Patent Publication Number: US-2022226657-A1

Title: Responsive neurostimulation for the treatment of chronic cardiac dysfunction

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/234,097, filed Dec. 27, 2018, which is a continuation of U.S. patent application Ser. No. 15/805,062, filed Nov. 6, 2017, now U.S. Pat. No. 10,166,391, which is a continuation of U.S. patent application Ser. No. 15/267,922, filed Sep. 16, 2016, now U.S. Pat. No. 9,808,626, which is a continuation of U.S. patent application Ser. No. 14/861,390, filed Sep. 22, 2015, now U.S. Pat. No. 9,446,237, which is a continuation of U.S. application Ser. No. 14/271,714, filed May 7, 2014, now U.S. Pat. No. 9,272,143, the entire disclosures of each of which are incorporated herein by reference. 
    
    
     FIELD 
     This application relates to neuromodulation. 
     BACKGROUND 
     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 neuroexcitatory 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. For instance, VNS has been demonstrated in canine studies as efficacious in simulated treatment of AF and heart failure, such as described in Zhang et al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control and Attenuates Systemic Inflammation and Heart Failure Progression in a Canine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699 (Sep. 22, 2009), the disclosure of which is incorporated by reference. The results of a multi-center open-label phase II study in which chronic VNS was utilized for CHF patients with severe systolic dysfunction is described in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A New and Promising Therapeutic Approach for Chronic Heart Failure,” European Heart Journal, 32, pp. 847-855 (Oct. 28, 2010). 
     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 the control of a physician, with the patient given time between successive increases in VNS therapy intensity to adapt to the new intensity. As stimulation is chronically applied at each new intensity level, the patient&#39;s side effect threshold gradually increases, allowing for an increase in intensity during subsequent titration sessions. 
     Conventional general therapeutic alteration of cardiac vagal efferent activation through electrical stimulation targets only the efferent nerves of the parasympathetic nervous system, such as described in Sabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,” Heart Fail. Rev., 16:171-178 (2011), the disclosure of which is incorporated by reference. The Sabbah paper discusses canine studies using a vagus nerve stimulation system, manufactured by BioControl Medical Ltd., Yehud, Israel, which includes an electrical pulse generator, right ventricular endocardial sensing lead, and right vagus nerve cuff stimulation lead. The sensing lead enables stimulation of the right vagus nerve in a highly specific manner, which includes closed-loop synchronization of the vagus nerve stimulation pulse to the cardiac cycle. An asymmetric tri-polar nerve cuff electrode is implanted on the right vagus nerve at the mid-cervical position. The electrode provides cathodic induction of action potentials while simultaneously applying asymmetric anodal block that leads to preferential activation of vagal efferent fibers. Electrical stimulation of the right cervical vagus nerve is delivered only when heart rate is above a preset threshold. Stimulation is provided at an intensity intended to reduce basal heart rate by ten percent by preferential stimulation of efferent vagus nerve fibers leading to the heart while blocking afferent neural impulses to the brain. Although effective in partially restoring baroreflex sensitivity, increasing left ventricular ejection fraction, and decreasing left ventricular end diastolic and end systolic volumes, a portion of the therapeutic benefit is due to incidental recruitment of afferent parasympathetic nerve fibers in the vagus. Efferent stimulation alone is less effective than bidirectional stimulation at restoring autonomic balance. 
     Accordingly, a need remains for an approach to efficiently providing neurostimulation therapy, and, in particular, to neurostimulation therapy for treating chronic cardiac dysfunction and other conditions. 
     SUMMARY 
     In accordance with embodiments of the present invention, a neurostimulation system is provided, comprising: an electrode assembly; a neurostimulator coupled to the electrode assembly, said neurostimulator adapted to deliver a stimulation signal to a patient in the patient&#39;s neural fulcrum zone, said stimulation signal comprising an ON time and an OFF time; a physiological sensor configured to acquire a physiological signal from the patient; and a control system coupled to the neurostimulator and the physiological sensor. The control system is programmed to: monitor a baseline signal acquired by the physiological sensor during the OFF time periods of the stimulation signal; monitor a response signal acquired by the physiological sensor during the ON time periods of the stimulation signal; and in response to the monitored baseline signal and the monitored response signal, adjust one or more parameters of the stimulation signal to deliver the stimulation signal in the patient&#39;s neural fulcrum zone. 
     In accordance with other embodiments of the present, a method of operating an implantable medical device (IMD) comprising a physiological sensor configured to acquire a physiological signal from the patient, and a neurostimulator coupled to an electrode assembly, said neurostimulator adapted to deliver a stimulation signal to a patient. The method comprises: activating the neurostimulator to deliver a stimulation signal in a patient&#39;s neural fulcrum zone, said stimulation signal comprising an ON time and an OFF time; monitoring a baseline signal acquired by the physiological sensor during the OFF time periods of the stimulation signal; monitoring a response signal acquired by the physiological sensor during the ON time periods of the stimulation signal; and in response to the monitored baseline signal and the monitored response signal, adjusting one or more parameters of the stimulation signal to deliver the stimulation signal in the patient&#39;s neural fulcrum zone. 
     Still other embodiments of the present invention will become readily apparent to those skilled in the art from the following detailed description, wherein are described embodiments by way of illustrating the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments and its several details are capable of modifications in various obvious respects, all without departing from the spirit and the scope of the present invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive. 
    
    
     
       BRIEF DESCRIPTION OF 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. 2A and 2B  are diagrams respectively showing the implantable neurostimulator and the simulation therapy lead of  FIG. 1 . 
         FIG. 3  is a diagram showing an external programmer for use with the implantable neurostimulator of  FIG. 1 . 
         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. 
