Neuromodulation Technology

Abstract

The presently disclosed subject matter generally relates to techniques for applying mechanical or ultrasonic energy to a region of interest 44 of a subject to induce modulation of one or more neural pathways. The region of interest may include at least a portion of a neural ganglion.

Description

Technical Field

[0001] The subject matter disclosed herein relates to neuromodulation, and more particularly, to neuromodulation techniques for modulating physiological responses using energy applied from an energy source. Background Art

[0002] Neuromodulation has been used to treat a variety of clinical conditions. For example, electrical stimulation at various locations along the spinal cord has been used to treat chronic back pain. Implantable devices can periodically generate electrical energy applied to tissue to activate certain nerve fibers, which may result in reduced pain. Regarding spinal cord stimulation, the stimulating electrodes are usually located in the epidural space, although the pulse generator can be located slightly away from the electrodes, for example, in the abdomen or gluteal region, but connected to the electrodes by wires. In other embodiments, deep brain stimulation can be used to stimulate specific areas of the brain to treat movement disorders, and the stimulation location can be guided by neuroimaging. This central nervous system stimulation usually targets local nerves or brain cell functions and is mediated by electrodes that transmit electrical pulses and are located at or near the target nerve. However, it is extremely challenging to position the electrode at or near the target nerve. For example, this technology may involve surgical placement of electrodes that deliver energy. In addition, specific tissue targeting via neuromodulation is challenging. Electrodes positioned at or near certain target nerves mediate neuromodulation by triggering action potentials in nerve fibers, which in turn results in the release of neurotransmitters at the synapse and synaptic communication with the next nerve. Because current implementations of implanted electrodes stimulate many nerves or axons at once, this propagation may result in relatively larger or more diffuse physiological effects than expected. Because neural pathways are complex and interconnected, more selective and targeted modulation may be more clinically useful. Summary of the invention

[0003] Certain embodiments are summarized below. These embodiments are not intended to limit the scope of the claimed subject matter, but rather these embodiments are intended only to provide a brief overview of possible embodiments. In fact, the present disclosure may include a variety of forms that may be similar or different from the embodiments set forth below.

[0004] In one embodiment, a method may include applying mechanical energy or ultrasonic energy to an area of ​​interest in a subject to induce modulation of one or more neural pathways. The area of ​​interest may include at least a portion of a nodose ganglion or a sacral ganglion.

[0005] In another embodiment, a method may include applying mechanical energy or ultrasonic energy to an area of ​​interest in a subject to induce modulation of two or more neural pathways. The area of ​​interest may include at least a portion of a nerve ganglion.

[0006] In another embodiment, a system may include: an energy application device that can apply mechanical energy or ultrasonic energy to an area of ​​interest in a subject to modulate one or more neural pathways; and a controller that can spatially select the area of ​​interest and control one or more modulation parameters of the energy application device. The area of ​​interest may include at least a portion of a nodose ganglion or a sacral ganglion. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] These and other features, aspects and advantages of the present disclosure will be better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters refer to like parts throughout, and in which:

[0008] Figure 1 is a schematic diagram of a neuromodulation system according to an embodiment of the present disclosure.

[0009] Figure 2 is a block diagram of a neuromodulation system according to an embodiment of the present disclosure;

[0010] Figure 3 is a schematic diagram of an ultrasonic energy application device in operation according to an embodiment of the present disclosure.

[0011] Figure 4 is a schematic diagram of an ultrasonic energy application device for applying energy to a sacral ganglion according to an embodiment of the present disclosure.

[0012] Figure 5 is a flow chart of a neuromodulation technique according to an embodiment of the present disclosure;

[0013] Figure 6 According to the embodiments of the present disclosure, Figure 1 Schematic diagram of an energy application device used in a neuromodulation system;

[0014] Figure 7 is a schematic diagram of an experimental setup for applying ultrasound energy to achieve a target physiological result according to an embodiment of the present disclosure;

[0015] Fig. 8A shows the concentration of tumor necrosis factor (TNF) in the blood after application of ultrasonic energy to the spleen, right adrenal gland, sacral ganglion, nodose ganglion, and nucleus tractussolitarii (NTS) of an animal model of lipopolysaccharide (LPS)-induced hyperglycemia according to an embodiment of the present disclosure;

[0016] Figure 8Bshows the concentration of acetylcholine (ACh) in the blood after applying ultrasonic energy to the spleen, right adrenal gland, sacral ganglion, nodose ganglion, and NTS of an LPS-induced hyperglycemia animal model according to an embodiment of the present disclosure;

[0017] Figure 8C shows the concentration of norepinephrine (NE) in the blood after applying ultrasonic energy to the spleen, right adrenal gland, sacral ganglion, nodose ganglion, and NTS of an animal model of LPS-induced hyperglycemia according to an embodiment of the present disclosure;

[0018] Fig.8D shows the concentration of dopamine (DA) in the blood after applying ultrasonic energy to the spleen, right adrenal gland, sacral ganglion, nodose ganglion, and NTS of an animal model of LPS-induced hyperglycemia according to an embodiment of the present disclosure;

[0019] Fig. 9 shows the effects of applying ultrasonic energy to the spleen, right adrenal gland, sacral ganglion, nodose ganglion, and NTS of an animal model of LPS-induced hyperglycemia according to embodiments of the present disclosure; and

[0020] Fig.10 The effects of applying ultrasound energy to the liver of an animal model of LPS-induced hyperglycemia according to embodiments of the present disclosure are shown. DETAILED DESCRIPTION

[0021] One or more specific embodiments are described below. In an effort to provide a brief description of these embodiments, not all features of an actual embodiment are described in this specification. It should be understood that in the development of any such actual embodiment, as in any engineering or design project, many implementation-specific decisions must be made to achieve the developer's specific goals, such as complying with system-related and business-related constraints, which may vary from one embodiment to another. In addition, it should be understood that such development work may be complex and time consuming, but will nevertheless be a routine task of design, manufacturing, and production for a person of ordinary skill having the benefit of this disclosure.

[0022] Any embodiment or illustration given herein should not be considered in any way as a limitation, restriction or express definition of any term used therein. On the contrary, these embodiments or illustrations should be considered as descriptions relative to various specific embodiments, and are illustrative only. It will be understood by those of ordinary skill in the art that any one or more terms used with these embodiments or illustrations will cover other embodiments that may or may not be given therewith or given elsewhere in the specification, and all such embodiments are intended to be included within the scope of the term or terms. The language specifying such non-limiting embodiments and illustrations includes, but is not limited to, "for example", "for example", "such as", "as", "including", "in certain embodiments", "in some embodiments" and "in one (one) embodiment".

[0023] When introducing elements of various embodiments of the present disclosure, the articles "a," "an," "the," and "said" are intended to indicate that there are one or more elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements in addition to the listed elements. Furthermore, any numbered examples in the following discussion are intended to be non-limiting, and thus additional values, ranges, and percentages are within the scope of the disclosed embodiments.

[0024] The human nervous system is a complex network of nerve cells, or neurons, located centrally in the brain and spinal cord, and peripherally in various nerves of the body. Neurons have a cell body, dendrites, and axons. A nerve is a group of neurons that serve a specific part of the body. A nerve may contain hundreds of neurons to hundreds of thousands of neurons. A nerve typically contains afferent neurons and efferent neurons. Afferent neurons transmit signals to the central nervous system, while efferent neurons transmit signals to the periphery. The peripheral nervous system (PNS) transmits signals between the central nervous system and, for example, the skin, muscles, and internal organs.

[0025] The electrical signal of a neuron is called an action potential. Neuronal excitability is the tendency of a neuron to initiate an action potential. When the potential across the cell membrane exceeds a certain threshold, an action potential is activated, thereby activating a voltage-gated ion pathway. The action potential then propagates along the length of the neuron. The action potential of a nerve is complex and represents the sum of the action potentials of individual neurons in it. The connection between the axon terminal of a neuron and the receiving cell is called a synapse. The action potential travels along the axon of the neuron to its axon terminal, which is the distal end of the axon nerve branch that forms the presynaptic terminal or synaptic terminal of a nerve fiber. The electrical pulse of the action potential triggers the migration of vesicles containing neurotransmitters to the presynaptic membrane of the presynaptic axon terminal, and ultimately releases neurotransmitters into the synaptic cleft (e.g., the space formed between the presynaptic and postsynaptic cells) or the axoextracellular space. Synapses that convert the electrical signal of an action potential into a chemical signal by releasing neurotransmitters are chemical synapses. In contrast to chemical synapses, electrical synapses cause an ionic current to flow into the presynaptic axon terminal and across the cell membrane into the postsynaptic cell.

[0026] The physiological effects of action potentials are mediated by the movement of ions across the cell membrane. Neurons facilitate + , K + and Cl - The ion pump that ions migrate through the neuron membrane actively maintains the static membrane potential. Different types of neurons can maintain different static membrane potentials (e.g., -75mV to -55mV). Action potentials are generated by the influx of ions (i.e., charge migration) to produce large deviations related to the temporary increase of transmembrane voltage on the membrane potential. For example, the increase in membrane potential can be within the range of 30mV-60mV. The action potential in the postsynaptic neuron can be initiated in response to the release of neurotransmitters from presynaptic (e.g., upstream) neurons. The neurotransmitters released from the presynaptic neuron bind to the receptors of the postsynaptic neuron, which in turn causes ions to flow in and subsequently depolarize across the membrane. Then, as the process occurs between subsequent neurons in the nerve, the action potential propagates along the nerve.

