Non-invasive neurotherapy

Abstract

The present invention relates to a system for providing non-invasive cranial nerve stimulation and methods of use thereof. The present invention administers treatment via electrodes non-invasively connected to one or more cranial nerves of a subject. The system can be used to enhance rehabilitation and recovery by improving neuroplasticity and coupling muscle training with feedback.

Description

[0001] Citations of Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 673,578, filed May 18, 2018, and U.S. Provisional Patent Application No. 62 / 757,775, filed November 9, 2018, the contents of which are incorporated herein by reference in their entirety.

[0003] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0004] This invention was made with government support under Grant No. P2HCD086844 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0005] Premature and full-term infants with hypoxic-ischemic encephalopathy (HIE) are at high risk for motor disorders, primarily manifesting as feeding delays during their neonatal hospitalization. Oral motor disorders are common in both groups of infants and often require 3-6 weeks of oral feeding in the hospital before infants receive enough breast milk or formula to maintain adequate growth for discharge. Typically, infants receive daily specialized care to ensure that feeding details, such as nipple selection and frequency of oral feedings, are not physiologically taxing, and to guide the learning of these motor skills. Feeding difficulties are a major cause of delayed discharge for infants born prematurely or with HIE. Many of these infants will not master this motor skill until they are of full age (40-42 weeks of gestation) and will receive a gastrostomy tube (G-tube) for direct gastric feedings, allowing them to eventually be discharged home from the hospital. An average of 40 G-tubes are placed in the neonatal intensive care unit (NICU) each year. The procedure requires general anesthesia for insertion and eventual removal of the tube and leaves a scar in the epigastric area. The G-tube also reinforces the parent's feeling that the child is not normal and that his or her developmental potential is more limited than that of a "normal" child.

[0006] Even after severe brain injury, it is known that infants have neuroplasticity that can lead to improved or even near-normal outcomes. This neuroplasticity, which involves stimulating neurogenesis and reparative interneuronal connections, has been shown to improve motor skills in neonatal animal models and in adults following stroke. Furthermore, it is known that rehabilitation training can be enhanced by using brain stimulation in various modalities.

[0007] Feeding a newborn involves a sequence of sucking, swallowing, and breathing that requires coordination of facial, head, and neck muscles with myelinated vagal regulation of the bronchi and heart. In premature infants, the muscles required for feeding are underdeveloped, leading to the need for OT rehabilitation to "learn" how to eat. The inability to feed effectively in premature infants is a major cause of extended hospital stays. In newborns with HIE, the development of the cortex and basal ganglia is interrupted, and depending on the severity, normal developmental plasticity is hindered, further contributing to their feeding disability. Both types of feeding difficulties involve complex motor learning that requires the integration of sensory and motor pathways.

[0008] Therefore, there is a need in the art for improved systems and methods for implementing neural stimulation to enhance neural plasticity and muscle training. The present invention satisfies this need. Summary of the Invention

[0009] In one aspect, the present invention provides a method for enhancing oral motor skills, comprising the following steps: 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 to a cheek or jaw muscle of a subject, and securing the at least one stimulating electrode to a cranial nerve of the subject; providing a food source to the subject; measuring muscle activation exceeding a minimum threshold using the at least one sensing electrode; and stimulating the cranial nerve using the at least one stimulating electrode in response to the measured value of muscle activation exceeding the minimum threshold.

[0010] In one embodiment, the cranial nerve is selected from the group consisting of: trigeminal nerve, facial nerve, accessory nerve, hypoglossal nerve, auricular branch of vagus nerve, and main bundle of vagus nerve. In one embodiment, the measuring step and the implementing step are repeated in a closed loop. In one embodiment, the at least one stimulating electrode is non-invasively fixed to the subject's ear canal, tragus, cymba concha, lobe, helix, anti-helix, mastoid or neck.

[0011] In one embodiment, the minimum threshold is an absolute value selected from the group consisting of about 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 μV, 300 μV, 400 μV, 500 μV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In one embodiment, the minimum threshold is a change from a baseline measurement at rest selected from the group consisting of 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 μV, 300 μV, 400 μV, 500 μV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In one embodiment, the minimum threshold is a percentage of the muscle's maximum potential selected from the group consisting of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0012] In one embodiment, the stimulus has an intensity selected from the group consisting of about 0.01 mA, 0.05 mA, 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 mA, 1.5 mA, 2 mA, 2.5 mA, 3 mA, 3.5 mA, 4 mA, 4.5 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, and 10 mA. In one embodiment, the stimulus has a frequency selected from the group consisting of about 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, and 50 Hz. In one embodiment, the stimulation has a pulse width selected from the group consisting of about 10μs, 20μs, 30μs, 40μs, 50μs, 60μs, 70μs, 80μs, 90μs, 100μs, 150μs, 200μs, 250μs, 300μs, 350μs, 400μs, 450μs, 500μs, 550μs, 600μs, 650μs, 700μs, 750μs, 800μs, 850μs, 900μs, 950μs and 1ms. In one embodiment, the stimulation has an on-duration and an off-duration, each selected from the group consisting of about 0.1 seconds, 0.5 seconds, 1.5 seconds, 2 seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, and 1 hour.

