Electrical stimulation method and device for improving blood management

Abstract

In an exemplary embodiment, a method and system for increasing coagulation potential and / or inducing a higher platelet activation rate in a subject through auricular nerve stimulation comprises contacting the skin of a subject with one or more therapeutic electrodes, each electrode being positioned in each region of the neural structure of the auricular temporal nerve (ATN), the neural structure connected to the ATN, the neural structure of the auricular branch of the vagus nerve (ABVN), or the neural structure connected to the ABVN, and applying one or more stimulation patterns to the electrodes.

Description

Background Technology

[0001] Related applications

[0002] The present application claims priority to U.S. Provisional Application No. 63 / 447,162, filed February 21, 2023, titled “Electrical stimulation method and device for improving blood management”; U.S. Provisional Application No. 63 / 535,996, filed August 31, 2023, titled “Electrical stimulation method and device for improving blood management”; and U.S. Patent Application No. 18 / 583,160, filed February 21, 2024, titled “Electrical stimulation method and device for improving blood management”. This application relates to the prior patent applications filed by Spark Biomedical, Inc. concerning stimulation therapy and stimulation devices, specifically U.S. Patent No. 10,967,182, registered April 6, 2021, titled “Device and method for reducing inflammation using electrical stimulation” and U.S. Patent No. 11,351,370, registered June 7, 2022, titled “Device and method for treating cognitive impairment and depression using electrical stimulation.”

[0003] background

[0004] Improper blood management can be life-threatening. If an injury occurs, blood loss must be minimized.

[0005] About 20 years ago, the inventors of U.S. Patent No. 8,729,129, including Christopher Czura, the inventor of the present application, proposed vagal nerve stimulation as a potential solution to induce a reduction in bleeding time and blood volume in humans. The inventors published mouse data obtained from experiments using implantable vagal nerve stimulation. Interestingly, while a reduction in bleeding was observed, no significant change was observed in prothrombin time (PT) (e.g., see Figure 5 of U.S. Patent No. 8,729,129). PT evaluates the time it takes for platelets to coagulate. In other words, it did not demonstrate increased coagulation activity / increased coagulation rate, or so-called coagulation potential (CPot—a term used herein, meaning the potential ability to increase the coagulation rate, particularly at the site of injury). In 2017, inventors including those described in U.S. Patent No. 8,729,129 proposed a non-invasive approach using mechanical stimulation, claiming that similar results could be obtained, in an application eventually registered as U.S. Patent No. 10,912,712. However, as with the previous patent, the only data presented regarding hemorrhage control in U.S. Patent No. 10,912,712 was obtained from rodents using implantable electrical stimulation. In 2019, inventors including the same two inventors described in U.S. Patent No. 8,729,129 again proposed a method using both invasive and non-invasive trigeminal nerve stimulation to achieve hemorrhage control, which was recently registered as U.S. Patent No. 11,660,443. As with the previous patents listed above, only data collected from rodent experiments using subcutaneous electrodes was presented. A few months later, a patent application assigned to the same agency and designating a different inventor proposed the combined use of trigeminal and vagus nerve stimulation to control bleeding and was registered as U.S. Patent No. 11,260,229. Unlike previous applications, no data was presented in this application.

[0006] Furthermore, despite the medical community's long-standing demand for hemorrhage control and continuous publications on the subject of hemorrhage control using nerve stimulation, not only have no commercial solutions emerged, but to the best of the inventors' knowledge, no human subject data demonstrating significant hemorrhage control results has been published prior to the data presented in this application. To the inventors' knowledge, only small animal studies exist to date, which involve major cervical surgery involving stimulation using implantable electrodes that access the vagus nerve and make direct contact with the nerve. Due to the invasive nature of these studies, they could not be easily replicated in human subjects.

[0007] In all hemorrhage or potential hemorrhage scenarios, blood volume loss must be minimized; furthermore, if the hemorrhage volume is likely to lead to hypovolemia, perfusion and oxygenation of tissues, particularly brain tissues, must be enhanced to prevent permanent damage and the possibility of death. Moreover, some hemorrhages can lead to sepsis, whether or not they result in hypovolemia. For example, the risk of sepsis increases in the treatment of some postpartum hemorrhage and in patients with intracerebral hemorrhage. Both hypovolemia and sepsis involve the release of pro-inflammatory cytokines into the circulation, causing high levels of systemic inflammation. In the case of sepsis, not only is tissue perfusion and oxygenation critical, but inflammation and circulating pro-inflammatory cytokines must also be reduced to prevent further complications and organ damage or failure. Furthermore, sepsis can actually lead to hypovolemia. In other words, the primary cause of sepsis is infection, not hemorrhage. Sepsis is a very costly and resource-intensive condition; For example, in the UK, sepsis patients are estimated to account for about one-third of hospital bed days and slightly less than half (~45%) of intensive care unit (ICU) bed days. In the United States, sepsis is the largest healthcare cost incurred condition, costing over $18,000 per hospitalization and $24 billion annually. While sepsis accounts for 13% of total U.S. hospital spending, it represents only about 3.5% of hospitalizations.

[0008] The inventors recognized the need for a new system and method designed to alleviate blood loss after injury while simultaneously increasing oxygen supply and / or perfusion to brain tissue in cases where blood loss is significant or blood flow is substantially affected. Additionally, the inventors recognized the need to reduce systemic inflammation not only during blood loss alleviation but also during septic episodes. Furthermore, the inventors recognized the need to increase the coagulation potential of an individual to prophylactically alleviate the risk of bleeding before any bleeding occurs. Advantageously, this new system and method can be easily and rapidly applied in a non-invasive manner in home, clinical, and / or field settings.

[0009] Some people use the term hypovolemia to describe both systemic fluid and intravascular fluid volume reduction. In this description, hypovolemia is used to describe the latter scenario. Additionally, while hypovolemia is classified by severity, this document uses the term to describe a significant loss of blood volume to the extent that tissue oxygenation and perfusion can lead to organ dysfunction or failure.

[0010] Sepsis can be explained as the secretion of pro-inflammatory cytokines and the occurrence of systemic inflammation due to an immune overreaction. Like hypovolemia, sepsis is classified according to its severity. If left untreated, sepsis tends to progressively worsen and can lead to organ dysfunction or failure. Interestingly, as will be explained later, regulating splenic activity can reduce sepsis and achieve faster hemostasis.

[0011] In one aspect, the present disclosure relates to a system and method for increasing the coagulation potential (CPot) of mammals, including humans.

[0012] In some embodiments, a transient increase in coagulation potential occurs by triggering splenic activity to treat acute scenarios. For example, splenic activity may be triggered by activating the splenic nerve through stimulation of the descending or efferent vagal nerve fibers (VEF). The splenic nerve and / or the spleen directly may also be stimulated in a non-invasive manner using ultrasound (e.g., focal or confocal ultrasound / high-intensity ultrasound). In some examples, acute scenarios may include injuries that could potentially result in significant blood loss, surgery or other medical procedures with a potential for significant bleeding, medical procedures with a potential for bleeding during the recovery period, and / or transient systemic conditions such as nosebleeds, abnormal uterine bleeding, and / or menorrhagia.

[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 in a preventive / preventive manner. For example, stimulation may be performed prior to an anticipated event, e.g., before a menstrual cycle, or prior to a surgical procedure, e.g., before, during, and after the event, to prevent or minimize future bleeding. For example, stimulation may be provided before and / or during surgery to overcome the effects of anticoagulants in the patient's body. In this way, stimulation may provide the benefit of shortening the approval time for patients requiring surgery who have been taking anticoagulants, such as for thrombotherapy.

[0014] In some implementations, 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 in a corrective / therapeutic manner. For example, stimulation may provide a protective effect to patients undergoing emergency surgery without the opportunity to remove anticoagulants from the body. As another example, stimulation may be performed to shorten postoperative recovery times, such as wound closure (e.g., surgical access site), by promoting postoperative coagulation. In some scenarios, the surgical team may use a combination of various hemostatic approaches, such as applying other available hemostatic agents along with VEF stimulation. In some scenarios, non-invasive VEF stimulation may be used to identify individuals who respond to treatment (respondents) by demonstrating an increase in Cpot before utilizing invasive approaches (e.g., electrode implantation to stimulate the vagus nerve and / or splenic nerve).

[0015] In specific implementations where a temporary increase in coagulation potential is required in therapeutic scenarios, such as post-hemorrhage 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 these types of scenarios, stimulation may be applied continuously until bleeding stops. After bleeding stops, stimulation may be continued to prevent further bleeding, as in the prophylactic scenario described earlier. When stimulation is discontinued, the coagulation potential will gradually return to the level prior to stimulation.

[0016] In some embodiments, direct and / or indirect splenic stimulation (e.g., via VEF, splenic nerve and / or splenic ganglion) is performed to achieve a sustained increase in coagulation potential to treat chronic scenarios such as those previously described. Additionally, in some embodiments, splenic stimulation is performed to achieve a sustained increase in coagulation potential in scenarios with chronic coagulation deficiencies, such as in the case of people suffering from hemophilia (e.g., hemophilia A, B, or C), von Willebrand disease (vWD), 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 Glantzmann thrombocytopenia.

[0017] In some embodiments related to chronic coagulation deficiency, non-invasive indirect and / or direct splenic stimulation may be applied by clinicians while exploring the feasibility of an implantable solution. For example, stimulation may be performed in a clinical setting to test whether a patient responds to stimulation therapy. If the applicability study is successful, the patient may be offered the option of receiving an implantable device instead of relying on the external stimulation therapy described herein. The applicability study may include multiple stimulation therapy sessions. Multiple therapy sessions may include multiple electrode placements to evaluate the patient's response to VEF stimulation, multiple stimulation patterns, multiple stimulation intensities, and / or multiple durations of the stimulation sessions.

[0018] In some implementations, splenic stimulation (e.g., direct and / or indirect) is applied, for example, in a preventive / preventive or corrective / therapeutic manner to achieve a transient anti-inflammatory response. For example, in a preventive / preventive application, VEF, splenic ganglion, celiac ganglion, and / or splenic stimulation may be applied prior to a scheduled event where a pro-inflammatory response is expected, for example, a scheduled surgical procedure or external physical activity, such as in the case of a baseball pitcher who may anticipate an inflammatory response after pitching. In a corrective / therapeutic application, where an inflammatory response has already begun—for example, in scenarios involving trauma, infection, sepsis, or potential sepsis—VEF, splenic ganglion, celiac ganglion, and / or splenic stimulation may be applied as soon as possible and sustained as necessary to trigger, maintain, and / or accelerate the anti-inflammatory response. In these scenarios, stimulation may be applied continuously until the desired response appears, after which stimulation may be applied to prevent further inflammation, as in the preventive scenario described above.

[0019] In one aspect, the present disclosure relates to stimulating a branch of the trigeminal nerve to increase blood pressure and / or increase vascular patency, thereby triggering an increase in cerebral blood flow, i.e., what is referred to herein as a pressor response. For example, a pressor response may be triggered to temporarily treat or prevent hypovolemic damage to tissues, including brain tissue, in scenarios where a large amount of blood has been lost or is likely to be lost. For example, triggering a pressor response may be beneficial in scenarios involving penetrating wounds and / or non-compressive injuries (e.g., gunshot wounds or stab wounds, large cuts, or internal bleeding scenarios such as gastrointestinal bleeding). For example, stimulation may be applied as quickly as possible and may be sustained as necessary to trigger, maintain, and / or accelerate the desired response.

[0020] In one aspect, the present disclosure relates to stimulating the Arnold nerve (also known as the auricular branch of the vagus nerve - ABVN) and / or the auricular temporal nerve (ATN) to trigger a trigeminal-parasympathetic response (TPSr). In another aspect, the present disclosure relates to stimulating the Arnold nerve and / or ATN to trigger an increase in CPot by modulating VEF activity. In some embodiments, both TPSr and CPot increases are triggered. For example, the triggered increase in TPSr and / or CPot can be used to temporarily treat or prevent hypovolemic tissue damage in various organs, including the brain, in scenarios where a large amount of blood has been lost or is likely to be lost. As an example, triggering an increase in TPSr and / or CPot may be beneficial in scenarios involving penetrating wounds and / or non-compressive injuries (e.g., gunshot wounds or knife wounds, or internal bleeding scenarios). For example, the stimulus is applied as quickly as possible and can be sustained as needed to trigger, maintain, and / or accelerate the desired response.

[0021] The above general description of exemplary implementations and the following detailed description thereof are merely exemplary aspects of the teachings of the present disclosure and are not limiting. Brief explanation of the drawing

[0022] The accompanying drawings, which are incorporated into and form part of this specification, illustrate one or more embodiments and describe such embodiments together with the detailed description of the invention. The accompanying drawings are not necessarily drawn to scale. Any dimensions shown in the accompanying graphs and drawings are provided 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 description of basic features. In the drawings: Figure 1 is a block diagram of an exemplary anti-inflammatory pathway. Figure 2a is a block diagram of an exemplary pressure response and brain perfusion pathway. Figure 2b is a block diagram of an exemplary trigeminal-parasympathetic response and brain perfusion pathway. Figure 3a is a block diagram of an exemplary platelet calcium-concentration pathway. Figure 3b is a block diagram of an exemplary platelet priming pathway. Figure 4 is a block diagram of an exemplary hemostatic pathway. Figure 5 is a block diagram identifying neural structures and pathways. FIGS. 6a and 6b are diagrams showing an electrode configuration and an equivalent circuit for providing treatment according to the first embodiment. FIGS. 6c and 6d are diagrams showing an electrode configuration and an equivalent circuit for providing treatment according to a second embodiment. FIGS. 6e and FIGS. 6f are diagrams showing the electrode configuration and equivalent circuit for providing therapeutic rice according to the third embodiment. Figures 7a and 7b illustrate timing diagrams of an exemplary process for triggering a stimulus. FIGS. 8a through 8e are graphs showing the results of human stimulation according to embodiments of the present disclosure. FIG. 9 is a block diagram of the components of an exemplary pulse generator communicating with an exemplary auricular treatment device. FIGS. 10a through 10d, FIGS. 11, and FIGS. 12 illustrate exemplary target nerve regions for directing treatment using a wearable auricular nerve stimulator (WANS) device. FIG. 13 illustrates an exemplary system comprising a treatment device, sensor(s), and a sensor signal conditioning and / or analysis circuit. Figure 14 is a block diagram of an exemplary sensor data analysis system for providing neurostimulation therapy customized to the wearer. Specific details for implementing the invention

[0023] The description provided below in connection with the attached drawings is intended to describe various exemplary embodiments of the disclosed subject matter. Specific features and functions are described in relation to each exemplary embodiment; however, those skilled in the art will understand that the disclosed embodiments may be practiced without each specific feature and function.

[0024] Throughout the specification, the terms “one embodiment” or “embodiment” mean that a specific feature, structure, or characteristic described in relation to the embodiment is included in at least one embodiment of the disclosed subject matter. Accordingly, the appearance of the phrases “in one embodiment” or “in an embodiment” in various places throughout the specification does not necessarily refer to the same embodiment. Furthermore, a specific feature, structure, or characteristic may be combined in any appropriate manner in one or more embodiments. Additionally, the embodiments of the disclosed subject matter are intended to include modifications and variations thereof.

[0025] It should be noted that the singular forms "a," "an," and "the" used in this specification and the appended claims include plural references unless otherwise indicated in the context. That is, unless otherwise specified, words such as "a," "an," and "the" used herein mean "one or more." Furthermore, it should be understood that terms such as "left," "right," "top," "bottom," "front," "rear," "side," "height," "length," "width," "above," "below," "inside," "outside," etc., which may be used herein, are merely reference points and do not limit the embodiments of the invention to a specific direction or configuration. Additionally, terms such as "first," "second," "third," etc., merely identify one of the many parts, components, steps, actions, functions, and / or reference points disclosed herein, and do not limit the embodiments of the present disclosure to a specific configuration or direction.

[0026] Additionally, terms such as “approximately,” “about,” “approximate,” “slight variation,” and similar terms generally refer to a range including values ​​identified within a margin of 20%, 10%, or preferably 5% in a particular embodiment, and values ​​in between.

[0027] All features described in relation to one embodiment are intended to be applicable to additional embodiments described below, except where explicitly stated or where a feature or feature is incompatible with additional embodiments. For example, where a given feature or feature is explicitly described in relation to one embodiment but not explicitly stated in relation to an alternative embodiment, it should be understood that the inventor intended that such feature or feature may be deployed, utilized, or implemented in relation to the alternative embodiment, except where such feature or feature is incompatible with the alternative embodiment.

[0028] Although the term hypovolemia has been used to describe both systemic fluid volume reduction and vascular fluid volume reduction, the term hypovolemia herein refers to the latter definition. Generally, hypovolemia is classified according to severity; however, in this disclosure, hypovolemia applies to situations involving significant blood volume loss accompanied by tissue oxygenation and / or perfusion effects that may lead to organ dysfunction or failure.

[0029] Sepsis can be described as an immune hyperreaction that induces the secretion of pro-inflammatory cytokines and systemic inflammation. Like hypovolemia, sepsis is also classified according to its severity. If left untreated, sepsis tends to become progressively more severe and can lead to organ dysfunction or failure, and in some cases, death. As described below, regulating splenic activity can reduce sepsis and achieve hemostasis more quickly.

