R-R interval analysis for ECG waveforms to assess autonomic response to vagus nerve stimulation

An assessment system is provided for vagus nerve stimulation treatment with a neurostimulator configured to deliver a stimulation signal having a plurality of ON-periods and OFF-periods. The assessment system includes a wand assembly configured to generate a delivery detection signal indicating delivery of the stimulation signal, a lead assembly configured to acquire an ECG signal, and a data acquisition system configured to capture the delivery detection and ECG signals. The assessment system further includes a processor and a non-transitory computer-readable memory storing instructions that, when executed by the processor, cause the assessment system to record the ECG signal over at least one successive pair of ON- and OFF-periods, determine a heart rate dynamic response from the ECG signal, and determine an instantaneous heart rate for each determined R-R interval to determine heart rate dynamics for assessment of autonomic engagement in response to the vagus nerve stimulation treatment.

TECHNICAL FIELD

The present disclosure relates generally to systems and methods of neurostimulation therapy and, in particular, to systems and methods for assessing autonomic response to vagus nerve stimulation therapy in the treatment of congestive heart failure.

BACKGROUND

Autonomic regulation neurostimulation therapy delivered by vagus nerve stimulation (“VNS”) is a treatment for congestive heart failure. VNS therapy commonly requires implantation of a neurostimulator, which, when activated, applies or delivers a stimulation signal to the vagus nerve of a patient. A vagus nerve stimulation signal is typically a periodic current pulse signal defined by an output current amplitude or intensity. Following implantation and activation of the neurostimulator, a full therapeutic dose of VNS is not immediately delivered to the patient to avoid causing significant patient discomfort and other undesirable side effects. Instead, to allow the patient to adjust to the VNS therapy, a titration process is utilized in which the intensity is gradually increased over a period of time under the control of a physician with the patient given time between successive increases in VNS therapy intensity to adapt to the new intensity. As stimulation is chronically applied at each new intensity level, the patient's side effect threshold gradually increases, allowing for an increase in intensity during subsequent titration sessions.

SUMMARY

Embodiments of systems and methods are provided for monitoring physiological response to vagus nerve neurostimulation therapy. One embodiment relates to an assessment system for vagus nerve stimulation therapy treatment for congestive heart failure in a subject implanted with a neurostimulator configured to deliver a periodic stimulation signal having a plurality of ON-periods and OFF-periods. Each ON-period is defined as time between an initiating pulse and a terminating pulse of a plurality of stimulation pulses delivered to the subject, and each OFF-period is defined as a time between consecutive ON-periods. The assessment system includes a wand assembly in communication with the neurostimulator and configured to generate a delivery detection signal indicating delivery of the stimulation signal, a lead assembly configured to acquire an ECG signal of the subject over the plurality of ON-periods and OFF-periods, and a data acquisition system coupled to the wand and lead assemblies and configured to capture each of the delivery detection signal and the ECG signal. The assessment system further includes a processor and a non-transitory computer-readable memory storing instructions that, when executed by the processor, cause the assessment system to record the ECG signal over at least one successive pair of ON- and OFF-periods including, for each pair of ON- and OFF-periods, synchronizing a start of the recorded ECG signal to provide a first portion of the recorded ECG signal corresponding to the ON-period and a second portion of the recorded ECG signal corresponding to the OFF-period. The instructions also cause the assessment system to determine a heart rate dynamic response from the ECG signal, including detecting each QRS complex in each of the first and second portions of the recorded digital ECG signal, identifying each potential R-wave in each QRS complex in each of the first and second portions of the recorded ECG signal, verifying each identified R-wave in each of the first and second portions of the recorded ECG signal, and determining an R-R interval between each pair of successive verified R-waves. The instructions further cause the assessment system to determine an instantaneous heart rate for each determined R-R interval to determine heart rate dynamics for assessment of autonomic engagement in response to the vagus nerve stimulation treatment.

Another embodiment relates to an assessment system for vagus nerve stimulation therapy treatment for congestive heart failure in a subject. The assessment system includes a lead assembly configured to acquire an analog ECG signal of the subject over a delivery period of vagus nerve stimulation delivered to the subject and defined by an initiating pulse and a terminating pulse, the delivery period being a time between the initiating and terminating pulses, a data acquisition system coupled to the lead assembly and configured to convert the analog ECG signal to a digital ECG signal over the delivery period, and a processor and a non-transitory computer-readable memory. The memory stores instructions that, when executed by the processor, cause the assessment system to detect each QRS complex in the digital ECG signal over the delivery period, identify each potential R-wave in each QRS complex of the digital ECG signal, confirm each R-wave of the digital ECG signal, determine a time interval between each pair of successive confirmed R-waves of the digital ECG signal, and determine an instantaneous heart rate from each determined time interval.

