Methods and systems for stimulating phrenic nerves to treat sleep apnea

Abstract

A method of identifying a patient with obstructive sleep apnea implants a phrenic nerve stimulator in the patient or connects the phrenic nerve stimulator to the diaphragm, and adjusts the stimulation energy applied by the phrenic nerve stimulator to the phrenic nerve of the sleeping patient based on airway occlusion in the airway of the patient.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 426,072, filed on November 17, 2022, and U.S. Provisional Application No. 63 / 442,331, filed on January 31, 2023, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to an implantable device for stimulating the phrenic nerve to treat airway collapse in patients suffering from obstructive sleep apnea (OSA). The present invention can be implemented to utilize the pharyngeal mechanical reflex to reinforce the airway or reverse airway collapse, improve gas exchange, and / or enhance sleep quality. The present invention aims to keep the sleeping patient comfortable and asleep while stimulating the phrenic nerve and triggering a reflex to open the blocked airway in the patient's breathing passage. Background Art

[0004] Healthy sleep is an important part of life. It improves physical and mental health. Sleep occurs in stages (including REM sleep and non - REM sleep). When a human sleeps, their body has the opportunity to rest and regain energy. A good night's sleep can help cope with stress, solve problems, or recover from illness. Lack of sleep can lead to many health problems, affecting thinking and feeling.

[0005] During sleep, a person typically experiences four sleep stages: non - REM N1, N2, N3, and REM (rapid eye movement). These sleep stages progress in a cycle from N1 to REM sleep and then the cycle starts again from N1 or N2. Healthy children and adults spend nearly 50% of their total sleep time in N2 sleep, about 20% in REM sleep, and the remaining 30% in other stages.

[0006] During N1 (light sleep), one drifts between sleep and wakefulness and may be easily awakened. Eye movements are very slow and muscle activity slows down. People waking up from N1 sleep often remember fragmented visual images.

[0007] When entering N2 sleep, eye movements stop and brain waves (fluctuations in electrical activity that can be measured by EEG electrodes) slow down, and occasional bursts of fast waves called sleep spindles occur.

[0008] EEG stands for electroencephalogram. Sleep EEG is a record of the electrical activity of the brain as a person wakes up and then falls asleep. It involves attaching small electrodes that record brain activity to the scalp.

[0009] In N3, extremely slow brain waves called delta waves begin to appear, interspersed with smaller, faster waves until almost all that appear are delta waves. It is difficult to wake someone during N3 (also known as deep or slow-wave sleep).

[0010] When transitioning into REM sleep, breathing becomes faster, irregular, and shallow, the eyes move rapidly in all directions, and the limb muscles become temporarily paralyzed during sleep. The heart rate increases and blood pressure rises. When people wake up during REM sleep, they often describe dreams.

[0011] The first REM sleep period usually occurs about 70 to 90 minutes after falling asleep. A complete sleep cycle on average takes 90 to 110 minutes. The first sleep cycle of each night contains a relatively short REM period and a long deep sleep period. As the night progresses, the length of the REM sleep period increases while deep sleep decreases. By morning, healthy individuals spend almost all of their sleep time in stages 1, 2, and REM.

[0012] Although the neurophysiology of sleep is not fully understood, it is undisputed that a good night's sleep is continuous and uninterrupted throughout the night, cycling through sleep stages (including REM) without interruption. Sleep disorders (such as OSA) often disrupt and interrupt these continuous sleep patterns and lead to daytime sleepiness, fatigue, and have many other serious harmful effects on both mental and physical health.

[0013] Obstructive sleep apnea (OSA) is a recognized dangerous disease that affects millions of people. It can be interpreted as a sleep disorder that causes periodic interruptions in pulmonary ventilation, further disrupting sleep.

[0014] The pathogenesis of upper airway (UA) obstruction during sleep is due to: (a) primary sleep-related loss of UA neuromotor tone; and (b) secondary lack of sufficient compensatory reflex responses to relieve the obstruction.

[0015] In healthy individuals, upper airway stability during sleep is ensured by the coordinated and synchronous central control of approximately 20 (twenty) airway dilator and constrictor muscles (collectively referred to as "airway muscles"). The central nervous system (CNS) pattern generator (respiratory center) in the medulla of the brain receives input from physiological sensors (also known as receptors) via various afferent sensory nerve fibers and controls the airway muscles via efferent motor fibers. These physiological sensors provide physiological feedback that the medulla uses to trigger reflexes in a closed-loop reflex arrangement. These reflexes are referred to as "autonomic" because they do not depend on consciousness. In some cases, the reflexes become insufficient to maintain optimal health. The inventors believe that obstructive sleep apnea (OSA) may be caused by a lack of or insufficient reflex response to airway obstruction.

[0016] Sensory input to the respiratory center includes signals from chemoreceptors that respond to oxygen (O2) and carbon dioxide (CO2) in arterial blood and many distributed mechanoreceptors, including mechanoreceptors that respond to transmural pressure across the airway wall. In patients with central sleep apnea (CSA), the former "neurochemical" control loop becomes disrupted and may be hyperactive. In patients with snoring and OSA, the latter "neuromuscular" control loop may become insufficiently active to maintain airway patency.

[0017] The airway muscles that keep the upper airway open are accessory respiratory muscles that maintain pharyngeal patency during tidal inspiration. The basal tone of these muscles typically decreases at the onset of sleep. The loss of tone makes the airway prone to collapse during sleep and obstructs airflow.

[0018] Afferent receptors in the tracheobronchial tree and lungs detect changes in airway pressure, temperature, airflow, and lung stretch, which may be indicators of airway collapse. The afferent receptors provide feedback signals to the spinal cord or CNS, which can respond to the feedback signals by triggering a reflex response that stimulates the upper airway muscles, which can then relieve airway obstruction.

[0019] Previous researchers have proposed that patients with obstructive sleep apnea rely heavily on the above reflexes to maintain upper airway patency during wakefulness, and the loss or reduction of reflex activation of the airway muscles during inspiration leads to an increase in airway collapse during sleep.

[0020] Over time, in patients with chronic OSA, the afferent receptors may gradually become desensitized. The patient's brain may not be able to adapt to the gradual development of airflow obstruction. The occurrence of OSA may be because the brain does not receive sufficient signals from the afferent receptors indicating airway obstruction. In these cases, airway neuromuscular activity no longer compensates for airway obstruction that occurs during sleep.

[0021] Current evidence suggests that neuromuscular responses in the upper airway musculature must be coordinated with the inspiratory activation of the diaphragm and respiratory pump muscles to maintain patency during sleep.

[0022] Existing neuromodulation therapies address airway collapse by selectively increasing neural signals in the selected efferent branches of the hypoglossal nerve (HGN). These branches control the protrusion of the tongue via the genioglossus muscle (GGM). There is also some experimental work aimed at selectively increasing other efferent motor control signals to various dilator muscles, including the ansa cervicalis, which can contribute to airway stiffening.

[0023] In patients with OSA, increasing lung volume, especially during exhalation, can improve airway patency during sleep. In Tehrani's U.S. Patent 7,970,475, "Device and method for biasing lung volume", a device and method for increasing lung volume by electrical stimulation of the phrenic nerve are described. This technique and other existing technologies teach the application of stimulation to the phrenic nerve to create mechanical traction on the airway, which stiffens the airway and expands the lungs to generate additional lung volume. One problem with this approach is that high stimulation energy levels are required to treat moderate to severe sleep apnea, which may wake the patient and be intolerable to the patient. SUMMARY OF THE INVENTION

[0024] An innovative method and system have been developed and disclosed herein for stimulating peripheral nerves involved in respiration to utilize existing physiological autonomic control reflex circuits. By artificially triggering or otherwise enhancing the physiological autonomic control reflex circuits, the method enhances and restores the natural control of airway stability and treats OSA by using the reflex to open closed airways during sleep.

[0025] In one embodiment, the method enhances the afferent branches of the pharyngeal mechanical reflex (e.g., the negative pressure reflex (NPR)), which naturally dilates and stabilizes the airway in response to increased negative transmural pressure in the airway. The NPR has been described in the scientific literature and it has been recognized that a reduction in this reflex during sleep in at least some OSA patients results in snoring and airway collapse.

[0026] In healthy humans during wakefulness, pharyngeal patency is protected by dilator muscles, where airway negative pressure (collapse pressure) acts as a local stimulus for graded activation of the dilator muscles. The respiratory pump can be modeled as a bellows or cylinder, where a rapid descent of the diaphragm causes fresh air to rush in through the nose and down along the airway into the lungs. This airflow creates a significant pressure gradient along the airway, which increases as the upstream resistance increases. Since the airway is a collapsible tube, a force must be counteracted against the negative pressure exerted during inspiration to prevent collapse. This counteraction is the main role of the NPR.

[0027] When a rapid suction (negative) pressure pulse is applied by inhaling ambient air through the nose, the NPR is manifested as a strong and very rapid (within 30 milliseconds to 50 milliseconds) activation of the pharyngeal dilator muscles. Such activation may be a protective reflex that allows the pharynx to resist closure during potential collapse perturbations under conditions of increased ventilation drive during inspiration, exercise, or gasping, while counteracting anatomical challenges such as obesity.

[0028] During sleep, afferent nerve feedback through the NPR can be used to induce coordinated responses in multiple accessory muscles that maintain pharyngeal patency without waking the patient from sleep.

[0029] When performing phrenic nerve stimulation experiments to manipulate the lung volume of sleeping patients, the inventors realized that these concepts involving reflexes could be used therapeutically and implemented in an embedded software algorithm using known or co-developed device hardware and implantation procedures.

[0030] The method of intentionally triggering the NPR to treat OSA disclosed herein is counterintuitive and goes against some deeply ingrained beliefs and clinical practices. First, airway negative pressure causes airway collapse, and the method of stimulating the phrenic nerve will potentially further collapse the airway by increasing the negative pressure in the airway. It is counterintuitive to increase negative pressure to open the airway. Second, the clinical practice of phrenic nerve stimulation in individuals with central nervous diseases (e.g., congenital hypoventilation) often requires a tracheostomy to prevent airway collapse caused by increased negative pressure. Third, when healthy individuals are placed in a negative pressure ventilator (e.g., an iron lung), their normal breathing efforts and central chemoreflexes often result in a reduction or elimination of ventilation drive. It has been observed that in individuals with OSA, the use of negative pressure ventilation increases the collapsibility of the airway. Fourth, OSA treatment serves to prevent obstruction in the airway. To trigger the NPR, an obstruction is needed, or at least is thought to be needed. Treating OSA in a way that may cause airway obstruction (albeit briefly) is counterintuitive.

[0031] Breaking with traditional and popular concepts, the inventors propose using the negative pressure conditions in the airway to trigger NPR for treating airway collapse. When observing sleep OSA patients treated by phrenic nerve stimulation, the inventors observed, to their surprise, that certain patterns of phrenic nerve stimulation triggered neural feedback from mechanosensory input that almost immediately opened the collapsed airway while acting on the closed upstream airway and acting on the collapsing negative pressure without waking the patient and disrupting the continuous sleep cycle. Surprisingly, the forceful diaphragmatic contractions applied in a relatively short period of time in response to phrenic nerve stimulation, when applied during the late expiratory and early inspiratory phases of natural breathing when the airway is considered more collapsible and vulnerable, are effective in treating OSA. During an inspiratory pattern known as paradoxical breathing, a significant sudden negative pressure is demonstrated by a decrease in chest circumference as the abdomen expands.

[0032] In one proposed embodiment, the present invention enhances and restores NPR in OSA patients during sleep by periodically stimulating one or both phrenic nerves and generating forceful relatively short diaphragmatic contractions (e.g., less than or equal to 50% of the patient's natural breathing duration), which typically coincide with a specific part of the respiratory cycle, more specifically with the late expiratory - early inspiratory period. In the inventors' experiments, the inventors observed that such negative pressure pulses can enhance and restore airway patency in sleeping patients with severe sleep apnea and attributed it to reflex activation. The negative pressure spikes generated by the violently descending diaphragm, when occurring in the environment of an obstructed or resistive airway, may enable an enhancement of the afferent signals from the baroreceptors located in the pharyngeal mucosa. These afferent signals are known to conduct information to the respiratory control centers of the brain via the afferent fibers of the pharyngeal nerves (e.g., the superior laryngeal nerve, which may be from mechanoreceptors in the laryngeal structures, and the glossopharyngeal nerve via the pharyngeal mucosa), independent of the phrenic nerve.

[0033] This enhanced neural discharge can increase the afferent signals above the threshold, forcing the respiratory control center to generate efferent signals to various dilator muscle groups sufficient to stiffen the airway and restore airflow. In such a case, if the stimulation bursts occur frequently (e.g., at a natural breathing rate of 6 to 20 times per minute), the airway will not remain closed long enough to significantly impede ventilation or gas exchange in any significant way and maintain oxygen saturation. It is possible and may be desirable to synchronize the diaphragmatic contractions with the patient - initiated inspiration, or set a physiologically acceptable rate and make the patient synchronized with the stimulation. In some embodiments, only the breaths per second or other rates are stimulated.

[0034] In natural physiology, lung inflation inhibits inspiration. Phrenic nerve stimulation can increase relative inspiratory time by overriding central control. Stimulating the phrenic nerve during expiration inhibits exhalation, resulting in dynamic pulmonary hyperinflation. As lung volume increases, it exerts a caudal traction on the upper airway structures and stiffens the pharynx.

[0035] In another embodiment of the present invention, phrenic nerve stimulation (PNS) is used to bias or displace the diaphragm, or more generally, to inhibit exhalation, producing moderate dynamic pulmonary hyperinflation. This mode of stimulation may be particularly effective in patients with reduced lung volume. It is recognized that increased lung volume during the exhalation phase of the respiratory cycle exerts a mechanical caudal traction on the airway. In patients with reduced lung volume (e.g., due to a large amount of abdominal visceral fat), restoring lung volume may contribute to airway patency.

[0036] Sleep-induced reduction in lung volume can lead to a significant reduction in the longitudinal traction on the airway, resulting in a more collapsible pharynx even in patients with normal lung volumes while awake. Some individuals may rely very much on this mechanism to maintain airway patency while awake and lose airway patency during sleep. Lung volume biasing may be combined with the periodic contraction of the diaphragm to induce NPR in some patients.

[0037] Lung volume can be "statically" increased by biasing the lung by applying a constant low-level tension to the phrenic nerve, which prevents the lung from fully contracting and exerts a caudal traction and stiffens the pharynx.

[0038] Lung volume can also be increased "dynamically" by "expiratory interruption" that increases the inspiratory to expiratory (I:E) ratio or increases the frequency of the thoracic segment of the phrenic nerve, which "dynamically" traps air and prevents complete lung deflation to exert a caudal traction and stiffen the pharynx. An increase in the severity of upper airway obstruction will further impede exhalation and increase the degree of airway trapping and dynamic hyperinflation.

[0039] Obstructive sleep apnea (OSA) is an intermittent cessation of breathing during sleep due to collapse of the pharyngeal airway. Once the airway is completely collapsed, in the absence of intervention, in a person asleep, the airway generally remains collapsed until the patient wakes up (is aroused) due to air hunger. The restoration of the airway usually takes long enough to cause significant intermittent and periodic decreases in oxygen saturation, which have serious consequences for the patient's health. This delay is inherent in physiology because it takes some time for blood to reach the chemical sensors in the brain from the lungs. In a diseased person, such as a patient with heart disease, this delay may be particularly long.

[0040] The pharynx (also known as the pharyngeal airway or simply "airway" for simplicity) is a tube that connects the nasal and oral cavities to the larynx and esophagus. The pharynx is divided into the nasopharynx, oropharynx, and laryngopharynx. The pharynx is muscular and collapsible at any point along its passage. There are 20 or more muscles surrounding the passage in the pharynx. These muscles actively contract and dilate the upper airway lumen. These muscles also contribute to airway stiffening, which is defined as its ability to withstand negative transmural pressure regardless of its caliber. In the context of this patent, airway stiffening by mechanical or neural intervention is referred to as airway stabilization.

[0041] The airway muscles can be divided into four groups: muscles that regulate the position of the soft palate (levator veli palatini, tensor veli palatini, palatoglossus); the tongue (genioglossus, geniohyoid, hyoglossus, styloglossus); the hyoid complex (hyoid bone, geniohyoid, digastric, mylohyoid, sternohyoid); and the posterolateral pharyngeal wall (palatopharyngeus, pharyngeal constrictors).

[0042] These muscle groups interact in complex ways to keep the airway open or closed. The soft tissue structures that form the walls of the tonsils and upper airway include: the soft palate, uvula, tongue, and lateral pharyngeal walls.

[0043] The sites of airway collapse are important in the pathophysiology of OSA and in any targeted treatment to prevent collapse. The sites of airway collapse commonly described in the literature are associated with: the retropalatal space (base of the tongue), the velopharyngeal space (soft palate obstruction), and / or the hypopharyngeal space (lateral wall of the airway obstruction). The soft palate (velar), oropharynx, base of the tongue, and epiglottis (VOTE) classification in drug-induced sleep endoscopy (DISE) is widely used for classifying the sites of collapse in obstructive sleep apnea (OSA) syndrome.

[0044] Figure 1 The balance of forces that keep the airway open during inspiration is shown. The inspiratory negative pressure and the extraluminal positive pressure tend to cause the pharynx to collapse. The upper airway dilator muscles and the increased lung volume (as the lungs are filled with air) tend to maintain pharyngeal patency. Patient 1 inhales air at atmospheric pressure through the nostrils. The inhaled air travels down the pharyngeal airway 2. The soft palate 8 (sometimes called the velum palatinum) defines the velopharyngeal or velopharyngeal space 9, which is the most common site of airway collapse.

[0045] The variables that tend to promote pharyngeal collapse include the negative pressure 3 within the airway generated by the inspiratory force and the positive pressure 4 outside the airway. The positive pressure 4 is the product of pressures caused by posture and gravity, fat deposition, and other anatomical factors (such as micrognathia 6). The sum of these pressures 4 and the pressure 3 defines the transmural pressure sensed by the mechanoreceptors in the airway. The inspiratory negative pressure 3 is dynamic and exists at any point along the airway during inspiration. The inspiratory negative pressure is proportional to the airflow and upstream resistance, but increases at any level of ventilation drive whenever there is upper airway obstruction. In contrast, through the pharyngeal dilator muscles 5 (e.g., genioglossus and others known butFigure 1 Activation of other muscles (not shown in the figure) and maintenance of patency by an increase in lung volume 7, which tends to keep the airway open by longitudinal traction. Thus, the dilating forces (e.g., muscle activation) have a complex interaction with the collapsing forces generated by the anatomy and airway negative pressure.

[0046] Figure 2A and Figure 2B Figure 7 shows the reflex control of the airway. The central nervous system (CNS) pattern generator (respiratory center) 10 is located in the medulla 16 of the brain. The rhythmic center in the medulla of the brainstem controls the spontaneous respiration during sleep and consists of interneurons that discharge during inspiration (I neurons) or expiration (E neurons). The I neurons stimulate the neurons that innervate the respiratory muscles (bringing about inspiration). The E neurons inhibit the I neurons ("switching off" the I neurons and bringing about expiration). The apnea center (located in the pons) stimulates the I neurons (facilitating inspiration). The respiratory regulatory center (also located in the pons) inhibits the apnea center and inhibits inspiration. This inhibition can be overcome by phrenic nerve stimulation that directly affects the respiratory pump.

[0047] The respiratory center 10 receives input from the physiological sensors 11 via various afferent sensory nerve fibers and maintains airway patency by reinforcement and dilation by synchronously contracting and relaxing the muscles via the efferent motor fibers. An important airway dilator muscle is the genioglossus muscle 14, which protrudes and retracts the tongue. The genioglossus muscle has a direct effect on the palatopharyngeal space 9 where airway obstruction often occurs. Such a physiological feedback arrangement is called a closed-loop reflex. Generally, such reflexes are called "autonomous" because they do not depend on consciousness.

[0048] The negative pressure reflex (NPR) can be an example of a pharyngeal mechanical reflex that activates the dilator muscles. A mechanical reflex is a reflex triggered by the stimulation of a mechanoreceptor. Muscle spindle stretch receptors, baroreceptors, shear stress receptors, or flow receptors can be examples of mechanoreceptors that respond to mechanical perturbations such as deformation and generate an afferent nerve signal consisting of a series of action potentials in a nerve fiber bundle.

