Patent Publication Number: US-11642527-B2

Title: Contingent cardio-protection for epilepsy patients

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of and claims priority to co-pending U.S. patent application Ser. No. 13/288,886 entitle “Classifying Seizures As Epileptic or Non-Epileptic Using Extra-Cerebral Body Data”, filed on Nov. 3, 2011, which claims priority to and is a continuation-in-part of U.S. patent application Ser. No. 13/098,262 entitled “Detecting, Quantifying, and/or Classifying Seizures Using Multimodal Data”, filed on Apr. 29, 2011 (now U.S. Pat. No. 8,382,667), which claims priority to and is a continuation-in-part of U.S. patent application Ser. No. 12/896,525 entitled “Detecting, Quantifying, and/or Classifying Seizures Using Multimodal Data”, filed on Oct. 1, 2010 (now U.S. Pat. No. 8,337,404) and the presently presented application is a continuation-in-part of and claims priority to co-pending U.S. patent application Ser. No. 16/679,216 entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed on Nov. 10, 2019, which is a continuation-in-part of and claims priority to co-pending U.S. patent application Ser. No. 15/437,155 entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed on Feb. 20, 2017 (now U.S. Pat. No. 10,682,515), which claims priority to and is a divisional application of U.S. patent application Ser. No. 14/050,173 entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed on Oct. 9, 2013 (now U.S. Pat. No. 9,579,506), which claims priority to and is a continuation-in-part of U.S. patent application Ser. No. 13/601,099 entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed on Aug. 31, 2012 (now U.S. Pat. No. 9,314,633), which claims priority to and is a continuation-in-part of U.S. patent application Ser. No. 12/020,195 entitled “Method, Apparatus and System for Bipolar Charge Utilization during Stimulation by an Implantable Medical Device”, filed on Jan. 25, 2008 (now U.S. Pat. No. 8,260,426) and claims priority to and is a continuation-in-part of U.S. patent application Ser. No. 12/020,097 entitled “Changeable Electrode Polarity Stimulation by an Implantable Medical Device”, filed on Jan. 25, 2008 (now U.S. Pat. No. 8,565,867) all of which are incorporated herein by reference in their entireties. 
    
    
     BACKGROUND OF THE DISCLOSURE 
     This disclosure relates generally to medical devices, and, more particularly, to methods, apparatus, and systems for performing vagus nerve stimulation (VNS) for treating epileptic seizures characterized by cardiac changes, including ictal tachycardia. This disclose also relates to medical device systems and methods capable of classifying an occurring or impending seizure as epileptic or non-epileptic using extra-cerebral body data. 
     DESCRIPTION OF THE RELATED ART 
     While seizures are the best known and most studied manifestation of epilepsy, cardiac alterations are prevalent and may account for the high rate of sudden unexpected death (SUDEP) in these patients. These alterations may include changes in rate (most commonly tachycardia, rarely bradycardia or asystole), rhythm (PACs, PVCs), conduction (e.g., bundle branch block) and repolarization abnormalities (e.g., Q-T prolongation, which occurs primarily during (ictal) but also between seizures (inter-ictally). In addition, S-T segment depression (a sign of myocardial ischemia) is observed during epileptic seizures. Significant elevations in heart-type fatty acid binding protein (H-FABP), a cytoplasmic low-molecular weight protein released into the circulation during myocardial injury have been documented in patients with epilepsy and without evidence of coronary artery disease, not only during seizures but also during free-seizure periods. H-FABP is a more sensitive and specific marker of myocardial ischemia than troponin I or CK-MB. Elevations in H-FABP appear to be un-correlated with duration of illness, of the recorded seizures, or with the Chalfont severity score of the patients. 
     The cardiac alterations in epilepsy patients, both during and between seizures, have a multi-factorial etiology, but a vago-sympathetic imbalance seems to play a prominent role in their generation. The majority of epileptic seizures enhance the sympathetic tone (plasma noradrenaline and adrenaline rise markedly after seizure onset) causing tachycardia, arterial hypertension and increases in the respiratory rate, among others. Recurrent and frequent exposure to the outpouring of catecholamines associated with seizures in patients with pharmaco-resistant epilepsies may, for example, account for abnormalities that increase the risk of sudden death such as prolongation of the Q-T interval which leads to often fatal tachyarrhythmias such as torsade de pointe. Further evidence in support of the role of catecholamines in SUDEP is found in autopsies of SUDEP victims, revealing interstitial myocardial fibrosis (a risk factor for lethal arrhythmias), myocyte vacuolization, atrophy of cardiomyocytes, leukocytic infiltration, and perivascular fibrosis. Restoration of the sympathetic-parasympathetic tone to normal levels, a therapeutic objective that may be accomplished by enhancing parasympathetic activity through among others, electrical stimulation of the vagus nerve, may decrease the rate and severity of cardiac and autonomic co-morbidities in these patients. 
     While there have been significant advances over the last several decades in treatments for epileptic seizures, the management of co-morbidities—in particular the cardiac alterations associated with seizures—remains largely unaddressed. There is a need for improved epilepsy treatments that address cardiac impairments associated with seizures. Pharmacological therapies for neurological diseases (including epilepsy) have been available for many decades. A more recent treatment for neurological disorders involves electrical stimulation of a target tissue to reduce symptoms or effects of the disorder. Such therapeutic electrical signals have been successfully applied to brain, spinal cord, and cranial nerves tissues improve or ameliorate a variety of conditions. A particular example of such a therapy involves applying an electrical signal to the vagus nerve to reduce or eliminate epileptic seizures, as described in U.S. Pat. Nos. 4,702,254, 4,867,164, and 5,025,807, which are hereby incorporated herein by reference in their entirety. 
     The endogenous electrical activity (i.e., activity attributable to the natural functioning of the patient&#39;s own body) of a neural structure may be modulated in a variety of ways. One such way is by applying exogenous (i.e., from a source other than the patient&#39;s own body) electrical, chemical, or mechanical signals to the neural structure. In some embodiments, the exogenous signal (“neurostimulation” or “neuromodulation”) may involve the induction of afferent action potentials, efferent action potentials, or both, in the neural structure. In some embodiments, the exogenous (therapeutic) signal may block or interrupt the transmission of endogenous (natural) electrical activity in the target neural structure. Electrical signal therapy may be provided by implanting an electrical device underneath the skin of a patient and delivering an electrical signal to a nerve such as a cranial nerve. 
     In one embodiment, the electrical signal therapy may involve detecting a symptom or event associated with the patient&#39;s medical condition, and the electrical signal may be delivered in response to the detection. This type of stimulation is generally referred to as “closed-loop,” “active,” “feedback,” “contingent” or “triggered” stimulation. Alternatively, the system may operate according to a predetermined program to periodically apply a series of electrical pulses to the nerve intermittently throughout the day, or over another predetermined time interval. This type of stimulation is generally referred to as “open-loop,” “passive,” “non-feedback,” “non-contingent” or “prophylactic,” stimulation. 
     In other embodiments, both open- and closed-loop stimulation modes may be used. For example, an open-loop electrical signal may operate as a “default” program that is repeated according to a programmed on-time and off-time until a condition is detected by one or more body sensors and/or algorithms. The open-loop electrical signal may then be interrupted in response to the detection, and the closed-loop electrical signal may be applied—either for a predetermined time or until the detected condition has been effectively treated. The closed-loop signal may then be interrupted, and the open-loop program may be resumed. Therapeutic electrical stimulation may be applied by an implantable medical device (IMD) within the patient&#39;s body or, in some embodiments, externally. 
     Closed-loop stimulation of the vagus nerve has been proposed to treat epileptic seizures. Many patients with intractable, refractory seizures experience changes in heart rate and/or other autonomic body signals near the clinical onset of seizures. In some instances the changes may occur prior to the clinical onset, and in other cases the changes may occur at or after the clinical onset. Where the changes involves heart rate, most often the rate increases, although in some instances a drop or a biphasic change (up-then-down or down-then-up) may occur. It is possible using a heart rate sensor to detect such changes and to initiate therapeutic electrical stimulation (e.g., VNS) based on the detected change. The closed-loop therapy may be a modified version of an open-loop therapy. See, e.g., U.S. Pat. Nos. 5,928,272, and 6,341,236, each hereby incorporated by reference herein. The detected change may also be used to warn a patient or third party of an impending or occurring seizure. 
     VNS therapy for epilepsy patients typically involves a train of electrical pulses applied to the nerve with an electrode pair including a cathode and an anode located on a left or right main vagal trunk in the neck (cervical) area. Only the cathode is capable of generating action potentials in nerve fibers within the vagus nerve; the anode may block some or all of the action potentials that reach it (whether endogenous or exogenously generated by the cathode). VNS as an epilepsy therapy involves modulation of one or more brain structures. Therefore, to prevent the anode from blocking action potentials generated by the cathode from reaching the brain, the cathode is usually located proximal to the brain relative to the anode. For vagal stimulation in the neck area, the cathode is thus usually the upper electrode and the anode is the lower electrode. This arrangement is believed to result in partial blockage of action potentials distal to or below the anode (i.e., those that would travel through the vagus nerve branches innervating the lungs, heart and other viscerae). Using an upper-cathode/lower-anode arrangement has also been favored to minimize any effect of the vagus nerve stimulation on the heart. 
     Stimulation of the left vagus nerve, for treatment of epilepsy has complex effects on heart rate (see Frei &amp; Osorio, Epilepsia 2001), one of which includes slowing of the heart rate, while stimulation of the right vagus nerve has a more prominent bradycardic effect. Electrical stimulation of the right vagus nerve has been proposed for use in the operating room to slow the heart during heart bypass surgery, to provide a surgeon with a longer time period to place sutures between heartbeats (see, e.g., U.S. Pat. No. 5,651,373). Some patents discussing VNS therapy for epilepsy treatment express concern with the risk of inadvertently slowing the heart during stimulation. In U.S. Pat. No. 4,702,254, it is suggested that by locating the VNS stimulation electrodes below the inferior cardiac nerve, “minimal slowing of the heart rate is achieved” (col. 7 lines 3-5), and in U.S. Pat. No. 6,920,357, the use of a pacemaker to avoid inadvertent slowing of the heart is disclosed. 
     Cranial nerve stimulation has also been suggested for disorders outside the brain such as those affecting the gastrointestinal system, the pancreas (e.g., diabetes, which often features impaired production of insulin by the islets of Langerhans in the pancreas), or the kidneys. Electrical signal stimulation of either the brain alone or the organ alone may have some efficacy in treating such medical conditions, but may lack maximal efficacy. 
     While electrical stimulation has been used for many years to treat a number of conditions, a need exists for improved VNS methods of treating epilepsy and its cardiac co-morbidities as well as other brain and non-brain disorders. 
     Non-epileptic generalized seizures, also known as pseudo-seizures, psychogenic seizures, or hysterical seizures, are often misdiagnosed as epileptic at large cost to the patient, caregivers, and the health care system. The diagnosis of non-epileptic seizures is difficult, as evidenced by the long mean latency (7 years) between the onset of manifestations and accurate diagnosis that the patient&#39;s seizures are non-epileptic. Approximately 10-30% of patients referred to epilepsy centers because of suspected epileptic seizures are diagnosed as having non-epileptic seizures. While carrying the incorrect diagnosis of epileptic seizures, patients are treated with anti-seizure medications. Since these lack efficacy (due to the fundamental pathophysiologic differences between epileptic and non-epileptic seizures), emergency room visits and hospitalizations are frequent. The observation that the prevalence of non-epileptic seizures is higher in patients with epilepsy (estimates put the number of patients having both epileptic and non-epileptic seizures at 10-50% of all epileptic patients seen at specialty centers) than in the general population, makes accurate differentiation between them even more challenging. 
     Video-EEG monitoring, the current “gold standard” for differentiation, requires hospitalization, usually for several days, at high expense to the health care system and great inconvenience to the patient and his/her loved ones. 
     SUMMARY OF THE DISCLOSURE 
     In one aspect, the present disclosure relates to a method of treating a patient having epilepsy comprising receiving at least one body data stream, analyzing the at least one body data stream using a seizure or event detection algorithm to detect whether or not the patient is having and/or has had an epileptic seizure, receiving a cardiac signal of the patient, applying a first electrical signal to a vagus nerve of the patient based on a determination that the patient is not having and/or has not had an epileptic seizure characterized by a decrease in the patient&#39;s heart rate, wherein the first electrical signal is not a vagus nerve conduction blocking electrical signal, and applying a second electrical signal to a vagus nerve of the patient based on a determination that the patient is having and/or has had an epileptic seizure characterized by a decrease in the patient&#39;s heart rate, wherein the second electrical signal is a pulsed electrical signal that blocks action potential conduction in the vagus nerve. 
     In one aspect, the present disclosure relates to a method of treating a patient having epilepsy comprising sensing a cardiac signal and a kinetic signal of the patient, analyzing at least one of the cardiac signal and the kinetic signal; determining whether or not the patient has had an epileptic seizure based on the analyzing; in response to a determination that the patient has had an epileptic seizure, determining whether or not the seizure is characterized by a decrease in the patient&#39;s heart rate, applying a first electrical signal to a vagus nerve of the patient based on a determination that the patient has had an epileptic seizure characterized by a decrease in the patient&#39;s heart rate, wherein the first electrical signal is a pulsed electrical signal that blocks action potential conduction in the vagus nerve; and applying a second electrical signal to a vagus nerve of the patient based on one of a) a determination that the patient has not had an epileptic seizure, and b) a determination that the patient has had an epileptic seizure that is not characterized by a decrease in the patient&#39;s heart rate, wherein the second electrical signal is not a vagus nerve conduction blocking electrical signal. 
     In one aspect, the present disclosure relates to a system for treating a medical condition in a patient, comprising at least one electrode coupled to a vagus nerve of the patient, a programmable electrical signal generator, a sensor for sensing at least one body data stream, a seizure detection module capable of analyzing the at least one body data stream and determining, based on the analyzing, whether or not the patient is having and/or has had an epileptic seizure, a heart rate determination unit capable of determining a heart rate of a patient proximate in time to an epileptic seizure detected by the seizure detection module, and a logic unit for applying a first electrical signal to the vagus nerve using the at least one electrode based on a determination by the seizure detection module that the patient is having and/or has had an epileptic seizure characterized by a decrease in the patient&#39;s heart rate, wherein the first electrical signal is a pulsed electrical signal that blocks action potential conduction in the vagus nerve, and for applying a second electrical signal to the vagus nerve using the at least one electrode as a cathode based upon one of a) a determination that the patient is not having and/or has not had an epileptic seizure, and b) a determination that the patient is having and/or has had an epileptic seizure that is not characterized by a decrease in the patient&#39;s heart rate, wherein the second electrical signal is not a vagus nerve conduction blocking electrical signal. In one embodiment, the seizure detection module may comprise the heart rate determination unit. 
     In one aspect, the present disclosure relates to a method of treating a patient having epilepsy comprising applying a first electrical signal to a vagus nerve of the patient, wherein the first electrical signal is an open-loop electrical signal having a programmed on-time and a programmed off-time, sensing at least one body signal of the patient, determining the start of an epileptic seizure based on the at least one body signal, determining whether or not the seizure is characterized by a decrease in the patient&#39;s heart rate, applying a second, closed-loop electrical signal to a vagus nerve of the patient based on a determination that the epileptic seizure is not characterized by a decrease in the patient&#39;s heart rate, and applying a third, closed-loop electrical signal to a vagus nerve of the patient based on a determination that the seizure is characterized by a decrease in the patient&#39;s heart rate, wherein the third electrical signal is applied to block action potential conduction on the vagus nerve. 
     In one aspect, the present disclosure relates to a method of controlling a heart rate of an epilepsy patient comprising sensing a kinetic signal of the patient; analyzing said kinetic signal to determine at least one kinetic index; receiving a cardiac signal of the patient; analyzing the cardiac signal to determine the patient&#39;s heart rate; determining if the patient&#39;s heart rate is commensurate with the at least one kinetic index; and applying a first electrical signal to a vagus nerve of the patient based on a determination that the patient&#39;s heart rate is not commensurate with the kinetic index. In one embodiment, the at least one kinetic index comprises at least one of an activity level or an activity type of the patient, and determining if the heart rate is commensurate with the kinetic index comprises determining if the heart rate is commensurate with the at least one of an activity level or an activity type. 
     In one aspect, the present disclosure relates to a method of controlling a heart rate of an epilepsy patient comprising sensing at least one of a kinetic signal and a metabolic (e.g., oxygen consumption) signal of the patient; receiving a cardiac signal of the patient; analyzing the cardiac signal to determine the patient&#39;s heart rate; determining if the patient&#39;s heart rate is commensurate with the at least one of a kinetic and a metabolic signal of the patient; and applying a first electrical signal to a vagus nerve of the patient based on a determination that the patient&#39;s heart rate is not commensurate with the at least one of a kinetic signal and a metabolic signal. In one embodiment, the method further comprises determining at least one of an activity level or an activity type of the patient based on the at least one of a kinetic and a metabolic signal, and determining if the heart rate is commensurate with the kinetic signal comprises determining if the heart rate is commensurate with the at least one of an activity level or an activity type. 
     In one aspect, the present disclosure relates to a method of treating a patient having epilepsy comprising sensing at least one body signal of the patient; determining whether or not the patient is having or has had an epileptic seizure based on the at least one body signal; sensing a cardiac signal of the patient; determining whether or not the seizure is associated with a change in the patient&#39;s cardiac signal; applying a first therapy to a vagus nerve of the patient based on a determination that the patient is having or has had an epileptic seizure that is not associated with a change in the patient&#39;s cardiac signal, wherein the first therapy is selected from an electrical, chemical, mechanical (e.g., pressure) or thermal signal. The method further comprises applying a second therapy to a vagus nerve of the patient based on a determination that the patient has had an epileptic seizure associated with a change in the patient&#39;s cardiac signal, wherein the second therapy is selected from an electrical, chemical, mechanical (e.g., pressure) or thermal signal. In some embodiments, a third therapy may be applied to a vagus nerve based a determination that the patient has not had an epileptic seizure, wherein the third therapy is selected form an electrical, chemical, mechanical or thermal signal. 
     In one embodiment, the present disclosure provides a method of distinguishing a non-epileptic seizure from an epileptic seizure in a patient, comprising: detecting a seizure in a patient based on at least one first body signal of the patient selected from an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, and a tissue stress marker signal; analyzing at least one second body signal of the patient selected from an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, and a tissue stress marker signal; determining, based on the analyzing of the at least one second body signal, at least a first classification index comprising at least one of an epileptic seizure index and a non-epileptic seizure index; and classifying the seizure as one of a non-epileptic seizure or an epileptic seizure based on the at least a first classification index. 
     In one embodiment, the present disclosure provides a method of distinguishing an epileptic seizure from a non-epileptic seizure, comprising: identifying an unclassified seizure that is one of an epileptic seizure or a non-epileptic seizure; determining a first seizure classification index having an index class selected from a neurologic index class, an autonomic index class, a motor index class, a tissue stress marker index class, or a metabolic index class; determining a second seizure classification index having an index class selected from a neurologic index class, an autonomic index class, a motor index class, a tissue stress marker index class, or a metabolic index class; classifying said seizure as one of an epileptic seizure or a non-epileptic seizure based on both said first and said second seizure classification indices; and taking at least one further action based on said classifying, wherein said at least one further action is selected from: 
     issuing a notification that the seizure is non-epileptic; issuing a notification that the seizure is epileptic; administering a therapy for a non-epileptic seizure; administering a therapy for an epileptic seizure; or logging at least one of whether the seizure is an epileptic or non-epileptic seizure and at least one of the date of the seizure, the time of occurrence of the seizure, the severity of the seizure, the time elapsed from a previous seizure, or the frequency per unit time of the same type of seizure. 
     In one embodiment, the present disclosure provides a method, comprising: receiving a kinetic signal from at least one target of the patient&#39;s body; determining at least one kinetic index based on said kinetic signal; identifying an unclassified seizure based on the at least one kinetic index; receiving at least one of a non-kinetic neurologic index and an autonomic index; and classifying the seizure as an epileptic seizure or non-epileptic seizure based on the at least one of a non-kinetic neurologic index and an autonomic index. 
     In one embodiment, the present disclosure provides a medical device system, comprising: at least one sensor configured to receive at least one of an autonomic signal indicative of an autonomic activity of a patient, a neurologic signal indicative of a neurologic activity of said patient, a metabolic signal indicative of a metabolic activity of said patient, an endocrine signal indicative of an endocrine activity of said patient, or a tissue stress marker signal indicative of a tissue stress marker activity of said patient; a seizure detection unit configured to detect a seizure in a patient based on said at least one autonomic, neurologic, metabolic, endocrine, or tissue stress marker signal; at least one classification index determination unit configured to determine at least a first classification index selected from an autonomic index, a neurologic index, a metabolic index, an endocrine index, and a tissue stress marker index; and a seizure classification unit configured to classify said epileptic seizure as one of an epileptic seizure and a non-epileptic seizure based at least in part on said at least a first classification index. 
     In one embodiment, the present disclosure provides a non-transitive, computer-readable storage device for storing data that when executed by a processor, perform a method as described above. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The disclosure may be understood by reference to the following description taken in conjunction with the accompanying drawings, in which like reference numerals identify like elements, and in which: 
         FIGS.  1 A- 1 E  provide stylized diagrams of an implantable medical device implanted into a patient&#39;s body for providing first and second electrical signals to a vagus nerve of a patient for treating epileptic seizures, in accordance with one illustrative embodiment of the present disclosure; 
         FIG.  2    illustrates a block diagram depiction of an implantable medical device of  FIG.  1   , in accordance with one illustrative embodiment of the present disclosure; 
         FIG.  3    illustrates a block diagram depiction of an electrode polarity reversal unit shown in  FIG.  2   , in accordance with one illustrative embodiment of the present disclosure; 
         FIG.  4    illustrates a flowchart depiction of a method for providing first and second electrical signals to a main trunk and a cardiac branch of a vagus nerve, respectively, based upon whether or not the patient is having and/or has had an epileptic seizure, in accordance with an illustrative embodiment of the present disclosure; 
         FIG.  5    illustrates a flowchart depiction of a method for providing first and second electrical signals to a main trunk and a cardiac branch of a vagus nerve, respectively, based upon whether or not at least one of a cardiac signal and a kinetic signal indicates that the patient is having and/or has had an epileptic seizure, and whether the seizure is characterized by an increase in heart rate, in accordance with an illustrative embodiment of the present disclosure; 
         FIG.  6    illustrates a flowchart depiction of a method for providing a first, open-loop electrical signal to a main trunk of a vagus nerve, a second, closed-loop electrical signal to the main trunk of the vagus nerve based upon the patient having had an epileptic seizure not characterized by an increase in heart rate, and a third, closed-loop electrical signal to a cardiac branch of a vagus nerve based upon the patient having had an epileptic seizure characterized by an increase in heart rate, in accordance with an illustrative embodiment of the present disclosure; and 
         FIG.  7    is a flowchart depiction of a method for providing closed-loop vagus nerve stimulation for a patient with epilepsy by stimulating a right vagus nerve in response to detecting a seizure with tachycardia and stimulating a left vagus nerve in the absence of such a detection. For example if a recumbent person&#39;s heart rate is 55 bpm and it increases to 85 during a seizure, this is not clinical/pathological tachycardia, but may be considered tachycardia within the meaning of some embodiments of the present disclosure. 
         FIG.  8    is a flowchart depiction of a method for providing a closed-loop therapy to a vagus nerve of a patient with epilepsy in response to detecting a seizure associated with a heart rate decrease, wherein said therapy blocks impulse conduction along at least one vagus nerve. 
         FIG.  9    is a flowchart depicting a method for providing closed-loop vagus nerve stimulation based on an assessment of whether the patient&#39;s heart rate is commensurate with the patient&#39;s activity level or activity type. 
         FIG.  10    is a flowchart depicting a method for providing closed-loop vagus nerve stimulation based on a determination that the patient&#39;s heart rate is incommensurate with the patient&#39;s activity level or activity type, and further in view of whether the incommensurate changes involves relative tachycardia or relative bradycardia. 
         FIG.  11    is a graph of heart rate versus time, according to one embodiment. 
         FIG.  12    is another graph of heart rate versus time, according to one embodiment. 
         FIG.  13    is another graph of heart rate versus time, according to one embodiment. 
         FIG.  14    is another graph of heart rate versus time, according to one embodiment. 
         FIG.  15    is another graph of heart rate versus time, according to one embodiment. 
         FIG.  16    is a flowchart of a therapy procedure, according to one embodiment. 
         FIG.  17    is a graph relating to the automated detection and control of ictal and peri-ictal chronotropic instability, according to one embodiment. 
         FIG.  18    is a graph relating to the automated detection and control of ictal and peri-ictal chronotropic instability, according to one embodiment. 
         FIG.  19    is a graph relating to the automated detection and control of ictal and peri-ictal chronotropic instability, according to one embodiment. 
         FIG.  20    is a graph relating to the automated detection and control of ictal and peri-ictal chronotropic instability, according to one embodiment. 
         FIG.  21    is a graph relating to the automated detection and control of ictal and peri-ictal chronotropic instability, according to one embodiment. 
         FIG.  22    provides a stylized diagram of a medical device for classifying a seizure as epileptic or non-epileptic, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  23    provides a block diagram of a medical device system that includes a medical device and a monitoring unit, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 A  provides a block diagram of an autonomic signal module of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 B  provides a block diagram of a neurologic signal module of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 C  provides a block diagram of a metabolic signal module of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 D  provides a block diagram of an endocrine signal module of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 E  provides a block diagram of a stress marker signal module of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  24 F  provides a block diagram of a classification unit of a medical device, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  25    shows a flowchart depiction of a method, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  26    shows a flowchart depiction of a method, in accordance with one illustrative embodiment of the present disclosure. 
         FIG.  27    shows a flowchart depiction of a method, in accordance with one illustrative embodiment of the present disclosure. 
         FIGS.  28 A and  28 B  compare simulated, non-limiting (a) epileptic and (b) non-epileptic movements of an arm, as represented by the path traced by an accelerometer, as seen from in front of, to the side of, and above a patient. 
     
