Patent Description:
Even with significant brain injury, it is known that neuroplasticity in infants may lead to improved, and even near normal outcomes. This neuroplasticity involves stimulating neurogenesis and reparative inter-neuronal connections to improve motor skills in neonatal animal models and in adults after stroke. In addition, it is known that rehabilitative training may be enhanced by brain stimulation using a variety of modalities.

Feeding in neonates involves a sequence of sucking, swallowing, and breathing that requires coordination of the face, head, and neck muscles with the myelinated vagal regulation of the bronchi and the heart. In preterm neonates, the muscles needed to feed are underdeveloped, resulting in the need for OT rehabilitation to 'learn' feeding patterns. Preterm neonates' inability to feed effectively is the primary reason for prolonged hospital stays. In neonates with HIE, development of cortex and basal ganglia is interrupted, and depending on the severity, normal developmental plasticity is hindered, further contributing to their inability to feed. Both types of feeding difficulties involve complex motor learning, which requires integration of sensory and motor pathways.

<CIT>, <CIT> and <CIT> shows devices for transdermal / transcutaneous stimulation of a nerve of the human body. <CIT> shows a system for monitoring and analyzing baby feeding habits. <CIT> shows a computer controlled bottle system for a preterm infant oral feeding, <CIT> shows a system to replace and/or enhance a normal satiety signal with an appetite control signal to curb appetite.

Thus, there is a need in the art for improved systems for administering neural stimulation for enhancing neuroplasticity and muscle training. The present invention meets this need.

The present invention provides a system as defined in claim <NUM>. The dependent claims define preferred features and embodiments of the present invention.

The present disclosure provides a non-claimed method of enhancing oromotor skills, comprising the steps of: providing a cranial nerve stimulation system comprising at least one sensing electrode and at least one stimulating electrode; securing the at least one sensing electrode adjacent to a subject's cheek or jaw muscle and the at least one stimulating electrode to a subject's cranial nerve; providing the subject with a source of food; measuring muscle activation using the at least one sensing electrode that surpasses a minimum threshold; and administering stimulation using the at least one stimulating electrode to the cranial nerve in response to the measurement of muscle activation surpassing the minimum threshold.

In one embodiment, the cranial nerve is selected from the group consisting of: the trigeminal nerve, the facial nerve, the accessory nerve, the hypoglossal nerve, the auricular branch of the vagus nerve, and the main bundle of the vagus nerve. In one embodiment, the measuring step and the administering step are repeated in a closed loop. In one embodiment, the at least one stimulating electrode is noninvasively secured to a subject's ear canal, tragus, cymba conchae, lobe, helix, anti-helix, mastoid, or neck.

In one embodiment, the minimum threshold is an absolute value selected from the group consisting of about: <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, or <NUM> mV. In one embodiment, the minimum threshold is a change from a base measurement taken at rest selected from the group consisting of about: <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, or <NUM> mV. In one embodiment, the minimum threshold is a percentage of a maximum potential of the muscle selected from the group consisting of about: <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>%.

In one embodiment, the stimulation has an intensity selected from the group consisting of about: <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA. <NUM> mA, <NUM> mA. <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, and <NUM> mA. In one embodiment, the stimulation has a frequency selected from the group consisting of about: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. In one embodiment, the stimulation has a pulse width selected from the group consisting of about: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. In one embodiment, the stimulation has an on duration and an off duration, each selected from the group consisting of about: <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> minute, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, and <NUM> hour.

The present disclosure also provides a non-claimed method of enhancing muscle rehabilitation, comprising the steps of: providing a cranial nerve stimulation system comprising at least one sensing electrode and at least one stimulating electrode; securing the at least one sensing electrode adjacent to a subject's muscle group of interest and the at least one stimulating electrode to a subject's cranial nerve; measuring muscle group activation using the at least one sensing electrode that surpasses a minimum threshold; and administering stimulation using the at least one stimulating electrode to the cranial nerve in response to the measurement of muscle group activation surpassing the minimum threshold.

In one embodiment, the cranial nerve is selected from the group consisting of: the trigeminal nerve, the facial nerve, the accessory nerve, the hypoglossal nerve, the auricular branch of the vagus nerve, and the main bundle of the vagus nerve. In one embodiment,the measuring step and the administering step are repeated in a closed loop.

The following detailed description will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown in the drawings, but the scope of the present invention is defined by the appended claims.

It is to be understood that the figures and descriptions have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements typically found in the art. 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, the present invention is defined by the appended claims.

