Electrical stimulation methods and devices for improving blood management

Abstract

In one exemplary embodiment, a method and system for improving coagulation ability and / or triggering higher platelet activation rates in a subject via auricular nerve stimulation includes contacting the subject's skin with one or more treatment electrodes, each electrode positioned in a respective region of a nerve structure of the auriculotemporal nerve (ATN), a nerve structure connected to the ATN, a nerve structure of the auricular branch of the vagus nerve (ABVN), or a nerve structure connected to the ABVN, and applying one or more stimulation patterns to the electrodes.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 447,162, entitled "Electrical Stimulation Methods and Devices for Improving Blood Management," filed February 21, 2023; U.S. Provisional Patent Application No. 63 / 535,996, entitled "Electrical Stimulation Methods and Devices for Improving Blood Management," filed August 31, 2023; and U.S. Provisional Patent Application No. 18 / 583,160, entitled "Electrical Stimulation Methods and Devices for Improving Blood Management," filed February 21, 2024. This application is related to the following prior patent applications by Spark Biomedical Inc. relating to stimulation therapy and stimulation devices: U.S. Patent No. 10,967,182, issued April 6, 2021, entitled "Methods and Devices for Reducing Inflammation Using Electrical Stimulation," and U.S. Patent No. 11,351,370, issued June 7, 2022, entitled "Devices and Methods for Treating Cognitive Dysfunction and Depression Using Electrical Stimulation." [Background technology]

[0002] Improper blood management can be life-threatening. After an injury occurs, blood loss must be minimized.

[0003] Nearly 20 years ago, inventors of U.S. Patent No. 8,729,129, including Christopher Czura, an inventor on the present application, proposed vagus nerve stimulation as a potential solution for shortening bleeding time and reducing bleeding volume in humans. The inventors published mouse data from studies using implanted vagus nerve stimulators. Interestingly, while they were able to demonstrate reduced bleeding, they failed to demonstrate significant changes in prothrombin time (PT) (see, e.g., Figure 5 in U.S. Patent No. 8,729,129). PT measures the time it takes for platelets to clot. That is, they failed to demonstrate what we refer to as clotting activity / clotting rate or coagulation potential (CPot—as used herein, meaning the potential to accelerate clotting, particularly at the site of injury). In 2017, the same inventors, including the same individuals named in U.S. Patent No. 8,729,129, proposed a non-invasive approach using mechanical stimulation that allegedly achieves similar results in an application eventually granted as U.S. Patent No. 10,912,712. However, as with the earlier patent, the only data presented in U.S. Patent No. 10,912,712 related to hemorrhage control were obtained in rodents using implanted electrical stimulation. Again in 2019, inventors, including two of the same individuals named in U.S. Patent No. 8,729,129, proposed the use of both invasive and noninvasive trigeminal nerve stimulation to achieve hemorrhage control in a further application, recently granted as U.S. Patent No. 11,660,443. As with the earlier patents listed above, only data collected from rodent studies using subcutaneous electrodes were presented. A few months later, a patent application assigned to the same institution, but naming a different inventor, proposed the combined use of trigeminal and vagus nerve stimulation to control hemorrhage, which eventually resulted in granting of U.S. Patent No. 11,260,229. In contrast to the earlier applications, no data were presented in this final application.

[0004] Additionally, despite a long-standing need in the medical community for bleeding control and continued publications on the topic of bleeding control using nerve stimulation, not only have no commercial solutions emerged, but to the inventors' knowledge, prior to the data presented in this application, no human subject data demonstrating significant bleeding control have been published. Instead, to the inventors' knowledge, only small animal studies have existed to date, and the tests involve significant neck surgery to access and stimulate the vagus nerve with implanted electrodes that directly contact the nerve. Due to the invasive nature of these tests, they have not been easily repeatable in human subjects.

[0005] In any hemorrhagic or potential hemorrhagic scenario, blood loss must be minimized. Furthermore, if the amount of hemorrhage is such that hypovolemia occurs, tissue perfusion and oxygenation in certain brain tissues must be enhanced to prevent permanent damage and possible death. Furthermore, some hemorrhages, regardless of whether they lead to hypovolemia, can lead to sepsis. For example, the risk of sepsis is increased by some postpartum hemorrhage procedures and in patients with intracerebral hemorrhage. Both hypovolemia and sepsis result in high levels of systemic inflammation, with proinflammatory cytokines released into the circulation. In the case of sepsis, not only are tissue perfusion and oxygenation important, but reducing inflammation and circulating proinflammatory cytokines is necessary to avoid further complications and organ damage or failure. Furthermore, sepsis can actually lead to hypovolemia. However, the primary cause of sepsis is infection, not hemorrhage. Sepsis is an extremely costly and resource-intensive condition. For example, in the UK, it is estimated that patients with sepsis account for approximately one-third of hospital stays and just under half (approximately 45%) of intensive care unit (ICU) stays. In the United States, sepsis is the most costly condition, costing an average of over $18,000 per hospitalization and $24 billion annually. Sepsis represents 13% of all U.S. hospital expenditures but accounts for only approximately 3.5% of hospitalizations.

[0006] The inventors have recognized a need for new systems and methods designed to reduce blood loss after injury while increasing oxygenation and / or perfusion of brain tissue when blood loss is massive and / or blood flow is significantly affected. Further, the inventors have recognized a need to achieve a reduction in systemic inflammation during blood loss reduction and during the onset of sepsis. Additionally, the inventors have recognized a need to reduce the likelihood of bleeding before it occurs by improving an individual's coagulation capabilities. Advantageously, the novel systems and methods can be easily and quickly applied non-invasively in home, clinical, and / or field settings. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 8,729,129 [Patent Document 2] U.S. Patent No. 10,912,712 [Patent Document 3] U.S. Patent No. 11,660,443 [Patent Document 4] U.S. Patent No. 11,260,229 Summary of the Invention

[0008] Some use the term hypovolemia to refer to both a decrease in total body fluid and intravascular fluid volume. Herein, hypovolemia is used to describe the latter scenario. Hypovolemia is further classified according to severity. However, here, hypovolemia is used to describe a large amount of blood loss such that tissue oxygenation and perfusion may be impaired, leading to organ failure or injury.

[0009] Sepsis can be described as an immune hyperreaction that leads to the release of pro-inflammatory cytokines and systemic inflammation. Similar to hypovolemia, sepsis is also classified according to severity. If left untreated, sepsis tends to become progressively more severe and may lead to organ failure or damage. Interestingly, as described below, sepsis can be alleviated and faster hemostasis achieved by regulating splenic activity.

[0010] In one aspect, the present disclosure relates to systems and methods for increasing the coagulation potential (CPot) of mammals, including humans.

[0011] In some embodiments, temporary enhancement of coagulation potential occurs by triggering splenic activity to treat acute scenarios. For example, splenic activity may be triggered by activating the splenic nerve via stimulation of the vagus nerve descending fibers or vagal efferent fibers (VEFs). The splenic nerve and / or directly the spleen can be stimulated non-invasively using ultrasound (e.g., focal or confocal ultrasound / high-intensity ultrasound). Acute scenarios, in some examples, can include injuries that may result in significant blood loss, such as surgical or other medical procedures with a high potential for bleeding, medical procedures with a potential for bleeding during the recovery phase, and / or temporary systemic conditions such as nosebleeds, abnormal uterine bleeding, and / or heavy menstrual bleeding, including menorrhagia.

[0012] In some embodiments, the systems and methods described herein for stimulating the spleen directly and / or indirectly (e.g., via the VEF, splenic nerve, and / or splenic ganglion) are used preventatively / prophylactically. Illustratively, stimulation may be performed before an anticipated event, e.g., before a menstrual cycle, or before a surgical procedure, e.g., in the period leading up to the event, during the event itself, and after the event, to prevent or minimize further bleeding. Stimulation may be provided before and / or during a surgical procedure, e.g., to partially overcome the effects of anticoagulants in the patient's system. In this manner, stimulation may provide the advantage of accelerating the approval time for patients requiring surgery who are taking anticoagulants, e.g., for the treatment of a blood clot.

[0013] In some embodiments, the systems and methods described herein for stimulating the spleen directly and / or indirectly (e.g., via the VEF, splenic nerve, and / or splenic ganglion) are used correctively / therapeutically. For example, stimulation may provide the benefit of providing protection to patients undergoing emergency surgery without the opportunity to remove anticoagulant medication from the patient's system. In another example, stimulation may be performed post-operatively to accelerate clotting, thereby shortening post-operative recovery time, e.g., wound (e.g., surgical access site) closure time. In some scenarios, a surgical team may use a combination of hemostatic approaches, for example, by applying VEF stimulation in conjunction with another available hemostatic agent(s). In some scenarios, non-invasive VEF stimulation may be used to identify responders to treatment (responders) by demonstrating an improvement in Cpot before utilizing an invasive approach (e.g., implanted electrodes stimulating the vagus nerve and / or splenic nerve).

[0014] In certain embodiments where a temporary increase in coagulation potential is desired in therapeutic scenarios, such as post-bleeding applications or pre-operative scenarios, direct and / or indirect stimulation of the spleen is initiated as soon as possible and continued as necessary to accelerate the ongoing coagulation process and limit blood loss. In this type of scenario, stimulation may be applied continuously until bleeding has stopped. After bleeding has stopped, stimulation may continue to be applied to prevent further bleeding, as in the prophylactic scenario described above. When stimulation is stopped, coagulation potential gradually returns to pre-stimulation levels.

[0015] In some embodiments, direct and / or indirect splenic stimulation (e.g., via the VEF, splenic nerve, and / or splenic ganglion) is performed to achieve sustained improvement in coagulation function to treat chronic scenarios such as those described above. Furthermore, splenic stimulation is performed in some embodiments to achieve sustained improvement in coagulation function in scenarios where chronic coagulation defects exist, such as in individuals suffering from hemophilia (e.g., hemophilia A, B, or C), von Willebrand's disease (vWD), and other coagulation factor-related deficiencies (e.g., factor I deficiency, factor II deficiency, factor V deficiency, factor VII deficiency, factor X deficiency, factor XII deficiency, or factor XIII deficiency), and / or other chronic conditions such as Bernard-Soulier syndrome and Glanzmann's thrombasthenia.

[0016] In some embodiments involving chronic coagulation failure, non-invasive indirect and / or direct stimulation of the spleen can be applied by a clinician while exploring the feasibility of an implantable solution. For example, stimulation may be performed in a clinical setting to test whether the patient will respond to stimulation therapy. If the feasibility test is successful, the patient may be offered the option of accepting an implanted device rather than relying on external stimulation therapy as described herein. The feasibility test may include multiple stimulation therapy sessions. The multiple therapy sessions may include multiple electrode placements, multiple stimulation patterns, multiple stimulation intensities, and / or multiple stimulation session durations to evaluate the patient's response to VEF stimulation.

[0017] In some embodiments, splenic (e.g., direct and / or indirect) stimulation is applied to achieve a transient anti-inflammatory response, e.g., in preventative / prophylactic or corrective / therapeutic settings. In preventative / prophylactic applications, for example, VEF, splenic ganglion, celiac ganglion, and / or splenic stimulation can be applied before a planned event in which a pro-inflammatory response is expected, e.g., before a planned surgical procedure or unrelated physical activity, as in the case of a baseball pitcher who may expect an inflammatory response after pitching a ball. In corrective / therapeutic applications, for example, when an inflammatory response has already begun, such as in trauma, infection, or a sepsis or potential sepsis scenario, VEF, splenic ganglion, celiac ganglion, and / or splenic stimulation can be applied as soon as possible and continued as needed to trigger, maintain, and / or accelerate an anti-inflammatory response. In these types of scenarios, stimulation can be applied continuously, as in the preventative scenario described above, until a desired response is achieved, and thereafter to prevent further inflammation.

[0018] In one aspect, by stimulating the trigeminal nerve branch, the present disclosure relates to triggering an increase in cerebral blood flow by either increasing blood pressure and / or increasing vascular patency, referred to herein as a hypertensive response. For example, a hypertensive response may be triggered to temporarily treat or prevent hypovolemic injury to tissue, including brain tissue, in scenarios where significant blood loss is occurring or is likely. Illustratively, triggering a hypertensive response may be beneficial in scenarios involving penetrating and / or non-compressive injury (e.g., bullet or knife wounds, large cuts, or internal bleeding scenarios such as gastrointestinal bleeding). Stimulation may be applied, for example, as soon as possible and continued as needed to trigger, maintain, and / or accelerate the desired response.

[0019] In one aspect, the present disclosure relates to triggering a trigemino-parasympathetic response (TPSr) by stimulating the Arnold's nerve (also known as the auricular branch of the vagus nerve—ABVN) and / or the auriculotemporal nerve (ATN). In another aspect, the present disclosure relates to triggering an increase in CPot through modulation of VEF activity by stimulating the Arnold's nerve and / or the ATN. In some embodiments, both a TPSr and an increase in CPot are triggered. Triggered TPSr and / or an increase in CPot may be utilized to temporarily treat or prevent hypovolemic tissue damage to various organs, including the brain, for example, in scenarios where significant blood loss has occurred or is likely to occur. Illustratively, triggering a TPSr and / or an increase in CPot may be beneficial in scenarios involving penetrating and / or non-compressive injuries (e.g., bullet or knife wounds or internal bleeding scenarios). Stimulation may be applied, for example, as soon as possible and sustained as needed to trigger, maintain, and / or accelerate the desired response.

[0020] The foregoing general description and the following detailed description of exemplary embodiments are merely exemplary aspects of the teachings of the present disclosure and are not restrictive.

[0021] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate one or more embodiments and, together with the description, explain these embodiments. The accompanying drawings are not necessarily drawn to scale. Dimensions of values ​​shown in the accompanying graphs and drawings are for illustrative purposes only and may or may not represent actual or preferred values ​​or dimensions. Where applicable, some or all features may not be shown to aid in the explanation of underlying features. In the drawings: [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a block diagram of an exemplary anti-inflammatory pathway. [Figure 2A] FIG. 1 is a block diagram of an exemplary pressure response and cerebral perfusion pathway. [Figure 2B]FIG. 1 is a block diagram of an exemplary trigeminal-parasympathetic response and cerebral perfusion pathway. [Figure 3A] FIG. 1 is a block diagram of an exemplary platelet calcium concentration pathway. [Figure 3B] FIG. 1 is a block diagram of an exemplary platelet priming pathway. [Figure 4] FIG. 1 is a block diagram of an exemplary hemostasis pathway. [Figure 5] FIG. 1 is a block diagram identifying neural structures and pathways. [Figure 6A] FIG. 2 is a diagram illustrating an electrode configuration and equivalent circuit for providing therapy according to a first embodiment. [Figure 6B] FIG. 2 is a diagram illustrating an electrode configuration and equivalent circuit for providing therapy according to a first embodiment. [Figure 6C] FIG. 10 depicts an electrode configuration and equivalent circuit for providing therapy according to a second embodiment. [Figure 6D] FIG. 10 depicts an electrode configuration and equivalent circuit for providing therapy according to a second embodiment. [Figure 6E] FIG. 10 depicts an electrode configuration and equivalent circuit for providing therapy according to a third embodiment. [Figure 6F] FIG. 10 depicts an electrode configuration and equivalent circuit for providing therapy according to a third embodiment. [Figure 7A] FIG. 10 is a timing diagram of an exemplary process for triggering stimulation. [Figure 7B] FIG. 10 is a timing diagram of an exemplary process for triggering stimulation. [Figure 8A] 1 is a graph showing the results of human stimulation according to an embodiment of the present disclosure. [Figure 8B] 1 is a graph showing the results of human stimulation according to an embodiment of the present disclosure. [Figure 8C] 1 is a graph showing the results of human stimulation according to an embodiment of the present disclosure. [Figure 8D] 1 is a graph showing the results of human stimulation according to an embodiment of the present disclosure. [Figure 8E]1 is a graph showing the results of human stimulation according to an embodiment of the present disclosure. [Figure 9] FIG. 1 is a block diagram of components of an exemplary pulse generator in communication with an exemplary auricle treatment device. [Figure 10A] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 10B] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 10C] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 10D] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 11] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 12] 1 illustrates an exemplary target nerve region for directing therapy using a wearable auricular nerve stimulator (WANS) device. [Figure 13] 1 illustrates an exemplary system including a treatment device, sensor(s), and sensor signal conditioning and / or analysis circuitry. [Figure 14] FIG. 1 is a block diagram of an example sensor data analysis system for delivering customized neural stimulation therapy to a wearer. DETAILED DESCRIPTION OF THE INVENTION

[0023] The following description, set forth in conjunction with the accompanying drawings, is intended to be a description of various exemplary embodiments of the disclosed subject matter. Specific features and functions are described in connection with each exemplary embodiment. However, it will be apparent to one skilled in the art that the disclosed embodiments may be practiced without each of these specific features and functions.

[0024] References throughout this specification to "one embodiment" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with one embodiment is included in at least one embodiment of the disclosed subject matter. Thus, the appearances of the phrases "in one embodiment" or "in one embodiment" in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, embodiments of the disclosed subject matter are intended to encompass modifications and variations thereof.

[0025] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. That is, unless expressly specified otherwise, the terms "a," "an," "the," etc., as used herein, have the meaning "one or more." Additionally, terms such as "left," "right," "upper," "lower," "front," "rear," "side," "height," "length," "width," "upper," "lower," "internal," "external," "inside," and "outside" that may be used herein are understood to merely describe points of reference and do not necessarily limit embodiments of the present disclosure to any particular orientation or configuration. Furthermore, terms such as "first," "second," and "third" merely identify one of several parts, components, steps, operations, functions, and / or points of reference disclosed herein and, similarly, do not necessarily limit embodiments of the present disclosure to any particular orientation or configuration.

[0026] Additionally, the terms "approximately," "about," "approximate," "variable," and similar terms generally refer to ranges that include the identified value within a margin of 20%, 10%, and preferably 5%, in certain embodiments, and any value therebetween.

[0027] All of the features described in connection with one embodiment are intended to be applicable to the additional embodiments described below, unless expressly stated otherwise or unless the feature or function is incompatible with the additional embodiments. For example, if a given feature or function is explicitly described in connection with one embodiment but not explicitly mentioned in connection with an alternative embodiment, it should be understood that the inventors intend that the feature or function can be developed, utilized, or implemented in connection with the alternative embodiment, unless the feature or function is incompatible with the alternative embodiment.

[0028] Although hypovolemia has been used to describe both a decrease in total body fluid and vascular fluid volume, in this disclosure the term hypovolemia refers to the latter definition. Generally, hypovolemia is classified according to severity. However, in this disclosure, hypovolemia applies to situations involving significant blood loss, including effects on tissue oxygenation and / or perfusion, which may result in organ failure or injury.

[0029] Sepsis can be described as an immune hyperreaction that results in the release of pro-inflammatory cytokines and systemic inflammation. Similar to hypovolemia, sepsis is classified according to severity. If left untreated, sepsis tends to become progressively more severe, leading to organ failure or damage, and in some cases, death. As discussed below, reducing sepsis and achieving faster hemostasis can be achieved by regulating splenic activity.