[0030] Stopping bleeding

[0031] Hemostasis is the process of stopping bleeding, which is generally triggered by molecules exposed to the circulating blood at the site of vascular injury. Endothelial collagen (SEndC) and tissue factor (TF, i.e., coagulation factor 3 or fIII) are examples of such molecules. Circulating platelets (i.e., platelets) bind to the exposed SEndC, whereas TF binds to a specific circulating molecule called coagulation factor 7 (fVII). The interaction between TF and fVII leads to the activation of fVII (fVIIa) and the formation of a TF-fVIIa complex called exogenous tenase (i.e., exogenous Xase). This TF-fVIIa complex activates coagulation factor 10 (fX) and coagulation factor 9 (fIX) into fXa and fIXa, respectively, initiating the coagulation cascade (see below). Platelets attached directly or indirectly to SEndC begin to aggregate, forming an initial plug that stops the bleeding. This plug is called a platelet plug or thrombus. Platelet plugs are reinforced by the attachment 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 reinforced by cross-linked fibrin (i.e., activated coagulation factor 1 or fIa) is referred to as secondary hemostasis. Platelets are anucleated blood cells produced primarily from megakaryocytes in the bone marrow. Under normal conditions, approximately 100 billion platelets are produced daily, resulting in a blood platelet concentration ranging from 150 million to 400 million per milliliter. Platelets enter the bloodstream and, in humans, circulate for about 7 to 10 days before being cleared by the liver and spleen. Interestingly, platelets accumulate in the spleen during circulation, where about one-third of all circulating platelets reside. In humans, it takes approximately 30 minutes for platelets to pass through the spleen.

[0032] Platelets contain mitochondria and two types of granules: alpha granules (αG) and dense or delta granules (δG). Ionized calcium (Ca), a key component of coagulation... 2+Coagulation factor 4 (or fIV) is stored inside platelets, specifically within mitochondria, the dense tubular system (DTS), and delta granules. Platelets circulate in the blood in an inactivated state and do not aggregate; however, when they bind to SEndC exposed after injury, the platelets become activated.

[0033] Platelets bind to SEndC directly via GP VI or GP Ia / IIa receptors, or indirectly via von Willebrand factor (vWF) through GP Ib-V-IX receptors. Activated platelets undergo conformation changes and release granule contents through the membrane. The contents of alpha granules include fibrinogen (i.e., coagulation factor 1 or fI), platelet-derived growth factor (PDGF), vWF, TGF beta, coagulation factor 5 (fV), platelet factor 4 (Pf4), and insulin-like growth factor 1 (IGF1). Delta granules (δG) contain Ca 2+These include ADP, ATP, and serotonin (5-HT). Activated platelets promote changes in the membrane receptor GP IIb / IIIa (i.e., integrin αIIbβ3), allowing this receptor to bind not only to fibrinogen but also to vWF. Additionally, thromboxane A2 (TxA2) is secreted from activated platelets. TxA2 and ADP activate circulating platelets, and the platelets begin to aggregate with other activated platelets via the GP IIb / IIIa-vWF-GP IIb / IIIa and GP IIb / IIIa-fibrinogen-GP IIb / IIIa bridges. This aggregation causes platelet accumulation at the site of injury, creating the aforementioned platelet plug. Although weak, this platelet plug is the first step in restricting and eventually stopping blood leakage from the vascular system. Thromboconstriction is significantly influenced by the presence of GP IIb / IIIa receptors on the surface of platelets. Thromboconstriction helps wound healing by bringing the separated edges of the wound closer together until the wound heals. Therefore, by promoting changes in GP IIb / IIIa receptors, subjects receiving treatment as described herein may enjoy the additional benefit of a shortened healing time.

[0034] As previously mentioned, the plug is reinforced by fibrin fibers and further reinforced by cross-linking by activated coagulation factor 13 (fXIIIa). Fibrin is not only produced during circulation, but platelet-secreted fibrinogen is converted into fibrin by thrombin (i.e., activated coagulation factor 2 or fIIa). Additionally, circulating prothrombin (i.e., coagulation factor 2 - fII) is cleaved to produce thrombin. Thrombin can also be produced from prothrombin in relatively small amounts by fXa bound to the surface of platelets. Thrombin not only converts fibrinogen into fibrin but can 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 formed from fXa on the platelet surface and Ca 2+ It binds dependently to form prothrombinase (fXa-fVa complex). This prothrombinase complex can convert large amounts of prothrombin into thrombin. In fact, the prothrombinase complex cleaves thrombin from prothrombin at a rate hundreds of thousands of times faster (e.g., about 250,000 times) than fXa alone. Consequently, the presence of prothrombinase on the surface of platelets significantly accelerates the coagulation process.

[0035] As previously mentioned, fX can be activated to fXa by exogenous tenase; however, fX can also be activated by endogenous tenase composed of fVIIIa and fIXa. For endogenous tenase to bind, both fVIII and fIX must be activated. Thrombin can activate fVIII, while exogenous tenase and fXIa can activate fIX.

[0036] The pathway in which fXa is activated by exogenous tenase is generally known as the exogenous pathway, and the pathway in which fXa is activated by endogenous tenase is called the endogenous pathway. The coagulation step from the activation of fXa to fibrin cross-linking by fXIIIa is called the common pathway. As can be seen in the text and Figure 4, which illustrates the hemostatic pathway (400), the role of thrombin is essential for hemostasis to occur.

[0037] It is important to note the significant quantitative difference between the endogenous pathway (402) and the exogenous pathway (404). Under normal conditions, thrombin (406) is generated 50 to 100 times faster through the endogenous pathway (402) than through the exogenous pathway (404). Therefore, under normal conditions, it is reasonable to assume that while the exogenous pathway (404) initiates the hemostasis process, the endogenous pathway (402) ultimately induces it.

[0038] Platelets are not homogeneous; they exhibit significant differences that become apparent after platelet activation during hemostasis. One of the most important differences between platelet subtype populations is that some of the activated platelets become procoagulant (though controversial, some refer to them as procoagulant collagen- and thrombin-activated platelets or COAT platelets), while others become non-coagulant platelets (pro-aggregatory platelets). Thrombin (406) is mostly produced by procoagulant platelets, but non-coagulant platelets are more prone to aggregation; therefore, both types are required for proper coagulation. Although there are significant differences among subjects, on average, only 30% of activated platelets turn into procoagulant platelets.

[0039] In many, or perhaps all, cases, coagulable platelets swell and phosphatidylserine (PS) is exposed on the membrane surface, making the phospholipid membrane more negative. When the platelet membrane becomes more negative, the binding affinity of prothrombinase increases significantly; therefore, prothrombinase is much more likely to bind to coagulable platelets (pCP) than to non-coagulable (nCP) platelets. As previously mentioned, since prothrombinase (408) can generate thrombin (406) up to 250,000 times (250,000 times) faster than fXa alone, it is clear that most of the thrombin (406) at or around the site of injury will be generated from pCP.

[0040] Considering the hemostasis process discussed above, it is evident that even a slight increase in the pCP / nCP ratio can increase the rate of thrombin production at or near the site of injury, thereby promoting the activation of platelets and fXIII as well as fibrin production. Therefore, increased thrombin production not only induces faster platelet aggregation but also increases the rate of fibrin binding and cross-linking (410), thereby promoting a reduction in bleeding time and bleeding volume.

[0041] Additionally, the faster / higher production of thrombin (406) at the site of injury can compensate for the reduced or deficient production of endogenous tenase (412) resulting from deficiencies and limitations in the hemostatic process (e.g., bleeding / coagulation disorders), such as the deficiency of fVIII, fIX, or fXI or levels lower than normal (including complete deficiency) as seen in hemophilia A, hemophilia B, and hemophilia C, respectively. Interestingly, studies have shown that levels of pCP are significantly lower in hemophilic individuals compared to healthy individuals. As previously mentioned, vWF not only promotes the attachment of platelets to the endothelial tissue at the site of injury but also supports platelet-to-platelet adhesion after platelet activation at or near the site of injury. Furthermore, vWF acts as a carrier for fVIII in the plasma in the form of a vWF-fVIII complex. Consequently, a lower amount of circulating / available fVIII is also observed in vWD 2N. Since faster / higher production of thrombin (406) leads to a higher platelet activation rate and consequently a higher fibrinogen release rate, another situation in which the hemostatic process can be compensated for by faster / higher production of thrombin (406) at or near the site of injury is when platelet adhesion and aggregation are low due to a small or insufficient number of available or fully functioning vWF, such as in vWD types 1, 2A, 2M, and 3. Another example in which higher / faster thrombin production can compensate for existing hemostatic deficiency is in vWD type 2B, where platelet adhesion / aggregation is low as well as platelet count is reduced. The fact that compensation is made does not suggest that the hemostatic process will be restored to the level expected in a normal subject (e.g., without deficiency and restriction) in any case. Instead, the term compensation is used to refer to a hemostatic process that is much faster than the one that occurs when considering deficiency and limitation, in the absence of additional thrombin.One way this compensation occurs is by locally increasing the coagulation-promoting / anticoagulant activity ratio at or near the site of injury.

[0042] Strong activation is required for platelets to be activated into pCPs; however, this alone is not sufficient. Experiments using dual agonists (e.g., collagen and thrombin) have shown that activation of platelets into the pCP type occurs at a small rate. Some argue that the acronym COAT is inaccurate, as activation by both collagen and thrombin alone is not only insufficient to significantly promote platelet activation into the pCP type, but is also not the only factor. It is not the only factor, in that very high concentrations of thrombin can also activate platelets into the pCP type. Several factors have been identified as contributing to the determination of whether platelets convert to the pCP type after activation. These factors include platelet age, size, number of mitochondria, number and content of granules, and reference Ca 2+ Concentration is included. Interestingly, under similar circumstances, young platelets are more likely to become coagulable platelets than old platelets (as mentioned earlier, human platelets circulate for about 7–10 days before being cleared by the liver and / or spleen).

[0043] According to recent research data by Abbasian and colleagues, cytoplasmic Ca in pCP 2+ Concentration ([Ca 2+ ] cyt ) is [Ca in nCP 2+ ] cyt It was at least 50 times higher (>100 nM vs. 1-2 nM). See Abbasian, Nima, et al. "Supramaximal calcium signaling triggers procoagulant platelet formation." Blood Advances 4.1 (2020): 154-164. Most platelets contain Ca2+ Although they can be activated into pCPs upon treatment; generally, most platelets are activated into nPCs when stimulated with platelet activators. This is [Ca 2+ ] cyt a. It suggests that, although not the most important, it is one of the factors determining whether platelets are activated into pCP or nCP.

[0044] Platelets contain Ca between the extracellular and intracellular spaces 2+ Multiple membrane-penetrating Cas allowing exchange 2+ There are channels (see table below). One or more of these channels, or a combination thereof, are activated to produce pure positive Ca 2+ Allowing inflow of total Ca from platelets 2+ It can increase the amount. This Ca within platelets 2+ It generally moves to internal storage via one or various mechanisms, including mitochondria, the dense tubular system (DTS), lysosomes, and δG. High [Ca 2+ ] cyt It can lead to platelet activation, and if activated at a location other than the site of injury, it can lead to unwanted thrombotic events. Therefore, Ca 2+ It is important that it is segregated in an internal (e.g., intracellular) reservoir and released into the cytoplasmic space only upon injury-related activation. This can be achieved in various ways; for example, transmembrane Ca 2+ Activating one of the channels to convert Ca into platelets 2+ Induces inflow and Ca from internal storage into the cytoplasmic space 2+ It is to temporarily or partially block the mechanism by which [it] is released. This standard Ca 2+ Increase in (e.g., total intracellular pre-activation Ca not present in the cytoplasmic space) 2+ ) is [Ca when activated 2+ ] cytIt increases the likelihood of a rise in pCP, thereby generally increasing the probability of platelets being activated into pCP and enhancing coagulation potential. In the event of injury, the higher the individual's coagulation potential, the greater the production of thrombin at the injury site. Higher-than-normal thrombin production at the injury site not only causes platelets to be activated more rapidly and locally, but also leads to fibrin attaching to and cross-linking with the blood clot. Therefore, a higher coagulation potential accelerates the coagulation process, which can reduce the amount of bleeding and shorten the bleeding time.

[0045] Table 1: Platelet transmembrane calcium channels

[0046]

[0047] As revealed 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 control the release of acetylcholine (ACh), and nAChRα7 transmembrane Ca 2+ Considering that it is a channel, the presence of nAChRα7 on the platelet membrane indicates platelet Ca 2+ This suggests that influx can be regulated by ANS. Furthermore, since Bennett et al. showed that ACh inhibits platelet activation, ACh prevents platelet activation while Ca through nAChRα7. 2+It can be used to increase. See Bennett JA, True 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 FIG. 1, platelets (124a) circulating in the spleen (116) activate VEF to increase Ca 2+ It can be concentrated to produce concentrated platelets (124b), which trigger cells in the celiac ganglion (112). As another example, the splenic ganglion and / or spleen (116) is Ca 2+ The platelets (124a) circulating in the spleen (116) may be directly and / or indirectly stimulated to concentrate to produce concentrated platelets (124b).

[0048] For convenience, a single ganglion is referred to; however, since the left and right celiac ganglia are both connected, the activity of one ganglion influences the activity of the other. Therefore, while this document primarily refers to the activity of a single ganglion, any mention of a specific ganglion should be understood as referring to both ganglia when both the right and left ganglia are present.

[0049] Interestingly, sympathetic and parasympathetic fibers interact in the celiac ganglion, where both can influence the activity of postganglionic sympathetic fibers innervating the spleen. Specifically, sympathetic preganglionic efferent fibers (SPgF), which typically originate at the T5–T9 spinal cord level, leave the spinal cord as spinal nerve roots that become the great splenic nerves and form synapses with postganglionic neurons in the celiac ganglion. SPgF secretes ACh while forming synapses with their targets in the celiac ganglion. Fibers leaving the celiac ganglion form what is known as the celiac plexus, from which fibers continue as the splenic plexus. Splenic nerves arising from fibers of the splenic plexus innervate the spleen. The activity of SPgF is regulated, among other things, by the activity of the RVLM, which in turn is regulated by the activity of the TCC and LC. It should also be noted that the ABVN is connected to the trigeminal region, specifically the trigeminal nucleus, which is considered part of the TCC for the purposes of this document. Therefore, activation of SPgf through the activation of TCC and / or LC, and / or VEF, etc., leads to Ca via a common pathway following interactions in the celiac ganglion. 2+ It can regulate the production of concentrated platelets.

[0050] Looking at Fig. 3a, platelet Ca 2+An exemplary block diagram of the enrichment pathway (300) is shown. Acetylcholine (ACh) (302), a natural agonist of nAChRα7, is an important neurotransmitter that regulates several aspects of the ANS. Increasing activity in the parasympathetic branches of the ANS (e.g., parasympathetic nervous system - PNS) can, for example, activate VEF (304) to trigger the release of ACh (302) in the celiac ganglion (112) and / or splenic ganglion (306). The same applies when increasing the activity of the visceral nerve (320) that forms synapses in the celiac ganglion (112), as this nerve also secretes ACh (302). Innervation of the spleen (116) is carried out through neural connections between the splenic ganglion (306) and the target of the spleen (116), where norepinephrine (NE) (308) is released. Interestingly, Rosas-Ballina showed that NE (308) released from the spleen (116) activates T-cells (312), which in turn release ACh (302). 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. When this ACh (302) reaches nAChRα7 on platelets (314) circulating slowly through the spleen (116), Ca into the platelets (314). 2+ (316) Inflow of standard Ca 2+(316) can be effectively increased, thereby producing calcium-rich platelets (318), which are also referred to herein as activated platelets. This detailed description is for the celiac ganglion and the splenic ganglion (306); however, the splenic ganglion (306) is sometimes considered an extension of the celiac ganglion (112). Additionally, many ganglia are known to form what are called plexuses (e.g., plexuses (306)). Therefore, for the purposes of this description, plexuses and ganglia are interchangeable.

[0051] Referring to FIG. 3b, in some embodiments, platelets are activated through the activation of a platelet activation pathway (330) that stimulates the activity of the spleen (310). In particular, the ABVN (102) and / or ATN (104) protruding to the NTS (108) may be stimulated. As illustrated, the TCC (106) receives an afferent connection from the ATN (104) and projects to the NTS (108) and RVLM (342), whereas the ABVN (102) projects directly to the NTS (108).

[0052] As can be seen in FIG. 3b, specific platelet activation pathways also include other nuclei or regions such as the locus coeruleus (LC) (332), periaqueductal gray (PAG) (334), and nucleus raphe magnus (NRM) (322). Each of these nuclei or regions is connected to the nucleus ambiguous (NA) (338), providing a pathway to the vagus nerve (110). Other regions that supply the vagus nerve (110) include the dorsal motor nucleus (DMV) (not shown) of the vagus nerve and the spinal trigeminal nucleus (considered in this invention to be part of the TCC (106)). The vagus nerve (110) is stimulated indirectly through various pathways so that the vagus nerve (110) may innervate the celiac ganglion (112) and / or the splenic plexus (348). Splenic nerves (350) originating from fibers of the splenic plexus (348) nerve-distribute to the spleen (310), thereby increasing platelet activation within the spleen (310), so that more inactive platelets (340a) are converted into activated platelets (340b). For example, stimulation using low-frequency low-mid-range pulses on the Arnold nerve and high-frequency low-mid-range pulses on the ATN for a short period of time can induce a noticeable increase in activated platelets, which can be evaluated, for example, as a decrease in PT.

