Systems and methods for ultrasound modulation of the adrenal glands for treating health conditions

Abstract

A system and method for applying ultrasound stimulation to the adrenal glands is presented. The method includes using a processor to select ultrasound stimulation parameters. The method further includes using an ultrasound device to apply ultrasound stimulation that is directed toward an adrenal gland of the patient. The ultrasound stimulation is applied using the ultrasound stimulation parameters, which can also be modified based on feedback information associated with varying body function or health condition and applicable for treating a wide range of disorders and diseases.

Description

Client Ref. UMN 2024-172 Quarles 920171.00654 SYSTEMS AND METHODS FOR ULTRASOUND MODULATION OF THE ADRENAL GLANDS FOR TREATING HEALTH CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on, claims priority to, and incorporates herein by reference for all purposes, U.S. Provisional Patent Application No. 63 / 673,949 filed on July 22, 2024. BACKGROUND

[0002] Ultrasound (US) stimulation has been proposed for treatment of various clinical conditions and diseases. However, the full extent of the clinical applications has yet to be determined. Thus, further work is needed to determine precise anatomical and mechanistic targets. Moreover, stimulation parameters for specific anatomical or clinical targets need to be optimized to improve treatment efficacy. SUMMARY OF THE DISCLOSURE

[0003] The present disclosure addresses the aforementioned drawbacks by providing a system and method for modulating adrenal function in a patient. The method includes using a processor to select ultrasound stimulation parameters. The method further includes using an ultrasound device to apply ultrasound stimulation that is directed toward an adrenal gland of the patient. The ultrasound stimulation is applied using the ultrasound stimulation parameters.

[0004] In other aspects, a system for adrenal gland modulation is presented. The system includes a processor that is configured to determine stimulation parameters. The system also includes an ultrasound device that includes a stimulation module, which is configured to apply ultrasound stimulation directed to an adrenal gland of a subject.

[0005] These are but a few, non-limiting examples of aspects of the presentClient Ref. UMN 2024-172 Quarles 920171.00654 disclosures. Other features, aspects and implementation details will be described hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Various objects, features, and advantages of the disclosed subject matter can be more fully appreciated with reference to the following detailed description of the disclosed subject matter when considered in connection with the following drawings, in which like reference numerals identify like elements.

[0007] FIG. 1A is a flowchart setting forth the steps of an example process for applying ultrasound stimulation to an adrenal gland.

[0008] FIG.1B is a flowchart setting forth the steps of another example process for applying ultrasound stimulation to an adrenal gland.

[0009] FIG.1C is a flowchart setting forth the steps of another example process for applying ultrasound stimulation to an adrenal gland.

[0010] FIG. 2 is an example ultrasound stimulation system that may be used in accordance with the systems and methods of the present disclosure.

[0011] FIG. 3 is a block diagram of an ultrasound system that may be used in accordance with the systems and methods of the present disclosure.

[0012] FIG. 4A is a block diagram of a non-limiting example of an ultrasound device for providing stimulation.

[0013] FIG.4B is a profile view of a non-limiting example therapy module housing.

[0014] FIG.4C is a profile view of a non-limiting example therapy module base.

[0015] FIG. 4D is a profile view of a non-limiting example assembled therapy module.

[0016] FIG. 5 is a block diagram for a non-limiting example ultrasound systemClient Ref. UMN 2024-172 Quarles 920171.00654 configuration.

[0017] FIG. 6 shows example experimental data of cortisol levels affected by ultrasound stimulation of the adrenal gland.

[0018] FIG. 7 shows example experimental data of cortisol levels affected by ultrasound stimulation of the adrenal gland measured at two points throughout the day.

[0019] FIG. 8A shows example experimental data of the effect of adrenal gland ultrasound stimulation on rheumatoid arthritis.

[0020] FIG.8B shows additional example experimental data of the effect of adrenal gland ultrasound stimulation on rheumatoid arthritis.

[0021] FIG. 9A demonstrates the adrenal gland position with respect to nearby abdominal organs and blood vessels.

[0022] FIG. 9B further demonstrates the adrenal gland position with respect to nearby abdominal organs and blood vessels.

[0023] FIG.10A further demonstrates the adrenal gland position with respect to nearby abdominal organs and blood vessels.

[0024] FIG.10B further demonstrates the adrenal gland position with respect to nearby abdominal organs and blood vessels.

[0025] FIG.11 summarizes adrenal gland physiology and hormone production.

[0026] FIG.12 summarizes the role of the hypothalamic-pituitary-adrenal (HPA) axis in various clinical conditions.

[0027] FIG. 13 summarizes neural pathways that are involved in regulative mechanisms of the sympathoadrenal system. DETAILED DESCRIPTION

[0028] Before any aspects of the present disclosure are explained in detail, it is toClient Ref. UMN 2024-172 Quarles 920171.00654 be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Unless specified or limited otherwise, the terms “mounted,” “connected,” “supported,” and “coupled” and variations thereof are used broadly and encompass both direct and indirect mountings, connections, supports, and couplings. Further, “connected” and “coupled” are not restricted to physical or mechanical connections or couplings.

[0029] In prior work, researchers have stimulated the vagus nerve and splenic nerve into the spleen in order to drive a neural effect in the spleen. This neural effect causes a cascade of physiological effects that drive anti-inflammatory effects (e.g., immune cells reduce production of cytokines in the blood, signaling effects that reduce cytokines in the blood). For example, splenic ultrasound neuromodulation has been demonstrated in ex-vivo cells, in anesthetized animals, and in humans. However, other novel targets exist that can provide further modulation of various physiological parameters.

[0030] The present disclosure provides systems and methods for applying ultrasound energy to the adrenal glands in order to stimulate modulation of systemic levels of steroid hormones. As will be shown, the disclosed methods provide the ability to apply ultrasound stimulation of the adrenal glands for altering or modulating the circulating levels of glucocorticoids or other hormones in humans or animals. The adrenalClient Ref. UMN 2024-172 Quarles 920171.00654 glands are one of the main organ targets known to alter cortisol levels and hormones throughout the body, which in turn can alter inflammatory states in the body. In some implementations, ultrasound energy can be targeted directly to one (e.g., left or right) or both adrenal glands. In some implementations, the ultrasound energy can be targeted to both the spleen and one or both adrenal glands. For example, the beam may be targeted at the spleen area and have an elongated spread of energy, which also modulates the adrenal glands to increase cortisol levels. In other implementations, the beam may be targeted directly to one or both adrenal glands. Thus, it is to be understood that discussion herein of “adrenal glands” can be understood as referring to one or both adrenal glands.

[0031] Without wishing to be bound by theory, the function of the adrenal gland may be directly or indirectly modulated by the applied ultrasound stimulation. For example, the adrenal gland cells that signal release of hormones, cortisol, or cytokines may be directly stimulated to have a desired effect. In other implementations, the adrenal gland may be stimulated to modulate cells or receptors that act like adrenal sensory neural feedback sensors that provide feedback signals to the brainstem to indirectly cause the release of cortisol by the adrenal glands. This stimulation can provide feedback from the adrenal gland to the brain, via neural pathways or the blood stream, which activates brain regions that affect hormone or cytokine levels in the body. The brain responds within the feedback circuit, sending neural signals back down to the adrenal gland using various signaling pathways that cause the adrenal gland to respond (e.g., by releasing cortisol, hormones, cytokines, and so forth). As a non-limiting example, stimulation can activate the hypothalamus (e.g., neuropeptide Y) or pituitary gland. Activating the hypothalamus can cause release of corticotropin releasing hormone (CRH) that then travels to the pituitary gland to release adrenocorticotropic hormone (ACTH).Client Ref. UMN 2024-172 Quarles 920171.00654 ACTH travels through the bloodstream to reach the kidneys and adrenal glands to release cortisol. In this way, applying the ultrasound stimulation directed toward the adrenal gland may directly or indirectly affect the adrenal function.

[0032] In other implementations, the stimulation of the adrenal glands could modulate the function of the adrenal glands to cause downstream effects on other organ systems. As non-limiting examples, stimulation of the adrenal glands could modulate adrenal cells or receptors with feedback signals that are communicated to the brain (e.g., via the blood stream or neural feedback pathways). These signals activate brain regions (e.g., nucleus of the solitary tract (NTS), locus coeruleus, rostral ventrolateral medulla, amygdala, thalamus, or another cortical region). These brain regions then project back down to the body via the vagus nerve or spinal cord to another organ (e.g., the spleen, gut, and so forth) that control or otherwise modify inflammation levels in the body or immune system. In this way, ultrasound of the adrenal glands can directly affect cortisol modulation or provide feedback to the brain to cause reduction of inflammation in the body.

[0033] In some implementations, ultrasound stimulation of the adrenal glands can be provided using point-of-care ultrasound systems. Such systems may be configured to treat patients in a clinic or hospital or in an at-home or portable setting.

