Patent Publication Number: US-2013253616-A1

Title: Method and apparatus for synchronizing neural stimulation to cardiac cycles

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a divisional of U.S. application Ser. No. 12/469,012, filed May 20, 2009, which is a divisional of U.S. application Ser. No. 11/099,141, filed Apr. 5, 2005, now U.S. Pat. No. 7,542,800, each of which is hereby incorporated by reference in its entirety. 
    
    
     FIELD OF THE INVENTION 
     This document generally relates to neural stimulation systems and particularly to a system providing for synchronization of neural stimulation to cardiac cycles. 
     BACKGROUND 
     The heart is the center of a person&#39;s circulatory system. The left portions of the heart draw oxygenated blood from the lungs and pump it to the organs of the body to provide the organs with their metabolic needs for oxygen. The right portions of the heart draw deoxygenated blood from the body organs and pump it to the lungs where the blood gets oxygenated. These pumping functions are accomplished by cyclic contractions of the myocardium (heart muscles). Each cycle, known as the cardiac cycle, includes systole and diastole. During systole, the heart ejects blood. During diastole, the heart is filled with blood for the next ejection (systolic) phase, and the myocardial tissue is perfused. In a normal heart, the sinoatrial node generates electrical impulses called action potentials. The electrical impulses propagate through an electrical conduction system to various regions of the heart to excite the myocardial tissue of these regions. Coordinated delays in the propagations of the action potentials in a normal electrical conduction system cause the various portions of the heart to contract in synchrony to result in efficient pumping functions indicated by a normal hemodynamic performance. A blocked or otherwise abnormal electrical conduction and/or deteriorated myocardial tissue result in systolic dysfunction—because the myocytes do not contract in unison—and diastolic dysfunction—because the myocytes do not relax in unison. Decreased systolic and diastolic performance each contribute to a poor overall hemodynamic performance, including a diminished blood supply to the heart and the rest of the body. 
     The hemodynamic performance is modulated by neural signals in portions of the autonomic nervous system. For example, the myocardium is innervated with sympathetic and parasympathetic nerves. Activities in these nerves, including artificially applied electrical stimuli, modulate the heart rate and contractility (strength of the myocardial contractions). Electrical stimulation applied to the sympathetic nerves is known to increase the heart rate and the contractility, shortening the systolic phase of a cardiac cycle, and lengthening the diastolic phase of the cardiac cycle. Electrical stimulation applied to the parasympathetic nerves is known to have essentially the opposite effects. 
     The ability of the electrical stimulation of the autonomic nerves in modulating the heart rate and contractility is utilized to treat abnormal cardiac conditions, such as to control myocardial remodeling and to prevent arrhythmias following myocardial infarction. It is observed that the effects of such electrical stimulation are dependent on timing of the delivery of electrical stimuli in relation to the cardiac cycle. Thus, it is desirable to synchronize the delivery of the electrical stimuli to the cardiac cycle. Because the electrical stimuli are delivered to portions of nerves external to the heart, there is a need for detecting a timing reference signal for synchronizing the delivery of the electrical stimuli to the cardiac cycle without intracardiac sensing. 
     SUMMARY 
     A neural stimulator senses a reference signal indicative of cardiac cycles each including a predetermined type timing reference event using a sensor external to the heart and blood vessels. The delivery of the neural stimulation pulses are synchronized to that timing reference event. 
     In one embodiment, a neural stimulation system includes a stimulation output circuit, a reference signal sensor, a reference event detection circuit, and a stimulation control circuit. The stimulation output circuit delivers neural stimulation pulses. The reference signal sensor senses a reference signal indicative of cardiac cycles each including a predetermined type timing reference event. The reference signal sensor may be placed in a site external to the circulatory system. The reference event detection circuit detects the predetermined type timing reference event. The stimulation control circuit controls the delivery of the neural stimulation pulses and includes a synchronization module. The synchronization module synchronizes the delivery of the neural stimulation pulses to the predetermined type timing reference event. 
     In one specific embodiment, the neural stimulation system includes a stimulation output circuit, one or more electrodes, a cardiac event detection circuit, and a stimulation control circuit. The stimulation output circuit delivers neural stimulation pulses. The one or more electrodes sense an electrocardiographic (ECG) signal. The cardiac event detection circuit detects predetermined type cardiac events from the ECG signal. The stimulation control circuit controls the delivery of the neural stimulation pulses and includes a synchronization module. The synchronization module synchronizes the delivery of the neural stimulation pulses to the predetermined type cardiac events. 
     In another specific embodiment, the neural stimulation system includes a stimulation output circuit, an acoustic sensor, a heart sound detection circuit, and a stimulation control circuit. The stimulation output circuit delivers neural stimulation pulses. The implantable acoustic sensor senses an acoustic signal indicative of heart sounds. The heart sound detection circuit detects predetermined type heart sounds using the acoustic signal. The stimulation control circuit controls the delivery of the neural stimulation pulses and includes a synchronization module. The synchronization module synchronizes the delivery of the neural stimulation pulses to the predetermined type heart sounds. 
