Method and system for stimulating the phrenic nerve to treat sleep apnea

Abstract

1. A method of identifying a patient with obstructive sleep apnea, implanting a phrenic nerve stimulator in the patient or connecting it to the diaphragm, and adjusting stimulation energy applied by the phrenic nerve stimulator to the phrenic nerve in a sleeping patient based on airway obstruction in the patient's airway.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to U.S. Provisional Application No. 63 / 426,072, filed November 17, 2022, and U.S. Provisional Application No. 63 / 442,331, filed January 31, 2023, the entire contents of each of which are incorporated herein by reference. [Technical field]

[0002] This invention relates to an implantable device that stimulates the phrenic nerve to treat airway collapse in patients with obstructive sleep apnea (OSA). The invention can be implemented to utilize the pharyngeal mechanoreceptor reflex to stiffen or reverse airway collapse, improve gas exchange, and / or enhance sleep quality. The invention is intended to stimulate the phrenic nerve to trigger a reflex that opens obstructed airways in a sleeping patient's respiratory pathway while keeping the patient comfortable and asleep. [background]

[0003] Healthy sleep is an important part of our lives. Healthy sleep improves physical and mental health. Sleep occurs in multiple stages, including REM sleep and non-REM sleep. When we sleep, our bodies have the opportunity to rest and recharge. Getting a good night's sleep can help us cope with stress, solve problems, or recover from illness. Not getting enough sleep can lead to many health concerns and affects the way we think and feel.

[0004] During sleep, people typically go through four sleep stages: non-REM N1, N2, and N3, and REM (rapid eye movement). These stages of sleep progress in cycles from N1 to REM sleep, after which the cycle begins again at N1 or N2. Healthy children and adults spend approximately 50 percent of their total sleep time in N2 sleep, about 20 percent in REM sleep, and the remaining 30 percent in the other stages.

[0005] During N1, a light sleep stage, we can drift in and out of sleep and be easily awakened. Our eyes move very slowly and muscle activity slows. People awakened from N1 sleep often remember fragmented visual images.

[0006] When we enter N2 sleep, our eye movements stop and our brain waves (fluctuations in electrical activity that can be measured with EEG electrodes) become slower, with occasional bursts of fast waves called sleep spindles.

[0007] EEG is an abbreviation for electroencephalogram. A sleep EEG is a recording of the brain's electrical activity while awake and then asleep. A sleep EEG involves placing small electrodes on the scalp that record brain activity.

[0008] In N3, extremely slow brain waves called delta waves begin to appear, interspersed with smaller, faster waves until delta waves are almost exclusively present. It is very difficult to wake someone up during N3, also known as deep or slow-wave sleep.

[0009] When we switch to REM sleep, our breathing becomes more rapid, irregular, and shallow, our eyes move rapidly in different directions, and our limb muscles become temporarily paralyzed during sleep. Our heart rate increases and our blood pressure rises. People often talk about dreaming when they wake up during REM sleep.

[0010] The first REM sleep period usually occurs about 70 to 90 minutes after we fall asleep. One complete sleep cycle takes an average of 90 to 110 minutes. The first sleep cycle each night encompasses a relatively short REM period and a long period of deep sleep. As the night progresses, REM sleep periods increase in length, while deep sleep decreases. By morning, healthy people spend almost all of their sleep time in stages 1, 2, and REM.

[0011] Although the neurophysiology of sleep is not fully understood, it is undisputed that a night of deep sleep is a continuous, uninterrupted night's sleep that cycles uninterruptedly through sleep stages, including REM. Sleep disorders such as OSA frequently disrupt and fragment these continuous sleep patterns, resulting in daytime sleepiness, fatigue, and many other serious adverse effects on both mental and physical health.

[0012] Obstructive sleep apnea (OSA) is a well-recognized and dangerous condition that affects millions of people. OSA can be described as a sleep disorder that results in periodic interruptions of pulmonary ventilation, further fragmenting sleep.

[0013] The pathogenesis of upper airway (UA) obstruction during sleep is due to (a) a primary, sleep-related loss of UA neuromotor tone and (b) a secondary, lack of appropriate compensatory reflex responses to relieve the obstruction.

[0014] In healthy individuals, upper airway stability during sleep is ensured by coordinated and synchronized central control of approximately 20 airway dilator and constrictor muscles (collectively "airway muscles"). A central nervous system (CNS) pattern generator (respiratory center) in the brain's medulla oblongata receives input from physiological sensors (also called receptors) via various afferent sensory nerve fibers and controls airway muscles via efferent motor fibers. These physiological sensors provide physiological feedback used by the medulla oblongata to trigger reflexes in a closed-loop reflex mechanism. These reflexes are known as "autonomic" because they are not dependent on conscious awareness. In some cases, reflexes are insufficient for optimal health. The inventors believe that obstructive sleep apnea (OSA) may result from a lack of a reflex response to an obstructed airway or an insufficient reflex response to an obstructed airway.

[0015] Sensory input to the respiratory center includes signals from chemoreceptors, which respond to oxygen (O2) and carbon dioxide (CO2) in arterial blood, and numerous distributed mechanoreceptors, including those that respond to transmural pressure within and across the airway wall. In patients with central sleep apnea (CSA), the former "neurochemical" control loop may be disrupted and overactive. In patients with snoring and OSA, the latter "neuromuscular" control loop may be insufficiently active to maintain airway patency.

[0016] The airway muscles that hold the upper airway open are accessory muscles of respiration that maintain pharyngeal patency during inspiration. Basal tone in these muscles typically decreases during sleep onset. This loss of tone predisposes the airway to collapse, obstructing airflow during sleep.

[0017] Afferent receptors in the tracheobronchial tree and lungs detect alterations in airway pressure, temperature, airflow, and lung distension that may be indicative of a collapsed airway. The afferent receptors provide feedback signals to the spinal cord or CNS, which may respond by triggering a reflex response that stimulates upper airway muscles, which then allows relief of airway obstruction.

[0018] Previous researchers have suggested that patients with obstructive sleep apnea rely heavily on these reflexes to maintain upper airway patency during wakefulness, and that loss or reduction of reflex activation of airway muscles during inspiration leads to increased airway collapsibility during sleep.

[0019] Over time, afferent receptors may progressively desensitize in patients with chronic OSA. The patient's brain may be unable to adapt to the gradual onset of airflow obstruction. OSA may develop because the brain does not receive appropriate signals from afferent receptors indicating airway blockage. Under these circumstances, airway neuromuscular activity no longer compensates for the airway obstruction that occurs during sleep.

[0020] Current evidence indicates that neuromuscular responses in the upper airway muscles must be coordinated with inspiratory activation of the diaphragm and respiratory pump muscles to maintain patency during sleep.

[0021] Existing neuromodulation treatments address airway collapsibility by selectively increasing nerve signals in selected efferent branches of the hypoglossal nerve (HGN). These branches control tongue protrusion via the genioglossus muscle (GGM). Experimental work also exists targeting selectively increasing other efferent motor control signals to various dilator muscles, including the cervical fasciculus, which may contribute to airway stiffening.

[0022] Increasing lung volume, especially during exhalation, can improve airway patency during sleep in patients with OSA. U.S. Patent 7,970,475 to Tehrani, entitled "Device and Method for Biasing Lung Volume," describes a device and method for increasing lung volume by electrically stimulating the phrenic nerve. This and other prior art teach that stimulation of the phrenic nerve is applied to create mechanical traction on the airway, which stiffens the airway and expands the lung, creating additional lung volume. One concern with this approach is that it requires high stimulation energy levels to treat moderate to severe sleep apnea, which can arouse patients and is not tolerated by them. [overview]

[0023] Inventive methods and systems have been developed and are disclosed herein for stimulating peripheral nerves involved in breathing to take advantage of existing physiological autonomic control reflex loops. By artificially triggering or otherwise enhancing the physiological autonomic control reflex loops, the methods enhance and restore the natural control of airway stability, using reflexes to open airways that close during sleep, thereby treating OSA.

[0024] In one embodiment, the method enhances the afferent limb of a pharyngeal mechanoreceptor reflex, e.g., the negative pressure reflex (NPR), which naturally dilates and stabilizes the airway in response to increased transmural negative pressure in the airway. The NPR has been described in the scientific literature, and it is recognized that a progressive decline in this reflex during sleep contributes to snoring and airway collapse in at least some OSA patients.

[0025] In awake, healthy people, pharyngeal patency is protected by dilator muscles, and negative airway pressure (collapse pressure) acts as a local stimulus for progressive activation of the dilator muscles. The respiratory pump can be modeled as a bellows or pneumatic cylinder, where rapid depression of the diaphragm causes an influx of fresh air through the nose, down the airways, and into the lungs. This airflow creates a significant pressure gradient along the airways that rapidly rises with increasing upstream resistance. Because the airway is a collapsible tube, the force exerted by this negative pressure during inspiration must be countered to prevent collapse. This counteraction is the primary role of NPR.

[0026] NPR is manifested by robust and very rapid (within 30–50 ms) activation of pharyngeal dilator muscles when a rapid pulse of suction (negative) pressure is applied by inhaling ambient air through the nose. Presumably, such activation is a protective reflex that allows the pharynx to resist closure during potential collapse disturbances under conditions of increased ventilatory drive during sniffing, exercise, or gasping for air, despite anatomical challenges such as excess body weight.

[0027] During sleep, afferent neural feedback through NPR can be used to induce coordinated responses in multiple accessory muscles that maintain pharyngeal patency without briefly arousing the patient from sleep.

[0028] While conducting phrenic nerve stimulation experiments to manipulate lung volume in sleeping patients, the inventors recognized that these concepts involving reflexes could be harnessed for therapeutic treatment and implemented in embedded software algorithms using known or co-developed device hardware and implantation procedures.

[0029] The disclosed approach to treating OSA by intentionally triggering NPR is counterintuitive and contradicts certain established beliefs and clinical practice. First, negative airway pressure collapses the airway, and stimulating the phrenic nerve increases negative airway pressure, potentially further collapsing the airway. Increasing negative pressure to open the airway is counterintuitive. Second, clinical practice of phrenic nerve stimulation in individuals with central nervous system disorders, such as congenital hypoventilation, frequently required tracheotomy to prevent airway collapse induced by increased negative pressure. Third, when healthy individuals are placed in a negative pressure ventilator, e.g., an iron lung, their normal respiratory effort and central chemoreflexes frequently reduce or eliminate ventilatory drive. It has been observed that the use of negative pressure ventilation in individuals with OSA increases airway collapsibility. Fourth, treatment of OSA acts to prevent obstruction within the airway. Because NPR requires, or at least is thought to require, obstruction to trigger it, it seems counterintuitive to treat OSA in a manner that would allow for even temporary obstruction of the airway.

[0030] The inventors break with convention and popular concepts and propose to utilize negative pressure conditions within the airway to trigger NPR and treat airway collapse. While observing sleeping OSA patients receiving treatment with phrenic nerve stimulation, the inventors were surprised to observe that a specific pattern of phrenic nerve stimulation triggered neural feedback from mechanosensory input, which almost immediately opened the collapsed airway, acting against the closed upper airway and against the collapsing negative pressure, without waking the patient or disrupting their continuous sleep cycle. Surprisingly, the forceful diaphragmatic contraction in response to phrenic nerve stimulation applied over a relatively short period was effective in treating OSA when applied during the late expiratory and early inspiratory phases of natural breathing, when the airway is perceived as more collapsible and vulnerable. The substantial sudden negative pressure was manifested by a decrease in chest circumference with abdominal expansion during an inspiratory pattern known as paradoxical breathing.

[0031] In one proposed embodiment, the present invention enhances and restores NPR in sleeping OSA patients by periodically stimulating one or both phrenic nerves and generating relatively brief (e.g., less than 50% of the patient's natural breathing duration) vigorous contractions of the diaphragm, generally coinciding with specific portions of the respiratory cycle, more specifically, the late-expiration-early-inspiration period. In our experiments, we observed that such pulses of negative pressure can enhance and restore airway patency in sleeping patients with severe sleep apnea, which we attribute to reflex activation. The spikes of negative pressure generated by vigorous diaphragm depression can result in enhanced afferent signals from baroreceptors located in the pharyngeal mucosa when they occur in the setting of an obstructed or resistant airway. These afferent signals are known to carry information from mechanoreceptors in laryngeal structures, independent of the phrenic nerve, via afferent fibers of pharyngeal nerves, possibly the superior laryngeal nerve, and from the pharyngeal mucosa via the glossopharyngeal nerve to the respiratory control center in the brain.

[0032] This increased neural firing can increase afferent signals above a threshold that forces the respiratory control center to generate efferent signals to various groups of dilator muscles sufficient to stiffen the airway and restore airflow. In this context, if stimulation bursts are delivered frequently, e.g., at a natural breathing rate of 6-20 breaths per minute, the airway will not remain closed long enough to impede ventilation or gas exchange in any significant way, and oxygen saturation will be maintained. It may be desirable to synchronize diaphragmatic contraction with patient-initiated inspiration, or to set a physiologically acceptable rate that allows the patient to synchronize with the stimulation. In some embodiments, only every other breath, or other ratio of breaths, is stimulated.

[0033] In natural physiology, lung inflation inhibits inspiration. Phrenic nerve stimulation can increase relative inspiratory time by overriding central control. Phrenic nerve stimulation during expiration inhibits expiration and leads to dynamic lung hyperinflation. As lung volume increases, it exerts caudal traction on upper airway structures and stiffens the pharynx.

[0034] In another embodiment of the invention, phrenic nerve stimulation (PNS) is used to implement diaphragmatic bias or offset, or more generally, to inhibit exhalation and produce mild dynamic lung hyperinflation. This stimulation modality may be particularly effective in patients with reduced lung volume. It is well accepted that increased lung volume during the expiratory phase of the respiratory cycle exerts mechanical caudal traction on the airway. In patients with reduced lung volume, such as due to significant abdominal visceral fat, restoration of lung volume may contribute to airway patency.

[0035] Sleep-induced reductions in lung volume can result in a significant reduction in longitudinal traction on the airway, resulting in an increasingly collapsible pharynx, even in patients with normal lung volumes while awake. Some individuals may be highly dependent on this mechanism to maintain airway patency while awake and lose airway patency during sleep. Lung volume bias can be combined with periodic contractions of the diaphragm, causing NPR in some patients.

[0036] Lung volume can be increased "statically" by pulmonary bias using application of a constant, low level of tension to the phrenic nerve, which prevents complete lung contraction, applies caudal traction, and stiffens the pharynx.

[0037] Lung volume can also be dynamically increased by "expiratory block" through increased phrenic nerve bust frequency or increased inspiratory:expiratory (I:E) ratio, which "dynamically" traps air, prevents complete lung deflation, applies caudal traction, and stiffens the pharynx. Increasing severity of upper airway obstruction further impedes exhalation, increasing the degree of airway trapping and dynamic hyperinflation.

[0038] Obstructive sleep apnea (OSA) is the intermittent cessation of breathing during sleep due to collapse of the pharyngeal airway. Once a sleeping person's airway completely collapses without intervention, it typically remains collapsed until the patient is awakened by air hunger (a short-term arousal). It typically takes the airway long enough to recover, resulting in significant intermittent and periodic oxygen desaturations that can have serious consequences for the patient's health. This delay is inherent in physiology, because it takes some time for blood to flow from the lungs to the chemosensors in the brain. This delay can be particularly long in sicker individuals, such as those with heart disease.

[0039] The pharynx (also called the pharyngeal airway, or simply the "airway" for brevity) is the 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 can collapse at any point along its path. There are over 20 muscles surrounding the pharyngeal passages. These muscles actively constrict and dilate the upper airway lumen. These muscles also contribute to airway stiffness, which is defined as the ability of the airway to withstand transmural negative pressure, regardless of airway diameter. In the context of this patent, stiffening of the airway by mechanical or neural intervention is referred to as airway stabilization.

[0040] The airway muscles can be divided into four groups: those that regulate the position of the soft palate (ala naris, tensor veli palatini, levator veli palatini), the tongue (genioglossus, geniohyoid, hyoglossus, styloglossus), the hyoid complex (hyoglossus, genioglossus, digastric, geniohyoid, sternohyoid), and the posterolateral wall of the pharynx (palatoglossus, pharyngeal constrictor).

[0041] These muscle groups interact in a complex manner to keep the airway open or closed. The soft tissue structures that form the walls of the upper airway and tonsils include the soft palate, uvula, tongue, and lateral pharyngeal walls.

[0042] The site of airway collapse is significant in the pathophysiology of OSA and in targeting any therapeutic measures to prevent collapse. Sites of airway collapse commonly identified in the literature are associated with the posterior tongue space (tongue base), velopharyngeal space (soft palate obstruction), and / or hypopharyngeal space (airway lateral wall obstruction). The Velum (soft palate), Oropharynx, Tongue base, and Epiglottis (VOTE) classification for drug-induced sleep endoscopy (DISE) is widely used to classify sites of collapse for obstructive sleep apnea (OSA) syndromes.

[0043] Figure 1 illustrates the balance of forces that keep the airway open during inspiration. Negative inspiratory pressure and positive extraluminal pressure tend to promote pharyngeal collapse. Upper airway dilator muscles and increased lung volume (as the lungs fill with air) tend to maintain pharyngeal patency. A patient 1 inhales air at atmospheric pressure through the nostrils. The inhaled air flows down the pharyngeal airway 2. The soft palate 8 (sometimes called the velum) defines the velopharynx or velopharyngeal space 9, the most common site of airway collapse.

[0044] Variables that tend to promote pharyngeal collapse include negative pressure 3 within the airway resulting from inspiratory effort and positive pressure 4 outside the airway. Positive pressure 4 is a product of pressures generated by posture and gravity, fat deposits, and other anatomical factors, such as a small mandible 6. The sum of these pressures 4 and 3 defines the transmural pressure sensed by mechanoreceptors within the airway. Negative inspiratory pressure 3 is dynamic and present during inspiration at every point along the airway. Negative inspiratory pressure 3 is proportional to airflow and upstream resistance, but increases at every level of ventilatory drive whenever the upper airway is obstructed. Conversely, patency is maintained by activation of pharyngeal dilator muscles 5 (e.g., the genioglossus and other muscles known but not depicted in Figure 1 ) and by increased lung volume 7, which tends to keep the airway open by longitudinal traction. As a result, distension forces (eg, muscle activation) interact in a complex manner with collapse forces generated by anatomical structures and negative airway pressure.

[0045] Figures 2A and 2B illustrate reflex control of the airway. The central nervous system (CNS) pattern generator (respiratory center) 10 resides in the medulla oblongata 16 of the brain. The medullary rhythmic center in the brainstem controls automatic breathing during sleep and consists of interacting neurons that fire either during inspiration (I neurons) or expiration (E neurons). I neurons stimulate neurons that innervate the respiratory muscles (resulting in inspiration). E neurons inhibit I neurons ("blocking" I neurons, resulting in expiration). The tonic inspiratory center (located in the pons) stimulates I neurons (facilitating inspiration). The respiratory control center (also located in the pons) inhibits the tonic inspiratory center, inhibiting inspiration. Phrenic nerve stimulation, which directly affects the respiratory pump, can overcome this inhibition.

[0046] The respiratory center 10 receives input from physiological sensors 11 via various afferent sensory nerve fibers and maintains a patent airway through stiffening and dilatation by synchronizing muscle contraction and relaxation via efferent motor fibers. A key airway dilator muscle is the genioglossus 14, which protrudes and retracts the tongue. The genioglossus has a direct effect on the velopharyngeal space 9, where airway obstruction often occurs. Such physiological feedback mechanisms are known as closed-loop reflexes. Generally, such reflexes are known to be "autonomous" because they are not dependent on conscious awareness.