[0049] The NPR is an important physiological reflex that is induced and utilized during the proposed treatment. The NPR is naturally manifested during each breath by the forceful and very rapid (within 30 milliseconds to 50 milliseconds) activation of the pharyngeal dilator muscles. The NPR can also be caused by a rapid pulse of suction (negative) pressure applied through the nose and sensed by the transmural pressure sensors in the pharyngeal mucosa. The NPR can be enhanced or induced by electrical stimulation of the phrenic nerve, which causes contraction of the diaphragm. The amplitude of the signal sensed by sensor 11 is proportional to the intensity of the diaphragmatic contraction and the degree of obstruction of the airway (especially in the palatopharyngeal space 9). If the airway is obstructed (e.g., completely obstructed, partially obstructed, etc.), the negative pressure becomes more negative, and the afferent feedback reflected to the CNS becomes stronger. The response of the CNS center 10 is in turn proportional to the input from the afferent branch 12. This response generates a stronger output in the efferent branch 13, which leads to a stronger contraction of the dilator muscle 14. Eventually, the entire closed-loop response becomes strong enough to open the airway and allow air to enter. The opening of the airway in turn causes a decrease in the sensed signal and negative pressure in the afferent branch 12. The closed-loop system enters a steady state, and respiratory stability can be restored.

[0050] Figure 1 , Figure 2A and Figure 2B are simplified to show the main elements of the pharyngeal anatomy and innervation. Due to the physiological importance of maintaining pharyngeal patency and the many tasks required of this part of the airway (speaking, swallowing, etc.), a complex motor control system has evolved in which approximately 20 upper airway muscles play a role. The following paragraphs elaborate on the complexity of this natural arrangement for maintaining airway patency and previous attempts to improve this arrangement in patients with OSA.

[0051] During natural inspiration, the negative intraluminal pressure pulls the three soft tissue elements of the tongue, posterior pharyngeal wall, and soft palate towards each other, thereby reducing the airway lumen in the palatopharyngeal region. This airway collapse effect is counteracted by the pharyngeal dilator muscles, including the genioglossus, geniohyoid, and tensor veli palatini and levator veli palatini muscles. Additionally, the activation of the pharyngeal constrictor muscles stiffens the airway wall.

[0052] This elaborate natural activation of the pharyngeal muscles keeps the airway open during wakefulness, but often fails during the sleep state. One objective of the described invention is to induce, strengthen, and utilize this natural airway constriction process through the NPR when the natural excitatory signal transmission to the corresponding motor neurons is insufficient to keep the airway open during sleep. This method is new because although the NPR has been known since the 1980s, it has never been proposed as a treatment method. It is superior to the prior art because the prior art proposes only controlling specific efferent motor neurons (rather than sensory afferent neurons) to induce individual, uncoordinated responses from the pharyngeal dilator muscles.

[0053] The soft palate (velum) consists of muscles and tissues, which endow it with mobility and flexibility. When a person swallows, the soft palate rises to seal the opening of the airway, preventing the pressure from escaping through the nose. The shape, position, and movement of the soft palate are maintained by five pairs of muscles, including the tensor veli palatini (TVP), levator veli palatini (LVP), palatopharyngeus (PP), palatoglossus (PG), and musculus uvulae (MU). The tensor veli palatini (tensor palatior tensor muscle of the velum palatinum) is a broad and thin band-like muscle in the head that is used to tense the soft palate.

[0054] The tensor veli palatini is innervated by the nerve to the medial pterygoid, a branch of the mandibular nerve (the third branch of the trigeminal nerve), which is the only muscle in the palate not innervated by the pharyngeal plexus (formed by the vagus and glossopharyngeal nerves). The tensor veli palatini tenses the soft palate and, by doing so, aids the levator veli palatini in elevating the palate to occlude the nasopharynx during swallowing and prevent food from entering the nasopharynx.

[0055] The palatoglossus acts as an antagonist to the levator veli palatini. The palatoglossus arises from the palatine aponeurosis of the soft palate, where it is connected to the muscle on the opposite side, and extends downward, forward, and laterally in front of the palatine tonsil, inserting into the side of the tongue. Some of its fibers are distributed on the dorsal surface of the tongue, while other fibers penetrate into the organ parenchyma and interweave with the transverse muscle of the tongue. The palatoglossus is innervated via the vagus nerve (via the pharyngeal branch to the pharyngeal plexus). The palatoglossus elevates the posterior tongue, closes the oropharyngeal isthmus, and helps initiate swallowing. This muscle also prevents saliva from overflowing from the vestibule into the oropharynx by maintaining the palatoglossal arch.

[0056] The genioglossus muscle (GGM) receives input from the brainstem respiratory central pattern generator via the hypoglossal nerve (HGN). The presence of "preactivation" (the hypoglossal nerve discharges 50 ms to 100 ms before the phrenic nerve) confirms the existence of premotor input to the hypoglossal motor nucleus in the medulla.

[0057] The functions of the GGM in health and disease have been extensively studied and described in the literature. For example: Cori JM et al., Sleeping tongue: current perspectives of genioglossus control in healthy individuals and patients with obstructive sleep apnea, Nature and Science of Sleep, June 15, 2018; 10: 169 - 179.

[0058] The hypoglossal nerve (also known as the twelfth cranial nerve, cranial nerve XII, or simply CN XII) innervates the GGM and is the basis for the first neuromodulation technique successfully used to treat OSA. HGN stimulation for treating OSA is disclosed in U.S. Patents 5,158,080 and 5,540,733.

[0059] Although successful in some patients, HGN stimulation is not an effective solution for many patients. In some cases, effectiveness can be restored by increasing the power applied to the nerve, but many patients cannot tolerate the increased power regimen for one reason or another. The possible reason is that the acceptable level of GGM activity is insufficient to overcome other physiological changes that occur and persist during sleep, such as low activity of other dilator muscles, changes in the co - activation pattern with other dilator muscles, and low lung volumes that result in reduced airway caudal traction. These limitations are addressed in the present application by new methods, such as manipulating lung volume and trans - wall airway pressure via phrenic nerve stimulation.

[0060] Figure 3 The role of NPR in the pathogenesis of OSA is further demonstrated. During wakefulness, in healthy individuals and unhealthy OSA patients, pharyngeal patency 21 is maintained by the phasic activation 20 of pharyngeal dilator muscles, where negative airway pressure (collapse pressure) acts as a local stimulus for pharyngeal dilator muscle activation. The negative pressure reflex is a protective reflex that causes the pharynx to resist closure during collapse perturbations. The dilator muscles respond to pharyngeal negative pressure within tens of milliseconds, thus maintaining airway patency.

[0061] To overcome impaired pharyngeal anatomy 22 (e.g., common obesity, poor tongue anatomy, or poor mandibular anatomy, etc.), the upper airway dilator muscles of patients with OSA must be more active during wakefulness than those of healthy individuals. During wakefulness, NPR responds to the increased (more negative) negative pressure in patients with anatomically impaired structures. The sensed response is a smaller pharyngeal cavity and the need for greater pharyngeal pressure to generate sufficient airflow. This increased negative pressure drives the pharyngeal dilator muscles to be more active. Thus, the airway muscles compensate for the anatomical defects in OSA patients during wakefulness and maintain ventilation. Even in patients with very severe OSA, respiratory disturbance events only occur during sleep, highlighting the importance of central control in the pathogenesis of this disease.

[0062] It is known that neuromuscular reflexes are reduced during sleep<23>. Even in healthy individuals, the ability of the pharyngeal dilator muscles to respond to negative pressure is significantly attenuated during sleep. The loss of these excitatory inputs to the efferent hypoglossal motoneurons can greatly reduce the ability of the genioglossus and other upper airway dilator muscles to respond to negative pressure compared to the waking state<25>. The loss or reduction of this reflex mechanism during sleep is expected to lead to a substantial decrease in muscle activity and subsequent airway closure<26>. Thus, if an individual's pharyngeal anatomy is compromised, their airway will not be protected by NPR during sleep and will be prone to collapse. In OSA, airway closure results in hypoxia and hypercapnia<27>, which elicits CNS chemoreflexes. Unlike mechanical reflexes such as NPR, chemoreflexes rely on blood circulation for their response and may take up to 15 seconds to 90 seconds to generate a response from the respiratory pump<28> and increased respiratory effort. These delays manifest as periodic breathing and apnea, hyperpnea cycles. Eventually, the increased respiratory effort is usually accompanied by arousal<29> and a restoration of the waking activity level of the pharyngeal dilator muscles<20>. Since this cycle can be repeated frequently, 20 to 90 times per hour, the patient's sleep is disrupted.

[0063] The present invention may be embodied as a method for treating obstructive sleep apnea (OSA) by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the patient's pharyngeal airway is naturally obstructed.

[0064] The present invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the airway is closed (e.g., completely obstructed) or partially obstructed (e.g., obstructed to an extent sufficient to cause, for example, a decrease in blood oxygen saturation).

[0065] The present invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the airway is characterized by an increase in obstruction.

[0066] The present invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied artificially when the airway is closed.

[0067] The present invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the airway is closed or partially obstructed, wherein the stimulation is applied with an energy sufficient to produce a diaphragmatic contraction sufficient to generate an airway negative pressure sufficient to trigger the NPR to open the airway.

[0068] The stimulation can include a stimulation burst initiated at airway closure. A significant proportion (e.g., greater than 50%, 75%, or 85%) of the stimulation bursts can be stimulation bursts initiated at airway closure. The stimulation burst can be applied first at a first energy level sufficient to generate an action potential in the phrenic nerve and subsequently at a second energy level sufficient to reflexively open the collapsed airway by activating the upper airway muscles. The stimulation burst can be applied first at a first energy level sufficient to generate an action potential in the phrenic nerve and further at a second energy level sufficient to reflexively open the collapsed airway by enhancing the mechanical reflex. The mechanical reflex can be the negative pressure reflex. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 is a cross-sectional view of an upper portion of a patient's airway passage.

[0070] Figure 2A and Figure 2B shows the patient's head, brain, and upper airway to illustrate reflex control of the patient's airway.

[0071] Figure 3 is a flowchart showing the connection between airway stability and the negative pressure reflex (NPR).

[0072] Figure 4 is a flowchart showing restoration of pharyngeal muscle tone by phrenic nerve stimulation that induces the NPR.

[0073] Figure 5 is a cross-sectional view of a patient with a phrenic nervous system that includes an implanted electrode and an implanted pulse generator.

[0074] Figure 6 is a graph showing the variation over time of airway flow, respiratory flow, oxygen level, and electrical stimulation current applied to the phrenic nerve.

[0075] Figure 7 is a graph showing the variation over time of air passage flow velocity and respiratory effort during stimulated breathing.

[0076] Figure 8 is a flowchart for adjusting parameters for stimulating the phrenic nerve to treat sleep apnea.

[0077] Figure 9 is a graph showing an energy titration curve comparing the degree of diaphragmatic contraction with the energy (current in mA) applied to the phrenic nerve through the electrode.

[0078] Figure 10A is a flowchart of an algorithm for detecting the capture threshold.

[0079] Figure 10BIs a flowchart of an algorithm for detecting a treatment threshold.

[0080] Figure 11A Is a graph showing an example of ramping the stimulation energy during treatment titration to determine the optimal stimulation energy and then applying the optimal stimulation energy during the treatment night. Figure 11B Is a graph showing different parameters that can be set according to certain example embodiments.

[0081] Figure 12 Shows a patient in bed during sleep therapy, where the patient has electrodes for stimulating the phrenic nerve, an implanted pulse generator, and a bedside computer monitor that communicates wirelessly with the implanted pulse generator and with a cloud computer.

[0082] Figure 13 Schematically shows an implanted pulse generator for stimulating the phrenic nerve to treat OSA.

[0083] Figure 14 Is a block diagram of the electronic components of an implanted pulse generator.

[0084] Figure 15A Is a flowchart of an algorithm for optimizing the use of negative pressure reflex in a sleeping or resting patient.

[0085] Figure 15B Is a flowchart of an algorithm for increasing lung volume to treat OSA.

[0086] Figure 16A and Figure 16B Is a graph showing adjusting the stimulation rate to optimize phase locking of breathing using the phase angle between the stimulation pulse train and the patient's spontaneous breathing effort.

[0087] Figure 17A and Figure 17B Is a graph showing using lung volume to optimize and improve the effectiveness of phrenic nerve stimulation in treating OSA.

[0088] Figure 18A and Figure 18B Is a graph showing spectral power analysis. Detailed Description

[0089] The use of sections in the detailed description is only to guide the reader to the general topic of each section; as will be seen below, the description of many features spans multiple sections, and the headings should not be construed as affecting the meaning of the description included in any section.

[0090] Figure 4 Description

[0091] Figure 4Restoration of pharyngeal muscle tone by phrenic nerve stimulation inducing NPR is shown. This is the basis of the proposed treatment. Falling asleep 23 inevitably results in a natural reduction in NPR 24. The reduced reflex results in a reduced natural occurring periodic efferent signal transmission to the muscles responsible for maintaining airway patency 25. This results in a substantial increase in inspiratory airway resistance and may lead to intermittent airway collapse.

[0092] The inventors have developed a treatment that includes periodic stimulation 30 of the phrenic nerve, which produces strong (e.g., burst lengths greater than 200 ms, 250 ms, or 300 ms) and forceful diaphragm contractions (e.g., greater than 100 μA above the diaphragm twitch capture threshold as discussed elsewhere herein). The diaphragm contraction immediately (e.g., within tens of milliseconds) creates a negative pressure 31 within the airway. This pressure change is picked up by pressure sensors in the pharyngeal mucosa, and the afferent limb of NPR is enhanced 32. This results in reflex activation of the efferent limb and contraction of dilator muscles (including but not limited to the genioglossus muscle) 33, which restores airway patency. Since NPR is very fast, this process can be cyclically repeated at a rate consistent with natural breathing (6 to 20 times per minute). Due to this periodic activity, the airway never remains closed long enough to induce hypoxia and activate respiratory chemoreflexes. OSA patients naturally require tens of seconds of apnea to drop below a standard desaturation threshold (e.g., hemoglobin oxygen saturation that has dropped 3% to 4% from baseline), which is considered clinically significant. When some of the example techniques discussed herein are applied on every beat or every other breath, the apnea-hypopnea oscillatory cycle does not occur or is greatly attenuated, and sleep disruption is prevented.

[0093] Figure 5 Description: Phrenic Nerve Stimulation System

[0094] Figure 5 A physical embodiment of the invention is schematically shown. Patient 1 is implanted with a nerve stimulation system 46, which includes an implantable pulse generator (IPG) 41 that is electrically connected to an electrode system 42 implanted near the phrenic nerve 44. Stimulation bursts from the IPG produce a forceful contraction and descent of the diaphragm 43. The contraction of the diaphragm fills the lungs 45 with air and creates a negative pressure in the airway 2, which may be closed. This negative pressure is sensed by the receptor 11, activating the afferent limb of NPR. The respiratory center 10 responds by generating an efferent signal 12 that activates dilator muscles shown by the genioglossus muscle 14. It should be understood that other dilator muscles are also co-activated in the natural physiological sequence. The airway is dilated and stiffened by the synchronous action of the muscle groups activated by the reflex. If the airway is blocked, the negative pressure is strongest, and this helps to restore airway patency.

[0095] In the field of implantable and partially implantable nerve stimulators, phrenic nerve stimulation to assist or replace natural breathing is known. As Figure 5 shown, the phrenic nerve stimulation system 46 can include an electrode subsystem 42 that is adapted to apply current to one or both of the phrenic nerves 44 (e.g., the left phrenic nerve and / or the right phrenic nerve) in a certain pattern. The pattern can be programmed into and / or embedded in a memory (e.g., a microprocessor memory) included in the IPG 41. The pattern can be predefined and / or dynamically determined based on one or more characteristics of the patient. In some examples, the pattern of the current supplied by the IPG is controlled by an external computing device (e.g., a wand computing device 48) that communicates (via wired or wireless communication) with the IPG to cause the current to be supplied to the phrenic nerve 44 according to the pattern controlled by the external computing device. The stimulation can be monopolar, bipolar, or multipolar, and energy is applied to either or both of the left and right phrenic nerves.

[0096] The phrenic nerve stimulation system 46 also includes a lead 47 that electrically connects the IPG 41 and the electrode 42. In certain example embodiments, the phrenic nerve stimulation system 46 can also include sensors and / or processing for detecting the respiratory state (inhalation, exhalation), sensing air flow, chest movement, and / or pressure.

[0097] Example implantable devices and systems suitable for phrenic nerve stimulation are available from Integer Holdings Corporation.

[0098] The electrode subsystem 42 can be a nerve cuff, an intravascular electrode, a paddle electrode, or a percutaneously inserted tubular electrode lead that is proximate to the phrenic nerve in the neck or chest. The electrode subsystem 42 can be connected by a flexible lead to a subcutaneous wireless antenna or an IPG that communicates with an external pulse generator (EPG) (not shown) (e.g., placed outside the patient's body). It should be understood that the techniques discussed herein in connection with the IPG 41 can be similarly applied in connection with an EPG.

[0099] The IPG 41 can include an implanted battery. The battery can be rechargeable or disposable. In some examples, energy can be wirelessly transmitted from an external device outside the patient's body via a percutaneous RF link. In some examples, the IPG 41 can be equipped to provide telemetry, such as via a Bluetooth transceiver. For example, additional details of an example implementation of the IPG are discussed below in connection with Figure 13 and Figure 14 to discuss additional details of an example implementation of the IPG.

[0100] In some examples, the IPG / EPG components of the phrenic nerve stimulation system 46 include any one or all of the following: a hardware processor (e.g., a microprocessor), a transceiver, a memory (e.g., flash RAM, cache, volatile memory, non-volatile memory, read-only memory, etc.), associated circuitry, and embedded software (which may include firmware and / or be firmware in some examples) configured to be executed by the hardware processor of the IPG / EPG to perform the operations defined in the instructions. Such instructions may include instructions required to activate (e.g., IPG / EPG) and deactivate (e.g., IPG / EPG) by a doctor, patient, or other user. In some examples, one or more computing devices may provide a user interface (e.g., a graphical user interface) for adjusting stimulation parameters, which may include current, voltage, pulse duration, and frequency (e.g., the pulse frequency as discussed below, which may be, for example, between 20 Hz and 50 Hz), pulse burst rate, duty cycle, and train shape parameters. The values of such stimulation parameters may be stored in the IPG 41. Illustrative values of these stimulation parameters are discussed below.

[0101] Wireless communication with the IPG 41 can be performed using a handheld computer device 48 (e.g., a "wand computing device") configured to modify stimulation parameters, the embedded software of the IPG, and upload / download data to / from the IPG when brought within close proximity to the IPG implanted within a patient's body. The computer device 48 may include a display and user input keys to allow a user such as a doctor (or in some examples a patient or other user) to view data collected from the IPG and change operating parameters such as stimulation parameters (e.g., rate and energy level, etc.).

[0102] Phrenic nerve stimulation (PNS) can improve airway patency by activating the physiological mechanisms of mechanical reflexes (e.g., NPR) and increasing lung volume. PNS can be achieved by using a hardware system (e.g., in combination with Figure 5Implemented by the described phrenic nerve stimulation system 46). The PNS can be embedded in such a hardware system. One of the fundamental problems in any nerve stimulation therapy (e.g., PNS) is the trade-off between effectiveness and the patient's ability to tolerate the therapy. The effectiveness of the therapy is typically proportional to the electrical field energy applied to the nerve by the IPG. The IPG generates current pulses that cause action potentials to be generated in the target nerve fibers (e.g., motor fibers in the phrenic nerve bundle) that innervate the target muscle fibers. Typically, non-target nerve fibers are also activated, limiting the patient's tolerance. Tolerance can include many factors such as pain, muscle twitching, unpleasant sensations, and interference with respiratory mechanics, gas exchange, and sleep quality. Thus, the embedded software in the IPG (or other components of the example hardware system) can include features for titrating the energy to achieve a compromise between effectiveness and tolerance.

[0103] Figures 6 to 7 Description: Illustrative clinical data

[0104] Figure 6 and Figure 7 The data in the graph shown in was obtained from patients wearing a nasal mask attached to a precise airflow meter. The patients were equipped with thoracic and abdominal respiratory belts, a finger pulse oximeter, and the standard polysomnogram (PSG) lead configuration (montage) commonly used during sleep studies. Percutaneous electrodes were inserted into the patient's neck near the left phrenic nerve and connected to a bedside electrical pulse generator operating in a constant current mode. The stimulation parameters included a bipolar train of square pulses 150 microseconds long, applied at a current of 1 mA to 5 mA and 30 Hz. The operator adjusted the stimulation current in 0.25 mA increments to achieve the desired respiratory stabilization.

