# Patent

## Title
Vagus nerve stimulation and subcutaneous defibrillation system

## Abstract

Systems and methods are provided for delivering vagus nerve stimulation and cardioversion/defibrillation therapies to patients for treating chronic heart failure. The vagus nerve stimulation and cardioversion/defibrillation therapies may be provided using a single implantable pulse generator, which can coordinate delivery of the therapies to provide an acute vagus nerve stimulation therapy in advance of delivering cardioversion-defibrillation energy.

## Background
FIELD
This application relates to stimulation therapies.
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 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'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's office to have the titration performed. Scheduling conflicts in the provider'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.
CHF patients are also at a significantly elevated risk of life-threatening ventricular arrhythmias, and in particular, ventricular fibrillation and ventricular tachycardia. Implantable cardioverter-defibrillators (ICDs) are a common, effective therapy for these arrhythmias. Traditional ICD systems include a battery-powered electrical impulse generator and have utilized transvenous lead systems to detect cardiac arrhythmias and deliver electrical impulses to correct the arrhythmia. More recently, subcutaneous ICD systems have been developed to allow for less invasive implantation, and to avoid the complications and risks associated with transvenous lead insertion. Although ICDs can provide an effective therapy to treating acute events, they fail to provide effective chronic therapies to improve the patient's general condition.
Accordingly, there is a need for improved treatment methods utilizing stimulation therapies for treating chronic cardiac dysfunction and other conditions.
SUMMARY
Systems and methods are provided for delivering vagus nerve stimulation and cardioversion/defibrillation therapies to patients for treating chronic heart failure. The vagus nerve stimulation and cardioversion/defibrillation therapies may be provided using a single implantable pulse generator, which can coordinate delivery of the therapies to provide an acute vagus nerve stimulation therapy in advance of delivering cardioversion-defibrillation energy.
In accordance with embodiments of the present invention, an implantable neurostimulation system is provided, comprising: a pulse generation module comprising a control system, a vagus nerve stimulation (VNS) subsystem, and an implantable cardioverter-defibrillator (ICD) subsystem; a first electrode assembly coupled to the pulse generation module, said first electrode assembly comprising a VNS electrode configured to couple to a vagus nerve; and a second electrode assembly coupled to the pulse generation module, said second electrode assembly comprising a first subcutaneous electrode.
In accordance with embodiments of the present invention, an implantable neurostimulation system is provided, comprising: a primary pulse generation module comprising a primary control system and an implantable cardioverter-defibrillator (ICD) subsystem; a secondary pulse generation module comprising a secondary control system and a vagus nerve stimulation (VNS) subsystem, wherein the secondary pulse generation module is in data communication with the primary pulse generation module; a first electrode assembly coupled to the primary pulse generation module, said first electrode assembly comprising a first subcutaneous electrode; and a second electrode assembly coupled to the secondary pulse generation module, said second electrode assembly comprising a VNS electrode configured to couple to a vagus nerve.
In accordance with embodiments of the present invention, a method of operating an implantable neurostimulation system is provided, comprising: delivering a chronic VNS therapy to the vagus nerve with a vagus nerve stimulation (VNS) subsystem of a pulse generation module; and in response to detection of a cardiac event, delivering electrical cardioversion-defibrillation energy with an implantable cardioverter-defibrillator (ICD) subsystem of the pulse generation module.
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.
FIGS. 9A-9G illustrate front anatomical diagrams showing various configurations of ICD/VNS systems, in accordance with embodiments of the present invention.
FIG. 10 illustrates a block diagram of an implantable pulse generation module, in accordance with embodiments of the present invention.
FIG. 11 illustrates a method for delivering coordinated VNS and ICD therapies, 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 and to adjust stimulation parameters during the initial stimulation titration process. 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'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 19a-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'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'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'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'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'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'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'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'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 set screws 26 to electrically couple the lead assembly 13 to the neurostimulator 12. 