Neuromodulation catheter including ultrasound transceivers

Abstract

A neuromodulation catheter includes an elongate body configured to transform from a relatively low profile configuration to an expanded configuration, a therapy delivery element, and a sensor array. The sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration. Control circuitry is configured to cause at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal, and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal. The control circuitry may assess efficacy of nerve ablation by monitoring blood flow (e.g., indicative of a sympathetic nerve response in response to a stimulation) based on a travel time of the at least one ultrasound signal across the blood flow.

Description

NEUROMODULATION CATHETER INCLUDING ULTRASOUND TRANSCEIVERSCROSS-REFERENCE TO RELATED APPLICATION S)

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 676,086, filed July 26, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure generally relates to neuromodulation.BACKGROUND

[0003] A denervation procedure may include ablating target nerves, for example, by delivering ablative energy to a target site via a catheter. For example, renal denervation may include ablating renal nerves.SUMMARY

[0004] The present disclosure describes neuromodulation catheters a therapy delivery element and a sensor array including ultrasound transceivers, systems including the neuromodulation catheters, and related methods.

[0005] Neuromodulation catheters may be used to deliver neuromodulation therapy, for example, by delivering energy (e.g., electrical and / or thermal energy) or a chemical agent to ablate a nerve. The energy or stimulus may include, for example, at least one of a radio frequency (RF) stimulus, a thermal stimulus, a cryogenic stimulus, a microwave stimulus, an ultrasonic stimulus, or other form of energy or stimulus. In some examples, a neuromodulation catheter includes a distal portion configured to transform from a relatively low-profile configuration to a deployed configuration (e.g., an expanded configuration). In the deployed configuration, the distal portion may define a loop, a helical configuration, a spiral configuration, a multi-finger configuration, a basket, a stent-like configuration, or a balloon. One or more therapy delivery elements are disposed on the catheter, such as on the distal portion.

[0006] In some examples, devices, systems, and techniques according to the present disclosure deliver ablative energy using one or more therapy delivery elements, and measure blood flow using a sensor array including ultrasound transceivers. For example, ablation of a nerve may affect an extent of a sympathetic nerve response to electrical stimulation (e.g.,delivered by a stimulation element or by the therapy delivery element itself), and the sensor array is configured to sense a parameter that changes as a function of sympathetic nerve response of the blood vessel. Ultrasound transceivers may be used to determine blood flow, for example, indicative of a sympathetic nerve response of the blood vessel in response to the stimulation (e.g., electrical stimulation delivered in an attempt to generate a response from nerves). Thus, a neuromodulation system may assess efficacy of nerve ablation at a target site by monitoring blood flow (e.g., renal or hepatic blood flow) during and / or after delivery of stimulation to the target site based on a travel time of ultrasound signals across the blood flow. The efficacy of nerve ablation is related to an extent of or proportion of all nerves captured by the stimulation that are ablated. For example, the efficacy of nerve ablation may be indicative of an impact of the neuromodulation therapy on sympathetic tone.

[0007] In some examples, a neuromodulation catheter includes an elongate body configured to transform from a relatively low profile configuration to an expanded configuration. The neuromodulation catheter may further include a therapy delivery element disposed on the elongate body. The neuromodulation catheter may further include a sensor array disposed on the elongate body. The sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration.

[0008] In some examples, a neuromodulation system includes a neuromodulation catheter and control circuitry. The neuromodulation catheter includes an elongate body configured to transform from a relatively low profile configuration to an expanded configuration. The neuromodulation catheter may further include a therapy delivery element disposed on the elongate body. The neuromodulation catheter may further include a sensor array disposed on the elongate body. The sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration. The control circuitry is configured to cause at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal.

[0009] In some examples, a method includes introducing a neuromodulation catheter in a blood vessel. The neuromodulation catheter includes an elongate body configured to transform from a relatively low profile configuration to an expanded configuration. The neuromodulation catheter may further include a therapy delivery element disposed on theelongate body. The neuromodulation catheter may further include a sensor array disposed on the elongate body. The sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration. The method may further include causing, by control circuitry, at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal.

[0010] Further disclosed herein is a neuromodulation catheter that includes an elongate body configured to transform from a relatively low profile configuration to an expanded configuration, a therapy delivery element, and a sensor array, wherein the sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration, wherein a control circuitry is configured to cause at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal, and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal, and wherein the control circuitry may assess efficacy of nerve ablation by monitoring blood flow (e.g., indicative of a sympathetic nerve response in response to a stimulation) based on a travel time of the at least one ultrasound signal across the blood flow.

[0011] The details of one or more examples of the techniques of this disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF DRAWINGS

[0012] FIG. 1 A is a diagram illustrating an example system including a catheter configured to deliver neuromodulation therapy, a computing device, and a medical device.

[0013] FIG. IB is a diagram illustrating a partial side view of the catheter of FIG. 1 A in an expanded configuration in a blood vessel.

[0014] FIG. 1C is a diagram illustrating a partial front view of the catheter of FIG. 1 A in an expanded configuration in the blood vessel.

[0015] FIG. 2 is a diagram illustrating a partial cross-sectional view showing a pair of ultrasound transducers of the catheter in the expanded configuration of FIGS. IB and 1C in a blood vessel.

[0016] FIG. 3 is a timing diagram illustrating an example scheme for delivering neuromodulation therapy and electrical stimulation.

[0017] FIG. 4 is a block diagram illustrating an example configuration of the computing device of FIG. 1.

[0018] FIG. 5 is a flow diagram illustrating an example technique for monitoring neuromodulation therapy based on one or more blood flow characteristics determined using ultrasound sensors.

[0019] FIG. 6 illustrates an example technique for accessing a renal artery and modulating renal nerves with a neuromodulation catheter in accordance with some examples of the present disclosure.

[0020] FIG. 7 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS.

[0021] FIG. 8 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery.

[0022] FIG. 9 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys.

[0023] FIG. 10 is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys.

[0024] FIG. 11 is an anatomic view of the arterial vasculature of a human.

[0025] FIG. 12 is an anatomic view of the venous vasculature of a human.DETAILED DESCRIPTION

[0026] The present disclosure describes neuromodulation catheters including a therapy delivery element (e.g., configured to deliver neuromodulation therapy) and a sensor array (e.g., configured to detect a parameter indicative of nerve activity), as well as systems including the neuromodulation catheters and related methods. In examples herein, neuromodulation, such as renal or hepatic denervation, may be accomplished using one or more of a variety of treatment modalities, including one or more of radio frequency (RF) energy, microwave energy, ultrasound energy, heat, cryogenic cooling, a chemical agent, or the like. To perform intravascular neuromodulation, a clinician may deliver a neuromodulation catheter to a blood vessel, such as a renal artery or a hepatic artery, of apatient. The neuromodulation catheter includes one or more therapy delivery elements configured to deliver neuromodulation therapy to tissue of the patient. In some examples, the neuromodulation catheter is configured to position the one or more therapy delivery elements in apposition to the vessel wall to transfer energy (e.g., RF energy, heat, cooling, or the like) to or from tissue surrounding the vessel wall.

[0027] The present disclosure describes neuromodulation catheters including a therapy delivery element (e.g., configured to deliver neuromodulation therapy) and a sensor array (e.g., configured to detect a parameter indicative of nerve activity), as well as systems including the neuromodulation catheters and related methods. In examples herein, neuromodulation, such as renal or hepatic denervation, may be accomplished using one or more of a variety of treatment modalities, including one or more of radio frequency (RF) energy, microwave energy, ultrasound energy, heat, cryogenic cooling, a chemical agent, or the like. To perform intravascular neuromodulation, a clinician may deliver a neuromodulation catheter to a blood vessel, such as a renal artery or a hepatic artery, of a patient. The neuromodulation catheter includes one or more therapy delivery elements configured to deliver neuromodulation therapy to tissue of the patient. In some examples, the neuromodulation catheter is configured to position the one or more therapy delivery elements in apposition to the vessel wall to transfer energy (e.g., RF energy, heat, cooling, or the like) to or from tissue surrounding the vessel wall.

[0028] As used herein, the terms “distal” and “proximal” define a position or direction with respect to the treating clinician or clinician’s control device (e.g., a handle assembly). “Distal” or “distally” can refer to a position distant from or in a direction away from the clinician or clinician’s control device. “Proximal” and “proximally” can refer to a position near or in a direction towards the clinician or clinician’s control device.

[0029] The present disclosure relates to a neuromodulation system configured to assesses efficacy of neuromodulation therapy (e.g., extent of nerve ablation) based on one or more characteristics of blood flow (e.g., renal or hepatic blood flow or other blood flow depending on the target nerves and blood vessel in which the neuromodulation catheter is positioned) during and / or after stimulation (e.g., electrical stimulation delivered by a stimulation element). The efficacy of neuromodulation therapy is related to an extent of or proportion of all nerves captured by the stimulation that are modulated (e.g., ablated) by the therapy. In some examples, the neuromodulation system is configured to deliver stimulation (e.g., via a therapy delivery element or a separate stimulation element of the neuromodulation catheter, or from another device) to a target site before and after delivery of neuromodulation therapy.The response to the stimulation may be sensed to determine whether neuromodulation of nerves in the target site was achieved. For example, ablation of one or more nerves may affect an extent of a sympathetic nerve response to the stimulation.

[0030] If the nerves are sufficiently ablated, then the target site may exhibit a reduced sympathetic nerve response to the stimulation. For example, the sympathetic nerve response may include a sympathetic tone, blood pressure (systolic, diastolic, mean arterial pressure), heart rate, blood flow, vascular resistance, or vasoconstriction, or combinations thereof. In some examples, a sympathetic tone is reduced or blunted by neuromodulation therapy, which may cause an increase in blood flow. In some examples, a flow response or a change in flow is indicative of an impact of the neuromodulation therapy on sympathetic tone, and thus, indicative of an efficacy of the neuromodulation therapy. In some examples, a reduced vasoconstriction response is a lower vasoconstriction response relative to a baseline and / or a previously determined vasoconstriction response of the patient or a population of patients, and / or no vasoconstriction response. Thus, the neuromodulation system can monitor blood flow (e.g., a blood flow rate) in a blood vessel to determine efficacy of neuromodulation therapy. The neuromodulation system may monitor blood flow at any appropriate stage, for example, before any neuromodulation therapy is delivered, after neuromodulation therapy is delivered, and / or during delivery of neuromodulation therapy. In some examples, the neuromodulation system is configured to monitor blood flow rate before any neuromodulation therapy is delivered, and determine, based on the blood flow rate, determine whether neuromodulation therapy is to be delivered and / or parameters of the neuromodulation therapy.

[0031] In examples described herein, the system determines a blood flow rate of blood flowing through a vessel based on signals sensed by ultrasound transceivers, the blood flow rate being indicative of the sympathetic nerve response of the blood vessel in response to the stimulation (e.g., electrical stimulation delivered in an attempt to elicit a response from nerves). In some examples, a first ultrasound transceiver is configured to emit an ultrasound signal toward a second ultrasound transceiver, and control circuitry is configured to determine a travel time of the ultrasound signal from the first ultrasound transceiver to the second ultrasound transceiver. The control circuitry may be configured to determine a present blood flow rate of blood flowing through the blood vessel based on a correlation between travel time and blood flow rate.

[0032] In some examples, a neuromodulation catheter includes an elongate body and a distal portion of the elongate body (e.g., referred to herein as an elongate body distal portion or a distal catheter portion) is configured to transform from a relatively low profileconfiguration to a deployed configuration in which the distal catheter portion is in a radially expanded state relative to the relatively low profile configuration. For example, in some examples, the distal catheter portion can define a loop, a helical configuration, a spiral configuration, a multi-finger configuration, a basket, a stent-like shape, or a balloon when in the deployed configuration. The distal catheter portion includes a therapy delivery element disposed on the elongate body. The therapy delivery element is configured to deliver neuromodulation therapy to one or more target nerves of a patient, e.g., electrically induced (e.g., radiofrequency), ultrasound induced, chemically induced, or thermally induced ablation therapy. As noted above, in some examples, in addition to a therapy delivery element configured to deliver neuromodulation therapy, in some examples, the neuromodulation catheter further includes an electrode or another suitable stimulation element configured to deliver electrical stimulation. In other examples, the therapy delivery element can be used to deliver both the neuromodulation therapy and the electrical stimulation. In some examples, the distal catheter portion includes a plurality of therapy delivery elements.