    
    
     While the disclosure is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description herein of specific embodiments is not intended to limit the disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims. 
     DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS 
     Illustrative embodiments of the disclosure are described herein. For clarity, not all features of an actual implementation are provided in detail. In any actual embodiment, numerous implementation-specific decisions must be made to achieve the design-specific goals. Such a development effort, while possibly complex and time-consuming, would nevertheless be a routine task for persons of skill in the art given this disclosure. 
     This application does not intend to distinguish between components that differ in name but not function. “Including” and “includes” are used in an open-ended fashion, and should be interpreted to mean “including, but not limited to.” “Couple” or “couples” are intended to mean either a direct or an indirect electrical connection. “Direct contact,” “direct attachment,” or providing a “direct coupling” indicates that a surface of a first element contacts the surface of a second element with no substantial attenuating medium there between. Small quantities of substances, such as bodily fluids, that do not substantially attenuate electrical connections do not vitiate direct contact. “Or” is used in the inclusive sense (i.e., “and/or”) unless a specific use to the contrary is explicitly stated. 
     “Electrode” or “electrodes” may refer to one or more stimulation electrodes (i.e., electrodes for applying an electrical signal generated by an IMD to a tissue), sensing electrodes (i.e., electrodes for sensing a body signal), and/or electrodes capable of either stimulation or sensing. “Cathode” and “anode” have their standard meanings, as the electrode at which current leaves the IMD system and the electrode at which current enters the IMD system, respectively. Reversing the polarity of the electrodes can be effected by any switching technique known in the art. 
     A “pulse” is used herein to refer to a single application of electrical charge from the cathode to target neural tissue. A pulse may include both a therapeutic portion (in which most or all of the therapeutic or action-potential-generating effect occurs) and a charge-balancing portion in which the polarity of the electrodes are reversed and the electrical current is allowed to flow in the opposite direction to avoid electrode and/or tissue damage. Individual pulses are separated by a time period in which no charge is delivered to the nerve, which can be called the “interpulse interval.” A “burst” is used herein to refer to a plurality of pulses, which may be separated from other bursts by an interburst interval in which no charge is delivered to the nerve. The interburst intervals have a duration exceeding the interpulse interval duration. In one embodiment, the interburst interval is at least twice as long as the interpulse interval. The time period between the end of the last pulse of a first burst and the initiation of the first pulse of the next subsequent burst can be called the “interburst interval.” In one embodiment, the interburst interval is at least 100 msec. 
     A plurality of pulses can refer to any of (a) a number of consecutive pulses within a burst, (b) all the pulses of a burst, or (c) a number of consecutive pulses including the final pulse of a first burst and the first pulse of the next subsequent burst. 
     “Stimulate,” “stimulating” and “stimulator” may generally refer to applying a signal, stimulus, or impulse to neural tissue (e.g., a volume of neural tissue in the brain or a nerve) for affecting it neuronal activity. While the effect of such stimulation on neuronal activity is termed “modulation,” for simplicity, the terms “stimulating” and “modulating”, and variants thereof, are sometimes used interchangeably herein. The modulation effect of a stimulation signal on neural tissue may be excitatory or inhibitory, and may potentiate acute and/or long-term changes in neuronal activity. For example, the modulation effect of a stimulation signal may comprise: (a) initiating action potentials in the target neural tissue; (b) inhibition of conduction of action potentials (whether endogenous or exogenously generated, or blocking their conduction (e.g., by hyperpolarizing or collision blocking), (c) changes in neurotransmitter/neuromodulator release or uptake, and (d) changes in neuroplasticity or neurogenesis of brain tissue. Applying an electrical signal to an autonomic nerve may comprise generating a response that includes an afferent action potential, an efferent action potential, an afferent hyperpolarization, an efferent hyperpolarization, an afferent sub-threshold depolarization, and/or an efferent sub-threshold depolarization. The terms tachycardia and bradycardia are used here in a relative (i.e., any decrease or decrease in heart rate relative to a reference value) or in an absolute sense (i.e., a pathological change relative to a normative value). In particular, “tachycardia is used interchangeably with an increase heart rate and “bradycardia” may be used interchangeably with a decrease in heart rate. 
     A variety of stimulation therapies may be provided in embodiments of the present disclosure. Different nerve fiber types (e.g., A, B, and C-fibers that may be targeted) respond differently to stimulation from electrical signals because they have different conduction velocities and stimulation threshold. Certain pulses of an electrical stimulation signal, for example, may be below the stimulation threshold for a particular fiber and, therefore, may generate no action potential. Thus, smaller or narrower pulses may be used to avoid stimulation of certain nerve fibers (such as C-fibers) and target other nerve fibers (such as A and/or B fibers, which generally have lower stimulation thresholds and higher conduction velocities than C-fibers). Additionally, techniques such as a pre-pulse may be employed wherein axons of the target neural structure may be partially depolarized (e.g., with a pre-pulse or initial phase of a pulse) before a greater current is delivered to the target (e.g., with a second pulse or an initial phase such a stair step pre-pulse to deliver a larger quantum of charge). Furthermore, opposing polarity phases separated by a zero current phase may be used to excite particular axons or postpone nerve fatigue during long term stimulation. 
     Cranial nerve stimulation, such as vagus nerve stimulation (VNS), has been proposed to treat a number of medical conditions, including epilepsy and other movement disorders, depression and other neuropsychiatric disorders, dementia, traumatic brain injury, coma, migraine headache, obesity, eating disorders, sleep disorders, cardiac disorders (such as congestive heart failure and atrial fibrillation), hypertension, endocrine disorders (such as diabetes and hypoglycemia), and pain, among others. See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569; 5,269,303; 5,571,150; 5,215,086; 5,188,104; 5,263,480; 6,587,719; 6,609,025; 5,335,657; 6,622,041; 5,916,239; 5,707,400; 5,231,988; and 5,330,515. Despite the variety of disorders for which cranial nerve stimulation has been proposed or suggested, the fact that detailed neural pathways for many (if not all) cranial nerves remain relatively unknown, makes predictions of efficacy for any given disorder difficult or impossible. Even if such pathways were known, the precise stimulation parameters that would modulate particular pathways relevant to a particular disorder generally cannot be predicted. 
     Cardiac signals suitable for use in embodiments of the present disclosure may comprise one or more of an electrical (e.g., EKG), acoustic (e.g., phonocardiogram or ultrasound/ECHO), force or pressure (e.g., apexcardiogram), arterial pulse pressure and waveform or thermal signals that may be recorded and analyzed to extract features such as heart rate, heart rate variability, rhythm (regular, irregular, sinus, ventricular, ectopic, etc.), morphology, etc. 
     It appears that sympatho-vagal imbalance (lower vagal and higher sympathetic tone) plays an important role in generation of a wide spectrum of ictal and interictal alterations in cardiac dynamics, ranging from rare unifocal PVCs to cardiac death. Without being bound by theory, restoration of the vagal tone to a level sufficient to counteract the pathological effects of elevated catecholamines may serve a cardio-protective purpose that would be particularly beneficial in patients with pharmaco-resistant epilepsies, who are at highest risk for SUDEP. 
     In one embodiment, the present disclosure provides methods and apparatus to increase cardiac vagal tone in epilepsy patients by timely delivering therapeutic electrical currents to the trunks of the right or left vagus nerves or to their cardiac rami (branches), in response to increases in sympathetic tone, by monitoring among others, heart rate, heart rhythm, EKG morphology, blood pressure, skin resistance, catecholamine or their metabolites and neurological signals such as EEG/ECoG, kinetic (e.g., amplitude velocity, direction of movements) and cognitive (e.g., complex reaction time). 
     In one embodiment, the present disclosure provides a method of treating a medical condition selected from the group consisting of epilepsy, neuropsychiatric disorders (including but not limited to depression), eating disorders/obesity, traumatic brain injury, addiction disorders, dementia, sleep disorders, pain, migraine, endocrine/pancreatic disorders (including but not limited to diabetes), motility disorders, hypertension, congestive heart failure/cardiac capillary growth, hearing disorders, angina, syncope, vocal cord disorders, thyroid disorders, pulmonary disorders, gastrointestinal disorders, kidney disorders, and reproductive endocrine disorders (including infertility). 
       FIGS.  1 A- 1 E  depict a stylized implantable medical system  100  for implementing one or more embodiments of the present disclosure.  FIGS.  1 A and  1 B  illustrate an electrical signal generator  110  having main body  112  comprising a case or shell (commonly referred to as a “can”)  121 ) ( FIG.  1 B ) with a header  116  for connecting to a lead assembly  122 . An electrode assembly  125 , preferably comprising at least an electrode pair, is conductively connected to the distal end of an insulated, electrically conductive lead assembly  122 , which preferably comprises a plurality of lead wires (at least one wire for each electrode of the electrode assembly  125 ). Lead assembly  122  is attached at its proximal end to one or more connectors on header  116  ( FIG.  1 B ). 
     Electrode assembly  125  may be surgically coupled to a target tissue for delivery of a therapeutic electrical signal, which may be a pulsed electrical signal. The target tissue may be a cranial nerve, such as a vagus nerve  127  ( FIGS.  1 A,  1 C -E) or another cranial nerve such as a trigeminal nerve. Electrode assembly  125  includes one or more electrodes  125 - 1 ,  125 - 2 ,  125 - 3 , which may be coupled to the target tissue. The electrodes may be made from any of a variety of conductive metals known in the art, e.g., platinum, iridium, oxides of platinum or iridium, or combinations of the foregoing. In one embodiment, the target tissue is a vagus nerve  127 , which may include an upper main trunk portion  127 - 1  above a cardiac branch  127 - 2 , and a lower main trunk portion  127 - 3  below the cardiac branch. 
     In one embodiment, at least one electrode may be coupled to the main trunk of the vagus nerve, and at least one electrode  125 - 2  may be coupled to a cardiac branch  127 - 2  of the vagus nerve ( FIG.  1 C ). The at least one main trunk electrode may be coupled to an upper main trunk  127 - 1  (e.g., electrode  125 - 1 ,  FIG.  1 C ) or a lower main trunk  127 - 3  (e.g., electrode  125 - 3 ). The at least one main trunk electrode ( 125 - 1 ,  125 - 3 ) may be used as a cathode to provide a first electrical signal to the upper ( 127 - 1 ) or lower ( 127 - 3 ) main trunk. Cardiac branch electrode  125 - 2  may be used as a cathode to provide a second electrical signal to cardiac branch  127 - 2 . An additional electrode to function as the anode may be selected from one or more of the other electrodes in electrode assembly  125 , can  121 , or a dedicated anode. 
     In some embodiments ( FIGS.  1 D,  1 E ), electrode assembly  125  may include a main trunk electrode pair comprising a cathode  125 - 1   a  and an anode  125 - 1   b  for coupling to a main trunk of a vagus nerve  127 . The main trunk electrode pair  125 - 1   a ,  125 - 1   b  may be coupled to an upper main trunk  127 - 1  of a vagus nerve ( FIG.  1 D ), or to a lower main trunk  127 - 3  ( FIG.  1 E ) for delivering a first electrical signal. Without being bound by theory, it is believed that few or no vagal afferent fibers in the lower main trunk  127 - 3  pass into cardiac branch  127 - 2  and, accordingly, that effects of the first electrical signal on cardiac function may be minimized by coupling electrode pair  125 - 1   a  and  125 - 1   b  to the lower main trunk  127 - 3  instead of upper main trunk  127 - 1 . Cardiac effects may also be minimized by alternative embodiments in which the first electrical signal is applied to a lower main trunk  127 - 3  using a single electrode (e.g.,  125 - 3 ,  FIG.  1 C ) as a cathode and an anode that is not coupled to the vagus nerve  127  (e.g., by using can  121  as an anode). 
     In some embodiments ( FIGS.  1 D,  1 E ), electrode assembly  125  may include a cardiac branch electrode pair comprising a cathode  125 - 2   a  and an anode  125 - 2   b  for coupling to a cardiac branch of a vagus nerve. The second cardiac branch electrode pair may be used to provide a second electrical signal to a cardiac branch of the nerve to affect the cardiac function of the patient. 
     Referring again to  FIGS.  1 C- 1 E , a first electrical signal may be provided to generate afferent action potentials in a main trunk of a vagus nerve to modulate electrical activity of the patient&#39;s brain without significantly affecting the patient&#39;s heart rate. The second electrical signal may generate efferent action potentials to module the cardiac activity of the patient, and in particular to slow the patient&#39;s heart rate (e.g., to treat an epilepsy patient having seizures characterized by ictal tachycardia) and maintain or restore a sympathetic/parasympathetic balance to a non-pathological state. The first electrical signal may be applied to the main trunk of the vagus nerve in a variety of ways, so long as at least one electrode is coupled to the main trunk as a cathode. As noted, the cathode may be coupled to either an upper ( 127 - 1 ) or lower ( 127 - 3 ) main trunk, and an anode may be provided by any of the other electrodes on the vagus nerve (e.g.,  125 - 1   b ,  125 - 2   b ,  125 - 3 ,  FIGS.  1 C- 1 E ) or by a separate anode not coupled to the vagus nerve (e.g., can  121 ). In one alternative embodiment, an electrode  125 - 3  may be coupled to a lower main trunk  127 - 3  of the vagus nerve to function as an anode. In yet another embodiment, each individual electrode element in  FIGS.  1 A-E  (e.g.,  125 - 1 ,  125 - 2 ,  125 - 3 ,  125 - 1   a ,  125 - 1   g ,  125 - 2   a ,  125 - 2   b ) may comprise an electrode pair comprising both an anode and a cathode. In an additional embodiment, each individual electrode element may comprise three electrodes (e.g., one serving as cathode and the other two as anodes). Suitable electrode assemblies are available from Cyberonics, Inc., Houston, Tex., USA as the Model  302 , PerenniaFlex and PerenniaDura electrode assemblies. In view of the present disclosure, persons of skill in the art will appreciate that many electrode designs could be used in embodiments of the present disclosure including unipolar electrodes. 
     Embodiments of the present disclosure may comprise electrical signals with either charge-balanced or non-charge-balanced pulses (e.g., monopolar/monophasic, direct current (DC)). Charge-balanced pulses involve a first phase in which the stimulation occurs (i.e., action potentials are induced in target nerve fibers), and a second phase in which the polarity of the electrodes are reversed (i.e., the stimulation phase cathode becomes the charge-balancing phase anode, and vice versa). The result is a pulse having two opposite-polarity phases of equal charge, such that no net charge flows across the electrode during a pulse. Charge-balancing is often used to avoid damage to the electrodes that may result if a pulse results in a net charge flowing across the electrodes. 
     In some instances, charge-balancing may involve a passive discharge phase as illustrated in, e.g.,  FIG.  1 A  of US Publication 2006/0173493, which is hereby incorporated by reference in its entirety. In passive charge-balancing, the charge-balancing phase typically involves allowing a capacitor having a charge equal to the charge applied to the nerve during the stimulation phase to discharge through the polarity-reversed electrodes. Passive charge-balancing typically uses much lower initial current than the stimulation phase, with the current declining to zero over a much longer time period than the pulse width of the stimulation phase. A lower current is typically selected in the charge-balancing phase so as to avoid or minimize nerve recruitment during the charge-balancing phase. In active charge-balancing, the charge-balancing phase is not accomplished by the passive discharge of a capacitor, but by providing a second phase having an opposite polarity but the same charge magnitude (pulse width multiplied by current) as the first phase. As is usually the case with passive charge-balancing, active charge-balancing typically involves a much lower current that is applied over a longer time period than the stimulation phase, so as to avoid nerve recruitment. In some instances, however, the active charge-balancing phase may be used as a second stimulation phase by selecting a current magnitude of the cathode in the charge-balancing phase (typically a second electrode, which may be the anode of the initial stimulation phase) that is sufficient to generate action potentials in nerve fibers of the target tissue. 
     Embodiments of the present disclosure may be implemented using passive charge balancing or active charge-balancing, and the latter may be provided as a stimulation phase or a non-stimulation phase. Some embodiments may be implemented with non-charge-balanced pulses. Persons of skill in the art, having the benefit of the present disclosure, may select the type of charge balancing (if desired) based upon a number of factors including but not limited to whether or not the charge-balancing is intended to affect the cardiac cycle or not, whether afferent or efferent stimulation is desired, the number and location of available electrodes for applying the electrical signal, the fibers intended to be recruited during a particular phase and their physiological effects, among many other factors. 
     In the discussion of electrical signals in the present disclosure, unless otherwise stated, references to electrodes as cathodes or anodes refers to the polarities of the electrodes during a stimulation phase of a pulse, whether the pulse is a charge-balanced pulse or a non-charge-balanced pulse (e.g., monopolar/monophasic or DC). It will be appreciated that where charge-balanced pulses are employed, the polarities will be reversed during a charge-balancing phase. Where active charge-balancing is used, cardiac effects may be further amplified or ameliorated, depending upon the location of the electrodes being used. 
     Returning to  FIG.  1 A , in some embodiments, a heart rate sensor  130 , and/or a kinetic sensor  140  (e.g., a triaxial accelerometer) may be included in the system  100  to sense one or more of a cardiac signal or data stream and a kinetic data stream of the patient. In one embodiment, the heart rate sensor may comprise a separate element  130  that may be coupled to generator  110  through header  116  as illustrated in  FIG.  1 A . In another embodiment, the electrodes  125 - 1 ,  125 - 2 ,  125 - 3  and/or the can  121  may be used as sensing electrodes to sense heart rate. An accelerometer may be provided inside generator  110  in one embodiment to sense a kinetic signal (e.g., body movement) of the patient. One or more of the heart rate sensor  130  and the kinetic sensor  140  may be used by a seizure detection algorithm in the system  100  to detect epileptic seizures. In alternative embodiments, other body signals (e.g., blood pressure, brain activity, blood oxygen/CO 2  concentrations, temperature, skin resistivity, etc.) of the patient may be sensed and used by the seizure detection algorithm to detect epileptic seizures. Signal generator  110  may be implanted in the patient&#39;s chest in a pocket or cavity formed by the implanting surgeon below the skin (indicated by line  145 ,  FIG.  1 A ). 
     Returning to  FIGS.  1 A and  1 C , a first electrode  125 - 1  may be wrapped or otherwise electrically coupled to an upper main trunk  127 - 1  of a vagus nerve  127  of the patient, and a second electrode  125 - 2  may be wrapped or coupled to a cardiac branch  127 - 2  of the vagus nerve. In one embodiment, a third electrode  125 - 3  may be coupled to a lower main trunk  127 - 3  of the vagus nerve below the cardiac branch  127 - 2  of the vagus nerve, instead of or in addition to first electrode  125 - 1  coupled to the upper main trunk above the cardiac branch. In some embodiments, third electrode  125 - 3  may be omitted. Electrode assembly  125  may be secured to the nerve by a spiral anchoring tether  128  ( FIG.  1 C ), which in one embodiment does not include an electrode but in alternative embodiments may contain up to three electrodes that serve as cathode(s) and anode(s) in any possible combination. Lead assembly  122  may further be secured, while retaining the ability to flex, by a suture connection  130  to nearby tissue ( FIG.  1 C ). In particular embodiments, any of first, second and third electrodes  125 - 1 ,  125 - 2 , and  125 - 3  may be used as either a cathode or as an anode. In general, the foregoing electrodes may be used as a cathode when the particular electrode is the closest electrode (among a plurality of electrodes) to the target organ (e.g., heart, brain, stomach, liver, etc.) to be stimulated. While a single electrode (e.g.,  125 - 1 ,  125 - 2 , or  125 - 3 ) is illustrated in connection with upper main trunk  127 - 1 , cardiac branch  127 - 2 , and lower main trunk  127 - 3  in  FIGS.  1 A and  1 C  for simplicity, it will be appreciated that one or more additional electrodes can be provided on each of the foregoing neural structures to provide greater flexibility in stimulation. 
     In one embodiment, the open helical design of the electrodes  125 - 1 ,  125 - 2 ,  125 - 3 , is self-sizing, flexible, minimize mechanical trauma to the nerve and allow body fluid interchange with the nerve. The electrode assembly  125  preferably conforms to the shape of the nerve, providing a low stimulation threshold by allowing a large stimulation contact area with the nerve. Structurally, the electrode assembly  125  comprises an electrode ribbon (not shown) for each of electrodes  125 - 1 ,  125 - 2 ,  125 - 3 , made of a conductive material such as platinum, iridium, platinum-iridium alloys, and/or oxides thereof. The electrode ribbons are individually bonded to an inside surface of an elastomeric body portion of the spiral electrodes  125 - 1 ,  125 - 2 ,  125 - 3  ( FIG.  1 C ), which may comprise spiral loops of a multi-loop helical assembly. Lead assembly  122  may comprise three distinct lead wires or a triaxial cable that are respectively coupled to one of the conductive electrode ribbons. One suitable method of coupling the lead wires to the electrodes  125 - 1 ,  125 - 2 ,  125 - 3  comprises a spacer assembly such as that disclosed in U.S. Pat. No. 5,531,778, although other known coupling methods may be used. 
     The elastomeric body portion of each loop may be composed of silicone rubber or other biocompatible elastomeric compounds, and the fourth loop  128  (which may have no electrode in some embodiments) acts as the anchoring tether for the electrode assembly  125 . 
     In one embodiment, electrical pulse generator  110  may be programmed with an external computer  150  using programming software known in the art for stimulating neural structures, and a programming wand  155  to facilitate radio frequency (RF) communication between the external computer  150  ( FIG.  1 A ) and the implanted pulse generator  110 . In one embodiment, wand  155  and software permit wireless, non-invasive communication with the generator  110  after surgical implantation. Wand  155  may be powered by internal batteries, and provided with a “power on” light to indicate sufficient power for communications. Another indicator light may be provided to show that data transmission is occurring between the wand and the generator. In other embodiments, wand  155  may be omitted, e.g., where communications occur in the 401-406 MHz bandwidth for Medical Implant Communication Service (MICS band). 
     In some embodiments of the disclosure, a body data stream may be analyzed to determine whether or not a seizure has occurred. Many different body data streams and seizure detection indices have been proposed for detecting epileptic seizures. Additional details on method of detecting seizure from body data are provided in U.S. Pat. Nos. 8,337,404 and 8,382,667, both issued in the name of the present applicant and both entitled, “Detecting, Quantifying, and/or Classifying Seizures Using Multimodal Data,” as well as in co-pending U.S. patent application Ser. No. 13/288,886, filed Nov. 3, 2011, each hereby incorporated by reference in its entirety herein. Seizure detection based on the patient&#39;s heart rate (as sensed by implanted or external electrodes), movement (as sensed by, e.g., a triaxial accelerometer), responsiveness, breathing, blood oxygen saturation, skin resistivity/conductivity, temperature, brain activity, and a number of other body data streams are provided in the foregoing patents and co-pending applications. 
     In one embodiment, the present disclosure provides a method for treating a patient with epilepsy in which a body data stream is analyzed using a seizure detection algorithm to determine whether or not the patient has had an epileptic seizure. As used herein, the term “has had an epileptic seizure” includes instances in which a seizure onset has been detected, as well as instances in which the seizure onset has been detected and the seizure is still ongoing (i.e., the seizure has not ended). If the analysis results in a determination that the patient has not had an epileptic seizure, a signal generator may apply a first electrical signal to a main trunk of a vagus nerve of the patient. If the analysis results in a determination that the patient has had an epileptic seizure, the signal generator may apply a second electrical signal to a cardiac branch of a vagus nerve of the patient. In some embodiments, the application of the first electrical signal to the main trunk is terminated, and only the second electrical signal to the cardiac branch is provided once a seizure is detected. 
     In alternative embodiments, both the first and second electrical signals may be applied to the main trunk and cardiac branch, respectively, of the vagus nerve in response to a determination that the patient has had a seizure (i.e., the first electrical signal continues to be applied to the main trunk of the vagus nerve and the second signal is initiated). Where both the first and second electrical signals are provided, the two signals may be provided sequentially, or in alternating fashion to the main trunk and the cardiac branch. In one embodiment, the first signal may be provided to the main trunk by using one of the upper main trunk electrode  125 - 1  or the lower main trunk electrode  125 - 3  as the cathode and the cardiac branch electrode  125 - 2  as the anode, or by using both of the upper main trunk electrode and the lower main trunk electrode as the cathode and the anode. The second signal may be provided (e.g., by rapidly changing the polarity of the electrodes) by using the cardiac branch electrode  125 - 2  as the cathode and a main trunk electrode  125 - 1  or  125 - 3  as the anode. 
     In still other embodiments, the second electrical signal is applied to the cardiac branch of the vagus nerve only if the analysis results in a determination that the patient is having and/or has had an epileptic event that is accompanied by an increase in heart rate, and the second electrical signal is used to lower the heart rate back towards a rate that existed prior to the seizure onset. Without being bound by theory, the present inventors believe that slowing the heart rate at the onset of seizures—particularly where the seizure is accompanied by an increase in heart rate—may improve the ability of VNS therapy to provide cardio-protective benefits. 
     Prior patents describing vagus nerve stimulation as a medical therapy have cautioned that undesired slowing of the heart rate may occur, and have proposed various methods of avoiding such a slowing of the heart rate. In U.S. Pat. No. 6,341,236, it is suggested to sense heart rate during delivery of VNS and if a slowing of the heart rate is detected, either suspending delivery of the VNS signal or pacing the heart using a pacemaker. The present application discloses a VNS system that detects epileptic seizures, particularly epileptic seizures accompanied by an increase in heart rate, and intentionally applies an electrical signal to slow the heart rate in response to such a detection. In another aspect, the present application discloses VNS systems that provide a first electrical signal to modulate only the brain during periods in which no seizure has been detected, and either 1) a second electrical signal to modulate only the heart (to slow its rate) or 2) both a first electrical signal to the brain and a second electrical signal to the heart, in response to a detection of the onset of an epileptic seizure. These electrical signals may be delivered simultaneously, sequentially (e.g., delivery of stimulation to the brain precedes delivery of stimulation to the heart or vice versa), or delivery of the first and second signals may be interspersed or interleaved. 
     The first electrode may be used as a cathode to provide an afferent first electrical signal to modulate the brain of the patient via main trunk electrode  125 - 1 . Electrode  125 - 1  may generate both afferent and efferent action potentials in vagus nerve  127 . One or more of electrodes  125 - 2  and  125 - 3  are used as anodes to complete the circuit. Where this is the case, some of the action potentials may be blocked at the anode(s), with the result that the first electrical signal may predominantly modulate the brain by afferent actions traveling toward the brain, but may also modulate one or more other organs by efferent action potentials traveling toward the heart and/or lower organs, to the extent that the efferent action potentials are not blocked by the anode(s). 
     The second electrode may be used as a cathode to provide an efferent second electrical signal to slow the heart rate of the patient via cardiac branch electrode  125 - 2 . Either first electrode  125 - 1  or a third electrode  125 - 3  (or can  121 ) may be used as an anode to complete the circuit. In one embodiment, the first electrical signal may be applied to the upper ( 127 - 1 ) or lower ( 127 - 3 ) main trunk of the vagus nerve in an open-loop manner according to programmed parameters including an off-time and an on-time. The on-time and off-time together establish the duty cycle determining the fraction of time that the signal generator applies the first electrical. In one embodiment, the off-time may range from 7 seconds to several hours or even longer, and the on-time may range from 5 seconds to 300 seconds. It should be noted that the duty cycle does not indicate when current is flowing through the circuit, which is determined from the on-time together with the pulse frequency (usually 10-200, Hz, and more commonly 20-30 Hz) and pulse width (typically 0.1-0.5 milliseconds). The first electrical signal may also be defined by a current magnitude (e.g., 0.25-3.5 milliamps), and possibly other parameters (e.g., pulse width, and whether or not a current ramp-up and/or ramp-down is provided, a frequency, and a pulse width. 
     In one embodiment, a seizure detection may result in both applying the first electrical signal to provide stimulation to the brain in close proximity to a seizure detection (which may interrupt or terminate the seizure), as well as application of the second electrical signal which may slow the heart, thus exerting a cardio-protective effect. In a particular embodiment, the second electrical signal is applied only in response to a seizure detection that is characterized by (or accompanied or associated with) an increase in heart rate, and is not applied in response to seizure detections that are not characterized by an increase in heart rate. In this manner, the second electrical signal may help interrupt the seizure by restoring the heart to a pre-seizure baseline heart rate when the patient experiences ictal tachycardia (elevated heart rate during the seizure), while leaving the heart rate unchanged if the seizure has no significant effect on heart rate. 
     In still further embodiments, additional logical conditions may be established to control when the second electrical signal is applied to lower the patient&#39;s heart rate following a seizure detection. In one embodiment, the second electrical signal is applied only if the magnitude of the ictal tachycardia rises above a defined level. In one embodiment, the second electrical signal is applied to the cardiac branch only if the heart rate increases by a threshold amount above the pre-ictal baseline heart rate (e.g., more than 20 beats per minute above the baseline rate). In another embodiment, the second electrical signal is applied to the cardiac branch only if the heart rate exceeds an absolute heart rate threshold (e.g., 100 beats per minute, 120 beats per minute, or other programmable threshold). In a further embodiment, a duration constraint may be added to one or both of the heart rate increase or absolute heart rate thresholds, such as a requirement that the heart rate exceed the baseline rate by 20 beats per minute for more than 10 seconds, or exceed 110 beats per minute for more than 10 seconds, before the second electrical signal is applied to the cardiac branch in response to a seizure detection. 
     In another embodiment, the heart rate sensor continues to monitor the patient&#39;s heart rate during and/or after application of the second electrical signal, and the second electrical signal is interrupted or terminated if the patient&#39;s heart rate is reduced below a low heart rate threshold, which may be the baseline heart rate that the patient experienced prior to the seizure, or a rate lower or higher than the baseline pre-ictal heart rate. The low rate threshold may provide a measure of safety to avoid undesired events such as bradycardia and/or syncope. 
     In yet another embodiment, heart rate sensor  130  may continue to monitor heart rate and/or kinetic sensor  140  may continue to monitor body movement in response to applying the second electrical signal, and the second electrical signal may be modified (e.g., by changing one or more parameters such as pulse frequency, or by interrupting and re-initiating the application of the second electrical signal to the cardiac branch of the vagus nerve) to control the heart rate below an upper heart rate threshold and/or body movement exceeds one or more movement thresholds. For example, the frequency or duration of the second electrical signal applied to the cardiac branch of the vagus nerve may be continuously modified based the instantaneous heart rate as monitored during the course of a seizure to control what would otherwise be an episode of ictal tachycardia below an upper heart rate threshold. In one exemplary embodiment, the second electrical signal may be programmed to provide a 30-second pulse burst at 30 Hz, with the pulses having a pulse width of 0.25 milliseconds and a current of 1.5 milliamps. If, at the end of the 30 second burst, the heart rate remains above 120 beats per minute, and is continuing to rise, the burst may be extended to 1 minute instead of 30 seconds, the frequency may be increased to 50 Hz, the pulse width may be increased to 350 milliseconds, or combinations of the foregoing. In still further embodiments, additional therapies (e.g., oxygen delivery, drug delivery, cooling therapies, etc.) may be provided to the patient if the body data (heart rate, kinetic activity, etc.) indicates that the patient&#39;s seizure is not under control or terminated. 
     Abnormalities or changes in EKG morphology or rhythm relative to an interictal morphology or rhythm may also trigger delivery of current to the heart via the trunks of vagi or its cardiac rami. In other embodiments, pharmacological agents such as beta-blockers may be automatically released into a patient&#39;s blood stream in response to the detection of abnormal heart activity during or between seizures. 
     In one embodiment, the first electrical signal and the second electrical signal are substantially identical. In another embodiment, the first electrical signal may vary from the second electrical signal in terms of one or more of pulse width, number of pulses, amplitude, frequency, inter-pulse-interval, stimulation on-time, and stimulation off-time, among other parameters and degree, rate or type of charge balancing. 