Another embodiment relates to a method of real-time assessment of autonomic engagement response to vagus nerve stimulation therapy. The method includes determining, in real-time, R-R intervals in an ECG signal response to a stimulation cycle of the therapy, the stimulation cycle having an ON-period during which therapy is delivered and an OFF-period during which therapy is not delivered. The method further includes distinguishing the R-R intervals occurring during the ON-period from the R-R intervals occurring during the OFF-period to assess the autonomic engagement response to the stimulation cycle.

DETAILED DESCRIPTION

When delivering neurostimulation therapies to patients, it is generally desirable to avoid stimulation intensities that result in either excessive tachycardia or excessive bradycardia side effects. The neurostimulator may be adjusted to deliver varying stimulation intensities to the patient. To find a beneficial therapeutic level of neurostimulation, researchers have utilized the patient's heart rate changes. Some researchers have proposed that heart rate reduction serves as a functional response indicator or surrogate for effective recruitment of nerve fibers and engagement of the autonomic nervous system elements, which may be indicative of therapeutic levels of vagus nerve stimulation. A therapeutic level or dose of vagus nerve stimulation that results in a heart rate reduction of up to 5% has been described as treatment that is delivered within the desired “neural fulcrum zone.” The neural fulcrum zone corresponds to a combination of stimulation parameters at which autonomic engagement is achieved but for which a functional response determined by heart rate change is nullified due to the competing effects of afferently and efferently-transmitted action potentials. In this way, the tachycardia-inducing stimulation effects are offset by the bradycardia-inducing effects, thereby minimizing side effects, such as significant heart rate changes, while providing a therapeutic level of stimulation.

Shown inFIG.1is a graphic illustration of the neural fulcrum zone and heart rate change response as a function of increasing vagus nerve stimulation signal intensity and constant frequency. The x-axis represents the intensity level of the stimulation signal, and the y-axis represents the observed heart rate change from the patient's baseline basal heart rate observed when no stimulation is delivered. The patient's heart rate change response200is depicted as depending on the stimulation signal intensity. As the intensity (e.g., output current amplitude) is increased, a tachycardia zone is observed. This response200is more or less pronounced depending on the other stimulation parameters. As the intensity continues to be increased, the patient's heart rate change response200begins to decrease and eventually enters a bradycardia zone. The neural fulcrum zone is depicted as the response zone202between no heart rate change 0% (occurring at point204) and a heart rate reduction of 5% (occurring at point206).

In vagus nerve stimulation therapy, the titration process can take up to 10-12 weeks before a full therapeutic dosage can even be tolerated. In order to reduce or minimize the titration process time to a full therapeutic dose, it is desirable to monitor the physiological response to evaluate whether the applied stimulus dosage in the titration process is effective without inducing undesirable side effects. Accordingly, there remains a need for systems and methods to assess autonomic engagement response to delivery of a vagus nerve stimulation signal.

Shown inFIG.2is a system10for monitoring and assessing a physiological response of a subject patient SP to neurostimulation therapy and, in particular, for monitoring and assessing heart rate dynamic response to vagus nerve stimulation for the treatment of CHF, according to an exemplary embodiment. In various embodiments, the system10provides one or more indicators to a patient and/or clinician of the effectiveness of a delivered stimulation treatment by indicating autonomic engagement in the subject patient SP in a timeframe that is real-time, which includes a timeframe that is instantaneous, immediate, sequential, or proximate to a parameter change; encompassing a titration session; and/or within one minute, ten minutes, and/or an hour of a stimulation parameter change. In some embodiments, the one or more real-time indicators of the effectiveness of a delivered stimulation treatment allow and/or facilitate the modification of the stimulation therapy, the subject patient SP's advancement through the titration process, and/or the delivery of effective levels of therapy to the subject patient SP in a timeframe that is real-time, which includes a timeframe that is instantaneous, immediate, sequential, or proximate to a parameter change; encompassing a titration session; and/or within one minute, ten minutes, and/or an hour of a stimulation parameter change. Alternatively or additionally, the titration process can be automatically altered or increased in intensity with the detection, monitoring, and/or measurement by the system10occurring in real-time. The assessment can be read from system10in real-time, or, if needed or desired, the assessment can be read from the system10by a clinician at a later time in a clinic or other environment.

The system10captures the physiological response to the vagus nerve stimulation. In some embodiments, the system10(i) detects the electrical heart activity response, e.g., electrocardiogram (“ECG”) of the subject patient SP in response to the vagus nerve stimulation; (ii) determines the change in heart rate dynamics in response to the stimulation; and (iii) visually displays the change in heart rate dynamics in a manner that indicates the extent of autonomic engagement in response to the delivered stimulus. By providing the indication of autonomic engagement in real-time, the effectiveness of the stimulus treatment can be assessed by the patient or clinician, and the stimulus can be adjusted as needed in real-time to ensure delivery of an effective stimulus or the delivery of a stimulus that advances the titration of the subject patient SP to an effective stimulus. Moreover, by assessing a stimulation signal of a titration process in real-time, the stimulation signal can be optimized and the overall titration process and the therapy can be made more efficient by minimizing the time required to achieve a titrated delivery of a full therapeutic dose or intensity of a vagus nerve stimulus.