[0047] The negative pressure reflex (NPR) may be an example of a pharyngeal mechanoreceptor reflex that activates dilator muscles. A mechanoreceptor reflex is a reflex triggered by stimulation of a mechanoreceptor. Muscle spindle stretch receptors, baroreceptors, shear receptors, or flow receptors may be examples of mechanoreceptors that respond to mechanical disturbances such as deformation and generate an afferent nerve signal consisting of a train of action potentials in a bundle of nerve fibers.

[0048] NPR is an important physiological reflex that is elicited and utilized during proposed therapeutic interventions. It is naturally manifested with each breath by robust and very rapid (within 30–50 milliseconds) activation of pharyngeal dilator muscles. NPR can also be elicited by rapid pulses of suction (negative) pressure applied via the nose and detected by a transmural pressure sensor at the pharyngeal mucosa. NPR can be enhanced or induced by electrical stimulation of the phrenic nerve, which produces diaphragmatic contraction. The magnitude of the signal detected by sensor 11 is proportional to the strength of the diaphragmatic contraction and the degree of airway obstruction, particularly within the velopharyngeal space 9. When the airway is obstructed (e.g., completely, partially, etc.), pressure becomes more negative, and afferent feedback from the reflex into the CNS becomes stronger. The response of CNS centers 10, in turn, is proportional to the input from afferent limb 12. This response generates a stronger output in the efferent limb 13, which results in a stronger contraction of the dilator muscles 14. Eventually, the overall closed-loop response becomes strong enough to open the airway and allow air in. Airway opening, in turn, leads to a reduction in negative pressure and the signal sensed in the afferent limb 12. The closed-loop system reaches a steady state, and respiratory stability can be restored.

[0049] Figures 1, 2A, and 2B are simplified to illustrate the main elements of pharyngeal anatomy and innervation. Because of the physiological importance of maintaining pharyngeal patency and the many tasks required of this portion of the airway (speech, swallowing, etc.), a sophisticated motor control system has developed, involving approximately 20 upper airway muscles. The following paragraphs provide more detail on the complexity of this natural mechanism for maintaining an open airway and previous attempts to improve this natural mechanism in patients with OSA.

[0050] During natural inspiration, negative intraluminal pressure pulls three soft tissue elements—the tongue, the posterior pharyngeal wall, and the soft palate—toward one another, thereby reducing the airway lumen within the velopharyngeal region. This airway collapse is opposed by the pharyngeal dilator muscles, including the genioglossus, geniohyoid, and tensor veli palatini and levator veli palatini muscles. Additionally, activation of the pharyngeal constrictor muscles stiffens the airway walls.

[0051] This carefully orchestrated natural activation of pharyngeal muscles keeps the airway open during wakefulness, but often fails during sleep. One objective of the described invention is to trigger, enhance, and utilize this process of natural airway contraction by NPR when natural excitatory traffic to corresponding motor neurons is insufficient to keep the airway open during sleep. This approach is novel because NPR, although known since the 1980s, has never been proposed as a therapeutic treatment. This approach is advantageous over the prior art because the prior art proposed controlling only specific efferent motor neurons (rather than sensory afferents), resulting in individual, uncoordinated responses from pharyngeal dilator muscles.

[0052] The soft palate comprises muscles and tissues that allow it to move and be flexible. During swallowing, the soft palate rises to seal the opening of the airway and prevent 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 uvula (MU). The tensor veli palatini (tensor palati, or tensor muscle of the velum palatinum) is a broad, thin, ribbon-like muscle within the head that tensions the soft palate.

[0053] The tensor veli palatini muscle is supplied by the medial pterygoid nerve, a branch of the mandibular nerve and the third division of the trigeminal nerve, and is the only muscle in the palate that is not innervated by the pharyngeal plexus formed by the vagus and glossopharyngeal nerves. The tensor veli palatini muscle tensions the soft palate, thereby assisting the levator veli palatini muscle in elevating the palate, creating occlusion and preventing food from entering the nasopharynx during swallowing.

[0054] The Palatoglossus muscle functions as an antagonist to the levator veli palatini muscle. It emerges from the palatine aponeurosis of the soft palate, where it is continuous with the opposing muscle. It passes in front of the palatine tonsils, inferiorly, anteriorly, and laterally, and inserts onto the sides of the tongue. Some of its fibers extend across the dorsum of the tongue, while others extend deep into the organ to intersect with the transverse tongue muscle. The Palatoglossus muscle is innervated by the vagus nerve (via the pharyngeal branch to the pharyngeal plexus). The Palatoglossus muscle elevates the posterior part of the tongue, closes the oropharyngeal isthmus, and assists in the initiation of swallowing. By maintaining the palatoglossal arch, this muscle also prevents saliva from leaking from the vestibule into the oropharynx.

[0055] The genioglossus muscle (GGM) receives input from the brainstem respiratory central pattern generator via the hypoglossal nerve (HGN). The presence of "preactivation" (hypoglossal nerve firing 50-100 ms before phrenic nerve firing) supports the existence of premotor input to the hypoglossal motor nucleus in the medulla oblongata.

[0056] The function of the GGM in health and disease has been extensively studied and documented, for example, Cori JM et al., "Sleeping tongu: current perspectives of genioglossus control in healthy individuals and patients with obstructive sleep apnea," Nat Sci Sleep, 2018 Jun 15;10:169-179.

[0057] The hypoglossal nerve, also known as the 12th cranial nerve, 12th cranial nerve, or simply CN XII, innervates the GGM and was the basis of the first successful neuromodulation technique for the treatment of OSA. HGN stimulation for treating OSA is disclosed in U.S. Patents 5,158,080 and 5,540,733.

[0058] Although HGN stimulation has met with some success, it is not an effective solution for many patients. While efficacy can be restored in some cases by increasing the power applied to the nerve, many patients are unable to tolerate increased power therapy for a variety of reasons. A possible reason for this is that acceptable levels of HGN activity are not sufficient to overcome other physiological changes that occur and persist during sleep, such as underactivity of other dilator muscles, altered coactivation patterns with other dilator muscles, and reduced lung volume resulting from reduced caudal traction of the airway. This application addresses these limitations through a novel approach: manipulation of lung volume and transmural airway pressure via stimulation of the phrenic nerve.

[0059] Figure 3 further illustrates the role of NPR in the pathogenesis of OSA. During wakefulness, in healthy and unhealthy OSA patients, pharyngeal patency 21 is maintained by phasic activation of pharyngeal dilator muscles 20, with negative airway pressure (collapse pressure) acting as a local stimulus for activation of the pharyngeal dilator muscles. The negative pressure reflex is a protective reflex that allows the pharynx to resist closure during collapse. The dilator muscles respond to negative pharyngeal pressure within tens of milliseconds, thereby maintaining airway patency.

[0060] To overcome dysfunctional pharyngeal anatomy, such as that commonly seen in obesity, suboptimal tongue anatomy, or suboptimal mandibular anatomy, upper airway dilator muscles in OSA patients must be more active during wakefulness than those in healthy individuals. During wakefulness, the NPR responds to increased negative pressure in patients with dysfunctional anatomy. The sensed response is a product of a smaller pharyngeal lumen and the need for greater intrapharyngeal pressure to generate adequate airflow. This increased negative pressure drives greater pharyngeal dilator muscle activation. Thus, airway muscles compensate for the defective anatomy in OSA patients during wakefulness, and ventilation is maintained. Even in patients with very severe OSA, disordered breathing events occur only during sleep, highlighting the importance of central control in the pathogenesis of this disorder.

[0061] It is known that neuromuscular reflexes are reduced during sleep. The ability of pharyngeal dilator muscles to respond to negative pressure is substantially attenuated during sleep, even in healthy individuals. Loss of these excitatory inputs to efferent hypoglossal motoneurons may greatly reduce the ability of the genioglossus and other upper airway dilator muscles to respond to negative pressure compared to the awake state. 25 Loss or reduction of this reflex mechanism during sleep would be expected to result in a significant decrease in muscle activity and subsequent airway closure. 26 Consequently, if an individual's pharyngeal anatomy is dysfunctional, their airway is no longer protected by NPR and is more susceptible to collapse during sleep. In OSA, airway closure leads to hypoxia and hypercapnia, 27 which triggers CNS chemoreflexes. Chemoreflexes, unlike mechanoreceptor reflexes such as NPR, rely on blood circulation to respond and can take 15 to 90 seconds to produce a response from the respiratory pump and increased respiratory effort. 28 These delays manifest as periodic breathing and apnea-hyperpnea cycles. The eventual increase in respiratory effort is often accompanied by brief arousals29 and a return of pharyngeal dilator muscle activity to awake levels20. This cycle can be repeated as frequently as 20 to 90 times per hour, disrupting the patient's sleep.

[0062] The invention may be embodied as a method of treating obstructive sleep apnea (OSA) by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied while the patient's pharyngeal airway is naturally obstructed.

[0063] The present invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied while the airway is closed (e.g., completely closed) or partially obstructed (e.g., closed sufficiently to cause blood oxygen desaturation).

[0064] The invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied during a period when the airway is characterized by increasing obstruction.

[0065] The invention may be embodied as a method for treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied artificially while the airway is closed.

[0066] The invention may be embodied as a method of treating OSA by periodically stimulating at least one phrenic nerve in a patient, the stimulation being applied while the airway is closed or partially obstructed, and with sufficient energy to produce diaphragm muscle contraction sufficient to create negative airway pressure sufficient to trigger NPR, which opens the airway.

[0067] The stimulation may include a stimulation burst initiated during airway closure. A substantial proportion of the stimulation bursts, e.g., greater than 50%, 75%, or 85%, may be simulation bursts initiated during airway closure. The stimulation bursts may be applied initially at a first energy level sufficient to generate action potentials in the phrenic nerve and later at a second energy level sufficient to cause reflex opening of the collapsed airway by activation of upper airway muscles. The stimulation bursts may be applied initially at a first energy level sufficient to generate action potentials in the phrenic nerve and further at a second energy level sufficient to cause reflex opening of the collapsed airway by enhancement of a mechanoreceptor reflex. The mechanoreceptor reflex may be a negative pressure reflex. [Brief explanation of the drawings]

[0068] [Figure 1] FIG. 1 is a cross-sectional view of the upper portion of a patient's airway pathway. [Figure 2A] FIG. 2A shows the head, brain, and upper airway of a patient, illustrating reflex control of the airway in a patient. [Figure 2B] FIG. 2B shows the patient's head, brain, and upper airway, illustrating reflex control of the airway in the patient. [Figure 3] FIG. 3 is a flow chart illustrating the link between airway stability and the negative pressure reflex (NPR). [Figure 4] FIG. 4 is a flow chart illustrating restoration of pharyngeal muscle tone by phrenic nerve stimulation to induce NPR. [Figure 5] FIG. 5 is a cross-sectional view of a patient having a phrenic nervous system including an implanted electrode and an implanted pulse generator. [Figure 6] FIG. 6 is a chart showing the variations over time in airway flow, respiratory flow, oxygen levels, and the electrical simulation current applied to the phrenic nerve. [Figure 7] FIG. 7 is a chart showing the variation of airway flow and respiratory effort over time during stimulated breathing. [Figure 8]FIG. 8 is a flow chart for adjusting parameters for a simulation of the phrenic nerve to treat sleep apnea. [Figure 9] FIG. 9 is a chart illustrating an energy titration curve comparing the degree of diaphragm contraction to the energy (current in mA) applied by the electrodes to the phrenic nerve. [Figure 10A] FIG. 10A is a flow chart of the algorithm for detection of the capture threshold. [Figure 10B] FIG. 10B is a flow chart for an algorithm for detection of a therapeutic action threshold. [Figure 11A] FIG. 11A is a graph illustrating an example of ramping stimulation energy during treatment regimen titration to determine an optimal stimulation energy, which is then applied during an overnight treatment regimen. [Figure 11B] FIG. 11B is a graph illustrating different parameters that may be set in accordance with certain exemplary embodiments. [Figure 12] FIG. 12 shows a patient in bed during a sleep therapy regimen, with electrodes stimulating the phrenic nerve, an implanted pulse generator, and a bedside computer monitor in wireless communication with the implanted pulse generator and in communication with a cloud computer. [Figure 13] FIG. 13 illustrates schematically an implantable pulse generator for stimulating the phrenic nerve to treat OSA. [Figure 14] FIG. 14 is a block diagram of the electronic components of the implantable pulse generator. [Figure 15A] FIG. 15A is a flow chart of an algorithm for optimizing the use of the negative pressure reflex in a sleeping or resting patient. [Figure 15B] FIG. 15B is a flowchart of an algorithm for increasing lung volume to treat OSA. [Figure 16A]FIG. 16A is a chart illustrating that stimulation rate adjustment uses the phase angle between the stimulation pulse train and the patient's spontaneous breathing efforts to optimize respiratory phase locking. [Figure 16B] FIG. 16B is a chart illustrating that stimulation rate adjustment uses the phase angle between the stimulation pulse train and the patient's spontaneous breathing efforts to optimize respiratory phase locking. [Figure 17A] FIG. 17A is a chart illustrating the use of lung volume to optimize and improve the effectiveness of phrenic nerve stimulation to treat OSA. [Figure 17B] FIG. 17B is a chart illustrating the use of lung volume to optimize and improve the effectiveness of phrenic nerve stimulation to treat OSA. [Figure 18A] FIG. 18A is a chart illustrating the spectral power analysis. [Figure 18B] FIG. 18B is a chart illustrating the spectral power analysis. DETAILED DESCRIPTION OF THE INVENTION

[0069] [Detailed Description of the Invention] This detailed description uses sections solely for the purpose of orienting the reader to the general subject matter of each section. As will be seen below, the description of many features is spread across multiple sections, and headings should not be read as affecting the meaning of the descriptions contained in any section. [Explanation of Figure 4]

[0070] Figure 4 illustrates the restoration of pharyngeal muscle tone by phrenic nerve stimulation, which induces NPR. This is the basis for the proposed therapeutic intervention. Sleep onset 23 necessarily leads to a reduction in spontaneous NPR 24. The reduction in reflexes leads to a reduction in the natural periodic efferent loop 25, which signals the muscles responsible for maintaining airway patency. This results in a large increase in inspiratory airway resistance and possibly intermittent airway collapse.

[0071] The inventors have developed a therapeutic regimen involving periodic stimulation of the phrenic nerve 30, resulting in robust (e.g., train lengths greater than 200 ms, 250 ms, or 300 ms) and intense (e.g., greater than 100 μA above the diaphragmatic spasm capture threshold, as discussed elsewhere herein) diaphragmatic contractions. The diaphragmatic contractions immediately (e.g., within tens of milliseconds) generate negative pressure within the airway 31. This pressure change is picked up by pressure sensors in the pharyngeal mucosa, strengthening the afferent limb of the NPR 32. This leads to reflex activation of the efferent limb and contraction of dilator muscles, including but not limited to the genioglossus 33, which restores airway patency. Because the NPR is so rapid, this process can be repeated cyclically at a rate consistent with spontaneous breathing (6–20 / min). As a result of this cyclic activity, the airway never remains closed long enough to induce hypoxia and activate the respiratory chemoreflex. In OSA patients, of course, a drop above a standardized oxygen desaturation threshold (e.g., 3-4% oxyhemoglobin saturation from baseline) occurs within tens of seconds of apnea, which is considered clinically significant. When certain exemplary techniques discussed herein are applied beat-to-beat or every other breath, the oscillatory apnea-hyperpnea cycle is prevented or greatly attenuated, preventing sleep disruption. [Figure 5: Phrenic nerve stimulation system]

[0072] FIG. 5 schematically illustrates one physical embodiment of the present invention. Patient 1 is implanted with a neurostimulation system 46 including an implantable pulse generator (IPG) 41 electrically connected to an electrode system 42 implanted adjacent to phrenic nerve 44. Stimulus bursts from the IPG cause a forceful contraction and descent of diaphragm 43. The diaphragmatic contraction fills lungs 45 with air, creating negative pressure within airway 2, which may close. The negative pressure is sensed by receptors 11, which activate the afferent limb of the NPR. Respiratory center 10 responds by generating an efferent signal 12 that activates dilator muscles, illustrated by genioglossus 14. It is understood that other dilator muscles are also co-activated in a natural physiological sequence. The airway is dilated and stiffened by the synchronized efforts of reflex-activated muscles. The negative pressure is greatest when the airway is obstructed, which facilitates the restoration of airway patency.

[0073] Phrenic nerve stimulation to supplement or replace natural breathing is known in the art of implanted and partially implanted neurostimulators. As shown in FIG. 5 , a phrenic nerve stimulation system 46 can include an electrode subsystem 42 adapted to apply a pattern of current to one or two of the phrenic nerves 44 (e.g., the left and / or right phrenic nerves). The pattern can be programmed and / or embedded into memory (such as a microprocessor memory) included in the IPG 41. The pattern can be predefined and / or dynamically determined based on one or more patient characteristics. In some examples, the pattern of current delivered by the IPG is controlled by an external computing device (e.g., a wand 48) that communicates with the IPG (via wired or wireless communication) so that the current is delivered to the phrenic nerve 44 according to the pattern controlled by the external computing device. Stimulation can be unipolar, bipolar, or multipolar, and energy can be applied to either or both the right and left phrenic nerves.

[0074] Phrenic nerve stimulation system 46 further includes leads 47 electrically connecting IPG 41 and electrodes 42. In certain exemplary embodiments, phrenic nerve stimulation system 46 may also include sensors and / or processing for detecting respiratory states (inhalation, exhalation) and sensing airflow, thoracic motion, and / or pressure.

[0075] Exemplary implantable devices and systems suitable for phrenic nerve stimulation are available from Integer Holdings Corporation.

[0076] The electrode subsystem 42 may be a nerve cuff, an intravascular electrode, a paddle electrode, or a percutaneously inserted tubular electrode lead that approaches the phrenic nerve in the neck or thorax. The electrode subsystem 42 may be connected by a flexible lead to an IPG or to a subcutaneous wireless antenna in communication with an External Pulse Generator (EPG) (not shown) (e.g., located outside the patient's body). It will be appreciated that techniques discussed herein in connection with an IPG 41 may be similarly applied in connection with an EPG.

[0077] The IPG 41 can include an embedded battery. This battery can be rechargeable or single-use. In some examples, energy can be transmitted wirelessly via a transcutaneous RF link from an external device outside the patient's body. In some examples, the IPG 41 can be equipped to provide telemetry, such as via a Bluetooth™ transceiver. Additional details of example implementations of IPGs are discussed below, for example, in connection with FIGS. 13 and 14.

[0078] In some examples, the IPG / EPG component of the phrenic nerve stimulation system 46 includes any or all of: a hardware processor (e.g., a microprocessor; a transceiver; circuit elements associated with memory (e.g., flash RAM, cache, volatile memory, non-volatile memory, read-only memory, etc.); and embedded software (which may include and / or be firmware in certain examples) configured to be executed by the hardware processor of the IPG / EPG to perform operations specified in instructions. Such instructions may be entered by a physician, patient, or other user (e.g., the IPG). The IPG 41 may include instructions needed to activate (e.g., IPG / EPG) and deactivate (e.g., IPG / EPG). In certain examples, one or more computing devices may provide a user interface (e.g., a graphical user interface) for adjusting stimulation parameters, including current, voltage, pulse duration, and frequency (e.g., pulse frequency, which may be, for example, between 20 and 50 Hz, as discussed below), pulse burst rate, duty cycle, and burst shape parameters. Values ​​for such stimulation parameters may be stored in the IPG 41. Exemplary values ​​for these stimulation parameters are discussed below.

[0079] Wireless communication to the IPG 41 can be accomplished using a handheld computing device 48 (e.g., a "wand") configured to modify stimulation parameters, the IPG's embedded software, and upload / download data to / from the IPG when brought within close proximity of the IPG implanted within a patient's body. The computing device 48 can include a display and user input keys to allow a user, e.g., a physician (or, in certain instances, a patient or other user), to view data collected from the IPG and to change operating parameters such as stimulation parameters (e.g., rate and energy level).

