Renal nerve stimulation system for guiding radio frequency renal denervation

Abstract

Systems and methods for performing a treatment procedure using a treatment device comprising electrodes by applying stimulation signals from the electrodes to a vascular wall; observing a physiological response to the stimulation signal; applying a therapy to the vessel wall; applying another stimulation signal from the electrodes to the blood vessel; and observing a second physiological response to the second stimulation signal. The therapy is successful when the second physiological response differs from the first physiological response by more than a threshold.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 427,620, filed on November 23, 2022, the entire content of which is incorporated herein by reference. Technical Field

[0002] The present disclosure relates to systems and methods for enabling the positioning of a treatment device within luminal tissue to enhance ablation during a treatment procedure. In certain aspects, the present disclosure relates to methods and systems for denervating nerves in or around vascular tissue. Background Art

[0003] Catheters have been proposed for various medical procedures. For example, a catheter can be configured to deliver a neuromodulation (e.g., denervation) therapy to a target tissue site to alter 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 the primary involuntary body control system that is typically associated with the stress response. Chronic overactivation of the SNS is an adaptive adverse reaction that can drive the progression of many disease states. For example, overactivation of the renal SNS has been identified in experiments and humans as a possible cause of the complex pathophysiology of arrhythmias, hypertension, volume overload states (e.g., heart failure), and progressive kidney disease.

[0004] Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by overactivation of the SNS. During a renal denervation procedure, a clinician delivers a stimulus or energy, such as radiofrequency, ultrasound, cooling, or other energy, to the treatment site to reduce the activity of perivascular nerves. The stimulus or energy delivered to the treatment site can provide various therapeutic effects by altering sympathetic nerve activity.

[0005] During current denervation procedures, it is not possible for a clinician to see the nerves prior to applying the therapy. Instead, the denervation catheter is positioned based on the best judgment of the clinician, and several ablations are performed. As a result, the clinician has no indication that the ablation they are performing is actually ablating any nerves. In addition, there is no indication during the procedure that the ablation is successful. Accordingly, the present disclosure relates to systems and methods for addressing these drawbacks of the current technology. Summary of the Invention

[0006] One aspect of the present disclosure relates to a method of performing a treatment protocol. The method includes navigating a treatment device to a target tissue, the treatment device including a plurality of electrodes. The method further includes applying a first stimulation signal from the electrodes to a blood vessel wall. The method further includes observing a first physiological response to the first stimulation signal. The method further includes applying a therapy to the blood vessel wall. The method further includes applying a second stimulation signal from the electrodes to the blood vessel. The method further includes observing a second physiological response to the second stimulation signal, wherein a difference between the second physiological response and the first physiological response greater than a first threshold indicates a successful therapy. Other embodiments of this aspect include corresponding computer systems, devices, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0007] Particular implementations of this aspect of the present disclosure may include one or more of the following features. The method further includes adjusting a parameter of the first stimulation signal when the first physiological response is observed to be less than a second threshold. The method further includes applying the first stimulation signal to the blood vessel wall with the adjusted parameter before applying the therapy to the blood vessel wall. The method further includes adjusting a parameter of the therapy if the difference between the second physiological response and the first physiological response is less than the first threshold. The method further includes applying the therapy to the blood vessel wall with the adjusted parameter. Particular implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium, including software, firmware, hardware, or combinations thereof installed on a system, the software, firmware, hardware, or combinations thereof causing the system to perform actions in operation. One or more computer programs may be configured to perform particular operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the actions.

[0008] Another aspect of the present disclosure relates to a system for denervation of blood vessels and nerves. The system includes a treatment device configured to navigate within a blood vessel of a patient. The system further includes a plurality of electrodes formed on a distal portion of the treatment device. The system further includes a sensor configured to measure one or more physiological parameters of the patient at a location where the treatment device has been navigated. The system further includes a stimulation and therapy source. The system further includes a computing device that includes a memory and a processor and stores instructions thereon that, when executed: generate a first stimulation signal for application to the blood vessel wall via one of the plurality of electrodes, sense a first change in the physiological parameter caused by the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter indicates the presence of a nerve proximate to one of the plurality of electrodes, generate a therapy for application to the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via one of the plurality of electrodes, sense a second change in the physiological parameter caused by the application of the second stimulation signal, and determine based on the second sensed change in the physiological parameter whether the application of the therapy has denervated the nerve proximate to the electrode. Other embodiments of this aspect include corresponding computer systems, devices, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0009] Specific implementations of this aspect of the disclosure may include one or more of the following features. In the system, the first stimulation signal and therapy are a combined signal generated during an initial time period. Determination of the first sensed change occurs after the initial time period. The second stimulation signal and therapy are a combined signal generated during a second time period. The instructions, when executed by a processor, present an indication identifier on a user interface associated with the computing device, the indication identifier including one or more of the following: the presence of a nerve near one of the plurality of electrodes, or an indication identifier of successful denervation, or an indication identifier of unsuccessful denervation. The instructions, when executed by a processor, determine that the first sensed change in the physiological parameter indicates the absence of a nerve near one of the plurality of electrodes. The instructions, when executed by a processor, stop generation of the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters during a first time period. When executed by a processor, the instructions sense a third change in the physiological parameter due to applying the first stimulation signal with the adjusted parameters; and determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes. The instructions, when executed by a processor, determine that the nerve is deep and additional time is needed to complete denervation. Specific implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium, including software, firmware, hardware, or combinations thereof installed on the system, the software, firmware, hardware or combinations thereof causing the system to perform actions in operation. One or more computer programs may be configured to perform specific operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the actions.

[0010] Still another aspect of the disclosure relates to a method of evaluating a denervated site. The method includes positioning a treatment device in a blood vessel such that a plurality of electrodes contact the blood vessel wall. The method further includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes during a first duration. The method further includes sensing a physiological parameter of the blood vessel after applying the multiplexed stimulation and therapy. The method further includes determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold. The method further includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes during a second duration. The method further includes sensing a physiological parameter of the blood vessel after applying the multiplexed stimulation and therapy. The method further includes determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold. The method further includes indicating successful denervation to a user when the sensed physiological parameter is different after the second duration than after the first duration. Other implementations of this aspect include corresponding computer systems, devices, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0011] Specific implementations of this aspect of the disclosure may include one or more of the following features. The method further includes determining whether a power limit has been reached when a change in a determined physiological parameter after a second duration is less than a threshold. The method further includes increasing the power of the therapy if the power limit has not been reached. A plurality of electrodes are arranged in a first series of unique electrode pairs and a second series of unique electrode pairs, and applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes includes: applying a stimulation to a first pair in the first series of unique electrode pairs at a first time; applying a therapy to a first pair in the second series of unique pairs at the first time; switching to a second pair in the first series of unique pairs and applying a stimulation to the second pair at a second time; switching to a second unique pair in the second series of unique pairs and applying a therapy to the second pair at the second time; and repeating the switching of the first series of unique pairs and the second series of unique pairs within a first duration or a second duration. Applying a multiplexed stimulation signal and therapy includes: applying a stimulation signal between a first pair of the plurality of electrodes at a first time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal at the first time; applying a stimulation signal between a second pair of the plurality of electrodes at a second time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal at the second time; and switching between the first pair and the second pair to apply the stimulation signal and apply the therapy until a first duration or a second duration is completed. The sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, vascular stiffness, or pulse wave velocity. The first change in the determined physiological parameter is a decrease in systolic blood pressure. The second change in the determined physiological parameter is a decrease in systolic blood pressure, and the threshold is the systolic blood pressure at the end of the first duration. The method further includes determining that the first change in the physiological parameter is less than the threshold; and stopping the therapy portion of applying the multiplexed stimulation signal and therapy. The method further includes adjusting the stimulation signal and applying the adjusted stimulation signal to the alternating pairs of electrodes. The method further includes determining that the application of the adjusted stimulation signal results in a change in the physiological parameter exceeding the threshold; increasing the power of the therapy; and applying a multiplexed adjusted stimulation signal and increased-power therapy within a second duration. The method further includes determining that the application of the adjusted stimulation signal causes a change in the physiological parameter less than the threshold; and determining that the change in the physiological parameter is less than the threshold; and generating an indication for display on a user interface that no nerve has been detected at the location of the treatment device. Specific implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium, including software, firmware, hardware, or combinations thereof installed on a system, the software, firmware, hardware or combinations thereof causing the system to perform actions in operation. One or more computer programs may be configured to perform specific operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the actions.

[0012] Another aspect of the present disclosure relates to a method of performing a treatment protocol. The method further includes navigating a treatment device to a target tissue, the treatment device including a plurality of electrodes. The method further includes applying a first stimulation signal from a first pair of electrodes to a vessel wall. The method further includes applying therapy to the vessel wall using all the electrodes. The method further includes switching the stimulation signal to a second pair of electrodes. The method further includes applying a second stimulation from the second pair of electrodes to a second vessel. The method further includes applying therapy to the vessel wall using all the electrodes. The method further includes repeating the switching and applying the stimulation signal to each successive pair of electrodes and applying therapy using all the electrodes until a first time period expires. The method further includes sensing a physiological parameter of the vessel after the first time period expires. The method further includes determining that a first change in the physiological parameter of the vessel exceeds a first threshold. The method further includes repeating the switching and applying the stimulation signal to each successive pair of electrodes and applying therapy using all the electrodes until a second time period expires. The method further includes determining whether a second change in the physiological parameter of the vessel exceeds a second threshold. The method further includes indicating successful denervation to a user when the sensed physiological parameter is different after the second time period than after the first time period. Other embodiments of this aspect include corresponding computer systems, devices, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0013] Specific implementations of this aspect of the present disclosure may include one or more of the following features. The method further includes determining that a first change in the physiological parameter is less than a threshold; and stopping the application of therapy. The method further includes adjusting the stimulation signal and repeating the switching and applying the stimulation signal to each successive pair of electrodes and applying therapy using all the electrodes until the first time period expires. The method further includes determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that is less than a threshold; and determining that the change in the physiological parameter is less than a threshold; and generating an indication for display on a user interface that no nerves are detected at the location of the treatment device. The method further includes increasing the power of the therapy; and applying the adjusted stimulation signal and the therapy with increased power during the second time period. The method further includes determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that exceeds a threshold. Specific implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium, including software, firmware, hardware, or combinations thereof installed on a system, the software, firmware, hardware, or combinations thereof causing the system to perform actions in operation. One or more computer programs may be configured to perform specific operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the actions.

