Patent Abstract:
A system and method of neuromodulation adjunct (add-on) therapy for atrial fibrillation, refractory hypertension, and inappropriate sinus tachycardia comprises an implantable lead-receiver and an external stimulator. Neuromodulation is performed using pulsed electrical stimulation. The external stimulator contains a power source, controlling circuitry, a primary coil, and predetermined programs. The primary coil of the external stimulator inductively transfers electrical signals to the implanted lead-receiver, which is also in electrical contact with a vagus nerve. The external stimulator emits electrical pulses to stimulate the vagus nerve according to a predetermined program. In a second mode of operation, an operator may manually override the predetermined sequence of stimulation. The external stimulator may also be equipped with a telecommunications module to control the predetermined programs remotely.

Full Description:
This is a Continuation-in-Part application of Ser. No. 09/727,570 filed Nov. 30, 2000, now U.S. Pat. No. 6,356,788 which is a Continuation-in-Part of Ser. No. 09/178,060 filed Oct. 26, 1998, now U.S. Pat. No. 6,205,359. Priority is claimed from these applications, and the prior applications being incorporated herein by reference. Further, this application is related to the following applications filed Apr. 17, 2001, entitled 
     a) Apparatus and method for adjunct (add-on) treatment of coma and traumatic brain injury with neuromodulation using an external stimulator. 
     b) Apparatus and method for adjunct (add-on) treatment of Diabetes by neuromodulation with an external stimulator. 
     c) Apparatus and method for neuromodulation therapy for obesity and compulsive eating disorders using an implantable lead-receiver and an external stimulator. 
    
    
     FIELD OF INVENTION 
     This invention relates generally to medical device system for therapy of cardiovascular disorders, more specifically to adjunct (add-on) treatment of certain cardiovascular disorders by neuromodulation of a selected nerve or nerve bundle, utilizing an implanted lead-receiver and an external stimulator. 
     BACKGROUND 
     Electrical stimulation of the vagus nerve, and the profound effects of electrical stimulation of the vagus nerve on the central nervous system (CNS) activity extends back to the 1930&#39;s. Medical research has furthered our understanding of the role of nervous control of body functions. In the human body there are two vagal nerves (VN), the right VN and the left VN. The innervation of the right and left vagus nerves is different. The innervation of the right vagus nerve is predominately to the sinus (SA) node of the heart, and its stimulation results in slowing of the sinus rate. The cardiac innervation of the left vagus nerve is predominately to the AV node, and its stimulation results in delaying the conduction through the atrioventricular (AV) node. 
     The system and method of the current invention utilizes an implanted lead-receiver, and an external stimulator for adjunct (add-on) treatment or alleviation of symptoms for certain cardiovascular disorders, such as atrial fibrillation, inappropriate sinus tachycardia, and refractory hypertension. The system of this invention delivers neuromodulation pulses according to a limited number of predetermined programs, which are stored in the external stimulator, and can be activated by pressing a button. The predetermined programs contain unique combinations of pulse amplitude, pulse width, frequency of pulses, on-time and off-time. In one embodiment, the system contains a telecommunications module within the external stimulator. In such an embodiment, the external stimulator can be controlled remotely, via wireless communication. 
     Nervous Control of the Heart 
     FIGS. 1A and 1B are simplified schematic diagrams showing nervous control of cardiovascular function. As shown in FIG. 1A, The cardiovascular (CV) center  222  located in the medullary center in the brain influences and controls cardiovascular functions such as heart rate, contractactility, and blood vessels. The cardiovascular center  222  in the brain  220 , receives input from the higher centers in the brain  224  and from receptors  226  such as baroreceptors and propriocepters. The cardiovascular (CV) center  222  of the brain  220  controls the effector organs in the body by increasing the frequency of nerve impulses. The CV center  222  decreases heart rate by parasympathetic stimulation via efferent impulses carried by the 10 th  cranial nerve or the vagus nerve. The CV center can also increase heart rate and cause vasoconstriction via sympathetic stimulation. Thus, the CV center  222  in the brain  220  exerts its control via the opposing actions of the sympathetic and parasympathetic stimulation. 
     Further, as shown in FIG. 1B baroreceptors located in the aortic arch  262 , and in the carotid sinus  260  send blood pressure information to the cardiovascular (CV) center  222  located in Medulla Oblongata  240  of the brain  220 . This information is carried by afferent fibers of Glossopharyngeal Nerve  55  and Vagus Nerve  54 . 
     Additionally of interest to the current patent application, the efferent fibers of the right vagus nerve predominately innervate the sinus node  252  and stimulation of these fibers will be used to control (slow-down) heart rate for Inappropriate Sinus Tachycardia Syndrome. The efferent fibers from the left vagus nerve predominately innervate the A-V node  256  of heart, and efferent stimulation of the left vagus nerve  54  will be used for controlling heart rate as adjunct (add-on) therapy for atrial fibrillation in this invention. 
     Atrial Fibrillation 
     Atrial fibrillation (AF) is both the most common sustained arrhythmia encountered in clinical practice, and the most common arrhythmia-related cause of hospital admission. Although health utilization costs related to AF are significant, little is known about its incidence and prevalence. Estimates indicate that 2.2 million Americans have AF and that 160,000 new cases are diagnosed each year. The incidence is higher in older adults, whose risk for developing AF is associated with advanced age. During atrial fibrillation, the atria of the heart discharge at a rate between 350 and 600 per minute. The ventricular rate during atrial fibrillation is dependent on the conducting ability of the AV node which is itself influenced by the autonomic system. Atrioventricular conduction will be enhanced by sympathetic nervous system activity and depressed by high vagal tone. In patients with normal atrioventricular conduction, the ventricular rate ranges from 100 to 180 beats per minute. 
     AF is characterized by a rapid, irregular ventricular rate, the irregularity being in rhythm and arterial pulse pressure amplitude. This can occur to such an extent that multiple pulse deficits (absence of an arterial pulse following ventricular excitation) are present. Current therapies are designed to extinguish the fibrillation activity or to control or abolish atrioventricular (AV) conduction. 
     Thus, the two components of acute management of patients with atrial fibrillation include control of ventricular rate and conversion to sinus rhythm. The traditional first step in acute treatment of patients with symptomatic AF who have a rapid ventricular response is to slow the ventricular rate. The first line of defense is usually drugs such as Digoxin, Metoprolol, Esmolol and verapamil etc. Drugs typically have side effects, and some patients may be refractory to drugs. Non-pharmacologic adjunct therapy such as nerve stimulation offers an alternative mode of therapy. 