[0080] Phrenic nerve stimulation (PNS) can improve airway patency through the physiological mechanism of activating mechanoreceptor reflexes, such as the NPR, and by increasing lung volume. PNS can be achieved through the use of a hardware system, such as the phrenic nerve stimulation system 46 described in connection with FIG. 5. PNS can be incorporated into such a hardware system. One of the fundamental challenges of any neural stimulation therapy, such as PNS, is finding a compromise between efficacy and the patient's ability to tolerate the therapy. The efficacy of the therapy is generally proportional to the electric field energy applied to the nerve by the IPG. The IPG generates current pulses that result in the generation of action potentials in targeted nerve fibers (e.g., motor fibers in the phrenic nerve bundle) that innervate the targeted muscle fibers. Often, non-targeted nerve fibers are also activated, limiting patient tolerance. Tolerance can include many factors, such as pain, muscle spasm, unpleasant sensations, and interference with respiratory mechanics, gas exchange, and sleep quality. Therefore, the embedded software within the IPG (or other components of an exemplary hardware system) may include an energy titration feature, thereby achieving a compromise between efficacy and tolerability. [Figure 6-Figure 7: Exemplary Clinical Data]

[0081] The data for the graphs shown in Figures 6 and 7 were obtained from a patient wearing a nasal mask attached to a precision airflow meter. The patient was equipped with chest and abdominal respiratory belts, a finger pulse oximetry device, and a standard polysomnography (PSG) montage, as commonly used during sleep studies. Percutaneous electrodes were inserted into the patient's neck near the left phrenic nerve and connected to a clinical electrical pulse generator operating in constant current mode. Stimulation parameters included a bipolar pulse train of 150-microsecond long square-wave pulses applied at 30 Hz with a current of 1 to 5 mA. The stimulation current was adjusted by the operator in 0.25 mA increments to achieve the desired respiratory stabilization.

[0082] The patient was equipped with a standard PSG montage including EEG and EMS electrodes during the experiment. Sleep stage analysis during and after the experiment showed that the patient slept (in non-REM sleep) throughout the entire experiment. Mini-brief arousals were observed, terminating apnea. The fact that the patient quickly relapsed into apnea as soon as stimulation was turned off supports the notion that upper airway patency and ventilation can be stabilized during sleep without waking the patient, and that PNS can reduce AHI, desaturations, clinically significant short-term arousals, and sleep fragmentation, all of which should alleviate OSA clinical symptoms (hypersomnia, fatigue, etc.).

[0083] FIG. 6 shows a chart presenting the results of a therapeutic regimen associated with the application of artificial neural stimulation over a period of sleep; the illustrated therapeutic regimen was implemented by the inventors on a patient with very severe OSA. During a control time period 54, phrenic nerve stimulation was turned off. During the control period 54, the patient immediately experienced severe OSA, as evidenced by the absence of airflow during apneic periods 50 (first trace 50-a, showing airflow sensor signal), the presence of respiratory effort 51 during apnea (second trace 51-a, showing respiratory belt sensor signal), and oxygen desaturation 52 (third trace 52-a, showing pulse oximetry measurement). The suddenness of the transition to OSA is a clear indication that the patient was in a sleep state before and after the transition. OSA is a condition associated with sleep. Patients typically develop severe OSA immediately, without entering a sleep state.

[0084] Apneic period 50 is followed by a circulatory delay followed by a period of oxygen desaturation 52. The oxygen desaturation and accompanying CO2 rise allow for brief chemoreflex arousal of the patient (which may include waking the patient) and terminate the apneic period by restoring airway patency. This is the cycle that occurs naturally during OSA and is illustrated in FIG. 3. When stimulation is turned on during periods 53, 55, and 56, the patient's breathing improves significantly. A stimulation burst of sufficient magnitude (e.g., according to the settings of one or more of the stimulation parameters) will trigger a reflex, possibly including NPR, to open the airway almost immediately without waking the patient, as illustrated in FIG. 4. Blood gases O2 and CO2 are maintained, and the patient does not experience significant periodic breathing, sleep disruption, or prolonged apnea.

[0085] Element 53-a shows the output from an arbitrary waveform generator (AWG), which can be used in connection with controlling or delivering stimulation energy to a patient. The AWG can be used to define a current-shaped waveform, for example, to map an analog voltage to a current using a bipolar constant-current stimulator. In one particular example, the waveform to be generated is assigned a rise / fall and peak amplitude to provide a physiologically relevant diaphragmatic tetanic pull, where the rise is fast enough (e.g., between about 50 ms and 500 ms) to trigger the patient's NPR, but not so fast that it causes a short-term arousal from rapid tetanus (e.g., between about 0 ms and 50 ms). In one particular example, and as noted elsewhere herein, within the shaped waveform are multiple biphasic pulses, which can be between about 20 and 50 Hz. The amplitude of these pulses can be set to match their timely arrival on the current-controlled carrier waveform.

[0086] Increasing the energy level of phrenic nerve stimulation from level 55 to level 56 resulted in a gradual and more complete resolution of the airway obstruction. During the relatively low phrenic nerve stimulation level 55, the patient continued to experience airway obstruction, as evidenced by periods of no airflow in the airflow signal at 50 and corresponding episodes of little or no respiratory effort at 51 and a drop in blood oxygen levels at 52. Increasing the stimulation level from level 55 to level 56 caused the airway obstruction to cease (return to normal breathing), as evidenced by airflow as indicated by airflow signal 50-a, respiratory effort as indicated by 51-a, and higher and / or more consistent levels of blood oxygen levels at 52-a (all occurring during stimulation level 56). This process is further illustrated in FIG. 8.

[0087] The return to normal breathing occurs abruptly as phrenic nerve stimulation levels rise above an unknown threshold. This abruptness is indicated by a period of no airflow arrest, immediately followed by a period of relatively continuous, strong airflow. The abrupt transition indicates that a reflex is triggered when stimulation levels rise above the threshold, which may be the negative pressure reflex. When triggered, the reflex causes muscles in the airway to open the airway.

[0088] FIG. 7 includes an airflow chart 70-a and a respiratory effort over time chart 70-b. These charts illustrate data corresponding to two breaths from the same patient during a portion of the therapeutic regimen illustrated in FIG. 6. For example, stimulation bursts 60, 61, referred to as pulse trains, are applied at a respiratory rate approximating the patient's natural breathing rate (e.g., between approximately 6 and 20 BPM). The stimulation bursts in this case have a duration approximately equal to one-third of a breath (e.g., a 33% duty cycle or an I:E ratio of 1:3). In certain instances, an I:E ratio of approximately 4:1 to 1:4 can be used to trigger the reflex. In some instances, the reverse (e.g., longer inspiration than expiration and an equivalent I:E ratio (1:1)) can be beneficial when utilized in intensive care mechanical ventilation (e.g., in oxygen therapeutic regimens). In some instances, holding the peripheral airways open for a longer "I" time allows more time for perfusion, resulting in improved CO2 washout. This reduces hypoxemia and normalizes the person's breathing / perfusion outside of stimulation. The first stimulation burst 60 is initiated upon occlusion of the patient's airway, as evidenced by airflow signal 70-d being zero during period 66 despite the onset of inspiratory effort. Respiratory effort signal 70-c represents abdominal circumference measured using a respiratory belt, which increases upon onset of PNS (e.g., less than 50 mL is severe flow limitation / apnea, an increase in lung volume between approximately 50 and 150 mL corresponds to moderate flow limitation, while a lung volume greater than approximately 150 mL corresponds to a patent airway without such flow limitation), and increases even further as the airway opens and the lungs expand. Zero airflow in the presence of respiratory effort indicates that the airway is obstructed, that the patient is actually asleep, and that the patient's lower pharyngeal muscle tone is not sufficient to keep their airway open. This observed airway collapse (manifested by the absence of airflow during respiratory effort) is further evidence that OSA is a "sleep-induced" condition and therefore patients are asleep.

[0089] As shown in FIG. 7 , the airway suddenly opens, and inspiratory airflow begins 67 after a time delay 66. This time delay is the time it takes for natural and / or stimulated diaphragmatic respiratory effort and negative pharyngeal pressure to reach the afferent signal threshold that activated reflex opening. The patient then inhales at a peak airflow rate of >50 ml / min, indicating an unobstructed airway. The bottom trace illustrates a respiratory effort signal 70-c (e.g., based on or calibrated to a measured abdominal circumference minus lung volume (e.g., in mL)) indicating inspiratory effort (diaphragmatic mobility). In this example, the respiratory effort signal 70-c is calibrated to lung volume (mL). Effort onset 62 coincides with the stimulus 60 but precedes inspiratory airflow 67 by a delay 66, indicating diaphragmatic motion and the buildup of negative airway pressure against the obstructed airway. Inspiration stops and turns into expiration at time 63, at which point central control initiates the expiratory phase of breathing and phrenic nerve stimulation is turned off.

[0090] As shown in Figure 7, stimulation 60 of the phrenic nerve sufficient to trigger the negative pressure reflex (see level 56 in Figure 6) allows the patient's natural negative pressure reflex to rapidly open 67 the closed airway, allowing the patient to breathe during an inspiratory cycle. Without stimulation 60, the airway might remain closed during the inspiratory cycle and remain closed for two, three, or more inspiratory cycles until the patient awakens and gasps for air. Stimulation 60 triggers the negative pressure reflex, allowing the patient to breathe without experiencing a lack of airflow during multiple successive inspiratory cycles and without being awakened.

[0091] The next breath is initiated by the patient's respiratory center. The airway is obstructed, but not closed, as evidenced by airflow 69. Airflow is limited by airway resistance and peaks at approximately 10-30 ml / min (e.g., in the range where airway flow limitation may occur). However, a subsequent stimulated breath can then rise to a peak flow of approximately 30-60 ml / min, which may eliminate flow limitation (e.g., completely) without waking the patient (e.g., below the short-term arousal threshold). It will be appreciated that there is a threshold for the stimulus that can be delivered. For example, if the stimulus is too high, the patient may be short-term aroused and / or aroused (e.g., by a hit to hyperstretch receptors, which may trigger pain centers).

[0092] Inflection point 73 coincides with the start of the second stimulation burst 61 after a delay 71. Airflow accelerates and abdominal mobility indicates significant diaphragmatic contraction (effort). Inspiration is terminated by the respiratory center at time 74, where airflow is reversed and exhalation occurs at a moderate rate. Continuation of the PNS burst into the expiratory phase reduces expiratory flow to a moderate level until inflection point 75, where expiratory flow accelerates and returns to a normal level 75, similar to that without PNS. Normal level 75 coincides with the end of stimulation burst 61 and cessation of effort 65. In certain instances, respiratory effort can be tied 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 moderate flow limitation, anything greater than approximately 150 mL can be considered a normal patient airway with no limitation, and anything less than approximately 50 mL is severe flow limitation (e.g., apnea). [Figure 8: Treatment Selection Algorithm]

[0093] FIG. 8 illustrates an exemplary algorithm for selecting a therapy. A patient can be identified as having moderate or severe OSA based on a standard home PSG test. For example, the patient can have an apnea hypopnea index (AHI) of >20 events per hour. The patient is implanted with an IPG (e.g., as described herein in connection with FIG. 5, FIG. 13, or FIG. 14) and a phrenic nerve stimulation electrode. The IPG is confirmed to be operational (e.g., the IPG is confirmed to be capable of stimulating the phrenic nerve to produce diaphragmatic contractions within pressure parameters), and the patient is discharged from the hospital for a period of time required for healing, such as one month. In some examples, the patient is taken to a sleep specialist's clinic for therapy administration. In some examples, this step can also be performed in a home setting using a remote sleep monitoring device and a telehealth session.

[0094] While the patient is sleeping (80), the patient's breathing and sleep patterns are analyzed 81 by standard or custom instruments used for sleep studies. Stimulation of the phrenic nerve is initiated using an IPG controlled or set to an initial set of parameters (which are an example of stimulation parameters discussed herein) 82. In some examples, values ​​for the initial set of parameters can include setting a rate (e.g., pulse burst rate) to a number that approximates the patient's natural breathing or to a different reasonable rate that is comfortable for the patient. The duty cycle (burst duration) parameter can be set to an inspiratory:expiratory or (I:E) ratio of (1:3), (1:1), (1:2), or another suitable initial number, and the stimulation current is gradually increased until a diaphragmatic contraction corresponding to the stimulation burst is detected (e.g., clearly).

[0095] At 83, the process determines whether normal breathing has been restored to the patient based on the phrenic nerve stimulation from 82. In other words, the process determines whether the patient's OSA has resolved due to the phrenic nerve stimulation. For example, the process may determine that the patient's AHI has been reduced by at least 50%. If normal breathing has been restored, the patient may be placed on continued home therapy 85 with a selected set of parameters (e.g., based on the initial set of parameters or the modified parameters per 84, discussed below) and instructions to begin the therapy each night.

[0096] However, if the patient's normal breathing is not restored, the parameters may be changed at 84. Changing the values ​​for the parameters may include changing one or more of the parameters used to control stimulation of the phrenic nerve. For example, the stimulation parameters may be changed or titrated upward toward more stimulation power, energy, or intensity until the OSA resolves.

[0097] As an illustrative example, the stimulation current (which may represent or be related to, for example, the energy delivered to the nerve) may be increased, which generally results in a stronger diaphragm contraction until the muscle fibers fuse and the muscle can no longer contract.

[0098] Another example of adjusting the values ​​of the stimulation parameters may include changing the rate at which the amplitude of the pulses in the burst increases, often referred to as the ramp time, which can be shortened to produce a more intense and sudden diaphragmatic contraction.

[0099] Another example may include controlling the duty cycle parameter and / or stimulation rate (e.g., increased with the understanding that if stimulation bursts are more frequent or last longer, some air trapping may occur during stimulation). The duty cycle burst duration / breath duration may be or correspond to the I:E ratio discussed herein. However, in certain instances, the duty cycle may be expressed as a percentage of respiration (e.g., total respiration). Thus, for example, 30% may correspond to or mean that inspiration is 0.3 of the total respiration. Some patients may benefit from increased lung volume during sleep to prevent lung collapse and loss of the caudal traction exerted by lung expansion on the airway. All stimulation parameters are titrated based on patient tolerance. It is expected that the intensity of stimulation may be increased after the patient adapts to the treatment regimen. Therapeutic titration and auto-titration

[0100] A patient's tolerance to phrenic nerve stimulation is not a constant but a function of environmental factors and neuroplasticity. The changes that occur over time are often referred to as the nervous system's adaptation to the stimulation. In the case of the phrenic nerve, stimulation therapy is primarily applied during sleep. During sleep, the brain can adapt to intended or unintended proprioceptive input, muscle motion, or rhythmic sensations such as tingling. People sleep well, for example, on fast-moving trains and rocking boats after adapting to them.

[0101] After implanting the electrodes, some time must be allotted to allow healing and inflammation at the surgical site to subside. This may be, for example, a 30-day period. After that, the therapy can be activated and a period of adaptation and adjustment can begin. This process can be implemented entirely by the caregiver, by the patient, or can be at least partially automated. When the therapy is applied at home while sleeping, some automation may be beneficial.

[0102] Administration of a therapeutic regimen can include ramping up stimulation energy until the first evoked diaphragmatic contraction is detected (motor neuron capture). Capture is often described as a muscle "twitch." Energy can be further increased until full engagement of all nerve fibers within the nerve bundle and muscle fibers within the muscle, after which further increases in stimulation energy result in no further muscle contraction (muscle fusion or tetanus).

[0103] The gold standard for measuring the strength of diaphragmatic contraction (also called "respiratory effort," as shown, for example, in FIG. 7 ) is esophageal balloon pressure, but other methods, such as a breathing belt, bioimpedance, magnetic measurements, accelerometry, and inspiratory pressure measurements, can be used as dependent variables in developing treatment titration curves. These surrogate variables are intended to characterize or approximate the respiratory effort resulting from muscle contraction. Bioimpedance (e.g., electrical tissue impedance) in the context of this patent is the response of an organism to an externally applied electrical current. Bioimpedance is a method for estimating body composition, particularly the air contained in the lungs and airways, in which a weak electrical current is passed through the body and the voltage is measured to calculate the impedance (e.g., resistance) of body tissues that are part of a closed electrical circuit and in the current return path. Impedance can be used to track respiration because breathing changes the volume of air in the lungs.

[0104] The general need for uptitration of any nerve stimulation therapy is well recognized. For example, U.S. Patent 11,529,514 describes uptitration of hypoglossal nerve (HGN) stimulation therapy for OSA. In the case of HGN, the protrusive muscles are activated by stimulation and airway obstruction by the tongue, and in some cases, the soft palate is displaced. A so-called velopharyngeal space can be seen at the valve or trapdoor that opens or closes the pharyngeal airway in response to tongue protrusion. The phrenic nerve (PN) differs from the HGN in that the PN does not innervate pharyngeal muscles but instead innervates activated muscles of the respiratory pump. In the context of the proposed therapy, and compared to more conventional HGN stimulation, phrenic nerve stimulation, activation, and titration of the therapy are complicated by the need to induce the negative pressure reflex and airway traction while maintaining blood gases and lung volume critical 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. [Explanation of Figure 9]

[0105] 9 illustrates an energy titration curve 100 that can be initially created during an in-progress therapy regimen and adjusted at any later time, either scheduled or as needed. The curve can be generated as an automated experiment and stored in the IPG's non-transitory memory—for example, as a table or equation. The curve can be uploaded to cloud computer storage, become part of the patient's therapy history, and be made available in graphical form or converted to numerical form to physicians and patients to evaluate, monitor, and guide therapy regimens.

[0106] Curve 100 can be plotted as the relationship between stimulation energy 102 (horizontal axis) and diaphragmatic contraction strength 101 (vertical axis). In certain exemplary embodiments, diaphragmatic contraction strength may be expressed as an index based on, for example, and as discussed below, integrated diaphragmatic EMG, ultrasound imaging, esophageal pressure, accelerometry, expiratory airflow, lung volume, thoracic bioimpedance, and / or airway pressure. Stimulation energy in this context differs from the conventional electrical engineering definition. Nerve conduction is not, strictly speaking, electrical conduction in the conventional sense. Nerves are stimulated to generate or "fire" a series of action potentials. Different fibers within a nerve bundle have different activation energy thresholds. In more general terms, the more fibers firing in the phrenic nerve and the faster they fire action potentials, the stronger the diaphragmatic contraction and respiratory effort. This effort creates a negative pressure in the large airways, and if the airways are open, a pressure gradient creates airflow. Over time, this airflow translates into "breaths" or volume exchanges, also called tidal volumes, for individual breaths, and into minute ventilation for the volume of air inhaled and exhaled over one minute.

[0107] In popular constant-current systems, stimulation energy is typically expressed as stimulation current in mA, with voltage and pulse duration held constant. So-called constant-voltage systems may also be used in conjunction with the neural stimulation techniques discussed herein—and such constant-voltage systems may be interchangeable with necessary technical adjustments. From the perspective of neural firing, response current and pulse duration (e.g., the length of individual pulses within a given burst) maintain an inversely proportional relationship. Another way to adjust stimulation energy is to vary the voltage difference between the cathode and anode applied by a constant-voltage system, where the neural interface impedance is considered relatively stable.

[0108] In the case of the phrenic nerve, stimulation pulse train frequencies are typically maintained between 20 and 40 Hz, with individual pulse durations maintained between 50 and 250 microseconds. Diaphragmatic contraction strength cannot be easily measured, but can be approximated and / or indicated based on integrated diaphragmatic EMG, ultrasound imaging, esophageal pressure, accelerometry, expiratory airflow, lung volumes, thoracic bioimpedance, and / or airway pressure, as described in more detail later herein.

