WO2020210328A1 - Non-invasive neuromodulation to regulate blood pressure, respiration, and autonomic outflow - Google Patents

Abstract

A method for non-invasive neuromodulation includes the steps of positioning a vibratory earpiece within an external ear canal of a subject, applying vibrational energy through the vibratory earpiece to stimulate mechanoreceptors of sensory fibers on cranial nerves 5, 7, 9 and 10, and cervical nerves C2 and C3, and regulating the subject's breathing and blood pressure simultaneously based on the stimulation. A method for treating sleep-disturbed breathing and autonomic disorders includes the step of applying vibrational stimuli to sensory nerves for simultaneous regulation of blood pressure and respiration. A system for treating sleep-disturbed breathing and autonomic disorders includes a vibratory element operationally coupled to a controller, where the controller is configured to send a stimulus signal to the vibratory element capable of stimulating sensory nerves for simultaneous regulation of blood pressure and respiration.

Description

  NON-INVASIVE NEUROMODULATION TO REGULATE BLOOD PRESSURE,

RESPIRATION, AND AUTONOMIC OUTFLOW

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional application No.62/831,152, filed on April 8, 2019, incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION [0002] There exists a significant need to facilitate breathing and support blood pressure in a range of medical disorders. In addition, a variety of medical conditions require control over autonomic nervous system regulation. The respiratory-related syndromes are accompanied by such characteristics as diminished activation of all muscles of respiration (hypoventilation), obstructed air passage by reduced activation of upper airway muscles, especially during sleep (obstructive sleep apnea, OSA),⁹ or insufficient activation of thoracic, abdominal, or other respiratory musculature, such as in spinal cord injury or in generalized clonic-tonic epilepsy seizures. Additionally, patients with compromised action of smooth muscle air passages, such as those found with chronic obstructive pulmonary disease (COPD), or an impaired autonomic nervous system, including Phox2B mutations resulting in congenital central hypoventilation syndrome (CCHS), require intervention. CCHS subjects lose drive to all respiratory muscles during sleep. Another autonomic nervous system concern is Multiple System  

  Atrophy; patients typically show obstructed breathing or hypoventilation during sleep or at rest. A group of patients with inherited disorders that involve progressive muscle weakness and loss of muscle tissue, termed muscular dystrophy (MD), also are frequently afflicted with disordered breathing during sleep. A major concern in heart failure patients is the presence of central apnea, a cessation of action of both

diaphragmatic and upper airway musculature. This respiratory disorder is usually expressed as periodic or Cheyne-Stokes breathing in heart failure; that is, periods of breathing followed by cessation of all respiratory efforts for epochs of a minute or more; both Cheyne-Stokes and obstructive sleep apnea occur in over half of heart failure patients.

[0003] Another autonomic condition of concern is postural orthostatic tachycardia syndrome (POTS), a condition typically characterized by low resting blood pressure and impaired or deficient rise in blood pressure occurs with blood-pressure elevating behaviors. A device in such cases that normalizes resting blood pressure, and modifies the gain of the baroreflex to prevent postural collapse would benefit the art. Yet another autonomic regulation condition amenable to intervention by the proposed device is Cyclic Vomiting Syndrome (CVS), a condition of episodes of repeated vomiting and nausea that can last for hours or days.²⁵ CVS is sometimes called "intestinal migraine." The syndrome is sometimes treated with drugs for migraine, and is exacerbated with strong affect, particularly positive emotions, a clue that suggests a central brain origin, and susceptible to intervention by a device that has been used for classic migraine pain.

[0004] Incidence of conditions: [0005] The number of patients requiring supplementary ventilatory assistance in the United States alone is very large; approximately 20% of males and 10% of females are affected by obstructive sleep apnea, with the numbers rising with increased obesity. There are substantial numbers of pediatric cases, as well. Typical OSA numbers for the US approximate 34 million cases. The number of patients with partial or complete spinal cord injury in the US is also substantial, with approximately 12,000 new cases annually. Of these cases, a large number show sleep-disordered breathing, with conservative estimates of pediatric spinal cord injury patients (30%) showing obstructive apnea or hypoventilation at night; an additional sizeable number require assisted ventilation even during daylight hours. Although the number of cases of congenital central hypoventilation syndrome, a condition resulting from mutations in the PHOX2B gene, is small, (approximately 300 US cases), the costs for support for affected patients who typically require continuous nocturnal ventilation, and in some cases, 24 hour ventilatory assistance, is substantial. The failure to provide adequate nocturnal ventilation results in an exceptionally short survival rate, with a very large number of deaths occurring in teenage years. Between 25,000 and 100,000 Americans have Multiple Systems Atrophy, which is accompanied by hypoventilation, stridor, and obstructive sleep apnea, with sudden death a frequent outcome. Myotonic dystrophy has a prevalence estimated by genetic testing to be as high as 1/1000 in some populations; several recent studies suggest that sleep-disordered breathing can contribute to disease characteristics in these populations. Heart failure is the most common cause of admission in hospitals for patients over the age of 65 in the US, and affects approximately 5.7 million people in the U.S.; half of these heart failure patients show sleep-disordered breathing, and disrupted cardiovascular control accompanying the disrupted respiratory control. The prevalence of Cyclic Vomiting Syndrome is unclear, with estimates from 0.04 to 1.9% children;²⁵ however, recent evidence suggests that the prevalence in adults has been underestimated. The collective data suggest that the need for inexpensive, non-invasive autonomic and ventilatory support for all of these patient groups is very great, amounting to tens of millions of patients in the US alone.

[0006] Sources of drive to breathing - traditional:

[0007] Respiration is principally driven by the need to supply oxygen (O₂) to tissue and to remove carbon dioxide (CO₂) as a metabolic by-product of tissue metabolism. Levels of O₂ and C O₂ are normally precisely maintained by sensors located in the brain and in discrete sites in the principal arteries of the neck and aorta. Increased CO₂ leads to a perception of“air hunger,” and results in pronounced increases in ventilation; low O₂ also leads to increased ventilation, but that drive is somewhat more complex.