     The number of pulses applied to the main trunk or cardiac branch, respectively, before changing the polarity of the first and second electrodes need not be one. Thus, two or more pulses may be applied to the main trunk before applying pulses to the cardiac branch of the vagus nerve. More generally, the first and second signals can be independent of one another and applied according to timing and programming parameters controlled by the controller  210  and stimulation unit  220 . 
     In one embodiment, one or more pulse bursts of the first electrical signal are applied to the main trunk of the vagus nerve in response to a detected seizure before applying one or more bursts of the second electrical signal to the cardiac branch. In another embodiment, the first and second signals are interleaved on a pulse-by-pulse basis under the control of the controller  210  and stimulation unit  220 . 
     Typically, VNS can be performed with pulse frequency of 20-30 Hz (resulting in a number of pulses per burst of 140-1800, at a burst duration from 7-60 sec). In one embodiment, at least one of the first electrical signal and the second electrical signal comprises a microburst signal. Microburst neurostimulation is discussed by U.S. Ser. No. 11/693,451, filed Mar. 2, 2007 and published as United States patent Publication No. 20070233193, and incorporated herein by reference in its entirety. In one embodiment, at least one of the first electrical signal, the second electrical signal, and the third electrical signal is characterized by having a number of pulses per microburst from 2 pulses to about 25 pulses, an interpulse interval of about 2 msec to about 50 msec, an interburst period of at least 100 msec, and a microburst duration of less than about 1 sec. 
     Cranial nerves such as the vagus nerve include different types of nerve fibers, such as A-fibers, B-fibers and C-fibers. The different fiber types propagate action potentials at different velocities. Each nerve fiber is directional—that is, endogenous or natural action potentials can generally propagate action potentials in only one direction (e.g., afferently to the brain or efferently to the heart and/or viscera). That direction is referred to as the orthodromic direction. Exogenous stimulation (e.g., by electrical pulses) may induce action potentials in both the orthodromic direction as well as the antidromic direction. Depending upon the desired effects of stimulation (e.g., afferent modulation of the brain, efferent modulation of the heart, etc.) certain measures (e.g., cooling, pressure, etc.) may be taken to block propagation in either the efferent or the afferent direction. It is believed that the anode may block at least some action potentials traveling to it from the cathode. For example, referring to  FIG.  1   , both afferent and efferent action potentials may be generated in an upper main trunk of vagus nerve  127 - 1  by applying a pulse to the nerve using upper main trunk electrode  125 - 1  as a cathode. Action potentials generated at upper main trunk electrode  125 - 1  and traveling toward the heart on cardiac branch  127 - 2  may be blocked by cardiac branch anode  125 - 2 . Action potentials traveling from the upper main trunk  127 - 1  to the lower organs in lower main trunk  127 - 3  may be either blocked (by using lower main trunk electrode  125 - 3  as an anode either with or instead of cardiac branch electrode  125 - 2 ) or allowed to travel to the lower organs (by not using electrode structure  125 - 3  as an electrode). 
     Action potentials may be generated and allowed to travel to the heart by making the electrode  125 - 2  the cathode. If cardiac branch electrode  125 - 2  is used as a cathode, action potentials will reach the heart in large numbers, while action potentials traveling afferently toward the brain may be blocked in the upper trunk if upper electrode  125 - 1  is made the anode. 
     In a further embodiment of the disclosure, rapid changes in electrode polarity may be used to generate action potentials to collision block action potentials propagating in the opposite direction. To generalize, in some embodiments, the vagus nerve can be selectively stimulated to propagate action potentials either afferently (i.e., to the brain) or efferently (i.e., to the heart and/or lower organs/viscerae). 
     Turning now to  FIG.  2   , a block diagram depiction of an implantable medical device, in accordance with one illustrative embodiment of the present disclosure is illustrated. The IMD  200  may be coupled to various electrodes  125  and/or  127  via lead(s)  122  ( FIGS.  1 A,  1 C ). First and second electrical signals used for therapy may be transmitted from the IMD  200  to target areas of the patient&#39;s body, specifically to various electrodes associated with the leads  122 . Stimulation signals from the IMD  200  may be transmitted via the leads  122  to stimulation electrodes (electrodes that apply the therapeutic electrical signal to the target tissue) associated with the electrode assembly  125 , e.g.,  125 - 1 ,  125 - 2 ,  125 - 3  ( FIG.  1 A ). 
     The IMD  200  may comprise a controller  210  capable of controlling various aspects of the operation of the IMD  200 . The controller  210  is capable of receiving internal data and/or external data and controlling the generation and delivery of a stimulation signal to target tissues of the patient&#39;s body. For example, the controller  210  may receive manual instructions from an operator externally, may perform stimulation based on internal calculations and programming, and may receive and/or process sensor data received from one or more body data sensors such as electrodes  125 - 1 ,  125 - 2 ,  125 - 3 , or heart rate sensor  130 . The controller  210  is capable of affecting substantially all functions of the IMD  200 . 
     The controller  210  may comprise various components, such as a processor  215 , a memory  217 , etc. The processor  215  may comprise one or more micro controllers, microprocessors, etc., that are capable of executing a variety of software components. The processor may receive, pre-condition and/or condition sensor signals, and may control operations of other components of the IMD  200 , such as stimulation unit  220 , seizure detection module  240 , logic unit  250 , communication unit,  260 , and electrode polarity reversal unit  280 . The memory  217  may comprise various memory portions, where a number of types of data (e.g., internal data, external data instructions, software codes, status data, diagnostic data, etc.) may be stored. The memory  217  may store various tables or other database content that could be used by the IMD  200  to implement the override of normal operations. The memory  217  may comprise random access memory (RAM) dynamic random access memory (DRAM), electrically erasable programmable read-only memory (EEPROM), flash memory, etc. 
     The IMD  200  may also comprise a stimulation unit  220 . The stimulation unit  220  is capable of generating and delivering a variety of electrical signal therapy signals to one or more electrodes via leads. The stimulation unit  220  is capable of delivering a programmed, first electrical signal to the leads  122  coupled to the IMD  200 . The electrical signal may be delivered to the leads  122  by the stimulation unit  220  based upon instructions from the controller  210 . The stimulation unit  220  may comprise various types of circuitry, such as stimulation signal generators, impedance control circuitry to control the impedance “seen” by the leads, and other circuitry that receives instructions relating to the type of stimulation to be performed. 
     Signals from sensors (electrodes that are used to sense one or more body parameters such as temperature, heart rate, brain activity, etc.) may be provided to the IMD  200 . The body signal data from the sensors may be used by a seizure detection algorithm embedded or processed in seizure detection module  240  to determine whether or not the patient is having and/or has had an epileptic seizure. The seizure detection algorithm may comprise hardware, software, firmware or combinations thereof, and may operate under the control of the controller  210 . Although not shown, additional signal conditioning and filter elements (e.g., amplifiers, D/A converters, etc., may be used to appropriately condition the signal for use by the seizure detection module  240 . Sensors such as heart sensor  130  and kinetic sensor  140  may be used to detect seizures, along with other autonomic, neurologic, or other body data. 
     The IMD  200  may also comprise an electrode polarity reversal unit  280 . The electrode polarity reversal unit  280  is capable of reversing the polarity of electrodes ( 125 - 1 ,  125 - 2 ,  125 - 3 ) associated with the electrode assembly  125 . The electrode polarity reversal unit  280  is shown in more detail in  FIG.  3   . In preferred embodiments, the electrode polarity reversal unit is capable of reversing electrode polarity rapidly, i.e., in about 10 microseconds or less, and in any event at a sufficiently rapid rate to permit electrode polarities to be changed between adjacent pulses in a pulsed electrical signal. 
     The IMD  200  may also comprise a power supply  230 . The power supply  230  may comprise a battery, voltage regulators, capacitors, etc., to provide power for the operation of the IMD  200 , including delivering the stimulation signal. The power supply  230  comprises a power-source battery that in some embodiments may be rechargeable. In other embodiments, a non-rechargeable battery may be used. The power supply  230  provides power for the operation of the IMD  200 , including electronic operations and the stimulation function. The power supply  230  may comprise a lithium/thionyl chloride cell or a lithium/carbon monofluoride (LiCFx) cell. Other battery types known in the art of implantable medical devices may also be used. 
     The IMD  200  also comprises a communication unit  260  capable of facilitating communications between the IMD  200  and various devices. In particular, the communication unit  260  is capable of providing transmission and reception of electronic signals to and from an external unit  270 . The external unit  270  may be a device that is capable of programming various modules and stimulation parameters of the IMD  200 . In one embodiment, the external unit  270  comprises a computer system that is capable of executing a data-acquisition program. The external unit  270  may be controlled by a healthcare provider, such as a physician, at a base station in, for example, a doctor&#39;s office. The external unit  270  may be a computer, preferably a handheld computer or PDA, but may alternatively comprise any other device that is capable of electronic communications and programming. The external unit  270  may download various parameters and program software into the IMD  200  for programming the operation of the implantable device. The external unit  270  may also receive and upload various status conditions and other data from the IMD  200 . The communication unit  260  may be hardware, software, firmware, and/or any combination thereof. Communications between the external unit  270  and the communication unit  260  may occur via a wireless or other type of communication, illustrated generally by line  275  in  FIG.  2   . 
     In one embodiment, the communication unit  260  can transmit a log of stimulation data and/or seizure detection data to the patient, a physician, or another party. 
     In one embodiment, a method of treating an epileptic seizure is provided that involves providing simultaneously both a first electrical signal to a main trunk of a vagus nerve and a second electrical signal to a cardiac branch of the vagus nerve. As used herein “simultaneously” refers to the on-time of the first and second signals, and does not require that individual pulses of the first signal and the second signal be simultaneously applied to target tissue. The timing of pulses for the first electrical signal and the second electrical signal may be determined by controller  210  in conjunction with stimulation unit  220 . Where active charge-balancing is used, it may be possible to use the active charge-balancing phase of pulses of the first electrical signal as the stimulation phase of the second electrical signal by selecting a current magnitude of the cathode in the charge-balancing phase (typically a second electrode, which may be the anode of the initial stimulation phase) that is sufficient to generate action potentials in nerve fibers of the target tissue. Controller  210  may in some embodiments provide simultaneous delivery of first and second electrical signals by interleaving pulses for each of the first and second electrical signals based upon the programmed timing of pulses for each signal and the appropriate polarity of each of first and second electrodes  125 - 1  and  125 - 2 . In some embodiments, additional electrodes may be used to minimize the induction of action potentials to the heart or the brain provided by the first electrical signal or the second electrical signal. This may be accomplished, in one embodiment, by using an anode located on either the upper main trunk or the cardiac branch to block impulse conduction to the heart or brain from the cathode, or by providing dedicated electrode pairs on both the main trunk and cardiac branches ( FIGS.  1 D,  1 E ). When beneficial, steps to avoid collisions of actions potentials travelling in opposite directions may be implemented, while steps to promote collisions may be taken when clinically indicated. In some embodiments, the method further includes sensing a cardiac signal and a kinetic signal of the patient, and detecting a seizure event with a seizure detection algorithm. 
     In one embodiment, a first electrical signal is applied to a main trunk of a vagus nerve and a second electrical signal is simultaneously applied to a cardiac branch of a vagus nerve. A pulse of the first electrical signal is generated with the electrical signal generator  110  and applied to the main trunk of the vagus nerve using a first electrode (e.g.,  125 - 1 ,  125 - 1   a ) as a cathode and a second electrode (e.g.,  125 - 1   b ,  125 - 3 , or  125 - 2 ) as an anode. The method includes sensing a cardiac signal and a kinetic signal of the patient, and detecting a seizure event with a seizure detection algorithm. A pulse of the second electrical signal (having the appropriate pulse width and current) is generated and applied (under appropriate timing control by controller  110  and stimulation unit  220 ) to the cardiac branch of the vagus nerve using a second electrode (e.g.,  125 - 2 .  125 - 2   a ) as a cathode and another electrode (e.g.,  125 - 3 ,  125 - 1 ,  125 - 2   b ) as an anode. Another pulse of the first electrical signal may thereafter be generated and applied to the main trunk under timing and parameter control of controller  210  and stimulation unit  220 . By appropriate selection of cathodes and anodes, the first and second electrical signals may be interleaved and provided simultaneously to the main trunk and cardiac branches of the vagus nerve. In some embodiments, the number of electrodes may be minimized by provided a polarity reversal unit that may rapidly change the polarity of particular electrodes to allow their use in delivering both the first and second signals. 
     The IMD  200  is capable of delivering stimulation that can be contingent, periodic, random, coded, and/or patterned. The stimulation signals may comprise an electrical stimulation frequency of approximately 0.1 to 10,000 Hz. The stimulation signals may comprise a pulse width in the range of approximately 1-2000 micro-seconds. The stimulation signals may comprise current amplitude in the range of approximately 0.1 mA to 10 mA. Appropriate precautions may be taken to avoid delivering injurious current densities to target neural tissues, e.g., by selecting current, voltage, frequency, pulse width, on-time and off-time parameters to maintain current density below thresholds for damaging tissues. 
     The IMD  200  may also comprise a magnetic field detection unit  290 . The magnetic field detection unit  290  is capable of detecting magnetic and/or electromagnetic fields of a predetermined magnitude. Whether the magnetic field results from a magnet placed proximate to the IMD  200 , or whether it results from a substantial magnetic field encompassing an area, the magnetic field detection unit  290  is capable of informing the IMD of the existence of a magnetic field. The changeable electrode polarity stimulation described herein may be activated, deactivated, or alternatively activated or deactivated using a magnetic input. 
     The magnetic field detection unit  290  may comprise various sensors, such as a Reed Switch circuitry, a Hall Effect sensor circuitry, and/or the like. The magnetic field detection unit  290  may also comprise various registers and/or data transceiver circuits that are capable of sending signals that are indicative of various magnetic fields, the time period of such fields, etc. In this manner, the magnetic field detection unit  290  is capable of detecting whether the detected magnetic field relates to an input to implement a particular first or second electrical signal (or both) for application to the main trunk of cardiac branches, respectively, of the vagus nerve. 
     One or more of the blocks illustrated in the block diagram of the IMD  200  in  FIG.  2   , may comprise hardware units, software units, firmware units, or any combination thereof. Additionally, one or more blocks illustrated in  FIG.  2    may be combined with other blocks, which may represent circuit hardware units, software algorithms, etc. Additionally, one or more of the circuitry and/or software units associated with the various blocks illustrated in  FIG.  2    may be combined into a programmable device, such as a field programmable gate array, an ASIC device, etc. 
       FIG.  3    shows in greater detail an electrode polarity reversal unit  280  ( FIG.  2   ) in one embodiment. The electrode polarity reversal unit  280  comprises an electrode configuration switching unit  340 , which includes a switching controller  345 . The switching controller  345  transmits signals to one or more switches, generically, n switches  330 ( 1 ),  330 ( 2 ), . . .  330 ( n ) which effect the switching of the configuration of two or more electrodes, generically, n electrodes  125 ( 1 ),  125 ( 2 ), . . .  125 ( n ). Although  FIG.  3    shows equal numbers of switches  330  and electrodes  125 , persons of skill in the art having the benefit of the present disclosure will understand that the number of switches  330  and their connections with the various electrodes  125  can be varied as a matter of routine optimization. A switching timing unit  333  can signal to the electrode configuration switching unit  340  that a desired time for switching the electrode configuration has been reached. 
     Instructions for implementing two or more stimulation regimens, which may include at least one open-loop electrical signal and at least one closed-loop electrical signal, may be stored in the IMD  200 . These stimulation signals may include data relating to the type of stimulation signal to be implemented. In one embodiment, an open-loop signal may be applied to generate action potentials for modulating the brain of the patient, and a closed-loop signal may be applied to generate either action potentials for slowing the heart rate of the patient, or both action potentials to modulate the brain of the patient as well as action potentials for slowing the heart rate of the patient. In some embodiments, the open-loop and closed-loop signals may be provided to different target portions of a vagus nerve of the patient by switching the polarity of two or more electrodes using an electrode polarity reversal unit as described in  FIG.  3    above. In alternative embodiments, additional electrodes may be provided to generate each of the open-loop and closed-loop signals without electrode switching. 
     In one embodiment, a first open-loop mode of stimulation may be used to provide an electrical signal to a vagus nerve using a first electrode as a cathode on a main trunk (e.g.,  127 - 1  or  127 - 3  using electrodes  125 - 1  or  125 - 3 , respectively) of a vagus nerve, and a second electrode as an anode on either a main trunk (e.g., electrode  125 - 3 , when electrode  125 - 1  is used as a cathode) or cardiac branch (e.g., electrode  125 - 2 ) of a vagus nerve. The first open-loop signal may include a programmed on-time and off-time during which electrical pulses are applied (the on-time) and not-applied (the off-time) in a repeating sequence to the vagus nerve. 
     A second, closed-loop signal may be provided in response to a detected event (such as an epileptic seizure, particularly when accompanied by an increase in the patient&#39;s heart rate) using a different electrode configuration than the first, open-loop signal. In one embodiment, the second, closed-loop signal is applied to a cardiac branch using the second electrode  125 - 2  as a cathode and the first electrode on the main trunk (e.g.,  125 - 1  or  125 - 3 ) as an anode. The second, closed-loop signal may involve generating efferent action potentials on the cardiac branch of the vagus nerve to slow the heart rate. In some embodiments, the first, open-loop signal may be interrupted/suspended in response to the detected event, and only the second, closed-loop signal is applied to the nerve. In other embodiments, the first, open loop signal may not be interrupted when the event is detected, and both the first, open-loop signal and the second, closed-loop signal are applied to the vagus nerve. In another embodiment, a third, closed-loop signal may also be provided in response to the detected event. The third, closed-loop signal may involve an electrical signal using the same electrode configuration as the first, open-loop electrical signal, but may provide a different electrical signal to the main trunk of the vagus nerve than either the first, open-loop signal or the second, closed-loop signal. The first, open-loop signal may be interrupted, terminated or suspended in response to the detected event, and the third, closed-loop signal may be applied to the nerve either alone or with the second, closed-loop signal. In some embodiments, both the second and third closed-loop signals may be provided in response to a detected epileptic seizure by rapidly changing the polarity of the first ( 125 - 1 ) and second ( 125 - 2 ) electrodes from cathode to anode and back, as pulses are provided as part of the second and third electrical signals, respectively. In one embodiment, the third electrical signal may involve modulating the brain by using a main trunk electrode (e.g., upper main trunk electrode  125 - 1 ) as a cathode and another electrode (e.g., cardiac branch electrode  125 - 2  or lower main trunk electrode  125 - 3 ) as an anode. The third electrical signal may comprise, for example, a signal that is similar to the first electrical signal but which provides a higher electrical current than the first electrical signal, and for a longer duration than the first signal or for a duration that is adaptively determined based upon a sensed body signal (in contrast, for example, to a fixed duration of the first electrical signal determined by a programmed on-time). By rapidly changing polarity of the electrodes, pulses for each of the second and third electrical signals may be provided such that the second and third signals are provided simultaneously to the cardiac branch and main trunk of the vagus nerve. In other embodiments, the first, second and third electrical signals may be provided sequentially rather than simultaneously. 
     In some embodiments, one or more of the first, second and third electrical signals may comprise a microburst signal, as described more fully in U.S. patent application Ser. Nos. 11/693,421, 11/693,451, and 11/693,499, each filed Mar. 29, 2007 and each hereby incorporated by reference herein in their entirety. 
     In one embodiment, each of a plurality of stimulation regimens may respectively relate to a particular disorder, or to particular events characterizing the disorder. For example, different electrical signals may be provided to one or both of the main trunk and cardiac branches of the vagus nerve depending upon what effects accompany the seizure. In a particular embodiment, a first open-loop signal may be provided to the patient in the absence of a seizure detection, while a second, closed-loop signal may be provided when a seizure is detected based on a first type of body movement of the patient as detected by, e.g., an accelerometer, a third, closed-loop signal may be provided when the seizure is characterized by a second type of body movement, a fourth, closed-loop signal may be provided when the seizure is characterized by an increase in heart rate, a fifth, closed-loop signal may be provided when the seizure is characterized by a decrease in heart rate, and so on. More generally, stimulation of particular branches or main trunk targets of a vagus nerve may be provided based upon different body signals of the patient. In some embodiments, additional therapies may be provided based on different events that accompany the seizure, e.g., stimulation of a trigeminal nerve or providing a drug therapy to the patient through a drug pump. In one embodiment, different regimens relating to the same disorder may be implemented to accommodate improvements or regressions in the patient&#39;s present condition relative to his or her condition at previous times. By providing flexibility in electrode configurations nearly instantaneously, the present disclosure greatly expands the range of adjustments that may be made to respond to changes in the patient&#39;s underlying medical condition. 
     The switching controller  345  may be a processor that is capable of receiving data relating to the stimulation regimens. In an alternative embodiment, the switching controller may be a software or a firmware module. Based upon the particulars of the stimulation regimens, the switching timing unit  333  may provide timing data to the switching controller  345 . The first through nth switches  330 ( 1 - n ) may be electrical devices, electro-mechanical devices, and/or solid state devices (e.g., transistors). 
       FIG.  4    shows one embodiment of a method of treating a patient having epilepsy according to the present disclosure. In this embodiment, a first electrode is coupled to a main trunk of a vagus nerve of the patient ( 410 ) and a second electrode is coupled to a cardiac branch of the vagus nerve ( 420 ). An electrical signal generator is coupled to the first and second electrodes ( 430 ). 
     The method further involves receiving at least one body data stream of the patient ( 440 ). The data may be sensed by a sensor such as heart rate sensor  130  ( FIG.  1 A ) or a sensor that is an integral part of, or coupled to, an IMD  200  ( FIG.  2   ) such as electrical pulse generator  110  ( FIG.  1 A ), and the IMD may also receive the data from the sensor. The at least one body data stream is then analyzed using a seizure detection algorithm ( 450 ), and the seizure detection algorithm determines whether or not the patient is having and/or has had an epileptic seizure ( 460 ). 
     If the algorithm indicates that the patient is not having and/or has not had an epileptic seizure, the method comprises applying a first electrical signal from the electrical signal generator to the main trunk of a vagus nerve using the first electrode as a cathode ( 470 ). In one embodiment, applying the first electrical signal comprises continuing to apply a programmed, open-loop electrical signal periodically to the main trunk of the vagus nerve according a programmed on-time and off-time. 
     If the algorithm indicates that the patient is having and/or has had an epileptic seizure, the method comprises applying a second electrical signal from the electrical signal generator to the cardiac branch of the vagus nerve using the second electrode as a cathode ( 480 ). Depending upon which electrical signal (first or second) is applied, the method may involve changing the polarity of one or both of the first electrode and the second electrode. In one embodiment, the method may comprise suspending the first electrical and applying the second electrical signal. In one embodiment, the method comprises continuing to receive at least one body data stream of the patient at  440  after determining whether or not the patient is having and/or has had an epileptic seizure. 
     In an alternative embodiment, if the seizure detection algorithm indicates that the patient is having and/or has had an epileptic seizure, both the first electrical signal and the second electrical signal are applied to the main trunk and cardiac branches of a vagus nerve of the patient, respectively, at step  480 . In a specific implementation of the alternative embodiment, pulses of the first and second electrical signal are applied to the main trunk and cardiac branch of the vagus nerve under the control of controller  210  by rapidly changing the polarity of the first and second electrodes using the electrode polarity reversal unit  280  to apply the first electrical signal to the main trunk using the first electrode as a cathode and the second electrode as an anode, changing the polarity of the first and second electrodes, and applying the second electrical signal to the cardiac branch using the second electrode as a cathode and the first electrode as an anode. Additional pulses for each signal may be similarly applied by rapidly changing the polarity of the electrodes. 
     In some embodiments, the first electrical signal and the second electrical signal are applied unilaterally, i.e., to a vagal main trunk and a cardiac branch on the same side of the body. In other embodiments, the first and second electrical signals are applied bilaterally, i.e., the second electrical signal is applied to a cardiac branch on the opposite side of the body from the main vagal trunk to which the first electrical signal is applied. In one embodiment, the first electrical signal is applied to a left main trunk to minimize cardiac effects of the first electrical signal, and the second electrical signal is applied to a right cardiac branch, which modulates the sinoatrial node of the heart to maximize cardiac effects of the second electrical signal. 
     In alternative embodiments, both the first electrode and the second electrode may be coupled to a cardiac branch of a vagus nerve, with the first electrode (e.g., anode) being proximal to the brain relative to the second electrode, and the second electrode (e.g., cathode) being proximal to the heart relative to the first electrode. 
       FIG.  5    is a flow diagram of another method of treating a patient having epilepsy according to the present disclosure. A sensor is used to sense a cardiac signal and a kinetic signal of the patient ( 540 ). In a particular embodiment, the cardiac sensor may comprise an electrode pair for sensing an ECG (electrocardiogram) or heart beat signal, and the kinetic signal may comprise a triaxial accelerometer to detect motion of at least a portion of the patient&#39;s body. The method further comprises analyzing at least one of the cardiac signal and the kinetic signal using seizure detection algorithm ( 550 ), and the output of the algorithm is used to determine whether at least one of the cardiac signal and the kinetic signal indicate that the patient is having and/or has had an epileptic seizure ( 560 ). 
     If the patient is not having and/or has not had an epileptic seizure, the method comprises applying a first electrical signal to a main trunk of a vagus nerve of the patient using a first electrode, coupled to the main trunk, as a cathode ( 580 ). In one embodiment, the first electrical signal is an open-loop electrical signal having an on-time and off-time. 
     If the patient is having and/or has had an epileptic seizure, a determination is made whether the seizure is characterized by an increase in the patient&#39;s heart rate ( 570 ). If the seizure is not characterized by an increase in the patient&#39;s heart rate, the method comprises applying the first electrical signal to the main trunk of a vagus nerve using the first electrode as a cathode ( 580 ). In one embodiment, the cathode comprises an upper main trunk electrode  125 - 1  and the anode is selected from a cardiac branch electrode  125 - 2  and a lower main trunk electrode  125 - 3 . Conversely, if the seizure is characterized by an increase in the patient&#39;s heart rate, the method comprises applying a second electrical signal to a cardiac branch of a vagus nerve of the patient using a second electrode, coupled to the cardiac branch, as a cathode ( 590 ). The anode is an upper main trunk electrode  125 - 1  or a lower main trunk electrode  125 - 3 . In one embodiment, the method may comprise suspending the first electrical and applying the second electrical signal. 
     The method then continues the sensing of the cardiac and kinetic signals of the patient ( 540 ) and resumes the method as outlined in  FIG.  5   . 
       FIG.  6    is a flow diagram of a further method of treating a patient having epilepsy according to the present disclosure. The method includes applying a first, open-loop electrical signal to a main trunk of a vagus nerve ( 610 ). The open-loop signal is characterized by an off-time in which electrical pulses are applied to the nerve, and an off-time in which electrical pulses are not applied to the nerve. 
     A sensor is used to sense at least one body signal of the patient ( 620 ), and a determination is made whether the at least one body signal indicates that the patient is having and/or has had an epileptic seizure ( 630 ). If the patient is not having and/or has not had a seizure, the method continues applying the first, open-loop electrical signal to a main trunk of a vagus nerve ( 610 ). If the patient is having and/or has had an epileptic seizure, a determination is made whether the seizure is characterized by an increase in the patient&#39;s heart rate ( 640 ). In one embodiment, the increase in heart rate is measured from a baseline heart rate existing prior to the seizure, e.g., a median heart rate for a prior period such as the 300 beats prior to the detection of the seizure event, or the 5 minutes prior to the detection of the seizure. 
     If the seizure is not characterized by an increase in the patient&#39;s heart rate, the method comprises applying a second, closed-loop electrical signal to the main trunk of the vagus nerve  650 ). In one embodiment, the second, closed-loop electrical signal is the same signal as the open-loop electrical signal, except that the second signal (as defined, e.g., by a current intensity, a pulse frequency, a pulse width and an on-time) is applied at a time different from the programmed timing of the first electrical signal. For example, if the first electrical signal comprises an on-time of 30 seconds and an off-time of 5 minutes, but a seizure is detected 1 minute after the end of a programmed on-time, the second electrical signal may comprise applying a 30 second pulse burst at the same current intensity, frequency, and pulse width as the first signal, but four minutes earlier than would have occurred absent the detected seizure. In another embodiment, the second, closed-loop electrical signal is a different signal than the first, open-loop electrical signal, and the method may also comprise suspending the first electrical before applying the second electrical signal. For example, the second, closed-loop electrical signal may comprise a higher current intensity, frequency, pulse width and/or on-time than the first, open-loop electrical signal, and may not comprise an off-time (e.g., the second electrical signal may be applied for a predetermined duration independent of the on-time of the first, open-loop electrical signal, such as a fixed duration of 1 minute, or may continue for as long as the body signal indicates the presence of the seizure event). 
     Returning to  FIG.  6   , if the seizure is characterized by an increase in the patient&#39;s heart rate, the method comprises applying a third, closed-loop electrical signal to a cardiac branch of a vagus nerve to reduce the patient&#39;s heart rate ( 660 ). The method may comprise suspending the first electrical as well as applying the third, closed-loop electrical signal. In one embodiment of the disclosure, each of the first, open-loop electrical signal, the second, closed-loop electrical signal, and the third, closed-loop electrical signal are applied unilaterally (i.e., to vagus nerve structures on the same side of the body) to the main trunk and cardiac branch of the vagus nerve. For example, the first, open-loop electrical signal and the second, closed-loop electrical signal may be applied to a left main trunk of the patient&#39;s cervical vagus nerve, and the third, closed-loop electrical signal may be applied to the left cardiac branch of the vagus nerve. Similarly, the first, second and third electrical signals may all be applied to the right vagus nerve of the patient. In alternative embodiments, one or more of the first, second and third electrical signals may be applied bilaterally, i.e., one of the first, second and third electrical signals is applied to a vagal structure on the opposite side of the body from the other two signals. For example, in a particular embodiment the first, open-loop signal and the second, closed-loop signal may be applied to a left main trunk of the patient&#39;s cervical vagus nerve, and the third, closed-loop electrical signal may be applied to a right cardiac branch of the patient&#39;s vagus nerve. Because the right cardiac branch modulates the sinoatrial node of the patient&#39;s heart, which is the heart&#39;s “natural pacemaker,” the third electrical signal may have more pronounced effect in reducing the patient&#39;s heart rate if applied to the right cardiac branch. 