     In another specific embodiment, the neural stimulation system includes a stimulation output circuit, a hemodynamic sensor, a hemodynamic event detection circuit, and a stimulation control circuit. The stimulation output circuit delivers neural stimulation pulses. The hemodynamic sensor senses a hemodynamic signal. The hemodynamic event detection circuit detects a predetermined type hemodynamic event using the hemodynamic signal. The stimulation control circuit controls the delivery of the neural stimulation pulses and includes a synchronization module. The synchronization module synchronizes the delivery of the neural stimulation pulses to the predetermined type hemodynamic event. 
     In one embodiment, a method for neural stimulation is provided. A timing reference signal is sensed using a reference signal sensor placed external to the circulatory system. The timing reference signal is indicative of cardiac cycles each including a predetermined type timing reference event. The predetermined type timing reference event is detected from the reference signal. A delivery of neural stimulation pulses is synchronized to the detected timing reference event. 
     This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details about the present subject matter are found in the detailed description and appended claims. Other aspects of the invention will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof. The scope of the present invention is defined by the appended claims and their legal equivalents. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the drawings, which are not necessarily drawn to scale, like numerals describe similar components throughout the several views. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document. 
         FIG. 1  is an illustration of an embodiment of a neural stimulation system and portions of an environment in which the neural stimulation system is used. 
         FIG. 2  is a block diagram illustrating an embodiment of a circuit of a cardiac cycle-synchronized neural stimulation system. 
         FIG. 3  is a block diagram illustrating a specific embodiment of the circuit of  FIG. 2 . 
         FIG. 4  is a block diagram illustrating an embodiment of a circuit using a wireless ECG to synchronize neural stimulation to cardiac cycles. 
         FIG. 5  is an illustration of an embodiment of an electrode system for subcutaneous ECG sensing. 
         FIG. 6  is a block diagram illustrating an embodiment of a circuit using heart sounds to synchronize neural stimulation to cardiac cycles. 
         FIG. 7  is a block diagram illustrating an embodiment of a circuit using a hemodynamic signal to synchronize neural stimulation to cardiac cycles. 
         FIG. 8  is a flow chart illustrating an embodiment of a method for synchronizing neural stimulation to cardiac cycles. 
     
    
    
     DETAILED DESCRIPTION 
     In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural, logical and electrical changes may be made without departing from the scope of the present invention. The following detailed description provides examples, and the scope of the present invention is defined by the appended claims and their legal equivalents. 
     It should be noted that references to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. 
     This document discusses a neural stimulation system that synchronizes the delivery of neural stimulation pulses to cardiac cycles. The neural stimulation system includes an implantable neural stimulator that senses a reference signal indicative of cardiac cycles each including a predetermined type timing reference event using an implantable reference event sensor. The implantable reference event sensor is an extracardiac and extravascular sensor, i.e., a sensor that is placed external to a patient&#39;s circulatory system including the heart and blood vessels. The delivery of the neural stimulation pulses are synchronized to the timing reference event. Examples of the reference signal include a wireless ECG, an acoustic signal indicative of heart sounds, and a hemodynamic signal. 
     In this document, “Surface ECG” refers to a cardiac electrical signal sensed with electrodes attached onto the exterior surface of the skin. “Wireless ECG” refers to a signal approximating the surface ECG, acquired without using surface (non-implantable, skin contact) electrodes. “Subcutaneous ECG” is a form of wireless ECG and includes a cardiac electrical signal sensed through electrodes implanted in subcutaneous tissue, such as through electrodes incorporated onto an implantable medical device that is subcutaneously implanted. As reflected in their corresponding morphologies, the surface ECG results from electrical activities of the entire heart. The wireless ECG, including but not being limited to the subcutaneous ECG, has a morphology that approximates that of the surface ECG and reflects electrical activities of a substantial portion of the heart, up to the entire heart. 
     In this document, an “acoustic signal” includes any signal indicative of heart sounds. “Heart sounds” include audible mechanical vibrations caused by cardiac activity that can be sensed with a microphone and audible and inaudible mechanical vibrations caused by cardiac activity that can be sensed with an accelerometer. Known type heart sounds include the “first heart sound” or S1, the “second heart sound” or S2, the “third heart sound” or S3, the “fourth heart sound” or S4, and their various sub-components. S1 is known to be indicative of, among other things, mitral valve closure, tricuspid valve closure, and aortic valve opening. S2 is known to be indicative of, among other things, aortic valve closure and pulmonary valve closure. S3 is known to be a ventricular diastolic filling sound often indicative of certain pathological conditions including heart failure. S4 is known to be a ventricular diastolic filling sound resulted from atrial contraction and is usually indicative of pathological conditions. The term “heart sound” hereinafter refers to any heart sound (e.g., S1) and any components thereof (e.g., M1 component of S1, indicative of Mitral valve closure). 
     In this document, a “hemodynamic signal” includes a signal providing for monitoring, calculation, or estimation of one or more measures of hemodynamic performance such as blood pressure or pressure-related parameters, cardiac output, stroke volume, volume of blood flow, change in (e.g., derivative of) the volume of blood flow, and/or velocity of blood flow. 