     In a paper published by Van den Berg et al in the Aug. 19, 1997 issue of Circulation, the authors showed that heart rate variability in patients with atrial fibrillation is related to vagal tone. In an abstract published at the American Heart Association meeting, by Tabata et al from the Cleveland Clinic Foundation, the authors presented the results of heart rate reduction by vagus nerve stimulation on left ventricular systolic function. Their data showed a dramatic decrease in ejection fraction and stroke volume as atrial fibrillation was induced. Then, while still in atrial fibrillation, a return towards baseline of both ejection fraction and stroke volume, with vagus nerve stimulation of the atrio-ventricular (AV) node. 
     Thus, with the system of the present invention where an implanted lead-receiver is implanted within the body, and a stimulator with predetermined programs is external to the body, would be useful. The implantable and external components are inductively coupled. With turning the stimulator “on”, the symptoms of atrial fibrillation would be alleviated by decreasing the heart rate and increasing the stroke volume and ejection fraction. 
     Inappropriate Sinus Tachycardia 
     Inappropriate Sinus Tachycardia is a clinical syndrome with a relative or absolute increase of heart rate at rest or an exaggerated heart rate response inappropriate to the degree of physical or emotional stress. On the surface electrocardiogram, P-wave morphology during tachycardia is nearly identical to the P-wave morphology during normal sinus rhythm. The clinical manifestations of this syndrome complex are diverse. Young women make up most of the patient population, and clinical symptoms can range from intermittent palpitations to multiple system complaints. 
     Clinical signs and symptoms associated with inappropriate sinus tachycardia are often refractory to medical therapy with drugs. Drugs, such as β-adrenergic blockers or calcium channel blockers, usually either are not effective in controlling symptoms or are poorly tolerated. It is hypothesized that the inappropriate sinus tachycardia response in these patients is due to underlying autonomic dysregulation. The electrophysiologic findings are consistent with the diagnosis of inappropriate sinus tachycardia in the following circumstances: Gradual increase (warm-up) and decrease (cool-down) in heart rate during initiation and termination of isoproterenol infusion, consistent with an automatic mechanism of sinus node function; Surface P-wave morphology similar to that observed during sinus rhythm; and Earliest endocardial activation along the crista terminalis estimated from fluoroscopic images. Clinically, Inappropriate Sinus Tachycardia is divided into 2 subsets, a) postural orthostatic tachycardia syndrome (POTS), and b) non-postural orthostatic tachycardia syndrome (non-POTS). The second category, non-POTS would be alleviated by decreasing the heart rate by the system and method of the current invention. 
     Hypertension 
     Blood pressure (BP) is the hydrostatic pressure exerted by blood on the walls of a blood vessel. The arterial blood pressure is determined by physical and physiological factors. Mean arterial pressure is the pressure in the large arteries, averaged over time. Systolic and diastolic arterial pressures are then considered as the upper and lower limits of periodic oscillations about this mean pressure. The pressure of the blood in arteries and arterioles reaches a peak, called systolic pressure, with each contraction of the heart and then gradually decreases to a minimum, the diastolic pressure before the next contraction. Blood pressure is always expressed as two figures, for example, 120/80 in healthy young adults, representing respectively the systolic and diastolic pressures in millimeters of mercury (mm Hg). 
     About 20% of the adult population is afflicted with hypertension, the most common single disorder seen in the office of an internist. It is a major risk factor for coronary artery disease and a common cause of heart failure, kidney failure, stroke, and blindness. For adults over 50 years of age, the diagnosis is usually based on repeated resting levels of greater than 160/95 mm Hg in adults over 50 years of age. It is more common among males than females and far more common among blacks than whites. In refractory hypertension, the BP stays at these levels despite treatment with at least two anti-hypertensive drugs for a period of time that is normally adequate to relieve the symptoms. 
     There is considerable evidence that the nervous system is much involved in the regulation of arterial pressure. For example, hypertension can be induced in experimental animals by transection of arterial baroceptor nerves, by lesion of the nucleus tractus solitarius (NTS). For refractory hypertension where pharmacologic therapy either is not effective, or is not tolerated because of the side effects of drugs, non-pharmacologic therapy such as afferent nerve stimulation may be another alternative for adjunct (add-on) therapy. The neuromodulation of the vagus nerve is designed to control the patient&#39;s blood pressure, in the system and method of this invention. 
     Neuromodulation 
     One of the fundamental features of the nervous system is its ability to generate and conduct electrical impulses. These can take the form of action potentials, which is defined as a single electrical impulse passing down an axon, and is shown schematically in FIG.  2 . The top portion of the figure shows conduction over mylinated axon (fiber) and the bottom portion shows conduction over nonmylinated axon (fiber). These electrical signals will travel along the nerve fibers. 
     The nerve impulse (or action potential) is an “all or nothing” phenomenon. That is to say, once the threshold stimulus intensity is reached an action potential  7  will be generated. This is shown schematically in FIG.  3 . The bottom portion of the figure shows a train of action potentials. 
     Most nerves in the human body are composed of thousands of fibers of different sizes. This is shown schematically in FIG.  4 . The different sizes of nerve fibers, which carry signals to and from the brain, are designated by groups A, B, and C. The vagus nerve, for example, may have approximately 100,000 fibers of the three different types, each carrying signals. Each axon or fiber of that nerve conducts only in one direction, in normal circumstances. 
     In a cross section of peripheral nerve it is seen that the diameter of individual fibers vary substantially. The largest nerve fibers are approximately 20 μm in diameter and are heavily myelinated (i.e., have a myelin sheath, constituting a substance largely composed of fat), whereas the smallest nerve fibers are less than 1 μm in diameter and are unmyelinated. As shown in FIG. 5, when the distal part of a nerve is electrically stimulated, a compound action potential is recorded by an electrode located more proximally. A compound action potential contains several peaks or waves of activity that represent the summated response of multiple fibers having similar conduction velocities. The waves in a compound action potential represent different types of nerve fibers that are classified into corresponding functional categories as shown in the table below, 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Conduction 
                 Fiber 
                   