The system10includes a first interface or communication assembly20for communication with a stimulation delivery device22and a second interface assembly30for capturing the physiological response of the subject patient SP. In some embodiments, the second interface assembly30captures data suitable for generating the ECG waveform of the subject patient SP to the stimulation delivery. In various embodiments, as shown inFIG.2, the stimulation delivery device22is embodied as an implantable medical device (“IMD”) and, more particularly, an implantable neurostimulator22. Embodiments of the neurostimulator22are shown and described in U.S. Pat. Nos. 9,770,599 and 9,950,169, each of which is incorporated by reference in its entirety. As described in the cited patent documents, the implantable medical device includes a pulse generator22, a lead13, and electrodes14for delivering a pulse generated stimulus about a vagus nerve15of the subject patient SP. A commercially available embodiment of the implantable neurostimulator22includes the VITARIA™ Model 7103 Pulse Generator from Livallova USA, Inc. of Houston, Tex., USA.

Shown inFIG.3is another embodiment of a neurostimulator22′, for use with the assessment system10, which includes or incorporates an implantable cardioverter-defibrillator (“ICD”). An implantable VNS/ICD system is also shown and described in U.S. Pat. No. 9,770,599, which is incorporated by reference in its entirety. An embodiment of an implantable VNS/ICD system includes a pulse generation module with a control system, a VNS subsystem, and an ICD subsystem. A first electrode assembly14is coupled to the pulse generation module and includes a VNS electrode configured to couple to the vagus nerve15. A second electrode assembly16a,16bis coupled to the pulse generation module and includes a subcutaneous electrode. Another embodiment of an implantable VNS/ICD system includes a primary pulse generation module having a primary control system and an ICD subsystem and a secondary pulse generation module having a secondary control system and a VNS subsystem. The secondary pulse generation module is placed in data communication with the primary pulse generation module, with the second electrode assembly16a,16bcoupled to the primary pulse generation module, in which the second electrode assembly16a,16bincludes a subcutaneous electrode. Another electrode assembly is coupled to the secondary pulse generation module. This electrode assembly includes a VNS electrode14configured to couple to the vagus nerve15. In various embodiments, the implantable VNS/ICD system is configured to deliver a chronic VNS therapy to the vagus nerve15with a VNS subsystem of a pulse generation module. In response to detection of a cardiac event, the implantable VNS/ICD system is configured to deliver electrical cardioversion-defibrillation energy with an ICD subsystem of the pulse generation module.

Referring back toFIG.2, a computer processing device50is coupled with the first and second interfaces20,30for processing the captured ECG-suitable signal to determine, for example, in real-time, the heart rate dynamics in the subject patient SP in response to delivery of the stimulation signal to the vagus nerve15. The ECG-suitable signal allows the determination and display of a periodic waveform with repeating “cardiac cycles” as shown, for example, inFIG.13. A “cardiac cycle” may refer to one complete PQRSTU interval of the patient's heart functioning, ending with the P wave of the next succeeding cardiac cycle. An “interbeat interval” may refer to the time period between a predetermined point in a first cardiac cycle of the patient and the same predetermined point in the immediately succeeding cardiac cycle of the patient. Examples of interbeat intervals include an R-R interval, a P-P interval, or a T-T interval. Interbeat intervals may include a single interval or a moving average (either simple or weighted) of several consecutive intervals. Within a single cardiac cycle, a “cardiac period” is a length of time between a first point in the cardiac cycle of the patient and a second, later point. An exemplary cardiac period includes a P-wave, a Q-wave, an R-wave, an S-wave, a QRS complex, a T-wave, and a U-wave of the cardiac cycle, which can be readily identified by electrocardiography or other techniques of monitoring the electrical activity of the heart. For example, the R-wave presents the maximum amplitude of the cardiac cycle.

According to one embodiment of the processing of the ECG-suitable signal described herein, the heart rate dynamics are determined from an R-R interbeat interval analysis of the cardiac period QRS complex in the ECG waveform. From the heart rate dynamics, the computer processing device50displays in real-time an indication of autonomic engagement in the subject in response to the stimulus. The R-R interval analysis provides a desired resolution in the ECG waveform from which to determine and indicate the autonomic response in real-time.