[0013] In another aspect, the present invention provides a cranial nerve stimulation system comprising: at least one sensing electrode configured to be attached adjacent to at least one muscle; and at least one stimulating electrode configured to be attached adjacent to a cranial nerve; wherein the at least one stimulating electrode is electrically connected to the at least one sensing electrode, so that the at least one stimulating electrode is activated to stimulate the cranial nerve when the electrical energy measured by the at least one sensing electrode in the at least one muscle passes a minimum threshold.

[0014] In one embodiment, the at least one cranial nerve is selected from the group consisting of the trigeminal nerve, facial nerve, accessory nerve, hypoglossal nerve, auricular branch of the vagus nerve, and main fasciculus of the vagus nerve.

[0015] In one embodiment, the system further comprises a power source, a transmitter, and a processor communicatively coupled to a non-transitory computer-readable memory having stored thereon instructions that, when executed by the processor, initiate closed-loop synchronization between activation and deactivation of the at least one stimulation electrode as the at least one sensing electrode measures electrical energy passing a minimum threshold.

[0016] In one embodiment, the system further comprises a feeding bottle comprising at least one sensor, a power source, and a transmitter. In one embodiment, the at least one sensor is selected from the group consisting of a flow sensor, a pressure sensor, a suck sensor, a gyroscope, an accelerometer, a temperature sensor, and a volume sensor. In one embodiment, the system further comprises the power source, the transmitter, and a processor communicatively coupled to a non-transitory computer-readable memory having stored thereon instructions that, when executed by the processor, synchronize activation and deactivation of the at least one stimulation electrode with the at least one sensing electrode sensing the initiation of feeding from the feeding bottle and the termination of feeding from the feeding bottle.

[0017] In another aspect, the present invention provides a method for enhancing muscle rehabilitation, comprising the following steps: providing a cranial nerve stimulation system comprising at least one sensing electrode and at least one stimulating electrode; fixing the at least one sensing electrode near a muscle group of interest of a subject, and fixing the at least one stimulating electrode to a cranial nerve of the subject; using the at least one sensing electrode to measure activation of the muscle group exceeding a minimum threshold; and in response to the measurement of muscle group activation exceeding the minimum threshold, stimulating the cranial nerve using the at least one stimulating electrode.

[0018] In one embodiment, the cranial nerve is selected from the group consisting of: trigeminal nerve, facial nerve, accessory nerve, hypoglossal nerve, auricular branch of vagus nerve, and main fasciculus of vagus nerve.In one embodiment, the measuring step and the implementing step are repeated in a closed loop. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The following detailed description of exemplary embodiments of the present invention will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the invention is not limited to the precise arrangements and technical instrumentalities of the embodiments shown in the drawings.

[0020] Figure 1A and Figure 1B A diagram depicting an exemplary system for pairing non-invasive cranial neurostimulation with neonatal feeding is presented.

[0021] Figure 2 Depicted is a diagram showing an exemplary system for triggering cranial neural stimulation in a neonate while feeding.

[0022] Figure 3 Depicted is a diagram showing an exemplary system for triggering cranial nerve stimulation in muscle rehabilitation.

[0023] Figure 4 A flow chart depicting an exemplary method for feeding training a neonate is shown.

[0024] Figure 5 A flow chart depicting an exemplary method of training muscle rehabilitation.

[0025] Figure 6 Depicted is an exemplary electromyographic electrode setup for muscle activation detection and stimulation in training neonates for feeding behavior.

[0026] Figure 7 Depicted are the results of an experiment investigating the optimal electrode positions for delivering the most reliable stimulation triggered by visible sucking during feeding in newborns.

[0027] Figure 8 Depicted are the results of an experiment investigating the optimal electrode positions for delivering the highest stimulation rates while recording visual sucking during feeding in newborns.

[0028] Figure 9 Historical feeding data in a sample of infants with feeding difficulties are depicted.

[0029] Figure 10 Describes the results of cranial neurotherapy for 14 infants with feeding difficulties.

[0030] Figure 11 Depicts Figure 10 Results of statistical analysis for 8 responders in the treatment group shown; these responders had significant changes in oral feeding behavior as indicated by significant changes in the slope of the linear regression line.

[0031] Figure 12 Depicts Figure 10 Results of statistical analysis for the 6 non-responders in the treatment group are shown; non-responders had a linear regression slope not significantly different from zero, indicating that no improvement was achieved.

[0032] Figure 13A and Figure 13B Describes the results of an experiment investigating the effects of cranial neurotherapy on the integrity of white matter tracts in infants' brains. Figure 13A Shown are weekly changes in fractional anisotropy (FA) between responders (fully fed) and non-responders (G-tube) in the Left External Capsule and Right Corpus Callosum, two white matter regions of interest important in motor integration. Figure 13B The weekly axial kurtosis (K) of the left posterior thalamic radiation (PTR) and right inferior occipital fascia (IFOF) between responders (fully fed) and non-responders (G tube) is shown. || ) changes, and these two white matter regions of interest are important in sensorimotor integration. DETAILED DESCRIPTION

[0033] It should be understood that the accompanying drawings and description of the present invention have been simplified to illustrate the elements relevant to a clear understanding of the present invention, while for clarity, many other elements commonly present in the art have been eliminated. Those of ordinary skill in the art will recognize that other elements and / or steps are required and / or required when realizing the present invention. However, since such elements and steps are well known in the art, and because they do not promote a better understanding of the present invention, discussion of such elements and steps is not provided herein. The disclosure herein relates to all such variations and modifications of such elements and methods known to those skilled in the art.