               
               
                   
                 Fiber 
                 Velocity 
                 Diameter 
                   
               
               
                   
                 Type 
                 (m/sec) 
                 (μm) 
                 Myelination 
               
               
                   
                   
               
             
             
               
                   
                 A Fibers 
                   
                   
                   
               
               
                   
                 Alpha 
                  70-120 
                 12-20 
                 Yes 
               
               
                   
                 Beta 
                 40-70 
                  5-12 
                 Yes 
               
               
                   
                 Gamma 
                 10-50 
                 3-6 
                 Yes 
               
               
                   
                 Delta 
                  6-30 
                 2-5 
                 Yes 
               
               
                   
                 B Fibers 
                  5-15 
                 &lt;3 
                 Yes 
               
               
                   
                 C Fibers 
                 0.5-2.0 
                 0.4-1.2 
                 No 
               
               
                   
                   
               
             
          
         
       
     
     The diameters of group A and group B fibers include the thickness of the myelin sheaths. Group A is further subdivided into alpha, beta, gamma, and delta fibers in decreasing order of size. There is some overlapping of the diameters of the A, B, and C groups because physiological properties, especially in the form of the action potential, are taken into consideration when defining the groups. The smallest fibers (group C) are unmyelinated and have the slowest conduction rate, whereas the myelinated fibers of group B and group A exhibit rates of conduction that progressively increase with diameter. 
     Compared to unmyelinated fibers, myelinated fibers are typically larger, conduct faster, have very low stimulation thresholds, and exhibit a particular strength-duration curve or respond to a specific pulse width versus amplitude for stimulation. The A and B fibers can be stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (μs), for example. The A fiber conducts slightly faster than the B fiber and has a slightly lower threshold. The C fibers are very small, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring a wider pulse width (300-1,000 μs) and a higher amplitude for activation. Because of their very slow conduction, C fibers would not be highly responsive to rapid stimulation. Selective stimulation of only A and B fibers is readily accomplished. The requirement of a larger and wider pulse to stimulate the C fibers, however, makes selective stimulation of only C fibers, to the exclusion of the A and B fibers, virtually unachievable inasmuch as the large signal will tend to activate the A and B fibers to some extent as well. 
     The vagus nerve is composed of somatic and visceral afferents and efferents. Usually, nerve stimulation activates signals in both directions (bi-directionally). It is possible however, through the use of special electrodes and waveforms, to selectively stimulate a nerve in one direction only (unidirectionally). The vast majority of vagus nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the skull. The central projections terminate largely in the nucleus of the solitary tract, which sends fibers to various regions of the brain (e.g., the thalamus, hypothalamus and amygdala). 
     Vagus nerve stimulation is a means of directly affecting central function. As shown in FIG. 6, cranial nerves have both afferent pathway  19  (inward conducting nerve fibers which convey impulses toward the brain) and efferent pathway  21  (outward conducting nerve fibers which convey impulses to an effector). The vagus nerve  54  is composed of 80% afferent sensory fibers carrying information to the brain from the head, neck, thorax, and abdomen. The sensory afferent cell bodies of the vagus reside in the nodose ganglion and relay information to the nucleus tractus solitarius (NTS). 
     FIG. 7 shows the nerve fibers traveling through the spinothalamic tract to the brain. The afferent fibers project primarily to the nucleus of the solitary tract (shown schematically in FIG. 8) which extends throughout the length of the medulla oblongata. A small number of fibers pass directly to the spinal trigeminal nucleus and the reticular formation. As shown in FIG. 8, the nucleus of the solitary tract has widespread projection to cerebral cortex, basal forebrain, thalamus, hypothalamus, amygdala, hippocampus, dorsal raphe, and cerebellum. 
     In summary, neuromodulation of the vagal nerve fibers exert their influence on refractory hypertension via Afferent stimulation. And, neuromodulation of the vagal nerve fibers exert their influence on atrial fibrillation and in Inappropriate Sinus Tachycardia Syndrome via Efferent stimulation of the left and right vagus nerve respectively. 
     PRIOR ART 
     One type of non-pharmacologic, medical device therapy for cardiovascular disorders is generally directed to the use of an implantable lead and an implantable pulse generator technology or “cardiac-pacemaker like” technology. 
     U.S. Pat. No. 5,707,400 (Terry et al) is generally directed to using an implantable device like a “cardiac pacemaker” for treating refractory hypertension by nerve stimulation. The implanted pulse generator of this patent is programmed by an external personnel computer based programmer with a modified wand, shown in FIG.  9 A. Each parameter is independently programmable. Therefore, millions of different combinations of programs are possible. In the current patent application, a limited number of programs are pre-selected. This patent neither anticipates practical problems with an inductively coupled system, nor suggests any solutions for the same. 
     U.S. Pat. No. 5,690,681 (Geddes et al) is directed to a closed-loop implanted vagal stimulation apparatus for control of ventricular rate during atrial fibrillation. In this patent, implanted cardiac leads, and implanted pulse generator are used for sensing signals from atrial and ventricular electrograms and an adaptive control system (controller) is used for closing the loop for output stimulation to the vagus nerve. The communication to the fully implanted system of this patent is via an external programmer. In the current patent application, the patient acts as the feedback loop. 
     U.S. Pat. No. 5,916,239 (Geddes et al) is directed to apparatus and method for automatically and continuously adjusting the frequency of nerve stimulator as a function of signals obtained via atrial and ventricular electrograms. 
     U.S. Pat. No. 5,700,282 (Zabara) is directed to simultaneously stimulating vagus efferents and cardiac sympathetic nerve efferents. The rationale being to employ the brain&#39;s natural mechanisms for heart rhythm control. 
     U.S. Pat. No. 5,522,854 (Ideker et al) is generally directed to monitoring parasympathetic and sympathetic nerve activity and stimulating the afferent nerves with an implanted device, with the goal of preventing arryhthmias. 