[0027] Synapse can be located at the junction between two neurons, which allows action potential to propagate downward along nerve fibers. However, axonal endings may also form synapses at the junction between neurons and non-neuronal cells, or may terminate in tissue fluid or body fluid. The type of synapse, for example, includes synapses with immune cells at the neuro-immune junction, synapses with resident sensory cells in organs, or synapses with glandular cells. The release of neurotransmitters into the synaptic cleft, and the combination of neurotransmitters with receptors in the postsynaptic membrane of postsynaptic cells, can cause downstream effects, which depend on the properties of presynaptic neurons, the specific neurotransmitters released, and the properties of postsynaptic cells (for example, the types of available receptors of postsynaptic cells). In addition, action potential can be excitatory or inhibitory. Excitatory postsynaptic action potential increases the possibility that postsynaptic neurons excite or release subsequent action potentials. On the contrary, inhibitory postsynaptic action potentials can reduce the possibility that postsynaptic neurons excite or release subsequent action potentials. Multiple neurons can act together and release neurotransmitters that trigger downstream action potentials or inhibit downstream action potentials.

[0028] Neuromodulation applies energy from an external energy source to certain areas of the nervous system to activate and / or block one or more nerves or enhance and / or reduce neural function. Electrical neuromodulation applies one or more electrodes to or near the target nerve, and the applied energy is carried by the nerve (e.g., as an action potential) to cause a physiological response in the downstream area of ​​the energy application site. However, due to the complexity of the nervous system, it is difficult to predict the scope and final endpoint of the physiological response of a given energy application site. Although the strategy of ultrasound regulation of the central nervous system (i.e., brain tissue) has been proven to successfully regulate neural activity, attempts to regulate peripheral nerves have lagged behind. For example, ultrasound regulation of the central nervous system (CNS) involves stimulating areas of the cerebral cortex, which are rich in synaptic structures, while the target nerve trunks of the peripheral nerves that attempt to perform ultrasound stimulation are not rich in or lack synaptic structures. In addition, the nerve trunk contains tens of thousands of tightly bundled neuron bundles, making it difficult to preferentially regulate any one or a group of neurons. In contrast, the nerve fibers in the ganglion or nucleus are spaced apart by several millimeters to several centimeters, and comprise the synaptic connections between the incoming PNS sensory fibers, the outgoing PNS efferent fibers, and the connections with the CNS neurons extending into and out of the brain. Each ganglion serves as a communication hub for the neural pathways of a particular organ system, and therefore provides a target for the neuromodulation of one or more neural pathways at the same time. Further, stimulating neurons in the nerve trunk may require activation or regulation of voltage, mechanical or chemically gated ion channels (i.e., the gaps in the myelinated tissue of the peripheral nerve) (or other membrane-bound proteins) in the nodes of Ranvier. In this case, sufficient energy must be provided to the nerve fibers to activate those channels at the nodes of Ranvier, so that action potentials can be generated and then signals are sent to upstream or downstream fibers. However, there are more types of neural structures in the ganglion, including dendrites, axons, axonal endings, and structures involving presynaptic and postsynaptic molecules / neural signaling. In this case, it is possible to find ultrasound parameters that preferentially or more advantageously stimulate or regulate specific neural structures. Use of these specific parameters can allow for a variety of outcomes, including 1) preferential stimulation of broad dendritic structures, thereby enabling cumulative ion channel activation and stimulation of action potentials, 2) preferential stimulation of cell bodies, and / or 3) preferential stimulation of tissues to encourage post-synaptic versus per-synaptic activation. Spatial selection of specific ganglia or nuclei or specific locations within ganglia or nuclei can enable preferential activation or modulation of fibers associated with specific pathways (eliminating off-target or off-pathway modulation).Additionally or alternatively, stimulation of sites within a specific ganglion can simultaneously stimulate multiple organ system pathways at one time, thereby enabling simultaneous stimulation of multiple physiological systems at one time in a manner not possible with direct organ or direct CNA tissue neuromodulation or stimulation. Finally, different locations or ultrasound-dependent stimulation parameters within the same ganglion (or across two or more ganglia) can allow for dynamic stimulation of multiple pathways (i.e., stimulating one or more ganglia less than others, depending on the parameters selected).

[0029] A group or cluster of neuron cell bodies in one position is called a ganglion. The ganglion of the peripheral nervous system can be located between the structure of the nerve endings and the central nervous system (e.g., spinal cord). The nuclear structure similar to the ganglion in the brainstem provides connection between the peripheral nerves and the brain. Preganglionic neurons, postganglionic neurons, interneurons (i.e., neurons completely contained in the ganglion) and various non-neuronal cells are present in the ganglion and the nucleus. The electrical signal generated in the nerve (e.g., by stimulation, which can be intrinsic or externally applied) is conducted via neurons and nerves. Neurons release neurotransmitters at the synapses (connections) of adjacent receiving cells to allow electrical signals to be continuous and regulated. In the peripheral nervous system, ganglia usually serve as relay points between the central nervous system and the rest of the body (e.g., nerves of limbs and organs), and can be connected to one or more anatomical systems of the body. Preganglionic fibers form synapses with postganglionic fibers in the structure of the ganglion, and the propagation of these nerve signals can cause neurotransmitters to be released as part of the ganglion synaptic transmission. As provided herein, neuromodulation of peripheral nerve ganglia by direct energy application can not only lead to active regulation in the ganglia to which energy has been applied, but also can cause downstream changes in one or more characteristics of the organs dominated by the affected ganglia. This change can be achieved without directly applying energy to the terminal organ of interest. As long as the organ or structure of interest affects other physiological processes (e.g., glucose regulation), neuromodulation of one or more peripheral nerve ganglia, and therefore one or more downstream organs or other anatomical structures, is used to target specific target physiological results that are local and / or systemic for the organ or structure of interest. In addition, since a single ganglion includes different nerve fiber types that dominate different positions in the body, relative to other ganglia, the specific ganglia targeting the periphery will produce specific target physiological results, and these other ganglia will not produce the same effect when regulating. In this way, targeting specific ganglia allows multiple target physiological results in one or more organs or physiological systems to be regulated. For example, targeted stimulation can be performed to achieve regulation of inflammatory or anti-inflammatory pathways, rather than regulation of pathways that control or change metabolism. In another embodiment, targeted stimulation can be performed to achieve activation or modulation of one inflammatory or anti-inflammatory pathway (i.e., controlling the production or modulation of a first specific cytokine or hormone) to a greater or lesser extent than another inflammatory or anti-inflammatory pathway (i.e., controlling the production or modulation of a second specific cytokine or hormone). Secretory ganglia can also be selected and preferentially or otherwise modulated directly in glandular or humoral tissues. Yet another benefit is that spatial selection of peripheral ganglia to which energy is applied by an external device may not be as complex as targeting individual nerve fibers, which can be difficult to visualize.

[0030] Provided herein are techniques for neuromodulation based on direct and focused modulation of a targeted region of interest and resulting in targeted physiological outcomes due to neuromodulation. The targeted region of interest may include at least a portion of one or more ganglia. Neuromodulation of the targeted region of interest allows limited and non-ablative application of energy only to the targeted region of interest without applying energy outside the targeted region of interest. However, applying energy to the targeted region of interest may trigger effects outside the targeted region of interest (e.g., in a tissue or structure containing the targeted region of interest, or in an organ, tissue, or structure that does not contain the targeted region of interest). For example, applying energy to synapses within a peripheral nerve ganglion may modulate one or more pathways based on the specific type of ganglion targeted, such as a nodose ganglion or a sacral ganglion. In some embodiments, applying energy to synapses within a peripheral nerve ganglion may modulate (1) a neuroimmune pathway or an anti-inflammatory pathway (e.g., a cholinergic anti-inflammatory pathway (CAP)), (2) a dopamine production pathway, and / or (3) a glucose regulatory or insulin production pathway. Effects outside these targeted areas of interest can be achieved without applying energy directly to areas outside the targeted areas of interest. Therefore, systemic effects can be achieved by intermittent and discontinuous local energy application. In addition, these effects can be achieved hours and days after energy application. In certain embodiments, the neuromodulation provided herein can be used as a chronic disorder treatment to change the progression and / or reverse the effects of chronic disorders. In one embodiment, a patient diagnosed with a disease can receive neuromodulation therapy. After neuromodulation therapy, the patient can reach a clinical benchmark associated with a healthy patient. For example, a patient with diabetes may show abnormal blood sugar levels and / or insulin levels before neuromodulation therapy. After receiving neuromodulation therapy, the patient may have normal blood sugar levels and / or insulin levels. In another embodiment, a patient with an abnormal immune response can obtain normal immune response characteristics (e.g., by a changed immune cell population, changed lymphatic drainage, etc.) after receiving neuromodulation therapy.

[0031] In certain embodiments, neuromodulation of the targeted area of ​​interest as provided herein can produce changes in physiological processes by interrupting, reducing or increasing the activation or inactivation of one or more physiological pathways in the subject, thereby producing the desired physiological results. In addition, preferential and targeted neuromodulation can change different physiological pathways in different ways and at different locations in the body to cause an overall characteristic curve of physiological changes in the subject, because local energy application may cause systemic changes. Although these physiological changes may be complex, the neuromodulation technology of the present invention provides one or more measurable physiological results that are the result of targeted neuromodulation therapy and may not be achieved without targeted neuromodulation therapy. Although drug therapy and other types of interventions may produce a subset of physiological changes caused by neuromodulation, in certain embodiments, the curve of the induced physiological changes caused by neuromodulation therapy is unique to the neuromodulation therapy of the targeted area of ​​interest. In addition, the curve of the induced physiological changes may be different between different subjects undergoing neuromodulation therapy.