[0030] hemostasis Hemostasis, the process by which bleeding stops, is generally triggered by molecules exposed to circulating blood at the site of vascular injury. Subendothelial collagen (SEndC) and tissue factor (TF, also known as coagulation factor 3 or fIII) are examples of such molecules. Circulating platelets (i.e., thrombus) bind to exposed SEndC, while TF binds to a specific circulating molecule called coagulation factor 7 (fVII). The interaction of TF and fVII leads to the activation of fVII (fVIIa) and the formation of a TF-fVIIa complex called extrinsic tenase (i.e., extrinsic Xase). This TF-fVIIa complex initiates what is known as the coagulation cascade by activating coagulation factor 10 (fX) and coagulation factor 9 (fIX) to fXa and fIXa (see below), respectively. Platelets that adhere directly or indirectly to SEndC begin to aggregate, forming an initial clot to stop bleeding. This clot is known as a platelet thrombus or thrombus. The platelet plug is then strengthened by the deposition and cross-linking of fibrin. The process leading to the formation of a platelet plug is generally referred to as primary hemostasis, while the process leading to its strengthening by cross-linking fibrin (i.e., activated coagulation factor 1, or fia) is known as secondary hemostasis. Platelets are anucleated blood cells produced in the bone marrow, primarily from megakaryocytes. Under normal conditions, approximately 100 billion platelets are produced daily, resulting in blood concentrations ranging from 150 to 400 million per milliliter. Platelets enter the vascular circuit and, in humans, circulate for approximately 7 to 10 days before being removed by the liver and spleen. Interestingly, as they circulate, they pool in the spleen, where approximately one-third of all circulating platelets reside at any given time. In humans, the time it takes for platelets to pass through the spleen is approximately 30 minutes.

[0031] Platelets contain, among other things, mitochondria and two types of granules: alpha granules (αG) and compact or delta granules (δG). Ionized calcium (Ca), the main component for clotting, 2+Coagulation factor 4 (also known as fIV) is stored within platelets, at least in the mitochondria, the compact tubular system (DTS), and delta granules. Platelets circulate in the blood in an inactivated state; therefore, platelets do not aggregate. However, platelets become activated upon binding to exposed SEndCs after injury.

[0032] Platelets bind to SEndC either directly via GP VI or GP Ia / IIa receptors or indirectly via GP Ib-V-IX receptors through von Willebrand factor (vWF). Activated platelets undergo a shape change and secrete the contents of their granules through the membrane. The contents of alpha granules include, among other components, fibrinogen (also known as clotting factor 1 or fI), platelet-derived growth factor (PDGF), vWF, TGF-beta, clotting factor 5 (fV), platelet factor 4 (Pf4), and insulin-like growth factor 1 (IGF1). Delta granules (δG) contain, among other components, Ca 2+ Platelets contain GP IIb / IIIa receptors (ADP, ATP, and serotonin (5-HT). Activated platelets promote the conversion of these receptors to the membrane receptor GP IIb / IIIa (also known as integrin αIIbβ3), allowing them to bind vWF and fibrinogen. Additionally, thromboxane A2 (TxA2) is secreted from activated platelets. TxA2 and ADP activate circulating platelets, which begin to aggregate with other activated platelets via GP IIb / IIIa-vWF-GP IIb / IIIa and GP IIb / IIIa-fibrinogen-GP IIb / IIIa crosslinks. This aggregation leads to platelet accumulation at the site of injury, generating the platelet thrombus described above. This platelet thrombus, although weak, is the first step in restricting and ultimately preventing blood from leaving the vasculature. Clot contraction is significantly influenced by the presence of GP IIb / IIIa receptors on the platelet surface. Clot contraction aids wound healing by drawing the separated edges of the wound closer together until the wound is healed. Thus, by promoting changes to the GP IIb / IIIa receptor, subjects undergoing the treatments described herein will benefit from an accelerated time to healing.

[0033] As also mentioned above, the thrombus is then strengthened by fibrin fibers and their cross-linking by activated coagulation factor 13 (fXIIIa). Circulating fibrin is generated when platelet-secreted fibrinogen is converted to fibrin by thrombin (i.e., activated coagulation factor 2 or fIIa). Thrombin is then generated by cleavage from circulating prothrombin (also known as coagulation factor 2-fII). Thrombin can be generated in relatively small amounts from prothrombin by fXa bound to the platelet surface. Thrombin can not only convert fibrinogen to fibrin, but also activate other platelets and convert fV, coagulation factor VIII (fVIII), coagulation factor XI (fXI), and coagulation factor 13 (fXIII) into their activated forms (fVa, fVIIIa, fXIa, and fXIIIa, respectively). fVa is a Ca 2+ In a platelet-dependent manner, prothrombinase binds to fXa on the platelet surface to form prothrombinase (the fXa-fVa complex). The prothrombinase complex can convert large amounts of prothrombin to thrombin. In fact, the prothrombinase complex cleaves thrombin from prothrombin at a rate several hundred thousand times (e.g., approximately 250,000 times) faster than fXa alone. As a result, the presence of prothrombinase on the platelet surface greatly accelerates the coagulation process.

[0034] As mentioned above, fX can be activated to fXa by extrinsic tenase. However, fX can also be activated by intrinsic tenase, which is composed of fVIIIa and fIXa. To assemble intrinsic tenase, both fVIII and fIX must be activated. Thrombin can activate fVIII, and extrinsic tenase and fXIa can activate fIX.

[0035] The pathway in which fXa is activated by extrinsic tenase is commonly known as the extrinsic pathway, and the pathway in which fXa is activated by intrinsic tenase is referred to as the intrinsic pathway. The coagulation steps following activation of fXa up to fibrin cross-linking by fXIIIa are referred to as the common pathway. As can be appreciated from the text and from Figure 4, which illustrates the hemostatic pathway 400, the role of thrombin is essential for hemostasis to occur.

[0036] Importantly, there is a significant quantitative difference between the intrinsic pathway 402 and the extrinsic pathway 404. Under normal circumstances, thrombin 406 is generated 50-100 times faster via the intrinsic pathway 402 compared to the extrinsic pathway 404. Thus, it is reasonable to state that under normal circumstances, the extrinsic pathway 404 initiates the hemostatic process, but it is the intrinsic pathway 402 that carries it to the finish line.

[0037] Platelets are not homogeneous and exhibit significant differences that manifest in platelet activation during hemostasis. One of the most important differences between platelet subpopulations is that some activated platelets become procoagulant (though this is under debate; some refer to them as procoagulant collagen- and thrombin-activated or COAT platelets), while others become activated into non-clotting platelets (proaggregant platelets). While the majority of thrombin 406 is generated by procoagulant platelets, non-clotting platelets are more prone to aggregation. Thus, both types are necessary for proper clotting. Although there is considerable subject-to-subject variability, on average, only 30% of activated platelets become procoagulant platelets.

[0038] In many, or perhaps all, cases, procoagulant platelets swell, and their phospholipid membranes become more electrochromic due to the exposure of phosphatidylserine (PS) on their membrane surface. The more electrochromic platelet membranes result in a significant increase in the binding affinity of prothrombinase to them. Thus, prothrombinase is more likely to bind to procoagulant platelets (pCPs) than to noncoagulant (nCPs) platelets. As noted above, because prothrombinase 408 can generate thrombin 406 up to 250,000 times faster than fXa alone, it is clear that the majority of thrombin 406 at or near the site of injury is generated on pCPs.

[0039] Given the hemostatic process described above, it is clear that even a small increase in the pCP / nCP ratio can increase the rate of thrombin generation at or near the injury site, thereby accelerating platelet and fXIII activation and fibrin generation. Thus, in addition to leading to faster platelet aggregation, increased thrombin generation also increases the rate of fibrin binding and cross-linking 410, both of which promote shorter bleeding times and less blood loss.

[0040] Furthermore, faster / higher generation of thrombin 406 at the injury site can compensate for lower or absent intrinsic tenase 412 production due to defects and limitations in hemostatic processes (e.g., bleeding / coagulation disorders), such as deficiency or lower-than-normal (including complete absence) fVIII, fIX, or fXI (in hemophilia A, hemophilia B, and hemophilia C, respectively). Interestingly, studies have shown that pCP levels are significantly lower in hemophilia-affected individuals compared with healthy individuals. As previously mentioned, vWF not only promotes platelet adhesion to endothelial tissue at the injury site but also supports platelet-platelet adhesion after platelet activation at or near the injury site. In addition, vWF functions as a carrier of fVIII in the plasma in the form of vWF-fVIII complexes. Consequently, low amounts of circulating / available fVIII are also found in vWD type 2N. Another situation that leads to a deficiency and / or limitation of the hemostatic process that can be compensated for by faster / higher generation of thrombin 406 at or near the injury site is when platelet adhesion and aggregation are impaired due to low or absent available or fully functional vWF, for example, in vWD types 1, 2A, 2M, and 3, because faster / higher generation of thrombin 406 results in a faster rate of platelet activation and thereby a higher rate of fibrinogen release. Yet another example in which higher / faster thrombin generation can compensate for an existing hemostatic deficiency is in vWD type 2B, resulting in both lower platelet adhesion / aggregation and lower platelet counts. It is not suggested that compensating for this restores the hemostatic process to what would be expected in a normal subject (e.g., in the absence of a defect or limitation). Instead, the term compensation is used to refer to a significantly faster hemostatic process than would otherwise occur in light of the defect or limitation when an excess amount of thrombin is present. One way this compensation may be achieved is by locally increasing the ratio of procoagulant activity to anticoagulant activity at or near the site of injury.

[0041] Strong activation is required for platelets to become procoagulant platelets (pCPs). However, this is not sufficient. Experiments using dual agonists (e.g., collagen and thrombin) have shown that the proportion of platelet activation to the procoagulant form is reduced. Some have suggested that the acronym COAT is inaccurate because activation by both collagen and thrombin is neither sufficient nor unique to provide a significant boost in platelet activation to the procoagulant form. Very high concentrations of thrombin are also not unique in the sense that they can activate platelets to the procoagulant form. Several factors have been identified as contributing factors in determining whether a platelet becomes a procoagulant platelet upon activation. Some of these factors include platelet age, size, number of mitochondria, number and content of granules, and baseline Ca. 2+ Interestingly, under similar circumstances, younger platelets are more likely to be procoagulant than older platelets (as noted above, in humans, platelets circulate for approximately 7-10 days before being cleared by the liver and / or spleen).

[0042] Data from a recent study by Abbasian and colleagues suggest that cytosolic Ca in pCP 2+ Concentration ([Ca 2+ ] cyt ) in nCP is [Ca 2+ ] cyt (>100 nM vs. 1-2 nM) was shown to be at least 50-fold higher. See Abbasian, Nima et al., "Supramaximal calcium signaling triggers procoagulant platelet formation," Blood Advances 4.1 (2020): 154-164. 2+ Most platelets can be activated as pCPs when treated with [Ca]. However, in general, most platelets activate as nPCs when stimulated with some platelet activating agents. This is because [Ca] 2+ ] cytThese results suggest that β-glucan is one of, if not the most important, factors in determining whether platelets activate as pCPs or nCPs.

[0043] Platelets contain Ca 2+ Several transmembrane Ca molecules exchange Ca between the extracellular and intracellular spaces. 2+ channels (see table below). Two or more of these channels, or a combination of them, can be activated to allow net positive Ca 2+ allowing the influx of Ca within the platelets 2+ In platelets, this Ca 2+ is normally taken up into internal stores by one or various mechanisms, among which are mitochondria, the dense tubular system (DTS), lysosomes, and δG. 2+ ] cyt Ca may lead to platelet activation, which, if occurring at locations other than the site of injury, may result in undesirable thrombotic events. 2+ It is important that Ca is sequestered in internal (e.g., intracellular) stores so that it is released into the cytosolic space only upon damage-related activation. This can be achieved by various methods, e.g., transmembrane Ca 2+ Activation of one of the channels allows Ca transport from the internal store to the cytosolic space. 2+ By partially or transiently blocking the mechanisms involved in Ca release, 2+ This baseline Ca influx can be achieved by inducing Ca influx into platelets. 2+ Elevated (e.g., total intracellular pre-activated Ca that is not in the cytosolic space) 2+ ) is higher upon activation than [Ca 2+ ] cytThis increases the likelihood of platelets becoming activated as pCPs, thereby increasing the overall probability of platelet activation and resulting in high coagulation potential. In the event of injury, high coagulation potential translates into high thrombin generation at the injury site on an individual basis. The higher-than-otherwise generation of thrombin at the injury site translates into faster local platelet activation and fibrin adhesion and cross-linking into a clot. Thus, higher coagulation potential can lead to a faster clotting process, resulting in less bleeding and shorter bleeding times. [Table 1]

[0044] As shown by Schedel and colleagues, platelets express the α7-nicotinic acetylcholine receptor (nAChRα7). See Schedel, Angelika, et al., "Human platelets express functional α7-nicotinic acetylcholine receptors," Arteriosclerosis, thrombosis, and vascular biology 31.4 (2011):928-934. The autonomic nervous system (ANS) can regulate the release of acetylcholine (ACh), so nAChRα7 binds to transmembrane Ca 2+ Assuming that nAChRα7 is a channel, the presence of nAChRα7 on the platelet membrane may be responsible for platelet Ca 2+ Furthermore, Bennett et al. showed that ACh inhibits platelet activation, suggesting that ACh may be used to inhibit Ca influx via nAChRα7 while preventing platelet activation. 2+See Bennett JA, Ture SK, Schmidt RA, Mastrangelo MA, Cameron SJ, Terry LE, Yule DI, Morrell CN, Lowenstein CJ. Acetylcholine Inhibits Platelet Activation. J. Pharmacol Exp Ther. 2019 May;369(2):182-187. For example, as shown in Figure 1, platelets 124a circulating in the spleen 116 are enriched and stimulated by activating VEFs and triggering cells in the celiac ganglion 112 to increase Ca. 2+ The splenic ganglion and / or spleen 116 may, in another embodiment, be stimulated directly and / or indirectly to concentrate circulating platelets 124a within the spleen 116 and produce platelet concentrates 124b. 2+ A platelet concentrate 124b may be produced.

[0045] For simplicity, reference will be made to a single ganglion, but it will be understood that both the left and right celiac ganglia are connected, so that activity in one ganglion affects activity in the other, and although activity in one ganglion is most often referred to in this document, any reference to a particular ganglion encompasses reference to both the left and right ganglia, when they are present.

[0046] Interestingly, sympathetic and parasympathetic fibers interact in the celiac ganglion, where they can both influence the activity of postganglionic sympathetic fibers that excite the spleen. In particular, sympathetic preganglionic efferent fibers (SPgF), which typically arise from the T5-T9 spinal cord levels, exit the spinal cord as spinal roots, become larger splanchnic nerves, and synapse on postganglionic neurons in the celiac ganglion. SPgF release ACh upon synapsing on their targets in the celiac ganglion. Fibers exiting the celiac ganglion form what is known as the celiac plexus, from which fibers continue as the splenic plexus. The splenic nerve arises from fibers of the splenic plexus and innervates the spleen. SPgF activity is modulated, among other things, by activity in the RVLM, which in turn is modulated by activity in both the TCC and LC. It is notable that the ABVN also connects to the trigeminal region, specifically the spinal trigeminal nucleus, which for purposes of this specification is considered part of the TCC. Consequently, activation of SPgf and / or VEF by activity in TCCs and / or LCs, among others, may be mediated by Ca 2+ via a common pathway after interaction in the celiac ganglion. 2+ The production of platelet concentrates can be regulated.

[0047] Referring to Figure 3A, platelet Ca 2+An exemplary block diagram of the enrichment pathway 300 is shown. Acetylcholine (ACh) 302, the natural agonist of nAChRα7, is an important neurotransmitter that regulates many aspects of the ANS. Increasing activity in the parasympathetic branch of the ANS (e.g., the parasympathetic nervous system—PNS), for example, by activating VEF 304, can trigger the release of ACh 302 in the celiac ganglion 112 and / or splenic ganglion 306. The same is true when increasing activity of the splenic nerves 320, which synapse on the celiac ganglion 112, as they also release ACh 302. Innervation of the spleen 116 is carried out via neural connections between the splenic ganglion 306 and their targets within the spleen 116, where norepinephrine (NE) 308 is released. Interestingly, Rosas-Ballina showed that NE308 released in the spleen116 activates T cells312, which then release ACh302. See Rosas-Ballina et al., Acetylcholine synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052):98-101. doi:10.1126 / Science.1209985. Epub 2011 Sep 15. PMID:21921156; PMCID:PMC4548937. This ACh302, upon arriving at nAChRα7 on platelets314 circulating slowly in the spleen116, activates Ca 2+ 316 into platelets 314, effectively increasing baseline Ca 2+ 316, resulting in calcium-enriched platelets 318, which may also be referred to herein as primed platelets. This detailed description will refer to the celiac ganglion and the splenic ganglion 306. However, the splenic ganglion 306 may be considered an extension of the celiac ganglion 112. It is further understood that many ganglia form what is referred to as a nerve plexus (e.g., nerve plexus 306). Thus, for purposes of this description, the terms plexus and ganglion are interchangeable.

[0048] 3B, in some embodiments, platelets are primed via activation of the platelet priming pathway 330, which stimulates activity in the spleen 310. In particular, the ABVN 102 and / or the ATN 104, which have projections to the NTS 108, may be stimulated. As shown, the TCC 106 receives afferent connections from the ATN 104 and projects to the NTS 108 and the RVLM 342, while the ABVN 102 projects directly to the NTS 108.

[0049] As shown in FIG. 3B , certain platelet priming pathways also include other nuclei or regions, such as the locus coeruleus (LC) 332, the periaqueductal gray matter (PAG) 334, and the nucleus raphe magnus (NRM) 322. Each of these nuclei or regions then supplies the nucleus ambiguus (NA) 338, which provides a pathway to the vagus nerve 110. Other regions projecting to the vagus nerve 110 are the dorsal motor nucleus of the vagus nerve (DMV) (not shown) and the spinal trigeminal nucleus (considered part of the TCC 106 herein). Indirect stimulation of the vagus nerve 110 through various pathways allows the vagus nerve 110 to innervate the celiac ganglion 112 and / or the splenic plexus 348. The splenic nerve 350, arising from fibers in the splenic plexus 348, innervates the spleen 310, thereby enhancing platelet priming within the spleen 310 and resulting in the conversion of more unprimed platelets 340a to primed platelets 340b. For example, stimulation of the Arnold nerve with low-frequency, low-moderate pulses and / or brief stimulation of the ATN with high-frequency, low-moderate pulses can result in a significant increase in primed platelets, which can be assessed by a decrease in PT.

[0050] In another pathway shown in FIG. 3B, the LCs 332 and TCCs 106 each provide a pathway to the RVLM 342, which provides a pathway for indirect stimulation of sympathetic preganglionic efferent fibers (SPgF) 344, which exit the spine via the dorsal root ganglia (DRG) at the T5-T9 level 346 to form the larger splanchnic nerve 320, which connects to the stimulation of postganglionic nerves at the celiac ganglion 112, further triggering activity of the splanchnic nerve 320. Because the splanchnic nerve 320 feeds the celiac ganglion 112, indirect stimulation of SPgF 344 via the various pathways shown and described increases platelet priming in the spleen 310, converting more unprimed platelets 340a into primed platelets 340b, as described with respect to the vagus nerve-related pathway above. Similar to the pathway via the vagus nerve 110, stimulation of the Arnold nerve with low-frequency, low-moderate pulses and / or brief stimulation of the ATN with high-frequency, low-moderate pulses can result in a significant increase in primed platelets, which can be assessed by a decrease in PT.

[0051] Returning to Figure 3A, higher baseline Ca 2+ Given that platelets with 316 are more likely to activate as pCPs and thus improve the overall coagulation potential of a subject, situations in which higher coagulation potential is desired may involve the application of Ca 2+ The patient population would benefit from a method that results in a net influx of Ca 316 into the platelets 314. Increasing activity in the VEF 304 would increase Ca 316 activity during transit through the spleen 116, as discussed above. 2+ A cascade of events can be triggered that results in a net influx of 316 into platelets 314 .

