Renal vasoconstriction and renal blood flow response to stimulation as a guide to renal denervation

Abstract

A method of performing a therapeutic procedure includes navigating a therapeutic device to a location adjacent to target tissue, determining a first flow parameter within a blood vessel adjacent to the target tissue, applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue, applying therapy to the target tissue, applying neurostimulation to the target tissue, determining a second flow parameter within the blood vessel adjacent to the target tissue, comparing the second flow parameter to a flow parameter criteria, applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue, comparing the first images to the second images to determine a vasoconstriction metric, and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.

Description

RENAL VASOCONSTRICTION AND RENAL BLOOD FLOW RESPONSE TO STIMULATION AS A GUIDE TO RENAL DENERVATION

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 555,617, filed February 20, 2024, the entire content of which is incorporated herein by reference.Technical Field

[0002] This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure.Background

[0003] Catheters can be configured to deliver neuromodulation (e.g., denervation) therapy to a target tissue site to modify the activity of nerves at or near the target tissue site. The nerves can be, for example, sympathetic or parasympathetic nerves. The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Chronic over-activation of the SNS is a maladaptive response that can drive the progression of many disease states. For example, excessive activation of the renal SNS has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.

[0004] Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by over-activation of the SNS. During a renal denervation procedure, a clinician delivers stimuli or energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site to reduce activity of nerves surrounding a blood vessel. The stimuli or energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.

[0005] During current denervation procedures, it is not possible for a clinician to visualize the nerves prior to application of the therapy. Instead, denervation catheters are positioned to the best of the clinician’s abilities and several ablations performed. As a result, the clinicians have no indication the ablations they are performing are actually ablating any nerves. Further, there is no indication during the procedure that the ablation was successful.Accordingly, this disclosure is directed to systems and methods of addressing these shortcomings of the current technologies.SUMMARY

[0006] In accordance with the disclosure, a method of performing a therapeutic procedure includes navigating a therapeutic device to a location within a blood vessel adj acent to target tissue, determining a first flow parameter within a portion of a blood vessel adjacent to the target tissue, applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue, applying therapy to the target tissue, applying neurostimulation to the target tissue, determining a second flow parameter within the portion of the blood vessel adjacent to the target tissue, comparing the second flow parameter to a flow parameter criteria, applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue, comparing the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.

[0007] In accordance with another aspect of the disclosure, a method of performing a therapeutic procedure includes injecting a fluid into a blood vessel adjacent to target tissue, imaging blood vessels distal of the target tissue, identifying a first landmark adjacent to the target tissue, identifying a second landmark adjacent to the target tissue, identifying a first point in time at which the injected fluid flows past the first landmark, identifying a second point in time at which the injected fluid flows past the second landmark, determining a flow parameter of the injected fluid based on the identified first point in time and the identified second point in time, comparing the determined flow parameter to a flow parameter criteria, and applying therapy to the target tissue if the determined flow parameter satisfies the flow parameter criteria.

[0008] In accordance with another aspect of the disclosure, a system for performing a diagnostic and therapeutic procedure includes a workstation, the workstation including a processor and a memory, the memory storing instructions thereon, which when executed cause the processor to determine a first flow parameter within a portion of a blood vessel adjacent to target tissue, cause a stimulation source to output a neurostimulation signal viaat least one stimulation element to the target tissue and obtain first images of blood vessels distal of the target tissue, cause a therapy source to output a therapy signal via at least one therapy element to the target tissue, apply neurostimulation to the target tissue, determine a second flow parameter within the portion of the blood vessel adjacent to the target tissue, compare the second flow parameter to a flow parameter criteria, apply neurostimulation to the target tissue and obtain second images of the blood vessels distal of the target tissue, compare the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, and apply therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.

[0009] In accordance with another aspect of the disclosure, a method includes causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned at a location within a target vessel, wherein the at least one stimulation element is coupled to a therapeutic device, causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel, in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel, determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location, determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric, and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, outputting, by the computing device, an indication related to the location being a candidate for a denervation procedure.

[0010] In accordance with yet another aspect of the disclosure, a method includes, after a denervation procedure has been performed at a location of a target vessel, causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned proximate the location, wherein the at least one stimulation element is coupled to a therapeutic device, causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel, in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulationelement positioned at the location within the target vessel, determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location, determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric, and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, outputting, by the computing device, an indication related to a success of the denervation procedure.

[0011] In accordance with an additional aspect of the disclosure, a method may include applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

[0012] In accordance with another aspect of the disclosure, a method may include applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while applying the neuromodulation therapy to the target tissue: applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; and iteratively determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to anindication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

[0013] In accordance with a further aspect of the disclosure, a system may include a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in and / or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after the neuromodulation therapy is applied to the target tissue, cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

[0014] In accordance with another aspect of the disclosure, a system may include a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while the neuromodulation therapy is being applied to the target tissue: cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; and determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication ofinadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

[0015] Further disclosed herein is a method of performing a therapeutic procedure that includes navigating a therapeutic device to a location adjacent to target tissue, determining a first flow parameter within a blood vessel adjacent to the target tissue, applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue, applying therapy to the target tissue, applying neurostimulation to the target tissue, determining a second flow parameter within the blood vessel adjacent to the target tissue, comparing the second flow parameter to a flow parameter criteria, applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue, comparing the first images to the second images to determine a vasoconstriction metric , and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Various aspects and embodiments of the disclosure are described hereinbelow with references to the drawings, wherein:

[0017] FIG. l is a schematic diagram of a therapy system in accordance with the disclosure;

[0018] FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;

[0019] FIG. 3 is a perspective view of a therapeutic device of the therapy system ofFIG. 1 advanced within a portion of the patient’s anatomy and shown in a deployed condition in accordance with the disclosure;

[0020] FIG. 4 is a representation of an external stimulation energy transducer in accordance with the disclosure;

[0021] FIG. 5 is a representation of an internal stimulation energy transducer in accordance with the disclosure;

[0022] FIG. 6A is a graphical representation of changes in physiological parameters experienced by a patient as a result of a pre-therapy application of stimulation in accordance with the disclosure;

[0023] FIG. 6B is a graphical representation of changes in physiological parameters experienced by a patient as a result of post-therapy application of stimulation in accordance with the disclosure;

[0024] FIG. 7A is a visual representation of blood vessels before applying stimulation and therapy in accordance with the disclosure;

[0025] FIG. 7B is a visual representation of blood vessels after applying stimulation and before applying therapy in accordance with the disclosure;

[0026] FIG. 7C is a visual representation of blood vessels after applying therapy in accordance with the disclosure;

[0027] FIG. 7D is a visual representation of blood vessels after applying stimulation and therapy in accordance with the disclosure;

[0028] FIG. 8 is a graphical representation of a flow parameter within a blood vessel over a period of time in accordance with the disclosure;

[0029] FIG. 9 is a graphical representation of determining a flow parameter within a blood vessel in accordance with the disclosure;

[0030] FIG. 10 is a plan view of the therapeutic device of the therapy system of FIG. 1 including temperature sensors in accordance with the disclosure;

[0031] FIG. 11 A is a flow chart detailing a method of performing a therapeutic procedure in accordance with the disclosure;

[0032] FIG. 1 IB is a continuation of the flow chart of FIG. 11 A;

[0033] FIG. 12A is a flow chart detailing another method of performing a therapeutic procedure in accordance with the disclosure;

[0034] FIG. 12B is a continuation of the flow chart of FIG. 12A;

[0035] FIG. 13 A is a flow chart detailing yet another method of performing a therapeutic procedure in accordance with the disclosure;

[0036] FIG. 13B is a continuation of the flow chart of FIG. 13 A;

[0037] FIG. 13C is a continuation of the flow chart of FIG. 13B;DETAILED DESCRIPTION

[0038] The disclosure describes therapeutic systems and methods for ablation or neuromodulation of nerves such as the sympathetic or parasympathetic nerves, including, unmyelinated nerve fibers in and around blood vessels and other luminal tissues. To providefeedback related to neuromodulating the nerves, the therapeutic system is configured to identify a flow parameter associated with a blood vessel adjacent to the target nerves. The flow parameter may be identified before, during, and / or after neurostimulation and may be identified before and / or after the application of therapy to the target nerves. If the flow parameter changes in response to neurostimulation, or changes more than a threshold amount, this may indicate intact (functioning) target nerves. However, if the flow parameter does not change in response to neurostimulation, or changes less than a threshold amount, this may indicate that the target nerves have been successfully ablated. In some cases, there may be a third category, where the flow change parameter changes in response to neurostimulation, but not greater than a threshold amount, which indicates that some target nerves have been ablated but others are intact.

