Systems and methods for therapy

Abstract

A system for stimulating a subject is disclosed. The stimulation can be to provide therapy to treat the subject. The stimulation can be targeted to selected muscle groups and / or portions.

Description

[0001] Cross-reference to related applications

[0002] This application includes subject matter relating to U.S. Applications Nos. 16 / 752,253, 16 / 752,274, and 16 / 752,285, each filed on January 24, 2020. The entire disclosure of each of these applications is incorporated herein by reference. Technical Field

[0003] The present invention discloses a system for administering treatment to a subject, and particularly for providing treatment involving stimulation and / or activation of muscle tissue. Background Technology

[0004] This section provides background information in connection with this disclosure, which is not necessarily prior art.

[0005] Subjects may suffer from conditions that could be harmful to them over a period of time. For air-breathing subjects such as humans, one condition could include airway obstruction. Several conditions exist that can obstruct the airway, and these conditions are commonly referred to as obstructive sleep apnea (OSA) and / or upper airway restriction / resistance syndrome (UARS).

[0006] OSA and UARS can affect subjects by restricting airflow and thus oxygen saturation. Low oxygen saturation can cause a variety of other undesirable conditions. Treatment of these conditions usually requires external devices to assist in providing airflow to the subject. Summary of the Invention

[0007] This section provides a general overview of the disclosure and is not a full disclosure of the complete scope or all features of the disclosure.

[0008] Treatment for obstructive sleep apnea (OSA) and / or upper airway restriction / resistance syndrome (UARS) can be delivered by stimulating selected portions of the subject. Stimulation can be delivered by an implanted device. Therefore, treatment can be delivered without an externally applied system. Consequently, treatment can be automated and less sporadic or non-spontaneous.

[0009] In various implementations, a stimulation system may be provided to a subject to stimulate various parts of the subject. The stimulation system may include a system capable of providing electrical stimulation or other suitable stimulation to the subject from a source, such as via leads. The leads may include one or more contacts or electrodes to provide stimulation from the source to selected areas. The source may include a generator and / or a power source to provide stimulation to selected areas.

[0010] To treat OSA and / or UARS, stimulation may target a portion of the tongue muscles. Stimulation may be delivered from an implanted stimulator via a lead, based on at least one waveform and / or configuration. Furthermore, the system may include learning and / or testing phases to select one or more modes or configurations. The selected mode may be predetermined or determined in real time based on feedback from one or more selected sensors and / or individuals (e.g., subjects, clinicians, etc.).

[0011] In various embodiments, the subject can be a mechanical system to which stimulation (such as electrical stimulation) can be provided. For example, electrical stimulation can be provided to an electric component to provide movement of selected portions of the electric component. However, in various embodiments, stimulation can be provided to a human or animal subject to stimulate selected portions of the subject. Stimulation may include electrical stimulation to activate and tense or contract selected muscles. As is generally understood by those skilled in the art, muscle contraction may cause the muscle to shorten to induce movement of selected portions of the subject (such as appendages, muscle tissue portions, or other selected portions of the subject).

[0012] Further areas of applicability will become apparent from the description provided herein. The descriptions and specific examples in this overview are intended for illustrative purposes only and are not intended to limit the scope of this disclosure. Attached Figure Description

[0013] The accompanying drawings described herein are for illustrative purposes only, representing selected embodiments and not all possible specific implementations, and are not intended to limit the scope of this disclosure.

[0014] Figure 1 This is a schematic diagram of the stimulation system;

[0015] Figure 2 This is a schematic diagram of the implantation site of the stimulation system;

[0016] Figure 3 It is a detailed top view of the selected implantation site;

[0017] Figure 4 It is a side view of the selected implantation site according to various implementation schemes;

[0018] Figures 5A to 5G Exemplary waveforms for stimulating subjects according to various implementation schemes are shown;

[0019] Figures 6A to 6C Exemplary lead contact stimulation configurations (e.g., bipolar from anode to cathode) for stimulating a subject are shown according to various embodiments;

[0020] Figure 7 This is a flowchart illustrating the use / training / testing of the stimulation system according to various implementation schemes;

[0021] Figure 8 This is a flowchart illustrating the use / training / testing of the stimulation system according to various implementation schemes;

[0022] Figure 9 This is a flowchart illustrating the use / training / testing of the stimulus system according to various implementation schemes; and

[0023] Figure 10 This is a flowchart illustrating the use / training / testing of a stimulation system according to various implementation schemes.

[0024] In several views of all the accompanying drawings, the corresponding reference numerals indicate the corresponding parts. Detailed Implementation

[0025] Exemplary embodiments will now be described more fully with reference to the accompanying drawings.

[0026] First refer to Figure 1 and Figure 2 The diagram illustrates a stimulation component or system 20. Stimulation system 20 may include various components or selected components of system 20 as further discussed herein. In various embodiments, stimulation system 20 may be provided for the treatment of obstructive sleep apnea (OSA) and / or upper airway restriction / resistance syndrome (UARS). Stimulation system 20 may include various features and / or systems for treatment, and according to various embodiments, may include, for example, an implantable stimulation component 24 or an implantable device (ID) 30. The ID may be implanted and (e.g., by instructions stored therein) operated to provide stimulation to the tongue muscles (i.e., the tongue) of subject 62. Stimulation may be provided to ensure maintenance of an open airway and / or reopening of the airway.

[0027] As discussed herein, ID 30 can be implanted in subject 62. One or more lead assemblies 34, as part of implantable stimulatory assembly 24, can be interconnected with ID 30. In various embodiments, for example, lead assembly 34 can be connected to ID 30 at a selected connection point 36 and extend to a first lead or stimulator portion (also referred to as lead tip) 40 and a second lead or stimulator portion (also referred to as lead tip) 44. In various embodiments, as further discussed herein, stimulation can be provided to the subject through lead tips 40, 44 to treat OSA and / or UARS symptoms in subject 62. The two lead tips 40, 44 may be used in selected or varied ways to reduce or eliminate tongue muscle fatigue to help increase the efficacy or success of treatment.

[0028] ID 30 may also include various components, such as a power source (e.g., a battery) 48. Battery 48 may be rechargeable and may be recharged in selected ways, such as by inductive recharging, as is commonly understood in the art. Battery 48 may be charged via a wired or wireless charging system. Wireless or contactless recharging modes may include inductive recharging, resonant recharging, etc. Exemplary stimulation systems including rechargeable batteries include those sold by Medtronic Corporation (which has a business location in Minneapolis, Minnesota). An implantable neurostimulator is possible. However, it should be understood that any suitable power storage system can be provided, and the battery is merely exemplary. Power source 48 will provide selected current and / or voltage between one or more electrodes of lead assembly 34, as discussed further herein.

[0029] ID 30 may also include selected components to assist in providing stimulation via lead assembly 34. For example, ID 30 may include processor module 50, which may be any suitable processor, as further discussed herein, to execute instructions provided to ID 30 from an external source and / or stored on memory module 54. Memory module 54 may be any suitable memory system, such as those further discussed herein. Furthermore, ID 30 may include selected transceiver system or module 58 that can be used to transmit and / or receive information and / or instructions from an external source. Transceiver module 58 may be any suitable transceiver module, such as those further discussed.

[0030] According to various embodiments, the stimulation component 20 may include an implantable stimulation portion 24 as a separate system. In various embodiments, the memory module 54 may include any suitable instructions and / or algorithms for operating the stimulation portion 24. The processor module 50 may execute instructions from the memory module 54 and may provide a battery 48 to power the stimulation portion 24. However, it should be understood that the various portions may also be provided externally to the subject 62. Figure 2 To assist in interacting with ID 30.

[0031] Various sensors may be provided to transmit and / or receive signals about subject 62. Sensor 61 may be included in ID 30 (e.g., formed outside ID 30, placed inside ID 30, and / or connected to ID 30). Sensor 61 may include one or more of an accelerometer, GPS, pulse oximeter, electromyography sensor, etc. Sensor 61 may be used to assist in determining the choice of treatment for subject 62, as discussed herein. It should be understood that sensor 61 may also communicate with other systems. In addition, or in addition to sensor 61, external or wearable sensors 61' may be placed on subject 62. Wearable sensor 61' may be the same sensor as described above, including its redundant portions. Wearable sensor 61' may also include additional or different sensors. Sensors, particularly external sensors, may include position (e.g., relative to gravity) sensors, temperature sensors, CO2 detectors, airflow (e.g., nasal or oral) detectors, microphones (e.g., for detecting breathing sounds (e.g., snoring)), and impedance detectors (e.g., for detecting vital capacity). In addition, various sensors can be used to determine or monitor “sleep quality,” such as sensing via EEG or integration of the various sensors already mentioned. Sleep quality determination may be related to the effectiveness of OSA treatment. Regardless of type, the sensors in wearable sensor 61' can communicate with ID 30 and / or other parts of system 20.

[0032] An external system, as part of the stimulation component 20, may include a first external controller or transceiver 70. The first external transceiver 70 may also be referred to as a communication telemetry module (CTM) 70 capable of communicating with ID 30. In various embodiments, the stimulation component 20 may further include a second transmit and / or control module (CTM) 74. For various purposes, the second control module 74 may communicate with the first control module 70, may communicate directly with ID 30 as further discussed herein, and / or may communicate with ID 30 via the first transmit module 70. However, it should be understood that only one of the first transmit module 70 or the second transmit module 74 may be provided to the stimulation component 20.

[0033] A first CTM 70 can be provided to user 62 for personal and / or home use. As further discussed herein, user 62 can use CTM 70 to assist in controlling ID 30 to provide stimulation to user 62. CTM 70 can also be used to modify the operation of ID 30, such as by user 62, input instructions from user 62, or other suitable mechanisms.

[0034] In short, CTM 70 may include a main body or module portion 78, the size of which is configured to fit within the hand of user 62. Accordingly, CTM 70 may be movable relative to user 62 and / or allow for easy transport and use by user 62. Furthermore, CTM 70 may be positioned near user 62 at any appropriate time, such as during selected time periods or near user 62's sleep periods. CTM 70 may also include one or more input portions, such as physical or also referred to as hard buttons or hard selection components 82, which may include one or more buttons allowing user 62 to input operations or select operations of ID 30. For example, hard buttons 82 may include start and stop buttons 84, timer buttons 86, and / or power or emergency buttons 88. CTM 70 may also include a selected display 92 to provide user 62 with information such as pulse frequency, oxygen saturation value, respiratory rate, or other appropriate information. Display 92 may provide information such as historical information for clinicians to select the programming and operation of ID 30. Display 92 may also be a touchscreen or touch-sensitive, and therefore include one or more soft buttons.

[0035] The CTM 70 may include various components such as a processor module 100, a memory module 102, and a communication or transceiver module 104. The processor module 100, memory module 102, and transceiver module 104 may be similar to those discussed further herein. Figure 1 As shown, CTM 70 can transmit signals, such as wireless signal 108, to ID 30. Furthermore, ID 30 can transmit signals, such as wireless signal 110, to CTM 70. Accordingly, CTM 70 can receive information from ID 30 and / or transmit information to ID 30, and vice versa. As discussed herein, CTM 70 can be used to program or select the operation of ID 30, and ID 30 can include sensors to transmit information to CTM 70. CTM 70 can be configured as any suitable device and / or can be incorporated as an application into a suitable mobile computer (e.g., mobile phone, tablet, etc.). The application can be used with any suitable operating system, such as iOS. Operating system, etc. Furthermore, the CTM 70 may be powered in an appropriate manner, such as utilizing an internal battery that can be charged via a wired or wireless charging system. Wireless or contactless recharging modes may include inductive recharging, resonant recharging, etc.

[0036] The stimulation component 20 may also include a second control module, such as CTM 74. CTM 74 may include components similar to the first CTM 70. However, CTM 74 may be a larger and / or permanent device provided to the clinician for the operation of ID 30 and / or the programming of the first CTM 70. The second CTM 74 may generally be non-mobile, in other words, not intended to move with or by the subject 62. Accordingly, the second CTM 74 may include various hard buttons 120, a touchscreen 124, a processor module 126, a memory module 128, and a transceiver module 130. Thus, CTM 74 may transmit signals, such as wireless signals 140, to the first CTM 70 and / or ID 30. Therefore, ID 30 may also transmit signals 110 to CTM 74, and / or the first CTM 70 may transmit signals to the second CTM 74.