[0105] During the experiment, the patients were equipped with the standard PSG lead configuration including EEG and EMS electrodes. Based on the sleep stage analysis during and after the experiment, the patients were in sleep (non-REM sleep) throughout the experiment. Microarousals terminating the apnea were observed. The fact that the patients immediately returned to the apnea state when the stimulation was turned off supports the view that upper airway patency and ventilation can be stabilized during sleep without waking the patient, and that PNS can reduce AHI, desaturation, clinically significant arousals, and sleep fragmentation, all of which should be able to alleviate the clinical symptoms of OSA (drowsiness, fatigue, etc.).

[0106] Figure 6A graph is shown presenting treatment results related to the application of artificial nerve stimulation during a sleep period, where the treatment shown was performed by the inventors on a patient with very severe OSA. During the control time period 54, phrenic nerve stimulation was turned off. During the control period 54, the patient immediately experienced severe OSA, which was manifested as: no airflow during the apnea period 50 (the first trace from the top shows the airflow sensor signal 50-a), the presence of respiratory effort 51 during apnea (the second trace from the top shows the respiratory belt sensor signal 51-a), and a decrease in oxygen saturation 52 (the third trace from the top shows the pulse oximeter measurement 52-a). The sudden transition to OSA is a clear indication that the patient was in a sleep state both before and after the transition. OSA is a sleep-related disorder. Patients generally do not fall asleep instantly and suddenly develop severe OSA.

[0107] After a circulatory delay, the oxygen saturation decrease period 52 appears after the apnea period 50. The decrease in oxygen saturation and the accompanying increase in CO2 enable the chemical reflex to wake the patient (which may include waking the patient), and terminate the apnea period by restoring airway patency. This is the cycle that occurs naturally during OSA, as Figure 3 shown. When stimulation is turned on during periods 53, 55, and 56, the patient's breathing is greatly improved. A stimulation burst of sufficient amplitude (e.g., according to the setting for one or more of the stimulation parameters) induces a reflex that may include NPR and almost immediately opens the airway without waking the patient, as Figure 4 shown. The blood gases O2 and CO2 are maintained, and the patient does not experience significant periodic breathing, sleep interruption, or long periods of apnea.

[0108] Element 53-a shows the output from an arbitrary waveform generator (AWG), which can be used in combination with controlling the stimulation energy or delivering the stimulation energy to the patient. The AWG can be used to define a current shaping waveform and can be used, for example, to map an analog voltage to a current using a bipolar constant current stimulator. In certain examples, rise / fall and peak amplitudes are assigned to the waveform to be generated to provide a physiologically relevant diaphragmatic twitch, where the rise is designed to ensure a fast enough diaphragmatic twitch to trigger the patient's NPR (e.g., between about 50 ms and 500 ms), but not so fast as to cause waking from a rapid twitch (e.g., between about 0 ms and 50 ms). In certain examples, and as described elsewhere herein, within this shaped waveform are multiple biphasic pulses that can be between about 20 hz and 50 hz. The amplitudes of these pulses can be set to match their time position on the current control carrier waveform.

[0109] Increasing the energy level of phrenic nerve stimulation from level 55 to level 56 causes a more complete resolution of airway obstruction. During the relatively low level 55 of the phrenic nerve, the patient continues to experience airway obstruction, which is manifested as: periods of no airflow in the airflow at 50, and corresponding episodes of low or no respiratory effort at 51 and a decrease in blood oxygen level at 52. As confirmed by the airflow as shown in the airflow signal 50-a, the respiratory effort as shown in 51-a, and the higher and / or more consistent blood oxygen level in 52-a (all of which occur during stimulation level 56), increasing the stimulation level from level 55 to level 56 stops the airway obstruction (restores normal breathing). This process is shown by Figure 8 further illustrated.

[0110] When the phrenic nerve stimulation level exceeds an unknown threshold, a sudden return to normal breathing occurs. This suddenness is manifested as no periods of airflow cessation, and is immediately followed by a relatively continuous strong airflow level. The sudden transition indicates that a reflex is triggered when the stimulation level exceeds the threshold, where the reflex can be a negative pressure reflex. When triggered, the reflex will cause the muscles in the airway to open the airway.

[0111] Figure 7 including an airflow rate graph 70-a and a graph 70-b of respiratory effort over time. These graphs show that at Figure 6Data corresponding to two breaths from the same patient during a portion of the treatment session shown. Stimulation bursts 60, 61 (e.g., referred to as a train of pulses) are applied at a breathing rate close to the patient's natural breathing rate (e.g., between about 6 BPM and 20 BPM). In this case, the stimulation burst has a duration approximately equal to 1 / 3 of the breath (e.g., a duty cycle of 33% or an I:E ratio of 1:3). In some examples, an I:E ratio from about 4:1 to 1:4 can be used to trigger the reflex. In some examples, when used in intensive care mechanical ventilation (e.g., in oxygen therapy), an inverse (e.g., longer inspiration than expiration and an equal I:E ratio (1:1)) may be beneficial. In some examples, the longer the "I" time to keep the peripheral airways open, the more time is available for perfusion, thus improving the clearance of CO2. This reduces the hypoxic burden and normalizes breathing / perfusion in the absence of stimulation. When the patient's airway closes, the first stimulation burst 60 is initiated, which is manifested as: the airflow signal 70-d is zero during the period 66, although the inspiratory effort has started. The respiratory effort signal 70-c represents the abdominal circumference measured by the respiratory belt, which increases at the start of the PNS (e.g., less than 50 mL is severe flow limitation / apnea, an increase in lung volume between about 50 mL and 150 mL corresponds to mild flow limitation, and a lung volume greater than about 150 mL corresponds to an open airway without such flow limitation), and further increases when the airway opens and the lungs inflate. The presence of zero airflow accompanied by respiratory effort indicates that the airway is blocked, the patient is indeed in a sleep state, and the patient's basal pharyngeal muscle tone is insufficient to keep their airway open. This observed airway collapse (manifested as no airflow during respiratory effort) further demonstrates that the patient is in a sleep state because OSA is a "sleep-induced" disorder.

[0112] As Figure 7 shown, the airway suddenly opens, and the inspiratory airflow starts 67 after a time delay 66. This time delay is the time it takes for the respiratory effort of the diaphragm (natural and / or stimulated), as well as the pharyngeal negative pressure, to reach the threshold of the afferent signal to activate the reflex to open. Then the patient inhales at a peak airflow rate >50 ml / min, which indicates that the airway is not blocked. The bottom trace shows the respiratory effort signal 70-c indicating the inspiratory effort (diaphragm displacement) (e.g., the measured abdominal circumference-perimeter that has been calibrated based on or according to the lung volume (e.g., in mL)). The respiratory effort signal 70-c in this example has been calibrated to the lung volume (mL). The start 62 of the effort is coincident with the stimulation 60, but there is a delay 66 before the inspiratory airflow 67, which indicates the accumulation of diaphragmatic movement and airway negative pressure for the closed airway. When the central control initiates the expiratory phase of breathing and the phrenic nerve stimulation is turned off, the inhalation stops at point 63 and turns into exhalation.

[0113] As Figure 7 shown, phrenic nerve stimulation 60 sufficient to trigger a negative pressure reflex (see level 56 in Figure 6 ) causes the patient's natural negative pressure reflex to rapidly open the closed airway 67 so that the patient can inhale during the inhalation cycle. In the absence of stimulation 60, the airway can remain closed during the inhalation cycle and can remain closed for two, three, or more inhalation cycles until the patient wakes up and gasps for air. Stimulation 60 triggers the negative pressure reflex so that the patient can breathe without suffering from a lack of airflow during multiple consecutive inhalation cycles and without being awakened.

[0114] The next breath is initiated by the patient's respiratory center. The airway is blocked but not closed, as evidenced by the airflow 69. The airflow is limited by airway resistance and peaks at approximately 10 mL / min to 30 mL / min (e.g., the range where airway flow limitation may occur); however, subsequent stimulated breaths can then rise to a peak flow of approximately 30 mL / min to 60 mL / min, which can (e.g., completely) resolve the flow limitation without awakening the patient (e.g., below the awakening threshold). It should be understood that there is a threshold for the stimulation that can be delivered. For example, if the stimulation is too high, the patient may be awakened (e.g., due to hitting overly stretched receptors, which can trigger the pain center) and / or wake up.

[0115] The inflection point 73 coincides with the start of the second stimulus burst 61 after the delay time 71. The acceleration of the airflow and the abdominal movement indicate significant diaphragmatic contraction (effort). Inhalation is terminated by the respiratory center at point 74, where the airflow reverses and becomes exhalation at a moderate rate. The continuation of the PNS burst into the exhalation phase reduces the expiratory airflow rate to a moderate level until the inflection point 75, where the expiratory airflow rate accelerates and returns to a normal level 75 similar to the normal level without PNS. The inflection point 75 coincides with the termination of the stimulus burst 61 and the cessation of the effort 65. In some examples, the respiratory effort can be related to, based on, or derived from the tidal volume from the patient. In terms of ml volume, approximately 50 ml to 150 mL can be considered mild flow limitation, greater than approximately 150 mL can be considered an unrestricted normal patient airway, and less than about 50 mL is severe flow limitation (e.g., apnea).

[0116] Figure 8 Description: Treatment Selection Algorithm

[0117] Figure 8 An example algorithm for treatment options is shown. Based on a standard home PSG test, a patient can be identified as having moderate or severe OSA. For example, a patient can have: an apnea hypopnea index (AHI) > 20 events per hour. The patient is implanted with an IPG (e.g., as described herein, e.g., in combination with Figure 5, Figure 13 or Figure 14 ) and a phrenic nerve stimulation electrode. Confirm that the IPG is operable (e.g., confirm that the IPG can stimulate the phrenic nerve to cause diaphragmatic contraction within a pressure parameter range), and the patient is discharged within a period of time required for healing (e.g., one month). In some examples, the patient is taken to the office of a sleep medicine specialist for treatment activation. In some examples, this step can also be performed in a home environment using a remote sleep monitoring device and a telemedicine session.

[0118] When the patient is sleeping (80), analyze their respiratory pattern and sleep pattern 81 using standard or custom instrumentation for sleep studies. Use the IPG that is controlled or set to an initial parameter set (an example of the stimulation parameters discussed herein) to initiate stimulation of the phrenic nerve 82. In some examples, the values of the initial parameter set can include setting the rate (e.g., the pulse burst rate) to a number close to the patient's natural breathing or a different reasonable rate that is comfortable for the patient. The duty cycle (pulse burst duration) parameter can be set to an inspiration:expiration ratio (or (I:E) ratio) of (1:3), (1:1), (1:2), or another suitable initial number, and the stimulation current is gradually increased until diaphragmatic contraction corresponding to the stimulation burst is detected (e.g., clearly).

[0119] At 83, the process determines whether the patient's normal breathing has resumed based on the stimulation of the phrenic nerve from 82. In other words, the process determines whether the patient's OSA has resolved due to the stimulation of the phrenic nerve. For example, the process can determine that the patient's AHI has decreased by at least 50%. If normal breathing has resumed, the patient can be scheduled to continue treatment 85 at home using the selected parameter set (e.g., based on the initial parameter set or a modified parameter set according to 84 discussed below), and the patient is instructed to initiate treatment each night.

[0120] However, if the patient's normal breathing has not resumed, the parameters can be changed at 84. The change in the value of the parameter can include changing one or more of the multiple parameters used to control the stimulation of the phrenic nerve. For example, the stimulation parameters can be changed and titrated upward towards greater stimulation power, energy, or intensity until the OSA is resolved.

[0121] As an illustrative example, the stimulation current (e.g., which can represent the energy delivered to the nerve or related to the energy delivered to the nerve) can be increased. Such an increased current generally produces stronger diaphragmatic contractions until the muscle fibers fuse and the muscle cannot contract further.

[0122] Another example of adjusting the value of a stimulation parameter can include changing the rate at which the pulse amplitude increases in a burst (commonly referred to as the ramp time). The ramp time can be shortened to produce a more forceful sudden diaphragmatic contraction.

[0123] Another example can include controlling the duty cycle parameter and / or the stimulation rate (e.g., increasing in the understanding that some air trapping may occur during stimulation if the stimulation bursts are more frequent or last longer). The duty cycle pulse train duration / breathing duration can be or correspond to the I:E ratio discussed herein. However, in some examples, the duty cycle can be expressed as a percentage of the breath (e.g., total breath). Thus, for example, 30% can correspond to or mean that inspiration is 0.3 of the total breath. Some patients may benefit from an increase in lung volume during sleep to prevent lung collapse and loss of the caudal traction exerted by lung inflation on the airways. All stimulation parameters are titrated based on the patient's tolerance. It is expected that the intensity of the stimulation can be increased after the patient has adapted to the treatment.

[0124] Titration and Auto-Titration of Therapy

[0125] The patient's tolerance to phrenic nerve stimulation is not a constant but a function of environmental factors and neural plasticity. Changes that occur over time are commonly referred to as the nervous system's adaptation to the stimulation. In the case of phrenic nerve stimulation therapy, it is mainly applied during sleep. During sleep, the brain can adapt to rhythmic sensations, such as intentional or unintentional proprioceptive input, muscle movement, or even tingling. For example, after a person has adapted to a fast-moving train and a rocking boat, they can sleep well on them.

[0126] After implanting the electrodes, some time needs to be allowed for the surgical site to heal and the inflammation to subside. For example, this can be a 30-day period. After that, the treatment can be activated, and a period of adaptation and adjustment can begin. This process can be carried out entirely by a caregiver, by the patient, or at least partially automated. Some automation can be beneficial when the treatment is carried out during sleep at home.

[0127] Activation of the treatment can include ramping up the stimulation energy until the first induced diaphragmatic contraction (motor neuron capture) is detected. Capture is commonly described as a muscle "twitch". The energy can be further increased until all the nerve fibers in the nerve bundle and the muscle fibers in the muscle are fully involved, after which a further increase in the stimulation energy no longer produces more muscle contractions (fused or tetanic muscle).

[0128] Although used to measure the intensity of diaphragmatic contraction (also referred to as "breathing effort", e.g., as Figure 7The gold standard, as shown in [reference], is esophageal balloon pressure, but other methods such as respiratory belts, bioimpedance, magnetometers, accelerometers, and inspiratory pressure measurements can be used as the dependent variables for creating a treatment titration curve. These alternative variables are intended to characterize or approximate the respiratory effort generated by muscle contractions. In the context of this patent, bioimpedance (e.g., electrical tissue impedance) is the response of a living organism to an externally applied electric current. Bioimpedance is a method for estimating body composition (specifically the air contained in the lungs and airways), where a weak electric current flows through the body and the voltage is measured to calculate the impedance (e.g., resistance) of the body tissue that is part of the closed circuit and in the current return path. Since breathing changes the amount of air in the lungs, impedance can be used to track breathing.

[0129] The general need for upward titration of any neuromodulation therapy is well recognized. For example, U.S. Patent 11,529,514 describes upward titration for hypoglossal nerve (HGN) stimulation therapy for OSA. In the case of HGN, the genioglossus muscle is activated by stimulation, and in some cases, the airway is obstructed by the tongue and soft palate. The so-called palatopharyngeal space can be seen at a valve or trapdoor that opens or closes the pharyngeal airway in response to tongue protrusion. The phrenic nerve (PN) is different from the HGN in that it does not innervate the pharyngeal muscles but activates the muscles of the respiratory pump. In the context of the proposed therapy, the therapy of phrenic nerve stimulation, activation, and titration is complex compared to more traditional HGN stimulation because it is necessary to evoke the negative pressure reflex and airway traction while maintaining the blood gas and lung volume that are crucial for the overall function of the human body. This is further complicated by the desire to achieve such a response while keeping the patient comfortable and asleep.

[0130] Figure 9 description

[0131] Figure 9 An energy titration curve 100 is shown, which can be created first during treatment activation and adjusted at any time after treatment activation, according to a schedule, or as needed. The curve can be generated with automated assays and stored (e.g., as a table or equation) in the non-transitory memory of the IPG. The curve can be uploaded to cloud computer storage, become part of the patient's treatment history, and be provided to the doctor and patient in graphical or simplified numerical form to evaluate, monitor, and guide treatment.

[0132] Curve 100 can be plotted as the relationship between stimulus energy 102 (horizontal axis) and the intensity of diaphragmatic contraction 101 (vertical axis). In some example embodiments, the intensity of diaphragmatic contraction can be represented as an exponent that is based on, for example and as described below, integrated diaphragmatic EMG, ultrasound imaging, esophageal pressure, accelerometer, exhaled airflow, lung volume, thoracic bioimpedance, and / or airway pressure. In this context, stimulus energy is different from the traditional electrical engineering definition. Nerve conduction is not strictly electrical conduction in the traditional sense. The nerve is stimulated to generate or "fire" a series of action potentials. Different fibers in the nerve bundle have different activation energy thresholds. More generally, the more fibers that are fired in the phrenic nerve and the faster they fire action potentials, the stronger the diaphragmatic contraction and the respiratory effort will be. This effort becomes a negative pressure in the large airways, and if the airway is open, the pressure gradient generates airflow. Over time, the airflow becomes "breathing" or volume exchange, which is also called tidal volume for a single breath and minute ventilation for the volume inhaled and exhaled in one minute.

[0133] In a popular constant current system, with the voltage and pulse duration held constant, the stimulus energy is typically represented as the stimulus current in mA. So-called constant voltage systems can also be used in conjunction with the nerve stimulation techniques discussed herein and can be interchangeable with the necessary technical adjustments. In terms of nerve excitation, the response current and pulse duration (e.g., the length of an individual pulse within a given pulse train) maintain an inverse relationship. Another way to adjust the stimulus energy is to change the voltage difference between the cathode and anode applied by a constant voltage system, where the nerve interface impedance is considered to be relatively stable.

[0134] In the case of the phrenic nerve, the stimulus pulse train frequency typically remains between 20 Hz and 40 Hz, and the individual pulse duration is between 50 microseconds and 250 microseconds. The intensity of diaphragmatic contraction cannot be easily measured, but can be approximated and / or exponentiated (as developed later herein) based on integrated diaphragmatic EMG, ultrasound imaging, esophageal pressure, accelerometer, exhaled airflow, lung volume, thoracic bioimpedance, and / or airway pressure.

[0135] Typically, the IPG is set to deliver energy within an operating range that is restricted between a lowest (or low) capture level 103 and a highest (or high) muscle tetanic contraction level 106, at which all muscle fibers in the diaphragm are fused and the muscle can no longer contract. The therapeutic range 107 is defined as the range of energy delivery within which a clinically significant improvement in airway resistance can be expected. The upper limit level of the therapeutic range 107 is always higher than the capture limit 103 and lower than the tetanic contraction level 106.

[0136] There is a safety margin between level 105 and level 106, which is determined by patient comfort, diaphragmatic fatigue, or gas exchange that can be impeded by lung overinflation. This safety margin is reflected in two tolerance levels 105 (wake-up limit) and 109 (sensory tolerance limit). Sleep, Arousals from Sleep, and Wakefulness

[0137] Sleep disruptions and disorders are associated with cardiovascular, metabolic, and psychiatric disorders. Sleep dysfunction is typically evaluated in a sleep clinic by analyzing nocturnal polysomnography (PSG). PSG recordings involve measuring electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort, and oxygen saturation during nocturnal sleep. The PSG is performed overnight and yields a score for sleep-disordered breathing (SDB) events. These are the number of apneas or hypopneas per hour of sleep (referred to as the apnea-hypopnea index (AHI)), the number of periodic leg movement (PLM) events per hour of sleep (with or without associated arousals), and the sleep stages. Sleep stages are wake (W), non-REM sleep (stage N1, stage N2, or stage N3), or REM sleep, reported as a percentage of total sleep time. The AHI can be reported according to the "recommended" of the American Academy of Sleep Medicine (AASM), which includes only hypopneas associated with a 4% oxygen saturation drop; or the AASM's "alternative" AHI, which counts apneas associated with a 3% oxygen saturation drop and / or arousals. A typical sleep study also reports sleep latency (the latency from sleep onset to the first REM sleep period) and sleep efficiency (SE) (the percentage of time asleep in bed). A minor variant of sleep efficiency is wake after sleep onset (WASO), which, unlike SE, only considers wakefulness after sleep onset has occurred. In the context of sleep stage scoring, sleep stages are divided into consecutive 30-second epochs, this arbitrary approach being attributable to the historical use of paper printing in sleep studies.