[0034] In some implementations, the system can include an electrical stimulator that can be implanted on the nerves that go into the adrenal glands. For example, the implant can include an electrical stimulator implant or can be powered from the outside using ultrasound. In this way, the implant may be very small such that it can be implanted into or onto the adrenal gland nerves. Such nerves could include nerves traveling into the adrenal glands from the spinal cord pathways (e.g., through the celiac and superior mesenteric ganglia) or the splanchnic nerve.Client Ref. UMN 2024-172 Quarles 920171.00654

[0035] The described systems and methods for ultrasound stimulation of the adrenal glands can be used to treat a wide range of health disorders. In general, stimulation of one or both adrenal glands may be used to modulate a level of a hormone, cytokine, or other biomarker. The biomarker may be a measure of or otherwise indicate adrenal function. For example, such hormones may include hormones that are produced by the adrenal glands or hormones whose precursors are produced by the adrenal glands. Hormones may include cortisol, a glucocorticoid, aldosterone, androgenic steroid, dehydroepiandrosterone (DHEA), estrogen, androgen, epinephrine (adrenaline), or norepinephrine (noradrenaline). The biomarker may also include a measure of inflammation, such as a cytokine concentration. The biomarker may also include a measure of metabolism. For example, the biomarker may include a metabolite (e.g., amino acid, alcohol, vitamin (e.g., B2 and B12), polyols, organic acids, or nucleotide (e.g., inosine-5'-monophosphate, guanosine-5'-monophosphate)), molecules related to metabolism (e.g., glucose, protein, fat), or hormone related to metabolism (e.g., insulin, thyrotropin-releasing hormone (TRH), thyroid stimulating hormone (TSH)).

[0036] As a non-limiting example, steroid hormone levels (e.g., mineralocorticoids, glucocorticoids, androgens) can be modulated. Such steroid hormone level modulation may have applications including regulation of blood pressure and electrolyte balance, regulation of metabolism and immune system suppression, and restoring sex hormones and sexual function. As another example, health disorders that depend on cortisol can be treated. For example, cortisol levels can be modulated to affect stress levels, attentiveness, activity levels, fatigue, sleep disorders, energy levels, adrenal function for increased energy for intense tasks / war / competition, and so forth). The ability to modulate stress levels and alertness can be leveraged to improve or increase stress resilience, including in stressful situations or trauma inducing situations, and thusClient Ref. UMN 2024-172 Quarles 920171.00654 prevent or mitigate PTSD, trauma, emotional injury or other mental disorders (e.g., anxiety, depression) or cognitive disorders (e.g., memory loss or learning issues).

[0037] The adrenal glands can also be stimulated to affect chronic inflammatory conditions (e.g., rheumatoid arthritis, inflammatory bowel disease, myocarditis, pulmonary hypertension, tauopathies, epilepsy, Parkinson’s disease, stroke, spinal cord injuries and pain, neuropathic pain, acute kidney injury, heart failure, hypertension, depression, and so forth) and acute inflammatory conditions (e.g., sepsis, covid infections, colds, viral infections, bioterrorism attacks, and so forth).

[0038] Adrenal stimulation can also be harnessed to affect or treat metabolic disorders affected by cortisol or other hormones that are either produced by the adrenal glands or hormones whose precursors are produced by the adrenal glands, which have a pivotal role in glucose, protein, and fat metabolism as well as inhibition of thyrotropin- releasing hormone (TRH) and thyroid stimulating hormone (TSH) related to the thyroid gland. For example, adrenal stimulation can be used to treat or affect diabetes, hyperthyroidism, obesity, weight loss, and so forth. Adrenal stimulation can also affect overall health status (e.g., heart rate, respiration, and so forth).

[0039] Adrenal gland modulation can also affect adrenal androgen production, which can be used for improving sexual function or sexual drive, regulate hair growth (e.g., limit balding in humans, reduce unwanted facial hair growth), improve skin / acne conditions, and mitigate abnormal puberty in children. It can also modulate aldosterone biosynthesis, which can help regulate blood pressure by managing the levels of sodium and potassium in the blood and impacting blood volume. As another example, modulation of catecholamines can increase rapid response and produce a heightened awareness throughout the body in situations of stress, combat, or sport. This may be used as a pre- treatment before an expected stressful situation (travel, exams, combat deployment,Client Ref. UMN 2024-172 Quarles 920171.00654 etc.). This may also be used as a therapy after stressful situations, including to treat post- traumatic stress disorder (PTSD). As another example, adrenal stimulation can be used to correct dysfunctions of the adrenal gland, such as Cushing's syndrome or Addison's disease. As another example, the restoration of normal steroid hormone levels may improve an array of acute and chronic fatigue syndromes in addition to various clinical outcomes associated with post-acute sequelae of COVID-19 (PASC), also known as “Long COVID”. Other physiological processes may also be altered, as the adrenal glands are responsible for the production of various hormones associated with a wide range of physiological functions (see FIG.11).

[0040] Ultrasound stimulation of the adrenal glands can be used in conjunction with or in place of standard pharmaceutical treatments. In some implementations, ultrasound stimulation of the adrenal glands can replace pharmaceutical treatments, which are expensive and often associated with a number of side effects. Ultrasound stimulation is advantageously noninvasive and provides non-pharmaceutical therapy for a broad range of disorders. Ultrasound stimulation of the adrenal glands can also be used in addition to or in place of ultrasound stimulation of the spleen or liver, as targeting the adrenal glands may have a higher efficacy.

[0041] Various ultrasound stimulation parameters may be used. While non- limiting example ultrasound stimulation parameters are provided herein for exemplary purposes, other ultrasound stimulation parameters may also be used, which are not explicitly listed herein. As non-limiting examples, the ultrasound signal may have a center frequency between 50 kHz-7MHz, 100 kHz-7 MHz, 500 kHz-1 MHz, or 550 to 800 kHz. The ultrasound signal may have a pulse repetition rate of 20 to 60 Hz. The pulse repetition rate may also include stimulation of 0.1-0.5 ms, 1-5 ms, 10-50 ms, 50 ms-2 s, 0.2 ms, 1 ms, 25 ms, 100 ms, 350 ms, 500 ms, or 1 s, followed by a pause duration of 10Client Ref. UMN 2024-172 Quarles 920171.00654 ms-10 s, 24.8 ms, 500 ms, 650 ms, or 6 s. The duty cycle may be set between 1%-100%, 10%-100%, or 16%-50%. In some implementations, the ultrasound stimulation can be applied for a treatment duration, which may be repeated as desired (e.g., several times per day, once per day, several times per week, once per week, several times per month, and so forth). The treatment duration may be set between one minute and 2 hours (e.g., 18 minutes), 1 minute and 1 hour, or 2 and 30 minutes. The ultrasound stimulation may be characterized by a pressure at the target location (e.g., adrenal gland). The pressure may be defined as 25 kPa-10 MPa, 25 kPa-2MPa, 100 kPa-500 kPa, or 500 kPa-1MPa.

[0042] In some implementations, adrenal gland stimulation can be applied for a short treatment period (e.g., 2-3 minutes, <10 minutes) every day or every few days. In other implementations, the modulation may be applied for longer treatment periods (e.g., 10-20 minutes, 20-30 minutes, 30-60 minutes) every day or every few days. In some implementations, the stimulation period may not exceed tens of minutes per session in order to prevent damage to the adrenal glands or allow the adrenal glands to replenish. Thus, periodic stimulation of the adrenal gland can be used to benefit a patient’s health (e.g., reproduction state, growth / puberty, weight and metabolism, inflammatory / immune state, depression and mental or emotional state, overall health state, and so forth) without having adverse secondary effects (e.g., adrenal gland damage).

[0043] In some implementations, the adrenal gland stimulation can be adjusted based on feedback provided to the system. For example, additional sensors can be incorporated into the stimulation system or provide data to the stimulation system. These sensors can measure or track biomarkers (e.g., in the blood, in bodily fluids, in the body), clinical parameters, or behavioral characteristics. The stimulation settings or doses can be adjusted over time based on such feedback data.Client Ref. UMN 2024-172 Quarles 920171.00654

[0044] Such stimulation of the adrenal glands can increase cortisol levels and other relevant hormones. Such increased hormone levels reduce inflammatory responses in the body. For example, pro-inflammatory cytokine levels are reduced. Cytokines may include interleukin-1β (IL-1β), interferon‐gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase 14 (MAPK14), and others. Other biomarkers may also include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin / d-dimer, and so forth. Thus, modulation of various steroid hormones via adrenal gland ultrasound stimulation can be tailored for a specific patient based on the dose of stimulation, frequency of stimulation settings, and duration of treatment.

[0045] In some implementations, activation of the hypothalamic-pituitary-adrenal (HPA) axis may have profound inhibitory effects on the inflammatory immune response because many components of the immune response are inhibited by cortisol. Glucocorticoids may act as potent anti-inflammatory and immunosuppressive factors by influencing the traffic of circulating leukocytes and inhibiting vital functions of the immune cells. Furthermore, they may decrease the production of cytokines and other mediators of inflammation (e.g. platelet-activating factor, nitric oxide, prostanoids), induce cytokine resistance, and inhibit the expression of adhesion molecules and their receptors on the surface of immune cells. Glucocorticoids and catecholamines secreted during stress exert an immunomodulative effect by suppressing the T-helper 1 (Th1) response and causing a Th2 shift, thus protecting the tissues from the potentially destructive actions of type 1 proinflammatory cytokines and other products of activated macrophages.

