Systems and methods for improving sleep apnea

Abstract

The present invention provides a system and method for improving sleep apnea. **Solution**: The system and method include stimulating the activation of the hypoglossal nerve sheath that innervates one or more infrahyoid muscles by inducing the delivery of a stimulatory neuromodulation signal to the hypoglossal nerve sheath. By delivering an inhibitory neuromodulation signal to the hypoglossal nerve sheath, it is possible to block the activation of the efferent fibers that innervate one or more suprahyoid muscles. The inhibitory neuromodulation signal can reduce the undesired retrograde efferent activation of one or more suprahyoid muscles.

Description

Detailed Description of the Invention

[0001] (Related Applications) This application claims the benefit of U.S. Provisional Application No. 63 / 357,137, filed on June 30, 2022, which is hereby incorporated by reference in its entirety.

Technical Field

[0002] The present invention relates to a system and method for improving sleep disordered breathing via neuromodulation, utilizing a combination of blocking neuromodulation signals and stimulating neuromodulation signals.

Background Art

[0003] Sleep disordered breathing (SDB) occurs when there are partial or complete cessations of breathing that occur multiple times throughout the night. Obstructive sleep apnea (OSA) is a type of SDB that involves the cessation or significant reduction of airflow in the presence of respiratory effort. OSA is the most common type of SDB and is characterized by repeated episodes of upper airway collapse during sleep, which causes a decrease in blood oxygen saturation or neurological arousal after repeated breathing cessations. The pathophysiology of OSA may involve factors such as craniofacial anatomy, airway collapse, and neuromuscular control of the upper airway dilator muscle system. Electromyogram studies have shown that the tonic and phasic activities of the pharyngeal airway dilator muscles (such as the genioglossus muscle) gradually decrease from wakefulness to non-rapid eye movement and rapid eye movement sleep.

[0004] Continuous positive airway pressure (CPAP) therapy is the front-line treatment for OSA. CPAP therapy uses a device that includes a flow generator, a tube, and a mask designed to deliver a constant airflow to keep the airway of a typical OSA patient continuously open. However, the success of CPAP therapy is limited by compliance, and the reported rate range is from 50% to 70%. Hypoglossal nerve stimulation (HNS) has been established as an effective therapy for patients with obstructive sleep apnea (OSA) who cannot tolerate positive airway pressure ventilation. This therapy functions by expanding the pharyngeal airway by protruding and hardening the muscles of the tongue. However, only a small number of OSA patients have the anatomical structure suitable for hypoglossal nerve stimulation therapy, and many patients continue to experience airway collapse even under stimulation of the hypoglossal nerve muscle system.

Summary of the Invention

Means for Solving the Problems

[0005] The present invention provides a neuromodulation system and method for improving SDB by applying various combinations of stimulatory neuromodulatory signals and inhibitory neuromodulatory signals to various nerve target sites. In one aspect, a neuromodulation system for improving sleep disordered breathing may include a processor and a non-transitory computer-readable medium storing instructions executable by the processor. Such executable instructions may include stimulating the activation of the cervical ramus that innervates one or more infrahyoid muscles by inducing the delivery of a stimulatory neuromodulatory signal to the cervical ramus, and blocking the activation of the centrifugal fibers that innervate one or more suprahyoid muscles by inducing the delivery of an inhibitory neuromodulatory signal to the cervical ramus to reduce the unwanted retrograde centrifugal activation of one or more suprahyoid muscles.

[0006] In another aspect, the present invention provides a method for improving SDB in a patient suffering from SDB. Such a method may include stimulating the activation of the cervical nerve loop that innervates one or more infrahyoid muscles by inducing the delivery of a stimulatory neuromodulation signal to the cervical nerve loop. The method may further include blocking the activation of the efferent fibers that innervate one or more suprahyoid muscles by inducing the delivery of an inhibitory neuromodulation signal to the cervical nerve loop to reduce the undesired retrograde efferent activation of one or more suprahyoid muscles.

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0008] The present invention relates to a neuromodulation system and method for improving SDB. In particular, the system and method include delivering a neuromodulation signal to activate a neural target site and delivering a neuromodulation signal to block the neural target site. Blocking the neural target site refers to suppressing the action potential of neurons. For example, the present invention provides a system and method for activating a desired target muscle by stimulating the cervical nerve plexus, the hypoglossal nerve, the glossopharyngeal nerve, the pharyngeal nerve plexus and / or their branches, or a suitable combination thereof. The present invention also provides a system and method for blocking an undesired motor target of the cervical nerve plexus, a motor target of the hypoglossal nerve, an afferent sensory component of the glossopharyngeal nerve or a suitable combination thereof. Non-limiting examples of SDB include increasing the resistance of the upper airway, snoring, upper airway resistance syndrome (UARS), sleep apnea and combinations thereof. Sleep apnea can include obstructive sleep apnea (OSA), central sleep apnea (CSA) and mixed sleep apnea. References to "improvement" of a patient's SDB include reduction of SDB, alleviation of SDB symptoms or prevention of SDB. In certain aspects, the system and method for improving a patient's SDB are not essentially reactive but preventive. In other words, the system and method for improving a patient's SDB according to certain aspects include, for example, preventing SDB rather than detecting an apnea or hypopnea event and responding to such detected event. By preventing SDB, the treatment system and method can reduce the likelihood of airway collapse rather than responding to documented events. Patients suffering from SDB include mammals such as humans. As used herein with respect to the recited elements, unless otherwise specified, the terms "one" and "the" include at least one or more of the recited elements. Further, unless otherwise specified, the terms "or" and "and" refer to "and / or" and combinations thereof. As used herein, "patient" includes mammals such as humans. The term "machine learning" can refer to one or more statistical techniques (or algorithms) for gradually improving the performance of a particular task without being explicitly programmed. Executable instructions of a processor can be executed by the same processor or multiple processors.