[0053] In another pathway illustrated in FIG. 3b, the LC (332) and TCC (106) each provide a pathway to the RVLM (342), which provides a pathway to indirectly stimulate the sympathetic generalized ganglion efferent fiber (SPgF) (344), which exits the spine through the dorsal ganglion (DRG) at the T5-T9 level (346) to form the greater visceral nerve (320), which stimulates the post-ganglionic nerve in the celiac ganglion (112) and further triggers visceral nerve (320) activity. Since the visceral nerve (320) connects to the celiac ganglion (112), indirect stimulation of the SPgF (344) through the various pathways illustrated, as described above in relation to the vagus nerve-related pathway, increases platelet activation in the spleen (310), causing more inactive platelets (340a) to be converted into activated platelets (340b). Similar to the pathway through the vagus nerve (110), stimulation using low-frequency low-mid-range pulses on the Arnold nerve and high-frequency low-mid-range pulses on the ATN for a short period can induce a noticeable increase in activated platelets, which can be evaluated, for example, as a decrease in PT.

[0054] Returning to Fig. 3a, the reference Ca 2+ (316) Considering that platelets with a higher potential are more likely to be activated into pCP and thus increase the subject's overall coagulation potential, when applied to the subject in any situation where a higher potential for coagulation is required, Ca to platelets (314) 2+ It is evident that a method to induce a net influx of (316) would be beneficial. As previously mentioned, increasing the activity of VEF (304) causes Ca to enter the platelets (314) while the platelets pass through the spleen (116). 2+ A cascade of events leading to a net inflow of (316) can be triggered.

[0055] An individual's blood clotting ability can be evaluated using diagnostic tools such as thromboelography (TEG). TEG assesses blood clotting ability and identifies potential abnormalities found during the process of blood clot formation. TEG results include Reaction Time (R-Time), which quantifies the time it takes for blood to initiate a coagulation cascade after the addition of a coagulation activator; K-Time, which quantifies the duration from the initiation of the coagulation cascade until the clot reaches a hardness of 20 mm; Alpha Angle, which quantifies the rate of fibrin cross-linking during coagulation; Maximum Amplitude (MA), which quantifies the overall strength of coagulation in millimeters; and Dissolution at 30 Minutes (LY30), which quantifies the resistance of the coagulated blood to degradation (e.g., percentage of degradation after 30 minutes of MA time).

[0056] In some cases, TEG deficiency may manifest as hypofibrinogenemia (e.g., low fibrinogen levels), thrombocytopenia (e.g., low platelet count), or platelet dysfunction. If one or more deficiencies are identified through a patient's TEG analysis, transfusion therapy is often recommended (e.g., fresh frozen plasma, platelet transfusion, and / or cryoprecipitate transfusion).

[0057] There are many situations where a higher coagulation potential is required. These situations include both chronic (persistent) conditions and acute scenarios. As mentioned above, individuals with conditions that result in a coagulation potential lower than normal or lower than desired, such as patients with hemophilia or von Willebrand disease, can benefit from a higher coagulation potential. Another example is patients taking medications to prevent platelets from forming blood clots outside the site of injury (e.g., anticoagulants or blood thinners); these patients can benefit from a higher coagulation potential, particularly before and during surgery. In general, any patient or individual undergoing a medical procedure with a significant risk of bleeding, such as surgery, can benefit greatly from a temporary increase in coagulation potential. An increase in coagulation potential reduces bleeding time, which, while not always the case, means that overall procedure time is shortened and risk is reduced in many instances. Furthermore, increasing coagulation potential in a surgical setting can limit blood loss. For example, limiting blood loss can reduce the need for transfusions or decrease the volume of replacement blood required when a transfusion is necessary; Blood for transfusion is not only very expensive but, in some cases, limited or difficult to obtain. In the context of maternal delivery, postpartum hemorrhage is one of the leading causes of maternal mortality worldwide. Additionally, significant blood loss occurs during vaginal delivery, and even greater loss during a Cesarean section (C-section). There are many other surgical procedures with a high risk of massive hemorrhage, and patients undergoing such procedures can benefit from increased clotting potential. Another condition where limiting blood volume is highly desirable and beneficial is abnormal uterine bleeding (AUB), including menorrhagia (HMB). This condition affects one in four women of childbearing age. While deaths from AUB, including HMB, are rare, in some cases, it can be a predisposition to cancer if left untreated.HMB can cause severe anemia in women, which can lead to shortness of breath and increase the risk of cardiac complications. As previously mentioned, HMB is very common; while it is estimated that one-quarter of women of childbearing age suffer from HMB, only about one-third actually receive treatment if they perceive their menstrual bleeding to be heavier than desired. Therefore, there is a great need for new interventions that can help reduce blood loss in HMB and AUB in general, and these would be welcomed by both women and doctors, even if used as an adjuvant treatment.

[0058] inflammation

[0059] Pro-inflammatory responses are generally triggered when there is a possibility of bodily injury, for example, when infection and / or hemorrhagic injury occurs. Generally, these inflammatory responses aid in the body's healing. However, in many cases, hypersensitive inflammatory responses occur, triggering harmful effects that can lead to organ failure and death. Since at least a portion of the inflammatory response is carried out in the spleen, regulating splenic activity can result in changes to the inflammatory response. In particular, activating the parasympathetic nervous system induces an anti-inflammatory response in the spleen, leading to a decrease in circulating pro-inflammatory cytokines. Activation of splenic nerves (e.g., directly and / or through vagal efferent fiber (VEF) activation) induces the aforementioned anti-inflammatory response. In one example, a reduction in circulating pro-inflammatory cytokines can be achieved by regulating splenic activity through the NTS descending pathway.

[0060] In some embodiments, the anti-inflammatory effect is provided through the activation of the anti-inflammatory pathway (100) (i.e., the cholinergic anti-inflammatory pathway) as illustrated in FIG. 1. In particular, the ABVN (102) and / or ATN (104) having a projection to the NTS (108) may be stimulated; this projection induces the cholinergic anti-inflammatory effect through an efferent pathway; mostly through the vagus nerve (110). As illustrated, the TCC (106) receives an afferent connection from the ATN (104) and projects it to the NTS (108). Regulation of NTS (108) affects the activity of the efferent pathway through the celiac ganglion (112) and parasympathetic ganglion (114) via the vagus nerve (110), which in turn regulates the activity of the spleen (116), lungs (118), intestines (120) and / or heart (122) to induce an anti-inflammatory response. When the vagus nerve (110) indirectly mediates the function of the spleen (116) to reduce the amount of circulating pro-inflammatory cytokines, a systemic anti-inflammatory effect occurs. Additionally, a local anti-inflammatory effect occurs in the organs reached by the efferent pathway; for example, in the lungs (118), intestines (120), and heart (122).

[0061] hypovolemia

[0062] When blood circulation decreases to a level where tissue perfusion can no longer provide an adequate supply of oxygen, organs begin to fail and eventually become dysfunctional. Organ failure can lead to permanent damage and even death. This is especially true when the brain is the organ lacking adequate oxygen supply. The brain is highly vulnerable to hypoperfusion scenarios, particularly because it consumes a significant portion of the body's circulating oxygen, even when a person is at rest. There are brain regions (e.g., nuclei or brain regions) that regulate blood pressure and blood flow. When these brain regions are activated, blood flow increases. For example, activation of the rostral ventrolateral medulla (RVLM) has been shown to exhibit a hyperpressure response (see Fig. 2a) that induces increased blood pressure, perfusion, and blood flow.

[0063] Referring to FIG. 2a, as illustrated in the exemplary booster response and cerebral perfusion pathway (200), the RVLM (206) receives connections from several nuclei, including the trigeminal nerve-cervical complex (TCC) (204), and the TCC, in turn, receives afferent connections from trigeminal nerve branches. As illustrated, the TCC (204) receives afferent connections from the auriculotemporal nerve (ATN) (202). The RVLM (206) in turn regulates the cardiovascular system (208) (e.g., blood pressure) and the vascular system (210) (e.g., blood flow).

[0064] In addition to the RVLM (206), activation of the trigeminal nerve-parasympathetic pathway (220) (see FIG. 2b) has been shown to dilate the cerebral blood vessels (224) by releasing ACh into these vessels (224) at least partially by fibers of sphenopalatine origin (SPH) (222). The sphenopalatine nucleus (sphenopalatine ganglion) (222) also receives afferent fibers from trigeminal nerve branches, specifically the mandibular branch of the trigeminal nerve (V3) to which the ATN belongs.

[0065] Bleeding management

[0066] VEF activation can be triggered by directly activating nerve fibers or by activating regions directly and / or indirectly connected to nerve fibers. Referring to FIG. 5, for example, a functional diagram of neural structures and pathways (500) shows that activation of medullary structures such as the Nucleus Tractus Soltari (NTS) (504) and the Nucleus Ambiguity (NA) (522) can trigger VEF activation through efferent pathways (539). In particular, the NA (522) receives projections from the Periaqueductal Grey Area (PAG) (510). The NTS (504) receives afferent connections from ascending vagal branches as well as from the TCC (502). In turn, the TCC (502) receives afferent projections from the trigeminal nerve and cervical branches and projects them to the PAG (510) and RVLM. Activation of RVLM neurons can trigger the aforementioned booster response as illustrated in Fig. 2a. Interestingly, not all activation of the TCC (502) leads to the trigeminal-parasympathetic response arising from sphenopalatine nerve activation; studies suggest that activation of the bite nerve branch (MBTN) of the trigeminal nerve leads to this response. One way to activate the MBTN branch is through the auriculotemporal nerve (ATN) (202).

[0067] VEF activation can be achieved through stimulation via invasive and / or non-invasive approaches at various sites. Some invasive examples include stimulating cervical vagus nerve fibers using an implantable pulse generator (IPG) and / or subcutaneously stimulating vagus nerve fibers, such as the ABVN and / or trigeminal nerve fibers, using needle electrodes. Non-invasive approaches may involve transcutaneously stimulating not only ABVN fibers but also cervical vagus nerve fibers; additionally, trigeminal nerve fibers corresponding to the maxillary, orbital, and / or mandibular trigeminal branches may be stimulated. In some cases, VEF activation can be achieved through electrical, mechanical (e.g., ultrasound, pressure, massage, etc.), and / or light (e.g., laser and / or high-intensity light) stimulation. Furthermore, nAChRα7 activation in platelets can be achieved through chemical means, such as the local or systemic administration of nAChRα7 agonists like nicotine. nAChRα7 agonists can be applied non-invasively, such as by injection or using transdermal / penetrating skin patches, and in some cases, specially designed oral doses may be used. Additionally, since platelets express other calcium transmembrane channels; activating one or more of these channels (e.g., channels specified in Table 1 above) to [reduce] the intracellular standard Ca 2+ It can increase. For example, these channels can be chemically activated by respective agonists and / or partial agonists in a manner similar to that described above for nAChRα7. Ca 2+ The channels through which Ca exits platelets are, for example, temporarily or partially blocked using partial antagonists. 2+ It can prevent or slow down the flow of calcium from platelets into the extracellular space and allow it to move to intraplatelet reservoirs. In some or all cases, intracellular Ca 2+ These interventions that increase Ca 2+It is desirable and / or required to prevent platelets from being activated when they enter the intracellular space.

[0068] Under normal conditions, high concentrations of cytoplasmic Ca 2+ α can trigger platelet activation. To prevent thrombus formation at locations other than the site of injury, platelet activation must be primarily confined to the site of injury. Therefore, until the point where platelets need to be activated, [Ca 2+ ] cyt It is desirable to maintain a relatively low concentration. However, when activated, for platelets to be activated into pCP, a high [Ca 2+ ] cyt It is necessary. One method for this is to store Ca in the platelet's internal depot so that it is released into the cytoplasmic space upon platelet activation. 2+ It is to maintain.

[0069] As illustrated in FIG. 2a, a booster response can be achieved through invasive and / or non-invasive stimulation at various sites. In some examples, the booster response can be triggered by electrical, mechanical (e.g., ultrasound, pressure, massage, etc.) and / or light (e.g., laser and / or high-intensity light) stimulation.

[0070] As illustrated in FIG. 2b, trigeminal-parasympathetic responses can be achieved through invasive and / or non-invasive stimulation at various sites. In some examples, trigeminal-parasympathetic responses can be triggered through electrical, mechanical (e.g., ultrasound, pressure, massage, etc.) and / or light (e.g., laser and / or high-intensity light) stimulation.

[0071] Table 2: Examples of stimulus durations

[0072]

[0073] Table 3: Examples of treatment durations

[0074]

[0075] In prevention / prevention scenarios, to obtain a transient effect, the stimulus generating one or more of the responses described herein, e.g., a hyperstimulatory response, a trigeminal-parasympathetic response, and / or an increase in CPot, is applied for a very short period starting a short time prior to the event in some embodiments. For example, in situations of imminent trauma such as emergency surgery, the stimulus may be initiated for only a brief period immediately prior to the trauma (e.g., a surgical procedure). In other embodiments, the stimulus may be applied intermittently and repeatedly for a very short or short period starting a medium or long time prior to the event. For example, to avoid hemorrhage during delivery, a pregnant woman may receive intermittent or periodic stimulation for a short period during an uncertain labor period. As another example, in the case of medical interventions such as a cesarean section, prophylactic treatment can prevent unnecessary blood loss.

[0076] In some implementations, repetitive intermittent stimulation is applied with a predetermined duty cycle. For example, a 30% ON / 70% OFF duty cycle may be implemented by applying stimulation for 3 minutes ("ON") every 10 minutes. In other non-limiting examples, the duty cycle may consist of a 30% ON / 70% OFF duty cycle (e.g., 3 min ON / 7 min OFF or 6 min ON / 14 min OFF, etc.), a 50% ON / 50% OFF duty cycle (e.g., 1 min ON / 1 min OFF or 5 min ON / 5 min OFF, etc.), an 80% ON / 20% OFF duty cycle (e.g., 4 min ON / 1 min OFF, etc.), or a 97% ON / 3% OFF duty cycle (e.g., 5 min ON 10 second OFF, etc.). In another explanatory example, since the platelet donor may start stimulation at least 7 days prior to donating platelets, the donated platelets are activated platelets. If the donated platelets are activated platelets, the total amount of platelets to be donated may be significantly reduced. In this case, for example, stimulation may be applied repeatedly for short periods daily. In other examples, stimulation may be applied for short, medium, long, or very long periods. In other embodiments, stimulation may be started for a long period prior to the event or a very long period prior to the event.

[0077] For example, in preparation for a potentially dangerous scenario such as a military operation, a soldier may begin stimulation during training approximately three weeks or more prior to the start of the actual operation and stop the stimulation once the operation is over. In this case, the stimulation may be applied daily for a single or multiple very short, short, or intermediate durations.

[0078] Stimulations for generating one or more of the responses described herein, such as a hyperstimulatory response, a trigeminal-parasympathetic response, and / or an increase in CPot, are applied periodically, for example, in a repetitive pattern, in some embodiments. In some examples, stimulations 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 in part depending on the frequency of periodic stimulation. In some examples, stimulations may be applied once every 10 minutes for a short duration, once every hour for a medium duration, or once a day for a long duration. In other embodiments, to reduce total blood loss and / or total menstrual days, women suffering from HMB / menorrhea, including women with coagulation disorders, may start stimulation, for example, a few days before the start of menstruation and continue stimulation until the end of menstruation. In such cases, stimulations may be applied once a day, for example, for a very short or short period. In some cases, different schedules are possible depending on convenience, comfort, the intensity of the desired effect, and / or the potential severity of the outcome (e.g., potential patient harm due to insufficient or inappropriate prophylactic treatment).

[0079] In cases where the purpose is to treat a chronic disease, in exemplary embodiments, a stimulus that produces one or more of the responses described herein, such as increasing CPot, generating a hyperstimulatory response and / or a trigeminal-parasympathetic response, may be delivered in a repetitive pattern as needed. For example, the stimulus may be applied daily or multiple times a day, and the duration (e.g., very short, short, medium, long, or very long) may be set according to the relative frequency of treatment. As another example, after applying the stimulus at least daily during the first period, an initial level of coagulation potential may be generated in the individual (e.g., "kick-start") by administering less frequent treatments or gradually reducing the frequency of treatments to maintain the coagulation potential at a desired level. For example, after applying the stimulus daily during the first period (e.g., between 5 and 10 days), less frequent treatments (e.g., once a week or, in some cases, twice) may be administered to maintain the coagulation potential within a desired range. As another example, stimulation can be applied daily during the first period, three times a week during the second period, twice a week during the third period, and once a week to maintain the desired coagulation potential level. As yet another example, a treatment schedule can be customized to allow a specific individual to maintain the desired coagulation potential by setting the initial number of stimulation applications per week (e.g., 7 times) in the first week and a different number of applications per week (e.g., 5 times) in the second week. Additionally, in the aforementioned examples, the treatment duration can be adjusted by period.

