Optimizing neuromodulation therapies according to cardiac refractory periods

Abstract

A method, system, and device are provided for improving a therapeutic procedure. For example, the method may include receiving a data signal from one or more sensors, detecting, based on the received data signal, a cardiac electrical signal detected by a medical device, predicting, based on the cardiac electrical signal, a cardiac refractory period that lasts from a first time to a second time in duration, and synchronizing, relative to the cardiac refractory period, at least one of a neuromodulation therapy and a sensing of a response to the neuromodulation therapy.

Description

OPTIMIZING NEUROMODULATION THERAPIES ACCORDING TOCARDIAC REFRACTORY PERIODSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of and priority to U.S. Provisional Application No. 63 / 530,213 filed on August 1, 2023, entitled “OPTIMIZING NEUROMODULATION THERAPIES ACCORDING TO CARDIAC REFRACTORY PERIODS”, the entirety of which is hereby incorporated herein by reference.BACKGROUND

[0002] The present disclosure is generally directed to therapeutic neuromodulation, and relates more particularly to detecting signals with cardiac activity for supporting the therapeutic neuromodulation.

[0003] Neuromodulation therapy may be carried out by sending an electrical signal generated by a device (e.g., a pulse generator) to a stimulation target (e.g., nerves, non-neuronal cells, etc.), which may provide a desired electrophysiologic, biochemical, or genetic response in the stimulation target. Neuromodulation therapy systems may be used to deliver electrical stimulation for providing chronic pain treatment to a patient. In some neuromodulation therapies (e.g., closed-loop neuromodulation therapies), one or more signals resulting from the neuromodulation may be recorded and the therapy may be adjusted based on the recorded signals. Additionally or alternatively, the recorded signals may be used for monitoring and / or indicating conditions of the patient.BRIEF SUMMARY

[0004] Example aspects of the present disclosure include:

[0005] A method, including: receiving a data signal from one or more sensors; detecting, based on the received data signal, a cardiac electrical signal detected by a medical device; predicting, based on the cardiac electrical signal, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronizing, relative to the cardiac refractory period, at least one of a neuromodulation therapy and a sensing of a response to the neuromodulation therapy.

[0006] Any of the aspect herein, where both the neuromodulation therapy and the sensing of the response to the neuromodulation therapy are synchronized relative to the cardiac refractory period.

[0007] Any of the aspect herein, where the neuromodulation therapy comprises application of a high-frequency stimulation.

[0008] Any of the aspect herein, where the method further includes: introducing a low-frequency stimulation during a cardiac recording period, wherein the cardiac recording period is different from the cardiac refractory period.

[0009] Any of the aspect herein, where the low-frequency stimulation includes at least one frequency of 100Hz or less and where the high-frequency stimulation includes at least one frequency of more than 100Hz.

[0010] Any of the aspect herein, where the high-frequency stimulation includes at least one frequency between 100Hz and 10kHz.

[0011] Any of the aspect herein, where the neuromodulation therapy includes application of a first stimulation component and a second stimulation component, and where the second stimulation component is synchronized relative to the cardiac refractory period.

[0012] Any of the aspect herein, where the first stimulation component is applied during the cardiac refractory period.

[0013] Any of the aspect herein, where the second stimulation component includes a high- frequency stimulation and wherein the first stimulation component includes a low-frequency stimulation.

[0014] Any of the aspect herein, where the neuromodulation therapy is provided via one or more electrodes.

[0015] Any of the aspect herein, where the sensing of the response to the neuromodulation therapy is received via the one or more electrodes.

[0016] Any of the aspect herein, where the sensing of the response to the neuromodulation therapy is received via an electrode that is different from the one or more electrodes that provided the neuromodulation therapy.

[0017] Any of the aspect herein, where the nerve stimulation is delivered via one or more stimulation patterns during the cardiac refractory period and the cardiac refractory period includes at least one of a natural cardiac refractory period associated with a natural heartbeat and an artificial refractory period associated with at least one of a pacemaker and a cardiac monitoring device.

[0018] Any of the aspect herein, where the one or more stimulation patterns include one or more of a multiplexed pattern, a burst or a stochastic pattern, a cycling on / off, and include components of the neuromodulation therapy that are cycled.

[0019] Any of the aspect herein, where the one or more stimulation patterns include the burst, the method further including: setting an initial value for a number of stimulation pulses in the burst; measuring at least one parameter describing cardiac performance; and adjusting the number of stimulation pulses in the burst from the initial value to a different value based on the measured at least one parameter describing cardiac performance.

[0020] Any of the aspect herein, where the at least one parameter describing cardiac performance includes one or more of heart rate, heart rate variability, RMSSD, frequency domain information of the heart of the patient, QRS width, QT duration, a PR interval, night time heart rate of the patient, respiration rate, blood pressure, the position of the patient, and patient motion.

[0021] Any of the aspect herein, where the neuromodulation therapy is synchronized relative to the cardiac refractory period during a synchronized mode of operation, the method further including: detecting that a heartbeat has not occurred within an expected time interval; and in response to detecting that the heartbeat has not occurred within the expected time interval, switching from the synchronized mode of operation to a continuous mode of operation in which the nerve stimulation is applied via a continuous stimulation signal.

[0022] Any of the aspect herein, where the method further includes: detecting the heartbeat during the continuous mode of operation; and in response to detecting the heartbeat during the continuous mode of operation, switching from the continuous mode of operation back to the synchronized mode of operation.

[0023] Any of the aspect herein, where the neuromodulation therapy is synchronized relative to the cardiac refractory period during a synchronized mode of operation, the method further including: detecting that a heartbeat has not occurred within an expected time interval; and in response to detecting that the heartbeat has not occurred within the expected time interval, delaying the neuromodulation therapy at least until a next heartbeat is detected.

[0024] Another aspect of the present disclosure is directed toward a system, which may include: a processor; and a memory capable of storing data thereon that, when processed by the processor, cause the processor to: receive a data signal from one or more sensors; detect, based on the received data signal, a cardiac electrical signal; predict, based on the cardiac electrical signal, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronize, relative to the cardiac refractory period, at least one of a neuromodulation therapy and a sensing of a response to the neuromodulation therapy.

[0025] Any of the aspect herein, where the system further includes: a pulse generator to generate the neuromodulation therapy; and at least one electrode in communication with the pulse generator to deliver the neuromodulation therapy.

[0026] Any of the aspect herein, where the at least one electrode comprises a first electrode to deliver the neuromodulation therapy and a second electrode to sense the response to the neuromodulation therapy.

[0027] Any of the aspect herein, where the response to the neuromodulation therapy is sensed via at least one of a far-field cardiac signal, an evoked Compound Action Potential (eCAP), and an evoked compound muscle action potential (eCMAP).

[0028] Any of the aspect herein, where the system further includes: a device that transforms the data signal received from the one or more sensors into the cardiac electrical signal, where the device may include at least one of a medical device, a wearable device, and an implanted device.

[0029] Any of the aspect herein, where the cardiac electrical signal includes at least one of a natural heartbeat and an electrical signal generated by a device, such as a pacemaker and a cardiac monitoring device.

[0030] Another aspect of the present disclosure is directed toward a device for providing a therapy, the device may include: an electrode capable of being implanted proximate an anatomical element; and a generator to generate a stimulation signal for delivery to the anatomical element via the electrode, where the stimulation signal is generated by: detecting a cardiac action potential that triggers a cardiac event; predicting, based on the cardiac event, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronizing, relative to the cardiac refractory period, at least one of the stimulation signal and a sensing of a stimulation response to the stimulation signal.

[0031] Any aspect in combination with any one or more other aspects.

[0032] Any one or more of the features disclosed herein.

[0033] Any one or more of the features as substantially disclosed herein.

[0034] Any one or more of the features as substantially disclosed herein in combination with any one or more other features as substantially disclosed herein.

[0035] Any one of the aspects / features / embodiments in combination with any one or more other aspects / features / embodiments .

[0036] Use of any one or more of the aspects or features as disclosed herein.

[0037] It is to be appreciated that any feature described herein can be claimed in combination with any other feature(s) as described herein, regardless of whether the features come from the same described embodiment.

[0038] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.

[0039] The phrases “at least one”, “one or more”, and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and / or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together. When each one of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or class of elements, such as XI -Xn, Yl-Ym, and Zl-Zo, the phrase is intended to refer to a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., XI and X2) as well as a combination of elements selected from two or more classes (e.g., Y1 and Zo).

[0040] The term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0041] The preceding is a simplified summary of the disclosure to provide an understanding of some aspects of the disclosure. This summary is neither an extensive nor exhaustive overview of the disclosure and its various aspects, embodiments, and configurations. It is intended neither to identify key or critical elements of the disclosure nor to delineate the scope of the disclosure but to present selected concepts of the disclosure in a simplified form as an introduction to the more detailed description presented below. As will be appreciated, other aspects, embodiments, and configurations of the disclosure are possible utilizing, alone or in combination, one or more of the features set forth above or described in detail below.