[0109] Typically, an IPG is set to deliver energy over a limited operating range between a minimum (or low) capture level 103 and a maximum (or high) tetanic contraction level 106, at which all muscle fibers in the diaphragm are fused and the muscle can no longer contract. The therapeutic window 107 is defined as the range of energy delivery where clinically significant improvement in airway resistance can be expected. The upper level of the therapeutic window 107 is always above the capture limit 103 and below the tetanic contraction level 106.

[0110] Between levels 105 and 106, there exists a safety margin necessarily determined by patient comfort, diaphragm muscle fatigue, or blood gas exchange that may be impeded by lung overinflation. This safety margin is reflected in two tolerance levels: 105 (short-term arousal limit) and 109 (sensation tolerance limit). [Sleep, short-term arousals from sleep, and arousals]

[0111] Sleep dysregulation and sleep disorders are associated with cardiovascular, metabolic, and psychiatric disorders. Sleep dysfunction is typically assessed in sleep clinics through analysis of overnight polysomnography (PSG). PSG recording involves measuring electroencephalography (EEG), electroculography (EOG), electromyography (EMG), electrocardiography (ECG), airflow, respiratory effort, and blood oxygen saturation during a night's sleep. Performed overnight, PSG results in a score of sleep-disordered breathing (SDB) events: 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, both with and without associated brief arousals, and sleep stages. Sleep stages can be wakefulness (W), non-REM sleep (stage 1 N1, stage 2 N2, or stage 3 N3), or REM sleep, and are reported as a percentage of total sleep time. The AHI can be reported as either the American Academy of Sleep Medicine (AASM) "recommended" AHI, which includes only hypopneas associated with a 4% oxygen desaturation, or the AASM "alternate" AHI, which counts apneas associated with a 3% oxygen desaturation and / or brief awakenings. A typical sleep study also reports sleep latency, the latency from sleep onset to the first epoch of REM sleep, sleep efficiency (SE), and the percent of time asleep at bedtime. A minor variation on sleep efficiency is wake after sleep onset (WASO), which, unlike SE, only considers the occurrence of wakefulness. In the context of sleep stage scoring, sleep stages are ascribed to consecutive 30-second epochs, an arbitrary practice resulting from the historical use of paper printouts in sleep studies.

[0112] In sleep medicine, "short-term arousals" do not necessarily mean awakenings, but rather may mean a shift to a lighter sleep stage. In the context of this application, clinically significant short-term arousals are best defined according to the current "AASM Manual for the Scoring of Sleep and Associated Events" at the time of writing. In certain exemplary embodiments, an arousal is defined as any sleep stage shift to a wakeful state for a duration greater than 15 seconds. Today, the gold standard for detecting short-term arousals is through visual inspection of PSG recordings. Accepted practice and current standards distinguish between short-term arousals (3-15 seconds) and awakenings (>15 seconds), a distinction that may be arbitrary in some cases.

[0113] Short-term arousals can occur naturally as part of normal sleep-wake physiology, as a result of external stimuli such as PN or HGN stimulation, or internal sleep disorder events such as SDB (e.g., sleep apnea). Generally, short-term arousals are not considered clinically significant events unless they result in sleep stage disruption (e.g., when the patient ultimately feels less rested, has daytime sleepiness, or generally exhibits an inability to sleep soundly through the night).

[0114] In a simplified and more informal manner, short-term arousals can be defined as sleep disruptions that are significant and frequent enough to prevent deep, healthy sleep, while possibly not waking the patient. OSA events are typically associated with short-term arousals that occur at the end of apnea due to hypercapnia or hypoxia. These short-term arousals temporarily restore breathing and generally do not awaken the patient, but they prevent the patient from progressing to deeper sleep stages and REM sleep. If phrenic nerve stimulation produces frequent short-term arousals (e.g., potentially significant) that coincide with the stimulation bursts, the stimulation energy is likely too high.

[0115] 9, the patient's sensory tolerance limit 109 can be determined based on or as a level at which a conscious patient experiences pain or discomfort. The short-term arousal tolerance limit 105 can be determined based on or as a level at which a sleeping patient exhibits frequent and clinically significant short-term arousals that may be registered during a home PSG or sleep lab sleep study. Patient tolerance limits 105 and 109 are generally not constant, but rather vary due to different external and internal factors, including the patient's adaptation to a therapeutic treatment.

[0116] For an individual patient, the short-term arousal limit 105 can be lower or higher than the discomfort limit 109, with the lower limit generally determining the maximum acceptable energy for that particular patient during a particular period of time or for a set of health conditions. For example, a patient's limits may be permanently changed if the patient gains or loses weight, has surgery, etc. A patient's limits (e.g., including values ​​for other stimulation parameters) may only be fluctuating (e.g., temporarily changed) if the patient has a cold or flu, etc. Stimulation settings can be accepted as an e-prescription under these conditions.

[0117] One or more (e.g., several) settings and / or tolerance levels resulting from any (or all) of the different tests discussed herein may be stored in non-transitory memory in the IPG memory. It is generally expected that discomfort tolerance levels will increase with adaptation, with higher tolerance resulting in more effective therapeutic treatment.

[0118] The goal of a PNS therapy regimen is to treat OSA and maximize efficacy, such as minimizing AHI, within the patient's efficacy and tolerance. In this context, it is expected that the therapeutic effect may only become apparent at energy levels above the capture level (also referred to as the "capture threshold") 103. Above the capture level, there may be other threshold levels, which may include: 1) a reflex activation level 108 (e.g., where the negative pressure generated by the stimulus has a measurable / detectable effect on upper airway airflow limitation); and 2) a breathing normalization level 104 (e.g., where apneas and hypopneas are no longer detectable or clinically significant).

[0119] For example, clinical data represented by FIG. 6 illustrates how incremental increases in the energy level of phrenic nerve stimulation from level 55 to level 56 resulted in progressive and more complete relief of airway obstruction, as indicated by airflow, in a sleeping OSA patient.

[0120] Therapy titration may be implemented and / or adjusted during a polysomnography (PSG) study, sometimes called a sleep study, in a physician's office. However, this can result in frequent patient visits, repeated sleep tests, and potentially suboptimal results due to the patient's reaction and refusal to tolerate increased energy levels (or simply not showing up for the test). Therefore, there is a strong need to automate the process of initiating, dosing, and / or titrating therapy based on objective input measurements to optimize therapy effectiveness and reduce physician involvement and the number of clinic visits for IPG programming. It is recognized that a patient's response to therapy may vary from night to night, within the same night, and with changes in sleep position. Thus, these measurements will likely need to be repeated frequently.

[0121] In some instances, an IPG may have some built-in sensing capabilities, such as accelerometer, blood pressure pulse, oximetry, ECG sensing, or bioimpedance, etc. However, it will be recognized that the accuracy and / or responsiveness of such systems may not be comparable to home and office PSG systems.

[0122] One illustrative example of a device capable of providing sleep monitoring is the WatchPAT® Home Sleep Apnea Device (HSAT), which utilizes peripheral arterial signals for the diagnosis of OSA and CSA. It measures up to seven channels via three contact points, including tonometry, heart rate, oximetry, activity measurement, body position, snoring, and thoracic motion. The WatchPAT is commercially available from Zoll-Itamar. The algorithms described herein can be implemented using a home monitoring device similar to the WatchPAT, but modified to communicate with an IPG, either directly or using a suitable wireless interface. The communication device can include an antenna that is attached to or held near the patient during the night. Alternatively, as described in more detail in this application, a dedicated, custom, wearable device or system can be developed to monitor a patient's sleep at home and communicate with a sleep specialist, the patient, and the IPG.

[0123] In certain example embodiments, the techniques described herein may be implemented in a mobile device, such as a smartwatch or smartphone, that may be configured and / or programmed to communicate with an IPG as described herein.

[0124] Other exemplary systems for sleep monitoring may also be implemented. One example of such a system includes an inertial system configured to monitor or measure the acceleration, position, and / or angle of the thoracic wall (or other areas of the patient's body). With appropriate filtering and integration, data from such monitoring can produce a reliable signal that can then be implemented in the IPG designs described herein. This technique may tend to have weaker amplitudes during quiet, resting breathing, but may be more capable of detecting hyperventilation involving accessory muscles in the thorax and neck. Thus, periodic breathing can be detected.

[0125] When the terms "sleep state" and "wake state" are used, the determinations can be made using standard PSG methods described elsewhere in this patent in the latest edition of the AASM Manual for Scoring Sleep, as well as other widely accepted standards. To determine sleep quality and stages, FDA-cleared PSG systems typically rely on multi-electrode EEG (electroencephalogram), EOG (electrooculogram), EMG (electromyogram), ECG (electrocardiogram), pulse oximetry, and other advanced measurements. While these systems are available for sleep clinic and home use, they are generally not suitable for frequent use. These systems allow for strict criteria for the neurological definition of sleep stages, short-term arousals, AHI parameters of OSA, ODI parameters, and periodic breathing.

[0126] It is recognized that simplified methods for detecting a patient's sleep versus wakefulness and OSA versus normal breathing are also relevant and may be more practical in a nightly home setting, even if they are not as accurate as PSG. For example, when a patient is supine and not moving, the patient's heart rate (HR) is slow, constant, and stable. When the patient's breathing rate (BR) is slow, constant, and stable, the patient is likely asleep. In this context, "slow" refers to a set of individual values ​​for each patient, but typically, one can expect an HR of 50-70 beats per minute and a BR of 6-20 breaths per minute. In patients experiencing OSA episodes, the patient's breathing and heart rate are likely to be highly variable within a wider range. Heart rate can fluctuate between 40 and 120 beats per minute within a one- or five-minute time frame, and respiration can vary from barely detectable effort to hyperventilation and tachypnea at 20 to 30 breaths per minute. Thus, variance in HR and BR can be used as a measure of therapeutic success. The cyclical nature (periodicity) of these fluctuations is an indication of an OSA pattern. Expectedly, cycles of heart rate and respiration variability repeat every 30 to 120 seconds. This period, or frequency of periodic breathing, is another individual characteristic of the patient that is stored in system memory. Coherence between periodic signals such as respiratory volume, BR, HR, pulse pressure, and pulse oximetry can be another indication of periodic breathing. [Phase of Periodic Breathing and Muscle Mechanics]

[0127] Periodic breathing (PB) is often defined as a breathing pattern characterized by waxing and waning tidal volume changes and is usually due to a systematic mechanism that destabilizes breathing, such as heart failure. PB is associated with CSA, but may also be present in OSA. During the hyperventilation phase of the cycle, there is a reduction in CO2. If the CO2 partial pressure decreases below the apnea threshold, a pause in breathing results. During the apneic phase of the cycle, CO2 increases and the O2 partial pressure decreases, thereby driving subsequent hyperventilation. For the purposes of this patent, PB simply means that a patient's breathing pattern during sleep consists of discernible periods of apnea or hypopnea followed by periods of hyperventilation that persist unless interrupted by treatment or arousal. Patients likely receive a clinical diagnosis of moderate or severe OSA, CSA, or mixed apnea, according to existing AASM guidelines. OSA is by far the most common diagnosis. In such cases, first-line treatments such as weight loss, medication, and CPAP may not help the patient.

[0128] Hyperventilation, sometimes called hyperpnea, is breathing more than the body needs. In the case of OSA, bouts of hyperventilation follow prolonged apneic periods and often result in overcompensation, excessive removal of CO2 from the blood, and temporarily low respiratory drive, affecting both the respiratory pump and airway tone. This phenomenon is part of the pathogenesis of periodic breathing and is present in both OSA and CSA phenotypes. Hyperventilation occurs at the end of airway obstruction after the obstruction is relieved by chemoreflex-activated airway opening. Hyperventilation, in contrast to resting breathing, actively recruits muscles in the upper thorax. This phenomenon can be used to detect OSA using accelerometers, which are built into IPG designs and implanted within the upper thorax, subcutaneously in the thorax, above the pectoral muscles or elsewhere, and above the bony thorax.

[0129] From a functional standpoint, there are three groups of respiratory muscles: the diaphragm, the bony thoracic muscles, and the abdominal muscles. Each group acts on the thoracic wall and its compartments, e.g., the upper bony thoracic apposition to the lungs, the lower bony thoracic apposition to the diaphragm, and the abdomen. Contraction of the diaphragm expands the abdomen and the lower portion of the bony thoracic cage (abdominal bony thoracic). During restful sleep, contraction of the diaphragm is often all that is required to generate tidal volume and support metabolic needs.

[0130] The bony thoracic muscles, including the intercostal muscles, parasternal muscles, scalene muscles, and other neck muscles, generally act on the upper part of the bony thorax (the bony thorax of the lungs) and are used for both inspiration and expiration. 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 elevate the anterior ribs. Therefore, these muscles are used as accessory muscles for pulmonary ventilation.

[0131] Activity of the neck inspiratory muscles (NIM), particularly the scalene muscles, increases during hyperventilation and can be monitored to monitor for abnormal breathing. In certain exemplary embodiments, stimulation can be periodically interrupted over one or more breaths (e.g., several breaths, such as two, three, or four) to obtain (e.g., clean) EMG recordings. An acetometer can be integrated into the electrode system to directly monitor muscle contractions. A separate electrode subsystem can be added to electrically isolated leads from the phrenic nerve stimulation electrode to assess EMG.

[0132] The abdominal muscles act on the abdomen and abdominal rib cage and are used in expiration. To support the increased ventilatory effort during hyperventilation, highly coordinated engagement of two or three muscle groups is required. During quiet breathing, this is accomplished by coordinated activity of the diaphragm. [Feedback, initiation, and ramp-up of treatment interventions]

[0133] The algorithms (e.g., computer processes) described herein are examples and embodiments that may be implemented in software stored in non-transitory memory of the IPG 41. In some embodiments, the algorithms may be distributed among several internal and external devices connected by wired or wireless communication links. As an example, some steps or processes may be performed on an external device (e.g., a smartphone, smartwatch, etc.) that is in communication (e.g., wirelessly) with the IPG. Two embodiments are illustrated in FIGS. 10A and 10B. The primary function of the IPG is to deliver stimulation pulses to the patient's phrenic nerve. Control of how the stimulation pulses are delivered is performed (at least in part) by computer program code, which may be stored in memory. This control may be based on internal timing derived or obtained from a clock (e.g., a real-time clock). Sensing and logic functions may be integrated into the IPG or may reside outside the patient's body (e.g., on a separate computing device such as a smartphone, etc.). [Explanation of Figures 10A and 10B]

[0134] FIG. 10A illustrates a process that may be embodied as a computer-implemented algorithm for detecting and / or determining a capture threshold (e.g., 103 as shown in FIG. 9 ). At a certain point in time (e.g., when the patient is expected to go to sleep, is detected as being in bed, or the patient signals that they are beginning a sleep cycle), the process begins at 150 and patient monitoring is performed. The patient is monitored, for example, using activity and / or accelerometry, to ensure that the patient is supine and at rest at 152. A resting state may include a supine or reclined position maintained for some period of time and other parameters such as low motion activity, a stable low heart rate, or a respiration rate. If the patient is not at rest, the process loops back to 150 to perform further analysis. If the patient is at rest, stimulation energy from the IPG is increased at 154. In certain exemplary embodiments, this increase may be controlled via a microprocessor that is low-powered and in a hibernation or monitoring-only state. In certain examples, the total range of current from the IPG that may be delivered during a therapy treatment may be between 0 and 5.0 mA. The stimulation energy may be increased (e.g., at 154) in incremental steps of, for example, 0.1 mA to 0.25 mA over a range between 0.5 mA and 2.5 mA. Based on (or in response to or in conjunction with) the increase in stimulation energy, the process checks at 156 whether a capture threshold has been reached by detecting the first clear rhythmic twitch of the diaphragm muscle. If a capture threshold is detected, the values ​​used for the various parameters of the therapy treatment (and any other data about the test performed) are stored at 158, and the test is terminated. However, if a capture threshold is not detected, the process loops back to 154 to increase the stimulation energy. The process continues until either a capture threshold is detected or a threshold amount of stimulation energy is applied.In certain instances, a pulse train of stimulation pulses, for example, 0.5 to 1.5 seconds long, can be applied every 1 to 3 seconds to produce a distinct and easily detectable periodic pattern of contractions.

[0135] FIG. 10B illustrates a process that may be embodied as a computer-implemented algorithm for detecting a therapy threshold, which may include the threshold used in association with therapy zone 107 and / or any or all of thresholds 206 and 207. For this process, at 170, the patient is monitored using PSG or other monitoring techniques, which may be internal to the IPG, external to the patient / IPG, or a combination, to ensure the patient is supine, at rest, and possibly asleep. As part of this monitoring, the process determines at 172 whether OSA is detected. Periodic airway obstruction is generally associated with sleep states. If OSA is not detected, the process continues to monitor the patient. However, if OSA is detected, the stimulation energy may be increased in incremental steps. In certain examples, the initial or first simulation energy setting for the process performed in FIG. 10B may be the capture threshold determined / stored per process performed in FIG. 10A. Using this capture threshold, the process can increase the stimulation energy in steps (up to a specified maximum allowable threshold, such as 5.0 mA) at 174 to determine a therapeutic regimen between a first threshold (e.g., the lowest energy level at which the breathing pattern is altered in a systematic, cyclical manner) and a second threshold at which breathing is stabilized (apneas are no longer detected).

[0136] The process may also include determining whether the patient is aroused at 176. If the patient is aroused, data associated with this therapy may be stored at 178, and further instructions may be provided to reduce the applied stimulation energy. In certain examples, the arousal threshold for the patient may be stored in memory for future use and periodically updated. A pulse train of stimulation pulses with a duty cycle of 30-70% may be applied at (or as close as possible to) the patient's previously detected natural breathing rate while at rest but not yet exhibiting an OSA pattern. It is understood that natural breathing rates have normal variability typical of an organism.

[0137] One embodiment of a therapy optimization algorithm (which may be implemented, for example, using a microprocessor or the like) can be a gradual, periodic, and stepped increase in delivered energy to progressively accommodate the patient's need for sleep and to utilize brain plasticity to increase patient tolerance. The gradual, periodic, and stepped increase in delivered energy can be referred to as an "energy ramp." The energy ramp can be implemented in small increments, such as every breath, every quarter hour, every hour, or every night. Thus, for example, the processing performed at 174 may be limited to adjusting stimulation energy approximately every 15 minutes in some cases, and every breath or every other breath in some cases. [Explanation of Figures 11A and 11B]

[0138] In connection with such energy ramps, Figure 11A illustrates an example of an energy ramp for the purpose of therapy regimen titration and optimization during an overnight therapy regimen, both during and after the therapy regimen. Determination of an individual patient's operating range is performed during an operational visit to a physician's office that monitors operational overnight sleep in a sleep lab, or at home (e.g., using the process shown in Figure 10A). This could be, for example, PSG or home overnight monitoring, where the patient's sleep quality is monitored by a physician in real time using telemetry.

[0139] More specifically, referring to FIG. 11A , a graph 200 is shown with time duration in hours on the x-axis, corresponding to different points in time during the patient's sleep. On the y-axis is the stimulation energy applied to the patient via the IPG. First, a test ramp 201 is applied and used as a range-finding ramp. The ramp 201 shown in FIG. 11A is performed after the patient is in bed and at rest, but before they are asleep or exhibit OSA. The ramp 201 allows for the determination of a resting capture threshold 205 (e.g., as described in connection with FIG. 10A ). Simultaneously, other parameters, such as resting breathing rate, can be detected and stored for later use (e.g., in non-transitory memory on the device). Device memory can be included as part of the physical IPG microprocessor, coupled to the IPG microprocessor (e.g., on the same piece of silicon), or reside in the non-transitory memory of an external device in wireless communication with the IPG. Data relevant to an individual patient's therapy regimen, such as historical and current parameters, settings, preferences, and intentions, can also be stored. As used herein, data relevant to an individual patient's treatment regimen may be referred to as a patient treatment plan.