[0052] An individual's blood clotting ability can be assessed through diagnostic tools such as thromboelastography (TEG). TEG evaluates blood clotting ability and identifies potential abnormalities detected during the clot formation process. TEG results include reaction time (R-time), which quantifies the time it takes for the clotting cascade to begin after the addition of a clot activator; kinetic time (K-time), which quantifies the time it takes for the clot to reach a 20 mm firmness from the initiation of the clotting cascade; alpha angle, which quantifies the rate of fibrin cross-linking during clotting; maximum amplitude (MA), which quantifies the overall strength of the clot in millimeters; and lysis at 30 minutes (LY30), which quantifies the resistance of the clot to breakdown (e.g., the rate of lysis after 30 minutes of MA time).

[0053] TEG deficiencies, in some examples, may indicate hypofibrinogenemia (e.g., low fibrinogen levels), thrombocytopenia (e.g., low platelet count), or platelet dysfunction. When a patient's TEG analysis identifies one or more deficiencies, transfusion therapy (e.g., fresh frozen plasma, platelet transfusion, and / or cryoprecipitate transfusion) is often recommended.

[0054] There are many situations in which increased coagulation potential is desirable. These situations include both chronic (ongoing) situations and acute scenarios. As identified above, for example, individuals with conditions that result in lower-than-normal and / or lower-than-desired coagulation potential would benefit from increased coagulation potential, as would individuals with hemophilia or von Willebrand's disease. In another example, subjects taking medications (e.g., anticoagulants or "blood thinners") that prevent platelets from forming clots at locations other than the site of injury could benefit from increased coagulation potential, particularly in pre- or intra-operative situations. Generally, patients or individuals undergoing medical procedures in which bleeding is reasonably likely, such as entering surgery, would benefit greatly from a temporary increase in coagulation potential. Improved coagulation potential reduces bleeding time, often resulting in shorter, lower-risk procedures overall, if not all. Additionally, improved coagulation potential in a surgical setting reduces blood loss. For example, limiting blood loss can obviate the need for blood transfusions and / or reduce the amount of replacement needed when a transfusion is required. Blood for transfusion is very costly and, in some cases, is limited or unavailable. In an exemplary embodiment involving maternal delivery, postpartum hemorrhage is one of the leading causes of maternal death worldwide. Furthermore, significant amounts of blood are lost during vaginal delivery, and even more during cesarean section (C-section) delivery. There are many other surgical procedures that pose a high risk of significant bleeding, and patients undergoing such procedures would benefit from improved clotting ability. Another situation in which limiting blood loss is highly desirable and beneficial is in the case of abnormal uterine bleeding (AUB), including heavy menstrual bleeding (HMB), which also includes menorrhagia. This condition affects one in four women of reproductive age. While death from AUB, including HMB, is rare, in some cases, if left untreated, it can lead to a predisposition to cancer. HMB can lead women to a severe state of anemia, resulting in shortness of breath and an increased risk of cardiac complications. As alluded to earlier, HMB is very common, estimated to affect one-quarter of women of reproductive age, but in fact, one-third of women of reproductive age seek treatment for what they consider to be heavier than desired menstrual bleeding.Thus, HMB, and new interventions that can help reduce blood loss in AUB in general, would be highly desirable and would be welcomed by women and physicians alike, even if used as an adjunct.

[0055] inflammation A pro-inflammatory response is typically triggered, in some embodiments, when there is potential bodily injury, such as infection, and / or when a hemorrhagic injury occurs. This inflammatory response typically helps the body heal. However, in many cases, an overactive inflammatory response occurs, triggering harmful effects that can lead to organ damage and death. At least part of the inflammatory response is mediated by the spleen; therefore, modulating splenic activity can alter the inflammatory response. In particular, activation of the parasympathetic nervous system leads to an anti-inflammatory response in the spleen, resulting in a reduction in circulating pro-inflammatory cytokines. Activation of the splenic nerve (e.g., directly and / or via vagal efferent fiber (VEF) activity) leads to the above-mentioned anti-inflammatory response. In one embodiment, a reduction in circulating pro-inflammatory cytokines can be achieved by modulating splenic activity via the NTS descending pathway.

[0056] In some embodiments, the anti-inflammatory effect is provided through activation of the anti-inflammatory pathway 100 (also known as the cholinergic anti-inflammatory pathway), as shown in FIG. 1 . In particular, the ABVN 102 and / or ATN 104, which have projections to the NTS 108, may be stimulated. These projections induce cholinergic anti-inflammatory effects via efferent pathways, primarily the vagus nerve 110. As shown, the TCC 106 receives afferent connections from the ATN 104 and projects to the NTS 108. Modulation of the NTS 108 influences activity via the vagus nerve 110 in efferent pathways through the celiac ganglion 112 and parasympathetic ganglia 114, which in turn modulates activity in the spleen 116, lungs 118, intestine 120, and / or heart 122 such that an anti-inflammatory response is elicited. The systemic anti-inflammatory effect occurs when the vagus nerve 110 indirectly mediates spleen 116 function, thereby reducing the amount of circulating pro-inflammatory cytokines. In addition, local anti-inflammatory effects occur in organs reached by efferent pathways, such as the lungs 118, intestines 120, and heart 122.

[0057] hypovolemia When blood circulation declines to a level where tissue perfusion can no longer provide adequate oxygenation, organs begin to fail to the point where they begin to fail. Organ failure can lead to permanent damage and even death. This is especially true when the organ lacking adequate oxygenation is the brain. The brain consumes a large portion of the oxygen circulating in the body, especially when a person is at rest, making it highly vulnerable to hypoperfusion scenarios. There are brain regions (e.g., brain nuclei or regions) that regulate blood pressure and blood flow. Activation of such brain regions results in higher blood flow. For example, activation of the rostral ventrolateral medulla (RVLM) has been shown to have a hypertensive response (shown in Figure 2A), a response that results in increased blood pressure, perfusion, and flow.

[0058] 2A , as shown in an exemplary blood pressure response and cerebral perfusion pathway 200, the RVLM 206 receives connections from several nuclei, including the trigemino-cervical complex (TCC) 204, which in turn receives afferent connections from the trigeminal nerve branches. As shown, the TCC 204 receives afferent connections from the auriculotemporal nerve (ATN) 202. The RVLM 206 then regulates the cardiac system 208 (e.g., blood pressure) as well as the vascular system 210 (e.g., blood flow).

[0059] In addition to the RVLM 206, activation of the trigemino-parasympathetic pathway 220 (shown in Figure 2B) has been shown to dilate the cerebral vasculature 224, at least in part, by releasing ACh into this vasculature 224 by fibers of pterygopalatine origin (SPH) 222. The pterygopalatine nucleus (pterygopalatine ganglion) 222 also receives afferent fibers from the trigeminal nerve branches, particularly the mandibular branch of the trigeminal nerve (V3), of which the ATN is a part.

[0060] Control of bleeding Activity in the VEF can be triggered by directly activating nerve fibers or by activating regions with direct and / or indirect connections to nerve fibers. Referring to FIG. 5, for example, a functional diagram of neural structures and pathways 500 shows that activity in medullary structures, such as activity in the nucleus tractus solitarius (NTS) 504 and nucleus ambiguus (NA) 522, can trigger VEF activity via efferent pathways 539. Notably, the NA 522 receives projections from the periaqueductal gray area (PAG) 510. The NTS 504 receives afferent connections from the TCC 502 and the ascending vagus nerve branch. The TCC 502, in turn, receives afferent projections from the trigeminal and cervical branches and projects to the PAG 510 and RVLM. Activity in RVLM neurons can trigger the above-mentioned hypertensive response, as shown in FIG. 2A. Interestingly, not all activity in the TCC 502 results in a trigemino-parasympathetic response resulting from sphenopalatine activity. Studies suggest that activation of the masseteric branch of the trigeminal nerve (MBTN) results in this response. One way to activate the MBTN branch is via the auriculotemporal nerve (ATN).

[0061] Activation of the VEF can be achieved by stimulation via invasive and / or non-invasive approaches at various sites. Some invasive examples include the use of an implantable pulse generator (IPG) to stimulate cervical vagus nerve fibers and / or needle electrodes to percutaneously stimulate vagal nerve fibers, such as ABVN and / or trigeminal nerve fibers. Non-invasive approaches may percutaneously stimulate the fibers of the ABVN, as well as cervical vagus nerve fibers, as well as trigeminal nerve fibers corresponding to the maxillary, ophthalmic, and / or mandibular trigeminal branches. In some examples, VEF activation can be achieved by electrical, mechanical (e.g., ultrasound, pressure, massage, etc.), and / or optical (e.g., laser and / or high-intensity light) stimulation. Additionally, activation of nAChRα7 on platelets can be achieved by chemical means, such as local or systemic administration of nAChRα7 agonists, such as nicotine. nAChRα7 agonists can be injected or applied non-invasively, for example, using a transdermal / transcutaneous patch, or in some cases, by specially designed oral doses. Additionally, platelets express other calcium transmembrane channels. Thus, one or more of these channels (e.g., those identified in Table 1 above) may mediate platelet intracellular baseline Ca. 2+ For example, these channels can be chemically activated by their respective agonists and / or partial agonists, as described above for nAChRα7. 2+ The Ca channel that allows platelets to exit 2+ It can be temporarily or partially blocked, for example, with a partial antagonist, to prevent or slow the flux of Ca from platelets into the extracellular space and allow it to be transported to internal stores within the platelets. 2+ Intracellular Ca2+ is required to prevent platelet activation when Ca2+ enters the intracellular space. 2+ Any such intervention that increases the risk of heart failure would be desirable and / or required.

[0062] Under normal circumstances, high concentrations of cytosolic Ca 2+ can trigger platelet activation. To prevent thrombus formation at locations other than the injury site, platelet activation should be primarily localized at the injury site. Therefore, until the time when platelets need to be activated, [Ca 2+ ] cyt However, upon activation, platelets require high [Ca] for activation as pCPs. 2+ ] cyt One way to do this is by increasing the Ca concentration during platelet activation. 2+ The goal is to store platelets in an internal platelet reservoir and release them into the cytosolic space.

[0063] The hypertensive response can be achieved by invasive and / or non-invasive stimulation at various sites, as shown in Figure 2A. In some examples, the hypertensive response can be triggered by electrical, mechanical (e.g., ultrasound, pressure, massage, etc.), and / or optical (e.g., laser and / or high intensity light) stimulation.

[0064] The trigemino-parasympathetic response shown in Figure 2B can be achieved by invasive and / or non-invasive stimulation at various sites. In some embodiments, the trigemino-parasympathetic response can be triggered via electrical, mechanical (e.g., ultrasound, pressure, massage, etc.), and / or optical (e.g., laser and / or high-intensity light) stimulation. [Table 2] [Table 3]

[0065] Stimulation to generate one or more responses described herein that achieve a temporary effect in a prevention / prophylaxis scenario, such as stimulation to generate a blood pressure increase response, a trigemino-parasympathetic response, and / or an increase in CPot, can, in some embodiments, be initiated shortly before an event and applied for an ultrashort period of time. For example, in the context of an impending trauma, such as emergency surgery, stimulation can be initiated only for a short period of time before the trauma (e.g., surgical procedure). In other embodiments, stimulation can be initiated medium to long periods of time before an event and applied intermittently and repeatedly for an ultrashort period of time or for a short period of time. For example, to avoid hemorrhage during labor, a pregnant woman may be subjected to short, intermittent, or periodic stimulation throughout the indefinite duration of labor. In another example, in the case of a medical intervention, such as a C-section, preventative measures can prevent unnecessary blood loss, for example.

[0066] In some embodiments, the repetitive and intermittent stimulation is applied at a predetermined duty cycle. For example, a 30% on / 70% off duty cycle can be implemented by applying 3 minutes ("on") of stimulation every 10 minutes. In other non-limiting examples, the duty cycle may be configured as a 30% on / 70% off duty cycle (e.g., 3 minutes on / 7 minutes off or 6 minutes on / 14 minutes off), a 50% on / 50% off duty cycle (e.g., 1 minute on / 1 minute off or 5 minutes on / 5 minutes off), an 80% on / 20% off duty cycle (e.g., 4 minutes on / 1 minute off), or a 97% on / 3% off duty cycle (e.g., 5 minutes on / 10 seconds off). In yet another illustrative example, a platelet donor may begin stimulation 7 or more days before donating platelets so that the donated platelets are primed platelets. The total amount of platelets needed to be donated can be significantly reduced when the donated platelets are primed platelets. In this case, for example, stimulation may be applied repeatedly daily for a short period of time. In further examples, stimulation may be applied for a short, medium, long, or very long period of time. In other embodiments, stimulation may begin long-term before the event or very long-term before the event.

[0067] In preparation for potentially dangerous scenarios, such as military operations, military personnel can begin and train for stimulation approximately three or more weeks prior to the actual military operation and cease stimulation once the military operation has concluded. In this case, stimulation can be applied daily for single or multiple very short, short, or medium durations.

[0068] In some embodiments, one or more stimuli to generate one or more of the responses described herein, e.g., a hypertensive response, a trigeminal parasympathetic response, and / or an increase in CPot, are applied periodically, e.g., in a repetitive pattern. In some examples, the stimulation may be applied once every 10 minutes, once every 30 minutes, once every hour, four times a day, or once a day. The duration may vary based in part on the frequency of the cyclic stimulation. In some examples, the stimulation may be applied for a short time once every 10 minutes, a medium time once an hour, or a long time once a day. In another embodiment, to reduce total blood loss and / or total monthly bleeding days, women suffering from HMB / menorrhagia, including those with coagulation disorders, can begin stimulation, e.g., several days before their menstrual period and continue stimulation until the end of their menstrual period. In such cases, the stimulation may be applied, e.g., once a day, for a very short time, or for a short time. In some embodiments, other schedules are possible based on convenience, comfort, intensity of desired effect, and / or potential severity of consequences (e.g., potential harm to the patient due to lack of / inadequate prophylaxis).

[0069] In situations where the goal is treatment of a chronic condition, in one exemplary embodiment, stimulation to produce one or more responses described herein, e.g., an improvement in CPot, a hypertensive response, and / or a trigemino-parasympathetic response, may be delivered in a repetitive pattern for as long as necessary. For example, stimulation may be applied daily or several times daily for a duration (e.g., very short, short, medium, long, or very long) based in part on the relative frequency of treatment. In another example, an initial level of coagulation function may be produced (e.g., "started-in") in a human by applying stimulation at least daily for a first period of time, followed by less frequent treatment or a tapering frequency of treatment to maintain coagulation function at a desired level. For example, stimulation may be applied daily for a first period of time (e.g., 5-10 days), followed by less frequent treatment (e.g., once or possibly twice a week) to maintain coagulation function within a desired range. In another example, stimulation may be applied daily for a first period, then three times per week for a second period, then twice per week for a third period, followed by once per week to maintain a desired level of coagulation function. In a further example, a treatment schedule including stimulation applications per week for the first week (e.g., seven times), followed by a different number of stimulation applications per week for the second week (e.g., five times) can be customized for a particular individual to maintain a desired level of coagulation function. Additionally, the duration of treatment may be varied from period to period in any of the above examples.

[0070] Generally, stimulation duration is defined by the time the device is effectively delivering stimulation therapy, rather than the actual time stimulation is being generated. For example, the device may be initiated (e.g., powered on) for 1 hour while applying a particular frequency and a particular pulse duration (e.g., pulse width), as shown, for example, in Figures 7A and / or 7B. Furthermore, stimulation pulses may be applied according to a particular duty cycle, e.g., 5 minutes of delivery and 20 seconds of no delivery, or 30 seconds of delivery and 30 seconds of no delivery, etc. Additional exemplary duty cycles are shown in the timing diagrams of Figures 7A and 7B.

[0071] Referring to FIG. 6C, a WANS device 630 includes a front portion 632 including a conductive adhesive region 634 with a surrounding non-conductive adhesive region 644b, and a rear portion 636 including conductive adhesive regions 638 and 640 with a surrounding non-conductive adhesive region 644a. The non-conductive adhesive regions 644a and 644b may provide additional adhesion, for example, for robust skin / conductive adhesive contact. The conductive adhesive region 634 of the front portion 632 corresponds, for example, to the second electrode (II) 642b. Referring to the rear portion 636, the conductive adhesive region 638 corresponds to the first electrode (I) 642a, and the conductive adhesive region 640 corresponds to the third electrode (III) 642c. In some embodiments, the electrodes 642a-c and their corresponding conductive adhesive regions 634, 638, and 640 each have a similar shape and area. In other embodiments, the shape and / or surface area of ​​each of the electrodes 642a-c and / or their corresponding conductive adhesive regions 634, 638, and 640 may vary based on, for example, the shape of the underlying target neural structure and / or the anatomical structure into which the electrodes 642a-c and their corresponding conductive adhesive regions 634, 638, and 640 are configured to be placed.

[0072] The conductive adhesive region 634 is configured, in some embodiments, to contact the wearer's skin in the region of the auriculotemporal nerve (ATN) neural structures and / or neural structures connected to the ATN, such that delivery of therapeutic stimuli via the conductive adhesive region 634 modulates ATN activity. With reference to Figures 10A and 10B, for example, the ATN 1002 is shown in relation to a human ear 1000 (Figure 10A), extending generally in front of the ear 1000, and skeletal relation to the ear canal 1010 (Figure 10B). In an illustrative example, an electrode in electrical communication with the conductive adhesive region 634 may be positioned proximate the temporomandibular joint.

[0073] In some embodiments, the conductive adhesive region 638 is configured to contact the wearer's skin in the region of the auricular branch of the vagus nerve (ABVN) and / or neural structures connected to the ABVN, such that delivery of therapeutic stimulation via the conductive adhesive region 638 modulates ABVN activity. As shown in FIGS. 10A-10D , for example, the ABVN 1004 emerges through the mastoid canaliculus (MsC) 1012 (also known as Arnold's canal) ( FIG. 10D ) and is shown in relation to the ear 1000 ( FIG. 10A ), in relation to the ear canal 1010 ( FIG. 10B ), and in relation to the back of the ear ( FIG. 10C ). Referring to FIG. 11 , the posterior auricular nerve 1100 intersects with branches of the ABVN, providing another target for ABVN stimulation. In an exemplary embodiment, an electrode in electrical communication with the conductive adhesive region 638 may be positioned proximate to the MsC.

[0074] The conductive adhesive region 640, in some embodiments, is configured to contact the patient's skin as a return electrode, thereby completing an electrical circuit across the tissue with electrodes corresponding to the front conductive adhesive region 634 and the rear conductive adhesive region 636. While a single return electrode (e.g., third electrode 642c) is shown provided for both electrodes 642a and 642b corresponding to adhesive region 638 and adhesive region 634, in other embodiments, different, separate return electrodes may be provided for each electrode 642a, 642b. In further embodiments, three or more return electrode paths may be provided for the two positive electrodes. Other combinations are possible.

[0075] 6E, a wearable auricular nerve stimulator (WANS) 660 includes an anterior portion 666, a posterior portion 662, and an supra-auricular portion 664, each portion including at least one electrode (e.g., electrodes 670a, 670b, and 670c). When worn by a wearer, the WANS 660 may be wrapped around the ear such that the anterior portion 666 is positioned in front of the ear and the posterior portion 662 is positioned behind the ear. The supra-auricular portion 664, connected to the anterior portion 666 by a flexible connector 668, may be frictionally and / or adhesively held in the navicular region of the ear.

