Patent Description:
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.

Embodiments of systems and methods are provided for monitoring a physiological response to neurostimulation therapy. One embodiment relates to a system including a vagus nerve stimulation (VNS) device configured to deliver a vagus nerve stimulation signal for congestive heart failure treatment. The stimulation signal has an ON-period status in which a stimulus is being delivered to a subject and an OFF-period status in which no stimulus is being delivered to the subject. The system also includes a processor and a non-transitory computer readable memory. The memory stores instructions that, when executed by the processor, cause the system to synchronously record a first ECG profile of the subject during the ON-period status of the VNS device and synchronously record a second ECG profile of the subject during the OFF-period status of the VNS device, determine heart rate dynamics from the first and second ECG profiles, the heart rate dynamics including a plurality of R-R intervals in each ECG profile, generate display data configured to be displayed on a display, and transmit the display data to the display. The display data includes the R-R intervals for each of the first and second ECG profiles to indicate real-time heart rate variability and autonomic engagement by showing a change in the real-time heart rate variability in response to the vagus nerve stimulation signal during the ON-period status and OFF-period status of the VNS device. The display data further includes a Poincaré plot. The system further includes a display configured to display the display data. In some embodiments, the system also includes an ECG cable assembly configured to capture ECG signals from the subject.

Any methods described hereinafter are presented for illustrative purposes only and do not in themselves form part of the invention.

The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate exemplary embodiments of the systems and methods described herein, and together, with the general description given above and the detailed description given below, serve to explain the features of the systems and methods described herein.

Accordingly, 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 which that in a heart rate reduction of up to <NUM>% has been described as treatment that is being 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 in <FIG> is 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 response <NUM> is depicted as depending on the stimulation signal intensity. As the intensity (e.g., output current amplitude) is increased, a tachycardia zone is observed. This response <NUM> is more or less pronounced depending on the other stimulation parameters. As the intensity continues to be increased, the patient's heart rate change response <NUM> begins to decrease and eventually enters a bradycardia zone. The neural fulcrum zone is depicted as the response zone <NUM> between no heart rate change <NUM>% (occurring at point <NUM>) and a heart rate reduction of <NUM>% (occurring at point <NUM>).

Shown in <FIG> is a system <NUM> for monitoring and assessing a physiological response of a subject patient SP to neurostimulation therapy and, in particular, heart rate dynamic response to vagus nerve stimulation for the treatment of CHF, according to an exemplary embodiment. The system <NUM> provides a Poincaré plot to provide one or more visual indicators to a patient and/or clinician of an autonomic response in the patient to the vagus nerve stimulation treatment. The system <NUM> provides the plot and indicators 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 system <NUM> occurring in real-time. The assessment can be read from system <NUM> in real-time, or, if needed or desired, the assessment can be read from the system <NUM> by a clinician at a later time in a clinic or other environment.

The system <NUM> captures the physiological response to the vagus nerve stimulation. In some embodiments, the system <NUM> (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 system <NUM> includes a first interface or communication assembly <NUM> for communication with a stimulation delivery device <NUM> and a second interface assembly <NUM> for capturing the physiological response of the subject patient SP. In some embodiments, the second interface assembly <NUM> captures, data suitable for generating the ECG waveform of the subject patient SP to the stimulation delivery. In various embodiments, as shown in <FIG>, the stimulation delivery device <NUM> is embodied as an implantable medical device ("IMD") and, more particularly, an implantable neurostimulator <NUM>. Embodiments of the neurostimulator <NUM> are shown and described in <CIT> and <CIT>. As described in the cited patent documents, the implantable medical device includes a pulse generator <NUM>, a lead <NUM>, and electrodes <NUM> for delivering a pulse generated stimulus about a vagus nerve <NUM> of the subject patient SP. A commercially available embodiment of the implantable neurostimulator <NUM> includes the VITARIA™ Model <NUM> Pulse Generator from LivaNova USA, Inc. of Houston, Texas, USA.