Shown inFIG.4is a process100for capturing and analyzing the ECG-suitable signal response during vagus nerve stimulation treatment, according to an exemplary embodiment. At the beginning105of the titration or stimulation delivery process (e.g., as part of programming the titration process), a first determination step110is taken to determine when a stimulus signal is to be delivered from the neurostimulator22to the vagus nerve. In some embodiments, the stimulation signal is periodic having an ON-period in which stimulation of a particular current amplitude and frequency is delivered and an OFF-period of rest in which no stimulation signal is delivered to the vagus nerve. With the schedule of ON-periods determined, the process100includes a synchronization and recordation step115in which an ECG-suitable signal is captured and recorded over the ON-period. In a second determination step120, the OFF-period of the stimulation signal is identified. In some embodiments, the OFF-period is continuous with the ON-period and is identifiable as being the rest period between two adjacent ON-periods in the stimulation signal. With the OFF-period identified, a second synchronization and recordation step125is carried out to capture and record the ECG-suitable signal over the OFF-period. AlthoughFIG.4shows the determination and recordation steps as discrete steps, the steps may be carried out sequentially, concurrently, or in an alternate order.

Having captured and identified the ECG-suitable signals corresponding to each of the ON-period and OFF-period in the stimulation signal, a third determination step130is carried out to determine the QRS complex profile in the corresponding ECG waveforms for each period of the stimulation signal. A fourth determination step135includes determining each R-R interval between consecutive QRS complexes in each ECG-suitable signal corresponding to the ON-period and OFF-period in the stimulation signal. Accordingly, heart rate dynamic response, such as, for example, instantaneous heart rate, mean heart rate, and heart rate variability, can be determined and displayed in a subsequent step140for each of the ON-period and OFF-period in the stimulation signal. The process100can then conclude with an assessment step145in which the autonomic engagement response can be determined, indicated, and displayed for the subject patient and/or clinician.

Shown inFIG.5is another schematic view of the system10with the computer processing device50for assessing a vagus nerve stimulation treatment, according to an exemplary embodiment. The computer processing device50includes processing hardware52, such as, for example, a central processing unit54and associated memory or computer readable medium, such as, for example, system memory56aand storage memory56b, for processing ECG-suitable signals in a manner as described herein. The system memory56acan include volatile memory, such as, for example, RAM (random-access memory). The storage memory56bcan be non-volatile or persistent memory such as, for example, ROM (read-only memory), flash memory, ferroelectric RAM, most types of magnetic computer storage devices (e.g. hard disk drives, solid state drives, floppy disks, and magnetic tape), or optical discs. The computer processing device50includes one or more associated displays58for indicating the autonomic engagement response to the stimulus. The system memory56aand/or storage memory56bmay store instructions that are executable by the processor54to perform the functionalities described herein. The display56can be a touch-sensitive display, which can provide touch control buttons and keys. As shown, the processing hardware52and the display58communicate with one another over a communication bus or network60. Additionally or alternatively, the computer processing device50can include one or more peripheral input and output ports for connection and use with other peripheral input, output, or storage devices. The components of the computer processing device50can be integrated with one another or be separately housed components. For example, the processing hardware52can be housed separately from the display58. Alternatively, the display58can be housed with the processing hardware52in a single assembly. In some embodiments, the computer processing device50can be embodied using a general purpose programmable computer. A general purpose programmable computer can be a personal computer, laptop computer, Ultrabook computer, netbook computer, handheld computer, tablet computer, smart phone, or other form of computational device with an appropriate operating system. In other embodiments, the computer processing device50can be a specialized computer specifically designed and programmed to function with the neurostimulator22described herein.

Referring back toFIG.2, in the system10, the computer processing device50is coupled to each of the first and second interface communication assemblies20,30by a data acquisition system40. The data acquisition system40provides for digital conversion of incoming signals coming from the interface communication assemblies20,30(e.g., a wand assembly20, ECG sensor assembly30). The data acquisition system40, the processing hardware52, and the display58communicate with one another over a communication bus or network60(e.g., as shown inFIG.5). In some embodiments, the data acquisition system40for use in the system10is the BIOPAC MP36R from BIOPAC® Systems, Inc., which can simultaneously capture signals from multiple devices or sources. Additionally, in some embodiments, the computer processing device and the data acquisition system are different systems (e.g., shown as computer processing device50and data acquisition system40inFIG.2), while in other embodiments, the computer processing device and data acquisition system are incorporated into a single system (e.g., shown as computer processing device50′ inFIG.2).