Unless defined elsewhere, 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, exemplary methods and materials are described.

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

"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 ±<NUM>%, ±<NUM>%, ±<NUM>%, ±<NUM>%, and ±<NUM>% from the specified value, as such variations are appropriate.

Throughout this disclosure, various aspects of the invention can be presented in a range format. For example, description of a range such as from <NUM> to <NUM> should be considered to have specifically disclosed subranges such as from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, etc., as well as individual numbers within that range, for example, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and any whole and partial increments there between.

The present invention is based in part on systems for providing noninvasive cranial nerve stimulation. The systems administer therapy through electrodes that are noninvasively attached to one or more of a subject's cranial nerve. The systems can be used to enhancing rehabilitation and recovery by improving neuroplasticity and coupling muscle training with feedback.

Stimulation can be noninvasively administered to any suitable cranial nerve. Non-limiting examples include the trigeminal nerve, the facial nerve, the accessory nerve, the hypoglossal nerve, the auricular branch of the vagus nerve, the main bundle of the vagus nerve, and the like. The auricular branch of the vagus nerve can be accessed in a variety of ways, including but not limited to the ear canal, the tragus, the cymba conchae, the outer ear, the mastoid, and combinations thereof The main bundle of the vagus nerve can be accessed at any suitable location along the neck. In various embodiments, the stimulation is administered transcutaneously. Stimulation can be administered using one or more electrodes secured adjacent to a cranial nerve in any suitable manner, including but not limited to using an adhesive, a clip, a patch, an ear plug, a head band, a neck brace, a collar, a head covering, and the like.

The present invention provides therapeutic tools aimed at improving and accelerating learned feeding behavior in neonates. The systems provided change the way rehabilitation is conducted for preterm neonates, resulting in earlier discharge, lower hospital costs, improved parental perception of the developmental potential of their infant, and reduces stress and improves bonding with parents, both in and out of the hospital. The systems can serve as a take-home feeding aid for convalescing critically ill infants who have missed the developmental window to master the feeding skill, and for infants with congenital syndromes that make oral feeding challenging.

Treating oromotor difficulties during the learned task of feeding with noninvasive brain stimulation that promotes plasticity, poses a highly novel application of transcutaneous auricular vagus nerve stimulation (taVNS). The major premise is that in babies at high risk for motor problems, simultaneously delivered brain stimulation via taVNS will boost motor cortical plasticity involved in a learned feeding task, leading to better feeding. There may be a synergistic effect of surgically implanted VNS when combined with a paired stimulus that directs plastic changes to occur in the cortex. This invention utilizes novel forms of noninvasive vagus nerve stimulation (nVNS) (rather than surgically implanted) paired with feeding to accelerate and enhance the learning of feeding in neonates.

Referring now to <FIG> and <FIG>, an exemplary system <NUM> is depicted. In various embodiments, system <NUM> comprises several components that can be used alone or in combination to couple cranial nerve stimulation with feedback to train feeding behavior in infants. For example, in some embodiments system <NUM> comprises bottle <NUM>, wearable <NUM>, and computer platform <NUM>.

Bottle <NUM> can comprise any desired feeding bottle with reservoir connected to a mouthpiece having a nipple or other aperture suitable for engaging an infant's mouth typically used for feeding infants, with the further addition of at least one flow sensor <NUM>, pressure sensor <NUM>, gyroscope <NUM>, accelerometer <NUM>, temperature sensor <NUM>, volume sensor <NUM>, and combinations thereof. The at least one flow sensor <NUM> and pressure sensor <NUM> can be used to detect and measure the timing and amount of food obtained by an infant during a feeding session. The at least one gyroscope <NUM> and accelerometer <NUM> can be used to detect and measure the position of bottle <NUM> and monitor feeding behavior over time as a function of the movement of bottle <NUM>. The at least one temperature sensor <NUM> can be used to monitor the temperature of bottle <NUM> to indicate whether the contents are at a suitable temperature, or whether the contents are too cold or too hot for consumption. The at least one volume sensor <NUM> can be used to detect and measure the amount of food remaining in bottle <NUM>. Any suitable volume sensor <NUM> can be used, including float sensors, ultrasonic level sensors, laser level sensors, and the like. Additional sensors are also contemplated, such as suction sensors, blood pressure sensors, pulse oximetry sensors, glucose sensors, and the like. In some embodiments, bottle <NUM> can be powered by a power source <NUM> (such as a battery or an electrical plug). In some embodiments, bottle <NUM> can further include a wired or wireless transmitter <NUM> for transmitting data collected by the various sensors, and a non-transitory computer-readable medium <NUM> connected to a processor to store data collected by the various sensors.

