Patent Publication Number: US-2023146182-A1

Title: Evaluation of vagus nerve stimulation using heart rate variability analysis

Description:
CROSS REFERENCE TO RELATED PATENT APPLICATION 
     This application is a continuation of U.S. patent application Ser. No. 16/422,746, entitled “EVALUATION OF VAGUS NERVE STIMULATION USING HEART RATE VARIABILITY ANALYSIS,” filed May 24, 2019, which claims priority to U.S. Provisional Patent Application No. 62/676,883, entitled “EVALUATION OF VAGUS NERVE STIMULATION USING HEART RATE VARIABILITY ANALYSIS,” filed May 25, 2018, each of which is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND 
     The present disclosure relates generally to neurostimulation and, more specifically, to improved systems and methods for managing titration of stimulation. 
     Chronic heart failure (CHF) and other forms of chronic cardiac dysfunction (CCD) may be related to an autonomic imbalance of the sympathetic and parasympathetic nervous systems that, if left untreated, can lead to cardiac arrhythmogenesis, progressively worsening cardiac function and eventual patient death. CHF is pathologically characterized by an elevated neuroexitatory state and is accompanied by physiological indications of impaired arterial and cardiopulmonary baroreflex function with reduced vagal activity. 
     CHF triggers compensatory activations of the sympathoadrenal (sympathetic) nervous system and the renin-angiotensin-aldosterone hormonal system, which initially helps to compensate for deteriorating heart-pumping function, yet, over time, can promote progressive left ventricular dysfunction and deleterious cardiac remodeling. Patients suffering from CHF are at increased risk of tachyarrhythmias, such as atrial fibrillation (AF), ventricular tachyarrhythmias (ventricular tachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter, particularly when the underlying morbidity is a form of coronary artery disease, cardiomyopathy, mitral valve prolapse, or other valvular heart disease. Sympathoadrenal activation also significantly increases the risk and severity of tachyarrhythmias due to neuronal action of the sympathetic nerve fibers in, on, or around the heart and through the release of epinephrine (adrenaline), which can exacerbate an already-elevated heart rate. 
     The standard of care for managing CCD in general continues to evolve. For instance, new therapeutic approaches that employ electrical stimulation of neural structures that directly address the underlying cardiac autonomic nervous system imbalance and dysregulation have been proposed. In one form, controlled stimulation of the cervical vagus nerve beneficially modulates cardiovascular regulatory function. Vagus nerve stimulation (VNS) has been used for the clinical treatment of drug-refractory epilepsy and depression, and more recently has been proposed as a therapeutic treatment of heart conditions such as CHF. 
     VNS therapy commonly requires implantation of a neurostimulator, a surgical procedure requiring several weeks of recovery before the neurostimulator can be activated and a patient can start receiving VNS therapy. Even after the recovery 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 a 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&#39;s tolerance threshold, or tolerance zone boundary, gradually increases, allowing for an increase in intensity during subsequent titration sessions. The titration process can take significantly longer in practice because the increase in intensity is generally performed by a physician or other healthcare provider, and thus, for every step in the titration process to take place, the patient has to visit the provider&#39;s office to have the titration adjustments performed. Scheduling conflicts in the provider&#39;s office may increase the time between titration sessions, thereby extending the overall titration process, during which the patient in need of VNS does not receive the VNS at the full therapeutic intensity. 
     For patients receiving VNS therapy for the treatment of epilepsy, a titration process that continues over an extended period of time, such as six to twelve months, may be somewhat acceptable because the patient&#39;s health condition typically would not worsen in that period of time. However, for patients being treated for other health conditions, such as CHF, the patient&#39;s condition may degrade rapidly if left untreated. As a result, there is a much greater urgency to completing the VNS titration process when treating a patient with a time-sensitive condition, such as CHF. 
     Accordingly, a need remains for an approach to efficiently titrate neurostimulation therapy for treating chronic cardiac dysfunction and other conditions while minimizing side effects and related discomfort caused by the titration or by the VNS therapy itself. 
     SUMMARY 
     Systems and methods are provided for delivering neurostimulation therapies to patients. A titration process is used to gradually increase the stimulation intensity to a desired therapeutic level. This titration process can minimize the amount of time required to complete titration so as to begin delivery of the stimulation at therapeutically desirable levels. 
     According to one embodiment an implantable vagus nerve stimulation (VNS) system includes a sensor configured to measure ECG data for a patient, a stimulation subsystem configured to deliver VNS to the patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended, and a control system configured to perform a heart rate variability analysis with the ECG data. Performing the heart rate variability analysis with the ECG data includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately preceding R-R interval for each of the stimulation period and the baseline period. In some embodiments, performing the heart rate variability analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. 
     According to another embodiment a vagus nerve stimulation (VNS) system includes an external programmer and an implantable system. The implantable system includes a sensor configured to measure ECG data for a patient and transmit the measured ECG to the external programmer and a stimulation subsystem configured to deliver VNS to a patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended. The external programmer is configured to receive the measured ECG from the implantable system and perform a heart rate variability analysis with the ECG data. The heart rate variability analysis includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately preceding R-R interval for each of the stimulation period and the baseline period. In some embodiments, the heart rate variability analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. In some embodiments, the implantable system further includes a control system configured to control the stimulation subsystem to increase the VNS dose delivered to the patient according to a titration schedule. 
     According to another embodiment a vagus nerve stimulation (VNS) system includes a local telemetry device and an implantable system. The implantable system includes a sensor configured to measure ECG data for a patient and transmit the measured ECG to the local telemetry device and a stimulation subsystem configured to deliver VNS to the patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended. The local telemetry device is configured to receive the ECG data from the implantable system and perform a heart rate variability analysis with the ECG data. Performing the heart rate variability analysis includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately preceding R-R interval for each of the stimulation period and the baseline period. In some embodiments, performing the heart rate variability analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. More particularly, in some embodiments, performing the heart rate variability analysis includes determining the centroid of the stimulation period plot and the baseline period plot, and the local telemetry device is further configured to determine a distance between the centroids of the stimulation period plot and the baseline period plot and compare the distance to a threshold value. In some embodiments, the local telemetry device is further configured to, in response to the distance being less than the threshold value, send an alert to a physician of the patient or transmit a command to the implantable system to increase an intensity of the VNS dose applied to the patient. In some embodiments, the implantable system further includes a control system configured to increase the VNS dose delivered to the patient according to a titration schedule. Additionally, in some embodiments, the local telemetry device is configured to perform the heart rate variability analysis in response to an increase in the VNS dose. 
     According to another embodiment an implantable vagus nerve stimulation (VNS) system includes a sensor configured to measure ECG data for a patient, a stimulation subsystem configured to deliver VNS to the patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended, and a control system configured to perform a Poincaré analysis with the ECG data. Performing the Poincaré analysis includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately successive R-R interval for each of the stimulation period and the baseline period. In some embodiments, performing the Poincaré analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. 
     In some embodiments, the control system is further configured to perform the Poincaré analysis by determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. More particularly, in some embodiments, performing the Poincaré analysis includes determining the centroid of each of the stimulation period plot and the baseline period plot, and the control system is further configured to determine a distance between the centroids of the stimulation period plot and the baseline period plot and compare the distance to a threshold value. In some embodiments, the control system is further configured to, in response to the distance being less than the threshold value, perform at least one of sending an alert to a physician of the patient or modifying an intensity of the VNS dose applied to the patient. In some embodiments, the control system is further configured to control the stimulation subsystem to increase the VNS dose delivered to the patient according to a titration schedule. Additionally, in some embodiments, the control system is configured to perform the Poincaré analysis in response to an increase in the VNS dose. In some embodiments, the control system is configured to perform the Poincaré analysis periodically. Additionally, in some embodiments, the control system is configured to prepare periodic reports for a physician of the patient based on the Poincaré analysis. 
     According to another embodiment a vagus nerve stimulation (VNS) system includes an external programmer and an implantable system. The implantable system includes a sensor configured to measure ECG data for a patient and transmit the ECG data to the external programmer and a stimulation subsystem configured to deliver VNS to a patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended. The external programmer is configured to receive the ECG data from the implantable system and perform a Poincaré analysis with the ECG data. The Poincaré analysis includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately successive R-R interval for each of the stimulation period and the baseline period. In some embodiments, the Poincaré analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. 
     In some embodiments, the external programmer is further configured to perform the Poincaré analysis by determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. More particularly, in some embodiments, performing the Poincaré analysis includes determining the centroid of each of the stimulation period plot and the baseline period plot, and the external programmer is further configured to determine a distance between the centroids of the stimulation period plot and the baseline period plot and compare the distance to a threshold value. In some embodiments, the external programmer is further configured to, in response to the distance being less than the threshold value, display an alert or transmit a command to the implantable system to increase an intensity of the VNS dose applied to the patient. In some embodiments, the implantable system further includes a control system configured to control the stimulation subsystem to increase the VNS dose delivered to the patient according to a titration schedule. In some embodiments, the external programmer is further configured to display the stimulation period plot and the baseline period plot. In some embodiments, the sensor is configured to transmit the ECG data to the external programmer in real-time, and the external programmer is configured to receive the ECG data from the implantable system and perform the Poincaré analysis in real-time. 
     According to another embodiment a vagus nerve stimulation (VNS) system includes a local telemetry device and an implantable system. The implantable system includes a sensor configured to measure ECG data for a patient and transmit the ECG data to the local telemetry device and a stimulation subsystem configured to deliver VNS to the patient, wherein the VNS is delivered according to a duty cycle comprising an ON period during which a VNS dose is applied and an OFF period during which the VNS dose is suspended. The local telemetry device is configured to receive the ECG data from the implantable system and perform a Poincaré analysis with the ECG data. Performing the Poincaré analysis includes measuring R-R intervals between successive R-waves for the ECG data measured during at least a portion of the ON period and at least a portion of the OFF period, wherein the at least a portion of the ON period is a stimulation period and the at least a portion of the OFF period is a baseline period, and plotting each R-R interval against an immediately preceding R-R interval for each of the stimulation period and the baseline period. In some embodiments, performing the Poincaré analysis further includes determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. 