[0032] Neuromodulation technology provided herein can also cause the physiological results of targeting in a subject.For example, the physiological results of this targeting can include the treatment of glucose metabolism and related diseases, the change of disease progression and the control of systemic inflammation.In one embodiment, the neuromodulation of peripheral nerve ganglia or nuclei (such as solitary nucleus (nucleussolitarus tractus), cervical or tubercular ganglia, secretory ganglia at glandular tissue or ganglia in body fluid tissue) at the area of ​​interest can be used to treat diabetes (for example, type I diabetes or type II diabetes), hyperglycemia, sepsis, trauma, infection, diabetes-related dementia, obesity, hyperlipidemia, metabolic dysfunction or other diet or metabolic disorders.In another embodiment, neuromodulation can be used to promote weight loss by controlling appetite, or by increasing appetite, treat cachexia (cachexia).In another embodiment, neuromodulation provided herein can change the glucose regulation set point relative to the pre-treatment state to achieve a therapeutic effect that exceeds the treatment for several days, weeks and / or months of continuous treatment. In one embodiment, in diabetic patients, neuromodulation of ganglia containing connections to secretory tissues (i.e., pathways to glands) or sensory pathways containing ganglia / nuclei can produce an initial decrease in circulating glucose relative to baseline (before neuromodulation) during a treatment window (e.g., hours or days). This effect can be induced by preferential and / or additional stimulation of the secretory and / or sensory pathways, and glucose reduction can be achieved by modulating the release of hormones into the circulation or by altering glucose and / or metabolite sensing in peripheral or central sensory cells. After treatment is terminated, although circulating glucose may increase after treatment, the increase may stabilize at a new set point that is significantly lower than the set point before treatment.

[0033] Neuromodulation of a targeted area of ​​interest can produce therapeutic results that last beyond the duration of treatment. Neuromodulation can alter a patient's disease state to achieve lasting results. For example, treatment with repeated application of energy to a targeted area of ​​interest over a predetermined time period can produce sustained improvement in disease symptoms. In one embodiment, the improvement is relative to an untreated patient or a patient treated with conventional therapy. The predetermined time period can be a time window of hours or days in which the neuromodulation treatment occurs. In addition, the neuromodulation treatment can include one or more separate energy application events within a predetermined time period. Separate energy application events within a predetermined time period can be repeatedly administered to the same area of ​​interest. For example, neuromodulation treatment can be performed once a day at the area of ​​interest, whereby the once-a-day treatment can be performed for two days or more in a row according to preset regulation parameters.

[0034] In certain embodiments, neuromodulation can be used in conjunction with drug therapy to modify the patient's disease state to achieve long-term results. Combination therapy including neuromodulation and low-dose drugs to the targeted area of ​​interest can achieve improved and / or more effective physiological results than drug therapy alone. For example, neuromodulation can be used to reduce insulin resistance in patients with type 2 diabetes, thereby increasing the effectiveness of initial treatment (e.g., using metformin) and reducing the need for other drug administration (e.g., rosiglitazone or pioglitazone).

[0035] Based on a specific type of ganglion or targeted ganglion, such as tuberous ganglion or sacral ganglion, targeted regulation of peripheral nerve ganglion can regulate one or more neural pathways. Ganglion can include synapses between preganglionic axons and postganglionic neuron cell bodies. Disclosed synapses can be regulated to change the activity in the synapse, for example, neurotransmitter release from preganglionic axon terminals in synapses located above or below the ganglion or stimulation site. Therefore, the changed activity can cause local action and / or non-local (for example, systemic) action. The present technology allows energy to be focused on the tissue volume including one or more ganglia in a targeted manner to achieve the desired result. In this way, the targeted ganglion or ganglion in the region of interest is activated and causes downstream effects in the structure dominated by the postganglionic axons. Therefore, based on the approach of one or more postganglionic axons extending from the targeted ganglion, neuroregulation can preferentially target specific ganglion types, such as tuberous ganglion or sacral ganglion.

[0036] For example, in one embodiment, the postganglionic axon can have an axon terminal that forms an axon cell extracellular synapse with resident (that is, tissue resident or non-circulating) liver, pancreas or gastrointestinal tissue cells. That is, the axon cell extracellular synapse is formed at the junction between the axon terminal and non-neuronal cells or interstitial or body fluid. Therefore, the application of energy causes the regulation of the metabolic function of the axon coupling outside the region of interest but extending from the region of interest. However, it should be understood that, based on the colony of axon terminal types and the characteristics of the postganglionic axon, and then the postsynaptic cell (for example, immune cell, lymphocyte, mucosal cell, muscle cell, etc.) of the axon cell extracellular synapse formed with the postganglionic axon, different target physiological effects can be achieved.

[0037] In certain embodiments, application of energy to synapses in the spleen, liver, and right adrenal gland can modulate individual physiological pathways, respectively. For example, ultrasonic stimulation of synapses in the spleen or a portion thereof modulates neuroimmune pathways or anti-inflammatory pathways, such as the cholinergic anti-inflammatory pathway (CAP). In another embodiment, ultrasonic stimulation of synapses in the liver or a portion thereof modulates glucose regulation and / or insulin production pathways, and ultrasonic stimulation of synapses in the right adrenal gland or a portion thereof modulates dopamine production.

[0038] In certain embodiments, application of energy to a peripheral nerve ganglion or synapses within a ganglion can modulate one or more of the following: (1) a neuroimmune pathway or an anti-inflammatory pathway, (2) a dopamine production pathway, and / or (3) a glucose regulatory or insulin production pathway. In other embodiments, application of energy to a peripheral nerve ganglion or synapses within a ganglion can modulate two or more physiological pathways using a single stimulation point. For example, ultrasonic stimulation of a nodose ganglion or a portion thereof can modulate a neuroimmune pathway or an anti-inflammatory pathway, such as CAP and a glucose regulatory and / or insulin production pathway. Additionally, ultrasonic stimulation of a sacral ganglion or a portion thereof can modulate a neuroimmune or anti-inflammatory pathway, such as CAP and a dopamine production pathway.

[0039] Therefore, applying energy to the area of ​​interest in the peripheral nerve ganglion of the subject can activate the axon endings in the peripheral nerve ganglion and the extracellular synapses of its downstream axons (e.g., via the stimulation of axons and / or neuronal cell bodies), while at the same time, the axon endings (and related synapses) outside the area of ​​interest and not coupled to the ganglion of the area of ​​interest by one or more postganglionic axons can be unaffected. However, since regulation may cause systemic effects, non-targeted axon endings outside the area of ​​interest may experience certain systemic changes due to the activation of the ganglion in the area of ​​interest. As provided herein, preferential regulation (e.g., activation or inactivation) can refer to the regulation of inducing one or more targeted neural pathways by changing the neuronal excitability in the structure of the cell or ganglion that directly applies energy in the area of ​​interest. The area of ​​interest can be defined as the part of the tissue where the ultrasound or other energy that is stimulated is focused, as well as all nerves and non-neuronal cells in the defined anatomical region. The region of interest can be an entire ganglion (preferentially stimulated compared to other ganglia or neural tissues), a group of neurons associated with the internal ganglia of glandular or humoral tissues, a nerve nucleus containing connections and synapses between the central nervous system and the peripheral nervous system, or any of these tissues containing neurons associated with specific pathways (relative to other pathways through the same ganglion, nucleus or tissue). That is, the preganglionic axons or neuronal cell bodies of the ganglion can directly experience the energy applied as provided herein to induce downstream effects. Compared to the regulation of cells or structures in areas outside the region of interest that do not experience direct energy application, even if these areas experience physiological changes due to energy application, it can be considered preferred regulation.

[0040] In another embodiment, in one embodiment, a plurality of postganglionic axon endings can extend from ganglion neuron cell bodies. The synapses of axon synapses are formed at the junctions between axon endings and different anatomical systems (e.g., digestive system, inflammatory system or adrenal system) and / or resident cells of different neurons. Therefore, the application of energy can result in the regulation of one or more paths of specific nerve ganglia such as nodose ganglia or sacral ganglia based on targeting. For example, the application of energy can result in the regulation of neuroimmune pathways or anti-inflammatory pathways and dopamine production pathways, neuroimmune pathways or anti-inflammatory pathways and glucose regulation and / or insulin production pathways, dopamine production pathways and glucose regulation and / or insulin production pathways, or neuroimmune pathways or anti-inflammatory pathways, dopamine production pathways and glucose regulation and / or insulin production pathways.