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 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's vagus nerve oriented with the end of the helical electrodes 14 facing the patient's head. In an alternate embodiment, the helical electrodes 14 are positioned around the patient's vagus nerve 15, 16 oriented with the end of the helical electrodes 14 facing the patient'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, smart phone, 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 X5 and X50 personal data assistants, sold by Dell, Inc., Round Top, Tex., and 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 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 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 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'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's vagus nerve 61 oriented with the end of the helical electrodes 14 facing the patient'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 helical electrodes' 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'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'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 59a-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's physiological requirements prior to being programmed into the neurostimulator 12, such as described in commonly-assigned U.S. Patent application 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, now U.S. Pat. No. 8,630,709 issued Jan. 14, 2014, 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. Patent application 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, now U.S. Pat. No. 8,918,190 issued Dec. 23, 2014, and U.S. Patent application 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, now U.S. Pat. No. 8,918,191 issued Dec. 23, 2014, 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. Patent application 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, now U.S. Pat. No. 8,923,964 issued Dec. 30, 2014, 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 25%. The selection of duty cycle is a tradeoff 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). When including the ramp-up and ramp-down times, the total duty cycle may be calculated as the ON time plus the ramp-up and ramp-down times divided by the OFF time, ON time, and ramp-up and ramp-down times, and may be, e.g., between 15% and 30%, and more specifically approximately 23%. 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, anti-arrhythmic, anti-apoptotic, 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 tradeoff 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'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 some embodiments, 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 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'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'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's response to stimulation produces either no heart rate change or a mildly decreased heart rate change (e.g., <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'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'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 of 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'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 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.
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 health care provider. In some embodiments, the implanted medical device may be configured to automatically monitor the patient'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'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's body adjusts to the stimulation. Alternatively, this change could occur as a result of other changes in the patient's condition, such as changes in the patient's medication, disease state, circadian rhythms, or other physiological change.
If the changes in the patient's response to stimulation result in a change in the patient'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'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's physiological response is detected.
In some embodiments, the patient's physiological response may be substantially continuously monitored. In other embodiments, the patient'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'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 awoken from sleep. 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).
Implantable VNS/ICD System
Implantable cardioverter-defibrillators (ICDs) have been used to counter arrhythmic heart conditions and to prevent death from ventricular arrhythmias. Traditional ICD systems have utilized transvenous lead systems, but more recently, subcutaneous ICD systems have been developed to allow for less invasive implantation, and to avoid the complications and risks associated with transvenous lead insertion. As described above, patients suffering from congestive heart failure are at a significantly elevated risk for life-threatening ventricular arrhythmias, and, in particular, ventricular fibrillation and ventricular tachycardia, for which defibrillation is an effective therapy. In addition, VNS has been shown to decrease the defibrillation threshold. In accordance with embodiments of the present invention, an implantable VNS/ICD system is used to provide both neurostimulation for autonomic regulation therapy and defibrillation with a single implantable pulse generator. Combining the VNS functionality with the ICD functionality can minimize implant size, invasiveness, and complexity of implantation surgery, as well as provide other advantages described below.