[0008] Sources of drive to breathing - non-traditional:

[0009] There is increasing evidence that other, non-chemical, i.e. , not CO₂ or O₂, drives to breathe can assist respiration. Children with congenital central hypoventilation syndrome (CCHS) lack central chemosensation, and do not respond to increased CO₂ levels. However, if those children exercise in conditions that would normally increase CO₂ and deplete O₂, e.g., playing soccer, they ventilate normally.⁴’¹⁶ These movements induced by exercise increase breathing. The relationship between limb movement and enhanced ventilation has been repeatedly demonstrated,² and may result from afferent activity caused by peripheral limb action to activate the central brain areas associated with breathing. This outcome has been demonstrated by functional magnetic resonance imaging studies of peripheral foot movement.¹³ The mechanisms underlying the coupling of peripheral limb action with breathing are unclear, but likely derive from the need to provide immediate oxygenation for locomotor muscle action for escape, rather than waiting for accumulation of CO₂ to stimulate breathing. It is apparent from these data that ancillary sources of breathing stimulation exist, and these sources can be used to enhance ventilation. This concept has been used to develop a

proprioceptive stimulation device that has successfully assisted breathing in premature infants,¹² and spinal cord injury patients.²⁰ (and see Ronald M. Harper et al. PCT International Application No. PCT/ US14/47642, filed July 22, 2014 for Device, System and Method for Facilitating Breathing via Simulation of Limb Movement. Published January 29, 2015).

[0010] In the same fashion, circumstances such as sleep can distort normal regulation of blood pressure, leading to loss of perfusion; those blood pressure changes often accompany breathing pauses, but can occur independently of breathing. The blood pressure regulatory systems also depend on sensory input, especially from fields located in the auditory meatus, the sensory fields of cranial nerves 5, 7, 9, and 10; cranial nerve 9 plays an especially important role, with its direct projections to the baroreceptor system.

[0011 ] Other non-chemical processes that interfere with breathing timing or extent: [0012] Although reduced drive from chemosensation leads to impaired drive to breathe, many other mechanisms can lead to breathing failure. Obstructive sleep apnea patients show only modest CO₂ chemosensitive loss, as do heart failure, spinal cord or COPD patients. Heart failure patients, however, have deficits in timing of afferent signals from carotid chemoreceptors, a consequence of alterations in circulation time resulting from their primary circulatory condition, leading to the periodic or Cheyne- Stokes breathing.

[0013] Obstructive sleep apnea patients principally show a“disconnect” between activation of upper airway muscles and the diaphragm, i.e. diaphragmatic movements continue, but upper airway muscle actions are lost.⁹ Depending on segmental injury level, spinal cord patients show a reduced overall activation of the respiratory

musculature, including the upper airway.²⁰ A common process underlying many of these disturbed breathing patterns is a failure of timing or extent of drive to all airway muscles, or in the case of obstructive sleep apnea, a cluster of airway muscles. The device described here can overcome those deficits by providing exaggerated drive to specialized sensory systems that affect breathing timing and extent of drive to the different groups of respiratory muscles, and do that by stimulating branches of the associated nerves located in the auditory meatus; these nerves share branches in the oro-pharyngeal cavity.

[0014] Sensory nerves influencing breathing patterns:

[0015] The different sensory nerves influencing breathing patterns are complex, but can be summarized into several categories. [0016] Chemo-sensing: The principal sensory nerves for sensing CO₂ and O₂ levels include nerves from sensors in the aorta and carotid bodies which principally carry information on O₂ levels in the blood and on the pressure exerted by the blood on the inner walls of the arteries (blood pressure). The latter is an extremely important factor in respiratory timing; elevation of blood pressure suppresses breathing,²² principally to the upper airway muscles, but also to the diaphragm, and lowering of blood pressure enhances inspiratory efforts and breathing rate. Sensing of low O₂ provides overall facilitation of breathing. The carotid bodies also have a minor role in CO₂ sensing. A large part of CO₂ sensing occurs in central brain regions, and will not be considered further here. Critical to the discussion below, the sensory signals for blood pressure, O₂ and CO₂ signals are passed to the brain respiratory regulatory areas by a branch of the glossopharyngeal nerve (cranial nerve 9) for the carotid bodies, and cranial nerve 10 (vagus) for the aorta (see Figs. 1 A and 1 B).²¹ Cranial nerve 9 receives afferents from the carotid body, as well as sensory fibers from the posterior oral cavity and upper pharynx. The fibers in the oral cavity pass airflow information centrally, and the sinus nerve conducts baroreceptor and chemoreceptor fibers centrally as well. However, nerve 9 sends a tympanic branch (A), supplying the medial (inner) portion of the tympanic membrane which will be the focus of vibratory stimulation discussed here. Cranial nerve 10 (vagus) carries baroreceptor sensor information from the heart (Fig.

1 B) (C) and both motor and sensory fibers of the pharynx and sensory fibers of the soft palate (Fig. 1 B) (B). All of these sensory processes are important for breathing, including airflow and proprioceptive fibers from pharyngeal muscles. Those sensory processes, in sensing airflow, trigger central brain processes to elicit inspiratory and expiratory efforts. (As described later in various embodiments of the device and method described herein, the significance for vibratory stimulation of the auditory canal is that cranial nerves 5 (3^rd division), 9, and 10 provide sensory nerve innervation for that canal (Fig. 1 B) (A), and in that role can be excited to“trick” the brain into signaling that airflow occurs). The cervical nerves C2 and C3 also are stimulated by vibration of the auditory canal; C3 contributes to the phrenic nerve, the principal nerve driving the diaphragm, the major muscle for respiration, and cervical nerve C2 provides essential sensory information of movement of accessory respiratory muscles.

[0017] Lung stretch receptors: Significant breathing timing signals arrive to brain breathing drive areas from stretch receptors, sensing lung inflation. On inspiration, these signals project to the respiratory phase-switching area of the parabrachial pons of the brainstem, signaling the brain to shut off inspiration when approaching appropriate lung inflation; cranial nerve 10, the vagus nerve, carries those signals (Fig. 1 B) (D), and stimulation within the auricular vagus in the ear canal can trigger those inspiratory- expiratory phase switching signals. Forceful breathing efforts will also trigger accessory respiratory muscles of the upper thorax and cervical regions; cervical fibers of C2 and C3 also serve the external ear, and will interpret vibration of their sensory fields as a need to continue breathing efforts.