       FIG. 1  is an illustration of an embodiment of a neural stimulation system  100  and portions of an environment in which system  100  is used. System  100  includes implantable medical device  110  that delivers neural stimulation pulses through leads  106  and  108 , an external system  120 , and a telemetry link  125  providing for communication between implantable medical device  110  and external system  120 . For illustrative purpose only,  FIG. 1  shows that lead  106  includes an electrode  107  coupled to a nerve  102  of the sympathetic nervous system, and lead  108  includes an electrode  109  coupled a nerve  104  of the parasympathetic nervous system. Nerves  102  and  104  innervate a heart  101 . In various embodiments, implantable medical device  110  provides neural stimulation to any one or more nerves through one or more leads for modulating one or more functions of the circulatory system including heart  101 . Such leads include implantable neural leads each including at least one electrode for sensing neural activities and/or delivering neural stimulation pulses. One example of such an electrode includes a cuff electrode for placement around an aortic, carotid, or vagus nerve. 
     Implantable medical device  110  delivers the neural stimulation pulses and includes a cardiac cycle-synchronized neural stimulation circuit  130 . Cardiac cycle-synchronized neural stimulation circuit  130  detects a predetermined type timing reference event from a cardiac cycle and synchronizes the delivery of neural stimulation pulses to that timing reference event. In one embodiment, cardiac cycle-synchronized neural stimulation circuit  110  starts a predetermined offset time interval upon detection of the timing reference event and delivers a burst of neural stimulation pulses when the offset time interval expires. In one embodiment, implantable medical device  110  is capable of monitoring physiologic signals and/or delivering therapies in addition to the neural stimulation. Examples of such additional therapies include cardiac pacing therapy, cardioversion/defibrillation therapy, cardiac resynchronization therapy, cardiac remodeling control therapy, drug therapy, cell therapy, and gene therapy. In various embodiments, implantable medical device  110  delivers the neural stimulation in coordination with one or more such additional therapies. 
     External system  120  provides for control of and communication with implantable medical device  110  by a physician or other caregiver. In one embodiment, external system  120  includes a programmer. In another embodiment, external system  120  is a patient management system including an external device communicating with implantable medical device  110  via telemetry link  125 , a remote device in a relatively distant location, and a telecommunication network linking the external device and the remote device. The patient management system allows access to implantable medical device  110  from a remote location, for purposes such as monitoring patient status and adjusting therapies. In one embodiment, telemetry link  125  is an inductive telemetry link. In an alternative embodiment, telemetry link  125  is a far-field radio-frequency (RF) telemetry link. Telemetry link  125  provides for data transmission from implantable medical device  110  to external system  120 . This includes, for example, transmitting real-time physiological data acquired by implantable medical device  110 , extracting physiological data acquired by and stored in implantable medical device  110 , extracting patient history data such as occurrences of arrhythmias and therapy deliveries recorded in implantable medical device  110 , and/or extracting data indicating an operational status of implantable medical device  110  (e.g., battery status and lead impedance). Telemetry link  125  also provides for data transmission from external system  120  to implantable medical device  110 . This includes, for example, programming implantable medical device  110  to acquire physiological data, programming implantable medical device  110  to perform at least one self-diagnostic test (such as for a device operational status), and/or programming implantable medical device  110  to deliver one or more therapies and/or to adjust the delivery of one or more therapies. 
       FIG. 2  is a block diagram illustrating an embodiment of a circuit of a cardiac cycle-synchronized neural stimulation system  231 . System  231  includes a reference signal sensor  215  and cardiac cycle-synchronized neural stimulation circuit  130 . 
     Reference signal sensor  215  senses a reference signal indicative of cardiac cycles each including a predetermined type timing reference event. In one embodiment, reference signal sensor  215  is an implantable reference signal sensor. The timing reference event is a recurring feature of the cardiac cycle that is chosen to be a timing reference to which the neural stimulation is synchronized. In one embodiment, reference signal sensor  215  is configured for extracardiac and extravascular placement, i.e., placement external to the heart and blood vessels. Examples of reference signal sensor  215  include a set of electrodes for sensing a subcutaneous ECG signal, an acoustic sensor for sensing an acoustic signal indicative of heart sounds, and a hemodynamic sensor for sensing a hemodynamic signal indicative of hemodynamic performance. In one embodiment, implantable medical device  110  has an implantable housing that contains both a reference signal sensor  215  and cardiac cycle-synchronized neural stimulation circuit  130 . In another embodiment, reference signal sensor  215  is incorporated onto the housing of implantable medical device  110 . In another embodiment, reference signal sensor  215  is electrically connected to implantable medical device  110  through one or more leads. In another embodiment, reference signal sensor  215  is communicatively coupled to implantable medical device  110  via an intra-body telemetry link. 
     Cardiac cycle-synchronized neural stimulation circuit  130  includes a stimulation output circuit  232 , a reference event detection circuit  234 , and a stimulation control circuit  236 . Reference event detection circuit  234  receives the reference signal from reference signal sensor  215  and detects the timing reference event from the reference signal. Stimulation control circuit  236  controls the delivery of the neural stimulation pulses and includes a synchronization module  238 . Synchronization module  238  receives a signal indicative of the detection of each timing reference event and synchronizes the delivery of the neural stimulation pulses to the detected timing reference event. Stimulation output circuit  232  delivers neural stimulation pulses upon receiving a pulse delivery signal from stimulation control circuit  236 . 