In the system10, the communication assembly20wirelessly communicates with the neurostimulator22by providing control signals or commands to define parameters of the stimulation signal or pulses to be delivered by the neurostimulator22to the vagus nerve. In some embodiments, as shown inFIG.2, the communication assembly20includes an external programming wand24and a wand transmission detection cable26. The programming wand24wirelessly communicates with the implanted device22by telemetry or radio frequency signal. Embodiments of the external programming wand24are described, for example, in U.S. Pat. Nos. 9,770,599 and 9,950,169. A commercially available embodiment of the wand24includes NeuroCybernetic Prosthesis (NCP®) Programming Wand Model 201. The wand24is a hand-held device that can transmit programming and interrogation information signals or commands to the implantable neurostimulator22, such as, for example, the VITARIA™ Model 7103 Pulse Generator. The programming wand24alone or in conjunction with a computer and appropriate firmware, such as, for example VNS Therapy Programming Software, can store and retrieve telemetry data and revise stimulus signal parameters from the pulse generator22.

The wand transmission detection cable26is associated with the external programmer or wand24to detect or determine the stimulation delivery from the neurostimulator22to the vagus nerve15of the subject patient SP. In some embodiments, the wand transmission detection cable26detects or extracts the delivery schedule from the external wand24to determine the stimulation delivery from the neurostimulator22to the vagus nerve15. By detecting delivery of stimulation signals with the communication assembly20, the capture or recording of the subject's ECG-suitable signal can be synchronized with the ON-period and OFF-period of the stimulation signal in accordance with the process100for capturing and analyzing the ECG-suitable signal previously described.

In some implementations, the second interface assembly30is embodied as an ECG cable assembly with three leads or clips32a,32b,32cfor respectively connecting to three electrodes or contacts, for example, placed on the wrists of the subject patient SP. As seen inFIG.2, two leads32a,32bare connected to two electrodes on the left wrist and the remaining lead32cis connected to a single electrode on the patient's right wrist.

The computer processing device50operates under the control of one or more software applications, which are executed as program code as a series of process or method modules or steps by the programmed computer hardware. In some embodiments, a computer readable medium, such as a non-transitory computer readable medium, of the processing hardware52stores a program that can cause the computer processing device50to execute one or more processes described herein for assessing vagus nerve stimulation treatment.

In the embodiment of the system10and its operation100ofFIG.4, the system10processes the ECG-suitable signal response to determine the ECG waveform and the R-R intervals to derive heart rate dynamics in assessment of the stimulus treatment. Moreover, the system10distinguishes or identifies which portions of the ECG signal or waveform response correspond to the delivery of stimulation signal, i.e., the ON-periods of the periodic stimulation signal, and which portions of the ECG signal or waveform response correspond to the rest period, i.e., over the OFF-periods, of the periodic stimulation signal. By segregating ECG signals or portions of the ECG waveforms and their derivative components by ON-period and OFF-period, the ECG signals/waveforms and the heart rate dynamics derived therefrom can be compared to assess the extent of autonomic engagement resulting in the delivered stimulation signal.

Referring again toFIG.5, the computer processing device50and its hardware includes and executes firmware programming that provides for an R-R interval detector70and an ECG processor80for carrying out the assessment methods described herein. The R-R interval detector70and ECG processor80and the associated methods can be implemented using appropriate software programming for signal processing and hardware configuration. For example, an appropriate “graphical program” can be used to represent data structures and/or program instructions in memory (e.g., the system memory56aand/or storage memory56b) of the computer processing device50to carry out the signal processing, instrument access, and assessment methods described herein. An exemplary graphical program development environment in which to create a program for use in the system10includes LabVIEW from National Instruments Corp.

Shown inFIG.6is an embodiment of the assessment process400. With the subject patient SP connected to the system10, as shown inFIG.2, and the implanted neurostimulator medical device22delivering a stimulation signal to the vagus nerve of the patient, the process of assessment400begins with a determination step402to determine the start of stimulation delivery for synchronizing recordation of the cardiac response. In some embodiments, the programming wand24is placed in communication with the neurostimulator22, and the wand transmission detection cable26in combination with the computer processing device50detects the inductive telemetry signal between the components (step404). The computer processing device50processes the inductive telemetry signals to determine the stimulation ON-period (step406) and determine the stimulation OFF-period (step408). Additionally, in some embodiments, the computer processing device50captures the various defining parameters of the delivered stimulation signal from which recordation of the ECG or other measure of cardiac response can be synchronized. At step410, the computer processing device50synchronizes sampling of the ECG-suitable signal with the start of the ON-period of the delivered stimulation signal (e.g., such that, at step412, the ECG-suitable signal is continuously recorded).

Shown inFIG.7is an exemplary stimulus signal300defined by one or more of the following parameters: output current amplitude or intensity, signal frequency, or pulse width. The vagus stimulation signal300is delivered in a cyclical manner in which each cycle of is defined by an ON-period302in which the stimulation signal is delivered to the vagus nerve and an OFF-period or rest period304in which no stimulation is delivered. The ON-period302occurs at a constant interval with the OFF-periods304of rest between the repeating ON-periods302. In some embodiments, a treatment cycle can be defined by a combination of on and off times selected from the following exemplary ON-periods: 7 sec, 14 sec, 21 sec, 30 sec, 50 sec, and 60 sec; and exemplary OFF-periods: 12 sec, 18 sec, 24 sec, 30 sec, 42 sec, 54 sec, 66 sec, 78 sec, 90 sec, 120 sec, 180 sec, and 300 sec. For example, one exemplary treatment cycle is defined by a 14 second “on period” and a 66 second “off period.”