FIGS. 9A-9G are front anatomical diagrams showing, by way of example, various implantable VNS/ICD systems in accordance with embodiments of the present invention.
FIG. 9A is a front anatomical diagram showing a two-lead VNS/ICD system 900a, in accordance with embodiments of the present invention. The system 900a comprises a pulse generation module 910a having a first electrode assembly for providing VNS stimulation, as described above with respect to FIG. 1, and a second electrode assembly for providing stimulation for defibrillation. The first electrode assembly comprises a first lead assembly 920a and a bipolar electrode 14 which is implanted on either vagus nerve (e.g., the left vagus nerve 15, as shown in FIG. 9A). The second electrode assembly comprises a second lead assembly 930a and a unipolar electrode 940a, sometimes referred to as a shock coil, provided at a distal end of the second lead assembly 930a. In this embodiment, the housing of the pulse generation module 910a is used as the second electrode, which together with the unipolar electrode 940a produce an electric field delivering stimulation to the patient's heart.
Sensing electrodes 950 may also be provided at an intermediate position along second lead assembly 930a for detecting subcutaneous ECG to determine when to deliver the defibrillation stimulation. In other embodiments, stimulation electrodes (e.g., the unipolar electrode 940a, the housing of the pulse generation module 910a, and VNS bipolar electrode 14) may be used for sensing ECG in addition to the sensing electrodes 950 to provide additional ECG sensing vectors, or in place of the dedicated sensing electrodes 950 to reduce the total number of electrodes in the system 900a. 
FIG. 10 is a simplified block diagram of the implantable pulse generation module 910a. The pulse generation module 910a comprises an ICD subsystem 1010, a VNS subsystem 1020, a header assembly 1040, a control system 1030, a memory 1032, a communications interface 1034, and a battery 1036. The control system 1102 comprises a processor and other logic programmed to control the operation of the pulse generation module 910a. The memory 1032 may be used to store operational parameters for the pulse generation module 910a and data regarding sensed physiological signals and stimulation delivery. The communications interface 1034 may be used to communicate with other devices, such as an external programmer for programming and retrieving data from the module 910a, or one or more implanted or external sensors for detecting ECG or other patient physiological signals. The communications interface 1034 may comprise any of a variety of wireless communication systems suitable for use with an implanted device. The battery 1036 may comprise any type of battery suitable for powering the module 910a, such as a lithium carbon monofluoride primary battery or a rechargeable secondary cell battery. Because the power demands of defibrillation and VNS differ, in some embodiments, separate batteries may be used for powering the ICD subsystem 1010 and the VNS subsystem 1020.
The ICD subsystem 1010 comprises an ICD pulse generator 1012, an ICD electrode 1014, and an ECG sensing module 1016. The VNS subsystem 1020 comprises a VNS pulse generator 1022. The ICD pulse generator 1012 and the VNS pulse generator may be implemented as separate hardware components, or may be implemented using common hardware components.
As described above, the ICD electrode 1014 is used in conjunction with the unipolar electrode 940a to provide the defibrillation vector 960a, and may be implemented using the housing of the pulse generation module 910a. For example, the electrode may comprise the entire conductive exterior of the housing, an electrically active portion of the housing, or a discrete electrode coupled to or formed on an exterior surface of the housing. In other embodiments described below, the second defibrillation electrode may be provided on a lead assembly instead of the housing of the module 910a. 
In the embodiment shown in FIG. 9A, sensing electrodes 950 are provided as part of the second lead assembly 930a. The ECG sensing module 1016 receives the signals detected by the electrodes 950. The sensed ECG is used to determine when defibrillation should be initiated by monitoring cardiac rhythms. If tachycardia or fibrillation are detected, the control system 1030 will trigger the ICD subsystem 1010 to deliver the desired cardioversion/defibrillation energy to the patient's heart.
In various embodiments, the pulse generation module 910a and stimulating electrodes may be implanted in a variety of locations within the patient's body, depending on the desired stimulation vectors. For example, the module 910a may be positioned subcutaneously on either the left side, right side, or medial position in the patient's chest between the skin and the rib cage, proximal to or distal from the sternum, in an axillary location, or in a posterior location. The electrode 940a may be positioned subcutaneously in any of the above locations so as to provide the desired stimulation vector with the module 910a. Various examples of configurations are described herein, but other configurations are also possible. In some cases, it may be desirable for the module 910a to be positioned closer to the VNS electrode 14 while maintaining an effective defibrillation vector 960a with the electrode 940a, so as to minimize the difficulty of tunneling the first lead assembly 920a and the potential complications or patient discomfort that might be caused by an elongated lead assembly 920a. The second lead assembly 930a may be tunneled around the thorax to position the electrode 940a relative to the pulse generation module 910a so as to generate the desired defibrillation vector. In the embodiment illustrated in FIG. 9A, the pulse generation module 910a is in an anterior location and the electrode 940a is in a posterior location.