[0037] Accordingly, depending on the selected implementation and in various applications, the simulation component 20 may include various parts for the operation of ID 30. As further discussed herein, ID 30 may be implanted in subject 62 for stimulating subject 62 according to a selected mechanism or method. Various control modules may be provided at selected times to allow programming of ID 30, modification of ID 30 programming, receiving outputs from ID 30 (e.g., historical sensor data), and analysis of ID 30 operation, historical data, and other information. Thus, a first CTM 70 may be provided for substantially immediate and / or immediate use during and / or after the operation of ID 30. A second CTM 74 may be provided for initial programming, follow-up, and interaction with subject and / or central data storage and / or analysis systems by selected users (such as clinicians).

[0038] Continue to refer to Figure 1 And refer to other sources Figure 2 The stimulation component 24 can be implanted into selected subjects 62. For example... Figure 2 As shown, the selected subject 62 may be a human subject. However, it should be understood that any suitable subject may have the stimulation portion 24 positioned on their person at an appropriate time. It should also be understood that ID 30 may be positioned near or outside the subject 62, such that the lead portion 34 is percutaneously implanted into the subject 62, and the stimulation portion 30 (e.g., power supply and control) is outside the subject's body. Therefore, the discussion of the implantable device 30 herein should not be construed as eliminating selected components, such as power supply, stimulation reconnection, or other features or portions that may be placed in an external device for percutaneous delivery to the stimulation site of the subject 62 via the lead assembly 34.

[0039] Continue to refer to Figure 2ID 30 can be implanted in any suitable location within the subject 32, such as the abdominal wall, chest wall, subcutaneous tissue near the clavicle, or other suitable locations. Lead assembly 34 can be attached to ID 30 and pass through selected tissue to reach the selected location for stimulating the subject 62. In various embodiments, such as Figure 2 As shown, a stimulation lead assembly 34, including a first lead tip portion 40 and a second lead tip portion 44, can be positioned within tongue tissue (i.e., tongue 170). The lead assembly 34 can be positioned within the subject 62 along a single path, for a selected portion of the length of the lead assembly 34, and / or can be immediately divided into two lead portions for positioning within tongue 170. As those skilled in the art will understand, the tongue can be formed by multiple muscular portions that can work synergistically to induce movement of tongue 170. Accordingly, reference to tongue 170 should be understood to refer to the relevant portion of the tongue, as further discussed herein. Additionally, those skilled in the art will understand that tongue 170 can include multiple neural portions or structures, including those further discussed herein, including nerve endings, endplates, etc.

[0040] Continue to refer to Figure 2 And refer to other sources Figure 3 and Figure 4 The lead assembly 34 can be positioned at a selected location within the tongue 170. For example... Figure 2 and Figure 3 As shown, lead assembly 34 may include a first lead tip or point 40 and a second lead tip or point 44. Not limited to specific locations of the two leads 40, 44, the first lead tip 40 may be a left lead tip, and the second lead tip 44 may be a right lead tip. Furthermore, it should be understood that, except for specific locations relating to the tongue 170 (e.g., right and left), the two lead tips 40, 44 may be substantially identical to each other. Therefore, unless otherwise specifically stated, discussion herein of one or a single lead tip (such as lead tip 44) is to be understood as relating to both lead tips.

[0041] The tongue 170 may have branches of the hypoglossal nerve 176 therein. The hypoglossal nerve 176 extends from the seventh cranial nerve and enters the tongue 170. Naturally, the nerve distribution of the hypoglossal nerve 176 may cause movement or contraction of selected muscles in the tongue 170, such as through signal transmission from the brain and spinal cord. Therefore, the nerve distribution of the hypoglossal nerve 176 may cause partial contraction and / or tension of the tongue 170.

[0042] As is commonly understood by those skilled in the art, obstructive sleep apnea (OSA) may occur when the tongue 170 falls entirely or partially into or collapses into the airway 180. Obstruction of the airway 180 can reduce or eliminate the intake of air (e.g., including oxygen) by the subject 62. The obstruction can occur during the subject 62's sleep cycle and is therefore commonly referred to as OSA. A similar or related condition may be upper airway restriction / resistance syndrome (UARS). Contraction of the muscles in the tongue 170 can move the tongue 170 out of the airway 180 to reduce or treat the subject 62's OSA and / or UARS.

[0043] In some examples, a user (such as a surgeon) may implant one or more leads 40, 44 such that one or more electrodes 190, 194 are implanted within soft tissue, such as muscles of the tongue 170 near selected branches (such as medial branches) of one or both hypoglossal nerves 176. In some examples, one or more electrodes 190, 194 may be approximately 5 mm (e.g., approximately 2 mm to approximately 8 mm) from the trunk of the hypoglossal nerve 176. In some examples, one or more electrodes 190, 194 may be placed in a region of the extensor tongue muscle of the tongue 170, which includes motor points where each nerve axon terminates in muscle (also referred to as a neuromuscular junction and / or nerve endplate). These motor points are not concentrated in one location but are distributed throughout the extensor tongue muscle of the tongue 170. Leads 40, 44 may be implanted such that one or more electrodes 190, 194 are generally present in the region of the motor points (e.g., such that the motor points are within approximately 1 mm to approximately 10 mm from one or more electrodes 190, 194).

[0044] As described above, electrical stimulation therapy generated by IMD 30 and delivered via one or more electrodes 190, 194 can activate the extensor tongue muscles to move the tongue 170 forward, for example, to promote a reduction in upper airway obstruction or narrowing during sleep. As used herein, the term “activation” relating to electrical stimulation of the extensor tongue muscles of the tongue 170 refers to electrical stimulation that induces depolarization or action potentials in nerve cells (e.g., the hypoglossal nerve) that innervate the extensor tongue muscles and motor points of the tongue 170, and subsequent depolarization and mechanical contraction of the extensor tongue muscle cells of the tongue 170. In some examples, the extensor tongue muscles of the tongue 170 can be directly activated by electrical stimulation therapy.

[0045] In some examples, each of electrodes 190, 194 may have an equal electrode length (e.g., electrodes 190, 194 extend longitudinally along lead bodies 40, 44). The length may be approximately 3 mm, but lengths less than 3 mm are also possible. However, electrodes 190, 194 may have sequentially different electrode lengths (e.g., to optimize the placement of electrodes 190, 194 or the resulting stimulating electric field relative to target stimulation sites corresponding to the left and right hypoglossal nerves or branches of the hypoglossal nerve and / or the motor points of the extensor muscles of the tongue 170).

[0046] like Figure 3 As shown, the HG nerve 176 may include a left branch 176l and a right branch 176r. The tip or end 40 of the first or left guide may be located on the left side of the tongue 170, near the left branch 176l. The tip or end 44 of the second or right guide may be located on the right side of the tongue 170, near the right branch 176r. Therefore, the two guide ends 40, 44 may be provided on both sides or spaced apart from each other on one side. Figure 3 As shown, the leads 40 and 44 can be spaced apart from each other and away from the centerline of the tongue 170.

[0047] Providing two lead tips 40, 44 to the tongue 170 allows for the selection of stimulation patterns and / or bilateral stimulation within the tongue 170, as further discussed herein. As discussed herein, bilateral stimulation can include selected subject benefits. Therefore, stimulation can be bilateral. As discussed herein, bilateral stimulation can be provided to ensure or limit muscle fatigue, select tongue configuration, etc. Furthermore, bilateral stimulation can alternate between left and right and / or can be performed simultaneously on both sides.

[0048] The lead 40 may be positioned within the tongue 170 in any suitable manner, such as by passing through a portion of the muscles of the tongue 170 and / or near a nerve endplate. It should be understood that the lead 40 and / or the lead tip 44 may be positioned near or adjacent to a selected nerve to stimulate a selected portion of the tongue 170. Figure 3 and Figure 4As shown, the lead end 40 may include multiple electrodes or contacts, such as four contacts 190, each designated by a lowercase letter. Each of the electrodes or contacts 190 may be connected to a power supply 48 and is individually controlled to provide stimulation to one or more portions of the tongue 170. It should be understood that any suitable number of contacts 190n may be provided. Stimulation may be provided through the electrodes 190 in any suitable manner, as discussed further herein. In various embodiments, for example, one of these electrodes (such as electrode 190a) may operate as an anode, while a second electrode (such as contact 190b) may operate as a cathode. Thus, a voltage difference may be generated between the two electrodes 190a and 190b to provide stimulation to one or more portions of the tongue 170. As described above, stimulation of the HG nerve 176 may cause contraction of one or more portions of the muscles of the tongue 170 and cause the tongue 170 to exit the airway 180 at a selected time.

[0049] In short, the second lead tip 44 may also include one or more contacts, such as contact 194, each distinguished by a lowercase letter. It should be understood that any suitable number of contacts 194n can be provided. Similarly, each of the contacts 194 may operate in a selected manner, such as selecting one contact to operate as the anode and another contact to operate as the cathode.

[0050] The lead tips 40 and 44 can operate cooperatively or together, such that the lead electrode on the first lead tip 40 (such as electrode 190a) can operate as an anode, and the second electrode (such as electrode 194a on the second lead tip 44) can operate as a cathode. Therefore, stimulation can be provided on the tongue 170 between the two lead tips 40 and 44 (e.g., spaced apart on the tongue 170) and / or unilaterally (e.g., along one side of the tongue 170), such as between the individual lead tips 40 and 44. Likewise, as further discussed herein, stimulation of the tongue 170 can be operated unilaterally and / or bilaterally. For example, the left side of the tongue can be stimulated with the first lead tip 40, then the right side with the second lead tip 44, and then stimulation can be provided between the two lead tips 40 and 44. It should also be understood that various other possible stimulation anodes or techniques, as further discussed herein, can also be provided.

[0051] Continue to refer to Figure 3 and Figure 4The tips 40 and 44 of the lead wire can be positioned in appropriate portions of the tongue 170. Therefore, the tip 40 can be positioned substantially close to the lower portion of the tongue 170, such as near the mandible of the subject 62 or the bony portion of the mandible 198 and / or the fat or skin layer 200. It has been found that stimulation of one or more portions of the tongue 170 76 causes contraction of selected muscular portions of the tongue 170, causing the tongue tissue to move away from or out of the airway 180, thereby opening the airway 180 and relieving any obstruction caused by relaxation or movement of the tongue 170 into the airway 180.

[0052] In various implementations, and not limited to theory, the chosen location for the tongue can be the tongue of an conscious subject whose airway is open for breathing, and whose tongue is not protruding from the mouth. Typically, to alleviate OSA using stimulation therapy, the goal is to open or widen the upper airway. In various implementations, this can tighten the upper airway to prevent collapse during inspiration. This can occur by the tightening of accessory muscles due to stretching of accessory muscles when the primary muscles are stimulated and contract. Alternatively, muscle contraction can occur via a centrally mediated reflex (i.e., a neurosensory signal is sent to the central nervous system, which causes muscle contraction in the upper airway).

[0053] A stimulation system 20, comprising a stimulator portion or component 24, is provided to selectively stimulate portions of the subject 62, as described above. Stimulation of the subject 62 can be provided in a selected manner (such as bilateral, unilateral, or unilateral switching) via lead tips 40, 44 and between multiple contacts 190, 194 of the respective lead tips 40, 44. Reference Figures 5A to 5G Various types of stimulation can be provided to the tongue 170 via the lead assembly 34. Stimulation can be targeted at one or more portions of the tongue 170 to induce activation of one or more selected muscle groups or portions. Muscle activation (such as due to stimulation from system 20) may cause contraction (including tension) of the muscle portion. Therefore, stimulation of one or more selected portions of the tongue 170 and / or nerves and / or nerve endplates may induce activation of one or more muscle groups or portions.

[0054] Stimulation of one or more portions of the tongue 170 may be provided bilaterally, such as stimulation of the left ramus 176l and the right ramus 176r. In bilateral stimulation, stimulation may be provided simultaneously to both ramus 176l and 176r, or alternately between the two ramus, with and / or no interval between bilateral stimuli. Furthermore, the amplitudes of the bilateral stimuli may be the same or different, and may vary over time. Various exemplary stimulation patterns are discussed and illustrated herein. Bilateral stimulation may also induce bilateral (including simultaneous and / or bilaterally alternating) activation of muscle groups in the tongue 170.

[0055] In various implementations, various modes can be provided for providing discontinuous stimulation to at least selected portions (including the entire tongue) of the tongue 170. However, even when discontinuous stimulation is provided to specific portions or regions of the tongue 170, selected bilateral stimulation can allow substantially continuous stimulation to at least selected portions of the tongue 170. Thus, the tongue 170 may be subjected to discontinuous stimulation, bilateral continuous stimulation, bilateral alternating continuous stimulation, or combinations thereof.