[0014] Another aspect of the present disclosure relates to a system for denervation of blood vessels and nerves. The system includes a stimulation and therapy source and a computing device having a memory and a processor and storing instructions thereon that, when executed: generate a first stimulation signal for application to the blood vessel wall via one of a plurality of electrodes of a therapy device, sense a first change in a physiological parameter caused by the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter indicates the presence of a nerve proximate to one of the plurality of electrodes, generate a therapy for application to the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via one of the plurality of electrodes, sense a second change in the physiological parameter caused by the application of the second stimulation signal, determine whether the application of the therapy has denervated the nerve proximate to the electrode based on the second sensed change in the physiological parameter, and output an indication of successful application of the therapy. Other embodiments of this aspect include corresponding computer systems, devices, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0015] Specific implementations of this aspect of the present disclosure may include one or more of the following features. In the system, the first stimulation signal and the therapy are combined signals generated during an initial time period. Determination of the first sensed change occurs after the initial time period. The second stimulation signal and the therapy are combined signals generated during a second time period. The instructions, when executed by the processor, present an indication on a user interface associated with the computing device, the indication including one or more of: the presence of a nerve proximate to one of the plurality of electrodes, or an indication of successful denervation, or an indication of unsuccessful denervation. The instructions, when executed by the processor, determine the first sensed change in the physiological parameter and output an indication of the absence of a nerve proximate to one of the plurality of electrodes. The instructions, when executed by the processor, stop generation of the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters during a first time period. When executed by the processor, the instructions sense a third change in the physiological parameter caused by applying the first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter indicates the presence of a nerve proximate to one of the plurality of electrodes; and output an indication of the presence of a nerve proximate to one of the plurality of electrodes. Specific implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium, including software, firmware, hardware, or combinations thereof installed on a system, the software, firmware, hardware, or combinations thereof causing the system to perform actions in operation. One or more computer programs may be configured to perform specific operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the actions.

[0016] The present disclosure also discloses a system and method for performing a treatment protocol using a treatment device including an electrode by: applying a stimulation signal from the electrode to a blood vessel wall; observing a physiological response to the stimulation signal; applying a therapy to the blood vessel wall; applying another stimulation signal from the electrode to the blood vessel; and observing a second physiological response to the second stimulation signal, wherein the therapy is successful when the second physiological response differs from the first physiological response by more than a threshold value. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Aspects and embodiments of the present disclosure are described below with reference to the accompanying drawings, in which:

[0018] Figure 1 is a schematic diagram of a therapy system provided according to the present disclosure;

[0019] Figure 2 is Figure 1 a schematic diagram of a workstation of the therapy system of

[0020] Figure 3 is according to the present disclosure Figure 1 a perspective view of a treatment device of the therapy system of

[0021] Figure 4A is a graphical representation of a change in a physiological parameter experienced by a patient due to stimulation application before therapy;

[0022] Figure 4B is a graphical representation of a change in a physiological parameter experienced by a patient due to stimulation application after therapy;

[0023] Figure 5A is a graphical representation of two methods for performing diagnostic and treatment protocols according to the present disclosure;

[0024] Figure 5B is a graphical representation of a combined stimulation signal and therapy according to the present disclosure;

[0025] Figure 6 is a schematic diagram of a feedback system according to the present disclosure;

[0026] Figure 7 is a representation of a change that can be displayed on a user interface as a result of performing one or more of the methods of the present disclosure;

[0027] Figure 8 is a method for applying stimulation and therapy according to the present disclosure;

[0028] Figure 9 is a method for applying stimulation and therapy according to the present disclosure;

[0029] Figure 10 is a method of applying stimulation and therapy according to the present disclosure;

[0030] Figure 11 is a representation of a part of a treatment device according to aspects of the present disclosure;

[0031] Figure 12 is a method for determining the proximity of a nerve to an electrode of a treatment device and which electrodes should be used to apply therapy; and Figure 11 is another method for determining the proximity of a nerve to an electrode of a treatment device and which electrodes should be used to apply therapy.

[0032] Figure 13 is a method for determining the proximity of a nerve to an electrode of a treatment device and which electrodes should be used to apply therapy; and Figure 11 is another method for determining the proximity of a nerve to an electrode of a treatment device and which electrodes should be used to apply therapy. DETAILED DESCRIPTION

[0033] The present disclosure relates to treatment systems and methods for denervation or neuromodulation of nerves such as sympathetic or parasympathetic nerves, particularly unmyelinated nerve fibers in and around blood vessels and other luminal tissues. Specifically, the present disclosure relates to systems and methods that provide the following guidance: preoperative guidance regarding the correct placement of a therapy catheter, intraoperative guidance regarding the effectiveness of therapy, and postoperative analysis regarding the overall efficacy of therapy.

[0034] For ease of description, most of the following description focuses on the implementation of electrical stimulation and RF denervation. Those skilled in the art will recognize that the methods and systems described herein can employ any of the therapy modalities and / or nerve stimulation modalities described herein. Similarly, the following description focuses on navigating to the renal artery and applying nerve stimulation and / or therapy to the renal artery to denervate sympathetic nerves in, around, and near the renal artery or, in certain embodiments, parasympathetic nerves. However, the present disclosure is not limited thereto and can be used to denervate nerves accessible via any of the blood vessels described herein (e.g., hepatic, mesenteric, visceral, etc., and combinations thereof) through other luminal tissues (e.g., bile duct).

[0035] Turning now to the drawings, Figure 1Shown is a guidance and therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10. As will be described in further detail hereinafter, the guidance and therapy system 10 enables navigation of a treatment device 50 to a desired location within a patient's anatomy (e.g., the patient's renal artery), delivery of nerve stimulation to tissue within the renal artery, observation of a physiological response to the application of the nerve stimulation to the tissue, adjustment of the position of the treatment device within the renal artery based on the physiological response if desired, reapplication of the nerve stimulation to the tissue at the adjusted position, application of a denervation therapy to the tissue within the renal artery to denervate sympathetic nerves within the tissue, and delivery of nerve stimulation to the denervated tissue, observation of the physiological response to the nerve stimulation and assessment of the efficacy of the denervation therapy.

[0036] The guidance and therapy system 10 includes a workstation 20, a treatment device 50 operatively coupled to the workstation 20, and an imaging device 70 that may be operatively coupled to the workstation 20. The patient "P" is shown lying on an operating table 12, where the treatment device 50 is inserted through a portion of the patient's femoral artery, although it is contemplated that the treatment device 50 may be inserted into any suitable portion of the patient's vasculature that is in fluid communication with the desired blood vessel for therapy. Although generally described as having one treatment device 50, it is envisioned that the therapy system 10 may employ any suitable number of treatment devices 50. The treatment devices 50 may employ the same or different therapy modalities and may be operatively coupled to the workstation 20. Additionally, without departing from the scope of the present disclosure, the treatment device 50 may employ a guidewire or guiding catheter 58( Figure 3 ).

[0037] Continue Figure 1 And additionally referring Figure 2 , the workstation 20 includes a computer 22, a therapy source 24 (e.g., an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.) operatively coupled to the computer 22, and a stimulation source 24a operatively 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, and the therapy source 24 may generate both therapy modalities and stimulation modalities.

[0038] A computer is coupled to a display 26 configured to display one or more user interfaces 28. The computer 22 can be a desktop computer or a tower configuration with a display 26, or can be a laptop computer or other computing device. The computer 22 includes a processor 30 that executes software stored in a memory 32. The memory 32 can store one or more application programs 34 and / or algorithms 44 to be executed by the processor 30. A network interface 36 enables the workstation 20 to communicate with various other devices and systems via the Internet. The network interface 36 can connect the workstation 20 to the Internet via a wired or wireless connection. Additionally or alternatively, the communication can be via an ad-hoc or wireless network. The network interface 36 can be connected to the Internet via one or more gateways, routers, and network address translation (NAT) devices. The network interface 36 can communicate with a cloud storage system 38 in which additional data, image data, and / or video can be stored. The cloud storage system 38 can be remote from the hospital or within the hospital building, such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 can also serve as a host for more robust analysis of the acquired images (e.g., fluoroscopy, computed tomography (CT), magnetic resonance imaging (MRI), cone beam computed tomography (CBCT), etc.), data, etc. (e.g., additional or enhanced data for analysis and / or comparison). An input module 40 receives input from an input device, which can be such as a keyboard, a mouse, voice commands, an energy source controller (e.g., a foot pedal or a hand-held remote device that enables a clinician to start, terminate a therapy source 24 and / or a stimulation source 24a and optionally adjust various operating characteristics of the therapy source and / or the stimulation source, including but not limited to power delivery)), etc. An output module 42 connects the processor 30 and the memory 32 to various output devices, such as the display 26. In an embodiment, the display screen 26 can be a touch screen display.

[0039] Therapy source 24 generates and outputs one or more of RF energy (monopolar or bipolar), microwave energy, ultrasonic energy, cryogenic medium, or chemical ablation medium via an automatic control algorithm 44 stored on a memory 32 and / or under the control of a clinician. As can be understood, the therapy generated and / or output by therapy source 24 changes the temperature of the tissue (e.g., raises or lowers the temperature) to achieve the desired denervation of the nerve. Therapy source 24 can be configured to produce the selected modality and magnitude of energy and / or therapy for delivery to a treatment site via treatment device 50, as will be described in further detail below. Therapy source 24 can monitor the voltage and current applied to the target tissue via treatment device 50, and monitor the temperature of the target tissue or tissue near the target tissue and / or a portion of treatment device 50. Treatment device 50 or therapy source 24 can also measure and monitor the impedance of the tissue through which the energy is transmitted for treatment or guidance to provide an indication of the tissue state.

[0040] Stimulation source 24a generates a stimulation signal, such as a biphasic waveform at an energy level lower than the treatment (i.e., denervation energy) generated by therapy source 24, such that the stimulation generated by stimulation source 24a does not denervate the target tissue. Instead, stimulation source 24a generates a stimulation signal capable of eliciting a response from the nerve, the response indicating tissue that would be a candidate for denervation. The response can include an increase in blood pressure, an increase in vascular stiffness, a change in pulse wave velocity, an increase in pressure, a change in heart rate, etc., and combinations thereof. In one example, stimulation source 24a generates a biphasic waveform, wherein the leading phase of each successive pulse of the biphasic waveform is switched or otherwise reversed. In this way, a biphasic waveform with an initial pulse having an anodal leading phase and a cathodal trailing phase is followed by a second pulse having a cathodal leading phase and an anodal trailing phase, which is followed by a third pulse that returns to the anodal leading phase and cathodal trailing phase, and so on. Alternatively, a biphasic waveform with an initial pulse having a cathodal leading phase and an anodal trailing phase can be followed by a second pulse having an anodal leading phase and a cathodal trailing phase, which is followed by a third pulse that returns to the cathodal leading phase and anodal trailing phase. As can be understood, the leading phase of each pulse of the biphasic waveform can alternate during the duration of the nerve stimulation applied to the target tissue.