[0076] To enhance engagement of the WANS 660 with the wearer's tissue and / or to enhance electrical communication between the tissue and the electrodes 670a-c, in some embodiments, each electrode 670a-c is positioned in electrical communication with a corresponding conductive adhesive region 672a-c. The conductive adhesive regions 672a-c may form an electrical communication path from the electrodes disposed in or on the WANS 660 to the wearer's skin. To protect and maintain the cleanliness of the conductive adhesive regions 672a-c prior to wear, in some embodiments, the WANS 660 is provided with one or more liners, such as liners 674a-c. To provide robust skin contact, in some embodiments, the conductive adhesive regions 672a-c are surrounded by one or more non-conductive adhesive regions. In some embodiments, the electrodes 670a-c and their corresponding conductive adhesive regions 672a-c have similar shapes and areas. In other embodiments, the size and / or shape varies from electrode to electrode and / or from adhesive region to adhesive region based, for example, on the underlying neural structures being targeted and / or the topography of the anatomical structure in which the particular electrode and adhesive region is configured to be placed.

[0077] The conductive adhesive region 672a may be provided to provide an electrical communication path from the electrode 670a located on the supra-aural portion 664 of the WANS 660 to the wearer's skin at the front of the ear canal. Referring to Figure 12, such an electrode may be positioned, for example, to stimulate the ear canal nerve branch 1200 of the ATN 1002. In other embodiments, the conductive adhesive region 672a is positioned on the concha, navicularis concha, or tragus to stimulate branches of the ABVN.

[0078] 7A, a diagram of a timing diagram 700 illustrates the triggering of multiple channels 704, 706 using a master clock 702, according to one embodiment. In an exemplary embodiment, the clock 702 triggers pulses 708 at a predetermined clock frequency. In one embodiment, a first channel 704 can be configured to trigger stimulation patterns 710-712, and a second channel 706 can be configured to trigger a second stimulation pattern 714-716.

[0079] As shown, each cycle of the stimulus pattern 710-712 of the first channel 704 is configured to be triggered by a corresponding pulse 708 of the master clock 702, i.e., in a one-to-one ratio. In one example, each stimulus 712 (e.g., 712a, 712b, etc.) is configured to be triggered a specific time interval after the end of the pulse 708 (e.g., 708a, 708b, etc.) of the corresponding stimulus 710 (e.g., 710a, 710b, etc.).

[0080] As shown, each cycle of the stimulus patterns 714-716 is configured to be triggered every other pulse 708 of the master clock 702, i.e., in a 2:1 ratio with respect to the master clock 702. However, the triggering of each stimulus 714 (e.g., 714a, 714b, etc.) is configured to occur a specific time delay after the corresponding master clock pulse 708 (e.g., 708a, 708b, etc.). In some embodiments, each stimulus 714 (e.g., 714a, 714b, etc.) is configured to be triggered a specific time interval after the end of the corresponding pulse of the stimulus 712 (e.g., 712a, 712b, etc.). In one example, each stimulus 714 is offset from each corresponding stimulus 712 by a synchronization delay 718. As shown, the synchronization delay 718 is 2 ms. However, in certain embodiments, the synchronization delay 718 can be as small as zero, triggering both channels 704, 706 simultaneously, depending on the master clock ratio of each channel 704, 706. Furthermore, the synchronization delay 718 can be on the same order as the master clock 702 minus the composite time of each cycle of stimuli 710-712 and each cycle of stimuli 714-718 plus the time interval between cycles 710-712, 714-718. This delay can also be up to about 10 ms in the illustrated embodiment.

[0081] In some embodiments, the channels 704, 706 are synchronized using a master clock counter and register for each channel 704, 706. Each register can be set to a number of master clock pulses 708 to trigger the respective channel 704, 706, thereby configuring each channel 704, 706 to trigger when the channel register value is equal to the master clock pulse 708. In further embodiments, the counter for each channel 704, 706 can be reset after the channel 704, 706 is triggered. In an illustrative example, using a 6-bit counter and 6-bit register, the trigger frequency can be as high as the master clock frequency (1:1) and as low as 1 / 64th of the clock frequency (64:1).

[0082] Referring to Figure 7B, a timing diagram 720 illustrates triggering of multiple stimulation patterns 722 (ATN stimulation pattern 722a and Arnold neural stimulation pattern 722b) for simultaneous stimulation using a neuromodulation device, such as various devices described herein. Stimulation triggering is performed, in some embodiments, using a single master clock, such as master clock 702 of Figure 7A. The stimulation patterns 722a, 722b may be configured to deliver a platelet-concentrated therapy via the platelet priming pathway 330, for example, as described with respect to Figures 3A and 3B.

[0083] As shown, the duty cycle 724 of each of the stimulation patterns 722a, 722b consists of 5 minutes of active stimulation followed by 10 seconds of no stimulation (e.g., "short" according to Table 2 above). In other examples, the stimulation patterns 722a, 722b may consist of 4 minutes of active stimulation followed by 10 seconds of no stimulation, 4 minutes of active stimulation followed by 20 seconds of no stimulation, and / or 4 minutes of active stimulation followed by 1 minute of no stimulation. In other embodiments, the duty cycles 722a, 722b may include different stimulation durations (e.g., medium, long, or very long). In some cases, a high duty cycle (e.g., 90% on time) may be necessary to achieve a desired therapeutic effect, while in other cases a lower duty cycle (e.g., 50% on or even 30% on) may be sufficient. This may depend on the particular circumstances of a particular user. However, user preference may be taken into consideration, provided that a sufficiently high duty cycle is selected to be effective. For example, long periods of stimulation may cause fatigue (e.g., a feeling of boredom) in the wearer, while long pauses may be more noticeable to the wearer and may prove to be a welcome interruption to the sensation for some but irritating for others. Thus, in some embodiments, the duty cycle is customizable to some extent based on user preference / tolerance.

[0084] Additionally, the duty cycles of stimulation patterns 722a, 722b are aligned such that no stimulation is delivered during a 10 second period. While only 10 minutes of effective stimulation is shown (e.g., "ultra-short" according to Table 3 above), in some embodiments, duty cycles 722a, 722b may be repeated for longer treatment periods (e.g., short, medium, long, very long, or extremely long).

[0085] The stimulation pattern 722a configured to stimulate the ATN is delivered at a frequency 726a of approximately 100 Hz (e.g., a high frequency according to Table 5 below). Ultra-high frequencies (e.g., 150-200 Hz or higher) may be used in some embodiments. Furthermore, the pulse width 728 of each triggered stimulation (e.g., a low-medium pulse according to Table 6 below) is 250 microseconds, and the inter-pulse interval 730 is 100 microseconds.

[0086] Stimulation pattern 722b configured to stimulate the Arnold nerve is delivered at a frequency 726b of approximately 15 Hz (e.g., a low frequency according to Table 5 below). Medium frequencies (e.g., 30-40 Hz or higher) may also be used in some embodiments. 5 Hz stimulation, for example, may be uncomfortable or irritating for some wearers, while higher frequency stimulation (e.g., medium frequency rather than low frequency) may be more comfortable for certain wearers. Thus, in some embodiments, stimulation frequency is customizable to some extent (e.g., within a therapeutic range) based on user preference / tolerance.

[0087] Stimulation pattern 722b uses the same pulse width 728 and inter-pulse interval 730 as ATN stimulation pattern 722a. The pulse width 728 and inter-pulse interval 730 may be varied to account for trade-offs between amplitude and pulse width, particularly in signaling activation thresholds (e.g., lower amplitudes, wider pulse widths). Furthermore, the selected pulse width 728 and inter-pulse interval 730 (e.g., activation threshold) may be based in part on the fiber type and / or diameter of the sensory fibers targeted by stimulation. For example, certain devices described herein are designed to target Aβ fibers at current levels between 1 and 5 mA. Other fibers that can be targeted by treatment include Aα and Aδ fibers, as shown in Table 4 below. Conversely, C fibers are predominantly nociceptive and provide less effective treatment. [Table 4]

[0088] As shown, the pulse timing 732a of the ATN stimulation pattern 722a is offset from the pulse timing 732b of the Arnold neural stimulation pattern 722b by an approximately 2-5 millisecond gap 734. Thus, the ATN stimulation pattern 722a is configured to be delivered simultaneously with the Arnold neural stimulation pattern 722b without simultaneous pulse triggering between the two stimulation patterns 722a, 722b. To achieve this pulse timing, for example, the frequency of stimulation pattern 722b may be set to 14.28 Hz (e.g., 1 / 7 the frequency of stimulation pattern 722a).

[0089] In some embodiments where stimulation is applied to more than one site (e.g., directed to more than one nerve branch, etc.), the stimulation duration, frequency, pulse width, and / or duty cycle may vary across the stimulation sites, and in some embodiments, it is indeed beneficial to use different frequencies at different stimulation sites.

[0090] Stimulation delivery may vary based on the therapy provided by the treatment device. Frequency and / or pulse width parameters may be adjusted, for example, for one or more stimulation sites to which stimulation is delivered.

[0091] In some embodiments, the frequency and / or pulse width parameters are adjusted during treatment, for example, in response to feedback received from a monitored patient. In some examples, the feedback may be obtained using one or more sensors or other devices that assess heart rate, heart rate variability, electroencephalogram (EEG), blood pressure, and / or blood oxygen level.

[0092] In some embodiments, the system utilizes feedback to monitor and / or modify the therapy. The feedback may be obtained from one or more sensors capable of monitoring one or more symptoms being treated by the therapy. For example, upon reduction or elimination of one or more symptoms, the therapy output may be similarly reduced or discontinued. Conversely, upon enhancement or addition of one or more symptoms, the therapy output may be similarly activated or adjusted (increased, expanded, etc.). In some examples, the sensors may monitor one or more of electrodermal activity (e.g., sweating), motor activity (e.g., tremors, physiological movement), glucose levels, neural activity (e.g., via EEG), muscle activity (e.g., via EMG), and / or cardiopulmonary activity (e.g., EKG, heart rate, blood pressure (systolic, diastolic, and / or mean)). Imaging techniques such as MRI and fMRI can be used to adjust the therapy in a given user's clinical setting. In other embodiments, pupil changes (e.g., pupil dilation) can be imaged using, for example, a mobile phone and / or smart glasses to provide feedback for making therapy adjustments. In some embodiments, one or more sensors are integrated into the earpiece and / or concha device. In some embodiments, one or more sensors are integrated into the pulse generator. For example, periodic monitoring may be achieved by triggering the wearer to touch one or more electrodes on the system (e.g., electrodes integrated into the surface of the pulse generator) or otherwise interact with the pulse generator (e.g., holding the pulse generator extended away from the body and monitoring for tremors using a motion detector within the pulse generator). In further embodiments, one or more sensor outputs may be obtained from an external device, such as a fitness computer, smartwatch, or wearable health monitor.

[0093] Optical techniques have been used to assess thrombin concentrations (see Martinez-Perez, Paula et al., "Continuous detection of increasing concentrations of thrombin employing a label-free photonic crystal aptasensor," Micromachines 11.5 (2020):464). Thrombin concentrations are expected to increase after stimulation treatments described in the present invention. Thus, thrombin concentrations may be measured and applied by devices and / or systems described in the present invention to assess the effectiveness of treatment and adjust delivery parameters. Thrombin concentration measurements may also, in embodiments, be assessed using blood from the wound, and the resulting measurements may be delivered to a treatment device and / or system to adjust treatment application.

[0094] In another embodiment, the microfluidic chip may be used as a sensor system for actively monitoring coagulation in real time (see Lei, Kin Fong, et al., "Real-time electrical impedimetric monitoring of blood coagulation process under temperature and hematocrit variations conducted in a microfluidic chip," PLos One 8.10(2013):e76243). Electrical impedance measurements collected via the microfluidic chip may also be analyzed, in further embodiments, to assess the effectiveness of treatment in real time and adjust as needed.

[0095] In yet another example, the "lab-on-a-chip" concept can be used to monitor and / or control therapeutic applications. Closed-loop neuromodulation of hemostasis can be achieved using "lab-on-a-chip" microfluidic technology. For example, a drop of blood collected from a lancet-triggered fingerstick can be collected in a capillary tube and then placed on a test strip pre-loaded with bioreceptors that selectively recognize and bind biomarkers of interest. The bioreceptors are immobilized on the surface of a component of the test strip, and binding of the biomarker to the bioreceptor generates a signal that can be detected by a device engineered to accept the test strip and detect the signal. Biomarkers of interest include, for example, thrombin or the thrombin-antithrombin III complex. The bioreceptor can be an antibody, a synthetic chemical, or an engineered biological derivative (e.g., a nucleic acid, protein, or enzyme). The signal can be detected by a variety of means, including electrical, mechanical, thermal, piezoelectric, or optical means. Examples of optical sensing include spectral analysis of specific wavelengths of light, such as the streptavidin-peroxidase enzyme reaction, which produces a yellow color whose intensity is directly proportional to the concentration of the biomarker being analyzed. Devices that accept the test strip and read the signal can use microfluidics to wash away unbound material, or may be capable of operating within the intact sample.

[0096] In additional examples, activity in the locus coeruleus can be indirectly measured by pupillometry, as shown, inter alia, by Murphy and colleagues (Murphy, Peter R. et al., "Pupil diameter covaries with BOLD activity in human locus coeruleus," Human Brain Mapping 35.8 (2014): 4140-4154). As discussed above, activity in the LC can drive activity in sympathetic pathways that lead to splenic activation; therefore, pupillometry can be used not only to assess response to therapy but also to control its delivery. Several portable automated pupillometers are available (e.g., NPi®-200, Neuroptics Inc., Irvine, California, USA) that can be used (e.g., with minor modifications) to automatically transmit pupil diameter information for the processing devices and / or systems described herein. Additionally, as discussed above, imaging of pupil changes (e.g., pupil dilation) captured by common portable computing devices such as mobile phones and / or smart glasses can be used to monitor pupil diameter.

[0097] The monitoring used may be based in part on the treatment environment. For example, while EEG monitoring is easier in a hospital environment, heart rate monitoring may be achieved by a sensor such as a pulsometer built into an earpiece or another sensor built into a budget health monitoring device such as a fitness monitoring device or smartwatch. Furthermore, while microfluidic chips and lab-on-a-chip monitoring are more practical in a hospital or clinical environment, pupil dilation can be easily monitored in a variety of environments.

[0098] In exemplary examples, feedback related to electrodermal activity can be used to monitor and detect the rate or timing of symptoms and / or treatment results. In one example, electrodermal activity can be sensed by electrodes on a therapeutic earpiece device. In another example, electrodermal activity can be detected by electrodes on another part of the body and communicated to the system. In some embodiments, the electrodermal electrodes can be such that they detect certain substances (e.g., cortisol) within the skin via electrochemical means.

[0099] In some embodiments, the system can further include one or more motion detectors, such as an accelerometer or gyroscope, that can be used to gather information and adjust therapy. In one example, the one or more motion detectors are configured to detect tremors and / or physiological motion. In one aspect, the tremors and / or physiological motion can indicate an underlying condition and / or treatment of the underlying condition. In one example, the tremors and / or physiological motion can indicate symptoms associated with substance withdrawal. In one aspect, feedback from glucose monitoring can be used to adjust therapy.

[0100] In yet other embodiments, an EKG can be used to assess heart rate and heart rate variability to determine autonomic nervous system activity, in terms of the overall and / or relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system, and to tailor therapy. Autonomic activity can be indicative of symptoms associated with substance withdrawal. In one aspect, a treatment device can be used to provide therapy for treating cardiac conditions such as atrial fibrillation and heart failure. In one example, therapy can be provided for modulation of the autonomic nervous system. In some embodiments, a treatment device can be used to provide therapy that balances the ratio between any combination of the autonomic, parasympathetic, and sympathetic nervous systems.

[0101] In one aspect, the system can monitor impedance measurements that enable closed-loop neurostimulation. In one example, feedback monitoring can be used to alert the patient / caregiver if therapy is being delivered improperly and if the treatment device is removed.

[0102] In some embodiments, sensor data may be monitored to determine whether and when to initiate a particular therapy. For example, one or more blood tests may be performed automatically or semi-automatically (e.g., periodically) to monitor differences in the function of a subject's coagulation pathways. Tests may, for example, be manually initiated and automatically analyzed. As discussed above, coagulation pathways are typically divided into three: intrinsic, extrinsic, and common. Different tests are commonly used to assess the function of both the intrinsic and extrinsic pathways. For example, a test known as activated partial thromboplastin time (aPTT), also known as partial thromboplastin time (PPT), can be used to assess the function of coagulation via the intrinsic and common coagulation pathways. Thus, PPT tests evaluate clotting factors XII, XI, IX, VIII, X, V, II, and I. For example, individuals with coagulation disorders, such as hemophilia, have prolonged or elevated PTTs. However, because various embodiments of the blood management therapies described herein enhance platelet-driven coagulation independent of, or nearly independent of, clotting factors, PTT can be shortened by treatment, even in hemophilia patients. Another test that assesses the same pathway as PTT is the activated clotting time (ACT) test. Thus, PTT (or ACT) can assess when to apply neurostimulation therapy. On the other hand, prothrombin time (PT) is commonly used to test coagulation via the extrinsic and common coagulation pathways. Thus, PT assesses the function of clotting factors VII, X, V, II, and I. In another example, PT can be used to assess the effectiveness of therapy and thereby determine when to resume stimulation therapy. PT, as well as PTT and ACT, can be assessed via various handheld devices available today (e.g., the Coag-Sense® PT meter from Coag-Sense Inc., https: / / coag-sense.com / , and the CL1000 from Easy Diagnosis, https: / / www.easydiagnosis.com / CL1000.html).The PTT, PT, and / or ACT measurements may be automatically transmitted (e.g., via a wireless connection) to a treatment device and / or system described herein (e.g., a cloud-based analysis engine) for analysis, for example, in determining how to control therapy delivery.

[0103] In some embodiments, stimulation pulses are delivered in a pulse pattern. Individual pulses within the pattern may vary in frequency and / or pulse width. The pattern may be repeated in a stimulation cycle. The pulse pattern may be designed in part to, for example, increase stimulation to establish a wearer's comfort level for the sensation of stimulation. In another example, the pulse pattern may be designed in part to alternate stimulation between stimulation sites if more than one site is being stimulated during treatment. In examples including multiple stimulation sites, the stimulation pattern may be designed so that the stimulation frequency is not the same at all sites to which stimulation is delivered.

[0104] In some embodiments involving electrical stimulation utilizing either percutanous or transcutaneous (i.e., non-penetrating) electrodes, the stimulation frequencies vary within a set of ranges. For example, the stimulation frequencies applied in a stimulation pattern may include a first or low frequency within the range of about 1-30 Hz, a second or medium frequency within the range of about 30-70 Hz, a third or high frequency within the range of about 70-150 Hz, and / or a fourth or very high frequency within the range of about 150-300 Hz. [Table 5]

[0105] In one embodiment, the stimulation frequency varies between 2 Hz and 100 Hz. In yet another embodiment, the pulse width can be adjusted between 20 and 1000 microseconds to further allow for customization of treatment. Stimulation frequency is an important differentiating factor between neural networks. For example, the use of high frequencies has proven beneficial for activating desired trigeminal nervous system functions. In contrast, low frequencies are preferred for activating desired vagus nerve functions. Thus, in a preferred embodiment, a combination of low and high frequencies is applied to activate the vagus and trigeminal nerve branches, respectively, according to various embodiments described herein. In yet another embodiment, a variable frequency (e.g., stimulation at a non-constant frequency) can be used on one or more of the electrodes. The variable frequency can be a sweep and / or random / pseudo-random frequency variation around a center frequency (e.g., 15 Hz + / - 1.5 Hz or 100 Hz + / - 10 Hz). Randomly or pseudo-randomly varying the stimulation frequency can help prevent neural adaptation.