[0018] Oral, nasal, and pharyngeal airflow sensors. The movement of air through nasal, oral, and pharyngeal passages stimulates airflow receptors, and sensory activity from those receptors plays a vital role in facilitating breathing efforts. The sensory nerves for air movement are in trigeminal (cranial nerve 5, Fig 1 C,) afferents, as well as in cranial nerves 7, 9, and 10 (Figs. 1 E, 1A , 1 B). Fig. 1 C illustrates the potential for interaction with auditory canal vibratory stimulation and those afferents; the anterior auricular nerve (A), a branch of the third division of 5, serves the external ear and ear canal, while afferents in the second division of 5 (D) and third divisions of 5 (C), carry sensory information of airflow from the oral cavity (E), and also provide motor innervation (C) for the oral musculature. In addition, the chorda tympani (B) carries sensory information from the tongue, and travels with the third division of the trigeminal nerve. More detail of the chorda tympani is shown in Fig. 1 E, which also illustrates the close interactions between facial nerve branches and the geniculate ganglion of 7 in a pathological situation, with eruption of herpes zoster in the external auditory canal (Appendix 1 , Fig. 1 E (C)). The pathology extends to the posterior portion of the tragus (the small pointed eminence of the external ear, situated in front of the concha; Fig. 1 E (D)). The close interaction of nerves of cranial nerve 7 in the oral cavity conveyed by the chorda tympani are shown in Fig. 1 E (B). The statements on innervation and anatomy drawings are derived from Grant’s Atlas of Anatomy.²¹

[0019] Proprioceptive fibers of the tongue and other oral airway muscles: The genioglossal fibers of the tongue, as well as a number of oral airway muscles, including the tensor and levator palati, masseter, medial pterygoid, temporalis, and superior constrictor muscles, discharge phasically with the respiratory cycle;¹·⁶·⁷·⁸·⁹·¹⁷·¹⁸ these muscles lead to closure of the mandible and thus assist in airway dilation. The most well-studied of these muscles is the genioglossus, (Fig. 1 D), the principal oral dilator for breathing.⁹ Movement of all of those muscles is accompanied by proprioceptive sensory discharge, which is carried by their respective sensory fibers to respiratory regulatory sites, in addition to brain areas controlling other oral airway activities, including mastication and swallowing. The proprioceptive action is essential for timing and extent of upper airway muscle action. The cranial nerves carrying proprioceptive fibers include cranial nerve 12, ¹⁵ which is also the principal motor nerve for the genioglossal fibers of the tongue (Fig. 1 D, (B)). Those sensory fibers are presumably conveyed to the nodose ganglion (Fig. 1 D, (A)), although some of those fibers may pass through the second division of the trigeminal nerve to the mesencephalic nucleus of V. The proprioceptive fibers are carried, in addition to 5, in cranial nerves 7, 9, and 10 (Figs. 1 A, 1 B, 1 C, 1 E), of these, cranial nerves 5, 10, and 12 most likely carry

proprioceptive fibers, but both 7 and 9 also contain sensory fibers, some of which convey proprioceptive input.

[0020] Sensory Nerve Summary: Numerous sensory nerves participate in timing of the respiratory cycle and in modifying the extent of ventilatory efforts. Those nerves mediate multiple actions in addition to chemosensation, and are especially important for timing of onset of inspiratory effort relative to diaphragmatic efforts. The sensory modes involve blood pressure, lung inflation, air movement, and proprioception, in addition to classical CO₂ and O₂ sensing. Adequate functioning to maintain appropriate ventilation requires exquisitely precise interactions from multiple systems, in which timing is of essential importance.

[0021 ] What is needed in the art are devices and methods to facilitate breathing and support blood pressure while also regulating autonomic outflow that rely on the interactions described above to restore adequate function. SUMMARY OF THE INVENTION

[0022] According to one embodiment, a method for treating sleep-disturbed breathing and autonomic disorders includes the step of applying vibrational stimuli to sensory nerves for simultaneous regulation of blood pressure and respiration.

[0023] According to one embodiment, a system for treating sleep-disturbed breathing and autonomic disorders includes a vibratory element operationally coupled to a controller, where the controller is configured to send a stimulus signal to the vibratory element capable of stimulating sensory nerves for simultaneous regulation of blood pressure and respiration.

[0024] According to one embodiment, a method for non-invasive neuromodulation includes the steps of positioning a vibratory earpiece within an external ear canal of a subject; applying vibrational energy through the vibratory earpiece to stimulate mechanoreceptors of sensory fibers on cranial nerves 5, 7, 9 and 10 and cervical nerves C2 and C3; and regulating the subject’s breathing and blood pressure

simultaneously based on the stimulation. In one embodiment, the method includes the step of regulating autonomic outflow based on the stimulation of cranial nerves which also contain parasympathetic autonomic fibers and influence sympathetic outflow. In one embodiment, mechanoreceptors are stimulated simultaneously by the vibrational energy. In one embodiment, the application of vibrational energy is applied through at least a portion of the skin of at least one of the auditory canal, auricle, and concha of the subject's ear. In one embodiment, the stimulation is indicative of nerve sensations for airflow, upper airway muscle positioning, chemoreception and blood pressure changes. In one embodiment, the stimulation elicits reflexive motor actions to activate upper airway muscles, diaphragmatic muscles, ancillary thoracic musculature, and abdominal breathing musculature. In one embodiment, the method reduces blood pressure of the subject for regulating blood pressure. In one embodiment, the method increases or normalizes blood pressure of the subject for regulating blood pressure. In one embodiment, the stimulating enhances breathing extent of the subject, and reduces breathing variability. In one embodiment, the method regulates timing and extent of autonomic outflow of the subject. In one embodiment, the method is for treating autonomic disorders. In one embodiment, the method is for treating sleep-disturbed breathing of a periodic pattern, obstructed upper airway, central, or hypoventilatory nature.

[0025] In one embodiment, a device for non-invasive neuromodulation includes an earpiece comprising a housing molded substantially to fit within the external ear canal a subject; a vibratory motor embedded within the housing, wherein the vibratory motor transmits vibrational energy to an outer wall of housing; and a controller configured to generate a stimulation signal for stimulating one or more mechanoreceptors of sensory fibers of cranial nerves 5, 7, 9 and 10 and cervical nerves C2 and C3 when the housing is positioned in the external ear canal for simultaneously regulating the subject’s breathing and blood pressure.