[0039] Flow response to stimulation may be faster than response of other physiological parameters, but in some instances, those other physiological parameters may provide additional information regarding progress or success of target nerve ablation. For example, blood vessel and blood vessel branches adjacent to and / or distal of the target nerves may contract or otherwise constrict (vasoconstrict) in response the application of neurostimulation if the function of the target nerves is intact. This vasoconstriction can be indicative of nerves that are a candidate for neuromodulation or ablation. On the other hand, blood vessel and blood vessel branches adjacent to and / or distal of the target nerves may not contract or otherwise constrict in response the application of neurostimulation if the function of the target nerves is not intact. Vasoconstriction may provide more granular information that the flow parameter, e.g., may be specific to different downstream blood vessel branches. In this way, vasoconstriction may provide information about where neuromodulation therapy should be performed. However, vasoconstriction may be slower to occur after neurostimulation than changes in flow. Thus, using a combination of flow parameter and, if needed, vasoconstriction, may speed initial feedback of whether ablation has been successful, while allowing further information to be gathered if needed.

[0040] The flow parameters within the blood vessels may be measured or otherwise identified using flow sensors (disposed on or coupled to the therapeutic device), imaging blood vessels, or combinations thereof. It is envisioned that the flow sensor may be disposed on a guidewire. As can be appreciated, imaging blood vessels reveals landmarks or other structures within the patient’s anatomy, in addition to radiopaque surgical devices, that canbe used to determine distances along the length of the blood vessels. A contrast agent can be injected into the blood stream of the patient and the blood vessels can be imaged during or immediately after injection. The system identifies points in time at which the contrast agent flows past the identified landmarks, which can be used to determine the flow parameters within the blood vessels. In embodiments, a room temperature fluid may be injected into the blood stream of the patient and a temperature of fluid surrounding the therapeutic device may be monitored to identify changes in temperature. As an be appreciated, a change in temperature is indicative of the room temperature fluid flowing past the therapeutic device. In this manner, the system identifies points in time at which temperature changes occur at various locations along the length of the blood vessel. These points in time and identified distances between these locations can be used to identify or otherwise determine the flow parameters within the blood vessels.

[0041] For ease of description, much of the following description focuses on implementations of electrical stimulation and RF denervation. Those having skill in the art will recognize that the methods and systems described herein may employ any of the therapy and / or neurostimulation modalities described herein. Similarly, the following description focuses on navigation to and application of neurostimulation and / or therapy to the renal artery to denervate sympathetic or, in certain embodiments, parasympathetic, nerves in, around, and proximate the renal arteries. However, the present disclosure is not so limited and can be employed for denervating nerves accessible via any blood vessel described herein of other luminal tissue (e.g., a bile duct).

[0042] Turning now to the drawings, FIG. 1 illustrates a guidance and therapy system provided in accordance with the disclosure and generally identified by reference numeral 10. As will be described in further detail hereinbelow, the guidance and therapy system 10 enables navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., for example, the patient’s renal artery), delivery of neurostimulation to tissue within the renal artery, observing and / or measuring a physiological response to the application of neurostimulation to the tissue, if necessary, adjustment of a position of the therapeutic device within the renal artery based upon the physiological response, reapplication of the neurostimulation to the tissue at the adjusted position, application of denervation therapy to the tissue within the renal artery to denervate sympathetic nerves within the tissue, and delivery of neurostimulation to the denervated tissue to observe and / ormeasure the physiological response to the neurostimulation and assess the efficacy of the denervation therapy.

[0043] The guidance and therapy system 10 includes a workstation 20, a therapeutic device 50 operably coupled to the workstation 20, and an imaging device 70, which in embodiments, may be operably coupled to the workstation 20. The patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of the patient’s femoral artery, although it is contemplated that the therapeutic device 50 may be inserted into any suitable portion of the patient’s vascular network that is in fluid communication with a desired blood vessel for therapy. Although generally described as having one therapeutic device 50, it is envisioned that the therapy system 10 may employ any suitable number of therapeutic devices 50. It is envisioned that the therapeutic devices 50 may employ the same or different therapy modalities. As will be described in further detail hereinbelow, the therapeutic device 50 may employ a guidewire 64 and / or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.

[0044] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computer 22, a therapy source 24 e.g., for example, an ultrasound (US) generator, a Radio Frequency (RF) generator, a microwave generator, a heating and / or cooling source (e.g., for example, electrical energy and cryotherapy), a chemical source, and combinations thereof) operably coupled to the computer, and a neurostimulation source 24a operably coupled to the computer 22. Although generally described as being separate from the therapy source 24, it is envisioned that the stimulation source 24a may be integrated within the therapy source 24, as described hereinabove, and the therapy source 24 may generate both therapy and neurostimulation modalities.

[0045] The computer 22 is coupled to a display 26 that is configured to display one or more user interfaces 28. The computer 22 may be a desktop computer or a tower configuration with the display 26 or may include a laptop computer or other computing device. The computer 22 includes a processor 30 which executed software stored in a memory 32. The memory 32 may store one or more applications 34 and / or algorithms 44 to be executed by the processor 30. A network interface 36 enables the workstation 20 to communicate with a variety of other devices and systems via the Internet. The network interface 36 may connect the workstation 20 to the Internet via a wired or wireless connection. Additionally, or alternatively, the communication may be via an ad hocBluetooth® or wireless network enabling communication with a wide-area network (WAN) and / or a local area network (LAN). The network interface 36 may connect to the Internet via one or more gateways, routers, and network address translation (NAT) devices. The network interface 36 may communicate with a cloud storage system 38, in which further data, image data, and / or videos may be stored. The cloud storage system 38 may be remote from or on the premises of the hospital such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 could also serve as a host for more robust analysis of acquired images (e.g., for example, fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), ultrasound, and angiography) and data (e.g., for example, additional or reinforcement data for analysis and / or comparison). An input module 40 receives inputs from an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., for example, a foot pedal or handheld remote-control device that enables the clinician to initiate, terminate, and optionally, adjust various operational characteristics of the therapy source 24 and / or neurostimulation source 24a, including, but not limited to, power delivery). An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26, which in embodiments, may be a touchscreen display.

[0046] The therapy source 24 generates and outputs one or more of US energy, RF energy (monopolar or bipolar), microwave energy, cryogenic medium, and / or chemical ablation medium via an automated control algorithm 44 stored on the memory 32 and / or under the control of a clinician. As can be appreciated, the therapy generated or output by the therapy source 24 changes a temperature of the tissue (e.g, for example, increases or decreases the temperature) to achieve the desired denervation of the nerves. As will be described in further detail hereinbelow, the therapy source 24 may be configured to produce a selected modality and magnitude of energy and / or therapy for delivery to the treatment site via the therapeutic device 50. The therapy source may monitor voltage and current applied to target tissue via the therapeutic device 50, may monitor the temperature of the target tissue or tissue proximate the target tissue, and / or a portion of the therapeutic device 50. Utilizing the sensed voltage and current applied to the tissue, an application 34 on the computer 22 may be configured to calculate an impedance of the tissue through which therapy is transmitted to provide an indication of the status of the tissue. The computer 22may be configured to output the status to the display 26 on one or more user interfaces 28 to provide a clinician with both intraprocedural and post-procedural feedback regarding the therapy.