[0041] As described above, the amplitude, frequency, pulse width, and / or duration of the nerve stimulation can be selected and / or modified to ensure stimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or around the luminal tissue or causing excessive vasoconstriction around the treatment device (e.g., inhibiting movement of the treatment device within the luminal tissue). The pulse duration (pulse width) can be modified to ensure that anodic stimulation of the tissue is maintained because at certain pulse durations, the area of anodic stimulation can dissipate or otherwise disappear, resulting in a reduced stimulation effect. In one non-limiting embodiment, the stimulation source 24a generates a biphasic waveform having a frequency between about 10 Hz and 30 Hz, a voltage between about 5 V and 30 V, a current between about 2 mA and 500 mA, and a pulse width between about 2 ms and 10 ms. It is contemplated that in embodiments targeting unmyelinated nerve fibers, the pulse width of the biphasic waveform can be between about 2 ms and 120 ms. In another example, the stimulation parameters are a constant current of 20 mA for the vascular branch and a constant current of 30 mA for the main vessel, a pulse width of 5 mS, a frequency of about 20 Hz, and a duration between 10 seconds and 60 seconds.

[0042] Figure 3Depicts an embodiment of a treatment device 50 according to the present disclosure. The treatment device 50 includes an elongate shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongate shaft 52. The treatment device 50 includes an energy delivery assembly 54, at which one or more therapy electrodes 56 are located. The elongate shaft 52 of the treatment device 50 is configured to be advanced within a portion of a patient's vasculature, such as the femoral artery or other suitable portion of the patient's vascular network that is in fluid communication with the patient's renal artery. In an embodiment, the energy delivery assembly 54 is configured to transition from an initial undeployed configuration having a generally linear profile to a second deployed or expanded configuration, in which the energy delivery assembly 54 forms a generally helical and / or spiral configuration for delivering energy to a site to apply one or both of a stimulation signal or treatment energy at the treatment site. Those skilled in the art will recognize that, in the context of the present application, the application of treatment energy should be interpreted to include applying cryogenic cooling to a treatment site to effect thermally induced neuromodulation. In this manner, when in the second expanded configuration, the energy delivery assembly 54, and in particular the individual electrodes 56, press against or otherwise contact the wall of the patient's vascular system tissue. Although generally described as transitioning to a helical and / or spiral configuration, it is contemplated that the energy delivery assembly 54 may be deployed in other configurations without departing from the scope of the present disclosure. Additionally, the treatment device 50 may be configurable, for example, using one or more pull wires (not shown) to adjust the configuration to facilitate contact between the electrodes 56 and the wall of the renal artery. As such, the treatment device 50 may be capable of being placed in one, two, three, four, or more different configurations depending on the design requirements of the treatment device 50 or the location at which the therapy is to be applied.

[0043] As Figure 3 depicted, the elongate shaft 52 may be configured to be received within a portion of a guiding catheter or sheath (such as a 6F guiding catheter) 58 that is used to navigate the treatment device 50 to a desired location, at which point the guiding catheter 58 is retracted to expose the treatment device 50. As described above, retraction of the guiding catheter 58 may enable the energy delivery assembly 54 to transition from a first undeployed configuration to a second deployed or expanded configuration.

[0044] The elongate shaft 52 of the treatment device 50 may further include a lumen (not shown) at its distal end that is configured to slidably receive a guide wire, and the treatment device 50 is advanced over the guide wire either alone or in combination with the guiding catheter 58. In this manner, the guide wire is used to direct the treatment device 50 to the target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guide wire may be partially or fully removed from the treatment device 50 such that the treatment device 50 is able to transition from a first undeployed configuration to a second deployed or expanded configuration ( Figure 3)。As described elsewhere herein, the treatment device 50 can be transformed from the first undeployed configuration automatically (e.g., via shape memory alloy, etc.) or manually (e.g., via a pull wire controlled by a clinician, guide wire manipulation, etc.) into the second deployed configuration.

[0045] Continuing to refer Figure 3 , in an embodiment where the treatment device 50 is an RF ablation catheter, the energy delivery assembly 54 includes one or more electrodes 56 disposed on its outer surface, and the one or more electrodes are configured to contact a portion of the patient's vascular tissue when the treatment device 50 is placed in the second expanded configuration. As shown herein, the treatment device 50 includes four electrodes 56. However, the present disclosure is not limited thereto, and the treatment device 50 may have more or fewer electrodes 56 without departing from the scope of the present disclosure. Those skilled in the art will recognize that the electrodes 56 can be replaced with ultrasound transducers, microwave antennas, ports for delivering cryoablation media or chemical media, and other implements and / or ablation and denervation modalities without departing from the scope of the present disclosure.

[0046] As shown, the electrodes 56 are disposed along the length of the treatment device 50 in a spaced-apart relationship with each other, thereby forming the energy delivery assembly 54. As will be understood, these electrodes 56 are in communication with both the therapy source 24 and the stimulation source 24a. In one example, the therapy source 24 generates monopolar RF energy to denervate the sympathetic nerves of the associated blood vessel. The electrodes 56 can deliver RF energy independently of each other (e.g., monopolar), simultaneously, selectively, sequentially, and / or between any desired combination of the electrodes 56 (e.g., bipolar). It is contemplated that in one embodiment, the therapy source 24 is also the stimulation source 24a and includes a diagnostic mode and a denervation mode. In the diagnostic mode, the therapy source 24 generates nerve stimulation having, for example, a biphasic waveform, and in the denervation mode, the therapy source 24 generates RF energy to denervate the nerves of the associated blood vessel. It is expected that the therapy source 24 can be manually switched from the stimulation mode to the denervation mode and vice versa, or can be automatically switched by an algorithm 44 stored in the memory 32 of the computing device. Alternatively, the electrodes 56 communicate with an independent stimulation source 24a to deliver a stimulation signal to the blood vessel in question. The stimulation signal (e.g., biphasic waveform) is generated by the stimulation source 24a and transmitted to the electrodes 56, thereby causing stimulation of the sympathetic nerves as described herein.

[0047] In at least one embodiment, during the anodic phase of the biphasic pulse, the stimulation signal is applied to the target tissue via a first electrode of the electrodes 56 and received in a bipolar manner by a second electrode of the electrodes 56, and during the cathodic phase of the biphasic pulse, the nerve stimulation is applied to the target tissue via the second electrode of the electrodes 56 and received in a bipolar manner by the first electrode of the electrodes 56. It is contemplated that during the anodic or cathodic phase of the biphasic pulse, the stimulation signal is applied by two or more of the electrodes 56 or received by two or more of the electrodes 56 in any suitable configuration, such as the most proximal electrode 56 and the most distal electrode 56, the most proximal electrode 56 and the next most proximal 56, the most proximal electrode 56 and an electrode 56 disposed only proximal to the most distal electrode 56, etc.

[0048] Additionally, one or more algorithms 44 can be employed to stimulate the plurality of electrodes 56. For example, if there are four electrodes, there can be an excitation order in which the electrodes 56 apply nerve stimulation. In such examples, the electrodes 56 can be connected in a bipolar manner as follows. A first anodic phase between the first electrode and the fourth electrode, a first cathodic phase between the fourth electrode and the first electrode. This can be followed by a second cathodic phase between the fourth electrode and the first electrode, and a second anodic phase between the first electrode and the fourth electrode. This can be followed in a similar manner by different pairs of electrodes 56, such as between the first electrode and the third electrode 56, between the first electrode and the second electrode 56. Similar patterns can be followed between the second electrode and the fourth electrode and between the second electrode and the third electrode. Still additionally, the anodic and cathodic phases do not need to be between the same pair of electrodes. For example, the first anodic phase can be between the first electrode and the fourth electrode, and then followed by a cathodic phase between the fourth electrode and the second electrode. Alternatively, the first anodic phase can be between the first electrode and the fourth electrode, and then followed by a cathodic phase between the fourth electrode and the first electrode 56, as in the first example, however the second anodic phase can be between the second electrode and the fourth electrode, followed by a second cathodic phase between the fourth electrode and the second electrode. The excitation order of the electrodes 56 is limited only by the number of electrodes 56 and the biphasic waveform.

[0049] During the application of the stimulation signal to the target tissue, compared to conventional bipolar or monopolar stimulation, the leading phase of each successive pulse of the alternating biphasic waveform stimulates a greater number of nerves within the target tissue. By stimulating a greater number of nerves within the target tissue, it is easier to identify the optimal placement of the electrodes 56 for denervation within the target tissue to ensure effective renal denervation and optimal results. The position and / or orientation of the electrodes 56 relative to the tissue wall can be changed between the application of the stimulation signals to map or otherwise identify the optimal nerve candidates for denervation.

[0050] Figure 4A and Figure 4BDepicts an aspect of the present disclosure. As Figure 4A shown, a stimulation signal 102 is applied to the target tissue via an electrode 56. The duration of the stimulation signal is illustrated by trace 104. As a result of the stimulation signal 102, two physiological effects are observed during its application. The first effect is an increase in heart rate, as depicted by trace 106. It can be seen that even before the stimulation signal 102 stops, the heart rate begins to return to normal. In contrast, as depicted by trace 108, the mean arterial pressure both during and after the application of the stimulation signal 102 increases and remains elevated above the pre-stimulation mean arterial pressure. This change in one or both of the heart rate and mean arterial blood pressure indicates stimulation of the afferent nerves of the blood vessel (e.g., renal and / or hepatic artery) in which the treatment device 50 is positioned. In the case where the change in heart rate or mean arterial pressure exceeds a pre-determined threshold, the clinician can determine that the position of the energy delivery assembly 54 is suitable for the application of a denervation therapy, and the treatment energy can be applied to the target tissue at that location within the blood vessel. In one aspect of the present disclosure, as Figure 4B depicted, after the application of the treatment energy, the stimulation signal 102 can be applied again, as shown by trace 104. As shown, although the stimulation signal 102 is applied, in Figure 4B , very little response is observed either in the heat rate 106 or the mean arterial pressure 108. The difference between the observed response to the stimulation signal 102 applied before the therapy ( Figure 4A ) and the observed response to the stimulation signal 102 applied after the therapy ( Figure 4B ) indicates successful ablation or denervation of the afferent nerves (e.g., sympathetic or parasympathetic nerves) close to the placement of the treatment device 50 within the blood vessel. Thus, using the systems and methods of the present disclosure, a clinician can navigate the treatment device 50 to a location within a patient P, apply the stimulation signal 102 to confirm that the treatment device 50 is placed close to the afferent nerves, apply a therapy to the afferent nerves, and apply the stimulation a second time to confirm successful denervation of the afferent nerves or determine that further application of the therapy is needed. As will be appreciated, this cycle can be repeated as needed to achieve successful ablation.