Shown in <FIG> is another embodiment of a neurostimulator <NUM>' for use with the assessment system <NUM>, which includes or incorporates an implantable cardioverter-defibrillator ("ICD"). An implantable VNS/ICD system is also shown and described in <CIT>. 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 assembly <NUM> is coupled to the pulse generation module and includes a VNS electrode configured to couple to the vagus nerve <NUM>. A second electrode assembly 16a, 16b is coupled to the pulse generation module and includes a first 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 assembly 16a, 16b coupled to the primary pulse generation module, in which the second electrode assembly 16a, 16b includes a subcutaneous electrode. Another electrode assembly is coupled to the secondary pulse generation module. This electrode assembly includes a VNS electrode <NUM> configured to couple to the vagus nerve <NUM>. In various embodiments, the implantable VNS/ICD system is configured to deliver a chronic VNS therapy to the vagus nerve <NUM> with 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.

In various embodiments, a method of analyzing an autonomic engagement response to vagus nerve stimulation treatment may be used in which the autonomic response is indicated by a distinct variance in heart rate variability when a stimulation signal is delivered to the vagus nerve as compared to when no stimulation signal is delivered. For example, a Poincaré plot of ECG data may be used to graphically show that the application of vagus nerve stimulation can result in a significant change in instantaneous heart rate variability. Such a plot can provide a visual indicator of autonomic response to the stimulation. Methods of using a Poincaré plot to assess the application of vagus nerve stimulation are described in further detail in <NPL>). In this article, the underlying ECG data used in the Poincaré plot was derived at the conclusion of a titration study in which the ECG data was continuously monitored during stimulation treatment. Accordingly, the analysis and study using the Poincaré plot was a static analysis looking at historical data. By contrast, the system <NUM> of <FIG> and its methods of use provide a way of obtaining and dynamically analyzing ECG data to assess autonomic response to vagus nerve stimulation in real-time.

In the system <NUM>, a computer processing device <NUM> is coupled with the first and second interfaces <NUM>, <NUM> for processing an ECG-suitable signal and generating a Poincaré plot or map in a manner as described herein. The plot is generated in real-time, and synchronized with the delivered stimulation signal, so that the effects of the stimulation delivery can be rapidly assessed. Moreover, the plot is visually dynamic, showing change in the plot and the autonomic response in real-time. In some embodiments, the computer processing device <NUM> can 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 device <NUM> can be a specialized computer specifically designed and programmed to function with the neurostimulator <NUM> described herein.

The computer processing device <NUM> includes one or more associated displays <NUM> for displaying a Poincaré plot to show the autonomic response to the vagus nerve stimulation to the subject patient SP or assisting clinician. The display <NUM> can be a touch-sensitive display that can provide touch control buttons and keys. Shown in <FIG> is an embodiment of a computer-generated output to display <NUM>. In some embodiments, the computer-generated output shown in <FIG> is generated in a Windows® environment or similar operating system. The computer-generated output includes a graphical user interface ("GUI") <NUM> having one or more graphical user interface elements <NUM>, <NUM> and a graphical Poincaré plot <NUM>. The computer processing device <NUM> and its hardware includes and executes firmware programming that carries out the assessment methods and generation of output displays described herein. The methods and displays 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., system memory 56a and/or storage memory 56b of <FIG>) of the computer processing device <NUM> to carry out the signal processing, instrument access, assessment methods, GUI output, and plot generation described herein. An exemplary graphical program development environment in which to create a program for use in the system <NUM> includes Lab VIEW from National Instruments Corp.

<FIG> shows a detailed view of the Poincaré plot <NUM> and related GUI controls. The plot <NUM> provides a common grid in which two scatter plots of heart rate dynamics of the subject patient are provided. One scatter plot shows the heart dynamic response under a condition in which a stimulation signal is delivered to the vagus nerve. The other scatter plot shows the heart rate dynamics under a resting condition in which no stimulation is delivered to the vagus nerve. Heart rate dynamics are measured by heart rate variability, which looks at change in the R-R interval time between adj acent R-waves of the ECG signal response to the stimulation signal over time. Autonomic engagement is indicated by showing a change in the heart rate variability during the stimulation period as compared to the resting period.