     After applying one of the second ( 650 ) and third ( 660 ) electrical signals to a vagus nerve of the patient, the method then continues sensing at least one body signal of the patient ( 620 ) and resumes the method as outlined in  FIG.  6   . 
     In the methods depicted in  FIGS.  4 - 6   , one or more of the parameters defining the first, second, and third electrical signals (e.g., number of pulses, pulse frequency, pulse width, On time, Off time, interpulse interval, number of pulses per burst, or interburst interval, among others) can be changed by a healthcare provided using a programmer  150 . 
       FIG.  7    is a flow diagram of a method of treating patients having seizures accompanied by increased heart rate. In one embodiment, tachycardia is defined as a neurogenic increase in heart rate, that is, an elevation in heart rate that occurs in the absence of motor activity or that if associated with motor activity, the magnitude of the increase in heart rate is larger than that caused by motor activity alone. In one embodiment, a body signal is acquired ( 710 ). The body signal may comprise one or more body signals that may be altered, changed or influenced by an epileptic seizure. As non-limiting examples, the body signal may comprise one or more of a cardiac signal such as heart rate, heart rate variability, or EKG complex morphology, a kinetic signal such as an accelerometer signal, a postural signal or body position signal), blood pressure, blood oxygen concentration, skin resistivity or conductivity, pupil dilation, eye movement, EEG, reaction time or other body signals. The body signal may be a real-time signal or a stored signal for delayed or later analysis. It may be acquired, for example, from a sensor element (e.g., coupled to a processor), from a storage device in which the signal data is stored. 
     The method further comprises determining whether or not the patient is having and/or has had a seizure accompanied by an increase in heart rate ( 720 ). In one embodiment, the method comprises a seizure detection algorithm that analyzes the acquired body signal data and determines whether or not a seizure has occurred. In a particular embodiment, the method comprises an algorithm that analyzes one or more of a cardiac signal, a kinetic signal, a cognitive signal, blood pressure, blood oxygen concentration, skin resistivity or conductivity, pupil dilation, and eye movement to identify changes in the one or more signals that indicate a seizure has occurred. The method may comprise an output signal or data flag that may be asserted or set when the detection algorithm determines from the body signal(s) that the patient is having and/or has had a seizure. 
     The method also comprises determining ( 720 ) whether or not the seizure is accompanied by an increase in heart rate. In one embodiment, the body data signal comprises a heart beat signal that may be analyzed to determine heart rate. In some embodiments, the heart beat signal may be used by the seizure detection algorithm to determine whether a seizure has occurred, while in other embodiments seizures are not detected using heart rate. Regardless of how the seizure is detected, however, the method of  FIG.  7    comprises determining whether a detected seizure event is accompanied by an increase in heart rate. The increase may be determined in a variety of ways, such as by an increase in an instantaneous heart rate above a reference heart rate (which may be a predetermined interictal value such as 72 beats per minute (bpm), or a real-time measure of central tendency for a time window, such as a 5 minute median or moving average heart rate). Additional details about identifying increases in heart rate in the context of epileptic seizures are provided in U.S. Pat. Nos. 5,928,272, 6,341,236, 6,587,727, 6,671,556, 6,961,618, 6,920,357, 7,457,665, as well as US patent application Ser. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051, 12/886,419, 12/896,525, 13/098,262, and 13/288,886, each of which is hereby incorporated by reference in its entirety herein. 
     If the body data signal does not indicate that the patient is having and/or has had a seizure accompanied by tachycardia, the method comprises applying a first electrical signal to a left vagus nerve. If the body signal does indicate that the patient has experienced a seizure accompanied by tachycardia, the method comprises applying a second electrical signal to a right vagus nerve. 
     Without being bound by theory, it is believed that stimulation of the right vagus nerve, which enervates the right sinoatrial nerve that functions as the heart&#39;s natural pacemaker, will have a more prominent effect in slowing the heart rate than stimulation of the left vagus nerve. The present disclosure takes advantage of this electrical asymmetry of the left and right vagus nerves to minimize the effect of VNS on heart rate except where there is a need for acute intervention to slow the heart rate, i.e., when the patient has experienced and epileptic seizure, and the seizure is accompanied by an increase in heart rate. This may result in, for example, stimulation of the left vagus nerve either when there is no seizure (such as when an open-loop stimulation program off-time has elapsed and the program initiates stimulation in accordance with a programmed signal on-time), or when there is a detected seizure event that is not accompanied by an increase in heart rate (such as absence seizures); and stimulation of the right vagus nerve when there is a detected seizure event accompanied by a heart rate increase. In one embodiment, a programmed, open-loop electrical signal is applied to the left vagus nerve except when an algorithm analyzing the acquired body signal detects a seizure accompanied by a heart rate increase. In response to such a detection, a closed-loop electrical signal is applied to the right vagus nerve to slow the patient&#39;s (increased) heart rate. In some embodiments, the response to detecting a seizure accompanied by a heart rate increase may also include interrupting the application of the programmed-open-loop electrical signal to the left vagus nerve. The interrupted open-loop stimulation of the left vagus nerve may be resumed either when the seizure ends or the heart rate returns to a desired, lower heart rate. 
     In an additional embodiment of the disclosure, electrode pairs may be applied to each of the left and right vagus nerves of the patient, and used depending upon whether or not seizures accompanied by cardiac changes such as tachycardia are detected. 
       FIG.  8    is a flowchart depiction of a method of treating patients having seizures accompanied by a relative or absolute decrease in heart rate (i.e., a bradycardia episode). Epileptic seizures originating from certain brain regions may trigger decreases in heart rate of a magnitude sufficient to cause loss of consciousness and of postural tone (i.e., syncope). In some subjects the cerebral ischemia associated with the bradycardia may in turn lead to convulsions (i.e., convulsive syncope). If bradycardia-inducing seizures are not controllable by medications, the current treatment is implantation of a demand cardiac pacemaker. In one embodiment of the present disclosure, ictal bradycardia may be treated by preventing vagal nerve impulses from reaching the heart, either by preventing impulses traveling through all fiber types contained in the trunk of the nerve or in one of its branches, or by only blocking impulses within a certain fiber type. In another embodiment, the degree of the nerve impulse blocking within a vagus nerve may be determined based upon the magnitude of bradycardia (e.g., the larger the bradycardia change from the pre-existing baseline heart rate, the larger the magnitude of the block) so as to prevent tachycardia from occurring. 
     In one embodiment, a body signal is acquired ( 810 ). The body signal may comprise one or more body signals that may be altered, changed or influenced by an epileptic seizure. Changes in the body signal may be used to detect the onset or impending onset of seizures. As noted with reference to  FIG.  7   , the body signal may comprise one or more measure derived from a cardiac signal (e.g., heart rate, heart rate variability, change in EKG morphology), a kinetic signal (e.g., an accelerometer, force of muscle contraction, posture or body position signal), blood pressure, blood oxygen concentration, skin resistivity/conductivity, pupil dilation, eye movement, or other body signals. The body signal may be a real-time signal, a near-real-time signal, or a non-real-time signal, although in preferred embodiments, the signal is a real-time signal or a near-real-time signal. The signal may be acquired from a sensor element (e.g., coupled to a processor) or from a storage device. 
     Referring again to  FIG.  8   , the method further comprises determining whether or not the patient is having and/or has had a seizure that is accompanied by a decrease in heart rate ( 820 ). In one embodiment, the method comprises using a seizure detection algorithm using one or more of a cardiac, kinetic, neurologic, endocrine, metabolic or tissue stress marker to detect seizures, and to determine if the seizure is associated with a decrease in heart rate. In a particular embodiment, an algorithm—which may comprise software and/or firmware running in a processor in a medical device—analyzes one or more of a cardiac signal, a kinetic signal, blood pressure, blood oxygen concentration, skin resistivity or conductivity, pupil dilation, and eye movement to identify changes in the one or more signals that indicate the occurrence of an epileptic seizure. Such changes may be identified by determining one or more indices from the foregoing signals, such as a cardiac index (e.g., a heart rate), a kinetic index (e.g., a kinetic level or motion type, a magnitude of an acceleration or force, or other indices that may be calculated from an accelerometer signal). The method may include providing an output signal or setting a data flag when the detection algorithm determines from the body signal(s) that the patient is having and/or has had a seizure. In a preferred embodiment, the seizure detection occurs in real time and the output signal or data flag is set immediately upon detection of the seizure. 
     Once it is determined that the patient is having and/or has had a seizure, the method also comprises determining if the seizure is accompanied by a decrease in heart rate. In one embodiment, the acquired body data signal ( 810 ) comprises a heart beat signal that may be analyzed to determine heart rate. In some embodiments, the acquired heart beat signal may be used by the seizure detection algorithm to determine whether a seizure has occurred, while in other embodiments seizures are determined without regard to the patient&#39;s heart rate. Regardless of how the seizure is determined, the method of  FIG.  8    comprises determining whether a detected seizure event is accompanied by a decrease in heart rate ( 820 ). The decrease in heart rate may be determined in a variety of ways, such as by a decrease in an instantaneous heart rate below a reference heart rate value (which may be a predetermined interictal value such as 72 beats per minute (bpm), or a real-time measure of central tendency for a time window or number-of-beats window (e.g., a 5 minute median or moving average heart rate, or a media heart rate for a window selected from 3-300 beats such as a 5, 10, or 300 beat window)). Additional details about identifying decreases in heart rate in the context of epileptic seizures are provided in U.S. patent application Ser. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051, 12/886,419, 13/091,033, each of which is hereby incorporated by reference in its entirety herein. 
     In one embodiment, if the acquired body data signal does not indicate that the patient is having and/or has had a seizure accompanied by a HR decrease, the method comprises applying a first electrical signal to a vagus nerve ( 840 ), wherein the first electrical signal is sufficient to generate exogenous action potentials in fibers of the vagus nerve. The second electrical signal is a therapeutic electrical signal to treat the seizure. It may be applied to either the left or right vagus nerves, or both. The first electrical signal may be a signal defined by, among other parameters, an on-time during which electrical pulses are applied to the nerve, and an off-time during which no pulses are applied to the nerve. In some embodiments, the on-time may be determined by the duration and intensity of the change in heart rate, while in other embodiments it may be pre-programmed. Cathode(s) and anode(s) may be placed on the nerve trunks or branches to maximize flow of exogenously generated nerve impulses in a caudal direction (for control of heart rate changes) and a cephalic direction for seizure treatment. 
     If the body signal indicates that the patient is having and/or has had a seizure accompanied by a decrease in heart rate, the method comprises applying an action to decrease vagal/parasympathetic tone. In one embodiment, the method comprises blocking the passage of impulses through at least one of a vagus nerve trunk or branch. This may be accomplished by applying one or more of a second electrical signal (e.g., a high frequency electrical signal), a thermal signal (e.g., cooling), a chemical signal (e.g., applying a local anesthetic), and/or a mechanical signal (e.g., applying pressure or a vibration) to a vagus nerve of the patient ( 830 ). In another embodiment, the method comprises delivering at least one of an anti-cholinergic drug or a sympatho-mimetic drug. 
     As used herein, blocking vagus nerve activity means blocking intrinsic or native vagal activity (i.e., blocking action potentials not artificially or exogenously induced by an electrical signal generated by a device). The blocking signal may block the conduction of action potentials in all or at least some portion or fraction of the axons of a vagus nerve. In general, such blocking signals are incapable of inducing exogenous action potentials in the axons of the vagus nerve. In one embodiment, the blocking signal may comprise a high frequency, pulsed electrical signal, the pulse frequency being sufficient to inhibit propagation of at least some action potentials in vagus nerve fibers. The electrical signal may comprise a signal in excess of 300 Hz, or other frequency, so long as the frequency and other stimulation signal parameters (such as pulse width and pulse current or voltage) provide a signal capable of inhibiting some or all of the action potentials propagating along fibers of the vagus nerve. In alternative embodiments, the electrical signal may comprise generating unidirectional action potentials for collision blocking of endogenous action potentials. 
     High frequency vagus nerve stimulation (or other blocking signals such as collision blocking) may inhibit pathological vagus nerve activity associated with the seizure that may be acting to slow the patient&#39;s heart rate. By providing such stimulation only when the patient experiences a seizure accompanied by a reduced heart rate (e.g., bradycardia), a therapy may be provided that acts to maintain the patient&#39;s heart rate when the patient experiences a seizure involving excessive vagal activity—and consequent undesired slowing of—the heart. In one embodiment, the blocking electrical signal ( 830 ) is provided to a right vagus nerve. Without being bound by theory, because the right vagus nerve innervates the right sinoatrial node that functions as the heart&#39;s natural pacemaker, it is believed that right-side VNS will have a more significant effect upon the heart rate than stimulation of the left vagus nerve. In alternative embodiments, the blocking signal may be applied to the left vagus nerve, to both the right and left vagus nerves, or to one or both of the left and right cardiac branches of the vagus nerves. 
     In one embodiment, the method comprises applying a first electrical signal that may be a conventional vagus nerve stimulation signal defined by a plurality of parameters (e.g., a pulse width, a current magnitude, a pulse frequency, an on-time and an off-time). A seizure detection algorithm (e.g., using one or more of a cardiac, kinetic, metabolic, EEG, or other body signal) may be used to detect seizures, and the patient&#39;s heart rate may be determined proximate the seizure detection to determine if the seizure is accompanied by a decrease in the patient&#39;s heart rate. If the seizure is accompanied by a slowing of the patient&#39;s heart rate, the first electrical signal may be suspended, and a second electrical signal may be applied to slow the patient&#39;s heart rate. The method may further include sensing the patient&#39;s heart rate during or after application of the second electrical signal. In one embodiment, the second electrical signal may be modified (e.g., by changing current magnitude, pulse width, or pulse frequency), or suspended (and possibly resumed) to maintain the patient&#39;s heart rate between an upper heart rate threshold and a lower heart rate threshold. In some embodiments, the upper and lower heart rate thresholds may be dynamically set (e.g., as no more than 5 bpm above or below the baseline HR prior to the seizure detection). 
       FIG.  9    is a flow diagram of a method of treating a patient with epilepsy by providing closed-loop vagus nerve intervention (e.g., stimulation or blockage of impulse conduction) to maintain the patient&#39;s heart rate within a range that is both safe and also commensurate with the activity type or level and state of the patient (e.g., as determined from a kinetic signal from a sensing element such as a triaxial accelerometer or by measuring oxygen consumption). In one embodiment, the method comprises providing vagus nerve stimulation in response to determining that a heart rate is incommensurate with the kinetic signal of the patient, to restore cardiac function to a rate that is commensurate with the patient&#39;s kinetic signal. In one embodiment, the stimulation may comprise stimulating a right vagus nerve to slow the patient&#39;s heart rate to a level that is safe and/or commensurate with activity level. In another embodiment, the stimulation may comprise providing a blocking signal to increase a slow heart rate to a rate that is safe and/or commensurate with the activity level. Pharmacologic compounds (e.g., drugs) with sympathetic or parasympathetic effects (e.g., enhancing or blocking sympathetic or parasympathetic activity) may be used to restore heart rate to a rate commensurate with kinetic activity of the patient in still other embodiments. In one embodiment, the method involves determining a heart rate and one or more kinetic or metabolic (e.g., oxygen consumption) indices for the patient ( 910 ). Heart rate may be determined from an acquired cardiac signal (e.g., from a sensor or stored data). Kinetic and/or metabolic indices may likewise be determined from a kinetic sensor (e.g., an accelerometer, a positional sensor, a GPS device coupled to a clock, or a postural sensor), a metabolic sensor, or from stored data. Sensor data may be subjected to one or more operations such as amplifying, filtering, A/D conversion, and/or other pre-processing and processing operations to enable determination of heart rate (and in some embodiments other cardiac indices such as heart rate variability) and kinetic indices. 
     The activity level of the patient may be determined from multiple kinetic indications such as an activity level, a type of activity, a posture, a body position, a trunk or limb acceleration or force, or a duration of one of the foregoing, and may be adapted or modified as a function of age, gender, body mass index, fitness level or time of day or other indices of the patient&#39;s condition or environment. For example, the kinetic signal may be processed to provide indices that indicate moderate ambulatory motion for an upright patient, vigorous physical exercise (in which the patient may be upright as in running or in a prone position as in some calisthenics exercises), a fall (e.g., associated with a seizure), reclining, resting or sleeping, among other activity levels and kinetic states. 
     The one or more kinetic indices may then be used to determine (e.g., by retrieving stored data from a lookup table or by calculation using an algorithm) one or more heart rate ranges or values that would be commensurate with the kinetic activity and/or kinetic state, duration, time of day, etc. associated with the indices. In some embodiments, heart rate ranges may be established for particular levels or types of activity (e.g., running, walking), that may be adaptively adjusted depending upon various factors such as the duration of the activity, the patient&#39;s fitness level, the time of day, a level of fatigue, an environmental temperature, etc. A commensurate heart rate is one that is within expected ranges or values for the person&#39;s effort, and for factors inherent to the patient and the environment. 
     Returning to  FIG.  9   , the determined heart rate may be compared to the range(s)/value(s) identified as commensurate with the kinetic indices ( 920 ) at a given time point. If the actual heart rate of the patient is within the expected/commensurate range or value associated with the kinetic or metabolic indices at the time point, or is within a specified proximity of a particular range or value, no action may be taken, and the method may involve continuing to analyze the patient&#39;s cardiac and kinetic signals or metabolic signals. On the other hand, if the heart rate is outside the expected value or range of values for the kinetic or metabolic indices for that time point, then the heart rate is not commensurate with the kinetic signal of the patient, and a therapy may be provided to the patient by applying one of an electrical, thermal, mechanical or chemical signal to a vagus nerve of the patient ( 930 ) or administering to the patient (e.g., intravenously, through mucosae) a drug with cholinergic or anti-cholinergic or adrenergic actions, depending on the case or situation. In one embodiment, the method may comprise applying the signal to a main trunk of a vagus nerve of the patient, and in another embodiment, the signal may be applied to a cardiac branch of a vagus nerve. 
     In one embodiment, the heart rate of the patient may be higher than a value commensurate with the activity level or kinetic indices of the patient. In this case, the patient is having relative tachycardia. Where this is the case, as previously noted, vagus nerve stimulation may be applied to one or more of a right cardiac branch, left cardiac branch, or right main trunk of the patient&#39;s vagus nerve to reduce the patient&#39;s heart rate to a rate that is commensurate with the activity level. Embodiments of the disclosure may be used to treat epileptic seizures associated with tachycardia, and other medical conditions associated with tachycardia given the patient&#39;s activity level. Therapies (e.g., electrical, chemical, mechanical, thermal) delivered to a patient via the vagus nerves may be employed for tachyarrythmias, angina pectoris or pain in regions innervated by a vagus nerve. 
     In another embodiment, the patient&#39;s heart rate may be lower than a value commensurate with the patient&#39;s activity level or kinetic indices, that is, the patient is having relative or absolute bradycardia. High frequency (&gt;&gt;300 Hz) electrical pulses may be applied to the left or right vagus nerves (e.g., a main trunk of the right and/or left vagus nerves or to their cardiac branches) to block propagation of transmission of nerve impulses through their fibers. High-frequency VNS may be applied to block impulses traveling to the heart to abate neurogenic, cardiogenic or iatrogenic bradycardia, or to minimize the cumulative effects on the heart&#39;s conduction system and myocardium of epileptic seizures, especially in status epilepticus. Selective blockage of impulses traveling through a vagus nerve to the heart may be accomplished with electrical stimulation to treat adverse cardiac effects associated with disorders such as epilepsy, depression, diabetes or obesity. By blocking vagus nerve conduction to the heart, when the patient&#39;s heart rate is incommensurate with the activity level or kinetic indices, a therapy may be provided to revert the change in heart rate (whether the change involves bradycardia or tachycardia). In one embodiment, an electrical signal generator may be used to apply a first therapy signal to a vagus nerve of the patient, and an electrical signal generator (which may be the same or a different electrical signal generator) may apply a vagus nerve conduction blocking electrical signal to a vagus nerve (e.g., a cardiac branch of the vagus nerve) to block cardiac effects that would result from the first electrical signal, absent the vagus nerve conduction blocking electrical signal. 
     Referring again to  FIG.  9   , the method may comprise determining the patient&#39;s heart rate in response the therapy to determine whether the heart rate has been restored to a rate that is with commensurate with the patient&#39;s activity level/kinetic index ( 940 ). If not, then the therapy (e.g., VNS to reduce or increase heart rate to an appropriate value) may be continued, with or without parameter modification, or re-initiated after a delay period or confirmation period. 
     If the heart rate has returned to a range/value commensurate with the activity level of the patient, the method may, in some embodiments, further involve determining whether or not an adverse event has occurred ( 950 ). Adverse events may include, without limitation, side effects such as voice alteration, pain, difficulty breathing or other respiratory effects, adverse cardiac effects such as bradycardia (following a determination of relative tachycardia in step  920 ), tachycardia (following a determination of bradycardia in step  920 ), and alteration in blood pressure or gastro-intestinal activity. 
     If an adverse event has occurred, the method may involve changing one or more stimulation parameters to eliminate, reduce or ameliorate the adverse event ( 955 ). If no adverse event has occurred, the method may comprise continuing to apply a signal the vagus nerve until a predetermined signal application duration has been reached ( 960 ), at which time the signal application may be stopped ( 970 ). The method may further comprise determining, after the therapy has been stopped, if the patient&#39;s heart rate remains incommensurate with the patient&#39;s activity level or type ( 980 ), in which case the signal application may be resumed or other appropriate action may be taken (e.g., local or remote alarms or alerts, notification of caregivers/healthcare providers, etc.). If the heart rate has returned to a value that is commensurate or appropriate for the patient&#39;s activity level, the signal application may be discontinued ( 990 ). 
       FIG.  10    is a flow diagram of a method of treating a patient to with epilepsy by providing closed-loop vagus nerve stimulation to treat relative tachycardia or relative bradycardia by restoring the patient&#39;s heart rate to a rate that is commensurate with the activity type or level of the patient (e.g., as determined from a kinetic signal from a sensing element such as a triaxial accelerometer or by measuring oxygen consumption). In one embodiment, the method comprises identifying instances of relative tachycardia or relative bradycardia and responding with negative or positive chronotropic actions to restore the heart rate to a level commensurate with the patient&#39;s activity type or level. 
     In one embodiment, the method involves determining a heart rate and an activity type or level for the patient ( 1010 ). The patient&#39;s heart rate may be determined from an acquired cardiac signal or from stored data. The activity level or type of the patient may be determined from one or more sensor or from stored data. Sensors may include, for example, accelerometers, positional sensors, GPS devices coupled to a clock, postural sensors, and metabolic sensors. Sensor data may be subject to conventional signal processing, and may in addition be adapted or modified as a function of age, gender, body mass index, fitness level or time of day or other indices of the patient&#39;s condition or environment. 
     The patient&#39;s activity type or level may then be used to determine one or more heart rate ranges or values that are commensurate with the activity type or level ( 1020 ). In some embodiments, heart rate ranges may be established for particular levels or types of activity (e.g., running, walking), that may be adaptively adjusted depending upon various factors such as the duration of the activity, the patient&#39;s fitness level, the time of day, a level of fatigue, an environmental temperature, etc. A commensurate heart rate is one that is within expected ranges or values for the person&#39;s effort, and for factors inherent to the patient and the environment. 
     If the heart rate is commensurate with the activity level, in one embodiment no action may be taken, and the method may involve continuing to analyze the patient&#39;s cardiac and activity. On the other hand, if the heart rate is outside the identified value or range of values appropriate for the patient&#39;s activity type or level then the heart rate is not commensurate with the kinetic signal of the patient. Where this is the case, the method may further comprise determining whether the patient is experiencing relative tachycardia or is experiencing relative bradycardia ( 1030 ,  1040 ). 
     Where the heart rate of the patient is higher than a value commensurate with the activity level or type, the patient is experiencing relative tachycardia ( 1030 ), and the method may comprise initiating a negative chronotropic action ( 1035 ) to slow the heart rate to a rate that is commensurate with the activity level or type. In one embodiment, this may involve applying stimulation to one or more of a left or right main vagal trunk or cardiac branch of the patient. In other embodiments, the method may comprise providing a drug to enhance the parasympathetic tone of the patient. In still other embodiments, the method may comprise reducing the patient&#39;s sympathetic tone, such as by applying high-frequency stimulation to a sympathetic nerve trunk or ganglion or administering an anti-cholinergic drug. Negative chronotropic actions may be used to treat epileptic seizures associated with tachycardia, and other medical conditions associated with relative tachycardia given the patient&#39;s activity level. 
     Where the heart rate of the patient is lower than a value commensurate with the activity level or type, the patient is experiencing relative bradycardia ( 1040 ), and the method may comprise initiating a positive chronotropic action ( 1045 ) to increase the heart rate to a rate that is commensurate with the activity level or type. In one embodiment, this may involve applying high-frequency (&gt;&gt;300 Hz) electrical stimulation to one or more of a left or right main vagal trunk or cardiac branch of the patient to reduce the transmission of intrinsic vagus nerve action potentials in at least some vagal fibers. In other embodiments, the method may comprise providing a drug to reduce the parasympathetic tone of the patient. In still other embodiments, the method may comprise increasing the patient&#39;s sympathetic tone, such as by applying electrical signals to a sympathetic nerve trunk or ganglion or by administering a sympatho-mimetic drug. Positive chronotropic actions may be used to treat epileptic seizures associated with bradycardia, and other medical conditions associated with relative bradycardia given the patient&#39;s activity level. 
     The method may further comprise, after initiating the negative or positive chronotropic action, determining whether the patient&#39;s heart rate has been restored to a rate that is with commensurate with the patient&#39;s activity level/kinetic index ( 1050 ). If not, then the therapy (e.g., VNS to reduce or increase heart rate to an appropriate value) may be continued, with or without parameter modification, or re-initiated after a delay period or confirmation period. 
     If the heart rate has returned to a range/value commensurate with the activity level of the patient, the method may, in some embodiments, further involve determining whether or not an adverse event has occurred ( 1060 ). Adverse events may include, without limitation, side effects such as voice alteration, pain, difficulty breathing or other respiratory effects, adverse cardiac effects such as bradycardia (following a determination of relative tachycardia in step  1030 ), or tachycardia (following a determination of bradycardia in step  1040 ), and alteration in blood pressure or gastric activity. 
     If an adverse event has occurred, the method may involve changing one or more stimulation parameters to eliminate, reduce or ameliorate the adverse event ( 1070 ). If no adverse event has occurred, the method may comprise continuing to stimulate the vagus nerve (or a chemical, thermal or mechanical therapy) until a predetermined stimulation duration has been reached ( 1075 ), at which time the stimulation may be stopped ( 1080 ). The method may further comprise determining, after the therapy has been stopped, if the patient&#39;s heart rate remains incommensurate with the patient&#39;s activity level or type ( 1090 ), in which case the stimulation may be resumed or other appropriate action may be taken (e.g., local or remote alarms or alerts, notification of caregivers/healthcare providers, use of other forms of therapy, etc.). If the heart rate has returned to a value that is commensurate or appropriate for the patient&#39;s activity level, the stimulation may be discontinued ( 1095 ). 
     Additional embodiments consistent with the foregoing description and figures may be made. Non-limiting examples of some such embodiments are provided in the numbered paragraphs below. 
       100 . A method of controlling a heart rate of an epilepsy patient comprising:
         sensing at least one of a kinetic signal and a metabolic signal of the patient;   analyzing the at least one of a kinetic and a metabolic signal to determine at least one of a kinetic index and a metabolic index;   receiving a cardiac signal of the patient;   analyzing the cardiac signal to determine the patient&#39;s heart rate;   determining if the patient&#39;s heart rate is commensurate with the at least one of a kinetic index and a metabolic index; and   applying an electrical signal to a vagus nerve of the patient based on a determination that the patient&#39;s heart rate is not commensurate with the at least one of a kinetic signal and a metabolic signal of the patient.       
       101 . The method of numbered paragraph  100 , wherein determining at least one of a kinetic index and a metabolic index comprises determining at least one of an activity level or an activity type of the patient based on the at least one of a kinetic index and a metabolic index, and wherein determining if the patient&#39;s heart rate is commensurate with the at least one of a kinetic index and a metabolic index of the patient comprises determining if the heart rate is commensurate with the at least one of an activity level or an activity type. 
       102 . The method of numbered paragraph  101 , wherein determining if the patient&#39;s heart rate is commensurate with the at least one of a kinetic index and a metabolic index comprises determining if the patient&#39;s heart rate is above or below a rate that is commensurate with the one or more of a kinetic index and a metabolic index. 
       103 . A method of treating a patient having epilepsy comprising sensing at least one body signal of the patient;
         determining whether or not the patient is having or has had an epileptic seizure based on the at least one body signal;   sensing a cardiac signal of the patient;   determining whether or not the seizure is associated with a change in the patient&#39;s cardiac signal;   applying a first therapy to a vagus nerve of the patient based on a determination that the patient is having or has had an epileptic seizure that is not associated with a change in the patient&#39;s cardiac signal, wherein the first therapy is selected from an electrical, chemical, mechanical, or thermal signal; and   applying a second therapy to a vagus nerve of the patient based on a determination that the patient is having or has had an epileptic seizure associated with a change in the patient&#39;s cardiac signal, wherein the second therapy is selected from an electrical, chemical, mechanical (e.g., pressure) or thermal signal.       
       104 . The method of numbered paragraph  103 , further comprising applying a third therapy to a vagus nerve of the patient based a determination that the patient is not having or has not had an epileptic seizure, wherein the third therapy is selected from an electrical, chemical, mechanical or thermal signal. 
       105 . A method of treating a patient having epilepsy comprising: 
     coupling a first set of electrodes to a main trunk of the left vagus nerve of the patient; 
     coupling a second set of electrodes to a main trunk of the right vagus nerve of the patient; 
     providing an electrical signal generator coupled to the first electrode set and the second electrode set; receiving at least one body data stream; 
     