[0051] Figure 5A Schematically depicts the application of stimulation and therapy according to two aspects of the present disclosure. An initial stimulation signal 202 can be applied to the target tissue over a period of time T, and the change in a physiological parameter (here blood pressure) is observed, as shown by graph 204. If no response or an insufficient response to the stimulation is observed, the treatment device 50 can be moved within the blood vessel, as described elsewhere herein. Once a sufficient change in the physiological parameter is observed, the therapy can be applied over a pre-determined period of time. In Figure 5AIn this case, the therapy can be, for example, monopolar RF ablation energy 206. After applying the therapy 206, there are at least two alternatives. In the first alternative, similar to the method described above with respect to Figure 4A and Figure 4B a second stimulation signal 208 can be applied, and if it is determined that the change in a physiological parameter (e.g., mean arterial blood pressure) is below a threshold, the procedure can end. A change in the physiological parameter caused by the stimulation 208 exceeding the threshold indicates unsuccessful or incomplete denervation, and an additional therapy 210 is applied. This process of stimulation 208 and therapy 210 can be repeated until the change in the physiological parameter (e.g., mean arterial blood pressure) caused by the stimulation 208 drops below the threshold, as depicted in the graph 212. Alternatively, the change in the physiological parameter can be shown in the graph 204 as a result of the stimulation and compared with the threshold, and if the difference is greater than the threshold, it can be determined that the denervation is successful and the therapy ends. As another component of this aspect of the present disclosure, the magnitude of the therapy power (e.g., a change in one or more of current, voltage, and duration) can be changed with each successive application of the therapy 210. Additionally, a ramp rate can be employed such that at a particular interval of applying the therapy 210, a greater treatment power can be used than in the previous interval until the desired result (e.g., a physiological response to a stimulation below the desired threshold) is achieved.

[0052] Alternatively, after the initial therapy, a combined stimulation signal and therapy 214 can be applied by the treatment device 50. This combination can be applied for a pre-determined period of time and / or until a change in a physiological parameter (e.g., a decrease in mean arterial pressure) is observed during the combined stimulation signal portion. As will be understood and consistent with other aspects described herein, if the physiological parameter (e.g., mean arterial pressure) increases, the therapy power (e.g., a change in one or more of current, voltage, and duration) can be changed. The observed decrease in the physiological parameter can be recorded as shown in the graph 216, and the termination point of the application of the combined signal 212 can be, for example, the absolute change (e.g., the pressure increment observed from 204 and 214), or alternatively, the observed rate of change between successive stimulation signal portions of the combination 214. Although typically described with respect to mean arterial blood pressure, other physiological parameters can also be observed and employed without departing from the scope of the present disclosure, including pulse wave velocity, arterial stiffness, heart rate, and any combination of these or other parameters.

[0053] Figure 5BDepicts a graphical representation of the combined stimulation signal and ablation 214. It can be seen that there is a series of alternative times for applying the stimulation and ablation. As will be described hereinbelow, the combined signal can be applied within the time period T1, and after this time period, the efficacy of the ablation can be evaluated based on changes in physiological parameters (e.g., systolic blood pressure, MAP, etc.).

[0054] Furthermore, the electrode 56 can be selectively used to apply the stimulation, while other electrodes 56 are used to apply the therapy. In this regard, the stimulation 208 can be applied via the first electrode 56, and the therapy 210 can be applied by the second electrode 56. Alternatively, both the stimulation 208 and the therapy 210 can be delivered by the same selected electrode 56. Optionally, the combined signal 214 can be selectively delivered from the first electrode 56 during a first time period and then from the second electrode during a second time period. Other arrangements for selectively applying the stimulation and the therapy to the combination of electrodes 56 without departing from the scope of the present disclosure.

[0055] Figure 6Schematic diagram of a feedback system according to the present disclosure. As described elsewhere herein, the therapy source 24 and the stimulation source 24a apply energy and signals to the electrodes 56 of the treatment device 50, as described above. When therapy is applied to the electrodes 56 and then the target tissue attempts to denervate the afferent nerves located therein, the impedance of the tissue through which the energy passes can be measured by the therapy source 24. As will be understood by those skilled in the art, when energy (e.g., RF or microwave energy) is applied to tissue (here the vessel wall), the impedance of the tissue will begin to increase as it is heated. However, it is desirable to prevent the tissue from exceeding a predetermined temperature at which permanent damage to the vessel wall tissue will occur. Fortunately, nerve tissue tends to be more sensitive to heat and denervates or allows denervation at temperatures below those at which the surrounding tissue experiences permanent and irreversible damage. Thus, by controlling the impedance of the target tissue, the therapy source 24 can be controlled to prevent undesirable heating of the blood vessel. In a similar manner, each electrode 56 can incorporate a thermistor or other temperature sensor (not shown) to monitor the temperature of the electrode 56. As will be understood, the electrodes 56 are in direct contact with the inner wall of the blood vessel or other luminal tissue, so when energy passes through the electrodes 56, the electrodes themselves begin to heat. A thermistor, thermocouple, or other temperature sensor in communication with the electrode 56 generates a signal that is received by the therapy source 24. This signal represents the temperature of the electrode, and if the temperature of any of the electrodes 56 exceeds a predetermined threshold, a temperature below which damage to the vessel wall may occur, the therapy source 24 stops outputting treatment energy to the electrodes 56. As will be understood, the movement of blood through the blood vessel will rapidly cool the electrodes 56. Once the temperature of the electrodes 56 returns below the predetermined threshold, the therapy source 24 can again begin to apply therapy using one or more of the methods described herein to achieve the desired denervation or neuromodulation of the nerves around the blood vessel.

[0056] In addition to the above-described forms of feedback (which are primarily but not exclusively used to protect the patient and the patient's tissue during the procedure), another form of feedback can be provided via the blood pressure module. The blood pressure module 62 employs a blood pressure sensor 60 located on the treatment device 50, the catheter 58, or a separate component navigated close to the target tissue. In either case, the blood pressure sensor 60 monitors the blood pressure in the blood vessel to which the therapy is being applied. The measured blood pressure can be used directly as a feedback parameter or can be converted into one or more different metrics, including but not limited to pulse wave velocity, augmentation index (AIX), a measure of arterial stiffness, tricuspid regurgitation velocity (TR). As described above in connection with Figures 4A to 5B what has been described, the analysis of the blood pressure as a result of the application of the stimulation from the stimulation source can be used to determine whether greater therapy power is needed, whether more therapy is needed, whether the therapy duration should be increased, and when the therapy can be stopped.

[0057] Figure 7Depicts an example of the UI 28 that may appear on the display 26 in accordance with the present disclosure. As explained in more detail below, each electrode may be labeled E1 to E4. In accordance with the present disclosure, during the pre-operative mapping phase, a stimulation signal 202 is delivered from each of the electrodes 56, and one or more physiological parameters may be monitored to see if the stimulation signal has elicited a nerve response. As Figure 7 seen, electrodes E2 to E4 are associated with a nerve response and depict a green light, as will be described in more detail below. Stimulation of these electrodes may be associated with a change in systolic blood pressure measured in the blood vessel in which the treatment device 50 has been placed. However, electrode E1 has a red light associated with it, thereby indicating via the UI 28 that the stimulation signal from this electrode has not caused a change in a physiological parameter (e.g., systolic blood pressure).

[0058] As Figure 7 shown in graphical form, the stimulation signal 202 is followed by a therapy 206 that may be delivered from one or more of electrodes E1 to E4 to denervate the nerve of the blood vessel in which the treatment device 50 is placed. After the application of the therapy, during the post-operative mapping phase, the stimulation signal may again pass through the electrodes, particularly E2 to E4 that showed a change in physiological parameter during the pre-operative mapping phase. The indication markers associated with electrodes E2 and E3 show a green light or other positive indication markers, thereby alerting the user that the application of the therapy 206 has effectively changed the physiological response to the stimulation 202 associated with the post-operative mapping of the stimulation signal 202. In one example, the pre-operative change in systolic blood pressure from the stimulation 202 may be an initial value, and the post-operative mapping may be at a much lower level (e.g., below a certain threshold), thereby indicating that the application of the therapy has successfully ablated or denervated the nerves near electrodes E1 and E2. Electrode E4 has a yellow light or other indication marker that may be interpreted as indicating that although some reduction in the physiological parameter has been achieved, it is not sufficient to be considered a successful ablation / denervation of the nerves near electrode E4. This indication marker allows the user to understand the effectiveness of the therapy before deciding to apply more therapy or move the treatment device. These and other aspects of the present disclosure are described in more detail below.

[0059] Figure 8is a flowchart depicting method 800 according to the present disclosure. At step 802, a treatment device 50 is placed at a desired location within a patient's body (e.g., in a renal or hepatic artery). As part of the placement, the treatment device 50 can be advanced from a catheter 58 and allowed to expand such that the electrodes 56 contact the inner wall of the artery. At step 804, a pre-ablation stimulation is applied, such as a biphasic stimulation signal that can be transmitted between any two of the electrodes 56. The stimulation signal can alternate the leading phase of the stimulation signal. Additionally, the stimulation signal can alternate between pairs of electrodes 56 to stimulate the afferent nerves of the blood vessel. At step 806, it is determined whether a change in a physiological parameter (e.g., systolic blood pressure observed in the blood vessel) is greater than a pre-determined threshold. In one specific implementation, this determination employs a pressure sensor 60. If so, at step 808, the stimulation parameters are maintained at a nominal maximum current and duration setting, and ablation is started at step 810.

[0060] However, if no blood pressure change or an insufficient blood pressure change is observed at step 806, there are multiple options. In a first option, the current and duration parameters for stimulation can be adjusted (e.g., increased) at step 812, and the method can proceed to start ablation at step 810. An indication flag that alerts the user of the change can be generated, and the indication flag can be auditory, tactile, visual (e.g., on a user interface), or a combination of these. This can be an option where a change in pressure is observed, but the change is less than the threshold, indicating that the nerves being stimulated are farther from the electrodes or are surrounded by tissue that is attenuating the stimulation effect. Alternatively, the method can return to step 804 to determine the application of the pre-ablation stimulation, and then at step 806, the change in systolic blood pressure is compared again with the threshold, rather than proceeding to the start of ablation at step 810. Even further, the method can return to step 802 to adjust the position of the treatment device 50 at step 802 before applying the pre-ablation stimulation at step 804. These processes can be repeated as needed until the clinician is satisfied that the position in the patient's blood vessel and the energy level applied at that position have achieved a sufficient change in the monitored physiological parameter.