[0042] Numerous additional features and advantages of the present disclosure will become apparent to those skilled in the art upon consideration of the embodiment descriptions provided hereinbelow.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0043] The accompanying drawings are incorporated into and form a part of the specification to illustrate several examples of the present disclosure. These drawings, together with the description,explain the principles of the disclosure. The drawings simply illustrate preferred and alternative examples of how the disclosure can be made and used and are not to be construed as limiting the disclosure to only the illustrated and described examples. Further features and advantages will become apparent from the following, more detailed, description of the various aspects, embodiments, and configurations of the disclosure, as illustrated by the drawings referenced below.

[0044] Fig. 1 A is a diagram of a system according to at least one embodiment of the present disclosure;

[0045] Fig. IB illustrates a different configuration of the system according to at least one embodiment of the present disclosure;

[0046] Fig. 1C illustrates yet another configuration of the system according to at least one embodiment of the present disclosure;

[0047] Fig. 2 illustrates a response waveform according to at least one embodiment of the present disclosure;

[0048] Fig. 3A illustrates an electrocardiogram (ECG) signal measured in the absence of a neuromodulation therapy according to at least one embodiment of the present disclosure;

[0049] Fig. 3B illustrates a cardiac electrical signal measured in the presence of a neuromodulation therapy according to at least one embodiment of the present disclosure;

[0050] Fig. 4 illustrates an ECAP waveform according to at least one embodiment of the present disclosure;

[0051] Fig. 5 illustrates two types of multiplexed stimuli that may be presented during a cardiac refractory period wherein ECAP waveforms may also be recorded according to at least one embodiment of the present disclosure;

[0052] Fig. 6 illustrates an example where neuromodulation therapy is synchronized with a cardiac refractory period according to at least one embodiment of the present disclosure;

[0053] Fig. 7 illustrates another example of applying a neuromodulation therapy according to at least one embodiment of the present disclosure;

[0054] Fig. 8 is a flow diagram illustrating a method of applying stimulation pulses according to at least one embodiment of the present disclosure;

[0055] Fig. 9 illustrates an example where neuromodulation therapy is switching into and out of a continuous mode of operation according to at least one embodiment of the present disclosure;

[0056] Fig. 10 illustrates an example where a component of a neuromodulation therapy is delayed according to at least one embodiment of the present disclosure;

[0057] Fig. 11 illustrates an ECAP waveform that fluctuates with the phase of cardiac cycle and may be used to calculate HR according to at least one embodiment of the present disclosure;

[0058] Fig. 12 is a block diagram of a system according to at least one embodiment of the present disclosure;

[0059] Fig. 13 is a flowchart of a method according to at least one embodiment of the present disclosure;

[0060] Fig. 14 is a flowchart of a method according to at least one embodiment of the present disclosure;

[0061] Fig. 15 is a flowchart of a method according to at least one embodiment of the present disclosure;

[0062] Fig. 16 is a flowchart of a method according to at least one embodiment of the present disclosure; and

[0063] Fig. 17 is a flowchart of a method according to at least one embodiment of the present disclosure.DETAILED DESCRIPTION

[0064] It should be understood that various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example or embodiment, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, and / or may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the disclosed techniques according to different embodiments of the present disclosure). In addition, while certain aspects of this disclosure are described as being performed by a single module or unit for purposes of clarity, it should be understood that the techniques of this disclosure may be performed by a combination of units or modules associated with, for example, a computing device and / or a medical device.

[0065] In one or more examples, the described methods, processes, and techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware-based processing unit. Alternatively or additionally, functions may be implemented using machine learning models, neural networks, artificial neural networks, orcombinations thereof (alone or in combination with instructions). Computer- readable media may include non-transitory computer-readable media, which corresponds to a tangible medium such as data storage media (e.g., random-access memory (RAM), read-only memory (ROM), electrically erasable programmable ROM (EEPROM), flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and that can be accessed by a computer).

[0066] Instructions may be executed by one or more processors, such as one or more digital signal processors (DSPs), general purpose microprocessors (e.g., Intel Core i3, i5, i7, or i9 processors; Intel Celeron processors; Intel Xeon processors; Intel Pentium processors; AMD Ryzen processors; AMD Athlon processors; AMD Phenom processors; Cortex Mx; Apple A10 or 10X Fusion processors; Apple Al l, A12, A12X, A12Z, or A13 Bionic processors; or any other general purpose microprocessors), graphics processing units (e.g., Nvidia GeForce RTX 2000-series processors, Nvidia GeForce RTX 3000-series processors, AMD Radeon RX 5000-series processors, AMD Radeon RX 6000-series processors, or any other graphics processing units), application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry. Accordingly, the term “processor” as used herein may refer to any of the foregoing structure or any other physical structure suitable for implementation of the described techniques. Also, the techniques could be fully implemented in one or more circuits or logic elements.

[0067] Before any embodiments of the disclosure are explained in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Further, the present disclosure may use examples to illustrate one or more aspects thereof. Unless explicitly stated otherwise, the use or listing of one or more examples (which may be denoted by “for example,” “by way of example,” “e.g.,” “such as,” or similar language) is not intended to and does not limit the scope of the present disclosure.

[0068] The terms proximal and distal are used in this disclosure with their conventional medical meanings, proximal being closer to a device, operator, or user of the system, and distal being further from the device, operator, or user of the system.

[0069] For some neuromodulation therapies, a therapeutic electrical signal generated by a pulse generator may be sent to a stimulation target (e.g., nerves, non-neuronal cells, etc.). In a closed-loop neuromodulation therapy, a biopotential (e.g., a recorded signal) elicited with the therapeutic electrical signal may be recorded. The elicited biopotential may provide information by which to adjust the therapeutic electrical signal. Other types of closed-loop neuromodulation therapies may use and sense other types of signals to determine adjustments for the therapeutic electrical signal, such as outputs of other sensors implanted in or placed on a patient (e.g., posture sensor, accelerometer, etc.).

[0070] In some examples, spinal cord stimulation (SCS) (e.g., a form of neuromodulation that includes applying a therapeutic electrical signal or stimulation signal to nerves of the spinal cord or nerves near the spinal cord to elicit a desired electrophysiologic, biochemical, or genetic response) may be practiced in a closed-loop manner. When SCS is performed in a closed-loop manner, contacts (e.g., leads, electrodes, etc.) may be placed near a stimulation target (e.g., patient’s spinal cord or a proximate structure (such as the dorsal root ganglion) or one or more targets, where the contacts are configured to apply a therapeutic electrical signal to the stimulation target to obtain a desirable electrophysiologic, biochemical, or genetic state (e.g., that leads to pain relief). For example, the therapeutic electrical signal may be configured to change how the patient’s body interprets a pain signal based on causing a desired electrophysiologic, biochemical, or genetic response when applied to the stimulation target. Aspects of certain neuromodulation therapies (e.g., SCS) or measuring responses to neuromodulation therapies may be negatively impacted by cardiac events. For example, certain cardiac events may create interference or noise with respect to either application of the neuromodulation therapy or measuring a response to the neuromodulation therapy.

[0071] To mitigate such undesirable effects, it may be desirable to coordinate and / or synchronize application of a neuromodulation therapy to one or more cardiac events. Alternatively or additionally, it may be desirable to apply a neuromodulation therapy such that an anticipated response thereto is coordinated and / or synchronized relative to one or more cardiac events. As a nonlimiting example, it may be desirable to coordinate and / or synchronize the application of a neuromodulation therapy and / or the sensing of a response to the neuromodulation therapy to a cardiac refractory period.

[0072] In some SCS systems, electrical contacts (e.g., electrodes or leads) may be used to stimulate the nerve and other contacts may be used to record an evoked response, such as the Evoked Compound Action Potential (ECAP) or the Evoked Compound Muscle Action Potential (ECMAP), resulting from the stimulation. In other closed-loop neuromodulation therapies, other signals may berecorded. For example, in deep brain stimulation, local field potentials (LFPs) may be recorded in the brain. In various types of therapies provided, the desired signal to be recorded (e.g., ECAPs, LFPs, etc.) may be recorded at a distance from the stimulation, near the stimulation, or from multiple places. However, the recording may include stimulation induced electrical artifacts, which may mask, obscure, or otherwise corrupt at least a portion of the recording and thus, may interfere with the cardiac measures and / or the adjusted therapy provided.