[0056] As illustrated herein, each of the lead ends 40, 44 may operate with a selected duty cycle. In various embodiments, a pulsed stimulus can be emitted from any of the lead ends 40, 44. As discussed herein, the pulses can be repeated. Figures 5A to 5G The stimulation waveform shown may indicate the operating system and have a time period suitable for providing treatment to subject 62. Additionally, stimulation may be provided from ID 30 at a selected amplitude. The amplitude may refer to a selected frequency (e.g., from 10 Hz to approximately 200 Hz, including from approximately 20 Hz to approximately 80 Hz), voltage (e.g., from approximately 0.1 V to approximately 15 V, including from approximately 0.1 V to approximately 5 V), or current intensity (e.g., from approximately 0.1 mA to approximately 20 mA, including from approximately 0.1 mA to approximately 15 mA) provided during the on-time period. As discussed herein, ramping and descent may include a gradual or selected increase or decrease in the aforementioned amplitude.

[0057] First refer to Figure 5A The stimulus can be provided as shown in Figure 220. Figure 220 shows two axes, including an amplitude y-axis 224 and a time x-axis 228. It should be understood that the amplitude can be any suitable amplitude, including voltage, current, etc. Furthermore, the amplitude of the stimulus can be based on selected subjects and can be determined or learned from specific subjects and / or subject groups (e.g., subject groups or populations with similar characteristics). Accordingly, the stimulus graph is relative and can be provided for a specific subject based on specific values ​​for that specific subject.

[0058] Continue to refer to Figure 5AThe stimulation pattern 220 may include a left stimulation portion 230 (i.e., provided using a left lead 40) and a right stimulation portion 234 (i.e., provided using a right lead 44). Each of these stimulation portions may each include a corresponding rising phase 230a, 234a, a peak or selected stimulus 230b, 234b, and a falling phase 230c, 234c. The rising phases 230a, 234a and the falling phases 230c, 234c may increase or decrease over time. However, in various embodiments, rising or falling phases may not be provided, and therefore, the wave may be substantially square. Accordingly, the rising and falling phases include amplitudes that vary over time and are merely exemplary. However, rising and falling phases may be provided for subject behavior, selected stimulus, or contraction characteristics, etc.

[0059] The right stimulus portion 230 and the left stimulus portion 234 can be initiated and then stopped to achieve maximum stimulation 230b, 234b. Furthermore, stimulus portions 230, 234 can be provided in a substantially repetitive manner within a selected time period, as discussed further herein. Accordingly, the repeat ellipsis 240 can indicate the repetition of stimulus portions 230, 234 within a selected time period or a selected duration.

[0060] The stimulation portions, including left stimulus 230 and right stimulus 234, can be separated by selected time intervals or time portions 244. Accordingly, the left stimulus portion 230 can stimulate or induce stimulation of only the left side of the tongue 170 for a selected time period (such as about 1 second). The 1-second stimulation can include an ascending 230a and a descending 230c. However, it should also be understood that the stimulation of the left side portion 230 can last for any appropriate time, and 1 second is exemplary for the purposes of the present discussion. Similarly, the right stimulus portion 234 can be used to induce stimulation of only the right side of the tongue 170 for a similar or substantially equal time (such as about 1 second). When the corresponding lead ends 40, 44 are operated to stimulate one or more portions of the tongue 170, left and right stimuli can be provided to only the left side or only the right side of the tongue 170.

[0061] As shown in Figure 220, the right and left stimulation portions do not overlap and can be spaced apart from each other by a selected time period (such as time interval 244). Time interval 244 can be an appropriate time, such as about 0.25 seconds. However, it should be understood that the time interval can be any appropriate time interval. In various embodiments, time interval 244 can be provided to ensure a selected amount of relaxation of the tongue 170, or to ensure the dissipation of stimulation from either the left or right stimulation lead tip 40, 44. Thus, stimulation interval 244 can be from about 0.25 seconds to about 0.75 seconds, and also includes about 0.5 seconds.

[0062] Regardless of the length, ascent or descent time, or other characteristics of the left or right stimulation portion 230 or 234, the stimulation interval 244 can separate the stimulation on the left and right sides of the tongue 170. Therefore, the left lead 40 can stimulate only the left side of the tongue 170 for a selected time period, then the left lead 40 can stop stimulation for the selected time period (i.e., stimulation interval 244), and then stimulation can be initiated by the right lead 44 to stimulate only the right side for the selected time period. Thus, effectively, only one side of the tongue 170 is stimulated at a time. As described above, the stimulation pattern can then be repeated to stimulate the tongue 170 for the selected time period.

[0063] Steering Reference Figure 5B Figure 250 is shown. Figure 250 is similar to Figure 220 discussed above and will not be discussed in detail independently of the stimulus portions, which include a left stimulus portion 254 shown in solid lines, which can be repeated, including a repeating portion 254'. Additionally, a right stimulus 258 is shown in dashed lines. Similarly, as described above, the simulation pattern can be repeated, including... Figure 5B The portion shown along the repeating segment or section 262. Each stimulation portion in stimulation portions 254, 258 may include ascending, peaking, and descending portions, similar to those discussed above. Accordingly, the individual portions will not be discussed, as they are similar to... Figure 5A Those parts discussed in the text.

[0064] However, as Figure 5B As shown, the stimulation portion or segment can be extended for a selected time period, such as the first left stimulation portion, which can be stimulated between time zero and time two. In various embodiments, the time elapsed between zero and two can be any suitable time, such as about 1 second, as described above. However, the right stimulation 258 can be initiated or started at a selected time (such as time one). Time one can be a selected time between time zero and time two. For example, the time elapsed or time passed between time zero and time one can be about 0.5 seconds. Thus, the left stimulation 254 can be on for about 1 second, and the right stimulation 258 can be initiated approximately halfway through the left stimulation. Thus, the stimulation of the left and right sides can have a selected time overlap 266, such as about 0.5 seconds. Thus, while the left electrode 40 is being powered to stimulate the left side of the tongue 170, the right electrode 44 can be activated to simultaneously stimulate the right side of the tongue 170.

[0065] However, this allows for bilateral stimulation of the tongue 170, including selected simultaneous overlap 266. This overlap can occur at any appropriate time, such that the right stimulus 258 ascends, and a peak appears as the left stimulus begins to descend. However, it should be understood that other appropriate overlaps can be provided, and again, the specific length of the overlap can vary based on the selected subject. However, it should be understood that the stimulation system 24 can provide overlapping stimuli (such as...). Figure 5B (as shown) and / or include time intervals (such as...) Figure 5A (As shown).

[0066] Steering Reference Figure 5C Figure 280 is shown. Figure 280 may include axes, similar to those discussed above, and therefore will not be discussed in detail here. As shown in Figure 280, left stimulus 284 and right stimulus 288 are shown. Similarly, left stimulus 284 and right stimulus 288 may include selected ramp and ramp descent and peak periods, as shown in Figure 280, and because they are similar to those discussed above, they will not be discussed in detail here.

[0067] The left stimulus 284 can be applied from time zero to time one. The right stimulus can be applied from time one to time three. As described above, the left stimulus 284 and the right stimulus 288 can be separated by a selected time interval 244 and / or include a selected overlap 266. It should also be understood that the right stimulus 288 can begin immediately during a pause or end of the left stimulus 284, and / or vice versa. Similarly, the pattern of the left stimulus 284 and the right stimulus 288 can be repeated 292 within a selected time period.

[0068] like Figure 5C As shown, the left stimulus 284 can have a length of one, which can be any suitable time span, such as 1 second. The right stimulus 288 can include a selected time span, such as two, which can be any suitable time span, such as 2 seconds. Therefore, it should be understood that the left stimulus period and the right stimulus period can be periods of different lengths, such as one being twice the length of the other. It should also be understood that the changes in time can alternate and / or reverse, such that the left stimulus 284 can be longer than the right stimulus 288. In this way, the left stimulus 284 and the right stimulus 288 can provide stimulation to selected parts of the tongue (such as the left HG branch 176l and the right HG branch 176r) within different time lengths. Therefore, the tongue 170 can be stimulated according to different time lengths on the right and left sides.

[0069] Steering Reference Figure 5DFigure 300 is shown. Similarly, figure 300 may resemble the figures discussed above and will not be discussed in detail. As shown in figure 300, a left stimulus 304 and a right stimulus 308 are shown. As mentioned above, there may be an interval 244 between the stimuli, the stimuli may overlap 266, or when one stimulus begins or stops, another stimulus may stop and begin substantially accordingly. Furthermore, the pattern may be repeated, as indicated by the repetition symbol 312.

[0070] Left stimulus 304 and right stimulus 308 can also include different peak amplitude values. For example... Figure 5D As shown, the left stimulation peak 304a can have an amplitude of 2. However, the right stimulation peak 308a can have a different amplitude, such as amplitude 1. It should be understood that amplitude 1 and amplitude 2 can represent any suitable amplitude, such as amplitude 1 being about 1 volt and amplitude 2 being about 2 volts. However, the stimulation amplitude can also refer to other amplitudes, such as current. However, the left peak 304a and the right peak 308a can be different from each other. It should also be understood that the amplitude of the left stimulation 304a can be less than the amplitude of the right stimulation 308a, and vice versa. Furthermore, as mentioned above, the amplitudes can be different from each other, and the amplitudes can also alternate. Accordingly, after a selected time period, the left amplitude 304a can be less than the right amplitude 308a, and can also switch back.

[0071] Steering Reference Figure 5E Figure 320 is shown. Similarly, Figure 320 can be similar to the figures discussed above, and details will not be discussed here. Figure 320 shows a left stimulus 324 and a right stimulus 328. The left stimulus 324 includes a peak stimulus amplitude 324a, and the right stimulus includes a peak 328a. The peak stimuli can have the same amplitude or different amplitudes, as described above. Furthermore, the left stimulus 324 and the right stimulus 328 can overlap, can have an interval between them, or one can be immediately following the other. The stimulus pattern can be repeated in stimulus repetition 330.

[0072] The left stimulus 324 may include a ramp 324b and a ramp 324c. Similarly, the right stimulus 328 may include a right ramp 328b and a ramp 328c. The left stimulus 324 may begin at time zero and end at time two. The ramp 324b may last between time zero and time 0.75, and the ramp may last between time 1.25 and time 2. Accordingly, the ramp 324b and the ramp 324c may have a time elapse of approximately 0.75 seconds. It should be understood that the time elapsed can be any suitable time, and each may include a time elapsed of approximately 0.75 seconds.

[0073] The right stimulus 328 may begin at time two and have a ramp up until time 2.25. The ramp down 328c may have a ramp down time from time 2.75 to time three. Accordingly, ramp up 328b and ramp down 328c may have a time elapse of approximately 0.25 seconds. It should be understood that the elapsed time can be any suitable time, and 0.25 seconds is merely exemplary. However, the ramp up and ramp down of the right stimulus 328 may be approximately 0.25 seconds, while the ramp up 324b and ramp down 324c of the left stimulus 324 may be approximately 0.75 seconds. The peak stimulation times of the left stimulus peak 324 and the right stimulus peak 328 may be substantially similar or identical; however, the ramp up and ramp down times may differ. However, it should also be understood that the peak times may also differ, including different amplitudes or values, or differences in other aspects. However, it should be understood that the ramp up and ramp down times may differ in length and slope, such as... Figure 5E As shown.

[0074] Steering Reference Figure 5F Figure 350 is shown. Similarly, Figure 350 may include sections similar to those discussed above, and will not be repeated here. Furthermore, Figure 350 shows the left stimulus 354 in solid lines and the right stimulus 358 in dashed lines. Additionally, the stimulus pattern may be repeated, as shown in Repetition 362. Likewise, it should be understood that the left stimulus 354 and the right stimulus 358 may include various features, such as those discussed above, including interval 244, overlap 266, substantially simultaneous start and stop, etc.

[0075] Figure 350 illustrates that left stimuli 354 and right stimuli 358 can alternate between maximum or peak stimuli 354a and 358a and minimum stimuli 354b and 358b. Maximum stimuli 354a and 358a can be any suitable amplitude, and the maximum stimulus amplitudes of left stimuli 354 and right stimuli 358 can be chosen to be substantially the same. In various embodiments, maximum or peak stimuli 354a and 358a can be amplitude two. Minimum stimuli 354b and 358b can be selected amplitudes, such as amplitude one. Similarly, it should be understood that left stimuli 354 and right stimuli 358 can have different maximum and minimum stimuli, respectively, and the illustrations of minimum one and maximum two are merely exemplary. However, as shown in Figure 350, minimum stimuli 354b and 358b are not necessarily zero. As shown and discussed above, the stimuli can vary between zero and some selected amplitudes. However, it should be understood that the stimuli may not return to zero during the selected stimulus period. Accordingly, during stimulation, the left stimulus may alternate between one and two after the stimulus begins, and the right stimulus 358 may also alternate between one and two. During the stimulation period, the stimulation provided to the tongue 170 through both electrode tips 40 and 44 is not necessarily zero. Although the stimulation from any one or both of electrode tips 40 and 44 may alternate and increase or decrease over time, the stimulation from any one of the electrode tips is not necessarily zero. Therefore, bilateral continuous stimulation may occur, even if the stimulation changes over time.

