 volts, t = 500 microseconds, T = 1

millisecond, n = 100 pulses per group, and f = 20 per second. Other embodiments of regimens will vary the parameters within ranges previously specified.

[0059] The Tissue Models 924 are specific to the electrical properties of particular body locations where TNSS devices 934 may be placed. As noted previously, electric fields for production of action potentials will be affected by the different electrical properties of the various tissues that they encounter. Tissue Models 924 are combined with regimens from the Therapy Library 922 and

Electrode Placement Models 928 to produce desired actions. Tissue Models 924 may be developed by MRI, Ultrasound or other imaging or measurement of tissue of a body or particular part of a body. This may be accomplished for a particular User 932 and/or based upon a body norm. One such example embodiment of a desired action is the use of a Tissue Model 924 together with a particular Electrode Placement Model 928 to determine how to focus the electric field from electrodes on the surface of the body on a specific deep location corresponding to the pudendal nerve in order to stimulate that nerve selectively to reduce incontinence of urine. Other example embodiments of desired actions may occur when a Tissue Model 924 in combination with regimens from the Therapy Library 22 and

Electrode Placement Models 928 produce an electric field that stimulates a sacral nerve. Many other embodiments of desired actions follow for the stimulation of other nerves.

[0060] Electrode Placement Models 928 specify electrode configurations that the TNSS devices 934 may apply and activate in particular locations of the body. For example, a TNSS device 934 may have multiple electrodes and the Electrode Placement Model 928 specifies where these electrodes should be placed on the body and whicii of these electrodes should be active in order to stimulate a specific structure selectively without stimulating other structures, o to focus an electric field on a deep structure. An example embodiment of an electrode configuration is a 4 by 4 set of electrodes within a larger array of multiple electrodes, such as an 8 by 8 array. This 4 by 4 set of electrodes may be specified anywhere within the larger array such as the upper right corner of the 8 by 8 array. Other example embodiments of electrode configurations may be circular electrodes that may even consist of concentric circular electrodes. The TNSS device 934 may contain a wide range of multiple electrodes of which the Electrode Placement Models 928 will specify which subset will be activated. These Electrode Placement Models 928 complement the regimens in the Therapy Library 922 and the Tissue Models 924 and are used together with these other data components to control the electric fields and their interactions with nerves, muscles, tissues and other organs. Other examples may include TNSS devices 934 having merely one or two electrodes, such as but not limited to those utilizing a closed circuit.

Sensor/ Actuator Control

[0061] Independent sensors 938 and actuators 940 can be part of the TNSS system. Its functions can complement the electrical stimulation and electrical feedback that the TNSS devices 934 provide. An example of such a sensor 938 and actuator 940 include, but are not limited to, an ultrasonic actuator and an ultrasonic receiver that can provide real-time image data of nerves, muscles, bones, and other tissues. Other examples include electrical sensors that detect signals from stimulated tissues or muscles. The Sensor/Actuator Control module 950 provides the ability to control both the actuation and pickup of such signals, all under control of the MCP 910. Application Program Interfaces

[0062] The MCP 910 is also responsible for supervising the various Application Program Interfaces (APIs) that will be made available for 3rd party developers. There may exist more than one API 914 depending upon the specific developer audience to be enabled. For example many statistical focused apps will desire access to the Data Warehouse 926 and its cumulative store of data recorded from TNSS 934 and User 932 inputs. Another group of healthcare professionals may desire access to the Therapy Libraiy 922 and Tissue Models 924 to construct better regimens for addressing specific diseases or disabilities. In each case a different specific API 914 may be appropriate.

[0063] The MCP 910 is responsible for many software functions of the TNSS system including system maintenance, debugging and troubleshooting functions, resource and device management, data preparation, analysis, and communications to external devices or programs that exist on the smart phone or in the cloud, and other functions. However, one of its primary functions is to serve as a global request handler taking inputs from devices handled by the Communications Controller 930, external requests from the Sensor Control Actuator Module (950), and 3rd party requests 936.