[0026] In one embodiment, the stimulation signal is configured to regulate autonomic outflow. In one embodiment, the stimulation signal is configured to stimulate

mechanoreceptors simultaneously. In one embodiment, the stimulation signal is configured to reduce blood pressure of the subject for regulating blood pressure. In one embodiment, the stimulation signal is configured to increase blood pressure of the subject for regulating blood pressure. In one embodiment, the stimulation signal is configured to enhance breathing of the subject. In one embodiment, the stimulation signal is configured to regulate autonomic outflow of the subject. In one embodiment, a method for treating autonomic disorders or sleep-disturbed breathing comprising positioning the device into an external ear canal of a subject; and applying the

vibrational energy. In one embodiment, the vibratory motor is embedded within the housing. In one embodiment, the vibratory motor is releasably connected to the housing.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The foregoing purposes and features, as well as other purposes and features, will become apparent with reference to the description and accompanying figures below, which are included to provide an understanding of the invention and constitute a part of the specification, in which like numerals represent like elements, and in which:

[0028] Figure 1 A is a diagram of cranial nerve 9; Figure 1 B is a diagram of cranial nerve 10; Figure 1 C is a diagram of cranial nerve 5; Figure 1 D is a diagram of cranial nerve 12; and Figure 1 E is a diagram of cranial nerve 7.

[0029] Figure 2A is a flow chart of a method for non-invasive neuromodulation according to one embodiment; and Figure 2B is a diagram of a device for non-invasive neuromodulation according to one embodiment. [0030] Figure 3A shows a diagram of receptive fields of cranial nerves 5, 7, 9, and 10, and cervical nerves C2 and C3; Figure 3B shows the projection sites of cranial nerves 5, 7, 9, and 10 and cervical nerves C2 and C3 to the descending nucleus of 5, from which they will project to higher brain areas; Figure 3C shows a diagram of the carotid sinus nerve, a 9th nerve branch that extends from the carotid baroreceptors (blood pressure sensors); branches of the 9th nerve also serve sensory fields near the tympanic membrane, and thus are affected by mechanical vibration delivered by the device in the auditory canal (the brain will be unable to differentiate stimulation of branches of the 9^th nerve fibers from the carotid sinus and tympanic nerve, thus allowing modulation of blood pressure; and Figure 3D shows a diagram of a silicon impression 302 in one auditory meatus with embedded and bent metal probe in black to carry vibrations from a vibratory motor 304, which is powered through electrical wires from a remote 3volt power supply; the metal probe having a bend since the auditory canal often follows a curved path sometimes nearly at right angles, from the external surface to the tympanic membrane, and the bar must follow that path; and to the right a silicon impression and vibratory motor in situ of a patient is shown according to one

embodiment.

[0031 ] Figure 4A is a graph showing a decline in mean respiratory rate in

breaths/minute with auditory canal vibratory stimulation in 31 subjects over a 30 minute period according to one embodiment; and Figure 4B is a graph showing respiratory variability declined following a no-stim baseline and following stimulation (High Stim) with variability recovered post stimulation according to one embodiment. [0032] Figure 5A is a graph showing respiratory traces of disturbed breathing in a congenital central hypoventilation (CCHS) patient (No Vibration) according to one embodiment which is corrected by vibratory stimulation (Vibration); and Figure 5B is a graph showing periodic breathing in obstructive sleep apnea (No Vibration) according to one embodiment, and correction of that breathing pattern by the vibratory device (Vibration).

[0033] Figures 6A-6C show Systolic (Fig. 6A), Diastolic (Fig. 6B) and Mean Arterial Pressure (MAP) (Fig. 6C) during no vibration baseline, following low and high level vibration of the auditory canal, and after a second Post Stimulation) baseline with no vibration (total session time was 30 minutes) according to one embodiment.

[0034] Figure 7 is a graph of blood pressure values showing how vibratory stimulation normalizes blood pressure in those who have mildly low blood pressure according to one embodiment.

[0035] Figure 8 is a graph showing beat-by-beat systolic (SYS), mean (MAP), and diastolic (Dias) blood pressure during vibration and during CPAP (onset at arrow) according to one embodiment; CPAP was unable to maintain blood pressure in this hypertensive CCFIS patient (CCFIS patients show very high sympathetic tone; thus, they have overall high blood pressures). (MAP= Mean Arterial Pressure). DETAILED DESCRIPTION OF THE INVENTION

[0036] It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a more clear

comprehension of the present invention, while eliminating, for the purpose of clarity, many other elements found in systems and methods of non-invasive neuromodulation. Those of ordinary skill in the art may recognize that other elements and/or steps are desirable and/or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art.

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0038] As used herein, each of the following terms has the meaning associated with it in this section.

[0039] The articles“a” and“an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element. [0040] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1 %, and ±0.1 % from the specified value, as such variations are

appropriate.

[0041 ] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Where appropriate, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed

subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0042] Referring now in detail to the drawings, in which like reference numerals indicate like parts or elements throughout the several views, in various embodiments, presented herein are systems and methods for non-invasive neuromodulation.

[0043] Neuromodulation, using cranial and cervical nerve mechanical stimulation, can abolish obstructive and central (periodic breathing) events, and concurrently normalize extremes of blood pressure. Cutaneous sensory fields for cranial nerves 5, 7, 9, and 10, and cervical nerves C2 and C3, all lie in the auditory canal or surrounding pinna. Embodiments of the device and method described herein can abolish obstructive and periodic breathing in all subjects, creating a slow, deep, minimally- variant breathing pattern. Blood pressure in individuals with high systolic and diastolic values can be diminished to normative levels, while those with low blood pressure values can benefit from an increase to normative levels. Individual subjects with previously-demonstrated dramatic loss of blood pressure during sleep with modest support of breathing while using CPAP, can have blood pressure restored and oxygen saturations return to near 100%. Both blood pressure and breathing can be supported in sleep-disordered breathing subjects, correcting a blood pressure concern that has not been addressed with conventional devices.

[0044] Embodiments of the device use a different approach from proprioceptive stimulation; instead, the device activates sensory fields used by the breathing system to trigger respiratory movements by“tricking the brain” into perceiving that nerves carrying sensations of airflow, upper airway muscle positioning, chemoreception and blood pressure changes, and eliciting reflexive motor actions to activate upper airway and diaphragmatic muscles, as well as ancillary thoracic and abdominal breathing

musculature. Embodiments of the device use sensory fields that are distributed within the auditory meatus on one or both sides of the head, and share input with sensory fields of the upper airway (oro-pharynx).

