Neural monitoring methods and systems for treating pharyngeal disorders

Thisis anapplicationfor reissue of U.S. Pat. No. 10,463,266, whichis a divisional of U.S. application Ser. No. 13/752,273 filed Jan. 28, 2013, issued on Jul. 18, 2017 as U.S. Pat. No. 9,706,934, which claims benefit of U.S. Provisional Patent Application No. 61/591,078 filed Jan. 26, 2012 and entitled “Neural Monitoring Methods and Systems for Treating Pharyngeal Disorders,” the disclosures of which are hereby incorporated herein by reference in their entirety.

The invention generally relates to neural monitoring methods and systems for detecting, identifying and treating upper airway disorders such as sleep apnea/hypopnea, dysphagia, reflux, and/or snoring.

The pharynx serves multiple and diverse roles—mastication, breathing, swallowing, speaking, taste and smell, heat, humidify and filter air, protect airway. This single structure serves diverse and highly complex functions, many of which may not be carried out simultaneously. For example, the pharynx is a structure shared by both the respiratory and digestive pathways and acts as a mechanical “switch” to direct incoming air and solids to the appropriate anatomical systems during breathing and swallowing.

During normal respiration, structures of the pharynx assume positions that maximize the patency of the airway. As air is inhaled, tonic activation actively maintains pharyngeal position and phasic activation via the negative pressure reflex resists vacuum-induced changes in pharyngeal position. During normal swallowing, the pharynx propels food and fluid caudally while simultaneously positioning the airway to prevent aspiration of the food and fluid materials into the lungs. Indeed, swallowing is a coordinated pattern of activity involving more than 50 muscles throughout the upper airway and is generally divided into oral, pharyngeal, and esophageal phases.

Because the pharynx is situated at the literal crossroad of the respiratory and gastrointestinal intakes, pharyngeal structural and/or postural dysfunction may result in a variety of disorders including obstructive sleep apnea, dysphagia, snoring, and acid reflux/GERD. In addition to the immediate health concerns introduced by this assemblage of disorders, many of these disorders are associated with an increased risk of additional comorbidities such as heart attack, stroke, hypertension, diabetes, development of carotid artery atherosclerosis, pulmonary aspiration and aspiration pneumonia, among others.

Existing treatments for pharyngeal disorders such as apnea include continuous positive air pressure (CPAP) devices, surgical interventions, weight loss, medication, changes in sleeping position and/or dental appliances; many of these treatments suffer from limited effectiveness or compliance. Implantable monitor devices are under development that monitor thoracic pressure, blood oxygenation, or the bioelectric activity of the diaphragm, intercostal muscles, upper airway muscles, or the efferent nerves associated with these muscles. Other implantable devices have been described that terminate apnea using drug delivery, atrial overdrive pacing or electrical stimulation of the nerves or muscles that control respiratory activities. To date, the potential for the development of effective methods of preventing and/or treating disorders associated with pharyngeal dysfunction remains unfulfilled.

A need in the art exists for additional methods of detecting, preventing, and/or treating adverse pharyngeal conditions and/or treating pharyngeal disorders such as sleep apnea, snoring, dysphagia and/or GERD.

According to the invention, a method for monitoring a condition in a subject is provided. The method comprises obtaining one or more neural signals from one or more upper airway afferents of the subject; processing each of the one or more neural signals to obtain at least one neural activity profile; comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type; and processing each of the at least one neural activity profiles to determine an activity state characterizing the associated activity type.

Each neural activity profile may be characterized by at least one of: a neural signal timing, a neural signal amplitude, a neural signal phase, a neural signal position, a neural signal conduction velocity, and any combination thereof.

An associated activity type may be chosen from a respiratory activity type, a deglutition activity type, a vibration activity type, a reflux activity type, and any combination thereof.

The activity state may comprise: a respiratory state comprising respiratory timing, respiratory amplitude, respiratory phase, respiratory location, and any combination thereof; a deglutition state comprising solid contact, fluid contact, contact velocity, contact timing, contact amplitude, contact pressure, contact texture, contact temperature, a presence of a unswallowed bolus, and any combination thereof; a vibration state comprising vibration timing, vibration amplitude, vibration phase, vibration location, vibration pattern, and any combination thereof; and a reflux state comprising reflux timing, reflux pH, reflux location, and any combination thereof.

