System and method for improving glycemic control in ICU patients using transauricular vagus nerve stimulation

Abstract

A method of improving glycemic control is provided. The method includes stimulating a cutaneous distribution of a subject's vagus nerve within the subject's ear with a nerve stimulating signal. The method also includes monitoring the subject's blood glucose. The method further includes administering insulin infusions to the subject.

Description

CTSYSTEM AND METHOD FOR IMPROVING GLYCEMIC CONTROL IN ICU PATIENTS USINGTRANS AURICULAR VAGUS NERVE STIMULATIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 707,948, filed October 16, 2024, and to U.S. Provisional Application No. 63 / 708,309, filed October 17, 2024, which applications are hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under NS 128307 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] The present disclosure generally relates to systems and methods of improving glycemic control in ICU patients by applying transauricular vagus nerve stimulation (taVNS) in combination with insulin therapy and other glucose management techniques.

[0004] Hyperglycemia is common in critically ill patients, such as those suffering from subarachnoid hemorrhage (SAH), even those without diabetes, and is associated with increased morbidity and mortality. Tight glycemic control using intensive insulin therapy has been shown to improve outcomes in some studies, but carries risks of hypoglycemia. Vagus nerve stimulation has anti-inflammatory effects and may help modulate glucose metabolism.

[0005] The vagus nerve is a mixed-fiber nerve that affects many upstream cortical and subcortical structures. Non-invasive transcutaneous auricular VNS (taVNS) has been demonstrated to improve post-stroke functional recovery, enhance mood, relieve pain, improve sleep, reduce anxiety, and modulate cardiac and inflammatory effects ofCT neuroplasticity. Despite encouraging preclinical and clinical results, the neural response to non-invasive VNS and the mechanism through which it affects hyperglycemia remain poorly understood in humans. This gap has limited the advancement of this therapeutic strategy. A well-characterized neural response to VNS will be critical in translating this approach for improving glycemic control.

[0006] Accordingly, a system to improving glycemic control in ICU patients is needed.

[0007] This Background section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present disclosure, which are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.BRIEF DESCRIPTION

[0008] In a first aspect, a method of improving glycemic control is provided. The method includes stimulating the auricular branch of a patient's vagus nerve at the cymba concha of the patient’s ear with a nerve stimulating signal, monitoring blood glucose levels, and administering insulin to maintain glucose in a target range. The method also includes optionally, adjusting taVNS and insulin parameters based on glucose response. The method further includes optionally other glucose management techniques (e.g., nutrition modification), monitoring one or more statistics of the patient during the activity.

[0009] In a second aspect, a system for improving glycemic control is provided. The system includes a taVNS stimulation device with electrodes applied to the auricular branch of the vagus nerve, more specifically the cymba concha of the ear, a controller unit that has either preconfigured taVNS parameters or adjustable parameters, a glucose monitoring system for frequent or continuous glucose measurements, an insulin infusion pump for delivering IV insulin or an insulin algorithm for providing insulin, and software algorithms for optimizing the combination of taVNS and insulin to achieve target glucose levels.CT

[0010] In another aspect, at least one non -transitory computer-readable media having computer-executable instructions embodied thereon, when executed by a computing device including at least one processor in communication with at least one memory device, the computer-executable instructions may cause the at least one processor to: a) receive scan data of an object to be analyzed; b) generate a mask to apply to the scan data based on a shape of the object to be analyzed; c) apply the mask to the scan data; d) execute a multi-order Gaussian regression filter on the masked scan data to generate an output image of the object to be analyzed; e) analyze the output image of the object to be analyzed; and f) determine whether or not to approve the object based on the analysis. The non-transitory computer-readable media may have additional, less, or alternate functionalities, including those discussed elsewhere herein.

[0011] Advantages will become more apparent to those skilled in the art from the following description of the preferred embodiments which have been shown and described by way of illustration. As will be realized, the present embodiments may be capable of other and different embodiments, and their details are capable of modification in various respects. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The Figures described below depict various aspects of the systems and methods disclosed. Each Figure depicts an embodiment of a particular aspect of the disclosed systems and methods, and that each of the Figures is intended to accord with a possible embodiment. Further, wherever possible, the following description refers to the reference numerals included in the following Figures, in which features depicted in multiple Figures are designated with consistent reference numerals.

[0013] Figure 1 illustrates a system 100 for providing vagal nerve stimulation to a subject in accordance with at least one embodiment.

[0014] Figure 2 illustrates a process for improving glycemic control in a patient.CT

[0015] Figure 3 illustrates an example configuration of a client system shown in Figure 1, in accordance with one embodiment of the present disclosure.

[0016] Figures 4A-4D illustrate graphs of the impact of vagus nerve stimulation on inflammatory cytokines.

[0017] Figure 5 illustrates a graph of the Comparison of daily average blood sugar levels by diabetes status and treatment group.

[0018] Figure 6 illustrates a graph of the comparison of average daily blood sugar levels between VNS and Sham groups stratified by hemorrhage severity.

[0019] Figure 7 illustrates graphs of the comparison of the average daily blood sugar levels between Sham and VNS groups.

[0020] Figure 8 illustrates a graph of the mean Total Daily Dose (TDD) of insulin per kilogram of body weight for Sham and VNS patients.

[0021] Figure 9 illustrates a graph of the insulin dosage comparison stratified by ICU stay amongst patients who received insulin during their admission.

[0022] Figure 10 illustrates a graph of the average number of Hyperglycemic events by treatment group.

[0023] Figure 11 illustrates a graph of the comparison of the blood glucose levels.

[0024] Like reference symbols in the various drawings indicate like elements.DETAILED DESCRIPTION

[0025] A current trend in neuromodulation is the use of vagus nerve stimulation (VNS) as a means to promote neuroplasticity. The vagus nerve, which is comprised of 80% afferent fibers and 20% efferent fibers, is the main visceral sensory nerve and innervates many organs throughout the body. Stimulating the vagus nerve is typically performed using surgically implanted cuff electrodes - encircling the left vagus nerve within the carotid sheath - that are connected to a pulse generator implanted in the left side of theCT patient’s chest. The left vagus nerve is used because it has fewer efferent fibers descending to the heart than the right vagus nerve, making it a safer site for stimulation. VNS has been proven effective as a treatment for intractable epilepsy and treatment-resistant depression, and has recently been investigated for several neurological injuries such as stroke and traumatic brain injury.

[0026] The vagus nerve is known to have a direct ascending projection to the nucleus tractus solitarius (NTS) which in turn activates the locus coeruleus (LC) and nucleus basalis (NB). The LC (located in the pons) and NB (located in the basal forebrain) are part of a neuromodulatory system with diffuse projections throughout cortical and subcortical areas. The LC contains noradrenergic neurons (norepinephrine, NE), and the NB contains cholinergic neurons (acetylcholine, ACh), both of which are known to be plasticitypromoting neuromodulators. The releases of NE and ACh are important in processes such as arousal, memory encoding, and task-related behavior, as well as processes requiring high attentional load. Thus, NE and ACh could have an important role in the mechanism of action for VNS-paired rehabilitation involving goal-directed behavior.

[0027] VNS stimulation triggers bursts of NE and ACh neuromodulator release causing changes in cortical plasticity. It is thought that these changes in cortical plasticity may lead to the therapeutic effect. Specifically, VNS has been shown to lead to reorganization of rat auditory and motor cortex, with increased cortical representations of VNS-paired tones or movements, respectively. This is further supported by lesion studies that have shown that depleting NE or ACh concentrations leads to blocked cortical plasticity and impaired learning. VNS has the capability to improve human recognition memory when administered at a moderate intensity. VNS has also been shown to improve retention on the Hopkins Verbal Learning Test when delivered during the memory consolidation phase, as well as to enhance working memory evidenced by reduced error rates on an executive functioning task.

[0028] While invasive VNS has been studied for several decades, non- invasive stimulation of the vagus nerve, specifically the auricular branch, which innervates the cymba concha and tragus regions of the outer ear, has emerged as an exciting non- invasive alternative. Transcutaneous auricular VNS (taVNS) provides clear benefits in eliminating the need for an invasive surgery and reducing the possible side effects whichCT come with an implanted device. Several functional magnetic resonance imaging (fMRI) studies have demonstrated taVNS has central effects similar to invasive VNS. In comparison to sham earlobe stimulation, stimulating the left cymba concha has been shown to result in significant activation of the central vagal projections, such as the NTS and LC. Another fMRI study comparing the cymba concha and tragus as sites for taVNS found that both locations activated vagal projections, but only the cymba concha led to significant activations of the NTS and LC when compared to sham stimulation. Stimulating the vagus nerve via the outer ear has been investigated for many similar conditions as its invasive counterpart, such as epilepsy, depression, and tinnitus. Furthermore, similar to findings from invasive VNS, taVNS has also been shown to have cognitive benefits such as improved speech category learning and retention of non-native language tone categories, as well as enhanced associative memory in older adults.