[0009] Referring to FIG. 1, in one aspect, a neuromodulation system for improving a patient's SBD is provided. The neuromodulation system includes at least one neuromodulation device having at least one electrical contact implanted or positioned within the patient's body. System 10 may include a processor 12 and a non-transitory memory 14 in which computer-readable instructions 16 are stored. When the computer-readable instructions 16 are executed by the processor 12, various functions are performed on the at least one neuromodulation device. The computer-readable instructions may include algorithms for performing functions and may utilize machine learning 18. The instructions may include stimulating the activation of the hypoglossal nerve that innervates one or more infrahyoid muscles by inducing the delivery of a stimulatory neuromodulation signal to the hypoglossal nerve canal. The delivery may be induced, for example, to one or both of the superior and inferior roots of the hypoglossal nerve canal and may activate one or more infrahyoid muscles by activating centrifugal / motor fibers. Although not desired to be limited to a particular mechanism of action, activation of the infrahyoid muscles (e.g., tensing these muscles) can reduce upper airway compliance (e.g., stiffening the upper airway) by pulling the thyroid cartilage and / or hyoid bone together with their respective pharyngeal muscle attachments caudally. Upper airway compliance indicates the likelihood of airway collapse and may be relevant to the treatment of SDB. The processor can activate one or more infrahyoid muscles including the sternohyoid muscle, sternothyroid muscle, omohyoid muscle, thyrohyoid muscle, or a suitable combination thereof by inducing the delivery of a stimulatory neuromodulation signal.

[0010] The instructions may include blocking the activation of centrifugal fibers innervating one or more suprahyoid muscles by inducing the delivery of an inhibitory neuromodulation signal to the cervical nerve loop in order to reduce the unwanted retrograde centrifugal activation of one or more suprahyoid muscles that pull the hyoid bone and thyroid cartilage forward and / or upward. The delivery may be induced, for example, to the upper root of the cervical nerve loop. In some embodiments, the instructions include blocking the activation of centrifugal fibers innervating the geniohyoid muscle by inducing the delivery of an inhibitory neuromodulation signal to the cervical nerve loop. This is advantageous for reducing the unwanted retrograde centrifugal activation of one or more suprahyoid muscles because their contraction can inhibit or counteract the desired caudal movement of the thyroid cartilage and / or hyoid bone achieved by the activation of the infrahyoid muscles.

[0011] The processor may further induce the delivery of a stimulatory neuromodulation signal to the hypoglossal nerve to stimulate the genioglossus muscle by executing the instructions. In particular, the stimulatory neuromodulation signal can activate the centrifugal / motor fibers of the hypoglossal nerve to activate the genioglossus muscle. Activation of the hypoglossal nerve can cause contraction of the desired lingual muscle tissue to reduce or eliminate pharyngeal obstruction due to the depression of the posterior root of the tongue by moving the tongue forward. This obstruction may not be treatable by simply stimulating the cervical nerve loop.

[0012] In some embodiments, the processor may induce the delivery of an inhibitory neuromodulation signal to the hypoglossal nerve by executing the instructions to block the activation of centrifugal fibers innervating the styloglossus muscle, the hyoglossus muscle, or both. The inhibitory neuromodulation signal can reduce the unwanted centrifugal activation of the styloglossus muscle, the hyoglossus muscle, or both. Reducing the unwanted centrifugal activation of the styloglossus muscle, the hyoglossus muscle, or both may be advantageous because it retracts the tongue against the posterior pharyngeal wall and counteracts the desired forward shift.

[0013] The processor may further induce the delivery of a stimulatory neuromodulation signal to the glossopharyngeal nerve by executing an instruction, thereby stimulating the activation of the efferent fibers of the glossopharyngeal nerve. Such efferent fibers may innervate one or more pharyngeal constrictor muscles or the stylopharyngeus muscle, thereby activating one or more pharyngeal constrictor muscles, the stylopharyngeus muscle, or both. For example, the processor may induce the delivery of a stimulatory neuromodulation signal to the pharyngeal plexus or a branch thereof. When activated, such one or more pharyngeal constrictor muscles can increase pharyngeal muscle tone by strengthening the pharyngeal wall, thereby reducing pharyngeal airway collapse. Strengthening but not fully contracting the pharyngeal wall may be more effective in stimulating the carotid sinus and hypoglossal nerves. For the stylopharyngeus muscle, when activated, the stylopharyngeus muscle can move the pharyngeal wall laterally, increase the airway diameter, and counteract the pharyngeal narrowing component of the constrictor muscle activation that may occur when muscle activation exceeds the initial pharyngeal wall stiffening.

[0014] In some embodiments, the processor may induce the delivery of an inhibitory neuromodulation signal to the glossopharyngeal nerve by executing an instruction to block the activation of the afferent fibers of the glossopharyngeal nerve. The inhibitory neuromodulation signal may be capable of reducing unwanted afferent / sensory effects. Reducing unwanted afferent activation is advantageous. This is because afferent activation of central nervous system receptors may cause neural arousal during sleep or may result in unwanted muscle activation such as the pharyngeal gag reflex through an afferent / efferent reflex arc.