         FIG. 5  is a graph showing, by way of example, the relationship between the targeted therapeutic efficacy and the extent of potential side effects resulting from use of the implantable neurostimulator of  FIG. 1 . 
         FIG. 6  is a graph showing, by way of example, the optimal duty cycle range based on the intersection depicted in  FIG. 3 . 
         FIG. 7  is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS as provided by implantable neurostimulator of  FIG. 1 . 
         FIGS. 8A-8C  are illustrative charts reflecting a heart rate response to gradually increased stimulation intensity at different frequencies. 
         FIG. 9  illustrates a method of operating an implantable medical device comprising neurostimulator coupled to an electrode assembly. 
         FIG. 10  is an illustrative chart reflecting a heart rate response to gradually increased stimulation intensity delivered by an implanted VNS system at two different frequencies. 
         FIGS. 11A-11B  are block diagrams of neurostimulation systems in accordance with embodiments of the present invention. 
         FIG. 12  is an illustrative graph indicating monitoring periods during delivery of stimulation signals in accordance with embodiments of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     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 , in accordance with embodiments of the present invention. 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 stimulating nerve electrode assembly  125 , preferably 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 . In some embodiments, an external magnet may provide basic controls, such as described in commonly assigned U.S. Pat. No. 8,600,505, entitled “Implantable Device For Facilitating Control Of Electrical Stimulation Of Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,” the disclosure of which is incorporated by reference. For further 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, such as described in commonly assigned U.S. Pat. No. 8,571,654, entitled “Vagus Nerve Neurostimulator With Multiple Patient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” the disclosure of which is incorporated by reference. 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. 
     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. A study of the relationship between cardiac autonomic nerve activity and blood pressure changes in ambulatory dogs is described in J. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure in Ambulatory Dogs,” Heart Rhythm, Vol. 11(2), pp. 307-313 (February 2014). 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 toward 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. 2A and 2B  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 two 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. 2A , 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, such as firmware 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  internally includes a lead connector block (not shown) and a set of screws  26 . 
     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 heartbeat 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. 2B , 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 . During implantation, the connector pin  28  is guided through the receptacle  25  into the header  24  and securely fastened in place using the setscrews  26  to electrically couple the lead assembly  13  to the neurostimulator  12 . On a distal end, the lead assembly  13  terminates with the electrodes  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  is 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 monopolar cathode, 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, such as described in commonly assigned U.S. Pat. Nos. 8,600,505 and 8,571,654, cited supra.  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, smartphone, or other form of computational device. In one embodiment, the programming computer is a tablet computer that may operate under the iOS operating system from Apple Inc., such as the iPad from Apple Inc., or may operate under the Android operating system from Google Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd. In an alternative embodiment, the programming computer is a personal digital assistant handheld computer operating under the Pocket-PC, Windows Mobile, Windows Phone, Windows RT, or Windows operating systems, licensed by Microsoft Corporation, Redmond, Wash., such as the Surface from Microsoft Corporation, the Dell Axim X S and X50 personal data assistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personal data assistant, sold by Hewlett-Packard Company, Palo Alto, Calif. 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 . 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 that 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 embodiments of the present invention. 
     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 reports 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  enables 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. 
     Preferably, the electrodes  14  are helical and placed on the cervical vagus nerve  15 ,  16  at the location below where the superior and inferior cardiac branches separate from the cervical vagus nerve.  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 monopolar cathode, a proximal anode and a distal cathode, or a proximal cathode and a distal anode. In addition, an anchor tether  53  is fastened over the lead bodies  57 ,  58  that maintains the position of the helical electrodes 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 , such as described in commonly assigned U.S. Pat. No. 8,630,709, entitled “Computer-Implemented System and Method for Selecting Therapy Profiles of Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7, 2011, the disclosure of which is incorporated by reference. 
     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, such as respectively described in commonly assigned U.S. Pat. No. 8,577,458, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S. patent application, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011, pending, the disclosures of which are hereby incorporated by reference herein in their entirety. Additionally, where an integrated leadless heart rate monitor is available, the neurostimulator  12  can provide autonomic cardiovascular drive evaluation and self-controlled titration, such as respectively described in commonly-assigned U.S. Pat. No. 8,918,190, entitled “Implantable Device for Evaluating Autonomic Cardiovascular Drive in a Patient Suffering from Chronic Cardiac Dysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, and U.S. Pat. No. 8,918,191, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction with Bounded Titration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, the disclosures of which are incorporated by reference. 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, such as respectively described in commonly assigned U.S. Pat. No. 8,923,964, entitled “Implantable Neurostimulator-Implemented Method For Enhancing Heart Failure Patient Awakening Through Vagus Nerve Stimulation,” Ser. No. 13/673,811, filed on Nov. 9, 2012, the disclosure of which is incorporated by reference. 
     The VNS stimulation signal may be delivered as a therapy in a maintenance dose having an intensity that is insufficient to elicit undesirable side effects, such as cardiac arrhythmias. The VNS can be delivered with a periodic duty cycle in the range of 2% to 89% with a preferred range of around 4% to 36% that is delivered as a low intensity maintenance dose. Alternatively, the low intensity maintenance dose may comprise a narrow range approximately at 17.5%, such as around 15% to 20%. The selection of duty cycle is a trade-off among competing medical considerations. The duty cycle is determined by dividing the stimulation ON time by the sum of the ON and OFF times of the neurostimulator  12  during a single ON-OFF cycle. However, the stimulation time may also need to include ramp-up time and ramp-down time, where the stimulation frequency exceeds a minimum threshold (as further described infra with reference to  FIG. 7 ). 