As discussed above, a cycle of stimulation delivery is defined by a continuous ON-period and OFF-period. In some embodiments of treatment, there are 5-10 cycles. Each ON-period is defined by repeating pulse signals at a defined output current amplitude or intensity, signal frequency, and pulse width. In one exemplary ON-period, the pulse signals are defined by an output current of up to 3.0 mA, a frequency of 5-10 Hz, and a pulse width at 250-300 micro-seconds (“μsec”). Accordingly, each ON-period is defined by an initiating pulse306aand a terminating pulse306bthat are spaced apart over a time duration defining the ON-period302. The OFF-period304is thus defined by the time duration between a terminating pulse306bof one ON-period302and the initiating pulse306aof the consecutive, subsequent ON-period302. Shown inFIG.8is another embodiment of a stimulation signal300′, which includes a ramp up period308ato the initiating pulse306aand a ramp down period308bfrom the terminating pulse306b(e.g., with the ramping up period308aand the ramping down period308bboth being at a constant rate).

Referring again toFIG.5andFIG.6, with the start of ECG signal recording synchronized with the stimulation signal, the ECG-suitable signal is continuously sampled at step412by the data acquisition system40and the computer processing device50. For example, the ECG-suitable signal is sampled at a rate of 200 samples per second at a rate suitable for analysis and processing as described herein. In some embodiments, the ECG-suitable signal is recorded for at least one successive pair of ON- and OFF-periods. More particularly, in some embodiments, the ECG-suitable signal is recorded over a plurality of successive pairs of ON- and OFF-periods. In an exemplary ECG processing step414, the digitally converted ECG-suitable signal is segregated and designated into portions that correspond to the ECG response to the ON-period of stimulation delivery and the ECG response to the resting OFF-period.

As shown inFIG.5, in some embodiments, the computer processing device is programmed to provide for an R-R interval detector70and ECG processor80. Embodiments of the R-R interval detector70and the ECG processor80are shown inFIGS.9and10, respectively. The R-R interval detector70ofFIG.9includes an ECG stimulation period identifier72, a real-time QRS detector74, a band pass filter76, and an R-R interval verifier78. The ECG stimulation period identifier72identifies portions of the incoming ECG response as corresponding to either the ON-period or the OFF-period of the stimulation signal to complete step414ofFIG.6. Illustrated inFIG.11is a first portion220of the sampled ECG-suitable signal corresponding to the ON-period of the stimulation signal and a second portion230of the sampled ECG-suitable signal corresponding to the OFF-period of the stimulation signal.

Each of the designated portions220,230of the ECG waveform response is then processed to determine the components of the ECG waveform for further analysis and digital reconstruction. The real-time QRS detector74of the R-R interval detector70identifies the QRS-wave or complex, and the band pass filter76identifies the R-wave by detecting a maximum amplitude corresponding to the R-wave. Indicated inFIG.11are identified QRS complexes224a,224b,224cfor the ON-period ECG waveform portion220and the QRS complexes234a,234b,234cof the OFF-period ECG waveform portion230. Accordingly, each of the R-waves (226a,226b,226c) (236a,236b,236c) of the QRS complexes are also initially identified from baselines222,232.

The R-R interval (228a,228bfor the ON-period) (238a,238bfor the OFF-period), or time period between adjacent R-waves in the ECG waveform or equivalent ECG characterization, is then determined and verified by the R-R interval verifier78in real-time. The verifier78provides an interval timer or counter that determines the R-R interval and verifies that the R-R interval falls within a predetermined threshold value that corresponds to the periodic response of the incoming ECG-suitable signal. Accordingly, the R-R interval verifier78minimizes or eliminates mistakes in identification of the R-wave and R-R intervals. For example, the verifier78can filter out the amplitude of a T-wave from being mistaken for an R-wave by identifying the occurrence of the T-wave as being too close in time to the preceding R-wave. Thus, the R-R interval detector70completes the determination and filter steps416,418in the process400ofFIG.6.