[0046] FIGS.1A-1C provide flowcharts for example processes that may be used toClient Ref. UMN 2024-172 Quarles 920171.00654 apply ultrasound stimulation to the adrenal glands. In some implementations, the ultrasound stimulation can be generated in vivo using an ultrasound device. For example, the ultrasound device may be a portable or wearable device that can apply ultrasound stimulation intermittently over a period of time, such as hours, days, weeks, etc.

[0047] Referring to FIG. 1A, the process can include selecting stimulation parameters, as indicated in process block 102. Selecting stimulation parameters may include receiving an input from a user, such as a clinician or patient. The input may directly define the stimulation parameters or provide other information that can be used by a processor to select the stimulation parameters. For example, the stimulation parameters may be based on patient data (e.g., health history, demographics, condition type), characterization of symptoms or symptom changes, a biomarker (e.g., a hormone or cytokine level measured in the patient’s blood), a stimulation history, other relevant information, or a combination thereof.

[0048] Selecting stimulation parameters may include accessing or analyzing patient data. The patient data may include a condition type and severity, patient health history, age, weight, symptoms, demographic data, family history, historical biomarker data, current biomarker data, dynamic biomarker data, genetic expression data, metabolomic data, immune data, body dimension data, body mass index, and so forth) to determine effective stimulation parameters customized to the patient. The patient data may also include measures of biomarker concentrations (glucocorticoid, hormones, cortisol, cytokines, ESR, CRP, ferritin / d-dimer, IL-1β, IFN-γ, MCP-1, IL-6, IL-8 IL-10, TNF- α, NF-κB, metabolites, and others) or clinical outcome changes caused by previous stimulation treatments. Such patient data can be provided by a user (e.g., clinician), accessed from hospital records, or measured using external sensors. For example, a cytokine or hormone sensor may be implanted into the vascular system of the subject orClient Ref. UMN 2024-172 Quarles 920171.00654 through a wearable patch or device that is minimally invasive with microneedles into the skin, oral cavity area, or ear region (e.g., ear canal, tympanic membrane or other inner ear membranes with access to blood vessels near the membrane surface).

[0049] The ultrasound parameters may include the stimulation time or duration, the frequency of the ultrasound wave, the peak pressure of the ultrasound energy, and the pulse width and repetition frequency, as well as different ramping shapes or amplitude modulated waveforms. These parameters may be set as constant over the treatment time or may change dynamically over the treatment period. Treatment parameters may also include a duty cycle, in which the stimulation process may be repeated one time over the course of each duty cycle, separated by a desired treatment break.

[0050] Non-limiting example stimulation parameters include stimulation between 50 kHz to 7 MHz, such as between 500 kHz to 1.5 MHz, and pressures in a range of 100 kPa to 1 MPa or 25 kPa to 10 MPa depending on the stimulation frequency. The stimulation duration may occur over sessions between 1 minute and 1 hour or more specifically between 5 minutes to 20 minutes; and with pulse widths between 1 μs and 5 ms or more specifically 100 μs to 500 μs. The pulse repetition frequencies or pulse repetition rate can span between 10 Hz and 10 kHz or more specifically 20 and 60 Hz or between 1 and 2 kHz. The number of repetitions may be pre-determined between a single repetition to hundreds of repetitions of these sessions or more specifically one or two sessions per day. Alternatively, these parameters can be adjusted based on evaluation of the clinical outcome, as shown in FIG.1C.

[0051] The process also includes applying ultrasound stimulation directed toward the adrenal glands, as indicated in process block 104. Applying the ultrasound stimulation may include beam steering using a phased ultrasound array in order to targetClient Ref. UMN 2024-172 Quarles 920171.00654 the adrenal glands or a region or feature of the adrenal glands. In some implementations, as shown in FIG.1B, the process can include determining a localized stimulation target, as indicated in process block 106. For example, the stimulation target may include one or both adrenal glands, a specific region of the one or both adrenal glands, blood vessels of one or both adrenal glands, or nerves or axons associated with one or both adrenal glands. Determining the stimulation target may include acquiring or accessing imaging data to determine the location of the physiological target. For example, imaging data may include medical images acquired using ultrasound, magnetic resonance imaging (MRI), x- ray, computed tomography (CT), fluoroscopy, positron emission tomography (PET), single-photon emission computed tomography (SPECT), etc. In some implementations, determining the stimulation target may also include rib detection performed using a signal received by the ultrasound device.

[0052] In some configurations, the imaging may preferably utilize ultrasound. In this way, the adrenal glands or other specific target can be located shortly before applying treatment using the portable or wearable device. For example, the imaging ultrasound transducers may be integrated with those used for ultrasound stimulation, or dual-mode transducers may be used to simultaneously or alternatingly produce images and stimulation. Such images may be used to localize the target and guide the ultrasound stimulation target. For example, the image may be used to identify the precise location of the targeted glands (e.g., one or both adrenal glands), blood vessels (e.g., adrenal blood vessels), gland regions (e.g., adrenal medulla or adrenal cortex), or nerves. Localization of the target can then be used to steer the ultrasound beam using a phased array.

[0053] In some configurations, applying ultrasound stimulation may include directing stimulation to two or more locations. For example, the ultrasound stimulation may be simultaneously or alternatingly applied to both adrenal glands (e.g., left andClient Ref. UMN 2024-172 Quarles 920171.00654 right), may be simultaneously applied to adrenal gland blood vessels and nerves or blood vessels and cells within the adrenal gland, or may be simultaneously applied to one adrenal gland and another organ or target (e.g., spleen, liver, kidneys, gut, etc.). In this way, several ultrasound devices may be used (e.g., one positioned over the right adrenal gland and one positioned over the left adrenal gland or another organ).

[0054] Applying ultrasound stimulation to the adrenal gland may modulate the production of an adrenal product or downstream product, such as a hormone (e.g., cortisol, a glucocorticoid, aldosterone, androgenic steroid, DHEA, estrogen, androgen, epinephrine, or norepinephrine), a cytokine, or a metabolite. As a non-limiting example, adrenal modulation may cause an anti-inflammatory immune response, decreasing a cytokine level in a patient.

[0055] Thus, as demonstrated in FIG. 1C, the stimulation outcome can be measured after stimulation is applied, as indicated in process block 108. Measuring the stimulation outcome may include measuring a biomarker, such as a cytokine, a hormone, or a metabolism marker. Biomarkers can be measured as a concentration in the blood or other bodily fluid. Such biomarkers may be used alone or in combination with other biomarkers or other patient data (e.g., age, health condition, metabolomics, etc.). Ratios of various biomarkers or changes of biomarkers over time may also be used as a measure of inflammation state. Measuring the stimulation outcome may include measuring a biomarker in the patient’s blood (e.g., by blood draw, using an implantable sensor, optical methods, a wearable blood sensor, and so forth). Measuring the stimulation outcome may also include receiving an input from a clinician, patient, or other user. For example, a symptom level may be input by a patient using a user interface. Measuring the stimulation outcome may also include acquiring or accessing medical images (e.g., to assess inflammation of an organ, joint, skin, outer or inner ear region, or other bodyClient Ref. UMN 2024-172 Quarles 920171.00654 region).

[0056] In some implementations, the stimulation outcome can be measured by assessing a biomarker, symptom level, or other measure of health before and after stimulation is applied or throughout the course of treatment. For example, a biomarker (e.g., hormone or cytokine) can be measured before and after treatment or throughout the course of treatment. The stimulation outcome may also be characterized based on symptoms or symptom changes of the patient, medical images, or other health factors. In some implementations, the stimulation outcome may be measured <10 minutes, 1-10 minutes, <1 hour, 1-2 hours, <1 day, 1-3 days, <1 week, 1-5 weeks, or 1-6 months, or <1 year after treatment.

[0057] Measuring the stimulation outcome can be used to adjust stimulation parameters or inform further stimulation treatment session. For example, stimulation can be applied to a patient to reduce an inflammatory effect, as in process block 104; a cytokine level can be measured in the patient’s blood a short time after stimulation (e.g., the next day), in process block 108; stimulation can be adjusted based on the stimulation outcome (e.g., increase stimulation intensity, duty cycle, or duration if the effect measured was too small), as indicated in process block 110; and repeated as desired in process block 112.

[0058] In some implementations, the stimulation monitor or sensor may be wearable or portable. In this way, a patient’s health can be continuously or intermittently monitored (e.g., every hour throughout the course of a day) in order to determine if and when stimulation is needed or to determine a customized stimulation intensity.