         
         
           
             analyzing the at least one body data stream using a seizure detection algorithm to determine whether or not the patient is having and/or has had an epileptic seizure; 
             applying a first electrical signal from the electrical signal generator to the main trunk of the left vagus nerve, based on a determination that the patient is having and/or has had an epileptic seizure without a heart rate change; and applying a second electrical signal from the electrical signal generator to the main trunk of the right vagus nerve, based on a determination that the patient is having or has had an epileptic seizure with a heart rate change.
 
 106 . A method of treating a patient having epilepsy comprising:
 
             receiving at least one body data stream; 
             analyzing the at least one body data stream using a seizure detection algorithm to detect whether or not the patient has had an epileptic seizure; 
             receiving a cardiac signal of the patient; 
             analyzing the cardiac signal to determine a first cardiac feature; 
             applying a first electrical signal to a vagus nerve of the patient, based on a determination that the patient has not had an epileptic seizure characterized by a change in the first cardiac feature, wherein the first electrical signal is not a vagus nerve conduction blocking electrical signal; and applying a second electrical signal to a vagus nerve of the patient, based on a determination that the patient has had an epileptic seizure characterized by a change in the cardiac feature, wherein the second electrical signal is a pulsed electrical signal that blocks action potential conduction in the vagus nerve.
 
 107 . A method of treating a patient having epilepsy comprising:
 
             receiving at least one body data stream; 
             analyzing the at least one body data stream using a seizure detection algorithm to detect whether or not the patient has had an epileptic seizure; 
             receiving a cardiac signal of the patient; 
             analyzing the cardiac signal to determine a first cardiac feature; 
             applying a first electrical signal to a vagus nerve of the patient, based on a determination that the patient has not had an epileptic seizure characterized by a change in the first cardiac feature, wherein the first electrical signal is a pulsed electrical signal that blocks action potential conduction in the vagus nerve; and 
             applying a second electrical signal to a vagus nerve of the patient, based on a determination that the patient has had an epileptic seizure characterized by a change in the cardiac feature, wherein the second electrical signal is not a vagus nerve conduction blocking electrical signal. 
           
         
       