     In some embodiments, the local telemetry device is further configured to perform the Poincaré analysis by determining, based on the plot, at least one of a standard deviation from an axis of a line perpendicular to an identity line for each of the stimulation period plot and the baseline period plot or a centroid of each of the stimulation period plot and the baseline period plot. More particularly, in some embodiments, performing the Poincaré analysis includes determining the centroid of the stimulation period plot and the baseline period plot, and the local telemetry device is further configured to determine a distance between the centroids of the stimulation period plot and the baseline period plot and compare the distance to a threshold value. In some embodiments, the local telemetry device is further configured to, in response to the distance being less than the threshold value, send an alert to a physician of the patient or transmit a command to the implantable system to increase an intensity of the VNS dose applied to the patient. In some embodiments, the implantable system further includes a control system configured to increase the VNS dose delivered to the patient according to a titration schedule. Additionally, in some embodiments, the local telemetry device is configured to perform the Poincaré analysis in response to an increase in the VNS dose. In some embodiments, the local telemetry device is configured to perform the Poincaré analysis periodically. Additionally, in some embodiments, the local telemetry device is configured to prepare periodic reports for a physician of the patient based on the periodic Poincaré analysis. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a front anatomical diagram showing, by way of example, placement of an implantable vagus stimulation device in a male patient, in accordance with one embodiment. 
         FIGS.  2 A and  2 B  are diagrams respectively showing the implantable neurostimulator and the stimulation therapy lead of  FIG.  1   , according to an exemplary embodiment. 
         FIG.  3    is a diagram showing an external programmer for use with the implantable neurostimulator of  FIG.  1   , according to an exemplary embodiment. 
         FIG.  4    is a diagram showing electrodes provided as on the stimulation therapy lead of  FIG.  2    in place on a vagus nerve in situ, according to an exemplary embodiment. 
         FIG.  5    is a flowchart of a method for delivering vagus nerve stimulation therapy, according to an exemplary embodiment. 
         FIGS.  6 A and  6 B  are flowcharts of a titration process, according to an exemplary embodiment. 
         FIGS.  7 A and  7 B  are block diagrams of neurostimulation systems, according to an exemplary embodiment. 
         FIG.  8    is a diagram showing an example of a heart rate variability plot, according to an exemplary embodiment. 
         FIG.  9    is a diagram showing timing of an example of a heart rate variability analysis with respect to the timing of VNS stimulation, according to an exemplary embodiment. 
         FIG.  10    is a diagram showing another example of a heart rate variability plot, according to an exemplary embodiment. 
         FIG.  11    is a flowchart of a process of using an example heart rate variability analysis during neurostimulation therapy titration, according to an exemplary embodiment. 
     
    
    
     DETAILED DESCRIPTION 
     Various aspects of the disclosure will now be described with regard to certain examples and embodiments, which are intended to illustrate but not to limit the disclosure. Nothing in this disclosure is intended to imply that any particular feature or characteristic of the disclosed embodiments is essential. The scope of protection is defined by the claims that follow this description and not by any particular embodiment described herein. Before turning to the figures, which illustrate example embodiments in detail, it should be understood that the application is not limited to the details or methodology set forth in the description or illustrated in the figures. It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting. 
     CHF and other cardiovascular diseases cause derangement of autonomic control of the cardiovascular system, favoring increased sympathetic and decreased parasympathetic central outflow. These changes are accompanied by elevation of basal heart rate arising from chronic sympathetic hyperactivation along the neurocardiac axis. 
     The vagus nerve is a diverse nerve trunk that contains both sympathetic and parasympathetic fibers, and both afferent and efferent fibers. These fibers have different diameters and myelination, and subsequently have different activation thresholds. This results in a graded response as intensity is increased. Low intensity stimulation results in a progressively greater tachycardia, which then diminishes and is replaced with a progressively greater bradycardia response as intensity is further increased. Peripheral neurostimulation therapies that target the fluctuations of the autonomic nervous system have been shown to improve clinical outcomes in some patients. Specifically, autonomic regulation therapy results in simultaneous creation and propagation of efferent and afferent action potentials within nerve fibers comprising the cervical vagus nerve. The therapy directly improves autonomic balance by engaging both medullary and cardiovascular reflex control components of the autonomic nervous system. Upon stimulation of the cervical vagus nerve, action potentials propagate away from the stimulation site in two directions, efferently toward the heart and afferently toward the brain. Efferent action potentials influence the intrinsic cardiac nervous system and the heart and other organ systems, while afferent action potentials influence central elements of the nervous system. 
     An implantable vagus nerve stimulator, such as used to treat drug-refractory epilepsy and depression, can be adapted for use in managing chronic cardiac dysfunction (CCD) through therapeutic bi-directional vagus nerve stimulation.  FIG.  1    is a front anatomical diagram showing, by way of example, placement of an implantable medical device (e.g., a vagus nerve stimulation (VNS) system  11 , as shown in  FIG.  1   ) in a male patient  10 , according to an exemplary embodiment. The VNS provided through the stimulation system  11  operates under several mechanisms of action. These mechanisms include increasing parasympathetic outflow and inhibiting sympathetic effects by inhibiting norepinephrine release and adrenergic receptor activation. More importantly, VNS triggers the release of the endogenous neurotransmitter acetylcholine and other peptidergic substances into the synaptic cleft, which has several beneficial anti-arrhythmic, anti-apoptotic, and anti-inflammatory effects as well as beneficial effects at the level of the central nervous system. 
     The implantable vagus stimulation system  11  comprises an implantable neurostimulator or pulse generator  12  and a stimulating nerve electrode assembly  125 . The neurostimulator or pulse generator may be a voltage stimulator or, more preferably, a current stimulator. The stimulating nerve electrode assembly  125 , comprising at least an electrode pair, is conductively connected to the distal end of an insulated, electrically conductive lead assembly  13  and electrodes  14 . The electrodes  14  may be provided in a variety of forms, such as, e.g., helical electrodes, probe electrodes, cuff electrodes, as well as other types of electrodes. 
     The implantable vagus stimulation system  11  can be remotely accessed following implant through an external programmer, such as the programmer  40  shown in  FIG.  3    and described in further detail below. The programmer  40  can be used by healthcare professionals to check and program the neurostimulator  12  after implantation in the patient  10  and to adjust stimulation parameters during the stimulation titration process. In some embodiments, an external magnet may provide basic controls. For example, an electromagnetic controller may enable the patient  10  or healthcare professional to interact with the implanted neurostimulator  12  to exercise increased control over therapy delivery and suspension. For further example, an external programmer may communicate with the neurostimulation system  11  via other wired or wireless communication methods, such as, e.g., wireless RF transmission. Together, the implantable vagus stimulation system  11  and one or more of the external components form a VNS therapeutic delivery system. 
     The neurostimulator  12  is typically implanted in the patient&#39;s right or left pectoral region generally on the same side (ipsilateral) as the vagus nerve  15 ,  16  to be stimulated, although other neurostimulator-vagus nerve configurations, including contra-lateral and bi-lateral are possible. A vagus nerve typically comprises two branches that extend from the brain stem respectively down the left side and right side of the patient, as seen in  FIG.  1   . The electrodes  14  are generally implanted on the vagus nerve  15 ,  16  about halfway between the clavicle  19   a - b  and the mastoid process. The electrodes may be implanted on either the left or right side. The lead assembly  13  and electrodes  14  are implanted by first exposing the carotid sheath and chosen branch of the vagus nerve  15 ,  16  through a latero-cervical incision (perpendicular to the long axis of the spine) on the ipsilateral side of the patient&#39;s neck  18 . The helical electrodes  14  are then placed onto the exposed nerve sheath and tethered. A subcutaneous tunnel is formed between the respective implantation sites of the neurostimulator  12  and helical electrodes  14 , through which the lead assembly  13  is guided to the neurostimulator  12  and securely connected. Additionally, in various embodiments, the neurostimulator  12  connects to the electrodes  14  as shown in  FIG.  4    (e.g., at the top helices). 
     In one embodiment, the neural stimulation is provided as a low level maintenance dose independent of cardiac cycle. The stimulation system  11  bi-directionally stimulates either the left vagus nerve  15  or the right vagus nerve  16 . However, it is contemplated that multiple electrodes  14  and multiple leads  13  could be utilized to stimulate simultaneously, alternatively or in other various combinations. Stimulation may be through multimodal application of continuously-cycling, intermittent and periodic electrical stimuli, which are parametrically defined through stored stimulation parameters and timing cycles. Both sympathetic and parasympathetic nerve fibers in the vagosympathetic complex are stimulated. Generally, cervical vagus nerve stimulation results in propagation of action potentials from the site of stimulation in a bi-directional manner. The application of bi-directional propagation in both afferent and efferent directions of action potentials within neuronal fibers comprising the cervical vagus nerve improves cardiac autonomic balance. Afferent action potentials propagate toward the parasympathetic nervous system&#39;s origin in the medulla in the nucleus ambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, as well as towards the sympathetic nervous system&#39;s origin in the intermediolateral cell column of the spinal cord. Efferent action potentials propagate toward the heart  17  to activate the components of the heart&#39;s intrinsic nervous system. Either the left or right vagus nerve  15 ,  16  can be stimulated by the stimulation system  11 . The right vagus nerve  16  has a moderately lower (approximately 30%) stimulation threshold than the left vagus nerve  15  for heart rate effects at the same stimulation frequency and pulse width. 