[0033] The neuromodulation catheter further includes a sensor array configured to sense a parameter that changes as a function of sympathetic nerve activity of the blood vessel. For example, the sensor array may be positioned along the elongate body. The sensor array is configured to sense a physiological response to the stimulation, for example, changes in blood flow indicative of sympathetic nerve activity. The catheter is configured such that when it is deployed in a blood vessel, the sensor array is arranged within a lumen of the blood vessel and configured to sense blood flow through the blood vessel.

[0034] The sensor array includes at least one pair of sensors offset from each other (e.g., one or more of longitudinally, transversely, radially, or circumferentially offset) when the elongate body is in the deployed configuration. In some examples, the at least one pair of sensors is longitudinally and transversely offset from each other when the elongate body is in the deployed configuration. A first sensor of the at least one pair of sensors is configured to generate an ultrasound signal toward a second sensor of the at least one pair of sensors (e.g., a sensor across the vessel in a direction transverse across a direction of blood flow and / or to a longitudinal axis of the vessel), and receive an ultrasound signal generated by the second sensor. The travel time or delay between sending and receiving an ultrasound signal (e.g., a pulse) between pairs of sensors varies with speed of fluid (e.g., blood in the blood vessel) flowing between the sensors. Thus, a correlation between flow rate and the travel time may be used to determine blood flow rate. The blood flow rate may be determined at any one or more times, including before neuromodulation therapy (e.g., ablation), after neuromodulationtherapy, and before, during, or after stimulation. For example, the blood flow rate may be determined based on the correlation between flow rate and the travel time without using a Doppler effect or Doppler measurements.

[0035] In some examples, control circuitry of a neuromodulation system causes the first ultrasound transceiver to send a first ultrasound signal to the second ultrasound transceiver, and the second ultrasound transceiver to send a second ultrasound signal to the first ultrasound transceiver. The control circuitry may combine (e.g., average) blood flow measurements using the first ultrasound signal and the second ultrasound signal, for example, to compensate for variations in measurement directions along the blood flow and opposite the blood flow. In some examples, the sensor array includes at least one pair of sensors. In other examples, the sensor array includes additional sensor pairs for redundancy and / or additional accuracy, for example, further sensing with ultrasound sensors or other types of sensors for additional measurements of blood flow rate.

[0036] The blood flow rate may be substantially constant, or may exhibit acceleration or deceleration in response to cardiac cycles (e.g., pulsatile blood flow). In some examples, the control circuitry may determine a stage of a cardiac cycle, e.g., based on a sensed cardiac signal, based on the blood flow rate over a period of time, for example, by determining an acceleration, deceleration, constancy, or periodicity in the blood flow rate over the period of time. In some examples, the control circuitry may recreate a cardiac cycle waveform, and / or determine analytic features (e.g., integral or derivative features) of the cardiac cycle waveform. In some examples, the control circuitry may determine an increasing slope in a blood flow rate (e.g., based on a difference between timing of first ultrasound signal and second ultrasound signal) and determine a forward flow based on the increasing slope. In some examples, the control circuitry may determine blood flow rate associated with the increasing slope (e.g., based on one or both of the first ultrasound signal or the second ultrasound signal). In some examples, the control circuitry may implement an artificial intelligence or machine learning model to determine blood flow characteristics based on blood flow rate data (e.g., using training data based on a relation between blood flow rate and one or more of a timing of first ultrasound signal, a second ultrasound signal, an angle between the first ultrasound transducer and the second ultrasound transducer, or a separation or direct distance between the first ultrasound transducer and the second ultrasound transducer). In some examples, the control circuitry may use artificial intelligence or the machine learning model to extract features associated with sympathetic nerve activity, blood flow, or vasoconstriction, based on a plurality of blood flow rates and / or timing differencesbetween the first ultrasound signal and the second ultrasound signal over a period of time. For example, the control circuitry may determine a stage of a cardiac cycle, recreate the cardiac cycle or an analytic feature of the cardiac cycle, or a parameter associated with an extent of sympathetic nerve activity that accounts for the cardiac cycle.

[0037] Determining efficacy of neuromodulation therapy before, during, or shortly after the neuromodulation therapy may facilitate appropriate action in response to the efficacy determination. For example, neuromodulation therapy may be started, stopped, paused, or adjusted, based on the determined efficacy, while the patient is present at a location at which neuromodulation therapy is delivered and / or in course of the neuromodulation therapy. In this way, a clinician may assess efficacy of the neuromodulation therapy without a relatively long delay (e.g., days, weeks, or months) and take appropriate action, without requiring the patient to return to the location after an initial neuromodulation therapy to perform further neuromodulation therapy. For example, if the efficacy indicates that sufficient neuromodulation (e.g., ablation) was not achieved by an initial neuromodulation therapy, further neuromodulation therapy may be delivered, or some other action may be taken, to improve the efficacy of neuromodulation for the patient.

[0038] While blood flow response to neuromodulation can be determined via alternative modes such as angiograms, angiograms may be time consuming, and require additional equipment or intervention, such as use of contrast. Catheters, systems, and methods according to the present disclosure may provide quicker and more direct sensing compared to angiograms, and may not need additional equipment (e.g., in addition to the neuromodulation catheter) to assess efficacy of neuromodulation therapy. For example, ultrasound transceivers used to determine blood flow rate (and thus, a sympathetic nerve response to stimulation) may be disposed in a neuromodulation catheter used to deliver neuromodulation therapy, instead of using additional equipment.

[0039] FIG. 1 A is a diagram illustrating an example system 10 including a catheter 12 configured to deliver neuromodulation therapy, a computing device 14, and a medical device 16. In FIG. 1 A, catheter 12 is in a relatively low profile configuration. FIG. IB is a diagram illustrating a partial side view of catheter 12 of FIG. 1 A in an expanded configuration 12A in a blood vessel 34. FIG. 1C is a diagram illustrating a partial front view of the catheter of FIG. 1 A in an expanded configuration in blood vessel 34. Catheter 12 is also referred to as a neuromodulation catheter 12. Computing device 14 may be configured to send a control signal to medical device 16 or otherwise control the operation of one or both of catheter 12 or medical device 16. In some examples, system 10 does not include computing device 14, andmedical device 16 may be configured to perform functions described with respect to computing device 10. In some examples, the control signal sent by computing device 14 to medical device 16 is configured to cause medical device 16 to, based on the control signal received from computing device 14, generate an electrical signal. Medical device 16 may generate the electrical signal sent to catheter 12 to cause catheter 12 to deliver neuromodulation therapy. For example, the neuromodulation therapy may include renal neuromodulation, hepatic neuromodulation, or any other neuromodulation therapy.

[0040] Medical device 16 is configured to delivery neuromodulation therapy to one or more target nerves of a patient via one or more therapy delivery elements of catheter 14. In some examples, the neuromodulation therapy comprises an ablation signal (e.g., RF energy) configured to be delivered by one or more electrodes of catheter 12. For example, medical device 16 may include a control circuitry 40 and a therapy generation circuitry 42, and control circuitry 40 may be configured to control therapy generation circuitry 42 to generate the ablation signal. Medical device 16 may also include stimulation generation circuitry 44, and control circuitry 40 may be further configured to control stimulation generation circuitry 44 to generate a stimulation signal to determine an extent of denervation.

[0041] Catheter 12 includes a handle 18 and a catheter body 20 attached to handle 18. That is, handle 18 is positioned at a proximal portion of catheter body 20. Catheter body 20 may have any suitable outer diameter, and the diameter can be constant along the length of catheter body 20 or may vary along the length of catheter body 20. In some examples, catheter body 20 may be 2, 3, 4, 5, 6, or 7 French or another suitable size. Catheter body 20 extends along a central longitudinal axis L, and includes a distal catheter portion 20A and a proximal catheter portion 20B. Distal catheter portion 20A includes an expandable portion 22.

[0042] Expandable portion 22 is configured to transform from a relatively low-profile configuration (shown in FIG. 1 A) to a radially expanded deployed configuration 22 A (shown in FIGS. IB and 1C). Expandable portion 22 includes an elongate body 24. In some examples, elongate body 24 extends in a direction along a longitudinal axis L of catheter 12. Elongate body 24 is configured to expand from a respective relatively low-profile configuration (shown in FIG. 1 A) to an expanded configuration 24A (shown in FIGS. IB and 1C), such as a spiral, loop, multi -finger, or helical configuration, or a basket, a stent-like shape, or a balloon. In some examples, elongate body 24 includes a helical hollow strand configured to expand from a relatively low-profile configuration into an expanded helical configuration. The helical hollow strand may include a plurality of shape memory filars, theplurality collectively defining a lumen, the lumen being helical (or another suitable shape, such a loop, a spiral shape, a multi-finger configuration, a basket, a stent-like shape, or a balloon) in an expanded configuration.

[0043] Catheter 12 further includes a therapy delivery element 26 disposed on elongate body 24. Therapy delivery element 26 is configured to deliver neuromodulation therapy. For example, therapy delivery element 26 may include one or more of an electrode, a thermal probe, a cryogenic probe, a microwave transducer, an ultrasound transducer, or a chemical denervation agent source. In some examples, therapy delivery element 26 includes at least one electrode configured to deliver an ablation signal (e.g., RF energy, microwave energy, or the like). Therapy delivery element 26 may be coupled to a thermocouple. For example, control circuitry 40 may be configured to determine a respective temperature of therapy delivery element 26 via the thermocouple. In some examples, control circuitry 40 may be configured to terminate ablation therapy in response to a temperature sensed by the thermocouple, for example, to avoid excessive heating of catheter 12 or neighboring tissue.

[0044] In some examples, catheter 12 includes a plurality of therapy delivery elements disposed on the elongate body, the plurality of therapy delivery elements including therapy delivery element 26. Although FIG. 1 A illustrates four therapy delivery elements 26, in other examples, catheter 12 may include one, two, three, five, or more therapy delivery elements. In examples in which catheter 12 includes a plurality of therapy delivery elements 26, each therapy delivery element of the plurality of therapy delivery elements 26 may be identical, or differ in one or more of shape, size, spacing, orientation, or composition. For example, each therapy delivery element of the plurality of therapy delivery elements 26 may have a same length along longitudinal axis L of elongate body 24. In some such examples, each therapy delivery element of the plurality of therapy delivery elements 26 is identical in shape, size, form, and composition.

[0045] System 10 is further configured to deliver a stimulation signal. For example, catheter 12, or another component or device of system 10, or some other system may include at least one stimulation element configured to deliver an electric stimulation signal to tissue of a patient. In some examples, catheter 12 includes a stimulation element 28 disposed on elongate body 24. For example, stimulation element 28 may include at least one electrode configured to deliver an electrical stimulation signal. In some examples, therapy delivery element 26 may be configured to deliver the stimulation signal. Thus, in some such examples, catheter 12 may not include stimulation element 28. Control circuitry 40 may be configured to generate the ablation signal configured to be delivered by therapy deliveryelement 28, and generate the stimulation signal configured to be delivered by system 10 (e.g., by stimulation element 28). The stimulation signal is configured to stimulate nerves that may be present at the target site, for example, without causing denervation (e.g., ablation) at the target site. For example, the stimulation signal may include an electrical component (e.g., a DC component or an AC component) configured to elicit a response from the nerves.

[0046] Depending on the frequency components of the ablation signal or the stimulation signal, therapy generation circuitry 42 or stimulation generation circuitry 44 may include one or both of an alternating current (AC) generator or a direct current (DC) generator. In some examples, stimulation generation circuitry 44 includes circuitry configured to rectify an AC signal to generate a DC signal. For example, stimulation generation circuitry 44 may generate the stimulation signal including solely the DC signal. In other examples, one or both of the ablation signal or the stimulation signal may include an AC signal and a DC signal, but differ in the frequency band of the AC signal, or the amplitude of the DC signal. For example, the ablation signal may have a significantly higher frequency than the stimulation signal.

[0047] In examples in which one or both of therapy delivery element 26 or stimulation element 28 includes at least one electrode, the respective electrodes of therapy delivery element 26 or stimulation element 28 may have any suitable shape, size, or form. In some examples, at least one electrode of therapy delivery element 26 or stimulation element 28 is a ring electrode.

[0048] In some examples, at least one electrode of therapy delivery element 26 or stimulation element 28 includes gold, iridium oxide, or platinum iridium alloy.

[0049] Catheter 12 may be connected to medical device 16, for example, via wiring or any suitable electrical connection or coupling, e.g., via at least one electrical conductor and / or at least one lumen defined by handle 18 and catheter body 20.

[0050] Control circuitry 40, as well as other processors, processing circuitry, controllers, control circuitry, and the like, described herein, may include any combination of integrated circuitry, discrete logic circuity, analog circuitry, such as one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), or field- programmable gate arrays (FPGAs). In some examples, control circuitry 40 includes multiple components, such as any combination of one or more microprocessors, one or more DSPs, one or more ASICs, or one or more FPGAs, as well as other discrete or integrated logic circuitry, and / or analog circuitry.