[0034] Unless otherwise defined, 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, only exemplary methods and materials are described.

[0035] As used herein, each of the following terms has the meaning associated with it in this section.

[0036] The articles "a" and "an" are used herein to refer to one or more (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0037] As used herein, "about" when referring to a measurable value such as an amount, a time period, etc., is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, and ±0.1% of the stated value, where such variations are appropriate.

[0038] Throughout this disclosure, various aspects of the present invention can be provided in 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. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and each numerical value within that range. For example, a description of a range such as 1-6 should be considered to have clearly disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numbers within that range such as 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any whole and partial increments therebetween. This applies regardless of the breadth of the range.

[0039] Brain nerve stimulation system

[0040] The present invention is based in part on a system for providing non-invasive cranial nerve stimulation. The system delivers treatment via electrodes that are non-invasively attached to one or more cranial nerves of a subject. The system can be used to enhance rehabilitation and recovery by improving neuroplasticity and coupling muscle training with feedback.

[0041] Stimulation can be applied non-invasively 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 contacted in a variety of ways, including but not limited to, the ear canal, the tragus, the cymba conchae, the external ear, the mastoid, and combinations thereof. The main bundle of the vagus nerve can be contacted at any suitable location along the neck. In various embodiments, the stimulation is implemented transcutaneously. The stimulation can be implemented using one or more electrodes fixed near the cranial nerves in any suitable manner, including but not limited to the use of adhesives, clips, patches, earplugs, headbands, neck braces, collars, head covers, and the like.

[0042] In some embodiments, the present invention provides a therapeutic tool designed to improve and accelerate the learning of feeding behaviors in newborns. The provided system changes the way premature newborns are rehabilitated, resulting in earlier discharge from the hospital, lower hospital costs, improved parental perception of their infant's developmental potential, reduced stress, and improved parental connection both inside and outside the hospital. The system can be used as a take-home feeding aid for the rehabilitation of critically ill infants who have missed the developmental window for mastering feeding skills, as well as for infants with congenital syndromes that make oral feeding challenging.

[0043] The use of non-invasive brain stimulation to promote plasticity during a feeding learning task to treat oral motor difficulties has become a highly novel application of transcutaneous auricular vagus nerve stimulation (taVNS). The main premise is that in infants at high risk for movement disorders, brain stimulation delivered simultaneously via taVNS will enhance plasticity in the motor cortex involved in a learned feeding task, leading to better feeding. Surgically implanted VNS may produce a synergistic effect when combined with paired stimulation that guides plastic changes in the cortex. The present invention utilizes a new form of non-invasive vagus nerve stimulation (nVNS) paired with feeding (rather than through surgical implantation) to accelerate and enhance feeding learning in newborns.

[0044] Now refer to Figure 1A and Figure 1B , depicts an exemplary system 100. In various embodiments, system 100 includes multiple components that can be used individually or in combination to couple brain neurostimulation with feedback to train infant feeding behavior. For example, in some embodiments, system 100 includes a feeding bottle 102, a wearable device 122, and a computer platform 134.

[0045] The feeding bottle 102 can comprise any desired feeding bottle having a reservoir connected to a mouthpiece having a nipple or other aperture suitable for engaging an infant's mouth, typically for feeding, and further comprising at least one flow sensor 104, a pressure sensor 106, a gyroscope 108, an accelerometer 110, a temperature sensor 112, a volume sensor 114, and combinations thereof. The at least one flow sensor 104 and the pressure sensor 106 can be used to detect and measure the timing and amount of food received by the infant during a feeding session. The at least one gyroscope 108 and the accelerometer 110 can be used to detect and measure the position of the feeding bottle 102 and monitor feeding behavior over time as a function of the movement of the feeding bottle 102. The at least one temperature sensor 112 can be used to monitor the temperature of the feeding bottle 102 to indicate whether the contents are at the appropriate temperature or are too cold or too hot to consume. The at least one volume sensor 114 can be used to detect and measure the amount of food remaining in the feeding bottle 102. Any suitable volume sensor 114 can be used, including a float sensor, an ultrasonic level sensor, a laser level sensor, etc. Other sensors are also contemplated, such as aspiration sensors, blood pressure sensors, pulse oximetry sensors, glucose sensors, etc. In some embodiments, the feeding bottle 102 can be powered by a power source 116 (e.g., a battery or an electrical outlet). In some embodiments, the feeding bottle 102 can also include: a wired or wireless transmitter 118 for transmitting data collected by the various sensors; and a non-transitory computer-readable medium 120 connected to the processor to store the data collected by the various sensors.