[0073] Physiological signals, including cardiac electrogram signals can be recorded on SCS leads and be used to determine relevant metrics such as Heart Rate (HR), Heart Rate Variability (HRV), respiration, etc. Previous techniques have been developed for recording signals that indicate cardiac activity from or on SCS leads. The physiological signals can be detected in various positions. Accordingly, the physiological signals may be processed to better identify key features for the patient, which may include R-peaks (e.g., maximum amplitude of an R wave, where the R wave represents a component of electrical activity of the heart as it passes through an anatomical element of the patient). In some embodiments, predicted R-R intervals can be used to dynamically change between sensing cardiac and sensing neural signals.

[0074] As will be discussed in further detail herein, objective pain measures are of interest to show the efficacy of the SCS therapy (or other neuromodulation therapy) over time. Cardiac electrical signal and signals derived from cardiac electrical signals (e.g., respiration) are some of the physiological signals that can be used for objective pain measures. Recent advances in neuromodulation technologies have focused on sensing neural responses (e.g., ECAPs, LFPs, etc.) that occur in response of a stimulus in addition to delivering stimulation waveforms. Simultaneous sensing of cardiac electrical signals and neural responses are of interest. Stimulation artifacts and stimulation-evoked signals from SCS therapy can be superimposed on top of the cardiac electrical signal, resulting in poor sensing / saturation or / and additional restrictions placed on stimulation therapy to improve cardiac electrical signal sensing. As some non-limiting examples, stimulation settings (e.g., power, current, duration, etc.) may need to be reduced, stimulations may need to be paused, certain electrode configurations may be restricted, and recordings may be restricted to specific time(s) of day. For some SCS lead locations (e.g., cervical, near a blood vessel), heart rate can modulate an ECAPs amplitude measurement as well; that would require optimizing closed loop programming around such modulations. Embodiments of the present disclosure aim to address these and other issues.

[0075] In some embodiments, the application of a neuromodulation therapy and / or a sensing of response(s) to the neuromodulation therapy may be coordinated / synchronized relative to cardiacevents. As an example, ECAP timing may be coordinated and / or synchronized with a stimulus signal, while a cardiac electrical signal is running asynchronously. Certain neuromodulation therapies may include low-frequency stimulation components and high-frequency stimulation components. The low-frequency stimulation components may include signals having a frequency of 100Hz or less whereas the high-frequency stimulation components may include signals having a frequency between 100Hz and 10kHz. The low-frequency stimulation components may be relatively easy to filter out when looking at the cardiac electrical signal, but the high-frequency stimulation components may not be so easily filtered. For example, high-frequency stimulation components may frequently saturate the amplifier and thereby make data unavailable. It may also be the situation that the high-frequency stimulation components are more prone to saturation if there are some poststimulus effects that carry over from one stimulation to the other. Embodiments of the present disclosure consider the possibility of introducing a low-frequency stimulation component during a cardiac electrical signal recording time and coordinating / synchronizing the high-frequency stimulation component with a cardiac electrical signal refractory period, which may also be referred to as a cardiac refractory period. Embodiments of the present disclosure also consider the possibility of introducing a high-frequency stimulation component during a cardiac electrical signal recording time and coordinating / synchronizing the low-frequency stimulation component with a cardiac refractory period.

[0076] Other neuromodulation therapies may only have a single component (e.g., just a low- frequency stimulation component or just a high-frequency stimulation component). Illustratively, but without limitation, a neuromodulation therapy having a high-frequency stimulation component may create difficulties for recording a cardiac electrical signal. A typical cardiac electrical signal range is around 40 beats / min to 200 beats / min (0.6Hz to 3.3Hz). After an action potential initiates, the cardiac cell is sometimes unable to initiate another action potential for some duration of time (e.g., a cardiac refactory period, ~250ms). These and other needs may be addressed by embodiments of the present disclosure which consider the possibility of coordinating and / or synchronizing the application of a neuromodulation therapy and / or the sensing of a response to a neuromodulation therapy to a predicted cardiac refractory period. Cardiac refractory period(s) may be predicted based on the receipt and measurement of cardiac electrical signals.

[0077] The neuromodulation therapy(ies) depicted and described herein can be coordinated and / or synchronized relative to a cardiac refractory cycle that includes a natural heartbeat, a pacemaker signal, output from a cardiac monitoring device, combinations thereof, etc. In some embodiments, a patient may have one or more electronic devices that support cardiac functions (e.g, a pacemaker).The present disclosure contemplates the ability to coordinate and / or synchronize a neuromodulation therapy such that sensing of a response to the neuromodulation therapy avoids noise associated with a natural heartbeat and / or artifacts induced by electronic devices, such as pacemakers. For instance, a pacemaker is known to induce a pacer spike and different QRS morphologies. Embodiments of the present disclosure contemplate the ability to coordinate and / or synchronize a neuromodulation therapy so as to avoid overlap with such spikes or QRS morphologies.

[0078] Embodiments of the present disclosure beneficially enable neuromodulation therapies to be applied and effectively recorded. Embodiment of the present disclosure also beneficially help neuromodulation therapies minimize disruptions to the measurement / recording of cardiac electrical signals. A cardiac electrical signal may include a natural heartbeat, a signal from a pacemaker, a signal from a cardiac monitoring device, or combinations thereof. Indeed, concepts depicted and described herein relate to the synchronization of a stimulation being within the cardiac refractory window. Embodiments of the present disclosure also contemplate the ability control the stimulation to start a set time after the cardiac refractory period has begun so as to be within a specific phase of the cardiac cycle and / or be a specific duration after the start of a specific phase of the cardiac cycle. In other words, intelligently deciding on the type of stimulation to apply and when to apply it relative to the cardiac cycle. As a non-limiting example, a sequence of pulses may be delivered within the set time and the sequence of pulses may be initiated with knowledge of the cardiac cycle and / or predictions of upcoming cardiac events.

[0079] Turning to Figs. 1A-1C, aspects of a system 100 according to one or more embodiments of the present disclosure are shown. The system 100, in any suitable configuration, may be used to provide a neuromodulation therapy (e.g., provide electric signals) to a patient and / or carry out one or more other aspects of one or more of the methods disclosed herein. For example, the system 100 may include at least a device 102 that is capable of providing a stimulation applied to the spinal cord 108 of the patient and / or to one or more nerve endings for a patient (e.g., for SCS therapy). The configuration illustrated in Fig. 1 A shows application of a neuromodulation therapy and sensing of a response thereto at or near the spinal cord 108. In some examples, the device 102 may be referred to as an implantable pulse generator 106. More specifically, the implantable pulse generator 106 may be configured to generate a current or therapeutic electrical signal, such as a signal capable of stimulating a response in the spinal cord 108 or from one or more nerves. In some embodiments, as described herein, the device 102 may be implanted within the patient.

[0080] Additionally, the system 100 may include one or more leads 104 (e.g., electrical leads) that provide a connection between the device 102 and the spinal cord or nerves of the patient forenabling, for example, stimulation. In some embodiments, the leads 104 may be implanted wholly or partially within the patient.

[0081] In some embodiments, such as the one illustrated in Fig. 1 A, the one or more leads 104 may include a first lead 104A disposed on or connected to a first side of the spinal cord 108 of the patient and a second lead 104B disposed on or connected to a second side of the spinal cord 108 of the patient. For example, the first lead 104 A may be connected laterally to the righthand side of the spinal cord 108, while the second lead 104B may be connected laterally to the lefthand side of the spinal cord 108. However, the position and / or orientation of each lead relative to the spinal cord 108 may vary depending on, for example, the type of treatment, the type of lead, combinations thereof, and the like. In another example, the first lead 104A and the second lead 104B may overlap one another, and may be placed proximate one another on the dorsal side of the spinal cord 108 close to a midline of the spinal cord 108. In some examples, the first lead 104A and the second lead 104B may both be placed on the midline of the spinal cord 108, where one of the leads 104 is cranial (e.g., anterior or nearer the head of the patient) and the other of the leads 104 is caudal (e.g., posterior or nearer the tail of the patient). Additionally or alternatively, the first lead 104A and the second lead 104B may both be placed on one side of the midline of the spinal cord 108.

[0082] Additionally, the one or more leads 104 may be connected, placed, or otherwise implanted near or on the spinal cord 108 within the patient, such that at least one of the one or more leads 104 are located near the heart 110 of the patient. For example, as shown in the inset or zoomed-in portion of the example of Fig. 1 which depicts a side view of the encircled area within the patient, the first lead 104 A may be placed within the spinal canal behind the heart 110 (e.g., dorsally within the spinal canal, such as behind a foramen of the spine near the top of a vertebra of the thoracic vertebrae column of the spinal cord 108, or anteriorly within the spinal canal). Additionally or alternatively, as described previously, the exact placement of the one or more leads 104 may vary depending on, for example, the type of treatment, the type of lead, the patient, combinations thereof, and the like. While not specifically shown in the example of Fig. 1, the one or more leads 104 may also exit the spinal cord 108 at a lumbar vertebra lower down the spinal cord 108 (e.g., the L2 vertebra, but the exact location may vary). As described herein, the one or more leads 104 being placed proximate to the heart 110 may enable the system 100 to more effectively capture signals that include cardiac activity before, during, and / or after providing a neuromodulation therapy (e.g., SCS therapy).