[0051] Control circuitry 40 may be communicatively coupled to a memory that may store program instructions, such as software, which may include one or more program modules,which are executable by control circuitry 40. When executed by control circuitry 40, such program instructions may cause control circuitry 40 and medical device 16 to provide the functionality ascribed to control circuitry 40 and medical device 16 herein. The program instructions may be embodied in software and / or firmware. The memory, as well as other memories described herein, may include any volatile, non-volatile, magnetic, optical, or electrical media, such as a random access memory (RAM), read-only memory (ROM), nonvolatile RAM (NVRAM), electrically-erasable programmable ROM (EEPROM), flash memory, or any other digital media. Control circuitry 40 and the memory may be in a common housing, or be physically separate from each other.

[0052] Therapy generation circuitry 42 is configured to generate and deliver therapy to tissue of a patient via therapy delivery element 26 (e.g., via at least one electrode of therapy delivery element 26) for example, to modulate a target nerve of the patient. For example, therapy delivery element 26 may be coupled to therapy generation circuitry 42, and therapy generation circuitry 42 may deliver an ablation signal to tissue, or to a target site via therapy delivery element 26. Catheter 12 may thus deliver denervation therapy via therapy delivery element 26, and computing device 14 or control circuitry 40 may control catheter 12 to deliver denervation therapy.

[0053] Stimulation generation circuitry 44 is configured to deliver a stimulation signal via therapy delivery element, and / or via stimulation element 28 (e.g., via at least one electrode of stimulation element 28, another stimulation element of catheter 12, another component of system 10, or via some other device or system), for example, to assess efficacy of neuromodulation therapy. For example, a change in physiological response of the patient to stimulation before and after ablation may be indicative of an effect of neuromodulation therapy on nerve activity. In some examples, stimulation generation circuitry 44 is configured to deliver a monopolar stimulation signal using therapy delivery element 26 or stimulation element 28, such that electrical current flows from stimulation element 28 to a large dispersive electrode (e.g., a ground pad) external to catheter 12. In other examples, stimulation generation circuitry 42 is configured to deliver a bipolar stimulation signal using at least one pair of therapy delivery elements 26, at least one pair of stimulation elements 28, or at least one pair of one therapy delivery element 26 and one stimulation element 28, such that electrical current flows between the respective pair. Catheter 12 may thus deliver denervation therapy via therapy delivery element 26, deliver a stimulation signal via therapy delivery element 26 or stimulation element 28 (or some other element, device, or system), andcomputing device 14 or control circuitry 40 may control catheter 12 to deliver and assess denervation therapy.

[0054] Catheter 12 further includes a sensor array 30 disposed on elongate body 24. Sensor array 30 is configured to detect a response to the denervation therapy and / or the stimulation signal. For example, sensor array 30 may be configured to detect at least one physiological response or parameter. In some examples, sensor array 30 is configured to detect sympathetic nerve activity, (e.g., a parameter that changes as a function of sympathetic nerve activity), vasoconstriction (e.g., a parameter that changes as a function of vasoconstriction), at least one hemodynamic parameter, and / or a blood flow rate. In some examples, sensor array 30 is configured to ultrasonically detect the blood flow rate, for example, by sensing an ultrasound signal transmitted across blood flow in blood vessel 34.

[0055] Sensor array 30 may be arranged in any suitable orientation, spacing, or geometric configuration relative to therapy delivery element 26, or a plurality of therapy delivery elements 26, along elongate body 24. In some examples, sensor array 30 is longitudinally and / or circumferentially offset relative to plurality of therapy delivery elements 26 along elongate body 24 in expanded configuration 24A. In some examples, sensor array 30 is spaced from plurality of therapy delivery elements 26 along elongate body 24. In other examples, sensor array 30 is interleaved with plurality of therapy delivery elements 26 along elongate body 24, or plurality of therapy delivery elements 26 may be positioned between a pair of sensors of sensor array 30. The number of sensors in sensor array 30 may be less than, greater than, or the same as the number of therapy delivery elements 26, but greater than one.

[0056] In some examples, sensor array 30 includes a first ultrasound transceiver 30A and a second ultrasound transceiver 30B longitudinally and transversely offset from each other when elongate body 24 is in the expanded configuration 24A. For example, as shown in FIG. IB, first ultrasound transceiver 30A and second ultrasound transceiver 30B are longitudinally offset from each other, relative to an expanded longitudinal axis E about which catheter elongate body 24 (or catheter 12) extends in expanded configuration 24 A (along an X- direction shown in FIG. IB). In some examples, expanded longitudinal axis E is parallel to, aligned with, or in a same direction as a direction of blood flow B. As shown in FIG. 1C, first ultrasound transceiver 30A and second ultrasound transceiver 30B are transversely offset from each other (transverse to expanded longitudinal axis E, and along a Y-Z plane shown in FIG. 1C). In some examples, first ultrasound transceiver 30A and second ultrasound transceiver 30B are offset along an offset direction O (shown in FIG. 2) defining an angle 0 relative to the direction of blood flow B or relative to expanded longitudinal axis E defined byexpanded configuration 24A of elongate body 24. For example, angle 9 may be at least 10 degrees, at least 15 degrees, at least 20 degrees, at least 25 degrees, at least 30 degrees, at least 35 degrees, at least 40 degrees, at least 45 degrees, at least 50 degrees, at least 55 degrees, or at least 60 degrees. In some examples, angle 9 is less than or equal to 60 degrees, less than or equal to 55 degrees, less than or equal to 50 degrees, less than or equal to 45 degrees, less than or equal to 40 degrees, less than or equal to 35 degrees, less than or equal to 30 degrees, less than or equal to 25 degrees, less than or equal to 20 degrees, or less than or equal to 10 degrees. In some examples, angle 9 is in a range of from 30 degrees to 60 degrees. In some examples, the angle 9 is 45 degrees.

[0057] At least one of first ultrasound transceiver 30A or second ultrasound transceiver 30B is configured to emit at least one ultrasound signal transmitted through blood flowing through blood vessel 34 when elongate body 24 is in expanded configuration 24A, and at least another of first ultrasound transceiver 30A or second ultrasound transceiver 39B is configured to detect the at least one ultrasound signal. In some examples, first ultrasound transceiver 39A and second ultrasound transceiver 39B are each configured to emit and detect at least one ultrasound signal transmitted through blood flowing through blood vessel 34 when elongate body 24 is in expanded configuration 24A. In some examples, first ultrasound transceiver 39A is configured to be distal to second ultrasound transceiver 39B when elongate body 24 is in expanded configuration 24A. In some examples, first ultrasound transceiver 39A is positioned distal to second ultrasound transceiver 39B along the elongate body 24 (e.g., regardless of whether elongate body 24 is in the relatively low profile configuration or in the expanded configuration 24A).

[0058] In some examples, sensor array 30 further includes additional ultrasound transceivers. In the example shown in FIG. 1 A, sensor array 30 further includes third ultrasound transceiver 30C and fourth ultrasound transceiver 30D longitudinally and transversely offset from each other when elongate body 24 is in expanded configuration 24A. For example, as shown in FIG. IB, third ultrasound transceiver 30C and fourth ultrasound transceiver 30D are longitudinally offset from each other, relative to expanded longitudinal axis E (along an X-direction shown in FIG. IB). As shown in FIG. 1C, third ultrasound transceiver 39C and fourth ultrasound transceiver 39D are transversely offset from each other (transverse to expanded longitudinal axis E, and along a Y-Z plane shown in FIG. 1C).

[0059] In some examples, anatomical considerations, for example, vessel size or curvature, may affect an orientation, angle, or offset between ultrasound transceivers of sensor array 30. Including more than one set of ultrasound transceivers (e.g., third ultrasoundtransceiver 30C and fourth ultrasound transceiver 30D) may facilitate orienting at least one pair of ultrasound transceivers of sensor array 30 at a target orientation, angle, or offset relative to blood flow B in blood vessel 34. For example, when catheter 12 is introduced in blood vessel 34, a clinician may be able to position at least one pair of ultrasound transceivers of first ultrasound transceiver 30 A, second ultrasound transceiver 3 OB, third ultrasound transceiver 30C, fourth ultrasound transceiver 30D (or additional ultrasound transceivers) at a predetermined orientation, angle, or offset by manipulating catheter 12.

[0060] Third ultrasound transceiver 30C and fourth ultrasound transceiver 30D may alternate with first ultrasound transceiver 30A and second ultrasound transceiver 30B along elongate body 24. For example, as shown in FIGS. 1 A, third ultrasound transceiver 30C may be between first ultrasound transceiver 30A and second ultrasound transceiver 30B, and second ultrasound transceiver 30B may be between third ultrasound transceiver 30C and fourth ultrasound transceiver 30D along elongate body in a direction of longitudinal axis L. As shown in FIG. 1C, in expanded configuration 12A of catheter 12, first ultrasound transceiver 30A and second ultrasound transceiver 30B may be opposed across blood vessel 34 along a first direction (e.g., along a Z-axis), while third ultrasound transceiver 30C and fourth ultrasound transceiver 30D may be opposed across blood vessel 34 along a second direction transverse (e.g., perpendicular) to the first direction (e.g., along a Y-axis).

[0061] FIG. 2 is a diagram illustrating a partial cross-sectional view showing a pair of ultrasound transducers (e.g., first ultrasound transceiver 30A and second ultrasound transceiver 30B) of catheter 12A of FIGS. IB and 1C in blood vessel 34. For example, catheter 12 may be configured to position first ultrasound transceiver 30A and second ultrasound transceiver 30B transverse across a direction of blood flow (flow direction indicated by arrow B) through blood vessel 34 when elongate body 24 is placed in blood vessel 34 and when elongate body 24 is in the expanded configuration 24A (as shown in FIGS. IB and 1C). In some examples, a direction of blood flow B is parallel to or aligned with elongated longitudinal axis E defined by expanded catheter 12A. In some examples, first ultrasound transceiver 30A is configured to be downstream of second ultrasound transceiver 30B relative to the blood flow B when elongate body 24 is in expanded configuration 24A in blood vessel 34.

[0062] In some examples, each of first ultrasound transceiver 30A and second ultrasound transceiver 30B is configured to transmit a respective ultrasound signal toward the other of the ultrasound transceiver 30A and second ultrasound transceiver 30B. For example, as shown in FIG. 2, first ultrasound transceiver 30A may transmit a first ultrasound signal Uitoward second ultrasound transceiver 3 OB, and second ultrasound transceiver 3 OB may transmit a second ultrasound signal U2toward first ultrasound transceiver 30 A. In some such examples, each of first ultrasound transceiver 30A and second ultrasound transceiver 3 OB is configured to receive the respective ultrasound signal transmitted by the other of first ultrasound transceiver 30A and second ultrasound transceiver 3 OB. For example, as shown in FIG. 2, first ultrasound transceiver 30A may receive second ultrasound signal U2transmitted by second ultrasound transceiver 3 OB, and second ultrasound transceiver 3 OB may receive first ultrasound signal Ui transmitted by first ultrasound transceiver 30 A.

[0063] Computing device 16 or control circuitry 40 may be configured to cause at least one of first ultrasound transceiver 30A or second ultrasound transceiver 30B to emit at least one ultrasound signal (e.g., Ui or U2) transmitted through blood flowing through blood vessel 34 and at least another of first ultrasound transceiver 30A or second ultrasound transceiver 30B to detect the at least one ultrasound signal. In some examples, computing device 16 or control circuitry 40 may be configured to cause each of first ultrasound transceiver 30A and second ultrasound transceiver 30B to emit and detect at least one ultrasound signal (e.g., Ui or U2) transmitted through blood flowing through blood vessel 34. For example, control circuitry 40 may be configured to cause first ultrasound transceiver 30A to transmit first ultrasound signal Ui toward second ultrasound transceiver 30B through (e.g., across) blood flow B at a first transmission time TbControl circuitry 40 may be further configured to detect a signal from second ultrasound transceiver 30B indicative of a first receipt time Ri of first ultrasound signal Ui at second ultrasound transceiver 30B. Control circuitry 40 may determine a first transit time TTi for transmission of first ultrasound signal Ui based on a delay between first transmission time Ti and first receipt time R In other words, first transit time TTi is the time for first ultrasound signal Ui to travel from first ultrasound transceiver 30A to second ultrasound transceiver 30B across blood flow B through blood vessel 34.