[0041] The neuromodulation techniques provided herein involve targeting one or more peripheral nerve ganglia to preferentially regulate one or more of the following: (1) neuroimmune pathways or anti-inflammatory pathways, (2) dopamine production pathways, or (3) glucose regulation or insulin production pathways. One or more energy pulses are applied to the subject's internal tissue containing the ganglion. Applying energy to the ganglion can cause activation of presynaptic nerve fibers (e.g., preganglionic nerve fibers), and / or activation of postsynaptic nerve fibers (e.g., postganglionic nerve fibers), and / or activation or regulation of supporting cells (i.e., resident immune or sensory cells) that change the excitability and / or activity of nerve fibers in the tissue; any of these types of regulation can be used to cause the targeted physiological results. The change in activity or activation can be the induction of the activity of ion channels (or other membrane proteins) to induce the action potential of the nerve fibers to rise or fall, and the change in activity can be a local change in the secretory function or gene expression in the region of interest (which will change the excitability or activity of these cells), or a change in the gene expression and / or secretory activity of adjacent non-neural supporting cells. For example, stimulation releases neurotransmitters or neuropeptides, or induces changes in the release of neurotransmitters and regulates neural activity. Therefore, regulation of other tissue structures or organs can be achieved without direct stimulation. In some embodiments, direct energy applied to the area of ​​interest comprising at least a portion of a peripheral nerve ganglion can result in stimulation of action potentials in projection neurons projected to different organs or structures (e.g., spleen or liver). Direct stimulation of an organ or structure may cause accidental activation of other pathways, thereby interfering with or drowning the desired physiological results. In addition, direct stimulation of an organ or structure may involve invasive steps. For example, the brain region around the hypothalamus constitutes an obstacle to direct stimulation of the hypothalamus by ultrasound. Therefore, the present technology allows the activity within the particle activation organ or structure to be more targeted and more specific than direct brain stimulation or peripheral nerve electrical stimulation. In addition, the present technology provides preferential regulation of the disclosed pathway without the use of inflammatory and / or metabolic drug therapies (e.g., anti-tumor necrosis factor (anti-TNF), insulin or metformin).

[0042] Additionally, ganglion modulation may involve directly activating a relatively small area of ​​tissue (e.g., an individual ganglion may be 5 cm or less in length) to achieve these effects. In certain embodiments, the area of ​​interest to which the subject applies energy may have a size of 1 cm 2 or smaller, 4cm 2 or smaller, 9cm 2 or smaller, 16cm 2 or smaller, or 25cm 2Or smaller surface area. In this way, the total energy applied is relatively small to achieve the desired physiological results. In some embodiments, the energy applied can come from a non-invasive extracorporeal energy source (e.g., an ultrasonic energy source, a mechanical vibrator). For example, a focused energy probe can apply energy through the subject's skin and focus on the area of ​​interest of the internal tissue. Such an embodiment achieves the desired physiological results without invasive steps or side effects that may be associated with other types of steps or therapies. In addition, in some embodiments, peripheral nerve ganglia (e.g., sacral ganglia or tuberosity ganglia) can be closer to the skin than certain tissues or certain organs such as the liver and spleen. The energy applied to the peripheral ganglia to achieve the desired physiological results can be less than the energy applied to the tissue or organ away from the skin to achieve the same or similar desired physiological results. Therefore, a lower power system or a wearable energy application system can be used to provide energy applied to the peripheral nerve ganglia. To this end, the disclosed neuromodulation technology can be used in combination with a neuromodulation system. In some embodiments, the system may include an energy application device that can apply mechanical or ultrasonic energy to the area of ​​interest of the subject to regulate one or more neural pathways. The system may also include a controller that can spatially select a region of interest and control one or more modulation parameters of the energy application device to apply energy to the region of interest to induce preferential modulation of one or more neural pathways. Neurons within the region of interest communicate with remote sites within the subject to cause changes in concentration of one or more molecules of interest at the remote sites. Figure 1 Schematic diagram of a system 10 for neuromodulation to achieve neurotransmitter release and / or activation of synaptic components (e.g., postsynaptic cells) to modulate (1) a neuroimmune pathway or anti-inflammatory pathway, (2) a dopamine production pathway, and / or (3) a glucose regulation or insulin production pathway (in response to energy application). The depicted system includes a pulse generator 14 coupled to an energy application device 12 (e.g., an ultrasonic transducer). The energy application device 12 is configured to receive energy pulses (e.g., via one or more leads or a wireless connection) and direct the energy pulses to an area of ​​interest (e.g., a peripheral ganglion or portion thereof), which in turn results in a targeted physiological outcome. In certain embodiments, the pulse generator 14 and / or the energy application device 12 can be non-invasive and extracorporeal. For example, the energy application device 12 can include a focused energy probe that applies energy through the skin of a subject and focuses on an area of ​​interest of internal tissue. For example, the energy application device 12 can be a microelectromechanical system (MEMS) transducer, such as a capacitive micromachined ultrasonic transducer or a dual probe.

[0043] In some embodiments, the energy application device 12 and / or the pulse generator 14 can, for example, communicate wirelessly with a controller 16, which can in turn provide instructions to the pulse generator 14. In other embodiments, the pulse generator 14 can be an extracorporeal device (e.g., can be operated to apply energy percutaneously or non-invasively from a location outside the body of a subject), and in some embodiments, can be integrated into the controller 16. In embodiments where the pulse generator 14 is extracorporeal, the energy application device 12 can be operated by a caregiver and positioned at a point on or above the subject's skin so that energy pulses are delivered percutaneously to a desired internal tissue. In some embodiments, the controller 15 can be robotic or digital. Once positioned to apply energy pulses to a desired site, the system 10 can initiate neuromodulation to achieve a targeted physiological outcome or clinical effect.

[0044] In some embodiments, the system 10 may include an assessment device 20 coupled to the controller 16 and configured to evaluate whether an indicator characteristic of a target physiological result of the adjustment has been achieved. In one embodiment, the targeted physiological result may be local, distal, or both. For example, the adjustment may result in changes in local tissue or changes in function, such as changes in tissue structure, local changes in the concentration of certain molecules, tissue displacement, increased fluid movement, etc. In some embodiments, the adjustment may result in systemic and / or non-local (e.g., distal) changes. The targeted physiological result may involve changes in circulating molecule concentrations or changes in tissue properties of the area of ​​interest that do not include direct application of energy. These changes may include local or distal blood flow, local or distal changes in the size or position of anatomical landmarks or tissues, changes in local or circulating molecule concentrations, changes in neural activity measured by functional imaging or electromagnetic sensors, changes in cellular lipid composition, and / or changes in the mechanical properties of local or distal tissues. Therefore, in some embodiments, the assessment device 20 may be configured to evaluate concentration changes. Although the depicted elements of the system 10 are shown separately, it should be understood that some or all of the elements may be combined with each other. Furthermore, some or all of the elements may be in communication with each other in a wired or wireless manner.

[0045] Based on the results of this evaluation, the regulation parameters of the controller 16 may be changed. For example, if the desired regulation is related to a concentration change (e.g., circulating concentration or tissue concentration of one or more molecules) within a defined time window (e.g., 5 minutes or 30 minutes after the start of the energy application procedure), or relative to the baseline at the beginning of the procedure, then the regulation parameters (e.g., pulse frequency) may need to be changed, which in turn can be provided to the controller 16 by the operator or through an automatic feedback loop to define or adjust the energy application parameters or regulation parameters of the pulse generator 14.

[0046] As provided herein, the system 10 can provide energy pulses according to various adjustment parameters. For example, the adjustment parameters can include various stimulation time modes from continuous to intermittent. When intermittent stimulation is adopted, energy is transmitted for a period of time at a certain frequency during the signal on time. After the signal on time, there is a period of time without energy transmission, which is called the signal off time. The adjustment parameters can also include the frequency and duration of stimulation application. The application frequency can be continuous or transmitted in different time periods, for example, within a day or a week. The treatment duration can last for different time periods, including but not limited to, a few minutes to a few hours. In some embodiments, the treatment duration with a specified stimulation mode can last for one hour, for example, repeated at intervals of 72 hours. In some embodiments, the treatment can be transmitted at a higher frequency, such as three hours, for a shorter duration, for example, 30 minutes. Therefore, according to adjustment parameters such as treatment duration and frequency, energy application can be controllable to achieve the desired result.

[0047] Figure 2 is a block diagram of certain components of the system 10. As provided herein, the system 10 for neuromodulation may include a pulse generator 14 adapted to generate a plurality of energy pulses applied to tissue of a subject. The pulse generator 14 may be separate or may be integrated into an external device such as a controller 16. The controller 16 includes a processor 30 for controlling the device. Software code or instructions are stored in a memory 32 of the controller 16 for execution by the processor 30 to control the components of the device. The controller 16 and / or the pulse generator 14 may be connected to the energy application device 12 via one or more leads 33 or wirelessly.

[0048] The controller 16 also includes a user interface having an input / output circuit 34 and a display 36, which is adapted to allow a clinician to provide a selection input or adjustment parameter to the adjustment program. Each adjustment program may include one or more groups of adjustment parameters, including pulse amplitude, pulse width, pulse frequency, etc. The pulse generator 14 modifies its internal parameters in response to a control signal from the controller 16 to change the stimulation characteristics of the energy pulse transmitted to the subject applying the energy application device 12 through the wire 33. Any suitable type of pulse generating circuit can be used, including but not limited to, constant current, constant voltage, multiple independent current or voltage sources, etc. The energy applied is a function of the current amplitude and pulse width duration. The controller 16 allows the energy to be adjustable controlled by changing the adjustment parameters and / or starting the energy application at a specific time, canceling the energy application at a specific time, or inhibiting the energy application at a specific time. In one embodiment, the adjustable control of the energy application device is based on information about the concentration of one or more molecules (e.g., circulating molecules) in the subject. If the information comes from the evaluation device 20, the feedback loop can drive the adjustable control. For example, if the circulating glucose concentration measured by the evaluation device 20 is above a predetermined threshold or range, the controller 16 can initiate energy application to the area of ​​interest (e.g., a peripheral ganglion) and use a regulation parameter associated with a decrease in circulating glucose. The initiation of energy application can be triggered by the glucose concentration drifting above a predetermined (e.g., desired) threshold or outside a predetermined range. In another embodiment, when the initial application of energy does not result in an expected change in the target physiological outcome (e.g., the concentration of a molecule of interest) within a predetermined time frame (e.g., 1 hour, 2 hours, 4 hours, 1 day), adjustable control can be performed in the form of changing the regulation parameter.