[0140] As the patient enters a sleep state and OSA manifests, the patient's individual OSA patterns, such as apnea duration / frequency and post-obstructive hyperventilation morphology, can be determined and stored in memory for use by future automated therapeutic interventions. These measurements can be taken with the patient sleeping in supine, side, prone, reclined, and other body and neck sleep positions. Simultaneously, the position detection system can be calibrated for future detection needs.

[0141] For example, depending on the patient's treatment plan stored in device memory, after the range-finding ramp is completed, stimulation can be turned off or continued at some low level of energy above the capture threshold to help the patient become accustomed to the rhythmic sensations.

[0142] After determining that the patient is likely asleep, stimulation can be increased to a level known from previous sleep history to be within the therapeutic energy window. The energy level can be specific to the patient's position, since many patients are expected to sleep on their side, back, or reclined position. Patient position can be determined using inertial sensors, such as accelerometers and gyroscopes, integrated into the IPG electronics, or by an external monitoring device, such as a wearable device or a radar-based motion monitoring device. The monitoring device can be an mmWave radar patient monitoring device or a motion-detecting camera. Millimeter-wave (mmWave) radar transmits electromagnetic waves, and any object in the path reflects the signal. The radar system can capture and process the reflected signal to determine the object's range, velocity, and angle. The potential of mmWave radar to provide millimeter-level accuracy in object range detection and its insensitivity to clothing and bed linens makes it a suitable non-contact technology for detecting human biosignals during sleep.

[0143] The ramp 202 is activated after the patient enters a sleep state and manifests OSA or other forms of periodic breathing. Periodic breathing can be detected by sensors and programmed logic included in the IPG or communicated to the IPG from an external device. The ramp is stopped after a first therapeutic intervention threshold 206 is reached, at which time periodic breathing is sufficiently reduced or eliminated. For example, a calculated AHI or O2 desaturation rate greater than 3% may be reduced for an individual patient from approximately 50-120 per hour to approximately 0-15 per hour as part of that patient's therapeutic intervention plan. A given percentage reduction in AHI from a baseline without therapeutic intervention (e.g., greater than 50 percent reduction, and in certain instances, greater than 90 percent and up to 100 percent reduction) may also be a goal for an individual patient. In certain exemplary embodiments, the percentage of sleep time with O2 saturation above 90% and / or other relevant criteria can be used individually or in combination with other factors, such as AHI, to improve treatment for the patient. As previously discussed, alternatives to PSG can be used to determine OSA severity and sleep quality.

[0144] During the night, at 203, the patient may awaken, sit up, stand, and walk around. In this case, the stimulation pulses may be stopped (e.g., with or without 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 re-enters sleep, a second treatment regimen ramp 204 may be implemented. In some examples, re-execution of the ramp (or implementation of the second ramp 204) may occur automatically and / or without any explicit input from the patient. It will be appreciated that automatic control of the stimulation pulses (including reinitialization of the stimulation pulses) and ramp control may be advantageous because individuals occasionally awaken during the night and eventually re-enter sleep. Thus, the automatic control described herein may alleviate the need for the patient to explicitly turn stimulation on and off. Rather, as discussed elsewhere herein, stimulation may be automatically controlled based on various factors, including the individual's position and the individual's determined sleep stage.

[0145] FIG. 11B is a graph 1100 illustrating different parameters that may be set according to certain exemplary embodiments. In some examples, the delivery of stimulation (either at the beginning or during an individual's sleep during the night) may be based on a latency parameter 1102 (e.g., a delay in the onset of the therapeutic regimen). The latency parameter may be determined manually, automatically, or otherwise dynamically. The latency parameter may be set to be between approximately 0 and 60 minutes, with a typical value being between approximately 30 and 40 minutes in certain examples. In certain exemplary embodiments, a therapeutic regimen ramp time parameter 1104 (e.g., the onset ramp shown in FIG. 11B ), which may be determined manually, automatically, or otherwise dynamically, may also be used. The value for the therapeutic regimen ramp time may be between 0 and 60 minutes, for example, and may typically be about 30 minutes in certain examples.

[0146] For example, a midnight interruption may use a lower value for the latency parameter than when the individual first enters a sleep state that night. In some examples, the time at which stimulation is initiated or resumed may be a function of the value of the latency parameter in combination with other measurements (e.g., any or all of the measurements from the individual). The combination of these values ​​may be used to calculate when to initiate (and / or stop) stimulation.

[0147] The ramp may be performed until a therapeutic threshold is found that meets preset criteria or until a pre-planned maximum tolerance limit is reached. The second therapeutic threshold 207 may be higher or lower than the first therapeutic threshold 206. For example, the patient may have been sleeping on their side during the first ramp and on their back during the second ramp, or may have otherwise changed some positional or physiological parameter that affects airway collapsibility. Additional parameters may be set similarly related to the therapeutic window and the time for ramp-off. [Figure 12: Interconnected and distributed system for monitoring patients at rest and during sleep]

[0148] FIG. 12 shows a patient in bed during a sleep therapy regimen. The patient may be asleep or at rest. An IPG 41 is implanted in the patient's thorax and connected to an electrode system 42 by stimulation leads 47. The electrode system 42 is in electrical contact with the phrenic nerve 44. The electrode system 42 may be an electrode cuff or paddle electrode. In some examples, the electrode system may include sensors such as EMG sensors, inertial sensors, microphone sensors, and / or other transducer sensors. In certain examples, sensors may be integrated with the electrode system (e.g., at the neck). The patient is equipped with a wearable monitoring system 210 in wireless communication with the IPG 41. The wearable monitoring system 210 may include or be configured to implement a medical implant communication system (MICS) for wireless communication with the IPG 41 (e.g., up to 2 meters away from the IPG). The wearable monitoring system 210 may also communicate with a bedside monitoring device 211, which may also be a MICS communication device. The monitoring device 211 may include a transceiver that allows data communication, such as internet communication, with a cloud computing system 212. Data communicated to the computing system 212 may be stored in non-transitory storage, allowing data sharing with a physician. The physician may provide data to modify or alter a treatment regimen, which may be communicated back to the IPG 41, the bedside monitor, and / or the wearable monitoring system 210 for storage in non-transitory memory of any or all of the IPG 41, the bedside monitor, and / or the wearable monitoring system 210. The updated treatment regimen may then be executed (e.g., in real time) by the IPG electronics. In some examples, the bedside monitor 211 device may be placed in a pocket of the patient's clothing, under a mattress, or under a pillow.

[0149] The implanted portion of the system may include sensing leads 213 that are connected to the IPG and tunneled subcutaneously into the patient's thorax to allow improved sensing of muscle EMG, thoracic impedance, or respiratory acceleration.

[0150] Different communication techniques may be used to facilitate communication between the IPG 41 and other devices communicating with the IPG. In some examples, an inductive link may be used. Inductive links have a long history of providing reliable communication with pacemakers, ICDs, IPGs, and the like. However, inductive communication may suffer from range limitations (e.g., the maximum separation distance between two coils, one inside the body and the other outside the body, must not exceed 6 cm) and data rate limitations (e.g., approximately 100 kbps). Such limitations may be problematic, for example, when the patient is sleeping, because the link may require realignment to account for the patient's movement while asleep. Thus, while inductive links may remain appropriate for certain types of devices and use cases, other (e.g., future) types of devices and use cases may use other communication techniques that enable faster communication over longer distances.

[0151] Other communication techniques that may be used in certain examples to enable communication to / from the IPG 41 include the Medical Implantable Communication Service (MICS), which operates in the 402-405 MHz band. MICS enables higher speed, lower power, non-voice transmissions to and from implanted medical devices, such as cardiac pacemakers and defibrillators. This band has good conductivity in the human body, higher data rates, and a communication range of up to 2 meters.

[0152] Another communication technique that may be used in certain examples to enable communication to / from the IPG 41 includes the Medical Device Wireless Communication Service (MedRadio), which operates in the 401-406 MHz range. The creation of the MedRadio service incorporates the existing MICS spectrum at 402-405 MHz, with additional spectrum added at 401-402 MHz and 405-406 MHz, for a total of 5 megahertz of spectrum for implanted devices and actual body-worn devices.

[0153] It will be appreciated that as other communication techniques are developed, such techniques may be used in conjunction with the examples described herein.

[0154] Another aspect of the system described in connection with FIG. 12 is the measurement of a patient's respiration / respiratory activity. Respiratory activity produces visible and measurable motion to the thoracic wall. In certain exemplary embodiments, radar technology can be used to perform non-contact and non-invasive measurements of respiration. Using such techniques, a radar device is aimed at the patient's rib cage, and the resulting motion is recorded and processed to obtain the respiration rate. In some cases, the use of radar technology may eliminate the need for both implanted and wearable respiration sensing. In some examples, the clinical radar can be integrated into or connected to the clinical monitor 211 to transmit respiratory cycle information to the IPG in real time, for example, using a MICS communication link. The IPG can then apply stimulation energy based on a timing synchronization signal from the clinical monitor 211.

[0155] It is recognized that non-contact technologies for body motion monitoring are rapidly developing and becoming more advanced and available. Examples include U.S. Patent 8,454,528. In certain examples, detection of paradoxical chest wall movement (which may reduce lung volume during inspiration) can be used as a surrogate for inspiratory airway resistance and negative air pressure in the airway distal to the obstruction. This variable can then be used in conjunction with automatic adjustment of stimulation energy being 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 recognize cardiac motion in a non-contact manner. Such sensors can be used to measure heart rate (HR) and / or rhythm using IR-UWB radar sensors, and thus can be used to detect / determine a patient's resting state, sleep state, periodic hyperventilation, and / or short-term arousal events. Such techniques may be simpler and / or more advantageous than (eg, electrocardiographs) in connection with certain exemplary embodiments.

[0156] In either case, respiratory data can be obtained from the patient using various sensors and other devices. Such data can be obtained by the external wearable 211 or the clinical monitoring device 210. The data can be used to generate commands or other data that can then be used to cause the IPG to act or change its operation. For example, a command generated based on the processed respiratory data can be communicated to the IPG, causing the IPG to increase the stimulation energy being applied. In order to act on the collected data, it must be transmitted as a command to the IPG, since it is ultimately the IPG that controls the flow of stimulation energy to the phrenic nerve.

[0157] The maximum allowable energy for each patient sleep position may not be constant from night to night. This maximum allowable energy can be increased or decreased remotely by a physician or automatically by logic within the device. For the first night or nights after operation, the maximum energy level can be set to a fraction of the maximum allowable limit determined during the patient's visit to the clinic or during an overnight study in a sleep lab (e.g., in connection with FIG. 10B).

[0158] The maximum lamp energy can also be set to a preset fraction of the device's operating range, which may be, for example, 1.0 to 5.0 mV. For example, the maximum energy level for the first night can be set at 50% of the operating range. The next night (which may be the second night) the energy level can be increased to 51%, the next night to 52%, and so on, with further increases of 0.05 to 5% each night, depending on the treatment plan. For example, the increments can be set to larger values ​​during the first few nights and then gradually decreased, following an asymptotic trajectory that approaches the maximum value at a rate that is quasi-infinite. In this way, the patient's central nervous system can be expected to gradually adapt to the higher energy levels, and a new, higher tolerance threshold can be established gradually and without frequent clinic visits.

[0159] Automatic telemetry can store relevant parameters, such as delivered energy, as well as corresponding physiological respiratory parameters, i.e., motion, posture, breathing, and oxygenation patterns. These parameters can be communicated to a physician overseeing the treatment or to a central analysis facility. In some instances, the physician can intervene by pausing, reversing, or adjusting, e.g., slowing or speeding up, the adaptive ramp. Removing some sensing and control functions from the IPG and redistributing them among external components that communicate wirelessly with each other and with the IPG has clear advantages. The IPG can be simpler, more reliable, and smaller, with better battery life. Additionally, surgical procedures can be simplified. At the same time, the quality of data signals related to the patient's body can be improved because the IPG's access to the patient's respiratory system can be limited.

[0160] Another embodiment of the novel system for optimizing phrenic nerve stimulation parameters to treat OSA can be a distributed system including an IPG in electrical communication with the cervical phrenic nerve and an external body component. The system can deliver controllable excitatory nerve stimulation pulse trains at precise time intervals, where the stimulation produces diaphragmatic contractions of variable intensity ranging from twitch capture to muscle fusion. In some examples, the system further includes a bedside monitoring controller in wireless communication (e.g., continuous) with the IPG. The bedside controller can be separated from the patient by a distance of more than 6 cm and up to 2 meters (e.g., within the communication range of the MICS). In some examples, the bedside controller (or another device in communication with the bedside controller) incorporates a mm-wave range radar motion detection device configured to detect thoracic motion and estimate respiratory rate, separate thoracic and abdominal movements, tidal volume and inspiratory time, patient motion, body position and blood pulsation, and heart rate. The acquired data is then processed and used by a computer to control starting, stopping, ramping, increasing or decreasing stimulation energy and adjusting stimulation rate (e.g., by communicating with an IPG to make such changes).

[0161] Paradoxical movement of the thoracic wall (which may reduce lung volume during inspiration) can be used as a surrogate for inspiratory airway resistance and negative air pressure in the airways distal to obstruction. Paradoxical movement can be explained by a compensatory pump inhaling against increased upper airway resistance or airway closure. Under these circumstances, particularly if the patient is hyperventilating in response to increased blood CO2 and hypoxia, a large amount of negative pressure can be achieved within the thorax. The thoracic muscles and structures cannot resist this negative pressure, and the rib cage collapses paradoxically while the abdomen expands. These patterns can be detected by a breathing belt, an accelerometer, or a non-contact radar-based motion detector. A paradoxical movement index can be derived. This calculated variable is used to automatically adjust energy delivery levels or timing, as described herein. [Figure 13: Implantable Pulse Generator (IPG) System Design]

[0162] 13 schematically illustrates an IPG 41 suitable for implantation in an OSA patient to stimulate the phrenic nerve in accordance with the techniques described herein. A phrenic nerve stimulator may be embodied within the IPG 41. In certain instances, the IPG 41 is an example of a phrenic nerve stimulator. This IPG is similar in aspects of hardware design and construction to commercially available implantable pulse generators / implantable neurostimulators available from suitable manufacturers such as Integer® Holdings Corporation.

[0163] The IPG 41 includes a header 301 for connecting to at least one stimulation lead 47 and an optional sensing lead 213. The header may include one or more connection ports (described below). The IPG 41 includes a hermetically sealed housing 202 for containing electronic circuitry 303 (e.g., electronics) and a suitable, sealed battery 304. In some examples, the battery 304 may be rechargeable using wireless energy transfer. In some examples, the IPG may include other sensors as part of the IPG 41. Such sensors may include an accelerometer, an oxygen sensor, a vibration sensor, or a sound sensor (e.g., a microphone), etc. Alternatively or additionally, the sensors may be integrated into the distal portion of the sensing lead 213 or the distal portion of the stimulation lead 47, with electrical connection to the electronic circuitry 303 within the IPG 41. The standard implantable connector may be similar in design and construction to the low-profile IS-1 connector system (compliant with ISO 5841-3) used in cardiac pacemakers. The IS-1 connector has been in use since the late 1980s and has been shown to be highly reliable, providing easy disconnection and reconnection for several implantable pulse generator changes over the life of a single pacing lead.

[0164] According to one desirable technical feature, the IPG desirably uses (e.g., as 303 or as part of 303) a standard, commercially available, low-power, flash (in-circuit programmable) programmable microcontroller or processor core within an application specific integrated circuit (ASIC). This device (or possibly two or more such devices for computationally complex applications involving sensor input processing) and other large semiconductor components may have custom packaging to reduce circuit board real estate requirements.

[0165] The IPG is controlled using a microprocessor with built-in resident operating system software (code). This 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 instruct it on what action to take to deliver the correct amount of energy at the correct time to the phrenic nerve. The inventors recognize that multiple platforms with different system software may be compatible with the application software techniques discussed herein.

[0166] The electronic circuit element 303 includes a wireless transceiver, which allows wireless telemetry communication between an external system and a therapy controller, which may be a wearable device, a handheld device, or a clinical device (e.g., one that is not typically implanted in a patient).

[0167] As an illustrative example, the IPG 41 may be responsible for detecting respiration, calculating respiration rate via a sensing system, determining the start time and duration of stimulation signals, and delivering a controlled electrical stimulation signal sequence (pulse train) via stimulation leads 47. The wearable monitoring system 210 may then wirelessly communicate with the IPG, and the bedside monitor 211 may be in data communication with a loud computer system 212, allowing for data sharing with a physician and modification of the therapy regimen, which may be stored in the IPG and bedside monitor's memory and executed in real time by the IPG's electronics. The IPG may also record and transmit therapy history data (device settings, status, measured data, device usage, respiratory data, stimulation delivery data, motion and sleep time-based statistics, measured signals, etc.) and implement the patient's therapy regimen.

[0168] As shown in FIG. 13 , the header 301 forms the top portion of the IPG and may be molded of polymer sealed to the housing 302. In some examples, the housing 302 may be a molded titanium casing. As discussed in the context of breath sensing, the housing may be used as an electrode for bioimpedance signals, including respiration measurements. Similarly, the electrode system on the lead may be used as an electrode for bioimpedance respiration measurements. For example, the housing may include current-emitting electrodes and voltage-sensing electrodes for respiration detection. Alternatively, separate electrodes may be included within the header of the device from which sensing or stimulation occurs.

[0169] As noted above, the header 301 can include one or more ports. In the illustrated example of Figure 13, there are two ports: one sensing lead port 305 (labeled "SENSING") for receiving the proximal connector of the sensing lead 213, and one stimulation lead port 306 (labeled "STIM") for receiving the proximal connector of the stimulation lead 47. More ports can be added for other leads.

[0170] The port configured to receive the stimulation lead 47 may include two set screws (labeled "-" for the cathode and "+" for the anode) with associated set screw seals and seals for mechanical and electrical connection to corresponding contacts on the lead's customary proximal plug-in male connector. This design and configuration of the lead-header interface is accepted as standard for this type of device.

[0171] Similarly, the ports configured to receive the sensing leads include set screws for the current emitting and voltage sensing electrodes with associated set screw blockers and seals for mechanical and electrical connection to corresponding contacts on the proximal connector of the sensing lead 213. Seals are located between the electrical contacts and between the distal-most electrical contact and the remainder of the proximal connector assembly. These seals electrically insulate each contact. The header may also include suture holes for using sutures to secure the IPG to subcutaneous tissue, such as the muscle fascia, during implantation in a subcutaneous pocket.

[0172] During operation, the IPG 41 generates a stimulation output for delivery to the phrenic nerve through the stimulation lead 47 in accordance with one or more stimulation parameters. To this end, the IPG has a bipolar stimulation output channel corresponding to the stimulation port, which provides a pulse train of biphasic constant-current pulses having, by way of example and not limitation, a frequency range of 20-50 Hz, typically at or about 30 Hz, a pulse width range of 30-215 μs, typically at or about 150 μs, an amplitude range of 0.4-5.0 mA, typically at or about 1.0-4.0 mA, and a stimulation duty cycle range of 30-70%, typically at or about 40-50%. These ranges may depend on the individual patient and the configuration of the electrode system, such as a nerve cuff or paddle electrode. In certain instances, the burst frequency range or the duration of each individual pulse may be determined or otherwise calculated to be as low as possible to generate smooth contractions while also being selected to conserve battery power. In certain instances, optimal calculations of values ​​for parameters may be performed, and the resulting values ​​may then be set within a margin (e.g., 1%, 2%, 5%, 10%, etc.) of those calculated values. Thus, in certain instances, values ​​may be calculated to, for example, be "no more than necessary."