       FIG. 5  is a graph  70  showing, by way of example, the relationship between the targeted therapeutic efficacy  73  and the extent of potential side effects  74  resulting from use of the implantable neurostimulator  12  of  FIG. 1 , after the patient has completed the titration process. The graph in  FIG. 5  provides an illustration of the failure of increased stimulation intensity to provide additional therapeutic benefit, once the stimulation parameters have reached the neural fulcrum zone, as will be described in greater detail below with respect to  FIG. 8 . As shown in  FIG. 5 , the x-axis represents the duty cycle  71 . The duty cycle is determined by dividing the stimulation ON time by the sum of the ON and OFF times of the neurostimulator  12  during a single ON-OFF cycle. However, the stimulation time may also include ramp-up time and ramp-down time, where the stimulation frequency exceeds a minimum threshold (as further described infra with reference to  FIG. 7 ). The y-axis represents physiological response  72  to VNS therapy. The physiological response  72  can be expressed quantitatively for a given duty cycle  71  as a function of the targeted therapeutic efficacy  73  and the extent of potential side effects  74 , as described infra. The maximum level of physiological response  72  (“max”) signifies the highest point of targeted therapeutic efficacy  73  or potential side effects  74 . 
     Targeted therapeutic efficacy  73  and the extent of potential side effects  74  can be expressed as functions of duty cycle  71  and physiological response  72 . The targeted therapeutic efficacy  73  represents the intended effectiveness of VNS in provoking a beneficial physiological response for a given duty cycle and can be quantified by assigning values to the various acute and chronic factors that contribute to the physiological response  72  of the patient  10  due to the delivery of therapeutic VNS. Acute factors that contribute to the targeted therapeutic efficacy  73  include beneficial changes in heart rate variability and increased coronary flow, reduction in cardiac workload through vasodilation, and improvement in left ventricular relaxation. Chronic factors that contribute to the targeted therapeutic efficacy  73  include improved cardiovascular regulatory function, as well as decreased negative cytokine production, increased baroreflex sensitivity, increased respiratory gas exchange efficiency, favorable gene expression, renin-angiotensin-aldosterone system down-regulation, antiarrhythmic, antiapoptotic, and ectopy-reducing anti-inflammatory effects. These contributing factors can be combined in any manner to express the relative level of targeted therapeutic efficacy  73 , including weighting particular effects more heavily than others or applying statistical or numeric functions based directly on or derived from observed physiological changes. Empirically, targeted therapeutic efficacy  73  steeply increases beginning at around a 5% duty cycle and levels off in a plateau near the maximum level of physiological response at around a 30% duty cycle. Thereafter, targeted therapeutic efficacy  73  begins decreasing at around a 50% duty cycle and continues in a plateau near a 25% physiological response through the maximum 100% duty cycle. 
     The intersection  75  of the targeted therapeutic efficacy  73  and the extent of potential side effects  74  represents one optimal duty cycle range for VNS.  FIG. 6  is a graph  80  showing, by way of example, the optimal duty cycle range  83  based on the intersection  75  depicted in  FIG. 5 . The x-axis represents the duty cycle  81  as a percentage of stimulation time over stimulation time plus inhibition time. The y-axis represents therapeutic points  82  reached in operating the neurostimulator  12  at a given duty cycle  81 . The optimal duty range  83  is a function  84  of the intersection  75  of the targeted therapeutic efficacy  73  and the extent of potential side effects  74 . The therapeutic operating points  82  can be expressed quantitatively for a given duty cycle  81  as a function of the values of the targeted therapeutic efficacy  73  and the extent of potential side effects  74  at their point of intersection in the graph  70  of  FIG. 5 . The optimal therapeutic operating point  85  (“max”) signifies a trade-off that occurs at the point of highest targeted therapeutic efficacy  73  in light of lowest potential side effects  74 , and that point will typically be found within the range of a 5% to 30% duty cycle  81 . Other expressions of duty cycles and related factors are possible. 
     Therapeutically and in the absence of patient physiology of possible medical concern, such as cardiac arrhythmias, VNS is delivered in a low-level maintenance dose that uses alternating cycles of stimuli application (ON) and stimuli inhibition (OFF) that are tuned to activate both afferent and efferent pathways. Stimulation results in parasympathetic activation and sympathetic inhibition, both through centrally mediated pathways and through efferent activation of preganglionic neurons and local circuit neurons.  FIG. 7  is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS  90 , as provided by implantable neurostimulator  12  of  FIG. 1 . The stimulation parameters enable the electrical stimulation pulse output by the neurostimulator  12  to be varied by both amplitude (output current  96 ) and duration (pulse width  94 ). The number of output pulses delivered per second determines the signal frequency  93 . In one embodiment, a pulse width in the range of 100 to 250 μSec delivers between 0.02 mA and 50 mA of output current at a signal frequency of about 10 Hz, although other therapeutic values could be used as appropriate. In general, the stimulation signal delivered to the patient may be defined by a stimulation parameter set comprising at least an amplitude, a frequency, a pulse width, and a duty cycle. 
     In one embodiment, the stimulation time is considered the time period during which the neurostimulator  12  is ON and delivering pulses of stimulation, and the OFF time is considered the time period occurring in-between stimulation times during which the neurostimulator  12  is OFF and inhibited from delivering stimulation. 
     In another embodiment, as shown in  FIG. 7 , the neurostimulator  12  implements a stimulation time  91  comprising an ON time  92 , a ramp-up time  97 , and a ramp-down time  98  that respectively precede and follow the ON time  92 . Under this embodiment, the ON time  92  is considered to be a time during which the neurostimulator  12  is ON and delivering pulses of stimulation at the full output current  96 . Under this embodiment, the OFF time  95  is considered to comprise the ramp-up time  97  and ramp-down time  98 , which are used when the stimulation frequency is at least 10 Hz, although other minimum thresholds could be used, and both ramp-up and ramp-down times  97 ,  98  last two seconds, although other time periods could also be used. The ramp-up time  97  and ramp-down time  98  allow the strength of the output current  96  of each output pulse to be gradually increased and decreased, thereby avoiding deleterious reflex behavior due to sudden delivery or inhibition of stimulation at a programmed intensity. 