[0064] The first transit time TTi varies with blood flow rate, for example, because the velocity of transmission of an ultrasound signal through flowing blood is influenced by the blood flow rate. For example, the transit time may be proportional to the blood flow rate. Thus, in some examples, control circuitry 40 is configured to determine a blood flow rate of the blood flow B based on a correlation between blood flow rate and transit time. Moreover, control circuitry 40 is configured to determine the blood flow rate without measuring a Doppler shift (e.g., of first ultrasound signal Ui), or without using the Doppler effect. The transit time may also depend on additional parameters, for example, a distance between first ultrasound transceiver 30A and second ultrasound transceiver 30B, or orientation or angle ofthe path of first ultrasound signal Ui relative to blood flow B. Thus, control circuitry 40 may compensate for, adjust, or select a correlation curve or table, based on at least one additional parameter.

[0065] In some examples, control circuitry 40 determines an average transit time based on two ultrasound signals. The transit time may be an average transit time for transmission of first ultrasound signal Ui across blood flow B through blood vessel 34 in a first direction (e.g., relative to blood flow B) and second ultrasound signal U2across the blood flow B through blood vessel 34 in a second direction opposite the first direction. For example, control circuitry 40 may be configured to cause second ultrasound transceiver 30B to transmit second ultrasound signal U2toward first ultrasound transceiver 30A (in a direction opposite that of first ultrasound signal Ui) through blood flow B at a second transmission time T2. Control circuitry 40 may be further configured to detect a signal from first ultrasound transceiver 30A indicative of a second receipt time R2. Control circuitry 40 may determine a second transit time TT2for transmission of second ultrasound signal U2based on a delay between second transmission time T2and second receipt time R2at first ultrasound transceiver 30B. In other words, second transit time TT2is the time for second ultrasound signal U2to travel from second ultrasound transceiver 30B to first ultrasound transceiver 30A across blood flow B through blood vessel 34. Control circuitry 40 may determine the transit time as a combination of (e.g., an average) of TTi and TT2. Using an average of TTi and TT2may reduce errors in blood flow rate measurement by canceling out or compensating for errors arising from fluctuations or variations in blood flow in opposite directions (for example, in an upstream direction relative to a downstream direction with reference to blood flow B).

[0066] In some examples, control circuitry 40 determines a blood flow rate F, for a direct distance L between first ultrasound transceiver 30A and second ultrasound transceiver 30B, with X = L cos 6, using EQUATIONS 1 and 2.(Equation 1)(Equation 2)

[0067] In some examples, control circuitry 40 applies a calibration factor to the calculation of A, or of V based on L and / or A(e.g., based on the magnitude of ff). For example, the calibration factor may a multiplicative term in EQUATIONS 1 or 2. Thecalibration factor may account for a deviation in angle 0 from a predetermined value (e.g., from 45 degrees), or on direct distance L between first ultrasound transceiver 30A and second ultrasound transceiver 3 OB.

[0068] Similar to first transit time TTi and second transit time TT2, control circuitry 40 may determine a third transit time TT3for transmission of a third ultrasound signal from third ultrasound transceiver 30C to fourth ultrasound transceiver 30D, and a fourth transit time TT4for transmission of a fourth ultrasound signal from fourth ultrasound transceiver 30D to third ultrasound transceiver 30C, across blood flow B through blood vessel 34. Control circuitry 40 may determine the transit time as an average of TTbTT2, TT3, and TT4. Using an average of TTi, TT2, TT3, and TT4may reduce errors in blood flow rate measurement by canceling out or compensating for errors arising from fluctuations or variations in blood flow in opposite directions (for example, in an upstream direction relative to a downstream direction with reference to blood flow B, and in transverse directions across blood flow B).

[0069] Wiring to deliver the therapy signal, the stimulation signal, or the ultrasound signal along a catheter may be positioned along an exterior or interior of the catheter. For example, in catheter 12, wiring may extend from a port (e.g., electrically coupled to control circuitry 40) in handle 18 along proximal catheter portion 20B to distal catheter portion 20A, and may include a first wiring extending through or along elongate body 24 and configured to deliver the ablation signal, a second wiring extending through or along elongate body 24 and configured to deliver the stimulation signal, and a third wiring extending through or along elongate body 24 and configured to deliver the ultrasound signal.

[0070] Distal catheter portion 20A of catheter 12 is configured to be advanced within an anatomical lumen of a human patient to locate one or more of therapy delivery element 26, stimulation element 28, or sensor array 30 at a target tissue site within or otherwise proximate to the anatomical lumen. For example, catheter 12 may be configured to position distal catheter portion 20A within a blood vessel (e.g., blood vessel 34), a ureter, a urethra, a duct, an airway, or another naturally occurring lumen within the human body. The examples described herein focus on the anatomical lumen being a blood vessel, such as a renal vessel, but it will be understood that similar techniques may be used with other anatomical lumens.

[0071] Catheter 12 can be configured for delivery to a target tissue site within vasculature of a patient via a guide member, which can include, for example, one or more of a guidewire or an outer sheath. In certain examples, intravascular delivery of distal catheter portion 20A includes percutaneously inserting a guidewire (not shown in FIG. 1 A) into a vessel of a patient and moving at least catheter body 20 (for example, at least expandable portion 22)along the guidewire until expandable portion 22 reaches a target tissue site (for example, a renal artery). For example, distal catheter portion 20A of catheter body 20 (e.g., first elongate body 24) may define a lumen configured to receive a guidewire for delivery of distal catheter portion to a target tissue site using over-the-wire (OTW) or rapid exchange (RX) techniques. In other examples, catheter 12 can be a steerable or non-steerable device configured for use without a guidewire. In still other examples, catheter 12 can be configured for delivery via an inner lumen of a guide member, for example, a guide catheter, an outer sheath (not shown in FIG. 1 A), or other guide device.

[0072] A distal end of catheter body 20 defines distal tip 32. Distal tip 32 is configured to facilitate navigation of distal catheter portion 20A within the vasculature of the patient to blood vessel 34. In some examples, distal tip 32 may be atraumatic, for example, to resist or avoid puncturing a vessel of blood vessel 34 during navigation of distal catheter portion 20A within blood vessel 34.

[0073] In the example illustrated in FIG. 1 A, catheter 12 is in a relatively low-profile delivery configuration, in which distal catheter portion 20A defines a relatively smaller radial extent (a relatively low-profile, such as a relatively linear configuration) relative to expanded (also referred to as a radially expanded and / or deployed) configuration 12A in which expandable portion 22 of distal catheter portion 20A defines a relatively larger radial extent. In some examples, the radial extent is measured in a direction orthogonal to central longitudinal axis L. Distal catheter portion 20A may be delivered through vasculature of the patient to the target tissue site in the low-profile configuration. In some examples, expandable portion 22 is configured to self-expand within blood vessel 34 of a patient, e.g., via a shape-memory element (e.g., a shape memory tube or a hollow helical strand) of elongate body 24. In some examples, expandable portion 22 (e.g., elongate body 24) extends along a straight line aligned with longitudinal axis L in the relatively low-profile configuration shown in FIG. 1 A. Expandable portion 22 may be constrained or restrained in the low-profile configuration by a guide member. The clinician may retract the guide member proximally relative to expandable portion 22 to un-constrain expandable portion 22 and cause or allow expandable portion 22 to transform from the low-profile configuration to an expanded configuration. Thus, expandable portion 22 may be configured to radially expand to the expanded configuration 22A.

[0074] In some examples, in the expanded configuration shown in FIGS. IB and 1C, elongate body 24A defines a loop, a helix, a spiral shape, a multi-finger configuration, a basket, a stent-like configuration, or a balloon. In the expanded configuration, elongate body24A is configured to position one or more sensors of sensor array 30 near a vessel wall, for example, in apposition with the vessel wall, and with at least one pair of sensors (e.g., first ultrasound transceiver 30A and second ultrasound transceiver 3 OB) offset along the vessel wall. Likewise, in the expanded configuration, elongate body 24A may be configured to position one or more of therapy delivery element 26 or stimulation element 28 near the vessel wall, for example, in apposition with the vessel wall.

[0075] In some examples, expandable portion 22 may be expanded or may self-expand as a result of proximal retraction of a guide member from distal catheter portion 20A. The clinician may retract the guide member to a location along distal catheter portion 20A proximal to expandable portion 22 to cause or allow expandable portion 22 to expand. In the expanded configuration, expandable portion 22 may place at least one electrode (for example, of therapy delivery element 26) at a first location relative to the vessel wall, for example, corresponding to a first rotational location. A clinician may control a therapy delivery device to deliver, provide, or facilitate neuromodulation therapy at the target tissue site, for example, through the vessel wall at the target tissue site to target tissue adjacent to blood vessel 34. The neuromodulation therapy may include, but is not limited to, radiofrequency (RF) energy, microwave energy, or the like.

[0076] The clinician may rotate handle 18, or otherwise proximal portion 20B, to apply a torque to distal portion 20A and cause expandable portion 22 to rotate about central longitudinal axis L from the first rotational location to a second rotational location. For example, the application of torque from handle 18 or proximal portion 20B to expandable portion 22 may cause expandable portion 22 to rotate about longitudinal axis L, for example, in a same direction as the torque. The clinician may control system 10 to deliver ablation therapy or stimulation at the second rotational location, or after further successive rotational locations of expandable portion 22.

[0077] In some examples, blood vessel 34 in which catheter 12 is introduced is a renal blood vessel. Thus, in such examples, control circuitry 40 may be configured to determine a parameter of renal blood flow (e.g., renal blood flow rate) through the renal blood vessel based on the transit time.

[0078] The blood flow rate is affected by sympathetic nerve activity in response to stimulation, which in turn is affected by extent of denervation. For example, as denervation advances, nerves may exhibit a reduced response to stimulation, and sympathetic nerve activity may be reduced, resulting in a reduced blood flow rate compared to a blood flow rate prior to denervation. In some examples, control circuitry 40 is configured to determine, basedon a comparison of blood flow rate at various stages, an extent of denervation and efficacy of neuromodulation therapy.

[0079] For example, in some examples, control circuitry 40 is further configured to determine a first blood flow rate based on a first transit time before a neuromodulation procedure, and a second blood flow rate based on a second transit time after the neuromodulation procedure. Control circuitry 40 may be further configured to determine an efficacy of the neuromodulation procedure based on a comparison of the first blood flow rate and the second blood flow rate. For example, a reduction of second blood rate relative to the first blood flow rate may be indicative of at least some denervation, and a degree of reduction may be indicative of an extent of denervation.

[0080] In some examples, control circuitry 40 may be configured to deliver, by stimulation generation circuitry 44, electrical stimulation to a target site before a neuromodulation procedure. Control circuitry 40 may be further configured to determine a first blood flow rate after delivering the electrical stimulation and before a neuromodulation procedure. Control circuitry 40 may be further configured to deliver, by stimulation generation circuitry 44, the electrical stimulation to the target site after the neuromodulation procedure. Control circuitry 40 may be further configured to determine the second blood flow rate after delivering the electrical stimulation and after the neuromodulation procedure.

[0081] In some examples, control circuitry 40 is further configured to determine sympathetic nerve activity based on the comparison of the first blood flow rate and the second blood flow rate, and determine the efficacy based on the sympathetic nerve activity. In some examples, control circuitry 40 is further configured to determine a presence or extent of vasoconstriction based on the comparison of the first blood flow rate and the second blood flow rate, and determine the efficacy based on the presence or extent of vasoconstriction. For example, control circuitry 40 may be further configured to determine the presence of vasoconstriction in response to determining that the second blood flow rate is lower than the first blood flow rate. In some examples, control circuitry 40 is further configured to determine the extent of vasoconstriction based on a magnitude of a difference between the second blood flow rate and the first blood flow rate.

[0082] Control circuitry 40 may generate an output, or initiate an action, based on the efficacy of the neuromodulation therapy. For example, control circuitry 40 may be further configured to generate an output indicative of the efficacy of the neuromodulation therapy. In some examples, the output includes one or more of a visual signal, an audio signal, or a tactile signal. In some examples, control circuitry 40 is further configured to generate a notificationin response to determining that the efficacy of the neuromodulation therapy is lower than a threshold value. For example, the notification may cause a clinician to investigate possible causes of insufficient denervation, and repeat the therapy, pause the therapy, or resume the therapy after taking appropriate action. In some examples, control circuitry 40 may be configured to perform automated actions in response to the efficacy. For example, control circuitry 40 may be further configured to control medical device 16 to adjust the neuromodulation therapy based on the efficacy. In some examples, control circuitry 40 is further configured to automatically adjust the neuromodulation therapy based on the efficacy. For example, control circuitry 40 may increase or decrease a magnitude, frequency, duration, or iterations of neuromodulation therapy, or generally, pause, resume, or stop, delivery of neuromodulation therapy by therapy delivery element 26. In some examples, control circuitry 40 is configured to stop neuromodulation therapy if the efficacy is greater than or equal to a predetermined threshold. In some examples, control circuitry 40 is configured to adjust at least one parameter of neuromodulation therapy (e.g., intensity of a therapy signal) or repeat delivery of neuromodulation therapy one or more times if the efficacy is less than (or, in some examples, less than or equal to) the predetermined threshold.