Any known techniques for subcutaneous defibrillation may be utilized in the operation of the defibrillation function of VNS/ICD system, in accordance with embodiments of the present invention. For example, any of a variety of detection algorithms may be used to control the initiation of the ICD stimulation. For instance, the detection algorithm may utilize one or more rhythm analyses for detecting events suitable for defibrillation by the VNS/ICD system. Various detection algorithms may also evaluate the rate, regularity, and abruptness of onset of rhythm changes. Alternatively, other physiological signals, such as respiratory rates, may be used instead of or in addition to the ECG signals to effectuate accurate detection of events.
Any of a variety of stimulation therapies may be delivered in response to the detection of a treatable event. For example, one or more defibrillation shocks may be delivered at any therapeutically effective stimulation intensity (e.g., between approximately 50-250 J, between approximately 50-100 J, or other desired energy level). After delivery of the one or more defibrillation shocks, the ICD subsystem 100 may also provide post-shock bradycardia pacing therapy.
Any of a variety of lead assemblies and electrodes may be used in accordance with embodiments of the present invention. For example, the second lead assembly 930a may comprise a silicone or polyurethane insulation surrounding a conductive lead. The electrode 940a may comprise a coil electrode having a suitable length, e.g., 5-10 cm. The sensing electrodes 950 may be smaller than the coil electrode 940a and may be spaced so as to provide level of QRS detection.
FIG. 9B is a front anatomical diagram showing a two-lead VNS/ICD system 900b, in accordance with other embodiments of the present invention. The system 900b comprises a pulse generation module 910b having a first lead assembly 920b, similar to first lead assembly 920a in FIG. 9A, and a second lead assembly 930b. In contrast with the system 900a in FIG. 9A, the housing of the pulse generation module 910b is not used as the second electrode for the defibrillation stimulation. In this embodiment, the second lead assembly 930b comprises a first ICD electrode 940a provided at a distal end of the assembly 930b, and a second ICD electrode 942b provided at an intermediate location along lead assembly 930b. The first ICD electrode 940a and second ICD electrode 942b are used to generate the electric field for defibrillation. Providing two ICD electrodes on the lead assembly 930b increases the complexity of the lead assembly 930b, but provides greater flexibility in the positioning of the pulse generation module 910b. Because the pulse generation module 910b is not used as an electrode for defibrillation, the location of the implantation site need not be constrained by the desired defibrillation vector alignment relative to the heart. The pulse generation module 910b may be positioned far from the defibrillation vector 960b, such as, for example, in the subclavicular pocket or other location closer to the VNS electrode 14 or more comfortable for the patient. In other embodiments, the pulse generation module 910b may function as a third ICD electrode, which can provide a second defibrillation vector 962b with first electrode 940b to supplement the first defibrillation vector 960b. This may limit the flexibility in positioning the module 910b in the patient, but could improve the defibrillation performance.
FIG. 9C is a front anatomical diagram showing a two-lead VNS/ICD system 900c, in accordance with other embodiments of the present invention. The system 900c comprises a pulse generation module 910c having a first lead assembly 920c and a second lead assembly 930c, similar to the second lead assembly 930a in FIG. 9A. In contrast with the system 900a in FIG. 9A, however, the first lead assembly 920c comprises the VNS electrode 14 and a second ICD electrode 942b provided at an intermediate location along the first lead assembly 920c. The first ICD electrode 940a and second ICD electrode 942b are used to generate the defibrillation vector 960c. As in FIG. 9B, providing two electrodes on the first lead assembly 920c increases the complexity of the lead assembly 930c, but provides greater flexibility in the positioning of the pulse generation module 910c. In some embodiments, the housing of the pulse generation module 910c is not used as an electrode for the defibrillation stimulation. In other embodiments, the pulse generation module 910c may function as a third ICD electrode, which can provide a second defibrillation vector 962c with first electrode 940c to supplement the first defibrillation vector 960c. 