[0046] The wearable device 122 includes a combination of sensing and stimulation components and can take the form of an article of clothing or a harness that is worn by a subject to position the component near an area of ​​interest for sensing and stimulation. The wearable device 122 includes at least one electrode 124. The at least one electrode 124 includes a stimulation electrode and can also include a sensing electrode. The stimulation electrode is configured to implement electrical stimulation, while the sensing electrode is configured to measure a physiological response. For example, the sensing electrode can include an electrocardiogram electrode, an electromyogram electrode, an electroencephalogram electrode, and the like. In some embodiments, the stimulation electrode is electrically connected to the sensing electrode. In various embodiments, the wearable 122 can also include one or more additional sensors, such as a temperature sensor, a blood pressure sensor, a pulse oximetry sensor, a glucose sensor, and the like. The wearable device 122 can also be powered by a power source 126 (such as a battery or an electrical plug). In some embodiments, the wearable device 122 can also include: a wired or wireless transmitter 128 for sending data collected by the electrodes and sensors; a wired or wireless receiver 130 for receiving instructions for activating the stimulation electrodes; and a non-transitory computer-readable medium 132 connected to the processor to store the data collected by the electrodes and sensors.

[0047] The computer platform 134 includes: a wired or wireless transmitter 138 for sending instructions to the wearable device 122; a wired or wireless receiver 140 for collecting data from the bottle 102, the wearable device 122, or both; and a non-transitory computer-readable medium 142 connected to the processor to store instructions and collected data and capable of being powered by a power source 136 (such as a battery or an electrical plug).

[0048] As described above, the components of the system 100 can be used individually or in combination to couple brain stimulation with feedback. In a first, non-limiting example, the feeding bottle 102 is coupled to the wearable device 122. The feeding bottle 102 can communicate with the wearable device 122 via a transmitter 118 to a receiver 130 when the feeding bottle 102 is in the feeding position. Figure 2 As shown, the feeding bottle 102 can sense a minimal change in volume, flow, and / or pressure that passes a threshold to activate a trigger. The feeding bottle 102 communicates with the wearable device 122 to supplement feeding behavior by activating electrodes 124 near cranial nerves, thereby stimulating the cranial nerves. Feeding behavior can be monitored and further verified by the feeding bottle 102. Feeding behavior can also be monitored and verified by electrodes 124 that sense cheek and jaw muscle activation. Feeding can continue by timing and synchronizing the sensing of feeding initiation from the feeding bottle 102 and stimulation from the wearable device 122.

[0049] In a second non-limiting example, the wearable device 122 can function alone as a closed-loop system. Sensing electrodes 124 near one or more cheek and jaw muscles can be used to sense the onset of eating by a minimal change in muscle activation that crosses a threshold to initiate a trigger. In response to the trigger, the wearable device 122 complements the eating behavior by activating stimulation electrodes 124 near the cranial nerves. Eating can continue by timing and synchronizing the sensing of the onset of eating from the electrodes 124 and the stimulation from the stimulation electrodes 124. In this way, the wearable device 122 acts as a closed-loop system between sensing the minimal cheek and jaw muscle activation that indicates the onset of eating and implementing cranial nerve stimulation.

[0050] The computer platform 134 can be used to supplement communication between the feeding bottle 102 and the wearable device 122. The computer platform 134 can also be used to facilitate operation, monitoring, and data collection / storage of the feeding bottle 102, the wearable device 122, or both. In some embodiments, the computer platform 134 can be used to adjust the timing and intensity of electrode stimulation in the wearable device 122 based on data received from the feeding bottle 102, the wearable device 122, or both. In some embodiments, the timing and intensity of electrode stimulation in the wearable device 122 are automatically adjusted to maintain measurable parameters within thresholds set by the computer platform 134. Measurable parameters include, but are not limited to, heart rate, blood pressure, muscle activation rate, neural patterns, feeding bottle volume, feeding bottle position, and the like. In some aspects of the present invention, software executing the instructions provided herein can be stored on a non-transitory computer-readable medium, wherein when executed on a processor, the software performs some or all of the steps of the present invention.

[0051] Aspects of the present invention relate to algorithms executed in computer software. Although certain embodiments may be described as being written in a specific programming language, or executed on a specific operating system or computing platform, it should be understood that the systems and methods of the present invention are not limited to any specific computing language, platform, or combination thereof. The software that executes the algorithms described herein can be written, compiled, or interpreted in any programming language known in the art, including but not limited to C, C++, C#, Objective-C, Java, JavaScript, Python, PHP, Perl, Ruby, or Visual Basic. It should be further understood that the elements of the present invention can be executed on any acceptable computing platform, including but not limited to, servers, cloud instances, workstations, thin clients, mobile devices, embedded microcontrollers, televisions, or any other suitable computing devices known in the art.

[0052] Components of the present invention are described as software running on a computing device. Although the software described herein may be disclosed as running on a specific computing device (e.g., a dedicated server or workstation), it should be understood in the art that the software is inherently portable and, for the purposes of the present invention, most software running on a dedicated server may also run on any wide range of devices including desktop or mobile devices, laptops, tablets, smartphones, watches, wearable electronic devices or other wireless digital / cellular phones, televisions, cloud stations, embedded microcontrollers, thin client devices, or any other suitable computing device known in the art.

[0053] Similarly, the components of the present invention are described as communicating over various wireless or wired computer networks. For the purposes of this invention, the terms "network," "networking," and "networked" should be understood to encompass wired Ethernet, fiber optic connections, wireless connections including any of the various 802.11 standards, such as 3G or 4G / LTE networks, Low Energy (BLE) or A cellular WAN infrastructure of communication links, or any other method by which one electronic device can communicate with another electronic device. In some embodiments, elements of the network portion of the present invention may be implemented over a virtual private network (VPN).