[0083] System 10 and / or catheter 12 may be used to deliver ablation and stimulation for neuromodulation according to any appropriate scheme.

[0084] FIG. 3 is a timing diagram illustrating an example scheme for delivering neuromodulation therapy and electrical stimulation. In the scheme shown in FIG. 3, neuromodulation system 10, which can include control circuitry 40 or other elements of medical device 14 or another device, such as computing device 14 in the discussion of FIG. 3, determines an initial ‘baseline’ renal blood flow rate (e.g., via an ultrasound transit time measurement). Then, neuromodulation system 10 causes stimulation to be delivered to a target site, and determines a ‘response’ renal blood flow rate (e.g., by repeating the ultrasound transit time measurement) after delivering stimulation. Further, neuromodulation system 10 may deliver a predetermined neuromodulation therapy. To assess the efficacy of the neuromodulation therapy, neuromodulation system 10 may deliver stimulation again after the neuromodulation therapy, and determine another ‘response’ renal blood flow rate (e.g., by repeating the ultrasound transit time measurement).

[0085] Thus, computing device 14 or control circuitry 40 of system 10 may control medical device 14 to deliver a neuromodulation therapy including ablation and stimulation via catheter 12 and / or another device. In some examples, computing device 14 controls control circuitry 40 to deliver ablation and stimulation via catheter 12. For example, computingdevice 14 may be configured to generate and send a control signal to control circuitry 40, and control circuitry 40 may be configured to generate, based on the control signal, an electrical signal sent to catheter 12. Further, computing device 14 may control control circuitry 40 to deliver ultrasound signals via catheter 12 to determine changes in blood flow rate after neuromodulation compared to a period before neuromodulation, and determine an efficacy of the neuromodulation.

[0086] FIG. 4 is a block diagram illustrating an example configuration of computing device 14 of FIG. 1A. In some examples, control circuitry 40 may include computing device 14, or include one or more components described with reference to computing device 14, or otherwise perform functions described with reference to computing device 14. Computing device 14 may include a workstation, a tablet computer, a laptop computer, or a desktop computer.

[0087] As shown in the example of FIG. 4, computing device 14 includes processing circuitry 170, storage device 172, communication circuitry 174, and a user interface 176. While computing device 14 may be a stand-alone device as shown in FIG. 4, in other examples, computing device 14 may be any component or system that includes processing circuitry or other suitable computing environment for executing software instructions and, for example, need not necessarily include one or more elements shown in FIG. 4 (e.g., in some examples components such as storage device 172 may not be co-located or in the same housing or structure as other components).

[0088] Processing circuitry 170, in some examples, is configured to implement functionality and / or process instructions for execution within at least one computing device 14. For example, processing circuitry 170 may be capable of processing instructions, including at least one application 180, stored in storage device 172. Examples of processing circuitry 170, as well as other processors, processing circuitry, controllers, control circuitry, and the like, described herein, may include any combination of integrated circuitry, discrete logic circuitry, analog circuitry, such as one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), or field-programmable gate arrays (FPGAs). In some examples, processing circuitry 170 includes multiple components, such as any combination of one or more microprocessors, one or more DSPs, one or more ASICs, or one or more FPGAs, as well as other discrete or integrated logic circuitry, and / or analog circuitry.

[0089] Storage device 172 (which can also be referred to as a memory) may be configured to store information within computing device 14, including at least one application 180 anddata 190. Storage device 172, in some examples, is a computer-readable storage medium. In some examples, storage device 172 includes a temporary memory or a volatile memory. Storage device 172, in one example, is used by at least one application 180 running on computing device 14 to temporarily store information during program execution. Storage device 172, in some examples, also includes one or more memories configured for long-term storage of information, e.g., including non-volatile storage elements. Examples of such nonvolatile storage elements include any volatile, non-volatile, magnetic, optical, or electrical media, such as a random access memory (RAM), read-only memory (ROM), non-volatile RAM (NVRAM), electrically-erasable programmable ROM (EEPROM), flash memory, or any other digital media.

[0090] Computing device 14 utilizes communication circuitry 174 to communicate with other devices, such as catheter 12, control circuitry 40, other computing devices, and system 10 of FIG. 1. Communication circuitry 174 may include a network interface card, such as an Ethernet card, an optical transceiver, a radio frequency transceiver, or any other type of device that can send and receive information. Other examples of such network interfaces may include 3G, 4G, 5G, and WiFi radios.

[0091] Computing device 14 may include a user interface 176. User interface 176 may be configured to provide output to a user using tactile, audio, or video stimuli and receive input from a user through tactile, audio, or video feedback. User interface 176 may include, as examples, a presence-sensitive display, a mouse, a keyboard, a voice responsive system, video camera, microphone, or any other type of device for detecting a command from a user, a sound card, a video graphics adapter card, or any other type of device for converting a signal into an appropriate form understandable to humans or machines, a speaker, a display device, such as, but not limited to, cathode ray tube (CRT) monitor, a liquid crystal display (LCD), or any other type of device that can generate intelligible output to a user. In some examples, a presence-sensitive display includes a touch-sensitive screen.

[0092] At least one application 180 executable by processing circuitry 170 of computing device 14 may include a stimulation interface application 182 and a monitoring system 184 that may utilize physiological data or other data (e.g., blood flow rate based on ultrasound transit time measurements) obtained during neuromodulation to monitor the progress of neuromodulation and effects of ablation. At least one application 180 further may include an ablation interface application 186 that controls delivery of ablation via control circuitry 40 and / or catheter 12.

[0093] Execution of stimulation interface 182 and ablation interface 186 by processing circuitry 170 configures computing device 14 to interface with system 10 or control circuitry 40 (or catheter 12). For example, stimulation interface 82 configures computing device 14 to communicate with control circuitry 40 via communication circuitry 174. Processing circuitry 170 may receive a signal from a physiological sensor (e.g., sensor array 30) indicative of a physiological parameter (e.g., blood flow rate), and store the physiological data 192 in storage device 172. Physiological parameters may include, but are not limited to, blood flow rate, electrical conduction, electrical impedance, tissue response (e.g., blood pressure), heat response (e.g., heart rate), or any other physiological parameter that may change as a result of ablation and be stimulated through stimulation. Stimulation interface 182 and / or ablation interface 186 also configures user interface 176 for a user to interact with control circuitry 40 (or catheter 12). One or more of stimulation interface 182, monitoring system 184, or ablation interface 186 may cause processing circuity 170 and computing device 14 to perform any of the techniques described herein related to neuromodulation by system 10.

[0094] FIG. 5 is a flow diagram illustrating an example technique for monitoring neuromodulation therapy based on one or more parameters of blood flow (e.g., blood flow rate) sensed via ultrasound sensors. The example technique of FIG. 5 is described with reference to processing circuitry 170 of computing device 14 and system 10 of FIG. 1A. However, the example technique may be implemented by any suitable computing device, controller, or system alone or in combination with processing circuitry 170.

[0095] The technique includes delivering, by therapy delivery element 26 disposed on elongate body 24 of neuromodulation catheter 12, neuromodulation therapy to a target site (200). Neuromodulation catheter 12 is introduced and / or placed in a vessel of a patient. For example, processing circuitry 170 may send a therapy signal to neuromodulation catheter 12 to cause therapy delivery element to deliver neuromodulation therapy. In some examples, processing circuitry 170 causes control circuitry 40 to generate the therapy signal, and to send the therapy signal to therapy delivery element 26 of neuromodulation catheter 12.

[0096] The technique further includes delivering a stimulation signal to the target site (202). For example, processing circuitry 170 may send the stimulation signal to neuromodulation catheter 12. In some examples, processing circuitry 170 causes control circuitry 40 to generate the stimulation signal, and to send the stimulation signal to neuromodulation catheter 12. One or more of therapy delivery element 26, stimulation element 28, or some other element, component, device, or system may deliver the stimulation signal.

[0097] The technique further includes determining, by processing circuitry 170, a blood flow rate in response to the stimulation signal (204). For example, processing circuitry 170 may cause at least one of ultrasound transceiver 30A or second ultrasound transceiver 30B to emit at least one ultrasound signal transmitted through blood flowing through blood vessel 34, and at least another of ultrasound transceiver 30A or second ultrasound transceiver 30B to detect the at least one ultrasound signal. In some examples, processing circuitry 170 causes each of the ultrasound transceiver 30A and second ultrasound transceiver 30B to emit and detect at least one ultrasound signal transmitted through blood flowing through blood vessel 34. Processing circuitry 170 may further determine a transit time for transmission of the at least one ultrasound signal across a direction of blood flow through blood vessel 34. In some examples, the transit time is an average transit time for transmission of first ultrasound signal Ui across blood flow B through blood vessel 34 in a first direction and second ultrasound signal U2across blood flow B through blood vessel 34 in a second direction opposite the first direction. In some examples, determining blood flow rate (204) includes determining, by processing circuitry 170 and based on a correlation between the transit time and blood flow rate, a blood flow rate of the blood flow B. In some examples, the transit time is proportional to the blood flow rate. Blood vessel 34 may be a renal blood vessel, and in such examples, processing circuitry 170 may further determine a renal blood flow through the renal blood vessel based on the transit time.

[0098] In some examples, the technique includes, by processing circuitry 170, determining blood flow rate at different stages or times. For example, processing circuitry 170 may determine a first blood flow rate based on a first transit time before a neuromodulation procedure (e.g., before delivering neuromodulation therapy 200), determine a second blood flow rate based on a second transit time after the neuromodulation procedure (e.g., after delivering neuromodulation therapy 200). Processing circuitry 170 may further determine an efficacy of the neuromodulation procedure based on a comparison of the first blood flow rate and the second blood flow rate.

[0099] In some examples, processing circuitry 170 may cause stimulation generation circuitry 44 to deliver electrical stimulation to the target site. In some examples, stimulation generation circuitry 44 uses therapy delivery element 26 to deliver the electrical stimulation to the target site. In other examples, neuromodulation catheter 12 further includes stimulation element 28 disposed on the elongate body, and stimulation generation circuitry 44 may use stimulation element 28 to deliver the electrical stimulation to the target site.

[0100] Processing circuitry 170 may cause stimulation generation circuitry 44 to deliver the electrical stimulation to the target site before the neuromodulation procedure, and determine the first blood flow rate after delivering the electrical stimulation and before the neuromodulation procedure. Processing circuitry 170 may further cause stimulation generation circuitry 44 to deliver the electrical stimulation to the target site after the neuromodulation procedure (e.g., delivery of the stimulation signal at 202), and determine the second blood flow rate after delivering the electrical stimulation and after the neuromodulation procedure (e.g., determination of the blood flow rate at 204).

[0101] Processing circuitry 170 may determine, based on the blood flow rate, an efficacy of neuromodulation therapy delivered at the target site (206). For example, attenuation of the blood flow rate may be indicative of a reduction in neural activity, and thus, successful ablation. In addition to blood flow rate, a physiological response including any physiological parameter of a biological that may be affected by the stimulation signal to the biological system may also be determined. In some examples, processing circuitry 170 determines a presence or an extent of vasoconstriction based on the comparison of the first blood flow rate and the second blood flow rate, and determines the efficacy (206) based on the presence or extent of vasoconstriction. In some such examples, processing circuitry 170 may further determine the presence of vasoconstriction in response to determining that the second blood flow rate is lower than the first blood flow rate. For example, processing circuitry may determine the extent of vasoconstriction based on a magnitude of a difference between the second blood flow rate and the first blood flow rate.

[0102] Processing circuitry 170 may initiate, continue, or terminate ablation in response to the comparison. For example, processing circuitry 170 may cause control circuitry 40 to initiate, continue, or terminate ablation in response to the comparison. For example, if the comparison indicates that neural traffic is attenuated, or that the target site has been sufficiently ablated or denervated, processing circuitry 170 may cause control circuitry 40 to terminate ablation. However, if the comparison indicates that neural traffic is not attenuated, or that the target site has not been sufficiently ablated or denervated, processing circuitry 170 may cause control circuitry 40 to initiate or continue ablation.

[0103] In some examples, the technique includes generating, by processing circuitry 170, an output indicative of the efficacy of the neuromodulation therapy. In some examples, the technique further includes generating, by processing circuitry 170, a notification in response to determining that the efficacy of the neuromodulation therapy is lower than a threshold value.