The one or more upper airway afferents may be chosen from pharyngeal afferents, laryngeal afferents, oral cavity afferents and nasal cavity afferents.

The one or more activity criteria may comprise: a respiratory criterion indicating a respiratory activity, a deglutition criterion indicating a deglutition activity, a vibration criterion indicating a vibration activity, and a reflux criterion. The respiratory criterion may comprise a time separation between peak neural signal amplitudes ranging from about 1 seconds to about 5 seconds, a periodically repeating pattern of neural signals with a period ranging from about 12 patterns per minute to about 60 patterns per minute, and any combination thereof. The deglutition criterion may comprise an anterior to posterior neural activation pattern, a stereotyped neural activation pattern with a duration of less than about 1 second, and any combination thereof. The vibration criterion may comprise a neural signal frequency ranging from about 10 Hz to about 400 Hz, a time separation between peak neural signal amplitudes ranging from about 1 second to about 5 seconds, and any combination thereof. The reflux criterion may comprise a signal conduction velocity of less than about 2 m/s.

Processing the one or more neural signals may further comprise analyzing a timing sequence of two or more activity patterns, wherein each of the two or more activity patterns is obtained from different upper airway afferents.

The method for monitoring a condition in a subject may further comprise processing the at least one activity state to obtain at least one condition of the subject. The at least one condition of the subject may be chosen from a respiratory condition, a deglutition condition, a vibration condition, a reflux condition, and any combination thereof. The respiratory condition may comprise apnea, tachypnea, hyperpnea, hypopnea, polypnea, dyspnea, bradypnea, cough, Cheyne-Stokes respiration, Biot's respiration, ataxic respiration, Kussmaul respiration, wheezing, irregular respiration, respiratory arrest, restrictive respiration, shallow breathing, hypoventilation and any combination thereof. The deglutition condition may comprise presence of unswallowed bolus, occurrence of swallow, occurrence of dysphagic swallow, presence of acid reflux, and any combination thereof. The vibration condition may comprise snoring, stridor, wheezing vocalization, and any combination thereof. The reflux condition may comprise esophageal reflux, pharyngeal reflux, laryngeal reflux and any combination thereof.

Alternatively, or in combination with the above, the method may further comprise assessing the at least one condition to predict a disorder. The disorder may be chosen from obstructive apnea, central apnea, mixed apnea, snoring, flow limitation, dysphagia, heart failure, uremia, asthma, cardiac arrest, organ failure, metabolic acidosis, COPD, pulmonary embolism, Ondine's curse, obesity hypoventilation syndrome, laryngeal penetration, aspiration, esophageal reflux, laryngeal reflux, presence of unswallowed bolus, acid reflux, GERD, laryngeal penetration, aspiration, and any combination thereof.

Any one or more of the at least one states, the at least one conditions, the at least one disorders, and any combination thereof may be displayed on a patient monitor device.

Any one or more of the at least one states, the at least one conditions, the at least one disorders, and any combination thereof may be communicated to a treatment system.

The invention also provides a system for monitoring a condition in a subject. The system may comprise at least one processor; aCardio Respiratory MonitoringComputer Readable Medium(CRM) containing a subject monitor application comprising a plurality of modules executable on the at least one processor; and a GUI module for generating one or more forms used to receive inputs to the system and to deliver output from the system. The plurality of modules may comprise: a neural signal acquisition module for obtaining one or more neural signals in one or more upper airway afiferents of the subject; a neural activity profile module for processing each of the one or more neural signals to obtain at least one neural activity profile; an activity type module for comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type; and an activity state module for processing each of the at least one neural activity profiles to determine an activity state characterizing the associated activity type. Each neural activity profile, activity type, and activity state may be characterized as described above. Suitable activity criteria are also described above.

The neural activity profile module may further analyze a timing sequence of two or more activity patterns, wherein each of the two or more activity patterns is obtained from different upper airway afferents.