[0064] Examples of High Level Master Control Program (MCP) functions are set forth in the following paragraphs. [0065] The manner in which the MCP handles these requests is shown in Fig 9B. The Request Handler (RH) 960 accepts inputs from the User 932, TNSS devices 934, 3rd party apps 936, sensors 938 and other sources. It determines the type of request and dispatches the appropriate response as set forth in the following paragraphs.

[0066] User Request: The RH 960 will determine which of the plurality of User Requests 961 is present such as: activation; display status, deactivation, or data input, e.g. specific User condition. Shown in Figure 9B is the RH's 960 response to an activation request. As shown in block 962, RH 960 will access the Therapy Library 922 and cause the appropriate regimen to be sent to the correct TNSS 934 for execution, as shown at block 964 labeled "Action,"

[0067] TNSS. Sensor Inputs: The RH 960 will perform data analysis over TNSS 934 or Sensor inputs 965. As shown at block 966, it employs data analysis, which may include techniques ranging from DSP decision making processes, image processing algorithms, statistical analysis and other algorithms to analyze the inputs. In Figure 9B two such analysis results are shown; conditions which cause a User Alarm 970 to be generated and conditions which create an Adaptive Action 980 such as causing a control feedback loop for specific TNSS 934 functions, which of course can iteratively generate further TNSS 934 or Sensor inputs 965 in a closed feedback loop. [0068] 3rd Party Apps: Applications can communicate with the MCP 910, both sending and recei ving communications. A typical communication would be to send informational data or commands to a TNSS 934. The RH 960 will analyze the incoming application data, as shown at block 972. Figure 9B shows two such actions that result. One action, shown at block 974 would be the presentation of the application data, possibly reformatted, to the User 932 through the MCP User Interface 912. Another result would be to perform a User 932 permitted action, as shown at 976, such as requesting a regimen from the Therapy Library 922.

[0069] Referring to Figure 10, an example TNSS is shown. The TNSS has one or more electronic circuits or chips 1000 that perform the functions of:

communications with the controller, nerve stimulation via one or more electrodes 1008 that produce a wide range of electric field(s) according to treatment regimen, one or more antennae 1010 that may also serve as electrodes and communication pathways, and a wide range of sensors 1006 such as, but not limited to, mechanical motion and pressure, temperature, humidity, chemical and positioning sensors. In another example, TNSS interfaces to transducers 1014 to transmit signals to the tissue or to receive signals from the tissue.

[0070] One arrangement is to integrate a wide variety of these functions into an SOC, system on chip 1000. Within this is shown a control unit 1002 for data processing, communications, transducer interface and storage and one or more stimulators 1004 and sensors 1006 that are connected to electrodes 1008. An antenna 1010 is incorporated for external communications by the control unit. Also present is an internal power supply 1012, which may be, for example, a battery. An external power supply is another variation of the chip configuration. It may be necessary to include more than one ch ip to accommodate a wide range of voltages for data processing and stimulation. Electronic circuits and chips will communicate with each other via conductive tracks within the device capable of transferring data and/or power.

[0071] The TNSS interprets a data stream from the control device, such as that shown in Figure 9A, to separate out message headers and delimiters from control instructions. In one arrangement, control instructions contain information such as voltage level and pulse pattern. The TNSS activates the stimulator 1004 to generate a stimulation signal to the electrodes 1008 placed on the tissue according to the control instructions. In another arrangement the TNSS activates a transducer 1014 to send a signal to the tissue. In another embodiment, control instructions cause information such as voltage level and pulse pattern to be retrieved from a library stored in the TNSS.