[0106] When electrical stimulation is used, different combinations of pulse widths can be used for each electrode. In some embodiments, the pulse widths can be the following: a first or short pulse width in the range of about 10-50 microseconds, or more particularly 10-20 microseconds, 20-30 microseconds, 30-40 microseconds, 40-50 microseconds; about 50-250 microseconds, or more particularly 50-70 microseconds, 70-90 microseconds, 90-110 microseconds, 110-130 microseconds, 130-150 microseconds, 150-170 microseconds, 170-190 microseconds, 190-210 microseconds, 210-230 microseconds, or more particularly 50-250 microseconds; Second or low-medium pulse widths in the range of 230-250 microseconds; about 250-550 microseconds or more particularly 250-270 microseconds, 270-290 microseconds, 290-310 microseconds, 310-330 microseconds, 330-350 microseconds, 350-370 microseconds, 370-390 microseconds, 390-410 microseconds, 410-430 microseconds, 430-450 microseconds, 450-470 microseconds, 470-490 microseconds, 490-510 microseconds a third or high-medium pulse width in the range of about 550-1000 microseconds or more particularly 550-600 microseconds, 600-650 microseconds, 650-700 microseconds, 700-750 microseconds, 750-800 microseconds, 800-850 microseconds, 850-900 microseconds, 900-950 microseconds, or 950-1000 microseconds; and / or a fourth or long pulse width in the range of about 1000-4000 microseconds or more particularly 550-600 microseconds, 600-650 microseconds, 650-700 microseconds, 700-750 microseconds, 750-800 microseconds, 800-850 microseconds, 850-900 microseconds, 900-950 microseconds, or 950-1000 microseconds; The pulse width may be in the range of one or more of the following: microseconds, or more particularly, fifth or ultra-long pulse widths within the ranges of 1000-1250 microseconds, 1250-1500 microseconds, 1500-1750 microseconds, 1750-2000 microseconds, 2000-2250 microseconds, 2250-2500 microseconds, 2500-2750 microseconds, 2750-3000 microseconds, 3000-3250 microseconds, 3250-3500 microseconds, 3500-3750 microseconds, 3750-4000 microseconds. Different embodiments may use different ranges of pulse widths at one or more of the electrodes.The selection of stimulation pulse width depends on the desired target fiber and output intensity. For example, given similar intensity, activation of C-type fibers generally requires a longer pulse width than activation of myelinated Aβ fibers. In preferred embodiments, low-to-moderate pulses are used to preferentially activate myelinated fibers. [Table 6]

[0107] Activity on the VEF can be modulated by electrical stimulation at various sites. For example, the vagus nerve ascends within the carotid sheath in the neck (e.g., the cervical vagus nerve), which can be stimulated noninvasively and percutaneously using a patch electrode or device such as that described in U.S. Patent No. 10,207,106 to Simon et al. The cervical vagus nerve can also be stimulated invasively using an externally powered implanted electrode or a fully implanted system such as that described in U.S. Patent No. 8,571,654 to Libbus et al. An implanted system may, for example, provide low-frequency stimulation (e.g., 1-30 Hz) to the cervical vagus nerve and / or descending vagus nerve pathways. These same invasive / implanted methods can be used to stimulate the splenic nerve, thereby increasing splenic activity. Other methods of stimulation can also be used; for example, in some embodiments, ultrasound (see, e.g., U.S. Patent Application Publication No. 2011 / 0190668 to Mishelevich) or light (see, e.g., U.S. Patent No. 8,562,658 to Shoham et al.) can be used to directly activate the spleen.

[0108] Activity in the VEF can also be modulated by stimulating the auricular branch of the vagus nerve (ABVN) and / or by stimulating branches of the trigeminal nerve. Each of these pathways activates neurons in the nucleus tractus solitarius (NTS), which directly and indirectly increases VEF activity. The trigeminal nerve approaches the subcutaneous region at several locations on the face. For example, the auriculotemporal nerve (ATN), supraorbital nerve, supratrochlear nerve, infratrochlear nerve, palpebral branch of the lacrimal nerve, external nasal nerve, infraorbital nerve, zygomaticofacial nerve, zygomaticotemporal nerve, mental nerve, and buccal nerve are potential trigeminal nerve targets for transcutaneous stimulation. Devices with electrodes positioned to stimulate any of these branches can be used to improve coagulation through activation of the VEF. For example, a device such as that described in U.S. Patent No. 10,207,106 to Simon et al. can be used to stimulate branches of the vagus nerve. Similarly, the device described by Rigaux in U.S. Patent No. 8,914,123 can be used to stimulate branches of the trigeminal nerve. Furthermore, although cumbersome, both devices can be used simultaneously or alternately to elicit vagal, trigeminal, or trigemino-vagal responses. The ABVN can be stimulated at the auricle, with preferred targets for this purpose being the navicular, concha, tragus, and / or ear canal, as well as behind the ear in or around the mastoid canal (McS), also known as Arnold's canal. The ATN can be stimulated in or around the auricle, e.g., immediately rostral to the auricle, above and / or above the temporomandibular joint (TMJ). The ABVN and trigeminal nerve branches can be activated individually, simultaneously, or sequentially, e.g., alternately. Furthermore, these nerves can be stimulated invasively using percutaneous electrodes (e.g., as described in U.S. Patent No. 8,942,814 to Szeles) or (e.g., as described in U.S. Patent Application Publication No. 2018 / 0200522 to Taca Jr.), or non-invasively using percutaneous electrodes (e.g., as described in U.S. Patent No. 11,351,370 to Covalin et al.).

[0109] 6A and 6B, in a preferred embodiment, stimulation may be provided transcutaneously using an auricular stimulation device 600. Auricular stimulation device 600 is shown having electrodes 602, 604, 606, and 608. Electrodes 602, 604, 606, and 608 may be configured to form corresponding circuits 610a and 610b, for example, according to one embodiment. In one example, equivalent circuit 610a may be formed by electrodes 602 and 606 configured to stimulate tissue portion 620. In this example, tissue portion 620 is positioned to target the navicular region of the concha, innervated by the auricular branch of the vagus nerve, and the area behind the ear, innervated by branches of the greater auricular nerve and the lesser occipital nerve. In one example, equivalent circuit 610b may be formed by electrodes 604 and 608 configured to stimulate tissue portion 622. In this embodiment, tissue portion 622 may be positioned to target the area rostral to the ear where the auriculotemporal nerve transmits and sends branches below, as well as the area behind the ear innervated by branches of the greater auricular nerve and the lesser occipital nerve.

[0110] In one embodiment, tissue portion 620 may be a portion of the concha, the navicularis concha, or both, which allows for ABVN stimulation and is stimulated at approximately 5 Hz, 15 Hz, or 30 Hz. In one embodiment, tissue portion 620 may be positioned in the region of the trigeminal nerve, which is stimulated at approximately 80 Hz, 100 Hz, 120 Hz, or 150 Hz.

[0111] In one embodiment, equivalent circuit 610a is stimulated by a first channel and equivalent circuit 610b is stimulated by a second channel.

[0112] 6C and 6D, in some embodiments, stimulation may be provided transcutaneously using electrodes 642a, 642b, and 642c of auricular stimulation device 630. Electrodes 642a, 642b, and 642c may be configured to form corresponding circuits 650a and 650b, for example.

[0113] In a first example, equivalent circuit 650a may be formed by electrodes 642b and 642c configured to stimulate tissue portion 652a. In this example, tissue portion 652a may be positioned to target the ATN in or around the rostral region of the pinna, adjacent to the TMJ. For example, equivalent circuit 650a may be designed to deliver stimulation that modulates activity in the VEF.

[0114] In a second example, equivalent circuit 650b may be formed by electrode 642a and electrode 642c configured to stimulate tissue portion 652b, which may be positioned to modulate VEF by stimulating active AVBN in or around the McS.

[0115] In yet another embodiment, to achieve synergistic results, both the AVBN and the ATN are stimulated in or around the McS and in or around the rostral region of the pinna adjacent to the TMJ, respectively. In this scenario, for example, both the AVBN and the ATN may be stimulated approximately simultaneously and alternately. Illustratively, each of electrodes 642a and 642b may be multiplexed with electrode 642c to form a circuit and pass current alternately through tissue 652a and tissue 652b. In another embodiment, the AVBN and the ATN may be stimulated simultaneously.

[0116] In some embodiments, equivalent circuit 650a is stimulated by a first channel and equivalent circuit 650b is stimulated by a second channel.

[0117] 6E and 6F, an auricular stimulation device 660 is shown having electrodes 670a, 670b, and 670c. Electrodes 670a, 670b, and 670c may be configured to form corresponding circuits 680a and 680b, for example, according to one embodiment. In one embodiment, equivalent circuit 680a may be formed by electrodes 670a and 670c configured to stimulate tissue portion 682. In this embodiment, tissue portion 682 may be positioned to target the navicular region of the concha innervated by the auricular branch of the vagus nerve (e.g., positioned for stimulation by first electrode 670a) and the region behind the ear innervated by branches of the greater auricular nerve and the lesser occipital nerve (e.g., positioned for stimulation by third electrode 670c). In a second embodiment, equivalent circuit 680b may be formed by electrodes 670b and 670c configured to stimulate tissue portion 684. In this example, tissue portion 684 may be positioned to target a rostral region of the ear innervated by the auriculotemporal nerve (e.g., positioned for stimulation by second electrode 670b) and a region behind the ear innervated by branches of the greater auricular nerve and the lesser occipital nerve (e.g., positioned for stimulation by third electrode 670c).

[0118] In some embodiments, tissue portion 682 is a tissue region of the concha, the navicularis, or part of both, which is stimulated at approximately 5 Hz, 15 Hz, or 30 Hz, hi some embodiments, tissue portion 684 is positioned in a region of the trigeminal nerve which is stimulated at approximately 80 Hz, 100 Hz, 120 Hz, or 150 Hz.

[0119] In some embodiments, equivalent circuit 682 is stimulated by a first channel and equivalent circuit 684 is stimulated by a second channel. The first and second channels may be activated simultaneously and / or alternately.

[0120] In some embodiments, the electrical stimulation therapy for hemorrhage management described herein is performed using splenic nerve stimulation. In other embodiments, the spinal roots (sometimes called dorsal root ganglia, or DRGs) that give rise to the large splanchnic nerves in the thoracic region can be the stimulation target (also known as splanchnic DRGs). In further embodiments, the celiac ganglion can be the target of stimulation. These neural structures, as well as the splenic nerve directly, can be stimulated percutaneously, for example, using ultrasound (e.g., focused or confocal ultrasound / high-intensity ultrasound). In another example, implanted electrodes or devices can be used to stimulate these neural structures (i.e., splenic nerve, celiac ganglion, DRGs) and the splenic nerve. The implanted mechanism, in further examples, can be configured to provide low-frequency stimulation (e.g., 1-30 Hz) when activated. Activation can be achieved through programming (e.g., periodic activation), external triggering (e.g., by wireless signal), and / or external power supply (e.g., by placing an external inductively coupled power source within range of the inductively charged implanted mechanism). With an external trigger, for example, treatment may be timed based on the patient's needs, e.g., power may be stored in a battery-powered device. Each therapeutic activation of the spleen or splenic nerve may include, for example, a series of short pulses, e.g., a brief on-time stimulation (e.g., 0.5, 1, 2, or 5 seconds, etc.), followed by a rest period of at least the same duration (e.g., 0.5, 1, 2, or 5 seconds, etc.) or up to about 5 times longer than the on-time (e.g., up to about 2.5, 5, 10, or 25 seconds, etc.).

[0121] Exemplary Human Trials Involving Non-Invasive Stimulation Using an Auricular Nerve Stimulation Device Figures 8A-8E demonstrate the results of three human studies using a noninvasive dual-nerve, dual-frequency approach. Using this novel approach, we were able for the first time to enhance hemostasis in both healthy humans and those suffering from platelet dysfunction. In all three experiments, we obtained relevant and clinically significant results demonstrating a clear enhancement of the hemostatic process.

[0122] In one study, blood loss was assessed during a clinical trial in which subjects with chronic conditions requiring continuous dialysis underwent dialysis port removal procedures. The subjects were randomly assigned to a sham group and an active group. Subjects in both groups were fitted with ear-worn neurostimulation devices as described in the present disclosure. However, only the active group received the neurostimulation treatment described herein.

[0123] Treatment provided to the efficacy group consisted of 30 minutes of stimulation prior to the surgical dialysis port removal procedure. Specifically, 30 Hz and 100 Hz stimulation was delivered transcutaneously to the skin in and around the pinna (transcutaneous auricular stimulation - tAN), in proximity to the AVBN and trigeminal nerve branches.

[0124] This study demonstrated a significant difference in blood loss between the two groups. As shown in graph 800 of Figure 8A, participants in the sham group lost, on average, nearly four times (367%) the amount of blood lost by participants in the active group. As shown, the sham group lost an estimated 37-38 mL of blood, while subjects in the active group lost an estimated 11-12 mL of blood. This is a significant result given that participants suffer from platelet dysfunction.

[0125] In a second human study, prothrombin time (PT) was measured before and after stimulation was administered to healthy human participants. PT assesses the rate at which clotting occurs and, therefore, plays an important role in determining blood loss after injury. In this experiment, PT was measured from blood samples taken from participants before stimulation delivery. Subjects were then fitted with ear-worn neurostimulators as described herein, and a stimulation protocol similar to that described in connection with timing diagram 720 of FIG. 7B was administered to all subjects for 15 minutes (e.g., a short period of time). In the study, a first stimulation pattern with a frequency of 100 Hz was directed to the ATN, and a second stimulation pattern with a frequency of 30 Hz was directed to the Arnold nerve. Following the stimulation session, new blood samples were obtained from each participant, and PT was assessed from the new blood samples.

[0126] Referring to FIG. 8B, graph 810 shows the difference in human prothrombin time before stimulation 812 (e.g., approximately 11.2 seconds) compared to after stimulation 814 (e.g., approximately 9.8 seconds). This represents a 12% (standard error 0.013) improvement in clotting rate (i.e., improved clotting ability). Notably, all subjects had the same qualitative response and very similar quantitative responses, as seen by the standard deviation (STD) and coefficient of variation (CV) in Table 7 below. In the study, PT was measured using whole blood via a fingertip lancet both before the start of stimulation and approximately 1 minute after stimulation cessation. [Table 7]

[0127] Figures 8C, 8D, and 8E show the results achieved through a third study involving healthy human subjects divided into two groups (ABVN and tAN groups). All participants in both groups were fitted with ear-worn neurostimulation devices as described herein, and all participants underwent a sham stimulation session followed by an active stimulation session. In all cases, baseline measurements were taken before the sham measurements. Analysis of the data demonstrated no significant differences between the baseline and sham measurements. Therefore, only the sham measurements are provided herein.

[0128] In the third study, the ABVN group received the stimulation treatment described herein on the auricular skin adjacent to or close to the area innervated by the ABVN, specifically the concha navicularis. The tAN group received the stimulation treatment described herein on the auricular skin both adjacent to or close to the area innervated by the ABVN (specifically the concha navicularis) and in an area adjacent to or close to the surface of the auriculotemporal nerve. Additionally, both groups received "sham" stimulation with electrodes placed in the same positions as when stimulation was actually applied (active stimulation). The only difference between active and sham stimulation was that during the sham stimulation period, the stimulation intensity was set to zero; i.e., no current was delivered during the sham stimulation period.

[0129] Both groups demonstrated increased hemostatic activity. Results differed qualitatively and initially quantitatively between groups. The experiment specifically assessed changes in the surface expression of two key molecules, glycoprotein (GP) IIb / IIIa and P-selectin. Some platelets showed an increase in only one of these molecules, while others showed an increase in both molecules (double staining). Referring to graph 820 in Figure 8C, sham results 822a, 822b establish a point of comparison. As shown in 60-minute post-activation measurements 826a, 826b, both groups demonstrated an increase in glycoprotein (GP) IIb / IIIa expression on the platelet surface. However, the increase in GP IIb / IIIa in the ABVN group was slower and lacked significant evidence of efficacy in the initial measurement period 824b, performed 10 minutes after stimulation treatment. Conversely, the initial tAN measurement 824a was virtually identical to the 60-minute post-activation measurement 826a.

[0130] Similar responses were obtained when looking at platelet abundance, which simultaneously showed changes in both P-selectin and GP IIb / IIIa surface expression. This is shown in graph 830 of Figure 8D. As shown, both groups showed an increase in cells expressing both P-selectin and GP IIb / IIIa 836a, 836b, but the tAN group responses 834a, 836a occurred more quickly compared to sham measurements 832a, 832b, while the ABVN group responses 834b, 836b did not register an increase until the 60-minute measurement.

[0131] Clot contraction is significantly influenced by the presence of GP IIb / IIIa receptors on the platelet surface. Clot contraction aids in wound healing by drawing the separated edges of the wound closer together until the wound is healed. Therefore, by promoting changes to GP IIb / IIIa receptors, both groups of subjects are expected to benefit from accelerated healing times.

[0132] Additionally, referring to Figure 8E, using thrompoelastography (TEG) to analyze the coagulation profile, the maximum clot density (TEG MA) significantly increased in the tAN group but not in the ABVN group. As illustrated, 10 minutes after active stimulation, tAN group result 844a demonstrated a mean increase in TEG MA of approximately 20% compared to sham results 842a and 842b. Furthermore, one hour after cessation of active stimulation, tAN group result 846a showed a mean increase of approximately 30%. All individuals represented in the tAN group demonstrated at least a 10% increase in TEG MA by the 60-minute analysis time point, with the majority of subjects demonstrating at least a 20% increase by the 60-minute analysis time point. The increased clot density resulted in a stronger clot. The majority of subjects experienced faster bleeding cessation. Conversely, individuals suffering from low TEG MA (e.g., having thrombocytopenia, thrombocytosis, etc.) are typically treated with platelet transfusions to manage bleeding because there are no available medications to increase clot density. Thus, based on initial results, and without being bound by theory, the inventors predict that the electrical stimulation treatments described herein will provide the benefit of enhancing platelet-mediated clotting. In other words, individual platelets are enhanced to clot better than they were prior to stimulation.

[0133] Referring to FIG. 9 , a block diagram 900 of example components of a pulse generator 950 in communication with example components of an auricular component 960 is shown. The multi-channel pulse generator circuit 950 includes at least one microcontroller or microprocessor 910, which in some embodiments has at least one core. If multiple microcontrollers or multiple cores are present, for example, one may control the wireless communication 920, while other core(s) may be dedicated to controlling therapy. In some implementations, a low-power programmable logic circuit (e.g., a field programmable gate array (FPGA) or programmable logic device (PLD)) 912 is also provided. For example, the microcontroller 910 may be configured to switch to a low-power mode as often as possible while the programmable logic circuit 912 controls therapy delivery.