The plurality of modules may further comprise a condition module for processing the at least one activity state to obtain at least one condition of the subject. The at least one condition of the subject may be chosen from a respiratory condition, a deglutition condition, a vibration condition, a reflux condition, and any combination thereof. Suitable respiratory, deglutition, vibration, and reflux conditions are described above.

Alternatively, or in combination with the above, the system may further comprise a disorder prediction module for assessing the at least one condition to predict a disorder. The disorder may be chosen from obstructive apnea, central apnea, mixed apnea, snoring, flow limitation, dysphagia, heart failure, uremia, asthma, cardiac arrest, organ failure, metabolic acidosis, COPD, pulmonary embolism, Ondine's curse, obesity hypoventilation syndrome, laryngeal penetration, aspiration, esophageal reflux, laryngeal reflux, pharyngeal reflux, presence of unswallowed bolus, acid reflux, GERD and any combination thereof.

The invention also provides a first method for treating and/or preventing a disorder in a subject in need thereof. The method comprises delivering at least one stimulation to modulate at least one reflex chosen from a swallowing reflex, a negative-pressure reflex, and any combination thereof. The disorder comprises at least one of: obstructive apnea, central apnea, obesity hypoventilation syndrome, dysphagia, esophageal reflux, presence of unswallowed bolus, acid reflux, GERD, and any combination thereof. Each of the at least one stimulations is delivered with subthreshold parameters insufficient to independently elicit the reflex or with suprathreshold parameters sufficient to independently elicit the reflex. The at least one stimulation is delivered according to a delivery schedule chosen from periodic, random, and continuous.

Each of the at least one stimulations may comprise an electrical stimulation or a mechanical stimulation.

Each electrical stimulation may be delivered to a reflex-related nerve, a reflex-related muscle, a reflex-related sensory receptor, and any combination thereof. Each mechanical stimulation may be delivered to a reflex-related sensory receptor.

The reflex-related nerve may comprise an afferent or an efferent. An afferent may be chosen from: superior laryngeal nerve, internal branch of the superior laryngeal nerve, recurrent laryngeal nerve, pharyngeal branch of vagus nerve, pharyngeal branch of glossopharyngeal nerve, tonsilar branch of glossopharyngeal nerve, lingual branch of glossopharyngeal nerve, pharyngeal plexus, intermediate nerve, palatine nerve, greater petrosal nervepterygopalatine nerve, pterygopalatine ganglion, pharyngeal branch of the pterygopalatine ganglion, superior alveolar nerve, buccal nerve, greater petrosal nerve, maxillary branch of the trigeminal nerve, posterior nasal branch of the maxillary nerve, nasociliary nerve, posterior ethmoidal nerve, infratrochlear nerve, anterior ethmoidal nerve, nasopalatine nerve, greater palatine nerve, lesser palatine nerve, or infraorbital nerve. An efferent may be chosen from: recurrent laryngeal nerve, external branch of superior laryngeal nerve, brancial motor branch of glossopharyngeal nerve and proximal fibers, mandibular nerve, medial pterygoid nerve, pharyngeal branch of vagus nerve and proximal fibers; branch of facial nerve and proximal fibers, and branch of hypoglossal nerve and proximal fibers.

The reflex-related sensory receptor may be situated in skin or mucosa of the subject, and may be chosen from: a mechanoreceptor sensitive to negative airway pressure, positive airway pressure, stretch, position, shear, slip, vibration, texture, touch, mechanical compression, muscle stretch, muscle drive, air flow, blood pressure or blood osmolarity; a chemoreceptor sensitive to CO2, O2, or pH; a thermoreceptor sensitive to temperature or airflow; and a nociceptor sensitive to polymodal pain.

Each of the at least one stimulations may be chosen from: a subthreshold electrical stimulation delivered to the reflex-related nerve or to the reflex-related sensory receptor to reduce the threshold of the reflex, to maintain muscle tone, and any combination thereof; a subthreshold electrical stimulation delivered to the reflex-related muscle to maintain muscle tone; a subthreshold mechanical stimulation delivered to the reflex-related sensory receptor to reduce the threshold of the at least one reflex; a suprathreshold electrical stimulation delivered to the reflex-related nerve, the reflex-related sensory receptor, the reflex-related muscle, or any combination thereof to maintain muscle tone, position and/or posture of one or more respiratory and/or deglutition structures of the subject; a suprathreshold mechanical stimulation delivered to the reflex-related sensory receptor to maintain muscle tone, position and/or posture of one or more respiratory and/or deglutition structures of the subject; a suprathreshold electrical stimulation delivered to the reflex-related nerve, the reflex-related sensory receptor, the reflex-related muscle, or any combination thereof to treat the disorder; and a suprathreshold mechanical stimulation delivered to the reflex-related sensory receptor to treat the disorder.