With each R-wave and R-R interval identified within the ECG waveform or equivalent, the computer processing device50determines one or more heart rate dynamics for assessment of the delivered stimulation signal. Referring again toFIG.10,FIG.10illustrates an exemplary ECG processor80that includes one or more of a heart rate calculator82, a heart rate variability calculator84, and an ECG waveform generator86. The heart rate calculator82determines an instantaneous heart rate (“IHR”) between adjacent R-waves. Shown inFIG.12are adjacent R-waves in each of the ON-period portion220′ and the OFF-period230′ of the illustrative ECG waveform with respective determined R-R intervals (228,238). Thus, in accordance with step420of the process400ofFIG.6, for each R-R interval, the IHR in beats per minute (“bpm”) is determined by the following:
IHR=1 beat/(R-Rinterval msec)×(1000 msec/sec)×(60 sec/min)

From the IHR several statistical aspects of the heart rate can also be determined by the heart rate calculator82. In some embodiments, the real-time heart rate can be determined at step422by taking a beat-to-beat average over a range of the latest recorded number of beats. For example, the real-time heart rate (“RTHR”) can be determined by the average of the last five or fewer instantaneous heart rates. In some embodiments, the RTHR can be determined in step422of the process400by the average of the last three instantaneous heart rates in a manner as follows:

RTHR=[IHR(N)+IHR(N−1)+IHR(N−2)]/3, where N is the most recent IHR value, where N−1 is an IHR value preceding the N value in time, and where N−2 is an IHR value preceding the N value in time.

As can be appreciated, the IHR values can be qualified values that meet a threshold level of data quality, with inaccurate or inconsistent IHR values being disregarded, discounted, weighted, or modified to improve the quality of the IHR values used in the determination of the RTHR value. As can also be appreciated, the IHR(N), IHR(N−1), and IHR(N−2) values can be ordered in time in a sequence with each value being adjacent to the next in time, ordered in time in a sequence with unqualified IHR values interposed between qualified IHR values and/or ordered in time in a sequence with a skipped IHR value or values interposed between qualified IHR values. The RTHR may also be displayed (e.g., via the display58) at step422.

In a continuous manner, the storage memory56b, in coordination with the R-R interval detector70, stores in one or more data arrays each IHR, associated verified R-R interval, associated status identifier as either ON-period or OFF-period, and associated cycle number in the number of cycles defining the stimulus treatment. Accordingly, the heart rate calculator82determines, in real-time, the mean heart rate for each ON-period of stimulation signal delivery and OFF-period of rest in a given treatment cycle in steps424,426, respectively, of the process400. For example, where a stimulation signal cycle is defined by a 14 second ON-period and a 66 second OFF-period, the heart rate calculator82takes the cumulative average of most or all the IHRs over the 14 second ON-period to determine the ON-period mean heart rate (“(MHR)ON”). To determine the OFF-period mean heart rate (“(MHR)OFF”), the heart rate calculator82takes the cumulative average of most or all IHRs over the 66 second OFF-period. In one embodiment, the IHR values corresponding to the ON-period and/or the OFF-period can be qualified to eliminate low-quality IHR values or to eliminate IHR values that overlap or are proximate to the start or cessation of stimulation.

Additionally or alternatively to taking the cumulative average of all determined instantaneous heart rates to calculate mean heart rates, the heart rate calculator82can apply a data quality process that prefers, uses, or takes the cumulative average of the instantaneous heart rates within 25% of the mean of instantaneous heart rates for a given ON-period or OFF-period. Thus, the heart rate calculator82eliminates extremes in instantaneous heart rates in each of the ON-period and OFF-period by defining the minimum instantaneous heart rate at 25% below the mean and defining the maximum instantaneous heart rate at 25% above the mean. The heart rate calculator82can then determine the mean heart rate (“MHR”) by taking the cumulative average of instantaneous heart rates falling between the maximum and minimums. The mean heart rate may also be displayed for the ON-period and OFF-period at steps424,426, respectively.

In step428of process400, the heart rate calculator82determines (e.g., in real-time) the extent of bradycardia response. For example, the heart rate calculator82determines a heart rate reduction response for each cycle of treatment by determining the difference between the cumulative averages of the instantaneous heart rates to indicate a heart rate reduction (“HRR”) as follows:
HRR=(MHR)OFF−(MHR)ON

A positive HRR indicates a bradycardia response, and a negative HRR indicates a tachycardia response. A positive HRR reduction of less than 5% from the mean heart rate for the OFF-period ((MHR)OFF) indicates a desired response of autonomic engagement (e.g., a response within the neural fulcrum zone). The HRR may also be displayed at step428.

Referring again toFIG.10, the ECG processor80includes a heart rate variability calculator84to determine heart rate variability in step430of an additional or alternate method400′ for assessing response to the vagus nerve stimulation as shown inFIG.13. In particular, the variability calculator84determines a difference in the heart rate variability response between the ON-period and the OFF-period. In an aspect, the storage memory56b, in coordination with the ECG processor80and variability calculator84, stores in one or more data arrays the R-R interval for each preceding R-R interval and stimulation status ON/OFF period for a number of cycles in the stimulation treatment. Accordingly, the stored data array can be defined as {R-R Interval(N+1), R-R Interval(N), ON/OFF-period Status, #Cycle}. The data can be aggregated for each cycle in a manner that differentiates ON-period of stimulation signal delivery and OFF-period of resting period. In some embodiments, for each cycle, the mean average of all the R-R Intervals for the ON-period and the mean average of all the R-R Intervals for the OFF-period are determined and compared. A separation in the mean average can be used to show an autonomic engagement response to the delivery of vagus nerve stimulation treatment.