[0173] 13 and 14 and the accompanying description of the IPG, the component designs, parameter values, and component configurations are provided by way of illustration and as possible examples, not limitations, of certain exemplary embodiments. Implantable neurostimulators are capable of rapid evolution, and conventional technology is expected to transition to batteryless and leadless stimulators. These improvements are designed to reduce the size and increase the useful life and reliability of the stimulator, rather than altering the stimulator's function in a substantive way.

[0174] Impedance sensing is optional for some embodiments of the present invention. The IPG circuitry may generate an excitation signal and measure voltage through the respiratory sensing lead 213 for bioimpedance respiratory sensing. To this end, the IPG has a respiratory sensing channel for obtaining bioimpedance sensing on a desired vector. The vector may lie between the sensing lead electrodes, the stimulation lead 47 electrodes, and the casing of the IPG implanted within the thorax.

[0175] In certain embodiments, the IPG 41 measures bioimpedance through port 305, where an internal electrical connection provides a small excitation current ("I") and measures voltage ("V"). The excitation signal may include biphasic constant current pulses at 10-50 kHz, with the positive and negative phases of each biphasic pulse being 500 μA in amplitude. The current ("I") may be fixed by the circuit, allowing the voltage ("V") to be a relative measure of impedance ("Z"), which corresponds to movement of muscles, lungs, airways, and other structures and produces a signal indicative of respiratory activity. [Figure 14: Electronic circuit element]

[0176] 14 schematically illustrates electronic circuitry 303 that may be contained within the IP 41. The electronic circuitry 303 may be or may include a circuit board having a microprocessor (also referred to herein as a hardware processor), memory, I / O, analog-to-digital (A / D) converters, etc. Some or all of the electronic circuitry 303 may reside within the sealed casing 302 of the IPG 41.

[0177] The microprocessor 400 is used to control telemetry communication with external components of the IPG, operate sensing circuitry for monitoring motion and respiration, control delivery of output stimuli, and monitor the accelerometer 411, magnetically sensitive proximity sensor (e.g., reed switch) 408, and real-time clock 409. The microprocessor may include or be 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), analog-to-digital (A / D) converters, timers, serial ports, digital I / O, etc. The microprocessor 400 (e.g., hardware processor) may be or form part of a controller / microcontroller as used herein.

[0178] In certain examples, microprocessor 400 may be comprised of several dedicated microprocessors communicating via serial links. Different functions (e.g., stimulation, monitoring, and telemetry communication) may be divided among various different microprocessors. In some examples, one microprocessor may be used to perform such functions.

[0179] The telemetry interface circuit, consisting of a tuned telemetry coil circuit 407 and a telemetry driver / receiver circuit 410, may enable digitally coded communication between external components and the microprocessor. As an alternative to a telemetry coil and inductive link, an RF antenna with associated circuit elements may be used to establish an RF link and provide longer-range telemetry. A proximity sensor or switch 408 provides a means for the IPG 41 to be controlled by using the magnet of a near-field communication (NFC) device placed in close proximity. A real-time clock 409 provides a basic time base (e.g., 768 Hz) for the IPG electronics 303 and a clock (year, day, hour, minute, second) that can be used to control the scheduled delivery of therapy treatments. The clock 409 can also be used to time-stamp information about the system's operation, which can be recorded by sleep epoch, hour, night, week, or month.

[0180] The bioimpedance breath sensing circuit consists of two main sections: an excitation current source (output) and a voltage sensing circuit (input) 415. Respiration can be sensed using a three-wire or four-wire impedance measurement circuit. In a four-wire measurement, an 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 three-wire measurement, the IPG housing (case 302) can be used as both the excitation and sensing electrodes. The excitation current circuit delivers bursts of biphasic pulses of low-level (e.g., 450 μA) current to selected electrode pairs every 100 ms during sensing. The voltage sensing amplifier circuit 415 synchronously monitors the voltage produced by the excitation current on the selected electrode pair. The resulting output signal is proportional to respiratory impedance (0.07 Ω to 10 Ω) and is applied to an A / D circuit within the microprocessor 400 for digitization and analysis. Other sensing circuitry may include an ECG signal amplifier (not shown) or a pulse oximetry interface.

[0181] The stimulation output circuit delivers bursts of biphasic stimulation pulses to the stimulation lead 47. These bursts may be synchronized with the sensed respiratory waveform to deliver stimulation, thereby generating negative airway pressure and reflexes that result in airway patency at the appropriate time. The stimulation output circuit may include an electrode polarity switching network (425 / 426), a current source circuit 421, and an output power supply 420. The electrode switching network allows for a charge balancing cycle following each stimulation pulse, during which the outputs are connected together and no output pulse is applied. The timing and polarity of pulse delivery are provided by a control output of the microprocessor 400. The microprocessor selects the amplitude (e.g., 0.4 mA to 5 mA) of the output current from the current source circuit, which is applied via the switching / pulse shaping network. Output power supply 420 converts the battery voltage (from 417) to a higher voltage (e.g., 5V-15V) sufficient to provide a selected current into the load impedance of the lead electrode system, which can be a bipolar or unipolar system in which the IPG casing 302 is used as a current return electrode. Microprocessor 400 can measure the voltage output from the electrodes resulting from the delivered current and the load impedance. Microprocessor 400 divides the output voltage by the output current, resulting in a measure of the load impedance (e.g., 400Ω-2800Ω), which can be an indicator of the integrity of the lead electrode system and the condition of the surrounding tissue.

[0182] The system may include an external controller including an implanted rechargeable battery (not shown), charging circuitry and a rechargeable battery coupled to the circuitry, the circuitry adapted for wireless telemetry and energy transfer, and a charging coil coupled to the external controller for generating a radio frequency magnetic field to transcutaneously recharge the rechargeable battery. During periods of recharging the rechargeable battery, the external controller may be adapted to be carried by a user without a connection to mains power, allowing the user to be fully mobile. Rechargeable IPG batteries and circuitry are well understood and available from OEMs, have certain advantages and disadvantages, and are often a matter of preference rather than necessity.

[0183] In some examples, the IPG 41 (or leads connected to the IPG) may include an oxygen sensor for monitoring oxygen levels, for example, during an overnight therapy session. The generated signal may be used to monitor the efficacy of the therapy. Alternatively, or additionally, the generated signal may be used to cause changes in stimulation delivery settings during a therapy session. For example, the IPG may be programmed to increase stimulation when oxygen desaturation is detected at a programmable threshold rate and / or severity. Additionally, the IPG may turn on stimulation once desaturation is detected, with the rate threshold and severity being programmable. Desaturation may serve to indicate a sleep or wake state. In a similar manner, an electroneurogram (ENG) may be used to monitor neural activity, which may also indicate a sleep and / or wake state. EMG may be used to monitor muscle activity, which may indicate spontaneous breathing efforts. The IPG may use the sleep or wake state indication to change stimulation settings. For example, stimulation may be increased when the patient is estimated to be in N3 or REM sleep, and stimulation levels may be reduced or turned off during stage N1 or wakefulness.

[0184] As illustrated by FIG. 12, not all sensors need to be implanted in the IPG of this patent, nor do they need to be implanted sensors 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 overall neurostimulation system.

[0185] The IPG circuitry may include an inertial sensor, such as a 3-axis accelerometer 411, that can be used to determine the patient's position (supine, prone, upright, left side, or right side) and / or detect motion events (awake states). The accelerometer may include gyroscope hardware and firmware. The accelerometer can measure the rotational speed and acceleration of the IPG with high accuracy. This data can be used to change stimulation settings or inhibit output. For example, the IPG can be programmed to increase stimulation intensity when the patient is in a particular position (e.g., supine, a more problematic position). The IPG can separate recorded therapy action statistics (e.g., cyclic variation detector events, oxygen desaturations) by position. For example, a patient's cyclic variation detector may record very few events in the lateral position and many events in the lateral position, indicating that the patient is receiving therapy in the lateral position.

[0186] The bioimpedance respiratory signal (“Z”) is generated by dividing the change in measured voltage (“V”) by the excitation current (“I”). The bioimpedance respiratory signal can indicate diaphragm motion and lung and airway expansion and contraction over time and is therefore a well-accepted measure of respiratory activity. The bioimpedance respiratory signal can be used to estimate respiratory effort, respiratory rate, tidal volume, minute ventilation, etc. in real time, with known imperfections. When the excitation current (I) is constant or assumed to be constant, bioimpedance (Z) is proportional to the measured voltage (V); therefore, voltage (V) can be used as a surrogate for bioimpedance (Z), thereby eliminating the division step. Diaphragm motion as used in this context includes the motion and shape changes of the diaphragm, lungs, large airways, and adjacent tissues that occur during normal and obstructed breathing. The bioimpedance waveform can be filtered to reduce noise and eliminate cardiac artifacts, 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 approaches can be used to filter the signal. The peaks (positive or negative) of the impedance signal correspond to the end of the inspiratory phase and the beginning of the expiratory phase. If the signal is normal, the positive peak is used; if the signal is inverted, the negative peak is used. The beginning of the inspiratory phase can occur somewhere between the peaks and may not be easily identifiable. The impedance signal typically provides reliable timing events for the end of inspiration and the beginning of expiration. The remainder of the respiratory cycle may need to be extrapolated based on the patient's medical history.

[0187] Body motion, often indicative of a patient's state of arousal, can be detected by an accelerometer and may also alter the bioimpedance signal (Z). Different sensitivity thresholds may be used so that minor movements are not confused with significant motion events, such as rolling over in bed from side to back, sitting up, standing up, or walking around. Upon determining a motion event, stimulation may be turned off or attenuated until motion stops or for a programmable time duration. The frequency and duration of these motion events may be recorded in the device history. Accelerometers may be used alone or in combination with impedance in a similar manner to detect and record motion events.

[0188] Waning and decaying of the bioimpedance signal (Z) often indicates apneas or hypopneas. This pattern, commonly referred to as cyclic variation, can be detected, for example, by assessing the increasing and decreasing trends of the mean PP amplitude value. Different thresholds of sensitivity can be utilized so that minor changes in PP values ​​are not declared cyclic variation events. Upon detection of cyclic variation, stimulation parameters can be initiated or modified (e.g., increased intensity, increased duty cycle, etc.) to improve the therapy. The frequency and duration of these cyclic breathing patterns can be recorded in a therapy history. These values ​​can be used as an indicator of how well the patient is being treated and provide an estimate of the AHI.

[0189] The IPG can be programmed to change stimulation levels between therapy sessions, between days, or between other programmable values. Stimulation levels can be recorded along with therapy session data, such as cyclic variation rate, frequency and severity of desaturations, stimulation duration, respiratory rate variability, respiratory prediction variability, etc. The processor 303 is equipped with different computer memory types that can store program code, settings, and patient data in areas with different electronic formats and different update rates of the memory contents. [Synchronization to breathing vs. entrainment of breathing]

[0190] Triggering of the negative pressure reflex based on physiological mechanisms can be achieved, for example, by diaphragmatic stimulation applied every breath or every other breath during the late expiratory-early inspiratory phase. Diaphragmatic stimulation can also be applied at any other time during inspiration, possibly with less effectiveness. Diaphragmatic stimulation applied during expiration is likely to be less effective and may be undesirable by prolonging expiratory time through the mechanism of the Herring-Bruer inflation reflex.

[0191] In people without OSA, inspiration typically accounts for 25-50% of the respiratory cycle, and variability in respiratory rate is common. Variability can cause actual inspiration timing to vary from breath to breath. The hypoglossal nerve normally or naturally activates approximately 300 ms before inspiration and remains active throughout the inspiratory 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 expiratory and early inspiratory phases, with a short pre-inspiratory period of approximately 300 ms. Because variability is expected, it may be advantageous to account for this variability by focusing stimulation on anticipated inspiration to maximize stimulation coverage of actual inspiration.

[0192] Techniques have been proposed to synchronize stimulation to respiration, including detection based on impedance, accelerometry, breath sounds, and intrathoracic and airway pressure signals. Because detecting the onset of inspiration can be more difficult, prediction and / or extrapolation based on the timing of peak inspiration and known patient history can be used in conjunction with certain instances.

[0193] Thoracic impedance requires the passage of sensing leads and is dependent on the current path vector, which complicates both device design and surgery. While both thoracic impedance and accelerometers can detect thoracic motion, they generally cannot detect airflow and therefore have problems detecting inspiration when the airway is closed or restricted by OSA. This is particularly true in mixed and obstructive apneas, where both normal and paradoxical thoracic motion are present during breathing. The system tends to overreact during the hyperventilation phase of the OSA cycle, when the respiratory rate can dramatically accelerate. The device responds to motion, coughing, sneezing, and other signals that are not true inspiration but can trigger the detection circuitry and cause discomfort to the patient.

[0194] An alternative to synchronization is to operate the device (e.g., IPG41) in an "asynchronous mode." This mode relies on the patient's tendency to synchronize, or at least "phase-lock," to external stimuli during sleep. For example, physiological oscillators tend to phase-lock to external stimuli. This does not always imply strict synchronization. A good example is the synchronization of sleep to the day-night cycle. The average person goes to sleep sometime during the night and awakens sometime in the morning. A similar pattern is observed in patients who "entrain" to mechanical ventilation.

[0195] "Phase locking" occurs when the patient's inspiratory effort occurs during one or more specific phases of the ventilator cycle, and inspiration is periodic in time. This situation can also be called "entrainment" or synchronization of the breaths. The phase locking pattern can be related to the ratio of the ventilator ventilation frequency to the breathing frequency. For example, in a 1:2 phase lock, there is one stimulation cycle for every two breathing periods.

[0196] The mechanism of entrainment is typically attributed to vagal afferents from stretch receptors in the lungs and airways, although possible contributions exist from phrenic and intercostal nerve afferents. Regardless of the exact mechanism, entrainment is proportional to lung inflation and rate-dependent, and may apply to mechanical ventilation and phrenic stimulation as well. Similarities also exist between entrainment in natural sleep and that of spontaneously breathing, sedated patients. Phase-locking physiology has been described by Graves et al. in "Respiratory phase-locking during mechanical ventilation in anesthetized human subjects," Am. J. Physiol 1986.

[0197] Human subjects were entrained 1:1 to mechanical ventilation over a range of ventilator frequencies within ±3–5 breaths / min of each subject's spontaneous breathing rate. Outside the range of 1:1 entrainment, more complex entrainment patterns were observed. In the case of phrenic stimulation, the central stimulator response was similar. Inspiratory activity could typically be expected to precede stimulation when the stimulation burst rate was greater than the spontaneous frequency, and inspiratory activity occurred during or after the stimulation burst portion of the respiratory cycle when the stimulation rate was less than the spontaneous frequency in sleeping subjects.

[0198] The pattern of entrainment, including the phase relationship, depends on the ratio between the "natural" respiratory cycle and the mechanical rhythm, and on the ratio between the natural and mechanical tidal volumes.

[0199] In the field of mechanical positive pressure ventilation, the phase relationship of inspiration relative to ventilator inflation is measured as delay. The delay is the time from the onset of mechanical inflation to the onset of spontaneous inspiration (typically diaphragmatic EMG). The phase angle θ is derived by dividing this delay by the ventilator period and multiplying by 360°. When mechanical inflation and EMG onset occur simultaneously, θ = 0°. When EMG activity precedes mechanical inflation, θ is between −180° and 0°; when EMG activity occurs during or after mechanical inflation, θ is between 0° and +180°. In certain instances, a similar technique can be implemented by a phrenic nerve stimulation system for stimulation of the phrenic nerve.

[0200] In published literature studies, in both anesthetized and sleeping subjects, inspiratory activity preceded a positive pressure mechanical ventilation cycle when the machine frequency was less than the spontaneous frequency (negative phase angle), and inspiratory activity occurred during or after ventilator-initiated lung inflation when the machine frequency was greater than the spontaneous frequency in sleeping subjects.

[0201] Entrainment of the natural breathing rhythm by stimulation of the phrenic nerve is known and has been used to treat central sleep apnea (CSA), as described in U.S. Patents 11,065,443 and 8,233,987.

[0202] In certain exemplary embodiments, a method is provided for the treatment of OSA by entraining breathing through application of a stimulation pulse train to the phrenic nerve, which causes a forceful contraction of the diaphragm during the late natural expiration / early inspiration portion of the respiratory cycle, causing a negative pressure reflex in the airway when the airway is closed.

[0203] Therefore, in connection with certain exemplary techniques described herein, it may be advantageous to synchronize breathing at a frequency rate that allows for spontaneous inhalation during or after lung inflation initiated by phrenic nerve stimulation, when the stimulation frequency is slightly higher than the patient's spontaneous frequency. This suggests knowing the patient's spontaneous breathing rate. We propose that this determination be made during a resting period when the patient is confirmed to be supine and at rest, and may be or may be entering a sleep state, but has not yet exhibited periodic breathing and OSA that would alter their natural resting breathing pattern.

[0204] It is believed that all patients find it easiest to initially entrain at a stimulation rate that is close to their natural breathing frequency (natural frequency stimulation rate). For example, a patient can first be entrained at their natural frequency stimulation rate, and then the rate can be gradually increased or decreased to achieve optimal timing of airway stimulation and negative pressure reflex activation.

[0205] Additionally, a processor (e.g., 400), such as in the IPG 41, can be programmed to automatically adjust based on the respiratory rate to achieve a desired phase angle θ between 0 and −180°, such as between 0 and −90°, where stimulation is applied after spontaneous inspiration during most of the respiratory cycle. The phase angle is the phase shift between the respiratory rate produced by stimulating the phrenic nerve with the IPG 41 and the spontaneous breathing rate without phrenic nerve stimulation. The automatic adjustment to the respiratory rate achieves a desired phase angle θ between 0 and +180°, such as between 0 and +90°, where stimulation is applied before spontaneous inspiration during the majority of the respiratory cycle. Depending on the patient's individual characteristics, some patients may benefit from the former mode of entrainment, and some patients may benefit from the latter mode.

[0206] EMG activity can be difficult to detect in the home setting, but the delay time from the onset of phrenic nerve stimulation distention to the onset of spontaneous inspiration can be detected using EMG, transthoracic cardiac impedance, or accelerometry. [Description of Figures 15A, 16A, and 16B: Optimizing Use of the Negative Pressure Reflex]

[0207] 15A illustrates a process (e.g., algorithm) that can be implemented in a system to optimize the use of the negative pressure reflex in a sleeping or resting patient. Entrainment is the phenomenon in which two oscillators interact with each other, typically through physical or chemical means, to synchronize their oscillations. This phenomenon occurs in biology to coordinate processes from the molecular scale to the organ and organism scale, and is well documented in the scientific literature.

[0208] The patient is entrained to the phrenic stimulation, and entrainment is confirmed using one of several available methods, such as spectral analysis or an Arnold Tongue plot. At 500, the patient's breathing pattern and / or motion 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 and continues monitoring the patient. If the patient is determined to be sleeping or resting, the process proceeds to 504, where a phase angle is calculated using the respiratory signal. Note that in certain examples, the phase angle may be calculated at 500. In either case, stimulation may be initiated or otherwise used (e.g., as discussed herein) at a rate based on (e.g., as close as possible to) the averaged spontaneous breathing rate. After the entrainment is confirmed, for example, by spectral analysis (described below in connection with FIGS. 18A and 18B), based on a determination (at 506) that the calculated phase angle is not on target, the stimulation rate can be increased or decreased (e.g., slightly) to achieve the desired timing. If the phase angle is on target, the process returns to 500 to monitor 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 to a rate that is 2-3 breaths below the spontaneous breathing rate. The phase angle is expected to be negative. Therefore, at 508, the stimulation rate can be increased in steps until the phase angle changes polarity and the stimulation precedes spontaneous inspiration by the desired delay, which can be 50-500 ms or 25% of the total spontaneous inspiration time.