[0029] VNS has been studied as a novel method of reducing inflammation. Substantial work has demonstrated that products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T-cell release of acetylcholine, which interacts with a7 nicotinic acetylcholine receptors (a7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. This neural-immunomodulatory circuit, referred to as the “cholinergic anti-inflammatory pathway,” presents opportunities for developing novel therapeutic strategies to treat inflammatory diseases. It has been successfully implemented in numerous models of inflammatory conditions. Harnessing its anti-inflammatory effects, non-invasive VNS has been used in ICH rat models. In another study, it was found that acute treatment with VNS demonstrated better functional outcomes at 24 hours after ICH (p=0.042 vs. sham).

[0030] Historically, VNS was performed by surgical neck dissection and placement of a cuff electrode directly around the nerve within the carotid sheath. Alternatively, VNS can be accomplished non-invasively by stimulating the auricular branch of the vagus nerve as it courses through the external ear, obviating the morbidity of a procedure and allowing rapid deployment of the intervention in critically ill patients. The external ear is an ideal target for non-invasive stimulation of the vagus nerve, where the auricular branch travels in the concha of the ear. This transcutaneous auricular approach has demonstrated good efficacy, with minimal morbidity.CT

[0031] In various aspects, systems and methods of applying vagus nerve stimulation (VNS) to a subject are disclosed. Due to the issues with the invasiveness of direct, VNS, non-invasive vagus nerve stimulation is desired. In some aspects, the non- invasive vagus nerve stimulation device may be any known non-invasive vagus nerve stimulation device without limitation. This could include electrical stimulation, vibration, or ultrasonic methods of activating the nerve. Non-limiting examples of non-invasive vagus nerve stimulation devices suitable for use in the systems and methods disclosed herein include a transcutaneous auricular vagus nerve stimulation (taVNS) device.

[0032] In some embodiments, the systems and methods do not require user intervention once it is placed and do not have to be held in place during the stimulation. This advantage eliminates the potential for user error or inherent subjectivity in pressure (which may exist in an alternative means of delivering vibration to the ear).

[0033] In various aspects, the systems disclosed herein may be used in a method of improving glycemic control subject in need. The subject being in need of glycemic control may result from hyperglycemia, hypoglycemia, or a disorder associated with glucose metabolism without limitation. Non-limiting examples of disorders that may require glycemic control using the systems and methods disclosed herein include, but are not limited to, obesity, prediabetes, metabolic syndrome (i.e., Syndrome X), type I diabetes, type II diabetes, and any other associated with glucose metabolism.

[0034] In various aspects, the VNS administered by the non-invasive vagus nerve stimulation device is configured for glycemic control of the subject. Without being limited to any particular theory, VNS is thought to modulate the inflammatory response through the cholinergic anti-inflammatory pathway in turn mitigating stress-induced hyperglycemia and reducing the insulin requirements and associated risks of hypoglycemia.

[0035] Elevated inflammatory cytokines, particularly interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a), play a significant role in the development of insulin resistance, a key feature of metabolic disorders such as type 2 diabetes. These cytokines are produced by adipose tissue and other immune cells in response to various stressors, including obesity and chronic inflammation. IL-6 and TNF-a can interfere with insulin signaling pathways, leading to a reduced effectiveness of insulin in promoting glucose uptake in tissues such as muscle and liver. This disruption occurs through various mechanisms, including theCT activation of serine kinases, which phosphorylate insulin receptor substrate proteins, impairing their function. As a result, the presence of elevated levels of these cytokines is not only indicative of systemic inflammation but also serves as a contributing factor to the state of insulin resistance, creating a vicious cycle that exacerbates metabolic dysregulation and health complications. This is particularly the case in the ICU with various diagnoses that contribute to an elevation of these cytokines. In the intensive care unit (ICU), a variety of diagnoses are associated with high levels of inflammation, particularly those involving elevated cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF). Conditions such as sepsis, severe pneumonia, acute respiratory distress syndrome (ARDS), and septic shock are prominent examples where these inflammatory markers play a critical role in disease progression. Additionally, patients with acute pancreatitis, major trauma, and burns often exhibit heightened IL-6 and TNF levels, reflecting the systemic inflammatory response syndrome (SIRS) associated with these diagnoses. Furthermore, conditions like cytokine release syndrome and certain autoimmune disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis, can also lead to significant inflammation driven by these cytokines, complicating patient management in the ICU setting.

[0036] In the Neuro ICU, several diagnoses are frequently associated with elevated levels of inflammation, particularly indicated by pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF). Conditions such as traumatic brain injury (TBI) often showcase heightened inflammatory responses, with excessive IL-6 and TNF levels correlating with poorer neurological outcomes. Similarly, subarachnoid hemorrhage (SAH) has been linked to significant inflammatory cascades that encompass increases in both IL-6 and TNF, contributing to complications like delayed cerebral ischemia. Other critical diagnoses, including ischemic stroke, intracerebral hemorrhage (ICH), and status epilepticus, also demonstrate marked elevations in these cytokines, emphasizing their role in mediating neuroinflammation and potentially guiding therapeutic interventions in the Neuro ICU setting.

[0037] In various aspects, the vagus nerve stimulation is delivered as characterized by a VNS parameter comprising at least one of a stimulation frequency, a pulse-width, a current intensity, and any combination thereof. The VNS parameters may be any suitable value without limitation. In some aspects, the stimulation frequency ranges from about 5 Hz to about 50 Hz. In some aspects, the stimulation frequency is selected fromCT20 Hz, 30 Hz, or 40 Hz. In some aspects, the pulse-width ranges from about 100 ps to about 500 ps. In some aspects, the pulse-width is selected from 100 ps, 250 ps, and 500 ps. In some aspects, the current intensity ranges from about 0.5 mA below a perceptual threshold to about the perceptual threshold, wherein the perceptual threshold comprises a current intensity sufficient to elicit a tingling sensation in the subject. In other aspects, the stimulation can be at a minimally tolerated level just below a pain threshold.

[0038] In various aspects, the systems disclosed herein may be used in a method for glycemic control in a subject in need. The method includes a glucose monitoring system, an insulin infusion pump, and a non-invasive vagus nerve stimulation device similar to the devices described above. The method further includes administering a vagus nerve stimulation (VNS) to the subject as described above, wherein the VNS is configured to enhance glycemic control of the subject. The method further includes monitoring blood glucose of the subject using the glucose monitoring system as described above. The method further includes administering an insulin infusions to the subject as described above. The method further optionally includes adjusting the VNS and insulin parameters based on glucose response. The method further includes optionally other glucose management techniques such as nutrition modification. Additionally, oral glycemic agents play a crucial role in managing blood glucose levels for individuals with type 2 diabetes. Commonly prescribed options include metformin, which enhances insulin sensitivity and reduces hepatic glucose production; sulfonylureas, such as glipizide and glyburide, which stimulate insulin secretion from the pancreas; DPP-4 inhibitors like sitagliptin and saxagliptin, which work by prolonging the action of incretin hormones; and SGLT2 inhibitors, including canagliflozin and empagliflozin, that promote glucose excretion through the urine. Additionally, thiazolidinediones, such as pioglitazone, improve insulin sensitivity, while alpha-glucosidase inhibitors like acarbose slow carbohydrate absorption in the gut. These agents, often used in combination, contribute to achieving and maintaining glycemic control in patients with diabetes. These also could be used in combination with taVNS.

[0039] The disclosed systems and methods combine non-invasive VNS with a glucose monitoring system, and an insulin pump to improve glycemic control in patients of need. In the examples herein, the optimal taVNS parameters to enhance glycemic control were determined by recording blood glucose levels. Without being limited to any particular theory, taVNS blunts the deleterious inflammatory response, mitigating stress-CT induced hyperglycemia, reducing the insulin requirements and associated risks of hypoglycemia. The disclosed systems and methods provide a mechanism-driven approach to designing, optimizing, and clinically translating taVNS glycemic control techniques to improve glycemic control in the ICU setting. Guided by encouraging findings from a non- invasively stimulation for subarachnoid hemorrhage (NAVSaH) data as described in the examples herein, there are numerous taVNS parameters that can be used to improve glycemic control. The effects of different stimulation parameters to determine the effects of stimulation frequency, pulse-width, and current intensity on the subjects’ glycemic control can both be personalized to the patient based on their medical, genetic, or diagnostic characteristics. These can also be dynamically altered to adapt to the therapies being performed or the goal glycemic endpoints.