[0015] In some embodiments, the processor may induce delivery of a neuromodulation signal for stimulation to a nerve site, such as the pharyngeal plexus or its branches, by executing instructions, to stimulate activation of the palatoglossus muscle, the palatopharyngeus muscle, or both. By electrically stimulating a nerve site that innervates the palatoglossus muscle and / or the palatopharyngeus muscle during sleep, the retropalatal space can be expanded, thereby opening the patient's upper airway without causing sleep arousal. This system may be used in patients with isolated palate collapse, or in combination with hypoglossal nerve stimulation, submental nerve stimulation, phrenic nerve stimulation, and other neuromodulation systems as part of a multi-level airway treatment for SDB such as OSA.

[0016] In some embodiments, the processor may induce delivery of a neuromodulation signal for stimulation to the phrenic nerve by executing instructions, to stimulate activation of the phrenic nerve and thereby activate the diaphragm. Phrenic nerve stimulation can be used to affect upper airway collapse or to treat central sleep apnea. Stimulating the phrenic nerve alone may cause airway collapse rather than prevent it. This is because diaphragmatic descent essentially creates a negative pressure gradient within the pharyngeal cavity, which may cause collapse before a stabilizing effect is achieved. Stimulating the cervical nerve loop and the phrenic nerve can better control airway collapse by individually controlling caudal traction and chest expansion during the respiratory cycle.

[0017] In some embodiments, the processor may induce delivery of any suitable combination of the above-described neuromodulation signals for stimulation and / or blocking signals by executing instructions using suitable neuromodulation parameters. Non-limiting examples of neuromodulation parameters include which (one or more) electrical contacts of the neuromodulation device provide stimulatory neuromodulation signals, which (plural) electrical contacts provide blocking neuromodulation signals, stimulation mode, signal pulse waveform, signal pulse width, signal pulse frequency, signal pulse phase, signal pulse polarity, signal pulse amplitude, signal pulse intensity, signal pulse duration, duty ratio, and electrical contact selections such as combinations thereof. This process can continue until a therapeutic effect is achieved with minimal side effects.

[0018] This process may also be assisted by machine learning 18. Machine learning 18 may include algorithms that can be trained to recognize specific effects from the delivery of neuromodulation signals. Machine learning 18 can actively adjust the neuromodulation parameters of the neuromodulation signal and provide a therapeutic effect with minimal side effects. Machine learning may employ, for example, one or more machine algorithms such as decision tree learning, association rule learning, artificial neural networks, deep learning, inductive logic programming, support vector machines, clustering, Bayesian networks, reinforcement learning, representation learning, similarity and metric learning, sparse dictionary learning, genetic algorithms, rule-based machine learning, learning classification systems, feature selection, etc.

[0019] Regarding the specific details of the system provided herein, the processor may include one or more microprocessors under the control of an appropriate software program. The processor can control various neuromodulation parameters of the neuromodulation device, such as stimulation mode, electrical contact selection, signal pulse waveform, signal pulse width, signal pulse frequency, signal pulse phase, signal pulse polarity, signal pulse amplitude, signal pulse intensity, signal pulse duration, duty ratio, and combinations thereof. The processor can be programmed to transmit various currents and voltages to the electrical contacts to regulate the activity of nerve target sites such as nerves, neurons, or nerve fibers. The processor can be programmed to control multiple electrical contacts, either independently or in various combinations as needed, to provide neuromodulation therapy.

[0020] The electrical nerve control signal may be constant, intermittent, variable, or adjustable with respect to current, voltage, pulse width, waveform, duty ratio, frequency, amplitude, etc. The waveform may be a sine wave, square wave, triangular wave, etc. The type of nerve regulation can be different and is related to different waveforms. The optimal stimulation pattern may need to delay the activation of one electrical contact or delay the activation in another adjustable way, regardless of the simultaneous activation or interleaved activation of the electrical contacts, in order to improve the patient's SDB, before activating other electrical contacts. In the case of the stimulation signal, the signal can have, for example, an amplitude of about 0.1 mA to about 5 mA, a pulse width of about 30 μs to about 250 μs, a pulse frequency of about 30 Hz to about 50 Hz, a sequence length of about 0.1 s to about 5 s, and a sequence interval encoded in the time of about 0.1 s to about 5 s or a percentage of the sequence length. In the case of the blocking signal, the signal can have, for example, an amplitude of about 0.1 mA to about 5 mA, a pulse width of about 100 μs to 1000 μs, a frequency of about 1 Hz to about 60 kHz, and a time parameter of 1 μs to 250 μs, and can be synchronized with the appropriate phase of the complementary stimulation signal that is simultaneously transmitted to the same target nerve for the blocking signal.

[0021] The nerve regulation system can include an electronic circuit such as one or more electronic circuits for centrifuging a nerve regulation device that is confined in a sealed housing and has a nerve regulation signal coupled to the nerve regulation device, such as a cuff electrode, conductive wire, or electrical contact having other form factors. FIG. 2 is a block diagram of a nerve regulation system 20 according to one aspect of the present invention. The nerve regulation system 20 can include a housing 22 enclosing a processor 24, an associated memory 26, a telemetry module 28, and a pulse generator 30 that electrically communicates with electrical contacts 32A and 32B of the nerve regulation device. The nerve regulation system 20 may include a power source 34.

[0022] The nerve modulation device can have different form factors such as an injectable micro stimulator, a neural jacket electrode, a cylindrical wire, a paddle-shaped wire, or a transcutaneous patch. Also, as described above, a plurality of target sites may be stimulated by the same nerve modulation device, or a single target site may be stimulated by a single nerve modulation device. The nerve modulation may be unilateral or bilateral nerve modulation of these nerve target sites.