FIG. 9D is a front anatomical diagram showing a single-lead VNS/ICD system 900d, in accordance with other embodiments of the present invention. The system 900d comprises a pulse generation module 910d having a single lead assembly 920d. The single lead assembly 920d includes the VNS electrode 14 at a distal end, and a first ICD electrode 940a and second ICD electrode 942b provided at intermediate locations along the lead assembly 920d. This embodiment advantageously reduces the number of leads implanted in the patient's body, which can simplify the header assembly of the pulse generation module 910d. In some embodiments, the housing of the pulse generation module 910d is not used as an electrode for the defibrillation stimulation. In other embodiments, the pulse generation module 910d may function as a third ICD electrode, which can provide a second defibrillation vector 962c with first electrode 940d to supplement the first defibrillation vector 960d. 
FIG. 9E is a front anatomical diagram showing a three-lead VNS/ICD system 900e, in accordance with other embodiments of the present invention. The system 900e comprises a pulse generation module 910e having a first lead assembly 920e having a VNS electrode 14, similar to the first lead assembly 920a in FIG. 9A, a second lead assembly 930e having the first ICD electrode 940e, similar to the second lead assembly 930a in FIG. 9A, and a third lead assembly 932e. A second ICD electrode 942e is provided at a distal end of the third lead assembly 932e, and can be used with first ICD electrode 940e to generate the defibrillation vector 960e. Providing the second ICD electrode 942e on its own lead assembly 932e can provide more flexibility in the positioning of the second ICD electrode 942e and pulse generation module 910e. This may also provide more flexibility in the positioning of the first ICD electrode 940e and the tunneling of the second lead assembly 930e over the embodiment shown in FIG. 9B, since a single lead assembly is not used to position both the first and second ICD electrodes. In some embodiments, the housing of the pulse generation module 910e is not used as an electrode for the defibrillation stimulation, and in other embodiments, the pulse generation module 910e may function as a third ICD electrode to provide a second defibrillation vector 962e. 
In embodiments described above, the pulse generation module, ICD electrodes, and VNS electrode are all positioned on the same side of the patient's body. In other embodiments, one or more of these components of the VNS/ICD system may be positioned on different sides of the body. In particular, in some patients, it may be desirable for the VNS stimulation to be applied to the right vagus nerve, while providing ICD stimulation to the left side of the thorax. FIG. 9F is a front anatomical diagram showing a two-lead VNS/ICD system 900e, similar to the two-lead VNS/ICD system 900a shown in FIG. 9A. However, in this embodiment, the VNS electrode 14 is positioned on the right vagus nerve 16, with first lead assembly 920f traversing the midline of the patient's body. In some embodiments, a third lead assembly having a second VNS electrode may be used to provide VNS stimulation to the left vagus nerve 15 in addition to the right vagus nerve 16.
It will be understood that the components and configurations of the ICD/VNS systems described herein may vary. For example, in FIG. 9A, sensing electrodes 950 are provided on second lead assembly 930a. In various embodiments, it is understood that physiological sensors (e.g., ECG electrodes) may be positioned on one or more of the lead assemblies, the pulse generation module, or other structure, such as a separate sensor having a wired or wireless connection with the pulse generation module. In some embodiments, a respiration sensor may be provided along the first lead assembly near the VNS electrode 14 for sensing respiratory activity in the throat.
In addition, in embodiments described herein, an ICD electrode on the pulse generation module generates an electric field with an ICD electrode provided at the end of a lead assembly. In other embodiments, both ICD electrodes may be provided on the pulse generation module. The housing of the pulse generation module would be configured to be long enough to permit adequate separation between the ICD electrodes to generate the desired defibrillation vector. In addition, the elongated housing may be curved so as to enable it to better conform to the patient's anatomy, such as in the axillary region, thereby improving patient comfort.
In some embodiments, the VNS functionality and the ICD functionality may operate independently, such that VNS stimulation is provided in accordance with any desired VNS therapeutic modality, and the ICD functionality is provided in accordance with any desired ICD therapeutic modality, without any coordination between the two therapies. In other embodiments, the control system of the ICD/VNS system may coordinate the VNS and ICD stimulation to provide improved therapeutic effect. For example, the VNS subsystem may be configured to deliver both a chronic VNS therapy, such as the VNS therapy described above to improve autonomic regulatory function, as well as an acute VNS therapy delivered in response to detection of a cardiac event.