[0040] In at least one embodiment, in diabetic patients, taVNS significantly reduces blood glucose (-39.649 mg / dL, p=0.03) and insulin requirements (-0.372 TDD / kg, p=0.05). Regression analyses revealed that taVNS attenuates the effect of elevated TNF-a on insulin requirements (interaction estimate: -0.029, p=0.005) and demonstrates a trend toward reduced blood glucose at higher TNF-a levels (interaction estimate: -3.85, p=0.057). The combined adverse event rate, including infections, vasospasm, and insulin drip usage, is significantly lower in taVNS groups (33.3%, p=0.018). Notably, in at least one study, no hypoglycemic events occurred in taVNS-treated patients. Non-diabetic patients showed no significant differences in glycemic parameters between treatment groups. Accordingly, taVNS improves glycemic control and reduces insulin requirements in diabetic SAH patients, potentially through TNF-a modulation. This novel neuromodulatory approach described herein may offer a safe adjunct therapy for glycemic management in critically ill diabetic patients

[0041] Definitions and methods described herein are provided to better define the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0042] Any publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or otherCT reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present disclosure.

[0043] Having described the present disclosure in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing the scope of the present disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

[0044] Figure 1 illustrates a system 100 for providing vagal nerve stimulation to a subject in accordance with at least one embodiment.

[0045] A current trend in neuromodulation is the use of vagus nerve stimulation (VNS) as a means to promote neuroplasticity. The vagus nerve, which is comprised of 80% afferent fibers and 20% efferent fibers, is the main visceral sensory nerve and innervates many organs throughout the body. Stimulating the vagus nerve is typically performed using surgically implanted cuff electrodes - encircling the left vagus nerve within the carotid sheath - that are connected to a pulse generator implanted in the left side of the subject’s chest. The left vagus nerve is used because it has fewer efferent fibers descending to the heart than the right vagus nerve, making it a safer site for stimulation. VNS has been proven effective as a treatment for intractable epilepsy and treatment-resistant depression, and has recently been investigated for several neurological injuries such as stroke and traumatic brain injury.

[0046] The vagus nerve is known to have a direct ascending projection to the nucleus tractus solitarius (NTS) which in turn activates the locus coeruleus (LC) and nucleus basalis (NB). The LC (located in the pons) and NB (located in the basal forebrain) are part of a neuromodulatory system with diffuse projections throughout cortical and subcortical areas. The LC contains noradrenergic neurons (norepinephrine, NE), and the NB contains cholinergic neurons (acetylcholine, ACh), both of which are known to be plasticitypromoting neuromodulators. The releases of NE and ACh are important in processes such as arousal, memory encoding, and task-related behavior, as well as processes requiring high attentional load. Thus, NE and ACh could have an important role in the mechanism of action for VNS-paired rehabilitation involving goal-directed behavior.CT

[0047] VNS stimulation triggers bursts of NE and ACh neuromodulator release causing changes in cortical plasticity. It is thought that these changes in cortical plasticity may lead to the therapeutic effect. Specifically, VNS has been shown to lead to reorganization of rat auditory and motor cortex, with increased cortical representations of VNS-paired tones or movements, respectively. This is further supported by lesion studies that have shown that depleting NE or ACh concentrations leads to blocked cortical plasticity and impaired learning. VNS has the capability to improve human recognition memory when administered at a moderate intensity. VNS has also been shown to improve retention on the Hopkins Verbal Learning Test when delivered during the memory consolidation phase, as well as to enhance working memory evidenced by reduced error rates on an executive functioning task.

[0048] While invasive VNS has been studied for several decades, non- invasive stimulation of the vagus nerve, specifically the auricular branch, which innervates the cymba concha and tragus regions of the outer ear, has emerged as an exciting non- invasive alternative. Transcutaneous auricular VNS (taVNS) provides clear benefits in eliminating the need for an invasive surgery and reducing the possible side effects which come with an implanted device. Several functional magnetic resonance imaging (fMRI) studies have demonstrated taVNS has central effects similar to invasive VNS. In comparison to sham earlobe stimulation, stimulating the left cymba concha has been shown to result in significant activation of the central vagal projections, such as the NTS and LC. Another fMRI study comparing the cymba concha and tragus as sites for taVNS found that both locations activated vagal projections, but only the cymba concha led to significant activations of the NTS and LC when compared to sham stimulation. Stimulating the vagus nerve via the outer ear has been investigated for many similar conditions as its invasive counterpart, such as epilepsy, depression, and tinnitus. Furthermore, similar to findings from invasive VNS, taVNS has also been shown to have cognitive benefits such as improved speech category learning and retention of non-native language tone categories, as well as enhanced associative memory in older adults.

[0049] The system 100 includes a VNS controller 105. The VNS controller 105 can be a computer device, such as a tablet, laptop, desktop, or other dedicated computer device including at least one processor in communication with at least one memory device.The VNS controller 105 can also include a user interface that that allows the VNS controller 105 to present information to a user and receive user inputs.

[0050] The VNS controller 105 is configured to control the stimulation to the vagus nerve. In some embodiments, the stimulation is vibration for the vibrotactile stimulation. In other embodiments, the stimulation includes electrical signals. In the example embodiment, the VNS controller 105 is in communication with a power supply to provide power for the VNS. In some embodiments, the VNS controller 105 is in direct communication with the form factors 115 and 120. The VNS controller 105 can also be in communication with one or more vibrating form factors, such as a first form factor 115 and an optional second form factor 120. The first form factor 115 and the second form factor 120 are configured to provide the stimulation to the subject. In some embodiments, there is just a single form factor 115. In other embodiments, the first form factor 115 is applied to a first ear of the subject and the second form factor 120 is applied to the second ear of the subject. In the exemplary embodiments, the first form factor 115 and the second form factor 120 are secured to the subject to prevent accidental removal, but both are easy to apply and remove to the subject. In the exemplary embodiments, the first form factor 115 and the second form factor 120 are temporarily attached to the subject’s ear(s) to stimulate the vagus nerve.

[0051] In the exemplary embodiments, the form factors 115 and 120 provide stimulation to one or more of the cymba of the ear, the concha of the each, and the ear canal. In some embodiments, the form factors 115 and 120 are placed along the concha of the ear to stimulate the vagus nerve where the auricular branch travels in the pinna of the ear. In the exemplary embodiment, the form factor 115 and 120 is attached to the subject’s left ear.

[0052] In at least one embodiment, the VNS controller 105 is configured to provide treatment to the vagus nerve by vibrational stimulation for a period of twenty minutes. In at least one embodiment, one of the attributes of the vibrational stimulation is 6 Hz. The attributes of the vibrational stimulation stay the same throughout the treatment. In at least one further embodiment, the vibrational stimulation is performed twice a day. In at least one embodiment, the attributes of the vibrational stimulation are selected to maximize vagus somatosensory evoked potentials while avoiding perception of pain.CT

[0053] In the exemplary embodiment, the VNS controller 105 controls the output of the VNS controller 105to provide the vibrational stimulation via the first form factor 115 and the second form factor 120.

[0054] In some further embodiments, VNS controller 105 is in communication with one or more user computer devices 125. The user computer device 125 may provide information to the VNS controller 105, such as one or more attributes of the subject that may alter the vibrational stimulation applied to the subject. Furthermore, the user computer device 125 may provide timing information to the VNS controller 105, such as when to apply the vibrational stimulation. Moreover, the user computer device 125 can receive information from the VNS controller 105, such as what were the attributes of the vibrational stimulation that was applied to the subject.

[0055] In some further embodiments, the first form factor 115 is applied to a first subject and the second form factor 120 is applied to a second subject. The VNS controller 105 controls the stimulation of each subject simultaneously. In some of these embodiments, the VNS controller 105 controls a plurality of form factors for a plurality of subjects receiving vibrotactile stimulation.

[0056] Sensors 130 can be used to determine the optimal taVNS parameters to enhance motor learning by recording invasive cortical physiology. The taVNS contributes to elevated gamma power that will increase brain activity and alertness, contributing to enhanced learning.