An illustrative stimulation signal <NUM> is shown in <FIG>. The stimulation signal <NUM> is periodic and delivered in a cyclical manner in which each cycle has an ON-period <NUM>, in which stimulation of a particular current amplitude and frequency is delivered to the vagus nerve, and an OFF-period <NUM> of rest, in which no stimulation signal is delivered. The ON-period <NUM> occurs at a constant interval with the OFF-periods <NUM> of rest between the repeating ON-periods <NUM>. A treatment cycle can be defined by a combination of on and off times selected from the following exemplary ON-periods: <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, and <NUM> sec; and exemplary OFF-periods: <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, <NUM> sec, and <NUM> sec. For example, one exemplary treatment cycle is defined by a <NUM> second "on period" and a <NUM> second "off period. " A cycle of stimulation delivery is defined by a continuous series of ON-periods <NUM> and OFF-periods <NUM>. In one treatment, there are <NUM>-<NUM> cycles delivered to the subject patient.

Each ON-period <NUM> is defined by repeating pulse signals at a defined output current amplitude or intensity, signal frequency, and pulse width. In one exemplary ON-period <NUM>, the pulses signals are defined by an output current of up to <NUM> mA, a frequency of <NUM>-<NUM>, and a pulse width at <NUM>-<NUM> micro-seconds ("µsec"). Accordingly, each ON-period <NUM> is defined by an initiating pulse 306a and a terminating pulse 306b that are spaced apart over a time duration defining the ON-period <NUM>. The OFF-period <NUM> is thus defined by the time duration between a terminating pulse 306b of one ON-period <NUM> and the initiating pulse 306a of the subsequent ON-period <NUM>. Shown in <FIG> is another embodiment of a stimulation signal <NUM>', which includes a ramp up period 308a to the initiating pulse 306a and a ramp down period 308b from the terminating pulse 306b.

<FIG> is an illustrative ECG signal recorded over ON-periods <NUM> and OFF periods <NUM>. The ECG-suitable signal allows the determination and display of a periodic waveform with repeating "cardiac cycles. " 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 cardia 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. In the system <NUM>, the Poincaré plot <NUM> heart rate dynamics are determined from the R-R interbeat interval analysis in the ECG response signals. As examples, R-R interval <NUM> (for the ON-period <NUM>) and R-R interval <NUM> (for the OFF-period <NUM>) are shown in <FIG>.

Referring back to <FIG>, the system <NUM> determines and stores in one or more data arrays the R-R interval for each preceding R-R interval and stimulation status ON/OFF period for number of cycles in the stimulation treatment. Accordingly, the stored data array can be defined as {R-R Interval(N+<NUM>), R-R Interval(N), ON/OFF-period Status, # Cycle}. In the plot <NUM> of <FIG>, the R-R interval (e.g., R-R Interval(N+<NUM>)), found along the vertical axis <NUM> is plotted as a function of the preceding R-R interval (e.g. , R-R Interval(N)) found along the horizontal axis <NUM>. To distinguish between the two scatter plots, the R-R interval values for the ON-period and OFF-period are shown using differentiating markers. R-R interval values for the ON-period are shown with a first type of marker, such as, for example, a "+" marker <NUM>, and the OFF-period values are shown with a second type of marker different than the first type, such as, for example, an "O" marker <NUM>. Accordingly, for example, the first and second markers can respectively include non-circular markers and circular markers. The plot <NUM> provides a visual indication of autonomic engagement response to the stimulation 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.