[0080] Generally, the stimulation duration is defined as the time during which the device actively delivers stimulation therapy, rather than the actual time during which the stimulation is generated. For example, as illustrated in FIG. 7a and / or FIG. 7b, the device may be activated (e.g., powered on) for one hour while stimulation is applied at a specific frequency and a specific pulse duration (e.g., pulse width). Additionally, stimulation pulses may be applied according to a specific duty cycle, for example, 5 minutes of delivery followed by 20 seconds of non-delivery, or 30 seconds of delivery followed by 30 seconds of non-delivery. Additional examples of duty cycles are illustrated in the timing diagrams of FIG. 7a and FIG. 7b.

[0081] Referring to FIG. 6c, the WANS device (630) comprises a front portion (632) comprising a conductive adhesive area (634) and a non-conductive adhesive area (644b) surrounding it, and a rear portion (636) comprising conductive adhesive areas (638 and 640) and a non-conductive adhesive area (644a) surrounding it. For example, the non-conductive adhesive areas (644a, 644b) may provide additional adhesion for a solid skin / conductive adhesive contact. The conductive adhesive area (634) of the front portion (632) corresponds, for example, to the second electrode (II) (642b). Returning to the rear portion (636), the conductive adhesive area (638) corresponds to the first electrode (I) (642a), and the conductive adhesive area (640) corresponds to the third electrode (III) (642c). In some embodiments, the electrodes (642a-c) and their corresponding conductive adhesive regions (634, 638, 640) each have similar shapes and areas. In other embodiments, the shape and / or surface area of ​​each electrode (642a-c) and / or their corresponding conductive adhesive region (634, 638, 640) may differ, for example, depending on the shape of the underlying target neural structure and / or the anatomical structure configured to have the electrodes (642a-c) and their corresponding conductive adhesive regions (634, 638, 640) located thereon.

[0082] In some embodiments, the conductive adhesive area (634) is configured to contact the wearer's skin in a neural structural area of ​​the auriculotemporal nerve (ATN) and / or a neural structure connected to the ATN, so that the delivery of therapeutic stimulation through the conductive adhesive area (634) modulates ATN activity. For example, in FIG. 10a and FIG. 10b, the ATN (1002) is depicted in relation to a human ear (1000) (FI. 10a), located along the front of the ear (1000), and skeletically related to the external auditory canal (1010) (FI. 10b). In an exemplary example, an electrode electrically communicating with the conductive adhesive area (634) may be located in close proximity to the temporomandibular joint.

[0083] In some embodiments, the conductive adhesive area (638) is configured to contact the wearer's skin in the area of ​​the neural structure of the auricular branch of the vagus nerve (ABVN) and / or the neural structure connected to the ABVN, so that the delivery of therapeutic stimulation through the conductive adhesive area (638) modulates ABVN activity. For example, as illustrated in FIGS. 10a through 10d, the ABVN (1004) is shown in a state where it emerges to the surface through the mastoid tube (MsC) (1012)) (also called Arnold's canal) (Fig. 10d), in a state for the ear (1000) (Fig. 10a), in a state for the external auditory canal (1010) (Fig. 10b), and in a state for the back of the ear (Fig. 10c). In FIG. 11, the posterior otolaryngeal nerve (1100) meets a branch of the ABVN and provides another target for ABVN stimulation. In an exemplary example, the electrode that electrically communicates with the conductive adhesive region (638) may be located near the MsC.

[0084] In some embodiments, the conductive adhesive region (640) is configured to contact the patient's skin with a return electrode, forming an electrical circuit across the tissue having electrodes corresponding to the anterior conductive adhesive region (634) and the posterior conductive adhesive region (636), respectively. Although it is illustrated that a single return electrode (e.g., a third electrode (642c)) is provided for both electrodes (642a and 642b) corresponding to the adhesive region (638) and the adhesive region (634), in other embodiments, different separate return electrodes may be provided for each electrode (642a, 642b). In other embodiments, three or more return electrode paths may be provided for the two electrodes. Other combinations are also possible.

[0085] Referring to FIG. 6e, a wearable auricular nerve stimulator (WANS) (660) comprises an anterior portion (666), a posterior portion (662), and an ear-wearing portion (664), each portion comprising at least one electrode (e.g., electrodes (670a, 670b, 670c)). When worn by a wearer, the WANS (660) can wrap 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 ear-wearing portion (664), connected to the anterior portion (666) by a flexible connector (668), can be secured to the simba area of ​​the ear by friction and / or adhesive.

[0086] To increase the bonding between the wearer tissue and the WANS (660) and / or to strengthen the electrical connection between the tissue and the electrodes (670a-c), in some embodiments, each electrode (670a-c) is positioned to communicate electrically with a corresponding conductive adhesive area (672a-c). The conductive adhesive area (672a-c) can create an electrical communication path from the electrode located inside or on the WANS (660) to the wearer's skin. To protect and maintain the cleanliness of the conductive adhesive area (672a-c) before wearing, in some embodiments, the WANS (660) is provided with one or more liners, such as a liner (674a-c). To provide a secure skin contact, in some embodiments, the conductive adhesive area (672a-c) is surrounded by one or more non-conductive adhesive areas. In some embodiments, the electrodes (670a-c) and the corresponding conductive adhesive areas (672a-c) have similar shapes and areas. In other embodiments, the size and / or shape vary according to electrode-to-electrode and / or adhesion area-to-adhesion area depending on, for example, the anatomical topography configured to position the target underlying neural structure and / or specific electrode and adhesion area.

[0087] A conductive adhesive area (672a) may be provided to create an electrical communication path from an electrode (670a) located on the ear-wearing portion (664) of the WANS (660) to the wearer's skin in front of the external auditory canal. Referring to FIG. 12, such an electrode may be positioned to stimulate, for example, the lateral auditory nerve branch (1200) of the ATN (1002). In other embodiments, the conductive adhesive area (672a) is positioned at the auricular horn, concha apex, or tragus to stimulate the ABVN branch.

[0088] Referring to FIG. 7a, the timing diagram (700) illustrates triggering multiple channels (704, 706) using a master clock (702) according to one embodiment. In an exemplary embodiment, the clock (702) triggers a pulse (708) at a predetermined clock frequency. For example, the first channel (704) may be configured to trigger a stimulation pattern (710-712), and the second channel (706) may be configured to trigger a second stimulation pattern (714-716).

[0089] As illustrated, each cycle of the stimulation patterns (710-712) of the first channel (704) is configured to be triggered by the corresponding pulse (708) of the master clock (702), that is, triggered at a 1:1 ratio. In the example, each stimulation (712) (e.g., (712a, 712b), etc.) is configured to be triggered after a specific time interval following the termination of the pulse (708) (e.g., (708a, 708b), etc.) of the corresponding stimulation (710) (e.g., (710a, 710b), etc.).

[0090] As illustrated, each cycle of the stimulation patterns (714-716) is configured to be triggered by all other pulses (708) of the master clock (702), i.e., at a 2:1 ratio with the master clock (702). However, the triggering of each stimulation (714) (e.g., (714a, 714b), etc.) is configured to occur after a specific time delay following the corresponding master clock pulse (708) (e.g., (708a, 708b), etc.). In some embodiments, each stimulation (714) (e.g., (714a, 714b), etc.) is configured to be triggered after a specific time interval following the termination of the corresponding pulse of the stimulation (712) (e.g., (712a, 712b), etc.). For example, each stimulation (714) is offset from each corresponding stimulation (712) by a synchronization delay (718). As illustrated, the synchronization delay (718) is 2 ms. However, in a specific implementation, the synchronization delay (718) may be at least 0, and the two channels (704, 706) may be triggered simultaneously according to the master clock ratio of each channel (704, 706). Additionally, the synchronization delay (718) may be extended by the value obtained by subtracting the total duration of each stimulus (710-712) cycle and each stimulus (714-718) cycle from the master clock (702) cycle, and adding the time interval between each stimulus (710-712, 714-718) cycle. This delay may be increased up to approximately 10 ms in addition to the example.

[0091] In some implementations, channels (704, 706) are synchronized using a master clock counter and a register per channel (704, 706). By setting each register to the number of master clock pulses (708) that trigger each channel (704, 706), each channel (704, 706) can be configured to be triggered when the channel register value is equal to the master clock pulse (708). In addition to the example, the counter for each channel (704, 706) can be reset after the channel (704, 706) is triggered. In the example, using a 6-bit counter and a 6-bit register, the trigger frequency can be as high as the master clock frequency (1:1) and as low as 1 / 64 of the clock frequency (64:1).

[0092] Referring to FIG. 7b, the timing diagram (720) illustrates the triggering of multiple stimulation patterns (722) (ATN stimulation pattern (722a) and Arnold neurostimulation pattern (722b)) for simultaneous stimulation using a neuromodulator such as the various devices described herein. In some embodiments, stimulation triggering is performed using a single master clock, such as the master clock (702) of FIG. 7a. For example, stimulation patterns (722a, 722b) may be configured to deliver platelet-rich therapy through the platelet activation pathway (330) as described in relation to FIG. 3a and FIG. 3b.

[0093] As described, the duty cycle (724) for each stimulation pattern (722a, 722b) consists of 10 seconds of no stimulation (e.g., "short duration" according to Table 2 above) following 5 minutes of active stimulation. In other examples, the stimulation pattern (722a, 722b) may consist of 10 seconds of no stimulation following 4 minutes of active stimulation, 20 seconds of no stimulation following 4 minutes of active stimulation, and / or 1 minute of no stimulation following 4 minutes of active stimulation. In other configurations, the duty cycle (722a, 722b) may include different stimulation durations (e.g., medium duration, long duration, or very long duration). In some cases, a high duty cycle (e.g., 90% ON time) may be required to produce the desired therapeutic effect, but in other cases, a low duty cycle (e.g., 50% ON or 30% ON) may be sufficient; This may vary depending on the specific condition of the particular user. However, if a duty cycle high enough to be effective has been selected, user preferences can be taken into account. For example, longer stimulation durations can cause fatigue (e.g., boredom with the sensation) in the wearer, while longer pauses are more noticeable to the wearer; while this may be welcomed as a sensory break for some, it can be perceived as annoyance by others. Therefore, some implementations allow the duty cycle to be customized to some extent based on the user's preferences or tolerance levels.

[0094] Additionally, the duty cycle of the stimulation pattern (722a, 722b) is aligned so that no stimulation is delivered for 10 seconds. Although only active stimulation for 10 minutes is exemplified (e.g., "very short period" according to Table 3 above), in some implementations, the duty cycle (722a, 722b) may be repeated for longer treatment periods (e.g., short period, medium period, long period, very long period, or extremely long period).

[0095] A stimulation pattern (722a) configured to stimulate the ATN is delivered at a frequency of approximately 100 Hz (726a) (e.g., high frequency according to Table 5 below). In some implementations, very high frequencies (e.g., 150-200 Hz or higher) may be used. Additionally, the pulse width (728) of each triggered stimulation (e.g., low-to-mid-range pulse according to Table 6 below) is 250 microseconds, and the interval between pulses (730) is 100 microseconds.

[0096] A stimulation pattern (722b) configured to stimulate the Arnold nerve is delivered at a frequency of approximately 15 Hz (726b) (e.g., low frequency according to Table 5 below). In some embodiments, a mid-range frequency (e.g., 30-40 Hz or higher) may be used. For example, while stimulation at 5 Hz may be uncomfortable or irritating to some wearers, higher frequency stimulation (e.g., mid-range frequency rather than low frequency) may be more comfortable for certain wearers. Thus, in some embodiments, the stimulation frequency may be customized to some extent (e.g., within the therapeutic range) according to the user's preference / tolerance.

[0097] The stimulation pattern (722b) uses the same pulse width (728) and pulse interval (730) as the ATN stimulation pattern (722a). The pulse width (728) and pulse interval (730) may be variable, particularly considering the trade-off between amplitude and pulse width when transmitting activation threshold signals (e.g., the pulse width becomes wider as the amplitude decreases). Additionally, the selected pulse width (728) and pulse interval (730) (e.g., activation threshold) may vary in part depending on the fiber type and / or diameter of the sensory fibers targeted by the stimulation. For example, the specific device described herein is designed to target Aβ fibers at current levels of 1–5 mA. Other fibers that may be targeted for treatment include Aα and Aδ fibers, as shown in Table 4 below. Conversely, C fibers are mostly nociceptive and therefore will not provide as effective treatment.

[0098] Table 4: Types of sensory fibers

[0099]

[0100] As described, the pulse timing (732a) of the ATN stimulation pattern (722a) is offset from the pulse timing (732b) of the Arnold neurostimulation pattern (722b) by an interval (734) of about 2-5 milliseconds. Thus, the ATN stimulation pattern (722a) is configured to be delivered simultaneously with the Arnold neurostimulation pattern (722b) without simultaneous pulse triggering between the two stimulation patterns (722a, 722b). To achieve pulse timing, for example, the frequency of the stimulation pattern (722b) can be set to 14.28 Hz (e.g., 1 / 7 of the frequency of the stimulation pattern (722a)).

[0101] In some implementations where stimulation is applied to one or more sites (e.g., two or more nerve branches), the stimulation duration, frequency, pulse width, and / or duty cycle may differ for each stimulation site. In practice, in some implementations, it is beneficial to use different frequencies for different stimulation sites.

[0102] Stimulation delivery may vary depending on the treatment provided by the treatment device. For example, frequency and / or pulse width parameters may be adjusted for one or more stimulation sites to which stimulation is delivered.

[0103] In some embodiments, frequency and / or pulse width parameters are adjusted during treatment, for example, based on feedback received from patient monitoring. In some examples, feedback may be obtained using one or more sensors or other devices that evaluate heart rate, heart rate variability, electroencephalogram (EEG), blood pressure, and / or blood oxygen concentration.

[0104] In some embodiments, the system utilizes feedback to monitor and / or modify the treatment. Feedback may be obtained from one or more sensors capable of monitoring one or more symptoms being treated by the therapy. For example, if one or more symptoms decrease or are eliminated, the treatment output may likewise decrease or stop. Conversely, if one or more symptoms increase or are added, the treatment output may likewise be activated or adjusted (increased, expanded, etc.). In some examples, the sensors may monitor one or more of the following: skin electrical activity (e.g., sweating), motor activity (e.g., tremors, physiological movements), blood glucose levels, neural activity (e.g., via EEG), muscle activity (e.g., via EMG), and / or cardiorespiratory activity (e.g., EKG, heart rate, blood pressure (systolic, diastolic, and / or average)). Imaging technologies such as MRI and fMRI may be used to adjust the treatment in a given user's clinical setting. In other embodiments, feedback for treatment adjustment may be provided by visualizing pupil changes (e.g., pupil dilation) using, for example, a standard mobile phone and / or smart-glasses. In some implementations, one or more sensors are integrated into the earpiece and / or earpiece. In some implementations, one or more sensors are integrated into the pulse generator. For example, periodic monitoring can be performed by inducing the wearer to touch one or more electrodes of the system (e.g., electrodes embedded in the surface of the pulse generator) or to interact with the pulse generator (e.g., keeping the pulse generator extended away from the body to monitor vibrations using the pulse generator's motion detector). In other implementations, one or more sensor outputs can be obtained from an external device such as a fitness computer, smartwatch, or wearable health monitor.

[0105] Thrombin concentrations were evaluated using optical technology [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 with the stimulation treatment described herein; therefore, thrombin concentrations can be measured and applied through the device and / or system described herein to evaluate the effect of the treatment and adjust delivery parameters. In addition to this example, thrombin concentrations can be measured using blood taken from a wound, and the resulting measurements can be transmitted to the treatment device and / or system to adjust the application of the treatment.

[0106] As another example, a microfluidic chip can be used as a sensor system to actively monitor coagulation in real time [Refer to 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.]. In addition to this example, electrical impedance measurements collected through a microfluidic chip can be analyzed to evaluate the therapeutic effect in real time and adjust it as needed.

[0107] As another example, the "lab-on-a-chip" concept can be used to monitor and / or control the application of treatment. Closed-loop neuromodulation of hemostasis can be achieved through "lab-on-a-chip" microfluidic technology. For example, a drop of blood collected from a lancet-induced finger prick can be gathered in a capillary and placed on a test strip pre-equipped with a bioreceptor that selectively recognizes and binds to a biomarker of interest. The bioreceptor is immobilized on the surface of a component of the test strip, and when the biomarker binds to the bioreceptor, a signal is generated that can be detected by a device designed to receive the test strip and detect the signal. Biomarkers of interest include, for example, thrombin or a thrombin-antithrombin III complex. The bioreceptor can be an antibody, a synthetic chemical, or an engineered biological derivative (e.g., nucleic acid, protein, or enzyme). The signal can be detected through various means, such as electrical, mechanical, thermal, piezoelectric, or optical. Examples of optical detection include spectral analysis of light at specific wavelengths, such as the streptavidin-peroxidase enzyme reaction that produces yellow, the intensity of which is directly proportional to the concentration of the biomarker to be analyzed. A device that receives the test strip and reads the signal can use microfluidics to wash away unbound material or operate on a complete sample.

[0108] In another example presented 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.], activity in the locus coeruleus can be measured indirectly through pupilography. As previously mentioned, activity in the LC can induce splenic activation by activating sympathetic pathways; therefore, pupilography can be used not only to evaluate the response to treatment but also to control its delivery. Several portable automated pupilographs (e.g., NPi ® Devices such as -200, Neuroptics Inc. (Irvine, CA, USA) are commercially available and can be used to automatically transmit pupil diameter information (e.g., with minor modifications) to the treatment devices and / or systems described in this document. Additionally, as previously discussed, images 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.