[0138] In sleep medicine, an "arousal" does not necessarily mean waking up, but may mean transitioning to a lighter sleep stage. In the context of the present application, a clinically significant arousal is best defined according to "The AASM Manual for the Scoring of Sleep and Associated Events" current at the time of writing of the present application. In some example embodiments, waking up is defined as any transition from any sleep stage to wakefulness for more than 15 seconds. As of today, the gold standard for detecting arousals is by visual inspection of PSG recordings. Accepted practice and current standards distinguish microarousals (3 seconds to 15 seconds) and awakenings (>15 seconds), this distinction also being arguably arbitrary.

[0139] Micro-awakenings can occur naturally as part of normal sleep-wake physiology due to external stimuli such as PN or HGN stimulation or internal sleep disorder events such as SDB (e.g., sleep apnea). Typically, micro-awakenings are not considered events of clinical significance unless they result in sleep stage disruption (e.g., if the patient ultimately feels unrested, sleepy during the day, or generally indicates poor night-time sleep).

[0140] In a simplified, less formal way, an arousal can be defined as a sleep disruption that may not wake the patient but is of sufficient clinical significance and occurs frequently enough to prevent deep, healthy sleep. OSA events are typically associated with arousals that occur when apnea is terminated by hypercapnia or hypoxia. These arousals temporarily restore breathing and generally do not wake the patient but prevent the patient from entering deeper sleep stages and REM sleep. If phrenic nerve stimulation causes frequent arousals consistent with the stimulation bursts (e.g., this may be significant), the stimulation energy may be too high.

[0141] Referring Figure 9 , the sensory tolerance limit 109 of the patient can be determined as being based on or at the level at which a conscious patient feels pain or discomfort. The arousal tolerance limit 105 can be determined as being based on or at the level at which a patient in sleep exhibits frequent clinically significant arousals that can be recorded during a home PSG or sleep laboratory sleep study. The patient tolerance limits 105 and 109 are generally not constant but can change due to different external and internal factors (including the patient's adaptation to treatment).

[0142] For an individual patient, the arousal limit 105 can be lower or higher than the discomfort limit 109, and generally the lower limit determines the maximum acceptable energy for that particular patient during a specific time period or for a set of health conditions. For example, if the patient gains or loses weight, undergoes surgery, etc., the patient's limits may change permanently. If the patient has a cold, flu, etc., the patient's limits (e.g., including the values of other stimulation parameters) may only fluctuate (e.g., change temporarily). Under these conditions, the stimulation settings can be considered an electronic prescription.

[0143] One or more (e.g., several) settings and / or tolerance levels obtained from any (or all) of the different tests discussed herein can be stored in the non-transitory memory of the IPG memory. It is generally expected that the discomfort tolerance level will increase with adaptation and that higher tolerance results in a more effective treatment.

[0144] The goal of PNS treatment for OSA is to maximize effectiveness (e.g., minimize AHI) within the range of effectiveness and tolerance of the patient. In this context, it can be expected that the treatment effect can only be manifested at an energy level above the capture level (also known as the "capture threshold") 103. Above this, there can be other threshold levels, which can include: 1) the reflex activation level 108 (e.g., the negative pressure generated by the stimulation has a measurable / detectable effect on upper airway airflow limitation); and 2) the breathing normalization level 104 (e.g., apnea and hypopnea are no longer detectable or no longer have clinical significance).

[0145] For example, Figure 6 The clinical data shown illustrates how the energy level of phrenic nerve stimulation in a patient with OSA during sleep is gradually increased from level 55 to level 56, such that the airway obstruction indicated by the airflow gradually and more completely subsides.

[0146] Treatment titration can be implemented and / or adjusted in a doctor's office during a polysomnogram (PSG) study (sometimes also called a sleep study). However, this can lead to frequent patient visits, repeated sleep examinations, and may result in suboptimal treatment due to patient resistance and refusal to accept (or simply failure to show up for testing) increased energy levels. Therefore, there is a strong need to automate the process of treatment initiation, delivery, and / or titration based on objective input measurements to optimize treatment effectiveness, reduce physician involvement, and reduce the number of clinic visits for IPG programming. It has been recognized that a patient's response to treatment can change from night to night, during the same night, and with changes in sleep position. Therefore, these measurements may need to be repeated frequently.

[0147] In some examples, the IPG can have some built-in sensing capabilities, such as an accelerometer, blood pressure pulse, oximetry, ECG sensing, or bioimpedance. However, it should be understood that the accuracy and / or responsiveness of such systems may not be comparable to home and office PSG systems.

[0148] An illustrative example of a device for sleep monitoring is Home Sleep Apnea Testing (HSAT) devices that use peripheral arterial signals for OSA and CSA diagnosis. They measure up to 7 channels via three contact points, including tonometry, heart rate measurement, blood oxygen measurement, body movement recording, body position, snoring sound, and chest movement. WatchPAT is commercially available from Zoll-Itamar. The algorithms described herein can be implemented using a home monitoring device (similar to WatchPAT), but modified to communicate directly or using a suitable wireless interface with an IPG. The communication device can include an antenna that is attached to or kept close to the patient during the night. Alternatively, a dedicated custom wearable device or system can be developed to monitor the patient's sleep at home and communicate with the sleep doctor, patient, and IPG, which is further developed in this application.

[0149] In some example embodiments, the techniques described herein can be implemented on a mobile device (e.g., a smartwatch or smartphone that can be configured and / or programmed to communicate with an IPG as described herein).

[0150] Other example systems for sleep monitoring can also be utilized. Examples of such systems include inertial systems configured to monitor or measure the acceleration, position, and / or angle of the chest wall (or other areas of the patient's body). When data from such monitoring is appropriately filtered and integrated, reliable signals can be generated and then utilized in the IPG designs described herein. Although this technique may tend to have a weaker amplitude during quiet resting breathing, hyperventilation that engages the accessory muscles in the chest and neck can be more easily detected. Thus, periodic breathing can be detected.

[0151] When using the terms "sleep" and "wakefulness", they can be determined using the standard PSG methods described elsewhere in this patent, the methods described in the current version of the AASM manual for sleep scoring, and other widely accepted standards. To determine sleep quality and stages, FDA-approved PSG systems typically rely on multi-electrode EEG (electroencephalogram), EOG (electrooculogram), EMG (electromyogram), ECG (electrocardiogram), pulse oximetry, and other complex measurements. These systems can be used in sleep clinics and at home, but are generally not suitable for frequent use. They have strict criteria for the neurological definition of sleep stages, awakenings, AHI, ODI parameters of OSA, and periodic breathing.

[0152] It should be understood that simplified methods for detecting a patient's sleep and wakefulness and OSA versus normal breathing states are also relevant and may be more practical in a home environment at night, even if these methods are not as accurate as PSG. For example, if a patient is lying supine and not moving, their heart rate (HR) is slow, constant, and stable. When a patient's breathing rate (BR) is slow, constant, and stable, the patient is likely in a sleep state. In this context, "slow" refers to a set of individual values for the patient, but generally, it can be expected that the HR is between 50 and 70 beats per minute, and the BR is between 6 and 20 breaths per minute. In patients experiencing OSA episodes, their breathing and heart rate may become highly variable over a wider range. Within a 1-minute or 5-minute time window, the heart rate can vary between 40 and 120 beats per minute, and the breathing can change from barely detectable effort to hyperventilation and shortness of breath at 20 to 30 breaths per minute. Therefore, changes in HR and BR can be used as criteria for treatment success. The periodicity (regularity) of these changes is an indication of the OSA pattern. It can be expected that the cycle of heart rate and respiratory variability repeats every 30 seconds to 120 seconds. This cycle or periodic respiratory rate is another individual characteristic of the patient stored in the system memory. The coherence between periodic signals such as tidal volume, BR, HR, pulse pressure, and pulse oximetry can be another indication of periodic breathing.

[0153] Phases and Myomechanics of Periodic Breathing

[0154] Periodic breathing (PB) is generally defined as a breathing pattern characterized by crescendo / decrescendo changes in tidal volume and is usually due to systemic mechanisms that destabilize breathing (e.g., heart failure). PB is associated with CSA but can also be present in OSA. During the hyperventilation phase of the cycle, there is a decrease in CO2. If the CO2 tension drops below the apnea threshold, apnea occurs. During the apnea phase of the cycle, CO2 increases and the O2 tension decreases, driving the subsequent hyperventilation. For the purposes of this patent, PB simply means that the patient's breathing pattern during sleep consists of discernible periods of apnea or hypopnea, followed by a period of hyperventilation that persists unless treated or interrupted by arousal. According to existing AASM guidelines, a patient may have a clinical diagnosis of mild or severe OSA, CSA, or mixed apnea. OSA is by far the most common diagnosis. In such cases, first-line treatments such as weight loss, medications, and CPAP may be ineffective for the patient.

[0155] Hyperventilation is sometimes referred to as overbreathing. Hyperventilation or overbreathing means breathing more than the body needs. In the case of OSA, episodes of hyperventilation occur after an extended apnea period and are usually overcompensatory, removing too much CO2 from the blood, resulting in a temporary hyporespiratory drive that affects both the respiratory pump and airway tone. This phenomenon is part of the pathogenesis of periodic breathing and is present in both the OSA and CSA phenotypes. Hyperventilation occurs at the end of airway obstruction after the airway is opened by chemically reflex-activated airway opening. In contrast to resting breathing, hyperventilation causes the muscles of the upper chest to move forcefully. This phenomenon can be used to detect OSA using an accelerometer built into the IPG design, which is implanted in the upper chest above the pectoral muscles or elsewhere under the chest skin and above the thoracic cavity.

[0156] Functionally, there are three groups of respiratory muscles: the diaphragm, the thoracic muscles, and the abdominal muscles. Each group acts on the chest wall and its compartments, such as the upper thoracic cavity that adheres to the lungs, the lower thoracic cavity that adheres to the diaphragm, and the abdomen. The contraction of the diaphragm expands the abdomen and the lower part of the thoracic cavity (the abdominothoracic cavity). During quiet sleep, the contraction of the diaphragm is usually necessary to generate tidal volume and support metabolic requirements.

[0157] The thoracic muscles (including the intercostal muscles, parasternal muscles, scalenes, and other neck muscles) act mostly on the upper part of the thoracic cavity (the pulmonary thoracic cavity) and have both an inspiratory and an expiratory function. The two sternocleidomastoid muscles originate from the mastoid process of the temporal bone and the superior nuchal line of the occipital bone. These muscles can lift the anterior ribs. Therefore, they are used as accessory muscles in pulmonary ventilation.

[0158] The activity of the neck inspiratory muscles (NIM), especially the activity of the scalenes, increases during hyperventilation and can be monitored to monitor abnormal breathing. In some example embodiments, one or more breaths (e.g., several breaths such as 2, 3, or 4 breaths) can be interrupted periodically to obtain (e.g., a clean) EMG record. An accelerometer can be integrated into the electrode system to directly monitor muscle contraction. A separate electrode subsystem can be added to the wire that is electrically isolated from the phrenic nerve stimulation electrode to evaluate the EMG.

[0159] The abdominal muscles act on the abdomen and the abdominothoracic cavity and are expiratory. During hyperventilation movements, highly coordinated recruitment of two or three muscle groups is required to support the increased ventilation effort. During resting breathing, this is accomplished by the coordinated activity of the diaphragm.

[0160] Feedback, Initiation, and Ramp Therapy

[0161] The algorithms (e.g., computer processes) described herein are illustrated and implemented in software that can be stored in the non-transitory memory of the IPG 41. In some embodiments, the algorithms can be distributed among several internal and external devices connected by a wired or wireless communication link. As an example, some steps or processes can be executed on an external device (e.g., a smart phone, a smart watch, etc.) that communicates with the IPG (e.g., wirelessly). Figure 10A and Figure 10B Two embodiments are shown. The primary function of the IPG is to deliver stimulation pulses to the phrenic nerve of a patient. At least partial control of how the stimulation pulses are delivered is performed by computer program code that can be stored in a memory. The control can be based on internal timing derived from or obtained from a clock (e.g., a real-time clock). Sensing and logic functions can be integrated into the IPG or reside external to the patient's body (e.g., on another computing device such as a smart phone).

[0162] Figure 10A and Figure 10B description

[0163] Figure 10A shown for detecting and / or determining a capture threshold (e.g., as Figure 9The process shown at 103), which can be embodied as a computer-implemented algorithm. At a certain time (e.g., when it is expected that the patient goes to bed, the patient is detected as being in bed, or the patient signals that the patient is starting a sleep cycle), the process starts at 150 and monitors the patient. At 152, the patient is monitored using, for example, actigraphy and / or an accelerometer to confirm that the patient is supine and at rest. The resting state can include maintaining a supine or reclined position for a period of time and other parameters, such as low motor activity, a stable low heart rate, or respiratory rate. If the patient is not at rest, the process loops back to 150 and performs further analysis. If the patient is at rest, the stimulation energy from the IPG is increased at 154. In some example embodiments, the increase can be controlled via a microprocessor that is in a low-power, sleep state, or a monitoring-only state. In some examples, the full range of the current from the IPG that can be supplied during treatment can be between 0 mA and 5.0 mA. The stimulation energy can be increased in graded steps, for example, in the range of 0.5 mA to 2.5 mA, in steps of 0.1 mA to 0.25 mA (e.g., at 154). Based on (or in response to or in combination with) the increase in stimulation energy, at 156, the process checks whether the capture threshold has been reached by detecting a first distinct rhythmic twitch of the diaphragm. If the capture threshold is detected, the values of various parameters for treatment (and any other data for the tests performed) are stored at 158, and the test is terminated. However, if the capture threshold has not been detected, the process loops back to 154 and increases the stimulation energy. The process continues until the capture threshold is detected or a threshold amount of stimulation energy is applied. In some examples, for instance, a pulse sequence of stimulation pulses that are 0.5 to 1.5 seconds long can be applied every 1 second to 3 seconds to produce a distinct, easily detectable periodic contraction pattern.

[0164] Figure 10B A process for detecting a treatment threshold is shown, which can be embodied as a computer-implemented algorithm, and the treatment threshold can include any or all of the thresholds used in conjunction with treatment range 107 and / or thresholds 206 and 207. For this process, at 170, the patient is monitored using a PSG or other monitoring techniques (which can be internal to the IPG, external to the patient / IPG, or a combination) to confirm that the patient is supine, at rest, and possibly sleeping. As part of this monitoring, at 172, the process determines whether OSA has been detected. Periodic airway obstruction is typically associated with the sleep state. If OSA is not detected, the process continues to monitor the patient. However, if OSA is detected, the stimulation energy can be increased in graded steps. In some examples, the initial or first stimulation energy setting for the process performed in Figure 10B can be according to Figure 10AThe capture threshold determined / stored by the process executed in []. Using the capture threshold, the process can gradually increase the stimulation energy at 174 (up to a defined maximum allowable threshold, such as 5.0 mA) to determine the treatment range between a first threshold (e.g., the lowest energy level that changes the breathing pattern in a system periodic manner) and a second threshold where breathing is stable (apneas are no longer detected).

[0165] The process can also include determining at 176 whether the patient has woken up. If the patient has woken up, data associated with the treatment at that time can be stored at 178 and further instructions can be provided to reduce the applied stimulation energy. In some examples, the wake-up threshold of the patient can be stored in memory for future use and updated periodically. A pulse sequence of stimulation pulses with a duty cycle of 30% to 70% can be applied at (or as close as possible to) the natural breathing rate of the patient, which can be previously detected when the patient is at rest but not yet showing an OSA pattern. It should be understood that the natural breathing rate has typical normal variability for a living organism.

[0166] The implementation of the treatment optimization algorithm (e.g., which can be implemented using a microprocessor, etc.) can be a gradually periodic stepwise increase in the delivered energy to gradually adapt to the patient's sleep needs and utilize brain plasticity to increase patient tolerance. The gradually periodic stepwise increase in the delivered energy can be referred to as an "energy ramp". The energy ramp can be implemented in small increments per breath, per quarter hour, per hour, or per night. Thus, for example, the process executed at 174 can be limited to adjusting the stimulation energy approximately every 15 minutes in some cases and every breath or every other breath in other cases.

[0167] Figure 11A and Figure 11B description

[0168] In combination with such an energy ramp, Figure 11A shows an example of an energy ramp for the purposes of treatment titration and optimization during a single night's treatment during and after treatment activation. The operating range of an individual patient is determined during a monitored activation sleep night in a sleep laboratory or at home during a visit to the doctor's office for activation (e.g., using the process shown in []). For example, this can be a PSG or home-monitored night where the doctor uses telemetry to monitor the patient's sleep quality in real time. Figure 10A as shown in [].

[0169] Referring more specifically to Figure 11A , a graph 200 is shown that includes a time length in hours on the x-axis. This corresponds to different time points during the patient's sleep. On the y-axis is the stimulation energy applied to the patient via the IPG. Initially, a test ramp 201 is applied and used as a ranging ramp. Figure 11AThe ramp 201 shown is performed after the patient is at rest in bed but before they fall asleep or exhibit OSA. This enables determination of the resting capture threshold 205 (e.g., as described in connection with Figure 10A ). At the same time, other parameters (such as the resting respiratory rate) can be detected and stored for later use (e.g., stored in the non-transitory memory of the device). The device memory can be included as part of the physical IPG microprocessor, coupled to the IPG microprocessor (e.g., on the same silicon die), or in the non-transitory memory of an external device that communicates wirelessly with the IPG. Data related to the treatment of an individual patient, such as historical and current parameters, settings, preferences, and decisions, can also be stored. As used herein, data related to the treatment of an individual patient can be referred to as a patient treatment plan.

[0170] When the patient falls asleep and exhibits OSA, their individual OSA pattern (e.g., the duration / frequency of apnea and the post-obstructive hyperventilation morphology) can be determined and stored in the memory for future automated treatment use. These measurements can be made for patients sleeping in the supine, lateral, prone, reclined, and other sleeping postures of the body and neck. The position detection system can be calibrated simultaneously to meet the needs of future detection.

[0171] For example, according to the patient's treatment plan stored in the device memory, after the ranging ramp is completed, the stimulation can be turned off, or continued at some low energy level above the capture threshold to help the patient get used to the rhythmic sensation.

[0172] After confirming that the patient is likely sleeping, the stimulation can be increased to a level within the treatment energy range known from the previous sleep history. The energy level can be specific to the patient's posture, as many patients can be expected to sleep in the lateral, supine, or reclined positions. The patient's posture can be determined using inertial sensors (e.g., accelerometers and gyroscopes) integrated into the IPG electronics or by an external monitoring device (e.g., a wearable device or a radar-based motion monitoring device). The monitoring device can be an mm-wave radar patient monitoring device, a motion detection camera device, etc. Millimeter-wave (mm-wave) radar emits electromagnetic waves, and any object in the path will reflect the signal back. By capturing and processing the reflected signal, the radar system can determine the distance, speed, and angle of the object. The mm-wave radar provides millimeter-level accuracy in object distance detection and its potential to ignore clothing and bedding, making it a suitable non-contact technology for sensing human bio-signals during sleep.

[0173] The ramp 202 is executed after the patient falls asleep and exhibits OSA or other forms of periodic breathing. The periodic breathing can be detected by sensors and programming logic included in the IPG or transmitted to the IPG from an external device. The ramp is stopped after reaching a first treatment threshold 206, where the periodic breathing is sufficiently reduced or eliminated. For example, for an individual patient, as part of their treatment plan, the calculated AHI or the rate of O2 saturation decrease (by more than 3%) can be reduced from about 50 to 120 per hour to about 0 to 15 per hour. In the absence of treatment, reducing the AHI from baseline by a given percentage (e.g., by more than 50%, and in some examples, by more than 90%, up to 100%) can also be a goal for an individual patient. In some exemplary embodiments, the percentage of sleep time with an O2 saturation above 90% and / or other relevant criteria can be used alone or in combination with other factors (e.g., AHI) to improve the treatment of the patient. As discussed previously, alternatives to PSG can be used to determine OSA severity and sleep quality.

[0174] During the night, at 203, the patient may wake up, sit up, and stand up and move around. In this case, the stimulation pulses can be stopped (e.g., at or within an explicit input from the patient) or reduced to a comfortable level, depending on the patient's treatment plan. After the patient returns to bed and falls asleep again, a second treatment ramp 204 can be executed. In some examples, the re-execution of the ramp (or the execution of the second ramp 204) can occur automatically and / or without any explicit input from the patient. It should be understood that the automatic control of the stimulation pulses (including the re-initialization of the stimulation pulses) and the control of the ramp can be advantageous because an individual will occasionally get out of bed during the night only to fall asleep again. Thus, the automatic control described herein can alleviate the need for the patient to explicitly turn the stimulation on / off. More precisely, as discussed elsewhere herein, the stimulation can be automatically controlled based on various factors including the individual's posture, their determined sleep stage, etc.