       FIG. 3  is a block diagram illustrating an embodiment of a circuit of a cardiac cycle-synchronized neural stimulation system  331 , which is a specific embodiment of system  231 . System  331  includes reference signal sensor  215  and a cardiac cycle-synchronized neural stimulation circuit  330 , which is a specific embodiment of cardiac cycle-synchronized neural stimulation circuit  130 . Cardiac cycle-synchronized neural stimulation circuit  330  includes stimulation output circuit  232 , a reference event detection circuit  334 , and a stimulation control circuit  336 . 
     Reference event detection circuit  334  is a specific embodiment of reference event detection  234  and includes a signal processor  342  and an event detector  344 . Signal processor  342  receives the reference signal sensed by reference signal sensor  215  and processes the reference signal in preparation for the detection of the timing reference events by event detector  344 . Event detector  344  includes a comparator having an input to receive the processed reference signal, another input to receive a detection threshold, and an output producing a detection signal indicating a detection of the timing reference signal. In one embodiment, signal processor  342  processes the reference signal to provide for extraction of the timing reference event based on a single cardiac cycle. In one specific embodiment, signal processor  342  includes a filter having a pass-band corresponding to a frequency range of the timing reference event to prevent unwanted activities in the reference signal from being detected by event detector  344 . In another specific embodiment, signal processor  342  includes a blanking period generator to generate a blanking period that blanks the unwanted activities in the reference signal. This approach is applied when an approximate timing relationship between the timing reference event and the unwanted activities, or an approximate timing relationship between another detectable event and the unwanted activities, is predictable. In another specific embodiment, the blanking period generator generates a blanking period that blanks cardiac pacing artifacts in the reference signal, i.e., unwanted activities caused by delivery of cardiac pacing pulses. In another specific embodiment, signal processor  342  includes a timing interval generator to generate a timing interval between an intermediate event and the timing reference event. This approach is applied when the intermediate event is more easily detectable than the timing reference event and when an approximate timing relationship between the intermediate event and the timing reference event is predictable. In another embodiment, signal processor  342  processes the reference signal to provide for extraction of the timing reference event based on a plurality of cardiac cycles. In one specific embodiment, signal processor  342  includes a signal averaging circuit that averages the reference signal over a predetermined number of cardiac cycles before the detection of the timing reference event by event detector  344 . 
     Stimulation control circuit  336  is a specific embodiment of stimulation control circuit  236  and includes a synchronization circuit  338 , an offset interval generator  339 , and a pulse delivery controller  340 . Synchronization circuit  338  includes one or both of a continuous synchronization module  346  and a periodic synchronization module  348 . Continuous synchronization module  346  synchronizes the delivery of the neural stimulation pulses to the timing reference event of consecutive cardiac cycles. Periodic synchronization module  348  synchronizes the delivery of the neural stimulation pulses to the timing reference event of selected cardiac cycles on a periodic basis. Offset interval generator  339  produces an offset interval starting with the detected timing reference event. Pulse delivery controller  340  sends the pulse delivery signal to start a delivery of a burst of a plurality of neural stimulation pulses when the offset interval expires. In one embodiment, pulse delivery controller  340  sends the pulse delivery signal after the detection of the timing reference event for each of consecutive cardiac cycles. In another embodiment, pulse delivery controller  340  sends the pulse delivery signal after the detection of the timing reference event for selected cardiac cycles according to a predetermined pattern or schedule, such as on a periodic basis. 
       FIG. 4  is a block diagram illustrating an embodiment of a cardiac cycle-synchronized neural stimulation system  431 , which is a specific embodiment of system  231  and uses a wireless ECG to synchronize neural stimulation to cardiac cycles. System  431  includes ECG electrodes  415  and a cardiac cycle-synchronized neural stimulation circuit  430 , which is a specific embodiment of cardiac cycle-synchronized neural stimulation circuit  230 . Cardiac cycle-synchronized neural stimulation circuit  430  includes stimulation output circuit  232 , a cardiac event detection circuit  434 , an arrhythmia detection circuit  452 , a cardiac parameter measurement circuit  454 , and a stimulation control circuit  436 . 
     In one embodiment, ECG electrodes  415  include surface ECG electrodes. In another embodiment, ECG electrodes  415  include electrodes for sensing a wireless ECG signal. In one embodiment, ECG electrodes  415  include subcutaneous electrodes for sensing a subcutaneous ECG signal. In one embodiment, the subcutaneous electrodes are incorporated onto the implantable medical device  110 , which is to be subcutaneously implanted. Examples of such subcutaneous electrodes are discussed below with reference to  FIG. 5 . In one embodiment, at least one subcutaneous electrode is placed in a selected location in the body near the base of the heart to allow selective detection of atrial depolarizations (P-waves). In another embodiment, multiple subcutaneous electrodes are placed near base and apex of the heart to allow P-wave detection by subtracting out unwanted activities including ventricular depolarizations (R-waves). This approach applies when it is difficult to isolate P-waves by selecting electrode sites and filtering. At least one subcutaneous electrode is placed near the apex of the heart to allow detection of R-waves. The detected R-waves are then used to isolate, by subtraction, P-waves from a subcutaneous ECG signal that includes both P-waves and R-waves. 