     Therapeutic vagus neural stimulation has been shown to provide cardioprotective effects. Although delivered in a maintenance dose having an intensity that is insufficient to elicit undesirable side effects, such as cardiac arrhythmias, ataxia, coughing, hoarseness, throat irritation, voice alteration, or dyspnea, therapeutic VNS can nevertheless potentially ameliorate pathological tachyarrhythmias in some patients. Although VNS has been shown to decrease defibrillation threshold, VNS has not been shown to terminate VF in the absence of defibrillation. VNS prolongs ventricular action potential duration, so may be effective in terminating VT. In addition, the effect of VNS on the AV node may be beneficial in patients with AF by slowing conduction to the ventricles and controlling ventricular rate. 
     Neural Fulcrum Zone 
     As described above, autonomic regulation therapy results in simultaneous creation of action potentials that simultaneously propagate away from the stimulation site in afferent and efferent directions within axons comprising the cervical vagus nerve complex. 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. Different parameter settings for the neurostimulator  12  may be adjusted to deliver varying stimulation intensities to the patient. The various stimulation parameter settings for current VNS devices include output current amplitude, signal frequency, pulse width, signal ON time, and signal OFF time. 
     When delivering neurostimulation therapies to patients, it is generally desirable to avoid stimulation intensities that result in either excessive tachycardia or excessive bradycardia. However, researchers have typically utilized the patient&#39;s heart rate changes as a functional response indicator or surrogate for effective recruitment of nerve fibers and engagement of the autonomic nervous system elements responsible for regulation of heart rate, which may be indicative of therapeutic levels of VNS. Some researchers have proposed that heart rate reduction caused by VNS stimulation is itself beneficial to the patient. 
     In accordance with embodiments of the present invention, a neural fulcrum zone is identified, and neurostimulation therapy is delivered within the neural fulcrum zone. This neural fulcrum zone corresponds to a combination of stimulation parameters at which autonomic engagement is achieved but for which a functional response determined by heart rate change is nullified due to the competing effects of afferently and efferently transmitted action potentials. In this way, the tachycardia-inducing stimulation effects are offset by the bradycardia-inducing effects, thereby minimizing side effects such as significant heart rate changes while providing a therapeutic level of stimulation. One method of identifying the neural fulcrum zone is by delivering a plurality of stimulation signals at a fixed frequency but with one or more other parameter settings changed so as to gradually increase the intensity of the stimulation. 
       FIGS. 8A-8C  provide illustrative charts reflecting the location of the neural fulcrum zone.  FIG. 8A  is a chart  800  illustrating a heart rate response in response to such a gradually increased intensity at a first frequency, in accordance with embodiments of the present invention. In this chart  800 , the x-axis represents the intensity level of the stimulation signal, and the y-axis represents the observed heart rate change from the patient&#39;s baseline basal heart rate observed when no stimulation is delivered. In this example, the stimulation intensity is increased by increasing the output current amplitude. 
     A first set  810  of stimulation signals is delivered at a first frequency (e.g., 10 Hz). Initially, as the intensity (e.g., output current amplitude) is increased, a tachycardia zone  851 - 1  is observed, during which period, the patient experiences a mild tachycardia. As the intensity continues to be increased for subsequent stimulation signals, the patient&#39;s heart rate response begins to decrease and eventually enters a bradycardia zone  853 - 1 , in which a bradycardia response is observed in response to the stimulation signals. As described above, the neural fulcrum zone is a range of stimulation parameters at which the functional effects from afferent activation are balanced with or nullified by the functional effects from efferent activation to avoid extreme heart rate changes while providing therapeutic levels of stimulation. In accordance with some embodiments, the neural fulcrum zone  852 - 1  can be located by identifying the zone in which the patient&#39;s response to stimulation produces either no heart rate change or a mildly decreased heart rate change (e.g., &lt;5% decrease, or a target number of beats per minute). As the intensity of stimulation is further increased at the fixed first frequency, the patient enters an undesirable bradycardia zone  853 - 1 . In these embodiments, the patient&#39;s heart rate response is used as an indicator of autonomic engagement. In other embodiments, other physiological responses may be used to indicate the zone of autonomic engagement at which the propagation of efferent and afferent action potentials are balanced, the neural fulcrum zone. 
       FIG. 8B  is a chart  860  illustrating a heart rate response in response to such a gradually increased intensity at two additional frequencies, in accordance with embodiments of the present invention. In this chart  860 , the x-axis and y-axis represent the intensity level of the stimulation signal and the observed heart rate change, respectively, as in  FIG. 8A , and the first set  810  of stimulation signals from  FIG. 8A  is also shown. 
     A second set  810  of stimulation signals is delivered at a second frequency lower than the first frequency (e.g., 5 Hz). Initially, as the intensity (e.g., output current amplitude) is increased, a tachycardia zone  851 - 2  is observed, during which period, the patient experiences a mild tachycardia. As the intensity continues to be increased for subsequent stimulation signals, the patient&#39;s heart rate response begins to decrease and eventually enters a bradycardia zone  853 - 2 , in which a bradycardia response is observed in response to the stimulation signals. The low frequency of the stimulation signal in the second set  820  of stimulation signals limits the functional effects of nerve fiber recruitment and, as a result, the heart response remains relatively limited. Although this low-frequency stimulation results in minimal side effects, the stimulation intensity is too low to result in effective recruitment of nerve fibers and engagement of the autonomic nervous system. As a result, a therapeutic level of stimulation is not delivered. 