[0109] The monitoring used can be partially based on the therapeutic environment. For example, EEG monitoring is more feasible in a hospital setting, and heart rate monitoring can be performed through sensors such as pulse meters embedded in earpieces or other sensors embedded in fitness monitoring devices or low-budget health monitoring devices like smartwatches. Additionally, microfluidic chip and lab-on-a-chip monitoring may be more practical in hospital or clinical settings, and pupil dilation can be easily monitored in various environments.

[0110] In an exemplary example, feedback related to skin electrical activity may be used to monitor and detect the speed or timing of symptoms and / or treatment results. For example, skin electrical activity may be detected by electrodes of a therapeutic earpiece device. In another example, skin electrical activity may be detected by electrodes located on other parts of the body and communicated to a system. In some embodiments, the skin electrical electrodes may be configured to detect specific substances within the skin (e.g., cortisol) via electrochemical means.

[0111] In some implementations, the system may additionally include one or more motion sensors, such as accelerometers or gyroscopes, which may be used to collect information for adjusting treatment. For example, one or more motion sensors are configured to detect tremors and / or physiological movements. In one aspect, tremors and / or physiological movements may indicate baseline conditions and / or treatment for baseline conditions. For example, tremors and / or physiological movements may indicate symptoms associated with substance withdrawal. In one aspect, feedback from blood glucose monitoring may be used to adjust treatment.

[0112] In other embodiments, an EKG may be used to evaluate heart rate and heart rate variability, measure the overall activity of the autonomic nervous system and / or the relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system, and to regulate treatment. Autonomic activity may indicate symptoms associated with substance withdrawal. In one aspect, a therapeutic device may be used to provide treatment for cardiac conditions such as atrial fibrillation and heart failure. For example, it may provide treatment for the regulation of the autonomic nervous system. In some embodiments, a therapeutic device may be used to provide treatment to balance the ratios between any combination of the autonomic, parasympathetic, and sympathetic nervous systems.

[0113] In one aspect, the system can enable closed-loop neural stimulation by monitoring impedance measurements. For example, using feedback monitoring, the patient or caregiver can be warned if treatment is not delivered properly or if the treatment device is removed.

[0114] In some implementations, sensor data can be monitored to determine whether and when to initiate specific treatments. For example, one or more blood tests can be performed automatically or semi-automatically (e.g., on a periodic basis) to monitor differences in a subject's coagulation pathway function. For instance, tests can be manually activated and automatically analyzed. As previously mentioned, coagulation pathways are generally divided into three types: the endogenous pathway, the exogenous pathway, and the common pathway. Various tests are typically used to evaluate the function of the endogenous and exogenous pathways. For instance, coagulation function through the endogenous and common pathways can be assessed using a test known as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PPT). Thus, the aPPT test evaluates coagulation factors XII, XI, IX, VIII, X, V, II, and I. For instance, individuals with coagulation deficiencies, such as hemophilia, have a long or high PTT. However, because the various implementations of blood management therapy described herein enhance platelet-driven coagulation in a manner independent or semi-independent of coagulation factors, treatment may also shorten PTT in patients with hemophilia. Another test that evaluates the same pathway as PTT is the Activated Coagulation Time (ACT) test. Therefore, PTT (or ACT) can be used to assess when to apply neurostimulation therapy. On the other hand, Prothrombin Time (PT) is generally used to test coagulation via exogenous and common coagulation pathways; thus, PT evaluates the function of coagulation factors VII, X, V, II, and I. As another example, PT can be used to evaluate the effect of treatment and determine when to resume stimulation therapy. PT, as well as PTT and ACT, can be evaluated using various portable devices currently available on the market [e.g., Coag-Sense® PT meter from Coag-Sense, Inc., https: / / coag-sense.[com / , CL1000 from EasyDiagnosis, https: / / www.easydiagnosis.com / CL1000.html]. For example, PTT, PT, and / or ACT measurements may be automatically transmitted (e.g., via a wireless connection) to a treatment device and / or system (e.g., a cloud-based analysis engine) as described herein and analyzed to determine a method for controlling treatment delivery.

[0115] In some embodiments, stimulation pulses are delivered as a pulse pattern. Individual pulses of the pattern may differ in frequency and / or pulse width. The pattern may be repeated as a stimulation cycle. For example, the pulse pattern may be designed to partially increase stimulation so that the wearer feels comfort when experiencing stimulation. In other examples, the pulse pattern may be partially designed to apply stimulation alternately between stimulation sites when two or more sites are stimulated during treatment. In examples involving multiple stimulation sites, the stimulation pattern may be designed so that the stimulation frequency is not the same across all sites where stimulation is delivered.

[0116] In some embodiments comprising electrical stimulation through the skin or using transdermal (i.e., non-penetrating) electrodes, the stimulation frequency varies within a series of ranges. For example, the stimulation frequency applied to the stimulation pattern may include a first or low frequency in the range of about 1-30 Hz, a second or mid-range frequency in the range of about 30-70 Hz, a third or high frequency in the range of about 70-150 Hz, and / or a fourth or very high frequency in the range of about 150-300 Hz.

[0117] Table 5: Electrotherapy: Frequency Table

[0118]

[0119] In one embodiment, the stimulation frequency is variable between 2 Hz and 100 Hz. In another embodiment, the pulse width is adjusted between 20 microseconds and 1000 microseconds to further facilitate the customization of treatment. The stimulation frequency is an important factor in distinguishing neural networks; for example, using high frequency has been shown to be beneficial for activating desired trigeminal nerve features; conversely, low frequency is more desirable for activating desired vagal nerve features. Accordingly, in a preferred embodiment, combinations of low and high frequencies are applied, respectively, according to the various embodiments described herein to activate the vagal and trigeminal nerve branches. In another embodiment, a variable frequency (e.g., stimulation at a non-constant frequency) may be used on one or more electrodes. The variable frequency may be a sweep and / or random / pseudo-random frequency variation centered around a central frequency (e.g., 15 Hz ± 1.5 Hz or 100 Hz ± 10 Hz). Varying the stimulation frequency in a random or pseudo-random manner can help prevent neural adaptation.

[0120] When using electrical stimulation, various pulse width combinations may be used at each electrode. In some examples, the pulse width may be in the range of one or more of the following: a first or short pulse width of about 10–50 microseconds, or more specifically within the range of 10–20 microseconds, 20–30 microseconds, 30–40 microseconds, or 40–50 microseconds; a second or lower mid-range pulse width of about 50–250 microseconds, or more specifically within the range of 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 230–250 microseconds; A third or high intermediate-range pulse width within the range of approximately 250-550 microseconds, or more specifically, 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, 510-530 microseconds, or 530-550 microseconds; A fourth or longer pulse width within the range of approximately 550-1000 microseconds, or more specifically, 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 fifth or very long pulse width in the range of about 1000-4000 microseconds, or more specifically 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, and 3750-4000 microseconds. In various implementations, different ranges of pulse widths may be used at one or more electrodes. The selection of the stimulation pulse width depends on the desired target fiber and output intensity. For example, activation of C-type fibers at similar intensities generally requires a longer pulse width than activation of myelinated Aβ fibers. In a preferred embodiment, a low-to-mid-range pulse is used to more effectively activate myelinated fibers.

[0121] Table 6: Electrotherapy: Pulse Width Table

[0122]

[0123] The activity of the VEF can be modulated by electrical stimulation of various sites. For example, the vagus nerve ascends along the neck into the carotid sheath (e.g., cervical vagus nerve) and can be stimulated percutaneously and non-invasively using patch electrodes or devices such as those described in U.S. Patent No. 10,207,106 of Simon et al. The cervical vagus nerve can also be stimulated invasively using externally powered implantable electrodes or fully implantable systems such as the system described in U.S. Patent No. 8,571,654 of Libbus et al. For example, an implantable system can provide low-frequency stimulation (e.g., 1-30 Hz) to the cervical vagus nerve and / or descending vagus nerve pathways. The same invasive / implantable methods can be used to stimulate the splenic nerve and increase splenic activity. Other stimulation methods may also be used, such as ultrasound or light (e.g., Shoham et al. U.S. Patent Application Publication No. 8,562,658) which directly activate the spleen (e.g., see U.S. Patent Application Publication No. 2011 / 0190668 of Mishelevich).

[0124] VEF activity can also be regulated by stimulating the auricular branch (ABVN) of the vagus nerve and / or branches of the trigeminal nerve. Each of these pathways activates neurons in the nucleus accumbens (NTS), thereby directly or indirectly increasing VEF activity. The trigeminal nerve accesses the subcutaneous region at various locations in the face; for example, the auricular-temporal nerve (ATN), supraorbital nerve, suprablastic nerve, subblastic nerve, eyelid branch of the lacrimal nerve, external nasal nerve, suborbital nerve, zygomatic-facial nerve, zygomatic-temporal nerve, frontal nerve, and buccal nerve are potential trigeminal nerve targets that deliver transcutaneous stimulation. A device that places electrodes to stimulate one of these branches can be used to activate the VEF and increase coagulation potential. For example, a device such as that described in U.S. Patent No. 10,207,106 by Simon et al. can be used to stimulate branches of the vagus nerve. In a similar manner, the device described in Rigaux’s U.S. Patent No. 8,914,123 can be used to stimulate branches of the trigeminal nerve. Additionally, although cumbersome, the two devices can be used simultaneously or alternately to induce vagus nerve, trigeminal nerve, or trigeminal-vagus nerve responses. The ABVN can be stimulated in the auricle, and the primary targets for this purpose are the concha, the angle of the ear, the tragus and / or inside the external auditory canal, and inside or around the mastoid tube (McS) behind the ear, i.e., the Arnold canal. The ATN can be stimulated inside or around the auricle, for example, above the temporomandibular joint (TMJ) and / or immediately anterior to the auricle. The ABVN and trigeminal nerve branches can be activated individually, simultaneously, or sequentially, for example, alternately. Additionally, these nerves can be stimulated by electrodes through the skin (e.g., as described in Szeles’ U.S. Patent No. 8,942,814 or Taca Jr.It can be stimulated invasively using a transdermal electrode (e.g., as described in U.S. Patent Application Publication No. 2018 / 0200522) and non-invasively using a transdermal electrode (e.g., as described in U.S. Patent No. 11,351,370 by Covalin et al.).

[0125] Referring to FIGS. 6a and 6b, in a preferred embodiment, stimulation may be provided transdermally using an auricular stimulation device (600). The auricular stimulation device (600) is illustrated as having electrodes (602, 604, 606, and 608). For example, the electrodes (602, 604, 606, and 608) may be configured to form corresponding circuits (610a and 610b) according to the embodiment. For example, an equivalent circuit (610a) may be formed by electrode (602) and electrode (606), and these electrodes are configured to stimulate a tissue portion (620). In this example, the tissue portion (620) is positioned to target the auricular region in which branches of the auricular branch of the vagus nerve are innervated, and the posterior ear region in which branches of the greater auricular nerve and branches of the lesser laryngeal nerve are innervated. For example, an equivalent circuit (610b) may be formed by electrodes (604) and (608), which are configured to stimulate a tissue portion (622). In this example, the tissue portion (622) may be positioned to target the anterior region of the ear where the auricular temporal nerve is transmitted and branches out, as well as the posterior region of the ear where branches of the greater auricular nerve and branches of the lesser occipital nerve are distributed.

[0126] For example, the tissue portion (620) may be the auricular angle, the auricular apex, or part of both, which allows ABVN stimulation and is stimulated at about 5 Hz, 15 Hz, or 30 Hz. For example, the tissue portion (620) may be placed in a trigeminal nerve area that is stimulated at about 80 Hz, 100 Hz, 120 Hz, or 150 Hz.

[0127] For example, the equivalent circuit (610a) is stimulated by the first channel, and the equivalent circuit (610b) is stimulated by the second channel.

[0128] Referring to FIGS. 6c and 6d, in some embodiments, stimulation may be provided transdermally using electrodes (642a, 642b, 642c) of the auricular stimulation device (630). For example, the electrodes (642a, 642b, 642c) may be configured to form corresponding circuits (650a and 650b).

[0129] In the first example, the equivalent circuit (650a) may be formed by electrodes (642b) and (642c) configured to stimulate a tissue portion (652a). In this example, the tissue portion (652a) may be positioned to target the ATN within or around the anterior auricular region adjacent to the TMJ. For example, the equivalent circuit (650a) may be designed to deliver a stimulus that modulates the activity of the VEF.

[0130] In the second example, the equivalent circuit (650b) may be formed by electrodes (642a) and (642c) configured to stimulate a tissue portion (652b). In this example, the tissue portion (652b) may be positioned to stimulate AVBN inside or around the McS to regulate the activity of the VEF.

[0131] In another example, to obtain a synergistic effect, both AVBN and ATN are stimulated, respectively, within or around the McS and in or around the anterior auricular region adjacent to the TMJ. In this scenario, for example, both AVBN and ATN can be stimulated alternately with each other almost simultaneously. In the example, each electrode (642a and 642b) can be multiplexed with electrode (642c) to form a circuit and force current alternately to tissue (652a) and tissue (652b). In another example, AVBN and ATN can be stimulated simultaneously.

[0132] In some embodiments, the equivalent circuit (650a) is stimulated by the first channel and the equivalent circuit (650b) is stimulated by the second channel.

[0133] Referring to FIGS. 6e and 6f, the auricular stimulation device (660) is illustrated as having electrodes (670a, 670b, 670c). For example, the electrodes (670a, 670b, 670c) may be configured to form corresponding circuits (680a) and (680b) according to the embodiment. In one embodiment, the equivalent circuit (680a) may be formed by the electrode (670a) and the electrode (670c) configured to stimulate a tissue portion (682). In this example, the tissue portion (682) may be positioned to target an area of ​​the auricular region innervated by a branch of the auricular branch of the vagus nerve (e.g., located for stimulation by the first electrode (670a)) and an area behind the ear innervated by a branch of the greater auricular nerve and a branch of the lesser laryngeal nerve (e.g., located for stimulation by the third electrode (670c)). In the second example, the equivalent circuit (680b) may be formed by electrodes (670b) and (670c) configured to stimulate a tissue portion (684). In this example, the tissue portion (684) may be positioned to target the area in front of the ear where the auricular temporal nerve is innervated (e.g., positioned for stimulation by the second electrode (670b)) as well as the area behind the ear where branches of the greater auricular nerve and branches of the lesser occipital nerve are innervated (e.g., positioned for stimulation by the third electrode (670c)).

[0134] In some embodiments, the tissue portion (682) is a tissue area of ​​the auricular angle, the auricular apex, or part of both, and is stimulated at about 5 Hz or 15 Hz or 30 Hz. In some embodiments, the tissue portion (684) is placed in a trigeminal nerve area stimulated at about 80 Hz or 100 Hz or 120 Hz or 150 Hz.

[0135] In some embodiments, the equivalent circuit (682) is stimulated by the first channel, and the equivalent circuit (684) is stimulated by the second channel. The first channel and the second channel may be activated simultaneously and / or alternately.

[0136] In some embodiments, electrical stimulation therapy for hemorrhage management as described herein is performed using splenic nerve stimulation. In other embodiments, the spinal nerve root forming the thoracic great splenic nerve (sometimes referred to as the dorsal root ganglion or DRG) may be the stimulation target (also known as the visceral DRG). In other embodiments, the celiac ganglion may be targeted for stimulation. For example, these neural structures as well as the spleen may be directly stimulated percutaneously using ultrasound (e.g., focal or confocal ultrasound / high-intensity ultrasound). As another example, these neural structures (e.g., splenic nerve, celiac ganglion, DRG) and the spleen may be stimulated using an implantable electrode or device. In addition to this example, the implantable mechanism may be configured to provide low-frequency stimulation (e.g., 1-30 Hz) upon activation. Activation can be achieved through programming (e.g., periodic activation), external triggering (e.g., via radio signals), and / or external power supply (e.g., inductively coupling external power into the range of an inductively charged implantable mechanism). For example, using external triggering allows the treatment time to be adjusted according to the patient's needs, thereby allowing power to be stored in a battery-operated device. For example, each therapeutic activation of the spleen or splenic nerve may include a short pulse train, that is, the stimulation may be turned on for a short time (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 duration of the stimulation (e.g., up to about 2.5, 5, 10, or 25 seconds, etc.).

[0137] Example: Human study including non-invasive stimulation using an auricular nerve stimulation device

[0138] Figures 8a through 8e show the results of three human studies using a non-invasive dual-neuron, dual-frequency approach. Using this novel approach, the inventors achieved the first results in improving hemostasis in both healthy individuals and those suffering from platelet dysfunction. In all three experiments, the inventors obtained relevant and clinically significant results demonstrating a clear improvement in the hemostasis process.

[0139] In one experiment, blood loss was evaluated during a clinical study in which subjects with a chronic condition requiring continuous dialysis underwent a dialysis port removal procedure. Subjects were randomly divided into a placebo group (sham group) and an active group. Subjects in both groups wore an ear-mounted neurostimulator as described herein, but only the active group received the neurostimulation treatment described herein.