[0049] In one embodiment, the memory 32 stores different operating modes that can be selected by an operator. For example, the stored operating modes may include instructions for executing a set of adjustment parameters associated with a specific treatment site (e.g., a peripheral nerve ganglion, such as a sacral ganglion or a tuberous ganglion). Different sites may have different associated adjustment parameters. Instead of having the operator manually input a mode, the controller 16 may be configured to execute appropriate instructions based on the selection. In another embodiment, the memory 32 stores operating modes for different types of treatments. For example, activation may be associated with different stimulation pressures or frequency ranges relative to those associated with inhibiting or preventing tissue function. In a specific embodiment, when the energy application device is an ultrasonic transducer, the time-averaged power (time-averaged intensity) and the peak positive pressure are at 1 mW / cm 2 -30,000mW / cm 2In one embodiment, the time-averaged intensity in the region of interest is less than 35 W / cm 2 , to avoid levels associated with thermal damage and ablation or cavitation. In another specific embodiment, when the energy application device is a mechanical actuator, the amplitude of the vibration is in the range of 0.1-10 mm. The selected frequency can depend on the mode of energy application (e.g., ultrasonic actuator or mechanical actuator).

[0050] In another embodiment, the memory 32 stores a calibration or setup mode that allows the adjustment or modification of the adjustment parameters to obtain the desired results. In one embodiment, the stimulation starts with a lower energy parameter and is gradually increased automatically or upon receiving operator input. In this way, the operator can achieve adjustment of the induced effect when changing the adjustment parameters.

[0051] The system may also include an imaging device that facilitates focusing the energy application device 12. In some embodiments, the imaging device may be integrated with the energy application device 12, or the imaging device may be the same device as the energy application device so that different ultrasound parameters (e.g., frequency, aperture or energy) are applied to select (e.g., spatially select) the region of interest and focus the energy on the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 32 stores one or more targeting or focusing modes for spatially selecting the region of interest within an organ or tissue structure. The spatial selection may include selecting a region of interest that includes a peripheral nerve ganglion or a portion thereof. Based on the spatial selection, the energy application device 12 may be focused on a selected volume in a subject corresponding to the region of interest. For example, the energy application device 12 may be configured to first operate in a targeting mode and apply a targeting mode energy for capturing image data to be used to identify the region of interest. The targeting mode energy does not reach a level and / or does not apply an adjustment parameter suitable for priority activation. However, once the region of interest is identified, the controller 16 may then operate in a treatment mode according to the adjustment parameters associated with the priority activation.

[0052] The controller 16 can also be configured to receive input related to the target physiological result as an input for selecting the adjustment parameter. For example, when the imaging modality is used to evaluate the tissue characteristics as a result of applying energy to the peripheral nerve ganglion, the controller 16 can be configured to receive a calculated index or parameter of the characteristic. Based on whether the index or parameter is above or below a predetermined threshold, the adjustment parameter can be modified. In one embodiment, the parameter can be a measure of tissue displacement of the diseased tissue or a measure of the depth of the diseased tissue. Other parameters can include evaluating the concentration of one or more molecules of interest (e.g., evaluating one or more of the concentration change, rate of change relative to a threshold or baseline / control, to determine whether the concentration is within a desired range). In addition, the energy application device 12 (e.g., an ultrasonic transducer) can be operated under the control of the controller 16 to (1) obtain image data that can be used to spatially select an area of ​​interest within the body, (2) apply energy modulation to the area of ​​interest, and (3) collect image data to determine that the target physiological result has occurred. In such an embodiment, the imaging device 12, the evaluation device 20 and the energy application device 12 can be the same device.

[0053] In another embodiment, the controller 16 can also store a desired set of adjustment parameters. In this way, subject-specific parameters can be determined. In addition, the effectiveness of these parameters can be evaluated over time. If a specific set of parameters becomes less effective over time, the subject may develop insensitivity to the activated pathway. If the system 10 includes an evaluation device 20, the evaluation device 20 can provide feedback to the controller 16. In some embodiments, feedback indicating the characteristics of the target physiological results can be received from the user or the evaluation device 20. The controller 16 can be configured to enable the energy application device to apply energy according to the adjustment parameters, and dynamically adjust the adjustment parameters based on feedback. For example, based on feedback, the processor 16 can automatically change the adjustment parameters (e.g., the frequency, amplitude or pulse width of the ultrasound beam or mechanical vibration) in real time and in response to feedback from the evaluation device 20.

[0054] In one embodiment, the present technology can be used to treat a subject suffering from metabolic dysfunction. The present technology can also be used to regulate the blood glucose level of a subject suffering from glucose regulation disorder. Therefore, the present technology can be used to promote the steady state of the molecule of interest or promote the desired circulating concentration or desired concentration range of one or more molecules of interest (e.g., glucose, insulin, glucagon (glucagon) or its combination). In one embodiment, the present technology can be used to control circulating glucose levels. In one embodiment, the following threshold values ​​can be used to maintain blood glucose levels in a dynamic balance within a normal range:

[0055] (A) Fasting:

[0056] (1) Less than 50 mg / dL (2.8 mmol / L): insulin shock;

[0057] (2) 50 mg / dL-70 mg / dL (2.8 mmol / L-3.9 mmol / L): hypoglycemia or hypoglycemia;

[0058] (3) 70 mg / dL-110 mg / dL (3.9 mmol / L-6.1 mmol / L): normal;

[0059] (4) 110 mg / dL-125 mg / dL (6.1 mmol / L-6.9 mmol / L): elevated or impaired (prediabetes); and

[0060] (5) 125 mg / dL (7 mmol / L): Diabetes.

[0061] (B) Not fasting (after a meal, about 2 hours after a meal):

[0062] (1) 70 mg / dL-140 mg / dL (3.9 mmol / L-7.8 mmol / L): normal;

[0063] (2) 140 mg / dL-199 mg / dL (8 mmol / L-11 mmol / L): elevated or borderline (prediabetes); and

[0064] (3) Greater than 200 mg / dL (11 mmol / L): Diabetes.

[0065] For example, energy is applied to the nodose ganglion according to the disclosed techniques (see Fig. 9 ) can be used to maintain circulating glucose concentrations below about 200 mg / dL and / or above about 70 mg / dL. The technology can be used to maintain glucose within a range of about 4 mmol / L-8 mmol / L or about 70-150 mg / dL. The technology can be used to maintain a normal blood glucose range for a subject (e.g., a patient), wherein the normal blood glucose range can be an individualized range based on individual factors of the patient such as body weight, age, and / or clinical history. Therefore, the energy application to one or more regions of interest is adjusted in real time based on the desired final concentration of the molecule of interest, and can be adjusted in a feedback loop based on input from the evaluation device 20. For example, if the evaluation device 20 is a circulating glucose monitor or a blood glucose monitor, real-time glucose measurement can be used as an input to the controller 16.

[0066] In another embodiment, the present technology can be used to induce a characteristic curve of physiological changes. For example, the characteristic curve can include a group of molecules of interest whose concentration in tissue and / or blood is increased due to energy application and another group of molecules of interest whose concentration in tissue and / or blood is decreased due to energy application. The characteristic curve can include a group of molecules that do not change due to energy application. The characteristic curve can define simultaneous changes associated with a desired physiological outcome. For example, the curve can include a decrease in circulating glucose and an increase in circulating insulin seen together.

[0067] Figure 3 is a specific embodiment in which the energy application device 12 includes an ultrasonic transducer 42 that applies energy to an area of ​​interest in a subject (e.g., an area of ​​interest including a targeted ganglion 43 such as a peripheral nerve ganglion). The energy application device 12 may include control circuitry for controlling the ultrasonic transducer 42. The control circuitry of the processor 30 may be integrated into the energy application device 12 (e.g., via the integrated controller 16) or may be a separate component. The ultrasonic transducer 42 may also be configured to acquire image data to assist in spatially selecting a desired or targeted area of ​​interest and focusing the applied energy on the selected area of ​​interest.