[0045] Embodiments of the device and method synchronize sensory information from multiple sources contributing to appropriate timing of airflow and action of respiratory muscles. At the same time, the intervention activates sensory fields of nerves which regulate blood pressure, particularly the nerve serving the baroreceptors, cranial nerve 9. The intervention will thus provide a means to stimulate an area sensitive to multiple sensory nerves serving airway and cardiovascular functions, and do so non-invasively, non-electrically, using an inexpensive vibratory device. The site responsive to multiple sensory processes is the human external ear canal because of its unique multiple sensory nerve innervations. The approach of stimulating the sensory nerves of the auditory canal has been used successfully for reduction of migraine pain in over 60 subjects. That use for pain has been described earlier (PCT Application No. PCT/US14/66191 filed November 18, 2014). The devices can be structured similarly, but vibration parameters for breathing during sleep will differ from those of pain, since long-term vibration will be needed for sleep studies, mandating lower amplitude levels for comfort.

[0046] Embodiments of the device, although similar in design to the auditory meatus used for migraine reduction, differ from regional devices described to assist support for breathing and pain reduction (PCT Application No. PCT/US17/32214 filed May 11 , 2017). The regional devices use vibratory stimuli, but do so outside the auditory canals, and exert their influences on local fields where relevant nerve fibers innervate the cutaneous surface.

[0047] In one embodiment, a method for treating sleep-disturbed breathing includes applying a vibrational stimulus to sensory nerves for simultaneous regulation of blood pressure and respiration. In one embodiment, a system for treating sleep-disturbed breathing includes a vibratory element operationally coupled to a controller, wherein the controller is configured to send a stimulus signal to the vibratory element capable of stimulating sensory nerves for simultaneous regulation of blood pressure and

respiration. In one embodiment, a method for maintaining or improving sleep integrity includes applying a vibrational stimulus to sensory nerves for simultaneous regulation of blood pressure and respiration. In one embodiment, a system for maintaining or improving sleep integrity includes a vibratory element operationally coupled to a controller, wherein the controller is configured to send a stimulus signal to the vibratory element capable of stimulating sensory nerves for simultaneous regulation of blood pressure and respiration.

[0048] With reference now to Fig. 2A, a method 100 for non-invasive

neuromodulation according to one embodiment includes the steps of positioning a vibratory earpiece within an external ear canal of a subject 102; applying vibrational energy through the vibratory earpiece to stimulate mechanoreceptors of sensory fibers on cervical nerves C2 and C3 and cranial nerves 5, 7, 9 and 10 104; and regulating the subject’s breathing and blood pressure simultaneously based on the stimulation 106. Since the targeted nerves include autonomic fibers, e.g., 7, 9, and 10, the stimulation can further be used to regulate autonomic outflow based on the stimulating.

Mechanoreceptors can be stimulated simultaneously by the vibrational energy. The application of vibrational energy is applied through at least a portion of the skin of at least one of the auditory canal, auricle, and concha of the subject's ear. The stimulation is indicative of nerve sensations for airflow, upper airway muscle positioning,

chemoreception and blood pressure changes. In one embodiment, the stimulation elicits reflexive motor actions to activate upper airway muscles, diaphragmatic muscles, ancillary thoracic musculature, and abdominal breathing musculature. The stimulation reduces blood pressure of the subject by regulating blood pressure, increases blood pressure of other subjects with low blood pressure by regulating blood pressure, enhances breathing of the subject, and regulates autonomic outflow of the subject. The method can treat autonomic disorders and sleep-disturbed breathing. A device 200 for non-invasive neuromodulation is shown with reference to Fig. 2B according to one embodiment, including an earpiece 202 comprising a housing molded substantially to fit within the external ear canal a subject, a vibratory motor 204 connected to the housing, wherein the vibratory motor transmits vibrational energy to an outer wall of the housing, and a controller 206 configured to generate a stimulation signal for stimulating one or more mechanoreceptors of sensory fibers of cranial nerves 5, 7, 9 and 10 when the housing is positioned in the external ear canal for simultaneously regulating the subject’s breathing and blood pressure. The vibratory motor 204 can be connected, embedded, or releasably connected to the earpiece 202. The controller generates a stimulation signal that can be configured to regulate autonomic outflow.

[0049] The stimulation signal can be configured to stimulate mechanoreceptors simultaneously, reduce blood pressure of the subject for regulating blood pressure, increase blood pressure of the subject with initial low blood pressure for regulating blood pressure, enhance breathing of the subject, regulate autonomic outflow of the subject, and treat autonomic disorders or sleep-disturbed breathing.

[0050] Vibrations within the external ear canal (external acoustic meatus) reach and affect the sensory input to a remarkable number of cranial nerves which also serve sensory attributes of air passages in breathing and sensory signals to baroreceptors and other cardiovascular receptors (Fig. 1 A). [0051 ] The respiratory-related nerves, in turn, all provide background tone to brain regulatory processes driving breathing activation, and also serve respiratory timing roles in breathing regulatory areas of the brain stem. The latter role is critical to, for example, dilating the upper airway before diaphragm descent, thus preventing airway obstruction which occurs if the diaphragm creates negative pressure with a flaccid upper airway.

The sensory fields of cranial nerve 9 provide signaling to adequately time changes in blood pressure with respiratory patterning alterations, an essential issue during obstructive sleep apnea (associated with major blood pressure changes) and periodic breathing (accompanied by significant declines in perfusion). In some conditions, such as congenital central hypoventilation syndrome, in which subjects have complete and sustained cessation of breathing during sleep (central apnea), the blood pressure signaling by the 9^th nerve (as well as cranial nerves 5, 7, and 10) are even more essential, since the ancillary signaling to blood pressure regulatory areas from respiratory receptor fields has disappeared, leaving 9, 10, 7, and 5 nerve activity alone to support blood pressure.

[0052] The external acoustic meatus (approximate length in the adult: 2-3 cm) is primarily innervated by sensory fibers of the trigeminal nerve (cranial nerve 5;

specifically, the mandibular division) and the vagus nerve (10); other fibers of those cranial nerves serve roles in sensing air flow, proprioception, lung expansion, and blood pressure regulation.

[0053] Vibrations also reach the tympanic membrane. Its external surface is innervated by a branch of the auriculotemporal nerve (CN 5); its internal surface is innervated by the glossopharyngeal nerve (9). The third division of 5 serves oral airflow and proprioceptive roles, and 9 serves essential roles in O₂ and CO₂ sensing, as well as blood pressure sensing. In addition, CN 9 carries vital air movement and other general sensory information from the posterior oral cavity. Cranial nerve 7 has the potential to carry oral airway flow and proprioceptive sensations via the chorda tympani;

demonstration of the role of the 7^th nerve role in innervation of the tragus of the ear can be shown in pathological cases such as herpes zoster (Fig. 1 E).