[0047] In contrast with the therapy source 24, the stimulation source 24a generates and outputs a non-therapeutic stimulation signal, for example a biphasic waveform, at an energy level that is less than the therapy signal (e.g., for example, denervation signal) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue. Rather, the stimulation source 24a generates a stimulation signal capable of effectuating a response from the nerves indicative of tissue that would be a candidate for denervation, such as, for example, a change in blood pressure, an increase in vessel stiffness, pulse wave velocity, augmentation pressure, heart rate variability, fluid flow through the vessel, a velocity of fluid flowing through the vessel, vasoconstriction, and combinations thereof. In one non-limiting embodiment, the stimulation source 24a generates a biphasic waveform where a leading phase of each successive pulse of the biphasic waveform is switched or otherwise inverted. In this manner, a biphasic waveform having an initial pulse with an anodal leading phase and a cathodal trailing phase is followed by a second pulse with a cathodal leading phase and an anodal trailing phase which will be followed by a third pulse returning to an anodal leading phase and a cathodal trailing phase, and so on. Alternatively, a biphasic waveform having an initial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase. As can be appreciated, the leading phase of each pulse of the biphasic waveform may be alternated for the duration of the application of neurostimulation to the target tissue.

[0048] As noted hereinabove, the amplitude, frequency, pulse width, and / or duration of the stimulation can be selected and / or modified to ensure neurostimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., for example, inhibiting the movement of the therapeutic device 50 within the luminal tissue). For example, a pulse duration (e.g., for example, a pulse width) of the stimulation may be modified to ensure that anodic stimulation of the tissue is maintained, as at certain pulse durations, regions of anodic stimulation may dissipate orotherwise disappear resulting in reduced stimulation effect. In one non-limiting embodiment, the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30 Hz, a voltage of between approximately 5 - 30 V, a current of between approximately 2 - 500 mA, and a pulse width of between approximately 2 - 10 ms. It is envisioned that in embodiments where unmyelinated nerve fibers are targeted, the pulse width of the biphasic waveform may be between approximately 2 - 120 ms. In embodiments, the stimulation parameters may be a constant current of 20 mA for blood vessel branches and 30 mA for main blood vessels, a pulse width of 5 ms, a frequency of approximately 20 Hz, and a duration of between 10 and 60 seconds.

[0049] Although generally described as generating a stimulation signal having biphasic waveform, the disclosure is not so limited. It is envisioned that the stimulation source 24a may generate and output a Focused Ultrasound signal (FUS) and / or a High Intensity Focused Ultrasound signal (HIFU). In this manner, the stimulation source 24a may be connected to a HIFU transducer 102 (FIG. 4) to produce a FUS at a frequency of between approximately 250 KHz and 700 KHz, though certain applications employing an external HIFU transducer can require up to 4 MHz, for example about 3.57 MHz. The duty cycle may range from about 5-about 10 % depending on the vessel wall composition. A therapy session (stimulation + therapy) may have a duration of between 30 and 120 seconds. The HIFU transducer 102 is acoustically coupled to a patient via a coupling medium (e.g., for example, saline) in a coupling chamber 104 that is placed on the skin of the patient. Alternatively, in place of the coupling medium in a coupling chamber 104, a gel material acoustically coupling the HIFU transducer 102 with the patient may be employed without departing from the scope of the disclosure. It is envisioned that the HIFU transducer 102 can be disposed external to the patient and may be employed to both image portions of the patient, apply FUS neurostimulation, and to apply US therapy signals to the sympathetic nerves of an identified artery. In embodiments, a neurostimulation catheter 110 may be employed having one or more HIFU transducers 112 configured to apply FUS stimulation to the nerves surrounding the blood vessel in accordance with aspects of the disclosure. A third possibility is a laparoscopic approach where the HIFU transducer, (e.g., for example, similar to that shown in FIG. 5) is placed substantially non-invasively proximate the nerves to be stimulated or denervated (e.g., for example, the nerves surrounding the renal or hepatic nerves). In such instances, a separate therapy device for application of therapy to the nerves(e.g., for example, the therapy device 50 of FIG. 3) may be required for the application of US or RF therapy to perform the denervation. In embodiments, the one or more HIFU transducers 112 of the neurostimulation catheter 110 can be employed to both image portions of the blood vessels from an internal perspective, apply FUS neurostimulation, and apply FUS neuromodulation.

[0050] In addition to, or in lieu of ultrasound imaging, it is contemplated that the imaging device 70 may be an angiography system suitable for capturing images of renal vessels with sufficient resolution to segment and / or determine dimensions of the renal vessels. In embodiments, the imaging device 70 may be a three-dimensional (3D) angiography system configured to capture, compare, and analyze angiographic images before and after stimulating treated nerves. In one non-limiting embodiment, the imaging device 70 is a 3D rotational angiography (3DRA) system.

[0051] Returning to FIG. 3, one embodiment of a therapeutic device 50 is illustrated in accordance with the disclosure. The therapeutic device 50 includes an elongated shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongated shaft 52. The therapeutic device 50 includes therapy delivery assembly 54 at which one or more therapy elements 56 are located. The elongated shaft 52 of the therapeutic device 50 is configured to be advanced within a portion of the patient’s vasculature, such as a femoral artery or other suitable portion of the patient’s vascular network that is in fluid communication with the patient’s renal artery. In embodiments, the therapy delivery assembly 54 is configured to be transformed from an initial, undeployed configuration having a generally linear profile, to a second, deployed or expanded configuration, where the therapy delivery assembly forms a radially expanded configuration, such as for example, a generally spiral and / or helical configuration, for delivering therapy to a site for either or both application of stimulation or therapy at the treatment site.

[0052] The elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath e.g., for example, a 6F guide catheter) 58 that is utilized to navigate the therapeutic device 50 to a desired location. As can be appreciated, once the therapeutic device 50 is navigated to the desired location, the guide catheter 58 may be retracted to uncover the therapy delivery assembly 54 of the therapeutic device 50. As noted hereinabove, retraction of the guide catheter 58 may enable the therapy delivery assembly 54 to transition from the first, undeployed configuration to the second, deployed orexpanded configuration. In this manner, when in the second, expanded configuration, the therapy delivery assembly 54, and in particular, the individual therapy elements 56, is pressed against or otherwise contacts the walls of the patient’s vasculature tissue. In embodiments, the elongated shaft 52 of the therapeutic device 50 may include an aperture (not shown) that is configured to slidably receive a guidewire 64 over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced. In this manner, the guidewire 64 is utilized to guide the therapeutic device 50 to the target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guidewire may be partially or fully removed from the therapeutic device 50, enabling the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration. Although generally described as transitioning to a spiral and / or helical configuration, it is envisioned that the therapy delivery assembly 54 may be deployed in other configurations (such as for example, an expanded frame or basket and a balloon) without departing from the scope of the disclosure. As such, the therapeutic device 50 may be capable of being placed in one, two, three, four, or more different configurations depending upon the design needs of the therapeutic device 50 or the location at which therapy is to be applied. In embodiments, the therapeutic device 50 may be configurable, for example, using one or more pull wires or other control mechanisms (not shown) to adjust the configuration to promote contact between the therapy elements 56 and the wall of the vascular tissue, may be formed from a shape memory alloy or other similar material configured to automatically transition from the first, undeployed configuration, to the second, deployed or expanded configuration, or combinations thereof when the guide catheter 58 and / or guidewire 64 are partially or fully removed.

[0053] Continuing with FIG. 3, the therapy elements 56 are disposed on an outer surface of the elongated shaft 52 and configured to contact a portion of the patient’s vascular tissue when the therapeutic device 50 is placed in the second, expanded configuration. Although generally illustrated as having four therapy elements 56, it is envisioned that the therapeutic device 50 may have more or fewer therapy elements 56 without departing from the scope of the disclosure. It is envisioned that the therapy elements 56 may be one or more of ultrasound transducers, RF electrodes, microwave antennae, ports for delivery of cryoablation medium or chemical medium and other implements and / or ablation and denervation modalities without departing from the scope of the disclosure. In embodiments,the therapy elements 56 may be combined mode therapy elements enabling the same therapy elements 56 to apply FUS stimulation and also US, RF, microwave, or other therapy to the blood vessel wall. Although generally described as being in contact with the patient’s vascular tissue, it is envisioned that one or all of the therapy elements 56 may not be in direct contact with the patient’s vascular tissue and in embodiments, may be disposed within an expanded frame or basket and a balloon (not shown).