     The VNS therapy is delivered autonomously to the patient&#39;s vagus nerve  15 ,  16  through three implanted components that include a neurostimulator  12 , lead assembly  13 , and electrodes  14 .  FIGS.  2 A and  2 B  are diagrams respectively showing the implantable neurostimulator  12  and the stimulation lead assembly  13  of  FIG.  1   . In one embodiment, the neurostimulator  12  can be adapted from a VNS Therapy Demipulse Model 103 or AspireSR Model 106 pulse generator, manufactured and sold by Cyberonics, Inc., Houston, Tex., although other manufactures and types of implantable VNS neurostimulators could also be used. The stimulation lead assembly  13  and electrodes  14  are generally fabricated as a combined assembly and can be adapted from a Model 302 lead, PerenniaDURA Model 303 lead, or PerenniaFLEX Model 304 lead, also manufactured and sold by Cyberonics, Inc., in three sizes based, for example, on a helical electrode inner diameter, although other manufactures and types of single-pin receptacle-compatible therapy leads and electrodes could also be used. 
     Referring first to  FIG.  2 A , the system  20  may be configured to provide multimodal vagus nerve stimulation. In a maintenance mode, the neurostimulator  12  is parametrically programmed to deliver continuously-cycling, intermittent and periodic ON-OFF cycles of VNS. Such delivery produces action potentials in the underlying nerves that propagate bi-directionally, both afferently and efferently. 
     The neurostimulator  12  includes an electrical pulse generator that is tuned to improve autonomic regulatory function by triggering action potentials that propagate both afferently and efferently within the vagus nerve  15 ,  16 . The neurostimulator  12  is enclosed in a hermetically sealed housing  21  constructed of a biocompatible material, such as titanium. The housing  21  contains electronic circuitry  22  powered by a battery  23 , such as a lithium carbon monofluoride primary battery or a rechargeable secondary cell battery. The electronic circuitry  22  may be implemented using complementary metal oxide semiconductor integrated circuits that include a microprocessor controller that executes a control program according to stored stimulation parameters and timing cycles; a voltage regulator that regulates system power; logic and control circuitry, including a recordable memory  29  within which the stimulation parameters are stored, that controls overall pulse generator function, receives and implements programming commands from the external programmer, or other external source, collects and stores telemetry information, processes sensory input, and controls scheduled and sensory-based therapy outputs; a transceiver that remotely communicates with the external programmer using radio frequency signals; an antenna, which receives programming instructions and transmits the telemetry information to the external programmer; and a reed switch  30  that provides remote access to the operation of the neurostimulator  12  using an external programmer, a simple patient magnet, or an electromagnetic controller. The recordable memory  29  can include both volatile (dynamic) and non-volatile/persistent (static) forms of memory, within which the stimulation parameters and timing cycles can be stored. Other electronic circuitry and components are possible. 
     The neurostimulator  12  includes a header  24  to securely receive and connect to the lead assembly  13 . In one embodiment, the header  24  encloses a receptacle  25  into which a single pin for the lead assembly  13  can be received, although two or more receptacles could also be provided, along with the corresponding electronic circuitry  22 . The header  24  may internally include a lead connector block (not shown), a setscrew, and a spring contact (not shown) that electrically connects to the lead ring, thus completing an electrical circuit. 
     In some embodiments, the housing  21  may also contain a heart rate sensor  31  that is electrically interfaced with the logic and control circuitry, which receives the patient&#39;s sensed heart rate as sensory inputs. The heart rate sensor  31  monitors heart rate using an ECG-type electrode. Through the electrode, the patient&#39;s heart beat can be sensed by detecting ventricular depolarization. In a further embodiment, a plurality of electrodes can be used to sense voltage differentials between electrode pairs, which can undergo signal processing for cardiac physiological measures, for instance, detection of the P-wave, QRS complex, and T-wave. The heart rate sensor  31  provides the sensed heart rate to the control and logic circuitry as sensory inputs that can be used to determine the onset or presence of arrhythmias, particularly VT, and/or to monitor and record changes in the patient&#39;s heart rate over time or in response to applied stimulation signals. 
     Referring next to  FIG.  2 B , the lead assembly  13  delivers an electrical signal from the neurostimulator  12  to the vagus nerve  15 ,  16  via the electrodes  14 . On a proximal end, the lead assembly  13  has a lead connector  27  that transitions an insulated electrical lead body to a metal connector pin  28  with a metal connector ring. During implantation, the connector pin  28  is guided through the receptacle  25  into the header  24  and securely fastened in place using the setscrew (not shown) to electrically couple one electrode of the lead assembly  13  to the neurostimulator  12  while a spring contact (not shown) makes electrical contact to the ring connected to the other electrode. On a distal end, the lead assembly  13  terminates with the electrode  14 , which bifurcates into a pair of anodic and cathodic electrodes  62  (as further described infra with reference to  FIG.  4   ). In one embodiment, the lead connector  27  is manufactured using silicone and the connector pin  28  and ring are made of stainless steel, although other suitable materials could be used, as well. The insulated lead body  13  utilizes a silicone-insulated alloy conductor material. 
     In some embodiments, the electrodes  14  are helical and placed around the cervical vagus nerve  15 ,  16  at the location below where the superior and inferior cardiac branches separate from the cervical vagus nerve. In alternative embodiments, the helical electrodes may be placed at a location above where one or both of the superior and inferior cardiac branches separate from the cervical vagus nerve. In one embodiment, the helical electrodes  14  are positioned around the patient&#39;s vagus nerve oriented with the end of the helical electrodes  14  facing the patient&#39;s head. In an alternate embodiment, the helical electrodes  14  are positioned around the patient&#39;s vagus nerve  15 ,  16  oriented with the end of the helical electrodes  14  facing the patient&#39;s heart  17 . At the distal end, the insulated electrical lead body  13  is bifurcated into a pair of lead bodies that are connected to a pair of electrodes. The polarity of the electrodes could be configured into a proximal anode and a distal cathode, or a proximal cathode and a distal anode. 
     The neurostimulator  12  may be interrogated prior to implantation and throughout the therapeutic period with a healthcare provider-operable control system comprising an external programmer and programming wand (shown in  FIG.  3   ) for checking proper operation, downloading recorded data, diagnosing problems, and programming operational parameters.  FIG.  3    is a diagram showing an external programmer  40  for use with the implantable neurostimulator  12  of  FIG.  1   . The external programmer  40  includes a healthcare provider operable programming computer  41  and a programming wand  42 . Generally, use of the external programmer is restricted to healthcare providers, while more limited manual control is provided to the patient through “magnet mode.” 
     In one embodiment, the external programmer  40  executes application software  45  specifically designed to interrogate the neurostimulator  12 . The programming computer  41  interfaces to the programming wand  42  through a wired or wireless data connection. The programming wand  42  can be adapted from a Model 201 Programming Wand, manufactured and sold by Cyberonics, Inc., and the application software  45  can be adapted from the Model 250 Programming Software suite, licensed by Cyberonics, Inc. Other configurations and combinations of external programmer  40 , programming wand  42  and application software  45  are possible. 
     The programming computer  41  can be implemented using a general purpose programmable computer and can be a personal computer, laptop computer, ultrabook computer, netbook computer, handheld computer, tablet computer, smart phone, or other form of computational device. For example, in one embodiment, the programming computer  41  is a tablet programmer with a wired or wireless data connection to the programming wand  42 . The programming computer  41  functions through those components conventionally found in such devices, including, for instance, a central processing unit, volatile and persistent memory, touch-sensitive display, control buttons, peripheral input and output ports, and network interface. The computer  41  operates under the control of the application software  45 , which is executed as program code as a series of process or method modules or steps by the programmed computer hardware. Other assemblages or configurations of computer hardware, firmware, and software are possible. 
     Operationally, the programming computer  41 , when connected to a neurostimulator  12  through wireless telemetry using the programming wand  42 , can be used by a healthcare provider to remotely interrogate the neurostimulator  12  and modify stored stimulation parameters. The programming wand  42  provides data conversion between the digital data accepted by and output from the programming computer and the radio frequency signal format that is required for communication with the neurostimulator  12 . In other embodiments, the programming computer may communicate with the implanted neurostimulator  12  using other wireless communication methods, such as wireless RF transmission. The programming computer  41  may further be configured to receive inputs, such as physiological signals received from patient sensors (e.g., implanted or external). These sensors may be configured to monitor one or more physiological signals, e.g., vital signs, such as body temperature, pulse rate, respiration rate, blood pressure, etc. These sensors may be coupled directly to the programming computer  41  or may be coupled to another instrument or computing device which receives the sensor input and transmits the input to the programming computer  41 . The programming computer  41  may monitor, record, and/or respond to the physiological signals in order to effectuate stimulation delivery in accordance with some embodiments. 
     The healthcare provider operates the programming computer  41  through a user interface that includes a set of input controls  43  and a visual display  44 , which could be touch-sensitive, upon which to monitor progress, view downloaded telemetry and recorded physiology, and review and modify programmable stimulation parameters. The telemetry can include reports on device history that provide patient identifier, implant date, model number, serial number, magnet activations, total ON time, total operating time, manufacturing date, and device settings and stimulation statistics and on device diagnostics that include patient identifier, model identifier, serial number, firmware build number, implant date, communication status, output current status, measured current delivered, lead impedance, and battery status. Other kinds of telemetry or telemetry reports are possible. 
     During interrogation, the programming wand  42  is held by its handle  46  and the bottom surface  47  of the programming wand  42  is placed on the patient&#39;s chest over the location of the implanted neurostimulator  12 . A set of indicator lights  49  can assist with proper positioning of the wand and a set of input controls  48  enable the programming wand  42  to be operated directly, rather than requiring the healthcare provider to awkwardly coordinate physical wand manipulation with control inputs via the programming computer  41 . The sending of programming instructions and receipt of telemetry information occur wirelessly through radio frequency signal interfacing. Other programming computer and programming wand operations are possible. 