[0076] Turn Figure 5G Figure 380 is shown. Figure 380 comprises parts similar to those discussed above, and will not be discussed in detail here. Figure 380 also includes a left stimulus waveform 384 shown in solid lines, and a left analog waveform 388 shown in dashed lines. Figure 5G As shown, the left analog can be essentially sinusoidal, ranging between zero and two amplitudes. Similarly, the right stimulus 388 can alternate between a minimum 388a of zero and a maximum 388b of two. Figure 5G As shown, the left curve 384 and the right curve 388 may alternate in a sinusoidal shape or manner, and may cross at any selected value, such as amplitude one.

[0077] The frequency, amplitude, and phase of the corresponding stimulus waves 384 and 388 can be altered to provide selected stimuli to subject 62, similar to the stimuli discussed above. Figure 5GAs shown, the intersection of the left stimulus 384 and the right stimulus 388 can be at an amplitude of one, so that there is no stimulus with a zero amplitude to the tongue 170. However, it should be understood that the corresponding curves 384 and 388 can be shifted so that the stimulus from both leads 40 and 44 can be zero at a selected time and / or within a selected time period. However, the stimulus from the left lead 40 and the right lead 44 can vary over time as a sine wave rather than a straight rising and falling and / or square wave, as described above. Therefore, peak stimulation can be provided for only a short period of time, and the stimulation is substantially constantly changing for any one or both leads 40 and 44. Furthermore, as described above, the corresponding stimulus curves 384 and 388 can be repeated within a selected time period 390.

[0078] Continue to refer to Figures 5A to 5G This may provide stimulation patterns from ID 30 to electrode tips 40, 44 in multiple waveforms, as described above. Furthermore, as... Figure 5F As shown, the stimulus amplitude may never reach zero. However, the minimum stimulus (as shown in Figure 1) can be an amount provided that is just or slightly below the level required to induce a selected muscle and / or contraction (e.g., about 0.1 volts to about 15 volts). Accordingly, while the stimulus amplitude may not be zero, it may be an amplitude that induces activation of the selected muscle. Therefore, the stimulus waveform can lie between a stimulus value that does not stimulate or induce muscle contraction and a value that induces a selected contraction of the muscle.

[0079] Furthermore, as mentioned above, any of the selected waveforms can include a substantially square wave, wherein the rise between zero or the selected minimum stimulus and the peak of the stimulus occurs substantially instantaneously. However, the stimulus waveform can also be a sine wave, a sawtooth shape, a triangle, etc. It should be understood that the waveform can be an appropriate graphic shape selected to stimulate the selected subject 52.

[0080] Furthermore, as mentioned above, the right-side and left-side stimulation waveforms can be out of phase with each other. Therefore, stimulation can be provided using only the left lead end 40 or only the right lead end 44. The phases of the two waveforms also include some overlap, but are not completely in phase.

[0081] Continue to refer to Figure 3 and Figure 4 And refer to other sources. Figures 6A to 6C Stimulation using the selected electrode lead 34 can include stimulation between the two lead tips 40, 44, or stimulation between various electrodes on the respective tips 40, 44, and can have various modes. Various exemplary modes are discussed herein, and... Figures 6A to 6CExemplary patterns are shown to illustrate various exemplary modes. Initially, the two lead ends 40, 44 can be positioned in the tongue 170 in a laterally aligned manner. In other words, the left lead end 40 can be placed near the left side of the tongue 170, and the right lead end 44 can be placed near the right side of the tongue 170. Thus, the lead ends 40, 44 can be spaced apart from each other on each side. However, the lead ends 40, 44 can be manipulated to provide bilateral stimulation, such that both the right and left sides of the tongue can be stimulated. In various embodiments, bilateral stimulation can be performed simultaneously, such that both sides are stimulated at the same time.

[0082] As described above, various waveforms or stimulation sequences can be used to stimulate one or more portions of the tongue 170. In addition to various waveforms, the electrodes may be operated in various ways to provide simulation to selected areas and / or selected simulated volumes within the tongue 10. Figure 6A As shown, electrode tips 40 and 44 are positioned in the tongue 170 with opposite sides aligned. Each electrode in electrodes 40 and 44 includes multiple electrode pads or contacts 192 and 194, respectively.

[0083] In various embodiments, for example, the first electrode contact 192a can act as a cathode and the fourth electrode contact 192d can act as an anode to generate a voltage between them. Therefore, in various embodiments, the voltage or current 400 between the first electrode contact 192a and the fourth contact electrode 192d can stimulate the region between them. Similarly, electrode contact 194a can act as an anode and the fourth contact 194d can act as a cathode, and a voltage 404 can be generated between them.

[0084] In the various formats described above, the left electrode tip 40 and the right electrode tip 44 can operate substantially independently. Simulation can occur between the two electrode contacts 192a and 192d, and these two electrode contacts can be arranged in series or sequentially with contacts 194a and 194d. Therefore, stimulation will not flow between the two electrode tips 40 and 44, but only between the selected electrode and the selected electrode tip. Furthermore, left stimulation can be applied only between the two electrode contacts 192a and 192d of the left electrode tip 40, and between the electrode contacts 194a and 194d of the right electrode. This allows stimulation to be provided in series, continuously, or bidirectionally in any suitable manner, as discussed above for the selected waveform.

[0085] Steering Reference Figure 6B The left lead tip or end 40 and the right lead tip or end 44 are positioned in the tongue 170, as described above. Lead tips 40, 44 include corresponding electrode contacts 192, 194, as described above. Except... Figure 6AIn addition to the examples shown, the contacts can also be used to provide varying or different stimuli to one or more portions of the tongue 170. For example, the left lead tip 40 can provide stimulation between two contacts 192a and 192b, such that, at a first time, the first contact 192a has an anode and the second contact 192b can be a cathode. It should be understood that in various embodiments, these contacts can be alternated or reversed. Furthermore, at a second time, the second contact 192b can provide stimulation 414 between the second contact 192b and the fourth contact 192d. Thus, at a first time, stimulation can be provided between the first contact 192a and the second contact 192b, and at a second time, stimulation can be provided between the second contact 192b and the fourth contact 192d.

[0086] At a third time, stimulation can be provided between the first contact 194a and the second contact 194b for the right electrode tip 44. Stimulation 418 can accompany the first contact 194a as an anode or cathode, and the second contact 194b as the opposite. At a fourth time, stimulation can be provided between the second contact 194b and the fourth contact 194d. Stimulation 420 can accompany the second contact 194b as an anode or cathode, and the fourth contact 194d as the opposite.

[0087] Therefore, in various embodiments, different contacts 192, 194 can operate as either anodes or cathodes to provide stimulation in selected areas. For example, the area stimulated by the first stimulation portion 410 or the third stimulation portion 418 may be proximal along the lead tips 40, 44, while the second and fourth analogs 414 may be more distal. In various embodiments, stimulating different areas may achieve different results for the subject 62.

[0088] Furthermore, different stimuli 410, 414, 418, and 420 can be provided at different times, as further discussed herein. For example, the left electrode tip 410 can induce stimulation 410 at the first moment, followed by stimulation 420 by the right electrode tip 44, and then any other appropriate stimulation, such as stimulation 414 induced by the left electrode tip 40 and / or stimulation 418 induced by the right electrode tip 44. Additionally, bilateral or simultaneous stimulation of both the left electrode tip 40 and the right electrode tip 44 can be induced at different locations, such as simultaneous stimulation using stimulation 410 of the corresponding left electrode tip 40 and stimulation 420 of the right electrode tip 44.

[0089] Steering Reference Figure 6CThe left electrode tip 40 and the right electrode tip 44 can be positioned within the tongue 170, as described above. As described above, the respective electrode tips or ends 40, 44 include corresponding electrodes 192, 194. According to various embodiments, stimulation can be provided between the separated left electrode 40 and right electrode 44. For example, a stimulation path can be provided along stimulation path 430 for the first electrode 192a of the left electrode tip 44 and the first electrode 194a of the right electrode tip 44. Therefore, stimulation can occur between the left electrode tip 40 and the right electrode tip 44.

[0090] As another example, stimulation can occur between electrode contacts at different points along the length of the electrode or lead tips 40, 44. For example, stimulation can occur between the second electrode contact 192b and the fourth electrode contact 194d. The stimulation path 434 can allow stimulation to occur at two levels or at different distances within the subject 62 relative to the proximal positions of the electrode leads 40, 44. Thus, stimulation can be provided on the tongue 170 between the two separated lead ends 40, 44.

[0091] refer to Figures 6A to 6C Stimulation can be provided at various times between the electrodes at the tips of electrode leads 40, 44. It should be understood that the stimulation pattern can occur or change over time, such as through programming based on ID 30. Therefore, the subject 62 can be stimulated at appropriate physical locations, and... Figure 6A The illustrations or examples in Figure 6D are merely exemplary. It should be understood that stimulation can be provided between any selected electrodes of the electrode lead tips 40, 44, and the above description of stimulation between different electrode contacts 192, 194 of the respective lead tips 40, 44 and / or between electrode lead tips 40, 44 is merely exemplary.

[0092] like Figures 6A to 6C As shown, the leads 40 and 44, placed at different locations within the tongue, can be manipulated to stimulate different areas within the tongue 170. The electrodes 190 and 194 at the corresponding leads 40 and 44 can be used to stimulate different separated physical locations on the tongue. Different physical locations can provide different therapeutic effects for OSA and / or UARS.

[0093] For further reference Figures 5A to 5G Furthermore, stimulation from ID 30 to subject 62 can be generated based on selected pulses and / or waves stimulating subject 62. Those skilled in the art will also understand that... Figures 5A to 5GThe various stimulation wave patterns shown are merely illustrative. These wave patterns can be used to stimulate subjects based on various amplitudes, time differences, and the difference between the left and right electrode positions. It should also be understood that more than two electrode tips can be positioned within the subject, allowing for the identification or placement of additional, third, and / or any appropriate number of electrode positions.

[0094] refer to Figures 5A to 5G and Figures 6A to 6C Therefore, it is possible to stimulate the subject in a way that reduces or eliminates muscle fatigue during prolonged stimulation therapy.62 Fatigue reduction can increase therapeutic efficacy and / or reach a threshold for efficacy or outcome parameters. For example, the waveform of the stimulation can be modified or altered, or the waveform may alternate with selected patterns or differences to ensure that continuous stimulation with a single amplitude is not maintained. Thus, the stimulation can be discontinuous and allow the subject's muscles to relax for a period of time, so that the muscles do not fatigue and no longer respond to the stimulation therapy. In addition, the physical location of the treatment can change over time, such as Figures 6A to 6C As illustrated in the example, this also helps reduce or eliminate muscle fatigue. Muscle fatigue can occur when a single muscle and / or a single area of ​​a muscle is stimulated for an extended period. After prolonged stimulation, the muscle may cease to respond or become unable to contract in a selected manner. Therefore, allowing muscle relaxation allows for a more and / or predictable response to stimuli from ID 30.

[0095] Therefore, in various implementations, as further discussed herein, stimulation may be provided to subject 62 in a selected manner to substantially reduce and / or eliminate muscle fatigue. Reduction and / or elimination of muscle fatigue may allow selected and / or optimal results for selected subject 62. As described above, stimulation of one or more portions of the tongue 170 may induce activation (e.g., contraction) of the tongue muscles or selected muscles of the tongue 170 to aid in the treatment of OAS and / or UARS.

[0096] As described above, stimulation can be provided to subject 62, particularly in the tongue, for the relief of various symptoms and / or to provide treatment to subject 62. Treatment can be provided to subject based on selected electrode stimulation patterns, stimulation wave patterns, and other characteristics or treatment types or amplitudes. As further discussed herein, treatment may be delivered to subject 62 in an appropriate manner, which may be based on various factors and / or inputs from various sensors, subject 62, clinicians, or other appropriate inputs. Treatment can be provided by ID 30 based on programming stored in its memory, programming from CTM 70, 74, or other appropriate processors. In various embodiments, treatment can be provided based on a set of instructions or a selected set of instructions, a selection from multiple instructions in a set of instructions, and / or adaptive or learning algorithms (e.g., machine learning algorithms or systems) to provide selected or optimal treatment to subject 62.