Each of the at least one stimulations is delivered either according to a predetermined schedule, in response to at least one stimulation signal, and any combination thereof.

The at least one stimulation signal may be received from a patient monitor device.

The first method for treating and/or preventing a disorder in a subject in need thereof may further comprise assessing at least one condition of the subject chosen from a respiratory condition, a deglutition condition, a vibration condition, a reflux condition, and any combination thereof to predict the occurrence of the disorder in the subject. Suitable respiratory, deglutition, vibration, and reflux conditions are described above.

The first method for treating and/or preventing a disorder in a subject in need thereof may further comprise obtaining one or more neural signals from one or more upper airway afferents of the subject; processing each of the one or more neural signals to obtain at least one neural activity profile; comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type; processing each of the at least one neural activity profiles to determine an activity state characterizing the associated activity type; and processing the activity state of the subject to obtain the at least one condition of the subject. Each neural activity profile, activity type, and activity state may be characterized as described above.

The first method for treating and/or preventing a disorder in a subject in need thereof may further comprise generating the at least one stimulation signal when: the disorder is predicted to time the delivery of the at least one stimulation to coincide with an occurrence of the disorder; the respiratory phase is an exhalation phase to time the delivery of the at least one stimulation to coincide with an exhalation of the subject; and any combination thereof.

The invention also provides a first system for treating and/or preventing a disorder in a subject. The system may comprise at least one processor and aCardio Respiratory MonitoringComputer Readable Medium(CRM) containing a disorder treatment application comprising a plurality of modules executable on the at least one processor. The plurality of modules may comprise: a reflex stimulation module for delivering at least one stimulation to modulate at least one reflex chosen from a swallowing reflex, a negative pressure reflex, and any combination thereof and a GUI module for generating one or more forms used to receive inputs to the system and to deliver output from the system. The disorder may be chosen from obstructive apnea, central apnea, snoring, mixed apnea, flow limitation, obesity hypoventilation syndrome, dysphagia, esophageal reflux, presence of unswallowed bolus, acid reflux, GERD, and any combination thereof. Each of the at least one stimulations is delivered at an intensity chosen from subthreshold stimulus parameters intensity insufficient to independently elicit the reflex and suprathreshold stimulus parameters sufficient to independently elicit the reflex. The at least one stimulation is delivered according to a delivery schedule chosen from periodic, random, and continuous.

Each of the one stimulations may comprise an electrical stimulation or a mechanical stimulation, as described above.

The plurality of modules may further comprise a stimulation timing module for timing the delivery of each of the at least one stimulations according to a predetermined schedule, in response to at least one stimulation signal, and any combination thereof.

The at least one stimulation signal may be received from a patient monitor system.

The plurality of modules may further comprise a disorder prediction module for assessing at least one condition of the subject chosen from a respiratory condition, a deglutition condition, a vibration condition, a reflux condition, and any combination thereof to predict the occurrence of the disorder in the subject. Suitable respiratory, deglutition, vibration, and reflux conditions are described above.

The plurality of modules may further comprise a neural signal acquisition module for obtaining one or more neural signals from one or more upper airway afferents of the subject; a neural activity profile module for processing each of the one or more neural signals to obtain at least one neural activity profile; and an activity type module for comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type. Each neural activity profile and activity type may be characterized as described above.

The stimulation timing module may generate the at least one stimulation signal when: the disorder prediction module predicts the disorder in order to time the delivery of the at least one stimulation to coincide with an occurrence of the disorder; the activity state module determines that the respiratory phase is an exhalation phase, to time the delivery of the at least one stimulation to coincide with an exhalation of the subject; and any combination thereof.