[0072] TNSS receives sensory signals from the tissue and translates them to a data stream that is recognized by the control device, such as the example in Figure 9A. Sensory signals include electrical, mechanical, acoustic, optical and chemical signals among others. Sensoiy signals come to the TNSS through the electrodes 1008 or from other inputs originating from mechanical, acoustic, optical, or chemical transducers. For example, an electrical signal from the tissue is

introduced to the TNSS through the electrodes 1008, is converted from an analog signal to a digital signal and then inserted into a data stream that is sent through the antenna 1010 to the control device. In another example an acoustic signal is received by a transducer 1014 in the TNSS, converted from an analog signal to a digital signal and then inserted into a data stream that is sent through the antenna 1010 to the control device. In certain cases sensory signals from the tissue are directly interfaced to the control device for processing.

APPLICATION TO AUTONOMIC NERVOUS SYSTEM

[0073] Functions controlled by the autonomic nervous system may be modified directly or indirectly using the principles described above. Referring to Figure 10, in some cases, electrical stimulation of efferent axons in the vagus nerve or its branches can, for example, produce slowing of the heart, reduction in biood pressure, treatment of asthma, or increase in peristaltic activit of the stomach and intestines or increase in secretion of digestive enzymes.

[0074] In other cases, electrical stimulation of afferent axons in the vagus nerve or its tributaries can cause action potentials that travel to the central nervous system and alter the activity in efferent nerves to the cardiovascular, respiratory and gastrointestinal systems. This can result in stimulation or inhibition of reflex activity affecting these systems, such as altered heart rate or gastrointestinal movement or secretion of digestive enzymes. This can also result in reduced inflammation. This may be useful for example in controlling irritable bowel disease.

[0075] In other cases, electrical stimulation of afferent axons in the vagus nerve or its tributaries can cause action potentials that travel to the central nervous system and alter the activity of other nerves within the central nervous system, resulting in sensations or altered behavior, such as a sensation of satiety and reduced consumption of food . This may be useful in controlling obesity. They may also result in reduction of seizures, which may be useful in controlling epilepsy. They may also result in reduction of headaches, migraines and depression.

[0076] Non-invasive methods of directing or focusing electrical stimulation from electrodes on the surface of the skin may be used to allow selective stimulation of nerves such as the vagus without the need for surgical implantation of electrodes or stimulators. A plurality of electrodes can be applied to the skin of the ear, neck or chest or abdomen in proximity to the vagus nerve or its branches or tributaries, and electric fields or electromagnetic beams produced by these electrodes can be directed towards the vagus nerve or its branches or tributaries to initiate action potentials. The electrodes on the surface of the skin are connected to or part of a Topical Nerve Stimulator and Sensor (TNSS).

[0077] Electrodes ma be applied to the skin of the ear to stimulate the auricular branch of the vagus nerve, which innervates the cavity and cymba of the concha of the ear. These electrodes may be part of a TNSS in the form of an earplug or earphone that stimulates the auricular branc of the vagus nerve selectively and may be controlled from a smartphone.

[0078} Electrodes may be applied to the skin of the neck to stimulate the vagus nerve in the carotid sheath. These electrodes may be part of a TNSS in the form of an adhesive patch that may be controlled from a smartphone. The TNSS may have multiple electrodes used to focus an electric field or electric beam selectively on the vagus nerve in the neck.

[0079] Axons in the vagus nerve may be activated selectively according to their diameter. Large axons can be activated with lower voltages and currents than small axons. This allows selectivity in using the electrical stimulation to affect functions influenced by the vagus nerve.

[0080] The stimulator may be operated voluntarily by the user or may be operated automatically in response to software programs or signals from sensors in the TNSS or elsewhere in a TNSS system shown in Figure 12.

Voluntary Operation by the User [0081 ] When the user becomes aware, for example, of a rapid heart rate or of symptoms of asthma or sensation such as hunger or a craving for food or, the user presses a button on the TNSS 1101 or a Control Device 1106 which may be a smartphone or a dedicated device. A dedicated device is a small portable device resembling a key fob and containing electronic circuits for storage and operation of programs and buttons that the user can operate. When the user presses a button on the Control Device this can cause it to transmit radio-frequency signals to the TNSS to control the operation of the TNSS. The Control Device can also receive radio-frequency signals from the TNSS.