[0083] In other embodiments, the one or more leads 104 may include at least the first lead 104A and the second lead 104B connected to other nerves of the patient (e.g., the vagus nerve, differenttrunks of the vagus nerve, etc.). For example, the first lead 104A may be connected to a first nerve (e.g., first vagal trunk of the patient, such as the anterior sub diaphragmatic vagal trunk at the hepatic branching point of the vagus nerve) and the second lead 104B may be connected to a second nerve (e.g., second vagal trunk of the patient, such as the posterior sub diaphragmatic vagal trunk at the celiac branching point of the vagus nerve). The first lead 104A and / or the second lead 104B may be configured to provide an electrical stimulation signal from the device 102 to the respective first and / or second nerve. The connection of the leads 104 to the respective nerve (or other nerves) of the patient may permit the device 102 to measure and / or stimulate one or more evoked potentials (e.g., ECAPs) in the patient based on the provided electrical stimulation from the implantable pulse generator 106.

[0084] As shown in Figs. IB and 1C, one lead (e.g., a first lead 104A) may be connected at or near the spinal cord 108 while another lead (e.g., a second lead 104B) may be connected at or near the patient’s brain. Such a configuration may be used to apply a neuromodulation therapy such as a Deep Brain Stimulation (DBS). While responses to the neuromodulation therapy may be measured using one or both of the leads 104A, 104B and cardiac activity may also be measured using traditional medical devices, it should be appreciated that other types of devices can be used to measure cardiac activity. As a non-limiting example, and as shown in Fig. 1C, a wearable device 112 may be provided with one or more sensors that receive a data signal from the patient and convert the received signal into a cardiac electrical signal. In other words, traditional medical devices (e.g., purpose-built ECG monitors, portable ECG monitors, etc.), wearable devices 112, or any other type of device may be used to measure cardiac activity. Outputs of such device(s) may be analyzed and used to predict an upcoming or future cardiac refractory period. As will be described in further detail herein, the neuromodulation therapy provided by the device 102 may be adjusted based on the predicted cardiac refractory periods. As a non-limiting example, both the neuromodulation therapy and the sensing of the response to the neuromodulation therapy may be coordinated or synchronized relative to the predicted cardiac refractory period.

[0085] In some examples, the leads 104 may provide the therapeutic electrical signals to the respective nerves via electrodes or electrode devices that are connected to the nerves (e.g., sutured in place, wrapped around the nerves, etc.). In some examples, the leads 104 may be referenced as cuff electrodes or may otherwise include the cuff electrodes (e.g., at an end of the leads 104 not connected or plugged into the device 102). For example, electrodes, electrode devices, cuff electrodes, paddle electrodes, or a different type of electrode may be disposed at a distal end of each of the leads 104.

[0086] In other examples, the leads 104 may be or comprise linear SCS leads capable of delivering one or more stimulation signals (e.g., generated by the device 102) to the spinal cord 108. The leads 104 may comprise a plurality of electrodes disposed along the length of the lead, such that the leads 104 contact the spinal cord 108 at multiple points along a length of the spinal cord 108. A first set of the electrodes on each lead may pass an electrical signal into the spinal cord 108, while a second set of the electrodes on each lead may sense one or more signals generated in response by the spinal cord 108 (e.g., recorded signals). In one embodiment, the electrodes may be able to sense, measure, or otherwise collected data related to ECAPs (e.g., ECAP waveforms). Additionally or alternatively, the electrodes may be able to sense, measure, or otherwise collected data related to cardiac metrics for the patient (e.g., HR, HRV, respiration, or other cardiac electrical signal measurements). In some examples, the device 102 may be used as a contact and / or may include additional contacts for sensing, measuring, or otherwise collecting data related to cardiac metrics for the patient. A plurality of these configurations can be used to record different heart vectors of cardiac activity towards deriving various cardiac metrics.

[0087] Additionally, the system 100 may include one or more processors (e.g., one or more Digital Signal Processors (DSPs), general purpose microprocessors, graphics processing units, Application Specific Integrated Circuits (ASICs), Field Programmable Gate Arrays (FPGAs), or other equivalent integrated or discrete logic circuitry) shown and described in Fig. 12 that are programmed to carry out one or more aspects of the present disclosure. In some examples, the one or more processors may include a memory or may be otherwise configured to perform the aspects of the present disclosure. For example, the one or more processors may provide instructions to the device 102, the leads 104, the electrodes, or other components of the system 100 not explicitly shown or described with reference to Fig. 1 for applying a neuromodulation therapy, stimulation, performing measurements (e.g., cardiac metrics, ECAPs, etc.), and analyzing the same, as described herein. In some examples, the one or more processors may be part of the device 102 or part of a control unit for the system 100 (e.g., where the control unit is in communication with the device 102 and / or other components of the system 100).

[0088] The device 102 and / or wearable device 112 may be programmed to measure and record movements of the patient (e.g., for the purpose of life, sleep, and activity tracking). For example, the device 102 and / or wearable device 112 may comprise an accelerometer and / or other components that are designed to track and record movements of the patient (e.g., whether the patient is moving, not moving, laying down, standing up, running, walking, etc.). Additionally, the leads 104 and / or electrodes disposed at the distal end of the leads 104 may be programmed to measure a physiologicalresponse of the patient. In some examples, the physiological response may comprise an evoked response (e.g., ECAP measurement) based on applying the therapeutic electrical signal (e.g., stimulation signal) generated by the device 102 to the spinal cord 108 (e.g., and / or to nearby nerves as described previously). Additionally or alternatively, as described herein, the physiological response may comprise cardiac signals (e.g., HR, HRV, respiration, other cardiac electrogram- related measurements, etc.) of the patient before and after the therapeutic electrical signal is applied. In some examples, the device 102 may be programmed to measure and record the cardiac signals (e.g., via an electrode vector and / or electrodes placed on an outer surface of the device 102 and / or within the device 102) in addition or alternative to the leads 104 and / or electrodes. Additionally or alternatively, an additional device (e.g., implanted within the patient, an external device, etc.) may be configured or programmed to record cardiac activity of the patient.

[0089] It should also be appreciated that the device 102 and / or wearable device 112 may include a case. In some embodiments, the case of the device itself or a portion of the case may be used to operate as an electrode.

[0090] Fig. 2 illustrates a response waveform 204 according to at least one embodiment of the present disclosure. In some embodiments, a response waveform 204 may correspond to or describe an ECAP response produced in response to application of a neuromodulation therapy 200. As an example, the ECAP response may be produced in response to application of SCS. Illustratively, and without limitation, the response waveform 204 may include a latency measured as the amount of time between application of the neuromodulation therapy 200 and recognition of first negative peak Nl. The response waveform 204 may also include an ECAP amplitude, measured as the amplitude between the first negative peak Nl and the second positive peak P2.

[0091] As previously mentioned, the simultaneous sensing of cardiac electrical signals and neural responses (e.g., response waveforms 204) are of interest. Fig. 3A illustrates an electrocardiogram (ECG) signal 300 measured in the absence of a neuromodulation therapy, whereas Fig. 3B illustrates a cardiac electrical signal 304 measured in the presence of a neuromodulation therapy. Although the cardiac electrical signal is present in Fig. 3B, it is difficult to visualize due to presence of large stimulus artifact. Fig. 4 illustrates an ECAP waveform 400 according to at least one embodiment of the present disclosure where the ECAP waveform 400 changes with cardiac cycle(s). In particular, the ECAP amplitude may change over time and especially over the course of a cardiac cycle. Embodiments of the present disclosure aim to provide improvements for sensing the cardiac electrical signal and responses to neuromodulation therapies.

[0092] Fig. 5 illustrates two waveforms 500, 504 in which a neuromodulation therapy is synchronized relative to a cardiac refractory period according to at least one embodiment of the present disclosure. In particular, waveform 500 illustrates an example of a stimulation waveform where the neuromodulation therapy (e.g., the stimulation signal) is applied at a time such that a corresponding sensing window 512 aligns in time with an anticipated cardiac refractory period. In some embodiments, the whole sensing window 512 is within the cardiac refractory period since there is stimulation, and it would be repeated tens of times within each cardiac refractory period. In addition, the ECAP sense window will be within this same sensing window 512. For scale, a cardiac signal QRS complex is approximately 0.1 sec, while the ECAP sensing window 512 is 0.003s (so about lOOx smaller). The ECAP sensing window 512 may be generally aligned with the stimulation. The stimulation as a whole may align with the cardiac refractory period.