[0023] The electrical contact 32 of the nerve modulation device can be positioned along the outer surface of the housing 22 and can be coupled to the pulse generator 30 via an insulating feedthrough or other connection. In other embodiments, the electrical contact 32 may be carried by a nerve modulation device that is a wire or insulated cable electrically coupled to a processor via a suitable insulating feedthrough or other electrical connection passing through the sealed housing. In other embodiments, the electrical contact can be incorporated into a housing operably positioned near the target site where the externally exposed surface is close to the nerve target site and configured to be electrically coupled to the processor. The electrical contact can be controllable to provide variable electrical signals such as voltage, frequency, amplitude, waveform, pulse width, current, intensity, duty ratio, polarity, duration, and combinations thereof. The electrical contact may also supply positive and negative currents from the electrical contact, or may stop the current from flowing out of the electrical contact or change the direction in which the current flows out of the electrical contact.

[0024] As described above, neuromodulation devices such as neural jacket electrodes can be placed at the same target site or different target sites. For example, if the target site includes two separate nerves or nerve segments, each neural jacket electrode has its own cathode and anode, but is connected to the same processor, or separate neural jacket electrodes are connected to the same processor, but one neural jacket electrode functions as the cathode and the other neural jacket electrode functions as the anode, and the generated electric field captures the two nerves or nerve segments. In some embodiments, a neuromodulation device configured to stimulate a nerve or nerve segment may be combined with a neuromodulation device configured to stimulate another nerve or ganglion. Alternatively, a neuromodulation device configured to stimulate a nerve or nerve segment may be part of a device separated from a neuromodulation device configured to stimulate another nerve or nerve segment.

[0025] The processor can include any one or more of a microprocessor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), or equivalent discrete or integrated logic circuitry. In some examples, the processor may include any combination of one or more microprocessors, one or more controllers, one or more DSPs, one or more ASICs, or one or more FPGAs, and multiple components such as other discrete or integrated logic circuitry. The functions attributed to the processor herein can be embodied as software, firmware, hardware, or any combination thereof. The processor can be programmed to transmit electrical signals having various characteristics. As described above, the electrical signals may be constant, intermittent, varying, or adjustable with respect to current, voltage, pulse width, waveform, period, frequency, amplitude, etc. The waveform may be a sine wave, a square wave, etc. The type of stimulus may be different and is associated with different waveforms. The optimal activation mode may need to optimally open the airway, regardless of delaying one electrode before activating another electrode or activating one electrode simultaneously in another coordinated manner or interleaving activation in a coordinated and adjustable manner.

[0026] Non-limiting examples of blocking neuromodulation signals include direct current (DC) blocking, kilohertz frequency alternating current blocking (kHFACb), anodic blocking, collision blocking, quasi-trapezoidal stimulation, and low-frequency alternating current blocking (LFACb). In the case of DC blocking, a ramp or DC current passes through the blocking electrical contact. However, this method can produce toxic electrochemical by-products and may damage nerves. Alternatively or in addition, kHFACb is a method that uses a sinusoidal charge-balanced waveform with a frequency range of approximately 1 kHz to approximately 40 kHz that can be transmitted. Since the waveform has a zero average and the duration of the period is short, the charge reverses itself and no pure charge is accumulated to avoid the possibility of nerve damage. To reduce the effects of DC block and kHFACb, a block waveform combining the two blocks can be generated. The charge-balanced DC (CBDC) bearing block is a method of reducing the activation to achieve a block using a ramp DC pulse or trapezoidal pulse that achieves charge balance by long but equal charge and discharge phases. Furthermore, the generation of reactive species can be prevented using a high-capacity material such as platinum black. LFACb is a pure-tone sinusoidal waveform modification of kHFACb and is distinguished by its amplitude and frequency. Phase blocking of the action potential can be achieved by reducing the frequency of the sinusoidal waveform to less than approximately 10 Hz, and the total current transport is less than the current transport required for kHFACb.

[0027] The processor can be programmed to control multiple electrical contacts, either independently or in various combinations as needed, to provide neuromodulation. In one example, a neuromodulation treatment protocol for improving SDB in a patient can be stored or encoded as a command in memory that is executed by the processor such that a pulse generator delivers treatment through the electrical contact according to the program protocol. Thus, the nerve stimulation device can pre-program the required stimulation parameters. The processor is shown as being located inside the neuromodulation device in FIG. 2, but alternatively, it may be an external controller that is remotely adjusted to the desired settings.

[0028] Memory 26 contains computer-readable instructions that, when executed by processor 24, cause the computer-readable instructions to cause the neuromodulation device to perform various functions belonging to the neuromodulation device through the present invention. The computer-readable instructions can be encoded within memory 26. The memory can include any volatile, non-volatile, magnetic, optical, or electrical medium, such as random access memory (RAM), read only memory (ROM), non-volatile RAM (NVRAM), electrically erasable programmable ROM (EEPROM), flash memory, or other digital media excluding transient propagated signals, including a non-transitory computer-readable storage medium.

[0029] Remote measurement module 28 and associated antenna 36 can be provided to establish two-way communication with an external device, including a patient programmer and / or a physician programmer. Examples of communication technologies used by the neuromodulation system and the external device include low-frequency or radio frequency (RF) telemetry, which can be an RF link established, for example, via Bluetooth®, WiFi, or MICS. Antenna 36 is located within housing 22 and may extend along or outside of the housing.