Wearable <NUM> comprises an assortment of sensing and stimulating components, and can be in the form of an article of clothing or harness that can be worn by a subject to position the components adjacent to regions of sensing and stimulating interest. Wearable <NUM> comprises at least one electrode <NUM>. The at least one electrode <NUM> includes stimulating electrodes and can also include sensing electrodes. Stimulating electrodes are configured to administer electrical stimulation, while sensing electrodes are configured to measure a physiological response. For example, sensing electrodes can include electrocardiography electrodes, electromyography electrodes, electroencephalography electrodes, and the like. In some embodiments, the stimulating electrodes are electrically linked to the sensing electrodes. In various embodiments, wearable <NUM> can further include one or more additional sensors, such as temperature sensors, blood pressure sensors, pulse oximetry sensors, glucose sensors, and the like. Wearable <NUM> can further be powered by a power source <NUM> (such as a battery or an electrical plug). In some embodiments wearable <NUM> can further include a wired or wireless transmitter <NUM> for transmitting data collected by the various electrodes and sensors, a wired or wireless receiver <NUM> for receiving instructions for activating stimulating electrodes, and a non-transitory computer-readable medium <NUM> connected to a processor to store data collected by the various electrodes and sensors.

Computer platform <NUM> comprises a wired or wireless transmitter <NUM> for transmitting instructions to wearable <NUM>, a wired or wireless receiver <NUM> to collected data from bottle <NUM>, wearable <NUM>, or both, a non-transitory computer-readable medium <NUM> connected to a processor to store instructions and collected data, and can be powered by a power source <NUM> (such as a battery or an electrical plug).

As described above, the various components of system <NUM> can be used alone or in combination to couple cranial nerve stimulation with feedback. In a non-limiting first example, bottle <NUM> is coupled with wearable <NUM>. Bottle <NUM> can communicate with wearable <NUM> by way of transmitter <NUM> to receiver <NUM> that bottle <NUM> is in position for feeding. As shown in <FIG>, bottle <NUM> can sense a minimum change in volume, flow, and/or pressure that passes a threshold to initiate a trigger. Bottle <NUM> communicates to wearable <NUM> to supplement feeding behavior by activating an electrode <NUM> adjacent to a cranial nerve, thereby stimulating the cranial nerve. Feeding behavior can be monitored and further verified by bottle <NUM>. Feeding behavior can also be monitored and verified by an electrode <NUM> sensing cheek and jaw muscle activation. Feeding can continue by timing and synchronizing sensing of feeding initiation from bottle <NUM> and stimulation from wearable <NUM>.

In a non-limiting second example, wearable <NUM> can be used alone as a closed loop system. A sensing electrode <NUM> adjacent to one or more cheek and jaw muscles can be used to sense feeding initiation through a minimum change in muscle activation that passes a threshold to initiate a trigger. In response to the trigger, wearable <NUM> supplements feeding behavior by activating a stimulating electrode <NUM> adjacent to a cranial nerve. Feeding can continue by timing and synchronizing sensing of feeding initiation from a sensing electrode <NUM> and stimulation from a stimulating electrode <NUM>. In this manner, wearable <NUM> functions as a closed-loop system between sensing a minimum cheek and jaw muscle activation indicating feeding initiation and administering cranial nerve stimulation.

Computer platform <NUM> can be used to supplement communication between bottle <NUM> and wearable <NUM>. Computer platform <NUM> can also be used to facilitate operation, monitoring, and data collection/storage for bottle <NUM>, wearable <NUM>, or both. In some embodiments, computer platform <NUM> can be used to adjust the timing and intensity of electrode stimulation in wearable <NUM> according to data received from bottle <NUM>, wearable <NUM>, or both. In some embodiments, the timing and intensity of electrode stimulation in wearable <NUM> is adjusted automatically to maintain measurable parameters within thresholds set by computer platform <NUM>. Measurable parameters include but are not limited to heart rate, blood pressure, muscle activation rate, neural patterns, bottle volume, bottle position, and the like. Software executing the instructions provided herein may be stored on a non-transitory computer-readable medium, wherein the software performs some or all of the steps of the present invention when executed on a processor.