[0104] In some examples, the technique further includes controlling, by processing circuitry 170, medical device 16 to adjust the neuromodulation therapy based on the efficacy. For example, processing circuitry may automatically adjust the neuromodulation therapy based on the efficacy.

[0105] Thus, example systems and techniques according to the present disclosure may be used to deliver, monitor, or control neuromodulation therapy.

[0106] FIG. 6 illustrates an example technique for accessing a renal artery and modulating renal nerves with a neuromodulation catheter. While FIG. 6 illustrates the use of catheter 12 for renal neuromodulation, catheter 12 may be used for other therapies and treatments within another blood vessel or other hollow anatomical body within the human body. Catheter 12 is configured to deliver energy (e.g., RF energy, ultrasound energy, electrical stimulation energy, or the like) to one or more target tissue sites within a renal vessel. Catheter 12 provides access to the renal plexus (RP) through an intravascular path (P), such as a percutaneous access site in the femoral (illustrated), brachial, radial, or axillary artery to the target tissue sites within a respective renal artery (RA). By manipulating proximal portion 20B or catheter body 22 from outside the intravascular path (P), a clinician may advance distal portion 20A of catheter body 22 through the sometimes-tortuous intravascular path (P) and remotely manipulate distal portion 20A (FIG. 1 A) of catheter body 20. Distal portion 20A may be remotely manipulated by the clinician using handle 18.

[0107] In the example illustrated in FIG. 6, distal portion 20A is delivered intravascularly to the treatment site using an inner member 123 in an over-the-wire (OTW) technique. Inner member 123 may be internal to catheter 12 (e.g., a guide wire, inner catheter, or the like) or external to catheter 12 (e.g., an outer sheath or the like). In some examples, inner member 123 is a navigation wire. Catheter 12 may define a passageway for receiving inner member 23 for delivery of catheter 12 using either an OTW or an RX technique. At the treatment site, inner member 123 can be at least partially withdrawn or removed relative to catheter 12 and distal portion 20A can transform into an expanded configuration (for example, a helical configuration, a spiral configuration, or the like) for delivering ultrasound energy. In other examples, catheter body 22 is self-steerable such that therapy may be delivered to the target tissue site without the aid of inner member 123.

[0108] In some examples, catheters described herein may be used to perform renal modulation. Renal modulation is the partial or complete incapacitation or other effective disruption of nerves of the kidneys (e.g., nerves terminating in the kidneys or in structures closely associated with the kidneys). In particular, renal neuromodulation can includeinhibiting, reducing, or blocking neural communication along neural fibers (e.g., efferent or afferent neural fibers) of the kidneys. Such incapacitation can be long-term (e.g., permanent or for a period of months, years, or decades) or short-term (e.g., for periods of minutes, hours, days, or weeks). Renal neuromodulation is expected to contribute to the systemic reduction of sympathetic tone or drive or benefit at least some specific organs or other bodily structures innervated by sympathetic nerves. Accordingly, renal neuromodulation is expected to be useful in treating clinical conditions associated with central sympathetic overstimulation. For example, renal neuromodulation is expected to efficaciously treat hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end state renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death, among other conditions.

[0109] Renal neuromodulation can be electrically induced or induced in another suitable manner through the delivery of energy (RF energy, ultrasound energy, microwave energy, or the like). The target tissue site can be within or otherwise proximate to a renal lumen (e.g., a renal artery, a ureter, a renal pelvis, a major renal calyx, a minor renal calyx, or another suitable structure), and the target tissue site can include tissue at least proximate to a wall of the renal lumen. For example, with regard to a renal artery, a treatment procedure can include modulating nerves in the renal plexus, which lay intimately within or adjacent to the adventitia of the renal artery. The following discussion provides further details regarding patient anatomy and physiology as it may relate to renal denervation therapy. This section is intended to supplement and expand upon the previous discussion regarding the relevant anatomy and physiology, and to provide additional context regarding the disclosed technology and the therapeutic benefits associated with renal denervation. For example, several properties of the renal vasculature may inform the design of the target tissue devices and associated methods for achieving renal neuromodulation via intravascular access and impose specific design requirements for such devices. Specific design requirements may include accessing the renal artery, positioning distal portion 20A within the renal artery, delivering the therapy to targeted tissue, or effectively modulating the renal nerves with the therapy delivery device.

[0110] As noted previously, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level (called sympathetic tone) and becomes more active during times of stress. Like other parts of the nervous system, the sympatheticnervous system operated through a series of interconnected neurons. Sympathetic neurons are frequently considered part of the peripheral nervous system (PNS), although many lie within the central nervous system (CNS). Sympathetic neurons of the spinal cord (which is part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. Within the ganglia, spinal cord sympathetic neurons are therefore called presynaptic (or preganglionic) neurons, while peripheral sympathetic neurons are called postsynaptic (or postganglionic neurons).[OHl] At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation may elicit the release of adrenaline from the adrenal medulla.

[0112] Once released, norepinephrine and epinephrine bind adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes a neuronal and hormonal response. The physiologic manifestations include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also seen due to binding of cholinergic receptors of the sweat glands.

[0113] The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulatory function to physiological features as diverse as pupil diameter, gut motility, and urinary output. This response is also known as sympatho-adrenal response of the body, as the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers) secrete acetylcholine, which activates the secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine). Therefore, this response that acts primarily on the cardiovascular system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines secreted from the adrenal medulla.

[0114] FIG. 7 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS. As shown in FIG. 7, the SNS provides a network of nerves that allows the brain to communicate with the body. Sympathetic nerves originate inside the vertebral column, e.g., toward the middle of the spinal cord in the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and are thought to extend to the second or third lumbar segments. Because SNS cells begin in the thoracic and lumbar regions of the spinal cord, the SNS is saidto have a thoracolumbar outflow. Axons of sympathetic nerves leave the spinal cord through the anterior rootlet / root. The axons pass near the spinal (sensory) ganglion, where the axons enter the anterior rami of the spinal nerves. However, unlike somatic innervation, the axons separate out through white rami connectors which connect to either the paravertebral (which lie near the vertebral column) or prevertebral (which lie near the aortic bifurcation) ganglia extending alongside the spinal column.

[0115] To reach the target organs and glands, the axons should travel long distances in the body, and, to accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic cell). The message is then carried to the final destination.

[0116] In the SNS and other component of the peripheral nervous system, these synapses are made at sites called ganglia, discussed above. The cell that sends its fiber to the ganglion is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic cell. As mentioned previously, the preganglionic cell of the SNS is located between the first thoracic (Tl) segment and third lumbar (L3) segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target organs or glands.

[0117] The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle, and inferior), which send sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia, which send sympathetic fibers to the gut.

[0118] FIG. 8 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery. As FIG. 8 shows, the kidney is innervated by the renal plexus (RP), which is intimately associated with the renal artery. The renal plexus (RP) is an autonomic plexus that surrounds the renal artery and is embedded within the adventitia of the renal artery. The renal plexus (RP) extends along the renal artery and is embedded within the adventitia of the renal artery. Fibers contributing to the renal plexus (RP) arise from the celiac ganglion, the superior mesenteric ganglion, the aorticorenal ganglion and the aortic plexus. The renal plexus (RP), also referred to as the renal nerve, is predominantly comprised of sympathetic components. There is no (or at least very minimal) parasympathetic innervation of the kidney.

[0119] Preganglionic neuronal cell bodies are located in the intermediolateral cell column of the spinal cord. Preganglionic axons pass through the paravertebral ganglia to become thelesser splanchnic nerve, the least splanchnic nerve, the first lumbar splanchnic nerve, the second lumbar splanchnic nerve, and travel to the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion. Postganglionic neuronal cell bodies exit the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion to the renal plexus (RP) and are distributed to the renal vasculature.

[0120] Messages travel through the SNS in a bi-directional flow. Efferent messages may trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate, widen bronchial passages, decrease motility (movement) of the large intestine, constrict blood vessels, increase peristalsis in the esophagus, cause pupil dilation, piloerection (goose bumps) and perspiration (sweating), or raise blood pressure. Afferent messages carry signals from various organs and sensory receptors in the body to other organs and, particularly, the brain.

[0121] Hypertension, heart failure, and chronic kidney disease are a few of the many disease states that result from chronic activation of the SNS, especially the renal sympathetic nervous system. Chronic activation of the SNS is a maladaptive response that drives the progression of theses disease states. Pharmaceutical management of the renin-angiotensin- aldosterone system (RAAS) has been a longstanding, but somewhat ineffective, approach for reducing over-activity of the SNS.

[0122] As mentioned above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure) and progressive renal disease, both experimentally and in humans. Studies employing radiotracer dilution methodology to measure overflow of norepinephrine from the kidneys to plasma revealed increased renal norepinephrine (NE) spillover rates in patients with essential hypertension, particularly so in young hypertensive subjects, which in concert with increased NE spillover from the heart, is consistent with the hemodynamic profile typically seen in early hypertension and characterized by an increased heart rate, cardiac output, and renovascular resistance. It is now known that essential hypertension is commonly neurogenic, often accompanied by pronounced sympathetic nervous system overactivity.

[0123] Activation of cardiorenal sympathetic nerve activity is even more pronounced in heart failure, as demonstrated by an exaggerated increase of NE overflow from the heart and the kidneys to plasma in this patient group. In line with this notion is the recent demonstration of a strong negative predictive value of renal sympathetic activation on allcause mortality and heart transplantation in patients with congestive heart failure, which isindependent of overall sympathetic activity, glomerular filtration late, and left ventricular ejection fraction. These findings support the notion that treatment regimens that are designed to reduce renal sympathetic stimulation have the potential to improve survival in patients with heart failure.

[0124] Both chronic and end state renal disease in some patients are characterized by heightened sympathetic nervous activation. In patients with end state renal disease, plasma levels of norepinephrine above the media have been demonstrated to be predictive for both all-cause death and death from cardiovascular disease. This can also be true for patients suffering from diabetic or contrast nephropathy. There is compelling evidence suggesting that sensory afferent signals originating from the diseased kidneys are major contributors to initiating and sustaining elevated central sympathetic outflow in this patient group; this facilitates the occurrence of the well-known adverse consequences of chronic sympathetic over activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, and metabolic syndrome.

[0125] Sympathetic nerves to the kidneys terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules. Stimulation of the renal sympathetic nerves cause increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These components of the neural regulation of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone and clearly contribute to the rise in blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate as a result of renal sympathetic efferent stimulation may be a cornerstone of the loss of renal function in cardio-renal syndrome, which is renal dysfunction as a progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient’s clinical status and treatment. Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). However, the current pharmacologic strategies can have significant limitations including limited efficacy, compliance issues, side effects, and others.

[0126] The kidneys communicate with integral structures in the central nervous system via renal sensory afferent nerves. Several forms of “renal injury” may induce activation of sensory afferent signals. For example, renal ischemia, reduction in stroke volume or renalblood flow, or an abundance of adenosine enzyme may trigger activation of afferent neural communication.

[0127] FIG. 9 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys. FIG. 1) is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys. As shown in FIGS. 9 and 10, the afferent communication might be from kidney to the brain or might be from one kidney to the other kidney (via the central nervous system). These afferent signals are centrally integrated and may result in increased sympathetic outflow. This sympathetic drive is directed towards the kidneys, thereby activating the RAAS and inducing increased renin secretion, sodium retention, volume retention, and vasoconstriction. Central sympathetic over activity also impacts other organs and bodily structures innervated by sympathetic nerves such as the heart and the peripheral vasculature, resulting in the described adverse effects of sympathetic activation, several aspects of which also contribute to the rise in blood pressure.

[0128] The physiology therefore suggests that (i) modulation of tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and reduction of renal blood flow, and that (ii) modulation of tissue with afferent sensory nerves will reduce the systemic contribution to hypertension and other disease states associated with increased central sympathetic tone through its direct effect on the posterior hypothalamus as well as the contralateral kidney. In addition to the central hypotensive effects of afferent renal denervation, a desirable reduction of central sympathetic outflow to various other sympathetically innervated organs such as the heart and the vasculature is anticipated.

[0129] As provided above, renal denervation is likely to be valuable in the treatment of several clinical conditions characterized by increased overall and particularly renal sympathetic activity such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end state renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome and sudden death. Since the reduction of afferent neural signals contributing to the systemic reduction of sympathetic tone / drive, renal denervation might also be useful in treating other conditions associate with systemic sympathetic hyperactivity. Accordingly, renal denervation may also benefit other organs and bodily structures innervated by sympathetic nerves, including those identified in FIG. 10. For example, as previously discussed, a reduction in central sympathetic drive may reduce the insulin resistance that afflicts people with metabolic syndrome and Type II diabetics.Additionally, patients with osteoporosis may also be sympathetically activated and might also benefit from the down regulation of sympathetic drive that accompanies renal denervation.