[0061] After ablation at step 810, a post-ablation stimulus can be applied at step 814, and the physiological parameter can be measured again at step 816. If the change in the physiological parameter is greater than a threshold, the method moves to step 818, where the power or duration of the ablation energy is adjusted, and the method returns to step 810. An indication can be generated to alert the user of the change, and the indication can be audible, tactile, visual (e.g., on a user interface), or a combination of these. This can be repeated as needed until the change in the measured physiological parameter is not greater than a certain threshold (i.e., less than the threshold). This indicates that the ablation has successfully denervated the nerves in the blood vessel at that location. At this point, the method can optionally end or return to step 802 to reposition the treatment device 50 for denervation at another location following the same method 800. An indication of successful denervation can be generated to alert the user of the success.

[0062] Figure 9 An alternative method 900 employing a combination of stimulation and ablation techniques is depicted, as noted above with respect to FIG. 5. Method 900 focuses on providing guidance regarding the placement and efficacy of therapy application at the placement location of the treatment device 50. Similar to method 800, method 900 begins with placing the treatment device 50 at a desired location within the patient (e.g., in a renal or hepatic artery). As part of the placement, the treatment device 50 can be advanced from the catheter 58, and the treatment device 50 is allowed to expand such that the electrodes 56 contact the inner wall of the artery. At step 904, a combined stimulation signal and therapy (e.g., signal 214 in FIG. 5) can be applied to the vessel wall. During the application of the combined stimulation signal and therapy, the stimulation signal is switched to the therapy and then back to the stimulation signal at regular intervals. This repeated switching allows a series of data points related to the observed physiological parameter (e.g., systolic blood pressure) to be generated via the sensor 60 on the treatment device 50.

[0063] At step 906, after applying the combined stimulation signal and therapy 214 within the time period T1, it is determined whether the change in the physiological parameter (e.g., systolic blood pressure) is greater than a pre-determined threshold. If it is determined to be yes at step 908, the combined stimulation signal and therapy 214 are continued to be applied until the expiration of the second duration T2. At step 910, it is determined whether the measured physiological parameter (e.g., systolic blood pressure) measured at time T2 is different from the physiological parameter measured at time T1. For example, in the case of measuring systolic blood pressure, step 910 will evaluate whether the systolic blood pressure at time T2 is less than the systolic blood pressure at time T1. However, without departing from the scope of the present disclosure, other parameters may be employed, where the determination is aimed at judging whether the measurement of the physiological parameter at time T2 is greater than at time T1. If the answer at step 910 is yes, a green light or other indication mark may be displayed on the UI 28 and shown to the user to signal that successful ablation has been achieved. The process may then optionally end or return to step 902, at which step the treatment device 50 may be repositioned to ablate another location within the same blood vessel or another blood vessel.

[0064] Return to step 906. If the change in the physiological parameter at time T1 is less than the threshold, the therapy is stopped and the stimulation signal parameters are adjusted at step 916. At step 917, an indication mark of the absence of stimulation may be generated to alert the user of the change, and the indication mark may be audible, tactile, visual (e.g., on the user interface), or a combination of these, and the adjusted stimulation signal is applied within the duration T1. At step 918, it is determined whether the change in the physiological parameter is greater than the threshold, which may be the same as or different from the threshold used in step 906. If the change in the physiological parameter is less than the threshold, method 900 proceeds to step 920, at which an indication mark, such as a red light, is displayed in the UI 28 to indicate that no nerve is located at that position. Then the method returns to step 902, at which step the treatment device 50 is moved to another position and the process starts again.

[0065] However, if there is a change in the physiological parameter greater than the threshold when stimulated with the adjusted stimulation signal at step 918, then at step 922 this change is an indication mark that the nerve at that position is farther from the blood vessel wall (e.g., deeper into the tissue). Therefore, in order to achieve the desired ablation effect on the nerve tissue, the protocol requires additional energy to be applied more, such as by increasing the power, increasing the ablation duration, changing the frequency or pulse duration, adding additional electrodes to the array, or a combination thereof. An indication mark may be generated and, for example, an indication mark regarding the required adjustment is displayed on the UI 28. The parameters may be adjusted at step 924, and the method returns to step 904, at which step the process is repeated as described above.

[0066] Figure 10 Depicts another method 1000 that utilizes a combined stimulation signal and therapy. Method 1000 is similar to methods 800 and 900 and begins by positioning the treatment device 50 within a blood vessel that requires therapy (e.g., ablation, denervation). At step 1004, a combined stimulation signal and therapy 214 (e.g., as shown in FIG. 5) is applied to the blood vessel wall. At step 1006, it is determined whether a change in a physiological parameter (e.g., systolic blood pressure, MAP, etc.) exceeding a threshold is observed after a duration T1. If it is determined at step 1006 that the change in the physiological parameter exceeds the threshold, the method proceeds to step 1008, where the combined stimulation signal and therapy is continuously applied until time T2 expires. At the end of time T2, at step 1010, it is determined whether the physiological parameter measured at time T2 (e.g., systolic blood pressure) is different from the physiological parameter measured at time T1. For example, in the case of measuring systolic blood pressure, step 910 will evaluate whether the systolic blood pressure at time T2 is less than the systolic blood pressure at time T1. However, other parameters can be employed without departing from the scope of the present disclosure, where the determination is aimed at judging whether the measurement of the physiological parameter is greater at time T2 than at time T1. If the answer at step 1010 is yes, the method proceeds to step 1012, and a signal such as a green light can be displayed on the UI 28 to signal successful ablation at that location. Optionally, method 1000 can then end or can return to step 1002, where the treatment device 50 can be repositioned for further ablation / denervation procedures.

[0067] However, if at step 1010 the physiological parameter is not different from the physiological parameter measured at time T1 or has not moved in the correct direction (e.g., a decrease in systolic blood pressure), the method proceeds to step 1014, where it is determined whether the power limit has been reached. If the power limit has been reached, the method can proceed to step 1018, where an indication sign such as a red light is displayed on the UI 28 to signal to the user that insufficient ablation has been received at that location within the blood vessel. The method can then optionally end or return to step 1002 to reposition the treatment device 50 and for further therapy.

[0068] If the power limit has not been reached at step 1014, the method proceeds to step 1016, where the power to be applied during the therapy portion of the combined stimulation signal and therapy is increased. Then the method returns to step 1008, where the combined stimulation signal and therapy with increased power is applied to the blood vessel until time T2 expires. The method continues as described above until successful ablation is achieved or unsuccessful ablation is achieved and the power limit has been reached.

[0069] Return to step 1006. If the application of the combined stimulation signal and therapy within time T1 does not cause a change in the physiological parameter greater than the threshold (e.g., a change in systolic blood pressure), the method proceeds to step 1020, where the application of the combined stimulation signal and therapy is stopped. At step 1022, the stimulation signal (e.g., frequency, current, voltage, etc.) is adjusted, and the stimulation signal is again applied to the vessel wall by the treatment device 50 for a duration T1. At step 1024, it is determined whether the change in the physiological parameter (e.g., a change in systolic blood pressure) is greater than the threshold. In some instances, this may be the same threshold as used at step 1006, but another threshold may be used without departing from the scope of the present disclosure. If the determination at step 1024 is yes, the method proceeds to step 1016, where the power of the therapy is increased. Once increased, at step 1008, a combined stimulation signal and therapy with both the adjusted stimulation and the increased therapy power are applied to the patient's vessel. The method proceeds as described above until successful ablation / denervation is achieved or the power limit is reached.

[0070] In the case where the answer to the query at step 1024 is no, meaning that neither the original stimulation nor the adjusted stimulation signal was able to cause a change in the physiological parameter greater than the threshold, the method proceeds to step 1026. In step 1026, an indication sign such as a blue indication sign can be displayed on the UI 28 to alert the user that there is no detectable nerve at that location, and the method returns to step 1002 to reposition the treatment device 50.

[0071] The methods 800 to 1000 are exemplary, and without departing from the scope of the present disclosure, the steps of these methods can be performed in a different order or eliminated. Additionally, as known to those skilled in the art, other methods can be employed to determine the location of the nerve for therapy, measure physiological parameters, and apply the therapy to the patient's nerve.

[0072] Figure 11 A schematic diagram depicting the distal portion of the treatment device 50 showing the electrodes 56 is presented. These electrodes 56 are labeled E1 to E4 respectively. Additional aspects of the present disclosure are described herein with respect to this arrangement of the electrodes 56. As described above, methods 900 and 1000 describe the application of a combined stimulation signal and therapy. Although FIG. 5 includes one depiction of the signal, by using multiple electrodes 56, multiplexed signals can be employed with the electrodes 56 in different pairings and timings to provide a more accurate determination of where the nerve is located, more complete ablation or denervation of the nerve, and a more accurate determination of the success of the procedure.

[0073] According to one aspect of the present invention, two pairs of electrodes 56 are established. The first pair (e.g., E1 and E2) can be used as stimulation electrodes during a first phase, and a stimulation signal is transmitted between the two electrodes for a set duration. During the same duration, the second pair (e.g., E3 and E4) is used to apply therapy for a set duration. In one example, the therapy is monopolar RF, where energy is transmitted from electrodes E3 and E4 to a pad placed on the patient. The duration can be, for example, 10 seconds. At the end of the duration, the pair is switched and E1 and E2 become the therapy electrodes and E3 and E4 become the stimulation electrodes. This back-and-forth switching between the pair applying therapy and the pair applying stimulation can continue (e.g., switching every 10 seconds) until the end of a longer duration (e.g., 50 seconds). In this way, all the electrodes 56 of the treatment device 50 are used for the stimulation of the patient's nerves and the application of therapy, such that a larger area can receive the therapy, and when the treatment device 50 is formed as depicted in Figure 3 , a substantially circumferential ablation around the diameter of the blood vessel can be formed, thereby substantially reducing the likelihood of nerves (e.g., sympathetic nerves) remaining after the application of therapy.