The plot <NUM> shows a first best-fit circle <NUM> about a first group or aggregate of R-R interval ON-period data and a second best-fit circle <NUM> about a second group or aggregate of R-R interval OFF-period data. The best-fit circles <NUM>, <NUM> are defined by a radius about centroids <NUM>, <NUM>, which are determined by the respective means of the ON-period and OFF-period R-R interval data. The radii of the best fit circles <NUM>, <NUM> are calculated or defined by a minimum and maximum in the R-R interval values about the mean. In some embodiments, the 25th quartile and the 75th quartile of the R-R interval values are determined, and the mean of values falling between the 25th and the 75th quartiles is determined about which to determine the best fit circles. The gap G is defined as the straight line distance between the centroids <NUM>, <NUM> to indicate an extent of autonomic engagement. The gap G indicating autonomic engagement is may a horizontal gap ranging from <NUM>-<NUM> milliseconds (msec) as measured along the horizontal axis <NUM> of the plot <NUM>. It should be understood that autonomic engagement can be indicated by smaller or larger gap ranges provided a sufficient differential exists. Alternatively, the minimum R-R interval value is defined as <NUM>% below the mean, and the maximum R-R interval value is defined as <NUM>% above the mean. Thus, embodiments provide that the first and second group are aggregated as being within <NUM>%-<NUM>% of a common center. In another alternative, the best-fit circles <NUM>, <NUM> include or circumscribe each of the minimum and maximum values.

Shown in <FIG> are additional graphical indicators in a plot <NUM>' indicating heart rate variability response to the vagus nerves stimulation treatment. The computer processing device <NUM> of <FIG> can determine and aggregate the R-R interval data to the best fit ellipses <NUM>, <NUM> for 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 computer processing device <NUM> can determine each of the major axis SD2 and the minor axis SD1 for each of the ellipses <NUM>, <NUM>. In some embodiments, the minor axis SD1 is determined as reflecting the standard deviation of the instantaneous heart rates IHR about the mean and the major axis SD2 is determined as the standard deviation of the continuous heart rate about the mean. The major axis SD2 can be found by a best fit to the data with the axis SD2 passing through the centroid or mean <NUM>, <NUM> of the R-R interval. The minor axis SD1 extends transverse to the major axis SD2 and passes through the centroid <NUM>, <NUM>. Accordingly, the ellipse <NUM>, <NUM> is a best fit that is centered about the centroid <NUM>, <NUM>, respectively, and passes through the axes SD2, SD1 while encompassing the data disposed about the respective centroid <NUM>, <NUM>.

The computer processing device <NUM> of <FIG> can record, process, and maintain a history of ECG signals over several cycles of the stimulation signal and dynamically present the change in heart rate dynamics over the cycles of the stimulation signal. Thus, for example, the computer processing device <NUM> can record ECG-suitable signal data for a first cycle, including the ECG signal data during at least one stimulation delivery ON-period and at least one no stimulation delivery OFF-period, and the device <NUM> can record ECG-suitable signal data for a second cycle subsequent to the first cycle, in which the second cycle includes ECG signal data during at least one stimulation delivery ON-period and at least one no stimulation delivery OFF-period. From the data for the first and second cycles, the computer processing device <NUM> can determine R-R interval data for each of the first and second cycles. The Poincaré plot <NUM> displays the R-R interval data of the first and second cycles and indicates that the data of the first cycle is older than the data of the second cycle. In one aspect, the Poincaré plot can be configured to shows the aging of cycle data by variation in brightness of the data as it appears in the plot <NUM>. For example, as seen in <FIG>, R-R interval data of the latest cycle 906a can be shown at a brightness level that is greater than that of the brightness level R-R interval data of an earlier cycle 906b. Moreover, as R-R interval data of a cycle ages it can eventually fade or be deleted from the plot <NUM> altogether. The plot <NUM> shown on the display <NUM> can include additional historical indicators such as, for example, a cycle counter <NUM> and a running clock <NUM> showing the running time of the Poincaré plot from the time of the first recorded data to the latest.