[0093] After a cardiac action potential initiates, the cardiac cell is unable to initiate another action potential for some duration of time (e.g., approximately 250 ms). This period of time is referred to as the refractory period, which helps to protect the heart. This refractory period is for cardiac activity, which provides a prime opportunity for sensing the neural action potential. A primary goal during this time that main goal here is to reduce stimulus and post-stimulus artifact in cardiac recording so that it is easier to detect the cardiac signal. It is desirable to stimulate during the cardiac refractory period and not stimulate during the heart beat because it is difficult to clearly detect the heart beat during stimulation.

[0094]

[0095] Fig. 6 illustrates additional details related to the coordination or synchronization of a neuromodulation therapy with a cardiac event. Specifically, Fig. 6 illustrates an example where neuromodulation therapy (e.g., a stimulus 508) is synchronized or coordinated with a cardiac refractory period according to at least one embodiment of the present disclosure. More specifically, but without limitation, a neuromodulation therapy may be applied in a continuous stimulation mode where the stimulus 508 is continuous. During the continuous stimulation mode, the ECAP sensing 504 may also be on as appropriate. When an event 500 occurs such that the cardiac electrical signal is enabled, the cardiac electrical signal sensing may also begin.

[0096] In response to initiation of the cardiac electrical signal sensing, the stimulus 508 may be switched from a continuous stimulation mode to a synchronized mode of operation. During the synchronized mode, the stimulus 508 may be applied periodically so as to temporally align with a predicted cardiac refractory. In some embodiments, during the synchronized mode, a number N of stimulation pulses can be delivered in a burst, and the burst may be applied during a cardiacrefractory period plus some additional time Tpredicted. The number N could vary depending upon detection of activity or sleep since heart rate varies with each and can be refined as cardiac electrical signal recording continues. Information regarding activity and / or sleep may be obtained using a wearable device 112 as compared to using the device 102 that is applying the stimulus 508 and / or recording responses thereto.

[0097] It should be appreciated that a burst of stimulation pulses can be delivered in a number of different forms or factors. Illustratively, and without limitation, a burst may be provided as a train of pulses, or it can refer to Abbott’s Burst pattern. Many of the examples depicted and described herein may refer to the implementation of a burst as a train of pulses.

[0098] In some embodiments, the stimulus 508 can be temporary paused at the beginning of the cardiac electrical signal recording window for initial beat detection. It may also be possible to adjust the additional time Tpredicted (increase or decrease). As an example, it may be possible for additional time Tpredicted to be added to the cardiac refractory time to extend a duration of the stimulus 508. As can be appreciated, the additional time Tpredicted can impact the number N of stimulation pulses in a burst. For instance, if the additional time Tpredicted is increased, then it may be desirable to decrease the number N of stimulation pulses in a burst. Some intentional delay can be added after a beat is detected to align the stimulation burst with a specific time of a cardiac cycle.

[0099] Fig. 7 illustrates another example of applying a neuromodulation therapy according to at least one embodiment of the present disclosure. The neuromodulation therapy illustrated in Fig. 7 shows a stimulus 508 having a high-frequency stimulation component and a low-frequency stimulation component. In this non-limiting embodiment, the low-frequency stimulation component may be applied continuously, even during cardiac electrical signal sensing, while the high-frequency stimulation component may be applied with a synchronized mode of operation. In other words, the low-frequency stimulation component can continue running continuously during the cardiac electrical signal recording time whereas the high-frequency stimulation component may be synchronized and / or coordinate with the cardiac refractory period.

[0100] With reference now to Fig. 8, a flow diagram illustrating a method of applying stimulation pulses will be described in accordance with at least one embodiment of the present disclosure. The method begins when cardiac electrical signal sensing is enabled (step 804). The cardiac electrical signal sensing may correspond to an event that triggers the stimulus to change from a continuous mode of operation to a non-continuous mode of operation (e.g., a synchronized mode of operation).

[0101] The method continues by measuring a cardiac signal to get a resting and / or active R-R interval (step 808). The accuracy of the R-R interval measured from the cardiac signal may be basedon the type of device used to measure the cardiac signal and / or a quality of sensors used for the same. Based on the measured R-R interval, the method continues by setting an initial value for the number N of stimulation pulses to include in a stimulation burst (step 812). The initial value for the number N may be based on one or more of the following factors: patient activity level, patient history, a look-up table for stimulation settings (e.g., a predetermined or pre- calculated value), a minimum default value, etc.

[0102] The value of the number N determined in step 812 may then be used for the initial application of a neuromodulation therapy. It should be appreciated that the number N may be adjusted upward (step 816) or downward (step 820) depending upon conditions surrounding the patient. As an example, the number N may be increased (step 816) if the patient’s heartrate decreases, if the R-R interval exceeds a predetermined upper R-R interval threshold, if the patient’s activity level decreases, and / or if the patient falls asleep. As another example, the number N may be decreased (step 820) if the patient’s heartrate increases, if the R-R interval falls below a predetermined lower R-R interval threshold, and / or if the patient’s activity level increases.

[0103] It should be appreciated that the method illustrated in Fig. 8, or any of the methods described herein, could be used to align delivery of a neuromodulation therapy with the time after a heartbeat. For instance, it may be possible to see if the therapy has a different effect when applied 50ms after a beat vs 100ms after a beat vs 500ms after a beat. It is possible that different therapeutic effects may be realized by engaging the parasympathetic in a more time-specific way.

[0104] Fig. 9 illustrates an example where the neuromodulation therapy is switching into and out of a continuous mode of operation according to at least one embodiment of the present disclosure. In the illustrated example, a missing beat is detected, which may cause the neuromodulation therapy to switch from a synchronized mode of operation into a continuous mode of operation. When a new heartbeat is detected (or after a predetermined number of heartbeats are detected), the neuromodulation therapy may switch back to a synchronized mode of operation.

[0105] In the illustrated example, when a heartbeat is not detected within an expected time interval, a missing R-R timer 904 may be initiated. If the missing R-R timer 904 exceeds a predetermined time limit T limit, then the stimulus 508 may switch out of the synchronized mode and into the continuous mode. The stimulus 508 may be applied continuously until a new beat is detected or a reliable cardiac electrical signal recording is established for more than a predetermined number of beats. After this time, the stimulus 508 may be applied in the synchronized mode again. If the number of missing beats exceeds a specified amount, then it may be desirable to stay in the continuous mode of operation.

[0106] It should be appreciated that the stimulus 508 illustrated in Fig. 9 is shown to include a low-frequency stimulation component and a high-frequency stimulation component. The method illustrated in Fig. 9 could be applied to a stimulus 508 that does not have two or more separate stimulation components.

[0107] Fig. 10 illustrates an example where neuromodulation therapy is delayed according to at least one embodiment of the present disclosure. In this example, the stimulus 508 may be applied in a continuous mode of operation, then applied in a synchronized mode of operation after cardiac electrical signal sensing is enabled. The stimulus 508 may include a low-frequency stimulation component and a high-frequency stimulation component. Initially, the low-frequency stimulation component may be applied continuously whereas the high-frequency stimulation component may be synchronized with a cardiac refractory period. This may continue until a missing beat 1004 is detected. When a missing beat is detected, the high-frequency stimulation component may be delayed (e.g., no longer applied) whereas the low-frequency stimulation component is still applied continuously. If the stimulus delay exceeds a predetermined amount of time or the number of missing beats exceeds a specific amount, then it may be preferred to apply both the low-frequency stimulation component and the high-frequency stimulation component in the continuous mode of operation.

[0108] Fig. 11 illustrates an ECAP waveform that fluctuates with the phase of cardiac cycle and may be used to calculate HR, according to at least one embodiment of the present disclosure. It should be appreciated that some lead locations (e.g., cervical and some thoracic lead locations), ECAP amplitude can vary with the cardiac cycle. If beats are missed in the cardiac electrical signal sensing data, then ECAP sensing data 1104 (e.g., variability in the ECAP amplitude) can be used to estimate heartrate. The estimates of heartrate can be used to determine an R-R interval and estimate cardiac refractory periods.

[0109] Turning to Fig. 12, a block diagram of a system 1200 according to at least one embodiment of the present disclosure is shown. The system 1200 may be used to apply neuromodulation therapy and coordinate the same with cardiac events as described herein. In some examples, the system 1200 may implement aspects of or may be implemented by aspects of Figs. 1-10 as described herein. For example, the system 1200 may be used with a device 1214, leads 1216, and / or electrodes 1218, and / or carry out one or more other aspects of one or more of the methods disclosed herein. The device 1214 may represent an example of the device 102 or a component of the device 102 as described with reference to Fig. 1 (e.g., implantable pulse generator). Alternatively or additionally, the device 1214 may represent an example of a wearable device 112.