    
     In  FIG.  11   , a graph of heart rate versus time is shown, according to one embodiment. A first graph  1100  includes a y-axis  1102  which represents heart rate where the heart rate goes from a zero value to an Nth value (e.g., 200 heart beats, etc.). Further, the first graph  1100  includes an x-axis  1104  which represents time from 1 minute to Nth minutes (and/or 0.001 seconds to Nth seconds). In this example, a first heart rate versus time line  1106  for the patient is shown. In this example, the patient&#39;s heart rate goes from 80 heart beats per minute to 118 heart beats per minute with a first rise  1108 A and a first run  1108 B during a first event  1108 C. In addition, the patient&#39;s heart rate goes from 70 heart beats per minute to 122 heart beats per minute during a second event  1108 D which has a first percentage change  1110  associated with the second event  1108 D. Further, the patient&#39;s heart rate goes from 70 beats per minute to 113 beats per minute during an nth event  1108 E which surpasses a first threshold amount  1112 , and/or a second threshold amount  1114 , and/or an Nth threshold amount  1116 . In one example, only the Nth threshold amount  1116  needs to be reached to trigger a therapy and/or an alert. In another example, only the second threshold amount  1114  needs to be reached to trigger a therapy and/or an alert. In another example, only the first threshold  1112  needs to be reached to trigger a therapy and/or an alert. In another example, both the Nth threshold  1116  and the second threshold  1114  need to reached to trigger a therapy and/or an alert. In another example, all of the Nth threshold  1116 , the second threshold  1114  and the first threshold  1112  need to reached to trigger a therapy and/or an alert. In one example, only the Nth threshold amount  1116  needs to be reached during a specific time period to trigger a therapy and/or an alert. In another example, only the second threshold amount  1114  needs to be reached during a specific time period to trigger a therapy and/or an alert. In another example, only the first threshold  1112  needs to be reached during a specific time period to trigger a therapy and/or an alert. In another example, both the Nth threshold  1116  and the second threshold  1114  need to reached during a specific time period to trigger a therapy and/or an alert. In another example, all of the Nth threshold  1116 , the second threshold  1114  and the first threshold  1112  need to reached during a specific time period to trigger a therapy and/or an alert. In these examples, one or more triggering events may occur based on a determination of the rise and run of a change in heart rate, a percentage change in heart rate, a threshold amount being reached or exceeded (or within any percentage of the threshold), and/or any combination thereof. A triggering event may initiate one or more actions to increase and/or decrease the patient&#39;s heart rate. For example, if the patient&#39;s heart rate is increasing which determines the triggering event, then the system, device, and/or method may initiate one or more actions to decrease the heart rate of the patient to help reduce, dampen, eliminate, and/or buffer the increase in the patient&#39;s heart rate. Further, the system, device, and/or method may oscillate between decreasing the patient&#39;s heart rate and increasing the patient&#39;s heart rate depending on any changes to the patient&#39;s heart rate. For example, the system, device, and/or method may initiate one or more actions to decrease a patient&#39;s heart rate based on the patient&#39;s heart rate going from 80 heart beats per minute to 130 heart beats per minute which results in the patient&#39;s heart rate falling from 130 heart beats per minute to 65 heart beats per minute in a first time period. Based on the change in the heart rate from 130 heart beats per minute to 65 heart beats per minute in the first time period, the system, device, and/or method may initiate one or more actions to increase the patient&#39;s heart rate and/or stabilize the patient&#39;s heart rate. In another example, the system, method, and/or device may stop and/or modify any initiated action based on one or more feedback signals. In addition, one or more warnings may be transmitted to the patient, a caregiver, a doctor, a medical professional, and/or logged. 
     In  FIG.  12   , another graph of heart rate versus time is shown, according to one embodiment. A second graph  1200  illustrating a second heart rate versus time line  1202  for the patient is shown. In this example, the patient&#39;s heart rate goes from 80 heart beats per minute to 120 heart beats per minute which creates a first system alert event  1204  (e.g., A1). Further, the system, device, and/or method initiates a first therapy  1206  (e.g., X1) based on the first system alert event  1204 . In addition, a second system alert event  1208  (e.g., A2) occurs and a second therapy  1210  (e.g., X2) is initiated based on the second system alert event  1208 . In addition, a third system alert event  1212  (e.g., A3) occurs and a third therapy (e.g., X3)  1214  is initiated based on the third system alert event  1212  (e.g., A3). In addition, a fourth system alert event  1216  (e.g., A4) occurs and a fourth therapy  1218  (e.g., X4) is initiated based on the fourth system alert event  1216  (e.g., A3). Further, a fifth therapy  1220  (e.g., X5) is initiated based on the effects of the fourth therapy  1218  (e.g., X4). In addition, a fifth system alert event  1222  (e.g., A5) occurs and a sixth therapy (e.g., X6)  1224  is initiated based on the fifth system alert event  1222  (e.g., A5). In addition, a sixth system alert event  1226  (e.g., A6) occurs and a seventh therapy (e.g., X7)  1228  is initiated based on the sixth system alert event  1226  (e.g., A6). In addition, a seventh system alert event  1230  (e.g., A7) occurs and an eighth therapy (e.g., X8)  1232  is initiated based on the seventh system alert event  1230  (e.g., A7). In addition, a first stop stimulation event  1234  (e.g., B1) occurs which turns off all therapies and/or system alerts may occur when the heart rate returns to the approximate starting heart rate and/or a target value. In these examples shown with  FIG.  12   , a rise over run heart rate calculation was completed to determine the one or more system alerts. However, it should be noted that any calculation (e.g., % increase, % decrease, etc. can be utilized). Further, all systems alerts and/or therapies may occur as independent events and/or examples. For example, the seventh system alert may be the first system alert in a specific example. In other words, no other events and/or therapies occurred before the seventh system alert. Therefore, the seventh system alert becomes the first system alert. In addition, one or more warnings may be transmitted to the patient, a caregiver, a doctor, a medical professional, and/or logged. In addition, there may be up to an Nth alerts, an Nth stop stimulation (and/or therapy) event, and an Nth therapy in any of the examples disclosed in this document. 
     In  FIG.  13   , another graph of heart rate versus time is shown, according to one embodiment. A third graph  1300  illustrating a third heart rate versus time line  1302  for the patient is shown. In this example, the patient&#39;s heart rate goes from 80 heart beats per minute to 116 heart beats per minute which creates a first system alert event  1304  (e.g., A1). Further, the system, device, and/or method initiates a first therapy  1306  (e.g., X1) based on the first system alert event  1304 . In addition, a first stop stimulation event  1308  (e.g., B1) occurs which turns off all therapies and/or system alerts occurs when the heart rate returns to the approximate starting heart rate and/or a target value. Further, the patient&#39;s heart rate goes from 80 heart beats per minute to 123 heart beats per minute which creates a second system alert event  1310  (e.g., A2). Further, the system, device, and/or method initiates a second therapy  1312  (e.g., X2) based on the second system alert event  1310 . In addition, a second stop stimulation event  1314  (e.g., B2) occurs which turns off all therapies and/or system alerts occurs when the heart rate returns to the approximate starting heart rate and/or a target value. In these examples shown with  FIG.  13   , a percentage change in heart rate calculation was completed to determine the one or more system alerts. However, it should be noted that any calculation (e.g., rise over run, etc. can be utilized). Further, all systems alerts and/or therapies may occur as independent events and/or examples. For example, the second system alert may be the first system alert in a specific example. In other words, no other events and/or therapies occurred before the second system alert. Therefore, the second system alert becomes the first system alert. In addition, one or more warnings may be transmitted to the patient, a caregiver, a doctor, a medical professional, and/or logged. 
     In  FIG.  14   , another graph of heart rate versus time is shown, according to one embodiment. A fourth graph  1400  illustrating a fourth heart rate versus time line  1402  for the patient is shown. In this example, the patient&#39;s heart rate goes from 80 heart beats per minute to 120 heart beats per minute which creates a first system alert event  1404  (e.g., A1) because the 120 heart beats per minutes meets or exceeds a first threshold value  1416  (e.g., 115 heart beats per minute). In this example, a second system alert event  1406  (e.g., A2) is created because the heart beats of the patient meets or exceeds the first threshold value  1416  (e.g., 115 heart beats per minute). Further, the system, device, and/or method initiates a first therapy  1408  (e.g., X1) based on the first system alert event  1404  and the second system alert event  1406  occurring. The first system alert event  1404  and the second system alert event  1406  may be time dependent. For example, the first system alert event  1404  and the second system alert event  1406  may have to occur within a first time period for the initiation of the first therapy  1408 . In another example, the first system alert event  1404  and the second system alert event  1406  may not be time dependent. Further, a third system alert event  1410  (e.g., A3) is created because the heart beats of the patient meets or exceeds (and/or within a specific rate of the threshold—in this example within 5 percent—heart rate is 110) the first threshold value  1416  (e.g., 115 heart beats per minute). Further, the system, device, and/or method initiates a second therapy  1412  (e.g., X2) based on the first system alert event  1404 , the second system alert event  1406 , and/or the third system event occurring. It should be noted that the second therapy  1412  has a time delay factor utilized with the second therapy  1412 . In another example, no time delay is utilized. In addition, one or more time delays can be used with any therapy, any warning, and/or any alert in this document. The first system alert event  1404 , the second system alert event  1406 , and the third system alert event  1410  may be time dependent. For example, the first system alert event  1404 , the second system alert event  1406 , and the third system alert event  1410  may have to occur within a first time period for the initiation of the second therapy  1412 . In another example, the first system alert event  1404 , the second system alert event  1406 , and the third system alert event  1410  may not be time dependent. Further, a first stop stimulation event  1414  (e.g., B1) occurs which turns off all therapies and/or system alerts occurs when the heart rate returns to the approximate starting heart rate and/or a target value. Further, all systems alerts and/or therapies may occur as independent events and/or examples. For example, the third system alert may be the first system alert in a specific example. In other words, no other events and/or therapies occurred before the third system alert. Therefore, the third system alert becomes the first system alert. In addition, one or more warnings may be transmitted to the patient, a caregiver, a doctor, a medical professional, and/or logged. 
     In  FIG.  15   , another graph of heart rate versus time is shown, according to one embodiment. A fifth graph  1500  illustrating a fifth heart rate versus time line  1502  for the patient is shown. In this example, the patient&#39;s heart rate goes from 80 heart beats per minute to 40 heart beats per minute which creates a first system alert event  1504  (e.g., A1) because the 40 heart beats per minutes meets or exceeds a first threshold value  1520  (e.g., 50 heart beats per minute). It should be noted that no alert was generated when the heart rate fell to 52 heart beats per minute because 52 heart beats per minute is above the threshold value of 50 heart beats per minute. Further, the system, device, and/or method initiates a first therapy  1506  (e.g., X1) based on the first system alert event  1504  occurring. Further, the patient&#39;s heart rate goes from 80 heart beats per minute to 50 heart beats per minute which creates a second system alert event  1508  (e.g., A2) because the 50 heart beats per minutes meets or exceeds the first threshold value  1520  (e.g., 50 heart beats per minute). Further, the system, device, and/or method initiates a second therapy  1510  (e.g., X2) based on the second system alert event  1508  occurring. Further, a first stop stimulation event  1512  (e.g., B1) occurs which turns off all therapies and/or system alerts occurs when the heart rate returns to the approximate starting heart rate and/or a target value. In addition, the patient&#39;s heart rate goes from 80 heart beats per minute to 45 heart beats per minute which creates an nth system alert event  1514  (e.g., A3) because the 45 heart beats per minutes meets or exceeds the first threshold value  1520  (e.g., 50 heart beats per minute). Further, the system, device, and/or method initiates an Nth therapy  1516  (e.g., X3) based on the nth system alert event  1514  occurring. Further, an nth stop stimulation event  1518  (e.g., B2) occurs which turns off all therapies and/or system alerts occurs when the heart rate returns to the approximate starting heart rate and/or a target value. Further, all systems alerts and/or therapies may occur as independent events and/or examples. For example, nth system alert event  1514  alert may be the first system alert in a specific example. In other words, no other events and/or therapies occurred before nth system alert event  1514 . Therefore, nth system alert event  1514  becomes the first system alert. In addition, one or more warnings may be transmitted to the patient, a caregiver, a doctor, a medical professional, and/or logged. 
     In regards to  FIGS.  11 - 15    as related to this disclosure, the systems, devices, and/or methods may use a base line heart rate for the patient (e.g., a specific patient Bob, a general patient John Doe with a first health condition, a first age, etc.) over a first time period (e.g. one week, one month, one year, etc.), 50 percentile of all measured heart rates, an average of all heart rates, and/or any other method of determine a baseline heart rate. Further, the threshold level may be determined based on being the 40 percentile of the baseline, 39 percentile of the baseline, 38 percentile of the baseline, . . . , 10 percentile of the baseline, . . . , etc. In addition, the threshold level may be determined based on being the 75 percentile of the baseline, 76 percentile of the baseline, 77 percentile of the baseline, . . . , 90 percentile of the baseline, . . . , 99 percentile of the baseline, . . . , etc. In one example, the threshold value may be the 75 percentile of every recorded heart rate data. In another example, the oscillation does not matter whether the heart rate change is in an increasing direction or a decreasing direction. In various examples, the systems, devices, and/or method may reduce an amplitude of change (e.g., damping the change in heart rate) to enhance system performance and/or to reduce side effects. In addition, the determination of one or more side effects may initiate a reduction in therapy, a stoppage of therapy, a modification of therapy (e.g., changing a therapy that reduces heart rate to another therapy that increases heart rate), one or more warnings, and/or one or more logging of data. 
     In  FIG.  16   , a flowchart of a therapy procedure is shown, according to one embodiment. A method  1600  includes obtaining one or more data points and/or characteristics relating to heart rate of a patient (step  1602 ). The method  1600  may also include determining a monitored value based one the obtained one or more data points and/or characteristics relating to the heart rate (step  1604 ). The method  1600  may further compare the monitored value to one or more threshold values (step  1606 ). The method  1600  may via one or more processors (of a medical device(s) and/or medical device system) determine whether a triggering event has occurred (step  1608 ). If no triggering event has occurred, then the method  1600  moves back to step  1602 . If a triggering event has occurred, then the method  1600  may determine via one or more processors (of a medical device(s) and/or medical device system) whether an action which increases heart rate should be implemented (step  1610 ). If an action which increases heart rate should be implemented, then the method  1600  may increase a sympathetic tone via one or more actions and/or decrease a parasympathetic tone via one or more actions and/or implement another action which increases heart rate (step  1612 ). After the implements of one or more actions, the method  1600  returns to step  1602 . If an action which increases heart rate should not be implemented, then the method  1600  may determine via one or more processors (of a medical device(s) and/or medical device system) whether an action which decreases heart rate should be implemented (step  1614 ). If an action which decreases heart rate should be implemented, then the method  1600  may decrease a sympathetic tone via one or more actions and/or increase a parasympathetic tone via one or more actions and/or implement another action which decreases heart rate (step  1616 ). After the implements of one or more actions, the method  1600  returns to step  1602 . 
     In one embodiment, a system for treating a medical condition in a patient includes: a sensor for sensing at least one body data stream; a heart rate unit capable of determining a heart rate of the patient based on the at least one body data stream; and a logic unit configured via one or more processors to compare a monitored value which is determined based on one or more data points relating to the heart rate to one or more threshold values, the logic unit further configured to determine a triggering event based on the comparison. Further, the one or more processors may initiate one or more actions to change the heart rate of the patient based on the determination of the triggering event. 
     In another example, the system includes at least one electrode coupled to a vagus nerve of the patient and a programmable electrical signal generator. In another example, the one or more processors may increase a sympathetic tone to increase the heart rate of the patient. In another example, the one or more processors may decrease a parasympathetic tone to increase the heart rate of the patient. In another example, the one or more processors may decrease a sympathetic tone to decrease the heart rate of the patient. In another example, the one or more processors may increase a parasympathetic tone to decrease the heart rate of the patient. In another example, the system includes a seizure detection unit which analyzes the at least one body data stream to determine an epileptic seizure status. In another example, the system includes at least one electrode coupled to a vagus nerve of the patient and a programmable electrical signal generator. Further, the one or more processors may apply an electrical signal to the vagus nerve of the patient based on a determination that a seizure is characterized by a decrease in the heart rate of the patient where the electrical signal is applied to block action potential conduction on the vagus nerve. 
     In another embodiment, a system for treating a medical condition in a patient, includes: a sensor for sensing at least one body data stream; at least one electrode coupled to a vagus nerve of the patient; a programmable electrical signal generator; a heart rate unit capable of determining a heart rate of the patient based on the at least one body data stream; and a logic unit configured via one or more processors to compare a monitored value which is determined based on one or more data points relating to the heart rate to one or more threshold values, the logic unit further configured to determine a triggering event based on the comparison. Further, the one or more processors may initiate one or more actions to change the heart rate of the patient based on the determination of the triggering event. 
     In another example, the one or more processors may increase a sympathetic tone to increase the heart rate of the patient based on a first triggering event. Further, the one or more processors may decrease a sympathetic tone to decrease the heart rate of the patient based on a second triggering event. Further, the one or more processors may decrease a parasympathetic tone to increase the heart rate of the patient based on a third triggering event. Further, the one or more processors may increase a parasympathetic tone to decrease the heart rate of the patient based on a fourth triggering event. 
     In another example, the one or more processors may increase the sympathetic tone to increase the heart rate of the patient based on a second triggering event. Further, the one or more processors may increase the sympathetic tone to increase the heart rate of the patient based on a third triggering event. Further, the one or more processors increase the sympathetic tone to increase the heart rate of the patient based on an nth triggering event. 
     In another example, the one or more processors decrease a sympathetic tone to decrease the heart rate of the patient based on a first triggering event. Further, the one or more processors decrease the sympathetic tone to decrease the heart rate of the patient based on a second triggering event. Further, the one or more processors may decrease the sympathetic tone to decrease the heart rate of the patient based on a third triggering event. In addition, the one or more processors decrease the sympathetic tone to decrease the heart rate of the patient based on an nth triggering event. 
     Cardio-protection in epilepsy is a rapidly growing field of vital importance. In this disclosure, systems, devices, and/or method of protecting the heart from standstill or fatal arhythmias are disclosed. Further in this disclosure, systems, devices, and/or methods of automated detections, warnings, reportings, treatments, controls and/or any combination thereof of ictal and peri-ictal chronotropic instability are shown. 
     In  FIG.  17   , a graph shows monotonic increase and decrease in heart rate. In  FIG.  17   , a first triggering event, a first warning event, and/or a first therapy event  1702  are shown. Further, a second triggering event  1704 , a second warning event, and/or a second therapy event  1704  are shown. In addition, an Nth triggering event, an Nth warning event, and/or an Nth therapy event  1706  are shown. In  FIG.  18   , the heart rate of the patient increases which is followed by a decrease in heart rate, then an increase heart rate and a final decrease in heart rate. In this example, the first drop in heart rate crossed downwardly the detection threshold which would have temporarily disabled the warning system and the delivery of the therapy. While the first peak was not temporally correlated with paroxysmal activity on any of the intra-cranial electrodes used in this patient, it is likely that the first increase in heart rate was caused by epileptic discharges from a brain site that was not being investigated. In this example, the x-axis is time in hours and the y-axis is heart beats per minute. In this example, an electrographic onset in the brain  1810  is shown and an electrographic termination in the brain  1812  is shown. 
     In  FIG.  19   , a change in ictal heart rate is shown. In this example, the drop in heart rate during the seizure, is even more prominent that the one depicted in  FIGS.  17 - 18   , as it is below the inter-ictal baseline. It should be noted that the oscillations in heart rate during the post-ictal period are indicative of cardiac instability. In this example, a seizure onset point  1910  and a seizure termination point  1912  are shown. 
     In  FIG.  20   , large amplitude tachycardia cycles occurring quasi-periodically after termination of paroxysmal activity recorded with intra-cranial electrodes. While the mechanisms responsible for these oscillations are unknown, the probability that they are epileptic in nature cannot be excluded, since electrographic and imaging data used to guide intra-cranial electrode placement pointed to the existence of only one epileptogenic site. 
     In  FIG.  21   , small amplitude continuous quasi-periodic oscillations preceding and following a seizure recorded with intra-cranial electrodes (same patient as  FIG.  20   ). In various embodiments, ictal and peri-ictal cardiac instability are shown. The mechanisms leading to SUDEP have not been elucidated, in part due to the inability to record data during the critical events that culminate in cardiac fibrillation or in standstill (or in respiratory arrest). In this example, a first triggering event, a first warning event, and/or a first therapy event  2102  are shown. Further, an Nth triggering event, an Nth warning event, and/or an Nth therapy event  2104  are shown. 
     The data obtained in intractable epileptics undergoing epilepsy surgery evaluation not only supports a cardiac mechanism (of course, not at the exclusion of catastrophic respiratory failure) but more specifically points to chronotropic instability as backdrop against which, lethal arrhythmias or cardiac standstill may ensue. Moreover, the instability is not restricted to the ictal period but, in certain cases, precedes and/or follows it for several minutes.  FIGS.  17 - 21    illustrate the spectrum of instability in intractable epileptics. This phenomenon is referred herein to as Ictal and Pre-Ictal Chronotropic Instability. 
     The challenges that for accurate quantification and delivery of efficacious therapies, ictal chronotropic instability poses, were addressed and strategies to manage them are outlined. Here, the attention is focused on Ictal and Pre-Ictal Chronotropic Instability, a more prolonged and serious pathological phenomenon in intractable epileptics and on the vital issues of cardio-protection. 
     The aim of this disclosure is to contingently and adaptively dampen based on the slope, amplitude, duration and “direction” (positive or negative chronotropic and its magnitude relative to an adaptive baseline/reference heart rate) the heart oscillations present before, during or after epileptic seizures. 
     While several embodiments may be envisioned, on embodiment (for efficacy, practicality and cost-effectiveness) is to electrically stimulate/activate the trunk or a branch of the right vagus nerve in the case of elevations in heart (to reduce the heart rate, when there are more than 2 consecutive oscillations/cycles or 1 that is large and prolonged. The intensity and duration of stimulation as well as other parameters are determined by the slope, amplitude and duration of the oscillations, while ensuring adequate blood perfusion to all organs. In the case of negative chronotropic effects (decreases in heart rate) the trunk or a branch of the right vagus nerve may be “blocked” using certain electrical stimulation techniques or through cooling; the effect of this intervention is to increase heart rate. 
     In one embodiment, the “height” of the oscillation is the only feature considered. While obviously important, this embodiment does not take into consideration a possibly more important feature: the rate at which the oscillation occurs: the consequences of waiting to intervene until an oscillation reaches a certain height (e.g., 120 bpm) are different if it takes, 30 seconds for the heart rate to reach the value than if it takes 2 seconds to reach the value. Estimating the rate of change of the heart rate, provides life-saving information. Another aspect is the inter-maxima or inter-minima interval between oscillations. Having heart rate oscillation occur every 2-3 seconds is much more serious than every 1-2 hours. In one example, one benefit may be that the window to act is lengthen which can save lives. In one embodiment, a system for treating a medical condition in a patient includes: a sensor for sensing at least one body data stream; a heart rate unit which determines a heart rate and a heart rate oscillation of the patient based on the at least one body data stream; and a logic unit which compares via one or more processors a monitored value which is determined based on one or more data points relating to the heart rate and to the heart rate oscillation to a threshold value, the logic unit determines a triggering event based on the comparison where the one or more processors initiate one or more actions to change the heart rate of the patient based on the determination of the triggering event. 
     In another example, the system includes at least one electrode coupled to a vagus nerve of the patient and a programmable electrical signal generator. Further, the one or more processors may increase a sympathetic tone to increase the heart rate of the patient. In another example, the one or more processors may decrease a parasympathetic tone to increase the heart rate of the patient. In another example, the one or more processors may decrease a sympathetic tone to decrease the heart rate of the patient. Further, the one or more processors may increase a parasympathetic tone to decrease the heart rate of the patient. In addition, the system may include a seizure detection unit which analyzes the at least one body data stream to determine an epileptic seizure status. The system may include at least one electrode coupled to a vagus nerve of the patient and a programmable electrical signal generator where the one or more processors apply an electrical signal to the vagus nerve of the patient based on a determination that a seizure is characterized by a decrease in the heart rate of the patient and where the electrical signal is applied to block action potential conduction on the vagus nerve. In addition, the heart unit may determine an inter-maxima interval and an inter-minima interval between a first oscillation and a second oscillation. Further, the logic unit may compare the inter-maxima interval and the inter-minima interval to an interval threshold. In addition, the one or more processors may initiate one or more actions based on the interval threshold being reached. 
     The particular embodiments disclosed above are illustrative only as the disclosure may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown other than as described in the claims below. It is, therefore, evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the disclosure. Accordingly, the protection sought herein is as set forth in the claims below. In addition, all examples, embodiments, and/or elements may be combined in any manner that are disclosed in this document. In other words, an element from a first example can be combined with any other element, such as, a second element from an Nth example. For brevity, all these examples are not written out but are part of this document. 
     Identification of changes in brain state (whether physiologic or pathologic) has traditionally been accomplished through analysis of electrical brain signals and behavioral observation. Continuous (e.g., round-the-clock) automated monitoring of changes in brain state imposes certain limitations on the utilization of these traditional methods, due to the difficulties inherent to automated ambulatory video, the large amount of data produced per unit time, and the excessive demands on human and technical resources required to maintain an acceptable signal/noise for electrical signals recorded from the scalp. Additionally, scalp signals have poor temporo-spatial resolution, a characteristic which results in both low sensitivity and specificity of state-of-brain detection changes. 
     Implanted sensors or electrodes beneath the scalp but above the outer skull table or intra-cranial (epidural, subdural or depth) have been used to overcome the limitations of scalp recordings. However, although the quality of recordings (especially for intracranial electrodes) is much better (e.g., typically has a higher S/N) than that from scalp electrodes, the quality is still limited and there are risks (e.g., infection, bleeding, brain damage) associated with these devices, not to mention cost and scarcity of neurosurgeons to perform this type of procedures. 
     While electrical brain signals and behavioral observation may provide information for classification of brain states, this task can be accomplished more efficiently, and/or more cost-effectively through monitoring of other biological signals under control of the brain such those generated by the heart, muscle, skin, eyes, tympanic membrane temperature, and body posture/movement, since they may not require surgery, or if surgery is required for implantation, the procedures are much shorter, simpler, and cheaper that those required for recording of brain signals and there is no shortage of human resources. 
     Certain highly valuable neurological signals (e.g., cognitive) for detection, quantification, and classification of state changes may obtained non-invasively and can be used in this disclosure. 
     In one aspect, the present disclosure is directed to differentiating between generalized or convulsive epileptic and non-epileptic seizures. In another aspect, extra-cerebral signals may be also used to detect and distinguish partial epileptic from partial non-epileptic seizures. 
     Extra-cerebral signals (e.g., EKG, body movements, respirations, etc.) denote herein body signals that may be recorded/obtained without placing sensors or electrodes on the head (e.g., scalp or under it) or inside the head/skull (e.g., subdural electrodes/sensors, depth or intra-cerebral electrodes/sensors) and are directly or indirectly under control of the central or peripheral nervous system. Cognitive signals such as attention/responsiveness, language, memory among others, while directly generated by the brain are considered extra-cerebral herein, since they may be recorded/obtained without resorting to sensors/electrodes placed on/inside the head. Extra-cerebral signals provide valuable and reliable information about the state of the brain since they are either generated by the brain or under its control. 
     Aspects of extra-cerebral signals such as magnitude, rate of change (including return to non-seizure levels), and morphology (e.g., waveform), vary depending on whether the event affecting the extra-cerebral signal(s) is epileptic or non-epileptic. The present disclosure discloses methods and apparatus for using such signals to distinguish between these seizure types. For example, although movements, cardiac and respiratory rate increase during both epileptic and non-epileptic seizures, the type, magnitude and duration of changes (much different and greater with epileptic seizures) can be used, according to the present disclosure, for accurate classification of the seizure as epileptic or non-epileptic. 
     Although in many embodiments discussed herein, at least one extra-cerebral signal may be used for differentiation of non-epileptic seizures from epileptic ones, nothing in this disclosure precludes the use of cerebral signals for said purpose. 
     These extra-cerebral (e.g., autonomic, neurologic, etc.) signals can be used individually or in combination to monitor continuously the brain and generate a state-of the-system/organ report, in real-time for the detection, quantification, classification, validation, control and logging of physiologic or pathologic state changes. This approach takes advantage of the inherent and finely tuned dynamical coupling among these systems. For instance, changes in brain state/activity may result in changes in heart activity, muscle activity, and skin properties. 
     Herein, Applicant describes a method, systems, and devices that may: a) detect in real-time pre-specified changes in brain state; b) quantify their duration, intensity, extent of spread, and time of occurrence; c) classify their type (e.g., epileptic vs. non-epileptic seizures; primarily vs. secondarily generalized seizures; generalized vs. partial seizures; complex vs., simple partial seizures; d) use as a basis for warning and control/therapy, and/or e) save this information to memory for future retrieval for optimization of detection, quantification and classification of state changes and assessment and optimization of therapeutic (e.g., control) efficacy. Non-epileptic movements in this disclosure refer to those resembling movements seen during tonic-clonic seizures but which are not caused by those abnormal electrical activity that characterizes epileptic seizures. 
     In embodiments where extra-cerebral data is the basis for a detection, cerebral signals, such as EEG/ECoG, evoked potentials, field potentials, or single unit activity, among others, may be used for validation, confirmation, or the like of the extra-cerebral detections or determinations made from extra-cerebral data. 
     The extra-cerebral epileptic and/or non-epileptic event detection disclosed herein provides a comprehensive, cost-effective, valuable alternative to systems of epileptic or non-epileptic event detection based on brain electrical signals such as EEG. To date, no extra-cerebral systems for detection of both epileptic and non-epileptic seizures have been developed or commercialized. Extra-cerebral epileptic and non-epileptic event detection may make use of one or more signals of autonomic, neurologic, endocrine, metabolic, gastro-intestinal, and/or dermal origin and of tissue/organ stress markers, such as those presented in Table 1. 
     Extra-cerebral detection of state changes takes advantage of the fact that certain brain structures directly or indirectly influence autonomic, endocrine, gastro-intestinal, dermal and metabolic functions and that certain abnormal states (e.g. seizures) stress the body tissues and result in the elevation of certain compounds or molecules (e.g., stress markers) that may be used to detect, quantify and verify the occurrence of said abnormal state. 
     It has been established that seizures in humans originating from or spreading to central autonomic structures induce changes in heart rate, among other cardio-vascular indices, and also in respiratory activity. It should be stated that seizure-induced heart rate or respiratory increases (which are far more frequent than heart rate or respiratory rate decreases) are not primarily the result of increased motor activity or of metabolic changes, but are instead largely a neurogenic phenomenon. 
     In the present disclosure, a highly robust, efficient and reliable system is provided for detecting, quantifying and/or classifying epileptic and/or non-epileptic seizures based upon at least one extra-cerebral signal and, if desired, using this information to provide warnings, or notification, of the type of seizure event (epileptic or non-epileptic) detected. In some embodiments, systems of the present disclosure may take appropriate therapeutic interventions that reflect (for efficacy and safety purposes) their etiologic and patho-physiologic differences. Systems of the present disclosure are suitable for long-term implantable or external devices, and may provide reliable and accurate indications of seizure events for a wide variety of epilepsy and/or non-epilepsy patients. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Extra-cerebral Multimodal Signals 
               
               
                   
               
             
            
               
                 Autonomic 
               
               
                 Cardiac: EKG, PKG, Echocardiography, Apexcardiography (ApKG), Intra-cardiac pressure,_Cardiac 
               
               
                 blood flow, cardiac thermography; from which can be derived, e.g., heart rate (HR), change of HR, 
               
               
                 rate of change of HR, heart rate variability (HRV), change of HRV, rate of change of HRV, HRV vs. 
               
               
                 HR. Also, blood pressure, heart sounds, heart rhythm, heartbeat wave morphology, heartbeat 
               
               
                 complex morphology, and thoracic wall deflection. 
               
               
                 Vascular: Arterial Pressure, Arterial and venous blood wave pressure morphology; Arterial and 
               
               
                 venous blood flow velocity, arterial and venous blood flow sounds, arterial and venous thermography 
               
               
                 Respiratory: Frequency, tidal volume, minute volume, respiratory wave morphology, respiratory 
               
               
                 sounds, end-tidal CO2, Intercostal EMG, Diaphragmatic EMG, chest wall and abdominal wall 
               
               
                 motion, from which can be derived, e.g., respiration rate (RR), change of RR, rate of change of RR. 
               
               
                 Also, arterial gas concentrations, including oxygen saturation, as well as blood pH can be considered 
               
               
                 respiratory signals. 
               
               
                 Other autonomic: Skin resistance, skin temperature, skin blood flow, sweat gland activity, body 
               
               
                 temperature, organ temperature. 
               
               
                 Concentrations of catecholamines (and their metabolites) and acetylcholine or acetylcholinesterase 
               
               
                 activity in blood, saliva and other body fluids concentrations and its rate of change. 
               
               
                 Neurologic 
               
               
                 Cognitive/behavioral: Level of consciousness, attention, reaction time, memory, visuo-spatial, 
               
               
                 language, reasoning, judgment, mathematical calculations, auditory, and/or visual discrimination. 
               
               
                 Kinetic: Direction, speed/acceleration, trajectory (1D to 3D), pattern, and quality of movements, force 
               
               
                 of contraction, body posture, body orientation/position, body part orientation/position in reference to 
               
               
                 each other and to imaginary axes, muscle tone, agonist-to-antagonist muscle tone relation, from which 
               
               
                 can be derived, e.g., information about gait, posture, normal or abnormal head, ocular, trunk, pelvis, 
               
               
                 and limb movements and falls. 
               
               
                 Vocalizations: Formed, unformed, rate of production/unit time, pitch, loudness, duration. 
               
               
                 Endocrine 
               
               
                 Prolactin, luteinizing hormone, follicle stimulation hormone, growth hormone, ACTH, cortisol, 
               
               
                 vasopressin, beta-endorphin, beta, lipotropin-, corticotropin-releasing factor (CRF). 
               
               
                 Tissue Stress Markers 
               
               
                 CK, lactic acid, troponin, neuron-specific enolase, reactive oxygen and nitrogen species including but 
               
               
                 not limited to iso- and neuro-prostanes and nitrite/nitrate ratio, glutathione, glutathione disulfide and 
               
               
                 glutathione peroxidase activity, citrulline, protein carbonyls, thiobarbituric acid, the heat shock 
               
               
                 protein family, catecholamines, lactic acid, N-acetylaspartate, and metabolites of any of the foregoing. 
               
               
                 Metabolic 
               
               
                 Arterial pH and gases, lactate/pyruvate ratio, electrolytes, glucose, oxygen consumption. 
               
               
                   
               
            
           
         
       
     