[0140] The treatment provided to the active group consisted of 30 minutes of stimulation prior to the surgical removal of the dialysis port. Specifically, 30 Hz and 100 Hz stimulations were delivered transcutaneously into and out of the auricle to the skin very close to the AVBN and trigeminal nerve branches, respectively (Transcutaneous Auricular Stimulation - tAN).

[0141] This study showed a significant difference in blood loss between the two groups. As illustrated in the graph (800) in Fig. 8a, the blood loss of participants in the placebo group was nearly four times (367%) the average blood loss of participants in the active group. As illustrated, the placebo group lost approximately 37-38 ml of predicted blood volume, while the subjects in the active group lost approximately 11-12 ml of predicted blood volume. This is a notable result considering that the participants were suffering from platelet dysfunction.

[0142] In the second human study, prothrombin time (PT) was measured in healthy human participants before and after stimulation. Since PT evaluates the rate at which coagulation occurs, it plays a significant role in the amount of blood lost after injury. In this experiment, PT was measured in blood samples taken from the participants before stimulation was applied. Next, subjects were fitted with an ear-mounted neurostimulator as described herein, and a stimulation protocol similar to that described in relation to the timing diagram (720) in FIG. 7b was applied to all subjects for 15 minutes (e.g., a short time). In this study, a first stimulation pattern at a frequency of 100 Hz was applied to the ATN, and a second stimulation pattern at a frequency of 30 Hz was applied to the Arnold nerve, respectively. After the stimulation session, a new blood sample was taken from each participant, and PT was evaluated in the new blood sample.

[0143] In FIG. 8b, graph (810) shows the difference in human prothrombin time before stimulation (812) (e.g., about 11.2 seconds) and after stimulation (814) (e.g., about 9.8 seconds). This indicates that the coagulation rate (i.e., increase in coagulation potential) improved by 12% (standard deviation 0.013). As can be seen from the standard deviation (STD) and coefficient of variation (CV) in Table 7 below, the qualitative response of all subjects was identical, and the quantitative response was also very similar. In this study, whole blood was collected using a fingertip lancet before the start of stimulation and about 1 minute after the end of stimulation to measure prothrombin time.

[0144] Table 7: Human Study Results: Prothrombin Time

[0145]

[0146] Figures 8c, 8d, and 8e show the results obtained from a third study in which healthy human subjects were divided into two groups (ABVN group and tAN group). All participants in both groups wore an ear-mounted neurostimulator as described herein, and all participants received an active stimulation session following a placebo stimulation session. In all cases, baseline measurements were taken prior to the placebo measurements. As data analysis revealed no significant difference between baseline and placebo measurements; therefore, only placebo measurements are provided herein.

[0147] In the third study, the ABVN group received stimulation therapy as described herein on the auricular skin, particularly at the apex of the condyle, in locations adjacent to or very close to the area nerve-distributed by the ABVN. The tAN group received stimulation therapy as described herein on both the auricular skin, in locations adjacent to or very close to the area nerve-distributed by the ABVN (particularly the apex of the condyle), and at locations adjacent to or very close to the area emerging from the surface of the auricular temporal nerve. Additionally, both groups received "placebo" stimulation with electrodes placed in the same locations where actual stimulation was applied (active stimulation). The only difference between the active stimulation and the placebo stimulation was that the stimulation intensity was set to zero during the placebo stimulation period; that is, no current was delivered during the placebo stimulation period.

[0148] Both groups showed an increase in hemostatic activity. The results were qualitatively distinct between the two groups, and initially, quantitatively distinct. The experiment evaluated, among other things, 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 (double staining). Looking at the graph (820) in Fig. 8c, the placebo results (822a, 822b) establish a point of comparison. As can be seen in the activity measurements after 60 minutes (826a, 826b), glycoprotein (GP) IIb / IIIa expression increased on the platelet surface in both groups. However, the increase in GP IIb / IIIa in the ABVN group was slower, and there was no evidence of significant efficacy in the initial measurements (824b) taken 10 minutes after stimulation treatment. Conversely, the initial tAN measurement (824a) was nearly identical to the active measurement (826a) after 60 minutes.

[0149] A similar response was obtained when observing the amount of platelets that showed simultaneous changes in both P-selectin and GP IIb / IIIa surface expression, as illustrated in graph (830) of Fig. 8d. As illustrated, both groups showed an increase in cells expressing both P-selectin and GP IIb / IIIa (836a, 836b), but compared to the placebo measurements (832a, 832b), the response of the tAN group (834a, 836a) was faster, whereas the response of the ABVN group (834b, 836b) did not increase until the measurement point after 60 minutes.

[0150] Thromboconstriction is significantly influenced by the presence of GP IIb / IIIa receptors on the surface of platelets. Thromboconstriction helps wound healing by bringing the separated edges of the wound closer together until the wound heals. Therefore, by promoting changes in GP IIb / IIIa receptors, subjects in both groups are expected to benefit from a reduction in healing time.

[0151] Additionally, referring to Figure 8e, analysis of the coagulation profile using thrombectomy (TEG) showed that the maximum thrombus density (TEG MA) increased significantly in the tAN group but not in the ABVN group. As can be seen in the figure, compared to the placebo results (842a, 842b), the tAN group results (844a) showed an average increase of approximately 20% in TEG MA 10 minutes after active stimulation. Furthermore, 1 hour after the active stimulation was stopped, the average increase in the tAN group results (846a) was nearly 30%. All subjects in the tAN group showed an increase of at least 10% in TEG MA by the 60-minute analysis point, while the majority of subjects showed an increase of at least 20% by the 60-minute analysis point. An increase in thrombus density makes the thrombus stronger and allows for faster stopping of bleeding. Conversely, individuals with low TEG MA (e.g., thrombocytopenia, thrombopathia, etc.) generally receive platelet transfusions for bleeding management because there are no pharmacological solutions available to increase thrombus density. Therefore, relying on initial results and not bound by theory, the inventors anticipate that the electrical stimulation therapy described herein will provide the benefit of enhancing platelet-mediated coagulation. In other words, individual platelets show improved coagulation performance compared to before stimulation.

[0152] Referring to FIG. 9, a block diagram (900) of exemplary components of a pulse generator (950) communicating with exemplary components of two components (960) is illustrated. In some embodiments, the multichannel pulse generator circuit (950) has at least one microcontroller or a microprocessor (910) having at least one core. For example, if multiple microcontrollers or multiple cores exist, one may control wireless communication (920) and the other core(s) may be dedicated to treatment control. In some embodiments, a low-power programmable logic circuit (e.g., a field programmable gate array (FPGA) or a 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 treatment delivery.

[0153] In some embodiments, the inverter circuit (945a-n) is used to generate a dual-phase / dual-polarity pulse. In some embodiments, one inverter circuit (945a-n) is used per channel (970a-n), whereas in other embodiments, one inverter circuit (945) is used for multiple channels (970a-n). For example, each channel (9a-n) can target a different anatomical region (e.g., tissue region) (948a-n). High-voltage compliance (e.g., >50V, >70V in other embodiments, >90V in yet another embodiment) can be used to ensure sufficient potential margin to generate the current required by the intensity control unit (942a-n) of each inverter circuit (945a-n) by providing one or more high-voltage inverters (940a-n) per inverter circuit (945a-n). To enhance safety, in some embodiments, an overcurrent detection circuit (944a-n) is provided in each inverter circuit (945a-n). In some embodiments, an impedance measurement circuit (946a-n) is provided in each inverter circuit (945a-n). For example, the impedance measurement circuit (946a-n) can support impedance tracking over time to identify failure of sufficient treatment delivery. In some examples, treatment delivery may be impaired when the electrode does not make contact with or does not make proper contact with the target tissue (948a-n), when the cable or connector between the multichannel pulse generators (950) is disconnected from one of the two components (960), or when the electrode deteriorates or is defective. Impedance monitoring over time provides the additional advantage of being able to track the condition of the contact electrode; thus, the controller can warn the user when the contact electrode reaches the end of its life or is no longer usable. The FPGA (912) can control the inverter circuit (945a-n) and receive feedback from the inverter control components (938a-n).

[0154] In some implementations, a battery (932) is used to power a pulse generator (950). For example, the battery (932) may power components of the pulse generator (950) and / or two components (960) through 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-940n) to deliver electrical stimulation therapy through one or more channels (945a-n).

[0155] 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 performed wirelessly using inductive coupling (not shown). The battery (932) can be charged via a battery charging circuit (930).

[0156] In some embodiments, the isolation port (918) is used to communicate with the microcontroller(s) (910) (e.g., via the communication port (916)). Communication can be bidirectional, and instructions or entirely new code can be uploaded to the microcontroller(s) (910) and information stored in memory (922) can be downloaded. In some embodiments, memory (922) or additional memory may be added to the circuit as an external component (e.g., wireless or wired communication with the pulse generator (950)). For example, the isolation port (918) (e.g., USB) may be used to connect the memory to the pulse generator (950). In other embodiments, at least a portion of the memory (922) may be located inside the microcontroller(s) (910). In some embodiments, the FPGA (912) may also have internal memory.

[0157] In some implementations, an external trigger circuit (924) is included to start and / or stop stimulation via an external signal. In some implementations, the external trigger signal may pass through an isolation port (918); in other implementations, the trigger signal may pass through a modified USB configuration (i.e., not using a standard USB pin configuration). Using a modified USB configuration requires the use of a custom USB cable, thus preventing accidental external triggering using a commercially available USB cable. As another example, the external trigger signal may be transmitted wirelessly (e.g., Bluetooth) from a separate source.

[0158] In some embodiments, a hardware user interface is provided for interacting with the multichannel pulse generator (950) via a user interface circuit (926). For example, the user interface circuit (926) may include a button, an LED, a tactile (e.g., piezoelectric) device such as a buzzer and / or a display, or a combination thereof. In some embodiments, the user interface circuit (926) includes a signal processing component for interpreting user interface commands transmitted via an external device (e.g., via wireless communication (920)). In some embodiments, the external device may be a smartphone app, a tablet computer, or a medical monitoring device (e.g., within a hospital).

[0159] In some implementations, an external master clock (928) is used to drive the microcontroller(s) (910) and / or FPGA (912). In other implementations, the component clock may be located within, integrated with, or co-packaged with the microcontroller(s) (910) and / or FPGA (912). In some implementations, one or more oscillators, including, in some cases, an adjustable oscillator (914), are used to set pulse parameters, such as frequency and / or pulse width.

[0160] In some embodiments, the bilateral component (960) is fabricated from a thin flex PCB or printed electronics so that it is lightweight and can be easily bent to fit various anatomical structures. In some embodiments, the bilateral component (960) has one or more channels. The bilateral component (960) or each of its channels may include a peak suppression circuit (947a-n) and an electrode (965a-n) for contacting the skin at the location of the target tissue (948a-n). In some embodiments, the bilateral component (960) includes a unique chip identifier or a unique ID chip (949). The unique ID chip may be used to track usage and prevent other unauthorized circuits from being connected to the multichannel pulse generator (950). At least one bilateral component (960) is connected to the multichannel pulse generator (950).

[0161] In some embodiments, the bilateral component (960) is fabricated from a thin flex PCB or printed electronics so that it is lightweight and can be easily bent to fit various anatomical structures. In some embodiments, the bilateral component (960) has two or more channels. The bilateral component (960) or each of its channels may include a peak suppression circuit (947a-n) and an electrode (965a-n) for contacting the skin at the location of the target tissue (948a-n). In some embodiments, the bilateral component (960) includes a unique chip identifier or a unique ID chip (949). The unique ID chip may be used to track usage and prevent other unauthorized circuits from being connected to the multichannel pulse generator (950). At least one bilateral component (960) is connected to the multichannel pulse generator (950).

[0162] In some embodiments, the method and system of the present disclosure use feedback to monitor and / or modify treatment. Referring to FIG. 13, an environment (1350) and a system (1360) for using feedback for neural stimulation are illustrated. The environment (1350) and / or system (1360) may include elements of various treatment devices described herein, such as the treatment device (600) of FIG. 6a, the treatment device (630) of FIG. 6c, and / or the treatment device (660) of FIG. 6e. Additionally, the environment (1350) may include peripheral devices (1354, 1358, 1356, 1390) and / or a network system (1532). Additionally, the system (1360) may include aspects of a multichannel pulse generator described in detail below. For example, the environment (1350) and the system (1360) can be used to analyze sensor data in real time, thereby enabling closed-loop neurostimulation based on feedback data related to the wearer of the neurostimulation device. As another example, feedback monitoring can alert patients, caregivers, and / or clinical resources to treatment progress and / or treatment-related issues. For example, if treatment is not provided properly or the treatment device is removed, the clinical / caregiver computing system (1390) can contact the caregiver or clinician.

[0163] In some implementations, the system (1360) is at least partially activated by initiating power supply to the system (1360) through a power control circuit (1384). For example, one or more control elements (1386) may allow a wearer or patient to activate the system (1360) and / or set initial treatment parameters. In certain implementations, the treatment may be remotely activated and / or adjusted via an external device, such as a portable computing device (1354).

[0164] In some embodiments, one or more sensor interfaces (1362) of the system (1360) receive feedback from one or more sensors (1370). For example, various sensors (1370) may be provided to monitor one or more symptoms treated by therapy, e.g., in some examples, stress and / or anxiety, pain, nausea, fatigue, inflammation and / or disorientation / vertigo. In other examples, specific sensors (1370) may be provided to monitor the wearer's activity or movement to coordinate therapeutic stimuli with the corresponding activity / movement. In some examples, the sensor (1370) may include one or more motion sensors (1370a) for monitoring exercise activity (e.g., tremors, physiological movements) (e.g., motion sensors, accelerometers, and / or gyroscopes), one or more skin electrical sensors (1370b) including electrochemical sensors for monitoring skin electrical 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., electrocardiogram (EKG) sensing electrodes, heart rate sensors, blood pressure (systolic, diastolic, and average) sensors, etc.), and / or muscle response sensors (1370f) for monitoring muscle response activity (e.g., electromyogram (EMG) sensors). In another example, the sensor (1370) may include one or more audio sensors (1370g) (e.g., microphone, bone conduction microphone, vibration sensor, etc.) for obtaining sound signals (e.g., speech and / or utterance, breath sounds, heart sounds, etc.). In yet another example, the sensor (1370) may include one or more ultrasound sensors (1370h) for measuring deep tissue signals, in some examples central blood pressure, cerebral blood flow velocity (CBFV), heart rate and / or cardiac output.

[0165] The sensor (1370) may communicate with the sensor interface (1362) of the system (1360) via wired and / or wireless communication. For example, a specific sensor (1370) may be integrated into an earpiece and / or earpiece of a neurostimulator mounted on the ear, such as the various devices described in this disclosure. In another example, one or more sensors (1370) may be integrated into a pulse generator for delivering neurostimulator therapy. In addition to this example, periodic monitoring may be achieved by inducing the wearer to touch one or more electrodes of the system (1360) (e.g., electrodes embedded on the surface of the pulse generator) or to interact with components of the system (1360), such as the pulse generator (e.g., holding the pulse generator away from the body and monitoring vibrations using the pulse generator's motion detector). For example, these prompts may be provided through one or more speaker elements (1380a) (e.g., voice commands) and / or one or more lighting elements (1380b) (e.g., an LCD display, LED display, 7-segment digital display and / or LED indicator next to information printed on the surface of the system (1360)) via the user interface (1366).

[0166] In some implementations, a user interface (1366) is used to deliver part of the therapy to the wearer. For example, the system (1360) can coordinate the neurostimulation therapy with a virtual reality (VR) device (1392). In some examples, the VR device (1392) can provide audio, visual, and / or tactile outputs tailored to the purpose of a specific therapy. For example, to reduce stress and anxiety, the system can configure the VR device (1392) to provide comforting audio and / or visual outputs to the wearer during neurostimulation therapy. As another example, to overcome PTSD, phobias, cravings, and / or other addiction-related triggers, the VR device (1392) can be configured to present audio and / or visual content triggers during neurostimulation therapy. Although illustrated as a separate VR device (1392), in other embodiments, neurostimulation electrodes are embedded in the VR device (e.g., VR headset) as a virtual reality-based neurostimulation therapy device.

[0167] In some implementations, feedback data, such as sensor feedback collected by the system (1360), may be provided to one or more peripheral devices (1354, 1390) via a pulse generator. For example, the feedback may include sensor signals related to the symptoms of a patient being treated by the system (1360). A clinical user monitoring sensor indicators related to these signals may manually adjust the delivery of treatment using one or more adjustable controls provided by the application. Additionally, in some implementations, the feedback may be used to generate notifications that can be reviewed by a patient, caregiver, or clinician on one of the peripheral devices (1354, 1390). For example, the notifications may include low power notifications, device removal notifications, or malfunction notifications. In an exemplary example, the system (1360) may allow closed-loop neural stimulation by monitoring impedance measurements. For example, a notification regarding removal or malfunction may be issued when an impedance measurement indicates a lack of proper contact between one or more electrodes of the treatment device and the tissue above or around the patient's ear. The notification may be issued to the patient and / or one or more third parties, for example, through an application running on one of the peripheral devices (1354, 1390). For example, the application may issue an audible warning, display a visual notification, or generate a tactile output from the peripheral device (1354, 1390). Additionally, in some embodiments, the application may issue the notification through communication means, such as sending an email, text message, or other electronic message to one or more authorized users, such as a patient, a caregiver, and / or a clinician.