[0057] In some embodiments, the sensors 130 include stereotactic electroencephalography (sEEG). The sensors 130 can then be used to monitor the effects of stimulation parameters on the subject’s brain activity, especially during motor or memory tasks. During these tasks, the sensors 130 may report the effect of stimulation frequency, etc. on the subject’s brain activity. This may be used to find ideal parameters and / or adjust parameters to each individual subject. In at least one embodiment, parameter monitoring may be performed by monitoring a subject while they engage in a motor learning task paradigm (Serial Reaction Time Task, SRTT). In another embodiment, parameter monitoring may be performed by monitoring a subject while they engage in a memory -based task. The sensors 130 may also be used to monitor a subject’s response and other attributes, such as, but not limited to, arousal state, behavioral response, skin conductance, and / or eyeCT tracking. The user computer device 125 can collect electrophysiological, behavioral, and kinematic data in order to fully characterize the effects of taVNS on motor or memory learning. Other sensors 130 can include, but are not limited to, temperature, brain wave activity, galvanic response, blood pressure, heart rate, and / or any other attribute or statistic of the subject that is desired.

[0058] In at least one embodiment, the system 100 includes a form factor 115 and 120 including an ear cup, a cushioning base that provides soft contact with the head, a T-head bolt that connects the contact tip and the ear cup via ear cup covers. In this embodiment, the VNS controller 105 controls an eccentric rotating mass (ERM) vibration motor of 5 mm diameter, which is held in at the contact tip. The motor’s power cable passes through the T-head bolt. The T-head bolt allows individual adjustment of the depth of the contact. In addition, rotating the T-head bolt allows switching the stimulation target between the concha area and the earlobe. A digital stimulation box supplies 5 V power, such as at 6 Hz to the eccentric Rotating Mass vibration motor. A study aiming to characterize locus coeruleus (LC) response to VNS has found that LC activity increases in response to stimulation frequencies ranging from 7.5 Hz to 120 Hz and that higher stimulation frequencies result in greater maximal discharge. As LC activity and performance of tasks have an inverted-U relationship, 6 Hz vibrotactile taVNS was chosen to increase Locus coeruleus activity and avoid exceeding the optimal value. An elastic strap stabilizes the vibrotactile device on the head. During the VNS session, vibrotactile stimulation is delivered to the concha area of the outer ear.

[0059] In various aspects, the disclosed system 100 for glycemic control includes a glucose monitoring system for frequent or continuous glucose measurements, an insulin infusion pump 135 for delivering IV insulin, and a non-invasive vagus nerve stimulation device 105 to administer vagus nerve stimulation (VNS) to the subject prior to, after, or during at least a portion of the treatment. The VNS is configured to enhance a glycemic control of the subject. In these aspects, the system 100 includes one or more glucose measuring systems to monitor the glucose levels of the subject.

[0060] In some aspects, the transcutaneous stimulation of the auricular branch of the vagus nerve is implemented using a VNS device 105 that provides electrical signals and / or vibration to stimulate the vagus nerve through an ear of the subject. WithoutCT being limited to any particular theory, the external ear is an effective position for non- invasive stimulation of the vagus nerve, where the auricular branch travels in the pinna of the ear. In one aspect, the ear clips (form factors 115 and 120) used for the VNS treatment are positioned along the concha of the ear. In another aspect the device 105 can be wholly configured to be affixed to the ear which include the VNS device 105, power 110, electronics, and wearable form factor 115 and 120. In yet other form factors the stimulation can occur in the external auditory meatus or other areas of the ear that have branches of the vagus nerve.

[0061] In further embodiments, the sensors 130 monitor blood glucose levels, insulin requirements, inflammatory makers, and adverse events, for example. The sensors 130 then report the readings to the user computer device 125. The user computer devices 125 use those readings to adjust one or more of the taVNS signals and / or an insulin infusion pump 135 attached to the patient. The taVNS signals are configured to improve the glycemic control in patients by attenuating systemic inflammation. The taVNS signals may also affect secondary outcomes, including, but not limited to, insulin requirements and adverse events. In some of these embodiments, glucose levels, total daily dose (TTD)(either standard or normalized to the patient’s weight), and various cytokines are recorded by the one or more sensors 130 and reported to the user computer devices 125. Examples of cytokines include, but are not limited to, GM CSF, IFNy, IL- 10, IL- 12, IL-13, IL- 17 A, IL- ip, IL-2, IL-4, IL-5, IL-6, IL-8, and / or TNF-a. In some embodiments, the sensor 130 perform measurements every day, every hour, every few days, and / or any other period of time as needed by the individual sensor and based on the individual patient. In some embodiments, the user computer device 125 is programmed to monitor aggregated glycemic and insulin administration metrics. These include, but are not limited to, mean and median blood glucose levels and total daily dose normalized by weight (TDD / kg), daily trends in glucose and insulin levels, interaction between cytokine levels and treatment group with particular emphasis on pro-inflammatory markers such as TNF-a and IL-6, and the occurrence of adverse effects.

[0062] In some of these embodiments, providing taVNS to a patient reduces the number of adverse events, including those associated with poor glycemic control, such as, but not limited to, infections, vasospasm, and insulin drip usage. Furthermore, the taVNS may reduce the number of hyperglycemic and hypoglycemic events.CT

[0063] In various aspects, the glucose monitoring system may be any suitable device suitable for measuring glucose without limitation. In some aspects, the glucose monitoring sensors 130 may be a point-of-care glucose meter or continuous glucose monitoring device integrated to a controller unit that integrates data from the glucose monitor 130 and insulin pump 135 and controls the timing and parameters of the taVNS stimulation.

[0064] In various aspects, the VNS administered by the non-invasive vagus nerve stimulation device 105 is configured for glycemic control of the subject. Without being limited to any particular theory, VNS modulates the inflammatory response through the cholinergic anti-inflammatory pathway in turn mitigating stress-induced hyperglycemia and reducing the insulin requirements and associated risks of hypoglycemia.

[0065] In various aspects, the vagus nerve stimulation is delivered as characterized by a VNS parameter comprising at least one of a stimulation frequency, a pulse-width, a current intensity, and any combination thereof. The VNS parameters may be any suitable value without limitation. In some aspects, the stimulation frequency ranges from about 5 Hz to about 50 Hz. In some aspects, the stimulation frequency is selected from 20 Hz, 30 Hz, or 40 Hz. In some aspects, the pulse-width ranges from about 100 ps to about 500 ps. In some aspects, the pulse-width is selected from 100 ps, 250 ps, and 500 ps. In some aspects, the current intensity ranges from about 0.5 mA below a perceptual threshold to about the perceptual threshold, wherein the perceptual threshold comprises a current intensity sufficient to elicit a tingling sensation in the subject. In other aspects, the stimulation can be at a minimally tolerated level just below a pain threshold.

[0066] Figure 2 illustrates a process 200 for improving glycemic control in a patient. Figure 2 illustrates a process 200 for providing vagal nerve vibration stimulation. In the exemplary embodiment, portions of process 200 are performed by a user computer device 125 (shown in Figure 1), which may be, but is not limited to, a tablet, a laptop, a desktop, and / or and other computer device including at least one processor in communication with at least one memory device. In another exemplary embodiment, step 220 is optional.

[0067] In the exemplary embodiment, the user computer device 125 stimulates 205 the cutaneous distribution of a patient's vagus nerve within the ear with a nerve stimulating signal. The nerve stimulating signal is provided by the VNS controller 105 via one or more form factors 115 and 120 (all shown in Figure 1)CT

[0068] In the exemplary embodiment, the user computer device 125 monitors 210 blood glucose levels of the patient, such as via one or more sensors 130 (shown in Figure 1). In some of these embodiments, glucose levels, total daily dose (TTD)(either standard or normalized to the patient’s weight), and various cytokines are monitored by the one or more sensors 130 and reported to the user computer devices 125. Examples of cytokines include, but are not limited to, GM CSF, IFNy, IL- 10, IL- 12, IL-13, IL- 17 A, IL- ip, IL-2, IL-4, IL-5, IL-6, IL-8, and / or TNF-a. In some embodiments, the sensor 130 perform measurements every day, every hour, every few days, and / or any other period of time as needed by the individual sensor and based on the individual patient.

[0069] In the exemplary embodiment, the user computer device 125 administers 215 insulin infusions to maintain glucose. In an alternative embodiment, the user computer device 125 provides parameter data for a caregiver to adjust. These insulin infusions are determined based on the attributes of the patient based on the sensor data and monitored attributes of the patient.