     A third set  830  of stimulation signals is delivered at a third frequency higher than the first and second frequencies (e.g., 20 Hz). As with the first set  810  and second set  820 , at lower intensities, the patient first experiences a tachycardia zone  851 - 3 . At this higher frequency, the level of increased heart rate is undesirable. As the intensity is further increased, the heart rate decreases, similar to the decrease at the first and second frequencies but at a much higher rate. The patient first enters the neural fulcrum zone  852 - 3  and then the undesirable bradycardia zone  853 - 3 . Because the slope of the curve for the third set  830  is much steeper than the second set  820 , the region in which the patient&#39;s heart rate response is between 0% and −5% (e.g., the neural fulcrum zone  852 - 3 ) is much narrower than the neural fulcrum zone  852 - 2  for the second set  820 . Accordingly, when testing different operational parameter settings for a patient by increasing the output current amplitude by incremental steps, it can be more difficult to locate a programmable output current amplitude that falls within the neural fulcrum zone  852 - 3 . When the slope of the heart rate response curve is high, the resulting heart rate may overshoot the neural fulcrum zone and create a situation in which the functional response transitions from the tachycardia zone  851 - 3  to the undesirable bradycardia zone  853 - 3  in a single step. At that point, the clinician would need to reduce the amplitude by a smaller increment or reduce the stimulation frequency in order to produce the desired heart rate response for the neural fulcrum zone  852 - 3 . 
       FIG. 8C  is a chart  880  illustrating mean heart rate response surfaces in conscious, normal dogs during 14-second periods of right cervical vagus VNS stimulation ON-time. The heart rate responses shown in z-axis represent the percentage heart rate change from the baseline heart rate at various sets of VNS parameters, with the pulse width the pulse width set at 250 μSec, the pulse amplitude ranging from 0 mA to 3.5 mA (provided by the x-axis) and the pulse frequency ranging from 2 Hz to 20 Hz (provided by the y-axis). Curve  890  roughly represents the range of stimulation amplitude and frequency parameters at which a null response (i.e., 0% heart rate change from baseline) is produced. This null response curve  890  is characterized by the opposition of functional responses (e.g., tachycardia and bradycardia) arising from afferent and efferent activation. 
       FIG. 9  illustrates a method of operating an implantable medical device (IMD) comprising neurostimulator coupled to an electrode assembly. This method can be implemented using, for example, the VNS systems described above. 
     In step  901 , the IMD is activated to deliver to the patient a plurality of stimulation signals at a first frequency (e.g., 2 Hz, as described above with respect to  FIG. 9 ). Each of the plurality of stimulation signals is delivered having at least one operational parameter setting different than the other stimulation signals. For example, as described above, the output current amplitude is gradually increased while maintaining a fixed frequency. In other embodiments, different parameters may be adjusted to increase the intensity of stimulation at a fixed frequency. 
     In step  902 , the patient&#39;s physiological response is monitored. In the example described above with respect to  FIG. 8 , the physiological response being observed is the patient&#39;s basal heart rate during stimulation at the various intensities at the first frequency. The physiological response may be measured using an implanted or external physiological sensor, such as, e.g., an implanted heart rate monitor  31 , as well as other available physiological data, for instance, as derivable from an endocardial electrogram. 
     In step  903 , the neural fulcrum zone for that first frequency is identified. In the example described above with respect to  FIG. 8 , the neural fulcrum zone corresponds to the range of stimulation parameter settings that result in a heart rate change of about 0% to about a decrease of 5%. In other embodiments, a different range of target heart rate changes or other physiological responses may be used to identify the neural fulcrum zone. 
     In accordance with some embodiments, stimulation at multiple frequencies may be delivered to the patient. In step  904 , the IMD is activated to deliver to the patient a plurality of stimulation signals at a second frequency. In step  905 , the patient&#39;s physiological response (e.g., basal heart rate) at the second frequency is observed. In step  906 , the neural fulcrum zone for the second frequency is identified. Additional frequencies may be delivered, and corresponding neural fulcrum zones may be identified for those frequencies. 
     As described in the various embodiments above, neural fulcrum zones may be identified for a patient. Different neural fulcrum zones may be identified using different stimulation signal characteristics. Based on the signal characteristics, the patient&#39;s physiological response to the stimulation may be mild with a low slope, as with, for example, the first set of stimulation signals  810  at a low frequency, or may be extreme with a large slope, as with, for example, the third set of stimulation signals  830  at a high frequency. Accordingly, it may be advantageous to identify a frequency at which the reaction is moderate, producing a moderate slope corresponding to a wide neural fulcrum zone in which therapeutically effective stimulation may be provided to the patient. 
     The observation of tachycardia in the tachycardia zone  851 - 2  and bradycardia in the bradycardia zone  853 - 2  indicates that the stimulation is engaging the autonomic nervous system, which suggests that a therapeutically effective intensity is being delivered. Typically, clinicians have assumed that stimulation must be delivered at intensity levels where a significant physiological response is detected. However, by selecting an operational parameter set in the neural fulcrum zone  852 - 2  that lies between the tachycardia  851 - 2  and the bradycardia zone  853 - 2 , the autonomic nervous system may still be engaged without risking the undesirable effects of either excessive tachycardia or excessive bradycardia. At certain low frequencies, the bradycardia zone may not be present, in which case the neural fulcrum zone  852 - 2  is located adjacent to the tachycardia zone. While providing stimulation in the neural fulcrum zone, the autonomic nervous system remains engaged, but the functional effects of afferent and efferent activation are sufficiently balanced so that the heart rate response is nullified or minimized (&lt;5% change). Ongoing stimulation therapy may then be delivered to the patient at a fixed intensity within the neural fulcrum zone. 