     U.S. Pat. No. 5,199,428 (Obel et al) is directed to an implantable electrical nerve stimulator/pacemaker for decreasing cardiac workload for myocardial ischemia. The methodology involves stimulating the carotid sinus nerves or the stellate gantglion. 
     U.S. Pat. No. 5,330,507 (Schwartz) is generally directed to stimulating right or left vagus nerve with an implanted device which is an extension of a dual chamber cardiac pacemaker. The system is shown in FIG.  9 B. 
     U.S. Pat. No. 3,796,221 (Hagfors) is directed to controlling the amplitude, duration and frequency of electrical stimulation applied from an externally located transmitter to an implanted receiver by inductively coupling. Electrical circuitry is schematically illustrated for compensating for the variability in the amplitude of the electrical signal available to the receiver because of the shifting of the relative positions of the transmitter-receiver pair. By highlighting the difficulty of delivering consistent pulses, this patent points away from applications such as the current application, where consistent therapy needs to be continuously sustained over a prolonged period of time. The methodology disclosed is focused on circuitry within the receiver, which would not be sufficient when the transmitting coil and receiving coil assume significantly different orientation, which is likely in the current application. The present invention discloses a novel approach for this problem. 
     U.S. Pat. Nos. 4,702,254, 4,867,164 and 5,025,807 (Zabara) generally disclose animal research and experimentation related to epilepsy and the like and are directed to stimulating the vagas nerve by using “pacemaker-like” technology, such as an implantable pulse generator. The pacemaker technology concept consists of a stimulating lead connected to a pulse generator (containing the circuitry and DC power source) implanted subcutaneously or submuscularly, somewhere in the pectoral or axillary region, and programming with an external personal computer (PC) based programmer. Once the pulse generator is programmed for the patient, the fully functional circuitry and power source are fully implanted within the patient&#39;s body. In such a system, when the battery is depleted, a surgical procedure is required to disconnect and replace the entire pulse generator (circuitry and power lo source). These patents neither anticipate practical problems of an inductively coupled system, nor suggest solutions to the same for an inductively coupled system for neuromodulation therapy. 
     U.S. Pat. No. 5,304,206 (Baker, Jr. et al) is directed to activation techniques for implanted medical stimulators. The system uses either a magnet to activate the reed switch in the device, or tapping which acts through the piezoelectric sensor mounted on the case of the implanted device, or a combination of magnet use and tapping sequence. 
     U.S. Pat. No. 4,573,481 (Bullara) is directed to an implantable helical electrode assembly configured to fit around a nerve. The individual flexible ribbon electrodes are each partially embedded in a portion of the peripheral surface of a helically formed dielectric support matrix. 
     U.S. Pat. No. 3,760,812 (Timm et al.) discloses nerve stimulation electrodes that include a pair of parallel spaced apart helically wound conductors maintained in this configuration. 
     U.S. Pat. No. 4,979,511 (Terry) discloses a flexible, helical electrode structure with an improved connector for attaching the lead wires to the nerve bundle to minimize damage. 
     Apparatus and method for neuromodulation, of the current application has several advantages over the prior art implantable pulse generators. The external stimulator described here can be manufactured at a fraction of the cost of an implantable pulse generator. The stimulation therapy can be freely applied without consideration of battery depletion, and surgical replacement of the pulse generator is avoided. The programming is much simpler, and can be adjusted by the patient within certain limits for patient comfort. And, the implanted hardware is much smaller. 
     SUMMARY OF THE INVENTION 
     The system and method of the current invention also overcomes many of the disadvantages of the prior art by simplifying the implant and taking the programmability into the external stimulator. Further, the programmability of the external stimulator can be controlled remotely, via the wireless medium, as described in a co-pending application. The system and method of this invention uses the patient as his own feedback loop. Once the therapy is prescribed by the physician, the patient can receive the therapy as needed based on symptoms, and the patient can adjust the stimulation within prescribed limits for his/her own comfort. 
     The stimulation is to the right vagus nerve for controlling Inappropriate Sinus Tachycardia, and to the left vagus nerve for adjunct (add-on) treatment of atrial fibrillation and refractory hypertension. 
     The system consists of an implantable lead-receiver containing passive circuitry, electrodes, and a coil for coupling to the external stimulator. The external stimulator, which may be worn on a belt or carried in a pocket, contains electronic circuitry, power source, predetermined programs, and primary coil. The external primary coil and subcutaneous secondary coil are inductively coupled. The patient may selectively activate stimulation corresponding to symptoms, or leave the stimulation on according to predetermined program. 
     In one aspect of the invention, the pulse generator contains a limited number of predetermined programs packaged into the stimulator, which can be accessed directly without a programmer. The limited number of programs can be any number of programs even as many as 100 programs, and such a number is considered within the scope of this invention. For patient convenience, less than 20 programs are currently incorporated. 
     In another feature of the invention, the system provides for proximity sensing means between the primary (external) and secondary (implanted) coils. Utilizing current technology, the physical size of the implantable lead-receiver has become relatively small. However, it is essential that the primary (external) and secondary (implanted) coils be positioned appropriately with respect to each other. The sensor technology incorporated in the present invention aids in the optimal placement of the external coil relative to a previously implanted subcutaneous coil. This is accomplished through a combination of external and implantable or internal components. 
     In another feature of the invention, the external stimulator has predetermined programs built into the stimulator, as well as, a manual “on” and “off” button. Each of these programs has a unique combination of pulse amplitude, pulse width, frequency of stimulation, on-time and off-time. After the therapy has been initiated by the physician, the patient has a certain amount of flexibility in adjusting the intensity of the therapy (level of stimulation). The patient has the flexibility to decrease (or increase) the level of stimulation (within limits). The manual “on” button gives the patient flexibility to immediately start the stimulating pattern at any time. Of the pre-determined programs, patients do not have access to at least one of the programs, which can be activated only by the physician, or an appropriate person. 
    