[0030] The power source 46 may be a battery or other power source. The battery can be charged by inductive coupling. The power source may be inside the neuromodulation device (as shown in FIG. 2), at a distal site within or on the patient's body, or at a remote location away from the patient's body. When at a location away from the body, the nerve stimulation device can supply power by contacting an external power source of the patient's body to the patient's skin, or at a location away from the patient's body (e.g., a location where electrical energy is first transported through another medium). When the neuromodulation device is configured as an external power supply device, the power source may provide the power necessary to be worn by the patient during sleep to generate stimulation pulses, or may be adjacent to the patient (e.g., the patient's bed, under the patient's pillow, the patient's cot, etc.). For example, the power source may be a battery-powered device including a primary coil for transmitting power induction to a secondary coil included in the neuromodulation device. The power source can include one or more original batteries or rechargeable batteries, and thus can include a power adapter and plug for recharging with a standard 110V or 220V wall mount socket. In some embodiments, when the neuromodulation device is implemented as a rechargeable or external power supply device, the functions necessary to transmit power to the neuromodulation device and program the neuromodulation device to control therapy delivery can be implemented in a single external device.

[0031] The neuromodulation system may include other components such as an analog front end or A / D converter, multiplexer, and other components.

[0032] In another aspect, the neuromodulation system can include one or more sensors (not shown) to enable open-loop or closed-loop control. For example, in an open-loop system, the system includes one or more sensors so that the system can manage the improvement of SDB (e.g., prophylactically) based on feedback (e.g., detected signals) from one or more sensors by the patient. Such detected signals can indicate the onset of SDB, such as changes in the electrical activity of muscles or nerves, tongue position, and airflow in the oropharynx. Upon noticing one or more signals, the patient can trigger or activate the neuromodulation device to prevent or reduce SDB.

[0033] In another aspect, the neuromodulation system can include one or more sensors that enable closed-loop control by automatically responding (e.g., by activating the neuromodulation device) in response to, for example, sensed physiological parameters or related symptoms or omens, where the related symptoms or omens indicate the degree and / or presence of SDB. Physiological parameters include changes in muscle or nerve electrical activity, tongue position, changes in heart rate or blood pressure, pressure changes in response to respiratory effort, airflow in the oro-pharynx, and the like. The sensors used as part of a closed-loop or open-loop system can be placed at any suitable anatomical location on the patient's body, including the skin surface, oral cavity, nasal cavity, mucosal surface, or subcutaneous location.

[0034] Referring to FIG. 3, in one aspect, a method 100 for treating SDB in a patient suffering from SDB includes stimulating the activation of the hypoglossal nerve that innervates one or more infrahyoid muscles 102 by inducing the delivery of a neuromodulation signal for stimulation to the hypoglossal nerve, and blocking the activation of the efferent fibers that innervate one or more suprahyoid muscles 104 by delivering a neuromodulation signal for blocking to the hypoglossal nerve. The neuromodulation signal for blocking can reduce the unwanted retrograde efferent activation of one or more suprahyoid muscles (e.g., including the geniohyoid muscle).

[0035] Regarding the nerve modulation signal for stimulation, by delivering such a signal, it is possible to stimulate the activation of the motor fibers of the cervical nerve loop and activate, for example, the sternothyroid muscle. The nerve modulation signal for stimulation can also be transmitted to the cervical nerve loop that innervates the upper abdomen and / or the lower abdomen of the sternohyoid muscle in order to activate part or all of the sternohyoid muscle. For example, an exemplary target site for delivering the nerve modulation signal for stimulation may be the upper root of the cervical nerve loop, or a branching point close to the upper root that innervates the sternohyoid muscle, or a branching point of the upper root that innervates the sternohyoid muscle in order to activate the sternohyoid muscle and the sternothyroid muscle. In some embodiments, the nerve modulation signal for stimulation may be delivered proximal to or at the upper root of the cervical plexus in order to activate part or all of the omohyoid muscle.

[0036] In some embodiments, the stimulating neuromodulation signal can be transmitted simultaneously to the cervical plexus to stimulate the nerve branches of the sternothyroid, sternohyoid, and omohyoid muscles that are innervated by the superior and inferior roots of the cervical plexus. In some embodiments, by sending the stimulating neuromodulation signal to a target site (e.g., near or at the bifurcation of the common trunk nerve, or a nerve generated from the cervical plexus that combines nerve fibers from the superior and inferior roots and supplies at least the sternohyoid muscle and variably the sternoglossus and omohyoid muscles), at least the sternohyoid muscle can be activated, and in some embodiments, the sternohyoid muscle is activated and optionally the omohyoid muscle is activated. In some embodiments, sending the stimulating neuromodulation signal to a target site (e.g., a bifurcation proximal or distal to the common trunk nerve of the cervical plexus or a nerve located adjacent to the sternothyroid nerve) can activate the sternothyroid muscle. The branch of the sternothyroid muscle can be a single nerve fiber or several closely arranged nerve fibers. It should be noted that the above target sites are merely illustrative, and the neuromodulation device can be placed at other sites of the cervical muscles including its branches. Also, the stimulation can be applied to any combination of the above sites and branches. For example, the nerve stimulation device can be placed at the proximal or distal end of the omohyoid muscle branch, whereby the stimulation captures only the sternothyroid / sternohyoid fibers. As another example, one or more cuff electrodes can surround a single fiber or multiple fibers that innervate the sternothyroid-like muscles.

[0037] For the blocking neuromodulation signal, for example, if only activation of the infrahyoid muscles is required, this signal can be transmitted to the superior root of the cervical plexus to reduce or eliminate the centrifugal activation of the retrograde movement of the suprahyoid muscles towards the target.