     Certain body signals may fall within more than one class. For example, pH is listed in Table 1 as both an autonomic signal, since it is under respiratory control, and a metabolic signal, since it is also influenced by metabolic by-products. 
     Generally, when the term “reference value” is used herein without further qualification, it refers to a value of an index determined from autonomic, neurologic, endocrine, metabolic, or stress marker data and derived from an interictal, ictal or postictal period of an epileptic or of a non-epileptic seizure. The evolution of non-epileptic seizures at long temporal scales (e.g., days to years) behaves similarly to that of epileptic seizures, having “interictal” periods when no abnormal activity occurs, “ictal” periods when the abnormal activity is visible (e.g., “loss of consciousness and generalized abnormal motor activity) and “postictal” periods (e.g., the abnormal movements cease but the patient remains “unresponsive”). Reference values or ranges thereof for any of the autonomic, neurologic, endocrine, metabolic or stress marker features may be dependent upon the patient&#39;s level of consciousness (e.g., wakefulness), level of physical (e.g., exercise) or cognitive activity (e.g., attentive), time of day (e.g., circadian), or seizure history (e.g., mean or median time between seizures, seizure severity, etc., over short-term or long-term time periods) and are thus non-stationary. Although reference values for a certain feature in a certain patient state and/or time are most directly comparable to corresponding signals in the same patient state and/or time of day, they may be comparable to corresponding signals from other states, times, or both. 
     A reference value may be a mean, median, or another statistical indicator of the central tendency of a data series or of its distribution (e.g. probability distribution or density function). The reference value may be a threshold that is useful—depending upon the underlying index or feature being considered—for distinguishing between an epileptic (ictal) state and a non-ictal state, and also for distinguishing a convulsive/generalized epileptic from a convulsive/generalized non-epileptic state. Body movements of several body parts occur during both convulsive/generalized epileptic and non-epileptic seizures but differences in velocity, force direction and number of planes which the movement traverses, may be used to distinguish epileptic from non-epileptic seizures. 
     The reference value may be from a data series taken from the same patient on whom the present methods may be performed, or a plurality of data series taken from each member of a population of patients. If the reference value is derived from the patient&#39;s own data, it is desirable for the patient to have an epileptic and/or a non-epileptic seizure history, in order to identify activity that is indicative of an epileptic and/or non-epileptic seizure, and thereby to obtain data that may be used as reference value for comparison purposes. The reference value may be empirical in origin or derived from accepted wisdom in the field. 
     The various embodiments disclosed by parent U.S. Patent Application Ser. Nos. 13/098,262 and 12/896,525 may be also used to distinguish epileptic generalized from psychogenic non-epileptic generalized seizures whose kinetic activity, but not patho-physiology, resembles that of epileptic seizures. 
     An extra-cerebral signal approach relying on multiple body signals such as kinetic, autonomic and metabolic signals, and that may be performed in ambulatory patients (unlike video-EEG monitoring, the current “gold standard” that requires hospitalization for several days) is ideally suited for classifying seizures as either epileptic or non-epileptic, given the high sensitivity and specificity inherent to a multimodal “extra-cerebral” signal approach according to the disclosure described herein. Embodiments of the present disclosure may be implemented in small portable devices, which would provide a cost-effective solution (no hospital admission would be necessary) to a pressing medical need. 
     The following are a few examples of features of epileptic and/or non-epileptic seizures, one or more of which may be used to distinguish between epileptic generalized/convulsive seizures and non-epileptic generalized/convulsive seizures: a) The intensity of non-epileptic movements, unlike that of epileptic movements, waxes and wanes (crescendo-decrescendo pattern) throughout the event; b) Non-epileptic movements, unlike epileptic movements, are multi-directional or multi-planar, said changes in direction or plane occurring rapidly and often in a random sequence. For example, vertical movements may give way to horizontal movements, and these in turn to oblique or rotary or flapping movements; c) Body joints movements in non-epileptic seizures, unlike in epileptic seizures, are incoherent or disorganized: e.g., while the right upper extremity is moving in the vertical plane at a certain speed and with certain amplitude and phase, the direction, speed, phase and amplitude of movement of the left upper extremity at the same time may be different; d) in non-epileptic seizures, unlike in epileptic seizures, co-activation of agonist and antagonist muscle groups is rarely seen: Co-activation of the abdominal and paraspinal muscles during an epileptic generalized tonic-clonic seizure keeps the torso straight while the sole activation of paraspinal muscles, a common observable in non-epileptic generalized seizures, manifests as an arched back (opisthotonus); unopposed activation of neck, trunk, hip flexors results in the so-called “fetal position”, also a common occurrence in non-epileptic seizures; e) Involvement (in the form of movements) of certain body parts is commonly found in non-epileptic seizures while they are rarely if ever seen in epileptic generalized seizures; pelvic thrust, pelvic gyrations, and other pelvic movements are nearly pathognomic of non-epileptic seizures; f) Metabolic (lactic) acidosis occurs with epileptic generalized tonic-clonic seizures and not with non-epileptic generalized seizures; g) oxygen desaturation and carbon dioxide retention are seen in epileptic convulsive but not in non-epileptic convulsive seizures. 
     Although not limited to the following, an exemplary system capable of implementing embodiments of the present disclosure is described below. 
     Turning now to  FIG.  22   , a stylized medical device system is depicted. The medical device system comprises a medical device  2300  and at least one sensor  2312 . 
     In some embodiments, the medical device  2300  may be implantable, while in other embodiments, such as that shown in  FIG.  22   ; the medical device  2300  may be completely external to the body of the patient. In still other embodiments, the present disclosure may comprise systems with some implantable portions and some external portions. 
     The sensor  2312  may be implanted in the patient&#39;s body, worn external to the patient&#39;s body, or positioned in proximity to but not in contact with the patient&#39;s body. The sensor  2312  may be configured to receive cardiac activity data, body movement data, responsiveness data, awareness data, or other data from the patient&#39;s body. 
       FIG.  22    depicts the medical device  2300  being in wired communication  2311  with the at least one sensor  2312 . In other embodiments (not shown), the medical device  2300  may be in wireless communication with the at least one sensor  2312 . 
     Turning now to  FIG.  23   , a block diagram depiction of a system comprising a medical device  2300  is provided, in accordance with one illustrative embodiment of the present disclosure. In some embodiments, the medical device  2300  may be implantable, while in other embodiments the medical device  2300  may be completely external to the body of the patient. In still other embodiments, the medical device may include both implanted and non-implanted portions.  FIG.  23    illustrates various components, units and/or modules that perform functions discussed more fully below. It will be appreciated that these components and units or modules may be equivalently described using similar terms, and the use of particular terms herein is not intended to exclude embodiments involving different components performing the same function, or which may be described using different but similar terms. 
     The medical device  2300  may comprise a controller  2310  capable of controlling various aspects of the operation of the medical device  2300 . The controller  2310  is capable of receiving internal data or external data and is capable of affecting substantially all functions of the medical device  2300 . 
     The controller  2310  may comprise various components, such as a processor  2315 , a memory  2317 , etc. The processor  2315  may comprise one or more microcontrollers, microprocessors, etc., capable of performing various executions of software components. The memory  2317  may comprise various memory portions where a number of types of data (e.g., internal data, external data instructions, software codes, status data, diagnostic data, etc.) may be stored. In one embodiment, the memory  2317  may be configured to store at least one reference value of an autonomic activity, a neurologic activity, a metabolic activity, an endocrine activity, or a stress marker activity. The memory  2317  may comprise one or more of random access memory (RAM), dynamic random access memory (DRAM), electrically erasable programmable read-only memory (EEPROM), flash memory, etc. 
     The medical device  2300  may also comprise a power supply  2330 . The power supply  2330  may comprise a battery, voltage regulators, capacitors, etc., to provide power for the operation of the medical device  2300 , including delivering the therapeutic electrical signal. The power supply  2330  comprises a power source that in some embodiments may be rechargeable. In other embodiments, a non-rechargeable power source may be used. The power supply  2330  provides power for the operation of the medical device  2300 , including electronic operations and the electrical signal generation and delivery functions. The power supply  2330  may comprise a lithium/thionyl chloride cell or a lithium/carbon monofluoride (LiCFx) cell if the medical device  2300  is implantable, or may comprise conventional watch or 9V batteries for external (i.e., non-implantable) embodiments. Other battery types known in the art of medical devices may also be used. 
     The medical device  2300  may also comprise a communication unit  2360  capable of facilitating communications between the medical device  2300  and various devices. In particular, the communication unit  2360  is capable of providing transmission and reception of electronic signals to and from a monitoring unit  2370 , such as a handheld computer or PDA that can communicate with the medical device  2300  wirelessly or by cable. The communication unit  2360  may include hardware, software, firmware, or any combination thereof. 
     The medical device  2300  may also comprise one or more sensor(s)  2312  coupled via sensor lead(s)  2311  to the medical device  2300  (or in wireless communication with the medical device  2300 , not shown). The sensor(s)  2312  are capable of receiving signals related to a physiological parameter, such as an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, or a stress marker signal, among others, and delivering the signals to the medical device  2300 . The at least one sensor(s)  2312 , in one embodiment, may comprise an accelerometer. The at least one sensor(s)  2312 , in another embodiment, may comprise an inclinometer. In another embodiment, the at least one sensor(s)  2312  may comprise an actigraph. One or more of the at least one sensor(s)  2312  may be external structures that may be placed on the patient&#39;s skin, such as over the patient&#39;s heart or elsewhere on the patient&#39;s torso. The at least one sensor(s)  2312 , in one embodiment, may comprise a multimodal signal sensor capable of detecting various signals, such as autonomic and neurologic signals. 
     In one embodiment, the medical device  2300  may comprise a autonomic signal module  2365  that is capable of collecting autonomic data, e.g., cardiac data comprising fiducial time markers of each of a plurality of heart beats, a blood SaO2 value, a blood CO2 concentration, a blood pH value, a body temperature, or an infrared activity of a portion of a patient&#39;s body, among others. The autonomic signal module  2365  may also process or condition the autonomic data. The autonomic data may be provided by the sensor(s)  2312 . The autonomic signal module  2365  may be capable of performing any necessary or suitable amplifying, filtering, and performing analog-to-digital (A/D) conversions to prepare the signals for downstream processing. The autonomic data module  2365 , in one embodiment, may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the autonomic signal module  2365  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the autonomic signal module  2365  may comprise hardware, firmware, software and/or any combination thereof. A more detailed illustration of the autonomic signal module  2365  is provided in  FIG.  24 A  and accompanying description below. 
     The autonomic signal module  2365  is capable of collecting autonomic data and providing the collected autonomic data to a detection unit  2385 , a classification unit  2386 , or both. 
     In one embodiment, the medical device  2300  may comprise a neurological signal module  2375  that is capable of collecting neurologic data, e.g., signals indicative of a motor activity of the patient, such as a crescendo-decrescendo pattern of a motor activity, a force of a motor activity, a velocity of a motor activity, a multi-directionality of a motor activity, a multi-planarity of a motor activity, a frequency of a motor activity, an incoherence or asymmetry between a first motor activity and a second motor activity, a lack of coactivation during certain motor activity of an agonist muscle group and an antagonist muscle group, or a pelvic motor activity, among others. (“Lack” and “absence” may be used interchangeably herein). The neurological signal module  2375  may also process or condition the neurologic data. The neurologic data may be provided by the sensor(s)  2312 . The neurological signal module  2375  may be capable of performing any necessary or suitable amplifying, filtering, and performing analog-to-digital (A/D) conversions to prepare the signals for downstream processing. The neurological signal module  2375 , in one embodiment, may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the neurological signal module  2375  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the neurological signal module  2375  may comprise hardware, firmware, software and/or any combination thereof. Further description of the neurologic signal module  2375  is provided in  FIG.  24 B  and accompanying description below. 
     The neurological signal module  2375  is capable of collecting neurologic data and providing the collected neurologic data to a detection unit  2385 , a classification unit  2386 , or both. 
     In one embodiment, the medical device  2300  may comprise a metabolic signal module  2376  that is capable of collecting metabolic data, e.g., signals indicative of a metabolic activity of the patient, such as a lactic acid concentration or a potassium concentration, among others. The metabolic signal module  2376  may also process or condition the metabolic data. The metabolic data may be provided by the sensor(s)  2312 . The metabolic signal module  2376  may be capable of performing any necessary or suitable amplifying, filtering, and performing analog-to-digital (A/D) conversions to prepare the signals for downstream processing. The metabolic signal module  2376 , in one embodiment, may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the metabolic signal module  2376  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the metabolic signal module  2376  may comprise hardware, firmware, software and/or any combination thereof. Further description of the metabolic signal module  2376  is provided in  FIG.  24 C  and accompanying description below. 
     The metabolic signal module  2376  is capable of collecting metabolic data and providing the collected metabolic data to a detection unit  2385 , a classification unit  2386 , or both. 
     In one embodiment, the medical device  2300  may comprise an endocrine signal module  2378  that is capable of collecting endocrine data, e.g., signals indicative of an endocrine activity of the patient, such as a prolactin concentration, a luteinizing hormone concentration, a follicle-stimulating hormone (FSH) concentration, a growth hormone concentration, an ACTH concentration, a cortisol concentration, a vasopressin concentration, a β-endorphin concentration, a β-lipotropin concentration, or a CRF concentration, among others. The endocrine signal module  2378  may also process or condition the endocrine data. The endocrine data may be provided by the sensor(s)  2312 . The endocrine signal module  2378  may be capable of performing any necessary or suitable amplifying, filtering, and performing analog-to-digital (A/D) conversions to prepare the signals for downstream processing. The endocrine signal module  2378 , in one embodiment, may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the endocrine signal module  2378  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the endocrine signal module  2378  may comprise hardware, firmware, software and/or any combination thereof. Further description of the endocrine signal module  2378  is provided in  FIG.  24 D  and accompanying description below. 
     The endocrine signal module  2378  is capable of collecting endocrine data and providing the collected endocrine data to a detection unit  2385 , a classification unit  2386 , or both. 
     In one embodiment, the medical device  2300  may comprise a stress marker signal module  2379  that is capable of collecting stress marker data, e.g., signals indicative of a stress marker activity of the patient, such as a reactive oxygen concentration, a reactive nitrogen concentration, or a catecholamine concentration, among others. The stress marker signal module  2379  may also process or condition the stress marker data. The stress marker data may be provided by the sensor(s)  2312 . The stress marker signal module  2379  may be capable of performing any necessary or suitable amplifying, filtering, and performing analog-to-digital (A/D) conversions to prepare the signals for downstream processing. The stress marker signal module  2379 , in one embodiment, may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the stress marker signal module  2379  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the stress marker signal module  2379  may comprise hardware, firmware, software and/or any combination thereof. Further description of the stress marker signal module  2379  is provided in  FIG.  24 E  and accompanying description below. 
     The stress marker signal module  2379  is capable of collecting stress marker data and providing the collected stress marker data to a detection unit  2385 , a classification unit  2386 , or both. 
     The detection unit  2385  may be capable of detecting a seizure. The detection unit  2385  may make use of an autonomic signal provided by autonomic signal module  2365 , a neurological signal module  2375 , other modules depicted in  FIG.  23   , modules not shown in the figures, or two or more thereof. The detection unit  2385  can implement one or more algorithms. The detection unit  2385  may comprise software module(s) that are capable of performing various interface functions, filtering functions, etc. In another embodiment, the detection unit  2385  may comprise hardware circuitry that is capable of performing these functions. In yet another embodiment, the detection unit  2385  may comprise hardware, firmware, software and/or any combination thereof. Further description of an exemplary detection unit  2385  is provided in U.S. patent application Ser. Nos. 13/098,262 and 12/896,525. 
     In another embodiment, the medical device  2300  may further comprise a therapy unit. The therapy unit (not shown) may be configured to at least one of administer a non-epileptic seizure therapy, prevent delivery of an epilepsy therapy, or warn against delivery of an epilepsy therapy, in response to receiving from the detection unit an indication the seizure is non-epileptic. In one embodiment, the medical device  2300  may further comprise a notification unit. The notification unit (not shown) may be configured to notify at least one of the patient, a caregiver, or a medical professional that the seizure is non-epileptic, based upon an indication that the seizure is non-epileptic. In one embodiment, the medical device  2300  may further comprise a logging unit. The logging unit (not shown) may be configured to log at least one of the date of occurrence of the seizure, the time of occurrence of the seizure, or the severity of the seizure. 
     In addition to components of the medical device  2300  described above, a medical device system may comprise a storage unit to store an indication of at least one of seizure or an increased risk of a seizure. The storage unit may be the memory  2317  of the medical device  2300 , another storage unit of the medical device  2300 , or an external database, such as a local database unit  2355  or a remote database unit  2350 . The medical device  2300  may communicate the indication via the communications unit  2360 . Alternatively or in addition to an external database, the medical device  2300  may be adapted to communicate the indication to at least one of a patient, a caregiver, or a healthcare provider. 
     In various embodiments, one or more of the units or modules described above may be located in a monitoring unit  2370  or a remote device  2392 , with communications between that unit or module and a unit or module located in the medical device  2300  taking place via communication unit  2360 . For example, in one embodiment, one or more of the autonomic signal module  2365 , the neurologic signal module  2375 , or the detection unit  2385  may be external to the medical device  2300 , e.g., in a monitoring unit  2370 . Locating one or more of the autonomic signal module  2365 , the neurologic signal module  2375 , or the detection unit  2385  outside the medical device  2300  may be advantageous if the calculation(s) is/are computationally intensive, in order to reduce energy expenditure and heat generation in the medical device  2300  or to expedite calculation. 
     The monitoring unit  2370  may be a device that is capable of transmitting and receiving data to and from the medical device  2300 . In one embodiment, the monitoring unit  2370  may be a computer system capable of executing a data-acquisition program. The monitoring unit  2370  may be controlled by a healthcare provider, such as a physician, at a base station in, for example, a doctor&#39;s office. In alternative embodiments, the monitoring unit  2370  may be controlled by a patient in a system providing less interactive communication with the medical device  2300  than another monitoring unit  2370  controlled by a healthcare provider. Whether controlled by the patient or by a healthcare provider, the monitoring unit  2370  may be a computer, preferably a handheld computer or PDA, but may alternatively comprise any other device that is capable of electronic communications and programming, e.g., hand-held computer system, a PC computer system, a laptop computer system, a server, a personal digital assistant (PDA), an Apple-based computer system, a cellular telephone, etc. The monitoring unit  2370  may download various parameters and program software into the medical device  2300  for programming the operation of the medical device, and may also receive and upload various status conditions and other data from the medical device  2300 . Communications between the monitoring unit  2370  and the communication unit  2360  in the medical device  2300  may occur via a wireless or other type of communication, represented generally by line  2377  in  FIG.  23   . This may occur using, e.g., wand  155  ( FIG.  1 A ) to communicate by RF energy with an implantable signal generator  110 . Alternatively, the wand may be omitted in some systems, e.g., systems in which the MD 2300 is non-implantable, or implantable systems in which monitoring unit  2370  and MD 2300 operate in the MICS bandwidths. 
     In one embodiment, the monitoring unit  2370  may comprise a local database unit  2355 . Optionally or alternatively, the monitoring unit  2370  may also be coupled to a database unit  2350 , which may be separate from monitoring unit  2370  (e.g., a centralized database wirelessly linked to a handheld monitoring unit  2370 ). The database unit  2350  and/or the local database unit  2355  are capable of storing various patient data. These data may comprise patient parameter data acquired from a patient&#39;s body, therapy parameter data, seizure severity data, and/or therapeutic efficacy data. The database unit  2350  and/or the local database unit  2355  may comprise data for a plurality of patients, and may be organized and stored in a variety of manners, such as in date format, severity of disease format, etc. The database unit  2350  and/or the local database unit  2355  may be relational databases in one embodiment. A physician may perform various patient management functions (e.g., programming parameters for a responsive therapy and/or setting references for one or more detection parameters) using the monitoring unit  2370 , which may include obtaining and/or analyzing data from the medical device  2300  and/or data from the database unit  2350  and/or the local database unit  2355 . The database unit  2350  and/or the local database unit  2355  may store various patient data. 
     One or more of the blocks illustrated in the block diagram of the medical device  2300  in  FIG.  23    may comprise hardware units, software units, firmware units, or any combination thereof. Additionally, one or more blocks illustrated in  FIG.  23    may be combined with other blocks, which may represent circuit hardware units, software algorithms, etc. Additionally, any number of the circuitry or software units associated with the various blocks illustrated in  FIG.  23    may be combined into a programmable device, such as a field programmable gate array, an ASIC device, etc. 
     Turning to  FIG.  24 A , an autonomic signal module  2365  is shown in more detail. The autonomic signal module  2365  can comprise a cardiovascular signal unit  2412  capable of providing at least one cardiovascular signal. Alternatively or in addition, the autonomic signal module  2365  can comprise a respiratory signal unit  2414  capable of providing at least one respiratory signal. Alternatively or in addition, the autonomic signal module  2365  can comprise a blood parameter signal unit  2423  capable of providing at least one blood parameter signal (e.g., blood glucose, blood pH, blood gas, SaO2 value, CO2 concentration, etc.). Alternatively or in addition, the autonomic signal module  2365  can comprise a temperature signal unit  2416  capable of providing at least one temperature signal. Alternatively or in addition, the autonomic signal module  2365  can comprise an optic signal unit  2418  capable of providing at least one optic signal. Alternatively or in addition, the autonomic signal module  2365  can comprise a chemical signal unit  2420  capable of providing at least one body chemical signal. Alternatively or in addition, the autonomic signal module  2365  can comprise one or more other autonomic signal unit(s)  2424 , such as a skin resistance signal unit or an infrared activity unit configured to provide at least one signal relating to an infrared activity of a portion of a patient&#39;s body, among others. 
     The autonomic signal module  2365  can also comprise an autonomic signal processing unit  2430 . The autonomic signal processing unit  2430  can perform any filtering, noise reduction, amplification, or other appropriate processing of the data received by the signal units  2412 - 2424  desired prior to calculation of the autonomic signal. 
     The autonomic signal module  2365  can also comprise an autonomic signal calculation unit  2440 . The autonomic signal calculation unit  2440  can calculate an autonomic signal from the data passed by the autonomic signal processing unit  2430 . A calculated autonomic signal herein refers to any signal derivable from the provided signals, with or without processing by the autonomic signal processing unit  2430 . 
     More description regarding the autonomic signal module  2365  may be found in U.S. patent application Ser. Nos. 13/098,262 and 12/896,525. 
     Turning to  FIG.  24 B , an exemplary embodiment of a neurologic signal module  2375  is shown. The neurologic signal module  2375  can comprise at least one of a neuro-electrical signal unit  24012  capable of providing at least one neuro-electrical signal; a neuro-chemical signal unit  24014  capable of providing at least one neuro-chemical signal; a neuro-electrochemical signal unit  24016  capable of providing at least one neuro-electrochemical signal; a kinetic signal unit  24018  capable of providing at least one kinetic signal; or a cognitive signal unit  24020  capable of providing at least one cognitive signal. The cognitive signal unit  24020  may be a component of a remote device. 
     In one embodiment, the cognitive signal unit comprises at least one of a cognitive aptitude determination unit  24020   a  capable of processing at least one cognitive aptitude indication; an attention aptitude determination unit  24020   b  capable of processing at least one attention aptitude indication; a memory aptitude determination unit  24020   c  capable of processing at least one memory indication; a language aptitude determination unit  24020   d  capable of processing at least one language indication; a visual/spatial aptitude determination unit  24020   e  capable of processing at least one visual/spatial indication; one or more other neurologic factor determination unit(s)  24020   g ; or a responsiveness determination unit  24020   h.    
     The neurologic signal module  2375  can also comprise a neurologic signal processing unit  24030 . The neurologic signal processing unit  24030  can perform any filtering, noise reduction, amplification, or other appropriate processing of the data received by the signal units  24012 - 24020  desired prior to calculation of the neurologic signal. 
     The neurologic signal module  2375  can also comprise a neurologic signal calculation unit  24040 . The neurologic signal calculation unit  24040  can calculate a neurologic signal from the data passed by the neurologic signal processing unit  24030 . A calculated neurologic signal herein refers to any signal derivable from the provided signals. 
     For example, the neurologic signal calculation unit  24040  may calculate a motor activity signal, such as a signal relating to a crescendo-decrescendo pattern of a motor activity, a force of a motor activity, a velocity of a motor activity, a multi-directionality of a motor activity, a multi-planarity of a motor activity, a frequency of a motor activity, an incoherence or asymmetry between a first motor activity and a second motor activity, a lack of coactivation during motor activity of an agonist muscle group and an antagonist muscle group, or a pelvic motor activity. 
     Other motor activity signal(s) that may be calculated from relevant data include those relating to the body&#39;s (or of a portion thereof such as the head, eyes, an arm, or a leg) acceleration; direction; position; smoothness, amplitude, force of movements and number of movements per unit time, and whether there are extraneous or abnormal body oscillations during resting conditions or movement. The data sources from which the signal may be calculated include electromyography, a mechanogram, an accelerometer, an actigraph, an inclinometer, or a video/optical signal, as received by kinetic capability determination unit  24018 , and, optionally, further processed by neurologic data processing unit  24030 . 
     More description regarding the neurologic signal module  2375  may be found in U.S. patent application Ser. Nos. 13/098,262 and 12/896,525. 
     Turning to  FIG.  24 C , an exemplary embodiment of a metabolic signal module  2376  is shown. The metabolic signal module  2376  can comprise at least one of a lactic acid signal unit  24110  capable of providing at least one signal relating to lactic acid content in the patient&#39;s blood and/or a tissue; or a potassium signal unit  24112  capable of providing at least one signal relating to a potassium content in the patient&#39;s blood or tissue. 
     The metabolic signal module  2376  can also comprise a metabolic signal processing unit  24130 . The metabolic signal processing unit  24130  can perform any filtering, noise reduction, amplification, or other appropriate processing of the data received by the signal units  24110 - 24112  desired prior to calculation of the metabolic signal. 
     The metabolic signal module  2376  can also comprise a metabolic signal calculation unit  24140 . The metabolic signal calculation unit  24140  can calculate a metabolic signal from the data passed by the metabolic signal processing unit  24130 . A calculated metabolic signal herein refers to any signal derivable from the provided signals. 
     For example, the metabolic signal calculation unit  24140  may calculate a lactic acid signal, such as may be determinable from signals yielded by a blood lactic acid sensor, as received by the lactic acid signal unit  24110  and, optionally, further processed by metabolic data processing unit  24130 . 
     For another example, the metabolic signal calculation unit  24140  may calculate a potassium signal, such as the potassium ion content of the patient&#39;s blood. The signal may be received by potassium signal unit  24112 , and, optionally, further processed by metabolic data processing unit  24130 . 
     Turning to  FIG.  24 D , an exemplary embodiment of an endocrine signal module  2378  is shown. The endocrine signal module  2378  can comprise at least one of a prolactin signal unit  24210  capable of providing at least one signal relating to prolactin content in the patient&#39;s blood; a luteinizing hormone signal unit  24211  capable of providing at least one signal relating to luteinizing hormone content in the patient&#39;s blood; an FSH signal unit  24212  capable of providing at least one signal relating to FSH content in the patient&#39;s blood; a growth hormone signal unit  24213  capable of providing at least one signal relating to growth hormone content in the patient&#39;s blood; an ACTH signal unit  24214  capable of providing at least one signal relating to ACTH content in the patient&#39;s blood; a cortisol signal unit  24215  capable of providing at least one signal relating to cortisol content in the patient&#39;s blood; a vasopressin signal unit  24216  capable of providing at least one signal relating to vasopressin content in the patient&#39;s blood; a β-endorphin signal unit  24217  capable of providing at least one signal relating to β-endorphin content in the patient&#39;s blood; a β-lipotropin signal unit  24218  capable of providing at least one signal relating to β-lipotropin content in the patient&#39;s blood; a CRF signal unit  24219  capable of providing at least one signal relating to CRF content in the patient&#39;s blood; or another endocrine signal unit  24220  capable of providing at least one signal relating to another endocrine property. 
     The endocrine signal module  2378  can also comprise an endocrine signal processing unit  24230 . The endocrine signal processing unit  24230  can perform any filtering, noise reduction, amplification, or other appropriate processing of the data received by the signal units  24210 - 24220  desired prior to calculation of the endocrine signal. 
     The endocrine signal module  2378  can also comprise an endocrine signal calculation unit  24240 . The endocrine signal calculation unit  24240  can calculate an endocrine signal from the data passed by the endocrine signal processing unit  24230 . A calculated endocrine signal herein refers to any signal derivable from the provided signals. 
     For example, the endocrine signal calculation unit  24240  may calculate a cortisol signal, such as may be determinable from signals yielded by a blood cortisol sensor, as received by the cortisol signal unit  24215  and, optionally, further processed by endocrine data processing unit  24230 . 
     Turning to  FIG.  24 E , an exemplary embodiment of a stress marker signal module  2379  is shown. The stress marker signal module  2379  can comprise at least one of a reactive oxygen signal unit  24310  capable of providing at least one signal relating to the content of at least one reactive oxygen species in the patient&#39;s blood or a tissue; a reactive nitrogen signal unit  24311  capable of providing at least one signal relating to the content of at least one reactive nitrogen species in the patient&#39;s blood or a tissue; a catecholamine signal unit  24312  capable of providing at least one signal relating to catecholamine content in the patient&#39;s blood or a tissue; or another stress marker signal unit  24313  capable of providing at least one signal relating to another stress marker. 
     The stress marker signal module  2379  can also comprise a stress marker signal processing unit  24330 . The stress marker signal processing unit  24330  can perform any filtering, noise reduction, amplification, or other appropriate processing of the data received by the signal units  24310 - 24313  desired prior to calculation of the stress marker signal. 
     The stress marker signal module  2379  can also comprise a stress marker signal calculation unit  24340 . The stress marker signal calculation unit  24340  can calculate a stress marker signal from the data passed by the stress marker signal processing unit  24330 . A calculated stress marker signal herein refers to any signal derivable from the provided signals. 
     For example, the stress marker signal calculation unit  24340  may calculate a reactive oxygen signal, such as may be determinable from signals yielded by a sensor of peroxide and/or superoxide ions in the patient&#39;s blood, as may be received by the reactive oxygen signal unit  24310  and, optionally, further processed by stress marker data processing unit  24330 . 