     Fine Control of Neurostimulation 
     In accordance with embodiments of the present invention, fine control of neurostimulation intensity settings may be achieved for locating the neural fulcrum zone. A patient&#39;s physiological response to stimulation may vary depending on stimulation frequency and other stimulation parameters, and may be monitored by a clinician as a parameter indicative of the patient&#39;s autonomic balance. In accordance with embodiments of the present invention, one physiological response indicative of autonomic balance is a heart rate response. 
     In the embodiment shown in  FIG. 8B , the patient&#39;s varying heart rate response to stimulation at different stimulation frequencies is shown. At low stimulation frequencies, such as the 5 Hz frequency corresponding to the second set  820  of stimulation signals in  FIG. 8B , the slope of the heart rate response curve is very low, and a step change in stimulation intensity results in a small change in cardiac response. In contrast, at high stimulation frequencies, such as the 20 Hz frequency corresponding to the third set  830  of stimulation signals in  FIG. 8B , the slope of the heart rate response curve is large, particularly in the neural fulcrum zone  852 - 3 , and a step change in stimulation intensity results in a large change in cardiac response. In accordance with embodiments of the present invention, an understanding of the relationship between the neural fulcrum zone and the stimulation parameters may be used to enable fine control of intensity settings when attempting to locate the neural fulcrum zone. 
       FIG. 10  is an illustrative chart reflecting a heart rate response to gradually increased stimulation intensity delivered by an implanted VNS system at two different frequencies. In this simplified example, the intensity setting along the x-axis comprises the stimulation output current, a first set  1010  of stimulation signals is delivered at a first frequency (e.g., 20 Hz), and a second set  1020  of stimulation signals is delivered at a second frequency (e.g., 10 Hz). 
     In various embodiments, the various stimulation parameter settings for the VNS system are adjusted according to predefined increments. In the example shown in  FIG. 10 , adjustments to the stimulation output current are made in 0.5 mA increments. In other cases, the adjustments to the stimulation output current may be made in different increments, such as, for example, 0.25 mA or 1.0 mA. In some cases, these predefined increments may be dictated by hardware or software limitations, such as a VNS pulse generator that can only be adjusted in 0.5 mA increments. In other cases, the predefined increments may be imposed by the manufacturer or the clinician to improve consistency, simplicity, or administrative ease. 
     If the VNS system were used to deliver a continuous range of output currents at the first and second frequencies, the continuous heart rate response curves  1010  and  1020  shown in  FIG. 10  would be detected. However, in accordance with embodiments of the present invention, the VNS system is configured to deliver stimulation output currents at predetermined increments of 0.5 mA. As a result, when a first set  1010  of stimulation signals is delivered at 20 Hz, four points along the heart rate response curve are detected:  1012 - 1 ,  1012 - 2 ,  1012 - 3 , and  1012 - 4 . The heart rate responses at  1012 - 1 ,  1012 - 2 , and  1012 - 3  detected at the first three current levels (0.5 mA, 1.0 mA, and 1.5 mA) all fall within the tachycardia zone  851 - 1  for the first frequency. When the output current is increased by the predetermined increment of 0.5 mA, the next detected heart rate response at  1012 - 4  falls in the bradycardia zone  853 - 1 . Because of the steep slope of the heart rate response curve in the neural fulcrum zone  852 - 1 , when increasing the output current by the predefined 0.5 mA increment, a heart rate response in the neural fulcrum zone  852 - 2  is not detected. 
     When attempting to locate the neural fulcrum for a particular patient, if the detected heart rate response transitions from the tachycardia zone  851 - 1  to the bradycardia zone  853 - 1  in response to a single increment increase of the intensity setting, it may be desirable to use a different stimulation frequency to locate the neural fulcrum. Accordingly, the stimulation frequency is decreased (e.g., to 10 Hz, as shown in  FIG. 10 ), and a second set  1020  of stimulation signals are delivered to the patient at the lower frequency. As with the first set  1010 , the intensity of the stimulation is increased by predefined increments (e.g., of 0.5 mA) to provide heart rate response points  1022 - 1 ,  1022 - 2 ,  1022 - 3 , and  1022 - 4 . Unlike the first set  1010 , the heart rate response curve for the second frequency has a lower slope, which provides a clinician with a finer resolution investigation of the heart rate response curve in the neural fulcrum zone  852 - 2 , even when limited by the same 0.5 mA predefined increment of output current. As shown in  FIG. 10 , the first two stimulation signals at 0.5 mA and 1.0 mA result in heart rate response points  1022 - 1  and  1022 - 2 , respectively, which fall within the tachycardia zone  851 - 2 . Increasing the output current to 1.5 mA results in heart rate response point  1022 - 3 , which falls squarely within the neural fulcrum zone  852 - 2 . If the output current is increased by another predefined increment to 2.0 mA, a heart rate response point  1022 - 4  falling within the bradycardia zone  853 - 1  is detected. 
     As a result, a clinician may determine that the stimulation parameter settings resulting in the heart rate response point  1022 - 3  correspond to the neural fulcrum zone. Accordingly, the VNS system may be configured to chronically deliver stimulation signals corresponding to the identified neural fulcrum zone to treat chronic cardiac dysfunction. 
     In some situations, such as that illustrated in the second set  820  of stimulation signals of  FIG. 8B , the stimulation frequency may be so low that stimulation signal limits the functional effects of nerve fiber recruitment, and the heart rate response remains relatively limited. Although this low frequency stimulation results in minimal side effects and never induces bradycardia, despite increases in the output current, the overall stimulation intensity remains too low to result in effective recruitment of nerve fibers and engagement of the autonomic nervous system. As a result, a therapeutic level of stimulation is not delivered. This is illustrated in  FIG. 8B  by the low slope of the heart rate response to the second set  820  of stimulation signals. Despite increases in the output current up to maximum levels tolerable by the patient, the stimulation signals never reach the level of autonomic engagement. 