[0074] In the multiplexing arrangement described above, the electrode pairs 56 remain constant and the form of the energy or signal is switched. However, in another form of multiplexing, the pairs themselves can be changed continuously. In this example, in the first phase, E1 and E2 can apply stimulation and E3 and E4 can apply therapy. In the second phase, E2 and E3 apply stimulation and E1 and E4 apply therapy. The third phase can see E3 and E4 applying stimulation and E1 and E2 applying therapy. Additionally, in the fourth phase, E2 and E4 apply stimulation and E1 and E3 apply therapy. These pairings can be made until all the potential pairs of electrodes have been achieved. Each phase can last from 50 milliseconds to 5 seconds. Then the pattern can be repeated until the total therapy duration (e.g., 50 seconds) is reached. In this way, each pair of electrodes applies stimulation, thereby providing a better understanding of the effect of that stimulation between each pair of electrodes. A clearer understanding of the therapy effect can be further obtained. In fact, using the generated data as well as method 900 and method 1000, a more refined determination of the ablation effect achieved by each electrode 56 can be evaluated, thereby allowing the indication identification on the UI (e.g., red light, green light, blue light) to be displayed not only for the entire procedure but also for individual electrodes 56 to provide a better understanding of the efficacy of the procedure.

[0075] Another example of the stimulation and therapy pattern includes the inversion of the polarity of the electrodes 56 for stimulation. Similarly, an electrode pair can be employed (e.g., E1 and E2 can be a stimulation pair). According to this aspect, a combined stimulation signal and therapy can be employed (similar to 214 of FIG. 5). During a first stimulation phase, the stimulation signal is transmitted from E1 to E2. Then, after the stimulation, therapy is applied using all four electrodes 56 for a duration (e.g., 10 seconds). A second stimulation phase can again transmit the stimulation signal from E1 to E2 and then again apply the therapy from all electrodes 56. In subsequent phases, the polarity of the stimulation signal can be inverted, being transmitted from E2 to E1. Therapy can be applied after this reverse stimulation signal, and then another stimulation and ablation cycle can be performed. It has been observed that the change in the polarity of the stimulation signal increases the likelihood of response to the stimulation and thus increases the determination of the success or failure of the procedure.

[0076] The switching of the polarity of the stimulation is not limited to only electrodes E1 and E2, but can be between any two pairs of electrodes. Thus, the stimulation pair can be switched between E1 and E2, E3 and E4, E2 and E3, E2 and E4, E1 and E3, E1 and E4, and each pairing can include the application of stimulation of a first polarity and reverse polarity stimulation. Between each stimulation, all electrodes can be used for the application of therapy. As described in connection with method 800, method 900, method 1000, this process can be repeated until the set duration of stimulation and therapy is reached.

[0077] In a further specific implementation of the devices and systems of the present disclosure, and particularly with reference to method 800, when applied with a non-combined stimulation signal and therapy, the stimulation signal 208 (FIG. 5) can utilize an inverted electrode pair polarity scheme. In one example, the stimulation signal can be applied from electrode E1 to E4 for a first duration and then in a reverse polarity manner from E4 to E1 for a second duration. As described elsewhere, inverting the polarity enhances the neural response to the stimulation.

[0078] Yet another specific implementation employs combined stimulation, where two pairs of electrodes are employed simultaneously. In this example, a stimulation signal is applied between E1 and E2 during a first time period. Simultaneously, electrodes E3 and E4 are also used to apply stimulation during this same time period. During a second time period, stimulation is applied between electrodes E1 and E4 while stimulation is applied between electrodes E2 and E3. In a third time period, stimulation can be applied between electrodes E2 and E4 while stimulation is applied between E1 and E3. Each of these time periods can be very short, e.g., 1 millisecond to 25 milliseconds, and the switching between electrode pairs can be performed until the duration of the stimulation is reached. In some embodiments, this process can be supplemented with the application of reverse polarity stimulation as described in other aspects herein.

[0079] Figure 12 Depicts the reverse polarity stimulation method 1200. The method 1200 is an automated stimulation sequence whereby electrode pairs E1 to E4 are utilized with both an initial polarity and a reverse polarity to determine which electrodes are closer to the nerve and which electrodes should be used to effectively ablate / denerve the nerve. After initializing the system at step 1202, at step 1204, a stimulation signal is passed between electrodes E1 and E4. This represents the longest path between two electrodes. At step 1206, it is determined whether a physiological response above a threshold (e.g., a change in systolic blood pressure) is achieved. If the answer at step 1206 is yes, the method proceeds to step 1208, where a stimulation is applied between electrodes E1 and E2. At step 1210, it is determined whether a stimulation response above a threshold is experienced. If yes at step 1210, the method moves to step 1212, where a stimulation is applied between electrodes E1 and E3. At step 1214, it is determined whether a stimulation response above a threshold is experienced. If the answer is yes, there is a nerve around E1 for ablation / denerve, and then at step 1216, this information is stored in the memory 32 for use with one or more applications 34. If no stimulation response is experienced at step 1214, the method proceeds to step 1218, where a stimulation is applied between electrodes E3 and E1. At step 1220, it is determined whether a pressure response above a threshold is experienced. If the answer is yes, there is a nerve around E3 for ablation / denerve, and then at step 1222, this information is stored in the memory 32 for use with one or more applications 34.

[0080] If no pressure response above a threshold exists at step 1210, the method proceeds to step 1224, where a stimulation is applied between electrodes E2 and E1. At step 1225, it is determined whether a stimulation response above a threshold is experienced. If the answer is yes, there is a nerve around E2 for ablation / denerve, and then at step 1226, this information is stored in the memory 32 for use with one or more applications 34.

[0081] Referring back to step 1206, if the stimuli from E1 and E4 do not experience a supra-threshold stimulus response, the method moves to step 1228 where a reverse-polarity stimulus from E4 to E1 is applied (compared to step 1204). If a supra-threshold pressure response is detected at step 1230, the method proceeds to step 1232 where a stimulus is applied from electrode E4 to E3. At step 1234, it is determined whether the stimulus response is above the threshold. If the answer is yes, there is a nerve for ablation / denervation around E4, and then at step 1236, this information is stored in the memory 32 for use with one or more applications 34.

[0082] If the determination at step 1234 is no, the method advances to step 1238 where a stimulus is applied between electrodes E3 and E4 (essentially opposite in polarity to step 1232). At step 1240, it is asked whether a supra-threshold stimulus response is observed in response to step 1238. If the answer is yes, there is a nerve for ablation / denervation around E3, and then at step 1242, this information is stored in the memory 32 for use with one or more applications 34.

[0083] Referring back to step 1230, if no stimulus response is detected, the method advances to step 1244 where a stimulus is applied between electrodes E2 and E4. At step 1246, it is asked whether the stimulus response is above the threshold. If the answer is yes, there is a nerve for ablation / denervation around E2, and then at step 1248, this information is stored in the memory 32 for use with one or more applications 34. If the answer to the query at step 1246 is no, the method proceeds to step 1250 where a stimulus is applied between electrodes E3 and E2. At step 1252, it is asked whether the stimulus response is above the threshold. If the answer is yes, there is a nerve for ablation / denervation around E3, and then at step 1254, this information is stored in the memory 32 for use with one or more applications 34.

[0084] As described above, method 1200 can be part of an application 34 stored in the memory 32. The results of method 1200 can also be stored in the memory and displayed on the UI 28 or used by an application that executes any one of method 800, method 900, or method 1000 to limit which electrodes are used to ablate / denervate the patient's nerves at any given location where the treatment device 50 is placed.

[0085] Table 1 depicts a table illustrating a method for determining which electrodes 56 are adjacent to a nerve and should thus be employed in a denervation procedure.

[0086]

[0087]

[0088] Table 1

[0089] As Figure 13 depicted, after navigating the therapy device 50 to an artery to denervate by applying stimulation to electrodes E1 and E2, method 1300 begins at step 1302. If no response is observed at step 1304, no nerve is located near electrode E1 or electrode E2, and the method moves to step 1322 where an indication that no nerve is near E1 or E2 is stored in memory, and the method moves to step 1323, as described below. However, if a response is observed, then as described at step 1306, method E1 or E2 or both are near a nerve. To obtain additional information, at step 1308, stimulation is applied to electrode E1. If a response is observed at step 1310, that response indicates that electrode E1 is near a nerve and should be used for the denervation procedure. Then at step 1312, E1 is stored in memory as the electrode to be used for the denervation procedure. If no response is detected, then at step 1314, E1 will be indicated in memory as an electrode not to receive energy for therapy application. Regardless of the result of the determination at step 1310, after stimulation to E1, stimulation will be delivered to E2 at step 1316. Similarly, if a response is detected at step 1318, E2 is stored in memory at step 1320 as the electrode for therapy application, and if no response is detected, E2 is indicated at step 1321 as an electrode not to receive energy during therapy.

[0090] Once electrodes E1 and E2 have been evaluated, the method proceeds to step 1323, where stimulation is applied to both E3 and E4. If no response is detected at step 1324, then at step 1326, electrodes E3 and E4 will be indicated in the memory as not receiving energy during the therapy, and the method ends. If a response is detected at step 1324, then the method advances to step 1328, where stimulation is applied to E3. If a response is detected at step 1330, then at step 1332 an indication that E3 receives energy during the therapy is stored in the memory, and if no response is detected, then at 1336 an indication that E3 does not receive energy during the therapy is stored in the memory. In any case, the method advances to step 1338, where stimulation is applied to E4. If a response to the stimulation is detected at step 1340, then at step 1342 an indication that E4 receives energy during the therapy is stored in the memory, and if no response is detected, then at 1344 an indication that E4 does not receive energy during the therapy is stored in the memory, and regardless of the determination at step 1340, the method ends.

[0091] By following method 1300, an evaluation is made of a portion of the blood vessel in which the treatment device 50 has been placed and the proximity of each of electrodes E1 - E4 to the nerve for denervation. Since the responses to the stimulation from each individual electrode 56 and electrode pairs 56 along the treatment device are evaluated and stored in the memory, a determination can be made as to which of electrodes E1 to E4 is used to apply the therapy. This results in a more targeted application of the therapy, ensuring that the therapy is more likely to be effective and eliminating unnecessary destruction of blood vessel tissue. The method 1300 can be used as part of the methods of stimulation and therapy described herein to ensure that when the therapy is applied, the therapy targets those portions of the blood vessel that may be beneficial to the patient and prevents the unnecessary application of the therapy to other portions of the blood vessel. Method 1300 can also be used separately from other methods to map the location of the nerve or to evaluate the placement of the treatment device 50.