[0038] In some embodiments, a method of improving SDB includes additionally transmitting an electrical signal to a target site proximate to the hypoglossal nerve that innervates the genioglossus muscle to activate the genioglossus muscle. Since the target site can approach the hypoglossal nerve, the electrical signal can be transmitted to activate the motor fibers of the hypoglossal nerve and thus activate the genioglossus muscle. In some embodiments, the electrical signal is not transmitted to the hypoglossal nerve near its bifurcation point. This is because another neuromodulation device may be required to potentially provide different intensities or durations of stimulation to the cervical nerve snare and the hypoglossal nerve. In other embodiments, the hypoglossal nerve can be stimulated at the proximal or distal end of the bifurcation point of the posterior muscular branches of the styloglossus muscle and / or the hyoglossus muscle. Activation of the hypoglossal nerve can stiffen the muscular tissue of the tongue and reduce or eliminate pharyngeal obstruction due to the depression of the posterior root of the tongue, which may not be treatable, for example, by the cervical nerve snare.

[0039] In some embodiments, the method further includes blocking the activation of the centrifugal fibers innervating the styloglossus muscle, the hyoglossus muscle, or both by delivering a blocking neuromodulation signal to the hypoglossal nerve. This blocking neuromodulation signal can avoid the undesired centrifugal activation of the styloglossus muscle, the hyoglossus muscle, or both. When the upstream electrical contacts activate multiple centrifugal motor targets, it may be necessary to block the undesired motor centrifugation.

[0040] In some embodiments, activating one or more pharyngeal constrictor muscles or the stylopharyngeus muscle includes separately delivering a stimulating neuromodulation signal to the centrifugal fibers innervating the glossopharyngeal nerve of one or more pharyngeal constrictor muscles or the stylopharyngeus muscle. By way of example, the nerve target site may include the pharyngeal nerve plexus or its branches. When activated, the one or more pharyngeal constrictor muscles can increase pharyngeal muscle tone and reduce the collapse of the pharyngeal airway. When activated, the stylopharyngeus muscle can move the pharyngeal wall laterally.

[0041] The lateral walls of the pharynx are composed of the pharyngeal constrictor muscles, which are innervated by the pharyngeal plexus of nerves, which contains fibers from cranial nerves IX and X. The nerves that innervate these muscles form a plexus on the outer surface of the pharyngeal constrictor muscles and then penetrate the pharyngeal constrictor muscles to reach the palatoglossus and palatopharyngeus muscles. The motor branches of cranial nerve IX may be responsible for the respiratory control of the constrictor muscles and may be recognized in the region of the stylopharyngeus muscle. An increase in constrictor muscle tension during respiration can reduce pharyngeal collapse by strengthening the pharyngeal wall. Strengthening the pharyngeal wall without complete contraction may be more effective in stimulating the carotid sinus and hypoglossal nerves. Stimulation of the stylopharyngeus muscle can increase the airway diameter by moving the pharyngeal wall laterally and can also counteract the pharyngeal stenosis component of constrictor muscle activation that can occur when muscle activation exceeds the initial pharyngeal wall stiffening.

[0042] Stimulating the efferent fibers of the glossopharyngeal nerve that innervate one or more pharyngeal constrictor muscles or the stylopharyngeus muscle can be combined with stimulating other nerve target sites described herein. Stimulation of the carotid sinus can anchor the lower end of the pharynx by preventing the upward movement of the thyroid and hyoid cartilages, thereby allowing the contractions of the pharyngeal constrictor and palatopharyngeus muscles to oppose a solid anchor rather than a point of insertion of movement. In this way, the effectiveness of co-stimulation of the carotid sinus and the efferent fibers of the glossopharyngeal nerve or stimulation of the palatopharyngeus muscle can be enhanced.

[0043] In some embodiments, the method includes delivering a neuromodulation signal to the efferent fibers of the glossopharyngeal nerve. The neuromodulation signal is independent of sensory or input signals detected or sensed regarding the neuromuscular state of the airway. For example, the electrical signal may be transmitted based on tension or at a duty ratio independent of the sensory or input signal detected or detected regarding the detected airway neuromuscular state. In other words, even though sensory or input signals regarding the neuromuscular state of the airway can be measured, in some embodiments, this sensory information may not be able to determine the stimulation parameters of the electrical signal transmitted to the target site. In some aspects, the electrical signal is not transmitted to the sensory fibers that innervate the mucosal layer of the pharyngeal wall.

[0044] In some embodiments, the method includes blocking the activation of the afferent fibers of the glossopharyngeal nerve by delivering a blocking neuromodulation signal to the glossopharyngeal nerve. The blocking neuromodulation signal can avoid undesired sensory effects. For example, the blocking neuromodulation signal may be delivered upstream of the main glossopharyngeal nerve.

[0045] In some embodiments, a method of improving SDB includes improving SDB in a patient suffering from SDB by additionally delivering a neuromodulation signal to a nerve that innervates palatal muscles (e.g., the palatoglossus muscle, the palatopharyngeus muscle, or both). The palatoglossus muscle and the palatopharyngeus muscle are muscles of the soft palate (also referred to as "palatal muscles"). The palatoglossus muscle originates from the palatine aponeurosis at the posterior hard palate. It descends laterally downward and inserts into the lateral surface posterior to the tongue. It is covered medially by mucosa as it passes through the posterior oral cavity and forms the palatoglossal arch. The function of the palatoglossus muscle is to close the oral cavity and the palate by lifting the posterior tongue and pulling the soft palate downward. This muscle is innervated by one branch of the pharyngeal plexus, and its function is independent of the hypoglossal nerve and other internal and external lingual muscle tissues. The palatopharyngeus muscle forms the palatopharyngeal arch. It attaches above the hard palate and the palatine aponeurosis and attaches below the pharyngeal side wall and the thyroid cartilage. Its action is to tighten the soft palate during swallowing, pull the pharyngeal wall upward, forward, and inward, effectively separating the nasopharynx and the oropharynx.