     Cardiac event detection circuit  434  is a specific embodiment of reference event detection circuit  234 . In one embodiment, cardiac event detection circuit  434  includes a signal processor such as signal processor  342  and an event detector such as event detector  344 . The signal processor includes a wireless ECG sensing circuit to amplify and filter the subcutaneous ECG signal sensed through ECG electrodes  415 . An example of electrodes and a circuit for sensing wireless ECG signals including subcutaneous ECG signals is discussed in U.S. patent application Ser. No. 10/795,126, entitled “WIRELESS ECG IN IMPLANTABLE DEVICES,” filed on Mar. 5, 2004, assigned to Cardiac Pacemakers, Inc., which is incorporated herein by reference in its entirety. In one embodiment, as illustrated in  FIG. 4 , the timing reference event is a P-wave. Cardiac event detection circuit  434  includes a P-wave detector  450  to detect P-waves from the wireless ECG signal. In one specific embodiment, P-wave detector  450  includes a filter having a pass-band corresponding to a frequency range of P-waves. In another specific embodiment, P-wave detector  450  includes an R-wave detector to detect R-waves from one subcutaneous signal and a blanking period generator to generate blanking periods to blank unwanted activities including the R-waves in another wireless ECG signal. In another specific embodiment, P-wave detector  450  includes an R-wave detector to detect R-waves from the subcutaneous signal and a timing interval generator to generate a timing interval upon detection of each R-wave. A P-wave is estimated to occur at the end of the timing interval. 
     Arrhythmia detection circuit  452  and cardiac parameter measurement circuit  454  provide for control of neural stimulation based on cardiac conditions. Arrhythmia detection circuit  452  detects one or more types of arrhythmia from the wireless ECG signal. Cardiac parameter measurement module  454  measures one or more cardiac parameters such as a heart rate and an atrioventricular interval from the wireless ECG signal. 
     Stimulation control circuit  436  is a specific embodiment of stimulation control circuit  336  and includes a synchronization module  438 . Synchronization module  438  synchronizes the delivery of the neural stimulation pulses to the detected cardiac events such as P-waves. In one embodiment, stimulation control circuit  436  includes elements corresponding to those of stimulation circuit  336 , including offset interval generator  339  and pulse delivery controller  340 . Synchronization circuit  438  includes one or both of a continuous synchronization module to synchronize the delivery of the neural stimulation pulses to the P-wave of each of consecutive cardiac cycles and a periodic synchronization module to synchronize the delivery of the neural stimulation pulses to the P-wave of each of selected cardiac cycles on a periodic basis. The offset interval generator produces an offset interval starting with each detected P-wave. The pulse delivery controller sends the pulse delivery signal to start a delivery of a burst of a plurality of neural stimulation pulses when the offset interval expires. In one embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the P-wave for each of consecutive cardiac cycles. In another embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the P-wave for each of selected cardiac cycles according to a predetermined pattern or schedule, such as on a periodic basis. 
     In one embodiment, stimulation control circuit  436  also controls the delivery of the neural stimulation pulses based on the cardiac rhythm detected by arrhythmia detection circuit  452  and/or the cardiac parameters measured by cardiac parameter measurement circuit  454 . In one embodiment, stimulation control circuit  436  withholds or adjusts the delivery of the neural stimulation pulses when an arrhythmia is detected. In another embodiment, stimulation control circuit  436  starts, stops, or adjusts the delivery of the neural stimulation pulses based on the measured cardiac parameter, such as the heart rate and the atrioventricular interval. 
       FIG. 5  is an illustration of an embodiment of an electrode system for sensing one or more subcutaneous ECG signals. An electrode system for subcutaneous ECG sensing includes two or more implantable electrodes. These implantable electrodes are selected from the electrodes including, but not being limited to, those illustrated in  FIG. 5 . The electrodes are selected to allow for sensing electrical activities from a substantial portion of the heart, up to the entire heart.  FIG. 5  shows an implantable medical device  510 , which is a specific embodiment of implantable medical device  110 , and electrodes incorporated onto that device. Implantable medical device  510  is to be subcutaneously implanted in a patient in need of neural stimulation to modulate cardiac functions. In one embodiment, ECG electrodes  415  include one or more electrodes shown in  FIG. 5 . In another embodiment, in addition to one or more electrodes shown in  FIG. 5 , ECG electrodes  415  include one or more electrodes each electrically connected to implantable medical device  510  through a lead. 
     Implantable medical device  510  includes a hermetically sealed can  511  to house its circuit. Can  511  has an outer surface subject to contact with body tissue. Can  511  includes or provides for a base of a can electrode  514  that is selectable as one of the electrodes for sensing a subcutaneous ECG signal. At least a portion of the outer surface of can  511  is made of electrically conductive material. In one embodiment, can  511  is used as can electrode  514 . In one specific embodiment, can electrode  514  includes at least one conductive portion of can  511 . In another embodiment, can electrode  514  is incorporated onto the outer surface of can  511  and is electrically insulated from any conductive portion of can  511  using a non-conductive layer. In one specific embodiment, a hermetically sealed feedthrough including a conductor provides for an electrical connection between can electrode  514  and the circuit housed in can  511 . 