     From any one or more signal(s) calculated by any calculation unit depicted in  FIGS.  24 A- 24 E , one or more autonomic activities, neurologic activities, metabolic activities, endocrine activities, or stress marker activities may be determined. Turning to  FIG.  24 F , a block diagram of classification unit  2386  is depicted. The classification unit  2386  comprises a calculated signal receiving unit  24610  capable of receiving data indicative of a calculated signal from one or more of the autonomic signal module  2365 , the neurologic signal module  2375 , the metabolic signal module  2376 , the endocrine signal module  2378 , the stress marker signal module  2379 , or a memory  2317  storing prior outputs of such a module, and seizure classification unit  24620  capable of determining from the received data whether a seizure is epileptic, non-epileptic, another type of behavior or motor changes (e.g., behavior changes arising from dissociation or motor changes arising from Huntington&#39;s chorea or paroxysmal choreo-athetosis, or unclassifiable. The seizure classification unit  24620  may implement any appropriate algorithm(s) for classifying a seizure from at least one autonomic signal, neurologic signal, metabolic signal, endocrine signal, or stress marker signal. 
     The classification unit  2386  may be configured to classify the seizure as a non-epileptic seizure, based on at least one of the following: an autonomic activity being not indicative of an epileptic seizure, a neurologic activity being not indicative of an epileptic seizure, a metabolic activity being not indicative of an epileptic seizure, an endocrine activity being not indicative of an epileptic seizure, or a stress marker activity being not indicative of an epileptic seizure. 
     In the embodiment shown in  FIG.  24 F , the classification unit  2386  may further comprise a seizure quantification unit  24630  capable of quantifying from the received data one or more quantifiable characteristics of one or both of an epileptic seizure and a non-epileptic seizure. Exemplary quantifiable characteristics include, but are not limited to, event severity, event duration, duration of stages of the event, or values and/or ranges thereof of one or more body signals (e.g., a blood chemical value, a lactic acid content, a parameter of a motor activity, etc.), among others. 
     The classification unit  2386  may send the output of the seizure classification unit  24620  to one or more other units or modules of the medical device  2300  and/or one or more external units. The one or more other modules may then store the output, report the output to the patient, a physician, and/or a caregiver; warn the patient or a caregiver that the event under consideration is non-epileptic, etc. 
     The medical device system of one embodiment of the present disclosure provides for software module(s) that are capable of acquiring, storing, and processing various forms of data, such as patient data/parameters (e.g., physiological data, side-effects data, heart rate data, breathing rate data, brain-activity parameters, disease progression or regression data, quality of life data, etc.) and therapy parameter data. Therapy parameters in the case of epileptic seizures may include, but are not limited to, electrical signal parameters (e.g., frequency, pulse width, wave shape, polarity, geometry of electrical fields, on-time, off-time, etc.) that define therapeutic electrical signals delivered by the medical device in response to the detection of the seizure, medication type, dose, or other parameters, and/or any other therapeutic treatment parameter. 
     In one embodiment, the medical device  2300  or an external unit  2370  may also be capable of detecting a manual input from the patient. The manual input may include a magnetic signal input, a tap input, a button, dial, or switch input, a touchscreen input, a wireless data input to the medical device  2300 , etc. The manual input may be used to allow capture of the patient&#39;s subjective assessment of his or her epileptic events. For example, the medical device  2300  may comprise one or more physical or virtual (e.g., touchscreen-implemented) buttons accessible to the patient&#39;s fingers or a caregiver&#39;s, through which the patient or caregiver may indicate he or she is having an epileptic event or is not having an epileptic event. Alternatively or in addition, the manual input may be used to gauge the patient&#39;s responsiveness. Turning now to  FIG.  25   , a flowchart depiction of a method according to one illustrative embodiment of the present disclosure is presented. A seizure in a patient may be detected at  2510  using any appropriate technique(s), such as those described above. In one embodiment, detecting at  2510  may comprise observing at least one abnormal motor activity of the patient (i.e., motor activity associated with an epileptic seizure). 
     At least one signal indicative of an activity of the patient may be received at  2520 . The at least one signal may be any one or more of the following: an autonomic signal indicative of an autonomic activity of the patient, a neurologic signal indicative of a neurologic activity of the patient, a metabolic signal indicative of a metabolic activity of the patient, an endocrine signal indicative of an endocrine activity of the patient, or a stress marker signal indicative of a stress marker of the patient, among others. 
     Based on the at least one received signal, the seizure may be classified at  2530  as a non-epileptic seizure based on at least one of the following: the autonomic activity being an autonomic activity not indicative of an epileptic seizure, the neurologic activity being a neurologic activity not indicative of an epileptic seizure, the metabolic activity being a metabolic activity not indicative of an epileptic seizure, the endocrine activity being an endocrine activity not indicative of an epileptic seizure, or the stress marker activity being a stress marker activity not indicative of an epileptic seizure. 
     In a particular example, the autonomic activity not indicative of an epileptic generalized/convulsive seizure may be at least one of: a lack of a decrease of SaO2 value of the patient&#39;s blood after the onset of a generalized motor activity, relative to a reference SaO2 value, a lack of an increase in CO2 concentration of the patient&#39;s blood after the onset of a generalized motor activity, relative to a reference CO2 concentration, a lack of a decrease in a pH value of the patient&#39;s blood after the onset of a generalized motor activity essentially unchanged relative to a reference pH value, a lack of an increase in the patient&#39;s body temperature after the onset of a generalized motor activity during the seizure, relative to a reference temperature value, a lack of change in the patient&#39;s cardiac activity after the onset of a generalized motor activity, relative to a reference cardiac activity value, or a lack of an increase in an infrared activity of a portion of the patient&#39;s body after the onset of a generalized motor activity, relative to a reference infrared activity. 
     In an even more particular example, the autonomic activity not indicative of an epileptic seizure may be a lack of a decrease in a pH value of the patient&#39;s blood after the onset of a generalized motor activity essentially unchanged relative to a reference pH value. 
     In another particular example, the neurologic activity not indicative of an epileptic seizure is at least one of: a recurring crescendo-decrescendo pattern of a motor activity of the patient, a force of a motor activity of the patient, a range of motion of a motor activity of the patient, a velocity of a motor activity of the patient, a multi-directionality of a motor activity of the patient, a multi-planarity of a motor activity of the patient, a frequency of a motor activity of the patient, an incoherence between a first motor activity and a second motor activity of the patient, a lack of coactivation during motor activity of an agonist muscle group and an antagonist muscle group of the patient, or a pelvic motor activity of the patient that is the most prominent body movement of the patient. 
     Body movement is a type of motor activity. However, some motor activity may be associated with a lack of body movement; e.g., a tonic phase of a seizure is associated with a marked increase in muscle tone but is also associated with substantially no movement of the patient&#39;s body. 
     “Crescendo-decrescendo” is used herein to refer to a pattern of increasing amplitude of a motor activity, followed by a decreasing amplitude of the motor activity. The crescendo-decrescendo pattern may be recurrent and periodic or aperiodic. 
     In this context, coherence or being in phase refers to any feature of movement that is the same in terms of timing, between homologous parts of the body. Incoherence or not being in phase refers to any feature of movement that differs in such terms between hemihalves of the body. 
     A body movement may be considered in terms of planes in which the movement occurs. Various planes relating to human anatomy have been defined in the medical arts. These include a coronal plane (a plane dividing the body into front and rear portions), a sagittal plane (a plane dividing the body into left and right portions), and a transverse plane (a plane dividing the body into upper and lower portions). 
     Generally speaking, epileptic movements typically are predominantly uniplanar (i.e., they typically occur substantially mainly in one body plane) and in certain joints are bi-directional (e.g. elbow flexion/extension). Non-epileptic movements are often multiplanar and/or multidirectional.  FIGS.  28 A- 28 B  compare a non-limiting example of (a) a generally planar epileptic movement and (b) a generally non-planar non-epileptic movement of an arm  2810 , as represented by the path traced by an accelerometer  2820  (e.g., disposed on a lower arm of a patient, as seen from in front of, to the side of, and above the patient. 
     Body movements of the same joint(s) or muscle(s)/muscle group(s) on the right and left sides of the body may be considered “synchronized” or “synchronous” if their initiation and/or termination is substantially simultaneous. In general, epileptic movements involving more than one limb or body part are more synchronous and symmetrical than non-epileptic movements. Body movements of the same joint(s) or muscle(s)/muscle group(s) on the right and left sides of the body may be considered “symmetrical” if they have substantially similar ranges of motion, velocities, amplitudes, directionalities, and/or planarities. 
     In a further embodiment, the neurologic activity not indicative of an epileptic seizure may further comprise at least one of: an electroencephalographic (EEG) signal not indicative of an epileptic brain activity of the patient, or a videographic motor activity analysis not indicative of an epileptic motor activity of the patient. Such further activities may assist in the classification performed at  2530 . 
     In another particular example of body signals, the metabolic activity not indicative of an epileptic seizure may be at least one of: a lack of lactic acidosis of the patient&#39;s blood sometime after the onset of a generalized motor activity during the seizure, relative to a reference lactic acid value, or a lack of a normo-kalemic metabolic acidosis of the patient&#39;s blood sometime after the onset of a generalized motor activity during the seizure, relative to a reference normo-kalemic value. 
     Any seizure may be subjected to the classification at  2530 . For example, the method of this embodiment may allow the distinction of non-epileptic generalized seizures from epileptic generalized seizures. For another example, the method of this embodiment may allow the distinction of non-epileptic partial seizures from epileptic partial seizures. The partial seizures may be simple partial or complex partial seizures. 
     If the seizure is to be classified as epileptic, this may be done at  2550 . 
     If the signals are not indicative of an epileptic seizure, then the seizure may be classified as non-epileptic at  2540 . In one embodiment, no further actions need be taken. 
     In one optional embodiment, the method depicted in  FIG.  25    further comprises at least one of: issuing at  2542  a notification that the seizure is non-epileptic, based upon classifying the seizure as non-epileptic; cancelling at  2543  a notification or warning of an epileptic seizure, based upon classifying the seizure as non-epileptic; logging at  2544  at least one of the seizure classification (epileptic or non-epileptic), the date of the seizure, the time of occurrence of the seizure, the severity of the seizure, the duration of the seizure, or the time between seizures; preventing or warning at  2545  against delivery of a therapy for an epileptic seizure, based upon classifying the seizure as non-epileptic; administering at  2546  a therapy for the non-epileptic seizure, based upon classifying the seizure is non-epileptic; or discontinuing at  2547  delivery of a therapy for an epileptic seizures. 
     A notification that may be issued at  2542  may be issued to the patient, to a caregiver, or to medical personnel. In some embodiments, the medical personnel may be an emergency medical technician or an emergency room nurse or physician. The present inventor has firsthand knowledge of a situation in which a patient presented at a rural emergency room in apparent status epilepticus, a life-threatening complication of epilepsy. A helicopter ambulance service retrieved the patient and brought him to the present inventor&#39;s current institution, a state university medical center having an advanced epilepsy care center. Upon the patient&#39;s arrival, it was rapidly determined that the patient&#39;s seizure was non-epileptic. Employment of the present method such that the rural emergency room personnel might have received a notification issued at  2542  would have freed the helicopter ambulance service and the advanced epilepsy care center for patients suffering from epileptic events. 
     Regarding logging at  2544 , the date and time of occurrence of the seizure need no further discussion. Severity may be defined using any appropriate technique. In one embodiment, seizure severity may be defined from one or more of the peak intensity of the seizure, the duration of the seizure, or the extent of spread of the seizure. Intensity, duration, and extent of spread may be measured using neurologic, autonomic, metabolic, or other signals as described herein and/or in patents and applications incorporated herein by reference. 
     Therapies that may be administered at  2546  may comprise cognitive therapy, behavioral therapy, or biofeedback. For example, the patient may receive a message that the seizure is non-epileptic, which may be followed by instructions to relax, breathe deeply, or the like. The response to one or more administered therapies may be measured (not shown) using body signals described above. 
     In another optional embodiment, a confirmatory notification of the non-epileptic seizure may be issued at  2548 . The issuance at  2548  may be based on at least one of: an autonomic activity being an autonomic activity not indicative of an epileptic seizure, a neurologic activity being a neurologic activity not indicative of an epileptic seizure, a metabolic activity being a metabolic activity not indicative of an epileptic seizure, an endocrine activity being an endocrine activity not indicative of an epileptic seizure, or a stress marker activity being a stress marker activity not indicative of an epileptic seizure, wherein the activity on which the issuing is based is different from the activity on which the classifying is based. 
     Turning to  FIG.  26   , a flowchart depiction of a method of distinguishing an epileptic seizure from a non-epileptic seizure is presented. 
     A first index and a second index, each selected from a neurologic index, an autonomic index, a metabolic index, an endocrine index, or a tissue stress marker index are analyzed at  2610 . The indices may be any one or more of the indices described above. In one embodiment, the analysis may comprise determining whether the first index suggests the seizure is epileptic or non-epileptic; and determining whether the second index suggests the seizure is epileptic or non-epileptic. 
     Thereafter, a determination may be made at  2620  as to whether the analysis at  2610  indicates (e.g., by matching signatures, features, values, or characteristics of indices belonging to the same class, or by cross-referencing signatures, features, values, or characteristics of indices belonging to different classes) an epileptic event or a non-epileptic event. “Indicating” here does not refer a 100% match or perfect fit/correspondence to the signature, value or characteristic. Rather, as used herein, the match is to whichever of the epileptic signature or features or the non-epileptic signature is closer to the analysis made at  2610 . 
     At least one further action may then be taken based on the analysis at  2610 . The at least one further action may be selected from: issuing at  2632  a notification that the seizure is non-epileptic, based upon the analysis of the first and second index indicating that the seizure is non-epileptic; issuing at  2642  a notification or warning that the seizure is epileptic, based upon the analysis of the first and second index indicating that the seizure is epileptic; administering at  2634  a therapy appropriate for a non-epileptic seizure, based upon the analysis indicating that the seizure is non-epileptic; administering at  2644  a therapy for an epileptic seizure, based upon the analysis indicating that the seizure is an epileptic seizure; or logging at  2656  at least one of the date of the seizure, the time of occurrence of the seizure, or the severity of the seizure, which may be desirable whether the seizure is epileptic or non-epileptic.  FIG.  27    presents a flowchart depiction of a method of distinguishing an epileptic seizure from a non-epileptic seizure. The method may comprise determining at  2710  a first index selected from a neurologic index, an autonomic index, a metabolic index, an endocrine index, or a tissue stress marker index based on body data of a patient. In one embodiment, the first index is an autonomic index selected from a cardiac index, a respiratory index, a temperature index, an ocular index (e.g., pupillary size, rate change and hippus), a chemical index (e.g., a concentration of a chemical in a body tissue), and a blood index. In one embodiment, the first index is a neurologic index selected from a kinetic index, a cognitive index, and a neurochemical index. 
     The first index may be compared to a reference value, as indicated at  2715 . Where the index crosses or exceeds the reference value, the first index may be used to trigger collection of additional body data and/or to determine additional body indices at  2720 . For example, a cardiac index (or an EEG, kinetic or endocrine index) may be used to trigger determination of either additional cardiac indices or of indices belonging to other classes (e.g., metabolic, neurologic, etc.). This may include collection of, e.g., a second, third, fourth, etc. index for use in determining whether the seizure is epileptic or non-epileptic. In some embodiment, each additional index may be triggered by some or all of the existing indices that have been determined. 
     The indices determined at  2710  and  2720  may be analyzed at  2725  to determine one or both of an epileptic signature,  2730  or a non-epileptic signature,  2740 . The term “signature” is used herein to encompass values, characteristics, and other properties of the indices that are indicative of epileptic seizures or non-epileptic seizures. 
     The latency between the onset and termination of abnormal electrical activity in the case of epileptic seizures and the first change from an interictal baseline value varies among the different indices. Similarly, the time required for an index to return to its baseline value may vary widely. For example, the onset of abnormal/convulsive motor activity and loss of consciousness occurs nearly simultaneously with the onset of abnormal generalized brain electrical activity, while oxygen desaturation may lag behind them by a few seconds and accumulation of lactic acid will not peak for a few minutes after the appearance of abnormal kinetic/convulsive activity. 
     Recovery of these indices to interictal reference value does not parallel the temporal sequence of changes from inter-ictal to ictal: Oxygen saturation will recover shortly after the cessation of convulsive active while recovery of consciousness and cognitive functions and resolution of the lactic acidosis will take upwards of 30 min, in a healthy subject. The application to this disclosure of microscopic, mesoscopic and macroscopic scales is appropriate and useful as they encompass the multifarious times required for the various indices to change from interictal to ictal and from ictal to post-ictal and finally to interictal. 
     As previously noted, differences in the planarity of patient motions may be useful in embodiments of the present disclosure to distinguish between epileptic and non-epileptic movements. In many cases, generalized epileptic movements are characterized by a high level of planarity. This is not to imply that epileptic movements are completely planar, but rather that such movements may be distinguished from movements in non-epileptic seizures by comparing the movements in terms of their degree of uni-planarity, with epileptic seizures being characterized by a significantly higher level of uni-planarity. In  FIG.  28 ( a ) , an accelerometer  2820  worn, for example, on a lower arm of a patient, may be used to determine a kinetic index or movement score that indicates the movement is generally planar. As seen in the side and top views, the arm movement occurs in a single plane. Although not fully shown, the movement may also include flexion and/or bending at the elbow, while still remaining substantially planar. 
     In  FIG.  28 ( b ) , in contract, as seen most clearly in the front and top views, non-epileptic seizures are typically characterized by occurring in a random, multiplanar way. A kinetic index characterizing the level of planarity of these movements would show a significantly different value from the largely planar movements characteristic of seizures and depicted in  FIG.  28 ( a ) . In embodiments of the present disclosure, accelerometer calculations of the planarity of the movement—either alone or in conjunction with other kinetic indices such as force, magnitude of acceleration, etc.—may be used to characterize a seizure as either epileptic or non-epileptic. 
     In one embodiment, a method of distinguishing a non-epileptic seizure from an epileptic seizure in a patient may include: detecting a seizure in a patient based on at least one first body signal of the patient selected from an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, and a tissue stress marker signal; analyzing at least one second body signal of the patient selected from an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, and a tissue stress marker signal; determining, based on the analyzing of the at least one second body signal, at least a first classification index comprising at least one of an epileptic seizure index and a non-epileptic seizure index; and/or classifying the seizure as one of a non-epileptic seizure or an epileptic seizure based on the at least a first classification index. 
     In another example, classifying the seizure as one of a non-epileptic seizure or an epileptic seizure comprises classifying the seizure as non-epileptic may be based on at least one of an epileptic seizure index reaching or exceeding a threshold indicative of an epileptic seizure, and/or a non-epileptic seizure index reaching or exceeding a threshold indicative of a non-epileptic seizure. Further, the at least one second body signal may include at least two body signals, each of said at least two body signals being selected from an autonomic signal, a neurologic signal, a metabolic signal, an endocrine signal, and a tissue stress marker signal. In addition, the at least a first classification index may be at least one index selected from: an SaO2 index indicating that the patient&#39;s blood oxygen saturation is above a reference value after the onset of a generalized motor activity, a CO2 index indicating that the patient CO2 blood concentration is below a reference CO2 blood concentration after the onset of a generalized motor activity, a pH index indicating that the pH of the patient&#39;s arterial blood is above a reference value after the onset of a generalized motor activity relative to a reference pH value, a pH index indicating the lack of a decrease in a pH value of said patient&#39;s arterial blood after the onset of a generalized motor activity relative to a reference value, a body temperature index indicating that the patient&#39;s body temperature is below a reference value after the onset of a generalized motor activity, a cardiac index remaining below a reference value following onset of generalized motor activity, an infrared index from a target portion of the patient&#39;s body remaining below a reference value after the onset of a generalized motor activity; and/or a skin resistance index from a target portion of the patient&#39;s body remaining outside the range of value of a resistance index indicative of a generalized tonic, clonic, or tonic-clonic epileptic seizure. In addition, the at least a first classification index may be at least one kinetic index indicative of at least one of: at least one of a repeating, periodic, or aperiodic crescendo-decrescendo pattern of a motor activity of said patient, a force of a motor activity that is outside epileptic seizure reference values; a range of motion of a motor activity of said patient that is outside a range indicative of an epileptic seizure, a velocity of a motor activity of said patient that is outside a range indicative of an epileptic seizure, a multi-directionality of a motor activity of said patient that is outside a range of an epileptic seizure, a multi-planarity of a motor activity of said patient that is outside a range indicative of an epileptic seizure, a frequency of a motor activity of said patient that is outside a frequency range of motor activity of an epileptic seizure; a phase asynchrony between a first and second homologous body portions in a patient without pre-existing motor deficit; at least one of a difference in amplitude, force, velocity and direction of movement between homologous first and second body portions in a patient without pre-existing motor deficit having bilateral movements; and/or a pelvic thrust or pelvic motor activity of said patient that is the most prominent body movement of said patient. In addition, the at least a first classification index may be a neurological index indicative of at least one of: a spontaneous or evoked cortical electrical signal not indicative of epileptic brain activity of said patient; and/or a videographic image signal that is not indicative of an epileptic motor activity of said patient. In addition, the at least a first classification index may be at least one of a metabolic index selected from: a lactic acid concentration in the patient&#39;s blood that remains below a reference concentration; a lactic acid concentration in the patient&#39;s blood indicative of a lack of lactic acidosis in said patient&#39;s blood after the onset of a generalized motor activity, relative to an inter-ictal lactic acid value, and/or a normal serum potassium concentration in a patient with metabolic acidosis after the onset of a generalized motor activity. In addition, the method may include: issuing a notification that the seizure is non-epileptic, based upon classifying said seizure as non-epileptic; logging at least one of the date of the non-epileptic seizure, the time of occurrence of the non-epileptic seizure, or the severity of the non-epileptic seizure; and/or administering a therapy for said non-epileptic seizure, based upon classifying said seizure as non-epileptic. In addition, the method may include determining at least a second classification index selected from: an autonomic index having a value or characteristic that is not indicative of an epileptic seizure, a neurologic index having a value or characteristic that is not indicative of an epileptic seizure, a metabolic index having a value or characteristic that is not indicative of an epileptic seizure, an endocrine index having a value or characteristic that is not indicative of an epileptic seizure, and/or a tissue stress marker index having a value or characteristic that is not indicative of an epileptic seizure, where classifying the seizure as a non-epileptic seizure is based at least in part upon both the first classification index and said second classification index. In addition, classifying the seizure as a non-epileptic seizure based on the at least a first classification index may include classifying the seizure as a non-epileptic seizure only if the at least a first classification index is within non-epileptic seizure reference values. 
     In another embodiment, a medical device system may include: at least one sensor configured to receive at least one of an autonomic signal indicative of an autonomic activity of a patient, a neurologic signal indicative of a neurologic activity of said patient, a metabolic signal indicative of a metabolic activity of said patient, an endocrine signal indicative of an endocrine activity of said patient, or a tissue stress marker signal indicative of a tissue stress marker activity of said patient; a seizure detection unit configured to detect a seizure in a patient based on said at least one autonomic, neurologic, metabolic, endocrine, or tissue stress marker signal; at least one classification index determination unit configured to determine at least a first classification index selected from an autonomic index, a neurologic index, a metabolic index, an endocrine index, and a tissue stress marker index; and/or a seizure classification unit configured to classify said epileptic seizure as one of an epileptic seizure and a non-epileptic seizure based at least in part on said at least a first classification index. 
     In addition, the classification index determination unit is configured to determine at least one kinetic index indicating one of the onset or a lack of generalized motor activity; and at least one autonomic index selected from at least one of: an SaO2 index indicating that the patient&#39;s blood oxygen saturation remains above a reference value after said kinetic index indicates the onset of a generalized motor activity, a CO2 index indicating that the patient&#39;s CO2 blood concentration remains below a reference CO2 blood concentration after said kinetic index indicates the onset of a generalized motor activity, a pH index indicating that the pH of the patient&#39;s arterial blood remains above a reference value after said kinetic index indicates the onset of a generalized motor activity relative to a reference pH value, a pH index indicating the lack of a decrease in a pH value of said patient&#39;s arterial blood after said kinetic index indicates the onset of a generalized motor activity relative to a reference value; a body temperature index indicating that the patient&#39;s body temperature remains below a reference value after said kinetic index indicates the onset of a generalized motor activity, a cardiac index indicating that cardiac indices are below a reference value after said kinetic index indicates the onset of generalized motor activity, and/or an infrared index indicating that infrared radiation from a target portion of the patient&#39;s body remains below a reference value after said kinetic index indicates the onset of a generalized motor activity. In addition, a first classification index is a neurological index comprising a kinetic index indicative of at least one of: a direction of movement of a target portion of the patient&#39;s body in one plane, indicative of an epileptic seizure; a force of a motor activity of said patient that exceeds an epileptic seizure reference value, a range of motion of a motor activity of said patient that is within a range indicative of an epileptic seizure, a velocity of a movement of a target portion of the patient&#39;s body that is indicative of an epileptic seizure, a degree of synchronization or symmetry between movement of a right portion of the patient&#39;s body and a left portion of the patient&#39;s body indicative of an epileptic seizure; a frequency of a movement of said patient that is indicative of an epileptic seizure; a joint position that is indicative of an epileptic seizure; a body posture that is indicative of an epileptic seizure; a repeating, periodic or aperiodic crescendo-decrescendo pattern of a motor activity of said patient characteristic of a non-epileptic seizure, a velocity of a motor activity of said patient that is outside a range indicative of an epileptic seizure, a range of motion of a motor activity of said patient that is indicative of a non-epileptic seizure, a velocity of a movement of a target portion of the patient&#39;s body that is indicative of a non-epileptic seizure; a force of a motor activity that is indicative of a non-epileptic seizure; a multi-directionality of a motor activity of said patient that is indicative of a non-epileptic seizure, a multi-planarity of a motor activity of said patient that is indicative of a non-epileptic seizure, a frequency of a movement of a target portion of the patient&#39;s body that is indicative of a non-epileptic seizure; a degree of synchronization or symmetry between movement of a right portion of the patient&#39;s body and a left portion of the patient&#39;s body indicative of a non-epileptic seizure; a joint position that is indicative of an epileptic seizure; a body posture that is indicative of an epileptic seizure; and/or a pelvic thrust or pelvic motor activity of said patient that is the most prominent body movement of said patient and is indicative of a non-epileptic seizure. In addition, the at least a first classification index is at least one metabolic index selected from: a lactic acid concentration in the patient&#39;s blood that remains below a reference concentration; a lactic acid concentration in the patient&#39;s blood indicative of a lack of lactic acidosis in said patient&#39;s blood after the onset of a generalized motor activity, relative to an inter-ictal lactic acid value, and a normal potassium concentration in a patient with metabolic acidosis after the onset of a generalized motor activity. In addition, the medical device system may include a therapy unit configured to provide at least one response to said classification unit classifying a detected seizure as a non-epileptic seizure, wherein said at least one response is selected from administering a therapy appropriate for a non-epileptic seizure, discontinuing delivery of a therapy for epileptic seizures, preventing delivery of a therapy for epileptic seizures, warning against delivery of a therapy for epileptic seizure, cancelling a warning for an epileptic seizure; providing a notification that the seizure is a non-epileptic seizure; and/or logging the seizure as non-epileptic along with at least one of the date, time of occurrence, duration, or intensity of the non-epileptic seizure. In addition, the medical device system may include a notification unit configured to notify at least one of said patient, a caregiver, or a medical professional that said seizure is non-epileptic, based upon said classification unit classifying a detected seizure as a non-epileptic seizure. 
     In another embodiment, a method of distinguishing an epileptic seizure from a non-epileptic seizure may include: identifying an unclassified seizure; determining a first seizure classification index having an index class selected from a neurologic index class, an autonomic index class, a motor index class, a tissue stress marker index class, or a metabolic index class; determining a second seizure classification index having an index class selected from a neurologic index class, an autonomic index class, a motor index class, a tissue stress marker index class, or a metabolic index class; classifying said seizure as one of an epileptic seizure or a non-epileptic seizure based on both said first and said second seizure classification indices; and/or taking at least one further action based on said classifying, wherein said at least one further action is selected from: issuing a notification that the seizure is non-epileptic; issuing a notification that the seizure is epileptic; administering a therapy for a non-epileptic seizure; administering a therapy for an epileptic seizure; or logging at least one of whether the seizure is an epileptic or non-epileptic seizure and at least one of the date of the seizure, the time of occurrence of the seizure, the severity of the seizure, the time elapsed from a previous seizure and the frequency per unit time of the same type of seizure. In addition, the classifying may include determining if said first and second seizure classification indices match one of a signature of an epileptic seizure, a pattern of an epileptic seizure, a characteristic of an epileptic seizures, a signature of a non-epileptic seizure, a pattern of a non-epileptic seizure, and a characteristic of a non-epileptic seizure. 
     In another embodiment, a method may include: receiving a kinetic signal from at least one target of the patient&#39;s body; determining at least one kinetic index based on said kinetic signal; identifying an unclassified seizure based on the at least one kinetic index; receiving at least one of a non-kinetic neurologic index and an autonomic index; and/or classifying the seizure as an epileptic seizure or non-epileptic seizure based on the at least one of a non-kinetic neurologic index and an autonomic index. 
     The above methods may be performed by a non-transitive computer readable program storage device encoded with instructions that, when executed by a computer, perform the method described herein. 
     All of the methods and apparatuses disclosed and claimed herein may be made and executed without undue experimentation in light of the present disclosure. While the methods and apparatus of this disclosure have been described in terms of particular embodiments, it will be apparent to those skilled in the art that variations may be applied to the methods and apparatus and in the steps, or in the sequence of steps, of the method described herein without departing from the concept, spirit, and scope of the disclosure, as defined by the appended claims. It should be especially apparent that the principles of the disclosure may be applied to selected cranial nerves other than, or in addition to, the vagus nerve to achieve particular results in treating patients having epilepsy, depression, or other medical conditions. 
     The particular embodiments disclosed above are illustrative only as the disclosure may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown other than as described in the claims below. It is, therefore, evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the disclosure. Accordingly, the protection sought herein is as set forth in the claims below. 
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