[0054] It is envisioned that the therapy elements 56 may be disposed in spaced relation to one another along a length of the therapeutic device 50 forming the therapy delivery assembly 54. The therapy elements 56 may be in communication with one or both the therapy source 24 and the stimulation source 24a, and in embodiments, the therapy source 24 may also be the stimulation source 24a and may include a diagnostic mode, where the therapy source 24 generates a stimulation signal, and a denervation mode, where the therapy source 24 generates therapy signals to denervate the nerves of the relevant blood vessel. It is contemplated that the therapy source 24 may be manually switched from a stimulation mode to a denervation mode and vice versa or may be automatically switched by an algorithm 44 stored on the memory 32 of the computer 22. In one non-limiting embodiment, the therapy elements 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question. The stimulation is generated by the stimulation source 24a and communicated to the therapy elements 56 causing stimulation of the sympathetic nerves as described herein.

[0055] Turning to FIGS. 6 A and 6B, as can be appreciated, the application of stimulation to target tissue may effectuate myriad physiological changes. In this manner, as stimulation is applied to the target tissue via the therapy delivery assembly 54 of the therapy device 50, a change in heart rate, a change in arterial pressure, and / or a change in vessel size can be measured and / or observed. As depicted in FIG. 6A, the duration of the stimulation signal 120 is depicted by trace 122. During the application of the stimulation signal 120 to the target tissue, an increase in heart rate, depicted by trace 124, and a mean arterial pressure, depicted by trace 126, can be observed. As can be seen, even before cessation of the stimulation signal 120, the heart rate begins to return to normal. Conversely, the mean arterial pressure, both during and following the application of the stimulation signal 120 elevates and remains elevated compared to the pre-stimulation mean arterial pressure. This change in either or both heart rate and mean arterial blood pressure is indicative ofstimulation of the afferent nerves of the blood vessel in which the therapeutic device 50 is positioned (e.g., for example, the renal and / or hepatic arteries). In instances where the change in heart rate or mean arterial pressure is in excess of a predetermined threshold value or satisfies a heart rate or arterial pressure criteria, the clinician may determine that the location of the therapy delivery assembly 54 is appropriate for the application of therapy to achieve denervation, and therapy may be applied to the target tissue at that location within the blood vessel.

[0056] With additional reference to FIGS. 7A-7D, vasoconstriction resulting from the application of the stimulation signal 120 may be observed. As can be appreciated, vasoconstriction, in which the application of the stimulation signal 120 effectuates a change in dimension of the blood vessels distal of the target tissue, such as for example, a reduction in blood vessel diameter and a reduction in cross-sectional area, at and around the target tissue, may be visually identified using external or internal imaging modalities. In embodiments, the change in dimension of the blood vessels may be identified as a vasoconstriction metric. In instances where the vasoconstriction metric satisfies a vasoconstriction criteria, such as for example, a change in vessel dimension that is in excess of a predetermined threshold value, the clinician may determine that the location of the therapy delivery assembly 54 is appropriate for application of therapy to achieve denervation and therapy may be applied to the target tissue at that location within the blood vessel. Vasoconstriction induced by neurostimulation may be local to or may radiate outward from the location where neurostimulation has been applied. Where neurostimulation has been applied adjacent to a primary bifurcation of the blood vessels, vasoconstriction can be imaged and identified at the location where the neurostimulation has been applied in addition to blood vessels distal of the primary bifurcation (FIG. 7B). As can be appreciated, identifying vasoconstriction within the blood vessels distal of the primary bifurcation can be utilized to assess the efficacy of denervation therapy applied to the afferent and efferent nerves. In this manner, the blood vessels 130 adjacent to or distal of the location where neurostimulation is to be applied (FIG. 7A) are imaged from within the blood vessels or external to the blood vessels using any suitable imaging modality, such as, for example, ultrasound, CT, CBCT, fluoroscopy, and angiography. Thereafter, neurostimulation is applied to the target sympathetic nerves and the target blood vessels are once again imaged (FIG. 7B). The images captured during or after the application ofneurostimulation are compared to the images captured before neurostimulation to identify constricted blood vessels 132 at and / or distal of the location where neurostimulation was applied. In embodiments, the images captured before or after the application of neurostimulation may be compared to a vasoconstriction criteria, such as for example, a predetermined threshold value, which may be based on a percentage of initial vessel diameter, a predetermined vessel diameter, a percentage of an initial vessel cross-sectional area, and a predetermined vessel cross-sectional area. . As can be appreciated, the application of neurostimulation and ultrasound imaging may be performed as many times as necessary at the same or different locations to identify sympathetic nerves that are candidates for denervation or to identify an efficacy of the therapy applied to the target tissue. With the candidate tissue identified, therapy is applied to the candidate tissue to denervate the nerves, and thereafter, the target blood vessels 130 are imaged again (FIG. 7C). Thereafter, neurostimulation is again applied to the target sympathetic nerves and the target blood vessels 130 are once again imaged and compared to the images captured before neurostimulation but after therapy, or in embodiments, to the images captured during or after the application of neurostimulation but before therapy, to identify the presence, or absence, of vasoconstriction (FIG. 7D).

[0057] As can be appreciated, the above-described process may require multiple applications of neurostimulation and / or therapy at many locations within the blood vessels, which can take a substantial amount of time and energy. A reduction in the amount of neurostimulation and / or therapy required to complete a denervation procedure would not only reduce procedure time but also reduce costs. It has been demonstrated that vasoconstriction in the renal arteries is predicated by a change in flow parameters or flow metrics within the renal vascular system. These changes in flow parameters resulting from stimulation of the sympathetic nerves can be measured and / or observed using external or internal imaging modalities, flow instrumentation, changes in temperature response, and combinations thereof. As can be appreciated, identifying a change in flow parameters resulting from stimulation of the blood vessel, occurring even before vasoconstriction can be observed, can reduce the length of time stimulation must be applied in order to identify whether the target blood vessel is a candidate for denervation or to determine the efficacy of therapy applied to the target blood vessel. Additionally, identified changes in flow parameters may be combined with other modalities for identifying candidate tissue as anadditional data point. Although generally described as determining a change in flow, it is envisioned that any parameter indicative of movement of fluid within a blood vessel may be used, such as for example, velocity.

[0058] Referring back to FIG. 3 and with additional reference to FIG. 8, it is envisioned that the guidewire 64 may be a doppler flow wire or may generally include one or more flow sensors 66 (FIG. 3) operably coupled thereto and in embodiments, operably coupled to the workstation 20 using any suitable means, such as for example, wirelessly, hardwired, and combinations thereof. Although generally illustrated as being disposed on a distal portion of the guidewire 64, it is envisioned that the one or more flow sensors 66 may be disposed at any location along the length of the guidewire, or in embodiments, may be disposed on the therapeutic device 50, the elongate shaft 52, or combinations thereof without departing from the scope of the disclosure. The flow sensors 66 are configured to measure or otherwise determine a flow parameter or flowrate of a fluid through the blood vessels. When stimulation is applied to the nerves of the target tissue, the blood vessels constrict and effectuate a corresponding reduction of flow through the blood vessels. It is envisioned that the flow parameter within the blood vessel adjacent to target tissue may be determined before neurostimulation to determine a baseline or initial flow parameter to which subsequent flow parameter determinations can be compared. In this manner, after neurostimulation, the flow parameter is determined again and compared to a predetermined threshold value, which may be a predetermined percentage of the baseline flow parameter. As can be appreciated, a flow parameter that satisfies a flow parameter criteria, such as for example, a flow parameter that is less than the predetermined threshold value, is indicative of candidate tissue whereas a flow parameter that is not less than the predetermined threshold value indicates that the target tissue is not a candidate for denervation. It is contemplated that the flow parameter may be measured after the application of therapy to the target tissue to determine the efficacy of therapy.