     In accordance with embodiments of the present invention, if incremental increases of an intensity setting (e.g., output current) at a first frequency do not result in an adequate change in the heart rate, the frequency of stimulation may be increased to produce a heart rate response curve with a larger slope. The output current may be reduced to an initial level (e.g., 0.5 mA), with subsequent stimulation signals delivered at incrementally increasing output currents. After transitioning past the tachycardia zone, a stimulation signal delivered at the higher frequency at one output current level will induce a heart rate response point that falls within the neural fulcrum zone, and a subsequent stimulation signal with a single predefined incremental increase in the output current level induces a heart rate response in the bradycardia zone. The output current level may then be reduced by the predefined increment to bring the stimulation back into the neural fulcrum zone. 
     Dynamic Stimulation Adjustment 
     In some embodiments described herein, the stimulation parameters may be manually adjusted by a clinician in order to locate the neural fulcrum zone. In accordance with other embodiments of the present invention, computer-implemented methods are used for monitoring the patient&#39;s response to stimulation and dynamically adjusting stimulation parameters in order to locate the neural fulcrum zone. This monitoring and dynamic adjustment may be performed in clinic utilizing an external control system, or it may be automatically performed by an implanted control system coupled to an implanted physiological sensor, such as, for example, an ECG sensor for monitoring heart rate. 
       FIG. 11A  is a simplified block diagram of an implanted neurostimulation system  1100  in accordance with embodiments of the present invention. The implanted neurostimulation system  1100  comprises a control system  1102  comprising a processor programmed to operate the system  1100 , a memory  1103 , a physiological sensor  1104 , and a stimulation subsystem  1106 . The physiological sensor  1104  may be configured to monitor any of a variety of patient physiological signals, and the stimulation subsystem  1106  may be configured to deliver a stimulation signal to the patient. In one example, the physiological sensor  1104  comprises an ECG sensor for monitoring heart rate, and the stimulation subsystem  1106  comprises a neurostimulator  12  programmed to deliver ON-OFF cycles of stimulation to the patient&#39;s vagus nerve. 
     The control system  1102  is programmed to activate the neurostimulator  12  to deliver varying stimulation intensities to the patient and to monitor the physiological signals in response to those stimulation signals. 
       FIG. 12  is an illustrative graph indicating monitoring periods during delivery of stimulation signals in accordance with embodiments of the present invention. First, the control system  1102  activates the physiological sensor  1104  to monitor the patient&#39;s heart rate (or other physiological signal) during a resting period  1202  in which the neurostimulator  12  is in an OFF time period with no stimulation signals being delivered to the patient. The monitoring heart rate during the resting period  1202  establishes the patient&#39;s baseline heart rate. 
     Next, during the stimulation ON time period  92 , the control system  1102  activates the physiological sensor  1104  to monitor the patient&#39;s heart rate response to the stimulation during a response period  1206 . As described above, the heart rate response during stimulation can be used to locate the neural fulcrum zone. For example, if tachycardia is detected, the control system  1102  may be configured to automatically increase the intensity of subsequent stimulation signals in order to travel farther along the response curve described above with respect to  FIG. 8B . The control system  1102  may be further programmed to gradually increase the stimulation intensity until bradycardia is detected and the neural fulcrum is located. 
     In accordance with some embodiments, the control system  1102  may be programmed to maintain a stimulation parameter setting for a plurality of cycles, while monitoring the baseline heart rate and heart rate response for each stimulation cycle. The control system  1102  may be programmed to calculate one or more statistical descriptors (e.g., mean, median, minimum, maximum, etc.) of the baseline heart rates and heart rate responses in order to provide a more accurate measurement of the patient&#39;s response to stimulation by aggregating the multiple responses to stimulation. In addition, the control system  1102  may store the physiological measurements in the memory  1103  for performing these calculations for later analysis. 
     In accordance with some embodiments, the control system  1102  may be programmed to utilize a delay period  1208  following completion of an ON time period prior to monitoring the baseline heart rate during resting period  1202 . This delay period  1208  may comprise, for example, between one and five seconds, or more, and may provide the patient&#39;s heart with a period of time to return to its baseline heart rate before resuming monitoring. In accordance with some embodiments, the control system  1102  may be programmed to utilize an ON time delay period (not shown) following initiation of an ON time period prior to monitoring the heart rate response during the response period  1206 . This ON time delay period may comprise, for example, between one and five seconds, or more, and may provide the patient&#39;s heart with a period of time to adjust from the baseline rate and stabilize at the stimulation response rate before initiating monitoring during the response period  1206 . In some embodiments, the physiological sensor  1104  may continuously monitor the patient&#39;s heart rate (or other physiological signal), and the control system  1102  is programmed to locate the heart rate during the particular periods of interest (e.g., resting period  1202  and response period  1206 ). 
     The synchronization of the stimulation signal delivery and the monitoring of the patient&#39;s heart rate may be advantageously implemented using control system in communication with both the stimulation subsystem  1106  and the physiological sensor  1104 , such as by incorporating all of these components into a single implantable device. In accordance with other embodiments, the control system may be implemented in a separate implanted device or in an external programmer  1120 , as shown in  FIG. 11B . The external programmer  1120  in  FIG. 11B  may be utilized by a clinician or by the patient for adjusting stimulation parameters. The external programmer  1120  is in wireless communication with the implanted medical device  1110 , which includes the stimulation subsystem  1116 . In the illustrated embodiment, the physiological sensor  1114  is incorporated into the implanted medical device  1110 , but in other embodiments, the sensor  1114  may be incorporated into a separate implanted device, may be provided externally and in communication with the external programmer  1120 , or may be provided as part of the external programmer  1120 . 