[0130] In accordance with the present technology neuromodulation of a left or right renal plexus (RP), which is intimately associated with a left or right renal artery, may be achieved through intravascular access. FIG. 11 is an anatomic view of the arterial vasculature of a human. As FIG. 11 shows, blood moved by contractions of the heart is conveyed from the left ventricle of the heart by the aorta. The aorta descends through the thorax and branches into the left and right renal arteries. Below the renal arteries, the aorta bifurcates at the left and right iliac arteries. The left and right iliac arteries descend, respectively, through the left and right legs and join the left and right femoral arteries.

[0131] FIG. 12 is an anatomic view of the venous vasculature of a human. As FIG. 1@ shows, the blood collects in veins and returns to the heart, through the femoral veins into the iliac veins and into the inferior vena cava. The inferior vena cava branches into the left and right renal veins. Above the renal veins, the inferior vena cava ascends to convey blood into the right atrium of the heart. From the right atrium, the blood is pumped through the right ventricle into the lungs, where it is oxygenated. From the lungs, the oxygenated blood is conveyed into the left atrium. From the left atrium, the oxygenated blood is conveyed by the left ventricle back to the aorta.

[0132] The femoral artery may be accessed and cannulated at the base on the femoral triangle just inferior to the midpoint of the inguinal ligament. A catheter may be inserted percutaneously into the femoral artery through this access site, passed through the iliac artery and aorta, and placed into either the left or right renal artery. This comprises an intravascular path that offers minimally invasive access to a respective renal artery or other renal blood vessels.

[0133] The wrist, upper arm, and shoulder region provide other locations for introduction of catheters into the arterial system. For example, catheterization of either the radial, brachial, or axillary artery may be utilized in select cases. Catheters (e.g., catheter 12) introduced via these access points may be passed through the subclavian artery on the left side (or via the subclavian and brachiocephalic arteries on the right side), through the aortic arch, down the descending aorta and into the renal arteries using standard angiographic techniques. Other access sites can also be used to access the arterial system.

[0134] Since neuromodulation of a left or right renal plexus (RP) may be achieved in accordance with the present technology through intravascular access, properties and characteristics of the renal vasculature may impose constraints upon or inform the design ofapparatus, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary across the patient population or within a specific patient across time, as well as in response to disease states, such as hypertension, chronic kidney disease, vascular disease, end-stage renal disease, insulin resistance, diabetes, metabolic syndrome, and the like. These properties and characteristics, as explained herein, may have bearing on the efficacy of the procedure and the specific design of the intravascular device. Properties of interest may include, for example, material / mechanical, spatial, fluid dynamic / hemodynamic or thermodynamic properties.

[0135] As discussed previously, a catheter may be advanced percutaneously into either the left or right renal artery via a minimally invasive intravascular path. However, minimally invasive renal arterial access may be challenging, for example, because as compared to some other arteries that are routinely accessed using catheters, the renal arteries are often extremely tortuous, may be of relatively small diameter, or may be of relatively short length.Furthermore, renal arterial atherosclerosis is common in many patients, particularly those with cardiovascular disease. Renal arterial anatomy also may vary significantly from patient to patient, which further complicates minimally invasive access. Significant inter-patient variation may be seen, for example, in relative tortuosity, diameter, length, or atherosclerotic plaque burden, as well as in the take-off angle at which a renal artery branches from the aorta. Further, some patients include multiple left renal arteries or right renal arteries. Apparatus, systems, and methods for achieving renal neuromodulation via intravascular access should account for these and other aspects of renal arterial anatomy and its variation across the patient population when minimally invasively accessing a renal artery.

[0136] In addition to complicating renal arterial access, specifics of patient anatomy can also complicate establishment of stable contact between neuromodulatory apparatus and a luminal surface or wall of a blood vessel (e.g., a renal artery). For example, navigation can be impeded by the tight space within a renal artery, as well as tortuosity of the artery.Furthermore, establishing consistent contact can be complicated by patient movement, respiration, or the cardiac cycle because these factors may cause movement of the renal artery relative to the aorta, and the cardiac cycle may transiently distend the renal artery (i.e., cause the wall of the artery to pulse).

[0137] The neuromodulation system may also be configured to allow for adjustable positioning and repositioning of distal portion 20A (FIG. 1 A) within the renal artery since location of treatment may also impact clinical efficacy. Additionally, variable positioning and repositioning of the neuromodulatory apparatus may prove to be useful in circumstanceswhere the renal artery is particularly tortuous or where there are proximal branch vessels off the renal artery main vessel, making treatment in certain locations challenging.

[0138] As noted above, an apparatus positioned within a renal artery may be configured so that distal portion 20A of catheter 12 may intimately contact the vessel wall or extend at least partially through the vessel wall. Renal artery vessel diameter, DRA, typically is in a range of about 2-10 mm, with most of the patient population having a DRA of about 4 mm to about 8 mm and an average of about 6 mm. Renal artery vessel length, LRA, between its ostium at the aorta / renal artery juncture and its distal branchings, generally is in a range of about 5-70 mm, and a significant portion of the patient population is in a range of about 20-50 mm. Since the target renal plexus is embedded within the adventitia of the renal artery, the composite Intima-Media Thickness, IMT, (i.e., the radial outward distance from the artery's luminal surface to the adventitia containing target neural structures) also is notable and generally is in a range of about 0.5-2.5 mm, with an average of about 1.5 mm. Although a certain depth of treatment is important to reach the target neural fibers, the treatment should not be too deep (e.g., > 10 mm from inner wall of the artery) to avoid non-target tissue and anatomical structures such as anatomical structures of the digestive system of psoas muscle.

[0139] An additional property of the renal artery that may be of interest is the degree of renal motion relative to the aorta induced by respiration or blood flow pulsatility. A patient’s kidney, which is located at the distal end of the renal artery, may move as much as 10 centimeters cranially with respiratory excursion. This may impart significant motion to the renal artery connecting the aorta and the kidney, thereby requiring from the neuromodulatory apparatus a unique balance of stiffness and flexibility to maintain contact between the energy delivery element and the vessel wall during cycles of respiration. Furthermore, the take-off angle between the renal artery and aorta may vary significantly between patients, and also may vary dynamically within a patient, e.g., due to kidney motion. The take-off angle generally may be in a range of about 30°-135°.

[0140] In general, the devices, systems, and techniques described herein may be used in conjunction with neuromodulation performed from within any suitable anatomical lumen that has nerves adjacent to the anatomical lumen. Example anatomical lumens include the celiac trunk and its branches (including the common hepatic artery and its branches, the gastroduodenal artery and its branches, the right gastric artery and its branches, and the proper hepatic artery and its branches, the left gastric artery and its branches, and the splenic artery and its branches), the superior mesenteric artery and its branches, the gonadal artery and its branches, the inferior mesenteric artery and its branches, and the like. Further, although thedisclosure primarily describes neuromodulation from within one or more arteries, the devices, systems, and techniques of the disclosure also may be applied to neuromodulation from within one or more veins, such as a renal vein and its branches, a hepatic vein and its branches, an intercostal vein and its branches, or the like.

[0141] In some implementations, the devices, systems, and techniques described herein may be used to perform neuromodulation from within two or more anatomical lumens, e.g., in the renal arteries and the common hepatic artery, or any other combination of two or more anatomical lumens, either simultaneously or sequentially. In addition, the systems, devices, and methods described herein may be useful in conjunction with neuromodulation within a body lumen other than a vessel, for extravascular neuromodulation and / or for use in conjunction with therapies other than neuromodulation.

[0142] The following enumerated clauses describe examples according to the present disclosure.

[0143] Clause 1 : A neuromodulation catheter including: an elongate body configured to transform from a relatively low profile configuration to an expanded configuration; a therapy delivery element disposed on the elongate body; and a sensor array disposed on the elongate body, where the sensor array includes a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration.

[0144] Clause 2: The neuromodulation catheter of clause 1, where the elongate body is configured to define a loop, a helix, or a spiral in the expanded configuration.

[0145] Clause 3 : The neuromodulation catheter of clauses 1 or 2, where the elongate body is configured to be placed in a blood vessel, where at least one of the first ultrasound transceiver and the second ultrasound transceiver is configured to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel when the elongate body is in the expanded configuration in the blood vessel, and where at least another of the first ultrasound transceiver or the second ultrasound transceiver is configured to detect the at least one ultrasound signal.

[0146] Clause 4: The neuromodulation catheter of clause 3, where the first ultrasound transceiver and the second ultrasound transceiver are configured to be transverse across a direction of blood flow through the blood vessel when the elongate body is in the expanded configuration in the blood vessel.

[0147] Clause 5: The neuromodulation catheter of clause 4, where the first ultrasound transceiver and the second ultrasound transceiver are offset along an offset direction relativeto an expanded longitudinal axis defined by the elongate body in the expanded configuration, where the offset direction defines a minor angle relative to the direction of blood flow in a range of from 30 degrees to 60 degrees.

[0148] Clause 6: The neuromodulation catheter of clause 5, where the minor angle is 45 degrees.

[0149] Clause 7: The neuromodulation catheter of any of clauses 3 to 6, where the first ultrasound transceiver is configured to be downstream of the second ultrasound transceiver relative to the blood flow when the elongate body is in the expanded configuration in the blood vessel.

[0150] Clause 8: The neuromodulation catheter of any of clauses 1 to 7, where each of the first ultrasound transceiver and the second ultrasound transceiver is configured to transmit a respective ultrasound signal toward the other of the first ultrasound transceiver and the second ultrasound transceiver.

[0151] Clause 9: The neuromodulation catheter of clause 8, where each of the first ultrasound transceiver and the second ultrasound transceiver is configured to receive the respective ultrasound signal transmitted by the other of the first ultrasound transceiver and the second ultrasound transceiver.

[0152] Clause 10: The neuromodulation catheter of any of clauses 1 to 9, where the first ultrasound transceiver is configured to be distal to the second ultrasound transceiver when the elongate body is in the expanded configuration.

[0153] Clause 11 : The neuromodulation catheter of any of clauses 1 to 10, where the first ultrasound transceiver is positioned distal to the second ultrasound transceiver along the elongate body.

[0154] Clause 12: The neuromodulation catheter of any of clauses 1 to 11, where the therapy delivery element includes one or more of an electrode, a thermal probe, a cryogenic probe, a microwave transducer, an ultrasound transducer, or a chemical denervation agent source.

[0155] Clause 13: The neuromodulation catheter of any of clauses 1 to 12, where the sensor array is distal to the therapy delivery element along the elongate body.

[0156] Clause 14: The neuromodulation catheter of any of clauses 1 to 12, where the sensor array is proximal to the therapy delivery element along the elongate body.

[0157] Clause 15: The neuromodulation catheter of any of clauses 1 to 14, further including a plurality of therapy delivery elements disposed on the elongate body, the plurality of therapy delivery elements including the therapy delivery element.

[0158] Clause 16: The neuromodulation catheter of any of clauses 1 to 15, where the sensor array further includes a third ultrasound transceiver and a fourth ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration.

[0159] Clause 17: The neuromodulation catheter of clause 16, where the sensor array is interleaved with the plurality of therapy delivery elements along the elongate body.

[0160] Clause 18: The neuromodulation catheter of clause 17, where the sensor array is longitudinally or circumferentially offset relative to the plurality of therapy delivery elements along the elongate body when the elongate body is in the expanded configuration.

[0161] Clause 19: The neuromodulation catheter of clause 16, where the sensor array is spaced from the plurality of therapy delivery elements along the elongate body.

[0162] Clause 20: A neuromodulation system including: the neuromodulation catheter of any of clauses 1 to 19, where the neuromodulation catheter is configured to be introduced in a blood vessel; and control circuitry configured to cause at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal.

[0163] Clause 21 : The neuromodulation system of clause 20, where the control circuitry is further configured to determine a transit time for transmission of the at least one ultrasound signal across a direction of blood flow through the blood vessel.

[0164] Clause 22: Then neuromodulation system of clause 21, where the transit time is an average transit time for transmission of a first ultrasound signal across the direction of the blood flow through the blood vessel in a first direction and a second ultrasound signal across the direction of the blood flow through the blood vessel in a second direction opposite the first direction.

[0165] Clause 23: The neuromodulation system of clauses 21 or 22, where the control circuitry is further configured to determine, based on a correlation between the transit time and blood flow rate, a blood flow rate of the blood flow.