[0175] Figure 11B is a graph 1100 showing different parameters that can be set according to certain example embodiments. In some examples, the execution of the stimulation (at the start or in the middle of an individual's night-time sleep) can be based on a delay time parameter 1102 (e.g., treatment start delay). The delay time parameter can be determined manually, automatically, or dynamically. The delay time parameter can be set to be between about 0 minutes and 60 minutes, and in some examples, where typical values are between about 30 minutes and 40 minutes. In some exemplary embodiments, a treatment ramp time parameter 1104 (e.g., Figure 11B(the starting ramp shown in ), which can be determined manually, automatically, or otherwise dynamically. The value of the treatment ramp time can be, for example, between 0 minutes and 60 minutes, and in some examples can typically be about 30 minutes.

[0176] For example, the midnight interruption can use a value of the latency time parameter that is lower than when the individual initially fell asleep at night. In some examples, the time to execute or resume stimulation can be a function of the value of the latency time parameter in combination with other measured values (e.g., any or all of the measured values from the individual). The combination of these values can be used to calculate when to execute (and / or stop) the stimulation.

[0177] The ramp can be executed until a treatment threshold that meets a preset criterion is found or a pre-planned maximum tolerance limit is reached. The second treatment threshold 207 can be higher or lower than the first treatment threshold 206. For example, the patient may sleep on their side during the first ramp and on their back during the second ramp, or otherwise change some posture or physiological parameter that affects airway collapsibility. Additional parameters can be set similarly in combination with the treatment window and the time of ramp closure.

[0178] Figure 12 Description: An interconnected distributed system for monitoring a patient during rest and sleep

[0179] Figure 12Shows a patient in bed during sleep therapy. The patient may be sleeping or resting. The IPG 41 is implanted in the patient's chest and connected to the electrode system 42 via a stimulation lead 47. The electrode system 42 is in electrical contact with the phrenic nerve 44. The electrode system 42 can be an electrode belt or paddle electrodes. In some examples, the electrode system can include sensors, such as EMG, inertial, microphone, and / or other transducer sensors. In certain examples, the sensors can be integrated with the electrode system (e.g., in the neck). The patient is equipped with a wearable monitoring system 210 that wirelessly communicates with the IPG 41. The wearable monitoring system 210 can include a Medical Implant Communication System (MICS) or be configured to implement MICS in order to perform wireless communication with the IPG 41 (e.g., up to 2 meters from the IPG). The wearable monitoring system 210 can also communicate with a bedside monitor device 211, which can also be a MICS communication device. The monitor device 211 can include a transceiver that allows for data communication (e.g., Internet communication) with a cloud computing system 212. The data transmitted to the computing system 212 can be stored in a non-transitory storage device to allow for sharing of the data with a doctor. The doctor can provide data to modify the treatment plan, which can be transmitted back to the IPG 41, the bedside monitor, and / or the wearable monitoring system 210 for storage in any or all of their non-transitory storage devices. The updated treatment plan can then be executed by the electronics of the IPG (e.g., in real time). In some examples, the bedside monitor 211 device can be placed in a pocket of the patient's clothing or under the mattress or under the pillow.

[0180] The implanted portion of the system can include a sensing lead 213 connected to the IPG and running under the skin of the patient's chest to enable improved sensing of muscle EMG, thoracic impedance, or acceleration from respiration.

[0181] Different communication technologies can be used to facilitate communication between the IPG 41 and other devices that communicate with the IPG. In some examples, an inductive link can be used. Inductive links have a long history of providing reliable communication with pacemakers, ICDs, IPGs, etc. However, inductive communication can be affected by range (e.g., the maximum separation between two coils should not exceed 6 cm, with one coil inside the body and the other outside the body) and data rate limitations (e.g., approximately 100 kbps). For example, such limitations can be a problem when the patient is sleeping, as the link may need to be realigned to account for the patient's movement while sleeping. Thus, while inductive links may still be suitable for certain types of devices and use cases, other (e.g., future) communication technologies that allow for faster communication over longer distances can be used.

[0182] Other communication technologies that can be used in some examples to implement communication with the IPG 41 include Medical Implant Communication Service (MICS) operating in the 402 MHz to 405 MHz frequency band. MICS allows for faster, lower-power, non-voice transmissions to and from implantable medical devices (e.g., pacemakers and defibrillators). This frequency band has good conductivity in the human body, higher data rates, and a communication range of up to 2 m.

[0183] Another communication technology that can be used in some examples to implement communication with the IPG 41 includes Medical Device Radio Service (MedRadio) operating in the range of 401 MHz to 406 MHz. The creation of the MedRadio service combines the existing MICS spectrum at 402 MHz to 405 MHz and adds additional spectrum at 401 MHz to 402 MHz and 405 MHz to 406 MHz, for a total of five megahertz of spectrum for implantable devices and devices worn on the actual body.

[0184] It should be understood that as other communication technologies are developed, such technologies can be adopted in combination with the examples described herein.

[0185] Combined Figure 12 Another aspect of the described system is the measurement of the patient's respiration / breathing activity. Breathing activity causes visible and measurable movement of the chest wall. In some example embodiments, radar technology can be used to make non-contact and non-invasive measurements of respiration. When using such technology, the radar device is aimed at the patient's chest, and the resulting movement is recorded and processed to obtain the rate of respiration. In some cases, the use of radar technology can eliminate the need for both implantable and wearable sensing of respiration. In some examples, a bedside radar can be integrated into or connected to the bedside monitor 211 and use, for example, a MICS communication link to send respiration cycle information to the IPG in real time. The IPG can then apply stimulation energy based on the timing synchronization signal from the bedside monitor 211.

[0186] It should be understood that non-contact technologies for body movement monitoring are rapidly evolving and becoming more advanced and available. Examples include U.S. Patent 8,454,528. In some examples, detection of abnormal movement of the chest wall (where lung volume may decrease during inspiration) can be used as a surrogate variable for inspiratory airway resistance and negative pressure in the airways distal to the obstruction. This variable can then be used in combination with the automatic adjustment of the stimulation energy delivered to the patient via the IPG. Heart rate can also be detected by non-contact sensors. For example, impulse radio ultra-wideband (IR-UWB) radar can be used to non-contact identify cardiac movement. Such sensors can be used to measure heart rate (HR) and / or rhythm using an IR-UWB radar sensor, and thus to detect / determine a patient's rest, sleep onset, periodic hyperventilation, and / or arousal events. In combination with certain example embodiments, such technologies can be simpler and / or more advantageous (e.g., simpler and / or more advantageous than an electrocardiograph).

[0187] In any event, various sensors and other devices can be used to obtain respiratory data from a patient. Such data can be obtained by an external wearable device 211 or a bedside monitoring device 210. The data can be used to generate commands or other data, which are then used to cause the IPG to function or change its operation. For example, commands generated based on the processed respiratory data can be transmitted to the IPG, which cause the IPG to increase the stimulation energy being applied. Since ultimately the IPG controls the flow of stimulation energy to the phrenic nerve, the commands need to be streamlined and sent to the IPG to perform an operation based on the collected data.

[0188] The maximum allowable energy for each sleeping position of a patient may not be constant from night to night. The maximum allowable energy can be increased or decreased remotely by a doctor or automatically by the logic in the device. On the first night or several nights after activation, the maximum energy level can be set to a fraction (e.g., combined Figure 10B ) of the maximum tolerable limit determined during a patient's office visit or a test night in a sleep laboratory.

[0189] The maximum ramp energy can also be set to a preset fraction of the device's operating range, which can be, for example, from 1.0 mV to 5.0 mV. For example, the maximum energy level on the first night can be set to 50% of the operating range. The energy level can be increased to 51% on the next night (which can be the second night), to 52% after the second night, and then further increased by 0.05% to 5% each subsequent night, depending on the treatment plan. For example, on the initial night, the increment can be set to a larger value and then gradually decreased following an asymptotic trajectory, approaching the maximum value at a decreasing rate. In this way, it can be expected that the patient's central nervous system will gradually adapt to higher energy levels, and a new, higher tolerance threshold can be gradually established without frequent clinic visits.

[0190] Automatic telemetry can store relevant parameters, such as the delivered energy and corresponding physiological respiration parameters: movement, posture, respiration, and oxygenation patterns. These parameters can be transmitted to a doctor or a central analysis facility for treatment supervision. In some examples, the doctor can intervene by pausing, reversing, or adjusting (e.g., slowing down or accelerating) the adaptation ramp. Removing some sensing and control functions from the IPG and reallocating them between external components and the IPG that communicate wirelessly with each other has significant advantages. The IPG can be made simpler, more reliable, smaller, and have better battery life. Additionally, the surgery can be simplified. At the same time, the quality of the data signal regarding the patient's body can be improved because the IPG may have limited access to the patient's respiratory system.

[0191] Different embodiments of a new system for optimizing phrenic nerve stimulation parameters to treat OSA can be a distributed system that includes an IPG in electrical communication with the cervical phrenic nerve and components external to the body. The system is capable of delivering a sequence of controllable excitatory nerve stimulation pulses at precise time intervals, where the stimulation causes diaphragmatic contractions of variable intensity ranging from twitch capture to fusion of the muscle. In some examples, the system also includes a bedside monitoring controller that communicates wirelessly (e.g., continuously) with the IPG. The bedside controller can remotely control the patient at distances exceeding 6 cm and up to 2 meters (e.g., within the MICS communication range). In some examples, the bedside controller (or another device communicating with the bedside controller) includes a millimeter-wave range radar motion detection device configured to detect chest movement, estimate respiratory rate, separate movement of the chest and abdomen, tidal volume and inspiratory time, patient movement, posture, and blood pulsation, as well as heart rate. The data obtained is then processed by a computer and used to control the start, stop, ramp up, increase, or decrease of the stimulation energy, and to adjust the stimulation rate - for example, such changes are performed by communicating with the IPG.

[0192] Paradoxical motion of the chest wall, in which lung volume may decrease during inspiration, can be used as a surrogate variable for inspiratory airway resistance and negative pressure in the airways distal to the obstruction. Paradoxical motion can be explained by the respiratory pump inhaling against increased upper airway resistance or airway closure. In this situation, particularly if the patient hyperventilates in response to increased blood CO2 and hypoxia, a large negative pressure can be achieved in the chest. The chest muscles and structures cannot resist this negative pressure, and the chest collapses paradoxically while the abdomen bulges. These patterns can be detected by a respiratory belt, accelerometer, or non-contact radar-based motion detector. A paradoxical motion index can be derived. As described herein, the calculated variable is used to automatically adjust the energy delivery level or timing.

[0193] Figure 13 Description: Implantable Pulse Generator (IPG) System Design

[0194] Figure 13 IPG 41 is schematically shown and is adapted to be implanted into a patient with OSA to stimulate the phrenic nerve according to the techniques described herein. A phrenic nerve stimulator can be implemented within IPG 41. In some instances, IPG 41 is an example of a phrenic nerve stimulator. The IPG is similar in hardware design and construction to commercially available implantable pulse generators / implantable nerve stimulators, which can be obtained from suitable manufacturers such as Holdings, Inc.

[0195] IPG 41 includes a header 301 for connection to at least one stimulation lead 47 and an optional sensing lead 213. The header can include one or more connection ports (described below). IPG 41 includes an airtight housing 202 for accommodating an electronic circuit 303 (e.g., electronics) and a suitable airtight sealed battery 304. In some examples, the battery 304 can be rechargeable using wireless energy transfer. In some examples, the IPG can include other sensors as part of IPG 41. Such sensors can include accelerometers, oxygen sensors, vibration sensors, sound sensors (e.g., microphones), etc. Alternatively or additionally, sensors can be incorporated into the distal portion of the sensing lead 213 or the distal portion of the stimulation lead 47 and electrically connected to the electronic circuit 303 inside IPG 41. Standard implantable connectors can be similar in design and construction to the low-profile IS-1 connector system used in cardiac pacemakers (in accordance with ISO5841-3). The IS-1 connector has been used since the late 1980s and has proven to be reliable and provides easy release and reconnection during the lifespan of a single pacing lead through several implantable pulse generator replacements.

[0196] According to a desired technical feature, IPG desirably uses (e.g., as part of 303 or 303) a standard, commercially available, micro-power, flash (in-circuit programmable) programmable microcontroller or processor core in an application-specific integrated circuit (ASIC). The device (or possibly more than one such device for computationally complex applications with sensor input processing) and other large semiconductor components may have a custom package to reduce the printed circuit board space (real estate) requirements.

[0197] A microprocessor with embedded resident operating system software (code) is used to control the IPG. The operating system software can be further broken down into subgroups including system software and application software. The system software controls the operation of the IPG, while the application software interacts with the system software to indicate what actions the system software should take to deliver an appropriate amount of energy to the phrenic nerve at the appropriate time. The inventors recognize that multiple platforms with different system software can be compatible with the application software techniques discussed herein.

[0198] The electronic circuit 303 includes a wireless transceiver. This enables wireless telemetry communication with external systems and treatment controllers, which can be wearable, handheld, or bedside devices (e.g., those that are not typically implanted within the patient).

[0199] As an illustrative example, the IPG 41 can be responsible for detecting respiration and calculating the respiration rate via a sensing system, determining the start time and duration of a stimulation signal, and delivering a sequence of controlled electrical stimulation signals (pulses) via the stimulation lead 47. Then, the wearable monitoring system 210 can communicate wirelessly with the IPG, and the bedside monitor 211 can communicate data with the cloud computer system 212 to enable sharing of data with a doctor and modification of the treatment plan, which can be stored in the memories of the IPG and the bedside monitor and executed in real time by the electronics of the IPG. The IPG can also record and transmit treatment history data (device settings, status, measured data, device usage, respiration data, stimulation delivery data, statistics based on movement and sleep time, measured signals, etc.) and implement the patient treatment plan.

[0200] As shown by Figure 13As shown, the connector 301 forms the top portion of the IPG and can be molded from a polymer that is hermetically sealed to the housing 302. In some examples, the housing 302 can be a shaped titanium outer shell. As mentioned in the context of respiratory sensing, the housing can serve as an electrode for bioimpedance signals including respiratory measurements. Similarly, the electrode system on the wire can serve as an electrode for bioimpedance respiratory measurements. For example, the housing can include a current emitting electrode and a voltage sensing electrode for respiratory detection. Alternatively, separate electrodes can be included in the connector of the device for sensing or stimulation from that connector.

[0201] As described above, the connector 301 can include one or more ports. In Figure 13 the illustrated example, there are two ports: one sense wire port 305 (labeled "SENSE") for receiving the proximal connector of the sense wire 213, and one stimulation wire port 306 (labeled "STIM") for receiving the proximal connector of the stimulation wire 47. More ports can be added for other wires.

[0202] The port configured to receive the stimulation wire 47 can include two set screws (labeled "-" for cathode and "+" for anode) and associated set screw blocks and seals for mechanical and electrical connection to corresponding contacts on the common proximal male plug connector of the wire. This design and configuration of the wire-connector interface is accepted as standard for this type of device.

[0203] Similarly, the port configured to receive the sense wire includes set screws for the current emitting electrode and the voltage sensing electrode and associated set screw blocks and seals for mechanical and electrical connection to corresponding contacts of the proximal connector of the sense wire 213. The seals are located between the electrical contacts and between the most distal electrical contact and the remainder of the proximal connector assembly. These seals electrically isolate each contact. The connector can also include suture holes for using sutures to fix the IPG to subcutaneous tissue (such as muscle fascia) when implanted in a subcutaneous pocket.

[0204] During operation, the IPG 41 generates a stimulation output according to one or more stimulation parameters for delivery to the phrenic nerve via the stimulation lead 47. For this purpose, the IPG has bipolar stimulation output channels corresponding to the stimulation ports, through which a pulse sequence of biphasic constant current pulses is provided, with a frequency range of 20 Hz to 50 Hz (usually 30 Hz or about 30 Hz), a pulse width range of 30 μs to 215 μs (usually 150 μs or about 150 μs), an amplitude range of 0.4 mA to 5.0 mA (usually 1.0 mA to 4.0 mA), and a stimulation duty cycle range of 30% to 70% (usually 40% to 50%), by way of example and not limitation. These ranges can depend on the individual patient and the configuration of the electrode system (such as a nerve cuff or paddle electrode). In some examples, the duration of an individual pulse or the burst frequency range can be determined or otherwise calculated to be as low as possible to generate smooth contractions while also being selected to conserve battery power. In some examples, an optimal calculation of the values of the parameters can be performed. The resulting values can then be set within a margin (such as 1%, 2%, 5%, 10%, etc.) of these calculated values. Thus, in some examples, these values can be calculated to be, for example, "no more than the required length".

[0205] As Figure 13 and Figure 14 As shown in the component design, parameter values, and component configuration in the accompanying description of the IPG, by way of illustration, these are possible examples in some example embodiments and not limitations. Implantable nerve stimulators can evolve rapidly, and it is expected that conventional techniques will give way to battery-free and lead-free stimulators. These improvements are intended to reduce the size of the stimulator and increase its lifespan and reliability without substantially changing its function.

[0206] Impedance sensing is optional for some embodiments of the present invention. The IPG circuit can generate an excitation signal and measure the voltage through the respiration sensing lead 213 for bioimpedance respiration detection. For this purpose, the IPG has a respiration sensing channel for obtaining bioimpedance sensing of a desired vector. The vector can be between the sensing lead electrode, the stimulation lead 47 electrode, and the housing (case) of the IPG implanted in the chest.

[0207] In some embodiments, the IPG 41 measures bioimpedance via port 305, where internal electrical connections provide a small excitation current (“I”) and a measured voltage (“V”). The excitation signal can include a biphasic constant current pulse from 10 kHz to 50 kHz, where the positive and negative phases of each biphasic pulse have an amplitude of 500 μA. The current (“I”) can be fixed by the circuit, allowing the voltage (“V”) to be a relative measure of the impedance (“Z”), which corresponds to the movement of muscles, lungs, airways, and other structures to produce a signal indicative of respiratory activity.

[0208] Figure 14 Description: Electronic circuit

[0209] Figure 14 Schematically shown is the electronic circuit 303 that can be included within the IP 41. The electronic circuit 303 can be a circuit board or include a circuit board that has a microprocessor (also referred to herein as a hardware processor), memory, I / O, an analog-to-digital (A / D) converter, and the like. Any or all of the electronic circuit 303 can reside within the sealed housing 302 of the IPG 41.

[0210] The microprocessor 400 is used to control telemetry communication with external components of the IPG, operate the sensing circuit to monitor movement and respiration, control the delivery of output stimulation, and monitor the accelerometer (411), the magnetosensitive proximity sensor (e.g., reed switch) (408), and the real-time clock (409). The microprocessor includes or is coupled to (e.g., as part of the same integrated circuit or on the same silicon chip) RAM (e.g., volatile memory), flash memory (e.g., non-volatile memory), an analog-to-digital (A / D) converter, a timer, a serial port, digital I / O, and the like. The microprocessor 400 (e.g., hardware processor) can be a controller / microcontroller as used herein or can form part of a controller / microcontroller as used herein.

[0211] In some examples, the microprocessor 400 can be composed of several dedicated microprocessors that communicate via a serial link. Different functions (e.g., stimulation, monitoring, and telemetry communication) can be divided among the various different microprocessors. In some examples, one microprocessor can be used to perform such functions.

[0212] The telemetry interface circuit can consist of a tuned telemetry coil circuit 407 and a telemetry driver / receiver circuit 410 to allow digital encoded communication between external components and the microprocessor. As an alternative to the telemetry coil and inductive link, an RF antenna with associated circuitry can be used to establish an RF link for longer distance telemetry. The proximity sensor or proximity switch 408 provides a means for the IPG 41 to be controlled by using a magnet of a near field communication device (NFC) placed in close proximity. The real-time clock 409 provides a basic time base (e.g., 768 Hz) for the IPG electronic circuit 303 and a clock (year, day, hour, minute, second) that can be used to control the implementation of the treatment plan. The clock 409 is also used to timestamp information about the operation of the system that can be recorded on a sleep period, hourly, nightly, weekly, or monthly basis.