[0068] The desired or targeted area of ​​interest includes a target ganglion 43, such as a peripheral nerve ganglion or portion thereof, which includes axons that synapse with a neuronal cell body from which a postganglionic axon 45a, 45b may extend and form axonal extracellular synapses in one or more downstream structures or organs (shown as organs 46, 48), or extend sensory neurons and form synapses with other nerves (including nerves that project to the central nervous system). Synapses within the target ganglion 43 are stimulated by applying energy directly to axonal terminals within the focal region of an ultrasonic transducer 42 focused on an area of ​​interest 44 that includes all or a portion of the target ganglion 43 to cause the release of molecules into the synaptic space. Similar release may occur at downstream axonal extracellular synapses of postganglionic axons, for example, at synapses with hepatocytes, and the release of neurotransmitters and / or changes in ion channel activity may cause downstream effects such as activation of glucose metabolism. The region of interest 44 can be selected to include a certain type of ganglion 43, such as those including neuronal cell bodies, which include postganglionic axons of a specific neuronal type and / or form synapses with a certain type of non-neuronal cells. Therefore, the region of interest 44 can be selected to correspond to the target ganglion 43 with the desired postganglionic axon terminals (and associated non-neuronal cells). In some embodiments, energy application can be selected to preferentially trigger the release of one or more molecules (e.g., neurotransmitters) from the nerves in the synapse. In some embodiments, energy application can be selected to preferentially trigger the release of one or more molecules (e.g., neurotransmitters) by directly activating the neuronal cells in the region of interest 44 by direct energy transduction (i.e., mechanical transduction or voltage-activated proteins in non-neuronal cells). In some embodiments, energy application can be selected to preferentially trigger the release of one or more molecules (e.g., neurotransmitters) by causing activation in the neuronal cells that cause the desired physiological effect in the region of interest 44.

[0069] The energy can be concentrated or substantially concentrated on the region of interest 44 and all or only a portion of the target ganglion 43 (e.g., less than about 75%, 50%, 25%, 10%, or 5% of the total volume of the ganglion 43). In one embodiment, energy can be applied to a region of interest 44 that is larger than the target ganglion 43, for example, about 105% to about 200% of the volume of the ganglion 43 to include the entire target ganglion 43. In one embodiment, energy can be applied to two or more regions of the target ganglion 43. In one embodiment, energy is applied to only about 1% to 50% of the total volume of the ganglion 43, or to about 25% to 100% of the total volume of the ganglion 43. In certain embodiments, energy can be concentrated or focused on less than about 25 mm 3 In some embodiments, the energy can be concentrated or focused within a volume of about 0.5 mm3 -50 mm 3 The focal volume and focal depth used to focus or concentrate energy within the area of ​​interest 44 can be affected by the size or configuration of the energy application device 12. The focal volume of energy application can be defined by the area focused by the energy application device 12. For example, for an ultrasonic transducer, the focal area can be defined by an ultrasonic lens attached to the surface of the ultrasonic transducer or the arrangement of transducer elements of the ultrasonic transducer. The focal area defines the size and / or shape of the energy entering the subject and the area of ​​interest 44 from the energy application device 12. As provided herein, energy can be applied substantially only to one or more areas of interest 44 to preferentially activate the ganglia 43. Thus, only a subset of the multiple different types of ganglia in the body are exposed to direct energy application.

[0070] The region of interest 44 containing the ganglion 43 may be identified by imaging, reference to anatomical landmarks (eg, carotid arch), etc., to perform spatial selection. Figure 4 is an embodiment in which the energy application device 12 includes an ultrasonic transducer 42 that applies energy to a region of interest 44 that includes a sacral ganglion 43. The region of interest 44 may be selected based on an entry point 47a of the sacral ganglion 43 into an organ 46 or an entry point 47b of the sacral ganglion into a bone structure 48. Return to Reference Figure 3 , individual ganglia 43 included in the region of interest can be selected based on factors including, but not limited to, historical or experimental data (e.g., data showing that specific locations are associated with desired or targeted physiological outcomes). Alternatively or additionally, the system 10 can apply energy to the region of interest containing individual ganglia 43 or portions thereof until the desired target physiological effect is achieved. The disclosed selection of ganglia 43 to be preferentially activated by applying energy directly to the region of interest using spatial information of visualized nerves can be used in conjunction with other organs or structures (e.g., liver, pancreas, or gastrointestinal tissue).

[0071] In other embodiments, the region of interest can be determined by the presence or absence of one or more biomarkers. This marker can be evaluated by staining the tissue and obtaining an image indicating the staining to determine the tissue region including the biomarker. In some embodiments, the information of the biomarker can be obtained by in vivo staining techniques to obtain the position data of the biomarker in the subject in real time. In other embodiments, the biomarker information can be obtained by in vitro staining techniques to obtain position data from one or more representative images for predicting the position of the biomarker in the subject. In some embodiments, the region of interest is selected to correspond to a tissue rich in or lacking a specific biomarker. For example, the one or more biological markers can include markers of neuronal structure (e.g., myelin markers).

[0072] The region of interest in the organ or tissue can be spatially selected based on operator input. For example, the operator can specify the region of interest on the acquired image by directly manipulating the image (e.g., drawing or writing the region of interest on the image) or by providing image coordinate information corresponding to the region of interest. In another embodiment, the region of interest can be automatically selected based on the image data to achieve spatial selection. In some embodiments, the spatial selection includes storing data related to the region of interest in a memory and accessing the data.

[0073] The disclosed techniques can be used for evaluation of neuromodulatory effects, which in turn can be used as input or feedback for selecting or modifying neuromodulatory parameters. The disclosed techniques can use direct evaluation of tissue condition or function as a target physiological outcome. The evaluation can be performed before (i.e., baseline evaluation), during, and / or after neuromodulation.

[0074] The evaluation technique may include at least one of the following: functional magnetic resonance imaging, diffusion tensor magnetic resonance imaging, positive emission tomography, diagnostic imaging ultrasound or acoustic monitoring, thermal monitoring. The evaluation technique may also include protein and / or marker concentration evaluation. The system may receive images from the evaluation technique for automatic or manual evaluation. Based on the image data from the evaluation technique, the adjustment parameters may be modified. For example, changes in tissue size or displacement can be used as a marker for local neurotransmitter concentration and as a surrogate marker for exposing local cells to phenotypically regulatory neurotransmitters, and effectively as a marker for the expected effect on glucose metabolic pathways or systemic inflammatory pathways (e.g., neuroimmune or anti-inflammatory pathways or dopamine production pathways). Local concentration may refer to the concentration within the focal area of ​​energy application.

[0075] Additionally or alternatively, the system can evaluate the presence or concentration of one or more molecules in a tissue region or blood. The concentration in the tissue can be referred to as a local concentration or a resident concentration. The tissue can be obtained by fine needle aspiration, and the presence or level of the molecule of interest (e.g., a metabolic molecule, a metabolic pathway marker, a peptide transmitter, a catecholamine) can be evaluated by any suitable technique known to those of ordinary skill in the art.

[0076] Figure 5 5 is a flow chart of a method 50 for stimulating a peripheral nerve ganglion. In the method 50, a region of interest is spatially selected 52. In step 54, an energy application device is positioned so that an energy pulse is focused on a desired region of interest, and in step 56, a pulse generator applies a plurality of energy pulses to the region of interest of the target tissue to activate synapses in the target ganglion, for example, to stimulate axon terminals to release neurotransmitters and / or induce changes in neurotransmitter release and / or induce changes in neuronal cell bodies (within synapses) activity, thereby, in step 58 provided herein, for example, by preferentially activating one or more organs, structures or pathways, leading to a targeted physiological outcome. In certain embodiments, the method may include a step of evaluating the effect of the stimulation. For example, one or more direct or indirect evaluations of the state of ganglion function or condition may be used. Based on the evaluated function, one or more adjustment parameters of the energy pulses may be modified (e.g., dynamically or adjustably controlled) to achieve the targeted physiological outcome.

[0077] In one embodiment, an evaluation can be performed before and after application of an energy pulse to evaluate the change in concentration of one or more molecules of interest (e.g., glucose, TNF, acetylcholine (ACh), norepinephrine (NE), or dopamine (DA)) due to modulation. If the concentration of the molecule of interest is above or below a threshold, the modulation parameters can be modified appropriately. For example, if the glucose concentration is inconsistent with the desired physiological outcome, the energy applied during neuromodulation can be returned to a minimum level that supports the desired outcome. If the change in the molecule of interest relative to the threshold is not correlated with an insufficient change in the molecule of interest, certain modulation parameters can be changed, including but not limited to, modulation amplitude or frequency, pulse shape, stimulation mode and / or stimulation site.

[0078] In addition, the characteristic or condition evaluated can be a value or indicator, such as flow rate, concentration, cell population or any combination thereof, which can then be analyzed by suitable techniques. For example, a relative change exceeding a threshold value can be used to determine whether the adjustment parameter is modified. The desired adjustment can be evaluated by measuring clinical outcomes such as an increase in tissue structure size (e.g., lymph node size) or a change in concentration of one or more released molecules (e.g., a change in baseline concentration relative to neuromodulation) to determine whether there is. In one embodiment, the desired adjustment may involve an increase in concentration exceeding a threshold value (e.g., an increase of more than about 50%, 100%, 200%, 400%, 1000% relative to the baseline concentration). For blocking therapy, the evaluation may involve tracking the decrease in molecule concentration over time (e.g., the concentration of the molecule of interest decreases by at least 10%, 20%, 30%, 50% or 75%). In addition, for some subjects, the desired blocking therapy may involve maintaining a relatively stable concentration of a specific molecule in the presence of other clinical events that may tend to increase the concentration of the molecule. That is, the desired blocking can block potential increases. This increase or decrease or other induced and measurable effect can be measured within a certain time window from the start of treatment (eg, within about 5 minutes or within about 30 minutes).

[0079] In certain embodiments, if it is determined that the physiological outcome of neuromodulation is desired, the change in neuromodulation can serve as an instruction to stop applying energy pulses. In another embodiment, if the physiological outcome of neuromodulation is not desired, one or more parameters of neuromodulation can be changed. For example, the change in the modulation parameter can be an increase in the pulse repetition frequency, such as a stepwise increase in frequency from 10 Hz to 100 Hz, and the evaluation of the desired characteristics will continue until the desired physiological outcome of neuromodulation is obtained. In another embodiment, the pulse width can be changed. In other embodiments, two or more parameters can be changed together (e.g., in parallel or in series). If the physiological outcome of neuromodulation is not desired after multiple parameter changes, the focus (i.e., location) of energy application can be changed.