Aspects of the present disclosure relate to algorithms executed in computer software. Though certain embodiments may be described as written in particular programming languages, or executed on particular operating systems or computing platforms, it is understood that the system of the present invention is not limited to any particular computing language, platform, or combination thereof. Software executing the algorithms described herein may be written in any programming language known in the art, compiled or interpreted, including but not limited to C, C++, C#, Objective-C, Java, JavaScript, Python, PHP, Perl, Ruby, or Visual Basic. It is further understood that elements of the present invention may be executed on any acceptable computing platform, including but not limited to a server, a cloud instance, a workstation, a thin client, a mobile device, an embedded microcontroller, a television, or any other suitable computing device known in the art.

Parts of this invention are described as software running on a computing device. Though software described herein may be disclosed as operating on one particular computing device (e.g. a dedicated server or a workstation), it is understood in the art that software is intrinsically portable and that most software running on a dedicated server may also be run on any of a wide range of devices including desktop or mobile devices, laptops, tablets, smartphones, watches, wearable electronics or other wireless digital/cellular phones, televisions, cloud instances, embedded microcontrollers, thin client devices, or any other suitable computing device known in the art.

Similarly, parts of this invention are described as communicating over a variety of wireless or wired computer networks. For the purposes of this disclosure, the words "network", "networked", and "networking" are understood to encompass wired Ethernet, fiber optic connections, wireless connections including any of the various <NUM> standards, cellular WAN infrastructures such as <NUM> or <NUM>/LTE networks, Bluetooth®, Bluetooth® Low Energy (BLE) or Zigbee® communication links, or any other method by which one electronic device is capable of communicating with another. In some embodiments, elements of the networked portion of the invention may be implemented over a Virtual Private Network (VPN).

It should be understood that the components of system <NUM> are not limited to use in training feeding behavior and can be used to enhance infant development in a variety of manners. In some embodiments, cranial nerve stimulation is effective in increasing brain white matter integrity and inter-regional communication among the various regions of the brain. In some embodiments, cranial nerve stimulation is effective in enhancing motor function, such that activities including head lifting, rolling, sitting up, gripping, lifting, throwing, crawling, walking, climbing, and descending can be trained and improved. In some embodiments, cranial nerve stimulation is effective in modulating behavior. Behavior modulation can include positive reinforcement for good behavior, negative reinforcement for bad behavior, and the reduction or treatment of neurological and psychological disorders or injury.

It should be understood that the components of system <NUM> are not limited to use in infants and can be used in children, adults, and the elderly. In various embodiments, the components of system <NUM> are further applicable to animals, including mammals, reptiles, birds, fish, and the like. In some embodiments, cranial nerve stimulation is effective in treating muscle-related disorders and rehabilitation, such as post-stroke upper and lower motor limb rehab paradigms, wherein muscle groups involved in specific rehabilitation paradigms are targeted. For example, referring now to <FIG>, components of system <NUM> (such as a sensing electrode <NUM> on wearable <NUM>) can measure muscle activation in one or more muscle groups of interest that passes a minimum threshold to initiate a trigger. Wearable <NUM> can supplement muscle activation by activating a stimulating electrode <NUM> adjacent to a cranial nerve, thereby stimulating the cranial nerve. Further activation of the one or more muscle groups of interest can be monitored and verified by a sensing electrode <NUM>. Muscle activation can continue by timing and synchronizing sensing of muscle activation initiation from a sensing electrode <NUM> and stimulation from a stimulating electrode <NUM>, such as in a closed loop system. In some embodiments, cranial nerve stimulation is effective in modulating muscular or neural diseases or disorders, including but not limited to Parkinson's disease, dyskinesia, dystonia, and the like.

The present invention can be used in exemplary, non-claimed methods for administering noninvasive cranial nerve stimulation. As described elsewhere herein, the methods are effective in enhancing rehabilitation and recovery by improving neuroplasticity and coupling muscle training with feedback.

In some embodiments, the methods relate to enhancing oromotor skills. Referring now to <FIG>, an exemplary method <NUM> is depicted. Method <NUM> begins with step <NUM>, wherein a cranial nerve stimulation system is provided, the system comprising at least one sensing electrode and at least one stimulating electrode. In step <NUM>, the at least one sensing electrode is noninvasively secured adjacent to a subject's cheek or jaw muscle, and the at least one stimulating electrode is noninvasively secured adjacent to a subject's cranial nerve. In step <NUM>, the subject is provided with a source of food. In step <NUM>, muscle activation is measured using the at least one sensing electrode that surpasses a minimum threshold, indicating feeding initiation. In step <NUM>, stimulation is administered using the at least one stimulating electrode to the cranial nerve in response to the measurement of muscle activation surpassing the minimum threshold.