[0070] In the exemplary embodiment, the user computer device 125 adjusts one or more parameters of the nerve stimulating signal to change the blood glucose level of the patient. In these embodiments, the user computer device 125 instructs the VNS controller 105 to vary the parameters of the nerve stimulating signal to elicit a change in the blood glucose level of the patient. This may cause the inflammation to reduce and thereby reduce the amount of insulin needed by the patient. In some of these embodiments, the user computer device 125 detects one or more trends in the attributes of the patient and adjusts the nerve stimulating signal to counteract that trend.

[0071] In the exemplary embodiment, the user computer device 125 includes other glucose management techniques. Other glucose management techniques include inpatient and outpatient techniques as described herein.

[0072] In some further embodiments, the user computer device 125 is configured to adjust the nerve stimulating signal to reduce the blood glucose and insulin requirements for diabetic patients. This is in addition to the normal metabolic improvements. This can be used with diabetic ICU patients that may exhibit heightened insulin resistance, requiring higher insulin doses to maintain euglycemia. In particular, increased insulin administration is associated with mortality in the ICU, further underscoring the importanceCT of interventions like VNS that may reduce insulin dependence while maintaining glycemic stability.

[0073] TNF-a is a pro-inflammatory cytokine implicated in insulin resistance. Analyses have revealed a significant interaction between TNF-a and insulin use, with VNS markedly attenuating insulin requirements at higher TNF-a levels. This effect aligns with VNS’ s known anti-inflammatory properties, including its ability to downregulate TNF-a production via the cholinergic anti-inflammatory pathway. Inflammatory cytokines, such as TNF-a, interfere with insulin signaling by inducing serine phosphorylation of insulin receptor substrate-1 (IRS-1), which inhibits downstream pathways such as phosphatidylinositol 3-kinase (PI3K) and Akt . Elevated TNF-a levels have been shown to reduce glucose uptake in skeletal muscle and adipose tissue, thus exacerbating hyperglycemia. By suppressing TNF-a, VNS mitigates these effects, improving both insulin sensitivity and glycemic control. In order to address the limitations of the low levels of insulin used throughout the entire ICU admission, blood glucose levels are analyzed and the interaction between VNS and TNF-a. Glucose and insulin are highly correlated. The observed trend reinforces the role of TNF-a modulation in VNS’s therapeutic effects.

[0074] Glycemic control is not only a metabolic goal but also a determinant of clinical outcomes in SAH patients. Poor glycemic control has been higher rates infections, insulin drip usage, and vasospasm - three critical complications. Hyperglycemia is a well- known-risk factor for infections, as elevated blood glucose levels impair neutrophil function, reduce chemotaxis, and enhance microbial growth - and these infections significantly worsen prognosis and prolong ICU stays. Continuous insulin infusions, often required to manage severe hyperglycemia, have been linked to increased ICU mortality, potentially due to associated risks with hypoglycemia. Lastly, vasospasm is a devastating complication of SAH, associated with delayed cerebral ischemia and poor neurological outcomes. Evidence has emerged suggesting that hyperglycemia exacerbates vasospasm through endothelial dysfunction and potentially through oxidative stress as well. Aggregation analysis reveals a significant decrease in adverse event rate in VNS patients which can be considered secondary to improved glycemic control.

[0075] A notable finding is the absence of hypoglycemic events in VNS patients, even as glycemic control improved, Hypoglycemia as previously mentioned is aCT critical concern in ICU management as it increases mortality. The safety profile of VNS may be attributed to the graded effect on glycemic control, as interaction analyses suggest that VNS predominantly stabilizes glucose and insulin at higher TNF-a levels, where glucose levels are increased and lesser impact at lower levels of TNF-a where hypoglycemia risk would be higher.

[0076] While the most pronounced effects of VNS on glycemic control and insulin requirements have been observed in diabetic patients, it is important to acknowledge the implications of this findings. Diabetic patients inherently exhibit greater glycemic variability and heightened insulin resistance compared to non-diabetic patients, potentially amplifying the detectability of VNS-induced changes in this subgroup. Accordingly significant reductions in blood glucose and insulin use have been observed in diabetic patients, as their dysregulated metabolic state and elevated baseline inflammatory state, which includes elevated TNF-a, may render them more sensitive to the anti-inflammatory and insulin-sensitizing effects of VNS.

[0077] The present disclosure describes exploring the role of VNS in modulating glycemic control, particularly in critically ill patients. This disclosure highlights the complexity of translating VNS effects from preclinical to clinical settings and the need for targeted approaches in specific subgroups such as critically ill diabetic patients. Furthermore, this disclosure identifies a distinct mechanistic pathway connecting TNF-a attenuation to reduced insulin requirements, diverging from the vagal branch modulation of the pancreas and other glycemic-related organs observed in preclinical studies.

[0078] In critically ill populations, current guidelines from the Society of Critical Care Medicine lack recommendations for neuromodulation techniques such as VNS. This disclosure suggests that VNS may offer an adjunctive approach by reducing the insulin burden and improving glycemic stability without increasing the risk of hypoglycemic events. This aligns with broader neuromodulation research, such as that demonstrating glycemic improvements with neuromuscular electrical stimulation and other work with carotid sinus nerve modulation for metabolic regulation.

[0079] Overall, this disclosure leverages a robust methodological framework to address a critical gap in understanding the role of VNS in glycemic control amongst critically ill patients, particularly those with SAH. By integrating cytokine data,CT employing mixed-effects models, and stratifying results by diabetic status, this system provides a nuanced analysis that goes beyond aggregate metrics to uncover mechanistic and clinical insights. The inclusion of TNF-a as a biomarker and its interaction with VNS highlights a potential anti-inflammatory pathway for glycemic modulation. Additionally, the use of clinically meaningful adverse events offers direct relevance to ICU practice, addressing both mechanistic underpinnings and practical applications.

[0080] This disclosure provides methodology for the role of VNS in modulating glycemic control among critically ill SAH patients. By using VNS to provide significant reductions in insulin requirements and exploring the anti-inflammatory pathways underlying this effect, this disclosure adds a novel facet to the growing field of neuromodulation. This disclosure highlights the use of VNS as a tool to improve metabolic outcomes and reduce complications in the ICU.

[0081] Inpatient techniques include example ICU Glycemic Control Methods, such as, but not limited to, Intravenous (IV) insulin infusion, Sliding scale insulin protocols, Computerized insulin dosing algorithms, Continuous glucose monitoring (CGM) systems, Frequent blood glucose monitoring (every 1-2 hours), Tight glycemic control protocols (target range 140-180 mg / dL), Nutrition management and control, Stress-dose steroids when necessary, Treatment of underlying conditions causing hyperglycemia, Electrolyte management, especially potassium, Avoidance of dextrose-containing IV fluids when possible, and / or Transition protocols from IV to subcutaneous insulin. Any of these techniques may be combined with the taVNS described herein to improve patient outcomes.

[0082] Outpatient techniques include example Outpatient Glycemic Control Methods, such as, but not limited to, Oral medications (e.g., metformin, sulfonylureas, DPP -4 inhibitors), Injectable medications (e.g., GLP-1 receptor agonists), Subcutaneous insulin therapy (basal-bolus regimens), Insulin pumps, Continuous glucose monitoring (CGM) systems, Self-monitoring of blood glucose (SMBG) with glucometers, Dietary management and meal planning, Regular physical activity and exercise, Diabetes education and self-management training, Regular HbAlc testing, Lifestyle modifications (weight management, stress reduction), Medication adherence strategies, Regular follow-up with healthcare providers, Telemedicine and remote monitoring, and / or BehavioralCT interventions and psychological support. Any of these techniques may be combined with the taVNS described herein to improve patient outcomes.

[0083] These methods are often used in combination and tailored to individual patient needs and circumstances in both ICU and outpatient settings.