FIG. 11 illustrates a method for delivering coordinated VNS and ICD therapies, in accordance with embodiments of the present invention. In step 1101, the ICD/VNS system delivers chronic VNS therapy in accordance with any desired VNS therapeutic modality, such as the autonomic regulatory therapy in the neural fulcrum, as described herein. In step 1102, a cardiac event is detected. This may occur when the ECG sensing module detects the occurrence of an arrhythmia or conditions that are likely to result in arrhythmia or potentially lethal tachycardia. In response to this detection, the VNS subsystem delivers an acute event-driven VNS therapy to the patient. This can be an anti-arrhythmic therapy comprising high intensity VNS stimulation which may suppress the event, or enhance the performance of the subsequent ICD defibrillation stimulation. The high intensity VNS stimulation may comprise the increase of any of the VNS stimulation parameters, such as, e.g., the duty cycle, pulse width, or amplitude of VNS stimulation. Although the increase in VNS intensity may result in temporary discomfort to the patient, this may be outweighed if the acute VNS is successful in terminating the event, thereby avoiding the delivery of a defibrillation stimulation, which is likely to be far more uncomfortable.
In optional step 1105, the ICD/VNS system senses the patient's physiological signals (e.g., ECG) to determine whether the detected event was not suppressed by the acute VNS therapy in step 1103 (e.g., reconfirms the continued presence of the arrhythmia). At decision step 1105, if the detected event is not suppressed, the method proceeds to step 1106 in which the ICD subsystem delivers a defibrillation stimulation to the patient. If the detected event was suppressed by the acute VNS therapy, then the method terminates at step 1107. As described above, the acute delivery of high intensity VNS can enhance the performance of a subsequent ICD defibrillation stimulation. The acute high intensity VNS may lower the defibrillation threshold, thereby improving the defibrillation efficacy. In other embodiments, the acute VNS therapy is delivered in advance of the defibrillation to provide this improved defibrillation efficacy, and not necessarily to terminate the event. Accordingly, steps 1104 and 1105 may be omitted, and the ICD/VNS system would deliver the defibrillation shock in step 1106 immediately after the acute VNS therapy is delivered, without determining whether the event has been terminated.
The acute VNS therapy may be provided over any desired period of time, such as, for example, between several seconds to a minute or more. In some embodiments, the acute VNS therapy is delivered during the period of time required by the ICD subsystem to confirm the presence of a treatable event and to charge its capacitors in preparation for delivering the defibrillation stimulation. This period of time may be, for example, approximately five seconds. Therefore, the acute VNS therapy delivered during that five-second window would not cause any delay in the delivery of the defibrillation.
In embodiments described above with respect to FIGS. 9A-9F, the VNS and ICD subsystems are provided within a single pulse generation module housing. In other embodiments, the VNS subsystem may be provided in a separate implanted device. FIG. 9G illustrates a two-device VNS/ICD system 900g, in accordance with other embodiments of the present invention. The system 900g comprises a primary pulse generation module 910g and a secondary pulse generation module 970g. The secondary pulse generation module 970g is coupled to a first lead assembly 920g having a VNS electrode 14 and is used to deliver the VNS therapy to the patient. The primary pulse generation module 910g is coupled to a second lead assembly 930g comprising a first ICD electrode 940g for delivering the ICD therapy. The primary pulse generation module 910g also contains the primary control system for the VNS/ICD system 900g and is in wired or wireless communication with the secondary pulse generation module 970g. The secondary pulse generation module 970g comprises a battery, a secondary control system, and a communications interface for communicating with the primary pulse generation module 910g, and can have a reduced size because much of the control logic and other components of the ICD/VNS system 900g are contained in the primary pulse generation module 910g. The secondary pulse generation module 970g may operate as a slave system delivering therapy as directed by the primary pulse generation module 910g. 
This two-device configuration may permit greater flexibility in the positioning of the primary pulse generation module 910g and improve the ease of implantation while also avoiding the use of a lead assembly crossing the patient's sternum. In the illustrated embodiment, the secondary pulse generation module 970g is positioned in the patient's neck proximal to the VNS electrode 14, but in other embodiments, the secondary pulse generation module 970g may be positioned in other parts of the patient's body, preferably on the same side as the VNS electrode 14. In some embodiments, another secondary pulse generation module may be provided on the left side of the patient's body for delivering stimulation to the left vagus nerve 15.
It will be understood that the ICD/VNS systems described above are merely exemplary, and in other embodiments, different configurations may be used.
In various embodiments described above, the patient's heart rate response is used as the patient parameter indicative of the desired physiological response to VNS, and ECG is used to determine the occurrence of an event treatable by defibrillation. 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 desired physiological response.
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.