[0082] The TNSS and the Control Device are under software control, responding to an action from the user. There will be safeguards to prevent false activations or unnecessary repetitive activations. The activation by the user causes a stimulator in the TNSS to send electrical stimulation signals 1202 to activate the vagus nerve 1203 or one of its branches or tributaries innervating the heart, lungs or intestines, as described above.

[0083] The TNSS can stimulate the appropriate nerve(s) to produce a desired effect with a preset pulse signal, or the user can select from variety of pulse signals and their intensities; this might be implemented as one or more of a plurality of virtual buttons on the interface of a smartphone or physical buttons on a dedicated device. The user can select from programs to deal with a variety of desired effects on the heart, lungs or intestines or on the brain; the programs may provide an intermi ttent or a continuous pulse signal and the signal may have a timeout of a duration chosen by the user. The user can reactivate the TNSS either immediately if the appetite for food is not completely abated, or the next time he/she feels the appetite for food.

Automatic Operation

[0084] In some cases it will be possible to control the stimulation automatically, without the intervention of the user. The normal command signal to cause the TNSS to be activated comes from the user, who communicates to the Control Device 1206 as described previously. There is a plurality of other non-invasive portable methods of obtaining sensory information that can control stimulation in parallel with or separately from this command signal.

{0085] For example, the TNSS system may include a sen sor of blood pressure or heart rate that may transmit a signal to the TNSS or Control Device. The TNSS will then automatically stimulate the vagus nerve or one of its branches or tributaries as described above to reduce blood pressure or heart rate before the user becomes aware of the need to do so. This automatic mode of operation will make use of the various feedback loops shown in Figure 12. For example, the blood pressure or the rate of the heart 1204 may be sensed and transmitted 1205 to the TNSS which may act upon the signal to send a signal 1202 to stimulate the branches of the vagus nerve 1203 that control the blood pressure or the rate of the heart 1204. The TNSS may also send signals 1207 to a Control Device 1206 that can respond with signals 1205 to control the TNSS. The Control Device 1206 may also send signals 121.0 to the User who may respond with signals 1208 to modify the actions of the Control Device 1206. The Control Device 1206 may also send signals 1203 via the Internet to other users who may respond with signals 1214 to modify the actions of the Control Device 1206.

Adaptive Operation

[0086] With training using data from one or many individuals, software in the TNSS or in the Control Device 1206 or in other computing systems available via the internet may use machine learning to recognize patterns in time or space and improve control of the blood pressure or heart rate or other body functions controlled via the vagus nerv e.

[0087] There may be additional functions in addition to the operations described above. These include logging functions, incorporating data from the cloud, and data from other sensors and sources. They may also include adaptive control of motilit of the stomach and intestines and control of secretions of the

gastrointestinal tract and its associated glands.

[0088] Upon activation of the TNSS one or more of the following functions can occur. [0089} The user's activation profile is recorded by the TNSS and shared with the Control Device 1206. The activation profile consists of a User ID, stimulation signal identifier and stimulus parameters, date and time of day, and if the user interface permits, user conditions at the time of activation. Historical data can be gathered and analyzed for the user's benefit.

[0090] The Control Device 1206 and/or the TNSS may accept data from other users via the internet. Types of data may be instructions from a healthcare professional, population data, statistical analyses and trend data relative to the individual user or across populations. This data can be passed through to the user, or cause actions to be taken, such as alarms or notifications.

[0091} Data can be gathered from other sensors on a continuous basis or only when the TNSS is activated. When the TNSS is activated, these data can be used to alter or modify the stimulation signals that the TNSS transmits to the user. An example would be a senso of heart rate that would allow the TNSS to gather heart rate data over time and learn the patterns of heart rate variability , as compared to historical conditions.