[0059] FIG. 2 shows a block diagram of an ultrasound stimulation system 200, which provides a non-limiting example of a system that can be used to apply ultrasound stimulation to an adrenal gland (i.e., cells within different regions of the adrenal gland asClient Ref. UMN 2024-172 Quarles 920171.00654 shown in FIG. 11) or associated adrenal structures (e.g., blood vessels or nerves). As a non-limiting example, system 200 may carry out a process outlined in FIGS. 1A-1C or combinations thereof. The system includes a controller 202, which may generally include an ultrasound stimulation pattern module 210, an ultrasound target module 212, a control module 216, a processor 220, a power source 230, a memory 232, a clock module 234, and a communication module 236. The system may also include an ultrasound device 246. The ultrasound device 246 can include an ultrasound stimulation module, which can apply ultrasound stimulation with a specified waveform to a target. The ultrasound device 246 may also include an ultrasound imaging module, which can acquire ultrasound images. The ultrasound device 246 will be described in further detail below.

[0060] The system 200 may also include external devices 242. For example, the external devices 242 may include a server that may store patient data, system instructions, imaging data, etc. The external devices 242 may also include a user interface that may display system parameters or accept user inputs or operational instructions. Specifically, the input may include various user interface elements, such as a mouse, keyboard, touchpad, touch screen, buttons, and the like. The input may also include various drives and receptacles, such as flash-drives, USB drives, CD / DVD drives, and other computer-readable medium receptacles, for receiving various data and information. To this end, the input may also include various communication ports and modules, such as Ethernet, Bluetooth, WiFi, etc. for exchanging data and information with various external computers, systems, devices, machines, mainframes, servers or networks. The external devices 242 may also include various other sensors, such as external imaging devices, hormone or cytokine sensors, localization sensors, etc. The ultrasound device 246 and external devices 242 may be connected to the controller 202Client Ref. UMN 2024-172 Quarles 920171.00654 via proper connections, such as data cables, Wi-Fi, Bluetooth, etc.

[0061] The external devices 242 may also be controlled by the processor 220, which may determine instructions and provide them to the external device 242 via the control module 216. For example, the external device 242 may include a biomarker sensor, and the control module 216 may trigger a biomarker measurement at various times throughout the stimulation process, after stimulation is applied, or at regular intervals outside of stimulation sessions.

[0062] The controller 202 may also include various connections, terminals, or wireless communication connections for transmitting signals generated by the ultrasound stimulation pattern module 210, the ultrasound target module 212, or control module 216, or signals measured by external devices 242. Any or all of the elements may be housed in one or more wearable devices, in one or more portable devices carried externally to the body, or on an external server with proper wired or wireless connections between elements.

[0063] The processor 220 can be configured or programmed to perform a variety of functions for operating the controller 202 using instructions stored in memory 232, in the form of a non-transitory computer readable medium, or instructions received via input. In some implementations, the processor 220 may control the sending and receiving of instructions and operational parameters (for example, via a wireless transcutaneous link in the communication module 236), the storage of the operational or stimulation parameters and instructions in memory 232, the transmission of the operational parameters and selective triggering to the ultrasound device 246, as well as synchronizing various functions using the clock module 234. For instance, the processor 220 may communicate with the clock module 234 to determine the timing and synchronization of various stimulations. The processor 220 may also communicate withClient Ref. UMN 2024-172 Quarles 920171.00654 the clock module 234 ultrasound stimulation pattern module 210, as well as other hardware and digital logic circuitry, to accurately store activation times and parameters in memory 232. By way of example, the processor 220 can be a programmable microprocessor or microcomputer.

[0064] The ultrasound stimulation pattern module 210 may determine ultrasound stimulation parameters and provide instructions to the ultrasound device 246. For example, the ultrasound stimulation pattern module 210 can provide the ultrasound device with waveform parameters, such as ultrasound intensity, ultrasound frequency, pressure, pulse width, pulse timing, pulse pattern, duty cycle, etc. The ultrasound stimulation pattern module 210 may determine such ultrasound stimulation parameters based on input data from external devices 242. For example, the ultrasound parameters may be informed by measured biomarker levels or other patient data.

[0065] The ultrasound target module 212 can determine the target location for ultrasound stimulation. For example, the ultrasound target module 212 can use data provided by external devices 242, such as imaging data or a user interface, to determine the target location for ultrasound stimulation. For example, the ultrasound target module 212 can automatically identify a target location based on imaging data. For example, the ultrasound target module 212 may automatically analyze imaging data to identify an adrenal gland, a region of an adrenal gland, or a feature (e.g., blood vessel or nerve) of an adrenal gland. Alternatively, a user can input a target location using a user interface. The ultrasound target module 212 may also localize the ultrasound device based on imaging data acquired by the ultrasound imaging module of the ultrasound device or using other imaging data provided by external imaging devices or servers.

[0066] The ultrasound target module 212 can also provide localization instructions to the ultrasound device 246 or a user. For example, the ultrasound targetClient Ref. UMN 2024-172 Quarles 920171.00654 module 212 can determine settings for a phased array to stimulate the target location with high localization precision. For example, the phased array may achieve 1 mm x 1 mm x 1 mm spatial precision. The ultrasound target module 212 may also provide instructions to the device user via an external device 242, such as a user interface or display. Such instructions may direct the user or patient how to position the device on the patient to target the desired location.

[0067] In some implementations, the ultrasound target module 212 may perform rib detection, as described in International Application Number PCT / US2024 / 051603, published as WO 2025 / 085533, which is incorporated herein in its entirety by reference. The ultrasound target module 212 can use signal received by the ultrasound device 246 to determine the position of the ultrasound device 246 and ultrasound focus with respect to a rib of the subject. In this way, targeting the adrenal gland may include steering the ultrasound beam to avoid ribs of the patient to direct the ultrasound stimulation toward the adrenal gland. As another example, the ultrasound target module 212 can instruct a user to adjust the placement of the ultrasound device 246 to avoid the ribs. In some implementations, the ultrasound target module 212 can process real-time signal from the ultrasound device 246 to detect rib location while the patient is moving (e.g., walking, breathing, and so forth) in order to cause stimulation to occur only when stimulation of the adrenal gland is not obscured by the ribs.

[0068] In some implementations, the controller 202, along with the ultrasound device 246, may be part of a standalone stimulation system. Alternatively, the controller 202 may be a portable, wearable, or implantable unit that is programmable or configurable using an external device, computer or system. To this end, the communication module 236 may be configured to send and receive various signals, as well as receive power. Specifically, the communication module 236 may include anClient Ref. UMN 2024-172 Quarles 920171.00654 antenna, or an input-output wire coil, a receiver and transmitter, data converters, as well as other hardware components. As a non-limiting example, the receiver and transmitter may be configured to receive and transmit radio-frequency (RF) signals. In some implementations, the antenna may be configured for transcutaneous wireless two-way communication with an external wearable device, sending and receiving signals when the external wearable device is placed in close proximity. The communication signals may be transmitted through magnetic induction and include information for operating and / or programming the processor 220. For instance, the communication signals may include triggers or command signals for generating stimulations or for communicating patient data. In some configurations, transmitted signals may also be configured to power or recharge battery components powering the controller 202. The antenna may be connected to a receiver and transmitter, which in turn may be connected to serial-to- parallel and parallel-to-serial data convertors, respectively. Any information sent or received, as described, may then be processed by the processor 220.

[0069] The controller 202 may be powered by an internal and / or external power source 230. For example, an internal source may include a standard rechargeable battery, comparable to batteries used in implantable devices (e.g., pacemakers). Alternatively or additionally, the internal power source may include a capacitor in combination with a regulator, such as a single ended primary inductor converter or dc-dc converter, that together can generate a constant current or voltage output for short periods of time. In some implementations, the capacitor may be charged by an external wearable device. As such, the controller 202 may include an induction coil, or thin, tightly wound wire that allows for RF telemetry and / or battery recharge by an external wearable or portable device, configured either as part of the communication module 236, or as separate hardware. Other methods of charging may also be utilized. In some implementations,Client Ref. UMN 2024-172 Quarles 920171.00654 external ultrasound energy can be used to power an implanted device.

[0070] FIG. 3 shows an example ultrasound system that may be used to apply ultrasound modulation of the adrenal glands according to the present disclosure. As a non-limiting example, the ultrasound system 300 may be a part of the stimulation system 200 as the ultrasound device 246 in FIG. 2. The ultrasound system 300 includes a transducer. The transducer may be a transducer array 302 that includes a plurality of separately-driven transducer elements 304. The transducer array 302 can include any suitable ultrasound transducer array, including linear arrays, curved arrays, phased arrays, and so on. Similarly, the transducer array 302 can include a 1D transducer, a 1.5D transducer, a 1.75D transducer, a 2D transducer, a 3D transducer, and so on.

[0071] When energized by a transmitter 306, a given transducer element 304 produces a burst of ultrasonic energy. The ultrasonic energy reflected back to the transducer array 302 (e.g., an echo) from the object or subject under study is converted to an electrical signal (e.g., an echo signal) by each transducer element 304 and can be applied separately to a receiver 308 through a set of switches 310. The transmitter 306, receiver 308, and switches 310 are operated under the control of a controller 312, which may include one or more processors. As one example, the controller 312 can include a computer system.