[0134] In some embodiments, inverter circuits 945a-n are used to generate biphasic / bipolar pulses. In some embodiments, one inverter circuit 945a-n is used per channel 970a-n, while in other embodiments, a single inverter circuit 945 is used for multiple channels 970a-n. Each channel 940a-n may target, for example, a different anatomical region (e.g., tissue region) 948a-n. By providing one or more high-voltage inverters 940a-n per inverter circuit 945a-n using high voltage compliance (e.g., >50V, in other embodiments >70V, and in yet other embodiments >90V), sufficient potential margin may be ensured to generate the current required by the intensity control 942a-n of each inverter circuit 945a-n. For added safety, in some embodiments, an overcurrent detection circuit 944a-n is provided for each inverter circuit 945a-n. In some embodiments, an impedance measurement circuit 946a-n is provided for each inverter circuit 945a-n. The impedance measurement circuitry 946a-n may support, for example, tracking impedance over time to identify failure of sufficient therapy delivery. In some examples, therapy delivery may be impaired if the electrodes are not in or poorly in contact with the target tissue 948a-n, if a cable or connector becomes disconnected between the multi-channel pulse generator 950 and the pinna component(s) 960, or if the electrodes are degraded or defective. Monitoring impedance over time provides the added benefit of being able to track the condition of the contact electrodes, thereby enabling the controller to alert the user when the contact electrodes are nearing the end of their life or are no longer viable. The FPGA 912 may control the inverter circuits 945a-n and may receive feedback from the inverter control components 938a-n.

[0135] In some implementations, a battery 932 is used to power the pulse generator 950. The battery 932 may power the components of the pulse generator 950 and / or pinna component(s) 960, for example, via one or more low-voltage converters 934. Additionally, the pulse generator 950 may include a high-voltage converter 936 coupled to one or more high-voltage inverters 940a-n for delivery of electrical stimulation therapy via one or more channels 945a-n.

[0136] In some embodiments, an isolated port 918, such as a Universal Serial Bus (USB), is used to charge the battery 932. In other embodiments, battery charging is achieved wirelessly via inductive coupling (not shown). The battery 932 may be charged via a battery charging circuit 930.

[0137] In some implementations, the isolation port 918 is used to communicate with the microcontroller(s) 910 (e.g., via the communication port 916). The communication can be bidirectional, allowing instructions or entire new code to be uploaded to the microcontroller(s) 910 and information stored in the memory 922 to be downloaded. In some embodiments, the memory 922 or additional memory can be added to the circuit as an external component (e.g., in wireless or wired communication with the pulse generator 950). For example, the isolation port 918 (e.g., USB) can be used to connect the memory to the pulse generator 950. In other embodiments, at least a portion of the memory 922 can be internal to the microcontroller(s) 910. In some embodiments, the FPGA 912 can also have internal memory.

[0138] In some embodiments, an external trigger circuit 924 is included, which allows stimulation to be started and / or stopped via an external signal. In some embodiments, the external trigger signal can be passed through the isolated port 918. In yet other embodiments, a modified USB configuration (i.e., not using the standard USB pin configuration) can be used to pass the trigger signal. Using a modified USB configuration, a custom USB cable is used, thereby ensuring that an off-the-shelf USB cable cannot be used to accidentally provide an external trigger. In a further example, the external trigger signal may be transmitted wirelessly (e.g., via Bluetooth) from a separate source.

[0139] In some embodiments, a hardware user interface is provided for interacting with the multi-channel pulse generator 950 via user interface circuitry 926. In one example, the user interface circuitry 926 can include tactile (e.g., piezoelectric) devices such as buttons, LEDs, buzzers, and / or displays, or any combination thereof. In some embodiments, the user interface circuitry 926 includes signal processing components for interpreting user interface commands delivered via an external device (e.g., through wireless communication 920). The external device, in some examples, can be a smartphone app, a tablet computer, or a medical monitoring device (e.g., in a hospital environment).

[0140] In some embodiments, an external master clock 928 is used to drive the microcontroller(s) 910 and / or FPGA 912. In other embodiments, the component clock(s) may be internal to, embedded in, or packaged together with the microcontroller(s) 910 and / or FPGA 912. In some embodiments, one or more oscillators, including possibly an adjustable oscillator 914, are used to set pulse parameters such as frequency and / or pulse width, for example.

[0141] In some embodiments, the pinna component 960 is made from a thin, flexible PCB or printed electronics that is lightweight and can be easily bent to accommodate various anatomical structures. In some embodiments, the pinna component 960 has two or more channels. The pinna component 960, or each of its channels, may include peak suppression circuitry 947a-n and electrodes 965a-n that contact the skin at the location of the target tissue 948a-n. In some embodiments, the pinna component(s) 960 include a unique chip identifier or unique ID chip 949. The unique ID chip can be used to track usage and prevent other unauthorized circuits from being connected to the multi-channel pulse generator 950. At least one pinna component(s) 960 is connected to the multi-channel pulse generator 950.

[0142] In some embodiments, the pinna component 960 is made from a thin, flexible PCB or printed electronics that is lightweight and can be easily bent to accommodate various anatomical structures. In some embodiments, the pinna component 960 has two or more channels. The pinna component 960, or each of its channels, may include peak suppression circuitry 947a-n and electrodes 965a-n that contact the skin at the location of the target tissue 948a-n. In some embodiments, the pinna component(s) 960 include a unique chip identifier or unique ID chip 949. The unique ID chip can be used to track usage and prevent other unauthorized circuits from being connected to the multi-channel pulse generator 950. At least one pinna component(s) 960 is connected to the multi-channel pulse generator 950.

[0143] In some embodiments, methods and systems of the present disclosure use feedback to monitor and / or modify therapy. Referring to FIG. 13 , an environment 1350 and system 1360 for using feedback in neurostimulation are shown. Environment 1350 and / or system 1360 may incorporate elements of various treatment devices described herein, such as treatment device 600 of FIG. 6A , treatment device 630 of FIG. 6C , and / or treatment device 660 of FIG. 6E . Furthermore, environment 1350 may include peripheral devices 1354, 1358, 1356, 1390, and / or network system 1532. Additionally, system 1360 may include aspects of a multi-channel pulse generator, as described in more detail below. Environment 1350 and system 1360 may be used, for example, to analyze sensor data in real time to enable closed-loop neurostimulation based on feedback data associated with the wearer of the neurostimulation device. In another example, feedback monitoring can be used to alert the patient, caregiver, and / or clinical resources regarding treatment progress and / or treatment problems. For example, if treatment is not being delivered properly and / or if a treatment device is removed, a caregiver or clinician may be contacted at the clinical / caregiver computing system(s) 1390.

[0144] In some implementations, system 1360 is initiated at least in part by initiating power to system 1360 via power control circuitry 1384. One or more control elements 1386 may provide, for example, the ability for a wearer or patient to initiate system 1360 and / or set initial treatment parameters. In certain embodiments, treatment may be activated and / or adjusted remotely through an external device, such as portable computing device 1354.

[0145] In some embodiments, one or more sensor interfaces 1362 of system 1360 obtain feedback from one or more sensors 1370. For example, various sensors 1370 may be provided to monitor one or more symptoms to be treated by the therapy, such as, in some embodiments, symptoms of stress and / or anxiety, pain, nausea, fatigue, inflammation, and / or disorientation / dizziness. In other embodiments, certain sensors 1370 may be provided to monitor the wearer's activity or movements and adjust the therapeutic stimulus and activity / movement. In some examples, sensors 1370 may include one or more motion sensors 1370a (e.g., motion sensors, accelerometers, and / or gyroscopes) for monitoring motion activity (e.g., tremors, physiological motion), one or more electrodermal sensors 1370b, possibly electrochemical sensors for monitoring electrodermal activity (e.g., sweating, cortisol, etc.), one or more glucose sensors 1370c for monitoring glucose levels, one or more neural sensors 1370d for monitoring neural activity (e.g., via electroencephalogram (EEG) sensing electrodes), one or more cardiopulmonary sensors 1370e for monitoring cardiopulmonary activity (e.g., one or more electrocardiogram (EKG) sensing electrodes, heart rate sensor(s), blood pressure (systolic, diastolic, and mean) sensor(s), etc.), and / or muscle response sensor(s) 1370f (e.g., electromyogram (EMG) sensors) for monitoring muscle response activity. In another example, sensors 1370 include one or more acoustic sensors 1370g (e.g., microphones, bone conduction microphones, vibration sensors, etc.) for acquiring audio signals (e.g., phonation and / or speech, respiratory sounds, heart sounds, etc.). In additional examples, sensors 1370 may include one or more ultrasonic sensors 1370h for measuring deep tissue signals such as, in some examples, central blood pressure, cerebral blood flow velocity (CBFV), heart rate, and / or cardiac output.

[0146] The sensors 1370 may communicate wired and / or wirelessly with the sensor interface(s) 1362 of the system 1360. A particular sensor 1370 may be incorporated into the earpiece and / or concha device of an ear-worn neurostimulation device, such as the various devices described in this disclosure. In another example, one or more sensors 1370 may be incorporated into a pulse generator for delivery of neurostimulation therapy. In further examples, periodic monitoring may be achieved by prompting the wearer to touch one or more electrodes on the system 1360 (e.g., electrodes embedded on the surface of the pulse generator) or otherwise interact with a component of the system 1360, such as the pulse generator (e.g., holding the pulse generator extended away from the body and monitoring for tremors using a motion detector in the pulse generator). Prompts may be provided, for example, via user interface 1366, by one or more speaker elements 1380a (e.g., verbal commands) and / or one or more lighting element(s) 1380b (e.g., LCD displays, LED displays, seven-segment digital displays, and / or LED indicator(s) next to information printed on the surface of system 1360).

[0147] In some implementations, user interface 1366 is used to deliver portions of the therapy to the wearer. For example, system 1360 may coordinate the neurostimulation therapy with a virtual reality (VR) device 1392. In some examples, VR device 1392 may deliver audio, visual, and / or haptic output consistent with a particular therapy goal. In examples, to reduce stress and anxiety, the system may configure VR device 1392 to provide relaxing audio and / or visual output to the wearer during the neurostimulation therapy. In another example, to overcome PTSD, phobias, cravings, and / or other addiction-related triggers, VR device 1392 may be configured to present triggering audio and / or visual content during the neurostimulation therapy. While illustrated as a separate VR device 1392, in other embodiments, the neurostimulation electrodes are incorporated into the VR device (e.g., a VR headset) as a virtual reality-enabled neurostimulation therapy device.

[0148] In some embodiments, feedback data collected by the system 1360, e.g., sensor feedback, may be provided by the pulse generator to one or more of the peripheral devices 1354, 1390. The feedback may include, for example, sensor signals related to a patient's condition being treated by the system 1360. A clinical user monitors sensor metrics related to these signals and may manually adjust therapy delivery using one or more adjustable controls provided by the application. Additionally, in some embodiments, the feedback may be used by one of the peripheral devices 1354, 1390 to generate notifications for review by the patient, caregiver, or clinician. Notifications may include, for example, low power notifications, device removal notifications, or malfunction notifications. In the illustrated example, the system 1360 may monitor impedance measurements that enable closed-loop neural stimulation. A notification regarding removal or malfunction may be issued, for example, when impedance measurements are determined to indicate a lack of proper contact between one or more electrodes of the treatment device and tissue on or around the patient's ear. The notification may be delivered to the patient and / or one or more third parties, for example, via an application executing on one of the peripheral devices 1354, 1390. For example, the application may sound an audible alarm, present a visual notification, or generate a tactile output on the peripheral device 1354, 1390. Additionally, in some embodiments, the application may issue the notification via a communication means, such as, for example, sending an email, text message, or other electronic message to one or more authorized users, such as the patient, caregiver, and / or clinician.

[0149] Conversely, in some embodiments, a cloud platform with sensor data analytics 1352 accessible over a network may receive feedback, review current metrics, and relay instructions to the pulse generator (e.g., over a Wi-Fi network or indirectly via a local portable device 1354). In further examples, the pulse generator may collect feedback from one or more fitness monitor and / or health monitor devices 1354, 1390, analyze the feedback, and determine whether to adjust treatment accordingly.

[0150] In other embodiments, the pulse generator is included in the auricle component of the treatment device. That is, the pulse generator and auricle component may be co-located so that there is no need for an extension cable connecting them. The auricle component and pulse generator may be wirelessly connected to an electronic device (e.g., a personal computer, tablet, or phone) 1354, 1390 and / or a remote server 1352. In turn, in some embodiments, the electronic device 1354, 1390 is also wirelessly connected to the remote server 1352.

[0151] In some embodiments, the system 1360 includes at least one isolation port for wired connection to peripheral device(s) 1354, 1390. The isolation port may, in some examples, be a Universal Serial Bus (USB) connection (e.g., a mini-USB connection, a micro-USB connection, a USB-C port, etc.), an Ethernet port, or a Serial ATA (SATA) connector. The isolation port may be included in the pulse generator, for example, to update the software version running on the pulse generator or to program the pulse generator's treatment settings. The isolation port(s) may be connected to a network communication interface 1368 to enable communication between the peripheral device(s) 1354, 1390 and the system 1360 via the isolation port. The network communication interface 1368 may couple the isolation port to the system control circuitry 1372. For example, the network communication interface 1368 may establish a direct (eg, wired) communication link with one of the peripheral device(s) 1354, 1390 to transfer data from the memory 1376 to the peripheral device 1354, 1390.

[0152] Additionally, a wireless radio frequency (RF) antenna (e.g., a transmitter or transmitter / receiver) is included in the network communication interface 1368 in some embodiments. The RF antenna can communicate wirelessly with the peripheral device(s) 1354, 1358, either directly or over a network. The RF antenna, in combination with processing circuitry for generating wireless communications, may function as a broadcast antenna, providing information to any RF receiver within the reception range of the system 1360. For example, the RF antenna may broadcast sensor data, sensor metrics, alerts, alarms, or other operational information for reception by one or more peripheral devices 1354, 1390. In other embodiments, the RF antenna, in combination with additional processing circuitry, may establish a wireless communication link with a particular peripheral device 1354, 1390. The wireless communication link, in some embodiments, is a secure wireless communication link (e.g., HIPAA compliant) for sharing patient data with the peripheral device(s) 1354, 1390. The wireless communication link may be used to receive control settings from the peripheral device(s) 1354, 1390, for example, to control pulse generator functions.

[0153] In some implementations, sensor data is received from one or more portable wireless computing devices 1354 via network communication interface 1368. In some examples, sensor elements of a typical smartphone, smart glasses, smart ring, and / or smart watch (e.g., accelerometer, gyroscope, microphone, image sensor (e.g., camera), heart rate monitor, oxygen saturation, blood pressure, glucose sensor, etc.) may be used by applications designed to interoperate with system 1360 to provide sensor data to system 1360. Illustratively, footage (e.g., video) of pupil changes (e.g., pupil dilation) may be captured by the smartphone or smart glasses and used by system 1360 as feedback to make therapy adjustments. Pupillometry may be used, for example, as a measure of attention, vigilance, or wakefulness (or lack thereof). Thus, feedback may be used to adjust therapy to maintain a desired level of attention, vigilance, and / or wakefulness.

[0154] In some implementations, sensor data is received from one or more additional sensor devices 1356 via network communication interface 1368. In some examples, the additional sensor devices 1356 may include a fitness monitor and / or activity tracker (e.g., to provide data similar to that collected by motion sensor(s) 1370a, electrodermal sensor(s) 1370b, and / or cardiopulmonary sensor(s) 1370e), a home health monitoring device (e.g., a digital smart blood pressure cuff to provide data similar to that collected by cardiopulmonary sensor(s) 1370e, a digital smart thermometer, etc.), and / or a remote patient monitoring device (e.g., a glucometer to provide data similar to that collected by glucose sensor(s) 1370c, a pulse oximeter, a wearable cardiac monitor, e.g., a Holter monitor to provide data similar to that collected by cardiopulmonary sensor(s) 1370e, etc.).

[0155] In some implementations, sensor data is received from one or more clinical devices and / or appliances 1358 via network communication interface 1368. Illustratively, imaging techniques such as magnetic resonance imaging (MRI) and / or functional MRI (fMRI) can be used to tailor therapy in a clinical setting for a given user. In other examples, data similar to that collected by neural sensor(s) 1370d, cardiopulmonary sensor(s) 1370e, glucose sensor(s) 1370c, and / or muscle response sensor(s) 1370f may be provided by various clinical appliances 1358.

[0156] In some embodiments, the types of monitoring used by system 1360 and / or reliance (e.g., reliance) on various incoming sensor data may be based in part on the treatment setting. For example, neurological data captured by sensors such as neural sensor(s) 1370d may be easier to capture in a hospital setting, while certain cardiopulmonary data captured by sensors such as cardiopulmonary sensor(s) 1370e (e.g., heart rate monitoring) may be achieved by capturing signals from a pulsometer built into an earpiece or another sensor (e.g., additional sensor device 1356) built into a budget health monitoring device such as a fitness monitoring device or smartwatch.

[0157] In some implementations, sensor interface(s) 1362 collect signals from sensor(s) 1370 and provide the signals to signal processing circuit 1364. Signal processing circuit 1364 may include one or more filters (e.g., bandpass filters), amplifiers, and / or other circuitry to, for example, remove noise, isolate useful input signals, and / or increase signal strength. In some embodiments, signal processing circuit 1364 converts analog signals into digital signal components.

[0158] In some embodiments, sensor signals from the sensors 1370, the portable wireless computing device(s) 1354, the additional sensor device(s) 1356, and / or the clinical device(s) / apparatus 1358 are provided to the system control circuitry 1372 for data analysis. The system control circuitry 1372, in some examples, may perform thresholding, pattern analysis, and / or temporal variation analysis to recognize physiological, biological, and / or physical behavior of the wearer of the therapeutic stimulation device that corresponds to adjustments in treatment. For example, sensor data may be collected in memory or temporary data storage 1376 to analyze the sensor data over a predetermined period of time. The period of time may, in some examples, vary based on the type of treatment provided, the type of data being analyzed, and / or the treatment goals. Adjustments in treatment, in some examples, may include starting treatment, ceasing treatment, and / or adjusting one or more treatment parameters (e.g., voltage, frequency, stimulation pattern, stimulation location(s), etc.).

[0159] In some implementations, system control circuitry 1372 provides the sensor data to external sensor data analysis system 1352 via network communication interface 1368. Sensor data analysis system 1352, in some examples, can include an edge router, a cloud computing platform, and / or one or more network servers configured to analyze the sensor data to identify conditions that trigger adjustments in therapy. The analysis, in some embodiments, includes biometric fingerprint analysis, in which physiological, biological, and / or physical behavior captured in the sensor data is analyzed taking into account baseline or historical physiological, biological, and / or physical behavior of a particular wearer.

[0160] In some embodiments, based on the sensor data by the system control circuitry 1372 and / or the sensor data analysis system 1352, therapy parameter adjustments are provided to the therapy controller 1374 to adjust stimulation parameters delivered via a therapy delivery circuitry 1378 (e.g., a pulse generator circuit) to a set of stimulation electrodes 1382. The therapy delivery circuitry 1378 and stimulation electrodes 1382 are discussed in more detail above with reference to FIG.

[0161] In a first exemplary embodiment, upon reduction or elimination of one or more symptoms, the therapeutic output may be similarly reduced or discontinued. Conversely, upon increase or addition of one or more symptoms, the therapeutic output may similarly be activated or modulated (increased, expanded, etc.).

[0162] In another exemplary embodiment, feedback related to electrodermal activity can be used to monitor and detect the rate or timing of symptoms and / or treatment results. In one embodiment, electrodermal activity can be sensed by electrodermal sensors 1370b. For example, an electrodermal patch having one or more electrodermal sensors 1370b can be used to estimate an individual's stress level by assessing cortisol levels in sweat.