[0054] Thus, non-invasive, vibratory stimulation of the external ear canal will excite multiple and massive sensory input of the following cranial nerves: trigeminal (5), facial (7), glossopharyngeal (9), and vagus (10); these nerves are all involved in respiratory timing and ventilatory extent, and all contribute to blood pressure regulation. They have been previously shown to induce sleep, reduce migraine pain, vestibular migraine symptoms, respiratory rate and variability, and normalize systolic and diastolic blood pressure in hypertensive cases.³’¹⁰’²⁶’²⁷’²⁸

[0055] Connections between the respective sensory and motor nuclei within the brain stem are well-known, and form the basis for knowledge of stimulation of cardiovascular and respiratory control mechanisms. The vagus (cranial nerve 10) projects to pontine respiratory phase-switching and blood pressure regulation sites, as well as to the cardiorespiratory integrative site of the nucleus tractus solitarius (NTS), the glossopharyngeal (9) nerve projects to the NTS and receives baroreceptor information from cells of the carotid body, a portion of the facial nerve (7) projects to the NTS, and the trigeminal nerve projects to the mesencephalic proprioceptive nucleus of 5, integrating muscle coordination of the upper airway, as well as to the motor nucleus of 5, serving oral musculature. A key aspect is that cranial nerve 5 also projects to the NTS with essential cardiovascular roles.

[0056] A diagram of the device in place, with attached vibrator motor is shown below:

[0057] With reference to Fig. 3D, a diagram of silicon impression 302 in one auditory meatus with embedded metal probe to carry vibrations from a vibratory motor 304, which is powered through electrical wires from a remote 3volt power supply. The metal probe often has a bend, since the auditory canal often follows a curved path sometimes nearly at right angles, from the external surface to the tympanic membrane, and the bar must follow that path. A silicon impression and vibratory motor in situ of a patient is shown to the right.

[0058] Process:

[0059] The device to stimulate sensory nerves assisting breathing patterns and cardiovascular regulation is a vibratory device placed in the auditory meatus; various configurations of the vibratory device exist. The most useful is a configuration which contains a fixed magnetic disc cemented to a metallic bar which extends within the silicon impression, nearing the tip. A vibratory latch cable, with a vibratory motor and attached magnet at one end latches to the magnetic disc of the silicon impression. The vibratory motors are attached to leads which provide DC power from the power supply.

In another configuration, the vibratory motor can also be placed directly in the silicon impression and driven by directly coupled leads from a separate container with a battery supply and electronic circuitry. Three variations of vibratory stimulation may prove useful; 1 ) a variable-frequency continuous stimulation (stimulation similar to that shown to be effective with peripheral limb movement in premature infants and in congenital central hypoventilation syndrome); 2) a burst sequence of vibration timed to be slightly advanced over the subjects’ diaphragmatic action, and lasting for the duration of inspiration; 3) a burst of vibration at an effective respiratory interval, but not linked to diaphragmatic action, and lasting typically for an inspiratory duration. For cardiovascular regulation, sustained, uniform vibration at a near constant frequency has been found useful.

EXPERIMENTAL EXAMPLES

[0060] The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0061 ] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0062] Studies Supporting Effectiveness of Device: [0063] The objective is to provide breathing and cardiovascular support in conditions which are manifested with disturbed breathing, disrupted cardiovascular control, or conditions in which both aspects of physiology are dysregulated. A second objective is to regulate autonomic outflow in a range of conditions in which disruption of autonomic regulation is a principal characteristic. During the course of studying the influence of vibratory stimulation on migraine and trigeminal pain, concurrent influences on breathing and blood pressure were found. Those influences would be useful to conditions of disturbed breathing and cardiovascular control, and are presented here.

[0064] The first study (Figs. 4A-B), showed control of respiratory rate by continuous vibratory stimulation; respiratory rate slows, and variability decreases in 31 subjects (Figure C). The study shows that cessations of breathing are reduced, i.e. , fewer apnea, and that respiratory rate slows, with accompanying increased tidal volumes; oxygen saturation is maintained. Those properties could be effective in sleep-disordered breathing and heart failure conditions, among others.

[0065] Fig. 4A shows a decline in respiratory rate with auditory canal vibratory stimulation in 31 subjects over a 30-minute period. Fig. 4B shows respiratory variability declined following a no- stim baseline and during stimulation (High Stim); variability recovered post stim (From Feulner et al, 2017³).

[0066] Restoration of regular breathing patterns in sleep-disturbed breathing:

[0067] A major breathing pathology in several clinical conditions is obstructive sleep apnea and periodic breathing. Periodic breathing is a respiratory pattern consisting of a burst of breathing efforts followed by a pause in both upper airway and diaphragmatic actions. The pattern is also common in patients who also show obstructive sleep apnea, with the obstructed events mixed with periodic breathing, in premature infants, where periodic breathing is also mixed with apnea of infancy, and in congenital central hypoventilation syndrome, where the pattern is often mixed with episodes of prolonged central apnea. In some conditions, such as heart failure, the pattern is exaggerated, and called“Cheyne-Stokes” breathing. Periodic breathing normally cannot be treated with continuous positive airway pressure (CPAP) devices; although CPAP is useful for obstructive sleep apnea, servo-controlled CPAP pressures are exceptionally dangerous in patients with severe periodic breathing, such as those with heart failure. The need for effective intervention is urgent; periodic breathing is exceptionally dangerous to neural tissue, because the breathing pattern is a form of intermittent hypoxia, i.e. , episodes of reduced oxygen followed by a return of full oxygenation. That intermittent hypoxia pattern is more destructive to neural tissue than steady-state hypoxia, since the brain appears to adapt easier to continuous lower levels of oxygen, e.g., living at altitude.

[0068] The device considered here is exceptionally successful in abolishing periodic breathing in both congenital central hypoventilation and obstructive sleep apnea, as shown in Figs. 5A and 5B.

[0069] With reference to Fig. 5A, respiratory traces of disturbed breathing in a congenital central hypoventilation (CCFIS) patient in the transition to quiet sleep without vibratory stimulation showing short periods of apnea, and periodic breathing intermixed with breathing efforts. (Breathing ceases in CCFIS when entering sleep; thus, ethically, only transition periods can be recorded without support). With vibratory stimulation during sleep, very regular breathing efforts occur, and no apneic events are apparent. (Patient normally uses a diaphragmatic pacer, which was turned off for this study).