[0213] The bioimpedance respiration sensing circuit includes two main parts: an excitation current source (output) and a voltage sensing circuit (input) 415. A 3-wire or 4-wire impedance measurement circuit can be used to detect respiration. In a 4-wire measurement, the excitation current is driven through a pair of electrodes, and the resulting voltage is measured on a separate pair of electrodes. In one embodiment of a 3-wire measurement, the IPG housing (outer housing 302) can be used as both the excitation electrode and the sensing electrode. The excitation current circuit delivers a burst of biphasic pulses of low level (e.g., 450 uA) current to the selected pair of electrodes every 100 ms during sensing. The voltage sensing amplifier circuit 415 synchronously monitors the voltage generated by the excitation current on the selected pair of electrodes. The resulting output signal is proportional to the respiration impedance (0.07 Ω to 10 Ω) and is applied to the A / D circuit in the microprocessor 400 for digitization and analysis. Other sensing circuits can include an ECG signal amplifier (not shown) or a pulse oximetry interface.

[0214] The stimulation output circuit delivers bursts of biphasic stimulation pulses to the stimulation lead 47. These bursts can be synchronized with the sensed respiratory waveform to deliver stimulation and thereby create airway negative pressure and reflexes to cause airway opening at appropriate times. The stimulation output circuit can include an electrode polarity switching network (425 / 426), a current source circuit 421, and an output power supply 420. The electrode switching network allows a charge balancing cycle after each stimulation pulse, during which the outputs are connected together without an output pulse being applied. The timing and polarity of pulse delivery are provided by the control outputs of the microprocessor 400. The microprocessor selects the amplitude of the output current from the current source circuit applied through the switch / pulse shaping network (e.g., 0.4 mA to 5 mA). The output power supply 420 converts the battery voltage (from 417) to a higher voltage (e.g., 5 V to 15 V) that is sufficient to supply the selected current into the load impedance of the lead electrode system, which can be a bipolar or monopolar system where the IPG housing 302 serves as the current return electrode. The microprocessor 400 can measure the voltage output from the electrodes generated by the delivered current and the load impedance. The microprocessor 400 divides the output voltage by the output current to obtain a measurement of the load impedance (e.g., 400 Ω to 2800 Ω), which can be an indicator of the integrity of the lead electrode system and the condition of the surrounding tissue.

[0215] The system can include an implantable rechargeable battery (not shown) and an external controller that includes a charging circuit, a rechargeable battery coupled to the circuit, and circuitry adapted for wireless telemetry and energy transfer, and a charging coil coupled to the external controller for generating a radio frequency magnetic field for transcutaneous recharging of the rechargeable battery. During recharge of the rechargeable battery, the external controller can be adapted to be carried by the user without connection to a power main to allow the user full mobility. Rechargeable IPG batteries and circuitry are well understood and can be obtained from OEMs; they have certain advantages and disadvantages and are generally a matter of preference rather than necessity.

[0216] In some examples, the IPG 41 (or the leads connected to the IPG) can include an oxygen sensor to monitor oxygen levels, for example, during a treatment session at night. The generated signal can be used to monitor the efficacy of the treatment. Alternatively or additionally, the generated signal can be used to cause a change in the stimulation delivery settings during the treatment session. For example, the IPG can be programmed to increase the stimulation when a decrease in oxygen saturation to a programmable threshold rate and / or severity is detected. Additionally, once a decrease in saturation is detected, the IPG can turn on the stimulation, where the thresholds for rate and severity are programmable. A decrease in saturation can be used to indicate the sleep state or wakefulness. In a similar manner, electromyogram (EMG) can be used to monitor nerve activity, which can also indicate the sleep state and / or wakefulness. EMG can be used to monitor muscle activity that may indicate an effort of spontaneous breathing. The IPG can use the indication of the sleep state or wakefulness to change the stimulation settings. For example, the stimulation can be increased when it is estimated that the patient may be in N3 or REM sleep. During stage N1 or wakefulness, the stimulation level can be decreased or turned off.

[0217] As shown by Figure 12 not all sensors need to be implanted in the patient's IPG and the implanted sensors are electrically connected to the IPG, but rather can be distributed between the inside and outside (of the patient) and provided by different components of the entire nerve stimulation system.

[0218] The IPG circuitry can include an inertial sensor, such as a triaxial accelerometer 411 that can be used to determine the patient's body position (supine, prone, upright, left or right) and / or detect movement events (wakefulness). The accelerometer can include gyroscope hardware and firmware. The accelerometer can measure the rotation rate and acceleration of the IPG with high accuracy. This data can be used to change the stimulation settings or inhibit the output. For example, the IPG can be programmed to increase the stimulation intensity when the patient is in a particular body position (e.g., supine, a more challenging position). The IPG can separate the recorded treatment statistics (e.g., loop detector events, oxygen saturation decreases) relative to the body position. For example, the patient's loop detector can record very few events in the lateral position and many events in the supine position, indicating that the patient is being treated in the lateral position.

[0219] A bioimpedance respiratory signal (“Z”) is generated by dividing a change in a measured voltage (“V”) by an excitation current (“I”). The bioimpedance respiratory signal can reflect the movement of the diaphragm, the expansion and contraction of the lungs and airways over time, and is thus a reasonably good measure of respiratory activity. The bioimpedance respiratory signal can be used to estimate respiratory effort, respiratory rate, respiratory (tidal) volume, minute volume, etc. in real time in the presence of known deficiencies. If the excitation current (I) is constant or assumed to be constant, then the bioimpedance (Z) is proportional to the measured voltage (V), and thus the voltage (V) can be used as a surrogate for the bioimpedance (Z), eliminating the division step. As used in this context, diaphragm movement includes the movement and shape changes of the diaphragm, lungs, large airways, and adjacent tissues that occur during normal breathing and during obstructed breathing. The bioimpedance waveform can be filtered to reduce noise and eliminate cardiac artifacts, thus clarifying the occurrence of positive and negative, expiratory and inspiratory peaks. The signal can be filtered using a first-order low-pass filter. Alternatively, higher-order filtering methods can be utilized to filter the signal. The (positive or negative) peak of the impedance signal corresponds to the end of the inspiratory phase and the start of the expiratory phase. If the signal is normal, the positive peak is used; and if the signal is inverted, the negative peak is used. The start of the inspiratory phase occurs somewhere between the peaks and may not be easily distinguishable. The impedance signal typically provides a reliable timing event for the end-of-inspiration and start-of-expiration events. The remainder of the respiratory cycle may need to be extrapolated based on the patient's history.

[0220] Body movement, which typically indicates that the patient is awake, can be detected by an accelerometer and can also alter the bioimpedance signal (Z). Different sensitivity thresholds can be utilized such that minor movements are not confused with major movement events (such as rolling backward from side to side in bed, sitting up, standing, or walking around). When a movement event is determined, the stimulation can be turned off or reduced until the movement stops or for a programmable duration. The frequency and duration of these movement events can be recorded in the device history. The accelerometer can be used alone or in combination with impedance in a similar manner to detect and record movement events.

[0221] Fluctuations in the bioimpedance signal (Z) typically indicate apnea or hypopnea. This pattern is commonly referred to as cycling and can be detected, for example, by evaluating trends in the increase or decrease of the average P-P amplitude value. Different sensitivity thresholds can be utilized such that minor changes in the P-P value are not judged to be cycling events. When cycling is detected, the stimulation parameters (e.g., increasing intensity, increasing duty cycle, etc.) can be initiated or changed to improve treatment. The frequency and duration of these cyclical respiratory patterns can be recorded in the treatment history. These values can be used as an indicator of the degree to which the patient is being treated, providing an estimate of the AHI.

[0222] The IPG can be programmed to change the stimulation level between treatment sessions, days, or other programmable values. The stimulation level can be recorded together with treatment session data, such as cycle rate, frequency and severity of oxygen saturation drops, stimulation time, changes in respiratory rate, changes in respiratory prediction, etc. The processor 303 is equipped with different types of computer memory and can store program code, settings, and patient data in multiple regions in different electronic ways and with different memory content update speeds.

[0223] Synchronization of breathing Vs Entrainment of breathing

[0224] Triggering the physiological mechanism based on the negative pressure reflex can be achieved, for example, by applying diaphragmatic stimulation every breath or every other breath during the late exhalation - early inhalation phase. Diaphragmatic stimulation can also be applied at any other time during inhalation, with a potentially poorer effect. If applied during exhalation, it is less likely to be effective and may be harmful by prolonging the exhalation time through the Hering - Breuer inflation reflex mechanism.

[0225] In people without OSA, inhalation is typically 25% to 50% of the respiratory cycle, and variations in respiratory rate are common. The variations can cause the actual inhalation timing to differ from breath to breath. The hypoglossal nerve typically or naturally activates approximately 300 ms before inhalation and remains active throughout the inhalation phase, indicating the true start of the respiratory cycle. To mimic this natural physiology, it is desirable to deliver stimulation to the phrenic nerve during the late exhalation phase and the early inhalation phase, where the brief pre - inhalation period is approximately 300 ms. Since variability is expected, to maximize the stimulation coverage of actual inhalation, it may be advantageous to account for this variability by focusing the stimulation on the predicted inhalation.

[0226] Technical methods for synchronizing stimulation with breathing have been proposed, including sensing based on impedance, accelerometers, respiratory sounds, and chest and airway pressure signals. Since the start of inhalation may be more difficult to detect, prediction and / or extrapolation based on peak inhalation timing and known patient history can be used in some examples.

[0227] Thoracic impedance requires tunneling of the sensing leads and depends on the current path carrier. This complicates both device design and surgery. Both thoracic impedance and accelerometers can detect chest movement, but generally cannot detect airflow, and thus there are problems in detecting inspiration when the airway is closed or restricted due to OSA. This is especially true in mixed and obstructive apnea with normal and abnormal chest movements during respiration. During the hyperventilation phase of the OSA cycle, when the respiratory rate accelerates sharply, the system tends to overreact. The device responds to movement, coughing, sneezing, and other signals that are not true inspirations but may trigger the detection circuit, making the patient uncomfortable.

[0228] An alternative to synchronization is to operate the device (e.g., IPG 41) in an "asynchronous mode". This mode relies on the patient's tendency to synchronize or at least "phase-lock" with external stimuli during sleep. For example, physiological oscillators tend to phase-lock with external stimuli. This does not always mean precise synchronization. A good example is the synchronization of sleep with the circadian cycle. The average person falls asleep at a certain time at night and wakes up at a certain time in the morning. A similar pattern is seen in patients "entrained" on mechanical ventilation.

[0229] "Phase-locking" occurs when the patient's inspiratory effort occurs at one or more specific phases of the ventilator cycle and the inspiration is periodic in time. This situation can also be referred to as respiratory "entrainment" or respiratory synchronization. The phase-locking pattern can be related to the ratio of the ventilator frequency to the respiratory frequency. For example, in a 1:2 phase-lock, there is one stimulus cycle for two respiratory cycles.

[0230] The mechanism of entrainment is generally attributed to vagal afferents from stretch receptors in the lung and airway, but there may be a contribution from diaphragmatic and intercostal afferents. Regardless of the precise mechanism, entrainment can be proportional to lung inflation, rate-dependent, and similarly applied to mechanical ventilation and diaphragmatic stimulation. There are also similarities between entrainment in natural sleep and in patients with sedated spontaneous breathing. Phase-locking physiology was described by Graves et al. in "Respiratory phase-locking during mechanical ventilation in anesthetized human subjects". Am. J. Physiol 1986.

[0231] Human subjects are entrained 1:1 with mechanical ventilation over a ventilator frequency range that is ±3 to ±5 breaths per minute of each subject's spontaneous breathing rate. Outside of the 1:1 entrainment range, more complex entrainment patterns are seen. In the case of phrenic nerve stimulation, the response of the central stimulator is similar. In sleeping subjects, when the stimulation burst rate is greater than the spontaneous frequency, inspiratory activity is generally expected to be before the stimulation, and when the stimulation rate is less than the spontaneous frequency, inspiratory activity occurs during or after the stimulation burst portion of the respiratory cycle.

[0232] The entrainment pattern, including the phase relationship, depends on the ratio between the "natural" respiratory cycle and the mechanical rhythm and the ratio between the natural tidal volume and the mechanical tidal volume.

[0233] In the field of mechanical positive pressure ventilation, the phase relationship of inspiration relative to the inflation of the ventilator is measured as a delay. The delay is the time from the start of mechanical inflation to the start of spontaneous inspiration (usually diaphragmatic EMG). The phase angle θ is derived by dividing the delay by the ventilator period and multiplying by 360°. When the machine inflation and the EMG start simultaneously, the start of the machine inflation is θ = 0°. When the EMG activity is before the machine inflation, θ is between -180° and 0°, and when the EMG activity occurs during or after the machine inflation, θ is between 0 and +180°. In some examples, a similar technique can be implemented by a phrenic nerve stimulation system for stimulating the phrenic nerve.

[0234] In published literature studies, in both anesthetized and sleeping subjects, when the machine frequency is less than the spontaneous frequency (negative phase angle), inspiratory activity is before the positive pressure mechanical ventilation cycle, and when the machine frequency is greater than the spontaneous frequency of sleeping subjects, inspiratory activity occurs during or after the ventilator-initiated lung inflation.

[0235] Entrainment of the natural respiratory rhythm by stimulating the phrenic nerve is known. It is used to treat central sleep apnea (CSA), as described in U.S. Patents 11,065,443; 11,065,443 and 8,233,987.

[0236] In some example embodiments, a method of entrained breathing for treating OSA is provided that applies a train of stimulation pulses to the phrenic nerve during the late natural exhalation / early inspiratory portion of the respiratory cycle to cause a vigorous contraction of the diaphragm to induce a negative pressure reflex in the airway when the airway is closed.

[0237] In combination with certain example techniques described herein, it may be advantageous, therefore, to entrain respiration at a frequency rate that results in natural inspiratory activity during or after phrenic nerve stimulation-initiated lung inflation when the stimulation frequency is slightly higher than the patient's spontaneous frequency. This implies knowing the patient's natural breathing rate. We propose to determine this rate during a rest period when the patient is identified as supine and at rest and likely asleep or about to fall asleep but not yet exhibiting OSA and periodic breathing that alter their natural resting breathing pattern.

[0238] It is believed that all patients are most readily entrained initially at a stimulation rate close to their natural breathing frequency (inherent frequency stimulation rate). For example, a patient can be initially entrained at their inherent frequency stimulation rate and then that rate is gradually increased or decreased to achieve optimal timing of airway stimulation and activation of the negative pressure reflex.

[0239] In addition, a processor such as in the IPG 41 (e.g., 400) can be programmed to automatically adjust based on the breathing rate to achieve a desired phase angle θ between 0° and -180° (e.g., between 0° and -90°), where the stimulation is applied after natural inspiration during most respiratory cycles. The phase angle is the phase shift between the breathing rate caused by phrenic nerve stimulation with the IPG 41 and the natural breathing rate without phrenic nerve stimulation. Automatic adjustment of the breathing rate to achieve a desired phase angle θ between 0° and +180° (e.g., between 0° and +90°), where the stimulation is applied before natural inspiration during most respiratory cycles. Depending on the individual characteristics of the patient, some patients may benefit from the former mode of entrainment, while others may benefit from the latter mode of entrainment.

[0240] EMG activity may be difficult to detect in a home environment, but an EMG, transthoracic impedance, or accelerometer can be used to detect the delay time from the start of phrenic nerve stimulation inflation to the start of spontaneous inspiration.

[0241] Figure 15A , Figure 16A and Figure 16B Description: Optimized use of negative pressure reflection

[0242] Figure 15A A process (e.g., algorithm) is shown that can be implemented in the system to optimize the use of the negative pressure reflex in a sleeping or resting patient. Entrainment is the phenomenon by which two oscillators typically interact with each other physically or chemically to synchronize their oscillations. This phenomenon occurs in biology to coordinate processes from the molecular to the organ and organism levels and is well described in the scientific literature.

[0243] The patient entrains to the diaphragmatic stimulation, and entrainment is confirmed using one of the available methods (e.g., spectral analysis or Arnold Tongue plot). At 500, the patient's respiratory pattern and / or movement are analyzed. At 502, and based on the analysis at 500, the process determines whether the patient is resting or sleeping. If the patient is not resting or sleeping, the process loops back to 500 to continue monitoring the patient. If it is determined that the patient is sleeping or resting, the process moves to 504, and a phase angle is calculated using the respiratory signal. Note that in some examples, the phase angle can be calculated at 500. In any event, the stimulation can be initiated at a rate based on (e.g., as close as possible to) the average natural breathing rate or otherwise used (e.g., as discussed herein). After entrainment is confirmed, for example, by spectral analysis (described below in conjunction with Figure 18A and Figure 18B ), the stimulation rate can be increased or decreased (e.g., slightly) based on determining (at 506) that the calculated phase angle is on target, thereby achieving the desired timing. If the phase angle is on target, the process returns to 500 and monitors the patient. However, if the phase angle is not on target, the stimulation rate can be adjusted by increasing or decreasing the rate. For example, the stimulation rate can be set 2 to 3 breaths below the natural breathing rate. The phase angle would be expected to be negative. Thus, the stimulation rate can be incrementally increased at 508 until the phase angle changes polarity and the stimulation occurs with the desired delay prior to natural inspiration, which can be 50 ms to 500 ms or 25% of the total natural inspiration time.

[0244] In some embodiments, Figure 15A the elements shown in

[0245] Figure 16A and Figure 16B can each be performed by the IPG (e.g., its electronic circuitry). In other embodiments, some elements can be performed by the IPG and other elements can be performed by other devices that communicate with the IPG. For example, the analysis of respiration and movement performed at 500 can be carried out by a mobile device or a bedside monitor, which then communicates with the IPG to adjust the stimulation rate delivered to the patient.

[0246] Figure 16AA train of stimulation pulses 220 is shown being applied at a set rate that can be between 6 and 25 breaths per minute. This rate is lower than the patient's natural breathing rate. Breathing, represented by volume change 221, lags the stimulation by a delay period 222. Each breath represents the tidal volume resulting from a combination of natural effort and effort caused by the stimulation.

[0247] Figure 16B A stimulation rate increase is shown compared to the Figure 16A stimulation rate shown in Figure 16B In

[0248] Figure 16B A breathing and stimulation pattern similar to patient data from Figure 7 or represented by patient data from Figure 7 is also shown. Specifically, when the patient's airway is closed (as evidenced by zero air flow during period 66), a first train of stimulation pulses 60 is initiated. It should be understood that, as can be seen from Figure 7 the behavior of the biological oscillator is imperfect and the phase angle can change polarity between breaths. When applied to a series of spontaneous breaths that occur during hours of sleep at night, phase locking or entrainment should be interpreted as the dominant or statistically more frequent behavior. Thus, in connection with certain example embodiments discussed herein, when referring to "analyzing breaths" and the like, it should be understood that computer-controlled logic that is part of or embedded in the system is configured to average, analyze, and otherwise process a series of breaths before making changes to stimulation settings (such as the rate, duration, and length of the train of pulses). In the case of referring to a rate, it should be understood that the rate includes the rate of a train of pulses or burst consisting of individual pulses. For example, a train of pulses can be applied at a rate of 10 trains of pulses per minute and consist of individual biphasic pulses repeated at a frequency of 30 Hz (pulses per second). Thus, the terms pulse burst and train of pulses are used interchangeably herein.

[0249] Figure 15B Description: Use of Lung Volume

[0250] Figure 15B 、 Figure 17A and Figure 17B show the use of lung volume to optimize and improve the effectiveness of phrenic nerve stimulation for treating OSA.

[0251] The I:E ratio is the ratio of the duration of the inspiratory phase to the expiratory phase of breathing. In mechanical ventilation, the "normal" I:E ratio is approximately 1:2. In both spontaneous and mechanical breathing, it is important to ensure that the breath delivery includes sufficient expiratory time. The normal inspiratory to expiratory ratio (I:E) for a spontaneously breathing patient is typically around 1:3 to 1:5. This means that the ratio of the expiratory time is three to five times longer than the ratio of the inspiratory time.

[0252] As used herein, the terms I:E ratio and duty cycle are similar but not interchangeable. For example, an I:E of 1:1 corresponds to a duty cycle of 50% of the total respiratory cycle. As used herein, the phrenic nerve stimulation duty cycle (duty cycle) means the percentage of the stimulus burst duration in the total length of the stimulus cycle. These parameters are part of the IPG settings. For example, if the stimulation rate is set to 10 / min and the duty cycle is set to 40%, the cycle is 6 seconds long and the stimulus burst is 2.4 seconds long.