       FIG.  4    is a diagram showing the helical electrodes  14  provided as on the stimulation lead assembly  13  of  FIG.  2    in place on a vagus nerve  15 ,  16  in situ  50 . Although described with reference to a specific manner and orientation of implantation, the specific surgical approach and implantation site selection particulars may vary, depending upon physician discretion and patient physical structure. 
     Under one embodiment, helical electrodes  14  may be positioned on the patient&#39;s vagus nerve  61  oriented with the end of the helical electrodes  14  facing the patient&#39;s head. At the distal end, the insulated electrical lead body  13  is bifurcated into a pair of lead bodies  57 ,  58  that are connected to a pair of electrodes  51 ,  52 . The polarity of the electrodes  51 ,  52  could be configured into a proximal anode and a distal cathode, or a proximal cathode and a distal anode. In addition, an anchor tether  53  is fastened over or in connection with the lead bodies  57 ,  58  that maintains the helical electrodes&#39; position on the vagus nerve  61  following implant. In one embodiment, the conductors of the electrodes  51 ,  52  are manufactured using a platinum and iridium alloy, while the helical materials of the electrodes  51 ,  52  and the anchor tether  53  are a silicone elastomer. 
     During surgery, the electrodes  51 ,  52  and the anchor tether  53  are coiled around the vagus nerve  61  proximal to the patient&#39;s head, each with the assistance of a pair of sutures  54 ,  55 ,  56 , made of polyester or other suitable material, which help the surgeon to spread apart the respective helices. The lead bodies  57 ,  58  of the electrodes  51 ,  52  are oriented distal to the patient&#39;s head and aligned parallel to each other and to the vagus nerve  61 . A strain relief bend  60  can be formed on the distal end with the insulated electrical lead body  13  aligned, for example, parallel to the helical electrodes  14  and attached to the adjacent fascia by a plurality of tie-downs  59   a - b.    
     The neurostimulator  12  delivers VNS under control of the electronic circuitry  22 . The stored stimulation parameters are programmable. Each stimulation parameter can be independently programmed to define the characteristics of the cycles of therapeutic stimulation and inhibition to ensure optimal stimulation for a patient  10 . The programmable stimulation parameters include output current, signal frequency, pulse width, signal ON time, signal OFF time, magnet activation (for VNS specifically triggered by “magnet mode”), and reset parameters. Other programmable parameters are possible. In addition, sets or “profiles” of preselected stimulation parameters can be provided to physicians with the external programmer and fine-tuned to a patient&#39;s physiological requirements prior to being programmed into the neurostimulator  12 . 
     Therapeutically, the VNS may be delivered as a multimodal set of therapeutic doses, which are system output behaviors that are pre-specified within the neurostimulator  12  through the stored stimulation parameters and timing cycles implemented in firmware and executed by the microprocessor controller. The therapeutic doses include a maintenance dose that includes continuously-cycling, intermittent and periodic cycles of electrical stimulation during periods in which the pulse amplitude is greater than 0 mA (“therapy ON”) and during periods in which the pulse amplitude is 0 mA (“therapy OFF”). 
     The neurostimulator  12  can operate either with or without an integrated heart rate sensor. Additionally, where an integrated leadless heart rate monitor is available, the neurostimulator  12  can provide autonomic cardiovascular drive evaluation and self-controlled titration. Finally, the neurostimulator  12  can be used to counter natural circadian sympathetic surge upon awakening and manage the risk of cardiac arrhythmias during or attendant to sleep, particularly sleep apneic episodes. 
     Several classes of implantable medical devices provide therapy using electrical current as a stimulation vehicle. When such a system stimulates certain organs or body structures like the vagus nerve, therapeutic levels of electrical stimulation are usually not well tolerated by patients without undergoing a process known as titration. Titration is a systematic method or process of incrementally increasing the stimulation parameters employed by an implanted device to deliver a stimulation current to the patient at increasing levels that achieve or improve therapeutic benefit while minimizing side effects that could disrupt the stimulation therapy. Titration usually involves bringing the patient to an initial stimulation level that is tolerable to the patient (i.e., below an initial tolerance threshold), waiting for a period of time for the patient to adjust to the continuing delivery of the initial stimulation level and to define a higher tolerance threshold of the patient, and then increasing the initial stimulation level to a higher stimulation level that is, in some patients, greater than the initial tolerance threshold, and so on. This process is repeated in sequences that progress from a stimulation delivery provided over a waiting period, and then to an increase in a stimulation level than defines the next sequence of the stimulation delivery and the next waiting period. 
       FIG.  5    is a flow diagram showing a method for delivering vagus nerve stimulation therapy, according to an exemplary embodiment. A titration process  400  is used to gradually increase the stimulation intensity to a desired therapeutic level or maintenance dosage level. If the stimulation intensity is increased too quickly before the patient is fully accommodated to the stimulation signal, the patient may experience undesirable side effects, such as coughing, hoarseness, throat irritation, or expiratory reflex. The titration process gradually increases stimulation intensity within a tolerable level, and maintains that intensity for a period of time to permit the patient to adjust to each increase in intensity, thereby gradually increasing the patient&#39;s side effect tolerance zone boundary to so as to accommodate subsequent increases in intensity. The titration process continues until adequate adaptation is achieved. In embodiments, the titration process is automated and is executed by the implanted device without manual adjustment of the stimulation intensity by the subject or health care provider. As will be described in greater detail below, adequate adaptation is a composite threshold comprising one or more of the following: an acceptable side effect level, a target intensity level, and a target physiological response. In some embodiments, adequate adaption includes all three objectives: an acceptable side effect level, a target intensity level, and a target physiological response. 
     In some embodiments, the titration process is a mix of automation and physician input. As will be described in greater detail below, a physician may use intermediate holds to stop the automated titration at certain thresholds (e.g., a certain number of days or weeks, certain stimulation parameter values, etc.) and evaluate the patient before resuming the automated titration. The physician may receive a graphical titration history to review how the automated titration process has been progressing from one sequence to the next. The graphical titration history may include markers. The markers may represent intermediate holds, when target parameters are reached between adjacent sequences, etc. After the physician has resumed the automatic titration, the next sequence of automated titration may progress until the next intermediate hold is reached. 
     As described above, it may be desirable to minimize the amount of time required to complete the titration process so as to begin delivery of the stimulation at therapeutically desirable levels, particularly when the patient is being treated for an urgent condition such as CHF. In addition, it is desirable to utilize a maintenance dose intensity at the minimum level required to achieve the desired therapeutic effect. This can reduce power requirements for the neurostimulator and reduce patient discomfort. 
     It has been observed that a patient&#39;s side effect profile is more sensitive to the stimulation output current than to the other stimulation parameters, such as frequency, pulse width, and duty cycle. As a result, accommodation to the stimulation output current is a primary factor in completing the titration process. It has also been observed that if the other stimulation parameters are maintained at a level below the target levels, the output current can be increased to higher levels without eliciting undesirable side effects that would be result when the other parameters are at the target level. As a result, increasing the target output current while maintaining the other stimulation parameters (pulse width in particular) at reduced levels can result in a faster accommodation and shorter overall titration time than would be achieved by attempting to increase the output current while stimulating at the target pulse width. 
     Referring again to  FIG.  5   , in step  401 , a stimulation system  11 , including a neurostimulator  12 , a nerve stimulation lead assembly  13 , and a pair of electrodes  14 , is implanted in the patient. In step  402 , the patient undergoes an optional post-surgery recovery period, during which time the surgical incisions are allowed to heal and no VNS therapy occurs. This period may last, e.g., two weeks post surgery. In step  403 , the stimulation therapy is initiated with the initiation of a titration process. During this titration process, VNS therapy is titrated by adjusting one or more of the stimulation parameters, including output current, pulse width, signal frequency, and duty cycle, as will be described in greater detail below. Completion of the titration process determines the stimulation intensity to be used for subsequent maintenance doses delivered in step  404 . These maintenance doses may be selected to provide the minimum stimulation intensity necessary to provide the desired therapeutic result. 
       FIG.  6 A  is a flow diagram illustrating a titration process  500 , according to an exemplary embodiment. Process  500  includes setting titration parameters (step  501 ), initiating titration (step  502 ), stopping titration at an intermediate hold (step  503 ) and resuming titration (step  504 ). 
     In step  501 , a physician sets the titration parameters via programmer  40 , which are received by the implantable vagus nerve stimulation system  11 . In some embodiments, the titration parameters may be defined by one or more titration algorithms that may be selected by the physician, or may be presented to the physician as a preferred or recommended list of titration parameters that the programming physician can adopt. In other embodiments, rather than present the physician with a set titration algorithm with fixed algorithm values, the physician may be presented with default values that could be manually adjusted. The titration parameter starting values, target values, and/or increment values for amplitude, pulse width, frequency, and/or duty cycle may be adjustable, as may the time interval between titration steps. Time of day and delay to therapy start may also be programmable as a titration parameter. The titration parameters may also include one or more intermediate holds that maintain certain parameters until the physician indicates that the automated titration can continue. The physician may be limited so that modification can be made to only a select group of parameters, or some parameters may be considered to be in a locked state until unlocked by the physician. In some embodiments, the physician is able to modify a large number of titration parameters (e.g., 10-12 parameters). Alternatively, rather than give the physician control over the titration parameter values themselves, the physician&#39;s options for the titration process may be presented as a set of “aggressiveness” options to select from, each of which would be used by the system to determine the values to use. For example, the physician may be able to choose from an aggressive profile, a moderate profile, or a light profile (sensitive) that is appropriate for certain types of patients that do not require detailed titration parameter programming. More or fewer aggressiveness profiles could be used, and the aggressiveness profiles may correspond to the overall health status of the patient, the patient&#39;s sensitivity to stimulation therapies or titration processes, or the patient&#39;s medical history. The aggressiveness profile selected by the physician may result in a predetermined set of titration parameters being selected. The predetermined titration parameters may vary between different aggressiveness profiles, and some titration parameters may remain constant, or similar, between various aggressiveness profiles. For example, the aggressive profile may be suitable for patients that have a high toleration for the titration process and may include shorter time intervals between titration steps, higher intensity target values, and/or larger increment values (e.g., as compared to the moderate or light profiles) that may result in an achievement of a suitable therapy level more quickly as compared to the moderate or light profiles. While some of the parameters may promote a more aggressive titration progression, some of the parameters may be consistent with parameters of other profiles (e.g., titration holds). In some embodiments, each of the aggressiveness profiles may be mapped by the system to a set of parameters or a range of parameters. For example, if the user selects the aggressive profile, the system may receive the user selection and set the values of one or more parameters (e.g., amplitude, pulse width, frequency, duty cycle, intervals between titration steps, and/or other parameters) to a first set of values. If the user selects the moderate profile, the system may set the values of the parameters to a second predetermined set or range of values that is different than the set associated with the aggressive profile. In some embodiments, the physicians are limited to modification of the parameters within a range of boundary values. The ranges may be for the default parameters, or may be set individually for the aggressiveness options (e.g., the ranges for the aggressive profile and the moderate profile may be different, but may overlap for some parameters). The physician may be able to customize the parameters in the preset profiles. In step  502 , the physician initiates titration using the titration parameters defined at  501 . 