[0072] The transmitter 306 can be programmed to transmit unfocused or focused ultrasound waves. In some configurations, the transmitter 306 can also be programmed to transmit diverged waves, spherical waves, cylindrical waves, plane waves, or combinations thereof. Furthermore, the transmitter 306 can be programmed to transmit spatially or temporally encoded pulses.

[0073] The receiver 308 can be programmed to implement a suitable detection sequence for the imaging or rib detection task at hand. In some embodiments, theClient Ref. UMN 2024-172 Quarles 920171.00654 detection sequence can include one or more of line-by-line scanning, compounding plane wave imaging, synthetic aperture imaging, and compounding diverging beam imaging.

[0074] In some configurations, the transmitter 306 and the receiver 308 can be programmed to implement a high frame rate. For instance, a frame rate associated with an acquisition pulse repetition frequency (“PRF”) of at least 10 Hz or at least 100 Hz can be implemented. In some configurations, the ultrasound system 300 can sample and store at least one hundred ensembles of echo signals in the temporal direction.

[0075] The controller 312 can be programmed to implement an imaging or stimulation sequence using the techniques described in the present disclosure, or as otherwise known in the art. In some embodiments, the controller 312 receives user inputs defining various factors used in the design of the imaging or stimulation sequence.

[0076] A scan or stimulation can be performed by setting the switches 310 to their transmit position, thereby directing the transmitter 306 to be turned on momentarily to energize transducer elements 304 during a single transmission event according to the designed imaging or stimulation sequence. The switches 310 can then be set to their receive position and the subsequent echo signals produced by the transducer elements 304 in response to one or more detected echoes can be measured and applied to the receiver 308, for example, during imaging or stimulation sequences. The separate echo signals from the transducer elements 304 can be combined in the receiver 308 to produce a single echo signal.

[0077] In some configurations, the ultrasound system 300 may include more than one ultrasound array 302. At least one of the arrays may be used for transmitting ultrasound for therapeutic treatment, and at least one other array may be used to transmit and / or receive ultrasound for imaging. In one non-limiting example, the frequency used for treatment may be lower than the frequency used to produce high-Client Ref. UMN 2024-172 Quarles 920171.00654 quality images. In this way, the ultrasound system 300 can provide an integrated imaging and stimulation system, such that the imaging may inform the localization of the stimulation target. Additional ultrasound arrays 302 may be used to provide stimulation at multiple targets within a subject.

[0078] The echo signals are communicated to a processing unit (not shown), which may be implemented by a hardware processor and memory, to process echo signals or images generated from echo signals. As a non-limiting example, the processing unit can target an adrenal gland for ultrasound stimulation to treat inflammation using the methods described in the present disclosure. Images produced from the echo signals by the processing unit can be displayed on a display system 314.

[0079] In one non-limiting example, a wearable / miniaturized phased array ultrasound device may be used for ultrasound system 300, although other types of ultrasound stimulation devices (e.g., a conventional / cart-based ultrasound system, a portable system, etc.) may also be used. The wearable device may be placed on a subject and worn for extended periods of time. In some configurations, a reprogrammed smartphone or tablet device may be used to control and / or monitor the stimulation. In one non-limiting example, the reprogrammed smartphone or tablet device may allow for Bluetooth wireless control of the stimulation device. For example, the smartphone or tablet device may provide a user interface to input patient data, desired stimulation parameters, or a target location. In some configurations, the control and / or monitor system may be an application installed on a smartphone, tablet device, and the like. In another non-limiting example, a number of devices distributed around a subject may be used to provide the ultrasound stimulation. The overall size of a wearable device may be similar to that of other consumer electronic wearable devices, such as smart watches, when using miniaturized ultrasound array technology. In one non-limiting example, theClient Ref. UMN 2024-172 Quarles 920171.00654 total footprint of a device may be less than 1.2 cm x 1.2 cm. In another non-limiting example, the footprint of a device may be less than 40 mm x 40 mm. In some non-limiting examples, the total footprint of the device may be larger, such as to cover a larger region (e.g., a region that includes the adrenal glands and the spleen, liver, kidney, gut, target blood vessel, lymphatic tissue, or other organ. In one non-limiting example, the footprint of the device is the same size as an adrenal gland (e.g., 3-6 cm in each dimension). In another non-limiting example, the footprint of the device is the same size as a spleen, which may range from 8-16 cm, or another target organ.

[0080] In some configurations, the ultrasound transducer may be mobile. For example, the ultrasound transducer may be manually moveable or automatically moveable by a motorized system. In this way, the ultrasound stimulation may track blood flow.

[0081] In some configurations, the ultrasound transducer elements 304 can be activated in unison to form a plane wave front. In other configurations, the ultrasound transducer elements 304 can be activated sequentially to form an angled or focused wave front.

[0082] In some configurations, beam steering may be used to target selected locations, for example the adrenal gland or adrenal gland regions, with ultrasound stimulation. Locations may be selected to optimize the effects of treatment, such as by targeting blood vessels, nerves, or a particular region of the adrenal glands.

[0083] In some configurations, a wearable energy delivery device will have the capability to image and transmit ultrasound energy to a specified target. Imaging and / or beam steering may also be used to compensate for motion of the adrenal gland or target such as changes in depth due to subject motion or respiration. Target organs, nerves, or blood vessels may naturally move. For example, the adrenal gland moves within theClient Ref. UMN 2024-172 Quarles 920171.00654 abdominal cavity during heavy breathing and changes in body position. With imaging feedback, the ultrasound beam focus point can be realigned as the distance to the surface of the target changes relative to the transducer array. This provides the potential for closed-loop device operation with the implementation of automated re-targeting algorithms, which may include rib detection. The ultrasound beam focus point may also track blood flow, guided by imaging data.

[0084] To accomplish a beam steered scan, the transmitter 306 imparts a timedelay,Ti, to the respective pulses 316 that are applied to successive transducer elements304. If the time delay is zero,Ti= 0, all of the transducer elements 304 will be energizedsimultaneously and the resulting ultrasonic beam will be directed along an axis 318 normal to the face of the transducer 302 and originating from the center of the transducerarray 302. As the time delay increment,Ti, is increased, the ultrasonic beam is directedaway from the central axis 318 by an angle,θ. The relationship between the time delayincrement,T, added successiveithily to each signal from one end of the transducer array302,i = 1, to the other end,i= n, is given by the following relationship:

[0085] (1);

[0086] where S is an equal spacing between centers of adjacent transducer elements 304;cis the velocity of sound in the object under study;Ris a range, or depth, at which the transmit beam is to be focused; andT0is a delay offset that ensures that allcalculated time delay increment values,Ti, are positive values.

[0087] The second term in Eqn. (1) steers the beam to the desired angle,θ, andClient Ref. UMN 2024-172 Quarles 920171.00654 the third term is employed when the transmitted beam is to be focused at a fixed range,R. A sector scan is performed by progressively changing the time delays,T i, insuccessive excitations. In this manner, the angle, θ , is changed in increments to steer the transmitted beam in a succession of directions. When the direction of the beam is above the central axis 318, the timing of the pulses is reversed; however, Eqn. (1) still applies in this situation.

[0088] The echo signals produced by each burst of ultrasonic energy emanate from reflecting objects located at successive ranges, or depths, R , along the ultrasonic beam. These are sensed separately by each transducer element 304 in the transducer array 302, and a sample of the magnitude of each echo signal at a particular point in time represents the amount of reflection occurring at a specific range, R . Due to the differences in the propagation paths between a focal point, P , and each transducer element 304, however, these echo signals will not occur simultaneously and their amplitudes will not be equal. A function of the receiver 308 is to amplify and demodulate these separate echo signals, impart the proper time delay to each, and sum them together to provide a single echo signal that accurately indicates the total ultrasonic energy reflected from each focal point,P, located at successive ranges,R, along the ultrasonicbeam oriented at the angle,θ.

[0089] Under the direction of the digital controller 312, the receiver 308 provides delays during the scan such that the steering of the receiver 308 tracks with the direction of the beam steered by the transmitter 306, and such that the receiver 308 samples the echo signals at a succession of ranges, R , and provides the proper delays to dynamically focus at points, P , along the beam. Thus, each emission of an ultrasonic pulse results in the acquisition of a series of data points that represent the amount of reflected soundClient Ref. UMN 2024-172 Quarles 920171.00654 from a corresponding series of points, P , located along the ultrasonic beam.

[0090] In some configurations, a physical device, such as a cone, may be used to steer the ultrasound beam to the target location. It will be appreciated by one skilled in the art that other options for directing ultrasound to a target location may be used with the present disclosure.