[0092] According to method 1300, electrodes 56E1 to E4 are identified as being close to the nerve, and such an indication is stored in the memory 32. Thus, when methods such as method 800, method 900, method 1000 are taken, only those electrodes E1 to E4 from which a response to the stimulation applied through them is detected receive the stimulation and the therapy.

[0093] Those skilled in the art will recognize that the stimulation signals employed in the embodiments herein may have polyphase pulse waveforms (e.g., biphasic, triphasic, etc.). In one non-limiting embodiment, the nerve stimulation comprises a biphasic waveform, wherein each pulse of the biphasic waveform has an anodic leading phase and a cathodic trailing phase, or vice versa. The therapy system can be configured to alternate the leading phase of each pulse of the biphasic waveform during the application of the nerve stimulation, such that for example the first pulse comprises an anodic leading phase and a cathodic trailing phase, the subsequent second pulse comprises a cathodic leading phase and an anodic trailing phase, and the subsequent third pulse returns to an anodic leading phase and a cathodic trailing phase. The leading phase of each pulse of the biphasic waveform alternates during the duration of the applied nerve stimulation. As a result, compared to continuous first-phase biphasic waveforms and monophasic waveforms known in the art, the neural response to the nerve stimulation is enhanced. This in turn increases the likelihood of stimulating neural tissue and reduces the amount of time required to identify suitable neural tissue for denervation therapy. Further application of the nerve stimulation facilitates accurate determination of the suitability of the location for receiving therapy, as the alternating biphasic waveforms described herein stimulate a greater amount of neural tissue.

[0094] The treatment device 50 contemplated in the present disclosure can apply one or more of a variety of treatment modalities. For example, treatment modalities contemplated within the scope of the present disclosure include monopolar or bipolar radiofrequency, microwave, cryotherapy, ultrasound, chemical, and other modalities yet to be developed. Any of these therapy modalities can be incorporated into a treatment device (such as a catheter) that is configured for navigation to a desired location within a patient's body. A catheter configured to deliver one or more of these treatment modalities can be navigated percutaneously, for example via the femoral artery, to reach blood vessels of the aorta, including the celiac artery, hepatic artery, visceral arteries, mesenteric arteries, and other arteries that are sympathetically denervated or in proximity to one or more sympathetic ganglia. Such a catheter can also be placed laparoscopically in one or more of the blood vessels identified above, or in another luminal tissue, without departing from the scope of the present disclosure.

[0095] The treatment device 50 described herein is also configured to deliver stimulation to blood vessels or other luminal tissue. The amplitude, frequency, pulse width, and / or duration of the stimulation can be selected and / or modified to ensure stimulation of target nerves (e.g., unmyelinated nerve fibers) in the periluminal tissue without damaging the luminal tissue or nerves within or around the luminal tissue or causing excessive vasoconstriction around the treatment device (e.g., inhibiting movement of the treatment device within the luminal tissue).

[0096] As described above, the treatment device 50 is coupled to a therapy source 24 and a stimulation source 24a, but it is contemplated that the therapy source 24 and the stimulation source 24a can be the same and capable of generating both therapy and stimulation. For example, an electrical generator can be configured to generate biphasic pulses for supply to the electrodes 56 of the treatment device 50 and to supply monopolar RF energy to the electrodes 56.

[0097] In accordance with aspects of the present disclosure, the treatment device can be navigated within a blood vessel or luminal tissue in one configuration (e.g., a linear configuration), and once positioned at a desired location, deployed or otherwise actuated to achieve a second configuration.

[0098] In yet another aspect of the present disclosure, the application of stimulation 202 can effect one of a plurality of physiological responses, including an increase in systolic blood pressure, an increase in mean arterial blood pressure, an increase in vascular stiffness, an increase in pulse wave velocity, an increase in vascular hardness, and others.

[0099] As described herein, it is contemplated that the physiological responses to the application of nerve stimulation can be monitored by a control algorithm 44 stored on the computing device 22, where the location and results of the applied nerve stimulation are stored in the memory 32. As noted, the observed post-therapy and intraoperative physiological responses can be compared to the pre-operative responses to evaluate the efficacy of the therapy, determine if more therapy is needed, and when sufficient therapy has been applied to achieve the desired ablation / denervation.

[0100] To date, the treatment device 50 has been primarily associated with shape memory constructs where a shape memory alloy is released from the exit of the guiding catheter 58 to obtain a desired helical shape and the electrodes 56 are placed on the vessel wall. However, the present disclosure is not limited thereto, and the treatment device 50 can be formed such that the electrodes are placed on a balloon or other mechanism to achieve the desired contact with the vessel wall without departing from the scope of the present disclosure.

[0101] Although generally described above, it is contemplated that the memory 32 can include any non-transitory computer-readable storage medium for storing data and / or software, the data and / or software including instructions executable by the processor 30 and controlling the operation of the workstation 20, and in some embodiments, also controlling the operation of the treatment device 50. In an embodiment, the memory 32 can 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 can include one or more mass storage devices connected to the processor 30 via a mass storage controller (not shown) and a communication bus (not shown).

[0102] Although the description of computer-readable media contained herein refers to solid-state storage devices, those skilled in the art should understand that a computer-readable storage medium can be any available medium accessible by processor 30. That is, a computer-readable storage medium can include non-transitory, volatile and non-volatile, removable and non-removable media implemented in any method or technology for storing information such as computer-readable instructions, data structures, program modules, or other data. For example, a computer-readable storage medium can include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technologies, CD-ROM, DVD, Blu-ray or other optical storage devices, magnetic tape cartridges, tapes, magnetic disk storage devices or other magnetic storage devices, or any other medium that can be used to store the desired information and is accessible by workstation 20.

[0103] Although several embodiments of the present disclosure have been shown in the drawings, it is not intended to limit the present disclosure thereto, because it is desired to make the present disclosure as broad as permitted by the art and should be read in the same manner. Therefore, the above description should not be construed as restrictive, but merely as an illustration of embodiments. Those skilled in the art can envision other modifications within the scope and spirit of the appended claims herein.

[0104] The following examples are a non-limiting list of embodiments of one or more technologies according to the present disclosure.

[0105] Example 1. A method of performing a treatment protocol, the method comprising: applying a first stimulation signal from an electrode of a treatment device to a blood vessel wall; observing a first physiological response to the first stimulation signal; applying a therapy to the blood vessel wall; applying a second stimulation signal from the electrode to the blood vessel; observing a second physiological response to the second stimulation signal; and outputting an indication of a successful therapy when the second physiological response differs from the first physiological response by more than a first threshold.

[0106] Example 2. The method according to Example 1, the method further comprising adjusting a parameter of the first stimulation signal when the first physiological response is observed to be less than a second threshold.

[0107] Example 3. The method according to Example 2, the method further comprising applying the first stimulation signal to the blood vessel wall with the adjusted parameter before applying the therapy to the blood vessel wall.

[0108] Example 4. The method according to Example 1, the method further comprising adjusting a parameter of the therapy if the second physiological response differs from the first physiological response by less than the first threshold.

[0109] Example 5. The method according to Example 4, the method further comprising applying a therapy to the vessel wall with adjusted parameters.

[0110] Example 6. A system for denervation of a vascular nerve, the system comprising: a treatment device configured to navigate within a patient's blood vessel; a plurality of electrodes formed on a distal portion of the treatment device; a sensor configured to measure one or more physiological parameters of the patient at a location where the treatment device has been navigated; a stimulation and therapy source; a computing device comprising a memory and a processor and storing instructions thereon that, when executed: generate a first stimulation signal for application to the vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter caused by the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; generate a therapy for application to the vessel wall; generate a second stimulation signal for application to the vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter caused by the application of the second stimulation signal; based on the second sensed change in the physiological parameter, determine whether the application of the therapy has denervated the nerve near the electrode; and output an indication that the application of the therapy was successful.

[0111] Example 7. The system according to Example 6, wherein the first stimulation signal and the therapy are combined signals generated during an initial time period.

[0112] Example 8. The system according to Example 7, wherein the determination of the first sensed change occurs after the initial time period.

[0113] Example 9. The system according to Example 8, wherein the second stimulation signal and the therapy are combined signals generated during a second time period.

[0114] Example 10. The system according to Example 6, wherein the instructions, when executed by the processor, present an indication on a user interface associated with the computing device, the indication comprising one or more of: the presence of a nerve near one of the plurality of electrodes, or an indication of successful denervation, or an indication of unsuccessful denervation.

[0115] Example 11. The system according to Example 6, wherein the instructions, when executed by the processor, determine that the first sensed change in the physiological parameter indicates the absence of a nerve near the one of the plurality of electrodes and output an indication.

[0116] Example 12. The system according to Example 11, wherein the instructions, when executed by the processor, stop the generation of the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.

[0117] Example 13. The system according to Example 12, wherein, when executed by the processor, the instructions sense a third change in a physiological parameter caused by applying the first stimulation signal with the adjusted parameters; determine whether the third sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; and output an indication of the presence of a nerve near one of the plurality of electrodes.

[0118] Example 14. The system according to Example 13, wherein the instructions, when executed by the processor, determine that the nerve is deep and requires additional time to complete the denervation and reapply the therapy.

[0119] Example 15. A method for evaluating a denervated site, the method comprising: applying a multiplexed stimulation signal and therapy to an alternating pair of a plurality of electrodes of a treatment device to a blood vessel wall for a first duration; sensing a physiological parameter of the blood vessel after applying the multiplexed stimulation and therapy; determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold; applying the multiplexed stimulation signal and therapy to the alternating pair of the plurality of electrodes for a second duration; sensing the physiological parameter of the blood vessel after applying the multiplexed stimulation and therapy; determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold; and indicating successful denervation to a user when the sensed physiological parameter is different after the second duration than after the first duration.

[0120] Example 16. The method according to Example 15, the method further comprising: determining whether a power limit has been reached when the change in the physiological parameter determined after the second duration is less than the threshold; and increasing the power of the therapy if the power limit has not been reached.

[0121] Example 17. The method according to Example 16, the method further comprising applying the multiplexed stimulation signal and therapy if the power limit has been reached.

[0122] Example 18. The method according to Example 15, wherein applying the multiplexed stimulation signal and therapy comprises: applying a stimulation signal between a first pair of the plurality of electrodes at a first time; applying therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal at the first time; applying the stimulation signal between a second pair of the plurality of electrodes at a second time; applying therapy via the second pair of the plurality of electrodes simultaneously with the stimulation signal at the second time; and switching between the first pair and the second pair to apply the stimulation signal and to apply therapy until the first duration or the second duration is completed.