## Claims

1. A method of operating an implantable neurostimulation system, comprising:
delivering a chronic vagus nerve stimulation (VNS) therapy to a vagus nerve with a VNS subsystem of a pulse generation module via a VNS electrode provided on a single lead body;
in response to detection of a cardiac event, delivering electrical cardioversion-defibrillation energy with an implantable cardioverter-defibrillator (ICD) subsystem of the pulse generation module via a first vector between a conductive electrode of a housing containing the ICD subsystem in an anterior position of a thorax and a first subcutaneous electrode provided on the single lead body and positioned along an axillary axis of the thorax; and
delivering electrical cardioversion-defibrillation energy with the ICD subsystem via a second vector between the first subcutaneous electrode and a second subcutaneous electrode provided on the single lead body and positioned along a medial axis of the thorax.

2. The method according to claim 1, further comprising:
in response to detection of the cardiac event, delivering an acute VNS therapy with the VNS subsystem of the pulse generation module.

3. The method according to claim 2, wherein delivering the acute VNS therapy comprises applying a higher intensity electrical stimulation than the chronic VNS therapy.

4. The method according to claim 1, wherein:
the delivering electrical cardioversion-defibrillation energy with the ICD subsystem via the first vector comprises delivering electrical cardioversion-defibrillation energy with the ICD subsystem via the first vector between the conductive electrode of the housing positioned in a first anterior location of a thorax and the first subcutaneous electrode positioned in a posterior location of the thorax; and
the delivering electrical cardioversion-defibrillation energy with the ICD subsystem via the second vector comprises delivering electrical cardioversion-defibrillation energy with the ICD subsystem via the second vector between the first subcutaneous electrode and the second subcutaneous electrode positioned in a second anterior location of the thorax.

5. The method according to claim 1, wherein the delivering the chronic VNS therapy to the vagus nerve comprises delivering the chronic VNS therapy to the vagus nerve with a VNS electrode coupled to the vagus nerve between the clavicle and the mastoid process.

6. The method according to claim 1, wherein the cardiac event detected is an arrhythmia suitable for treatment with defibrillation.

7. The method according to claim 1, wherein:
the VNS electrode is provided at an end of the single lead body distal from the pulse generation module; and
the first subcutaneous electrode is provided at an intermediate location on the single lead body between the pulse generation module and the VNS electrode.

8. The method according to claim 7, wherein the second subcutaneous electrode is provided at a second intermediate location on the single lead body between the pulse generation module and the VNS electrode.

9. The method according to claim 1, further comprising detecting a cardiac event via a sensing electrode.

10. The method according to claim 9, wherein detecting the cardiac event via the sensing electrode comprises detecting the cardiac event via the sensing electrode provided at an intermediate location on a lead body between the pulse generation module and the first subcutaneous electrode.