[0253] As used herein, the I:E ratio means the ratio between the total inspiratory time and the expiratory time of the patient measured at the mask. This I:E ratio may incorporate both artificial or stimulus-induced inspiration and spontaneous inspiratory efforts. Since the airway may be blocked in OSA, the inspiratory time may not correspond one-to-one with the inspiratory effort.

[0254] As used herein, the duty cycle can be used to manipulate (e.g., increase) the I:E ratio of an entrained spontaneously breathing patient. The purpose of increasing the duty cycle is to increase the lung volume, and in particular the end-expiratory lung volume in a sleep patient with OSA. This phenomenon is commonly referred to as "air trapping".

[0255] It is generally recognized that for a ventilated patient, a significant deviation from the normal I:E ratio is uncomfortable and, in a mechanically ventilated patient, requires sedation. However, there are situations where increasing the I:E ratio is well tolerated and efficacious. Similar or identical aspects may apply to the phrenic nerve stimulation techniques discussed herein. For example, increasing the duty cycle from 30% to 50% may be beneficial, while increasing the duty cycle from 50% to 70% may make the patient uncomfortable. Thus, these settings are personalized and can be included in the patient's profile.

[0256] Prolonging the inspiratory time (e.g., an I:E of 1:1) increases the mean airway pressure. As the mean airway pressure increases, the lung volume increases and the atelectatic regions of the lung expand, resulting in improved oxygenation. However, this strategy may have its limitations because, for example, the lung may be better utilized for gas exchange.

[0257] In respiratory therapy, such as mechanical ventilation and CPAP, end-expiratory lung volume (EELV) is the natural functional residual capacity (FRC) plus the lung volume increased by the applied positive end-expiratory pressure (PEEP). It is believed that a moderate increase in EELV benefits patients with OSA by increasing the caudal traction on the airway, making it more resistant to collapse.

[0258] It is known that lung volume decreases during sleep. In these cases, increasing the inspiratory duty cycle can stabilize lung volume at the waking level by: (1) increasing the mean airway pressure, and (2) trapping air in the lungs when the allotted time is insufficient for the patient to exhale fully. Although this maneuver may be uncomfortable in conscious individuals, it is generally well tolerated during sleep if applied in a controlled manner.

[0259] Obesity is generally associated with a reduction in end-expiratory lung volume during wakefulness, which is further exacerbated during sleep and sedation. A decrease in lung volume during sleep is known to exacerbate upper airway obstruction and nocturnal hypoxemia in these individuals. The deleterious effects of low lung volume can be reversed by increasing the I:E ratio. The resulting elevation in lung volume effectively maintains pharyngeal patency and alleviates hypoxemia during sleep and sedation. These responses can be utilized to treat obstructive and central sleep apnea, respectively.

[0260] Figure 17A Description: Increase the duty cycle

[0261] Figure 17A An increase in the duty cycle of stimulation of a phrenic nerve is shown. The stimulation portion 230 of the first duty cycle is shorter than the stimulation portion 231 of the second duty cycle. By selectively applying different duty cycles (e.g., a shorter duty cycle 230 to a longer duty cycle 231), a controlled increase in end-expiratory lung volume 232 (EELV) can be achieved.

[0262] In patients with obstructive sleep apnea, an increase in lung volume can exert caudal traction on the upper airway structures, thereby preventing pharyngeal collapse and alleviating the increase in airway resistance. As lung volume increases, oxygenation may also improve due to a concomitant reduction in physiological shunt, oxygen reserve, and improved ventilation / perfusion ratio. The negative cardiac effects of increased intrinsic positive end-expiratory pressure (PEEP) and increased pulmonary vascular resistance can be well tolerated or even offset by reduced hypoxic vasoconstriction during reoxygenation of the reinflated regions of the lung.

[0263] Controlling and optimizing the ventilation I:E ratio for therapeutic purposes by varying the stimulation duty cycle can use a real-time feedback control loop, which can be implemented as, for example, a computer-controlled process embedded in the software of an IPG. For example, an increase in the patient's intrinsic or entrained respiratory rate may also shorten the expiratory time, further impeding exhalation and increasing lung volume. An increase in the stimulation duty cycle may have a similar effect on lung volume. In this regard, by controlling the duty cycle, the end-expiratory lung volume can be maintained at a desired level for an optimal respiratory rate (phase-locked respiratory rate).

[0264] In some examples, relatively healthy individuals may require a relatively small tidal volume during sleep to meet their metabolic needs. Thus, the inhaled air can be fully exhaled in a relatively short time without air trapping. Therefore, in a normal sleep breathing setting, a so-called reverse I:E ratio may be required to trap air in the lungs and increase the EELV. The expected duty cycle (e.g., as applied to such a situation) can be in the range of 50% to 70%. At the same time, some patients, especially those with heart or lung diseases, may have a rapid breathing rate and a high expiratory resistance. These patients may trap air with a smaller duty cycle. Thus, such data settings can be personalized for the patient and stored in the patient's profile for later use.

[0265] Figure 17B Description: Bilevel Stimulation

[0266] In another embodiment, we propose applying entrainment to the treatment of OSA by applying at least two levels of stimulation: an inspiratory level and an expiratory level. This can be referred to as "dual-level entrainment".

[0267] Dual-level entrainment involves increasing inspiration, using negative pressure response to open a collapsed airway, setting the respiratory rhythm, and maintaining an increased lung volume during exhalation. It is intended to maintain natural breathing while regulating the breathing to a rate set by the stimulation timing, while maintaining two corresponding lung expansion levels: the inspiratory volume and the end-expiratory "bias" volume.

[0268] The duty cycle can be set by a doctor or automatically adjusted if too much or too little air trapping is detected. For practical use, such treatment needs to be adaptive, where the stimulation levels for both the inspiratory and expiratory periods can be automatically adjusted based on the patient's breathing and body position.

[0269] Augmented inspiration can compensate for the reflex caused by the reduction in tidal volume caused by an increased residual lung volume, and this reflex is called the Herring-Breuer inflation reflex. It should be understood that entrainment can be applied per breath or for a period of time, followed by natural rhythm and recovery and re-evaluation of the respiratory rate and minute ventilation. Supplementing the minute ventilation by increasing the tidal volume may be an important part of the treatment for clinically indicated patients (such as sleep-induced hypoventilation, CSA, and / or obesity).

[0270] It should be understood that the proposed dual-level entrainment stimulation can treat various diseases commonly associated with OSA, such as obesity hypoventilation, central sleep apnea, and mixed sleep apnea (e.g., the type of apnea with airway instability accompanied by respiratory drive instability).

[0271] It can be expected that the proposed dual-level entrainment stimulation can also play an important role in the titration and auto-titration of phrenic nerve stimulation therapy. The processes of natural breathing and induced breathing are inherently periodic and follow a rhythm. This includes central and obstructive apnea and hypopnea. Although respiratory signals are usually noisy and difficult to distinguish, periodicity can be identified in the frequency domain using power spectral analysis tools. Such tools can be to some extent unaffected by random mechanical and electrical noise and changes in the patient's posture.

[0272] The stimulation is dual-level and consists of an inspiratory part and an expiratory part. The level of the expiratory part is lower than that of the inspiratory part, but is sufficient to bias the lungs and maintain the expiratory lung volume above the natural state. The bias (expiratory period) energy level can be adjusted in response to respiratory analysis. Of particular interest is to aim to reduce the power spectral density in the very low LF band, which reflects apnea hypopnea and is directly related to the treatment goal and mechanism.

[0273] The dual-level stimulation is shown in the Figure 17B figure. The X-axis shows time, and the Y-axis shows the air volume along the top and the stimulation energy along the bottom. Figure 17B The tidal volume (the integral of the respiratory airflow over time for each breath) is shown, with an inspiratory phase followed by an expiratory phase. The bottom trace along the figure shows the applied stimulation energy. The stimulus burst (e.g., based on the clock and software in the IPG) is set to a programmed frequency, which can be between 6 breaths per minute and 20 breaths per minute (0.1 Hz and 0.33 Hz), which is approximately the physiological range in which the patient's natural breathing can be expected and can be entrained by the stimulation. The combined effort of the patient and the induced phrenic nerve stimulation generates an inspiratory effort and produces the corresponding tidal volume shown along the upper part of the figure.

[0274] The stimulation during inspiration 233 corresponds to the inspiratory level of the stimulation energy, which reflects the pulse train generated by the IPG, and the pulse train is characterized by a certain frequency, duty cycle, and current directed to the phrenic nerve. In contrast, according to other aspects described herein, the expiratory stimulation level 234 is lower than the inspiratory level and is selected to maintain the bias of the lung and a certain desired end-expiratory lung volume to prevent the lung from completely deflating, keep it inflated, and improve the airway's resistance to obstruction and collapse.

[0275] In OSA, breathing decreases over time until apnea occurs. The bias stimulation level can be increased until breathing resumes. In a practical implementation of an auto-titration algorithm, when hypopnea is detected, the bias stimulation can be increased before apnea because it is easier to keep the airway open than to reopen the airway after it has completely collapsed. It can be preset based on the known behavior of the patient during the night as recorded in the patient's profile. It can be applied when the patient changes position (e.g., rolls onto the supine position).

[0276] In some examples, a separate airflow signal may not be sufficient to distinguish between obstructive and central apnea and hypopnea. Therefore, additional sensing of respiratory effort can be used. For example, transpulmonary impedance can be used as an indication of breathing. Some carriers can detect paradoxical movement of the chest wall, where lung volume may decrease during inspiration. In the case of using spectral analysis, these considerations are largely irrelevant because the analysis detects periodicity rather than the magnitude or direction of respiratory effort.

[0277] Figure 18A and Figure 18B Description: Spectral power analysis

[0278] Figure 18A and Figure 18B Illustrated is spectral power analysis that can be implemented by the IPG (e.g., in the software or firmware loaded therein) or an external device in wireless communication with the IPG, or spectral power analysis implemented on the IPG or an external device in wireless communication with the IPG. The advantage of respiratory analysis in the frequency domain is that it is more sensitive to the rate of breathing and less sensitive to the pattern of breathing, which is valuable in OSA patients who may exhibit paradoxical breathing airway obstruction. Even highly imperfect signals (e.g., integrated and band-pass filtered accelerometer readings) may produce an accurate estimate of the natural breathing rate over time while being relatively insensitive to occasional signal noise (e.g., coughing or rolling in bed).

[0279] [[ID=at18]]The power spectrum can be obtained by performing a fast Fourier transform (FFT) on the respiratory signal data acquired digitally for 1 minute to 10 minutes (in this example: chest movement, impedance change, or respiratory sound). The spectrum can be a power spectrum, power density spectrum, or amplitude spectrum.

[0280] The power spectrum allows an estimation of which cyclic frequencies contribute the most to the total variance of the signal in the frequency band of interest. The larger the amplitude, the higher the variance. It should be understood that there are many techniques for calculating the frequency distribution of a periodic signal, and such techniques can be employed in conjunction with the exemplary embodiments contemplated herein.

[0281] A "spectrum" can be calculated for the range of natural breathing frequencies, typically between 0 Hz and 1.0 Hz. In some exemplary embodiments, the frequency band of interest can be from about 0.1 Hz to 0.5 Hz. In the case of deliberately applied non-physiological high-frequency oscillations, the frequency band can be extended. In combination with the use of the techniques herein, the selected range is designated as the "breathing frequency band". Other frequency ranges can be selected, where the selection based on Figure 18A and Figure 18B is exemplary.

[0282] Now referring more specifically to Figure 18A , this figure shows an example of the respiratory power spectrum of a patient with apnea and natural breathing. The low-frequency (LF) power peak 320 corresponds to periodic breathing, apnea, or hypopnea, which may be present when the patient is resting and not yet asleep in the case of CSA, but typically manifests during sleep in the case of OSA. It should be understood that in this case, whether the patient has central or obstructive apnea is generally not important, since by definition both processes are periodic, as obstructive apnea is periodically interrupted by episodes of compensatory hyperventilation.

[0283] Unlike hypoglossal nerve stimulation, phrenic nerve stimulation may be beneficial for both OSA and CSA when applied asynchronously. For example, as shown by Figure 18A and Figure 18B , spectral analysis can help determine an initial stimulation rate, which can be set near the patient's natural breathing peak frequency, and help determine the amplitude of periodic breathing to be used as a basis for decisions to increase energy delivery or change the stimulation rate or duty cycle (titration therapy).

[0284] The apnea / hypopnea power frequency band typically encompasses around 60 to 120 events per hour (0.017 Hz and 0.033 Hz), and the integrated power in this band is attributed to the periodic breathing peak 320. The high-frequency HF peak 321 corresponds to respiration and may be rather dispersed in patients with irregular breathing, but generally is concentrated between 6 breaths per minute and 20 breaths per minute (between 0.1 Hz and 0.33 Hz).

[0285] Figure 18BShows the respiration of a patient with entrainment, where periodic breathing is addressed. The patient's respiration is phase-locked (entrained) to the stimulus applied at a constant asynchronous rate of 0.1 Hz (6 breaths per minute). The stimulus power peak 322 corresponds to this setting. If there is no capture of the diaphragm, the peak will not be distinguishable from the background noise. Thus, this technique helps to detect levels 103 and 109 on the titration curve (see Figure 9 ). In some examples, the software described herein can calculate or use the percentage of the calculated respiratory power concentrated in a specified frequency band (normalized relative to the total power after removing noise), rather than the absolute value.

[0286] It should be understood that the frequency numbers provided herein are chosen for illustrative purposes. In practice, the patient's natural respiration and the stimulus rate can be closer - for example, within 2 to 3 breaths per minute of each other. This means that the instantaneous respiration rate calculated based on the breath duration is statistically distributed around the stimulus rate. If the power distribution is skewed - for example, skewed towards frequencies higher than the stimulus rate - then the natural respiration rate may be higher than the stimulus rate, and the stimulus rate may need to be increased.

[0287] It should be understood that the illustrations are provided by way of example (e.g., they may be somewhat idealized) to help illustrate the principles of spectral analysis. In some examples, all three peaks may be present, and the power may be distributed among them in different proportions. In some example embodiments, the goal is to reduce the LF power of the spectrum and concentrate as much power as possible (without waking the patient or completely taking over natural respiration) in a narrow frequency band centered at the stimulus frequency.

[0288] It should be understood that the different techniques described herein can be applied differently and in different combinations to patients with different characteristics, diseases, underlying physiologies, and anatomical structures. Some patients may benefit from some increase in lung volume, while some patients may not benefit from some increase in lung volume. Some patients may benefit from (while some patients may not benefit from) locking their respiratory phase to a rate higher than their natural respiration at rest.

[0289] Although the invention has been described in connection with the presently considered most practical and preferred embodiments, it should be understood that the invention is not limited to the disclosed embodiments, but rather, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0290] Additional embodiments

[0291] Additional embodiments that can be implemented can include the following exemplary methods for treating sleep apnea.

[0292] Embodiment 1 A method for treating obstructive sleep apnea (OSA), comprising periodically and artificially stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied to the nerve when the pharyngeal airway of the patient is naturally blocked.

[0293] Embodiment 2 A method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the airway is closed or partially blocked.

[0294] Embodiment 3 A method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is applied when the airway is characterized by an increased obstruction.

[0295] Embodiment 4 A method for treating OSA by periodically stimulating at least one phrenic nerve of a patient, wherein the stimulation is artificially applied when the airway is closed.

[0296] Embodiment 5 The method according to any one of Embodiments 1 to 4, wherein the stimulation comprises a train of stimulation pulses initiated when the airway is closed.

[0297] Embodiment 6 The method according to any one of Embodiments 1 to 5, wherein most of the stimulation is a train of stimulation pulses initiated when the airway is closed.

[0298] Embodiment 7 The method according to Embodiment 5 or 6, wherein the train of stimulation pulses is first applied at a first energy level sufficient to generate an action potential in the phrenic nerve, and subsequently at a second energy level sufficient to reflexively open the collapsed airway by activating the upper airway muscles.

[0299] Embodiment 8 The method according to any one of Embodiments 5 or 6, wherein the train of stimulation pulses is first applied at a first energy level sufficient to generate an action potential in the phrenic nerve, and further at a second energy level sufficient to reflexively open the collapsed airway by enhancing the mechanical reflex.

[0300] Embodiment 9 The method according to Embodiment 9, wherein the mechanical reflex is a negative pressure reflex.

[0301] Embodiment 10 A method, comprising:

[0302] Identifying a patient suffering from OSA,

[0303] Implanting a phrenic nerve stimulator in the patient or connecting the phrenic nerve stimulator to the phrenic nerve, and

[0304] Adjusting the stimulation energy applied to the phrenic nerve of the patient by the phrenic nerve stimulator based on the detected airway obstruction in the airway of the sleeping patient.

[0305] Embodiment 11. The method according to Embodiment 10, wherein the phrenic nerve stimulator comprises a pulse generator and an electrode implanted near the phrenic nerve.

[0306] Embodiment 12. The method according to Embodiment 10 or 11, wherein the adjustment of the stimulation energy comprises making the adjustment until the airway obstruction opens in response to the stimulation burst.

[0307] Embodiment 13. The method according to any one of Embodiments 10 to 12, wherein the adjustment of the stimulation energy continues until airflow is restored in the sleeping patient.

[0308] Embodiment 14. The method according to any one of Embodiments 10 to 13, wherein the airway obstruction is detected by monitoring the airflow through the patient's air breathing passage, the patient's breath sounds, the patient's respiratory effort, the patient's airway pressure, and / or the oxygen saturation.

[0309] Embodiment 15. The method according to any one of Embodiments 10 to 14, wherein the stimulation energy is applied during respiration, wherein the rate of respiration is 6 to 20 breaths per minute, 8 to 14 breaths per minute, 6 to 15 breaths per minute, or 10 to 15 breaths per minute.

[0310] Embodiment 16. The method according to any one of Embodiments 10 to 15, wherein the applied energy is applied with a duty cycle of 30% to 50% of the respiratory period, 35% to 40% of the respiratory period, 40% to 60% of the respiratory period, or 25% to 60% of the respiratory cycle.

[0311] Embodiment 17. The method according to any one of Embodiments 10 to 16, wherein the rate is set based on the patient's natural resting respiratory rate.

[0312] Embodiment 18. The method according to any one of Embodiments 10 to 17, wherein at least 20% of the applied energy comprises a stimulation burst that coincides with the early inspiratory period of the natural expiration end of respiration.

[0313] Embodiment 19. The method according to any one of Embodiments 10 to 18, wherein the applied energy comprises applying a stimulation burst at a time in the early inspiratory period of the natural expiration end of respiration detected or predicted based on a previous respiration.

[0314] Embodiment 20. The method according to any one of Embodiments 10 to 19, wherein the stimulation of the phrenic nerve creates a negative pressure in the airway.

[0315] Embodiment 21. The method according to any one of Embodiments 10 to 20, wherein the stimulation of the phrenic nerve produces a diaphragmatic contraction, and the diaphragmatic contraction creates a negative pressure in the airway.

[0316] Embodiment 22. The method according to any one of Embodiments 10 to 21, wherein stimulation of the phrenic nerve produces contraction of the diaphragm, and the contraction of the diaphragm produces a negative pressure in the airway sufficient to trigger the negative pressure reflex.

[0317] Embodiment 23. The method according to Embodiment 22, wherein the negative pressure reflex activates the airway muscles of the patient.

[0318] Embodiment 24. The method according to Embodiment 23, wherein activation of the airway muscles restores patency of the airway.

[0319] Embodiment 25. The method according to Embodiment 23 or 24, wherein activation of the airway dilator muscles minimizes oxygen desaturation and / or hypercapnia.

[0320] Embodiment 26. A method for shortening the airway obstruction time of a sleeping patient, comprising periodically stimulating at least one phrenic nerve of the sleeping patient, wherein the stimulation is applied when the airway is closed.

[0321] Embodiment 27. The method according to Embodiment 26, wherein stimulation of the at least one phrenic nerve helps trigger the negative pressure reflex of the patient.

[0322] Embodiment 28. The method according to Embodiment 26 or 27, wherein when the airway collapses, stimulation of the at least one phrenic nerve causes contraction of the patient's diaphragm.

[0323] Embodiment 29. The method according to Embodiment 28, wherein contraction of the diaphragm produces a negative transmural airway pressure downstream of the obstruction site in the airway.

[0324] Embodiment 30. The method according to Embodiment 29, wherein the negative transmural airway pressure is sufficient to activate the negative pressure reflex of the patient.