     A header  512  is attached to can  511  and includes connectors providing for electrical access to the circuit housed in can  511 . In one embodiment, one or more of header electrodes  516 A-B are incorporated into the header. Header electrodes  516 A-B are each selectable as one of the electrodes for sensing a subcutaneous ECG signal. 
     In one embodiment, two or more concentric electrodes  517 A-C are incorporated onto the outer surface of can  511 . Each of the concentric electrodes  517 A-C is selectable as one of the electrodes for sensing a subcutaneous ECG signal. Concentric electrodes  517 A-C are insulated from the conductive portion of can  511  with a non-conductive layer and connected to the circuit housed in can  511  via hermetically sealed feedthroughs. In one embodiment, two electrodes, including an inner electrode and an outer electrode, are selected from concentric electrodes  517 A-C for the wireless ECG sensing. In one embodiment, the outer electrode has a ring shape. In another embodiment, the outer electrode has a shape approaching the contour of can  511 . 
     In one embodiment, implantable medical device  510  includes an antenna  513  used for a far-field RF telemetry link providing for communication between implantable medical device  510  and external system  120 . Antenna  513  is electrically connected to the circuit housed in can  511 . In one embodiment, antenna  513  projects from header  512  and extends along one side of can  511 . In one embodiment, antenna  513  includes a metal conductor with a distal portion exposed for functioning as an antenna electrode  518 , which is selectable as one of the electrodes for sensing a subcutaneous ECG signal. 
     It is to be understood that the electrodes illustrated in  FIG. 5  are intended to be examples but not limitations. Other electrode configurations are usable as long as they provide for sensing of surface ECG signals or signals that approximate the surface ECG or otherwise allows for detection of a timing reference signal for synchronizing the delivery of neural stimulation pulses to cardiac cycles. In various embodiments in which multiple subcutaneous ECG vectors are sensed, multiple pairs of electrodes are selected, simultaneously or one at a time, for a multi-channel (multi-vector) subcutaneous ECG sensing. In one specific embodiment, one or more of subcutaneous ECG vectors are sensed to approximate one or more vectors of a standard multi-lead surface ECG recording. In another specific embodiment, multiple subcutaneous ECG vectors are sensed based on needs of specific information for synchronizing the delivery of neural stimulation pulses to cardiac cycles. Such subcutaneous ECG vectors do not necessarily approximate standard surface ECG vectors. In one specific embodiment, implantable medical device  510  includes header electrodes  516 A-B and can electrode  514  for the subcutaneous ECG sensing. Implantable medical device  510  is programmable for sensing subcutaneous ECG vectors between (1) header electrodes  516 A and  516 B, (2) header electrode  516 A and can electrode  514 , and/or (3) header electrode  516 B and can electrode  514 . In another specific embodiment, implantable medical device  510  includes one of header electrodes  516 A-B, antenna electrode  518 , and can electrode  514  for the subcutaneous ECG sensing. Implantable medical device  510  is programmable for sensing subcutaneous ECG vectors between (1) header electrode  516 A or  516 B and antenna electrode  518 , (2) header electrode  516 A or  516 B and can electrode  514 , and/or (3) antenna electrode  518  and can electrode  514 . In another specific embodiment, implantable medical device  510  includes header electrodes  516 A-B, antenna electrode  518 , and can electrode  514  for the subcutaneous ECG sensing. Implantable medical device  510  is programmable for sensing subcutaneous ECG vectors between (1) header electrodes  516 A and  518 , (2) header electrode  516 A and antenna electrode  518 , (3) header electrode  516 A and can electrode  514 , (4) header electrode  516 B and antenna electrode  518 , (5) header electrode  516 B and can electrode  514 , and/or (6) antenna electrode  518  and can electrode  514 . Other specific embodiments involving any electrode combinations for the subcutaneous ECG sensing will be employed based on needs and consideration for synchronizing the delivery of neural stimulation pulses to cardiac cycles as well as needs and considerations for performing other diagnostic and/or therapeutic functions provided by implantable medical device  510 . 
     The selection of subcutaneous ECG vectors depends on the purpose for the subcutaneous ECG sensing. When the subcutaneous ECG signal is sensed for detecting P-waves, the subcutaneous ECG vector that provide for a reliable P wave detection are selected. When the subcutaneous ECG signal is sensed for detecting R-waves, one or more subcutaneous ECG vectors that provide for a reliable R wave detection are selected. In one embodiment, when more than one subcutaneous ECG vector provides for a reliable sensing for a particular purpose, the subcutaneous ECG vector showing the highest signal-to-noise ratio (SNR) for that purpose is selected. For example, if the subcutaneous ECG is sensed for detecting P waves, the subcutaneous ECG vector showing the highest SNR with P waves being considered as the signal that is selected. 
       FIG. 6  is a block diagram illustrating an embodiment of a cardiac cycle-synchronized neural stimulation system  631 , which is a specific embodiment of system  231  and uses heart sounds to synchronize neural stimulation to cardiac cycles. System  631  includes an acoustic sensor  615  and a cardiac cycle-synchronized neural stimulation circuit  630 , which is a specific embodiment of cardiac cycle-synchronized neural stimulation circuit  230 . Cardiac cycle-synchronized neural stimulation circuit  630  includes stimulation output circuit  232 , a heart sound detection circuit  634 , and a stimulation control circuit  636 . 