     In step  503 , titration is stopped at a titration hold. The titration hold may be an intermediate hold set by the physician during step  501 . The VNS system  11  may perform automated titration according to process  600 , described below. However, the physician is given the option (through the programmer  40 ) to designate intermediate points at which the titration algorithm would pause and await manual (programmer-based) activation by the physician. These hold points may be either time based (e.g. after 2, 4, 6, and/or 8 weeks of titration) or stimulation based (e.g. once stimulation amplitude reaches 1.0, 1.5, 2.0, and/or 2.5 mA). This would allow the physician to evaluate the patient in the clinic before deciding to continue titration. The physician releases the hold on the titration with the programmer  40  once the patient has been evaluated. The physician may also modify parameters during the clinical evaluations. 
     The holds may be predefined for the entire titration process during initial set up. Alternatively, the physician may have the option of setting a new intermediate hold when evaluating the patient. The intermediate holds may be consistent throughout the titration process (e.g., every 2 weeks, every 0.5 mA, etc.). In another embodiment, the intermediate holds are different for at least one hold (e.g., 4 weeks to the first hold, 2 weeks for every subsequent hold, etc.). In another embodiment, intermediate holds can be a combination of parameters (e.g., amplitude and pulse width). In some embodiments, the hold may be set to begin when both parameters are met, or when one parameter is met. In another embodiment, one parameter cannot exceed the hold value and will remain constant until the second parameter is reached. In some embodiments, both parameters will progress according to the automated titration until both parameters meet the intermediate hold value, but one parameter may exceed the intermediate hold until the second parameter reaches the intermediate hold value. The physician may have the option to set as many or as few intermediate holds as desired. 
     During the automated titration between intermediate holds, the VNS system  11  may be fully automated or partially automated. In some embodiments, titration is performed without any intervention from either the patient or the healthcare provider. This embodiment also automatically detects patient side effects and intolerance, and adjusts stimulation parameters to remain below the side effect threshold, as is described with respect to  FIG.  6 B . In another embodiment, the VNS system  11  may automatically adjust stimulation parameters slowly over time, without any additional intervention from the healthcare provider. Because the system may not be able to determine if stimulation causes an intolerable side effect, it may be configured to rely on the patient to swipe a magnet to indicate an intolerable level of a side effect. The VNS system  11  may then adjust stimulation parameters in response to patient magnet activation. 
     For example, patients may require a total of 10±2 clinic visits over a 10-week period to reach the target stimulation intensity. The frequency of required clinic visits is bothersome to both patients and providers, and creates a barrier to therapy adoption. In addition, the frequency of required clinic visits extends the time required to titrate patients to the target stimulation intensity. However, physician may be skeptical of completely automated titration and want to ensure the patients are not experiencing intolerable side effects and are adapting to stimulation adequately. By allowing the physician to set the parameters, and evaluate the patient intermediately, but still allow titration to perform automatically between visits, the time period to reach the target stimulation may be reduced, while giving the physicians more control over the titration process. Preferably, the number of clinic visits needed and the overall timeframe of the titration process is reduced by only the use of intermediate holds. Any time penalty related to the intermediate holds is believed to be significantly less than the time penalty resulting from an automated titration process that causes side effect and ultimately requires the patient to undergo a re-titration protocol. 
     In step  504 , titration is resumed. The physician may resume titration using the programmer  40  after evaluation of the patient. When the physician resumes titration, they may have the option to modify stimulation parameters and/or intermediate holds. The titration may resume using automated titration until the next intermediate hold is reached. This process may continue until the therapy parameters are reached. 
       FIG.  6 B  is a flow diagram illustrating a titration process  600  in accordance with exemplary embodiments. When first initiating the titration process, the neurostimulator  12  is configured to generate a stimulation signal having an initial stimulation parameter set. The initial parameter set may comprise an initial output current, an initial frequency, an initial pulse width, and an initial duty cycle. The various initial parameter settings may vary, but may be selected so that one or more of the parameters are set at levels below a predefined target parameter set level, such that the titration process is used to gradually increase the intensity parameters to achieve adequate adaptation. In some embodiments, the initial frequency is set at the target frequency level, while the initial output current, initial pulse width, and initial duty cycle are set below their respective target levels. In one embodiment, the target parameter set comprises a 10 Hz frequency, 250 μsec pulse width, a duty cycle of 14 sec ON and 1.1 minutes OFF, and an output current of between 1.5 mA—3.0 mA (e.g., 2.5 mA for right side stimulation and 3.0 mA for left side stimulation), and the initial parameter set comprises 10 Hz frequency, 130 μsec pulse width, a duty cycle of 14 sec ON and 1.1 minutes OFF, and an output current of between 0.25 mA—0.5 mA. In other embodiments, the target parameter set includes a 5 Hz frequency that is used instead of a 10 Hz frequency. The initial parameter set may also include one or more intermediate holds as discussed with respect to  FIG.  6 A . However, this is an exemplary embodiment and these values are not intended to be limiting. Other frequencies, pulse widths, duty cycles and output currents may be implemented. The initial and target parameters may vary from patient to patient based on the patient&#39;s sensitivity to stimulation. While the initial parameters are shown to be equal to the target parameters for some of the exemplary parameters (e.g., frequency and duty cycle), some or all of the parameters may have initial parameters that differ from the target parameters. 
     In step  601 , the stimulation system delivers stimulation to the patient. If this is the first titration session, then the stimulation would be delivered with the initial stimulation parameter set described above. If this is a subsequent titration session, then the stimulation intensity would remain at the same level provided at the conclusion of the previous titration session. Alternatively, the subsequent titration session can start at a level that is set by the physician, e.g., at the next titration level that follows the level provided at the conclusion of the previous titration session. 
     In step  602 , the output current is gradually increased until the stimulation results in an intolerable side effect level, the target intensity (e.g., 2.5 mA at a pulse width of 250 μs and frequency of 10 Hz) is reached, or adequate adaptation is achieved. As described above, adequate adaptation is a composite threshold comprising one or more of the following: an acceptable side effect level, a target intensity level, and a target physiological response. In accordance with some embodiments, the target physiological response comprises a target heart rate change during stimulation. The patient&#39;s heart rate may be monitored using an implanted or external heart rate monitor, and the patient&#39;s heart rate during stimulation is compared to the patient&#39;s baseline heart rate to determine the extent of heart rate change. In accordance with some embodiments, the target heart rate change is a heart rate change of between 4% and 5%. If at any point during the titration process  600  adequate adaptation is achieved, the titration process ends and the stimulation intensity which resulted in the adequate adaptation is used for ongoing maintenance dose therapy delivery. 
     The output current may be increased in any desired increment, but small increments, e.g., 0.1 mA or 0.25 mA, may be desirable so as to enable more precise adjustments. In some cases, the output current increments may be determined by the neurostimulator&#39;s maximum control capability. During the initial titration sessions, it is likely that the patient&#39;s side effect tolerance zone boundary will be reached well before the output current reaches the target level or adequate adaptation is achieved. At decision step  603 , if the target output current has not been achieved but the maximum tolerable side effects have been exceeded, the process proceeds to step  604 . 
     In step  604 , the output current is reduced one increment to bring the side effects within acceptable levels. In addition, the frequency is reduced. In embodiments in which the initial frequency was 10 Hz, in step  604 , the frequency may be reduced, e.g., to 5 Hz or 2 Hz. 
     Next, in step  605 , the output current is gradually increased again at the reduced frequency level until the stimulation results in an intolerable side effect level or the target output current (e.g., 2.5 mA) is reached. At decision step  606 , if the target output current has been reached and the maximum tolerable side effects have not been exceeded, the process proceeds to step  607  where the titration session is concluded. The stimulation system may be programmed to continue delivering the stimulation signal at the last parameter settings achieved prior to conclusion of the titration session. After a period of time, another titration session may be initiated and the process returns to step  601 . This can be any period of time sufficient to permit the patient to adjust to the increased stimulation levels. This can be, for example, as little as approximately two or three days, approximately one to two weeks, approximately four to eight weeks, or any other desired period of time. 