[0054] It should be understood that the components of system 100 are not limited to being used for training feeding behavior, and can be used to enhance infant development in various ways. In some embodiments, cranial nerve stimulation is effective in increasing white matter integrity and inter-regional communication between various regions of the brain. In some embodiments, cranial nerve stimulation is effective in enhancing motor function, so that activities including raising the head, rolling, sitting up, grasping, lifting, throwing, crawling, walking, climbing and descending can be trained and improved. In some embodiments, cranial nerve stimulation is effective in regulating behavior. Behavioral regulation can include positive reinforcement for good behavior, negative reinforcement for bad behavior, and reduction or treatment of neurological and psychological disorders or injuries.

[0055] It should be understood that the components of system 100 are not limited to use with infants and can be used with children, adults, and the elderly. In various embodiments, the components of system 100 are also suitable for use with animals, including mammals, reptiles, birds, fish, etc. In some embodiments, cranial nerve stimulation is effective in treating muscle-related diseases and rehabilitation, such as upper and lower limb motor limb rehabilitation paradigms after stroke, where muscle groups involved in a particular rehabilitation paradigm are targeted. For example, referring now to Figure 3, components of the system 100 (such as the sensing electrodes 124 on the wearable device 122) can measure muscle activation in one or more muscle groups of interest that initiate a trigger by a minimum threshold. The wearable device 122 can supplement muscle activation by activating the stimulation electrodes 124 near the cranial nerves, thereby stimulating the cranial nerves. Further activation of the one or more muscle groups of interest can be monitored and verified by the sensing electrodes 124. Muscle activation can continue by timed and synchronized sensing of the start of muscle activation from the sensing electrodes 124 and stimulation from the stimulation electrodes 124, such as in a closed-loop system. In some embodiments, cranial nerve stimulation can effectively modulate muscle or nerve diseases or disorders, including but not limited to Parkinson's disease, dyskinesia, dystonia, etc.

[0056] Cranial nerve stimulation methods

[0057] The present invention is also based in part on methods for implementing non-invasive brain neurostimulation, which, as described elsewhere herein, is effective in enhancing rehabilitation and recovery by improving neuroplasticity and coupling muscle training with feedback.

[0058] In some embodiments, the method involves enhancing oral motor skills. Figure 4 , depicting an exemplary method 200. Method 200 begins at step 202, where a cranial nerve stimulation system is provided, the system comprising at least one sensing electrode and at least one stimulating electrode. In step 204, the at least one sensing electrode is non-invasively secured near a cheek or jaw muscle of a subject, and the at least one stimulating electrode is non-invasively secured near a cranial nerve of the subject. In step 206, a food source is provided to the subject. In step 208, muscle activation is measured using the at least one sensing electrode that exceeds a minimum threshold, indicating the onset of eating. In step 210, stimulation of the cranial nerve is performed using the at least one stimulating electrode in response to the measurement of muscle activation exceeding the minimum threshold.

[0059] In some embodiments, the subject is an infant and the oral motor skills are related to sucking. 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 fasciculus of the vagus nerve, and the like. In various embodiments, the electrodes are non-invasively secured using adhesives, clips, patches, earplugs, headbands, neck collars, collars, head covers, and the like. In some embodiments, the steps are performed in the order recited. In various embodiments, steps 208 and 210 are repeated in a closed-loop system.

[0060] In some embodiments, the method involves muscle rehabilitation. Figure 5, depicting an exemplary method 300. Method 300 begins at step 302, where a cranial nerve stimulation system is provided, the system comprising at least one sensing electrode and at least one stimulating electrode. In step 304, the at least one sensing electrode is non-invasively affixed near a muscle group of interest in a subject, and the at least one stimulating electrode is non-invasively affixed near a cranial nerve of the subject. In step 306, muscle group activation is measured using the at least one sensing electrode that exceeds a minimum threshold. In step 308, in response to the measurement of muscle group activation exceeding the minimum threshold, the cranial nerve is stimulated using the at least one stimulating electrode.

[0061] 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 non-invasively secured using adhesives, clips, patches, earplugs, headbands, armbands, braces, collars, wraps, and the like. In some embodiments, the steps are performed in the order recited. In various embodiments, steps 306 and 308 are repeated in a closed-loop system.

[0062] In various embodiments, the methods of the present invention select certain minimum thresholds for muscle activation. In some embodiments, these methods select the minimum threshold for muscle activation determined by an absolute measurement. For example, the minimum threshold for muscle activation can be selected from an absolute value of about 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 μV, 300 μV, 400 μV, 500 μV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In some embodiments, these methods select the minimum threshold for muscle activation determined by a change from a baseline measurement at rest. For example, the minimum threshold for muscle activation can be selected from an increase or decrease of about 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 μV, 300 μV, 400 μV, 500 μV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In some embodiments, the methods select a minimum threshold for muscle activation that is determined by a percentage of the typical maximum potential of the muscle. For example, the minimum threshold for muscle activation can be selected from about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the typical maximum potential of the muscle.