     Acoustic sensor  615  senses an acoustic signal indicative heart sounds. In one embodiment, acoustic sensor  615  includes an implantable acoustic sensor. In one embodiment, acoustic sensor  615  includes an accelerometer. In another embodiment, acoustic sensor  615  includes a microphone. In one specific embodiment, acoustic sensor  615  is included in implantable medical device  110 . In another specific embodiment, acoustic sensor  615  is incorporated onto a lead connected to implantable medical device  110 . 
     Heart sound detection circuit  634  detects predetermined type heart sounds from the acoustic signal. Heart sound detection circuit  634  includes one or more of a first heart sound (S1) detector to detect S1, a second heart sound (S2) detector to detect S2, a third heart sound (S3) detector to detect S3, and a fourth heart sound (S4) detector to detect S4. In one embodiment, the type of heart sounds to be detected is determined based on whether each particular type of heart sounds is consistently recurring and reliably detectable in an individual patient. In one embodiment, cardiac event detection circuit  634  includes a signal processor such as signal processor  342  and an event detector such as event detector  344 . In one specific embodiment, heart sound detection circuit  634  includes a filter having a pass-band corresponding to a frequency range of the predetermined type heart sounds. In another specific embodiment, heart sound detection circuit  634  includes a signal averaging circuit to average the acoustic signal over a predetermined number of cardiac cycles before the detection of the predetermined type heart sounds. In another specific embodiment, heart sound detection circuit  634  receives an activity signal indicative of the patient&#39;s gross physical activity level and stops detecting heart sounds while the activity signal exceeds a predetermined threshold activity level. In another embodiment, heart sound detection circuit  634  includes an S2 detector and/or an S3 detector such as those discussed in U.S. patent application Ser. No. 10/746,853, “METHOD AND APPARATUS FOR THIRD HEART SOUND DETECTION,” filed on Dec. 24, 2003, assigned to Cardiac Pacemakers, Inc., which is incorporated by reference in its entirety. 
     Stimulation control circuit  636  is a specific embodiment and includes a synchronization module  638 . Synchronization module  638  synchronizes the delivery of the neural stimulation pulses to the predetermined type heart sounds. In one embodiment, stimulation control circuit  636  includes elements corresponding to those of stimulation circuit  336 , including offset interval generator  339  and pulse delivery controller  340 . Synchronization circuit  638  includes one or both of a continuous synchronization module to synchronize the delivery of the neural stimulation pulses to the predetermined type heart sound of each of consecutive cardiac cycles and a periodic synchronization module to synchronize the delivery of the neural stimulation pulses to the predetermined type heart sound of each of selected cardiac cycles on a periodic basis. The offset interval generator produces an offset interval starting with the detected predetermined type heart sound. The pulse delivery controller sends the pulse delivery signal to start a delivery of a burst of a plurality of neural stimulation pulses when the offset interval expires. In one embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the predetermined type heart sound for each of consecutive cardiac cycles. In another embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the predetermined type heart sound for each of selected cardiac cycles according to a predetermined pattern or schedule, such as on a periodic basis. 
       FIG. 7  is a block diagram illustrating an embodiment of a cardiac cycle-synchronized neural stimulation system  731 , which is a specific embodiment of system  231  and uses a hemodynamic signal to synchronize neural stimulation to cardiac cycles. System  731  includes a hemodynamic sensor  715  and a cardiac cycle-synchronized neural stimulation circuit  730 , which is a specific embodiment of cardiac cycle-synchronized neural stimulation circuit  230 . Cardiac cycle-synchronized neural stimulation circuit  730  includes stimulation output circuit  232 , a hemodynamic event detection circuit  734 , and a stimulation control circuit  736 . 
     Hemodynamic sensor  715  senses a hemodynamic signal indicative of hemodynamic performance, such as a signal indicative of blood pressure or flow. In one embodiment, hemodynamic sensor  715  is an implantable hemodynamic sensor. In one embodiment, hemodynamic sensor  715  includes a Doppler echocardiographic transducer to sense a peripheral blood flow. In another embodiment, hemodynamic sensor  715  includes a pressure sensor to sense a central or peripheral blood pressure. In another embodiment, hemodynamic sensor  715  includes a pulse oximeter to sense an oximetry signal, which is a plethysmographic signal indicative of blood flow. 
     Hemodynamic event detection circuit  734  detects predetermined type hemodynamic events from the hemodynamic signal. The hemodynamic events correspond to a recurring feature of the cardiac cycle that is chosen to be a timing reference to which the neural stimulation is synchronized. In one embodiment, hemodynamic event detection circuit  734  includes a peak detector that detects predetermined type peaks in the hemodynamic signal. In one specific embodiment, the peak detector is a pressure peak detector that detects predetermined type peaks in a blood pressure signal. In another specific embodiment, the peak detector includes a flow peak detector that detects predetermined type peaks in a blood flow signal. The predetermined type peaks are peaks indicative of a characteristic event that occurs during each cardiac cycle. In another embodiment, cardiac cycle-synchronized neural stimulation circuit  730  includes a derivative calculator to produce a derivative hemodynamic signal by calculating a time derivative of the hemodynamic signal. Hemodynamic event detection circuit  734  detects the predetermined type hemodynamic event from the derivative hemodynamic signal. In one embodiment, the peak detector detects predetermined type peaks in the derivative hemodynamic signal. In one specific embodiment, the peak detector is a pressure change peak detector that detects predetermined type peaks in a derivative hemodynamic signal indicative of changes in the blood pressure (e.g., dP/dt). In another specific embodiment, the peak detector includes a flow change peak detector that detects predetermined type peaks in a derivative hemodynamic signal indicative changes in the blood flow. 