[0163] In one example, one or more motion detectors 1370a may be configured to detect tremors and / or physiological motion. In one aspect, the tremors and / or physiological motion may indicate an underlying disease and / or treatment of the underlying disease. In one example, the tremors and / or physiological motion may indicate symptoms associated with substance withdrawal. In another example, exercise and sequential combinations of exercise may be used to assess the results of training protocols aimed at restoring performance in these exercises.

[0164] In a further embodiment, feedback from the glucose sensor 1370c can be used to adjust therapy. Individuals with type 2 diabetes lack the ability to control glucose levels, and vagus nerve stimulation has been shown to reduce hyperglycemia. Thus, assessment of glucose levels can be used to trigger stimulation to increase glycemic control.

[0165] In additional examples, neural sensor(s) 1370d and / or cardiopulmonary sensor 1370e may be used to assess heart rate and heart rate variability, determine autonomic nervous system activity in terms of overall and / or relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system, and tailor therapy. Autonomic activity may indicate symptoms associated with substance withdrawal. In one aspect, a treatment device may be used to provide therapy for treating cardiac conditions such as atrial fibrillation and heart failure. In one example, therapy may be provided for modulation of the autonomic nervous system. In some implementations, a treatment device may be used to provide therapy that balances the ratio between any combination of the autonomic, parasympathetic, and sympathetic nervous systems.

[0166] In a further exemplary embodiment, feedback signals collected by muscle response sensor(s) 1370f may be analyzed to prompt stimulation during physical motor recovery, such as arm motor recovery. For arm motor recovery, multiple muscle response sensors 1370f may be placed in a NeuroLife® EMG Sleeve provided by Battelle Memorial Institute of Norwell, Massachusetts.

[0167] In a final illustrative example, attention, vigilance, and / or alertness can be assessed by measuring cerebral blood flow velocity (CBFV) with ultrasound sensor(s) 1370. In such an example, CBFV can be used as feedback to adjust therapy.

[0168] In some embodiments, sensor data analysis system 1352 collects historical sensor data and treatment parameters across a population of patients and applies the collected data to perform machine learning analysis to refine treatment protocols and parameters at an individual level. This can result in, for example, faster and / or greater functional recovery. In an exemplary embodiment that may be used in a hospital setting, such as an intensive care unit (ICU) or neonatal intensive care unit (NICU), after a stroke or TBI, data collected via sensors 1370, in some embodiments, heart rate (ECG), arterial oxygen saturation (SpO2), arterial blood pressure (possibly using an arterial catheter), central venous pressure, core temperature, blood glucose, respiratory rate and / or volume, urine volume, and / or cardiac output sensors, can be analyzed and applied in automatically prescribing and / or adjusting neuromodulation treatment. In further embodiments, sensor data can provide insights regarding osmolality, serum electrolytes, and / or blood gases (arterial), which can then assist in decisions in automatically prescribing and / or adjusting neuromodulation treatment. In some examples, the sensor data may be analyzed for evidence of patient comfort (e.g., indicators of possible pain and / or stress in the patient), evidence of inflammation, and / or evidence of ischemic processes (e.g., evidence of metabolic waste accumulation).

[0169] In some embodiments, the sensor data analysis system 1352 applies machine learning and / or artificial intelligence (AI) analysis to refine the therapy session to deliver more effective and / or more efficient treatment. Referring to FIG. 14 , an exemplary sensor data analysis system 1402 and platform environment 1400 acquires data from a neurostimulation system (e.g., a device and / or pulse generator) 1404 and / or a computing device 1406, analyzes the data to ensure therapy goals are met, and / or automatically refines therapy parameters to improve the effectiveness of the therapy.

[0170] In some embodiments, the sensor data analysis system 1352 includes a therapy data collection engine 1408 configured to collect data from the neurostimulation system 1404 and associate the data with individual users. The therapy data collection engine 1408, in some examples, may collect data associated with each user of each neurostimulation system 1404 and store the data in a computer-readable data storage area (user data store) 1410. In some examples, the user data may include effective treatment parameter data 1412 (e.g., stimulation pattern(s), frequency(es), identification of a particular treatment routine, identification of a particular treatment setting, etc.), effective treatment feedback data 1414 (e.g., sensor data collected by the neurostimulation system 1404 and / or one or more other sensor devices in communication with the neurostimulation system 1404), and / or effective treatment context data 1416 (e.g., geographic location, time of day, day of the week, ambient temperature, speed / acceleration of the wearer, ambient noise level, etc.).

[0171] In some implementations, the external sensor data collection engine 1418 collects sensor data acquired by one or more devices external to the neurostimulation system 1404 and in communication with the sensor data analysis system 1402. In some examples, the devices may include fitness monitoring devices (e.g., a Fitbit, Apple Watch, or Garmin Smartwatch) and / or health monitoring devices (e.g., a blood glucose meter, a Holter monitor, an electrocardiogram (EKG) monitor, or an electroencephalogram (EEG) monitor). In further examples, the external devices may include clinical patient monitoring and / or management devices (e.g., brain monitoring, capnography monitoring, brain / somatic oximetry, pulse oximeter, regional and / or temperature management, etc.).

[0172] In some embodiments, the therapy data analysis engine 1420 analyzes user data stored in the user data store 1410 to assess the effectiveness of ongoing and / or recently completed therapy. Evidence of effectiveness may be based, for example, on a set of therapy target parameters 1422 associated with a given therapy. The therapy data analysis engine 1420 may, for example, compare the user effective treatment feedback data 1414 to thresholds and / or target ranges of values. In another example, the therapy data analysis engine 1420 may compare the duration of each symptom evidenced by the sensor data to a threshold duration before symptom reduction or cessation. In some embodiments, the therapy target parameters 1422 may be clinician-adjustable, allowing the clinician to customize the target parameters based on a particular patient. In certain embodiments, different sets of therapy target parameters 1422 are provided based, in some examples, on user demographics 1424 (e.g., age, gender, etc.), user medical condition 1426 (e.g., diagnosed diseases and / or disorders), and / or user clinical data 1428 (e.g., weight, body mass index (BMI), smoking status, substance use status, pregnancy status, etc.). In further embodiments, therapy target parameters 1422 are adjusted based on user physiological characteristics 1430 (e.g., baseline or typical physiological patterns exhibited by a particular wearer).

[0173] In some embodiments, the therapy analysis engine 1420 provides parameter differentials and / or other feedback information to a therapy parameter adjustment engine 1432 to determine a set of adjusted treatment parameters based on differences between the therapy target parameters 1422 and the user-active treatment feedback data 1414. The set of adjusted treatment parameters may include one or more device settings (e.g., frequency(ies), pattern(ies), repetition(ies), etc.). In one example involving repetitive rehabilitation exercises, stimulation duration may be systematically varied using motion sensors (e.g., including a 3-axis accelerometer and / or gyroscope) to establish a rate of improvement versus duration after stimulation trigger. Steps for varying stimulation may be stored, for example, as therapy stimulation parameters and / or routines 1438. Stimulation duration may be automatically adjusted to increase success rates and / or accelerate recovery of specific functions.

[0174] In a stroke patient rehabilitation exercise example, the therapy parameter adjustment engine 1432 may determine the next therapy routine and / or stimulation parameters based at least in part on the user effective treatment feedback data 1414 corresponding to the current activity or rehabilitation exercise. For example, if performance of the current task is satisfactory, the therapy parameter adjustment engine 1432 may provide instructions for the next task to the neurostimulation system 1404. The next task, in some examples, may be more difficult, may exercise a different muscle group, and / or may focus on linking learned skills to a sequence of performance. The next task may, for example, be selected from a hierarchy or sequence of tasks stored as part of the therapy stimulation parameters and / or routine 1438.

[0175] In some embodiments, the therapeutic stimulation parameters and / or routines 1438 include one or more priming routines, e.g., a motor skill training session or a PTSD recovery session, applied to the wearer of the neurostimulation system 1404 prior to the initiation of therapeutic stimulation. Illustratively, priming, or neurostimulation for preparing cognitive pathways for a therapeutic / training session, may begin for at least 1 minute, 1-10 minutes, up to 30 minutes, and / or within 1 hour of the therapeutic / training session. In another example, the priming routine may be introduced during a larger therapeutic routine that includes multiple treatment stages or phases. In a first illustrative example, therapeutic stimulation may be paired with activities in a first training phase to develop new pathways, for example, to restore a specific function. In a second priming phase, priming stimulation may be used for general cognitive boosting, for example, while performing a motor skill routine encompassing multiple functions (e.g., a combination of multiple movements / tasks). In a second example, a therapeutic stimulus may be paired with exposure to a stimulus input (e.g., auditory, visual, and / or tactile, etc.) in a first training phase, e.g., to overcome an adverse reaction. In a second priming phase, a priming stimulus may be used, e.g., to enhance a general sense of well-being, with breaks between stimulus input exposures.

[0176] In some embodiments, the sensor data analysis system 1402 provides the adjusted treatment parameters corresponding to the neurostimulation system 1404, either directly or via another computing device 1406. The user data archiving engine 1434 may also archive the user effective treatment parameter data 1412 to capture the treatment parameters prior to adjustment as user historical treatment parameter data 1436. The adjusted treatment parameters may also be added to or may replace previous versions of the user effective treatment parameter data 1412 corresponding to the target neurostimulation system 1404.

[0177] In some embodiments, the user data archiving engine 1434 collects the user data stored in the user data store 1410 for archiving as corresponding user historical treatment parameter data 1436, user historical treatment feedback data 1440, and / or user historical treatment context data 1442. The user data archiving engine 1434, in some embodiments, de-identifies at least a portion of the archived user data 1436, 1440, and / or 1442 for use in big data analytics across multiple users of the neurostimulation system 1404.

[0178] In some embodiments, in addition to automatically acquired sensor data and / or contextual data, the user feedback collection engine 1444 collects information from the wearer of the neurostimulation system 1404 and / or a clinician working with the wearer regarding their experience using the neurostimulation system 1404. The user feedback collection engine 1444 may collect user survey data 1446 regarding the wearer's experience, for example, during and / or after treatment. For example, the user may have a user interface with a corresponding software application running on one of the neurostimulation device 1404 and / or computing device 1406 to provide feedback regarding their experience. The wearer's feedback, in some embodiments, may include information regarding the stimulation comfort level, symptom level improvement, and / or wearing comfort level. The feedback, in some embodiments, may be provided on a numerical scale or a descriptive scale linked to a numerical scale (e.g., very good, good, fair, not very good, uncomfortable). In another embodiment, the wearer may provide feedback regarding distress (e.g., symptoms not improving / seemingly worsening, stimulation causing severe discomfort, etc.) in real time. The treatment parameter adjustment engine 1432 can take that into account when determining the adjusted treatment parameters.

[0179] In some embodiments, the user feedback collection engine 1444 collects clinical observation data 1448 regarding the clinician's experience during treatment and / or in working with patients prescribed the treatment. The clinical observation data 1448 may, in some examples, include outcome information (e.g., reduction or discontinuation of prescribed medication), diagnostic adjustment information (e.g., severity of disorder), and / or progress information (e.g., relative recovery of ability).

[0180] In some embodiments, the therapeutic model training engine 1450 accesses archived user historical treatment parameter data 1436, user historical treatment feedback data 1440, user historical treatment context data 1442, user survey data 1446, and / or clinical observation data 1448 over a period of time (e.g., one month, three months, six months, one year, etc.) and across a population of wearers of the neurostimulation system 1404 to develop one or more trained learning models 1452. The therapeutic model training engine 1450 may, for example, apply machine learning and / or artificial intelligence to derive promising therapeutic stimulation parameters and / or routines, such as the therapeutic stimulation parameters and / or routines 1438. The therapeutic model training engine 1450 may, for example, identify treatment parameters, treatment schedules, and / or context parameters (e.g., settings, timing, etc.) associated with successful treatments. The trained learning models 1452 may include one or more models per treatment type (e.g., therapeutic regimens aimed at treating a particular disease, disorder, symptom(s), etc.), per diagnosis (e.g., comorbidities such as smoking status, mental health diagnoses such as depression or PTSD), and / or per user demographic (e.g., age, gender, etc.), and / or per user type (e.g., military, athlete, etc.). The trained learning models 1452 may be designed to predict beneficial therapeutic stimulation parameters and / or routines 1438 for a particular patient based, for example, on user demographics 1424, user medical condition(s) 1426, and / or user clinical data 1428.

[0181] In some embodiments, after the trained learning model 1452 is initially trained, as more user history data 1436, 1440, and / or 1442, user survey data 1446, and / or clinical observation data 1448 are collected, the therapeutic model refinement engine 1454 uses the new training data to update the trained learning model 1452. The therapeutic model refinement engine 1454 may periodically or continuously refine the trained learning model 1452, for example, as new data is collected by the sensor data analysis system 1402.

[0182] Although the sensor data analysis system 1402 is shown separate from the neural stimulation system 1404, in some embodiments, portions of the sensor data analysis system 1402 are included within the neural stimulation system 1404 and / or within a computing device 1406 that communicates directly (e.g., via wired or short-range wireless transmission range) with the neural stimulation system 1404. For example, some of the functionality of the therapy data analysis engine 1420 may be performed in real time or near real time on a device local to the wearer to rapidly adapt ongoing neural stimulation therapy based on sensor feedback.

[0183] Reference has been made to the figures illustrating methods and systems according to embodiments of the present disclosure, aspects of which may be embodied by computer program instructions that can be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine whereby the instructions, executing via the processor of the computer or other programmable data processing apparatus, create means for performing the functions / acts specified in the figures.

[0184] One or more processors may be used to implement the various functions and / or algorithms described herein. Additionally, any of the functions and / or algorithms described herein may be executed on one or more virtual processors, e.g., on one or more physical computing systems, such as a computer farm or cloud drive.

[0185] Aspects of the present disclosure may be implemented by hardware logic (which, of course, also includes any necessary signal wiring, memory elements, etc.). Such hardware logic may operate without active software involvement beyond the initial system configuration and any subsequent system reconfiguration. Hardware logic may be synthesized on a reprogrammable computing chip, such as a field programmable gate array (FPGA), programmable logic device (PLD), or other reconfigurable logic device. Additionally, hardware logic may be hard-coded on a custom microchip, such as an application-specific integrated circuit (ASIC). In other embodiments, at least a portion of the functionality described herein may be performed using software stored as instructions on a non-transitory computer-readable medium, such as a memory device, an on-chip integrated memory unit, or other non-transitory computer-readable storage device.

[0186] Various aspects of the embodiments disclosed herein are executed on one or more computing devices, such as a laptop computer, tablet computer, mobile phone, or other handheld computing device, or one or more servers. Such computing devices include processing circuitry embodied in one or more processors or logic chips, such as a central processing unit (CPU), a graphics processing unit (GPU), a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), or a programmable logic device (PLD). Furthermore, the processing circuitry may be implemented as multiple processors cooperating cooperatively (e.g., in parallel) to execute instructions of the processes of the present invention described above.

[0187] The process data and instructions used to implement the various methods and algorithms described herein may be stored on a non-transitory (i.e., non-volatile) computer-readable medium or memory. The claimed advancement is not limited to the form of computer-readable medium on which the instructions for the processes of the present invention are stored. For example, the instructions may be stored on a CD, DVD, flash memory, RAM, ROM, PROM, EPROM, EEPROM, hard disk, or any other information processing device with which a computing device, such as a server or computer, communicates. The processing circuitry and stored instructions may enable the pulse generator 950 of FIG. 9, the system 1360 of FIG. 13, and / or the sensor data analysis system 1402 of FIG. 14 to execute the various methods and algorithms described above. Furthermore, the processing circuitry and stored instructions may enable the peripheral device(s) 1354, 1390 of FIG. 13 to execute the various methods and algorithms described above.

[0188] These computer program instructions can direct a computing device or other programmable data processing apparatus to function in a particular manner, whereby the instructions stored on a computer-readable medium produce an article of manufacture that includes instruction means that perform the functions / acts specified in the exemplary process flows.

[0189] Embodiments herein rely on network communications. As can be appreciated, the network can be a public network, such as the Internet, or a private network, such as a local area network (LAN) or a wide area network (WAN) network, or any combination thereof, and can also include PSTN or ISDN subnetworks. The network can also be wired, such as an Ethernet network, and / or wireless, such as a cellular network, including EDGE, 3G, 4G, and 5G wireless cellular systems. The wireless network can also include Wi-Fi, Bluetooth, Zigbee, or another wireless form of communication.

[0190] 13, in some embodiments, further includes a display controller for interfacing with a display, such as a built-in display or an LCD monitor. The general-purpose I / O interface of the computing device may interface with a keyboard, a manual movement tracking I / O device (e.g., a mouse, virtual reality gloves, a trackball, a joystick, etc.), and / or a touchscreen panel or touchpad on or separate from the display.

[0191] In some embodiments, an audio controller is also provided within the computing device, such as peripheral device(s) 1354, 1390 of FIG. 13, to interface with a speaker / microphone and thereby provide audio input and output.

[0192] Furthermore, the present disclosure is not limited to the particular circuit elements described in the present invention, nor is the disclosure limited to the particular sizes and classifications of these elements. For example, one skilled in the art will understand that the circuits described in the present invention can be adapted based on variations in battery size and chemistry or the requirements of the intended backup load being powered.

[0193] Certain functions and features described in the present invention may also be performed by various distributed components of the system. For example, one or more processors may perform these system functions, with the processors being distributed across multiple components communicating within a network. The distributed components may include one or more client and server machines that may share processing, as well as various human interface and communication devices (e.g., display monitors, smartphones, tablets, personal digital assistants (PDAs)). The network may be a private network such as a LAN or WAN, or a public network such as the Internet. Input to the system may be received via direct user input, or remotely, either in real time or in a batch process.

[0194] Although provided for context, in other implementations, the methods and logic flows described herein may be performed on modules or hardware other than those described, and therefore other implementations are within the scope that may be claimed.

[0195] In some embodiments, a cloud computing environment, such as Google Cloud Platform™, may be used to execute at least a portion of the methods or algorithms detailed above. Processes associated with the methods described herein may be executed on a computational processor at a data center. The data center may also include an application processor that may be used to interface with the systems described herein, for example, to receive data and output corresponding information. The cloud computing environment may also include one or more databases or other data storage devices, such as a cloud storage device and a query database. In some embodiments, a cloud storage database, such as Google Cloud Storage, may store data processed and unprocessed by the systems described herein.

[0196] The systems described herein may communicate with a cloud computing environment through a secure gateway, which in some embodiments includes a database query interface such as the Google BigQuery platform.

[0197] In some implementations, an edge server is used to transfer data between one or more computing devices and a cloud computing environment in accordance with various embodiments described herein. An edge server may be a computing device configured to perform processor-intensive operations, such as those that may be involved in performing machine learning processes, such as natural language processing operations. An edge server may include, for example, one or more GPUs capable of efficiently performing matrix operations, as well as substantial cache or other high-speed memory to service the GPUs. An edge server may be a standalone physical device. An edge server may be incorporated into other computing devices, such as laptop computers, tablet computers, medical devices, or other dedicated computing devices. Alternatively or additionally, an edge server may be located within a carrying case for such computing devices. In further examples, an edge server may be incorporated into the communications and processing capabilities of, or otherwise located within, a mobile unit, such as a vehicle or drone.