[0059] In some instances, as shown in FIG. 8, there may be a first threshold value 144 and a second threshold value 146. Each of the first and second threshold values 144 and 146 may be determined as a corresponding predetermined percentage of the baseline flow parameter or a flow parameter obtained pre-neuromodulation but post-neurostimulation. The predetermined percentage for the first threshold value 144 may be greater than the predetermined percentage for the second threshold value 146. A flow parameter 140 that isgreater than the first threshold value 144 may indicate that all nerves within the target tissue are sufficiently ablated and no further ablation need be performed at the target tissue location. A flow parameter 142 that is less than the second threshold value 146 may indicate that ablation is incomplete and either (1) further neuromodulation therapy should be delivered to the target tissue and / or (2) images should be obtained to ascertain which downstream blood vessels / blood vessel branches are still exhibiting vasoconstriction. A flow parameter that is less than the first threshold value 144 and greater than the second threshold value 146 may indicate that ablation is partially complete images should be obtained to ascertain which downstream blood vessels / blood vessel branches are still exhibiting vasoconstriction. The location of vasoconstriction may be used as a guide for where additional neuromodulation may be delivered. For instance, neuromodulation may be delivered to blood vessel branches that continue to exhibit vasoconstriction after the previous neuromodulation therapy has been delivered.

[0060] In embodiments, the flow through target blood vessels can be visualized and / or measured using the imaging device 70. In this manner, immediately following neurostimulation of the target blood vessels, a contrast agent or other similar fluid is injected into the patient’s blood stream at a substantially constant flowrate using any suitable means, such as for example, intravenous, via the therapeutic device 50, via a separate surgical device in fluid communication with the target blood vessels, and combinations thereof. In one non-limiting embodiment, the contrast agent is administered using a power injector. The imaging device 70 captures images, either individually or as a video, of the contrast agent flowing through the target blood vessels. As can be appreciated, the flow parameter, flow metric, or flowrate of the contrast agent through the target blood vessels can be estimated or determined using one or more natural, synthetic, or virtual landmarks, such as for example, structures within the blood vessels, markers (e.g., for example, radiopaque markers, fiducials, and combinations thereof) deposited within tissue surrounding the blood vessels, markers superimposed on the images captured by the imaging device 70, the therapy elements 56 of the therapeutic device 50 (FIG. 9), and combinations thereof. For purposes of brevity, the one or more landmarks will be described as being the therapy elements 56. The therapy elements 56 are disposed in spaced relation to one another (e.g., for example, a linear distance) along the length of the target tissue. Although the distance between each of the one or more therapy elements 56 may be calculated or known during the manufacturingprocess, it is contemplated that the distance between each of the therapy elements 56 may be identified and / or confirmed using the imaging device 70. The flow of the contrast agent through the blood vessels is monitored and a timepoint at which the contrast agent flows past each therapy element 56 is identified. The flow parameter of the contrast agent can be determined using the relationship between the distance between each therapy element 56 and the point in time the contrast agent flows past each corresponding therapy element 56, and in embodiments, a determined vessel size. As can be appreciated, this process can be repeated as many times as necessary before, during, and after neurostimulation and before, during, and after therapy is applied to candidate nerves, as described in detail hereinabove. It is envisioned that visualizing and analyzing the flow of contrast agent through candidate blood vessels may be completed on a branch-based approach (e.g., for example, a first branch of the renal artery, a second branch of the renal artery, and so forth).

[0061] With reference to FIG. 10, it is envisioned that the flow of a fluid through the target blood vessels may be measured or otherwise determined by identifying a change in temperature along a length of the blood vessel over a period of time. In this manner, the therapeutic device 50 may include one or more temperature sensors 80 disposed thereon or in operably coupled thereto, that are operably coupled to the workstation 20. In embodiments, one or more of the therapy elements 56 of the therapeutic device 50 may be associated with, or coupled to, a corresponding temperature sensor 80 such that the temperature sensors 80 measure a temperature of the respective therapy elements 56, the tissue in contact with the therapy elements 56, and / or the fluid flowing within the blood vessel. It is envisioned that the temperature sensor 80 may be any suitable temperature sensing device, such as for example, a thermocouple and a thermistor, and may be disposed proximate to, on, or within a portion of a respective therapy element 56. In one non-limiting embodiment, two or more temperature sensors 80 are coupled to the therapeutic portion 54 of the therapeutic device 50 and disposed in spaced relation a predetermined distance from one another.

[0062] As described in further detail hereinabove with respect to the therapy elements 56, the distance between each of the temperature sensors 80 may be calculated or known during the manufacturing process or identified or confirmed using the imaging device 70. As can be appreciated, the distance between the two or more temperature sensors 80 causes each temperature sensor 80 to measure a temperature of a fluid flowing through the bloodvessel at independent times. A fluid at substantially room temperature is injected into the patient’s blood stream at a substantially fixed flowrate using any suitable means, such as for example, those described hereinabove. The room temperature fluid flows over the temperature sensors 80 and causes the temperature sensors 80 to sequentially measure a lower temperature as compared to ambient. It is envisioned that the measured temperature of each of the temperature sensors 80 may be compared to one or more predetermined temperature metrics or criteria, which in embodiments, may be threshold values, where the point in time at which the measured temperature at each of the temperature sensors 80 satisfies a temperature criteria, such as for example, is less than a predetermined threshold value is identified. The identified points in time are compared to the identified distance between each of the temperature sensors 80 to determine or otherwise measure the flow parameter of the room temperature fluid within the blood vessel. Although generally described as a room temperature fluid, it is contemplated that the fluid injected into the patient’s blood stream may be at any temperature that can be differentiated from a temperature of the patient’s blood flowing through the target blood vessel.

[0063] It is envisioned that the flow parameter may be determined or otherwise calculating manually (e.g., for example, data displayed on the user interface 28) or via one or more algorithms 44 or software applications stored on the memory 32 of the workstation 20. In embodiments, the algorithm 44 may be applied to the data captured during the determination of the flow parameter within the target blood vessel, may be applied simultaneously during the determination of the flow parameter, may be a set of parameters or other input variables that are manually (e.g., for example, by the clinician) or automatically (e.g., for example, using the algorithm 44 or the computer 22), or combinations thereof.

[0064] As can be appreciated, the determined flow parameters may be approximate values due to volume and / or pathway assumptions (e.g., disregard 3D distances and instead utilize linear distances), tolerances, or other variables. In embodiments, the determined flow parameters may be utilized as a diagnostic tool or indication that further analysis should be conducted on certain locations within the blood vessel. In this manner, a flow parameter that satisfies a flow criteria, such as for example, is less than a predetermined threshold value, may indicate that vasoconstriction or other physiological responses should be considered when making a determination if the target blood vessel is a candidate for denervation. It isenvisioned that short durations of neurostimulation may be applied to various locations within the renal artery and the flow parameter monitored at each location. As the flow parameter occurs substantially simultaneously with the application of neurostimulation, and may occur before the onset of vasoconstriction, tissue that is not a candidate for denervation can quickly be distinguished from candidate tissue or tissue requiring further analysis. Further, vasoconstriction may persist for a period of time after applying neurostimulation, requiring a break or downtime before applying neurostimulation to another location of the target blood vessels. Using the flow parameter as an indication of candidate tissue can reduce downtime and provide more accurate determinations of candidate tissue as compared to relying on other physiological responses.

[0065] Turning to FIGS. 11 A and 1 IB, a method of performing a therapeutic procedure is illustrated and generally identified by reference numeral 200. At step 202, the therapeutic assembly of the therapeutic device is navigated to a location adjacent to target tissue. Once the therapeutic device is located adjacent to the target tissue, a flow parameter within the blood vessel adjacent to the target tissue is determined in step 204. At step 206, it is determined if the determined flow parameter satisfies a flow parameter criteria, which in embodiments, may be less than a first predetermined threshold value. If it is determined that the flow parameter does not satisfy the flow parameter criteria, or in embodiments, is not less than the first predetermined threshold value, the therapeutic portion of the therapeutic device is navigated to another location adjacent to the target tissue at step 208 and the method returns to step 204. If it is determined that the flow parameter satisfies the flow parameter criteria, or in embodiments, is less than the first predetermined threshold value, at step 210, stimulation is applied to the target tissue for a predetermined amount of time and first images of the blood vessels are obtained to identify vasoconstriction. At step 212, therapy is applied to the target tissue. At step 214, stimulation is again applied to the target tissue, and at step 216, a new flow parameter within the blood vessel adjacent to the target tissue is determined. At step 218, it is determined if the new flow parameter satisfies a flow parameter criteria, or in embodiments, is less than a second predetermined threshold value, which in embodiments, may be the first predetermined threshold value. If it is determined that the new flow parameter does not satisfy the flow parameter criteria, or in embodiments, is not less than the second predetermined threshold value, the method ends at step 220. If it is determined that the new flow parameter satisfies the flow parameter criteria, or inembodiments, is less than the second predetermined threshold value, at step 222, stimulation is applied to the target tissue for a predetermined period of time and second images of the blood vessels are obtained to identify vasoconstriction. At step 224, the second images are compared to the first images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, which in embodiments may be a change in blood vessel size. At step 226, it is determined if the vasoconstriction metric satisfies a vasoconstriction criterion, which in embodiments, may be an identified change in blood vessel size that is less than a predetermined threshold value. If it is determined that the vasoconstriction metric does not satisfy the vasoconstriction criteria, or in embodiments, the identified change in blood vessel size is not less than the predetermined threshold value, therapy is applied to the target tissue and the method returns to step 216. If it is determined that the vasoconstriction metric does satisfy the vasoconstriction criteria, or in embodiments, the change in blood vessel size is less than the predetermined threshold value, at step 230, it is determined if there are additional locations requiring treatment. If there are no additional locations requiring treatment, the method ends at step 220. If it is determined that additional location require treatment, the method returns to step 208. As can be appreciated, the above method may be repeated as many times as necessary and in any order without departing from the scope of the disclosure.