[0091] Referring to FIG.4A, a block diagram of a non-limiting example device for providing stimulation is shown. Other ultrasound or stimulation devices may also be used. A therapy module 400 may be included and is capable of providing ultrasound stimulation to a subject. A control module 410 may be used to control the therapy module 400. Control module 410 may include instructions stored for controlling the therapy module 400. Biomarker feedback sensor 440 may provide for feedback data, such as a measure of hormone or cytokine levels, and may be in contact with a subject such as through skin layer, through contact with blood via an IV or implanted sensor, or through another contact with the subject. Biomarker feedback sensor 440 may be in wireless communication 460 with control module 410. Power for the system may be provided by power supply / adapter 420. Power supply / adapter 420 may be an AC power adapter that plugs into the wall for standard power input or may be battery power. The therapy module 400 may be wired to the control module 410 using cable 430. Alternatively, the therapy module 400 may be in wireless communication with control module 410.

[0092] The control module may be used for device operation and power transformation to the transmitting transducer. In a non-limiting example, the control module 410 may generate + / - 90 V and 20 V DC outputs. These DC outputs are supplied to the therapy module 400 to power beam forming ICs, MCU and other secondary components. Based on pre-programmed parameters, the beam forming ICs may generate tone-burst pulses with maximum Peak to Peak voltage of approximately 180 V (+ / - 90 V).Client Ref. UMN 2024-172 Quarles 920171.00654 Using these tone-burst pulses, the phase array transducer may activate piezoelectric elements (such as 128 piezoelectric elements) in a pre-defined manner and produces ultrasound pressure waves. For each device, the ultrasound pressure outputs may be measured and tuned to ensured that the appropriate intensities are below safety thresholds.

[0093] Referring to FIGS. 4B-4D, a non-limiting example therapy module 400 is shown in greater detail. Referring to FIG. 4B, the therapy module 400 may include an outer housing 470, and a transmission array 472. Referring to FIG.4C, a base 474 may include a cut-out portion 476 for accommodating the transmission array 472. Referring to FIG.4D, a profile view of therapy module 400 is shown assembled with outer housing 470 and base 474. In some configurations, therapy module 400 may be a small, lightweight, wearable component. In a non-limiting example, the therapy module 400 houses the beam forming integrated circuits (ICs), phase array ultrasonic transducers, and other auxiliary circuits (Bluetooth, memory, and the like).

[0094] The therapy module 400 may be adhered to the body of a subject with a disposable adhesive coupling pad. In a non-limiting example placement, the therapy module 400 may be placed on the torso of a subject or otherwise near the target.

[0095] Referring to FIG. 5, a block diagram is shown for a non-limiting example ultrasound system configuration 500. A power generator 510, which in some configurations may be a DC power supply, may provide power for processor and beam forming integrated circuits 520, which control a stimulation delivered by phased array transducers 530. A clock generator 540 may provide a signal for triggering the beam forming integrated circuits 520. A wireless communication module 550 may be coupled to the beam forming integrated circuits 520, and may provide for diagnostic access, data input / output, user interface access, and the like.Client Ref. UMN 2024-172 Quarles 920171.00654

[0096] The system interface may allow for toggling of select features by an authorized user, such as a designated technician, professional, clinician or nurse, for administrate control via a custom tablet app. During therapeutic operation, use of the device may be limited to on / off operation with an automatic shutoff feature and may not require the use of a separate tablet device. Internal to the device, phasing algorithms may be provided for individual channel control to allow focusing and steering of the ultrasonic beam. This may allow the ultrasonic beam to be optimized for high intensity and pressure at the target site of the adrenal glands. Additional parameters include the pulse duration and repetition frequency, the values of which may be optimized to achieve the desired therapeutic effect.

[0097] In one configuration, a system may be configured with 128-channel or 256- channel beam forming capability for high resolution steering and focusing. Peak frequency may be 400 to 600 kHz and channel spacing at 1.5 mm, which is equivalent to less than half of the ultrasonic wavelength (λ / 2) in water at the 500 kHz ultrasonic frequency, optimizing the ability to steer and focus the ultrasound beam by avoiding energy loss due to side lobe generation. Peak frequency may also be between 600 kHz to 1 MHz or 1 MHz to 2 MHz. An ultra-compact design may be used with the wearable system being smaller than a standard business card.

[0098] In one configuration, a transducer for the system may include 128 transducer elements. Each element may be electrically and physically isolated, allowing for individual phasing and increasing the efficiency by nearly eliminating all acoustic cross-talk between channels. The 128-element array may be separated into four identical sections of 32 elements each. Each of the 32 elements in its respective section may be controlled in tandem with the three equivalent elements from the other sections. This allows the system to effectively operate in an equivalent manner as a 128-channel systemClient Ref. UMN 2024-172 Quarles 920171.00654 for center beam focusing for adrenal gland stimulation.

[0099] In one configuration, a transducer may include 32 channels tied to 32 elements for full steering and phasing in both X and Y axes. The transducer system can produce over 1 MPa of peak negative acoustic pressure and deliver energy to various depths, depending on the target location. For example, target depths may range between 1 mm to 30 cm. In some configurations, transducers may be provided with as high as 512 or more elements and channels for higher pressure and larger acoustic ranges.

[0100] For adrenal gland targeting, the systems have the ability to steer and focus the beam as necessary to achieve the desired therapeutic effect. In one configuration, by phasing the 64 channels of the system and transducer, the beam is able to steer efficiently towards the desired location. For the wearable device, a large number of programs may be stored into the internal memory for very fast rastering between steered and focused conditions. The phasing conditions may be preprogrammed based upon both the achievable targets of the ultrasonic device as well as the desired targets for therapy. For example, in the case of adrenal gland stimulation, the device may be configured for targeting a wide range of people with varying organ or tissue depths, and other bodily interferences such as ribs. For certain therapies this can include hundreds or thousands of phasing algorithms that may be used in a raster pattern (e.g., switched) very quickly, possibly hundreds of programs within 1 or a few seconds.

[0101] The phased array transducer can be designed to produce a customized ultrasonic beam profile with optimum energy or pressure profile (i.e., peak pressure, depth, beam area etc.).

[0102] The electrical system may include multi-channel beam forming microprocessor chips for 32 individual channel control for phasing and focusing. The wearable device may be wired to a power adapter that can accommodate standardClient Ref. UMN 2024-172 Quarles 920171.00654 electrical power inputs (i.e.100-240 V, 50 / 60 Hz).

[0103] In some configurations, the system includes a small wearable form factor, low cost, and amenability to scalable manufacturing. Existing instruments used for focused ultrasound medical applications are significantly more expensive; standard multi-channel systems routinely cost between $50,000 to $200,000 per unit, with large cart-based or desktop form factors. Conventional wearable ultrasound energy emission devices are designed for other purposes, such as wound-healing, and operate at inappropriate ultrasound frequencies or with only single or few channel operation, incapable of adequate beamforming for focusing. Hand-held medical ultrasound devices are designed for imaging purposes and are also inadequate for the energy delivery requirements of stimulating specific targets in the body or adrenal gland cell stimulation, due to the linear array design which can beam form in only one axis or the tendency to operate at high frequencies, such as more than 3 to 10 MHz.

[0104] In some configurations, hybrid systems and transducers may be provided for ultrasonic imaging feedback. As targeting of blood, immune cells, organs, and obstructions is performed, a beam steering mechanism to avoid artifacts in a resulting image can be used in the process.

[0105] The systems and methods in accordance with the present disclosure may be configured to use feedback provided by biomarker sensors, some of which provide immediate or near-term information regarding cytokine levels that may be relevant to the therapy delivered by the system.

[0106] A non-limiting example biomarker sensor includes a portable biosensor system capable of detecting cytokines (e.g., IL-1β, IFN-γ, MCP-1, IL-8, TNF-α, NF-κB, IL-6, IL-10, MAPK14, MCP-1) in unprocessed whole blood using filter paper-based immunosensors and smartphone imaging. This biosensor may detect small variations inClient Ref. UMN 2024-172 Quarles 920171.00654 cytokine levels in under 20 minutes. The paper-based immunosensor generates a colorimetric signal and the pixel intensity of the colorimetric signal may be evaluated using the real-time densitometry enabled by the user-guided smartphone application. The biosensor could also be electrochemical aptamer-based sensing platform that measures concentrations of specific molecules directly in blood and even in the living body, or could also be label-free electrochemical impedance immunosensing platform with various types of electrodes. The ultrasound stimulation system can be controlled via Bluetooth using a smartphone app that could also receive information from this biosensing app for cytokines that is housed on the same smartphone device; in some embodiments the biosensing app may be integrated into the ultrasound stimulation system app. Levels of ultrasound stimulation could be adjusted in response to detected increases or decreases in cytokines based on a predetermined algorithm and thresholds, incorporating data from past hours or days of cytokine monitoring.

[0107] A non-limiting example biomarker sensor includes a miniaturized sensor that uses a fluid such as saliva or sweat to measure a cytokine, hormone, or other biomarker relevant to inflammation levels or adrenal function. These devices may use various technologies, such as light waves (i.e., ultraviolet or infrared).

[0108] Communication with the system may be provided in real-time or delayed using the communication protocols Bluetooth, RFID, near-field, or WiFi. In some configurations, the biomarker sensors may be physically detached from the rest of the system while communicating wirelessly. Direct integration of a biomarker sensor into the system may also be provided. In this configuration, the biomarker sensor may be integrated directly into the device.