    
     Various other features, objects and advantages of the invention will be made apparent from the following description taken together with the drawings. 
     BRIEF DESCRIPTION OF THE DRAWINGS 
     For the purpose of illustrating the invention, there are shown in accompanying drawing forms which are presently preferred, it being understood that the invention is not intended to be limited to the precise arrangement and instrumentalities shown. 
     FIG. 1A is a schematic diagram showing inputs and outputs to the cardiovascular center in the brain. 
     FIG. 1B is a simplified schematic diagram showing nervous control of the heart. 
     FIG. 2 is a schematic diagram of myelinated and nonmyelinated axon. 
     FIG. 3 is a schematic diagram of a single nerve impulse and a train of nerve impulses. 
     FIG. 4 is a diagram of the structure of a peripheral nerve. 
     FIG. 5 is a diagram showing recordings of compound action potentials. 
     FIG. 6 is a schematic diagram of brain showing afferent and efferent pathways. 
     FIG. 7 is a schematic diagram showing pathways along the spinothalamic tract. 
     FIG. 8 is a schematic diagram showing relationship of Nucleus of the Solitary Track and how it relays information to other parts of the brain. 
     FIG. 9A is a prior art figure showing an implantable neurocybernetic prosthesis, and a personnel computer based programmer along with an external sensor. 
     FIG. 9B is a diagram of another prior art pulse generator. 
     FIG. 10 is a schematic diagram of a patient with an implanted lead-receiver and an external stimulator with predetermined programs. 
     FIG. 11A is a diagram showing the implanted lead-receiver in contact with the vagus nerve at the distal end. 
     FIG. 11B is a diagram showing two coils along their axis in a configuration such that the mutual inductance would be maximum. 
     FIG. 12 shows external stimulator coupled to the implanted unit. 
     FIG. 13 is a top-level block diagram of the external stimulator and proximity sensing mechanism. 
     FIG. 14 is a diagram showing the proximity sensor circuitry. 
     FIG. 15 is a block diagram of programmable array logic interfaced to the programming station. 
     FIG. 16 is a block diagram showing details of programmable logic array unit. 
     FIG. 17 is a diagram showing details of the interface between the programmable array logic and interface unit. 
     FIG. 18 is a diagram showing the circuitry of the pulse generator. 
     FIG. 19 shows the pulse train to be transmitted to the implant unit. 
     FIG. 20 shows the ramp-up and ramp-down characteristic of the pulse train. 
     FIG. 21 is an overall schematic diagram of the external stimulator, showing wireless communication. 
     FIG. 22 is a schematic diagram showing application of Wireless Application Protocol (WAP). 
     FIG. 23A is a diagram of the implanted lead receiver. 
     FIG. 23B is a schematic diagram of the proximal end of the lead receiver implanted lead receiver. 
     FIG. 24 is a schematic of the passive circuitry in the implanted lead-receiver. 
     FIG. 25A is a schematic of an alternative embodiment of the implanted lead-receiver. 
     FIG. 25B is another alternative embodiment of the implanted lead-receiver. 
     FIG. 26 is a diagram of a hydrogel electrode. 
     FIG. 27 is a diagram of a lead-receiver utilizing a fiber electrode at the distal end. 
     FIG. 28 is a diagram of a fiber electrode wrapped around Dacron polyester. 
     FIG. 29 is a diagram of a lead-receiver with a spiral electrode. 
     FIG. 30 is a diagram of an electrode embedded in tissue. 
     FIG. 31 is a diagram of an electrode containing steroid drug inside. 
     FIG. 32 is a diagram of an electrode containing steroid drug in a silicone collar at the base of electrode. 
     FIG. 33 is a diagram of an electrode with steroid drug coated on the surface of the electrode. 
     FIG. 34 is a diagram of cross sections of implantable lead-receiver body showing different lumens. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following description is of the current embodiment for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be determined with reference to the claims. 
     The system and method of neuromodulation therapy of this invention consists of delivering pulsed electrical stimulation, using an implanted lead-receiver and an external stimulator with predetermined programs of stimulation. The implanted lead-receiver and external stimulator are inductively coupled. The predetermined programs contain unique combination of stimulation parameters for neuromodulation, and differ in the aggressiveness of the therapy. Some of the predetermined programs are “locked-out” to the patient or caretaker, and can be accessed and controlled by the physician only. 
     Referring now to FIG. 10, which shows a schematic diagram of a patient  32  with an implantable lead-receiver  34  and an external stimulator  42 , clipped on to a belt  44  in this case. The external stimulator  42 , may alternatively be placed in a pocket or other carrying device. The primary (external) coil  46  of the external stimulator  42  is inductively coupled to the secondary (implanted) coil  48  of the implanted lead-receiver  34 . As shown in FIG. 11A, the implantable lead-receiver  34  has circuitry at the proximal end  49 , and has two stimulating electrodes at the distal end  61 , 62 . The negative electrode (cathode)  61  is positioned towards the brain and the positive electrode (anode)  62  is positioned away from the brain. During the surgical implant procedure, the stimulating electrodes are tunneled subcutaneously and the spiral shaped electrodes are wrapped around the vagus nerve  54  which is surgically isolated from the carotid artery  56  and jugular vein  58 . The incisions are surgically closed and the chronic stimulation process can begin when the tissues are healed from the surgery. 
     For therapy to commence, the primary (external) coil  46  is placed on the skin on top of the surgically implanted (secondary) coil  48 . An adhesive tape is then placed on the skin  60  and external coil  46  such that the external coil  46 , is taped firmly to the skin  60 . For efficient energy transfer to occur, it is important that the primary (external) and secondary (internal) coils  46 , 48  be positioned along the same axis and be optimally positioned relative to each other (FIG.  11 B). In the present embodiment, the external coil  46  is connected to proximity sensing circuitry  50 . The correct positioning of the external coil  46  with respect to the internal coil  48  is indicated by turning “on” of a light emitting diode (LED) on the external stimulator  42 . 
     Optimal placement of the external (primary) coil  46  is done with the aid of proximity sensing circuitry incorporated in the system. Proximity sensing occurs utilizing a combination of external and implantable or internal components. The internal components contains a relatively small magnet composed of materials that exhibit Giant Magneto-Resistor (GMR) characteristics such as Samarium-cobalt, a coil, and passive circuitry. As shown in FIG. 12, the external coil  46  and proximity sensor circuitry  50  are rigidly connected in a convenient enclosure which is attached externally on the skin. The sensors measure the direction of the field applied from the magnet to sensors within a specific range of field strength magnitude. The dual sensors exhibit accurate sensing under relatively large separation between the sensor and the target magnet. As the external coil  46  placement is “fine tuned”, the condition where the external (primary) coil  46  comes in optimal position, i.e. is located adjacent and parallel to the subcutaneous (secondary) coil  48 , along its axis, is recorded and indicated by a light emitting diode (LED) on the external stimulator  42 . 
     FIG. 13 shows an overall block diagram of the components of the external stimulator and the proximity sensing mechanism. The proximity sensing components are the primary (external) coil  46 , supercutaneous (external) proximity sensors  198 ,  202  (FIG. 14) in the proximity sensor circuit unit  50 , and a subcutaneous secondary coil  48  with a Giant Magneto Resister (GMR) magnet  53  associated with the proximity sensor unit. The proximity sensor circuit  50  provides a measure of the position of the secondary implanted coil  48 . The signal output from proximity sensor circuit  50  is derived from the relative location of the primary and secondary coils  46 ,  48 . The coil sub-assemblies consist of the coil and the associated electronic components, that are rigidly connected to the coil. 
     The proximity sensors (external) contained in the proximity sensor circuit  50  detect the presence of a GMR magnet  53 , composed of Samarium Cobalt, that is rigidly attached to the subcutaneous secondary coil  48 . The proximity sensors, are mounted externally as a rigid assembly and sense the actual separation between the coils, also known as the proximity distance. In the event that the distance exceeds the system limit, the signal drops off and an alarm sounds to indicate failure of the production of adequate signal in the secondary implanted circuit  167 , as applied in the present embodiment of the device. This signal is provided to the location indicator LED  140 . 
     FIG. 14 shows the circuit used to drive the proximity sensors  198 ,  202  of the proximity sensor circuit. The two proximity sensors  198 ,  202  obtain a proximity signal based on their position with respect to the implanted GMR magnet  53 . This circuit also provides temperature compensation. The sensors  198 ,  202  are ‘Giant Magneto Resistor’ (GMR) type sensors packaged as proximity sensor unit  50 . There are two components of the complete proximity sensor circuit  51 . One component is mounted supercutaneously  50 , and the other component, the proximity sensor signal control unit  57  is within the external stimulator  42 . The resistance effect depends on the combination of the soft magnetic layer of magnet  53 , where the change of direction of magnetization from external source can be large, and the hard magnetic layer, where the direction of magnetization remains unchanged. The resistance of this sensor varies along a straight motion through the curvature of the magnetic field. 