[0066] With reference to FIGS. 12A and 12B, another embodiment of a method of performing a therapeutic procedure is illustrated and generally identified by reference numeral 300. At step 302, the therapeutic assembly of the therapeutic device is navigated to a location adjacent to target tissue. Once the therapeutic device is located adjacent to the target tissue, an initial, or baseline flow parameter, or flow parameter metric, within the blood vessel adjacent to the target tissue is determined at step 304. At step 306, neurostimulation is applied to the target tissue, and thereafter, at step 308, the flow parameter is again determined. At step 310, it is determined if the determined flow parameter satisfies a flow parameter criteria, which in embodiments, is less than a predetermined threshold value. If the determined flow parameter is does not satisfy the flow parameter criteria, or in embodiments, is not less than the predetermined threshold value, the therapeutic portion of the therapeutic device is navigated to another location adjacent to the target tissue at step 312 and the method returns to step 304. If the determined flow parameter satisfies the flow parameter criteria, or in embodiments, is less than thepredetermined threshold value, at step 314, it is determined if the determined flow parameter falls between a first predetermined threshold value and a second predetermined threshold value. If the determined flow parameter falls between the first predetermined threshold value and the second predetermined threshold value, at step 316, the therapeutic portion of the therapeutic device is navigated within a branch of the target tissue and the method returns to step 304. If the determined flow parameter does not fall between the first predetermined threshold value and the second predetermined threshold value, at step 318, therapy is applied to the target tissue. Optionally, at step 320, if the determined flow parameter satisfies the flow parameter criteria, or in embodiments, is less than the predetermined threshold value, the target tissue is imaged to identify vasoconstriction of the target tissue adjacent to and distal of the location where neurostimulation was applied. At step 322, it is determined if a vasoconstriction metric based on at least one dimension of blood vessels distal of the target tissue, such as for example, a diameter of the target tissue, satisfies a vasoconstriction criterion, which in embodiments, may be is less than a predetermined value. If the vasoconstriction metric of the target tissue satisfies the vasoconstriction criteria, or in embodiments, is less than the predetermined value, the method returns to step 318. If the vasoconstriction metric of the target tissue does not satisfy the vasoconstriction criteria, or in embodiments, is not less than the predetermined value, at step 324, it is determined if there are additional locations requiring treatment. If there are no other locations requiring treatment, the method ends at step 326. If additional locations require treatment, the method returns to step 302. As can be appreciated, the above method may be repeated as many times as necessary and in any order without departing from the scope of the disclosure.

[0067] With reference to FIGS. 13A-13C, another embodiment of a method of performing a therapeutic procedure is illustrated and generally identified by reference numeral 400. At step 402, the therapeutic assembly of the therapeutic device is navigated to a location adjacent to target tissue. Once the therapeutic device is located adjacent to the target tissue, a flow parameter within the blood vessel adjacent to the target tissue is determined in step 404. At step 406, stimulation is applied to the target tissue. During the application of stimulation, at step 408, a flow parameter within blood vessels adjacent to the target tissue is monitored. At step 410, it is determined if the flow parameter satisfies a first flow parameter criterion. If it is determined that the flow parameter does not satisfy the first flow parameter criteria, the therapeutic device is navigated to a new location at step 412 andthe method returns to step 404. If it is determined that the flow parameter satisfies the first flow parameter criteria, at step 414, stimulation is applied to the target tissue for a predetermined period of time and first images of blood vessels distal of the target tissue are captured to identify vasoconstriction. At step 416, therapy is applied to the first location and at step 418, stimulation is applied to the target tissue. At step 420, during stimulation of the target tissue, a flow parameter within the blood vessels adjacent to the target tissue is monitored. At step 422, it is determined if the flow parameter satisfies a second flow parameter criteria. If it is determined that the flow parameter does not satisfy the second flow parameter criteria, the method ends at step 424. If it is determined that the flow parameter satisfies the second for parameter criteria, at step 426, stimulation is applied to the target tissue for a predetermined period of time and second images of blood vessels distal of the target tissue to identify vasoconstriction. At step 428, the first images are compared to the second images, or in embodiments, the first and second images are compared to a baseline, to identify a vasoconstriction metric. At step 430, it is determined if vessels have been identified that meet the vasoconstriction metric. If it is determined that no vessels that meet the vasoconstriction metric have been identified, the method ends at step 424. If it is determined that vessels that meet the vasoconstriction metric have been identified, in at step 432, the therapeutic device is navigated to the identified vessels and therapy is applied to each identified vessel. At step 434, the therapeutic device is navigated to the first location. At step 436, stimulation is applied to the target tissue, and at step 438, as the target tissue is stimulated, a flow parameter within the blood vessels adjacent to the target tissue is monitored. At step 440, it is determined if the flow parameter satisfies the second flow parameter criteria. If it is determined that the flow parameter does not satisfy the second flow parameter criteria, the method returns to step 426. If it is determined that the flow parameter satisfies the second flow parameter, the method ends at step 424. As can be appreciated, the above method may be repeated as many times as necessary and in any order without departing from the scope of the disclosure.

[0068] In some implementations, a technique may include applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall. The neurostimulation may be delivered by any device described herein and in accordance with any of the neurostimulation parameters described herein. For instance, neurostimulation source 24a may be used to deliver neurostimulationto target tissue in and / or adjacent to a blood vessel wall of a renal artery, a common hepatic artery, or the like in accordance with any of the stimulation parameters described above.

[0069] The technique also may include, in response to applying the neurostimulation, obtaining a first flow parameter related to blood flow within the blood vessel. The first flow parameter may be obtained using any of the devices and / or techniques described herein, including flow sensors, angiography, or the like. The first flow parameter may include a flow velocity, a volumetric flow rate, a mass flow rate, or the like. The first flow parameter may be obtained anywhere within the blood vessel, e.g., upstream of the target tissue, downstream of the target tissue, adjacent the target tissue, or the like.

[0070] Additionally, the technique may include, in response to applying the neurostimulation, obtaining first images of the blood vessel downstream of the target tissue. The first images may be obtained using any of the techniques described herein, including, for example, fluoroscopy, ultrasound imaging, or the like. In some instances, the images may be obtained after a delay after applying neurostimulation to the target tissue, e.g., to allow time for vasoconstriction to develop in response to the neurostimulation.

[0071] In some examples, in addition to obtaining a first flow parameter and first images in response to neurostimulation, the technique may include obtaining a flow parameter and / or images prior to delivering neurostimulation. The flow parameter and images obtained prior to delivering neurostimulation may serve as baselines for subsequent analysis. The flow parameter and images obtained prior to delivering neurostimulation may be obtained using any of the techniques described herein.

[0072] Regardless of whether flow parameters and images are obtained before or only after applying neurostimulation to the target tissue, the technique may include applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue. The neuromodulation therapy may be applied using any of the devices and techniques described herein.