[0110] The leads 1216 and the electrodes 1218 may represent the leads 104 and corresponding electrodes / cuff electrodes as described with reference to Figs. 1A-1C. The system 1200 is further illustrated to include a computing device 1202, a system 1212, a database 1230, and / or a cloud or other network 1232. Systems according to other embodiments of the present disclosure may comprise more or fewer components than the system 1200. For example, the system 1200 may not include one or more components of the computing device 1202, the database 1230, and / or the cloud 1232.

[0111] The system 1212 may comprise the device 1214, leads 1216, and the electrodes 1218. As previously described, the device 1214 may be configured to generate a current (e.g., therapeutic electrical signal, stimulation signal, electrical stimulation signal, etc.), and the leads 1216 and the electrodes 1218 may comprise a plurality of electrodes configured to carry the current from the device 1214 and apply the current to an anatomical element based on the electrodes being implanted on or near the anatomical element (e.g., stimulation target, such as the spinal cord 108 and / or nearby nerves to the spinal cord 108). In some examples, the device 1214, leads 1216, and electrodes 1218 may be configured to measure a physiological response of the patient (e.g., prior to applying the current to the anatomical element, after the current is applied, etc.).

[0112] The system 1212 may communicate with the computing device 1202 to receive instructions for applying a current to the anatomical element and / or delivering the pharmacological agent to the anatomical element. The system 1212 may also provide data (such as data received from an electrodes 1218 capable of recording data), which may be used to optimize the electrodes 1218 and / or to optimize parameters of the current generated by the device 1214.

[0113] The computing device 1202 comprises a processor 1204, a memory 1206, a communication interface 1208, and a user interface 1210. Computing devices according to other embodiments of the present disclosure may comprise more or fewer components than the computing device 1202.

[0114] The processor 1204 of the computing device 1202 may be any processor described herein or any similar processor. The processor 1204 may be configured to execute instructions stored in the memory 1206, which instructions may cause the processor 1204 to carry out one or more computing steps utilizing or based on data received from the system 1212, the database 1230, and / or the cloud 1232.

[0115] The memory 1206 may be or comprise RAM, DRAM, SDRAM, other solid-state memory, any memory described herein, or any other tangible, non-transitory memory for storing computer- readable data and / or instructions. The memory 1206 may store information or data useful for completing, for example, any steps of the methods described herein. The memory 1206 may store,for example, instructions and / or machine learning models that support one or more functions of the system 1212. For instance, the memory 1206 may store content (e.g., instructions and / or machine learning models) that, when executed by the processor 1204, enable a signal measurement 1220, cardiac identification 1222, prediction 1224, synchronization 1226, and a therapy determination 1228.

[0116] The signal measurement 1220 enables the processor 1204 to measure (e.g., via the leads 1216, one or more of the electrodes 1218, etc.) one or more signals including cardiac activity from the patient. For example, the signals may include cardiac electrogram signals and may include cardiac-derived metrics such as HR, HRV, respiration, etc. In some examples, the one or more signals may be measured when the patient is stationary or in a specific position. In some embodiments, instructions stored in the memory 1206 may cause the processor 1204 to perform the cardiac signal measurement 1220 as described.

[0117] The cardiac identification 1222 enables the processor 1204 to determine one or more cardiac-derived metrics and / or save processed cardiac data. Cardiac identification 1222 may be used in conjunction with prediction 1224 to determine or predict R-R intervals, to detect missing heartbeats, detect a recurrence of a heartbeat after a missing heartbeat, to detect anomalies in the cardiac activity, etc. The cardiac identification 1222 may also be configured to transform electrical signals into a cardiac signal, suitable for analysis.

[0118] The synchronization 1226 may enable the processor 1204 to determine whether to apply a neuromodulation therapy in a synchronized mode of operation, whether a particular component of a neuromodulation therapy (e.g., high-frequency stimulation component or low- frequency stimulation component) should be applied in a synchronized mode of operation, whether to switch between a continuous mode of operation and a synchronized mode of operation, etc. The synchronization 1226 may also be configured to provide instructions to the device 1214 that enables the device to operate its pulse generator 1234 such that a neuromodulation therapy is applied at an appropriate time so that a sensing window for the neuromodulation therapy aligns with a cardiac refractory period. The synchronization 1226 may also be configured to determine adjustments to a neuromodulation therapy (e.g., whether to increase or decrease a number N, whether to adjust an additional time Tpredicted, timing of pulses, frequency, amplitude, cycling duration, pulse width, method for achieving charge balance, etc.).

[0119] The therapy determination 1228 enables the processor 1204 to determine one or more parameters for applying the neuromodulation therapy to the anatomical element based at least in part on outputs of the prediction 1224 and synchronization 1226. For instance, the therapy determinationmay determine parameters or instructions that cause the device 1214 to employ the pulse generator 1234 to generate a stimulus 508.

[0120] Content stored in the memory 1206, if provided as in instruction, may, in some embodiments, be organized into one or more applications, modules, packages, layers, or engines. Alternatively or additionally, the memory 1206 may store other types of content or data (e.g., machine learning models, artificial neural networks, deep neural networks, etc.) that can be processed by the processor 1204 to carry out the various method and features described herein. Thus, although various contents of memory 1206 may be described as instructions, it should be appreciated that functionality described herein can be achieved through use of instructions, algorithms, and / or machine learning models. The data, algorithms, and / or instructions may cause the processor 1204 to manipulate data stored in the memory 1206 and / or received from or via the system 1212, the database 1230, and / or the cloud 1232.

[0121] The computing device 1202 may also comprise a communication interface 1208. The communication interface 1208 may be used for receiving data (for example, data from the electrodes 1218 capable of recording data) or other information from an external source (such as the system 1212, the database 1230, the cloud 1232, and / or any other system or component not part of the system 1200), and / or for transmitting instructions, images, or other information to an external system or device (e.g., another computing device 1202, the system 1212, the database 1230, the cloud 1232, and / or any other system or component not part of the system 1200). The communication interface 1208 may comprise one or more wired interfaces (e.g., a USB port, an Ethernet port, a Firewire port) and / or one or more wireless transceivers or interfaces (configured, for example, to transmit and / or receive information via one or more wireless communication protocols such as 902.1 la / b / g / n, Bluetooth, NFC, ZigBee, and so forth). In some embodiments, the communication interface 1208 may be useful for enabling the device 1202 to communicate with one or more other processors 1204 or computing devices 1202, whether to reduce the time needed to accomplish a computing-intensive task or for any other reason.

[0122] The computing device 1202 may also comprise one or more user interfaces 1210. The user interface 1210 may be or comprise a keyboard, mouse, trackball, monitor, television, screen, touchscreen, and / or any other device for receiving information from a user and / or for providing information to a user. The user interface 1210 may be used, for example, to receive a user selection or other user input regarding any step of any method described herein. Notwithstanding the foregoing, any required input for any step of any method described herein may be generated automatically by the system 1200 (e.g., by the processor 1204 or another component of the system1200) or received by the system 1200 from a source external to the system 1200. In some embodiments, the user interface 1210 may be useful to allow a surgeon or other user to modify instructions to be executed by the processor 1204 according to one or more embodiments of the present disclosure, and / or to modify or adjust a setting of other information displayed on the user interface 1210 or corresponding thereto.

[0123] Although the user interface 1210 is shown as part of the computing device 1202, in some embodiments, the computing device 1202 may utilize a user interface 1210 that is housed separately from one or more remaining components of the computing device 1202. In some embodiments, the user interface 1210 may be located proximate one or more other components of the computing device 1202, while in other embodiments, the user interface 1210 may be located remotely from one or more other components of the computer device 1202.

[0124] Though not shown, the system 1200 may include a controller, though in some embodiments the system 1200 may not include the controller. The controller may be an electronic, a mechanical, or an electro-mechanical controller. The controller may comprise or may be any processor described herein. The controller may comprise a memory storing instructions for executing any of the functions or methods described herein as being carried out by the controller. In some embodiments, the controller may be configured to simply convert signals received from the computing device 1202 (e.g., via a communication interface 1208) into commands for operating the system 1212 (and more specifically, for actuating the device 1214 and the pulse generator(s) 1234 thereof). In other embodiments, the controller may be configured to process and / or convert signals received from the system 1212. Further, the controller may receive signals from one or more sources (e.g., the system 1212) and may output signals to one or more sources.