[0325] Embodiment 31. The method according to any one of Embodiments 26 to 30, wherein the efferent output of the negative pressure reflex to the airway muscles exceeds the natural efferent output of the negative pressure reflex that occurs during the patient's sleep.

[0326] Embodiment 32. The method according to any one of Embodiments 26 to 31, wherein contraction of the patient's diaphragm is sufficient to produce a negative transmural airway pressure downstream of the obstruction site in the airway and is more negative than the naturally occurring negative transmural airway pressure that occurs during the patient's sleep.

[0327] Embodiment 33. The method according to any one of Embodiments 26 to 32, further comprising shortening the period of airway obstruction of the sleeping patient to prevent oxygen desaturation from exceeding 3%.

[0328] Embodiment 34. The method according to any one of Embodiments 26 to 32 further includes automatically adjusting the stimulation current based on at least one of the airflow in the breath of the sleeping patient, the breath sound of the sleeping patient, the breathing effort of the sleeping patient, the airway pressure of the sleeping patient, and the oxygen saturation of the sleeping patient.

[0329] Embodiment 35. A method includes:

[0330] identifying a patient suffering from OSA, and

[0331] adjusting the stimulation energy to the phrenic nerve of the patient based on the detected airway obstruction in the patient's airway and while the patient is sleeping.

[0332] Embodiment 36. The method according to Embodiment 35 further includes confirming that the patient remains asleep after adjusting the stimulation energy.

[0333] Embodiment 37. The method according to Embodiment 36 further includes selecting a stimulation energy that both stops the obstruction and opens the airway and does not wake the patient.

[0334] Although the present invention has been described in connection with the presently considered most practical and preferred embodiments, it should be understood that the invention is not limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0335] List of elements identified in the figures

[0336] Patient 1

[0337] Pharyngeal airway (pharynx, airway) 2

[0338] Negative inspiratory pressure in the airway 3

[0339] Positive pressure outside the airway 4

[0340] Pharyngeal dilator muscle (e.g., genioglossus muscle) 5

[0341] Mandible 6

[0342] Increase in lung volume 7

[0343] Soft palate (velum) 8

[0344] Palatopharyngeal or palatopharyngeal space 9

[0345] CNS respiratory center 10

[0346] Physiological sensor 11

[0347] Genioglossus muscle 14

[0348] Afferent branch of the reflex 12

[0349] Efferent limb of the reflex 13

[0350] Medulla 16

[0351] Phasic activation of the pharyngeal dilator muscles 20 Pharyngeal patency 21

[0352] Impaired pharyngeal anatomy 22 Reduced reflex 24

[0353] Falling asleep 23

[0354] Reduced response to negative pressure 25

[0355] Airway closure 26

[0356] Hypoxia and hypocapnia 27 Increased respiratory effort 28

[0357] Arousal 29

[0358] Phrenic nerve stimulation 30

[0359] Enhanced negative pressure 31

[0360] Activation of the NPR afferent limb 32 Restored activity of the dilator muscles 33 Implantable pulse generator (IPG) 41 Electrode system 42

[0361] Diaphragm 43

[0362] Phrenic nerve 44

[0363] Lung 45

[0364] Stimulation system 46

[0365] Lead 47

[0366] Handheld computer programming instrument 48

[0367] Airflow 50

[0368] Respiratory effort 51

[0369] Drop in oxygen saturation during apnea 52

[0370] Control period when stimulation is off 52 54

[0371] Period when on 53, 55, 56

[0372] Stimulation current level 55

[0373] Increased current level 56

[0374] The first trace of the airflow sensor signal is shown in the 50-a curve graph. The second trace of the respiratory belt sensor signal is shown in the 51-a curve graph. The third trace of the pulse oximeter measurement is shown in the 52-a curve graph. 53-a arbitrary waveform generator

[0375] The first stimulation pulse train 60

[0376] The second stimulation pulse train 61

[0377] The start of effort 62

[0378] The transition from inspiration to expiration 63

[0379] The cessation of effort 65

[0380] Time delay 66

[0381] The airway opens and the inspiratory airflow begins 67

[0382] Obstructed but unclosed airflow 69

[0383] Delay time 71

[0384] Inflection point 73

[0385] Inspiration is terminated by respiration 74

[0386] Expiration point 75

[0387] 70-a airflow rate graph

[0388] 70-b graph of respiratory effort over time

[0389] 70-c respiratory effort signal

[0390] 70-d airflow signal for detecting sleep onset and OSA 80

[0391] Analyze respiration 81

[0392] Stimulate the phrenic nerve 82

[0393] Normal respiration resumes 83

[0394] Adjust parameters 84

[0395] Accept parameters 85

[0396] Curve of contraction intensity versus stimulation energy 100 Diaphragm contraction intensity 101

[0397] Stimulation energy 102

[0398] Minimum capture level 103

[0399] Respiratory normalization level 104

[0400] Tolerance level 105

[0401] Maximum myotonic contraction level 106 Therapeutic range 107

[0402] Reflex activation level 108

[0403] Analyze respiration and movement 150

[0404] Patient at rest 152

[0405] Increase energy 154

[0406] Capture detected 156

[0407] Store data and stop test 158 Analyze respiration and movement 170

[0408] OSA detected 172

[0409] Increase energy 174

[0410] Wake up 176

[0411] Reduce energy and store data 178 Graph 200

[0412] Test ramp 201

[0413] First treatment ramp 202

[0414] Nighttime rest capture threshold 205

[0415] First treatment threshold 206

[0416] Second treatment ramp 204

[0417] Second treatment threshold 207

[0418] Wearable monitoring system 210

[0419] Bedside monitoring device 211

[0420] Cloud computer system, 212

[0421] Sensing wire 213

[0422] Stimulus burst 220

[0423] Volume change 221

[0424] Delay 222

[0425] Increased stimulation rate 223

[0426] Respiratory rate 224

[0427] Positive phase shift 225

[0428] Stimulation portion of the first duty cycle 230

[0429] Stimulation portion of the second duty cycle 231

[0430] End - expiratory lung volume 232

[0431] Stimulation during inspiration 233

[0432] Connector 301

[0433] Housing 302

[0434] Electronic circuitry 303

[0435] Battery 304

[0436] Sense lead port 305

[0437] Stimulation lead port 306

[0438] Low - frequency LF power peak 320

[0439] High - frequency HF peak 321

[0440] Stimulation power peak 322

[0441] Microprocessor 400

[0442] Tuned telemetry coil circuit 407

[0443] Proximity sensor or switch 408

[0444] Real - time clock 409

[0445] Telemetry driver / receiver circuit 410

[0446] Tri - axis accelerometer 411

[0447] Voltage sensing circuit 415

[0448] Excitation current 416

[0449] Battery 417

[0450] Voltage reference 418

[0451] Amplifier / digital - to - analog converter 419

[0452] Power supply 420

[0453] Current source circuit 421

[0454] Polarity switching network, positive 425

[0455] Polarity switching network, negative 426

[0456] Sensor 430

[0457] Analyze respiration and movement 500

[0458] Determine whether in rest or sleep 502

[0459] Calculate phase angle 504

[0460] Phase angle determination on target 506

[0461] Adjustment rate 508

[0462] Analyze respiration and movement 550

[0463] OSA detected 552

[0464] Increase lung volume 554

[0465] Determine waking up 556

[0466] Restart treatment 558

[0467] Delay time parameter 1102

[0468] Treatment ramp time parameter 1104.

Claims

1. A system configured to treat obstructive sleep apnea (OSA), the system comprising: a phrenic nerve stimulator configured to deliver stimulation energy to the phrenic nerve of a sleeping patient; at least one sensor configured to output one or more signals indicative of an obstruction state in an airway; and a controller configured to perform a process including the steps of: receiving the one or more signals, and controlling the phrenic nerve stimulator to deliver the stimulation energy based on the one or more signals.

2. The system according to claim 1, wherein, The sensor is configured to detect a partial or complete obstruction in the airway of the sleeping patient and output the one or more signals in the presence of a partially or completely obstructed airway.

3. The system according to any one of the preceding claims, wherein, The step of controlling the phrenic nerve stimulator includes: in response to receiving from the at least one sensor one or more signals identifying the airway as being partially or completely obstructed, commanding the phrenic nerve stimulator to deliver the stimulation energy or increase the delivery of the stimulation energy when the airway is partially or completely obstructed.

4. The system according to any one of the preceding claims, wherein, The step of controlling the phrenic nerve stimulator includes: determining an obstruction state of the airway based on the one or more signals from the at least one sensor, determining whether the airway is partially or completely obstructed, and if it is determined that the airway is partially or completely obstructed, commanding the phrenic nerve stimulator to deliver the stimulation energy or increase the delivery of the stimulation energy when the airway is partially or completely obstructed.

5. The system according to any one of the preceding claims, wherein, The process configured to be performed by the controller includes the following further steps: for a given patient, receiving or determining a diaphragmatic contraction threshold sufficient to cause diaphragmatic contraction and generate a negative airway pressure; and wherein the step of controlling the phrenic nerve stimulator includes maintaining the stimulation energy at or above the diaphragmatic contraction threshold when the airway is partially or completely obstructed.

6. The system according to any one of the preceding claims, wherein, The process configured to be performed by the controller includes the following further steps: for a given patient, receiving or determining a patient arousal threshold insufficient to arouse the patient; and wherein the step of controlling the phrenic nerve stimulator includes maintaining the stimulation energy below the patient arousal threshold when the airway is partially or completely obstructed.

7. The system according to any one of the preceding claims, wherein, The process configured to be performed by the controller includes the following further steps: determining whether the patient is at rest or sleeping.

8. The system according to claim 7, wherein, Determining whether the patient is at rest or sleeping includes: receiving from a user interface communicatively coupled to the controller a command indicating that the patient is at rest or sleeping, and / or receiving from a user interface communicatively coupled to the controller a command indicating that the patient is interrupting rest or sleep.

9. The system according to claim 7 or 8, wherein Determining whether the patient is at rest or sleeping includes: identifying the current time of day, Compare the current time of the day with one or more preset time intervals stored in a memory communicatively connected to or as part of the controller, and indicating one or more time periods during the day when the patient is considered to be at rest or asleep.

10. The system according to claim 7 or 8 or 9, wherein, Determining whether the patient is at rest or asleep includes: Receiving one or more vital sign signals from one or more vital sign detectors of the patient, the vital sign sensors being communicatively connected to the controller, and Based on the one or more vital sign signals, determining that the patient is at rest, optionally asleep, and / or determining that the patient has interrupted rest or interrupted sleep.

11. The system according to claim 10, wherein, The one or more vital sign detectors include: A motion sensor, optionally an inertial sensor part of the controller or configured to be coupled to the patient.

12. The system according to claim 10 or 11, wherein, The one or more vital sign detectors include: A respiratory sensor, Optionally, wherein the one or more vital sign detectors include both a motion sensor and a respiratory sensor, and wherein the controller determines whether the patient is at rest or asleep based on signals from both the respiratory sensor and the motion sensor.

13. The system according to claim 10, 11 or 12, wherein The one or more vital sign detectors include: ECG and / or A blood pressure sensor.

14. The system according to claim 10, 11, 12 or 13, wherein The one or more vital sign detectors include: An oxygen saturation sensor, optionally a finger pulse oximeter.

15. The system according to any one of claims 7 to 14, wherein, The controller is configured to command the phrenic nerve stimulator to deliver the stimulation energy or increase the delivery of the stimulation energy when the patient is determined to be at rest or asleep.

16. The system according to any one of the preceding claims, wherein, The process that the controller is configured to execute repeats at a time interval, optionally repeating periodically 6 to 20 times per minute.

17. The system according to any one of the preceding claims, wherein, The process that the controller is configured to execute repeats at a time interval, optionally repeating periodically, until it is detected or determined that the airway is no longer partially or completely blocked.

18. The system according to claim 16 or 17, when combined with any one of claims 7 to 15, wherein, The process that the controller is configured to execute repeats at a time interval when the patient is determined to be at rest or asleep, optionally repeating periodically.

19. The system according to any one of the preceding claims 16 to 18, wherein, At each repetition of the process, the controller is configured to control the phrenic nerve stimulator to change, optionally increase, the delivery of the stimulation energy.

20. The system according to any one of the preceding claims, wherein, The controller is configured to control the phrenic nerve stimulator to deliver the stimulation energy in the form of a pulse train.

21. The system according to claim 20, wherein, Controlling the phrenic nerve stimulator to deliver the stimulation energy in the form of a pulse train includes controlling one or more of the following pulse train parameters: The number of individual pulses in the pulse train, The frequency of individual pulses in the pulse train, The amplitude of individual pulses in the pulse train, The duration of individual pulses in the pulse train.

22. The system according to claim 21, wherein, Controlling the phrenic nerve stimulator to increase the delivery of the stimulation energy includes one of the following: Increasing the number of individual pulses in the pulse train, Increasing the frequency of individual pulses in the pulse train, Increasing the amplitude of individual pulses in the pulse train, Increasing the number and frequency of individual pulses in the pulse train, Increasing the amplitude and frequency of individual pulses in the pulse train, Increasing the amplitude and number of individual pulses in the pulse train, or Increasing the number, frequency, and amplitude of individual pulses in the pulse train; Optionally, wherein the duration remains constant.

23. The method according to claim 21 or 22, wherein: The number of individual pulses in the pulse train is maintained between 5 and 40.

24. The system according to any one of claims 21 to 23, wherein: The frequency of an individual pulse is maintained between 20 Hz and 50 Hz.

25. The system according to any one of claims 21 to 24, wherein: The duration of an individual pulse is maintained between 30 microseconds and 250 microseconds.

26. The system according to any one of claims 21 to 25, wherein: The amplitude of an individual pulse is maintained between 0.4 mA and 5.0 mA, optionally between 1.0 mA and 4.0 mA.

27. The system according to any one of the preceding claims, wherein, The step of controlling the phrenic nerve stimulator to deliver the stimulation energy includes: Commanding a ramp or step - up in the delivery of energy at time intervals, optionally at periodic time intervals, when: Whenever the controller receives from the at least one sensor one or more signals identifying that the airway is partially or completely obstructed, and / or Whenever the controller determines that the airway is partially or completely obstructed.

28. The system according to any one of the preceding claims, wherein, The process that the controller is configured to perform includes: Receiving or determining a treatment range, and Controlling the phrenic nerve stimulator to deliver the stimulation energy within the treatment range, wherein the treatment range is between a first threshold and a second threshold higher than the first threshold, optionally, wherein the treatment range is stored in a memory communicatively connected to the controller.

29. The system according to claim 28, wherein The process includes determining the treatment range by: gradually increasing the stimulation energy and detecting the first threshold as the stimulation energy threshold at which a first detectable patient event occurs, optionally detecting the first threshold as the stimulation energy threshold at which the patient's breathing pattern changes in a systematic and periodic manner; and detecting the second threshold as another stimulation energy threshold at which a second detectable patient event occurs, wherein at the other stimulation energy threshold, the patient's breathing is stable and no partial or complete airway obstruction is detected.

30. The system according to claim 28 or 29, wherein The process that the controller is configured to perform includes receiving or determining multiple treatment ranges for the same patient, the multiple treatment ranges including treatment ranges determined for each respective different posture of the patient during rest or sleep.

31. The system according to any one of the preceding claims, when combined with claims 7 and 27, wherein The step of controlling the phrenic nerve stimulator to deliver the stimulation energy includes: stopping the ramp or step - up in the delivery of energy if it is determined that the patient is no longer at rest or asleep.

32. The system according to any one of the preceding claims, wherein, The step of controlling the phrenic nerve stimulator to deliver the stimulation energy includes: actuating the phrenic nerve stimulator to deliver the stimulation energy as one or more stimulation bursts initiated when the airway is obstructed.

33. The system according to any one of the preceding claims, wherein, The stimulation energy includes at least one first stimulation burst, and the at least one first stimulation burst is first applied at a first energy level sufficient to generate an action potential in the phrenic nerve of the patient and is applied at at least one second energy level that is applied after the first stimulation burst and is sufficient to induce a reflexive opening of the occluded airway through activation of the upper airway muscles.

34. The system according to any one of the preceding claims, wherein, The stimulation energy includes at least one first stimulation burst and further at least one second stimulation burst, the at least one first stimulation burst is first applied at a first energy level sufficient to generate an action potential in the phrenic nerve of the patient, and the at least one second stimulation burst is applied at a second energy level sufficient to induce a reflexive opening of the occluded airway through enhancement of the mechanical reflex.

35. The system according to any one of the preceding claims, wherein, The phrenic nerve stimulator includes a pulse generator and electrodes configured to be implanted near the phrenic nerve.

36. The system according to any one of the preceding claims, wherein, The controller and the phrenic nerve stimulator are within an implantable pulse generator (IPG).

37. The system according to any one of the preceding claims 1 to 35, wherein, A first part of the controller and the phrenic nerve stimulator are within the implantable pulse generator, and a second part of the controller is located on an external, optionally portable, device communicatively coupled to the first part of the controller.

38. The system according to any one of the preceding claims, wherein, The controller is configured to cause the phrenic nerve stimulator to adjust the stimulation energy until the airway is opened in response to the stimulation energy.

39. The system according to any one of the preceding claims, wherein, The at least one sensor configured to output one or more signals indicative of an occlusion state in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter including: The airflow through the air breathing passage in the patient's airway.

40. The system according to any one of the preceding claims, wherein, The at least one sensor configured to output one or more signals indicative of an occlusion state in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter including: The breath sounds of the patient.

41. The system according to any one of the preceding claims, wherein, The at least one sensor configured to output one or more signals indicative of an occlusion state in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter including: The respiratory effort of the patient.

42. The system according to any one of the preceding claims, wherein, The at least one sensor configured to output one or more signals indicative of an occlusion state in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter including: The airway pressure and / or oxygen saturation of the patient.

43. The system according to any one of claims 39 to 42, wherein, The at least one sensor or the controller is configured to detect or determine the presence of a partial or complete occlusion by comparing the monitored at least one patient parameter with a corresponding patient parameter threshold, optionally, wherein the controller is configured to receive the / each corresponding patient parameter threshold from a user interface or from a memory communicatively coupled to the controller.

44. The system according to any one of the preceding claims, wherein, The controller is configured to cause the phrenic nerve stimulator to deliver the stimulation energy during the respiration of the sleeping patient, wherein the rate of the respiration is 6 to 20 breaths per minute, 8 to 14 breaths per minute, 6 to 15 breaths per minute, or 10 to 15 breaths per minute.

45. The system according to any one of the preceding claims, wherein, The controller is configured to cause the phrenic nerve stimulator to deliver the stimulation energy during a duty cycle of 30% to 50% of the respiratory period, 35% to 40% of the respiratory period, 40% to 60% of the respiratory period, or 25% to 60% of the respiratory period.

46. The system according to any one of the preceding claims, wherein, The controller is configured to automatically adjust the stimulation energy based on the at least one sensor, the at least one sensor being configured to detect at least one of the following patient parameters: Airflow in the respiration of the sleeping patient; Respiratory sound of the sleeping patient; Respiratory effort of the sleeping patient; Airway pressure of the sleeping patient; Or Oxygen saturation of the sleeping patient.

47. The system according to any one of the preceding claims, wherein, The controller includes one or more processors; and wherein the system includes a computer-readable storage device communicatively coupled to the one or more processors and having instructions stored thereon that, when executed by the one or more processors, cause the one or more processors to perform the processes and / or controller steps described in any one of the preceding claims.

48. A non-transitory computer-readable storage medium communicatively coupled to a controller of the system according to any one of claims 1 to 46, wherein, The non-transitory computer-readable storage medium stores instructions that, when executed by the controller, cause the controller to perform the processes and / or controller steps described in any one of the preceding claims.

49. A non-transitory computer-readable storage medium communicatively coupled to one or more processors of a controller of the system according to claim 47, wherein, The non-transitory computer-readable storage medium stores instructions that, when executed by the one or more processors, cause the one or more processors to perform the processes and / or controller steps described in any one of the preceding claims.

50. A controller for a system configured to treat obstructive sleep apnea (OSA), the system including: A phrenic nerve stimulator configured to deliver stimulation energy to the phrenic nerve of a sleeping patient; At least one sensor configured to output one or more signals indicative of an obstruction state in the airway; And Wherein the controller is configured to perform a process including the following steps: Receiving the one or more signals, and Controlling the phrenic nerve stimulator to deliver the stimulation energy based on the one or more signals.

51. The controller according to claim 50, wherein, The controller is configured to perform the steps and / or processes of the controller of the system according to any one of claims 1 to 46.

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