The interface assembly <NUM> can continuously read the ECG signal response of the patient. However, in some embodiments, recordation of the signal for plotting by the computer processing device <NUM> is not continuous and can instead be controlled by the patient or clinician. Accordingly, as seen in <FIG>, a GUI of the output display <NUM> is provided to control generation and viewing of the Poincaré plot <NUM>. For example, the display may include a toggle switch <NUM> to initiate recording of the ECG data and generation of the map or plot <NUM>. Moreover, the toggle switch <NUM> can also pause or stop the plot generation and recordation of the data. The GUI <NUM> may further includes scroll controls <NUM> to scroll the view of the Poincaré plot <NUM>. The scroll controls <NUM> provide zoom control to define a visible range of the R-R intervals over which to view the plot. For example, the scroll controls <NUM> can define the range of the horizontal axis of the plot <NUM>.

Shown in <FIG> is another schematic view of the system <NUM> with the computer processing device <NUM> for assessing a vagus nerve stimulation treatment, according to an exemplary embodiment. The computer processing device <NUM> includes processing hardware <NUM>, such as, for example, a central processing unit <NUM> and associated memory or computer readable medium, such as, for example, system memory 56a and storage memory 56b, for storing and processing ECG-suitable signals in a manner as described herein. The system memory 56a can include volatile memory, such as, for example, RAM (random-access memory). The storage memory 56b can 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 device <NUM> operates 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 hardware <NUM> stores a program that can cause the computer processing device <NUM> to execute one or more processes described herein for assessing vagus nerve stimulation treatment. The hardware <NUM> includes and executes firmware programming that provides for an R-R interval detector <NUM> and an ECG processor <NUM> for carrying out the assessment methods and displaying the assessment as described herein. The R-R interval detector <NUM> and the ECG processor <NUM> and the associated methods can be implemented using appropriate software programming, such as, for example, an appropriate graphical program as previously described.

As shown, the processing hardware <NUM> and the display <NUM> communicate with one another over a communication bus or network <NUM>. Additionally or alternatively, the computer processing device <NUM> can 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 device <NUM> can be integrated with one another or be separately housed components. For example, the processing hardware <NUM> can be housed separately from the display <NUM>. Alternatively, the display <NUM> can be housed with the processing hardware <NUM> in a single assembly.

Referring back to <FIG>, in the system <NUM>, the computer processing device <NUM> is coupled to each of the first and second interface communication assemblies <NUM>, <NUM> by a data acquisition system <NUM>. The data acquisition system <NUM> provides for digital conversion of incoming signals coming from the interface communication assemblies <NUM>, <NUM> (e.g., a wand assembly <NUM>, ECG sensor assembly <NUM>). The data acquisition system <NUM>, the processing hardware <NUM>, and the display <NUM> communicate with one another over a communication bus or network <NUM> (e.g., as shown in <FIG>). In some embodiments, the data acquisition system <NUM> for use in the system <NUM> is 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 data acquisition system are different systems (e.g., shown as computer processing device <NUM> and data acquisition system <NUM> in <FIG>), while in other embodiments, the computer processing device and data acquisition system are incorporated into a single system (e.g., shown as computer processing device <NUM>' in <FIG>).

In the system <NUM>, the communication assembly <NUM> wirelessly communicates with the neurostimulator <NUM> by providing control signals or commands to define parameters of the stimulation signal or pulses to be delivered by the neurostimulator <NUM> to the vagus nerve <NUM>. In some embodiments, the communication assembly <NUM> includes an external programming wand <NUM> and a wand transmission detection cable <NUM>. The programming wand <NUM> wirelessly communicates with the implanted device <NUM> by telemetry or radio frequency ("RF") signal. Embodiments of the external programming wand <NUM> are described, for example, in <CIT> and <CIT>. A commercially available embodiment of the wand <NUM> includes NeuroCybernetic Prosthesis (NCP®) Programming Wand Model <NUM>. The wand <NUM> is a hand-held device that can transmit programming and interrogation information signals or commands to the implantable neurostimulator <NUM>, such as, for example, the VITARIA™ Model <NUM> Pulse Generator. The programming wand <NUM>, alone 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 generator <NUM>.