     Long-Term Monitoring 
     In accordance with embodiments of the present invention, the implanted device includes a physiological sensor configured to acquire a physiological signal from the patient and a non-volatile memory for recording the physiological signals over extended periods of time on an ambulatory basis. In some embodiments, the physiological sensor comprises a heart rate sensor for measuring heart rate variability. This can permit the device to deliver neurostimulation signals to the patient on a chronic basis, while recording the patient&#39;s physiological response to the stimulation outside of the clinic over extended periods of time. The physiological signals may be recorded over periods of time such as, for example, days, weeks, months, or years. The recording of the physiological signals may be continuous (e.g., 24 hours per day, 7 days a week), or may be intermittent. In systems where the monitoring and recording is intermittent, the recording may be performed for any desired length of time (e.g., minutes, hours, etc.) and at any desired periodicity (e.g., during certain periods of the day, once per hour, day, week, month, or other period of interest). 
     The implanted device may include a communication interface for wirelessly transmitting the recorded physiological signals to an external computing device, such as the external programmer described above. The recorded signals can then be analyzed, evaluated, or otherwise reviewed by a clinician. As a result, the clinician can set the stimulation parameters for the patient&#39;s implanted device, and then can review the patient&#39;s response to chronic stimulation at that parameter setting over extended periods of time. The extended ambulatory data can permit the clinician to adjust or refine the stimulation parameters to achieve the optical therapeutic effect, without being limited to the physiological signals of short duration recorded in clinic. 
     Closed-Loop Neurostimulation 
     As described above, embodiments of the implanted device may include a physiological sensor, such as a heart rate sensor, configured to monitor a physiological signal from the patient over extended periods of time on an ambulatory basis. In accordance with embodiments of the present invention, the implanted device may be configured to adjust stimulation parameters to maintain stimulation in the neural fulcrum zone based on detected changes in the physiological response to stimulation. 
     In some embodiments described above, the identification of the neural fulcrum zone and the programming of the stimulation parameters to deliver stimulation signals in the neural fulcrum zone may be performed in a clinic by a healthcare provider. In some embodiments, the implanted medical device may be configured to automatically monitor the patient&#39;s physiological response using an implanted physiological sensor to initially identify the neural fulcrum zone and set the stimulation parameters to deliver signals in the neural fulcrum zone. In addition, under certain circumstances, the patient&#39;s physiological response to those initial stimulation parameters may change. This change could occur as the stimulation is chronically delivered over an extended period of time as the patient&#39;s body adjusts to the stimulation. Alternatively, this change could occur as a result of other changes in the patient&#39;s condition, such as changes in the patient&#39;s medication, disease state, circadian rhythms, or other physiological change. 
     If the changes in the patient&#39;s response to stimulation results in a change in the patient&#39;s response curve, the initially identified stimulation parameters may no longer deliver stimulation in the neural fulcrum zone. Therefore, it may be desirable for the implanted medical device to automatically adjust one or more stimulation parameters (e.g., pulse amplitude) so that subsequent stimulation signals may be delivered in the neural fulcrum zone. For example, in embodiments described above, where the monitored physiological response is the patient&#39;s heart rate, then if tachycardia is later detected in response to stimulation signals that had previously resulted in a transition heart rate response, the IMD may be configured to automatically increase the pulse amplitude (or other stimulation parameters) until a transition heart rate response is again detected. Subsequent stimulation may continue to be delivered using the new stimulation parameters until another change in the patient&#39;s physiological response is detected. 
     In some embodiments, the patient&#39;s physiological response may be substantially continuously monitored. In other embodiments, the patient&#39;s physiological response may be monitored on a periodic basis, such as, for example, every minute, hour, day, or other periodic or aperiodic schedule that may be desired in order to provide the desired monitoring schedule. In other embodiments, the patient&#39;s physiological response may be monitored in response to a control signal delivered by an external device, such as a control magnet or wireless data signal from a programming wand. The external control signal to initiate monitoring may be delivered when it is desired to monitor the physiological response when a patient condition is changing, such as when the patient is about to take a medication, is about to go to sleep, or has just wakened. In some embodiments, the external control signal may be used by the patient when an automatically increasing stimulation intensity in response to monitoring physiological signals is causing undesirable side effects. When the IMD receives such a control signal, the IMD may be programmed to automatically reduce the stimulation intensity until the side effects are alleviated (as indicated, for example, by a subsequent control input). 
     It will be understood that output current is merely one example of a stimulation parameter that may be adjusted in order to identify the neural fulcrum zone. In other embodiments, the stimulation may be varied by adjusting the other intensity parameters, such as, for example, pulse width, pulse frequency, and duty cycle. 
     In various embodiments described above, the patient&#39;s heart rate response is used as the patient parameter indicative of the patient&#39;s autonomic regulatory function in response to the stimulation for locating the neural fulcrum zone. In other embodiments, different patient parameters may be monitored in conjunction with stimulation, including, for example, other heart rate variability parameters, ECG parameters such as PR interval and QT interval, and non-cardiac parameters such as respiratory rate, pupil diameter, and skin conductance. Increases and decreases in these patient parameters in response to changes in stimulation intensity may be used to identify the patient&#39;s neural fulcrum. If the change in the patient parameter in response to an incremental increase in a stimulation parameter is too large to enable identification of the neural fulcrum zone (e.g., the slope of the response curve is large), the frequency of the stimulation may be decreased and an additional set of stimulation signals may be delivered to the patient. At the lower frequency, the slope of the response curve will decrease, enabling a finer resolution identification of the neural fulcrum zone. Conversely, if the change in the patient parameter is too low (e.g., the slope of the response curve is too small), the frequency may be increased in order to achieve finer resolution identification of the neural fulcrum zone. 
     While the invention has been particularly shown and described as referenced to the embodiments thereof, 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.