[0063] In each embodiment, the method of the present invention selects certain parameters for cranial nerve stimulation. In some embodiments, these methods select stimulation intensity. For example, the stimulation intensity can be selected from about 0.01mA, 0.05mA, 0.1mA, 0.2mA, 0.3mA, 0.4mA, 0.5mA, 0.6mA, 0.7mA, 0.8mA, 0.9mA, 1mA, 1.5mA, 2mA, 2.5mA, 3mA, 3.5mA, 4mA, 4.5mA, 5mA, 6mA, 7mA, 8mA, 9mA or 10mA. In some embodiments, these methods select the frequency of stimulation. For example, the stimulation frequency can be selected from about 1Hz, 2Hz, 3Hz, 4Hz, 5Hz, 6Hz, 7Hz, 8Hz, 9Hz, 10Hz, 15Hz, 20Hz, 25Hz, 30Hz, 35Hz, 40Hz, 45Hz or 50Hz. In some embodiments, the methods select a pulse width for stimulation. For example, the pulse width for stimulation can be selected from about 10 μs, 20 μs, 30 μs, 40 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 150 μs, 200 μs, 250 μs, 300 μs, 350 μs, 400 μs, 450 μs, 500 μs, 550 μs, 600 μs, 650 μs, 700 μs, 750 μs, 800 μs, 850 μs, 900 μs, 950 μs, or 1 ms. In some embodiments, the methods select the duration of the stimulation on and off periods. For example, the duration of the stimulation on and off periods can be selected from about 0.1 seconds, 0.5 seconds, 1.5 seconds, 2 seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, and 1 hour. The on and off periods can have the same duration or different durations.

[0064] Experimental Examples

[0065] The present invention is further described in detail with reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise stated. Therefore, the present 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 that become apparent as a result of the teachings provided herein.

[0066] Without further description, it is believed that one of ordinary skill in the art can use the foregoing description and the following illustrative examples to prepare and utilize the compounds of the present invention and to practice the claimed methods. Therefore, the following working examples specifically point out exemplary embodiments of the present invention and should not be construed as limiting the remainder of the disclosure in any way.

[0067] Example 1: How to measure sucking in infants? Closing the loop on transcutaneous auricular vagus nerve stimulation (taVNS) to enhance Impaired oromotor development in infants: Which electrode is best?

[0068] Feeding difficulties resulting from oromotor disorders are a primary problem for infants born prematurely or with hypoxic-ischemic encephalopathy (HIE). Vagus nerve stimulation (VNS) can increase neuroplasticity and, when paired with rehabilitation, enhance motor learning. Recently, it has been demonstrated that non-invasive VNS can be achieved using a new approach called transcutaneous auricular vagus nerve stimulation (taVNS), which electrically stimulates the auricular branch of the vagus nerve. The goal of this study was to develop a closed-loop, automated system that pairs taVNS with muscle activation from sucking, using electromyography (EMG) as a trigger. This system could achieve better pairing of sucking and stimulation while also being less labor-intensive.

[0069] These studies were designed to test the optimal placement of the reference electrode and the fidelity of stimulation matched to sucking. Figure 6 Three different EMG electrode placements (A, B, C) were compared in two premature infants enrolled in a study (see the example shown in Figure 1) to optimize the specificity and sensitivity of the automated system. Trigger stimulation was delivered using the left ear electrode at 0.1 mA below the perception threshold, a frequency of 25 Hz, a pulse width of 500 μs, and a training time of 3.5 seconds. The primary outcome of this study was specificity (correct pairing of stimulation with visual sucking, Figure 7 ) and sensitivity (visible sucking triggered or occurring during stimulation, Figure 8 ).

[0070] Positions A, B, and C had mean specificities of 49.3 ± 31.8 (n = 3), 37.9 ± 13.4 (n = 7), and 58.3 ± 18.5 (n = 6), respectively. Positions A, B, and C had mean sensitivities of 77 ± 15.9 (n = 3), 82 ± 13.8 (n = 7), and 75.2 ± 16.2 (n = 6), respectively. Electrode position C was feasible and better tolerated. This position produced the highest mean stimulation rate (60%) induced by actual visual sucking, while minimizing stimulation triggered by non-visual sucking (40%). All positions appeared to perform equally well, with a triggering rate of approximately 77% to 81% induced by visual sucking.

[0071] These results indicate that EMG electrode position C was most effective, with 58% of stimulations trained to the correct pairing with the visual suck, while maintaining good sensitivity to the visual suck. EMG used in a closed-loop taVNS system is a safe and effective method to trigger taVNS stimulation in infants.

[0072] Example 2: Treatment of neonates using cranial nerve stimulation

[0073] In premature infants with brain maturation defects or term infants with hypoxic-ischemic encephalopathy (HIE), feeding difficulties are a major reason for delayed discharge from the hospital. The inability to fully achieve oral feeding may be due to the closure of a critical developmental window of neuroplasticity or to the significant brain damage in infants with HIE. Current treatment is limited to once-daily feeding by an occupational or speech therapist and placement of a gastrostomy tube (g-tube).

[0074] This study monitored infant intake for 20 days after the initiation of oral (PO) feedings. Infants who failed to feed on average at 49 days were identified as G-tube candidates and enrolled in a cranial nerve stimulation trial ( Figure 9 ). Fourteen infants were analyzed in the interim analysis ( Figure 10 All infants were G-tube candidates and had attempted oral feedings for an average of 49 days before enrollment. Treatment was implemented according to the previous protocol (stimulation using a left ear electrode at 0.1 mA below the perception threshold, 25 Hz frequency, 500 μs pulse width, and 3.5-second training time). 57% of infants (8 of 14) achieved adequate PO intake (complete oral feeding), which is clinically required for discharge without a G-tube. The results showed that in more than half of the infants, cranial nerve stimulation promoted their recovery, enhanced neuroplasticity, and promoted motor learning.