[0166] Clause 24: The neuromodulation system of clause 23, where the transit time is proportional to the blood flow rate.

[0167] Clause 25: The neuromodulation system of any of clauses 21 to 24, where the blood vessel is a renal blood vessel, and where the control circuitry is further configured to determine a parameter of blood flow through the renal blood vessel based on the transit time.

[0168] Clause 26: The neuromodulation system of any of clauses 20 to 25, where the control circuitry is further configured to determine: a first blood flow rate based on a first transit time before a neuromodulation procedure, a second blood flow rate based on a second transit time after the neuromodulation procedure, and an efficacy of the neuromodulation procedure based on a comparison of the first blood flow rate and the second blood flow rate.

[0169] Clause 27: The neuromodulation system of any of clauses 20 to 26, further including stimulation generation circuitry configured to deliver electrical stimulation to a target site.

[0170] Clause 28: The neuromodulation system of clause 27, where: the stimulation generation circuitry is configured to deliver the electrical stimulation to the target site at a first time before the neuromodulation procedure, the control circuitry is configured to determine the first blood flow rate after the stimulation generation circuitry delivers the electrical stimulation to the target site at the first time before the neuromodulation procedure; the stimulation generation circuitry is configured to deliver the electrical stimulation to the target site at a second time after the neuromodulation procedure; and the control circuitry is configured to determine the second blood flow rate after the stimulation generation circuitry delivers the electrical stimulation to the target site at the second time after the neuromodulation procedure.

[0171] Clause 29: The neuromodulation system of clauses 27 or 28, where the stimulation generation circuitry is configured to cause the therapy delivery element to deliver the electrical stimulation to the target site.

[0172] Clause 30: The neuromodulation system of clauses 27 or 28, where the neuromodulation catheter further includes a stimulation element disposed on the elongate body, and where the stimulation generation circuitry is configured to cause the stimulation element to deliver the electrical stimulation to the target site.

[0173] Clause 31 : The neuromodulation system of any of clauses 26 to 30, where the control circuitry is further configured to determine: a presence or extent of vasoconstriction based on the comparison of the first blood flow rate and the second blood flow rate; and determine the efficacy based on the presence or extent of vasoconstriction.

[0174] Clause 32: The neuromodulation system of clause 31, where the control circuitry is further configured to determine the presence of vasoconstriction in response to determining that the second blood flow rate is lower than the first blood flow rate.

[0175] Clause 33: The neuromodulation system of clause 31 or clause 32, where the control circuitry is further configured to determine the extent of vasoconstriction based on a magnitude of a difference between the second blood flow rate and the first blood flow rate.

[0176] Clause 34: The neuromodulation system of any of clauses 26 to 33, where the control circuitry is further configured to generate an output indicative of the efficacy of the neuromodulation therapy.

[0177] Clause 35: The neuromodulation system of any of clauses 26 to 34, where the control circuitry is further configured to generate a notification in response to determining that the efficacy of the neuromodulation therapy is lower than a threshold value.

[0178] Clause 36: The neuromodulation system of any of clauses 26 to 35, where the control circuitry is further configured to control a medical device to adjust the neuromodulation therapy based on the efficacy.

[0179] Clause 37: The neuromodulation system of any of clauses 26 to 36, where the control circuitry is further configured to automatically adjust the neuromodulation therapy based on the efficacy.

[0180] Clause 38: A method including causing, by control circuitry: at least one of the first ultrasound transceiver or the second ultrasound transceiver of the neuromodulation catheter of any of clauses 1 to 19 to emit at least one ultrasound signal transmitted through blood flowing through a blood vessel; and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal, where the elongate body is placed in the blood vessel.

[0181] Clause 39: The method of clause 38, further including determining, by the control circuitry, a transit time for transmission of the at least one ultrasound signal across a direction of blood flow through the blood vessel.

[0182] Clause 40: Then method of clause 39, where the transit time is an average transit time for transmission of a first ultrasound signal across the direction of the blood flow through the blood vessel in a first direction and a second ultrasound signal across the direction of the blood flow through the blood vessel in a second direction opposite the first direction.

[0183] Clause 41 : The method of clauses 39 or 40, further including determining, by the control circuitry and based on a correlation between the transit time and blood flow rate, a blood flow rate of the blood flow.

[0184] Clause 42: The method of clause 41, where the transit time is proportional to the blood flow rate.

[0185] Clause 43: The method of any of clauses 38 to 42, where the blood vessel is a renal blood vessel, the method further including, determining by the control circuitry, a renal blood flow through the renal blood vessel based on the transit time.

[0186] Clause 44: The method of any of clauses 38 to 43, further including determining, by the control circuitry: a first blood flow rate based on a first transit time before a neuromodulation procedure; a second blood flow rate based on a second transit time after the neuromodulation procedure; and an efficacy of the neuromodulation procedure based on a comparison of the first blood flow rate and the second blood flow rate.

[0187] Clause 45: The method of any of clauses 38 to 44, further including delivering, by stimulation generation circuitry, electrical stimulation to a target site.

[0188] Clause 46: The method of clause 45, further including: delivering, by the stimulation generation circuitry, the electrical stimulation to the target site before the neuromodulation procedure; determining, by the control circuitry, the first blood flow rate after delivering the electrical stimulation and before the neuromodulation procedure; delivering, by the stimulation generation circuitry, the electrical stimulation to the target site after the neuromodulation procedure; and determining, by the control circuitry, the second blood flow rate after delivering the electrical stimulation and after the neuromodulation procedure.

[0189] Clause 47: The method of clauses 45 or 46, including further causing, by the stimulation generation circuitry, the therapy delivery element to deliver the electrical stimulation to the target site.

[0190] Clause 48: The method of clauses 45 or 46, where the neuromodulation catheter further includes a stimulation element disposed on the elongate body, the method further including causing, by the stimulation generation circuitry, the stimulation element to deliver the electrical stimulation to the target site.

[0191] Clause 49: The method of any of clauses 46 to 48, further including, by the control circuitry: determining a presence or an extent of vasoconstriction based on the comparison of the first blood flow rate and the second blood flow rate; and determining the efficacy based on the presence or extent of vasoconstriction.

[0192] Clause 50: The method of clause 49, further including determining, by the control circuitry, the presence of vasoconstriction in response to determining that the second blood flow rate is lower than the first blood flow rate.

[0193] Clause 51 : The method of clause 50, further including determining, by the control circuitry, the extent of vasoconstriction based on a magnitude of a difference between the second blood flow rate and the first blood flow rate.

[0194] Clause 52: The method of any of clauses 46 to 51, further including generating, by the control circuitry, an output indicative of the efficacy of the neuromodulation therapy.

[0195] Clause 53: The method of any of clauses 46 to 52, further including generating, by the control circuitry, a notification in response to determining that the efficacy of the neuromodulation therapy is lower than a threshold value.

[0196] Clause 54: The method of any of clauses 46 to 53, further including controlling, by the control circuitry, a medical device to adjust the neuromodulation therapy based on the efficacy.

[0197] Clause 55: The method of any of clauses 46 to 54, further including automatically adjusting, by the control circuitry, the neuromodulation therapy based on the efficacy.

[0198] Certain aspects of the present disclosure described in the context of particular examples may be combined or eliminated in other examples. Further, while advantages associated with certain examples have been described in the context of those examples, other examples may also exhibit such advantages, and not all examples need necessarily exhibit such advantages to fall within the scope of the present disclosure. Accordingly, the present disclosure and associated technology can encompass other examples not expressly shown or described herein.

[0199] Moreover, unless the word “or” is expressly limited to mean only a single term exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and / or additional types of other features are not precluded.

[0200] It should be understood that various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the techniques). In addition, while certain aspects of this disclosure are described as being performed by a single module, unit, or circuit for purposes of clarity, it should be understood that the techniques of this disclosure may beperformed by a combination of units, modules, or circuitry associated with, for example, a medical device.

[0201] In one or more examples, the described techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware-based processing unit. Computer-readable media may include non-transitory computer-readable media, which corresponds to a tangible medium such as data storage media (e.g., RAM, ROM, EEPROM, flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and that can be accessed by a computer).

[0202] Instructions may be executed by one or more processors that include processing circuitry, such as one or more digital signal processors (DSPs), general purpose microprocessors, application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry. Accordingly, the term “processor” or “processing circuitry” as used herein may refer to any of the foregoing structure or any other physical structure suitable for implementation of the described techniques. Also, the techniques could be fully implemented in one or more circuits or logic elements.

[0203] The above detailed descriptions of examples of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Although specific examples of the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative examples may perform steps in a different order. The various examples described herein may also be combined to provide further examples. All references cited herein are incorporated by reference as if fully set forth herein.

[0204] From the foregoing, it will be appreciated that specific examples of the present disclosure have been described herein for purposes of illustration, but that various modifications may be made without deviating from the present disclosure.

[0205] Various examples have been described. These and other examples are within the scope of the following claims.

Claims

CLAIMS1. A neuromodulation catheter comprising: an elongate body configured to transform from a relatively low profile configuration to an expanded configuration; a therapy delivery element disposed on the elongate body; and a sensor array disposed on the elongate body, wherein the sensor array comprises a first ultrasound transceiver and a second ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration.

2. The neuromodulation catheter of claim 1, wherein the elongate body is configured to define a loop, a helix, or a spiral in the expanded configuration.

3. The neuromodulation catheter of any one of claims 1 or 2, wherein the elongate body is configured to be placed in a blood vessel, wherein at least one of the first ultrasound transceiver and the second ultrasound transceiver is configured to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel when the elongate body is in the expanded configuration in the blood vessel, and wherein at least another of the first ultrasound transceiver or the second ultrasound transceiver is configured to detect the at least one ultrasound signal.

4. The neuromodulation catheter of claim 3, wherein the first ultrasound transceiver and the second ultrasound transceiver are configured to be transverse across a direction of blood flow through the blood vessel when the elongate body is in the expanded configuration in the blood vessel.

5. The neuromodulation catheter of claim 4, wherein the first ultrasound transceiver and the second ultrasound transceiver are offset along an offset direction relative to an expanded longitudinal axis defined by the elongate body in the expanded configuration, wherein the offset direction defines a minor angle relative to the direction of blood flow in a range of from 30 degrees to 60 degrees.

6. The neuromodulation catheter of any one of claims 1 to 5, wherein the first ultrasound transceiver is configured to be downstream of the second ultrasound transceiver relative to the blood flow when the elongate body is in the expanded configuration in the blood vessel.

7. The neuromodulation catheter of any one of claims 1 to 6, wherein each of the first ultrasound transceiver and the second ultrasound transceiver is configured to transmit a respective ultrasound signal toward the other of the first ultrasound transceiver and the second ultrasound transceiver.

8. The neuromodulation catheter of any one of claims 1 to 7, wherein the first ultrasound transceiver is positioned distal to the second ultrasound transceiver along the elongate body.

9. The neuromodulation catheter of any one of claims 1 to 8, wherein the therapy delivery element comprises one or more of an electrode, a thermal probe, a cryogenic probe, a microwave transducer, an ultrasound transducer, or a chemical denervation agent source.

10. The neuromodulation catheter of any one of claims 1 to 9, wherein the sensor array further comprises a third ultrasound transceiver and a fourth ultrasound transceiver longitudinally and transversely offset from each other when the elongate body is in the expanded configuration.

11. A neuromodulation system comprising: the neuromodulation catheter of any one of claims 1 to 10; and control circuitry configured to cause at least one of the first ultrasound transceiver or the second ultrasound transceiver to emit at least one ultrasound signal transmitted through blood flowing through the blood vessel and at least another of the first ultrasound transceiver or the second ultrasound transceiver to detect the at least one ultrasound signal.

12. The neuromodulation system of claim 11, wherein the control circuitry is further configured to determine a transit time for transmission of the at least one ultrasound signal across a direction of blood flow through the blood vessel.

13. Then neuromodulation system of claim 12, wherein the transit time is an average transit time for transmission of a first ultrasound signal across the direction of the blood flowthrough the blood vessel in a first direction and a second ultrasound signal across the direction of the blood flow through the blood vessel in a second direction opposite the first direction.

14. The neuromodulation system of any one of claims 12 or 13, wherein the control circuitry is further configured to determine, based on a correlation between the transit time and blood flow rate, a blood flow rate of the blood flow.

15. The neuromodulation system of any one of claims 11 to 14, wherein the control circuitry is further configured to determine: a first blood flow rate based on a first transit time before a neuromodulation procedure, a second blood flow rate based on a second transit time after the neuromodulation procedure, and an efficacy of the neuromodulation procedure based on a comparison of the first blood flow rate and the second blood flow rate.

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