[0097] Stimulation system 20 may include ID 30, which provides energy to stimulation lead tips 40, 44 according to appropriate modes and configurations, as described above. In addition to CTMs 70, 74, input sensors 61, 61' may also provide input to ID 30 and / or CTMs 70, 74. As described above, sensors 61, 61' may provide information about subject 62, including various oxygen saturation levels (arterial or tissue oxygen saturation), muscle activation (e.g., electromyography (EMG)), temperature, body position (e.g., using an accelerometer), heart rhythm (e.g., electrocardiography (ECG)) or other suitable sensors. As commonly understood by those skilled in the art, sleep studies may be performed on patients, including sensing various characteristics of subject 62 in polysomnography. Sensors 61, 61' may be used to sense one or more sensing elements of subject 62 to assist in providing appropriate stimulation to subject 62 as part of the treatment provided to subject 62.

[0098] Accordingly, refer to Figure 7 And continue to refer to Figures 1 to 6C A process or system flowchart 480 is shown. Process 480 can be executed by the processor module 50 in ID 30 and / or the processor module of either the first CTM 70 or the second CTM 74 via transmitting a signal to ID 30. Accordingly, process 480 can be used to provide selected treatment to subject 62 in a selected manner, as described above. Initially, process 480 can be started in start box 484. A process starting in box 484 can be any suitable start, such as powering ID 30, implanting ID 30, etc. Once the process is started in box 484, a determination can be made in box 500 whether stimulation should be initiated.

[0099] The initiation of a stimulus can be based on various inputs, such as the determination of proximity to one or more of the CTMs 70, 74. For example, the first CTM 70 may be located near the subject's sleep orientation and / or powered or activated by the subject 62 at the start of a sleep cycle. Thus, in box 500, proximity to the CTM 70 and / or receiving a signal from the CTM 70 can be provided to initiate the stimulus. Furthermore, as described above, various inputs from sensors (such as sensor 61 or external sensor 61') can be used to determine whether the initiation of a stimulus is possible. For example, the position of the subject 62 can be used to determine whether the subject 62 is in a supine or horizontal position. Therefore, the initiation of a stimulus or stimulus process can be based on the subject's position. In any case, the initiation of a stimulus can be determined in box 500.

[0100] If it is determined that stimulation initiation will not occur, the NO path 504 can be followed. The NO path 504 can then return to the start box 484. In various embodiments, for example, determining in box 500 whether stimulation initiation should occur can be based on a selected periodic cycle of ID 30. In various embodiments, for example, a low-power clock or timer can be included in ID 30. The timer can be set to a selected time period (e.g., 10 minutes). Accordingly, if ID 30 is not already in a stimulation cycle, start box 484 can be initiated every 10 minutes. However, it should be understood that start box 484 can be entered in any suitable manner.

[0101] If the initiation of a stimulus is determined in box 500, the YES path 510 can be followed. The YES path 510 can enter or subsequently reach box 520 to detect or sense a sensor signal. The sensor signal detected in box 520 can be an input from a sensor sensing any appropriate characteristic of the subject 62. For example, a measurement of arterial oxygen saturation (SPO2) and / or a measurement of tissue oxygen saturation (STO2) can be performed. Oxygen saturation can be measured at any appropriate location, such as at ID 30, using an external measuring device, or at any location along lead 34. In any case, the sensor can provide the selected oxygen saturation to a processor such as ID processor 50.

[0102] Other sensor information can be correlated with the EMG. The EMG can be sensed at the lead contacts at the lead tips 40, 44. In various embodiments, for example, the tip electrodes 40, 44 can be used to measure the chin EMG. The EMG can be a time-averaged signal (e.g., EMG averaged over a selected time period, such as 10 seconds). In any case, the EMG can be sensed and analyzed to determine the stimulus, as discussed further herein.

[0103] As described above, Subject 62 may have undergone a sleep study during a selected time period, such as before the implantation of ID 30. The sleep study of Subject 62 can be used to determine various selected thresholds for the information sensed by Subject 62. As further discussed herein, selected population values ​​can be determined for sensed information such as oxygen saturation, EMG signal values, etc. Regardless of the determined time and / or determined source, memory 54 and / or any suitable memory (such as memory 102 of CTM 70) can be used to store the selected values ​​for retrieval.

[0104] Calibration and / or retrieval of selected sensor information can be performed at any appropriate time, such as at the initial implantation of ID 30, during sleep studies of patient 62, or after initial implantation and use of ID 30, or after ID 30 has undergone a selected number of sleep cycles in subject 62. In any case, appropriate or selected sensory levels or values ​​can be determined and / or stored in memory 54 for retrieval by the processor 50 of ID 30.

[0105] Then, in box 540, a selected processor module (such as processor module 50 of ID 30) can compare the detected sensor signal from box 520 with the calibration or call value from box 538. The comparison result in box 540 can be based on comparing the selected sensor signal from box 520 with the call signal or value in box 538. This comparison can then be used to determine whether or should a stimulus be provided to subject 62, such as based on the calibration or determination value in box 538.

[0106] The calibration signal can be based on one or more sensed values ​​or a threshold used to determine one or more sensed values, such as oxygenation value, EMG value, etc. Accordingly, once a comparison is obtained in box 540 with the calibration value obtained in box 538, it is determined whether the sensor signal from box 520 is at a threshold or selected value. This determination is made in box 544. This comparison result can be obtained by the processor module 50 in ID 30 to determine whether a stimulus should be delivered to the subject 62.

[0107] Then, a determination can be made in box 544 whether the sensor signal is equal to or greater than a threshold to follow the selected path. If, during the comparison in box 540, the sensor signal from box 520 is equal to or greater than the threshold, the YES path 550 can be followed. The “YES” path 550 can be followed or allow determination that stimulation should not be turned on, and therefore stimulation is subsequently turned off 556. Stimulation can be turned off in box 556 to determine that stimulation should not be provided through the selected electrode lead 34. Accordingly, no stimulation or stimulation off may include sensing or stopping previous stimulation or not initiating stimulation through lead 34.

[0108] After determining in box 586 that the stimulus should be disconnected, a check or recheck can be performed in box 562 to determine whether the stimulus should be activated. Rechecking or re-examining the activation of the stimulus in box 562 can return to the activation of the stimulus in box 500. Accordingly, it should be understood that once ID 30 is activated or implanted in box 584, process 480 can be a cyclical process. Accordingly, the activation of the stimulus in box 500 can continue through the various steps until it is determined in box 544 whether the sensor signal is equal to or greater than a threshold, as described above.

[0109] Therefore, the determination of whether the sensor signal is equal to or greater than the threshold in box 544 can also follow the NO path in box 570. Once the NO path in box 570 is followed, the determination or invocation of the stimulation pattern or characteristic is performed in box 574.

[0110] The stimulation pattern or characteristic can be any suitable stimulation pattern or characteristic, as described above. The pattern can be pre-programmed in the memory 54 of ID 30 at any appropriate time, such as based on sleep studies of subject 62, learning based on a selected learning algorithm (as discussed further herein), or other appropriate determination. In any case, the stimulation pattern can be invoked or determined in box 574 to stimulate subject 62.

[0111] After a stimulus pattern or characteristic is invoked or determined in box 574, the stimulus can be turned on or off in box 578. As described above, a stimulus may not be delivered to subject 62 from ID 30 via lead 34 until a selection determination is made (such as the determination in box 544). Accordingly, once it is determined that a threshold for the selected sensor input has not been obtained in box 544, the NO path 570 is followed and the determination or invocation of the stimulus pattern is made in box 574. The stimulus invoked in box 574 can then be activated or turned on in box 578 to stimulate subject 62 according to the determined or selected stimulus pattern.

[0112] After stimulation is initiated, subject 62 may be stimulated for an appropriate period of time (e.g., a stimulation pattern selected from a defined set of stimulation patterns). Once the selected stimulus occurs in box 578, a check or re-check of when the stimulus should be initiated can occur in box 562. Accordingly, even after stimulation occurs in box 578, the stimulation determination can be re-checked or cycled according to process 480. Thus, process 480 can be a substantially continuous or cyclical process to provide stimulation to subject 62 when needed and / or when it is determined that appropriate treatment should be provided to subject 62.

[0113] Process 480 may allow stimulation or de-stimulation of subject 62. Process 480 may be cycled an appropriate number of times to provide treatment to subject 62. Thus, treatment of subject 62 may be performed by ID 30 according to process 480 based on selected calibrated or determined sensor signal levels or values ​​for various sensor inputs, as described above. Stimulation may then be turned on or off based on the result of a comparison between the sensed value and the calibrated or determined call value (such as in determination box 544).

[0114] Continue to refer to Figures 6A to 6C And refer to other sources Figure 8 This allows for the determination of a selected or appropriate stimulus pattern for subject 62 (e.g., including optimal or selected optimal configurations). Stimulus configurations can be made or tested based on a variety of different configurations.

[0115] like Figures 6A to 6C As shown, an exemplary configuration for stimulation between one or more contacts 192, 194 of the electrode ends 40, 44 can be made. A selection list of all possible configurations and / or selected configurations can be determined. Selected or possible configurations can be tested on subject 62 to help determine the optimal or selected best stimulation configuration.

[0116] Accordingly, refer to Figure 8 The diagram illustrates a testing and / or stimulation procedure 620. Procedure 620 can be a stimulation or electrode configuration stimulation testing procedure. Procedure 620 can begin in start box 630. After start box 630, such as after implantation of ID 30 into subject 62 and / or after selection of implantation (e.g., before surgery), a list of possible candidate electrode configurations can be constructed or invoked in box 638. The list of possible stimulation electrode configurations may include... Figure 6A , Figure 6B and Figure 6C The exemplary configurations shown are as illustrated in box 638. Furthermore, it should be understood that additional stimulus configurations may be made or determined, and these additional stimulus configurations may be included in the list in box 638. Accordingly, the exemplary configurations discussed above are not intended to be a limitation on possible stimulus configurations for subject 62.

[0117] After building or retrieving the list of possible configurations, multiple test scenarios can be identified and / or planned for each set of configurations to be tested in box 642. Test plans can be made based on the list and can be set for hours, days, several sleep cycles, etc. For example, it can be determined to test first such as Figure 6A Configure as shown, then test. Figure 6B The configuration shown is then tested. Figure 6CThe configuration shown allows you to determine the duration of testing each configuration for a selected number of sleep cycles, a selected number of sleep hours, or any other appropriate time. Furthermore, you can plan to apply the test configuration some time after implantation, such as starting a test period after a certain number of sleep cycles, sleep hours, etc. However, the selected plan can be determined.

[0118] After the test plan is determined, it can be stored in box 650. Storage in box 650 allows the test plan (including configuration) to be stored in an appropriate memory, such as memory module 54 of ID 30. It should be understood that the test plan can also be stored in any suitable memory, such as memory 102 of CTM 70. As described above, CTM 70 can send signals to ID 30 for execution by ID 30 (e.g., CTM 70 sends instructions to ID 30 for execution by processor 50). Therefore, the configuration and test plan can be stored in any suitable memory for execution by ID 30.

[0119] After the program is stored in box 650, it can be determined in box 654 whether a stimulus should be initiated. The determination of the initiating stimulus can be based on appropriate or selected inputs, including the location of the subject 62, the input of the CTM 70, proximity to the CTM 70, or other appropriate inputs. The initiation of the stimulus can be similar to that discussed above (such as in process 480).

[0120] If the initiation of the stimulus is not determined to be appropriate in box 654, the NO path 658 can be followed back to box 650 to store the invoked test plan. Therefore, the initiation of the stimulus can be used to determine or create a loop to allow the invocation of an appropriate stimulus plan (such as a test plan) for execution by ID 30. The loop can determine whether the stimulus should occur to ensure or determine the stimulus plan's duration for an appropriate period.

[0121] If the initiation of the stimulus is determined to be correct, the “YES” path 662 can be followed to invoke or retrieve the determined treatment rule in box 668. The invoked treatment rule can be similar to those discussed above, including initiating a specific treatment based on various inputs and / or sensor signals. Accordingly, sensor signals can include the location of ID 30 and / or various other sensor inputs, such as EMG, oxygen saturation, etc. However, treatment can be provided from ID 30 according to the rule invoked in box 668. Accordingly, rule 668 can be included in instructions stored in memory module 54, which can be executed by ID 30 via processor module 50.