The invention also provides a second method for treating and/or preventing a disorder in a subject in need thereof. The method may comprise obtaining one or more neural signals from one or more upper airway afferents of the subject; processing each of the one or more neural signals to obtain at least one neural activity profile; comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type; processing each of the at least one neural activity profiles to determine an activity state characterizing the associated activity type; processing the activity state of the subject to obtain the at least one condition of the subject; assessing the at least one condition to predict a disorder chosen from obstructive apnea, central apnea, obesity hypoventilation syndrome, dysphagia, esophageal reflux, presence of unswallowed bolus, acid reflux, GERD, and any combination thereof and delivering at least one stimulation to modulate at least one reflex chosen from a swallowing reflex, a negative-pressure reflex, and any combination thereof.

Each of the one stimulations may comprise an electrical stimulation or a mechanical stimulation, as described above.

Each neural activity profile, activity type, and activity state may be characterized as described above.

The at least one condition of the subject may be chosen from a respiratory condition, a deglutition condition, a vibration condition, a reflux condition, and any combination thereof. Suitable respiratory, deglutition, vibration, and reflux conditions are described above, as are suitable activity criteria.

Processing the one or more neural signals further comprises analyzing a timing sequence of two or more activity patterns, wherein each of the two or more activity patterns is obtained from different upper airway afferents.

Each of the at least one stimulations is delivered either according to a predetermined schedule, in response to at least one stimulation signal, and any combination thereof.

The second method for treating and/or preventing a disorder in a subject in need thereof may further comprise displaying any one or more of the at least one states, the at least one conditions, the at least one disorders, and any combination thereof on a patient monitor device.

The second method for treating and/or preventing a disorder in a subject in need thereof may further comprise generating the at least one stimulation signal when: the disorder is predicted, to time the delivery of the at least one stimulation to coincide with an occurrence of the disorder; the respiratory phase is an exhalation phase, to time the delivery of the at least one stimulation to coincide with an exhalation of the subject; and any combination thereof.

The invention also provides a second system for treating and/or preventing a disorder in a subject The system may comprise at least one processor; aCardio Respiratory MonitoringComputer Readable Medium(CRM) containing a disorder treatment application comprising a plurality of modules executable on the at least one processor; and a GUI module for generating one or more forms used to receive inputs to the system and to deliver output from the system. The plurality of modules may comprise: (i) a neural signal acquisition module for obtaining one or more neural signals in one or more upper airway alferents of the subject; (ii) a neural activity profile module for processing each of the one or more neural signals to obtain at least one neural activity profile; (iii) an activity type module for comparing each of the at least one neural activity profiles to one or more activity criteria to associate each neural activity profile with an associated activity type; (iv) an activity state module for processing each of the at least one neural activity profiles to determine an activity state characterizing the associated type; (v) a condition module for processing the at least one activity states to obtain at least one condition of the subject chosen from a respiratory condition, a deglutition condition, a condition, a reflux condition, and any thereof; (vi) a disorder prediction module for assessing the at least one condition to predict a disorder chosen from: from obstructive apnea, central apnea, obesity hypoventilation syndrome, dysphagia, esophageal reflux, presence of unswallowed bolus, acid reflux, GERD, and any combination thereof; (vii) a reflex stimulation module for delivering at least one stimulation to modulate at least one reflex chosen from a swallowing reflex, a negative-pressure reflex, and any combination thereof, wherein: each of the at least one stimulations is delivered at parameters chosen from subthreshold parameters insufficient to independently elicit the reflex and suprathreshold parameters sufficient to independently elicit the reflex; and the at least one stimulation is delivered according to a delivery schedule chosen from periodic, random, and continuous; and (viii) a stimulation timing module for timing the delivery of each of the at least one stimulations according to a predetermined schedule, in response to at least one stimulation signal, and any combination thereof. Each neural activity profile, activity type, and activity state may be characterized as described above. Suitable respiratory, deglutition, vibration, and reflux conditions are also described above, as are suitable activity criteria.

The neural activity profile module may further analyze a timing sequence of two or more activity patterns, wherein each of the two or more activity patterns is obtained from different upper airway afferents.