[0125] The database 1230 may store information such as patient data, results of a stimulation and / or blocking procedure, stimulation and / or blocking parameters, current parameters, electrode parameters, etc. The database 1230 may be configured to provide any such information to the computing device 1202 or to any other device of the system 1200 or external to the system 1200, whether directly or via the cloud 1232. In some embodiments, the database 1230 may be or comprise part of a hospital image storage system, such as a picture archiving and communication system (PACS), a health information system (HIS), and / or another system for collecting, storing, managing, and / or transmitting electronic medical records.

[0126] The cloud 1232 may be or represent the Internet or any other wide area network. The computing device 1202 may be connected to the cloud 1232 via the communication interface 1208, using a wired connection, a wireless connection, or both. In some embodiments, the computingdevice 1202 may communicate with the database 1230 and / or an external device (e.g., a computing device) via the cloud 1232.

[0127] The system 1200 or similar systems may be used, for example, to carry out one or more aspects of any of the methods as described herein. The system 1200 or similar systems may also be used for other purposes.

[0128] Figs. 13-17 depict various methods that may be used, for example, to enable simultaneous recording of cardiac signals and neural signals. The methods (and / or one or more steps thereof) may be carried out or otherwise performed, for example, by at least one processor. The at least one processor may be the same as or similar to the processor(s) 1204 of the computing device 1202 and / or wearable device 112 described above. The at least one processor may be part of the device 102 (such as an implantable pulse generator) or part of a control unit in communication with the device 102. A processor other than any processor described herein may also be used to execute the some or all of any method depicted and described herein. The at least one processor may perform the method(s) by executing elements stored in a memory such as the memory 1206. The elements stored in the memory and executed by the processor may cause the processor to execute one or more steps of a function as shown and described. One or more portions of a method may be performed by the processor executing any of the contents of memory, such as a signal measurement 1220, a cardiac identification 1222, a prediction 1224, a synchronization 1226, and / or a therapy determination 1228.

[0129] Referring now to Fig. 13, a first method 1300 will be described in accordance with at least some embodiments of the present disclosure. The method 1300 comprises receiving, via one or more sensors, one or more data signals (step 1304). The sensor(s) may include an SCS lead, an electrode, or any other sensor device capable of receiving a data signal from a patient. The method 1300 continues by detecting, based on the received data signal, a cardiac electrical signal (step 1308). The cardiac electrical signal may correspond to an ECG signal or the like. The cardiac signal may include a signal generated by a natural heartbeat, a signal generated by a device (e.g., a pacemaker or monitoring device), or a combination thereof. The cardiac electrical signal may be detected by a device 102, wearable device 112, and / or system 1212, For example, the one or more signals with cardiac activity may include cardiac electrogram signals and may be used to collect cardiac- derived metrics, including HR, HRV, respiration, etc. The cardiac signals may be collected and measured when the patient is stationary, in a specific position, or in motion.

[0130] Based on the cardiac electrical signal(s), the method 1300 continues by determining or predicting when a next cardiac refractory period will occur (step 1312). This step may include predicting a plurality of future cardiac refractory periods and may also include predicting afrequency of such cardiac refractory periods. In some embodiments, the cardiac refractory periods may be predicted based on a measured R-R interval obtained from the cardiac electrical signal(s). The predicted cardiac refractory period(s) may be predicted to last from a first time to a second time in duration.

[0131] The method 1300 may then continue by delivering a neuromodulation therapy that is synchronized and / or coordinated with respect to the predicted cardiac refractory period(s) (step 1316). In some embodiments, the neuromodulation therapy and / or sensing of a response to the neuromodulation therapy may be synchronized to the predicted cardiac refractory period(s). In this step, one or more parameters for the application of a neuromodulation therapy (e.g., stimulus amplitude, stimulus start time, stimulus end time, stimulus frequency, number N of pulses in a stimulation burst, time between bursts, etc.).

[0132] The method 1300 may then continue by delivering a neuromodulation therapy according to the parameters determined in step 1316 (step 1320). In some embodiments, a pulse generator may be provided with instructions to deliver a neuromodulation therapy (e.g., apply a stimulus), when to start delivery of the neuromodulation therapy, when to end delivery of the neuromodulation therapy, and the like. As will be discussed in further detail herein, the method 1300 may be modified or enhanced by determining whether any parameter(s) of the neuromodulation therapy should be adjusted or modified. Such determinations may be made during application of the neuromodulation therapy or between applications of the neuromodulation therapy.

[0133] Referring now to Fig. 14, another method 1400 will be described in accordance with at least some embodiments of the present disclosure. The method 1400 or any step thereof may be used to supplement any other method depicted and described herein.

[0134] The method 1400 includes generating a high-frequency stimulation component and a low- frequency stimulation component for a neuromodulation therapy (step 1404). The high-frequency stimulation component may include a stimulus having a frequency of more than 100Hz. In some embodiments, the high-frequency stimulation component may include a frequency between 100Hz and 10kHz. In some embodiments, the high-frequency stimulation component may include more than one stimulus, which may be the same or different frequencies. In other words, the high- frequency stimulation component may comprise a plurality of different frequencies without departing from scope of the present disclosure.

[0135] The low-frequency stimulation component may include a stimulus having a frequency of 100Hz or less. The low-frequency stimulation component may include more than one stimulus, which may be the same or different frequencies. In other words, the high-frequency stimulationcomponent may comprise a plurality of different frequencies without departing from the scope of the present disclosure.

[0136] The method 1400 continues by synchronizing one or both of the high-frequency stimulation component and the low-frequency stimulation component to a predicted cardiac refractory period (step 1408). In some embodiments, both the high-frequency stimulation component and low-frequency stimulation component are operated in a synchronization mode (e.g., synchronized to the cardiac refractory period). In some embodiments, just one of the components are operated in a synchronization mode while the other of the components are operated in a different mode (e.g., in a continuous mode). It may be possible to choose either the high-frequency stimulation component or the low-frequency stimulation component. In some embodiments, the low- frequency stimulation component may be easier to process because it may be possible to use blanking during the pulses and not miss a substantial amount of recording time (e.g., as blanking can need a couple ms to recover).

[0137] The method 1400 continues by providing one or both of the high-frequency stimulation component and the low-frequency stimulation component to the patient via one or more electrodes (step 1412). In some embodiments, one of the stimulation components is applied continuously (e.g., during a cardiac refractory period) while the other one of the stimulation components is synchronized relative to the cardiac refractory period. As can be appreciated, the stimulation component may be delivered via one or more stimulation patterns. The stimulation patterns may be delivered during a cardiac refractory period and may comprise one or more of a multiplexed pattern, a burst or a stochastic pattern, or may be cycled on / off. In some embodiments, certain components of the neuromodulation therapy may be cycled while other components of the neuromodulation therapy are not cycled.

[0138] Response(s) to the neuromodulation therapy are then received via one or more electrodes (step 1416). In some embodiments, the response(s) may be received on the same electrode(s) that were used to apply the neuromodulation therapy. In some embodiments, the response(s) may be received on different electrodes than were used to apply the neuromodulation therapy. It should be appreciated that the device case / housing can be used for either monopolar stimulation and / or monopolar sensing (e.g., with an electrode).

[0139] Referring now to Fig. 15, another method 1500 will be described in accordance with at least some embodiments of the present disclosure. The method 1500 or any step thereof may be used to supplement any other method depicted and described herein.

[0140] The method 1500 includes setting an initial value for a number N of stimulation pulses to include in a burst (step 1504). The number N may be initially determined based on one or more of: patient activity level, previous patient history, a look-up table for stimulation settings, a default number N, and / or a minimum number N.

[0141] The method 1500 continues by measuring at least one parameter describing a patient’s cardiac performance (step 1508). The parameter(s) that may be measured in this step include any metric that describes patient activity, patient health, or the like. For instance, the parameter(s) may include one or more of heart rate, heart rate variability, RMSSD, frequency domain information of a heart of a patient, QRS width, QT duration, a PR interval, night time heart rate, the respiration rate, blood pressure, a position of the patient, and patient motion, etc.

[0142] Based on the measured parameter(s) and whether one or more of the measured parameters exceeds or falls below a predetermined threshold, the number N of stimulation pulses in the burst may be adjusted (step 1512). In some embodiments, the number N of stimulation pulses in a burst may be increased if HR decreases or some other decreased activity level of the patient is detected. In some embodiments, the number N of stimulation pulses in a burst may be decreased if HR increases or some other increased activity level of the patient is detected.

[0143] Referring now to Fig. 16, another method 1600 will be described in accordance with at least some embodiments of the present disclosure. The method 1600 or any step thereof may be used to supplement any other method depicted and described herein.

[0144] The method 1600 includes detecting that a heartbeat has not occurred within an expected time interval (step 1604). If such an event is detected, then the method 1600 continues by switching a neuromodulation therapy (or component thereof) from a synchronized mode of operation to a continuous mode of operation (step 1608). In some embodiments, all components of the neuromodulation therapy are switched into the continuous mode of operation. In some embodiments, some components of the neuromodulation therapy may have already been operating continuously (e.g., before detecting the missed heartbeat), meaning that only those components that were operating in a synchronized mode of operation are switched into the continuous mode of operation.