[0109] Communication to the system via an intermediary system may also be provided, such as a networked server. The biomarker sensor may be internet-enabledClient Ref. UMN 2024-172 Quarles 920171.00654 and provide data to a managed server that will then push the data back through the internet to system, which may also be networked accordingly. The data may be processed by the intermediary server or passed to the system directly.

[0110] Example 1

[0111] Example experimental data are provided in FIGS. 6-8B. In these experiments, the ultrasound stimulation was targeted towards the spleen in 13 study participants. The beam used had an elongated spread of energy, which reached the adrenal gland. The ultrasound had a center frequency of approximately 715 kHz, pulse repetition rate of 40 Hz, pulse duration of 200 microseconds, and was applied for 18 minute treatment durations nearly daily for an average of 5 days a week over the course of 8 weeks. As FIGS.6-7 show, circulating cortisol levels increased over time, in which 12 of the 13 participants showed increases in cortisol levels demonstrating the robustness of the ultrasound modulation approach. Blood draws were performed in the morning or afternoon, and the increase in cortisol levels was consistent across both blood draw times (see FIG. 7). These results support that targeting the adrenal glands has a major contribution to the efficacy of ultrasound stimulation in the reduction of inflammation in the body. Without being bound by theory, increases in cortisol level and relevant hormones can in turn reduce inflammatory response in the body including pro- inflammatory cytokines (e.g., TNF-alpha, IL-1, IL-6, etc.).

[0112] Referring now to FIGS. 8A-8B, these figures show that this increase in cortisol is related to a clinically meaningful decrease in inflammation and rheumatoid arthritis symptoms. 13 patients suffering from rheumatoid arthritis were treated with daily ultrasound stimulation of the spleen. Standard multi-outcome measures called DAS28-CRP (FIG.8A) and DAS28-ESR (FIG.8B) were shown to decrease over the course of treatment. Adrenal gland stimulation can also modify adrenal androgen productionClient Ref. UMN 2024-172 Quarles 920171.00654 (e.g., affecting sexual activity level, hair growth, acne / skin effects, etc.), aldosterone biosynthesis (e.g., hormone regulating your blood pressure by managing the levels of sodium and potassium in your blood and impacting blood volume), stress hormones (e.g., epinephrine and norepinephrine), and glucocorticoids (e.g., to regulate glucose metabolism).

[0113] Example 2

[0114] Rat experiments were performed in which the adrenal gland was surgically exposed with the spleen pushed aside to allow ultrasound to be applied directly across the adrenal gland. The stimulation parameters include approximately 715 kHz for the center frequency, pulse repetition rate of 40 Hz, pulse duration of 200 microseconds, and application of stimulation for 18 minutes at approximately 900 kPa. Blood samples were collected before and after stimulation in which cortisol levels were measured at multiple time points. Before ultrasound stimulation of the adrenal gland, the cortisol level was 26.7 pg / mL. After ultrasound stimulation, the cortisol level increased substantially over time at 0.5, 1, 1.5 and 2 hours after stimulation: 62.6, 103.3, 189.7, and 326.6 pg / mL, respectively. This considerable increase in cortisol levels supports the human data that ultrasound stimulation of the adrenal gland modulates cortisol output.

[0115] Therapeutic effect attributed to adrenal gland stimulation

[0116] For the human rheumatoid arthritis study, ultrasound was applied to the spleen. Since the ultrasound beam is elongated in depth, it can span beyond the spleen to the adrenal gland. FIGS.9A-9B show the proximity of the left adrenal gland to the spleen. The spleen covers the adrenal gland on the left side of the body as the upper cap of the kidney. In the provided example for the human study, the main stimulation target was the center of the spleen where the veins and arteries come into the spleen, traversing right above the adrenal gland. Since the beam is elongated and provides significantClient Ref. UMN 2024-172 Quarles 920171.00654 energy spanning multiple centimeters beyond the spleen, the cortisol increases reflect the modulation of the adrenal gland. This adrenal stimulation was achieved with the beam profile of the ultrasound stimulation applied on the skin surface through the ribs and spleen area. In the rat experiments, ultrasound was applied across the adrenal gland without passing through the spleen or ribs and a substantial increase in cortisol was observed, further supporting a major contribution caused by ultrasound stimulation of the adrenal gland.

[0117] Moreover, FIGS. 10A-10B show that the liver is positioned over and covering the right adrenal gland. Other groups have investigated stimulation of the liver in multiple animal and human studies that ultrasound stimulation of the liver, especially emphasizing targeting the region near the hepatic portal vein. However, the portal vein is located near the adrenal gland on the right side. The adrenal gland cap is near where those veins and blood vessels are located. Thus, the effects cited by other groups, in which liver stimulation is associated with altered metabolism in the body (e.g., glucose levels and other metabolic biomarkers) can be due in large part or fully to ultrasound stimulation of the adrenal gland rather than the liver. Low levels of cortisol can cause fatigue and weight gain. Thus, stimulating the adrenal glands to cause an increase in cortisol levels would drive increased body activity, reducing weight and helping control or reduce high glucose levels. Such adrenal gland stimulation is also expected to improve glucose tolerance and improve insulin resistance condition.

[0118] Not wishing to be bound by theory, adrenal gland stimulation drives increases in glucocorticoids that drive a catabolic state, which can help with weight gain and liver gluconeogenesis. For example, glucocorticoids, the hormonal end-product of the HPA axis, may exert primarily catabolic effects as part of a generalized effort to utilize every available energy resource against the challenge posed by intrinsic or extrinsicClient Ref. UMN 2024-172 Quarles 920171.00654 stressors. Thus, glucocorticoids may increase hepatic gluconeogenesis and plasma glucose concentration, induce lipolysis (although they favor abdominal and dorsocervical fat accumulation) and cause protein degradation at multiple tissues (e.g. muscle, bone, skin) to provide amino acids that would be used as an additional substrate at oxidative pathways.

[0119] Adrenal gland physiology

[0120] The adrenal gland has a different texture / rigidity than the liver or spleen or surrounding structures. The adrenal gland also has one of the highest blood flows / vascularization of any other tissues in the body. The adrenal gland is also tightly secured in its position, as shown in FIGS.9A-10B. This creates a favorable situation where the ultrasound stimulation can vibrate the adrenal gland or portions of it relative to surrounding tissue that further tethers it in place. Thus, the anatomy and physiology supports the ability to mechanically deform portions of the adrenal gland better than mechanical deformation of the spleen or liver to allow greater modulation of cells via a mechanical mechanism of action that alters function associated with the adrenal glands.

[0121] The adrenal glands produce several hormones that regulate a wide variety of physiological processes, such as metabolism, immune system response, blood pressure, response to stress, and other physiological functions. Thus, the disclosed systems and methods can be used to modulate or affect a wide variety of medical conditions, promote overall health, or have other positive affects for a patient. FIG. 11 summarizes the hormones that are related to the adrenal glands, which may be modulated by adrenal gland stimulation for various purposes.

[0122] Because the adrenal glands and hypothalamic-pituitary-adrenal (HPA) axis play such an important and widespread role in health, adrenal modulation can be harnessed for many applications. For example, ultrasound stimulation of the adrenalClient Ref. UMN 2024-172 Quarles 920171.00654 glands to modulate cortisol or other glucocorticoids and the HPA-axis, can potentially treat conditions listed in FIG.12. To summarize details of the role, anatomy, and function of the adrenal gland and cortisol in the body: generally, the activation of the HPA axis is tightly regulated and is intended to be acute or at least of a limited duration. The time- limited nature of this process renders the induced adaptive anti-reproductive, antigrowth, catabolic and immunosuppressive effects temporarily beneficial rather than damaging and prevents significant adverse consequences. In contrast, prolongation of the HPA axis activation, as documented in chronic stressful conditions, would lead to the stress syndromal state that Selye described in 1936 characterized by anorexia, loss of weight, depression, hypogonadism, peptic ulcers, immunosuppression, adrenal enlargement and involution of the thymus and lymph nodes. Because CRH coordinates behavioral, neuroendocrine and autonomic adaptation during stressful situations, increased and prolonged production of CRH could explain the pathogenesis of the syndrome.

[0123] FIG.13 provides a schematic drawing of neural pathways that are involved in regulative mechanisms of the sympathoadrenal system. In some implementations, ultrasound stimulation of the adrenal glands can be used to modulate nerves or axon terminals that enter into the adrenal glands. Labels include C, adrenal cortex; DRG, dorsal root ganglia; GN, ganglion neurons; ILC, intermediolateral column; LC, locus ceruleus; M, adrenal medulla; OC, optic chiasm; PG preganglionic fibers; POG, postganglionic fibers; PPG, pre-, paravertebral ganglia; PVN, paraventricular nucleus; S, sensory fibers; SCN, suprachiasmatic nucleus; SN, splanchnic nerve. As demonstrated in FIG.13, such nerves may include the celiac or mesenteric nerve pathways or the splanchnic nerve that enters the adrenal glands. The ultrasound stimulation may also be applied to various cells of the different regions of the adrenal glands or the blood vessels of the adrenal glands. ForClient Ref. UMN 2024-172 Quarles 920171.00654 example, for blood cells, ultrasound can be applied to modulate the endothelial cells or smooth cells or be applied in other ways to cause vasodilation or increased blood flow, which can cause increased cortisol or hormone release and have a therapeutic effect.