     In some embodiments, the titration sessions are automatically initiated by the stimulation system or initiated by the patient without requiring any intervention by the health care provider. This can eliminate the need for the patient to schedule a subsequent visit to the health care provider, thereby potentially reducing the total amount of time needed for the titration process to complete. In these embodiments, the stimulation system may include a physiological monitor, e.g., an implanted heart rate sensor, that communicates with the stimulation system&#39;s control system to enable the control system to detect the patient&#39;s physiological response to the titration and automatically make adjustments to the titration processes described herein with reduced or no inputs from the patient or health care provider. The monitored signals can also enable the control system to detect when the target physiological response has been achieved and conclude the titration process. The stimulation system could in addition or alternatively include a patient control input to permit the patient to communicate to the control system that the acceptable side effect level has been exceeded. This control input may comprise an external control magnet that the patient can swipe over the implanted neurostimulator, or other internal or external communication device that the patient can use to provide an input to the control system. In these automatically initiated titration sessions, the stimulation system may be configured to wait a period of time after completing one session before initiating the next session. This period of time may be predetermined, e.g., two or three days, or programmable. In another embodiment, the stimulation system is configured to wait until authorization has been received before initiating the next session (i.e., an intermediate hold). 
     Returning to decision step  606 , if the target output current has not been reached but the maximum tolerable side effects have been exceeded, the process proceeds to step  608 . In step  608 , the output current is reduced one increment to restore an acceptable side effect condition, and the frequency is gradually increased until the stimulation results in an intolerable side effect level or the target frequency (e.g., 10 Hz) is reached. At decision step  609 , if the target frequency has not been reached but the maximum tolerable side effects have been exceeded, the frequency is reduced to restore an acceptable side effect level and the process proceeds to step  607 . Again, in step  607 , the current titration session is concluded and the stimulation system may be programmed to continue delivering the stimulation signal at the last parameter settings achieved prior to conclusion of the titration session. 
     At decision step  609 , if the target frequency has been reached before the maximum tolerable side effects have been exceeded, the duty cycle is gradually increased until the stimulation results in an intolerable side effect level or the target duty cycle (e.g., 14 sec ON and 1.1 min OFF) is reached, at which point the process proceeds to step  607  and the titration session is concluded and ongoing stimulation delivered at the last intensity eliciting acceptable side effect levels. 
     Returning to decision step  603 , if the target output current has been achieved before the maximum tolerable side effects are exceeded, the process proceeds to step  611 . In step  611 , the pulse width is gradually increased until the stimulation results in an intolerable side effect level or the target pulse width (e.g., 250 μsec) is reached. In some embodiments, before step  611 , the output current is reduced (e.g., by up to 50%), and the pulse width may be increased in step  611  at that reduced output current. After the target pulse width is achieved, the output current may be restored to the target output current. In other embodiments, the output current may be reduced (or may be retained at the reduced level established prior to step  611 , as described above), and the frequency and duty cycle are gradually increased in step  613  at that reduced output current. This reduction in output current after achieving the target output current may enable the patient to maintain tolerability with increasing pulse width, frequency, and duty cycle in subsequent titration steps. 
     At decision step  612 , if the target pulse width has not been achieved before the maximum tolerable side effects have been exceeded, the pulse width is reduced to restore an acceptable side effect level and the process proceeds to step  607 . Again, in step  607 , the current titration session is concluded. 
     If at decision step  612 , the target pulse width has been achieved before the maximum tolerable side effects have been exceeded, the process proceeds to step  613 . In step  613 , the frequency and/or duty cycle are increased until the stimulation results in an intolerable side effect level or the target frequency and target duty cycle are reached. The frequency and duty cycle can be increased in step  612  simultaneously, sequentially, or on an alternating basis. 
     At decision step  614 , if the target frequency and/or target duty cycle have not been achieved before the maximum tolerable side effects have been exceeded, the pulse width and/or frequency are reduced to restore an acceptable side effect level and the process continues to step  607  and the titration session is concluded. In some embodiments, the conclusion of the titration session represented in step  607  indicates an intermediate hold has been reached. A new titration session could then be initiated after visiting a physician to release the intermediate hold. 
     At decision step  614 , if the target pulse width and target frequency have been achieved before the maximum tolerable side effects have been exceeded, all of the stimulation parameters will have reached their target levels and the titration process concludes at step  615 . The stimulation therapy may proceed with the maintenance dose at the target stimulation levels. In some embodiments, the target frequency and duty cycle achieved are for a given titration session with an intermediate hold. In this case, the patient would visit a health care provider or physician for an evaluation. The physician would then release the hold on the titration processes, or initiate the beginning of therapy. 
     In some embodiments, in step  604 , instead of reducing the frequency in order to facilitate increase of the output current, the pulse width may be reduced. For example, embodiments where the target pulse width is 250 μsec, the pulse width may be reduced, e.g., to 150 μsec or less. Then, the method proceeds to step  605 , in which the output current is gradually increased again at the reduced pulse width level until the stimulation results in an intolerable side effect level or the target output current (e.g., 2.5 mA) is reached. 
     Therapy can also be autonomously titrated by the neurostimulator  12  in which titration progressively occurs in a self-paced, self-monitored fashion. The progression of titration sessions may occur on an autonomous schedule or may be initiated upon receipt of an input from the patient. Ordinarily, the patient  10  is expected to visit his healthcare provider to have the stimulation parameters stored by the neurostimulator  12  in the recordable memory  29  reprogrammed using an external programmer. Alternatively, the neurostimulator  12  can be programmed to automatically titrate therapy by up titrating the VNS through periodic incremental increases using titration sessions as described above. The titration process  600  will continue until the ultimate therapeutic goal is reached. 
     Following the titration period, therapeutic VNS, as parametrically defined by the maintenance dose operating mode, is delivered to at least one of the vagus nerves. The stimulation system  11  delivers electrical therapeutic stimulation to the cervical vagus nerve of a patient  10  in a manner that results in creation and propagation (in both afferent and efferent directions) of action potentials within neuronal fibers of either the left or right vagus nerve independent of cardiac cycle. 
       FIG.  7 A  is a simplified block diagram of an implanted neurostimulation system  700 , according to an exemplary embodiment. The implanted neurostimulation system  700  comprises a control system  702  comprising a processor programmed to operate the system  700 , a memory  703 , an optional physiological sensor  704 , and a stimulation subsystem  706 . The physiological sensor  704  may be configured to monitor any of a variety of patient physiological signals and the stimulation subsystem  706  may be configured to deliver a stimulation signal to the patient. In one example, the physiological sensor  704  comprises an ECG sensor or an accelerometer for monitoring heart rate and the stimulation subsystem  706  comprises a neurostimulator  12  programmed to deliver ON-OFF cycles of stimulation to the patient&#39;s vagus nerve. The implanted system  700  may include a patient input sensor  705 , described in more detail below. 
     The control system  702  is programmed to activate the neurostimulator  12  to deliver stimulation signals at varying stimulation intensities to the patient and to monitor the physiological signals in response to those delivered stimulation signals. 
     The external programmer  707  shown in  FIG.  7 A  may be utilized by a clinician or by the patient for communicating with the implanted system  700  to adjust parameters, activate therapy, retrieve data collected by the system  700  or provide other input to the system  700 . In some embodiments, the external programmer  707  may be used remote from the implanted system  700  (e.g., when the patient is not at a clinic). For example, instead of the patient coming into the clinic for a check-up during a titration hold, the clinician may check on the patient remotely (e.g., phone call, video call, etc.). The clinician could then use the external programmer  707  to activate the next titration session, or modify parameters of the titration. In some embodiments, the external programmer  707  may provide an alert indicating the patient has reached a titration hold. In some embodiments, the patient receives an alert indicating a titration hold has been reached (e.g., email, text message, etc.). In some such embodiments, the external programmer  707  may include communication circuitry adapted to communicate over a long distance using one or more protocols (e.g., cellular, Internet, etc.). In some embodiments, the external programmer  707  may be configured to program the implanted system  700  with a prescribed time or window of time during which titration sessions may be initiated. This can be used to prevent a titration session from occurring at night when the patient&#39;s sleep is likely to be disturbed by the increase in stimulation intensity and resulting side effects. 
     Patient inputs to the implanted system  700  may be provided in a variety of ways. The implanted system  700  may include a patient input sensor  705 . As described above, a patient magnet  730  may be used to provide external input to the system  700 . When the patient magnet  730  is placed on the patient&#39;s chest in close proximity to the implanted system  700 , the patient input sensor  705  will detect the presence of the magnetic field generated by the patient magnet  730  and provide a control input to the control system  702 . The system  700  may be programmed to receive patient inputs to set the time of day during which titration sessions are to be initiated. 
     In other embodiments, the patient input sensor  705  may comprise a motion sensor, such as an accelerometer, which is configured to detect tapping on the surface of the patient&#39;s chest. The patient may use finger taps in one or more predetermined patterns to provide control inputs to the implanted system  700 . For example, when the motion sensor detects three rapid taps to the patient&#39;s chest, that may trigger an operation on the implanted system  700  (e.g., to initiate a titration session). Alternatively, if the motion sensor detects a predetermined pattern of taps during a titration session, the implanted system  700  will interpret those taps as a patient input indicating that the patient&#39;s tolerance zone boundary has been exceeded. 
     In other embodiments, the patient input sensor  705  may comprise an acoustic transducer or other sensor configured to detect acoustic signals. The system  700  may be programmed to interpret the detection of certain sounds as patient inputs. For example, the patient may utilize an electronic device, such as a smartphone or other portable audio device, to generate one or more predetermined sequences of tones. The system  700  may be programmed to interpret each of these sequences of tones as a different patient input. 
     The titration of the stimulation signal delivery and the monitoring of the patient&#39;s physiological response (e.g., heart rate) may be advantageously implemented using a control system  702  in communication with both the stimulation subsystem  706  and the physiological sensor  704 , such as by incorporating all of these components into a single implantable device  700 . In accordance with other embodiments, an external control system  712  may be implemented in a separate implanted device or in an external programmer  720  or other external device, as shown in  FIG.  7 B  to provide control over and communication with an implanted physiological sensor  714  and a stimulation subsystem  716  similar to those describe with regard to  FIG.  6 A . The external programmer  720  in  FIG.  7 B  may be utilized by a clinician or by the patient for adjusting stimulation parameters. The external programmer  720  may be in wireless communication with the implanted medical device  710 , which includes the stimulation subsystem  716  and a memory  713 . In the illustrated embodiment, the physiological sensor  714  is incorporated into the implanted medical device  710 , but in other embodiments, the sensor  714  may be incorporated into a separate implanted device, may be provided externally and in communication with the external programmer  720 , or may be provided as part of the external programmer  720 . 