[0122] Once stimulation is initiated in box 654 and followed according to the rules or instructions invoked in box 668, stimulation can be performed according to one of the plans or configurations selected in box 674. As mentioned above, multiple configurations can be stored in box 650. Accordingly, during the testing or configuration phase, such as during process 620, one of the stimulation configurations in box 674 can be selected for testing or stimulating subject 62. Thus, for example, during the first testing period, Figure 6A The configuration shown can be used to stimulate subjects according to the rules invoked in box 668.

[0123] During stimulation according to a selected storage configuration among the plurality of storage configurations (such as that selected in box 674), the effectiveness of the treatment can be recorded in box 680. This recording can be based on various sensors incorporated into or included by the ID 30 worn by the subject 62 (e.g., external sensor 61') or other suitable sensors associated with the ID 30. In various embodiments, for example, oxygen saturation can be sensed, respiratory rate can be sensed, or other suitable information can be sensed and stored using the ID 30. As described above, a CTM 70 can also be provided for user access by the subject 62. The subject 62 can input or provide feedback regarding a selected sleep cycle, which can be associated with a selected test selected in box 674 or used to stimulate the subject. Accordingly, the subject can input information about perceived comfort, sleep effectiveness, or other suitable information. Furthermore, various additional sensors can be provided that can provide input or sensing for the subject 62 during selected time periods.

[0124] The information recorded in box 680 can be stored in any suitable memory, such as memory module 54, memory module 102, and / or other suitable memory modules. This information can be retrieved at a selected time for further determination and / or analysis. However, various sensors can record and / or store information about the parameters sensed by subject 62, and / or subject 62 can input information about sleep.

[0125] The recorded information can then be output in box 684 for selected analysis. This output can be transferred to a CTM 70, CTM 74, or other suitable system. However, the output can be stored for further analysis, such as after a selected number of sleep cycles. Various memory modules may include capacity for storing an appropriate amount of sensor data and / or user input data for further analysis.

[0126] After outputting the results in box 684 and / or storing the results in box 680, it can be determined in box 690 whether to test more electrode configurations. If another configuration is to be tested, the YES path 694 can be followed to determine in box 654 whether stimulation should be initiated. As described above, multiple electrode configurations can be made, such as... Figure 6B Configuration and / or Figure 6C The electrode configuration and / or other additional configurations. Decision box 690 can be used to determine whether additional electrode configurations have been included in the list of possible electrode configurations for testing. It should be understood that, as stated above, any appropriate number of electrode configurations can be stored for testing subject 62.

[0127] If a determination is made in box 690, the additional electrode configuration will not be tested, and the NO path 700 can be followed. Following the NO path 700, it can be determined in box 710 whether the selected configuration should be used and / or whether the selected configuration is the optimal configuration. The determination of the selected configuration can be the selection of a configuration that achieves a selected or optimal outcome for subject 62. As described above, various sensors can be used to sense subject 62. For example, respiratory rate and / or oxygen saturation of subject 62 can be measured. Accordingly, the stimulation configuration that achieves the selected or optimal sensor recording or selected sensor output rating can be used or determined as the optimal configuration for subject 62. For example, blood oxygen saturation level can be weighted as the most relevant factor. Accordingly, the electrode configuration that achieves the highest average, highest optimal, or other appropriate oxygen saturation threshold level can be used or associated with a specific electrode configuration, and this configuration can be determined as the optimal or selected configuration for the subject in box 710. The selection in box 710 can be based on the efficacy of the treatment for subject 62. This efficacy can be based on achieving the selected or threshold sensor value.

[0128] In various implementations, selected sensor readings can be based on a single subject or a group. For example, it can be selected that the oxygen saturation level is read at or near or greater than about 95%, and that it is maintained or sensed at or above at least about 90% during selected sleep periods. A normal or therapeutic respiratory rate for adults can be about 12 to 20 breaths per minute. A heart rate can be selected to achieve, or can be therapeutically provided to maintain, a heart rate of about 40 to about 100 beats per minute (BPM) during sleep. Furthermore, combinations of sensor readings, such as the coupling of a drop in oxygen levels with arousal (registered via an accelerometer measuring movement), can also be used as an alarm: insufficient stimulation is being delivered, an alarm intended to prevent apnea / hypoventricular hypoventricular activity. One or more sensor inputs can be used to consider sleep quality optimization using necessary feedback sensors (e.g., EEG, etc.).

[0129] A selected or optimal configuration can be made in box 710, or the configuration can be based on a determination of the efficacy of the treatment (including stimulation therapy) based on the results of the output in box 684. The optimal electrode configuration can be determined in box 710 based on this efficacy. Efficacy can be based on or determined as a comparison of the data values ​​in box 680 with predetermined threshold values ​​and / or subject thresholds or responses. For example, an oxygenation threshold can be determined. The stored values ​​in box 680 and the output in box 684 can be compared with a predetermined oxygenation threshold. Efficacy (e.g., efficacy value) can be determined based on whether or not a predetermined threshold is reached or exceeded, and by how much. Therefore, a more effective or more efficient treatment may include an electrode configuration that achieves higher oxygenation than another configuration. However, it should be understood that efficacy can be based on more than one value (e.g., sensor value) and / or the weighting of different parameters.

[0130] As mentioned above, the threshold can be a value outside the normal or selected range. The selected threshold can also be subject-specific and calibrated and stored for each subject. For example, if the blood oxygen level is below approximately 95. There is no standard or a lack of movement registered by position sensors (e.g., accelerometers) during sleep. There is no or a lack of normal chest rise and fall. For example, position sensors in the middle / upper part of the subject's chest can register rise and fall / movement, and if the chest stops moving for 10 seconds (i.e., a possible apnea event), apnea can be avoided by stimulation or increasing stimulation or initiating stimulation.

[0131] Once the optimal configuration is determined in box 710, ID 30 can be set to that configuration in box 720. Accordingly, for example, ID 30 with a set of test configurations can be implanted. Then, according to procedure 620, the set of test configurations invoked in box 650 can be tested in the subject 62 within a selected time period. After the optimal or selected configuration is determined in box 710, ID 30 can be set to the selected configuration in box 720. Therefore, the subject 62 can receive treatment according to the selected electrode configuration set in ID in box 720.

[0132] Electrode configurations can be set in box 720 at any selected time. For example, as described above, process 620 can be selected to run within a set time period. However, it should be understood that the determination in box 710 can be performed substantially in real time. For example, processor 50 can receive input and determine that a selected threshold (e.g., oxygenation) is not met. If the threshold is not met, the processor can invoke different electrode configurations in box 650 for stimulation. Therefore, process 620 can allow for the determination and utilization of electrode configurations for stimulation substantially in real time (e.g., once or multiple times during the current or a single sleep cycle).

[0133] Process 620 may also include determining in box 730 whether a new test phase should occur. Based on the selected signal, a new test phase can occur at any appropriate time. For example, after a three-month period, a selected number of sleep cycles, etc., a new test phase can be initiated in box 730. One or more of CTMs 70 and 74 can be used to initiate a new test phase in ID or determination box 730. Accordingly, process 620 can be used to test a selected number of configurations at any appropriate time. Furthermore, it should be understood that CTMs 70 and 74 can be used to send additional configurations to ID 30 for additional testing.

[0134] If no additional tests need to be performed, the process can be terminated in box 738 by following path NO 734. However, as discussed above, process 620 can be restarted at any appropriate time.

[0135] Furthermore, if a new testing phase is identified in box 730, the YES path 742 can be followed to determine in box 654 whether stimulation should be initiated. Accordingly, for example, subject 62 may be visited by a clinician at a selected time, and the clinician may determine that an additional testing phase should be performed. The clinician can initiate the new testing phase using CTM 74 by signaling to ID 30. ID 30 can then determine in box 730 that a new testing phase should occur, and the YES path 742 can be followed to determine in box 654 whether stimulation should be initiated. Accordingly, even if the clinician visits subject 62 during a non-sleep period, the clinician can initiate a new testing phase in box 730 and restart the testing phase by following the YES path 742.

[0136] As described above, the process and method can be used to utilize ID 30 to operate and / or determine selected or optimal operation (e.g., waveform for stimulation) for providing treatment to subject 62. Accordingly, refer to Figures 5A to 5G And refer to other sources Figure 9 The procedure or method 820 is illustrated. As discussed further herein, procedure 820 can be used to determine or select an appropriate stimulus waveform pattern to be provided to a subject. For example, as... Figure 8 As shown, process 620 can be used to determine or select a selected (e.g., optimal) stimulation configuration of the electrodes positioned on the electrode tips 40, 44. Additionally and / or alternatively, a stimulation wave pattern can also be tested and / or selected for the subject 62. Figures 5A to 5G As shown, an exemplary stimulation wave pattern may be provided by ID 30. Accordingly, process 820 may be used to determine (e.g., test) and / or select the wave pattern that may be optimal for subject 62 to provide appropriate or selected treatment to that subject.

[0137] Therefore, refer to Figure 9 The diagram illustrates process 820. Process 820 can begin in start box 830. Start box 830 can be any suitable start, as described above, including selecting ID 30, implanting ID 30, initiating (e.g., powering on and selecting an initial on period), or other suitable configuration of ID 30. After initiation in start box 830 and / or at an appropriate time, a selected list or possible waveforms can be determined in box 834. The constructed or determined waveforms can include those described above, including... Figures 5A to 5G The waveforms shown. These waveforms may include stimulus duration, stimulus overlap, stimulus amplitude, stimulus duration, or other appropriate waveforms. As mentioned above, these waveforms may include... Figures 5A to 5G The information shown contains more details, and the specific waveforms provided are for illustrative purposes only. Therefore, ID 30 can be used to deliver stimulation to the subject in an appropriate manner based on various waveforms or stimulus types, as described above. The selected waveform list may include any appropriate or all possible waveforms provided by the device, or a list selected by the user 62, clinician, or other appropriate individual.

[0138] Once the list of possible waveform patterns is determined in box 834, a test plan for each waveform can be made in box 838. This test plan, similar to the test plan discussed above in box 642, may include duration tests, including the number of sleep cycles, days, etc. The test pattern allows for the determination or selection of multiple data points to be collected for each of the possible or selected sleep stimulation patterns determined in box 834.

[0139] Once the plans for various patterns from 834 are determined by box 838, the test scheme plan can be stored in box 844. Storing the test scheme may include storing specific patterns from box 834, plans from box 838, or other suitable considerations. Furthermore, the contents stored in box 844 can be stored in any suitable memory module, such as memory module 54 for ID 30, memory module 102 for CTM 70, or other suitable memory modules. In any case, the test scheme can be invoked at appropriate times to test and operate ID 30 in an appropriate manner.

[0140] Once a test protocol has been stored and provided for recall during a selected test phase, determining rules for initiating and / or continuing stimulation can be invoked in box 850. These determining rules for initiating and / or continuing treatment (e.g., OSA and / or UARS treatment) can be stored in an appropriate memory module, such as memory module 54 of ID 30. As described above, the rules may include when and how to initiate OSA treatment, intensity, etc. However, as shown in process 820, various stimulation modes can be tested therein, and the rules invoked in box 850 may include general rules regarding the initiation of stimulation treatment and / or appropriate stimulation electrode configuration, as described above.

[0141] After invoking the rule in box 850, it can be determined in box 854 whether to initiate stimulation. The determination of initiation of treatment can be based on various sensors provided to subject 62 (e.g., sensors 61, 61'), initiation by CTM 70, proximity to CTM 70, or other appropriate initiation features. The determination in box 854 regarding whether stimulation should begin can be based on the rule invoked in box 850.

[0142] If initiation is not performed in box 854, the NO path 856 can be followed, which can loop back to the stimulus initiation determined in box 854. The loop can include a selected time delay, a pause to receive instructions from CTM 70, or other appropriate additional input.

[0143] If stimulus initiation is confirmed, the subject can be stimulated by following the “YES” path 860 according to at least one of the test protocols invoked in box 864. As described above, multiple wave patterns can be identified and stored in box 844. Once stimulation is initiated by following the YES path 860, the subject can be stimulated in box 864 using a selected wave pattern or one of the selected wave patterns.

[0144] During stimulation in box 864, effectiveness and / or sensor sensing and / or recording relative to subject 62 can be performed during treatment. For example, oxygenation levels, respiratory rate, EMG values, apnea-hypopnea index (AHI) index or values ​​can be measured and / or recorded and stored, in whole or in part, for subsequent analysis. For example, various sensors within the subject (such as sensors 61, 61') can be used to sense various data relative to subject 62. Information can be recorded and stored in a selected memory module, such as memory module 54 on ID 30, and / or information can be emitted to be stored on an additional memory module, such as memory module 102 of CTM 70.