[0198] In some embodiments, an edge server communicates with one or more local devices to the edge server. The edge server can be used, for example, to move a portion of computing power that would traditionally be migrated to a cloud computing environment to a local environment so that computationally intensive data processing and / or analysis required by one or more local devices can be accurately and efficiently performed. In some embodiments, the edge server is used to support one or more local devices in the absence of a connection to a remote computing environment. The edge server may be configured to communicate with one or more local devices directly or over a network. For example, the edge server may include a private wireless network interface, a public wireless network interface, and / or a wired interface through which the edge server can communicate with one or more local devices. In some embodiments, a particular local device may be configured to communicate with the edge server indirectly, for example, through another local device. Additionally, the edge server may be configured to communicate with a remote computing (e.g., cloud) environment via one or more public or private wireless network interfaces. Devices that interoperate with the edge server may share processing capabilities with the edge server, for example, via one or more APIs implemented by processes.

[0199] The systems described herein may include one or more artificial intelligence (AI) neural networks to perform automated analysis of data. The AI ​​neural networks, in some embodiments, may include synaptic neural networks, deep neural networks, transformer neural networks, and / or generative adversarial networks (GANs). The AI ​​neural networks, in some embodiments, may be trained using one or more machine learning techniques and / or classifiers, such as anomaly detection, clustering, and / or supervised and / or association. In one embodiment, the AI ​​neural networks may be developed and / or based on the Bidirectional Encoder Representation for Transformers (BERT) model from Google of Mountain View, California.

[0200] The systems described herein may be in communication with one or more underlying model systems (e.g., artificial intelligence neural networks). The underlying model system(s), in some examples, may be developed, trained, tuned, fine-tuned, and / or prompt engineered to evaluate data inputs, e.g., sensor inputs collected by system 1060 and / or sensor data analysis system 1352 of FIG. 13 and / or sensor inputs collected by sensor data analysis system 1402 of FIG. 14. The underlying model system, in some examples, may include or be based on generative pre-trained Transformer (GPT) models available through the OpenAI platform from OpenAI of San Francisco, California (e.g., GPT-3, GPT-3.5, and / or GPT-4) and / or generative AI models available through Azure OpenAI or Vertex AI (e.g., PaLM2) from Google of Mountain View, California.

[0201] A particular base model may be fine-tuned as a trained AI model to perform a particular task required by the system described herein. Training samples may be provided to a particular base model to adjust the training of the base model, for example, to perform an analysis of the type described in the present invention.

[0202] Multiple underlying model systems may be applied by the systems and methods described herein depending on the context. The context may include, for example, the type(s) of data, the type(s) of desired response output (e.g., at least one answer, at least one answer and explanation(s) of the reasoning leading to the answer, etc.). In another example, the context may include user-based context such as demographic information, entity information, and / or product information. In some embodiments, a single underlying model system may be dynamically adapted to various forms of analysis required by the systems and methods described herein using prompt engineering.

[0203] While specific embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the present disclosure. Indeed, the novel methods, apparatus, and systems described herein may be embodied in a variety of other forms. Furthermore, various omissions, substitutions, and changes in the form of the methods, apparatus, and systems described herein may be made without departing from the spirit of the present disclosure. The accompanying claims and their equivalents are intended to cover such forms or modifications as fall within the scope and spirit of the present disclosure.

Claims

1. 1. A method for improving coagulation in a subject, comprising: placing at least one electrode at a location on or through the skin of the subject, whereby each electrode of the at least one electrode is placed in electrical communication with i) a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, and / or ii) a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve; Electrical nerve stimulation therapy for each respective electrode of the at least one electrode in electrical communication with a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, applying via the respective electrode a first stimulation pattern within a frequency range of 70 to 150 hertz; and / or for each electrode of the at least one electrode in electrical communication with a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve, applying via the respective electrode a second stimulation pattern within a frequency range of 5 to 30 hertz; delivered by the electrical neurostimulation therapy improves the coagulation ability of the subject; and A method comprising:

2. 10. The method of claim 1, wherein the electrical neurostimulation therapy is delivered repetitively and periodically to treat a chronic condition.

3. 3. The method of claim 2, wherein the chronic condition is a chronic coagulation deficiency in the subject.

4. 4. The method of claim 3, wherein the chronic coagulation deficiency is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

5. 10. The method of claim 1, wherein the electrical neurostimulation therapy is delivered before and / or during a surgical procedure to at least partially overcome the effects of anticoagulant medication on the system of the subject.

6. 10. The method of claim 1 or 5, wherein the electrical neurostimulation therapy is delivered before and / or during a medical procedure likely to cause bleeding.

7. 7. The method of claim 6, wherein the electrical neurostimulation therapy is delivered to reduce the likelihood of and / or the amount of blood transfusion required.

8. 7. The method of claim 6, wherein the electrical neurostimulation therapy is delivered to reduce blood loss during postpartum hemorrhage.

9. 10. The method of any one of the preceding claims, wherein the electrical neurostimulation therapy is configured to cause a temporary enhancement of the coagulation capacity of the subject.

10. 10. The method of any one of the preceding claims, wherein the electrical neurostimulation therapy is delivered to treat abnormal uterine bleeding (AUB), heavy menstrual bleeding (HMB), and / or menorrhagia.

11. 11. The method of claim 10, wherein the AUB, HMB, and / or menorrhagia is the result of a bleeding disorder.

12. 10. The method of any one of the preceding claims, wherein the electrical neurostimulation therapy is delivered as a prophylactic or preventative treatment.

13. 13. The method of claim 12, wherein the electrical neurostimulation therapy is configured as the preventative measure to minimize bleeding in an individual with a bleeding disorder.

14. 14. The method of claim 13, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

15. The method of any one of claims 1 to 14, wherein the electrical neurostimulation therapy is delivered before and / or during military operations.

16. 10. The method of any one of the preceding claims, wherein the electrical neurostimulation therapy increases the rate of thrombin generation at or near the site of injury in the subject.

17. 1. A method for increasing the ratio of procoagulant to anticoagulant activity at or near an injury site in a subject, comprising: For each respective electrode of at least one electrode, contacting the subject's skin with the respective electrode in a region of: i) a neural structure of the auriculotemporal nerve (ATN), ii) a neural structure connected to the ATN, III) a neural structure of the auricular branch of the vagus nerve (ABVN), or iv) a neural structure connected to the ABVN; applying to each electrode of the at least one electrode a respective stimulation pattern of at least one stimulation pattern in a frequency range of 5 to 150 hertz, the respective stimulation pattern being configured to stimulate a neural pathway providing innervation of the spleen; the at least one stimulation pattern for at least one minute increases the ratio of procoagulant to anticoagulant activity at or near the injury site in the subject; and A method comprising:

18. 18. The method of claim 17, wherein the injury site comprises at least one of a penetrating injury or a non-compressive injury.

19. 19. The method of claim 18, wherein the non-compressible injury is gastrointestinal bleeding.

20. The method according to any one of claims 17 to 19, wherein the at least one stimulation pattern is applied before and / or during a surgical procedure.

21. 21. The method of claim 20, wherein the at least one stimulation pattern is applied to reduce the likelihood of blood transfusion and / or reduce the amount of blood required for said transfusion.

22. 22. The method of any one of claims 17 to 21, wherein the at least one stimulation pattern is configured to cause a temporary enhancement of the coagulation capacity of the subject.

23. 23. The method of any one of claims 17 to 22, wherein the at least one stimulation pattern is configured to increase the rate of thrombin generation at or near the injury site.

24. 1. A system for increasing the rate of thrombin generation at or near a site of injury in a subject, the system comprising:

1. An auricle stimulation device, comprising: an auricular stimulation device comprising at least one treatment electrode configured to be aligned with an area of ​​the subject's skin to place each respective treatment electrode in electrical communication with i) a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, and / or ii) a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve; a pulse generating circuit, via the at least one treatment electrode, and / or for each respective electrode of the at least one treatment electrode in electrical communication with a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, generating a first stimulation pattern within a frequency range of 70 to 150 hertz to stimulate the auriculotemporal nerve via the respective electrode. generating, for each respective electrode of the at least one treatment electrode in electrical communication with a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve, a second stimulation pattern within a frequency range of 5 to 30 hertz to stimulate the auricular branch of the vagus nerve via the respective electrode; configured to deliver electrical neurostimulation therapy by a pulse generating circuit, wherein the electrical neurostimulation therapy is configured to increase the rate of thrombin generation at or near the injury site in the subject; A system comprising:

25. 25. The system of claim 24, wherein the injury site comprises at least one of a penetrating injury or a non-compressive injury.

26. 26. The system of claim 25, wherein the non-compressible injury is gastrointestinal bleeding.

27. 26. The system of claim 24 or 25, wherein the at least one stimulation pattern is applied before and / or during a surgical procedure.

28. 28. The system of claim 27, wherein the at least one stimulation pattern is adapted to reduce the likelihood of and / or the amount of blood required for transfusion.

29. The system of any one of claims 24 to 28, wherein the at least one stimulation pattern is configured to cause a temporary enhancement of the coagulation capacity of the subject.

30. 1. A system for triggering a higher platelet activation rate in a subject, the system comprising: a wearable auricular nerve stimulator (WANS) configured to be wrapped around the subject's pinna, the WANS comprising at least one electrode, the electrode comprising: i) one or more auriculotemporal nerve (ATN) electrodes configured to contact respective areas of the subject's skin to position the at least one electrode in electrical communication with neural structures of the auriculotemporal nerve or neural structures connected to the auriculotemporal nerve when the WANS is worn by the subject; and / or ii) a wearable auricular nerve stimulation device including one or more auricular branch of the vagus nerve (ABVN) electrodes configured to contact respective areas of the subject's skin to position a second treatment electrode in electrical communication with a nerve structure of the auricular branch of the vagus nerve or a nerve structure connected to the auricular branch of the vagus nerve when the WANS is worn by the subject; a pulse generation circuit configured to deliver electrical neurostimulation via the at least one electrode, the delivering of the electrical neurostimulation comprising: For each respective ATN electrode of the one or more ATN electrodes, outputting a first stimulation pattern within a frequency range of 70 to 150 hertz to the respective ATN electrode; and / or for each respective ABVN electrode of the one or more ABVN electrodes, causing the respective ABVN electrode to output a second stimulation pattern within a frequency range of 5 to 30 hertz; a pulse generating circuit configured to stimulate the higher platelet activation rate in the subject; and A system comprising:

31. 31. The system of claim 30, wherein the electrical neurostimulation is delivered before the subject donates platelets such that the donated platelets include a higher ratio of primed platelets.

32. 32. The system of claim 30 or 31, wherein the higher platelet activation rate is triggered at or near a site of injury in the subject.

33. 1. A method for treating sepsis by reducing systemic inflammation via auricular nerve stimulation, the method comprising: placing a wearable neurostimulation device comprising at least one treatment electrode in at least one ear of the subject; the wearable neurostimulation device is positioned such that a first treatment electrode of the at least one treatment electrode contacts an area of ​​the subject's skin with a nerve structure of the auricular branch of the vagus nerve or a nerve structure connected to the auricular branch of the vagus nerve; delivering a stimulation therapy to reduce systemic inflammation in the subject via a pulse generator in electrical communication with the at least one treatment electrode; Including, the stimulation treatment includes a stimulation pattern to modulate activity in one or more organs of the subject via the vagus nerve to induce an anti-inflammatory response; delivering the stimulation therapy continuously applying a stimulation pattern for a first period of time to obtain an anti-inflammatory response; after obtaining the anti-inflammatory response, periodically applying the stimulation pattern to reduce the likelihood of further inflammation; A method comprising:

34. 34. The method of claim 33, wherein eliciting the anti-inflammatory response comprises reducing the amount of circulating pro-inflammatory cytokines by regulating their activity in the subject's spleen.

35. 1. A method for treating hypovolemia via auricular nerve stimulation, comprising: placing a wearable neurostimulation device comprising at least one treatment electrode in at least one ear of the subject; the wearable neurostimulation device is positioned such that a first treatment electrode of the at least one treatment electrode contacts an area of ​​the subject's skin with a neural structure of the auriculotemporal nerve (ATN) or a neural structure connected to the auriculotemporal nerve; delivering a stimulation therapy to treat hypovolemia via a pulse generator in electrical communication with the at least one treatment electrode; the stimulation therapy includes a stimulation pattern to modulate activity in the subject's cardiac system and / or vascular system via the ATN to elicit a hypertensive response; A method comprising:

36. 1. A method for enhancing platelet-mediated coagulation in a subject, the method comprising: implanting at least one electrode in the subject, whereby each electrode of the at least one electrode is positioned in physical contact with: i) the splenic nerve; ii) the spleen; III) the vagal efferent fibers (VEF); iv) the vagus nerve; v) the splenic nerve; vi) the splenic nerve; and / or vii) the splenic DRG; for each respective electrode of the at least one electrode, delivering electrical neurostimulation therapy via the respective electrode by applying a stimulation pattern within a frequency range of 1 to 30 hertz; the electrical nerve stimulation therapy enhances platelet-mediated coagulation in the subject; and A method comprising:

37. 37. The method of claim 36, wherein the platelet-mediated coagulation is enhanced to prevent or prophylactically minimize bleeding in the subject with a bleeding disorder.

38. 38. The method of claim 37, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

39. 39. The method of any one of claims 36-38, wherein enhancing the platelet-mediated coagulation comprises increasing the maximum density of thrombus by at least 10% as measured via thromboelastography analysis (TEG MA).

40. 40. The method of any one of claims 36-39, wherein enhancing the platelet-mediated coagulation comprises increasing the maximum density of thrombus by at least 20% as measured via thromboelastography analysis (TEG MA).

41. 41. The method of any one of claims 36 to 40, wherein enhancing platelet-mediated coagulation is configured to prevent or prophylactically minimize bleeding in an individual with a bleeding disorder.

42. 42. The method of claim 41, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

43. 1. A system for estimating a subject's responsiveness to an implantable neurostimulation therapy configured to improve coagulation through direct stimulation of vagal efferent fibers (VEF), a vagus nerve, a splanchnic nerve, a splanchnic DRG, a splenic nerve, and / or a spleen, the system comprising:

1. An auricle stimulation device, comprising: an auricular stimulation device comprising: at least one treatment electrode configured to be aligned with an area of ​​the subject's skin to place the respective treatment electrode in electrical communication with i) a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, and / or ii) a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve; and a pulse generating circuit for generating a pulse via the at least one treatment electrode; hand, and / or for each respective electrode of the at least one treatment electrode in electrical communication with a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve, generating a first stimulation pattern within a frequency range of 70 to 150 hertz to stimulate the auriculotemporal nerve via the respective electrode. generating, for each respective electrode of the at least one treatment electrode in electrical communication with a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve, a second stimulation pattern within a frequency range of 5 to 30 hertz to stimulate the auricular branch of the vagus nerve via the respective electrode; and configured to deliver electrical nerve stimulation by a pulse generating circuit, wherein the electrical neurostimulation therapy is configured to enhance the clotting ability of platelets in the subject; A system comprising:

44. 44. The system of claim 43, wherein the first stimulation pattern comprises a frequency of 100 Hertz and the second stimulation pattern comprises a frequency of 30 Hz.

45. 45. The system of claim 43 or 44, wherein one or more of the at least one treatment electrode in electrical communication with the neural structure of the auricular branch of the vagus nerve or the neural structure leading to the auricular branch of the vagus nerve is in electrical communication with Arnold's nerve.

46. receiving a plurality of sensor signals from one or more sensors monitoring the subject during treatment; analyzing the plurality of sensor signals; and adjusting at least one of a frequency and a pulse width of the first stimulation pattern and / or the second stimulation pattern in response to said analyzing.

46. ​​The system of any one of claims 43 to 45, further comprising a control circuit configured to:

47. 47. The system of claim 46, wherein the one or more sensors include a thrombin concentration measuring sensor.

48. 47. The system of claim 46, wherein a microfluidic chip comprises the one or more sensors.

49. a diagnostic device comprising the one or more sensors; 47. The system of claim 46, wherein receiving the plurality of sensor signals comprises receiving the plurality of sensor signals from the diagnostic device.

50. 47. The system of claim 46, wherein the one or more sensors are configured to measure prothrombin time, partial thromboplastin time, activated partial thromboplastin time, and / or activated clotting time.

51. 47. The system of claim 46, wherein the plurality of sensor signals includes a signal related to a pupil measurement.

52. 1. A system for increasing the rate of thrombin generation at or near a site of injury in a subject, the system comprising:

1. An auricle stimulation device, comprising: a plurality of electrodes, including a first subset of electrodes and a second subset of electrodes; the first subset of electrodes is configured to be aligned with a first tissue portion of the subject to place at least one first electrode of the first subset of electrodes in electrical communication with a neural structure of the auriculotemporal nerve or a neural structure connected to the auriculotemporal nerve; an auricular stimulation device comprising a plurality of electrodes, the second subset of electrodes being configured to be aligned with a second tissue portion of the subject to place at least one second electrode of the second subset of electrodes in electrical communication with a neural structure of the auricular branch of the vagus nerve or a neural structure connected to the auricular branch of the vagus nerve; A pulse generating circuit, via the plurality of electrodes, generating, for the first subset of electrodes, a first stimulation pattern within a frequency range of 70 to 150 Hz for stimulating the auriculotemporal nerve via the at least one first electrode of the first subset of electrodes; and / or generating, for the second subset of electrodes, a second stimulation pattern within a frequency range of 5 to 30 hertz for stimulating the auricular branch of the vagus nerve via the at least one second electrode of the second subset of electrodes; a pulse generating circuit configured to deliver electrical neurostimulation by A system comprising:

53. 53. The system of claim 52, further comprising a wearable auricular nerve stimulator (WANS) configured to be wrapped around the subject's pinna, the WANS comprising the plurality of electrodes.

54. 54. The system of claim 52 or 53, wherein the pulse generating circuitry is configured to deliver the electrical neurostimulation in a repetitive and cyclical manner.

55. 55. The system of claim 54, wherein repeatedly and periodically delivering the electrical neurostimulation comprises delivering the electrical neurostimulation according to a duty cycle comprising an effective period of at least 1 minute, followed by ceasing delivery of the electrical neurostimulation for at least 10 seconds.

56. 55. The system of claim 54, wherein repeatedly and periodically delivering the electrical neurostimulation comprises delivering the electrical neurostimulation according to a duty cycle comprising at least a 90% active period followed by an off period where no stimulation is present.

57. 57. The system of any one of claims 52-56, wherein the pulse generation circuitry is further configured to deliver the first stimulation pattern simultaneously with the second stimulation pattern while avoiding simultaneous pulse triggering between the first and second stimulation patterns.

58. receiving a plurality of sensor signals from one or more sensors monitoring the subject during treatment; analyzing the plurality of sensor signals; and adjusting at least one of a frequency and a pulse width of the first stimulation pattern and / or the second stimulation pattern in response to said analyzing.

58. The system of any one of claims 52 to 57, further comprising a control circuit configured to:

59. 59. The system of claim 58, wherein the one or more sensors include a thrombin concentration measuring sensor.

60. 60. The system of claim 58 or 59, wherein a microfluidic chip comprises the one or more sensors.

61. a diagnostic device comprising the one or more sensors; The system of any one of claims 58 to 60, wherein receiving the plurality of sensor signals comprises receiving the plurality of sensor signals from the diagnostic device.

62. 62. The system of any one of claims 58 to 61, wherein the one or more sensors are configured to measure prothrombin time, partial thromboplastin time, activated partial thromboplastin time, and / or activated clotting time.

63. A system according to any one of claims 58 to 62, wherein the plurality of sensor signals includes signals relating to pupil measurements.

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