     Stimulation control circuit  736  is a specific embodiment and includes a synchronization module  738 . Synchronization module  738  synchronizes the delivery of the neural stimulation pulses to the predetermined type hemodynamic events. In one embodiment, stimulation control circuit  736  includes elements corresponding to those of stimulation circuit  336 , including offset interval generator  339  and pulse delivery controller  340 . Synchronization circuit  738  includes one or both of a continuous synchronization module to synchronize the delivery of the neural stimulation pulses to the predetermined type hemodynamic event of each of consecutive cardiac cycles and a periodic synchronization module to synchronize the delivery of the neural stimulation pulses to the predetermined type hemodynamic event of each of selected cardiac cycles on a periodic basis. The offset interval generator produces an offset interval starting with each detected predetermined type hemodynamic event. The pulse delivery controller sends the pulse delivery signal to start a delivery of a burst of a plurality of neural stimulation pulses when the offset interval expires. In one embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the predetermined type hemodynamic event for each of consecutive cardiac cycles. In another embodiment, the pulse delivery controller sends the pulse delivery signal after the detection of the predetermined type hemodynamic event for each of selected cardiac cycles according to a predetermined pattern or schedule, such as on a periodic basis. 
       FIG. 8  is a flow chart illustrating an embodiment of a method for synchronizing neural stimulation to cardiac cycles. In one embodiment, the method is performed by cardiac cycle-synchronized neural stimulation system  231 , including any of its specific embodiments or any combination of its specific embodiments discussed above. 
     A reference signal is sensed at  800 . The reference signal is indicative of cardiac cycles each including a predetermined type timing reference event. In one embodiment, the reference signal is sensed using an implantable sensor placed external to the circulatory system. Examples of the reference signal include a cardiac signal such as a subcutaneous ECG signal, an acoustic signal indicative of heart sounds, and a hemodynamic signal such as a blood pressure or flow signal. 
     The predetermined type timing reference event is detected at  810 . In one embodiment, the reference signal is processed to allow or to facilitate the detection of the predetermined type timing reference event. In one specific embodiment, the predetermined type timing reference event is detected based on the reference signal sensed over a single cardiac cycle. In another embodiment, the predetermined type timing reference event is detected based on the reference signal sensed over a plurality of cardiac cycles. Examples of such processing include filtering, blanking unwanted activities from the reference signal, detecting an intermediate event having an approximately predictable timing relationship with the predetermined type timing reference event, and averaging the reference signal over a plurality of cardiac cycles. Examples of the predetermined type timing reference event include P-wave and R-wave detected from the cardiac signal such as the subcutaneous ECG signal, a predetermined type heart sound from the acoustic signal, and a point of peak amplitude or any other morphologically distinctive point in the hemodynamic signal such as the pressure or flow signal. 
     A delivery of neural stimulation pulses is synchronized to the predetermined type timing reference event at  820 . In one embodiment, the delivery of the neural stimulation pulses is synchronized to the predetermined type timing reference event of each of consecutive cardiac cycles on a continuous basis. In another embodiment, the delivery of the neural stimulation pulses is synchronized to the predetermined type timing reference event of each of selected cardiac cycles on a periodic basis. In one embodiment, a burst of neural stimulation pulses is delivered at the end of an offset interval starting with the predetermined type timing reference event. In one embodiment, the burst of neural stimulation pulses is delivered after the predetermined type timing reference event for each cardiac cycle of consecutive cardiac cycles. In another embodiment, the burst of neural stimulation pulses is delivered after the predetermined type timing reference event for each cardiac cycle of selected cardiac cycles according to a predetermined pattern or schedule, such as on a period basis. 
     In one embodiment, the delivery of the neural stimulation pulses is further controlled by the patient&#39;s cardiac condition and/or activity level. The patient&#39;s cardiac rhythm and one or more cardiac parameters indicative of the cardiac functions are monitored. In one embodiment, the delivery of the neural stimulation pulses is controlled based on the cardiac rhythm. In response to a detected arrhythmia, the delivery of the neural stimulation pulses is withheld or adjusted. In another embodiment, the delivery of the neural stimulation pulses is adjusted or optimized based on the one or more cardiac parameters. Examples of such cardiac parameters include heart rate, atrioventricular intervals, and interventricular intervals. The timing for the delivery of the neural stimulation pulses is adjusted, for example, for a desirable heart rate, an atrioventricular interval corresponding to a desirable hemodynamic performance, and/or a minimum interventricular interval. 
     It is to be understood that the above detailed description is intended to be illustrative, and not restrictive. Other embodiments will be apparent to those of skill in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of legal equivalents to which such claims are entitled.