[0145] Therefore, values ​​from the sensor can be sensed and recorded in box 868. Data can be output in box 872 for further analysis, such as determining the effectiveness of the selected test stimulus pattern. Data can be output on one or more screens, such as screen 92 of the CTM 70, screen 124 of the CTM 74, or other suitable output terminals. Output can occur at any suitable time, such as after a selected sleep cycle, upon completion of a planned waveform pattern, or at other appropriate times.

[0146] After one or more testing periods, it can be determined in box 880 whether to test more candidate waveforms. If it is determined that additional waveforms should be tested, the YES path 884 can be followed to return to the stimulus initiation determination box 854. Thus, the stimulation of the subject in 864 can be performed according to different or selected additional waveform patterns to allow sensing and recording of the subject 62 in box 868.

[0147] Once a selected number of waveforms have been tested, or if it is determined in box 880 that no additional waveforms need to be tested, the NO path 890 can be followed. When following the NO path 890, a selected candidate stimulation waveform can be determined in box 894. The selected stimulation waveform in box 894 can be the optimal waveform for stimulating subject 62. The optimal waveform can be a waveform that provides the selected treatment to the subject, such as based on the data sensed in box 868. Furthermore, it should be understood that the selected sensed value among the sensed values ​​can have a higher weight than other values, and therefore the optimal waveform may not be based on a single value and / or may include a selected optimal range for one sensed value but not applicable to another. The determination of the optimal waveform may include analysis of sensor data regarding the configuration of the stimulation electrodes, as described above. The selection in box 894 can be based on the efficacy of the treatment on subject 62. This efficacy can be based on achieving a selected or threshold sensor value. The threshold level can be selected or determined by the subject, but may include low SpO2 values ​​(e.g., less than about 90%), high respiratory rate (e.g., above about 15 breaths per minute), or high heart rate (e.g., above about 100 BPM). In various implementations, sleep quality can be a therapeutic feedback loop for optimization. Therefore, sleep quality can be an indicator of therapeutic effectiveness and / or efficacy.

[0148] The selected or optimal waveform in box 894 can be generated, or the waveform can be based on a determination of the efficacy of the treatment (including stimulation therapy) based on the results of the output in box 868. The optimal waveform in box 894 can be determined based on this efficacy. Efficacy can be based on or determined as a comparison of the data value in box 868 with a predetermined threshold and / or a subject threshold or response. For example, an oxygenation threshold can be determined. The stored value in box 868 and the output in box 872 can be compared with a predetermined oxygenation threshold. Efficacy (e.g., efficacy value) can be determined based on whether or not a predetermined threshold is reached or exceeded, and by how much. Therefore, a more effective or more efficient treatment could include a waveform that achieves higher oxygenation than another waveform. However, it should be understood that efficacy can be based on more than one value (e.g., sensor value) and / or the weighting of different parameters, such as those mentioned above.

[0149] After the selected waveform is determined in box 894, the waveform can be set in box 900. By setting the waveform in box 900, the selected waveform can be programmed or selected in ID 30 to provide stimulation to subject 62 within a selected time period. For example, test phase 820 can be used to test or select a waveform using ID 30 to stimulate subject 62. After a selected test phase or a selected time, the selected waveform can be selected in ID 30 and set as the stimulation waveform. Thus, for example, after a test period (e.g., one month), ID 30 can be set as the selected waveform to provide selected (e.g., optimal) treatment to subject 62.

[0150] A waveform can be set in box 910 at any selected time. For example, as described above, process 820 can be selected to run within a set time period. However, it should be understood that the determination in box 894 can be performed substantially in real time. For example, processor 50 can receive input and determine that a selected threshold (e.g., oxygenation) is not met. If the threshold is not met, the processor can invoke different waveforms in box 838 for stimulation. Therefore, process 820 can allow for the determination and utilization of waveforms for stimulation substantially in real time (e.g., once or multiple times during the current or a single sleep cycle).

[0151] However, it should be understood that a new testing phase can be selected or defined in box 910 after the selected time period. Selecting a new testing phase in box 910 can be any appropriate choice, such as a clinician's choice after the selected time has elapsed, such as transmitting a signal from the CTM 74, or other appropriate choices. Accordingly, a new testing phase can be initiated in box 910.

[0152] If a new testing phase is determined in box 910, the “YES” path 914 can be followed to construct or recall a list of possible candidate waveforms in box 834. Therefore, process 820 can be repeated at selected times. It should be understood that the list in box 834 can be the same as the list described above, and the test can be simply repeated, as the subject 62 can change over time (e.g., gain muscle stiffness, strength, etc.).

[0153] Furthermore, if no new testing phase is identified, path 920 can be followed, and process 820 can end in box 924. Ending the process in 924 can include stimulating subject 62 according to the selected waveform in box 900 for stimulating the subject at an appropriate time or in an appropriate manner. Thus, process 820 can be used to test and / or select an appropriate or optimal waveform for subject 62.

[0154] Accordingly, as described above, ID 30 can be used to provide stimulation to subject 62 in an appropriate manner. ID 30 can be used to configure electrodes or provide stimulation for selected electrode configurations, such that electrode tips 40, 44 are in various patterns or configurations. Furthermore, various waveforms can be used to stimulate subject 62. These selected configurations and / or waveforms can be tested or selected within a selected time period, such as after ID 30 implantation. It should be understood that the combination of electrode configurations, waveforms, or information sensed from subject 62 can all be tested simultaneously, sequentially, etc., to determine the optimal configuration, waveform, and other factors or parameters relative to subject 62, thereby providing treatment to subject 62. Therefore, ID 30 can be used to provide stimulation to subject 62 in a manner that substantially reduces and / or eliminates fatigue of the tongue muscles 170, and / or to provide selected or optimal treatment to subject 62 to provide treatment for selected conditions, such as OSA, UARS, or other appropriate conditions.

[0155] Turn Figure 10 The diagram illustrates a process or system 1000. System 1000 can be used to assist in generating parameters for treatment of subject 62 or any suitable subject. In various embodiments, process 1000 can be a machine learning process capable of incorporating or using any suitable machine learning algorithm (e.g., regression analysis, supervised or unsupervised algorithms, neural networks, or combinations thereof). Machine learning process 1000 can allow the acquisition or use of data from multiple subjects and / or one subject for the generation of specific treatment parameters.

[0156] For example, population parameters or data 1010 can be collected. Individual parameters or data can also be collected in box 1020. The parameters can be substantially the same between the population in box 1010 and the individuals in box 1020. For example, parameters may include body mass index (i.e., including weight), blood pressure, oxygen saturation in blood and tissues, EMG (e.g., chin EMG, chest or arterial EMG, etc.), respiratory rate, pulse rate, or other appropriate parameters. Parameter values ​​can be collected from the population in box 1010 or the individuals in box 1020, and the parameter values ​​may include those collected during a selected study (such as a sleep study). As described above, a sleep study of an individual or the population to which the individual belongs may include acquiring data in polysomnography. In a sleep study, various parameters about the individual may be collected during alarm states, sleep states, the subject's vertical position, horizontal position, or other orientations. The various parameters may include those described above, including oxygenation levels in various regions of the subject's body, brain waves, muscle activation, and other appropriate parameters. The various parameters may be used to identify or determine the onset and / or tendency of sleep apnea episodes. For example, respiratory rate, oxygenation level, etc., can be used to determine or understand the severity, duration, etc., of an apnea episode. Then, the subject may be stimulated (e.g., subject 62) or treated in an appropriate manner to help correct or stop the apnea episode.

[0157] Population parameters or data 1010 may include data about a population (such as multiple patients). The data may include patient data (e.g., weight and health status) and various parameters used to stimulate the tongue muscles of each individual in the population. Therefore, population data 1010 may include stimulation parameters (e.g., waveform and / or lead configuration) for treating OSA. Population data may also include a determined efficacy of the applied treatment (e.g., efficacy determined by an expert or clinician). Population data may include various inputs from the subject during stimulation (e.g., sensor inputs and subject inputs). Inputs may include those described above, including duration and frequency of apnea events, oxygen saturation, etc. Therefore, efficacy can be determined based on various inputs during stimulation.

[0158] Regardless, population parameters from box 1010 and individual parameters from box 1020 can be acquired and input into the machine learning system in box 1030. The machine learning system 1030 can include selected algorithms such as those discussed above, as well as various weights for the parameters. The machine learning system can acquire and analyze parameters from the population in box 1010 and the individuals in box 1020. The weights and algorithms associated with the machine learning system in box 1030 can be used to determine appropriate treatment parameters.

[0159] Then, treatment parameters can be determined and output in box 1040. Treatment parameters may include various features, such as those discussed above, including stimulation waveforms, lead configuration, various inputs from sensors associated with subject 62, etc. As mentioned above, various inputs may include an accelerometer to indicate the position of subject 62, an oxygenation sensor to determine oxygen saturation at various positions of the subject, and other appropriate sensors, including those discussed above.

[0160] The treatment parameters output in box 1040 may include parameters regarding treatment initiation, treatment waveform, treatment electrode configuration, etc. Furthermore, the treatment parameters may include multiple sets of treatment parameters that can be studied or tested relative to subject 62, as described above. However, in various embodiments, the treatment parameters output in box 1040 may include a single set of parameters, including waveform, electrode configuration, and selected sensor inputs (e.g., for initiating stimulation, including subject position, respiratory rate, etc.).

[0161] Therefore, ID 30 can be programmed post-implantation based on a machine learning system 1030, which may include population parameters from box 1010 and individual parameters from box 1020. In various embodiments, the individual parameters in box 1020 may include sleep studies of individual subjects, which may include information about apnea events during the sleep study. Accordingly, the treatment parameters in box 1040 may include initiating treatment based on a determined location of the subject (i.e., using sensors), receiving signals from ID 30 regarding the initiation of treatment, etc. The treatment parameters from box 1040 may also include specific waveforms, population parameters 1010, or feedback that can be selected (e.g., by a clinician), as discussed further herein.

[0162] The treatment parameters output in box 1040 can be used or applied to the subject, such as optionally applying treatment in box 1050. Applying treatment in box 1050 can include applying treatment to subject 62 based on the treatment parameters output in box 1040. The treatment parameters can be stored in ID 30, such as during programming in ID 30, programming using CTM 70, 74, or other appropriate programming. Subject 62 can then be treated within a selected time period in box 1050 (such as within a certain number of sleep hours, sleep cycles, set time periods, etc.). However, it should be understood that applying treatment in box 1050 is not necessary for process 1000, but this step is included or disclosed for clarity.

[0163] Treatment analysis may occur in box 1060. Treatment analysis may include data collected during treatment based on the treatment output in box 1040, as described in box 1050. However, treatment analysis in box 1060 may be an analysis of any appropriate treatment data. Treatment analysis may include data on the number of apnea episodes, the duration of apnea episodes, and the severity of apnea episodes (e.g., oxygen saturation, brain waves, or other appropriate considerations). The selection or analysis in box 1060 may be based on the efficacy of treatment on subject 62 or a subject population. This efficacy may be based on achieving selected or threshold sensor values ​​and / or subject or population feedback. Furthermore, increased or better efficacy may be achieved when one or more thresholds are reached or values ​​that show improvement relative to different treatment parameters (e.g., greater oxygenation).

[0164] In various implementation schemes, efficacy can be determined or assessed based on a reduction in the severity of apnea events. Various factors can include oxygen saturation levels, heart rate, and the duration of adverse indicators that may be associated with severity. For example, low or very low oxygen saturation levels (e.g., below approximately 85%) may be severe, with lower levels indicating greater severity of the apnea event. Very high heart rates (indicating high sympathetic stress) (e.g., above approximately 100 BPM) may be severe, with higher levels indicating greater severity of the apnea event. Furthermore, prolonged duration (e.g., minutes) of adverse factors (e.g., oxygenation levels, heart rate, etc.) may be severe, with longer durations indicating greater severity of the apnea event. Additionally, a higher frequency of apnea events may indicate a more severe condition or less effective treatment. Other indicators may include reduced or absent airflow. Typically, apnea events may trigger other arrhythmias (slow HR < 30 bpm, seizure-like apnea lasting longer than 3 seconds, arrhythmia, etc.).

[0165] Treatment analysis can be performed by ID 30, CTM 70, 74, or any suitable system. Treatment analysis may include determining the success or optimization of selected treatment outputs in box 1040. Accordingly, as described above, treatment analysis in box 1060 may include determining the number of apnea episodes during sleep periods (e.g., the frequency of apnea episodes per sleep minute or hour) and / or other factors of subject 62.