[0070] With reference to Fig. 5B, obstructive sleep apnea is often accompanied by periodic breathing, a condition imposing major injury to brain structures. Abolition of periodic breathing is corrected by vibratory stimulation, avoiding the intermittent hypoxia incurred during the stopped- or minimally-breathing periods. Thoracic and abdominal movement traces; Y axis is in arbitrary units.

[0071 ] Correction of hypertension; maintenance of blood pressure in sleep-disturbed breathing:

[0072] High blood pressure is reduced with vibratory stimulation to the auditory canal. Figs. 6A-6C show the decline of systolic, diastolic, and mean blood pressure in patients with relatively high blood pressure during vibratory stimulation, while Fig. 7 shows how blood pressure is normalized in those with relatively low pressure, a significant aspect, since in some conditions, such as postural orthostatic tachycardia syndrome, few interventions exist to correct low blood pressure. The plots displaying higher blood pressure show mean and variance of 22 subjects during baseline, at low and high levels of stimulation, and after the baseline at the end of the session.

[0073] Figs. 6A-6C show systolic, diastolic and Mean Arterial Pressure (MAP) during baseline, following low and high level vibration of the auditory canal, and after a second baseline vibration; total session time was 30 minutes. [0074] If initial blood pressure values were initially low in patients, the vibration outcome was to normalize those values, as seen in Figure 7. Blood pressure values showing how vibratory stimulation normalizes blood pressure in those who have mildly low blood pressure. MAP=Mean arterial pressure. The need for intervention in patients with hypotension is great; such patients frequently show syncope on sudden standing or movement, and few interventions are available.

[0075] The combined data suggest that momentary blood pressure declines which accompany apnea could also be corrected. One example of that possibility is shown with a CCHS patient, who was unable to maintain blood pressure despite either positive pressure ventilation or phrenic nerve stimulation to the diaphragm. Use of the device alone (i.e. , no positive ventilation or phrenic nerve stimulation) was able to support breathing near 100% oxygen saturation (CPAP was able to maintain only 90-92%, and was unable to support blood pressure), and blood pressure, which was supported adequately in the patient, significantly declined when respiratory support was switched from vibration to CPAP (Arrow, Fig. 8).

[0076] With reference now to Fig. 8, beat-by-beat systolic, mean, and diastolic blood pressure during vibration and during CPAP (onset at arrow) is shown. CPAP was unable to maintain blood pressure during sleep in this hypertensive CCFIS patient (CCFIS patients show very high sympathetic tone; thus, they have overall high blood pressures).

[0077] The data collectively indicate that stimulation of the cranial and cervical nerves which signal the brain for respiratory drive and timing and cardiovascular support is able to support breathing in sleep-disordered breathing conditions and conditions which require blood pressure support, and can do so simply, non-invasively, and inexpensively.

[0078] Advantages for the Field:

[0079] The current intervention of choice for sleep-disordered breathing and for heart failure is continuous positive airway pressure (CPAP), a poorly-tolerated means with significant limitations in patient comfort and oxygen delivery; only a third of patients prescribed CPAP devices comply with sustained use. Moreover, there are significant aerosol concerns with humidification of CPAP devices and the potential for coronavirus infection. However, the most concerning issue with the CPAP device is its failure to adequately control blood pressure; patients who use CPAP over the long term have only modest management of hypertension, a critical concern in obstructive sleep apnea.¹¹ Embodiments of the device here, however, directly manage that aspect;

through stimulation of the 9^th nerve, which receives projections from the baroreceptors in the carotid sinus, blood pressure is maintained. The difference in outcomes can be profound; an inability to maintain blood pressure during apnea leads to loss of perfusion, with resulting hypoxemia, resulting in damage to nerve cells, fibers, and supportive glia. An unfortunate consequence is that the neural injury preferentially occurs in blood pressure regulatory areas of the brain, namely in the insular cortex, ventral lateral medulla, and deep (autonomic) fastigial nuclei of the cerebellum²³’²⁴ which further leads to long-term failure to control blood pressure. [0080] Study Summary: Breathing patterns were evaluated, assessed by thoracic and abdominal wall movements, and beat-by-beat blood pressure, inferred from pulse transit time, following mechanical stimulation in 37 patients with obstructive or central apnea or no breathing disturbance over a 10 min baseline, 30 min stimulation, and 10 min post baseline. Blood pressure and breathing efforts were analyzed by ANCOVA (variates, sex and age). The intervention induced sleep in over a third of patients, and abolished obstructive and periodic breathing in all subjects, creating a slow, deep, minimally-variant breathing pattern. Blood pressure in individuals with high systolic and diastolic values diminished to normative levels, while those with initial low blood pressure values increased to normative levels. Individual subjects with previously- demonstrated dramatic loss of blood pressure during sleep with modest support of breathing while using CPAP, had blood pressure restored and oxygen saturations return to near 100%. Both blood pressure and breathing can be supported in sleep-disordered breathing subjects, correcting a blood pressure concern with conventional devices.

[0081 ] References

[0082] 1. Anch, A.M., Remmers, J.E., Sauerland, E.K. and DeGroot, W.J.

Oropharyngeal patency during waking and sleep in the Pickwickian syndrome:

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[0085] 4. Gozal, D., Marcus, C.L., Ward, S.L., Keens, T.G., 1996. Ventilatory responses to passive leg motion in children with congenital central hypoventilation syndrome. Am. J. Respir. Crit. Care Med. 153:761 -768 (1996).

[0086] 5. Gozal, D., Simakajornboon, N. Passive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome. Am. J. Respir. Crit. Care Med. 162:1747-1751 (2000).

[0087] 6. Flairston, L.E., Sauerland, E.K. and Orr, W.C. The role of oropharyngeal muscles in respiration: An electro-myographic study during wakefulness and sleep. Anat. Rec. 190:411 (1978).

[0088] 7. Flairston, L.E. and Sauerland, E.K. Electromyography of the human palate: Discharge patterns of the levator and tensor veli palatini. Electromyogr. Clin. Neurophysiol. 21 :287-297 (1981 ).

[0089] 8. Flairston, L.E. and Sauerland, E.K. Electromyography of the human pharynx: Discharge patterns of the superior pharyngeal constrictor during respiration. Electromyogr. Clin. Neurophysiol. 21 :299-306 (1981 )

[0090] 9. Flarper, R.M. and Sauerland, E.K. The Role of the Tongue in Sleep

Apnea. Chapter 14 in“Sleep Apnea Syndromes”, C. Guilleminault and W. Dement, Eds., Alan R. Liss, Inc., New York (1978). [0091 ] 10. Harper, R.M., Snodgrass, D., Yan-Go, F., Jen, J., Harper, R.K.