[0124] As used herein in the context of computer implementation, unless otherwise specified or limited, the terms "component," "system," "module," "controller," "framework," and the like are intended to encompass part or all of computer-related systems that include hardware, software, a combination of hardware and software, or software in execution. For example, a component may be, but is not limited to being, a processor device, a process being executed (or executable) by a processor device, an object, an executable, a thread of execution, a computer program, or a computer. By way of illustration, both an application running on a computer and the computer can be a component. One or more components (or system, module, and so on) may reside within a process or thread of execution, may be localized on one computer, may be distributed between two or more computers or other processor devices, or may be included within another component (or system, module, and so on).

[0125] In some implementations, devices or systems disclosed herein can be utilized or installed using methods embodying aspects of the disclosure. Correspondingly, description herein of particular features, capabilities, or intended purposes of a device or system is generally intended to inherently include disclosure of a method of using such features for the intended purposes, a method of implementing such capabilities, and a method of installing disclosed (or otherwise known) components to support these purposes or capabilities. Similarly, unless otherwise indicated or limited, discussion herein of any method of manufacturing or using a particular device or system, including installing the device or system, is intended to inherently include disclosure, as embodiments of the disclosure, of the utilized features and implemented capabilities ofClient Ref. UMN 2024-172 Quarles 920171.00654 such device or system.

[0126] As used herein, the phrase "at least one of A, B, and C" means at least one of A, at least one of B, and / or at least one of C, or any one of A, B, or C or combination of A, B, or C. A, B, and C are elements of a list, and A, B, and C may be anything contained in the Specification.

[0127] The present disclosure has described one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.

Claims

Client Ref. UMN 2024-172 Quarles 920171.00654 CLAIMS What is claimed is:

1. A method for modulating adrenal function in a patient, the method comprising the steps of: using a processor to select ultrasound stimulation parameters or based on stored settings of ultrasound stimulation parameters; and using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters.

2. The method of claim 1, wherein using a processor to select ultrasound stimulation parameters comprises analyzing medical images of the patient to determine a stimulation target based on localization of the adrenal gland of the patient.

3. The method of claim 2, wherein the medical images are ultrasound images, and the method further comprises using the ultrasound device to acquire the ultrasound images.

4. The method of claim 1, wherein the method further comprises the steps of monitoring a biomarker indicative of a stimulation outcome.

5. The method of claim 4, wherein the biomarker comprises a concentration of at least one of a hormone indicative of adrenal function or a cytokine indicative of inflammation.

6. The method of claim 1, wherein monitoring a level of one or more hormones comprises obtaining a blood sample from the patient and measuring level of the one or more hormones in the blood sample.

7. The method of claim 4, wherein the biomarker is monitored at least one of <10 minutes, <1 hour, <1 day, <1 week, or < 1 month after applying the ultrasound stimulation.Client Ref. UMN 2024-172 Quarles 920171.00654 8. The method of claim 5, wherein the hormone comprises at least one of cortisol, a glucocorticoid, aldosterone, androgenic steroid, dehydroepiandrosterone (DHEA), estrogen, androgen, epinephrine, or norepinephrine.

9. The method of claim 4, wherein the method further comprises analyzing the biomarker, adjusting the ultrasound stimulation parameters based on the biomarker, and applying ultrasound stimulation using the adjusted ultrasound stimulation parameters.

10. The method of claim 1, wherein the patient is believed to have at least one of rheumatoid arthritis, a metabolic disorder, diabetes, hyperthyroidism, or obesity.

11. The method of claim 1, wherein the ultrasound stimulation directed toward an adrenal gland is configured to treat or improve at least one of inflammatory bowel disease, myocarditis, pulmonary hypertension, tauopathies, epilepsy, Parkinson’s disease, stroke, spinal cord injuries and pain, neuropathic pain, acute kidney injury, heart failure, hypertension, depression, sepsis, a COVID-19 infection, a cold, a viral infection, an inflammatory condition caused by a bioterrorism attacks, an increased stress level, alertness or attention issues, post-traumatic stress disorder, weight loss, heart rate issues, respiration issues, blood pressure, sexual function or sexual drive, hair growth, skin / acne conditions, abnormal puberty in children, Cushing's syndrome, Addison's disease, chronic fatigue syndrome, or clinical outcomes associated with post- acute sequelae of COVID-19 (PASC).

12. The method of claim 1, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation to two or more different locations on the patient.

13. The method of claim 12, wherein the two or more different locations on the patient include at least one of the liver, the spleen, or the kidney of the patient.Client Ref. UMN 2024-172 Quarles 920171.00654 14. The method of claim 1, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation with a center frequency of at least one of: between 50 kHz-7MHz, between 100 kHz-7 MHz, between 500 kHz-1 MHz, or between 550 to 800 kHz.

15. The method of claim 1, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation with a pulse repetition rate of between 20 to 60 Hz.

16. The method of claim 15, wherein the pulse repetition comprises a stimulation of at least one of 0.1-0.5 ms, 1-5 ms, 10-50 ms, 50 ms-2 s, 0.2 ms, 1 ms, 25 ms, 100 ms, 350 ms, 500 ms, or 1 s, and wherein the stimulation is followed by a pause duration of at least one of 10 ms-10s, 24.8 ms, 500 ms, 650 ms, or 6 s.

17. The method of claim 16, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation with a duty cycle of at least one of between 1%-100%, between 10%-100%, or between 16%-50%.

18. The method of claim 17, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation for a duration of at least one of between 1 minute and 2 hours, between 1 minute and 1 hour, or between 2 minutes and 30 minutes.Client Ref. UMN 2024-172 Quarles 920171.00654 19. The method of claim 18, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: repeating the ultrasound stimulation at a frequency of at least one of one or more times per day, one or more times per week, or one or more times per month.

20. The method of claim 19, wherein using an ultrasound device to apply ultrasound stimulation directed toward an adrenal gland of the patient using the ultrasound stimulation parameters further comprises: using an ultrasound device to apply ultrasound stimulation with a pressure at a target location of at least one of between 25 kPa-10 MPa, between 25 kPa-2MPa, between 100 kPa-500 kPa, or between 500 kPa-1MPa.

21. A system for adrenal gland modulation, the system comprising: a processor configured to determine stimulation parameters or based on stored settings of ultrasound stimulation parameters; and an ultrasound device comprising a stimulation module configured to apply ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters.

22. The system of claim 21, wherein the ultrasound device further comprises an imaging module configured to acquire ultrasound images of the subject.

23. The system of claim 21, wherein the system is wearable.

24. The system of claim 21, further comprising a sensor configured to measure a level of biomarker.

25. The system of claim 21, wherein the stimulation module comprises a phased ultrasound array configured to direct the ultrasound stimulation to the adrenal gland of the subject.Client Ref. UMN 2024-172 Quarles 920171.00654 26. The system of claim 21, wherein the subject is believed to have at least one of a metabolic disorder, diabetes, hyperthyroidism, or obesity.

27. The system of claim 21, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation to two or more different locations on the subject.

28. The system of claim 27, wherein the two or more different locations on the subject include at least one of the liver, the spleen, or the kidney of the subject.

29. The system of claim 21, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation with a center frequency of at least one of: between 50 kHz-7MHz, between 100 kHz-7 MHz, between 500 kHz-1 MHz, or between 550 to 800 kHz.

30. The system of claim 21, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation with a pulse repetition rate of between 20 to 60 Hz.

31. The system of claim 30, wherein the pulse repetition comprises a stimulation of at least one of 0.1-0.5 ms, 1-5 ms, 10-50 ms, 50 ms-2 s, 0.2 ms, 1 ms, 25 ms, 100 ms, 350 ms, 500 ms, or 1 s, and wherein the stimulation is followed by a pause duration of at least one of 10 ms-10s, 24.8 ms, 500 ms, 650 ms, or 6 s.Client Ref. UMN 2024-172 Quarles 920171.00654 32. The system of claim 31, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation with a duty cycle of at least one of between 1%-100%, between 10%-100%, or between 16%-50%.

33. The system of claim 32, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation for a duration of at least one of between 1 minute and 2 hours, between 1 minute and 1 hour, or between 2 minutes and 30 minutes.

34. The system of claim 33, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: repeat applying the ultrasound stimulation at a frequency of at least one of one or more times per day, one or more times per week, or one or more times per month.

35. The system of claim 34, wherein the stimulation module, when applying ultrasound stimulation directed to an adrenal gland of a subject based on the ultrasound stimulation parameters, is further configured to: apply ultrasound stimulation with a pressure at a target location of at least one of between 25 kPa-10 MPa, between 25 kPa-2MPa, between 100 kPa- 500 kPa, or between 500 kPa-1MPa.

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