[0080] The energy application device 12 can be configured as an in vitro non-invasive device or an internal device (e.g., a minimally invasive device). As described herein, the energy application device 12 can be an in vitro non-invasive ultrasonic transducer or a mechanical actuator. For example, the energy application device 12 can be configured as a handheld ultrasonic probe including an ultrasonic transducer. However, it should be understood that other non-invasive embodiments can also be considered, including other methods of constructing, adhering or placing an ultrasonic transducer probe on an anatomical target. In addition, in addition to the handheld configuration, the energy application device 12 can include a steering mechanism that responds to instructions from the controller 16. The steering mechanism can orient or guide the energy application device 12 toward the target ganglion 43 (or structure), and then the controller 16 can focus the energy application on the area of ​​interest 44.

[0081] Figure 6 It is possible to Figure 1 An embodiment of an energy application device 12 used in conjunction with the system 10 includes a high-intensity focused ultrasound (HIFU) transducer 74A and an imaging ultrasound transducer 74B arranged in a single energy application device 12, as provided herein, and the single energy application device 12 can be controlled (e.g., by a controller 16) to apply energy and image the target tissue.

[0082] Example

[0083] Ultrasound Targeting of Neuromodulation in Specific Peripheral Nerve Ganglia

[0084] Before neuromodulation began, a GE Vivid E9 ultrasound system and 11L probe were used for ultrasound scanning. Focus areas corresponding to the internal areas of interest were marked on the animal's skin. The HIFU transducer was positioned over the marked areas. Another ultrasound scan was performed using a smaller imaging probe (3S), which was placed in the opening of the HIFU transducer. The imaging beam of the 3S probe was aligned with the HIFU beam. Therefore, using the image of the target organ (visualized on the ultrasound scanner), it was possible to confirm that the HIFU beam had targeted the area of ​​interest.

[0085] Animal subjects, ultrasound stimulation protocol and tissue analysis

[0086] Adult male Sprague-Dawley rats (8-12 weeks old, weighing 250-300 g; Charles River Laboratories) were housed at 25°C with a 12-hour light / dark cycle and acclimatized for 1 week prior to the experiments. Water and normal rodent chow were available ad libitum.

[0087] LPS-induced inflammation and hyperglycemia

[0088] Endotoxin (LPS, from Escherichia coli, 0111:B4; Sigma-Aldrich) was used to produce a state of inflammation and metabolic dysfunction (e.g., hyperglycemia and hyperinsulinemia) in naive adult Sprague Dawley rats. Animals were administered LPS (10 mg / kg; Rosa-Ballinas PNAS, 2008) by intraperitoneal (IP) injection, resulting in a significant increase in TNF and circulating glucose concentrations that peaked at 4 hours post-injection but remained elevated (up to 8 hours post-injection) compared to controls. Neuromodulation was performed using applied ultrasound energy to the spleen, right adrenal gland, sacral ganglia, nodose ganglia, and / or nucleus tractus solitaries. Ultrasound was applied for 1 minute before and after LPS injection. Blood samples were collected 15 minutes after the last ultrasound treatment to analyze changes in circulating catecholamine concentrations (e.g., norepinephrine and dopamine). Terminal blood samples were collected 60 minutes after the last ultrasound treatment to analyze changes in circulating TNF concentrations. Blood samples were stored with the anticoagulant (disodium) EDTA to prevent sample clotting. Samples were analyzed for changes in TNF (Lifespan) and acetylcholine (Lifespan) concentrations by ELISA assays. Catecholamines (e.g., norepinephrine and dopamine) concentrations were evaluated using HPLC assays or ELISA (Rocky Mountain Diagnostic).

[0089] Ultrasound stimulation protocol:

[0090] (A) Animals were anesthetized with 2%-4% isoflurane.

[0091] (B) The animals were placed in a prone position on a water-circulating heating pad to prevent hyperthermia during the procedure.

[0092] (C) Prior to stimulation, the area over the targeted area of ​​interest (eg, nerve of interest) for ultrasound stimulation was shaved with a disposable razor and animal clippers.

[0093] (D) Diagnostic imaging Ultrasound is used to spatially select a region of interest.

[0094] (E) Mark the area with a permanent marker for later identification.

[0095] (F) Place the FUS ultrasound probe or LogiQ E9 probe at the designated area of ​​interest previously determined by diagnostic imaging ultrasound.

[0096] (G) Ultrasound pulses are then administered, with the total duration of individual stimuli not exceeding a single 1-minute pulse. The energy of the ultrasound pulses will not reach levels associated with thermal damage and ablation or cavitation (e.g., 35 W / cm 2 ).

[0097] (H) LPS (10 mg / kg, can then be injected intraperitoneally (for acute or kinetic studies); alternatively, LPS can be injected at subsequent designated time points during the efficacy period.

[0098] (I) A second 1-minute ultrasound pulse may be applied.

[0099] (J) The animals were then incubated under anesthesia for acute studies (e.g., 1 hour) and kinetic studies (e.g., changes up to a maximum of 3 hours after LPS). Afterwards, the animals were sacrificed and tissue and blood samples were collected.

[0100] Tissue collection and sample preparation

[0101] An incision was made starting at the bottom of the peritoneal cavity, extending upward and all the way to the pleural cavity. Organs were quickly removed and homogenized in a PBS solution containing phosphatase (0.2 mM phenylmethylsulfonyl fluoride, 5 μg / mL aprotinin, 1 mM benzamidine, 1 mM sodium orthovanadate and 2 μM cantharidin) and protease (1 μL-20 mg tissue, according to Roche Diagnostics) inhibitors. All samples were applied with a target final concentration of 0.2 g tissue / mL PBS solution. Blood samples were stored with the anticoagulant (disodium) EDTA to prevent sample clotting. The samples were then stored at -80°C until analysis. Changes in TNF (Lifespan / Abcam / ThermoFisher) and acetylcholine (Lifespan) concentrations in the samples were analyzed by ELISA assay. Catecholamine concentrations were evaluated using high performance liquid chromatography (HPLC) detection or enzyme-linked immunosorbent assay (ELISA) (Rocky Mountain Diagnostic) analysis.

[0102] HPLC analysis

[0103] Serum samples were injected directly into the HPLC without pretreatment. The tissue homogenate was first homogenized with 0.1 M perchloric acid and centrifuged for 15 minutes. The supernatant was then separated and the sample was injected into the HPLC.

[0104] Catecholamines (e.g., norepinephrine and dopamine) were analyzed by HPLC with an online UV detector. The test column used in this analysis was a Supelco Discovery C18 (15 cm×4.6 mm ID, particle size 5 μm). The biphasic mobile phase consisted of [A] acetonitrile: [B] 50 mM KH2PO4, with the pH set to 3 (with phosphoric acid). The solution was then buffered with 100 mg / L EDTA and 200 mg / L 1-octanesulfonic acid. The final concentration of the mobile phase mixture was set to 5:95 (A:B). A flow rate of 1 mL / min was used to improve overall peak resolution, while the column was maintained at a constant 20°C to minimize column pressure compaction due to the viscosity of the mobile phase used. The UV detector was maintained at 254 nm, a wavelength known to capture the absorption of catecholamines (e.g., norepinephrine and dopamine).

[0105] Figure 7 An experimental setup for performing certain neuromodulation experiments focused on a target ganglion 43 (e.g., comprising a peripheral nerve ganglion or a portion thereof) as provided herein is shown. The energy application device 12 can be operated according to parameters set by the controller 16 to apply energy to the area of ​​interest in the target ganglion 43. As discussed herein, the target tissue can include a peripheral nerve ganglion or a portion thereof, such as a sacral ganglion or a tuberous ganglion. Although the experimental setup shown is shown with a 40W RF amplifier, this is for illustration only and other amplifiers (e.g., a linear amplifier) ​​can be used. In some settings, the rat head is inserted into a birdcage coil.

[0106] Provided herein is an experimental timeline for the application of ultrasonic energy for performing certain conditioning experiments. Before and after lipopolysaccharide injection, ultrasound application is performed for one minute. Lipopolysaccharide (LPS) is a bacterial membrane molecule that can cause a strong immune or inflammatory response. LPS of Escherichia coli 0111: B4 (Sigma-Aldrich) is used to produce significant inflammation and metabolic dysfunction (e.g., hyperglycemia and insulin resistance) states in naive adult Sprague Dawley (SD) rats. LPS is administered to animals (10 mg / kg) by intraperitoneal (IP) injection, resulting in a significant increase in the concentration of TNF, glucose and insulin. These concentrations peak at 1 hour, usually lasting up to 4 hours, but remain elevated up to 8 hours after injection compared to the control. The control group includes LPS sham rats (e.g., rats injected with LPS, and an ultrasonic transducer is placed on the rat without applying ultrasonic stimulation). Animals are killed for a period of time (e.g., one hour) after the ganglion or nucleus is ultrasonicated for organ collection and processing.