[0166] Treatment analysis can be used to provide feedback 1070 to the machine learning system 1030. Feedback can include simple feedback such as the number of sleep apnea episodes, selected treatments from box 1040, or other appropriate feedback. For example, feedback can include the subject's feedback on sleep success, sleep quality, etc. Therefore, feedback can be provided to the machine learning system 1030 for analysis or includes treatment analysis from box 1060, as well as various population parameters 1010 and individual parameters 1020.

[0167] As described above, machine learning can include selected algorithms and various features of these algorithms, such as weights, to aid in determining appropriate treatment parameters. Therefore, feedback 1070 can allow for modification or optimization of the treatment parameters output in box 1040. Treatment analysis can then occur in box 1060.

[0168] Therefore, process 1000 can be looped to analyze multiple treatment analyses from box 1060 and / or parameters used to provide or determine treatment for subject 62.

[0169] Therefore, process 1000 can be understood as a cyclical or iterative process for implementing treatment of subject 62. Thus, the cyclical process 1000 may include an end-of-cycle determination, such as determining in box 1080 whether further research should occur. If further research is to occur in box 1080, the YES path 1084 can be followed into feedback loop 1070. Therefore, machine learning process 1000 can be used to determine the optimal treatment or selected treatment for subject 62 based on various treatment analyses in box 1060. Feedback 1070 can be long-term, such as over multiple sleep cycles, and / or short-term or real-time, such as during the current sleep cycle. For example, in a real-time scenario, feedback could be: the duration of an apnea event is longer than a selected time threshold or the oxygenation level is below a threshold. Therefore, once it is determined that one or more thresholds have been reached, treatment parameters can be changed in real time.

[0170] If no further research is required or chosen, the NO path 1088 can be followed, ending in box 1090. The ending in box 1090 can be a programming of ID 30 within a selected time period (such as a selected time interval, selected sleep cycle, etc.). Therefore, treatment of subject 62 can be based on an analysis of the individual subject 62 and / or the subject population. The subject population (requiring population parameters from this population in box 1010) can include those subjects who have or have been diagnosed with sleep apnea, those who have not yet been diagnosed with sleep apnea, individuals from various backgrounds, etc. Therefore, population parameters 1010 can be used to provide or determine a selected or general set of parameters regarding the subjects (including those with sleep apnea). Therefore, process 1000 can be used to provide treatment to the subject, not limited to applying treatment using only individual parameters (such as an individual sleep study of subject 62).

[0171] Therefore, as described above, ID 30 can apply treatment to an individual or subject 62 based on various parameters. These parameters may include stimulation waveforms, stimulation electrode contact configurations, sensor inputs to determine when and / or the stimulation amplitude and / or other parameters and inputs used for treatment. Furthermore, various parts of the stimulation system 20 (such as processor 50 of ID 30) can execute instructions via a selected processor to determine whether stimulation should be initiated, as discussed above in process 480. Additionally, system 20 can be used to select and / or implement one or more stimulation parameters (e.g., waveform, electrode configuration, etc.) to provide treatment with selected efficacy to the subject. System 20 can be operated to determine and / or implement treatment through one or more of processes 620, 820, or 1000 as described above. Furthermore, combinations of one or more processes, such as selecting both waveform and electrode configuration, can be used for treatment.

[0172] It should be understood that the various aspects disclosed herein can be combined in combinations different from those specifically presented in the specification and drawings. It should also be understood that, depending on the example, certain actions or events of any process or method described herein may be performed in a different order, and may be completely added, combined, or omitted (e.g., performing the described technique may not require all the described actions or events). Furthermore, although for clarity some aspects of this disclosure are described as being performed by a single module or unit, it should be understood that the techniques of this disclosure can be performed by combinations of units or modules associated with, for example, a medical device.

[0173] In one or more examples, the described techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functionality may be stored as one or more instructions or code on a computer-readable medium (e.g., a memory module) and executed by a hardware-based processing unit. Computer-readable media may include non-transitory computer-readable media, which correspond to tangible media such as data storage media (e.g., RAM, ROM, EEPROM, flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and is accessible by a computer).

[0174] Instructions may be executed by one or more processors (e.g., processor modules), such as one or more digital signal processors (DSPs), general-purpose microprocessors, graphics processing units (GPUs), application-specific integrated circuits (ASICs), field-programmable arrays (FPGAs), or other equivalent integrated or discrete logic circuits. Therefore, the term "processor" as used herein may refer to any of the foregoing structures or any other physical structures suitable for implementing the described techniques. Furthermore, this technology may be fully implemented in one or more circuit or logic elements.

[0175] Exemplary embodiments are provided to make this disclosure thorough and to fully communicate the scope of this disclosure to those skilled in the art. Numerous specific details, such as examples of particular components, apparatus, and methods, are set forth to provide a thorough understanding of embodiments of this disclosure. It will be apparent to those skilled in the art that specific details are not required, that exemplary embodiments may be embodied in many different forms, and should not be construed as limiting the scope of this disclosure. In some exemplary embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

[0176] The foregoing description of embodiments has been provided for illustrative and descriptive purposes. The foregoing description is not intended to be exhaustive or limiting of this disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but are interchangeable and may also be used in selected embodiments where applicable, even if not specifically shown or described. The same element or feature may be varied in many ways. Such variations should not be considered as departing from this disclosure, and all such modifications are intended to be included within the scope of this disclosure.

Claims

1. A non-transitory computer-readable medium storing instructions that, when executed by a processing unit, cause the processing unit to perform a method for activating tongue muscles of a subject, the method comprising: Based on the first set of data about the population, a set of parameters is invoked to activate the tongue muscles in the population. Compare the first set of data with the second set of data about the subject; Based on the comparison results of the first set of data and the second set of data about the subject, at least one parameter is selected from the called set of parameters; During the initial stimulation of the subject, signals about the subject are received; as well as The first efficacy of the stimulus at the first time point is evaluated based on machine learning algorithms.

2. The non-transitory computer-readable medium according to claim 1, wherein the method further comprises: Receive the second set of data regarding the subject.

3. The non-transitory computer-readable medium according to any one of claims 1 or 2, wherein the machine learning algorithm includes evaluating the sleep characteristics of the subject.

4. The non-transitory computer-readable medium of claim 3, wherein assessing the sleep characteristics of the subject includes assessing at least one of the number of apnea episodes, the frequency of apnea episodes, the respiratory rate, the oxygen saturation level, or a combination thereof.

5. The non-transitory computer-readable medium of claim 3, wherein the signal comprising the sleep characteristics of the subject is transmitted.

6. The non-transitory computer-readable medium according to claim 3, further comprising: Operate the processor system to execute the machine learning algorithm; The machine learning algorithm is configured to evaluate the signal, which includes the sleep features, at least based on the weight of each sleep feature.

7. The non-transitory computer-readable medium according to claim 3, wherein the method further comprises: The set of parameters is changed based on the assessment of the sleep characteristics. as well as Generate a modified set of parameters that can be manipulated for later invocation.

8. The non-transitory computer-readable medium of claim 7, wherein the method further comprises: The modified set of parameters is compared with the second set of data about the subject; as well as At least one parameter is selected from the modified set of parameters based on the comparison results between the modified set of parameters and the second set of data about the subject.

9. The non-transitory computer-readable medium of claim 3, wherein the first efficacy is determined based on determining a relative value of the sleep characteristic of the subject with respect to a threshold of a selected sleep characteristic.

10. The non-transitory computer-readable medium according to any one of claims 1 or 2, wherein the method further comprises: Operate the processor system to execute the machine learning algorithm; Transmit a power signal including the first power to the processor system; The appropriateness of at least one selected parameter is determined based on the emitted power signal.

11. The non-transitory computer-readable medium of claim 6, wherein the method further comprises: It was determined that the first efficacy was outside the threshold; Choose the second parameter from the set of parameters called; as well as The second parameter is emitted at a second time to stimulate the subject.

12. The non-transitory computer-readable medium of claim 11, wherein evaluating the first efficacy includes determining a value for at least one of the following relative to a threshold: the number of apnea episodes, the frequency of apnea episodes, the respiratory rate, the oxygen saturation level, or a combination thereof.

13. A non-transitory computer-readable medium storing instructions that, when executed by a processing unit, cause the processing unit to perform a method for selecting parameters for activating tongue muscles of a subject, the method comprising: A set of parameters is invoked at the first moment to activate the tongue muscles in the group, the set of parameters being based on a first set of data about the group; The first set of data is compared with the second set of data regarding the subject's treatment parameters; Based on the comparison result between the first set of data and the second set of data, a first parameter is selected from the set of parameters called. Operating the processor system to: During the first time period when the subject is stimulated using the selected first parameter, a signal regarding the subject's treatment parameters is received; as well as The first efficacy of the stimulus at the first time point is determined by evaluating the subject's treatment parameters using a machine learning algorithm that assesses the first efficacy of the treatment on the subject. Compare the first efficacy with the threshold efficacy; The comparison result value is output based on the first efficacy being compared and the threshold efficacy.

14. The non-transitory computer-readable medium of claim 13, wherein the method further comprises: Based on the output comparison results, generate a modified set of parameters to be invoked at the second time.

15. The non-transitory computer-readable medium of claim 14, wherein the method further comprises: In the second time, the modified set of parameters is invoked to activate the group tongue muscles, the first set of parameters being based on a first set of data about the group; Based on the comparison results between the first set of data and the second set of data, the second parameter is selected from the modified set of parameters called. Operate the processor system to: During the second time period when the subject is stimulated using the selected second parameter, a second signal regarding the subject's treatment parameters is received; as well as The second efficacy of the stimulus at the second time point is determined by evaluating the subject's treatment parameters using the machine learning algorithm. Compare the second efficacy with the threshold efficacy; A second comparison result value is output based on the second power being compared with the threshold power.

16. The non-transitory computer-readable medium according to any one of claims 13 to 15, wherein the set of parameters includes stimulation waveforms, electrode configurations, or combinations thereof.

17. The non-transitory computer-readable medium of claim 16, wherein the set of parameters includes a plurality of stimulation waveforms, electrode configurations, or combinations thereof.

18. The non-transitory computer-readable medium of claim 17, wherein the method further comprises: Based on the output comparison results, a modified set of parameters to be invoked at a second time is generated, wherein the modified set of parameters includes at least one of a modified stimulation waveform, a modified electrode configuration, or a combination thereof.

19. A system for selecting parameters for activating tongue muscles in a subject, comprising: A memory system for storing a set of parameters for activating tongue muscles in a population at a first time, the set of parameters being based on a first set of data about the population; and Processor system, the processor system being configured to execute instructions to: The first set of data is compared with the second set of data regarding the subject's treatment parameters; Based on the comparison result between the first set of data and the second set of data, a first parameter is selected from the set of parameters called. During the first time period when the subject is stimulated using the selected first parameter, a signal regarding the subject's treatment parameters is received; as well as The first efficacy of the stimulus at the first time point is determined by evaluating the subject's treatment parameters using a machine learning algorithm that assesses the first efficacy of the treatment on the subject. Compare the first efficacy with the threshold efficacy; as well as The comparison result value is output based on the first efficacy being compared and the threshold efficacy.

20. The system of claim 19, further comprising: A stimulation system having a power source, a first lead end, and a second lead end; The stimulation system is configured to stimulate the subject through the first lead end and the second lead end according to the first parameter.

21. The system according to any one of claims 19 or 20, further comprising: A sensor configured to sense the subject's treatment parameters and transmit signals to the processor system, the signals including the sensed values ​​of the subject's treatment parameters.

22. The system of claim 21, wherein the processor system is further configured to execute instructions to generate a modified set of parameters to be invoked at a second time based on the output comparison result.

23. The system of claim 22, wherein the processor system is further configured to execute instructions to: In the second time, the modified set of parameters is invoked to activate the group tongue muscles, the first set of parameters being based on a first set of data about the group; Based on the comparison results between the first set of data and the second set of data, the second parameter is selected from the modified set of parameters called. During the second time period when the subject is stimulated using the selected second parameter, a second signal regarding the subject's treatment parameters is received; as well as The second efficacy of the stimulus at the second time point is determined by evaluating the subject's treatment parameters using the machine learning algorithm. Compare the second efficacy with the threshold efficacy; A second comparison result value is output based on the second power being compared with the threshold power.

24. The system according to any one of claims 19 or 20, wherein the set of parameters includes stimulation waveforms, electrode configurations, or combinations thereof.

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