[0168] Conversely, in some implementations, a cloud platform equipped with sensor data analysis (1352) accessible via a network may receive feedback, review current measurements, and transmit commands to a pulse generator (e.g., via a Wi-Fi network or indirectly via a local portable device (1354)). In another example, the pulse generator may collect feedback from one or more fitness monitors and / or health monitor devices (1354, 1390), analyze the feedback, and determine whether to adjust treatment accordingly.

[0169] In another implementation, the pulse generator is included in the auricular component of the treatment device; that is, the pulse generator and the auricular component are located together so that an extension cable to connect the two parts may not be required. The auricular component and the pulse generator may be wirelessly connected to an electronic device (e.g., personal computer, tablet, or mobile phone) (1354, 1390) and / or a remote server (1352). Additionally, in some embodiments, the electronic device (1354, 1390) is also wirelessly connected to the remote server (1352).

[0170] In some implementations, the system (1360) includes at least one isolation port for wired communication with peripheral devices (1354, 1390). In some examples, the isolation port may be a Universal Serial Bus (USB) connection (e.g., Mini-USB connection, Micro-USB connection, USB-C port, etc.), an Ethernet port, or a Serial ATA (SATA) connector. For example, the isolation port may be included in the pulse generator to update the software version running on the pulse generator or to reprogram the pulse generator's treatment settings. The isolation port may be connected to a network communication interface (1368) to enable communication between the peripheral devices (1354, 1390) and the system (1360) through the isolation port. The network communication interface (1368) may couple the isolation port to a system control circuit (1372). For example, the network communication interface (1368) can establish a direct (e.g., wired) communication link with one of the peripheral devices (1354, 1390) to transmit data from memory (1376) to the peripheral device (1354, 1390).

[0171] Additionally, in some implementations, a radio frequency (RF) antenna (e.g., a transmitter or a transmitter / receiver) is included in the network communication interface (1368). The RF antenna can communicate wirelessly with peripheral devices (1354, 1358) directly or through a network. The RF antenna can act as a broadcast antenna to provide information to any RF receiver in the receiving area of ​​the system (1360) in combination with processing circuitry for generating wireless communication. For example, the RF antenna can broadcast sensor data, sensor measurements, warnings, alarms, or other operational information so that one or more peripheral devices (1354, 1390) can receive them. In other implementations, the RF antenna can establish a wireless communication link with specific peripheral devices (1354, 1390) in combination with additional processing circuitry. In some implementations, the wireless communication link is a secure wireless communication link (e.g., HIPAA-compliant) for sharing patient data with peripheral devices (1354, 1390). The wireless communication link can be used to receive control settings from peripheral devices (1354, 1390) to control the function of a pulse generator, for example.

[0172] In some implementations, sensor data is received from one or more portable wireless computing devices (1354) via a network communication interface (1368). In some examples, sensor elements of a standard 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 an application designed to interact with the system (1360) to provide sensor data to the system (1360). For example, a video of pupil changes (e.g., pupil dilation) may be captured by a smartphone or smart glasses and used as feedback for treatment adjustments in the system (1360). For example, pupil measurements may be used as a measure of attention, alertness, or arousal (or lack thereof). Thus, the feedback may be used to adjust treatment to maintain a desired level of attention, alertness, and / or arousal.

[0173] In some implementations, sensor data is received from one or more additional sensor devices (1356) via a network communication interface (1368). In some examples, the additional sensor devices (1356) may include a fitness monitor and / or an activity tracker (e.g., to provide data similar to that collected from an exercise sensor (1370a), a skin electric sensor (1370b) and / or a cardiopulmonary sensor (1370e)), a home health monitoring device (e.g., a digital smart blood pressure monitor, a digital smart thermometer, etc., to provide data similar to that collected from a cardiopulmonary sensor (1370e)), and / or a remote patient monitoring device (e.g., a blood glucose meter, a pulse oximeter, a wearable heart monitor such as a Holter monitor, to provide data similar to that collected from a glucose sensor (1370c)).

[0174] In some implementations, sensor data is received from one or more clinical devices and / or equipment (1358) via a network communication interface (1368). In an example, imaging techniques such as magnetic resonance imaging (MRI) and / or functional MRI (fMRI) can be used to adjust treatment in a given user's clinical environment. In other examples, data similar to that collected from 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 equipment (1358).

[0175] In some implementations, the type of monitoring used in the system (1360) and / or dependency (e.g., trust) on various received sensor data may be partially based on the treatment environment. For example, while neurological data captured by a sensor such as the neurosensor (1370d) may be easier to capture in a hospital environment, specific cardiopulmonary data (e.g., heart rate monitoring) captured by a sensor such as the cardiopulmonary sensor (1370e) may be obtained by capturing signals from a pulse meter built into an earpiece or other sensors built into a low-budget health monitoring device such as a fitness monitoring device or a smartwatch (e.g., additional sensor device (1356)).

[0176] In some implementations, the sensor interface (1362) collects a signal from the sensor (1370) and provides the signal to the signal processing circuit (1364). For example, the signal processing circuit (1364) may include one or more filters (e.g., bandpass filters), amplifiers and / or noise removal, effective input signal separation and / or other circuits for increasing signal strength. In some implementations, the signal processing circuit (1364) converts the analog signal into digital signal components.

[0177] In some implementations, sensor signals from a sensor (1370), a portable wireless computing device (1354), an additional sensor device (1356), and / or a clinical device / equipment (1358) are provided to a system control circuit (1372) for data analysis. In some examples, the system control circuit (1372) may recognize physiological, biological, and / or physical behaviors of a therapeutic stimulation device wearer in accordance with therapeutic adjustments by performing threshold setting, pattern analysis, and / or analysis of changes over time. For example, sensor data may be collected in a memory or temporary data storage area (1376) for sensor data analysis over a predetermined period. In some examples, this period may vary depending on the type of treatment provided, the type of data analyzed, and / or the purpose of the treatment. In some examples, therapeutic adjustments may include starting treatment, stopping treatment, and / or adjusting one or more therapeutic parameters (e.g., voltage, frequency, stimulation pattern, stimulation location, etc.).

[0178] In some implementations, the system control circuit (1372) provides sensor data to an external sensor data analysis system (1352) via a network communication interface (1368). In some examples, the sensor data analysis system (1352) may include an edge router, a cloud computing platform, and / or one or more network servers configured to analyze sensor data to identify situations that trigger treatment adjustments. In some implementations, the analysis includes biometric fingerprint analysis, wherein physiological, biological, and / or physical behaviors captured in the sensor data are analyzed in consideration of a specific wearer's baseline or past physiological, biological, and / or physical behaviors.

[0179] In some implementations, based on sensor data analysis by a system control circuit (1372) and / or a sensor data analysis system (1352), a treatment controller (1374) is provided to adjust stimulation parameters that are transmitted to a set of stimulation electrodes (1382) via a treatment delivery circuit (1378) (e.g., a pulse generator circuit). The treatment delivery circuit (1378) and the stimulation electrodes (1382) were discussed in more detail above with reference to FIG. 9.

[0180] In the first exemplary example, if one or more symptoms are reduced or eliminated, the treatment output may similarly be reduced or discontinued. Conversely, if one or more symptoms are increased or added, the treatment output may similarly be activated or adjusted (increased, expanded, etc.).

[0181] In another exemplary example, feedback related to skin electrical activity can be used to monitor and detect the speed or timing of symptoms and / or treatment results. For example, skin electrical activity can be detected by a skin electrical sensor (1370b). For example, a skin electrical patch having one or more skin electrical sensors (1370b) can be used to predict an individual's stress level by evaluating cortisol levels in sweat.

[0182] For example, one or more motion detectors (1370a) may be configured to detect tremors and / or physiological movements. In one aspect, tremors and / or physiological movements may indicate an underlying condition and / or treatment for an underlying condition. For example, tremors and / or physiological movements may indicate symptoms associated with substance withdrawal. In another example, movements and combinations of a series of movements may be used to evaluate the results of a training protocol aimed at restoring the ability to perform these movements.

[0183] As another example, treatment can be adjusted using feedback from a glucose sensor (1370c). Patients with type 2 diabetes have a poor ability to control glucose levels, and vagal nerve stimulation has been shown to reduce hyperglycemia. Therefore, glucose levels can be evaluated to trigger stimulation that improves blood glucose control.

[0184] As another example, a neural sensor (1370d) and / or a cardiopulmonary sensor (1370e) may be used to evaluate heart rate and heart rate variability, measure the overall activity of the autonomic nervous system and / or the relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system, and regulate treatment. Autonomic activity may manifest symptoms associated with substance withdrawal. In one aspect, the therapeutic device may be used to provide treatment for cardiac conditions such as atrial fibrillation and heart failure. As an example, treatment for the regulation of the autonomic nervous system may be provided. In some embodiments, the therapeutic device may be used to provide treatment that balances the ratio between any combination of the autonomic nervous system, parasympathetic nervous system, and sympathetic nervous system.

[0185] In another exemplary example, feedback signals collected by muscle response sensor(s) (1370f) can be analyzed to trigger stimulation during physical exercise recovery, such as arm exercise recovery. For arm exercise recovery, NeuroLife provided by the Battelle Memorial Institute in Nowell, Massachusetts ® Multiple muscle response sensors (1370f) can be placed in a sleeve such as an EMG Sleeve.

[0186] In the last exemplary example, the ultrasound sensor(s) (1370h) can measure cerebral blood flow velocity (CBFV) to assess attention, alertness, and / or arousal. In this example, CBFV can be used as feedback to adjust treatment.

[0187] In some implementations, the sensor data analysis system (1352) collects historical sensor data and treatment parameters from an entire patient population and applies the collected data to machine learning analysis to improve treatment protocols and parameters at the individual level. This can lead, for example, to faster and / or higher functional recovery. In exemplary examples that may be used in hospital settings such as an intensive care unit (ICU) or a neonatal intensive care unit (NICU) after a stroke or TBI, data collected through the sensor (1370), in some examples, heart rate (ECG), arterial oxygen saturation (SpO2), arterial blood pressure (in some cases using an arterial catheter), central venous pressure, core body temperature, blood glucose levels, respiratory rate and / or diastolic volume, urine volume and / or cardiac output sensors, etc., can be analyzed and applied to automatically direct and / or adjust neuromodulatory treatment. In other examples, the sensor data may provide insights into osmotic pressure, serum electrolytes and / or blood gases (arterial), which can help in making decisions when automatically directing and / or adjusting neuromodulatory treatment. In some cases, sensor data can be analyzed for the patient's comfort level (e.g., indicators of the patient's potential pain and / or stress), evidence of inflammation and / or ischemic processes (e.g., evidence of metabolic waste accumulation).

[0188] In some implementations, the sensor data analysis system (1352) applies machine learning and / or artificial intelligence (AI) analysis to improve treatment sessions to provide more effective and / or efficient treatment. Referring to FIG. 14, an exemplary sensor data analysis system (1402) and platform environment (1400) obtain data from a neurostimulation system (e.g., device and / or pulse generator) (1404) and / or a computing device (1406), and analyze the data to determine whether treatment objectives have been achieved and / or to automatically improve treatment parameters to improve the effectiveness of the current treatment.

[0189] In some embodiments, the sensor data analysis system (1352) includes a treatment data collection engine (1408) configured to collect data from the neurostimulation system (1404) and associate said data with individual users. In some examples, the treatment data collection engine (1408) may collect data in relation to each user of each neurostimulation system (1404) and store it in a computer-readable data storage area (user data storage) (1410). In some examples, user data may include active treatment parameter data (1412) (e.g., stimulation pattern, frequency, identification of a specific treatment routine, identification of a specific treatment setting, etc.), active treatment feedback data (1414) (e.g., sensor data collected from the neurostimulation system (1404) and / or one or more other sensor devices communicating with the neurostimulation system (1404), and / or active treatment situation data (1416) (e.g., geographical location, time, day of the week, ambient temperature, speed / acceleration of the wearer, ambient noise level, etc.).

[0190] In some implementations, an external sensor data collection engine (1418) collects sensor data obtained from one or more devices that are located outside the neurostimulation system (1404) and communicate with the sensor data analysis system (1402). In some examples, these devices may include fitness-monitoring devices (e.g., Fitbit, Apple Watch, or Garmin Smartwatch) and / or health-monitoring devices (e.g., blood glucose meters, Holter monitors, electrocardiogram (EKG) monitors, or electroencephalogram (EEG) monitors). In other examples, the external devices may include clinical patient monitoring and / or management devices (e.g., brain monitoring, capnography monitoring, brain / body oxygen saturation measurement, pulse oxygen saturation measurement, local and / or body temperature management, etc.).

[0191] In some implementations, the treatment data analysis engine (1420) analyzes user data stored in the user data repository (1410) to measure the efficacy of ongoing or recently completed treatment. For example, evidence of efficacy may be based on a set of treatment target parameters (1422) associated with a given treatment. For example, the treatment data analysis engine (1420) may compare the user's active treatment feedback data (1414) with a threshold and / or target value range. As another example, the treatment data analysis engine (1420) may compare the duration of each symptom, as evidenced by sensor data, with the threshold duration before symptom reduction or discontinuation. In some implementations, the treatment target parameters (1422) are adjustable by the clinician, so the clinician may customize the target parameters according to a specific patient. In certain embodiments, various sets of therapeutic target parameters (1422) are provided in some examples based on user demographics (1424) (e.g., age, gender, etc.), user medical status (1426) (e.g., diagnosed diseases and / or disorders), and / or user clinical data (1428) (e.g., weight, body mass index (BMI), smoking status, drug use status, pregnancy status, etc.). In other embodiments, the therapeutic target parameters (1422) are adjusted based on user physiological characteristics (1430) (e.g., baseline or general physiological patterns exhibited by a specific wearer).

[0192] In some implementations, the treatment analysis engine (1420) provides parameter deltas and / or other feedback information to the treatment parameter adjustment engine (1432) based on the difference between the treatment target parameter (1422) and the user-active treatment feedback data (1414) to determine a set of adjusted treatment parameters. The set of adjusted treatment parameters may include one or more device settings (e.g., frequency, pattern, repetition, etc.). In one example involving repetitive rehabilitation exercises, the stimulation duration may be systematically adjusted to set the rate of improvement for the stimulation duration after trigger using an exercise sensor (e.g., a 3-axis accelerometer and / or gyroscope). For example, the steps for adjusting the stimulation may be stored as treatment stimulation parameters and / or routines (1438). The stimulation duration may be automatically adjusted to increase the success rate and / or accelerate the recovery of specific functions.

[0193] In an exemplary example of exercise skill recovery training for a stroke patient, the treatment parameter adjustment engine (1432) may determine the next treatment routine and / or stimulation parameters based at least partially on user active treatment feedback data (1414) corresponding to the currently active or rehabilitation exercise. For example, if the current task performance is sufficient, the treatment parameter adjustment engine (1432) may provide instructions to the neurostimulation system (1404) for the next task. In some examples, the next task may be more difficult, may exercise different muscle groups and / or focus on linking learned skills into a series of performances. The next task may be selected from a hierarchy or series of tasks stored, for example, as part of the treatment stimulation parameters and / or routine (1438).

[0194] In some embodiments, the therapeutic stimulation parameters and / or routines (1438) include one or more activation routines applied to the wearer of the neurostimulation system (1404) before initiating therapeutic stimulation, such as an exercise skill training session or a PTSD recovery session. In an example, neurostimulation for activation or cognitive pathway preparation for a therapy / training session may be initiated at least 1 minute, between 1 minute and 10 minutes, up to 30 minutes, and / or within about 1 hour after the start of the therapy training session. In another example, the activation routine may be introduced in the middle of a larger therapeutic routine that includes multiple stages or therapeutic stages. In the first example, the therapeutic stimulation may be paired with activation in the first training stage to develop a new pathway to recover a specific function, for example. In the second, activation stage, the activation stimulation may be used while performing an exercise skill routine that includes multiple functions (e.g., a combination of multiple movements / tasks) to improve general cognitive function. In the second example, the therapeutic stimulus may be paired with exposure to stimulus input (e.g., auditory, visual, and / or tactile, etc.) in the first training phase to overcome side effects, for example. In the second, activation phase, the activating stimulus may be used to enhance general emotional well-being, for example, while resting between exposures to stimulus input.

[0195] In some implementations, the sensor data analysis system (1402) provides the adjusted treatment parameters to the corresponding neurostimulation system (1404) directly or via another computing device (1406). The user data storage engine (1434) may also store user active treatment parameter data (1412) to capture the treatment parameters before adjustment as user past treatment parameter data (1436). The adjusted treatment parameters may also be added to or replace the previous version of the user active treatment parameter data (1412) corresponding to the subject neurostimulation system (1404).

[0196] In some implementations, the user data storage engine (1434) collects user data stored in the user data store (1410) to store corresponding user past treatment parameter data (1436), user past treatment feedback data (1440), and / or user past treatment situation data (1442). In some implementations, the user data storage engine (1434) de-identifies at least some of the stored user data (1436, 1440, and / or 1442) for use in big data analysis for multiple users of the neurostimulation system (1404).