In some embodiments, the subject is an infant, and the oromotor skills relate to suckling. In various embodiments, the cranial nerve can be selected from the group consisting of the trigeminal nerve, the facial nerve, the accessory nerve, the hypoglossal nerve, the auricular branch of the vagus nerve, the main bundle of the vagus nerve, and the like. In various embodiments, the electrodes are noninvasively secured using an adhesive, a clip, a patch, an ear plug, a head band, a neck brace, a collar, a head covering, and the like. In some embodiments, the steps are performed in the recited order. In various embodiments, step <NUM> and step <NUM> are repeated in a closed loop system.

In some embodiments, the methods relate to muscle rehabilitation. Referring now to <FIG>, an exemplary method <NUM> is depicted. Method <NUM> begins with step <NUM>, wherein a cranial nerve stimulation system is provided, the system comprising at least one sensing electrode and at least one stimulating electrode. In step <NUM>, the at least one sensing electrode is noninvasively secured adjacent to a subject's muscle group of interest, and the at least one stimulating electrode is noninvasively secured adjacent to a subject's cranial nerve. In step <NUM>, muscle group activation is measured using the at least one sensing electrode that surpasses a minimum threshold. In step <NUM>, stimulation is administered using the at least one stimulating electrode to the cranial nerve in response to the measurement of muscle group activation surpassing the minimum threshold.

In various embodiments, the cranial nerve can be selected from the group consisting of the trigeminal nerve, the facial nerve, the accessory nerve, the hypoglossal nerve, the auricular branch of the vagus nerve, the main bundle of the vagus nerve, and the like. In various embodiments, the electrodes are noninvasively secured using an adhesive, a clip, a patch, an ear plug, a head band, an arm band, a brace, a collar, a wrapping, and the like. In some embodiments, the steps are performed in the recited order. In various embodiments, step <NUM> and step <NUM> are repeated in a closed loop system.

In various embodiments, the methods of the present disclosure select certain minimum thresholds of muscle activation. In some embodiments, the methods select for a minimum threshold of muscle activation that is determined by an absolute measurement. For example, the minimum threshold of muscle activation can be selected from an absolute value of about <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, or <NUM> mV.

In some embodiments, the methods select for a minimum threshold of muscle activation that is determined by a change from a base measurement taken at rest. For example, the minimum threshold of muscle activation can be selected from an increase or decrease of about <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM>µV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, <NUM> mV, or <NUM> mV. In some embodiments, the methods select for a minimum threshold of muscle activation that is determined by a percentage of a typical maximum potential of the muscle. For example, the minimum threshold of muscle activation can be selected from about <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>% of the typical maximum potential of the muscle.

In various embodiments, the methods of the present disclosure select certain parameters for cranial nerve stimulation. In some embodiments, the methods select for an intensity of stimulation. For example, the intensity of stimulation can be selected from about <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, <NUM> mA, or <NUM> mA. In some embodiments the methods select for a frequency of stimulation. For example, the frequency of stimulation can be selected from about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. In some embodiments, the methods select for a pulse width of stimulation. For example, the pulse width of stimulation can be selected from about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. In some embodiments, the methods select for a duration of stimulation on and off periods. For example, the duration of stimulation on and off periods can be selected from about <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> seconds, <NUM> minute, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, <NUM> minutes, and <NUM> hour. The on and off periods can have the same duration or different durations.

The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which fall within the scope of the present invention as defined by the appended claims.

Feeding difficulty due to oromotor dyscoordination is a primary concern for infants who are born preterm or suffer hypoxic ischemic encephalopathy (HIE). Vagal Nerve Stimulation (VNS) can increase neural plasticity, and when paired with rehabilitation, can enhance motor learning. Recently, it was demonstrated that noninvasive VNS can be accomplished via electrical stimulation of the auricular branch of the vagus nerve using a new method called transcutaneous auricular vagus nerve stimulation (taVNS). The goal of the present study is to develop a closed-loop automatic system that pairs taVNS with muscle activation from sucking, using electromyography (EMG) as a trigger. This system may allow better suck and stimulus pairing that is also less labor-intensive.