In an aspect of the assessment method400′, the heart variability is graphically displayed in a display step432that provides the subject patient SP or clinician with a real-time indicator of autonomic engagement response to a delivered stimulus. More particularly, the R-R interval differential between the ON-period and OFF-period is displayed in a Poincaré plot900as illustrated inFIG.14andFIG.15. The display can be generated (e.g., in real-time) for the subject patient SP or clinician to view at the display58of the system10. The plot shows the R-R interval (R-R Interval(N+1)) along the vertical axis902in msec, as a function of the preceding R-R interval (R-R Interval(N)) along the horizontal axis904in msec. In step434of the process400′, the R-R intervals for the ON-period and OFF-period are distinguished from one another by differentiating markers, as shown inFIGS.14and15. R-R interval values for the ON-period are shown with “+” markers906, and the OFF-period values are shown with “O” markers908. In accordance with an aggregating step436of the process400′, the plot900provides a visual indication of autonomic engagement as determined by the separation or gap G between the cluster of ON-period R-R interval values from the cluster of OFF-period R-R interval values.

In another process step438, the plot900shows a first best-fit circle910about the R-R interval ON-period data (e.g.,906a,906b) and a second best-fit circle912about the R-R interval OFF-period data (e.g.,908a.908b). The best-fit circles910,912are defined by a radius about the centroids914,916, which are determined by the respective means of the ON-period and OFF-period R-R interval data at step440. The radii of the best-fit circles910,912are calculated or defined by a minimum and maximum in the R-R interval values about the mean. In some embodiments, the heart rate variability calculator84determines the 25th quartile and the 75th quartile of the R-R interval values and determines the mean of values falling between the 25th and the 75th quartiles about which to determine the best fit circles. The gap G is defined as the straight line distance between the centroids914,916to indicate an extent of autonomic engagement. Alternatively, the heart rate variability calculator84defines the minimum R-R interval value at 25% below the mean and defines the maximum R-R interval value at 25% above the mean. In another alternative, the best-fit circles910,912include or circumscribe each of the minimum and maximum values.

Shown inFIG.15, are additional graphical indicators in a plot900′ indicating heart rate variability response to the vagus nerve stimulation treatment. The heart rate variability calculator84can determine and aggregate, as alternatively provided in step438of the process400′ ofFIG.13, the R-R interval data to best-fit ellipses920,922for each of the ON-period and OFF-period data to indicate the extent of heart rate variability within each respective period during stimulation delivery and during the resting period. The calculator84can determine each of the major axis SD2and the minor axis SD1for each of the ellipses920,922as part of determining standard deviation and variability at step442of the process400′. In some embodiments, the minor axis SD1is determined as reflecting the standard deviation of the IHR about the mean, and the major axis SD2is determined as the standard deviation of the continuous heart rate about the mean. The major axis SD2can be found by a best fit to the data with the axis SD2passing through the centroid or mean914,916of the R-R interval. The minor axis SD1extends transverse to the major axis SD2and passes through the centroid914,916. Accordingly, the ellipse920,922is a best fit that is centered about the centroid914,916, respectively, and passes through the axes SD2, SD1while encompassing the data disposed about the respective centroid914,916.

Given the data compiled and collected by the computer processing device50, the ECG processor80can also include an ECG waveform generator86, as seen inFIG.10. At step450of method400, the waveform generator86can display a digital replica of the ECG waveform1010in the display58in real-time, as shown, for example, inFIG.16. The ECG replica1010includes all the PQRSTU intervals of the waveform to provide a visual indicator to the subject patient, clinician, and/or physician of any possible arrhythmia to accompany the assessment indicators previously described. Moreover, the display58can display back to the subject patient or clinician each of the determined values from the assessment processes previously described. For example, the display58can report back the real-time heart rate (RTHR), the mean heart rates for each of the OFF-Period and ON-Period ((MHR)OFF, (MHR)ON), and the Heart Rate Reduction (HRR). Additionally, in some embodiments, the display58can show the R-wave axis and/or mark the R-wave intervals for the subject patient or clinician.

While the present disclosure makes reference to certain embodiments, numerous modifications, alterations, and changes to the described embodiments are possible without departing from the sphere and scope of the present disclosure, as defined in the appended claims. Accordingly, it is intended that the present disclosure not be limited to the described embodiments, but that it has the full scope defined by the language of the following claims and equivalents thereof