[0084] Supplemental optimizations may include adaptive protocols that incorporate real-time glucose monitoring with taVNS administration. These protocols consider the temporal dynamics of both the neuromodulatory effects of taVNS and the more immediate impacts of insulin therapy. For instance, the timing of taVNS sessions might be coordinated with mealtimes or insulin administration to optimize synergistic effects on glucose regulation. Additionally, the integration includes clear guidelines for adjusting insulin dosages in response to taVNS-induced changes in glucose metabolism. This involves more frequent glucose monitoring in the initial stages of implementation to capture the full impact of combined taVNS and insulin therapy. Furthermore, the integration process includes the development of decision support systems that can help clinicians interpret the complex interplay between taVNS effects, insulin sensitivity, and other factors affecting glycemic control in critically ill patients. These systems might incorporate machine learning algorithms to predict individual patient responses and suggest optimal combinations of taVNS parameters and insulin dosing. Importantly, the successful integration of taVNS into ICU glycemic control protocols could include communications methods and systems (webbased, internet, mobile, etc.) that enable multidisciplinary interactions, involving collaboration between intensivists, endocrinologists, neurologists, and biomedical engineers to ensure that the combined therapy is both effective and safe across diverse patient populations. As this integration evolves, it includes a more holistic approach to metabolic management in the ICU, where neuromodulation becomes a standard component of glycemic control strategies, potentially reducing reliance on high-dose insulin regimens and their associated risks.

[0085] Transcutaneous auricular vagus nerve stimulation (taVNS) represents a promising frontier in the management of diabetes and glycemic control in the outpatient setting. This non-invasive neuromodulation technique harnesses the body's innate anti-inflammatory pathways to potentially improve glucose metabolism and insulin sensitivity. As healthcare continues to evolve towards more personalized and less invasiveCT treatments, taVNS offers a unique approach that could complement existing diabetes management strategies. By stimulating the auricular branch of the vagus nerve through simple, wearable devices, patients may have access to a novel tool that not only aids in glycemic control but also addresses the underlying inflammatory processes associated with diabetes. The integration of taVNS into outpatient care could revolutionize how we approach long-term diabetes management, offering a method that is both patient-friendly and potentially effective in mitigating the challenges of maintaining stable blood glucose levels.

[0086] A detailed summary of how transcutaneous auricular vagus nerve stimulation (taVNS) could be used in the outpatient setting to help diabetics with glycemic control:

[0087] 1. Non-invasive application: taVNS offers a non-invasive approach to stimulating the vagus nerve through the auricular branch in the ear. This makes it suitable for outpatient use, as it doesn't require surgical implantation like traditional VNS devices.

[0088] 2. Mechanism of action: taVNS works by modulating the inflammatory response through the cholinergic anti-inflammatory pathway. This can help mitigate stress-induced hyperglycemia and potentially reduce insulin requirements.

[0089] 3. Device design: For outpatient use, taVNS devices could be designed as portable, user-friendly units. These might take the form of specialized ear clips or earbuds that can deliver mild electrical pulses to specific areas of the outer ear.

[0090] 4. Treatment protocol: Based on the study described, a potential outpatient protocol might involve 20-minute stimulation sessions twice daily. The exact frequency and duration could be adjusted based on individual patient needs and responses.

[0091] 5. Integration with existing diabetes management: taVNS could be integrated into existing outpatient glycemic control methods, which include, but are not limited to, Oral medications (e.g., metformin, sulfonylureas), Injectable medications (e.g., GLP-1 receptor agonists), Subcutaneous insulin therapy, Continuous glucose monitoring (CGM) systems, Self-monitoring of blood glucose (SMBG), Dietary management and meal planning, and / or Regular physical activity.CT

[0092] 6. Personalized approach: The use of taVNS could be tailored to individual patients, considering factors such as diabetes type, severity, and current medication regimen. For instance, the study showed a more significant effect on blood glucose levels in Type 2 diabetic patients. Accordingly, Machine Learning could be used to tailor taVNS and / or insulin treatments to individual patients.

[0093] 7. Monitoring and adjustments: Patients using taVNS at home would need regular monitoring of their blood glucose levels. This data could be used to adjust taVNS parameters or insulin dosages as needed. Continuous glucose monitoring systems could be particularly useful in tracking the effects of taVNS over time.

[0094] 8. Potential benefits: In addition to improved glycemic control, taVNS might offer other benefits due to its anti-inflammatory effects, potentially addressing multiple aspects of diabetes simultaneously.

[0095] 9. Follow-up care: Regular follow-ups with healthcare providers would be crucial to assess the effectiveness of taVNS, make necessary adjustments, and monitor for any side effects.

[0096] 10. Patient education: Comprehensive education would be needed to ensure patients can correctly use the taVNS device at home, understand its potential effects, and integrate it effectively with their other diabetes management strategies.

[0097] 11. Combination with technology: The use of taVNS could be combined with smartphone apps or other digital health technologies to help patients track their usage, blood glucose levels, and overall diabetes management.

[0098] 12. Long-term management: As the effects of taVNS may be cumulative over time, long-term use and monitoring would be important to fully realize its potential benefits for glycemic control.

[0099] Different methods of stimulation the vagus nerve non-invasively. The auricular branch of the vagus nerve (AB VN) in the ear can be stimulated through various methods, primarily focused on non-invasive techniques. Transcutaneous electrical nerve stimulation (TENS) is a common approach, where electrodes are placed on the skin of the outer ear to deliver mild electrical pulses. Another method is transcutaneous vagus nerveCT stimulation (tVNS), which uses specialized ear clips or earbuds to target specific areas of the ear. Vibration therapy is also a potential option, utilizing mechanical stimulation to activate the ABVN. Manual stimulation techniques include acupuncture or acupressure applied to specific points on the ear. Some researchers have explored the use of low-level laser therapy (LLLT) to stimulate the ABVN. Additionally, there are emerging technologies such as ultrasound-based stimulation and magnetic stimulation that show promise for targeting the auricular branch. These methods vary in their invasiveness, effectiveness, and current level of scientific support, with electrical stimulation techniques being the most widely studied and applied, while vibration therapy is gaining attention as a potentially effective and non- invasive alternative.

[0100] In further embodiments, the user computer device 125 is in communication with a non-invasive vagus nerve stimulation device to administer vagus nerve stimulation (VNS) to the subject. In additional embodiments, the user computer device 125 is in communication with a glucose monitoring device 130. In still further embodiments, the user computer device 125 is also in communication with an insulin infusion pump 135. In these embodiments, the user computer device 125 is configured to improve glycemic control of the subject or patient.

[0101] In further embodiments, the non-invasive vagus nerve stimulation device is a transcutaneous auricular vagus nerve stimulation (taVNS) device.

[0102] In still further embodiments, the vagus nerve stimulation is characterized by a VNS parameter comprising at least one of a stimulation frequency, a pulse-width, a current intensity, and any combination thereof. In some of these embodiments, the stimulation frequency ranges from about 5 Hz to about 50 Hz. In other embodiments, the stimulation frequency is selected from 20 Hz, 30 Hz, or 40 Hz. In additional embodiments, the pulse-width ranges from about 100 ps to about 500 ps. In other embodiments, the pulse-width is selected from 100 ps, 250 ps, and 500 ps.

[0103] In further embodiments, the current intensity ranges from about 0.5 mA below a perceptual threshold to about the perceptual threshold, wherein the perceptual threshold comprises a current intensity sufficient to elicit a tingling sensation in the subject.CT

[0104] Figure 3 illustrates an example configuration of a user computer device 302, in accordance with one embodiment of the present disclosure. User computer device 302 is operated by a user 301. User computer device 302 includes a processor 305 for executing instructions. In some embodiments, executable instructions are stored in a memory area 310. In the example embodiments, user computer device 125 (shown in Figure 1) is similar to user computer device 302 Processor 305 may include one or more processing units (e.g., in a multi-core configuration). Memory area 310 is any device allowing information such as executable instructions and / or transaction data to be stored and retrieved. Memory area 310 may include one or more computer-readable media.

[0105] User computer device 302 also includes at least one media output component 415 for presenting information to user 301. Media output component 315 is any component capable of conveying information to user 301. In some embodiments, media output component 315 includes an output adapter (not shown) such as a video adapter and / or an audio adapter. An output adapter is operatively coupled to processor 305 and operatively coupleable to an output device such as a display device (e.g., a cathode ray tube (CRT), liquid crystal display (LCD), light emitting diode (LED) display, or “electronic ink” display) or an audio output device (e.g., a speaker or headphones). In some embodiments, media output component 315 is configured to present a graphical user interface (e.g., a web browser and / or a client application) to user 301. A graphical user interface may include, for example, subject attributes or the attributes of the vibrational stimulation. In some embodiments, user computer device 302 includes an input device 320 for receiving input from user 301. User 301 may use input device 320 to, without limitation, select to apply the vibrational stimulation to the subject. Input device 320 may include, for example, a keyboard, a pointing device, a mouse, a stylus, a touch sensitive panel (e.g., a touch pad or a touch screen), a gyroscope, an accelerometer, a position detector, a biometric input device, and / or an audio input device. A single component such as a touch screen may function as both an output device of media output component 315 and input device 320.