These investigations were designed to test the best location for reference electrode placement and the fidelity of stimulation paired with sucking. Three different EMG electrode placements (A, B, C) were compared to optimize the specificity and sensitivity of the automated system in <NUM> pre-term neonates enrolled in a larger pilot trial (example shown in <FIG>). Triggered stimulation was delivered using a left ear electrode at <NUM> mA below perceptual threshold, <NUM> frequency, <NUM> pulse width, for a <NUM> second train. The primary outcomes of this study were specificity (stimulations correctly paired to a visual suck, <FIG>) and sensitivity (visual sucks that triggered or occurred during stimulation, <FIG>).

Locations A, B, and C had a mean specificity of <NUM>±<NUM> (n=<NUM>), <NUM>±<NUM> (n=<NUM>), and <NUM>±<NUM> (n=<NUM>), respectfully. Locations A, B, and C had a mean sensitivity of <NUM>±<NUM> (n=<NUM>), <NUM>±<NUM> (n=<NUM>), and <NUM>±<NUM> (n=<NUM>), respectively. Electrode placement C was feasible and better tolerated. The placement produced the highest average (<NUM>%) rate of stimulation induced by a real visual suck while minimizing stimulation triggered by non-visual suck (<NUM>%). All placements seemed to perform equally at a rate of about <NUM>-<NUM>% triggers induced by a visual suck.

These results demonstrate that EMG electrode position C was the most efficient with <NUM>% of stimulation trains correctly pairing with visual sucks while maintaining good sensitivity to visual sucks. Using EMG in a closed-loop taVNS system is a safe and effective way to trigger taVNS stimuli in infants.

In preterm infants with brain dysmaturation or term infants with hypoxic ischemic encephalopathy (HIE), feeding difficulty is the primary reason for delayed hospital discharge. Failure to achieve full oral feedings may be due to closure of critical developmental windows of neuroplasticity, or due to overt brain injury in HIE infants. Current therapies are limited to feeding by occupational or speech therapists once a day, and gastrostomy tube (g-tube) placement.

The present study monitored intake of infants <NUM> days post-oral (PO) feeding initiation. Infants that have failed feeding on average for <NUM> days were determined to be g-tube candidates and were enrolled in the cranial nerve stimulation trial (<FIG>). <NUM> babies were analyzed in an interim analysis (<FIG>). All babies were g-tube candidates and had been attempting to feed orally for an average of <NUM> days before enrollment. Treatment was administered based on previous protocols (stimulation delivered using a left ear electrode at <NUM> mA below perceptual threshold, <NUM> frequency, <NUM> pulse width, for a <NUM> second train). <NUM>% of the babies (<NUM> of <NUM>) reached the adequate PO intake (full feeds orally) that is clinically required to be discharged without a g-tube. The results demonstrate that in more than half of babies, cranial nerve stimulation facilitates their rehabilitation, enhances neuroplasticity, and facilitates motor learning.

<FIG> and <FIG> depict the statistical analysis of the responder group and non-responder group. <FIG> shows that linear regression comparison of responders before and during stimulation treatment are significantly different, such that the slope increases after treatment. <FIG> shows that linear regression comparison of non-responders before and during stimulation treatment are not significantly different.

Treatment candidates were imaged to monitor the effects of treatment on brain development. Babies were scanned using MRI, treated for <NUM>-<NUM> weeks, and scanned again to investigate changes in white matter tracts. <FIG> and <FIG> demonstrate that cranial nerve stimulation had a greater effect on brain white matter tract integrity as indicated by fractional anisotropy (FA) and axial kurtosis (K∥) in the responder group (full feed) than in the non-responder group (g-tube). Specific white matter tracts related to motor and sensorimotor integration were all strengthened. Furthermore, FA changes in both responder and non-responder groups were greater than expected with normal development (<FIG>), demonstrating that there is more inter-regional communication across the brain tract.

Claim 1:
A system for enhancing oromotor skills, comprising:
at least one sensing electrode configured to attach adjacent to at least one cheek or jaw muscle; and
at least one stimulating electrode configured to attach adjacent to a cranial nerve;
wherein the at least one stimulating electrode is electrically linked to the at least one sensing electrode such that the at least one stimulating electrode configured to be activated to stimulate the cranial nerve when the at least one sensing electrode measures electrical energy in the at least one muscle passes a minimum threshold indicating feeding initiation;
the system further comprising a power source, a transmitter, and a processor communicatively connected to a non-transitory computer-readable memory with instructions stored thereon, which when executed by the processor, configure the processor to initiate a closed-loop synchronization between activation and deactivation of the at least one stimulating electrode with the at least one sensing electrode measuring electrical energy that passes the minimum threshold.