[0145] The method 1600 continues by delivering the neuromodulation therapy (or components thereof) using the continuous mode of operation (step 1612). The continuous mode of operation is applied until a next heartbeat or series of heartbeats are detected (step 1616). Alternatively or additionally, the continuous mode of operation may be applied until a reliable cardiac electrical signal recording is established for a predetermined number of heartbeats.

[0146] After a next heartbeat (or plurality of heartbeats) has been detected, or after a reliable cardiac electrical signal recording is established, then the method 1600 enables the neuromodulation therapy (or component thereof) to switch back into the synchronized mode of operation (step 1620). If the number of missing heartbeats exceeds a predetermined amount, then it may be desirable to remain in the continuous mode of operation for an extended period of time (e.g., even if a next heartbeat is later detected). While method 1600 specifically describes the approach related to changing a mode of operation, it may also be possible to adjust the expected refractory period rather than delaying a therapy or changing a mode of operation. For example, a scenario may exist where a heartbeat is detected before an expected time interval. In such a situation, it may be desirable to adjust the expected refractory period rather than delaying a therapy or changing a mode of operation.

[0147] Referring now to Fig. 17, another method 1700 will be described in accordance with at least some embodiments of the present disclosure. The method 1700 or any step thereof may be used to supplement any other method depicted and described herein.

[0148] The method 1700 includes detecting that a heartbeat has not occurred within an expected time interval (step 1704). If such an event is detected, then the method continues by delaying application of a neuromodulation therapy until a next heartbeat is detected (step 1708). This step may alternatively include switching the neuromodulation therapy to a continuous mode of operation.

[0149] Once a next heartbeat is detected (step 1712), the method 1700 may resume application of the neuromodulation therapy in a synchronization mode of operation (step 1716). In some embodiments, if the stimulation delay exceeds a predetermined amount of time or if the number of missing beats exceeds a predetermined amount, then it may be desirable to remain in a continuous mode of operation or to disable application of the neuromodulation therapy.

[0150] The foregoing is not intended to limit the disclosure to the form or forms disclosed herein. In the foregoing Detailed Description, for example, various features of the disclosure are grouped together in one or more aspects, embodiments, and / or configurations for the purpose of streamlining the disclosure. The features of the aspects, embodiments, and / or configurations of the disclosure may be combined in alternate aspects, embodiments, and / or configurations other than those discussed above. This method of disclosure is not to be interpreted as reflecting an intention that the claims require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed aspect, embodiment, and / or configuration. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the disclosure.

[0151] Moreover, though the foregoing has included description of one or more aspects, embodiments, and / or configurations and certain variations and modifications, other variations, combinations, and modifications are within the scope of the disclosure, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative aspects, embodiments, and / or configurations to the extent permitted, including alternate, interchangeable and / or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and / or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter.

Claims

CLAIMSWhat is claimed is:

1. A method, comprising: receiving a data signal from one or more sensors; detecting, based on the received data signal, a cardiac electrical signal detected by a medical device; predicting, based on the cardiac electrical signal, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronizing, relative to the cardiac refractory period, at least one of a neuromodulation therapy and a sensing of a response to the neuromodulation therapy.

2. The method according to claim 1, wherein both the neuromodulation therapy and the sensing of the response to the neuromodulation therapy are synchronized relative to the cardiac refractory period.

3. The method according to claim 1 or 2, wherein the neuromodulation therapy comprises application of a high-frequency stimulation.

4. The method according to claim 3, further comprising: introducing a low-frequency stimulation during a cardiac recording period, wherein the cardiac recording period is different from the cardiac refractory period.

5. The method according to claim 4, wherein the low-frequency stimulation comprises at least one frequency of 100Hz or less and wherein the high-frequency stimulation comprises at least one frequency of more than 100Hz.

6. The method according to any of claims 1 thru 3, wherein the high-frequency stimulation comprises at least one frequency between 100Hz and 10kHz.

7. The method according to any preceding claim, wherein the neuromodulation therapy comprises application of a first stimulation component and a second stimulation component, wherein the second stimulation component is synchronized relative to the cardiac refractory period.

8. The method according to claim 7, wherein the first stimulation component is applied during the cardiac refractory period.

9. The method according to claim 7, wherein the second stimulation component comprises a high-frequency stimulation and wherein the first stimulation component comprises a low-frequency stimulation.

10. The method according to any preceding claim, wherein the neuromodulation therapy is provided via one or more electrodes.

11. The method according to claim 10, wherein the sensing of the response to the neuromodulation therapy is received via the one or more electrodes.

12. The method according to claim 10, wherein the sensing of the response to the neuromodulation therapy is received via an electrode that is different from the one or more electrodes that provided the neuromodulation therapy.

13. The method according to any preceding claim, wherein the neuromodulation therapy is delivered via one or more stimulation patterns during the cardiac refractory period and wherein the cardiac refractory period includes at least one of a natural cardiac refractory period associated with a natural heartbeat and an artificial refractory period associated with at least one of a pacemaker and a cardiac monitoring device.

14. The method according to claim 13, wherein the one or more stimulation patterns comprise one or more of a multiplexed pattern, a burst pattern, a stochastic pattern, cycling on / off of the therapy, and including components of the therapy that are cycled.

15. The method according to claim 14, wherein the one or more stimulation patterns comprise the burst, the method further comprising: setting an initial value for a number of stimulation pulses in the burst; measuring at least one parameter describing cardiac performance; andadjusting the number of stimulation pulses in the burst from the initial value to a different value based on the measured at least one parameter describing cardiac performance.

16. The method according to claim 15, wherein the at least one parameter describing cardiac performance comprises one or more of heart rate, heart rate variability, RMSSD, frequency domain information of a heart of a patient, QRS width, QT duration, a PR interval, night time heart rate of the patient, respiration rate, blood pressure, a position of the patient, and patient motion.

17. The method according to any preceding claim, wherein the neuromodulation therapy is synchronized relative to the cardiac refractory period during a synchronized mode of operation, the method further comprising: detecting that a heartbeat has not occurred within an expected time interval; and in response to detecting that the heartbeat has not occurred within the expected time interval, switching from the synchronized mode of operation to a continuous mode of operation in which the neuromodulation therapy is applied via a continuous stimulation signal.

18. The method according to claim 17, further comprising: detecting the heartbeat during the continuous mode of operation; and in response to detecting the heartbeat during the continuous mode of operation, switching from the continuous mode of operation back to the synchronized mode of operation.

19. The method according to any preceding claim, wherein the neuromodulation therapy is synchronized relative to the cardiac refractory period during a synchronized mode of operation and is adjustable during the synchronized mode of operation, the method further comprising: detecting that a heartbeat has not occurred within an expected time interval; and in response to detecting that the heartbeat has not occurred within the expected time interval, delaying the neuromodulation therapy at least until a next heartbeat is detected or for a predetermined length of time.

20. A system, comprising: a processor; and a memory capable of storing data thereon that, when processed by the processor, cause the processor to:receive a data signal from one or more sensors; detect, based on the received data signal, a cardiac electrical signal; predict, based on the cardiac electrical signal, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronize, relative to the cardiac refractory period, at least one of a neuromodulation therapy and a sensing of a response to the neuromodulation therapy.

21. The system according to claim 20, further comprising: a pulse generator to generate the neuromodulation therapy; and at least one electrode in communication with the pulse generator to deliver the neuromodulation therapy.

22. The system according to claim 21, wherein the at least one electrode comprises a first electrode to deliver the neuromodulation therapy and a second electrode to sense the response to the neuromodulation therapy.

23. The system according to any of claims 20 thru 22, wherein the response to the neuromodulation therapy is sensed via at least one of a far-field cardiac signal, an evoked Compound Action Potential (eCAP), and an evoked compound muscle action potential (eCMAP).

24. The system according to any of claims 20 thru 23, further comprising: a device that transforms the data signal received from the one or more sensors into the cardiac electrical signal.

25. The system according to any preceding claim, wherein the cardiac electrical signal includes at least one of a natural heartbeat and an electrical signal generated by a device.

26. A device for providing a therapy, the device comprising: an electrode capable of being implanted proximate an anatomical element; and a generator to generate a stimulation signal for delivery to the anatomical element via the electrode, wherein the stimulation signal is generated by: detecting a cardiac action potential that triggers a cardiac event;predicting, based on the cardiac event, a cardiac refractory period that lasts from a first time to a second time in duration; and synchronizing, relative to the cardiac refractory period, at least one of the stimulation signal and a sensing of a stimulation response to the stimulation signal.

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