[0106] User computer device 302 may also include a communication interface 325, communicatively coupled to a remote device such as a VNS controller or another user computer device. Communication interface 325 may include, for example, a wired or wireless network adapter and / or a wireless data transceiver for use with a mobile telecommunications network.CT

[0107] Stored in memory area 310 are, for example, computer-readable instructions for providing a user interface to user 301 via media output component 315 and, optionally, receiving and processing input from input device 320. The user interface may include, among other possibilities, a web browser and / or a client application. Web browsers enable users, such as user 301, to display and interact with media and other information typically embedded on a web page or a website provided by a server. A client application allows user 401 to interact with, for example, a VNS controller. For example, instructions may be stored by a cloud service and the output of the execution of the instructions sent to the media output component 315.

[0108] Figures 4A-4D illustrate graphs of the impact of vagus nerve stimulation on inflammation cytokines. Figures 4A and 4B illustrate Serum and Figures 4C and 4D illustrate cerebrospinal fluid measurements of IL-6 and TNF-a over the course of admission following subarachnoid hemorrhage in pg / mL. Day 1 represents baseline prior initiation of first treatment. For these Figures, p<0.05, ICA= internal carotid artery, and taVNS= transauricular vagus nerve stimulation.

[0109] Figure 5 illustrates a graph Glycemic control figures. The graph includes a comparison of daily average blood sugar levels by diabetes status and treatment group. This figure demonstrates a statistically significant decrease in daily average blood sugar in Type 2 Diabetic patients treated with VNS compared to those treated with Sham.

[0110] Figure 6 illustrates a graph of the comparison of average daily blood sugar levels between VNS and Sham groups stratified by hemorrhage severity. A significant decrease in daily average blood sugar was observed in VNS patients compared to Sham patients in the high-grade hemorrhage group, while VNS patients exhibited a significant increase in daily average blood sugar compared to Sham patients in the low-grade hemorrhage group.

[0111] Figure 7 illustrates graphs of the comparison of the average daily blood sugar levels between Sham and VNS groups. The graph further shows a comparison of average daily blood sugar levels between Sham and VNS groups during the ICU stay (left) and post-ICU stay (right). No significant differences were observed between the groups during the ICU stay or post-ICU.CT

[0112] Figure 8 illustrates a graph of the comparison of average insulin dose between VNS and sham groups. The graph includes the mean Total Daily Dose (TDD) of insulin per kilogram of body weight for Sham and VNS patients. Sham patients received significantly higher insulin doses compared to VNS patients, with a p-value = 0.02, indicating a significant reduction in insulin requirements in the VNS group.

[0113] Figure 9 illustrates a graph of the comparison of insulin dosage between VNS and Sham within ICU status. The graph includes the insulin dosage comparison stratified by ICU stay amongst patients who received insulin during their admission. During the ICU stay, VNS patients received significantly less insulin (0.079 ± 0.11 mg / kg) compared to Sham patients (0.183 ± 0.27 mg / kg), p = 0.0006. This reduction was also observed post-ICU, where VNS patients continued to receive lower insulin doses compared to Sham patients, p = 0.002.

[0114] Figure 10 illustrates a graph of the average number of Hyperglycemic events by treatment group. The graph includes Comparison of the number of hyperglycemic events between VNS and Sham (groups. No statistically significant difference was observed between the two groups (p = 0.48). Further stratification by diabetes status did not reveal additional insights.

[0115] Figure 11 illustrates a graph of the comparison of the blood glucose levels for those with dexamethasone vs no dexamethasone. The graph includes a comparison of average daily blood glucose levels between steroid-administered and steroid-naive patients. No statistically significant difference was observed between the steroid- administered (131.16 ± 26.76 mg / dL) and steroid-naive (138.61 ± 36.83 mg / dL) groups (p = 0.05418). Further comparisons between VNS and Sham treated patients in both steroid- administered and steroid-naive groups also demonstrated no significant differences.

[0116] The methods and systems described herein may be implemented using computer programming or engineering techniques including computer software, firmware, hardware, or any combination or subset thereof, wherein the technical effects may be achieved by performing at least one of the following steps: a) stimulating the cutaneous distribution of a patient's vagus nerve within the ear with a nerve stimulating signal; b) monitoring blood glucose levels; c) administering insulin infusions to maintain glucose; d)CT optionally adjusting one or more parameters of the electrical signal to change the blood glucose level; and e) optionally including other glucose management techniques.ADDITIONAL CONSIDERATIONS

[0117] As will be appreciated based upon the foregoing specification, the above-described embodiments of the disclosure may be implemented using computer programming or engineering techniques including computer software, firmware, hardware or any combination or subset thereof. Any such resulting program, having computer- readable code means, may be embodied or provided within one or more computer-readable media, thereby making a computer program product, i.e., an article of manufacture, according to the discussed embodiments of the disclosure. The computer-readable media may be, for example, but is not limited to, a fixed (hard) drive, diskette, optical disk, magnetic tape, semiconductor memory such as read-only memory (ROM), and / or any transmitting / receiving medium such as the Internet or other communication network or link. The article of manufacture containing the computer code may be made and / or used by executing the code directly from one medium, by copying the code from one medium to another medium, or by transmitting the code over a network.

[0118] These computer programs (also known as programs, software, software applications, “apps,” or code) include machine instructions for a programmable processor and can be implemented in a high-level procedural and / or object-oriented programming language, and / or in assembly / machine language. As used herein, the terms “machine-readable medium” “computer-readable medium” refers to any computer program product, apparatus and / or device (e.g., magnetic discs, optical disks, memory, Programmable Logic Devices (PLDs)) used to provide machine instructions and / or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The “machine-readable medium” and “computer-readable medium,” however, do not include transitory signals. The term “machine-readable signal” refers to any signal used to provide machine instructions and / or data to a programmable processor.

[0119] As used herein, the terms “processor” and “computer” and related terms, e.g., “processing device”, “computing device”, and “controller” are not limited to just those integrated circuits referred to in the art as a computer, but broadly refers to a microcontroller,CT a microcomputer, a programmable logic controller (PLC), a reduced instruction set circuit (RISC), an application specific integrated circuit (ASIC), logic circuits, and any other circuit or processor capable of executing the functions described herein. The above examples are example only and are thus not intended to limit in any way the definition and / or meaning of the term “processor.”

[0120] As used herein, the terms “software” and “firmware” are interchangeable, and include any computer program stored in memory for execution by a processor, including RAM memory, ROM memory, EPROM memory, EEPROM memory, and non-volatile RAM (NVRAM) memory. The above memory types are example only, and are thus not limiting as to the types of memory usable for storage of a computer program.

[0121] As used herein, the term “database” can refer to either a body of data, a relational database management system (RDBMS), or to both. As used herein, a database can include any collection of data including hierarchical databases, relational databases, flat file databases, object-relational databases, object-oriented databases, and any other structured collection of records or data that is stored in a computer system. The above examples are example only, and thus are not intended to limit in any way the definition and / or meaning of the term database. Examples of RDBMS’ include, but are not limited to including, Oracle® Database, MySQL, IBM® DB2, Microsoft® SQL Server, Sybase®, and PostgreSQL. However, any database can be used that enables the systems and methods described herein. (Oracle is a registered trademark of Oracle Corporation, Redwood Shores, California; IBM is a registered trademark of International Business Machines Corporation, Armonk, New York; Microsoft is a registered trademark of Microsoft Corporation, Redmond, Washington; and Sybase is a registered trademark of Sybase, Dublin, California.)

[0122] In another example, a computer program is provided, and the program is embodied on a computer-readable medium. In an example, the system is executed on a single computer system, without requiring a connection to a server computer. In a further example, the system is being run in a Windows® environment (Windows is a registered trademark of Microsoft Corporation, Redmond, Washington). In yet another example, the system is run on a mainframe environment and a UNIX® server environment (UNIX is a registered trademark of X / Open Company Limited located in Reading, Berkshire, United Kingdom). In a further example, the system is run on an iOS® environment (iOS isCT a registered trademark of Cisco Systems, Inc. located in San Jose, CA). In yet a further example, the system is run on a Mac OS® environment (Mac OS is a registered trademark of Apple Inc. located in Cupertino, CA). In still yet a further example, the system is run on Android® OS (Android is a registered trademark of Google, Inc. of Mountain View, CA). In another example, the system is run on Linux® OS (Linux is a registered trademark of Linus Torvalds of Boston, MA). The application is flexible and designed to run in various different environments without compromising any major functionality.