Application of TNSS to Control Cardiac Function

[0092] An example of an application of TNSS to control cardiac function is as follows. [0093] Electrical signals are applied to an array of electrodes on the surface of the skin to produce an electrical field or an electromagnetic beam within the tissues that is focused on the vagus nerve or its branches innervating the heart. This produces action potentials in these nerves that are conducted directly or via reflex pathways to the heart where they cause a desired reduction in blood pressure or heart rate. In this way the effects of an excessive blood pressure or heart rate can be relieved with reduced need for medication and with more rapid and accurate control than with medication.

Application of TNSS to Control Gastrointestinal Motility

[00941 An example of an application of TNSS to control gastrointestinal motility is as follows.

[0095] Electrical signals are applied to an array of electrodes on the surface of the skin to produce an electrical field or an electromagnetic beam within the tissues that is focused on the vagus nerve or its branches innervating the stomach and intestines. This produces action potentials in these nerves that are conducted to the stomach and intestines where they cause a desired increase in motility. In this way the symptoms or signs of gastroparesis or constipation can be relieved with reduced need for medication and with more rapid and accurate control than with medication.

Appl ication of TNSS to Control Obesity [0096] An example of an application of TNSS to control obesity is as follows.

[0097] Electrical signals are applied to an array of electrodes on the surface of the skin to produce an electrical field or an electromagnetic beam within the tissues that is focused on the vagus nerve or its tributaries innervating the gastrointestinal tract. This produces action potentials in these nerves that are conducted to the brain where they produce a sensation of satiety and reduced appetite, resulting in reduced consumption of food and control of obesity.

Application of TNSS to Control Seizures

[0098] An example of an application of TNSS to control epilepsy or seizures is as follows.

[0099] Electrical signals are applied to an array of electrodes on the surface of the skin to produce an electrical field or an electromagnetic beam within the tissues that is focused on the vagus nerve or its tributaries. This produces action potentials in these nerves that are conducted to the brain where they reduce the frequency or intensity of seizures.

[00100] As outlined above, these signals may be applied in voluntary operation by the user. For example when the user becomes aware of an epileptic aura or other symptoms of an impending seizure, the user may initiate stimulation of the vagus nerve to reduce or prevent a seizure. [00101] As outlined above, these signals may also be applied in automatic and adaptive operation. For example, sensors in the TNSS sy stem may detect electrical activity from the brain similar to the electroencephalogram or from or other parts of the nervous system indicating an impending seizure. \ en this acti vity or pattern of activity is detected, stimulation of the vagus nerve may be initiated automatically using stored algorithms and software control to reduce the

frequency, duration or intensity of seizures.

Application of TNSS to Control Inflammation

[00102] An example of an application of TNSS to control epilepsy or seizures is as follows.

[00103] Electrical signals are applied to an array of electrodes on the surface of the skin to produce an electrical field or an electromagnetic beam within the tissues that is focused on the vagus nerve or its branches innervating the spleen. This produces action potentials in these nerves that can suppress pro -inflammatory cytokine production and improve symptoms of arthritis, colitis and other

inflammatory diseases.