[0073] After applying the neuromodulation therapy to the target tissue, the technique may include applying neurostimulation to the target tissue and, in response to applying the neurostimulation to the target tissue, obtaining a second flow parameter related to blood flow within the blood vessel. The second flow parameter may be obtained using any of the devices and / or techniques described herein, including flow sensors, angiography, or the like.

[0074] In some implementations, rather than applying neurostimulation to the target tissue after neuromodulation, neurostimulation may be applied to the target tissue which neuromodulation therapy is being applied to the target tissue. For instance, neuromodulation and neurostimulation may be applied in an interleaved fashion (e.g., neuromodulation for a time, followed by neurostimulation for a time, in a repeated manner). The second flow parameter may be obtained in response to each application of neurostimulation.

[0075] The technique also may include determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue. The flow parameter criteria may include a criterion related to blood flow before and after neuromodulation therapy. For example, the flow parameter criterion may be a threshold flow rate based on the first flow rate or a combination of the first flow rate and the pre-stimulation, pre-neuromodulation flow rate. As another example, the flow parameter criterion may be as shown in FIG. 8 and may include multiple flow parameter criteria. In examples in which neurostimulation is applied to the target tissue which neuromodulation therapy is being applied to the target tissue, the technique may include iteratively determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue. For instance, the determination may be made periodically at a set time interval based on the most recently obtained second flow parameter and the flow parameter criterion.

[0076] The technique also may include, in response to an indication of inadequate ablation of the nerves, e.g., a second flow parameter that is less than the first threshold value 144 shown in FIG. 8, obtaining second images of the blood vessel downstream of the target tissue. The images may be used to determine whether and / or where blood vessels and / or blood vessel branches downstream of the target tissue continue to exhibit vasoconstriction after the neuromodulation therapy has been delivered. Portions of the blood vessels and / or blood vessel branches that continue to exhibit vasoconstriction after the neuromodulation therapy has been delivered may be candidates to be sites for further neuromodulation therapy. For instance, the technique may include comparing the first (pre-neuromodulation) images and the second (post-neuromodulation) images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue. The technique also may include, in response to the vasoconstriction metric satisfying a vasoconstriction criterion (e.g., showing a similar level of vasoconstriction),applying neuromodulation therapy to at least a second target tissue (e.g., associated with the similar level of vasoconstriction.

[0077] However, if the second flow parameter and the flow parameter criterion indicate sufficient ablation (e.g., the flow parameter criterion is greater than the first threshold value 144 shown in FIG. 8), this may indicate that no further neuromodulation therapy is necessary.

[0078] Although described generally hereinabove, it is envisioned that the memory 32 may include any non-transitory computer-readable storage media for storing data and / or software including instructions that are executable by the processor 30 and which control the operation of the workstation 20 and, in some embodiments, may also control the operation of the therapeutic device 50, imaging device 70, and / or ECG machine. In an embodiment, memory 32 may include one or more storage devices such as solid-state storage devices, e.g., flash memory chips. Alternatively, or in addition to the one or more solid-state storage devices, the memory 32 may include one or more mass storage devices connected to the processor 30 through a mass storage controller (not shown) and a communications bus (not shown).

[0079] Although the description of computer-readable media contained herein refers to solid-state storage, it should be appreciated by those skilled in the art that computer-readable storage media can be any available media that can be accessed by the processor 30. That is, computer readable storage media may include non-transitory, volatile, and non-volatile, removable, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. For example, computer-readable storage media may include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technology, CD-ROM, DVD, Blu-Ray or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which may be used to store the desired information, and which may be accessed by the energy source 20.

[0080] While several embodiments of the disclosure have been shown in the drawings, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely asexemplifications of embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

[0081] The invention may be further described by reference to the following numbered examples.

[0082] Example 1. A method of performing a therapeutic procedure, comprising: navigating a therapeutic device to a location within a blood vessel adjacent to target tissue; determining a first flow parameter within a portion of a blood vessel adjacent to the target tissue; applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue; applying therapy to the target tissue; applying neurostimulation to the target tissue; determining a second flow parameter within the portion of the blood vessel adjacent to the target tissue; comparing the second flow parameter to a flow parameter criteria; applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue; comparing the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue; and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.

[0083] Example 2. The method according to Example 1 , wherein determining the first flow parameter includes determining the first flow parameter using a flow sensor disposed on the therapeutic device.

[0084] Example 3. The method according to Example 1 , wherein determining the first flow parameter includes: identifying a first point in time at which a contrast agent flowing through the blood vessel adjacent to the target tissue flows past a first landmark; and identifying a second point in time at which the contrast agent flowing through the blood vessel adjacent to the target tissue flows past a second landmark, the second landmark disposed distal of the first landmark.

[0085] Example 4. The method according to Example 1 , wherein determining the first flow parameter includes: identifying a first point in time at which a contrast agent flowing through the blood vessel adjacent to the target tissue flows past a first therapy element of the therapeutic device; and identifying a second point in time at which the contrast agent flowing through the blood vessel adjacent to the target tissue flows past a second therapy element of the therapeutic device, wherein the second therapy element is disposed distal of the first therapy element.

[0086] Example 5. The method according to Examples 3 or 4, wherein determining the first flow parameter includes imaging the target tissue to identify the contrast agent flowing through the blood vessel adjacent to the target tissue.

[0087] Example 6. The method according to any of the preceding Examples, further comprising injecting a fluid into the blood vessel adjacent to the target tissue.

[0088] Example 7. The method according to Example 6, wherein injecting the fluid into the blood vessel adjacent to the target tissue includes injecting a contrast agent into the blood vessel adjacent to the target tissue.

[0089] Example 8. The method according to Example 6, wherein injecting the fluid into the blood vessel adjacent to the target tissue includes injecting a room temperature fluid into the blood vessel adjacent to the target tissue.

[0090] Example 9. The method according to Example 8, wherein determining the first flow parameter includes: identifying a first point in time at which a change in temperature is measured at a first location within the target tissue as the room temperature fluid is flowing through the blood vessel adjacent to the target tissue; and identifying a second point in time at which a change in temperature is measured at a second location within the target tissue as the room temperature fluid is flowing through the blood vessel adjacent to the target tissue.

[0091] Example 10. The method according to any of the preceding paragraphs, further comprising advancing the therapeutic device over a guidewire, the guidewire including a flow sensor.

[0092] Example 11. A method of performing a therapeutic procedure, comprising: injecting a fluid into a blood vessel adjacent to target tissue; imaging blood vessels distal of the target tissue; identifying a first landmark adjacent to the target tissue; identifying a second landmark adjacent to the target tissue; identifying a first point in time at which the injected fluid flows past the first landmark; identifying a second point in time at which the injected fluid flows past the second landmark; determining a flow parameter of the injected fluid based on the identified first point in time and the identified second point in time; comparing the determined flow parameter to a flow parameter criteria; and applying therapy to the target tissue if the determined flow parameter satisfies the flow parameter criteria.

[0093] Example 12. The method according to Example 11, wherein identifying the first landmark includes identifying a first therapy element of a therapeutic device disposedwithin the blood vessel adjacent to the target tissue and identifying the second landmark includes identifying a second therapy element of the therapeutic device disposed within the blood vessel adjacent to the target tissue.

[0094] Example 13. The method according to any of the preceding Examples, further comprising: imaging the blood vessels distal of the target tissue after applying therapy to the target tissue; and identifying a vasoconstriction metric of the blood vessels distal of the target tissue.

[0095] Example 14. The method according to any of the preceding Examples, further comprising: comparing at least one dimension of the blood vessels distal of the target tissue to a vasoconstriction metric, the vasoconstriction metric based on at least one dimension of the blood vessels distal of the target tissue; and reapplying therapy to the target tissue if the vasoconstriction metric satisfies a vasoconstriction criteria.

[0096] Example 15. The method according to Example 11 , wherein identifying the first point in time at which the injected fluid flows past the first landmark includes identifying a change in temperature of fluid flowing past the first landmark, wherein identifying the second point in time at which the injected fluid flows past the second landmark includes identifying a change in temperature of fluid flowing past the second landmark.