     A bridge differential voltage is suitably amplified and used as the proximity signal. The Siemens GMR B6 (Siemens Corp., Special Components Inc. New Jersey) is used for this function in the present embodiment. The maximum value of the peak-to-peak signal is observed as the external magnetic field becomes strong enough, at which point the resistance increases, resulting in the increase of the field-angle between the soft magnetic and hard magnetic material. The bridge voltage also increases. In this application, the two sensors  198 ,  202  are oriented orthogonal to each other. 
     The distance between the magnet and sensor is not relevant as long as the magnetic field is between 5 and 15 KA/m, and provides a range of distances between the sensors  198 ,  202  and the magnetic material  53 . The GMR sensor registers the direction of the external magnetic field. A typical magnet to induce permanent magnetic field is approximately 15 by 8 by 5 mm 3 , for this application and these components. However, the sensors  198 ,  202  are sensitive to temperature, such that the corresponding resistance drops as temperature increases. This effect is quite minimal until about 100° C. A full bridge circuit is used for temperature compensation, as shown in temperature compensation circuit  50  of FIG.  14 . The sensors  198 ,  202  and a pair of resistors  200 ,  204  are shown as part of the bridge network for temperature compensation. It is also possible to use a full bridge network of two additional sensors in place of the resistors  200 ,  204 . 
     The signal from either proximity sensor  198 ,  202  is rectangular if the surface of the magnetic material is normal to the sensor and is radial to the axis of a circular GMR device. This indicates a shearing motion between the sensor and the magnetic device. When the sensor is parallel to the vertical axis of this device, there is a fall off of the relatively constant signal at about 25 mm. separation. The GMR sensor combination varies its resistance according to the direction of the external magnetic field, thereby providing an absolute angle sensor. The position of the GMR magnet can be registered at any angle from 0 to 360 degrees. 
     The external stimulator shown in FIG. 13, with indicator unit  140  which is provided to indicate proximity distance or coil proximity failure (for situations where the patch containing the external coil  46 , has been removed, or is twisted abnormally etc.). Indication is also provided to assist in the placement of the patch. In case of general failure, a red light with audible signal is provided when the signal is not reaching the subcutaneous circuit. The indicator unit  140  also displays low battery status. The information on the low battery, normal and out of power conditions will forewarn the user of the requirements of any corrective actions. 
     As was shown in FIG. 13, the programmable parameters are stored in a programmable logic  304 . The predetermined programs stored in the external stimulator are capable of being modified through the use of a separate Programming Station  77 . FIG. 15 shows the Programmable Array Logic Unit  304  and interface unit  312  interfaced to the programming station  77 . The programming station  77  can be used to load new programs, change the predetermined programs, or the program parameters for various stimulation programs. The programming station is connected to the Programmable Array Unit  75 , shown in FIG. 16 (comprising programmable array logic  304  and interface unit  312 ) with an RS232-C serial connection. The main purpose of the serial line interface is to provide an RS232-C standard interface. This method enables any portable computer with a serial interface to communicate and program the parameters for storing the various programs. The serial communication interface receives the serial data, buffers this data and converts it to a 16 bit parallel data. The Programmable Array Logic  304  component of Programmable Array Unit  75  receives the parallel data bus and stores or modifies the data into a random access matrix  340  (FIG.  16 ). This array of data also contains special logic and instructions along with the actual data. These special instructions also provide an algorithm for storing, updating and retrieving the parameters from long-term memory. The Programmable logic Array Unit  304 , interfaces with Long Term Memory to store the predetermined programs  71 . All the previously modified programs can be stored here for access at any time, as well as, additional programs can be locked out for the patient. The programs consist of specific parameters and each unique program will be stored sequentially in long-term memory. A battery unit  310  is present to provide power to all the components shown above. The logic for the storage and decoding is stored in the Random Addressable Storage Matrix (RASM)  340  (FIG.  16 ). 
     FIG. 16 shows greater details for the Programmable Logic Array Unit  304 . The Input Buffer block  343  is where the serial data is stored in temporary register storage. This accumulation allows for the serial to parallel conversion to occur. The serial to 16 bit parallel block  346  sets up 16 bits of data, as created from the RS232-C serial data. This parallel data bus will communicate the data and the address information. The decoder block  344  decodes address information for the Random Addressable Logic Storage Matrix  340  from which to access the data i.e. programmer parameters. The Output Buffer  342  provides an interface to the Long Term Memory  71 . 
     FIG. 17 shows schematically the details of the interface between the Programmable Array Logic  304  and Interface Unit  312  which is connected to the Predetermined Programs block (Long Term Memory)  71 . The patient override  73  is essentially a control scheme for initializing or starting a program at any intermediate point. The Programmable array provides a reconfigurable mechanism to store data and associated instructions for the programs. It supports adding, modifying or retrieving the data from a Random Addressable Logic Storage Matrix  340 . This is also a widely accepted scheme for treating “flexible” logic description and control. It is flexible by providing the ability to reprogram and even redesign existing programs previously installed as predetermined programs. It allows the manufacturer or authorized user to create, and modify the programs for execution. 
     The pulse generator circuitry, shown schematically in FIG. 18, exhibits typical multivibrator functionality. This circuit produces regularly occurring pulses where the amplitude, pulse width and frequency is adjustable. The battery  310  is the main external power source for this circuit. The capacitor  450  is connected in parallel with the battery  310 . The combination of transistors  412 ,  442  and  425 , and resistors  410 ,  444 ,  446  and  448  acts as a constant current source generated at the collector of transistor  426 . The transistor  412  has collector connected to the emitter of transistor  442  and base of transistor  425 . The transistors  412  and  442  are connected to provide a constant voltage drop. Likewise, transistor  426  also acts as a diode with a resistor  428  connected in series and further connected to the negative terminal of the line at terminal  460 . Capacitor  416  provides timing characteristics and its value helps determine pulse width and pulse frequency. The output of the oscillator appears at terminal  458 . 
     Initially, the capacitor  416  gets charged with current from the path of resistor  434  and  436  while all the transistors are turned off. As the capacitor charges up transistor  432  will become forward biased and current will flow via resistors  430  and  436  from the base to emitter resistors. This action turns on the transistor  418  and the positive voltage from the power supply  310  is made available at the base of transistor  438  through resistor  440 . This results in the transistor  438  getting turned on. The conduction of transistor  438  causes capacitor  416  to discharge. The time constant for the charge and discharge of capacitor  416  is determined by value of the resistors  428  and  440  and capacitor  416 . After the time constant, transistor  432  turns off, and this in turn turns off transistors  438  and  418 . A reset mechanism for this multivibrator can be provided by setting a positive voltage, for example 2.5 volts, to the base of transistor  420 . This positive increase in voltage turns on transistor  420  followed by transistor  438 . The turning on of transistor  438  discharges the capacitor  416  and the reset operation is complete. 
     Conventional microprocessor and integrated circuits are used for the logic, control and timing circuits. Conventional bipolar transistors are used in radio-frequency oscillator, pulse amplitude ramp control and power amplifier. A standard voltage regulator is used in low-voltage detector. The hardware and software to deliver the pre-determined programs is well known to those skilled in the art. 
     The pulses delivered to the nerve tissue for stimulation therapy are shown graphically in FIG.  19 . As shown in FIG. 20, for patient comfort when the electrical stimulation is turned on, the electrical stimulation is ramped up and ramped down, instead of abrupt delivery of electrical pulses. 
     The number of predetermined programs can be any number, say 100, and such a number is considered within the scope of the invention. For patient convenience, less than 20 programs are practical. One embodiment contains nine predetermined programs. 