[0075] Figure 11 and Figure 12 Statistical analysis of the responder and non-responder groups is depicted. Figure 11 Linear regression comparisons of responders before and during stimulation treatment showed that they were significantly different, such that the slope increased after treatment. Figure 12 Linear regression comparisons of non-responders before and during stimulation treatment showed no significant differences.

[0076] Treatment candidates are imaged to monitor the effects of treatment on brain development. Infants are scanned using MRI, treated for 2-4 weeks, and then scanned again to study changes in white matter tracts. Figure 13A and Figure 13B It was confirmed that cranial nerve stimulation had an effect on the fractional anisotropy (FA) and axial diffusion kurtosis (K) in the responder group (fully fed). ||) was more affected than in the non-responder group (g-tube). Specific white matter tracts involved in motor and sensorimotor integration were strengthened. In addition, the FA changes in both responder and non-responder groups were greater than those expected for normal development ( Figure 13A ), indicating more interregional communication throughout the brain tract.

[0077] The disclosures of each and all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entireties. Although the present invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the present invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

Claims

1. A brain neurostimulation system for enhancing oral motor skills, comprising: at least one sensing electrode configured to be attached proximate to at least one muscle, the muscle being a cheek or jaw muscle; and at least one stimulation electrode configured to be attached proximate to a cranial nerve 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 fasciculus of the vagus nerve; wherein the at least one sensing electrode is configured to measure muscle activation exceeding a minimum threshold, and the at least one stimulation electrode is electrically connected to the at least one sensing electrode such that the at least one stimulation electrode is activated to stimulate a cranial nerve when the at least one sensing electrode measures electrical energy in at least one muscle passing the minimum threshold, concurrently with at least one physiological response from the subject; The system further includes a power source, a transmitter, and a processor communicatively connected to a non-transitory computer-readable memory having instructions stored thereon that, when executed by the processor, initiate closed-loop synchronization between activation and deactivation of the at least one stimulation electrode and measurement of electrical energy passing a minimum threshold by the at least one sensing electrode.

2. The system of claim 1 , further comprising a feeding bottle comprising at least one sensor, a power source, and a transmitter. 3 . The system of claim 2 , wherein the at least one sensor is selected from the group consisting of: a flow sensor, a pressure sensor, a suck sensor, a gyroscope, an accelerometer, a temperature sensor, and a volume sensor.

4. The system of claim 2 , further comprising a power source, a transmitter, and a processor, the processor being communicatively connected to a non-transitory computer-readable memory having stored thereon instructions that, when executed by the processor, synchronize activation and deactivation of the at least one stimulation electrode with sensing of feeding from the bottle and cessation of feeding from the bottle by the at least one sensor.

5. The brain nerve stimulation system according to claim 1, wherein the minimum threshold is an absolute value selected from the group consisting of: 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 μV, 300 μV, 400 μV, 500 μV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV or 50 mV.

6. A brain nerve stimulation system according to claim 1, wherein the minimum threshold is a change relative to a baseline measurement value obtained at rest, selected from the group consisting of the following values: 0.1 μV, 0.5 μV, 1 μV, 5 μV, 10 μV, 50 μV, 100 μV, 200 µV, 300 µV, 400 µV, 500 µV, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV or 50 mV.

7. The cranial neural stimulation system of claim 1 , wherein the minimum threshold is a percentage of the muscle's maximum potential selected from the group consisting of: 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

8. A cranial nerve stimulation system according to claim 1, wherein the stimulation has an intensity selected from the group consisting of: 0.01 mA, 0.05 mA, 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 mA, 1.5 mA, 2 mA, 2.5 mA, 3 mA, 3.5 mA, 4 mA, 4.5 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA and 10 mA.

9. The cranial nerve stimulation system of claim 1, wherein the stimulation has a frequency selected from the group consisting of: 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, and 50 Hz.

10. The cranial nerve stimulation system of claim 1 , wherein the stimulation has a pulse width selected from the group consisting of: 10 μs, 20 μs, 30 μs, 40 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 µs, 150 µs, 200 µs, 250 µs, 300 µs, 350 µs, 400 µs, 450 µs, 500 µs, 550 µs, 600 µs, 650 µs, 700 µs, 750 µs, 800 µs, 850 µs, 900 µs, 950 µs, and 1 ms.

11. The cranial nerve stimulation system of claim 1 , wherein the stimulation has an on-duration and an off-duration, each selected from the group consisting of: 0.1 seconds, 0.5 seconds, 1.5 seconds, 2 seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, and 1 hour.