Claims

Claims
1. A method of modifying a nervous system signal by selectively electrically stimulating a mammalian nerve comprising:
applying a dermal patch having an integral electrode in proximity to an axon in a vagus nerve or one or more of its branches or tributaries;
determining a stimulation corresponding to the axon in the vagus nerve or the branch or tributary, by logic of the dermal patch;
applying the stimulation by the electrodes and a stimulator integral to the dermal patch to produce an electric field; and
selectively activating the axon in the vagus nerve or the branch or tributary by the electric field.
2. The method of claim 1, further comprising:
selectively activating an afferent axon in the vagus nerve or its tributaries;
the stimulation causing an action potential to travel to a central nervous system and alter an activity in an efferent nerve to a cardiovascular, respiratory or gastrointestinal system;
the stimulation causing a stimulation or inhibition of a reilex activity affecting the cardiovascular, respiratory or gastrointestinal system.
3. The method of claim 2, the stimulation causing an altered heart rate, an altered gastrointestinal movement or a secretion of digestive enzymes.
4. The method of claim 1 , further comprising the stimulation producing a slowing of a heart.
5. The method of claim 1, further comprising selectively activating the axon in the vagus nerve or its branches innervating a heart, producing an action potential in the vagus nerve or its branches innervating the heart that are conducted directly or via a reflex pathway to the heart causing a reduction in blood pressure or heart rate.
6. The method of claims 1 , further comprising the stimulation producing an increase in a peristaltic activity of a stomach or intestines.
7. The method of claim 1 , further comprising the stimulation producing an increase in a secretion of a digestive enzyme.
8. The method of claim I, further comprising selectively activating the axon in the vagus nerve or its branches innervating a stomach or an intestine, producing an action potential in the vagus nerve or its branches innervating the stomac or the intestine that is conducted to the stomach or the intestine causing an increase in motility.
9. The method of claim 1, further comprising selectively activating an afferent axon in the vagus nerve or its tributaries innervating the
gastrointestinal tract; the stimulation causing an action potential in the vagus nerve or its tributaries innervating the gastrointestinal tract that is conducted via a central nervous system to a brai that produces an action potential in another nerve within the central nervous system, resulting in a sensation of satiety or reduced appetite, or an altered behavior of reduced consumption of food.
10. The method of claim I, the stimulation producing an action potential in a nerve that is conducted to a brain to reduce a frequency or intensity of a seizure.
11. The method of claim I, further comprising selectively activating an axon in the vagus nerv e or its tributaries innervating a spleen, producing an action potential in the vagus nerve or its branches innervating the spleen to alter pro-inflammatory cytokine production.
12. The method of claim 1, the stimulation reducing a symptom of arthritis, colitis or another inflammatory disease.
13. The method of claim 1, further comprisi ng receiving a manual command to activate the stimulator from a remote control device.
14. The method of claims 1 , further comprising receiving physiological feedback from a sensor or a manual input; and iterati vely adjusting the stimulation based upon the feedback.
15. The method of claims 1 , further comprising receiving blood pressure or heart rate data from a sensor; and automatically activating the stimulation to selectively activate the axon of the vagus nerve or one of its tributaries that control blood pressure or heart rate, to reduce the blood pressure or heart rate.
16. The method of claims 1, further comprising detecting an electrical activity from the brain or from or other parts of a nervous system indicating an impending seizure; and automatically activating the stimulation to selectively activate the axon of the vagus nerve to reduce the frequency, duration or intensity of a seizure.
17. The method of claim 1, further comprising using machine learning to recognize a pattern in time or space and modify the stimulation to improve control of a bodily function controiied by the vagus nerve, a motility of a stomach or an intestine or control of a secretion of a gastrointestinal tract or its associated glands.
18. An apparatus for modifying an autonomic nervous system signal by selectively electrically stimulating a mammalian nerve comprising::
a dermal patch having an integral electrode configured to select an axon in a vagus nerve or one or more of its branches or tributaries;
logic to determine a stimulation corresponding to the axon in the vagus nerve or the branch or tributary to produce an electric field; and a stimulator to activate the electrodes in proximity to the vagus nerve or its branch or tributary to selectively activate the vagus nerve or the branch or tributary by the electric field.
19. The apparatus of claim 18, further comprising logic to receive a manual command to activate the stimulator from a remote control device.
20. The apparatus of claims 18, fuither comprising a sensor to receive physiological feedback from an efferent nerve to a cardiovascular, respiratory or gastrointestinal system, and automatically activating the stimulation based upon the feedback.
PCT/US2016/019032 2015-02-24 2016-02-23 Topical nerve stimulator and sensor for control of autonomic function WO2016137926A1 (en)

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