[0123] As used herein, an element or step recited in the singular and proceeded with the word “a” or “an” should be understood as not excluding plural elements or steps, unless such exclusion is explicitly recited. Furthermore, references to “example” or “one example” of the present disclosure are not intended to be interpreted as excluding the existence of additional examples that also incorporate the recited features. Further, to the extent that terms “includes,” “including,” “has,” “contains,” and variants thereof are used herein, such terms are intended to be inclusive in a manner similar to the term “comprises” as an open transition word without precluding any additional or other elements.

[0124] In some embodiments, numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term “about.” In some embodiments, the term “about” is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value. In some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicatedCT herein, each individual value is incorporated into the specification as if it were individually recited herein. The recitation of discrete values is understood to include ranges between each value.

[0125] Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0126] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and can also cover other unlisted steps. Similarly, any composition or device that “comprises,” “has” or “includes” one or more features is not limited to possessing only those one or more features and can cover other unlisted features.

[0127] Furthermore, as used herein, the term “real-time” refers to at least one of the time of occurrence of the associated events, the time of measurement and collection of predetermined data, the time to process the data, and the time of a system response to the events and the environment. In the examples described herein, these activities and events occur substantially instantaneously.

[0128] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0129] Groupings of alternative elements or embodiments of the present disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience or patentability. When any suchCT inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0130] In some embodiments, the system includes multiple components distributed among a plurality of computer devices. One or more components may be in the form of computer-executable instructions embodied in a computer-readable medium. The systems and processes are not limited to the specific embodiments described herein. In addition, components of each system and each process can be practiced independent and separate from other components and processes described herein. Each component and process can also be used in combination with other assembly packages and processes. The present embodiments may enhance the functionality and functioning of computers and / or computer systems.

[0131] The computer-implemented methods discussed herein can include additional, less, or alternate actions, including those discussed elsewhere herein. The methods can be implemented via one or more local or remote processors, transceivers, servers, and / or sensors (such as processors, transceivers, servers, and / or sensors mounted on vehicles or mobile devices, or associated with smart infrastructure or remote servers), and / or via computer-executable instructions stored on non-transitory computer-readable media or medium. Additionally, the computer systems discussed herein can include additional, less, or alternate functionality, including that discussed elsewhere herein. The computer systems discussed herein can include or be implemented via computer-executable instructions stored on non-transitory computer-readable media or medium.

[0132] As used herein, the term “non-transitory computer-readable media” is intended to be representative of any tangible computer-based device implemented in any method or technology for short-term and long-term storage of information, such as, computer-readable instructions, data structures, program modules and sub-modules, or other data in any device. Therefore, the methods described herein can be encoded as executable instructions embodied in a tangible, non-transitory, computer readable medium, including, without limitation, a storage device and / or a memory device. Such instructions, when executed by a processor, cause the processor to perform at least a portion of the methods described herein. Moreover, as used herein, the term “non-transitory computer-readableCT media” includes all tangible, computer-readable media, including, without limitation, non- transitory computer storage devices, including, without limitation, volatile and nonvolatile media, and removable and non-removable media such as a firmware, physical and virtual storage, CD-ROMs, DVDs, and any other digital source such as a network or the Internet, as well as yet to be developed digital means, with the sole exception being a transitory, propagating signal.

[0133] Additionally or alternatively, the machine learning programs may be trained by inputting sample data sets or certain data into the programs, such as images, object statistics and information, timing, previous results, and / or historical data. The machine learning programs may utilize deep learning algorithms that may be primarily focused on pattern recognition, and may be trained after processing multiple examples. The machine learning programs may include Bayesian Program Learning (BPL), voice recognition and synthesis, image or object recognition, signal processing, optical character recognition, and / or natural language processing - either individually or in combination. The machine learning programs may also include natural language processing, semantic analysis, automatic reasoning, and / or machine learning.

[0134] Supervised and unsupervised machine learning techniques may be used. In supervised machine learning, a processing element may be provided with example inputs and their associated outputs, and may seek to discover a general rule that maps inputs to outputs, so that when subsequent novel inputs are provided the processing element may, based upon the discovered rule, accurately predict the correct output. In unsupervised machine learning, the processing element may be required to find its own structure in unlabeled example inputs. In one embodiment, machine learning techniques may be used to determine brain responses to stimuli such as VNS settings.

[0135] Based upon these analyses, the processing element may learn how to identify characteristics and patterns that may then be applied to analyzing image data, model data, and / or other data. For example, the processing element may learn, to identify glucoses responses to stimuli and the VNS settings for different patients to provide optimal glucose levels. The processing element may also learn how to identify trends that may not be readily apparent based upon collected data, such as trends that identify when glucose levels will spike or decline.CT

[0136] The exemplary systems and methods described and illustrated herein therefore provide VNS treatments for improving glycemic control.

[0137] Although specific features of various embodiments may be shown in some drawings and not in others, this is for convenience only. In accordance with the principles of the systems and methods described herein, any feature of a drawing may be referenced or claimed in combination with any feature of any other drawing.

[0138] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

Claims

CTWHAT IS CLAIMED IS:

1. A system for improving glycemic control in a subject, the system comprising: a non-invasive vagus nerve stimulation device to administer vagus nerve stimulation (VNS) to the subject; a glucose monitoring device; and an insulin treatment regimen, wherein the non-invasive vagus nerve stimulation device is configured to: simulate the subject with a nerve stimulating signal; monitor the subject with the glucose monitoring device; and adjust the insulin treatment regimen based upon the monitoring of the glucose monitoring device.

2. The system of Claim 1, wherein the non-invasive vagus nerve stimulation device is a transcutaneous auricular vagus nerve stimulation (taVNS) device.

3. The system of Claim 1, wherein the nerve stimulating signal is characterized by a VNS parameter comprising at least one of a stimulation frequency, a pulse-width, a current intensity, and any combination thereof.

4. The system of Claim 3, wherein the stimulation frequency ranges from 5 Hz to 50 Hz.

5. The system of Claim 3, wherein the stimulation frequency is selected from 20 Hz, 30 Hz, or 40 Hz.

6. The system of Claim 3, wherein the pulse-width ranges from 100 ps to 500 ps.

7. The system of Claim 3, wherein the pulse-width is selected from 100 ps, 250 ps, and 500 ps.CT8. The system of Claim 3, wherein the current intensity ranges from about 0.5 mA below a perceptual threshold to about the perceptual threshold, wherein the perceptual threshold comprises a current intensity sufficient to elicit a tingling sensation in the subject.

9. The system of Claim 1, wherein the non-invasive vagus nerve stimulation device is further configured to adjust one or more parameters of the nerve stimulating signal to reduce a blood glucose level of the subject.

10. The system of Claim 1, wherein the system is configured to reduce an amount of insulin provided via the insulin treatment regime based upon the monitoring of the glucose monitoring device.

11. A method of improving glycemic control in a subject, the method comprising: administering insulin infusions to maintain glucose in a target range; administering a vagus nerve stimulation (VNS) to the subject; monitoring blood glucose of the subject; and adjusting the insulin treatment regimen based upon the monitoring of the glucose monitoring device.

12. The method of Claim 11 further comprising adjusting one or more parameters of the VNS based on glucose response.

13. The method of Claim 11 further comprising adjusting one or more insulin parameters based on the glucose response.

14. The method of Claim 11 further comprising administering another glucose management therapy based on glucose response.

15. The method of Claim 11 wherein the vagus nerve stimulation is a transcutaneous auricular vagus nerve stimulation (taVNS).CT16. The method of Claim 11, wherein the vagus nerve stimulation is delivered as characterized by a VNS parameter comprising at least one of a stimulation frequency, a pulse-width, a current intensity, and any combination thereof.

17. The method of Claim 15, wherein the stimulation frequency ranges from about 5 Hz to about 50 Hz.

18. The method of Claim 15, wherein the stimulation frequency is selected from 20 Hz, 30 Hz, or 40 Hz.

19. The method of Claim 15, wherein the pulse-width ranges from about 100 ps to about 500 ps.

20. The method of Claim 15, wherein the current intensity ranges from about 0.5 mA below a perceptual threshold to about the perceptual threshold, wherein the perceptual threshold comprises a current intensity sufficient to elicit a tingling sensation in the subject.

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