[0107] This example demonstrates a non-invasive method for stimulating specific axonal projections (directed to non-neuronal cells and / or other neurons) of neurons in specific peripheral nerve ganglia using ultrasonic energy application, thereby achieving stimulation and related physiological outcomes. For example, application of energy to synapses within specific peripheral nerve ganglia can modulate (1) neuroimmune or anti-inflammatory pathways, (2) dopamine production pathways, (3) glucose regulation or insulin production pathways, and / or (4) cognitive processing and plasticity.

[0108] The response of CAP to local ultrasound stimulation was monitored by measuring the blood concentrations of CAP-related neurotransmitters and cytokines including norepinephrine (NE), acetylcholine (ACh), and tumor necrosis factor (TNF). Ultrasonic stimulation of the sacral ganglia and the tuberous ganglia was found to be able to regulate NE and TNF concentrations in the blood. This result is similar to or related to ultrasound stimulation of the spleen and axons associated with the CAP pathway that regulates NE and TNF concentrations. In addition, it was found that ultrasound stimulation of the sacral ganglia and the tuberous ganglia was able to achieve regulation of dopamine concentrations in the blood. This result is similar to or related to ultrasound stimulation of the right adrenal gland and axons associated with dopamine production. In addition, ultrasound stimulation of the tuberous ganglia was shown to be able to adjust the sensory pathways that regulate blood glucose circulation. Overall, the data indicate that ultrasound neuromodulation within peripheral nerve ganglia can provide a precise neuromodulation method, thereby facilitating the stimulation of a subset of neurons within peripheral nerve ganglia to affect specific physiological pathways (e.g., regulating neuroimmune pathways, anti-inflammatory pathways, dopamine production pathways, and / or glucose regulation or insulin production pathways). Specifically, ultrasound stimulation focused on a subset of axons and synapses within the sacral ganglion can affect systemic inflammation (e.g., reduce systemic inflammation) through neuroimmune pathways or anti-inflammatory pathways and / or can affect systemic inflammation (e.g., reduce systemic inflammation) by producing dopamine in the right adrenal gland. In addition, ultrasound stimulation focused on a subset of axons and synapses within the tuberous ganglion can affect systemic inflammation (e.g., reduce systemic inflammation) through neuroimmune or anti-inflammatory pathways, can affect systemic inflammation (e.g., reduce systemic inflammation) by producing dopamine in the right adrenal gland, and / or can maintain glucose homeostasis.

[0109] Figure 8A-8D Shown are the mean concentrations of various neurotransmitters and cytokines relative to control after ultrasound stimulation of the spleen, right adrenal gland, sacral ganglia, nodose ganglia, or nucleus tractus solitarius. Fig. 8A Shown are mean TNF concentrations (and standard deviation) in blood following sonication of the disclosed targeted regions of interest. Figure 8B Shown are mean acetylcholine concentrations (and standard deviation) in blood following sonication of the disclosed targeted regions of interest. Figure 8CShown are mean NE concentrations (and standard deviations) in blood following sonication of the disclosed targeted regions of interest. Fig.8D Shown are the mean DA concentrations (and standard deviations) in the blood following sonication of the disclosed targeted regions of interest. Fig. 8A As shown in , ultrasound stimulation of the sacral and nodose ganglia produced results similar to ultrasound stimulation of the spleen and axons associated with the CAP pathway, reducing TNF concentrations relative to controls. Figure 8B and Figure 8C As shown in Figure 2, due to ultrasound stimulation of the spleen, sacral ganglia, and nodose ganglia, the concentration of NE in the blood increased, leading to an increase in the concentration of acetylcholine in the blood. Fig.8D As shown in , the results produced by ultrasonic stimulation of the sacral ganglia are similar to those of ultrasonic stimulation of the right adrenal gland and axons associated with dopamine production. Therefore, ultrasonic regulation within a peripheral nerve ganglion (e.g., a sacral ganglion or a nodular ganglion) can affect one or more specific physiological pathways (e.g., regulating neuroimmune pathways, anti-inflammatory pathways, dopamine production pathways, glucose regulation pathways, and / or insulin production pathways) based on the stimulation of a specific peripheral nerve ganglion. Specifically, ultrasonic regulation within the nodular ganglion can regulate neuroimmune pathways or anti-inflammatory pathways, such as CAP, as well as glucose regulation and / or insulin production pathways. In addition, ultrasonic regulation within the sacral ganglion can regulate neuroimmune pathways or anti-inflammatory pathways, such as CAP, as well as dopamine production pathways.

[0110] Fig. 9 Non-limiting examples are provided for preferentially applying ultrasound stimulation to various regions of an LPS-induced hyperglycemia animal model to achieve targeted regulation of blood glucose concentration. Fig. 9 The graph shows the relative blood glucose concentration at time points 10, 15, 30, and 60 minutes after LPS injection compared to the blood glucose concentration at the time point 0 minutes before LPS injection. LPS-induced hyperglycemia was observed in the group that received only LPS injection without ultrasound stimulation. Although there were no significant differences in circulating glucose concentrations relative to controls after ultrasound stimulation of the right adrenal gland, sacral ganglia (e.g., sacral dorsal root ganglia, and spatially selected by targeting the sacral plexus), and NTS, circulating glucose concentrations were significantly reduced relative to controls after ultrasound stimulation of the nodose ganglion. Therefore, ultrasound stimulation preferentially applied to the nodose ganglion was used to reverse LPS-induced hyperglycemia and regulate blood glucose concentrations. Therefore, ultrasound neuromodulation within the nodose ganglion affects glucose regulation and / or insulin production pathways. As shown Fig. 9 As shown in the embodiments of the present invention, applying ultrasound stimulation to the nodose ganglion provides protection against LPS-induced hyperglycemia in the model and limits and / or controls the increase in blood glucose concentration. Therefore, applying ultrasound energy to the nodose ganglion can be used as a protective treatment, or as a treatment applied prior to an anticipated systemic challenge or interruption.

[0111] Fig.10 Provided is a non-limiting example of preferentially ultrasonically stimulating the liver of an LPS-induced hyperglycemia animal model to achieve targeted regulation of blood glucose concentration. The graph of Figure 12 shows the relative blood glucose concentration at the time points of 5, 15, 30 and 60 minutes after LPS injection. In the group that only received LPS injection without ultrasonic stimulation, LPS-induced hyperglycemia was observed. The data further show that ultrasonic stimulation of the distal lobe of the liver does not significantly affect blood glucose concentration. Relatively speaking, preferentially applying ultrasonic stimulation on the porta hepatis can be used to reverse LPS-induced hyperglycemia and regulate blood glucose concentration.

[0112] The disclosed technology provided herein utilizes the natural layered structure and organization of the nervous system, allowing precise neuromodulation by simple non-invasive techniques. For example, applying energy to a peripheral nerve ganglion can use a single stimulation point to regulate one or more of the following: (1) a neuroimmune pathway or an anti-inflammatory pathway, (2) a dopamine production pathway and / or (3) a glucose regulation or insulin production pathway. Therefore, stimulation of a peripheral nerve ganglion or a portion thereof can regulate one disclosed pathway, two disclosed pathways, or three disclosed pathways based on the stimulated specific peripheral nerve ganglion. Although verified for the disclosed neural pathways, the technology can be applied to regulate other peripheral nerve circuits. In addition, relative to organs and tissues located deeper under the skin, less energy can be applied to the peripheral nerve ganglion in general to achieve the desired physiological results. Therefore, energy applied to the peripheral nerve ganglion can be provided using a lower power system or a wearable energy application system.

[0113] This written description uses embodiments to disclose the present disclosure, including the best mode, and also enables any person skilled in the art to practice the present disclosure, including making and using any device or system and performing any introduced method. The patentable scope of the present disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be included within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Claims

1. A system comprising: an energy application device configured to apply mechanical energy or ultrasonic energy to an area of ​​interest of a subject to modulate one or more neural pathways; Controller; and an assessment device configured to assess a physiological characteristic and connected to the controller to provide a feedback signal, Wherein, the controller is constructed as follows: spatially selecting the region of interest; controlling one or more regulatory parameters of the energy application device; and changing the one or more adjustment parameters based on a feedback signal from the evaluation device, Wherein the region of interest includes at least a portion of a peripheral nerve ganglion.

2. The system of claim 1 further comprising a pulse generator connected to the energy application device.

3. The system of claim 2, wherein the pulse generator communicates with the controller wirelessly or by wire.

4. The system of claim 3, wherein the pulse generator is integrated with the controller.

5. The system of claim 1, wherein the peripheral nerve ganglia include nodose ganglia and sacral ganglia.

6. The system of claim 2, wherein the controller further comprises a memory including instructions for selectable operating modes of the system.

7. The system of claim 1, wherein the characteristic comprises the concentration of one or more molecules, blood flow rate, size or location of an anatomical feature, a measure of neural activity, the composition or concentration of cellular lipids, or a mechanical property of a tissue.

8. The system of claim 1, wherein the one or more adjustment parameters include pulse time, site of energy application, pulse frequency, pulse width, pulse amplitude, signal on time, signal off time, frequency of applied stimulation, or duration of applied stimulation.

9. The system of claim 1, further comprising an imaging device.

10. The system of claim 9, wherein the imaging device is integrated with or identical to the energy application device.

11. A system according to claim 9, wherein the energy application device is configured to operate in a targeting mode to capture image data, and the energy application device is further configured to operate in a processing mode, the processing mode having adjustment parameters different from the adjustment parameters used in the targeting mode.

12. The system of claim 1, wherein the energy application device comprises an ultrasonic transducer.

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