     In various embodiments, a heart rate variability analysis may be used during the titration process to determine whether the VNS dose being applied to the patient is an effective dose. For example, a Poincaré analysis may be used during the titration process to verify that a VNS dose is an effective dose. In the cardiac stimulation context, performing a Poincaré analysis first includes measuring an interval between two successive R-waves (an “R-R interval”). As an illustration, R-R intervals are calculated as the time between successive QRS intervals in milliseconds. Each R-R interval (e.g., represented as Rn(s)) is then plotted against the successive R-R interval (e.g., represented as R n+1 (s)) to produce a scattergram termed a “Poincaré plot.” The process of using a Poincaré analysis to determine whether an applied VNS dose in an effective dose is described in I. Libbus et al., “Quantitative Evaluation of Heartbeat Interval Time Series Using Poincaré Analysis Reveals Distinct Patterns of Heart Rate Dynamics During Cycles of Vagus Nerve Stimulation in Patients with Heart Failure,” 50 J. of Electrocardiology 898-903 (2017), which is hereby incorporated by reference in its entirety. 
     An example of a heart rate variability plot is shown in  FIG.  8   . Specifically,  FIG.  8    illustrates a Poincaré plot  800 . As shown in  FIG.  8   , the Poincaré plot  800  includes a number of points  802  produced by measuring the RR n (s) and the RR n+1 (s) and plotting the RR n (s) versus the RR n+1 (s). Once the Poincaré plot  800  has been created, standard deviations for the plot  800  may be determined. For example, an ellipse  804  may be fitted to the plot  800 , with the center of the ellipse  804  coinciding with the center of the distribution of the points  802 . An identity line  806  and a line perpendicular to the identity line  808  may then be plotted through the ellipse  804 . Next, the standard deviation of points along the axis of the line perpendicular to the identity line  808  may be calculated (termed here as “SD1”), the standard deviation of points along the axis of the identity line  806  (termed here as “SD2”) may be calculated. SD1 and SD2 are useful as measures of heart rate variability. More specifically, SD1 depicts the instantaneous beat-to-beat variability of the data, and SD2 provides a quantification of continuous long-term R-R intervals. The identity line  806  and the line perpendicular to the identity line  808  overlap at a centroid  810  of the ellipse  804 , which represents the average heart rate. 
     A heart rate variability analysis may be used to determine whether an effective dose of VNS stimulation is being applied to a patient because effective stimulation may alter the patient&#39;s heart rate variability in observable ways. As an example, a Poincaré analysis may be used to determine whether an effective dose of VNS stimulation is being applied to a patient because if the patient is responding to the VNS stimulation, the centroid of the Poincaré plot will move up and to the right. Further, the SD1 of the Poincaré plot will increase in response to effective VNS stimulation. Accordingly,  FIG.  9    illustrates a diagram  900  showing an example timing of a heart rate variability analysis, specifically a Poincaré analysis, with respect to the timing of VNS stimulation. As shown in  FIG.  9   , the VNS stimulation is applied according to a duty cycle with an ON period  902  (e.g., during which a VNS dose is applied to the patient) and an OFF period  904  (e.g., during which the VNS dose is suspended). For example, the ON period  902  may be 14 seconds, and the OFF period  904  may be 66 seconds. Accordingly, a baseline period  906  for the Poincaré analysis may be determined for at least a portion of the OFF period  904 , and a stimulation period  908  for the Poincaré analysis may be determined for at least a portion of the ON period  902 . For example, the baseline period  906  may be determined for the five seconds immediately preceding the VNS dose onset, and the stimulation period  908  may be determined during the last five seconds of VNS stimulation on-time. 
     By taking heart rate variability measurements during VNS ON periods and VNS OFF periods, the effect of a VNS dose on heart rate variability may be measured or observed. For example, a Poincaré plot may be produced for the baseline period  906  and the stimulation period  908 . As an illustration of how the effect of a VNS dose on heart rate variability may be observed,  FIG.  10    shows an example plot, specifically an example Poincaré plot  1000 , showing points  1002  from the baseline period  906  (e.g., plotted from the R-R intervals measured during the baseline period  906 ) and points  1004  from the stimulation period  908  (e.g., plotted from the R-R intervals measured during the stimulation period  908 ). As further shown in  FIG.  10   , an ellipse  1006  may be fitted to the baseline period points  1002 , and an ellipse  1008  may be fitted to the stimulation period points  1004 . An identity line  1010  and a line perpendicular to the identity line  1012  may be plotted through the ellipse  1006  of the baseline period points  1002 , and the SD1 and SD2 may be calculated for the baseline period points  1002 . Similarly, an identity line  1014  and a line perpendicular to the identity line  1016  may be plotted through the ellipse  1008  of the stimulation period points  1004 , and the SD1 and SD2 may be calculated for the stimulation period points  1004 . As shown in  FIG.  10   , the VNS stimulation is being applied at an effective dose, as the stimulation period points  1004  have migrated upward and to the right relative to the baseline period points  1002 . This is particularly illustrated by a centroid  1018  of the baseline period points  1002  relative to a centroid  1020  of the stimulation period points  1004 . 
     If, however, the VNS stimulation is not being applied at an effective dose, the stimulation period points  1004  will remain in the same location or substantially the same location as the baseline period points  1002 . This may signal that the dose of VNS stimulation being applied to a patient is too low and that the intensity of the dose needs to be increased in order to deliver an effective dose to the patient. For example, a physician may increase the stimulation current amplitude of the dose, or the neurostimulator  12  may automatically increase the stimulation current amplitude of the dose, in response to a Poincaré plot showing little or no movement between the stimulation period points  1004  relative to the baseline period points  1002 . Alternatively, the fact that VNS stimulation is not being applied at an effective dose may be demonstrated by the SD1 of the stimulation period points  1004  remaining the same or substantially the same as the SD1 of the baseline period points  1002 . Accordingly, an increased VNS dose may be based on little to no increase in the SD1 of the stimulation period points  1004  compared to the baseline period points  1002 . 
       FIG.  11    is a flow diagram showing an example method of using heart rate variability analysis during neurostimulation therapy titration. More particularly,  FIG.  11    illustrate a method  1100  of using Poincaré analysis during neurostimulation therapy titration. At step  1101 , the ECG of the patient is measured during neuostimulation therapy titration. For example, ECG data for the patient may be measured by the physiological sensor  704  of the implanted system  700  or by the physiological sensor  714  of the implanted medical device  710 . At step  1102 , the R-R intervals of the ECG data are calculated. At step  1103 , artifacts and noise are removed from the data used for the Poincaré analysis. For example, a physician may manually determine outliers in the R-R intervals used in the Poincaré analysis. As another example, artifacts and noise may be automatically filtered from the ECG data used for the Poincaré analysis. 
     At step  1104 , the analysis is synchronized with the stimulation ON/OFF therapy cycles. As an example, the Poincaré analysis is synchronized with the ON periods and OFF periods of the VNS duty cycles, as shown in  FIG.  9   . Each R-R interval is characterized as occurring during the VNS ON period or during the VNS OFF period. Accordingly, the ECG for the patient is sampled during at least a portion of the OFF period to produce a baseline period data set and sampled during at least a portion of the ON period to produce a stimulation period data set. At step  1105 , each R-R interval is plotted against the previous R-R interval to create a Poincaré plot. Because the ECG data was sampled for baseline and stimulation periods in step  1104 , the Poincaré plot includes both baseline period points and stimulation period points, as shown in  FIG.  10   . 
     At step  1106 , the standard deviation of points along the axis of a line perpendicular to identity line (SD1) is calculated for the baseline period points and the stimulation period points. Likewise, at step  1107 , the standard deviation of points along the axis of an identity line axis (SD2) is calculated for the baseline period points and the stimulation period points. As an example, an ellipse is fitted to each of the baseline period points and the stimulation period points, with the center of each ellipse coinciding with the center of the distribution of respective set of points. The SD1 for each set of points is calculated based on the axis of the line perpendicular to the identity line for each ellipse, and the SD2 for each set of points is calculated based on the axis of the identity line for each ellipse. Additionally, at step  1108 , the centroid is determined for the baseline period points and the stimulation period points. For example, the centroid is determined to be the intersection point for the identity line and the line perpendicular to the identity line for each ellipse. 
     In some arrangements, the heart rate variability analysis, such as a Poincaré analysis, is performed by an external programmer, such as the programming computer  41  shown in  FIG.  3   , the external programmer  707  shown in  FIG.  7 A , or the external programmer  720  shown in  FIG.  7 B . In the various examples described herein, the neurostimulation system is the implanted neurostimulation system  700  shown in  FIG.  7 A . However, it should be understood that a heart rate variability analysis may be performed by the neurostimulator  12  and/or the programming computer  41 , by the implanted medical device  710  and/or the external programmer  720 , or by any other implantable medical device and/or external programmer configured for VNS. Accordingly, in one example embodiment, in response to a signal from the external programmer  707 , the physiological sensor  704  measures ECG data for the patient and transmits the ECG data back to the external programmer  707 . The external programmer  707  calculates the patient&#39;s R-R intervals from the ECG data, creates a Poincaré plot (e.g., including the SD1, SD2, and centroid for each of the baseline period points and stimulation period points), and displays the Poincare plot to a physician. Additionally, in some implementations, the display of the external programmer  707  may include coding in which the heartbeats measured during VNS ON periods are represented with different colors and/or symbols than the heartbeats measured during VNS OFF periods. The physician can then determine, based on the Poincaré plot, whether an effective dose of VNS stimulation is being delivered to the patient by the implanted system  700 . Additionally, the physiological sensor  704  may measure and transmit the patient&#39;s ECG data in real-time such that the physician can increase or decrease the VNS dose delivered to the patient (e.g., by sending a command to the control system  702  by the external programmer  707 ) and monitor in real-time whether the increased or decreased VNS dose affects the heart rate variability (e.g., as demonstrated by a Poincaré plot) for the patient. 