[0209] 15A may be implemented by the IPG (e.g., its electronic circuitry). In other embodiments, some elements may be implemented by the IPG and some elements may be implemented by other devices in communication with the IPG. For example, the respiration and motion analysis performed in 500 may be performed by a mobile device or bedside monitor, which then communicates with the IPG to adjust the stimulation rate being delivered to the patient.

[0210] 16A and 16B illustrate how the stimulation rate can be adjusted to optimize respiratory phase locking using the phase angle between the stimulation pulse train and the patient's spontaneous breathing efforts.

[0211] 16A illustrates a stimulation pulse train 220 applied at a set rate, which may be between 6 and 25 breaths per minute. This rate is below the patient's natural breathing rate. Breaths, represented by volume changes 221, lag the stimulation by a delay period 222. Each breath represents a tidal volume resulting from a combination of natural and stimulation-induced efforts.

[0212] FIG. 16B illustrates an increased stimulation rate compared to that shown in FIG. 16A. In FIG. 16B, a stimulation pulse train 223 induces a positive phase shift 225 and an acceleration of the patient's breathing rate 224. The combined tidal volume is reduced by the patient's central nervous system to maintain minute ventilation and blood gases in the normal range. Stimulation associated with certain exemplary embodiments occurs approximately during the late expiratory-early inspiratory phase of spontaneous breathing to optimize utilization of the negative pressure reflex. At the beginning of inspiration 226, zero exhaled or inhaled volume illustrates the lack of airflow through the closed airway.

[0213] FIG. 16B also illustrates a breathing and stimulation pattern similar to or represented by the patient data from FIG. 7. Specifically, a first stimulation burst 60 is initiated upon closure of the patient's airway, as evidenced by zero airflow during period 66. It is understood that, as can be seen from FIG. 7, the behavior of biological oscillators is imperfect, and phase angles may change polarity between breaths. Phase locking or entrainment, when applied to a series of spontaneous breaths occurring over several hours of nighttime sleep, should be interpreted as the dominant or statistically more frequent behavior. Thus, when referring to "breath analysis" or the like in connection with certain exemplary embodiments discussed herein, it should be understood that computer-controlled logic that is part of or incorporated into the system is configured to average, analyze, and otherwise process the series of breaths before making changes to stimulation settings, such as pulse train rate, duration, and length. When rate is mentioned, it should be understood that this includes the rate of pulse trains or bursts made up of individual pulses. For example, a pulse train can be applied at a rate of 10 pulse trains / minute and can be made up of individual bipolar pulses repeated at a frequency of 30 Hz (pulses / second). Thus, the terms pulse burst and pulse train are used interchangeably herein. [Figure 15B: Use of lung volume]

[0214] 15B, 17A, and 17B illustrate the use of lung volume to optimize and improve the effectiveness of phrenic nerve stimulation to treat OSA.

[0215] The I:E ratio is the ratio of the duration of the inspiratory and expiratory phases of breathing. In mechanical ventilation, a "normal" I:E ratio is approximately 1:2. In both spontaneous and mechanical ventilation, it is important to ensure that breath delivery includes adequate time for exhalation. A normal inspiratory-to-expiratory ratio (I:E) in spontaneously breathing patients is usually approximately 1:3 to 1:5. That is, the proportion of time spent exhaling is 3 to 5 times longer than the proportion of time spent inhaling.

[0216] 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, phrenic nerve stimulation duty cycle (duty cycle) refers to the percentage of stimulation burst duration relative to the total length of the stimulation 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 stimulation burst is 2.4 seconds long.

[0217] As used herein, the I:E ratio refers to the ratio between the total inspiratory time and the total exhalation time for a patient, as measured at the mask. The I:E ratio may combine artificial or stimulus-induced inspiration with spontaneous inspiratory effort. In OSA, inspiratory time may not correspond one-to-one with inspiratory effort because the airway may be obstructed.

[0218] Duty cycle, as used herein, can be used to manipulate (e.g., increase) the I:E ratio in entrained, spontaneously breathing patients. The purpose of increasing duty cycle is to increase lung volume, specifically, end-expiratory lung volume in sleeping OSA patients. This phenomenon is often referred to as "air trapping."

[0219] It is generally recognized that substantial deviations from the normal I:E ratio are uncomfortable for ventilated patients, and in ventilated patients, require sedation. Nevertheless, there are circumstances in which an increase in the I:E ratio is well tolerated and may be therapeutically beneficial. 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 be uncomfortable for the patient. As such, these settings may be individualized and included in a profile for the patient.

[0220] Lengthening the inspiratory time (e.g., 1:1 I:E) increases the mean airway pressure. As mean airway pressure increases, lung volume increases and atelectatic regions of the lung expand, leading to improved oxygenation. However, this strategy may have limitations, for example, as the lungs can be better utilized for gas exchange.

[0221] In respiratory therapy interventions such as mechanical ventilation and CPAP, end-expiratory lung volume (EELV) is the natural functional residual capacity (FRC) plus the augmented lung volume due to the application of positive end-expiratory pressure (PEEP). Moderate increases in EELV are thought to benefit OSA patients by increasing caudal traction on the airway, making it more resistant to collapse.

[0222] Lung volume is known to decline during sleep. Under these circumstances, increasing the inspiratory duty cycle can stabilize lung volume at awake levels by (1) increasing mean airway pressure and (2) trapping air inside the lungs when insufficient time is allotted for the patient to fully exhale. Although this maneuver can be uncomfortable in conscious individuals, it is usually well tolerated during sleep when applied in a controlled manner.

[0223] Obesity is often associated with reduced end-expiratory lung volume during wakefulness, which is further exacerbated during sleep and sedation. The decline in lung volume during sleep is known to exacerbate upper airway obstruction and nocturnal hypoxemia in these individuals. The adverse effects of low lung volume can be reversed by increasing the I:E ratio. The resulting increase 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. [Figure 17A: Increasing Duty Cycle]

[0224] 17A illustrates increasing the duty cycle of stimulation of one phrenic nerve. The stimulation portion of a first duty cycle 230 is shorter than the stimulation portion of a second duty cycle 231. By selectively applying different duty cycles (e.g., from a shorter duty cycle 230 to a longer duty cycle 231), a controlled increase in end-expiratory lung volume 232 (EELV) can be achieved.

[0225] In patients with obstructive sleep apnea, increased lung volume can exert caudal traction on upper airway structures, preventing pharyngeal collapse and mitigating increased airway resistance. As lung volume increases, oxygenation may also improve due to concomitant reductions in physiologic shunting, oxygen reserve, and improved ventilation / perfusion ratios. The negative cardiac effects from increased intrinsic positive end-expiratory pressure (PEEP) and increased pulmonary vascular resistance may be well tolerated or even counteracted in re-expanded regions of the lung due to the reduced hypoxic vasospasm that accompanies reoxygenation of these regions.

[0226] Controlling and optimizing the ventilation I:E ratio by varying the stimulation duty cycle for therapeutic purposes can use a real-time feedback control loop, which can be implemented, for example, as a computer-controlled process integrated into the IPG's software. For example, increasing the patient's intrinsic or entrained breathing rate can shorten expiratory time, further impeding exhalation and increasing lung volume. Increasing the stimulation duty cycle can have a similar effect on lung volume. In this regard, end-expiratory lung volume can be maintained at a desired level for an optimal breathing rate (phase-locked) by controlling the duty cycle.

[0227] In certain instances, a relatively healthy person may require a relatively smaller tidal volume during sleep to meet their metabolic needs. As a result, inhaled air can be completely exhaled within a relatively short time without air trapping. Therefore, in normal sleep breathing settings, a so-called inverse I:E ratio may be required to trap air in the lungs and increase EELV. An expected duty cycle (e.g., as applied in such cases) may be in the range of 50-70%. At the same time, some patients, particularly those with cardiac or pulmonary disease, may have rapid breathing and high expiratory resistance. These patients may trap air at a rate lower than the duty cycle. Therefore, such data settings can be personalized to the patient and stored in the patient's profile for later use. [Figure 17B: Two-stage stimulation]

[0228] 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, which can be referred to as "two-level entrainment."

[0229] Bilevel entrainment is directed to enhancing inspiration, opening collapsed airways using negative pressure responses, establishing a respiratory rhythm, and maintaining lung volume expansion during expiration. Bilevel entrainment is intended to maintain spontaneous breathing while maintaining two corresponding levels of lung expansion: inspiratory volume and end-expiratory "bias" volume, pacing breathing to a rate set by the timing of stimulation.

[0230] The duty cycle can be set by a physician or automatically adjusted if too much or too little air is detected. To be practical, such a therapy must be adaptive, where both the inspiratory and expiratory period stimulation levels can be automatically adjusted based on the patient's breathing and position.

[0231] Augmented inspiratory ventilation can compensate for the reflex-induced reduction in tidal volume caused by an increase in residual lung volume, known as the Hering-Breuer inflation reflex. It is understood that entrainment can be applied every other breath or over a period of time, followed by restoration and reassessment of the natural rhythm and respiratory rate and minute ventilation. Replenishing minute ventilation by increasing tidal volume can be an important part of the therapeutic regimen in patients with sleep-induced hypoventilation, CSA, and / or obesity when clinically indicated.

[0232] It will be appreciated that the proposed bilevel entrainment stimulation can treat a variety of conditions that often accompany OSA, such as obesity-induced hypoventilation, central sleep apnea, and mixed sleep apnea (e.g., a type of apnea where airway instability is accompanied by respiratory drive instability).

[0233] Promisingly, the proposed two-level synchronized stimulation can also contribute to the titration and auto-titration of phrenic stimulation therapy regimens. Spontaneous and induced breathing processes are periodic and rhythmic in nature. This includes central and obstructive apneas and hypopneas. Respiratory signals are often noisy and difficult to distinguish, but periodicity can be identified in the frequency domain using power spectrum analysis tools. To a certain extent, such tools can tolerate random mechanical and electrical noise—as well as changes in the patient's position.

[0234] The stimulation is two-phased, consisting of an inspiratory portion and an expiratory portion that is lower in level than the inspiratory portion but sufficient to provide a pulmonary bias and maintain expiratory lung volumes above natural levels. The bias (expiratory period) energy level can be adjusted in response to respiratory analysis. Of particular interest is the intended reduction of power spectral density in the very low LF band, which reflects apnea-hypopnea and is directly related to the goals and mechanisms of therapeutic intervention.

[0235] The graph in Figure 17B illustrates two-phase stimulation. The X-axis represents time, and the Y-axis represents both air volume along the top and stimulation energy along the bottom. Figure 17B illustrates tidal volume as a breath-by-breath respiratory airflow integrated over time, with the inspiratory phase followed by the expiratory phase. The trace at the bottom of the graph illustrates the applied stimulation energy. The stimulation pulse train is set at a programmed frequency (e.g., based on a clock and software within the IPG), which can be between 6 and 20 breaths / min (0.1-0.33 Hz), approximately the physiological range within which the patient's spontaneous breathing can be expected and within which stimulation entrainment is possible. The combination of the patient's effort and the induced diaphragmatic stimulation produces an inspiratory effort, generating a corresponding tidal volume, which is displayed along the upper portion of the graph.

[0236] The inhalation stimulation 233 corresponds to an inspiratory level of stimulation energy reflecting an IPG-generated pulse train characterized by a particular frequency, duty cycle, and current directed toward the phrenic nerve, whereas the exhalation stimulation level 234, in accordance with other aspects described herein, is lower than the inhalation level and is selected to maintain a pulmonary bias and a particular desired end-expiratory lung volume to prevent full lung contraction, and to keep the lungs inflated to improve airway resistance to obstruction and collapse.

[0237] In OSA, breathing gradually decreases over time until apnea becomes evident. The bias stimulation level can be increased until breathing resumes. In a practical embodiment of the automatic titration algorithm, the bias stimulation can be increased when hypopnea is detected, prior to apnea, because it is easier to keep the airway open than to reopen it after it has completely collapsed. The bias stimulation can be preset based on the patient's known behavior during the night, as recorded in the patient's profile. The bias stimulation can be applied when the patient changes position, for example, when rolling over to the supine position.

[0238] In certain instances, the airflow signal alone may not be sufficient to distinguish between obstructive and central apneas and hypopneas. Therefore, additional sensing of respiratory effort can be used. For example, transpulmonary impedance can be used as an indication of respiration, and certain vectors can detect paradoxical movement of the thoracic wall, which may reduce lung volume during inspiration. When spectral analysis is used, most of these considerations are irrelevant because the analysis detects the periodicity, not the magnitude or direction, of respiratory effort. [Explanation of Figures 18A and 18B: Spectral Power Analysis]

[0239] 18A and 18B illustrate spectral power analysis that may be implemented by / on an IPG (e.g., in software or firmware loaded onto the IPG) or by / on an external device in wireless communication with the IPG. The advantage of respiration analysis in the frequency domain is that it is more sensitive to respiration rate and less sensitive to respiration pattern, which is valuable for OSA patients who may exhibit paradoxical respiratory airway obstruction. Even highly imperfect signals, such as accelerometer readings that have undergone integration and bypass filtering, will produce accurate estimates of spontaneous respiration rate over time, while perhaps being relatively insensitive to occasional signal noise, such as coughing or tossing in bed.

[0240] The power spectrum can be obtained by performing a Fast Fourier Transform (FFT) on 1-10 minutes of digitally acquired respiratory signal data (in this example: thoracic motion, impedance changes, or respiratory sounds). This spectrum can be a power spectrum, a power density spectrum, or a magnitude spectrum.

[0241] The power spectrum allows for estimation of which periodic frequencies contribute most to the total variance of the signal in the band of interest. The higher the amplitude, the higher the variance. It will be appreciated that many techniques exist for calculating the frequency distribution of a periodic signal, and such techniques may be used in connection with the exemplary embodiments contemplated herein.

[0242] A "spectrum" may be calculated for a range of natural breathing frequencies, typically between 0 and 1.0 Hz. In certain exemplary embodiments, the frequency range of interest may be approximately 0.1 to 0.5 Hz. The inhibition may be extended if non-physiological high-frequency vibrations are intentionally applied. The selected range is referred to as the "respiratory frequency band" in connection with the use of the techniques herein. Other frequency ranges may be selected, and the selection of the range based on FIGS. 18A and 18B is exemplary.

[0243] 18A, this graph shows an example of a respiratory power spectrum in a patient suffering from apnea and breathing spontaneously. The low-frequency (LF) power peaks 320 correspond to periodic breathing, apneas, or hypopneas, which may be present when the patient is at rest and not yet asleep in the case of CSA, but which may generally manifest during sleep in OSA. It will be appreciated that in this context, it is generally immaterial whether the patient has central or obstructive apnea, since both processes are by definition periodic, and obstructive apneas are periodically interrupted by bouts of compensatory hyperventilation.

[0244] Unlike hypoglossal nerve stimulation, phrenic nerve stimulation, when applied asynchronously, can be beneficial for both OSA and CSA. For example, as illustrated in Figures 18A and 18B, spectral analysis can help determine an initial stimulation rate that can be set to approximately the patient's natural breathing peak frequency and determine the magnitude of periodic breathing to use as a basis for deciding to increase energy delivery or change the stimulation rate or duty cycle (uptitration of the therapeutic regimen).

[0245] The apnea / hypopnea power frequency band is generally encompassed between approximately 60 and 120 breaths per minute (0.017 to 0.033 Hz), and power integrated within this band is attributed to periodic respiratory peaks 320. High frequency HF peaks 321 correspond to respiration and may be quite diffuse in irregularly breathing patients, but are generally concentrated between 6 and 20 breaths per minute (0.1 to 0.33 Hz).

[0246] FIG. 18B shows entrained patient breathing with periodic breathing eliminated. The patient's breathing is phase-locked (entrained) to stimulation applied at a constant asynchronous rate of 0.1 Hz (6 breaths / min). Stimulation power peak 322 corresponds to this setting. In the absence of diaphragmatic capture, the peak will be indistinguishable from background noise. This technique thus contributes to the detection of levels 103 and 109 on the titration curve (see FIG. 9). In certain examples, the software described herein may calculate or use the percentage of calculated respiratory power centered in a specified frequency band, normalized to the total power after noise removal rather than the absolute value.

[0247] It will be appreciated that the frequencies provided herein are selected for illustrative purposes. In practice, the patient's spontaneous breathing and stimulation rates may be closer (e.g., within 2-3 breaths per minute of each other). This means that the instantaneous breathing rate calculated from the duration of the breath is statistically distributed around the stimulation rate. If the power distribution is skewed (e.g., toward frequencies higher than the stimulation rate), the spontaneous breathing rate may be higher than the stimulation rate, and the stimulation rate may need to be increased.

[0248] It will be appreciated that the illustration is provided as an example (e.g., may be somewhat idealized) to help illustrate the principles of spectral analysis. In certain instances, all three peaks may be present, and power may be distributed in different proportions among the peaks. The goal in certain exemplary embodiments is to reduce the LF power of the spectrum and concentrate as much power as possible within a narrow frequency band around the stimulation frequency (without arousing the patient or completely replacing natural breathing).

[0249] It will be recognized that the different techniques described herein may be applied in different ways and in different combinations to patients with different traits, diseases, underlying physiology, and anatomies. Some patients may benefit from some lung volume increase, and some may not. Some patients may benefit from phase-locking their breathing to a rate higher than their natural breathing at rest, and some may not.

[0250] While this invention has been described in connection with what is presently considered to be the most practical and most preferred embodiments, it is to be understood that the invention is not to be 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. [Additional Embodiments]

[0251] Additional embodiments that may be implemented may include the following exemplary method for treating sleep apnea.

[0252] Embodiment 1. A method of treating obstructive sleep apnea (OSA), comprising periodically artificially stimulating at least one phrenic nerve of a patient, the stimulation being applied to the nerve while the patient's pharyngeal airway is naturally obstructed.

[0253] Embodiment 2. A method of treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied while the airway is closed or partially obstructed.

[0254] Embodiment 3. A method of treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied during a period when the airway is characterized by increasing obstruction.

[0255] Embodiment 4. A method of treating OSA by periodically stimulating at least one phrenic nerve in a patient, wherein the stimulation is applied artificially while the airway is closed.

[0256] Embodiment 5 The method of any of embodiments 1 to 4, wherein said stimulation comprises a burst of stimulation initiated while said airway is closed.

[0257] Embodiment 6. The method of any of embodiments 1 to 5, wherein a substantial proportion of the stimulations are simulated bursts initiated upon closure of said airway.

[0258] Embodiment 7. The method of embodiment 5 or 6, wherein the stimulation burst is applied initially at a first energy level sufficient to generate action potentials in the phrenic nerve and later at a second energy level sufficient to cause reflex opening of the collapsed airway by activation of upper airway muscles.

[0259] Embodiment 8. The method of either embodiment 5 or 6, wherein the stimulation burst is applied initially at a first energy level sufficient to generate action potentials in the phrenic nerve, and further at a second energy level sufficient to cause reflex opening of the collapsed airway by enhancing the mechanoreceptor reflex.

[0260] Embodiment 9. The method of embodiment 9, wherein said mechanoreceptor reflex is a negative pressure reflex.

[0261] Embodiment 10. A method comprising:

[0262] Identifying patients with OSA,

[0263] Implanting a phrenic nerve stimulator in the patient or connecting it to the phrenic nerve; and

[0264] Adjusting stimulation energy applied by the phrenic nerve stimulator to the phrenic nerve in a sleeping patient based on airway obstruction detected in the patient's airway.

[0265] Embodiment 11. The method of embodiment 10, wherein the phrenic nerve stimulator includes a pulse generator and an electrical electrode implanted adjacent to the phrenic nerve.

[0266] Embodiment 12 The method of embodiment 10 or 11, wherein said adjusting said stimulation energy comprises adjusting said stimulation energy in response to said stimulation burst until said airway obstruction is relieved.