[0123] Example 19. The method according to Example 16, wherein the plurality of electrodes are arranged in a first unique series of electrode pairs and a second unique series of electrode pairs, and applying the multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes comprises: applying a stimulation to a first pair in the first unique series of electrode pairs at a first time; applying therapy to a first pair in the second unique series of pairs at the first time; switching to a second pair in the first unique series of pairs and applying a stimulation to the second pair at a second time; switching to a second unique pair in the second unique series of pairs and applying therapy to the second pair at the second time; and repeating the switching of the first unique series of pairs and the second unique series of pairs within the first duration or the second duration.

[0124] Example 20. The method according to Example 15, wherein the sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, vascular stiffness, or pulse wave velocity.

[0125] Example 21. The method according to Example 20, wherein the first change in the determined physiological parameter is a decrease in systolic blood pressure.

[0126] Example 22. The method according to Example 21, wherein the second change in the determined physiological parameter is a decrease in systolic blood pressure, and the threshold is the systolic blood pressure at the end of the first duration.

[0127] Example 23. The method according to Example 15, the method further comprising determining that the first change in the physiological parameter is less than the threshold; and stopping the application of the therapeutic portion of the multiplexed stimulation signal and therapy.

[0128] Example 24. The method according to Example 23, the method further comprising adjusting the stimulation signal and applying the adjusted stimulation signal to alternating pairs of electrodes.

[0129] Example 25. The method according to Example 24, the method further comprising determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that exceeds a threshold; increasing the power of the therapy; and applying the multiplexed adjusted stimulation signal and the increased-power therapy during the second duration.

[0130] Example 26. The method according to Example 24, the method further comprising determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that is less than the threshold; and generating an indication for display on a user interface that no nerve is detected at the location of the treatment device.

[0131] Example 27. A method of performing a treatment protocol, the method comprising: applying a first stimulation signal from of the treatment device a first pair of electrodes to a vessel wall; applying a therapy to the vessel wall using all electrodes; switching the polarity of the stimulation signal between the first pair of electrodes; applying a second stimulation from the first pair of electrodes to the vessel; applying a therapy to the vessel wall using all electrodes; switching to a second pair of electrodes; applying a second stimulation signal using the second pair of electrodes, applying a therapy using all electrodes, switching the polarity of the second pair of electrodes, applying the second stimulation signal using the second pair of electrodes, and applying a therapy using all electrodes; switching all subsequent electrode pairs and repeating for each subsequent electrode pair applying a stimulation, applying a therapy using all electrodes, switching the polarity of each subsequent electrode pair, applying a stimulation using each subsequent electrode pair, and applying a therapy using all electrodes; sensing a physiological parameter of the vessel after a first time period has elapsed; determining that a first change in the physiological parameter of the vessel exceeds a first threshold; repeating the switching of the stimulation signal and applying the stimulation signal to each electrode pair and applying a therapy using all electrodes until a second time period has elapsed, thereby determining whether a second change in the physiological parameter of the vessel exceeds a second threshold; and indicating successful denervation to a user when the sensed physiological parameter is different after the second time period than after the first time period.

[0132] Example 28. The method according to Example 27, the method further comprising determining that the first change in the physiological parameter is less than the threshold; and stopping the application of the therapy.

[0133] Example 29. The method according to Example 28, the method further comprising adjusting the stimulation signal and repeating the switching of the stimulation signal and applying the stimulation signal to each successive electrode pair and applying a therapy using all electrodes until a first time period has elapsed.

[0134] Example 30. The method according to Example 29, the method further comprising determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that is less than the threshold; and generating an indication flag for displaying on the user interface that no nerve is detected at the location of the treatment device.

[0135] Example 31. The method according to Example 29, the method further comprising determining that the application of the adjusted stimulation signal causes a change in the physiological parameter that exceeds the threshold.

[0136] Example 32. The method according to Example 30, the method further comprising increasing the power of the therapy; and applying the adjusted stimulation signal and the therapy with increased power during the second time period.

[0137] Example 33. A system for denervation of vascular nerves, the system comprising: a stimulation and therapy source; a computing device comprising a memory and a processor and storing instructions thereon, which when executed: generate a first stimulation signal for application to the blood vessel wall via one of a plurality of electrodes of a treatment device; sense a first change in a physiological parameter caused by the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; generate a therapy for application to the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter caused by the application of the second stimulation signal; based on the second sensed change in the physiological parameter, determine whether the application of the therapy has denervated the nerve near the electrode; and output an indication flag that the application of the therapy is successful.

[0138] Example 34. The system according to Example 33, wherein the first stimulation signal and the therapy are combined signals generated during an initial time period.

[0139] Example 35. The system according to Example 34, wherein the determination of the first sensed change occurs after the initial time period.

[0140] Example 36. The system according to Example 35, wherein the second stimulation signal and the therapy are combined signals generated during a second time period.

[0141] Example 37. The system according to Example 33, wherein the instructions, when executed by a processor, present an indication on a user interface associated with the computing device, the indication including one or more of the following: the presence of a nerve near one of the plurality of electrodes, or an indication of successful denervation, or an indication of unsuccessful denervation.

[0142] Example 38. The system according to Example 33, wherein the instructions, when executed by the processor, determine the first sensed change in the physiological parameter and output an indication of the absence of a nerve near the one of the plurality of electrodes.

[0143] Example 39. The system according to Example 38, wherein the instructions, when executed by the processor, stop generating the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first time period.

[0144] Example 40. The system according to Example 39, wherein, when executed by the processor, the instructions sense a third change in the physiological parameter due to applying the first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; and output an indication of the presence of a nerve near one of the plurality of electrodes.

[0145] Example 41. The system according to Example 40, wherein the instructions, when executed by the processor, determine that the nerve is deep and that additional time is required to complete the denervation and reapply the therapy.

[0146] Further disclosed herein is the subject matter of the following clauses:

[0147] 1. A system for denervation of a vascular nerve, the system comprising:

[0148] A stimulation and therapy source; and

[0149] A computing device including a memory and a processor and storing instructions thereon

[0150] which, when executed:

[0151] Generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes;

[0152] Sense a first change in a physiological parameter due to the application of the first stimulation signal;

[0153] Determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes;

[0154] Generate a therapy for application to the vessel wall;

[0155] Generate a second stimulation signal for application to the vessel wall via one of the plurality of electrodes;

[0156] Sense a second change in the physiological parameter caused by the application of the second stimulation signal;

[0157] Based on the second sensed change in the physiological parameter, determine whether the application of the therapy has denervated a nerve near the electrode;

[0158] And

[0159] Output an indication that the application of the therapy was successful.

[0160] 2. The system according to clause 1, further comprising:

[0161] A treatment device configured to navigate within a patient's blood vessel; a plurality of electrodes formed on a distal portion of the treatment device;

[0162] A sensor configured to measure one or more physiological parameters of the patient at the location where the treatment device has been navigated.

[0163] 3. The system according to clause 1 or 2, wherein the first stimulation signal and the therapy are combined signals generated during an initial time period.

[0164] 4. The system according to clause 3, wherein the determination of the first sensed change occurs after the initial time period.

[0165] 5. The system according to clause 4, wherein the second stimulation signal and the therapy are combined signals generated during a second time period.

[0166] 6. The system according to any one of clauses 1 to 5, wherein the instructions, when executed by the processor, present an indication on a user interface associated with the computing device, the indication including one or more of the following: the presence of a nerve near one of the plurality of electrodes, or an indication of successful denervation, or an indication of unsuccessful denervation.

[0167] 7. The system according to any one of clauses 1 to 6, wherein the instructions, when executed by the processor, determine that the first sensed change in the physiological parameter indicates the absence of a nerve near one of the plurality of electrodes and output an indication of identification.

[0168] 8. The system according to clause 7, wherein the instructions, when executed by the processor, stop the generation of the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first time period.

[0169] 9. The system according to clause 8, wherein the instructions, when executed by the processor

[0170] sense a third change in the physiological parameter caused by applying the first stimulation signal with the adjusted parameters;

[0171] determine whether the third sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; and

[0172] output an indication of the presence of a nerve near one of the plurality of electrodes.

[0173] 10. The system according to clause 9, wherein the instructions, when executed by the processor, determine that the nerve is deep and requires additional time to complete the denervation and reapply the therapy.

Claims

1. A system for denervation of blood vessels and nerves, the system comprising: A source of stimulation and therapy; And A computing device comprising a memory and a processor and storing instructions thereon which, when executed: Generate a first stimulation signal for application to the blood vessel wall via one of the plurality of electrodes; Sense a first change in a physiological parameter caused by the application of the first stimulation signal; Determine whether the first sensed change in the physiological parameter indicates the presence of a nerve near the one of the plurality of electrodes; Generate a therapy for application to the blood vessel wall; Generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; Sense a second change in the physiological parameter caused by the application of the second stimulation signal; Based on the second sensed change in the physiological parameter, determine whether the application of the therapy has denervated the nerve near the electrode; And Output an indication of the success of the application of the therapy.

2. The system according to claim 1, the system further comprising: A treatment device configured to navigate within a blood vessel of a patient; A plurality of electrodes formed on a distal portion of the treatment device; A sensor configured to measure one or more physiological parameters of the patient at the location where the treatment device has been navigated.

3. The system according to claim 1 or 2, wherein the first stimulation signal and the therapy are combined signals generated during an initial time period.

4. The system according to claim 3, wherein the determination of the first sensed change occurs after the initial time period.

5. The system according to claim 4, wherein the second stimulation signal and the therapy are combined signals generated during a second time period.

6. The system according to any one of claims 1 to 5, wherein the instructions, when executed by the processor, present an indication on a user interface associated with the computing device, the indication comprising one or more of the following: the presence of a nerve near the one of the plurality of electrodes, or an indication of successful denervation, or an indication of unsuccessful denervation.

7. The system according to any one of claims 1 to 6, wherein the instructions, when executed by the processor, determine that the first sensed change in the physiological parameter indicates the absence of a nerve near the one of the plurality of electrodes and output an indication.

8. The system according to claim 7, wherein the instructions, when executed by the processor, stop the generation of the therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters during a first time period.

9. The system according to claim 8, wherein the instructions, when executed by the processor, sense a third change in a physiological parameter caused by applying the first stimulation signal with the adjusted parameters; Determine whether the third sensed change in the physiological parameter indicates the presence of a nerve near one of the plurality of electrodes; and Output an indication identifying the presence of a nerve near one of the plurality of electrodes.

10. The system of claim 9, wherein the instructions, when executed by the processor, determine that the nerve is deep and requires additional time to complete the denervation and reapply the therapy.

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