     Additionally or alternatively, the physiological sensor  704  may measure historic ECG data for the patient (e.g., at predetermined intervals, such as for five minutes once a day). In response to an interrogation request from the external programmer  707 , the implanted system  700  may transmit the historic ECG data to the external programmer  707 . The external programmer  707  may then perform heart rate variability analyses, such as by creating Poincare plots, for the patient using the patient&#39;s historic ECG data such that the physician may see, e.g., how the patient&#39;s heart rate variability has changed over time. 
     Moreover, in another embodiment, in addition to or rather than displaying heart rate variability information, such as Poincaré plots, to the physician, the external programmer  707  may perform an automatic heart rate variability analysis of the ECG data and provide recommendations to the physician. For example, in response to an instruction from the physician, the external programmer  707  may calculate the R-R intervals of the ECG data received from the implanted system  700 , create a Poincaré plot for the ECG data, calculate the SD1 and SD2 for baseline period points and stimulation period points, and determine the centroids of baseline period points and the stimulation period points. The external programmer  707  may then use the SD1, SD2, and centroid for each of the baseline period points and stimulation period points to determine whether the patient&#39;s heart rate variability and/or average heart rate is different during stimulation periods as opposed to baseline periods and alert the physician of the results of the analysis. Further, if the patient&#39;s heart rate variability and/or average heart rate is not different during stimulation periods as opposed to baseline periods, the external programmer  707  may recommend a VNS dose adjustment to the physician (e.g., recommend that the physician increase the stimulation current intensity by a certain amount). For example, a distance between the centroid of the stimulation period points and the centroid of the baseline period points is less than a certain threshold value, the external programmer  707  recommends a VNS dose adjustment. As another example, if a difference between the SD1 of the stimulation period points and the SD1 of the baseline period points is less than a certain threshold value, the external programmer  707  recommends a VNS dose adjustment. 
     In other arrangements, the heart rate variability analysis is performed by the implantable neurostimulation system, such as the neurostimulator  12  shown in  FIG.  1   , the implanted system  700  shown in  FIG.  7 A , or the implanted medical device  710  shown in  FIG.  7 B . In one example embodiment, in response to a signal from the external programmer  707 , the physiological sensor  704  measures the patient&#39;s ECG data, and the control system  702  creates Poincaré plots for the patient using the ECG data. The implanted system  700  then transmits the plots to the external programmer  707  such that the external programmer  707  may, e.g., display the plots to the physician and/or determine adjustments to the VNS dose as described above. The physiological sensor  704  may measure ECG data in real-time and/or historic ECG data for the patient, and the control system  702  may accordingly perform real-time and/or historic heart rate variability analysis, such as by creating Poincaré plots, for the patient. 
     In another embodiment, the implanted system  700  does not perform the heart rate variability analysis in response to a signal from the external programmer  707 . Rather, the implanted system  700  performs the heart rate variability analysis in response to an event. In one example, after a certain time has elapsed since the VNS dose intensity was increased as part of the titration process, the physiological sensor  704  measures the patient&#39;s ECG data, and the control system  702  creates Poincaré plots for the patient using the ECG data. Using the Poincare plots, the control system  702  then determines whether the increased VNS dose causes the centroid of the stimulation pulse points to migrate upward and to the right and/or causes an increase in the SD1 of the stimulation pulse points when applied. If the VNS dose does not cause a change in the centroid and/or the SD1, the control system  702  notifies the physician (e.g., by sending the external programmer  707  an alert over a network, by sending the alert to a computing system associated with the physician over a network, by sending the alert to a local telemetry device that provides the alert to the external programmer  707 , etc.). The physician may then contact the patient to set up an appointment to check the current status of the VNS being applied to the patient, modify the VNS dose remotely (e.g., via the external programmer  707  communicating with the implanted system  700  over a network), and so on. Alternatively, or additionally, the control system  702  may automatically modify the VNS dose in response to determining that the VNS dose has not caused a change in the centroid and/or SD1 by a certain threshold value (e.g., the control system  702  may cause the stimulation subsystem  700  to increase the VNS dose to the next intensity level in the titration schedule). 
     In other embodiments, rather than performing the heart rate variability analysis in response to an event such as the next step in the titration schedule, the implanted system  700  performs the heart rate variability analysis periodically, such as once per day at a specified time, once per month at a specified time, and so on. Additionally, in some embodiments, the implanted system  700  may only perform the heart rate variability analysis once the titration schedule has been completed. The heart rate variability analysis is accordingly used to verify that the VNS stimulation is now at an effective dose and/or to verify that the VNS stimulation continues to be an effective dose. 
     In still another arrangements, the implantable neurostimulation system, such as the neurostimulator  12  shown in  FIG.  1   , the implanted system  700  shown in  FIG.  7 A , or the implanted medical device  710  shown in  FIG.  7 B , may communicate with a local telemetry device to perform the heart rate analysis. In one example embodiment, the physiological sensor  704  measures the patient&#39;s ECG data and provides the ECG data to a local telemetry device (e.g., transmits the ECG data via Bluetooth or RFID to a telemetry device located in the patient&#39;s home). For example, the physiological sensor  704  may measure and transmit the patient&#39;s ECG data every night when the patient is likely to be close to the local telemetry device. The telemetry device then creates Poincaré plots using the ECG and determines whether the current VNS dose causes the centroid of the stimulation pulse points to migrate upward and to the right and/or causes an increase in the SD1 of the stimulation pulse points when applied. If the VNS dose does not cause a change in the centroid and/or SD1 (e.g., by a certain threshold value), the telemetry device may send an alert to the physician (e.g., by sending an alert to the external programmer  707  or a computing system associated with the physician). The physician may then contact the patient to set up an appointment to check the current status of the VNS being applied to the patient, modify the VNS dose remotely (e.g., via the external programmer  707  communicating with the implanted system  700  over a network), and so on. Alternatively, the telemetry device may communicate with the implanted system  700  to modify the VNS dose (e.g., by sending a command to the control system  702  to increase the VNS dose). 
     In another embodiment, the implanted system  700  may provide ECG data to the telemetry device periodically, and the telemetry device may compile periodic reports for the physician. For example, the implanted system  700  may provide daily ECG data to the telemetry device, and the telemetry device may perform heart rate analyses (e.g., Poincaré analyses) on the data to compile monthly reports on the effect that titration is having on the patient (e.g., including analyses on whether a final titrated VNS dose continues to be effective for the patient). The telemetry device then transmits these reports to the physician (e.g., emails the reports to the physician, transmits the reports to the external programmer  707  over a network, and so on). 
     Using heart rate variability analysis in the context of VNS titration provides various technical advantages. For example, using a Poincaré analysis may provide technical advantages to a VNS therapy system or therapy monitoring system. Advantageously, as described herein, a Poincaré analysis may be used to show whether a given VNS dose is effective for a patient. Still, the Poincaré analysis is a computationally simple approach and thus performing a Poincare analysis does not require much battery or processing power from a device. As such, a device (e.g., an external programmer, an implantable neurostimulator, etc.) may determine whether a VNS dose is effective for a patient, while minimizing battery consumption and processing power, by performing a Poincaré analysis for the patient. In turn, battery and processing power are preserved for other functions of the device, which improves the functioning of the device. As an illustration, the Poincaré analysis may be performed for a patient by an implantable neurostimulator delivering a VNS dose to the patient, to verify that the VNS dose is effective, without placing strains on the limited battery power of the implantable neurostimulator. 
     While embodiments been particularly shown and described, those skilled in the art will understand that the foregoing and other changes in form and detail may be made therein without departing from the spirit and scope. For example, in various embodiments described above, the stimulation is applied to the vagus nerve. Alternatively, spinal cord stimulation (SCS) may be used in place of or in addition to vagus nerve stimulation for the above-described therapies. SCS may utilize stimulating electrodes implanted in the epidural space, an electrical pulse generator implanted in the lower abdominal area or gluteal region, and conducting wires coupling the stimulating electrodes to the generator. Additionally, while the foregoing discussion focuses on heart rate variability analysis with respect to Poincaré analysis, it should be understood that other types of heart rate variability analysis are contemplated and may be used without departing from the spirit and scope of the present disclosure. 
     The present disclosure contemplates methods, systems, and program products on any machine-readable media for accomplishing various operations. The embodiments of the present disclosure may be implemented using existing computer processors, or by a special purpose computer processor for an appropriate system, incorporated for this or another purpose, or by a hardwired system. Embodiments within the scope of the present disclosure include program products comprising machine-readable media for carrying or having machine-executable instructions or data structures stored thereon. Such machine-readable media can be any available media that can be accessed by a general purpose or special purpose computer or other machine with a processor. By way of example, such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to carry or store desired program code in the form of machine-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer or other machine with a processor. When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a machine, the machine properly views the connection as a machine-readable medium. Thus, any such connection is properly termed a machine-readable medium. Combinations of the above are also included within the scope of machine-readable media. Machine-executable instructions include, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions. 
     Although the figures may show a specific order of method steps, the order of the steps may differ from what is depicted. Also two or more steps may be performed concurrently or with partial concurrence. Such variation will depend on the software and hardware systems chosen and on designer choice. All such variations are within the scope of the disclosure. Likewise, software implementations could be accomplished with standard programming techniques with rule based logic and other logic to accomplish the various connection steps, processing steps, comparison steps and decision steps. 
     Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, Z, X and Y, X and Z, Y and Z, or X, Y, and Z. Thus, such conjunctive language is not generally intended to imply that certain embodiments require at least one of X, at least one of Y, and at least one of Z to each be present. 
     While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.