     In one arrangement, the predetermined programs are arranged in such a way that the aggressiveness of the therapy increases from program #1 to Program #9. Thus the first three programs provide the least aggressive therapy, and the last three programs provide the most aggressive therapy. 
     The following are examples of least aggressive therapy. 
     Program #1: 
     1.0 mA current output, 0.2 msec pulse width, 15 Hz frequency, 15 sec on-time, 1.0 min off-time, in repeating cycles. 
     Program #2: 
     1.5 mA current output, 0.3 msec pulse width, 20 Hz frequency, 20 sec on-time, 2.0 min off-time, in repeating cycles. 
     The following are examples of intermediate level of therapy. 
     Program #5: 
     2.0 mA current output, 0.3 msec pulse width, 25 Hz frequency, 20 sec on-time, 1.0 min off-time, in repeating cycles. 
     Program #6: 
     2.0 mA current output, 0.4 msec pulse width, 25 Hz frequency, 30 sec on-time, 1.0 min off-time, in repeating cycles. 
     The following are examples of most aggressive therapy. 
     Program #8: 
     2.5 mA current output, 0.3 msec pulse width, 30 Hz frequency, 40 sec on-time, 1.5 min off-time, in repeating cycles. 
     Program #9: 
     3.0 mA current output, 0.5 msec pulse width, 30 Hz frequency, 30 sec on-time, 1.0 min off-time, in repeating cycles. 
     The majority of patients will fall into the category that require an intermediate level of therapy, such as program #5. The above are examples of the predetermined programs that are delivered to the vagus nerve. The actual parameter settings for any given patient may deviate somewhat from the above. As shown schematically in FIG. 13, new predetermined programs can be loaded into the external stimulator  42 . 
     In one embodiment, the external stimulator can also have a telecommunications module, as described in a co-pending application, and summarized here for reader convenience. The telecommunications module has two-way communications capabilities. 
     FIG. 21 shows conceptually the communication between the external stimulator  42  and a remote hand-held computer. A desktop or laptop computer can be a server  500  which is situated remotely, perhaps at a physician&#39;s office or a hospital. The stimulation parameter data can be viewed at this facility or reviewed remotely by medical personnel on a hand-held personal data assistant (PDA)  502 , such as a “palm-pilot” from PALM corp. (Santa Clara, Calif.), a “Visor” from Handspring Corp. (Mountain view, Calif.) or on a personal computer (PC) available from numerous vendors. The physician or appropriate medical personnel, is able to interrogate the external stimulator  42  device and know what the device is currently programmed to, as well as, get a graphical display of the pulse train. The wireless communication with the remote server  500  and hand-held PDA  502  would be supported in all geographical locations within and outside the United States (US) that provides cell phone voice and data communication service. The pulse generation parameter data can also be viewed on the handheld devices (PDA)  502 . 
     The telecommunications component of this invention uses Wireless Application Protocol (WAP). The Wireless Application Protocol (WAP) is a set of communication protocols standardizing Internet access for wireless devices. While previously, manufacturers used different technologies to get Internet on hand-held devices, with WAP devices and services interoperate. WAP promotes convergence of wireless data and the Internet. The WAP programming model is heavily based on the existing Internet programming model, and is shown schematically in FIG.  22 . Introducing a gateway function provides a mechanism for optimizing and extending this model to match the characteristics of the wireless environment. Over-the-air traffic is minimized by binary encoding/decoding of Web pages and readapting the Internet Protocol stack to accommodate the unique characteristics of a wireless medium such as call drops. Such features are facilitated with WAP. 
     The key components of the WAP technology, as shown in FIG. 22, includes 1) Wireless Mark-up Language (WML)  400  which incorporates the concept of cards and decks, where a card is a single unit of interaction with the user. A service constitutes a number of cards collected in a deck. A card can be displayed on a small screen. WML supported Web pages reside on traditional Web servers. 2) WML Script which is a scripting language, enables application modules or applets to be dynamically transmitted to the client device and allows the user interaction with these applets. 3) Microbrowser, which is a lightweight application resident on the wireless terminal that controls the user interface and interprets the WML/WMLScript content. 4) A lightweight protocol stack  402  which minimizes bandwidth requirements, guaranteeing that a broad range of wireless networks can run WAP applications. The protocol stack of WAP can comprise a set of protocols for the transport (WTP), session (WSP), and security (WTLS) layers. WSP is binary encoded and able to support header caching, thereby economizing on bandwidth requirements. WSP also compensates for high latency by allowing requests and responses to be handled asynchronously, sending before receiving the response to an earlier request. For lost data segments, perhaps due to fading or lack of coverage, WTP only retransmits lost segments using selective retransmission, thereby compensating for a less stable connection in wireless. The above mentioned features are industry standards adopted for wireless applications and greater details have been publicized, and well known to those skilled in the art. 
     In this embodiment, two modes of communication are possible. In the first, the server initiates an upload of the actual parameters being applied to the patient, receives these from the stimulator, and stores these in its memory, accessible to the authorized user as a dedicated content driven web page. The physician or authorized user can make alterations to the actual parameters, as available on the server, and then initiate a communication session with the stimulator device to download these parameters. 
     The physician is also able to set up long-term schedules of stimulation therapy for their patient population, through wireless communication with the server. The server in turn communicates these programs to the neurostimulator. Each schedule is securely maintained on the server, and is editable by the physician and can get uploaded to the patient&#39;s stimulator device at a scheduled time. Thus, therapy can be customized for each individual patient. Each device issued to a patient has a unique identification key in order to guarantee secure communication between the wireless server  502  and stimulator device  42 . 
     The second mode of communication is the ability to remotely interrogate and monitor the stimulation therapy on the physician&#39;s handheld (PDA)  502 . 
     Moving now to the implantable portion of the system, FIG. 23A shows a diagram of the implanted lead-receiver  34 , and FIG. 23B shows a diagram of the proximal end  49  of the lead-receiver  34 . The proximal end  49  is a relatively flat portion and contains the electrical components on a printed circuit board. The distal end has the two spiral electrodes  61  and  62  for stimulating the nerve. The passive circuitry and electrodes are connected by electrically insulated wire conductors running within the lead body  59 . The lead body  59  is made of reinforced medical grade silicone in the presently preferred embodiment. 
     The circuitry contained in the proximal end  49  of the implantable lead-receiver  34  is shown schematically in FIG. 24, for the presently preffered embodiment. In this embodiment, the circuit uses all passive components. Approximately 25 turn copper wire of 30 gauge, or comparable thickness, is used for the primary coil  46  and secondary coil  48 . This wire is concentrically wound with the windings all in one plane. The frequency of the pulse-waveform delivered to the implanted coil  48  can vary and so a variable capacitor  152  provides ability to tune secondary implanted circuit  167  to the signal from the primary coil  46 . The pulse signal from secondary (implanted) coil  48  is rectified by the diode bridge  154  and frequency reduction obtained by capacitor  158  and resistor  164 . The last component in line is capacitor  166 , used for isolating the output signal from the electrode wire. The return path of signal from cathode  61  will be through anode  62  placed in proximity to the cathode  61  for “Bipolar” stimulation. In the current embodiment bipolar mode of stimulation is used, however, the return path can be connected to the remote ground connection (case) of implantable circuit  167 , providing for much larger intermediate tissue for “Unipolar” stimulation. The “Bipolar” stimulation offers localized stimulation of tissue compared to “Unipolar” stimulation and is therefore, used in the current embodiment. Unipolar stimulation is more likely to stimulate skeletal muscle in addition to nerve stimulation. The implanted circuit  167  in this embodiment is passive, so a battery does not have to be implanted. It is however possible to implant a battery source for use of active component logic in the implant. 
     The circuitry shown in FIGS. 25A and 25B can be used as an alternative, for the implanted lead-receiver. The circuitry of FIG. 25A is a slightly simpler version, and circuitry of FIG. 25B contains a conventional NPN transistor  168  connected in an emitter-follower configuration. 
     The fabrication of the lead-receiver  34  is designed to be modular. Thus, several different combinations of the components can be packaged without significantly altering the functionality of the device. As shown in FIG. 23A, the lead-receiver  34  components are the proximal end  49  containing coil  48 , electrical circuitry  167 , and case  78 . The lead body  59  containing the conductor  65 , 66  and the distal end has two electrodes cathode  61  and anode  62 . In the modular design concept, several design variables are possible, as shown in the table below. 
     