[0197] In some implementations, in addition to automatically collected sensor data and / or context data, the user feedback collection engine (1444) collects information about the experience of using the neurostimulation system (1404) from the wearer of the neurostimulation system (1404) and / or the clinician working with the wearer. For example, the user feedback collection engine (1444) may collect user survey data (1446) about the wearer's experience during and / or after treatment. For example, the user may submit feedback about the experience through a user interface with a corresponding software application running on one of the neurostimulation device (1404) and / or computing device (1406). In some examples, wearer feedback may include information about the level of stimulation comfort, the level of symptom improvement, and / or the level of wearing comfort. In some examples, feedback may be provided as a numeric scale or a descriptive scale connected to a numeric scale (e.g., very good, good, average, not very good, unpleasant). As another example, the wearer may submit real-time feedback regarding pain (such as symptoms not improving or appearing to worsen, or significant discomfort caused by stimulation), and the treatment parameter adjustment engine (1432) may determine adjusted treatment parameters by taking this into account.

[0198] In some embodiments, the user feedback collection engine (1444) collects clinical observation data (1448) regarding the experience of a clinician treating a patient who is being treated and / or prescribed treatment. In some examples, the clinical observation data (1448) may include outcome information (e.g., reduction or discontinuation of prescribed medication), diagnostic adjustment information (e.g., severity of disability), and / or progression information (e.g., relative recovery of function).

[0199] In some embodiments, the treatment model training engine (1450) develops one or more trained learning models (1452) by accessing user past treatment parameter data (1436), user past treatment feedback data (1440), user past treatment situation data (1442), user survey data (1446) and / or clinical observation data (1448) stored for a group of wearers of the neurostimulation system (1404) for a certain period (e.g., one month, three months, half a year, one year, etc.). For example, the treatment model training engine (1450) may apply machine learning and / or artificial intelligence to derive promising treatment stimulation parameters and / or routines such as treatment stimulation parameters and / or routines (1438). For example, the treatment model training engine (1450) may identify treatment parameters, treatment schedules and / or situation parameters (e.g., settings, timing, etc.) associated with successful treatment. The trained learning model (1452) may include one or more models by type of treatment (e.g., therapeutic therapy to treat specific diseases, disorders, symptoms, etc.), diagnosis (e.g., comorbidities such as smoking status, mental health diagnosis such as depression or PTSD), and / or user demographics (e.g., age, gender, etc.), and / or user type (e.g., soldier, athlete, etc.). For example, the trained learning model (1452) may be designed to predict therapeutic stimulus parameters and / or routines (1438) beneficial to a specific patient based on user demographics (1424), user health status (1426), and / or user clinical data (1428).

[0200] In some implementations, after the trained learning model (1452) is initially trained, when additional user historical data (1436, 1440 and / or 1442), user survey data (1446) and / or clinical observation data (1448) are collected, the treatment model improvement engine (1454) updates the trained learning model (1452) using the new learning data. For example, the treatment model improvement engine (1454) can improve the trained learning model (1452) on a periodic basis or continuously as new data is collected by the sensor data analysis system (1402).

[0201] Although the sensor data analysis system (1402) is depicted as being separate from the neurostimulation system (1404), in some implementations, a portion of the sensor data analysis system (1402) is included within the neurostimulation system (1404) and / or is included in a computing device (1406) that communicates directly with the neurostimulation system (1404) (e.g., wired or short-range wireless transmission range). For example, to rapidly adjust ongoing neurostimulation therapy based on sensor feedback, some of the functions of the therapy data analysis engine (1420) may be executed in real-time or near real-time on equipment near the wearer.

[0202] Reference has been made to drawings illustrating methods and systems according to an embodiment of the present disclosure. Aspects of the present invention may be implemented by computer program instructions. Such computer program instructions may be provided to a processor of a general-purpose computer, a special-purpose computer, or other programmable data processing device to create a machine, and instructions executed through the processor of the computer or other programmable data processing device create means for implementing the functions / operations specified in the drawings.

[0203] Various functions and / or algorithms described herein may be implemented using one or more processors. Additionally, any functions and / or algorithms described herein may be performed on one or more virtual processors, or on one or more physical computing systems, such as computer farms or cloud drives.

[0204] The aspects of the present disclosure may be implemented by hardware logic (hardware logic includes, of course, necessary signal wiring, memory elements, etc.), and such hardware logic may operate without active software intervention other than initial system configuration and subsequent system reconfiguration. Hardware logic may be synthesized on a reprogrammable computing chip, such as a Field Programmable Gate Array (FPGA), a Programmable Logic Device (PLD), or other reconfigurable logic device. Additionally, hardware logic may be hardcoded on a custom microchip, such as an Application-Specific Integrated Circuit (ASIC). In other embodiments, at least some of the functions described herein may be performed using software stored in the form of instructions on a non-transient computer-readable medium, such as a memory device, an on-chip integrated memory unit, or other non-transient computer-readable storage device.

[0205] Various aspects of the embodiments disclosed herein are performed on one or more computing devices, such as notebook computers, tablet computers, mobile phones or other portable computing devices, or one or more servers. Such computing devices include processing circuits implemented on 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). Additionally, processing circuits may be implemented with multiple processors that operate in cooperation (e.g., in parallel) to execute instructions of the process of the present invention described above.

[0206] Process data and instructions used to perform the various methods and algorithms derived herein may be stored in a non-transient (i.e., non-volatile) computer-readable medium or memory. The claimed improvements are not limited by the form of the computer-readable medium in which the instructions of the process of the present invention are stored. For example, instructions may be stored in a CD, DVD, FLASH memory, RAM, ROM, PROM, EPROM, EEPROM, hard disk, or other information processing device such as a server or computer with which the computing device communicates. The processing circuit and the 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 perform the various methods and algorithms described above. Additionally, the processing circuit and the stored instructions may enable the peripheral devices (1354, 1390) of FIG. 13 to perform the various methods and algorithms described above.

[0207] These computer program instructions can instruct a computing device or other programmable data processing device to operate in a specific manner, and instructions stored on a computer-readable medium can produce a manufactured product including instruction means that implements a function / operation specified in the illustrated process flow.

[0208] The implementation modes of this description depend on network communication. As can be seen, the network may be a public network such as the Internet, a private network such as a Local Area Network (LAN) or a Wide Area Network (WAN), or a combination thereof, and may also include a PSTN or ISDN subnetwork. The network may also be a wired network such as an Ethernet network, and a wireless network such as a cellular network including EDGE, 3G, 4G, and 5G wireless cellular systems. The wireless network may also include Wi-Fi, Bluetooth, Zigbee, or other wireless communication methods.

[0209] A computing device such as the peripheral device(s) (1354, 1390) of FIG. 13 further includes a display controller for interfacing with a display, such as an embedded display or an LCD monitor, in some implementation modes. The general-purpose I / O interface of the computing device may interface with a keyboard, a hand-operated motion tracking I / O device (e.g., mouse, virtual reality glove, trackball, joystick, etc.), and / or a touchscreen panel or touchpad that is on or separate from the display.

[0210] In some implementations, a sound controller is also provided on a computing device such as the peripheral device (1354, 1390) of FIG. 13 to interface with a speaker / microphone to provide audio input and output.

[0211] Furthermore, the present disclosure is not limited to the specific circuit elements described herein, nor are they limited to the specific sizes and classifications of such elements. For example, those skilled in the art will understand that the circuits described herein may be adjusted according to changes in battery size and chemical composition or the requirements of the backup load to be powered.

[0212] The specific functions and features described herein may be executed by various distributed components of the system. For example, one or more processors may execute these system functions, in which case the processors are distributed among several components communicating over a network. In addition to various human interfaces and communication devices (e.g., display monitors, smartphones, tablets, personal digital assistants (PDAs)), distributed components may include one or more client and server machines capable of sharing processing. 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 may be received remotely in real-time or batch processing.

[0213] Although provided for context, in other implementations, the methods and logical flows described herein may be performed in modules or hardware that are not identical to those described. Accordingly, other implementations are also within the scope of what can be claimed.

[0214] In some implementations, Google Cloud Platform ™At least part of the method or algorithm described in detail above may be performed using a cloud computing environment such as the one described herein. The process associated with the method described herein may be executed on a computing processor in a data center. For example, the data center may include an application processor that can be used as an interface with the system described herein to receive data and output corresponding information. The cloud computing environment may also include one or more databases or other data stores such as cloud storage and query databases. In some implementations, a cloud storage database such as Google Cloud Storage may store processed and unprocessed data provided by the system described herein.

[0215] The system described herein can communicate with a cloud computing environment through a security gateway. In some implementations, the security gateway includes a database query interface such as the Google BigQuery platform.

[0216] In some implementations, an edge server is used to transfer data between one or more computing devices and a cloud computing environment according to the various implementation modes described herein. For example, an edge server may be a computing device configured to execute processor-intensive tasks often associated with executing machine learning processes, such as natural language processing tasks. An edge server may include, for example, one or more GPUs capable of efficiently executing matrix operations and 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 integrated into other computing equipment, such as laptop computers, tablet computers, medical devices, or other specialized computing devices. Alternatively, an edge server may be located within the carrying case of such computing equipment. As another example, an edge server may be integrated into the communication and processing functions of a mobile unit, such as a vehicle or drone, or otherwise be located inside the mobile unit.

[0217] In some implementations, the edge server communicates with one or more local devices. For example, the edge server may be used to transfer some of the computing functions previously moved to a cloud computing environment to a local environment, enabling the accurate and efficient execution of any computationally intensive data processing and / or analysis required by one or more local devices. In some implementations, the edge server is used to support one or more local devices when there is no 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 that allows the edge server to communicate with one or more local devices. In some implementations, a specific local device may be configured to communicate indirectly with the edge server, for example, through another local device. Additionally, the edge server may be configured to communicate with a remote computing (e.g., cloud) environment through one or more public or private wireless network interfaces. For example, a device interoperable with an edge server can share processing functions with the edge server through one or more APIs implemented by a process.

[0218] The system described herein may include one or more artificial intelligence (AI) neural networks for performing automatic analysis of data. In some examples, the AI ​​neural network may include synaptic neural networks, deep neural networks, transducer neural networks, and / or generative adversarial networks (GANs). The AI ​​neural network may be trained using one or more machine learning techniques and / or classifiers, e.g., anomaly detection, clustering, and / or supervision and / or association in some examples. For example, the AI ​​neural network may be based on and / or developed from the Bidirectional Encoder Representations for Transformers (BERT) model at Google in Mountain View, California.

[0219] The system described herein may communicate with one or more underlying model systems (e.g., artificial intelligence neural networks). In some examples, the underlying model system may be developed, trained, tuned, fine-tuned, and / or immediately engineered to evaluate data inputs, such as sensor inputs collected by the system (1060) and / or the sensor data analysis system (1352) of FIG. 13 and / or sensor inputs collected by the sensor data analysis system (1402) of FIG. 14. In some examples, the underlying model system may include or be based on a generative pre-trained transducer (GPT) model (e.g., GPT-3, GPT-3.5, and / or GPT-4) available through the OpenAI Platform at OpenAI in San Francisco, California, and / or a generative AI model (e.g., PaLM 2) available through Google's Azure OpenAI or Vertex AI in Mountain View, California.

[0220] A specific base model can be fine-tuned as an AI model trained to perform specific tasks required for the system described herein. For example, training materials may be submitted to a specific base model to adjust the training of the base model to perform the type of analysis described herein.

[0221] The systems and methods described herein may apply multiple underlying model systems depending on the context. For example, contexts may include data types and desired response output types (e.g., at least one answer, at least one answer and an explanation of the reasoning leading to that answer, etc.). As another example, contexts may include user-based contexts such as demographic information, object information, and / or product information. In some implementations, a single underlying model system may be dynamically adapted to various forms of analysis requested by the systems and methods described herein using prompt engineering.

[0222] Although specific embodiments have been described, such embodiments are presented merely as examples and are not intended to limit the scope of the invention. In practice, the new methods, apparatuses, and systems described herein may be implemented in various other forms; furthermore, various omissions, substitutions, and modifications to the forms of methods, apparatuses, and systems described herein may be made without departing from the spirit of the invention. The appended claims and their equivalents are intended to encompass forms or modifications that fall within the scope and spirit of the invention.

Claims

Claim 1 A neurostimulator comprising at least one electrode configured to be placed on the skin of a subject or at a location penetrating the skin; and includes a pulse generating circuit configured to generate an electrical communication path such that each electrode of the at least one electrode electrically communicates with at least one of i) the auriculotemporal nerve or a neural structure extending thereto, or ii) the auriculobranch of the vagus nerve or a neural structure extending thereto, and to deliver electrical nerve stimulation therapy by applying one or more stimulation patterns, wherein applying the one or more stimulation patterns comprises: i) applying a first stimulation pattern within a frequency range of 70 to 150 Hertz among the one or more stimulation patterns through each electrode of the at least one electrode electrically communicating with the auriculotemporal nerve or a neural structure extending thereto, or ii) applying a second stimulation pattern within a frequency range of 5 to 30 Hertz among the one or more stimulation patterns through each electrode of the at least one electrode electrically communicating with the auriculobranch of the vagus nerve or a neural structure extending thereto; and the electrical nerve stimulation therapy is configured to stimulate a neural pathway in which nerves are distributed to the spleen of the subject, thereby A system that increases the solidification potential of the above-mentioned object. Claim 2 In claim 1, the electrical nerve stimulation therapy is a system that is repeatedly delivered on a periodic basis to treat a chronic condition. Claim 3 In paragraph 2, the above chronic condition is a system in which the subject's chronic coagulation deficiency is a system. Claim 4 In paragraph 3, the chronic coagulation deficiency is a system that is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand disease. Claim 5 A system according to claim 1, wherein the electrical nerve stimulation therapy is delivered before or during a surgical procedure to at least partially overcome the effect of an anticoagulant drug in the body of the subject, or delivered before and during the surgical procedure. Claim 6 A system according to claim 1, wherein the electrical nerve stimulation therapy is delivered before or during a medical procedure that may cause bleeding, or is delivered before and during the medical procedure. Claim 7 In paragraph 6, the electrical nerve stimulation therapy is delivered to reduce at least one of the possibility of transfusion or the amount of blood required for transfusion, in a system. Claim 8 In paragraph 6, the electrical nerve stimulation therapy is delivered to reduce blood loss in a postpartum hemorrhage situation, in a system. Claim 9 A system according to claim 1, wherein the electrical nerve stimulation therapy is configured to temporarily increase the coagulation potential of the subject. Claim 10 In claim 1, the electrical nerve stimulation therapy is delivered to treat at least one of abnormal uterine bleeding (AUB), hemorrhagic menstrual bleeding (HMB), or menorrhagia. Claim 11 In paragraph 10, at least one of the above AUB, HMB, or menorrhagia is a system resulting from a bleeding disorder. Claim 12 In claim 1, the electrical nerve stimulation treatment is delivered as a preventive treatment or a prophylactic treatment, in a system. Claim 13 In Clause 12, the electrical nerve stimulation therapy is configured as a preventive treatment to minimize bleeding in an individual with a bleeding disorder. Claim 14 In paragraph 13, the above bleeding disorder is a system that is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand disease. Claim 15 In claim 1, the electrical nerve stimulation therapy is provided before or during a military operation, or provided before and during a military operation, in a system. Claim 16 In claim 1, the electrical nerve stimulation therapy is a system that increases the rate of thrombin production at or near the site of injury of the subject. Claim 17 A system for increasing the coagulation potential of a subject, wherein the system comprises: an auricular stimulation device comprising at least one therapeutic electrode—each therapeutic electrode of said at least one therapeutic electrode is configured to be aligned to a skin area of ​​said subject to position said therapeutic electrode so as to electrically communicate with at least one of i) the auricular temporal nerve or a neural structure leading thereto, or ii) the auricular branch of the vagus nerve or a neural structure leading thereto—; A system comprising a pulse generating circuit configured to deliver electrical nerve stimulation therapy through at least one therapeutic electrode by applying one or more stimulation patterns, wherein applying the one or more stimulation patterns comprises: i) applying a first stimulation pattern within a frequency range of 70 to 150 Hertz to stimulate the auriculotemporal nerve among the one or more stimulation patterns through each electrode of the at least one therapeutic electrode that electrically communicates with the auriculotemporal nerve or a neural structure leading thereto; or ii) applying a second stimulation pattern within a frequency range of 5 to 30 Hertz to stimulate the auriculotemporal branch of the vagus nerve among the one or more stimulation patterns through each electrode of the at least one therapeutic electrode that electrically communicates with the auriculotemporal branch of the vagus nerve or a neural structure leading thereto; wherein the electrical nerve stimulation therapy is configured to stimulate a neural pathway in which nerves are distributed to the spleen of the subject, thereby increasing the coagulation potential of the subject. Claim 18 In claim 17, the electrical nerve stimulation therapy is configured to increase the rate of thrombin production at or near the site of injury of the subject. Claim 19 In paragraph 18, the system wherein the damaged area comprises at least one of penetrating damage or non-compressive damage. Claim 20 In paragraph 19, the above-mentioned non-compressive injury is a system in which gastrointestinal bleeding occurs. Claim 21 In claim 17, the electrical nerve stimulation therapy is applied before or during the surgical procedure, or applied before and during the surgical procedure, in a system. Claim 22 In paragraph 21, the electrical nerve stimulation therapy is applied to reduce at least one of the possibility of transfusion or the amount of blood required for transfusion, in a system. Claim 23 In paragraph 17, the electrical nerve stimulation therapy is configured to temporarily increase the coagulation potential of the subject. 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