[0267] Embodiment 13 The method of any of embodiments 10 to 12, wherein said adjusting said stimulation energy continues until airflow is restored in said sleeping patient.

[0268] Embodiment 14. The method of any of embodiments 10 to 13, wherein airway obstruction is detected by monitoring airflow through the patient's air breathing passages, the patient's breath sounds, the patient's respiratory effort, the patient's airway pressure and / or oxygen saturation.

[0269] Embodiment 15. The method of any of embodiments 10 to 14, wherein the stimulation energy is applied during one breath, and the breath is at a rate of 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.

[0270] Embodiment 16. The method of any of embodiments 10 to 15, wherein the applied energy is applied at a duty cycle of 30-50% of one respiratory period, 35%-40% of one respiratory period, 40%-60% of one respiratory period, or 25%-60% of one respiratory period.

[0271] Embodiment 17. The method of any of embodiments 10 to 16, wherein the rate is set based on the patient's natural resting breathing rate.

[0272] Embodiment 18. The method of any of embodiments 10 to 17, wherein at least 20% of the applied energy comprises stimulation bursts that coincide with the natural late-expiratory early-inspiration period of breathing.

[0273] Embodiment 19. The method of any of embodiments 10 to 18, wherein the applied energy comprises a stimulation burst applied during the time of the natural late-expiratory early-inspiration period of the breath that is detected or predicted based on a previous breath.

[0274] Embodiment 20 The method of any of embodiments 10 to 19, wherein said stimulation of said phrenic nerve generates negative pressure in said airway.

[0275] Embodiment 21 The method of any of embodiments 10 to 20, wherein said stimulation of said phrenic nerve produces diaphragmatic contraction that creates negative pressure in said airway.

[0276] Embodiment 22 The method of any of embodiments 10 to 21, wherein said stimulation of said phrenic nerve produces a diaphragmatic contraction that produces negative pressure in said airway sufficient to trigger a negative pressure reflex.

[0277] Embodiment 23 The method of embodiment 22, wherein the negative pressure reflex activates airway muscles of the patient.

[0278] Embodiment 24 The method of embodiment 23, wherein said activation of said airway muscles restores patency of said airway.

[0279] Embodiment 25 The method of embodiment 23 or 24, wherein said activation of said airway dilator muscles minimizes oxygen desaturation and / or hypercapnia.

[0280] Embodiment 26. A method of reducing the duration of airway obstruction in a sleeping patient, comprising periodically stimulating at least one phrenic nerve of the sleeping patient, the stimulation being applied while the airway is closed.

[0281] Embodiment 27 The method of embodiment 26, wherein said stimulation of said at least one phrenic nerve contributes to triggering a negative pressure reflex in said patient.

[0282] Embodiment 28 The method of embodiment 26 or 27, wherein said stimulation of at least one phrenic nerve induces contraction of the diaphragm in said patient upon collapse of said airway.

[0283] Embodiment 29 The method of embodiment 28, wherein said contraction of said diaphragm creates negative transmural airway pressure downstream of the site of obstruction in said airway.

[0284] Embodiment 30 The method of embodiment 29, wherein the transmural negative airway pressure is sufficient to activate the negative pressure reflex in the patient.

[0285] Embodiment 31. The method of any of embodiments 26 to 30, wherein the negative pressure reflex efferent output to the airway muscles exceeds the negative pressure reflex efferent output that occurs naturally while the patient is sleeping.

[0286] Embodiment 32. The method of any of embodiments 26 to 31, wherein contraction of the patient's diaphragm is sufficient to create a negative transmural airway pressure downstream of the obstruction in the airway that is more negative than the negative transmural airway pressure that occurs naturally while the patient is sleeping.

[0287] Embodiment 33 The method of any of embodiments 26 to 32, further comprising reducing the duration of airway obstruction in said sleeping patient to prevent oxygen desaturation of greater than 3%.

[0288] Embodiment 34. The method of any of embodiments 26 to 32, further comprising automatically adjusting the stimulation current based on at least one of airflow detected in the breathing of the sleeping patient, breath sounds of the sleeping patient, respiratory effort of the sleeping patient, airway pressure in the sleeping patient, and oxygen saturation of the sleeping patient.

[0289] Embodiment 35. A method comprising:

[0290] To identify patients with OSA, and

[0291] Adjusting stimulation energy to the phrenic nerve in the patient based on a detected airway obstruction in the patient's airway and while the patient is sleeping.

[0292] Embodiment 36 The method of embodiment 35, further comprising verifying that the patient remains asleep after said adjustment of said stimulation energy.

[0293] Embodiment 37 The method of embodiment 36, further comprising selecting a stimulation energy that causes both the cessation of the obstruction and the opening of the airway, and that does not arouse the patient.

[0294] While this invention has been described in connection with what is presently considered to be the most practical and most preferred embodiments, it is to be understood that the invention is not to be 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. [Explanation of symbols]

[0295] [List of elements identified in the diagram] 1...Patient, 2...Pharyngeal airway (pharynx, airway), 3...Negative inspiratory pressure within the airway, 4...Positive pressure outside the airway, 5...Pharyngeal dilator muscles (e.g., genioglossus), 6...Mandible, 7...Increased lung volume, 8...Soft palate / vellum, 9...Velopharynx or velopharyngeal space, 10...CNS respiratory center, 11...Physiological sensors, 14...Genioglossus, 12...Afferent limb of the reflex, 13...Efferent limb of the reflex, 16...Medulla oblongata, 20...Phasic activation of pharyngeal dilator muscles, 21...Pharyngeal patency, 22...Dysfunctional pharyngeal anatomy, 24...Diminished reflexes, 23...Sleep onset, 25...Diminished response to negative pressure, 26...Airway closure, 27...Hypoxia and hypocapnia, 2 8. Increased respiratory effort, 29. Short-term arousals, 30. Phrenic nerve stimulation, 31. Increased negative pressure, 32. Activation of the afferent limb of the NPR, 33. Restoration of dilator activity, 41. Implantable pulse generator (IPG), 42. Electrode system, 43. Diaphragm, 44. Phrenic nerve, 45. Lungs, 46. Stimulation system, 47. Leads, 48. Handheld computer programming device, 50. Airflow, 51. Respiratory effort, 52. Oxygen desaturation during apnea, 52 54...control period when stimulation is off, 53, 55, 56...period when stimulation is on, 55...stimulation current level, 56...increasing current level, 50-a...first trace in graph showing airflow sensor signal, 51-a...second trace in graph showing breathing belt sensor signal, 52-a...third trace in graph showing pulse oximetry measurement, 53-a...arbitrary waveform generator, 60...first stimulation burst, 61...second stimulation burst, 62...onset of effort, 63...inspiration changing to expiration, 65...pause of effort, 66...time delay, 67...opening of airway, onset of inspiratory airflow, 69...occluded but not closed airflow, 71...delay time, 73...inflection point, 74...end of inspiration by breathing, 75...expiration point, 70-a...airflow chart, 70-b...respiratory effort chart over time, 70-c...respiratory effort signal, 70-d...airflow signal, 80...sleep onset and OSA detection, 81...respiratory analysis, 82...phrenic nerve stimulation, 83...restoration of normal breathing, 84...parameter adjustment, 85...parameter acceptance, 100...contraction strength vs. stimulation energy curve, 101...diaphragm contraction strength, 102...stimulation energy, 103...minimum capture level, 104...respiratory normalization level, 105...tolerance level, 106...maximum tetanic contraction level, 107...therapeutic treatment range,108...Reflex activation level, 150...Respiration and motion analysis, 152...Patient at rest, 154...Energy increase, 156...Capture detection, 158...Storage of data & test stop, 170...Respiration and motion analysis, 172...OSA detection, 174...Energy increase, 176...Arousal, 178...Energy decrease and data storage, 200...Graph, 201...Test lamp, 202...First treatment action lamp, 205...Nighttime rest capture threshold, 206...First treatment action threshold, 204...Second treatment action lamp, 207... Second therapeutic action threshold, 210...wearable monitoring system, 211...clinical monitoring device, 212...cloud computer system, 213...sensing lead, 220...stimulation pulse train, 221...volume change, 222...delay, 223...increased stimulation rate, 224...respiratory rate, 225...positive phase shift, 230...stimulation portion of first duty cycle, 231...stimulation portion of second duty cycle, 232...end-expiratory lung volume, 233...stimulation during inspiration, 301...header, 302...housing, 303...electronic circuit elements , 304...Battery, 305...Sensing lead port, 306...Stimulation lead port, 320...Low frequency LF power peak, 321...High frequency HF peak, 322...Stimulation power peak, 400...Microprocessor, 407...Tuned telemetry coil circuit, 408...Proximity sensor or switch, 409...Real time clock, 410...Telemetry driver / receiver circuit, 411...3-axis accelerometer, 415...Voltage sensing circuit, 416...Excitation current, 417...Battery, 418...Voltage reference, 419...Amplifier / Digital-to-Analog Converter Converter, 420...power supply, 421...current source circuit, 425...polarity switching network, positive, 426...polarity switching network, negative, 430...sensor, 500...respiration and motion analysis, 502...determining sleep rest, 504...phase angle calculation, 506...determining whether phase angle is on target, 508...rate adjustment, 550...respiration and motion analysis, 552...OSA detection, 554...increasing lung volume, 556...determining arousal, 558...resuming therapy, 1102...latency parameter, 1104...therapy ramp time parameter.

Claims

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

2. 10. The system of claim 1, wherein the sensor is configured to detect partial or complete obstruction of 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 step of controlling the phrenic nerve stimulator further comprising:

10. The system of claim 1, further comprising: instructing the phrenic nerve stimulator to deliver the stimulation energy or increase the delivery of the stimulation energy while the airway is partially or completely obstructed in response to receiving one or more signals from the at least one sensor that determine the airway is partially or completely obstructed.

4. the step of controlling the phrenic nerve stimulator further comprising: determining the obstruction status 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; If the airway is determined to be partially or completely obstructed, commanding the phrenic nerve stimulator to deliver the stimulation energy while the airway is partially or completely obstructed or to increase the delivery of the stimulation energy; 10. A system according to any one of the preceding claims, comprising:

5. The procedure that the controller is configured to execute: receiving or determining, for a given patient, a diaphragm muscle contraction threshold sufficient to produce diaphragm muscle contraction and negative airway pressure; the step of controlling the phrenic nerve stimulator includes maintaining the stimulation energy above the diaphragm muscle contraction threshold while the airway is partially or completely obstructed. A system according to any one of the preceding claims.

6. The procedure that the controller is configured to execute: a further step of receiving or determining, for a given patient, a patient arousal threshold that is not sufficient to arouse said patient; the step of controlling the phrenic nerve stimulator includes maintaining the stimulation energy below the patient arousal threshold while the airway is partially or completely obstructed. A system according to any one of the preceding claims.

7. The procedure that the controller is configured to execute: and the further step of establishing whether the patient is at rest or asleep. A system according to any one of the preceding claims.

8. Establishing whether the patient is at rest or asleep receiving a command from a user interface communicatively connected to the controller indicating that the patient is at rest or asleep; and / or receiving a command from a user interface communicatively connected to the controller indicating that the patient is interrupting rest or sleep; The system of claim 7, comprising:

9. Establishing whether the patient is at rest or asleep Identifying a current time of day; comparing the current time of day to one or more preset time intervals, the one or more preset time intervals stored in a memory communicatively coupled to or part of the controller and indicating one or more periods of the day during which the patient is considered to be at rest or asleep; 9. The system of claim 7 or 8, comprising:

10. Establishing whether the patient is at rest or asleep receiving one or more vital sign signals from one or more detectors of vital signs of the patient, the sensors of vital signs being communicatively coupled to the controller; determining that the patient is at rest and voluntarily asleep based on the one or more vital sign signals and / or determining that the patient has interrupted rest or sleep; 10. The system of claim 7, 8 or 9, comprising:

11. the one or more detectors of vital signs a motion sensor, optionally an inertial sensor, that is part of the controller or that is configured to be coupled to the patient; The system of claim 10, comprising:

12. the one or more detectors of vital signs Breath Sensor and optionally, the one or more detectors of vital signs include both a motion sensor and a breath sensor, and the controller establishes whether the patient is at rest or asleep based on signals from both the breath sensor and the motion sensor.

12. A system according to claim 10 or 11.

13. the one or more detectors of vital signs ECG, and / or blood pressure sensor, 13. The system of claim 10, 11 or 12, comprising:

14. the one or more detectors of vital signs an oxygen saturation sensor, optionally a finger pulse oximetry device; 14. The system of claim 10, 11, 12 or 13, comprising:

15. 15. The system of claim 7, wherein the controller is configured to instruct the phrenic nerve stimulator to deliver the stimulation energy or to increase the delivery of the stimulation energy while the patient is established to be at rest or asleep.

16. 10. A system according to any one of the preceding claims, wherein the procedure the controller is configured to execute is repeated at time intervals, optionally periodically repeated between 6 and 20 times per minute.

17. 17. The system of claim 1, wherein the procedure the controller is configured to perform is repeated at time intervals, optionally periodically, until it is detected or confirmed that the airway is no longer partially or completely obstructed.

18. 18. The system of claim 16 or 17, when combined with any one of claims 7 to 15, wherein the procedure the controller is configured to execute is repeated at time intervals, and optionally periodically, while the patient is established to be at rest or asleep.

19. 19. The system of any one of claims 16 to 18, wherein the controller is configured to control the phrenic nerve stimulator to vary, and optionally increase, the delivery of stimulation energy with each repetition of the procedure.

20. 10. The system of 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 train of pulses.

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

22. controlling the phrenic nerve stimulator to increase the delivery of stimulation energy; Increasing the number of individual pulses in said train of pulses; increasing the frequency of individual pulses in said train of pulses; increasing the amplitude of individual pulses in said train of pulses; Increasing the number and frequency of individual pulses in said train of pulses; increasing the amplitude and frequency of individual pulses in said train of pulses; Increasing the amplitude and number of individual pulses in the train of pulses, or Increasing the number, frequency, and amplitude of individual pulses in the train of pulses; and Optionally, the duration is kept constant; 22. The system of claim 21.

23. 23. The system of claim 21 or 22, wherein the number of individual pulses in the train of pulses is maintained between 5 and 40.

24. 24. A system according to any one of claims 21 to 23, wherein the frequency of the individual pulses is maintained between 20 and 50 Hz.

25. A system according to any one of claims 21 to 24, wherein the duration of each pulse is maintained between 30 and 250 microseconds.

26. 26. A system according to any one of claims 21 to 25, wherein the amplitude of the individual pulses is maintained between 0.4 and 5.0 mA, optionally between 1.0 and 4.0 mA.

27. The step of controlling the phrenic nerve stimulator to deliver the stimulation energy comprises: each time the controller receives one or more signals from the at least one sensor that determine that the airway is partially or completely obstructed; and / or each time the controller determines that the airway is partially or completely obstructed; commanding a ramp or step increase in delivered energy at intervals of time, optionally at periodic intervals of time; 10. A system according to any one of the preceding claims.

28. The procedure that the controller is configured to execute: receiving or determining a treatment regimen; controlling the phrenic nerve stimulator to deliver the stimulation energy within the therapeutic area; Including, 10. The system of claim 1, wherein the therapeutic treatment range is between a first threshold and a second threshold higher than the first threshold, and optionally the therapeutic treatment range is stored in a memory communicatively connected to the controller.

29. The system of claim 28, wherein the procedure includes determining the therapeutic treatment zone by gradually increasing the stimulation energy and detecting the first threshold as a stimulation energy threshold at which a first detectable patient event occurs and, optionally, the patient's breathing pattern is altered in a systematic, periodic manner, and detecting the second threshold as a further stimulation energy threshold at which a second detectable patient event occurs and at which the patient's breathing is stabilized and partial or complete airway obstruction is no longer detected.

30. The system of claim 28 or 29, wherein the procedure the controller is configured to execute includes receiving or determining multiple treatment treatment zones for the same patient, the multiple treatment treatment zones including treatment treatment zones determined for each of different positions of the patient while at rest or asleep.

31. 28. The system of 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 the gradual increase in delivered energy when it is established that the patient is no longer at rest or asleep.

32. 10. The system of any one of the preceding claims, wherein the step of controlling the phrenic nerve stimulator to deliver the stimulation energy includes initiating the phrenic nerve stimulator to deliver the stimulation energy as one or more simulated bursts initiated upon an obstruction of the airway.

33. 10. The system of any one of the preceding claims, wherein the stimulation energy comprises at least one first stimulation burst initially applied at a first energy level sufficient to generate action potentials in the patient's phrenic nerve, and at least one second energy level applied after the first stimulation burst sufficient to cause reflex opening of the obstructed airway through activation of upper airway muscles.

34. 10. The system of any one of the preceding claims, wherein the stimulation energy initially comprises at least one first stimulation burst applied at a first energy level sufficient to generate action potentials in the patient's phrenic nerve, and further comprises at least one second stimulation burst at a second energy level sufficient to cause reflex opening of the obstructed airway by enhancing a mechanoreceptor reflex.

35. 35. The system of any one of claims 1 to 34, wherein the phrenic nerve stimulator includes a pulse generator and an electrical electrode configured to be implanted in proximity to the phrenic nerve.

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

37. 36. The system of any one of claims 1 to 35, wherein the first portion of the controller and the neurostimulator are present within an implantable pulse generator and the second portion of the controller is present on an external device, optionally an external portable device, communicatively connected to the first portion of the controller.

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

39. The sensor configured to output one or more signals indicative of an obstruction condition in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter being selected from: Airflow through the patient's respiratory pathway 10. The system of any one of the preceding claims, comprising:

40. The at least one sensor configured to output one or more signals indicative of an obstruction condition in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter being selected from: The patient's breath sounds 10. The system of any one of the preceding claims, comprising:

41. The at least one sensor configured to output one or more signals indicative of an obstruction condition in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter being selected from: the patient's respiratory efforts 10. The system of any one of the preceding claims, comprising:

42. The at least one sensor configured to output one or more signals indicative of an obstruction condition in the airway is adapted to monitor at least one patient parameter, the at least one patient parameter being selected from: the patient's airway pressure and / or oxygen saturation 10. The system of any one of the preceding claims, comprising:

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

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

45. 10. The system of 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 30-50% of a respiratory period, 35-40% of a respiratory period, 40-60% of a respiratory period, or 25-60% of a respiratory period.

46. The controller controls the following patient parameters: airflow in the breathing of the sleeping patient; breathing sounds of the sleeping patient; the patient's respiratory effort during sleep; airway pressure in the sleeping patient; or the oxygen saturation of the sleeping patient; 10. The system of claim 1, wherein the system is configured to automatically adjust the stimulation energy based on the at least one sensor configured to detect at least one of:

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

48. 47. A non-transitory computer-readable storage medium communicatively couplable to the controller of the system of any one of claims 1 to 46, the non-transitory computer-readable storage medium storing instructions that, when executed by the controller, cause the controller to perform the procedure and / or the controller steps of any one of the preceding claims.

49. 48. A non-transitory computer-readable storage medium communicatively couplable to the one or more processors of the controller of the system of claim 47, the non-transitory computer-readable storage medium storing instructions that, when executed by the one or more processors, cause the one or more processors to perform the procedure and / or the controller steps of any one of the preceding claims.

50. 1. A controller for a system configured to treat obstructive sleep apnea (OSA), the system comprising: a phrenic nerve stimulator configured to deliver stimulation energy to a phrenic nerve in a sleeping patient; at least one sensor configured to output one or more signals indicative of an obstruction condition within the airway; Equipped with The controller: receiving the one or more signals; controlling the phrenic nerve stimulator to deliver the stimulation energy based on the one or more signals; The controller is configured to execute a procedure including:

51. 51. The controller of claim 50, wherein the controller is configured to carry out the procedures and / or steps of the controller of the system of any one of claims 1 to 46.

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