The wand transmission detection cable <NUM> is associated with the external programmer or wand <NUM> to detect or determine the stimulation delivery from the neurostimulator <NUM> to the vagus nerve of the subject patient SP. In some embodiments, the detection cable <NUM> detects or extracts the delivery schedule from the external wand <NUM> to determine the stimulation delivery from the neurostimulator <NUM> to the vagus nerve <NUM>. By detecting delivery of stimulation signal with the communication assembly <NUM>, the capture or recording of the subject's ECG signal response can be synchronized with the ON-period and OFF-period of the stimulation signal in accordance with the processes for capturing and analyzing the ECG-suitable signal described herein.

In some implementations, the second interface assembly <NUM> is embodied as an ECG cable assembly with three leads or clips 32a, 32b, 320c for respectively connecting to three electrodes or contacts, for example, placed on the wrists of the subject patient SP. As seen in <FIG>, two leads 32a, 32b are connected to two electrodes on the left wrist, and the remaining lead 32c is connected to a single electrode on the patient's right wrist.

Shown in <FIG> is a method of using the system <NUM> in which a Poincaré plot provides an indication or assessment of autonomic response to vagus nerve stimulation in congestive heart failure treatment of a subject patient. In one embodiment of the system <NUM> and its operation <NUM>, the system <NUM> processes the ECG-suitable signal response to determine the ECG waveform and the R-R intervals of the ECG signal response to derive heart rate dynamics in assessment of the stimulus treatment. Moreover, the system <NUM> distinguishes or identifies which portions of the ECG signal or waveform response correspond to the delivery of stimulation signal (e.g., over the ON-period of the periodic stimulation signal) and which portions of the ECG signal or waveform response correspond to the rest period of the stimulation signal (e.g., over the OFF-periods of the periodic stimulation signal). By segregating ECG signals or portions of the ECG waveform and their derivative components by ON-period and OFF-period, the ECG signals/waveforms and the heart rate dynamics derived therefrom are visually compared in a Poincaré plot to assess the extent of autonomic engagement resulting the delivered stimulation signal.

At a beginning <NUM> of a titration or stimulation delivery process, the periodic stimulation signal is delivered from the neurostimulator <NUM> to the vagus nerve. During the ON-period of the stimulus delivery (step <NUM>), a recordation step <NUM> is carried out in which the ECG response signal is captured and recorded over the ON-period. During the OFF-period of the stimulation signal (step <NUM>), the ECG response signal is captured and recorded at step <NUM>. Having captured and identified the ECG signals corresponding to each of the ON-period and OFF-period in the stimulation signal, a determination step <NUM> is carried out to determine the heart rate dynamics and, in particular, heart rate variability for the ON- and OFF-periods. The difference in heart rate dynamics between the ON- and OFF-periods of the stimulation signal is displayed in step <NUM>, for example, in the Poincaré plot. The process then concludes with a determination step <NUM> in which the autonomic engagement response is assessed and determined from the separation between the heart rate dynamics for the ON- and OFF-periods.

Referring again to <FIG>, the ECG processor <NUM> includes a heart rate variability calculator that works with the R-R interval detector <NUM> to determine heart rate dynamics in the determination step <NUM> of the assessment process <NUM>. In an aspect, the storage memory 56b, in coordination with the R-R interval detector <NUM> and ECG processor <NUM>, stores in one or more data arrays the R-R interval for each proceeding R-R interval and stimulation status ON/OFF period for number of cycles in the stimulation treatment. Accordingly, the stored data array, as previously described, can be defined as {R-R Interval(N+<NUM>), R-R Interval(N), ON/OFF-period Status, # Cycle}. In this way, the data can be aggregated and mapped to the Poincaré plot for each cycle in a manner that differentiates the ON-period of stimulation signal delivery and the OFF-period of signal rest.