[0046] A method of transmitting an electrical signal to a nerve that controls such palatal muscles to improve SDB is an indirect method different from muscle stimulation such as transcutaneous electrical pacing. The latter has been found to be inconsistent and poorly tolerated by sleep patients. Direct intramuscular stimulation by filament electrode placement or other techniques is unrealistic for daily use because it requires daily uncomfortable puncturing of the skin or the inner wall of the oral cavity to penetrate the muscle tissue. By electrically stimulating the nerve that controls the palatoglossus muscle and / or the palatopharyngeal muscle during sleep, the retropalatal space can be expanded, thereby opening the patient's upper airway and not causing sleep arousal. This method can be used for patients with isolated palatal paralysis or, as part of a multi-level airway treatment for SDB of OSA, can be used in combination with hypoglossal nerve stimulation, cervical nerve loop stimulation, and / or phrenic nerve stimulation.

[0047] In some embodiments, the target site of the nerve that controls the palatoglossus muscle and / or the palatopharyngeal muscle is the pharyngeal plexus or its branches. Preferably, the electrical signal transmitted to the target site that controls the nerve of the palatoglossus muscle and / or the palatopharyngeal muscle stimulates the motor fibers that control the pharyngeal plexus of the patient's palate.

[0048] In some embodiments, the target site to be stimulated is not the cranial root of the accessory nerve because targeting the cranial root of the accessory nerve or the roots of the vagus nerve causes diffuse, non-specific stimulation. For example, activation of the vagus nerve root can simultaneously activate the levator veli palatini muscle, which is opposite to the actions of the palatoglossus muscle and the palatopharyngeal muscle. Stimulating the cranial root of the spinal accessory nerve can similarly cause non-specific activation of the pharyngeal plexus muscle tissue. Also, the cranial roots of the accessory nerve are not connected to the vagus nerve in all patients. If the cranial root of the accessory nerve is not connected to the pharyngeal plexus, it remains in the spinal root of the accessory nerve. Therefore, stimulating the cranial root of the accessory nerve causes unintended stimulation of the spinal root of the accessory nerve, which leads to unwanted activation of the sternocleidomastoid muscle and the trapezius muscle.

[0049] In some embodiments, a method for improving SDB includes activating one or more infrahyoid muscles by stimulating the carotid sinus and activating the diaphragm by simultaneously stimulating the phrenic nerve. Stimulation of the phrenic nerve affects the collapse of the upper airway. Stimulating the phrenic nerve alone does not prevent airway collapse, and since diaphragmatic descent essentially creates a negative pressure gradient within the pharyngeal cavity, it may cause collapse before a stabilizing effect is achieved. Stimulating the carotid sinus and the phrenic nerve can better control airway collapse by individually controlling caudal traction and chest expansion during the respiratory cycle.

[0050] Transmitting a neuromodulation signal to one or more of the above target sites can be achieved by placing one or more electrical contacts near the target site. The electrical contacts can be placed near the target site in various ways, such as transcutaneous, percutaneous, subcutaneous, intramuscular, intraluminal, transvascular, intravascular, or implants by direct open surgery. Neuromodulation (stimulation and / or blocking) can be unilateral or bilateral neuromodulation.

[0051] In some embodiments, instead of delivering a blocking neuromodulation signal to the above-described nerve target sites, the stimulation intensity of a part of any desired motor target of these nerves can be reduced to better balance the ratio in the desired muscle or change the replenishment ratio in the desired muscle.

[0052] The methods disclosed herein can be used as part of a closed-loop system (as described in more detail below). This method can include improving the patient's SDB by sensing physiological parameters related to SDB, generating a sensor signal based on the physiological parameters, and activating electrodes to apply an electrical signal to the target site in response to sensor signal adjustment.

[0053] Each of the disclosed aspects and embodiments of the present invention can be considered individually or in combination with other aspects, embodiments, and variations of the present disclosure. Unless otherwise specified, any step of the methods of the present disclosure is not limited to a particular order of execution. Further, although the above has been described with respect to electrical stimulation, other forms of energy such as, for example, ultrasonic, magnetic, or light energy can be used.

Claims

**Claim 1** A neuromodulation system for improving sleep apnea, comprising a processor, and a non-transitory computer-readable medium storing executable instructions of the processor, wherein when the executable instructions are executed by the processor, stimulating activation of the hypoglossal canal that innervates one or more infrahyoid muscles by inducing delivery of a stimulatory neuromodulation signal to the hypoglossal canal; and blocking activation of centrifugal fibers that innervate the one or more suprahyoid muscles by inducing delivery of a blocking neuromodulation signal to the hypoglossal canal that reduces unwanted retrograde centrifugal activation of the one or more suprahyoid muscles, **Claim 2** The neuromodulation system according to claim 1, further comprising instructions for stimulating activation of the genioglossus muscle by inducing delivery of a stimulatory neuromodulation signal to the hypoglossal nerve. **Claim 3** The neuromodulation system according to claim 1, further comprising instructions for blocking activation of centrifugal fibers that innervate the styloglossus muscle, the hyoglossus muscle, or both by inducing delivery of a blocking neuromodulation signal to the hypoglossal nerve that reduces unwanted centrifugal activation of the styloglossus muscle, the hyoglossus muscle, or both. **Claim 4** The neuromodulation system according to claim 1, further comprising instructions for stimulating activation of centrifugal fibers of the glossopharyngeal nerve by inducing delivery of a stimulatory neuromodulation signal to the glossopharyngeal nerve. **Claim 5** The neuromodulation system according to claim 1, further comprising instructions for blocking activation of afferent fibers of the glossopharyngeal nerve by inducing delivery of a blocking neuromodulation signal to the glossopharyngeal nerve that reduces unwanted sensory effects. **Claim 6** stimulating the genioglossus muscle by inducing delivery of a stimulatory neuromodulation signal to the hypoglossal nerve; and blocking activation of centrifugal fibers that innervate the styloglossus muscle, the hyoglossus muscle, or both by inducing delivery of a blocking neuromodulation signal to the hypoglossal nerve that reduces unwanted centrifugal activation of the styloglossus muscle, the hyoglossus muscle, or both, **Claim 7** stimulating activation of centrifugal fibers of the glossopharyngeal nerve by inducing delivery of a stimulatory neuromodulation signal to the glossopharyngeal nerve; and The nerve regulation system according to claim 1, further comprising a command to block the activation of the afferent fibers of the glossopharyngeal nerve by inducing the delivery of the blocking nerve regulation signal to the glossopharyngeal nerve to reduce the undesired sensory effect.