12. A brain neurostimulation system for enhancing oral motor skills, comprising: at least one sensing electrode configured to be attached proximate to at least one muscle, the muscle being a cheek or jaw muscle; at least one stimulation electrode configured to be attached proximate to a cranial nerve of the subject, the cranial nerve 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 fasciculus of the vagus nerve; and at least one sensor configured to sense the at least one physiological response, wherein the at least one sensor is selected from the group consisting of: a sensing electrode, a flow sensor, a pressure sensor, a suck sensor, a gyroscope, an accelerometer, a temperature sensor, and a volume sensor; wherein the at least one stimulation electrode is configured to stimulate the cranial nerve simultaneously with at least one physiological response from the subject; the at least one sensing electrode being configured to measure muscle activation exceeding a minimum threshold, the at least one stimulation electrode being electrically connected to the at least one sensing electrode such that the at least one stimulation electrode is activated to stimulate a cranial nerve when the at least one sensing electrode measures electrical energy in at least one muscle passing the minimum threshold, concurrently with at least one physiological response from the subject; The system further includes a power source, a transmitter, and a processor communicatively connected to a non-transitory computer-readable memory having instructions stored thereon that, when executed by the processor, initiate closed-loop synchronization between activation and deactivation of the at least one stimulation electrode and measurement of electrical energy passing a minimum threshold by the at least one sensing electrode.

13. A brain neurostimulation system for enhancing oral motor skills, comprising: at least one sensing electrode configured to be attached proximate to at least one muscle, the muscle being a cheek or jaw muscle; and at least one stimulation electrode configured to be attached proximate to a cranial nerve of the subject, the cranial nerve 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 fasciculus of the vagus nerve; wherein the at least one stimulation electrode is configured to stimulate the cranial nerve simultaneously with at least one physiological response from the subject; the at least one sensing electrode being configured to measure muscle activation exceeding a minimum threshold, the at least one stimulation electrode being electrically connected to the at least one sensing electrode such that the at least one stimulation electrode is activated to stimulate a cranial nerve when the at least one sensing electrode measures electrical energy in at least one muscle passing the minimum threshold, concurrently with at least one physiological response from the subject; The system further includes a power source, a transmitter, and a processor communicatively connected to a non-transitory computer-readable memory having instructions stored thereon that, when executed by the processor, initiate closed-loop synchronization between activation and deactivation of the at least one stimulation electrode and measurement of electrical energy passing a minimum threshold by the at least one sensing electrode.

14. The brain nerve stimulation system according to claim 12 further comprises a power supply, a transmitter and a processor, wherein the processor is communicatively connected to a non-transitory computer readable memory having instructions stored thereon, and when the instructions are executed by the processor, the instructions initiate activation and deactivation of the at least one stimulation electrode.

15. The brain nerve stimulation system according to claim 13 further comprises a power supply, a transmitter and a processor, wherein the processor is communicatively connected to a non-transitory computer readable memory having instructions stored thereon, and when the instructions are executed by the processor, the instructions initiate activation and deactivation of the at least one stimulation electrode.

16. The cranial nerve stimulation system of claim 13, further comprising at least one sensor configured to sense the at least one physiological response.

17. The brain nerve stimulation system according to claim 16, wherein the at least one sensor is selected from the group consisting of: a sensing electrode, a flow sensor, a pressure sensor, a suck sensor, a gyroscope, an accelerometer, a temperature sensor, and a volume sensor.

18. The brain nerve stimulation system according to claim 16 further comprises a power supply, a transmitter and a processor, wherein the processor is communicatively connected to a non-transitory computer-readable memory having instructions stored thereon, and when the instructions are executed by the processor, the instructions initiate closed-loop synchronization between activation and deactivation of the at least one stimulation electrode and measurement of electrical energy passing a minimum threshold by the at least one sensing electrode.

19. The brain nerve stimulation system according to claim 16, further comprising a feeding bottle, wherein the feeding bottle comprises at least one sensor, a power source and a transmitter.

20. The brain nerve stimulation system of claim 19, wherein the at least one sensor in the bottle is selected from the group consisting of: a flow sensor, a pressure sensor, a suck sensor, a gyroscope, an accelerometer, a temperature sensor, and a volume sensor.

21. The cranial nerve stimulation system of claim 20, further comprising a processor communicatively connected to a non-transitory computer-readable memory having stored thereon instructions, which, when executed by the processor, synchronize activation and deactivation of the at least one stimulation electrode with sensing of feeding from the bottle and cessation of feeding from the bottle by the at least one sensor.

22. The cranial neural stimulation system of claim 12, wherein the at least one physiological response is an attempt by the subject to eat.

23. The cranial neural stimulation system of claim 13, wherein the at least one physiological response is an attempt by the subject to eat.

24. The cranial neural stimulation system of claim 12, wherein the at least one physiological response is a visible sucking attempt by the subject.

25. The cranial neural stimulation system of claim 13, wherein the at least one physiological response is a visible sucking attempt by the subject.

26. The cranial neural stimulation system of claim 12, wherein the at least one physiological response is muscle activation of the subject exceeding a minimum threshold.

27. The cranial neural stimulation system of claim 13, wherein the at least one physiological response is muscle activation of the subject exceeding a minimum threshold.

28. The cranial nerve stimulation system of claim 12, wherein the at least one stimulation electrode is non-invasively fixed to the ear canal, tragus, cymba concha, lobe, helix, antihelix, mastoid process, or neck of the subject.

29. The cranial nerve stimulation system of claim 13, wherein the at least one stimulation electrode is non-invasively fixed to the ear canal, tragus, cymba concha, lobe, helix, antihelix, mastoid process or neck of the subject.

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