Shown in <FIG> is an embodiment of the assessment process <NUM>. With the subject patient SP connected to the system <NUM>, as shown in <FIG>, and the implanted neurostimulator medical device <NUM> delivering a stimulation signal to the vagus nerve of the patient, the process of assessment <NUM> begins with a determination step <NUM> to determine the start of stimulation delivery for synchronizing recordation of the cardiac response. In some embodiments, the programming wand <NUM> is placed in communication with the neurostimulator <NUM>, and the wand transmission detection cable <NUM> in combination with the computer processing device <NUM> detects the inductive telemetry signal between the components (step <NUM>). The computer processing device <NUM> processes the inductive telemetry signals to determine the stimulation ON-period (step <NUM>) and determine the stimulation OFF-period (step <NUM>). Additionally, in some embodiments, the computer processing device <NUM> captures 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 step <NUM>, the computer processing device <NUM> synchronizes sampling of the ECG-suitable signal with the ON-period of the delivered stimulation signal (e.g., such that the ECG signal is continuously recorded).

With the start of ECG signal recording synchronized with the stimulation signal, the ECG response signal is continuously sampled at step <NUM> by the digital acquisition system <NUM> and the computer processing device <NUM>. For example, the ECG-suitable signal is sampled at a rate of <NUM> 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 step <NUM>, 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.

In an aspect of the assessment method <NUM>, the ECG waveform response or equivalent is analyzed to determine the QRS complex and R-R intervals of the response signal (steps <NUM>, <NUM>). From the R-R intervals, the heart rate variability is determined at step <NUM> and is graphically displayed in a Poincaré plot at step <NUM>. More particularly, the R-R interval differential between the ON-period and OFF-period is displayed in a Poincaré plot <NUM> as illustrated in <FIG> or <FIG>. In step <NUM> of the process <NUM>, the R-R intervals for the ON-period and OFF-period are mapped in a distinguishing manner from one another by differentiating markers. Additionally, the data can be mapped and aggregated in steps <NUM>, <NUM>, <NUM>, <NUM> in a manner as shown and previously described with respect to <FIG> and <FIG>.

Referring again to the display <NUM> in <FIG>, additional visual indicators can be provided to indicate the autonomic response of the subject patient. For example, the display can include an indicator for any one of the following: heart rate, mean heart rate for OFF-periods of the stimulation signal, mean heart rate for ON-periods of the stimulation signal, and heart rate reduction. Heart rate reduction is defined as the difference between ON-period mean heart rate and OFF-period mean heart rate when stimulus is delivered to the subject. Moreover, given the storage and recordation of stimulation cycles, the display <NUM> and the computer processing device <NUM> can provide a display of historical heart rate dynamic parameters, including mean heart rates over the various periods of the stimulation signal. Additionally, the display <NUM> can show information regarding the stimulation signal itself, such as, for example, at least one of the following parameters: current amplitude, current frequency, pulse width, duty cycle, and/or an indicator indicating when a stimulus is being delivered to the subject patient.

Claim 1:
A system (<NUM>) for real-time assessment of vagus nerve stimulation for congestive heart failure treatment, the system comprising:
a display (<NUM>);
a vagus nerve stimulation, VNS, device (<NUM>) configured to deliver a vagus nerve stimulation signal for congestive heart failure treatment, the stimulation signal having an ON-period status in which a stimulus is being delivered to a subject and an OFF-period status in which no stimulus is being delivered to the subject;
a processor (<NUM>) and a non-transitory computer readable memory (56b) storing instructions that, when executed by the processor (<NUM>), cause the system (<NUM>) to:
synchronously record a first ECG profile of the subject during the ON-period status of the VNS device (<NUM>) and synchronously record a second ECG profile of the subject during the OFF-period status of the VNS device (<NUM>);
determine real-time heart rate dynamics from the first and second ECG profiles, the real-time heart rate dynamics including a plurality of R-R intervals in each ECG profile;
generate display data, configured to be displayed on the display (<NUM>), comprising the R-R intervals for each of the first and second ECG profiles to indicate real-time heart rate variability and real-time autonomic engagement, shown by a change in the real-time heart rate variability, in response to the vagus nerve stimulation signal during the ON-period status and OFF-period status of the VNS device (<NUM>), wherein the display data includes the R-R intervals in a dynamic, real-time Poincaré plot; and
transmit the display data to the display (<NUM>).