[0097] Example 16. A system for performing a diagnostic and therapeutic procedure, comprising: a workstation, the workstation including a processor and a memory, the memory storing instructions thereon, which when executed cause the processor to: determine a first flow parameter within a portion of a blood vessel adjacent to the target tissue; cause a stimulation source to output a neurostimulation signal via at least one stimulation element to the target tissue and obtain first images of blood vessels distal of the target tissue; cause a therapy source to output a therapy signal via at least one therapy element to the target tissue; apply neurostimulation to the target tissue; determine a second flow parameter within the portion of the blood vessel adjacent to the target tissue; compare the second flow parameter to a flow parameter criteria; apply neurostimulation to the target tissue and obtain second images of the blood vessels distal of the target tissue; compare the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue; and apply therapyto the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.

[0098] Example 17. The system according to Example 16, further comprising: a therapeutic device, the therapeutic device configured to be navigated within a luminal network of a patient, wherein the therapeutic device includes a therapeutic element; a therapy source, the therapy source operably coupled to the therapeutic device, wherein the therapy source is configured to deliver therapy to target tissue; and a stimulation source, the stimulation source operably coupled to the therapeutic device, wherein the stimulation source is configured to deliver neurostimulation to the target tissue.

[0099] Example 18. The system according to Example 17, wherein the memory stores thereon further instructions, which when executed cause the processor to determine the first flow parameter using a flow sensor disposed on the therapeutic device.

[0100] Example 19. The system according to any of Examples 16 to 18, further comprising an imaging device, the imaging device configured to capture images of the target tissue.

[0101] Example 20. The system according to Example 19, wherein the memory stores thereon further instructions, which when executed cause the processor to inject a fluid into the blood vessels adjacent to the target tissue.

[0102] Example 21. The system according to Example 20, wherein the memory stores thereon further instructions, which when executed cause the processor to: identify a first point in time at which the injected fluid flows past a first landmark adjacent to the target tissue; identify a second point in time at which the injected fluid flows past a second landmark adjacent to the target tissue; and compare a difference between the identified first point in time and the identified second point in time to a first predetermined threshold value, wherein a compared difference that is less than the first predetermined threshold value is indicative of tissue that is a candidate for denervation.

[0103] Example 22. A method comprising: causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned at a location within a target vessel, wherein the at least one stimulation element is coupled to a therapeutic device; causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel; in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, thestimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel; determining, by the computing device, based on the at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location; determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric; and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, outputting, by the computing device, an indication related to the location being a candidate for a denervation procedure.

[0104] Example 23. A method comprising: after a denervation procedure has been performed at a location of a target vessel, causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned proximate the location, wherein the at least one stimulation element is coupled to a therapeutic device; causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel; in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel; determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location; determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric; and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, outputting, by the computing device, an indication related to a success of the denervation procedure.

[0105] Example 24: A method comprising: applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criteria and the second flow parameter, whether thedenervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

[0106] Further disclosed herein is the subject-matter of the following clauses:

[0107] Clause 1 : A method comprising: applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

[0108] Clause 2: A method comprising: applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while applying the neuromodulation therapy to the target tissue: applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; and iteratively determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; andin response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

[0109] Clause 3: The method of clause 1 or 2, further comprising: prior to applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall: obtaining a third flow parameter related to blood flow within the blood vessel; and obtaining third images of the blood vessel downstream of the target tissue.

[0110] Clause 4: The method of clause 3, wherein determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining, based on the first, second, and third flow parameters, whether the denervation therapy adequately ablated the target nerves.

[0111] Clause 5: The method of any one of clauses 1 to 4, further comprising: comparing the first images and the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue; and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, applying neuromodulation therapy to at least a second target tissue.

[0112] Clause 6: The method of clause 5, wherein the second target tissue is in or adjacent to a blood vessel wall of a branch vessel of the blood vessel.

[0113] Clause 7: The method of clause 5 or 6, wherein the vasoconstriction metric satisfying the vasoconstriction criteria indicates that the second target tissue should be treated with the neuromodulation therapy.

[0114] Clause 8: The method of any one of clauses 1 to 7, wherein determining, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.

[0115] Clause 9: A system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in and / or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to bloodflow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after the neuromodulation therapy is applied to the target tissue, cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

[0116] Example 10: A system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while the neuromodulation therapy is being applied to the target tissue: cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; and determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

[0117] Clause 11 : The system of clause 9 or 10, wherein the memory further stores instructions thereon, which when executed by the one or more processors, cause the one or more processors to: prior to causing the neurostimulator to apply neurostimulation to target tissue in and / or adjacent to the blood vessel wall of the blood vessel to stimulate nerves in or adjacent to the blood vessel wall to: obtain a third flow parameter related to blood flow within the blood vessel; and obtain third images of the blood vessel downstream of the target tissue.

[0118] Clause 12: The system of clause 11, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determine, based on the first, second, and third flow parameters, whether the denervation therapy adequately ablated the target nerves.

[0119] Clause 13 : The system of any one of clauses 9 to 12, wherein the memory further stores instructions thereon, which when executed by the one or more processors, cause the one or more processors to: compare the first images and the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue; and in response to the vasoconstriction metric satisfying the vasoconstriction criteria, cause the therapy device to apply neuromodulation therapy to at least a second target tissue.

[0120] Clause 14: The system of clause 13, wherein the second target tissue is in or adjacent to a blood vessel wall of a branch vessel of the blood vessel.

[0121] Clause 15: The system of clause 13 or 14, wherein the vasoconstriction metric satisfying the vasoconstriction criteria indicates that the second target tissue should be treated with the neuromodulation therapy.

[0122] Clause 16: The system of any one of clauses 9 to 15, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.

Claims

CLAIMS1. A method comprising: applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

2. A method comprising: applying neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while applying the neuromodulation therapy to the target tissue: applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; anditeratively determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.

3. The method of claim 1 or 2, further comprising: prior to applying neurostimulation to target tissue in and / or adj acent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall: obtaining a baseline flow parameter related to blood flow within the blood vessel; and obtaining baseline images of the blood vessel downstream of the target tissue.

4. The method of claim 3, wherein determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining, based on the first, second, and baseline flow parameters, whether the denervation therapy adequately ablated the target nerves.

5. The method of any one of claims 1 to 4, further comprising: comparing the first images and the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue; and in response to the vasoconstriction metric satisfying a vasoconstriction criterion, applying neuromodulation therapy to at least a second target tissue.

6. The method of claim 5, wherein the second target tissue is in or adjacent to a blood vessel wall of a branch vessel of the blood vessel.

7. The method of claim 5 or 6, wherein the vasoconstriction metric satisfying the vasoconstriction criteria indicates that the second target tissue should be treated with the neuromodulation therapy.

8. The method of any one of claims 1 to 7, wherein determining, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.

9. A system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in and / or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after the neuromodulation therapy is applied to the target tissue, cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; determine, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

10. A system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and / or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while the neuromodulation therapy is being applied to the target tissue: cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; and determine, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtain second images of the blood vessel downstream of the target tissue.

11. The system of claim 9 or 10, wherein the memory further stores instructions thereon, which when executed by the one or more processors, cause the one or more processors to: prior to causing the neurostimulator to apply neurostimulation to target tissue in and / or adjacent to the blood vessel wall of the blood vessel to stimulate nerves in or adjacent to the blood vessel wall to: obtain a third flow parameter related to blood flow within the blood vessel; andobtain third images of the blood vessel downstream of the target tissue.

12. The system of claim 11, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determine, based on the first, second, and third flow parameters, whether the denervation therapy adequately ablated the target nerves.

13. The system of any one of claims 9 to 12, wherein the memory further stores instructions thereon, which when executed by the one or more processors, cause the one or more processors to: compare the first images and the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue; and in response to the vasoconstriction metric satisfying the vasoconstriction criteria, cause the therapy device to apply neuromodulation therapy to at least a second target tissue.

14. The system of claim 13, wherein the second target tissue is in or adjacent to a blood vessel wall of a branch vessel of the blood vessel.

15. The system of claim 13 or 14, wherein the vasoconstriction metric satisfying the vasoconstriction criteria indicates that the second target tissue should be treated with the neuromodulation therapy.

16. The system of any one of claims 9 to 15, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.

Images