8. By inducing the delivery of the stimulating nerve regulation signal to the hypoglossal nerve, the activation of the genioglossus muscle is stimulated, By inducing the delivery of the blocking nerve regulation signal to the hypoglossal nerve to reduce the undesired efferent activation of the styloglossus muscle, hyoglossus muscle or both, the activation of the efferent fibers that innervate the styloglossus muscle, the hyoglossus muscle or both is blocked, By inducing the delivery of the stimulating nerve regulation signal to the glossopharyngeal nerve, the activation of the efferent fibers of the glossopharyngeal nerve is stimulated, and The nerve regulation system according to claim 1, further comprising a command to block the activation of the afferent fibers of the glossopharyngeal nerve by inducing the delivery of the blocking nerve regulation signal to the glossopharyngeal nerve to reduce the undesired sensory effect.

9. The nerve regulation system according to claim 1, further comprising a command to stimulate the activation of the palatoglossus muscle, palatopharyngeal muscle or both by inducing the delivery of the stimulating nerve regulation signal to the nerve site.

10. The nerve regulation system according to claim 1, further comprising a command to stimulate the activation of the diaphragm by inducing the delivery of the stimulating nerve regulation signal to the phrenic nerve.

11. A method for improving sleep apnea in a patient suffering from sleep apnea, comprising: stimulating the activation of the cervical nerve loop that innervates one or more infrahyoid muscles by inducing the delivery of a stimulating nerve regulation signal to the cervical nerve loop; and blocking the activation of the efferent fibers that innervate the one or more suprahyoid muscles by inducing the delivery of a blocking nerve regulation signal to the cervical nerve loop to reduce the undesired retrograde efferent activation of the one or more suprahyoid muscles.

12. The method according to claim 11, further comprising stimulating the activation of the genioglossus muscle by delivering a stimulating nerve regulation signal to the hypoglossal nerve.

12. The method according to claim 11, further comprising blocking the activation of the efferent fibers that innervate the styloglossus muscle, the hyoglossus muscle or both by delivering a blocking nerve regulation signal to the hypoglossal nerve to avoid the undesired efferent activation of the styloglossus muscle, the hyoglossus muscle or both.

13. The method according to claim 11, further comprising stimulating the activation of the efferent fibers of the glossopharyngeal nerve by delivering a stimulatory nerve regulation signal to the glossopharyngeal nerve.

14. The method according to claim 11, further comprising blocking the activation of the afferent fibers of the glossopharyngeal nerve by delivering a blocking nerve regulation signal that avoids an undesired sensory effect to the glossopharyngeal nerve.

15. Stimulating the activation of the genioglossus muscle by delivering a stimulatory nerve regulation signal to the hypoglossal nerve; Blocking the activation of the efferent fibers that innervate the styloglossus muscle, the hyoglossus muscle, or both by delivering a blocking nerve regulation signal that reduces the undesired efferent activation of the styloglossus muscle, the hyoglossus muscle, or both to the hypoglossal nerve. The method according to claim 11, further comprising the above.

16. Stimulating the activation of the efferent fibers of the glossopharyngeal nerve by delivering a stimulatory nerve regulation signal to the glossopharyngeal nerve; Blocking the activation of the afferent fibers of the glossopharyngeal nerve by delivering a blocking nerve regulation signal that reduces an undesired sensory effect to the glossopharyngeal nerve. The method according to claim 11, further comprising the above.

17. Stimulating the activation of the genioglossus muscle by delivering a stimulatory nerve regulation signal to the hypoglossal nerve; Blocking the activation of the efferent fibers that innervate the styloglossus muscle, the hyoglossus muscle, or both by delivering a blocking nerve regulation signal that reduces the undesired efferent activation of the styloglossus muscle, the hyoglossus muscle, or both to the hypoglossal nerve; Stimulating the activation of the efferent fibers of the glossopharyngeal nerve by delivering a stimulatory nerve regulation signal to the glossopharyngeal nerve; Blocking the activation of the afferent fibers of the glossopharyngeal nerve by delivering a blocking nerve regulation signal that reduces an undesired sensory effect to the glossopharyngeal nerve. The method according to claim 11, further comprising the above.

18. The method according to claim 11, further comprising stimulating the activation of the palatoglossus muscle, the palatopharyngeal muscle, or both by delivering a stimulatory nerve regulation signal to a nerve site.

19. The method according to claim 11, further comprising stimulating the activation of the diaphragm by delivering a stimulatory nerve regulation signal to the phrenic nerve.

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