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
               
                 Table of lead-receiver design variables 
               
             
          
           
               
                   
                   
                   
                   
                 Conductor 
                   
                   
               
               
                   
                   
                   
                   
                 (connecting 
                   
                 Distal 
               
               
                 Proximal 
                 Lead 
                 Lead body- 
                   
                 proximal 
                   
                 End 
               
               
                 End 
                 body- 
                 Insulation 
                   
                 and distal 
                 Electrode- 
                 Electrode- 
               
               
                 Circuitry 
                 Lumens 
                 Materials 
                 Lead-Coating 
                 ends) 
                 Material 
                 Type 
               
               
                   
               
               
                 Bipolar 
                   
                 Polurethane 
                   
                 Alloy of 
                 Pure 
                 Standard ball 
               
               
                   
                   
                   
                   
                 Nickel- 
                 Platinum 
                 electrode 
               
               
                   
                   
                   
                   
                 Cobalt 
               
               
                 Unipolar 
                 Double 
                 Silicone 
                 Antimicrobial 
                   
                 Platinum- 
                 Hydrogel 
               
               
                   
                   
                   
                 coating 
                   
                 Iridium 
                 electrode 
               
               
                   
                   
                   
                   
                   
                 (Pt/IR) Alloy 
               
               
                   
                 Triple 
                 Silicone with 
                 Anti- 
                   
                 Pt/Ir coated 
                 Spiral 
               
               
                   
                   
                 Polytetra- 
                 Inflamatory 
                   
                 with Titanium 
                 electrode 
               
               
                   
                   
                 fluoro- 
                 coating 
                   
                 Nitride 
               
               
                   
                   
                 ethylene 
               
               
                   
                   
                 (PTFE) 
               
               
                   
                 Coaxial 
                   
                 Lubricious 
                   
                 Carbon 
                 Steroid 
               
               
                   
                   
                   
                 coating 
                   
                   
                 eluting 
               
               
                   
               
             
          
         
       
     
     Either silicone or polyurethane is a suitable material for the implantable lead-receiver body  59 . Both materials have proven to have desirable qualities which are not available in the other. Permanently implantable pacemaker leads made of polyurethane are susceptible to some forms of degradation over time. The identified mechanisms are Environmental Stress Cracking (ESC) and Metal Ion Oxidation (MIO). Silicone on the other hand is a softer material, therefore lead body has to be made bigger. In the presently preferred embodiment silicone re-enforced with polytetrafluroethyene (PTFE) is used. 
     Nerve-electrode interaction is an integral part of the stimulation system. As a practical benefit of modular design, any type of electrode described below can be used as the distal (cathode) stimulating electrode, without changing fabrication methodology or procedure significantly. When a standard electrode made of platinum or platinum/iridium is placed next to the nerve, and secured in place, it promotes an inflammatory response that leads to a thin fibrotic sheath around the electrode over a period of 1 to 6 weeks. This in turn leads to a stable position of electrode relative to the nerve, and a stable electrode-tissue interface, resulting in reliable stimulation of the nerve chronically without damaging the nerve. 
     Alternatively, other electrode forms that are non-traumatic to the nerve such as hydrogel, platinum fiber, or steroid elution electrodes may be used with this system. The concept of hydrogel electrode for nerve stimulation is shown schematically in FIG.  26 . The hydrogel material  100  is wrapped around the nerve  54 , with tiny platinum electrodes  102  being pulled back from nerve. Over a period of time in the body, the hydrogel material  100  will undergo degradation and there will be fibrotic tissue buildup. Because of the softness of the hydrogel material  100 , these electrodes are non-traumatic to the nerve. 
     The concept of platinum fiber electrodes is shown schematically in FIG.  27 . The distal fiber electrode  104  attached to the lead-receiver  34  may be platinum fiber or cable, or the electrode may be thin platinum fiber wrapped around Dacron polyester or Polyimide  106 . As shown in FIG. 28, the platinum fibers  108  may be woven around Dacron polyester fiber  106  or platinum fibers  108  may be braided. At implant, the fiber electrode  104  is loosely wrapped around the surgically isolated nerve, then tied loosely so as not to constrict the nerve or put pressure on the nerve. As a further extension, the fiber electrode may be incorporated into a spiral electrode  105  as is shown schematically in FIG.  29 . The two “pigs tail” coil electrodes are made from thin platinum coated braided yarn which is adhered to a substrate in the shape of a “pigs tail” and wraps around the nerve. The braid then continues up a silicone tube lead body. 
     Alternatively, steroid elution electrodes may be used. After implantation of a lead in the body, during the first few weeks there is buildup of fibrotic tissue in-growth over the electrode and to some extent around the lead body. This fibrosis is the end result of body&#39;s inflammatory response process which begins soon after the device is implanted. The fibrotic tissue sheath has the net effect of increasing the distance between the stimulation electrode (cathode) and the excitable tissue, which is the vagal nerve in this case. This is shown schematically in FIG. 30, where electrode  52  when covered with fibrotic tissue becomes the “virtual” electrode  114 . Non-excitable tissue is depicted as  120  and excitable tissue as  118 . A small amount of corticosteroid, dexamethasone sodium phosphate, which is commonly referred to as “steroid” or “dexamethasone” placed inside or around the electrode, has significant beneficial effect on the current or energy threshold, i.e. the amount of energy required to stimulate the excitable tissue. This is well known to those familiar in the art, as there is a long history of steroid elution leads in cardiac pacing application. It takes only about 1 mg of dexamethasone to produce the desirable effects. Three separate ways of delivering the steroid drug to the electrode nerve-tissue interface are being disclosed here. Dexamethasone can be placed inside an electrode with microholes, it can be placed adjacent to the electrode in a silicone collar, or it can be coated on the electrode itself. 
     Dexamethasone inside the stimulating electrode is shown schematically in FIG. 31. A silicone core that is impregnated with a small quantity of dexamethasone  121 , is incorporated inside the electrode. The electrode tip is depicted as  124  and electrode body as  122 . Once the lead is implanted in the body, the steroid  121  elutes out through the small holes in the electrode. The steroid drug then has anti-inflammatory action at the electrode tissue interface, which leads to a much thinner fibrotic tissue capsule. 
     Another way of having a steroid eluting nerve stimulating electrode, is to have the steroid agent placed outside the distal electrode  91  in a silicone collar  126 . This is shown schematically in FIG.  32 . Approximately 1 mg of dexamethasone is contained in a silicone collar  126 , at the base of the distal electrode  52 . With such a method, the steroid drug elutes around the electrode  52  in a similar fashion and with similar pharmacokinetic properties, as with the steroid drug being inside the electrode. 
     Another method of steroid elution for nerve stimulation electrodes is by coating of steroid on the outside (exposed) surface area of the electrode. This is shown schematically in FIG.  33 . Nafion is used as the coating matrix. Steroid membrane coating on the outside of the electrode is depicted as  128 . The advantages of this method are that it can easily be applied to any electrode, fast and easy manufacturing, and it is cost effective. With this method, the rate of steroid delivery can be controlled by the level of sulfonation. 
     A schematic representation of the cross section of different possible lumens is shown in FIG.  34 . The lead body  59  can have one, two, or three lumens for conducting cable, with or without a hollow lumen. In the cross sections,  132 A-F represents lumens(s) for conducting cable, and  134 A-C represents hollow lumen for an aid in implanting the lead. 
     Additionally, different classes of coating may be applied to the implantable lead-receiver  34  after fabrication. These coatings fall into three categories, lubricious coating, antimicrobial coating, and anti-inflammatory coating. 
     The advantage of modular fabrication is that with one technology platform, several derivative products or models can be manufactured. As a specific practical example, using a silicone lead body platform, three separate derivative or lead models can be manufactured by using three different electrodes such as standard ball electrode, spiral electrode, or steroid electrode. This is made possible by designing the fabrication steps such that the distal electrodes are assembled at the end, and as long as the electrodes are mated to the insulation and conducting cable, the shape or type of electrode does not matter. Similarly, different models can be produced by taking a finished lead and then coating it with lubricious coating or antimicrobial coating. In fact, considering the design variables disclosed in Table 1, a large number of combinations are possible. 
     While various embodiments of the present invention have been described in detail, it is apparent that modifications and adaptations of those embodiments will occur to those skilled in the art. However, it is to be expressly understood that such modifications and adaptations are within the spirit and scope of the present invention.

Technology Classification (CPC): 0