Yazdizadeh, M. and Sauerland, E.K. Neuromodulation of cranial nerves for migraine and trigeminal neuropathy pain. Society for Neuroscience Abstracts 145.20, 2016.

[0092] 11. Pengo MF, Soranna D, Giontella A, Perger E, Mattaliano P, Schwarz

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10.1183/13993003.01945-2019.

[0093] 12. Kesavan, K., Frank, P., Cordero, D., Benharash, P. and Harper, R.M.

Neuromodulation of limb proprioceptive afferents decreases apnea of prematurity and accompanying intermittent hypoxia and bradycardia. PLoS ONE. 2016 Jun

15;11 (6):e0157349. doi: 10.1371/journal.pone.0157349. eCollection PMID: 27304988

[0094] 13. Macey, P.M., Kumar, R., Woo, M.A., Harper, R.K. and Harper, R.M.

Respiratory brain area recruitment to passive foot motion in adolescents. Society for Neuroscience Abstracts 230.3 (2007).

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[0096] 15. Neuhuber, W. and Mysicka, A. Afferent neurons of the hypoglossal nerve of the rat as demonstrated by horseradish peroxidase tracing. Anat. Embryol. 158:349- 360 (1980). [0097] 16. Paton, J.Y., Swaminathan, S., Sargent, C.W., Hawksworth, A., Keens,

T.G., 1993. Ventilatory response to exercise in children with congenital central hypoventilation syndrome. Am. Rev. Respir. Dis. 147:1185-1191.

[0098] 17. Remmers, J.E., DeGroot, W.J., Sauerland, E.K. and Anch, A.M. Neural and mechanical factors controlling pharyngeal occlusion during sleep. Chapter 13 in “Sleep Apnea Syndromes,” C. Guilleminault and W. Dement, Eds. Alan Liss, Inc., New York (1978)

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R.K., Sauerland, E.K. and Harper, R.M. Neuromodulation of cranial nerves for migraine and trigeminal neuropathy pain: Cardiac effects. FASEB J April 2016 30:731.4.

[0101 ] 20. Woo, MS,. Valladares, E. Montes, L, Sarino, M., Harper, R.M.

Proprioceptor Stimulation Improves Sleep Disordered Breathing In Adolescents And Young Adults With Asia A Paraplegia. Am J Respir Crit Care Med 189;2014:A1280.

[0102] 21. Agur, A.M.R. Dailey, A.F., and Williams, D.J. Grant's Atlas of Anatomy,

Eleventh Edition, Williams and Wilkens, 2006.

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Affective brain areas and sleep-disordered breathing, Progress in Brain Research 209:275-293, 2014.

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2016. [0110] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention.

Claims

  CLAIMS What is claimed is: 1. A method for non-invasive neuromodulation comprising:

positioning a vibratory earpiece within an external ear canal of a subject;

applying vibrational energy through the vibratory earpiece to stimulate

mechanoreceptors of sensory fibers on cranial nerves 5, 7, 9 and 10 and cervical nerves C2 and C3; and

regulating the subject’s breathing and blood pressure simultaneously based on the stimulation. 2. The method of claim 1 further comprising:

regulating autonomic outflow based on the stimulation of cranial nerves which also contain parasympathetic autonomic fibers and influence sympathetic outflow. 3. The method of claim 1, wherein mechanoreceptors are stimulated simultaneously by the vibrational energy. 4. The method of claim 1, wherein the application of vibrational energy is applied through at least a portion of the skin of at least one of the auditory canal, auricle, and concha of the subject's ear. 5. The method of claim 1, wherein the stimulating is indicative of nerve sensations for airflow, upper airway muscle positioning, chemoreception and blood pressure changes. 6. The method of claim 1, wherein the stimulating elicits reflexive motor actions to activate upper airway muscles, diaphragmatic muscles, ancillary thoracic musculature, and abdominal breathing musculature.  

  /. The method of claim 1 , wherein the stimulating reduces blood pressure of the subject for regulating blood pressure.

8. The method of claim 1 , wherein the stimulating increases blood pressure of the subject for regulating blood pressure.

9. The method of claim 1 , wherein the stimulating enhances breathing extent of the subject, and reduces breathing variability.

10. The method of claim 1 , wherein the stimulating regulates autonomic outflow of the subject.

11. The method of claim 1 for treating autonomic disorders.

12. The method of claim 1 for treating sleep-disturbed breathing of a periodic pattern, obstructed upper airway, central, or hypoventilatory nature.

13. A device for non-invasive neuromodulation comprising:

an earpiece comprising a housing molded substantially to fit within the external ear canal of a subject;

a vibratory motor connected to the housing, wherein the vibratory motor transmits vibrational energy to an outer wall of housing; and

a controller configured to generate a stimulation signal for stimulating one or more mechanoreceptors of sensory fibers of cranial nerves 5, 7, 9 and 10 and cervical nerves C2 and C3 when the housing is positioned in the external ear canal for simultaneously regulating the subject’s breathing and blood pressure.

14. The device of claim 13, wherein the stimulation signal is configured to regulate autonomic outflow.

15. The device of claim 13, wherein the stimulation signal is configured to stimulate mechanoreceptors simultaneously.

16. The device of claim 13, wherein the stimulation signal is configured to reduce blood pressure of the subject for regulating blood pressure.

17. The device of claim 13, wherein the stimulation signal is configured to increase blood pressure of the subject for regulating blood pressure.

18. The device of claim 13, wherein the stimulation signal is configured to enhance breathing of the subject.

19. The device of claim 13, wherein the stimulation signal is configured to regulate autonomic outflow of the subject.

20. A method for treating autonomic disorders or sleep-disturbed breathing comprising:

positioning the device of claim 13 into an external ear canal of a subject; and applying the vibrational energy.

21. The device of claim 13, wherein the vibratory motor is embedded within the housing.

22. The device of claim 13, wherein the vibratory motor is releasably connected to the housing.

23. A method for treating sleep-disturbed breathing and autonomic disorders comprising:

applying vibrational stimulus to sensory nerves for simultaneous regulation of blood pressure and respiration.

24. A system for treating sleep-disturbed breathing and autonomic disorders comprising:

a vibratory element operationally coupled to a controller, wherein the controller is configured to send a stimulus signal to the vibratory element capable of stimulating sensory nerves for simultaneous regulation of blood pressure and respiration.